Interfacing with the Brain: How Nanotechnology Can Contribute

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1. 1

   Alivisatos, A. P.; Andrews, A. M.; Boyden, E. S.; Chun, M.; Church, G. M.; Deisseroth, K.; Donoghue, J. P.; Fraser, S. E.; Lippincott-Schwartz, J.; Looger, L. L.; Masmanidis, S.; McEuen, P. L.; Nurmikko, A. V.; Park, H.; Peterka, D. S.; Reid, C.; Roukes, M. L.; Scherer, A.; Schnitzer, M.; Sejnowski, T. J.; Shepard, K. L.; Tsao, D.; Turrigiano, G.; Weiss, P. S.; Xu, C.; Yuste, R.; Zhuang, X. W. Nanotools for Neuroscience and Brain Activity Mapping. ACS Nano 2013, 7, 1850– 1866,  DOI: 10.1021/nn4012847

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   Nanotools for Neuroscience and Brain Activity Mapping

   Alivisatos, A. Paul; Andrews, Anne M.; Boyden, Edward S.; Chun, Miyoung; Church, George M.; Deisseroth, Karl; Donoghue, John P.; Fraser, Scott E.; Lippincott-Schwartz, Jennifer; Looger, Loren L.; Masmanidis, Sotiris; McEuen, Paul L.; Nurmikko, Arto V.; Park, Hongkun; Peterka, Darcy S.; Reid, Clay; Roukes, Michael L.; Scherer, Axel; Schnitzer, Mark; Sejnowski, Terrence J.; Shepard, Kenneth L.; Tsao, Doris; Turrigiano, Gina; Weiss, Paul S.; Xu, Chris; Yuste, Rafael; Zhuang, Xiaowei

   ACS Nano (2013), 7 (3), 1850-1866CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

   A review. Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiol. approaches record the activities of one neuron or a few neurons at a time. Neurochem. approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chem. transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnol. are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale anal. tools and in the design and synthesis of nanomaterials have generated optical, elec., and chem. methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of tech. development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other phys. scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function.
2. 2

   Alivisatos, A. P.; Chun, M.; Church, G. M.; Deisseroth, K.; Donoghue, J. P.; Greenspan, R. J.; McEuen, P. L.; Roukes, M. L.; Sejnowski, T. J.; Weiss, P. S. The Brain Activity Map. Science 2013, 339, 1284– 1285,  DOI: 10.1126/science.1236939

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   The brain activity map

   Alivisatos, A. Paul; Chun, Miyoung; Church, George M.; Deisseroth, Karl; Donoghue, John P.; Greenspan, Ralph J.; McEuen, Paul L.; Roukes, Michael L.; Sejnowski, Terrence J.; Weiss, Paul S.; Yuste, Rafael

   Science (Washington, DC, United States) (2013), 339 (6125), 1284-1285CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

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   The BRAIN Initiative: Toward a Chemical Connectome

   Andrews, Anne M.

   ACS Chemical Neuroscience (2013), 4 (5), 645CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

   A review. On Apr. 2, 2013, I had the honor of visiting the White House for President Obama's announcement of the BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies). Earlier dubbed the BAM (Brain Activity Map) Project, this multiyear nationwide effort has been renamed to reflect its emphasis on technol., and particularly nanotechnol. Developing advanced technologies is expected to lead to new ways of investigating complex problems assocd. with understanding brain function.
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   Neuronal ensemble control of prosthetic devices by a human with tetraplegia

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   Nature (London, United Kingdom) (2006), 442 (7099), 164-171CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

   Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclin. results from intact animals to a clin. useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnol. to restore independence for humans with paralysis.
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    Reach and grasp by people with tetraplegia using a neurally controlled robotic arm

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    Nature (London, United Kingdom) (2012), 485 (7398), 372-375CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control phys. devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5 years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.
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    NeuroToxicology (2010), 31 (4), 331-350CODEN: NRTXDN; ISSN:0161-813X. (Elsevier B.V.)

    A review. Microelectrode arrays (MEAs) have been in use over the past decade and a half to study multiple aspects of elec. excitable cells. In particular, MEAs have been applied to explore the pharmacol. and toxicol. effects of numerous compds. on spontaneous activity of neuronal and cardiac cell networks. The MEA system enables simultaneous extracellular recordings from multiple sites in the network in real time, increasing spatial resoln. and thereby providing a robust measure of network activity. The simultaneous gathering of action potential and field potential data over long periods of time allows the monitoring of network functions that arise from the interaction of all cellular mechanisms responsible for spatio-temporal pattern generation. In these functional, dynamic systems, phys., chem., and pharmacol. perturbations are holistically reflected by the tissue responses. Such features make MEA technol. well suited for the screening of compds. of interest, and also allow scaling to high throughput systems that can record from multiple, sep. cell networks simultaneously in multi-well chips or plates. This article is designed to be useful to newcomers to this technol. as well as those who are currently using MEAs in their research. It explains how MEA systems operate, summarizes what systems are available, and provides a discussion of emerging math. schemes that can be used for a rapid classification of drug or chem. effects. Current efforts that will expand this technol. to an influential, high throughput, electrophysiol. approach for reliable detns. of compd. toxicity are also described and a comprehensive review of toxicol. publications using MEAs is provided as an appendix to this publication. Overall, this article highlights the benefits and promise of MEA technol. as a high throughput, rapid screening method for toxicity testing.
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    Yang, L.; Lee, K.; Villagracia, J.; Masmanidis, S. C. Open Source Silicon Microprobes for High Throughput Neural Recording. J. Neural Eng. 2020, 17, 016036,  DOI: 10.1088/1741-2552/ab581a

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    BRAIN 2.0: From Cells to Circuits, Toward Cures. https://braininitiative.nih.gov/vision/nih-brain-initiative-reports/brain-20-report-cells-circuits-toward-cures (accessed December 22, 2023).

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    Ilic, B.; Czaplewski, D.; Neuzil, P.; Stanczyk, T.; Blough, J.; Maclay, G. Preparation and Characterization of Platinum Black Electrodes. J. Mater. Sci. 2000, 35, 3447– 3457,  DOI: 10.1023/A:1004884723515

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    Preparation and characterization of platinum black electrodes

    Ilic, B.; Czaplewski, D.; Neuzil, P.; Stanczyk, T.; Blough, J.; Maclay, G. J.

    Journal of Materials Science (2000), 35 (14), 3447-3457CODEN: JMTSAS; ISSN:0022-2461. (Kluwer Academic Publishers)

    The authors have studied properties of electrodeposited platinum black by AFM and SEM. Platinum black was deposited on evapd. platinum electrodes. Deposition time and cure temp. influences the quality and morphol. of the platinum black layer. Morphol. inclusions were readily obsd. in films deposited for duration of <60 s at a bias of 1.5 V against a platinum counter electrode. Shorting of the microfabricated electrodes due to lateral outgrowth of high surface area platinum black was obsd. when current densities ∼100 mA cm-2 were employed. Further reproducibility of highly adherent platinized electrodes is achieved.
47. 47

    Cogan, S. F. Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng. 2008, 10, 275– 309,  DOI: 10.1146/annurev.bioeng.10.061807.160518

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    Neural stimulation and recording electrodes

    Cogan, Stuart F.

    Annual Review of Biomedical Engineering (2008), 10 (), 275-309CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews Inc.)

    A review. Elec. stimulation of nerve tissue and recording of neural elec. activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurol. disorders. An understanding of the electrochem. mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large nos. of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and max. electrochem. potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochem. properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes.
48. 48

    Cogan, S. F.; Guzelian, A. A.; Agnew, W. F.; Yuen, T. G.; McCreery, D. B. Over-Pulsing Degrades Activated Iridium Oxide Films Used for Intracortical Neural Stimulation. J. Neurosci. Methods 2004, 137, 141– 150,  DOI: 10.1016/j.jneumeth.2004.02.019

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    Over-pulsing degrades activated iridium oxide films used for intracortical neural stimulation

    Cogan, Stuart F.; Guzelian, Andrew A.; Agnew, William F.; Yuen, Ted G. H.; McCreery, Douglas B.

    Journal of Neuroscience Methods (2004), 137 (2), 141-150CODEN: JNMEDT; ISSN:0165-0270. (Elsevier Science B.V.)

    Microelectrodes using activated iridium oxide (AIROF) charge-injection coatings have been pulsed in cat cortex at levels from near-threshold for neural excitation to the reported in vitro electrochem. charge-injection limits of AIROF. The microelectrodes were subjected to continuous biphasic current pulsing, using an 0.4 V (vs. Ag/AgCl) anodic bias with equal cathodal and anodal pulse widths, for periods up to 7 h at a frequency of either 50 Hz or 100 Hz. At charge densities of 3 mC/cm2, histol. revealed iridium-contg. deposits in tissue adjacent to the charge-injection sites and SEM of explanted electrodes revealed a thickened and poorly adherent AIROF coating. Microelectrodes pulsed at 2 mC/cm2 or less remained intact, with no histol. evidence of non-biol. deposits in the tissue. AIROF microelectrodes challenged in vitro under the same pulsing conditions responded similarly, with electrodes pulsed at 3 mC/cm2 showing evidence of AIROF delamination after only 100 s of pulsing at 100 Hz (10,000 pulses total), while electrodes pulsed at 2 mC/cm2 for 7 h at 50 Hz (1.3×106 pulses total) showed no evidence of damage. In vitro electrochem. potential transient measurements in buffered physiol. saline indicate that polarizing the AIROF beyond the potential window for electrolysis of water (-0.6 to 0.8 V vs. Ag/AgCl) results in the obsd. degrdn.
49. 49

    Boehler, C.; Stieglitz, T.; Asplund, M. Nanostructured Platinum Grass Enables Superior Impedance Reduction for Neural Microelectrodes. Biomaterials 2015, 67, 346– 353,  DOI: 10.1016/j.biomaterials.2015.07.036

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    Nanostructured platinum grass enables superior impedance reduction for neural microelectrodes

    Boehler, C.; Stieglitz, T.; Asplund, M.

    Biomaterials (2015), 67 (), 346-353CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    Micro-sized electrodes are essential for highly sensitive communication at the neural interface with superior spatial resoln. However, such small electrodes inevitably suffer from high elec. impedance and thus high levels of thermal noise deteriorating the signal to noise ratio. In order to overcome this problem, a nanostructured Pt-coating was introduced as add-on functionalization for impedance redn. of small electrodes. In comparison to platinum black deposition, all used chems. in the deposition process are free from cytotoxic components. The grass-like nanostructure was found to reduce the impedance by almost two orders of magnitude compared to untreated samples which was lower than what could be achieved with conventional electrode coatings like IrOx or PEDOT. The realization of the Pt-grass coating is performed via a simple electrochem. process which can be applied to virtually any possible electrode type and accordingly shows potential as a universal impedance redn. strategy. Elution tests revealed non-toxicity of the Pt-grass and the coating was found to exhibit strong adhesion to the metalized substrate.
50. 50

    Kireev, D.; Seyock, S.; Lewen, J.; Maybeck, V.; Wolfrum, B.; Offenhausser, A. Graphene Multielectrode Arrays as a Versatile Tool for Extracellular Measurements. Adv. Healthc. Mater. 2017, 6, 1601433,  DOI: 10.1002/adhm.201601433

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    Santoro, F.; Dasgupta, S.; Schnitker, J.; Auth, T.; Neumann, E.; Panaitov, G.; Gompper, G.; Offenhäusser, A. Interfacing Electrogenic Cells with 3D Nanoelectrodes: Position, Shape, and Size Matter. ACS Nano 2014, 8, 6713– 6723,  DOI: 10.1021/nn500393p

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    Interfacing Electrogenic Cells with 3D Nanoelectrodes: Position, Shape, and Size Matter

    Santoro, Francesca; Dasgupta, Sabyasachi; Schnitker, Jan; Auth, Thorsten; Neumann, Elmar; Panaitov, Gregory; Gompper, Gerhard; Offenhaeusser, Andreas

    ACS Nano (2014), 8 (7), 6713-6723CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    An in-depth understanding of the interface between cells and nanostructures is one of the key challenges for coupling elec. excitable cells and electronic devices. Recently, various 3D nanostructures have been introduced to stimulate and record elec. signals emanating from inside of the cell. Even though such approaches are highly sensitive and scalable, it remains an open question how cells couple to 3D structures, in particular how the engulfment-like processes of nanostructures work. Here, the authors present a profound study of the cell interface with two widely used nanostructure types, cylindrical pillars with and without a cap. While basic functionality was shown for these approaches before, a systematic study linking exptl. data with membrane properties was not presented so far. The combination of electron microscopy studies with a theor. membrane deformation model allows the authors to predict the optimal shape and dimensions of 3D nanostructures for cell-chip coupling.
52. 52

    Weidlich, S.; Krause, K. J.; Schnitker, J.; Wolfrum, B.; Offenhausser, A. MEAs and 3D Nanoelectrodes: Electrodeposition as Tool for a Precisely Controlled Nanofabrication. Nanotechnology 2017, 28, 095302,  DOI: 10.1088/1361-6528/aa57b5

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    MEAs and 3D nanoelectrodes: electrodeposition as tool for a precisely controlled nanofabrication

    Weidlich, Sabrina; Krause, Kay J.; Schnitker, Jan; Wolfrum, Bernhard; Offenhaeusser, Andreas

    Nanotechnology (2017), 28 (9), 095302/1-095302/8CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)

    Microelectrode arrays (MEAs) are gaining increasing importance for the investigation of signaling processes between electrogenic cells. However, efficient cell-chip coupling for robust and long-term electrophysiol. recording and stimulation still remains a challenge. A possible approach for the improvement of the cell-electrode contact is the utilization of three-dimensional structures. In recent years, various 3D electrode geometries have been developed, but we are still lacking a fabrication approach that enables the formation of different 3D structures on a single chip in a controlled manner. This, however, is needed to enable a direct and reliable comparison of the recording capabilities of the different structures. Here, we present a method for a precisely controlled deposition of nanoelectrodes, enabling the fabrication of multiple, well-defined types of structures on our 64 electrode MEAs towards a rapid-prototyping approach to 3D electrodes.
53. 53

    Spira, M. E.; Hai, A. Multi-Electrode Array Technologies for Neuroscience and Cardiology. Nat. Nanotechnol. 2013, 8, 83– 94,  DOI: 10.1038/nnano.2012.265

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    Multi-electrode array technologies for neuroscience and cardiology

    Spira, Micha E.; Hai, Aviad

    Nature Nanotechnology (2013), 8 (2), 83-94CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

    A review. At present, the prime methodol. for studying neuronal circuit-connectivity, physiol. and pathol. under in vitro or in vivo conditions is by using substrate-integrated microelectrode arrays. Although this methodol. permits simultaneous, cell-non-invasive, long-term recordings of extracellular field potentials generated by action potentials, it is 'blind' to subthreshold synaptic potentials generated by single cells. On the other hand, intracellular recordings of the full electrophysiol. repertoire (subthreshold synaptic potentials, membrane oscillations and action potentials) are, at present, obtained only by sharp or patch microelectrodes. These, however, are limited to single cells at a time and for short durations. Recently a no. of labs. began to merge the advantages of extracellular microelectrode arrays and intracellular microelectrodes. This Review describes the novel approaches, identifying their strengths and limitations from the point of view of the end users - with the intention to help steer the bioengineering efforts towards the needs of brain-circuit research.
54. 54

    Eles, J. R.; Vazquez, A. L.; Snyder, N. R.; Lagenaur, C.; Murphy, M. C.; Kozai, T. D.; Cui, X. T. Neuroadhesive L1 Coating Attenuates Acute Microglial Attachment to Neural Electrodes as Revealed by Live Two-Photon Microscopy. Biomaterials 2017, 113, 279– 292,  DOI: 10.1016/j.biomaterials.2016.10.054

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    54

    Neuroadhesive L1 coating attenuates acute microglial attachment to neural electrodes as revealed by live two-photon microscopy

    Eles, James R.; Vazquez, Alberto L.; Snyder, Noah R.; Lagenaur, Carl; Murphy, Matthew C.; Kozai, Takashi D. Y.; Cui, X. Tracy

    Biomaterials (2017), 113 (), 279-292CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    Implantable neural electrode technologies for chronic neural recordings can restore functional control to paralysis and limb loss victims through brain-machine interfaces. These probes, however, have high failure rates partly due to the biol. responses to the probe which generate an inflammatory scar and subsequent neuronal cell death. L1 is a neuronal specific cell adhesion mol. and has been shown to minimize glial scar formation and promote electrode-neuron integration when covalently attached to the surface of neural probes. In this work, the acute microglial response to L1-coated neural probes was evaluated in vivo by implanting coated devices into the cortex of mice with fluorescently labeled microglia, and tracking microglial dynamics with multi-photon microscopy for the ensuing 6 h in order to understand L1's cellular mechanisms of action. Microglia became activated immediately after implantation, extending processes towards both L1-coated and uncoated control probes at similar velocities. After the processes made contact with the probes, microglial processes expanded to cover 47.7% of the control probes' surfaces. For L1-coated probes, however, there was a statistically significant 83% redn. in microglial surface coverage. This effect was sustained through the expt. At 6 h post-implant, the radius of microglia activation was reduced for the L1 probes by 20%, shifting from 130.0 to 103.5 μm with the coating. Microglia as far as 270 μm from the implant site displayed significantly lower morphol. characteristics of activation for the L1 group. These results suggest that the L1 surface treatment works in an acute setting by microglial mediated mechanisms.
55. 55

    Kozai, T. D.; Catt, K.; Du, Z.; Na, K.; Srivannavit, O.; Razi-ul, M. H.; Seymour, J.; Wise, K. D.; Yoon, E.; Cui, X. T. Chronic in Vivo Evaluation of PEDOT/CNT for Stable Neural Recordings. IEEE Trans. Biomed. Eng. 2016, 63, 111– 119,  DOI: 10.1109/TBME.2015.2445713

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    55

    Chronic In Vivo Evaluation of PEDOT/CNT for Stable Neural Recordings

    Kozai Takashi D Y; Catt Kasey; Du Zhanhong; Na Kyounghwan; Srivannavit Onnop; Haque Razi-Ul M; Seymour John; Wise Kensall D; Yoon Euisik; Cui Xinyan Tracy

    IEEE transactions on bio-medical engineering (2016), 63 (1), 111-9 ISSN:.

    OBJECTIVE: Subcellular-sized chronically implanted recording electrodes have demonstrated significant improvement in single unit (SU) yield over larger recording probes. Additional work expands on this initial success by combining the subcellular fiber-like lattice structures with the design space versatility of silicon microfabrication to further improve the signal-to-noise ratio, density of electrodes, and stability of recorded units over months to years. However, ultrasmall microelectrodes present very high impedance, which must be lowered for SU recordings. While poly(3,4-ethylenedioxythiophene) (PEDOT) doped with polystyrene sulfonate (PSS) coating have demonstrated great success in acute to early-chronic studies for lowering the electrode impedance, concern exists over long-term stability. Here, we demonstrate a new blend of PEDOT doped with carboxyl functionalized multiwalled carbon nanotubes (CNTs), which shows dramatic improvement over the traditional PEDOT/PSS formula. METHODS: Lattice style subcellular electrode arrays were fabricated using previously established method. PEDOT was polymerized with carboxylic acid functionalized carbon nanotubes onto high-impedance (8.0 ± 0.1 MΩ: M ± S.E.) 250-μm(2) gold recording sites. RESULTS: PEDOT/CNT-coated subcellular electrodes demonstrated significant improvement in chronic spike recording stability over four months compared to PEDOT/PSS recording sites. CONCLUSION: These results demonstrate great promise for subcellular-sized recording and stimulation electrodes and long-term stability. SIGNIFICANCE: This project uses leading-edge biomaterials to develop chronic neural probes that are small (subcellular) with excellent electrical properties for stable long-term recordings. High-density ultrasmall electrodes combined with advanced electrode surface modification are likely to make significant contributions to the development of long-term (permanent), high quality, and selective neural interfaces.
56. 56

    Kozai, T. D.; Alba, N. A.; Zhang, H.; Kotov, N. A.; Gaunt, R. A.; Cui, X. T. Nanostructured Coatings for Improved Charge Delivery to Neurons. In Nanotechnology and Neuroscience: Nano-Electronic, Photonic and Mechanical Neuronal Interfacing; Springer, 2014; pp 71– 134.

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    Kozai, T. D.; Gugel, Z.; Li, X.; Gilgunn, P. J.; Khilwani, R.; Ozdoganlar, O. B.; Fedder, G. K.; Weber, D. J.; Cui, X. T. Coatings for Improved Charge Delivery to Neurons. Biomaterials 2014, 35, 9255– 9268,  DOI: 10.1016/j.biomaterials.2014.07.039

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    Kolarcik, C. L.; Catt, K.; Rost, E.; Albrecht, I. N.; Bourbeau, D.; Du, Z.; Kozai, T. D.; Luo, X.; Weber, D. J.; Cui, X. T. Evaluation of Poly(3, 4-ethylenedioxythiophene)/Carbon Nanotube Neural Electrode Coatings for Stimulation in the Dorsal Root Ganglion. J. Neural Eng. 2015, 12, 016008,  DOI: 10.1088/1741-2560/12/1/016008

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    Lind, G.; Linsmeier, C. E.; Thelin, J.; Schouenborg, J. Gelatine-Embedded Electrodes─a Novel Biocompatible Vehicle Allowing Implantation of Highly Flexible Microelectrodes. J. Neural Eng. 2010, 7, 046005,  DOI: 10.1088/1741-2560/7/4/046005

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    Robinson, J. T.; Jorgolli, M.; Shalek, A. K.; Yoon, M.-H.; Gertner, R. S.; Park, H. Vertical Nanowire Electrode Arrays as a Scalable Platform for Intracellular Interfacing to Neuronal Circuits. Nat. Nanotechnol. 2012, 7, 180,  DOI: 10.1038/nnano.2011.249

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    Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits

    Robinson, Jacob T.; Jorgolli, Marsela; Shalek, Alex K.; Yoon, Myung-Han; Gertner, Rona S.; Park, Hongkun

    Nature Nanotechnology (2012), 7 (3), 180-184CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

    Deciphering the neuronal code - the rules by which neuronal circuits store and process information - is a major scientific challenge. Currently, these efforts are impeded by a lack of exptl. tools that are sensitive enough to quantify the strength of individual synaptic connections and also scalable enough to simultaneously measure and control a large no. of mammalian neurons with single-cell resoln. Here, the authors report a scalable intracellular electrode platform based on vertical nanowires that allows parallel elec. interfacing to multiple mammalian neurons. Specifically, the authors show that their vertical nanowire electrode arrays can intracellularly record and stimulate neuronal activity in dissocd. cultures of rat cortical neurons and can also be used to map multiple individual synaptic connections. The scalability of this platform, combined with its compatibility with silicon nanofabrication techniques, provides a clear path towards simultaneous, high-fidelity interfacing with hundreds of individual neurons.
61. 61

    Huang, S.-H.; Shmoel, N.; Jankowski, M. M.; Erez, H.; Sharon, A.; Abu-Salah, W.; Nelken, I.; Weiss, A.; Spira, M. E. Immunohistological and Ultrastructural Study of the Inflammatory Response to Perforated Polyimide Cortical Implants: Mechanisms Underlying Deterioration of Electrophysiological Recording Quality. Front. Neurosci. 2020, 14, 926,  DOI: 10.3389/fnins.2020.00926

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    Abbott, J.; Ye, T.; Ham, D.; Park, H. Optimizing Nanoelectrode Arrays for Scalable Intracellular Electrophysiology. Acc. Chem. Res. 2018, 51, 600– 608,  DOI: 10.1021/acs.accounts.7b00519

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    Optimizing Nanoelectrode Arrays for Scalable Intracellular Electrophysiology

    Abbott, Jeffrey; Ye, Tianyang; Ham, Donhee; Park, Hongkun

    Accounts of Chemical Research (2018), 51 (3), 600-608CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

    A review. Electrode technol. for electrophysiol. has a long history of innovation, with some decisive steps including the development of the voltage-clamp measurement technique by Hodgkin and Huxley in the 1940s and the invention of the patch clamp electrode by Neher and Sakmann in the 1970s. The high-precision intracellular recording enabled by the patch clamp electrode has since been a gold std. in studying the fundamental cellular processes underlying the elec. activities of neurons and other excitable cells. One logical next step would then be to parallelize these intracellular electrodes, since simultaneous intracellular recording from a large no. of cells will benefit the study of complex neuronal networks and will increase the throughput of electrophysiol. screening from basic neurobiol. labs. to the pharmaceutical industry. Patch clamp electrodes, however, are not built for parallelization; as for now, only ∼10 patch measurements in parallel are possible. It has long been envisioned that nanoscale electrodes may help meet this challenge. First, nanoscale electrodes were shown to enable intracellular access. Second, because their size scale is within the normal reach of the std. top-down fabrication, the nanoelectrodes can be scaled into a large array for parallelization. Third, such a nanoelectrode array can be monolithically integrated with complementary metal-oxide semiconductor (CMOS) electronics to facilitate the large array operation and the recording of the signals from a massive no. of cells. These are some of the central ideas that have motivated the research activity into nanoelectrode electrophysiol., and these past years have seen fruitful developments. This Account aims to synthesize these findings so as to provide a useful ref. Summing up from the recent studies, the authors will first elucidate the morphol. and assocd. elec. properties of the interface between a nanoelectrode and a cellular membrane, clarifying how the nanoelectrode attains intracellular access. This understanding will be translated into a circuit model for the nanobio interface, which the authors will then use to lay out the strategies for improving the interface. The intracellular interface of the nanoelectrode is currently inferior to that of the patch clamp electrode; reaching this benchmark will be an exciting challenge that involves optimization of electrode geometries, materials, chem. modifications, electroporation protocols, and recording/stimulation electronics, as the authors describe in the Account. Another important theme of this Account, beyond the optimization of the individual nanoelectrode-cell interface, is the scalability of the nanoscale electrodes. The authors will discuss this theme using a recent development from the groups as an example, where an array of ∼1000 nanoelectrode pixels fabricated on a CMOS integrated circuit chip performs parallel intracellular recording from a few hundreds of cardiomyocytes, which marks a new milestone in electrophysiol.
63. 63

    Xie, X.; Aalipour, A.; Gupta, S. V.; Melosh, N. A. Determining the Time Window for Dynamic Nanowire Cell Penetration Processes. ACS Nano 2015, 9, 11667– 11677,  DOI: 10.1021/acsnano.5b05498

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    Determining the Time Window for Dynamic Nanowire Cell Penetration Processes

    Xie, Xi; Aalipour, Amin; Gupta, Sneha V.; Melosh, Nicholas A.

    ACS Nano (2015), 9 (12), 11667-11677CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    Nanowire (NW) arrays offer opportunities for parallel, nondestructive intracellular access for biomol. delivery, intracellular recording, and sensing. Spontaneous cell membrane penetration by vertical nanowires is essential for these applications, yet the time- and geometry-dependent penetration process is still poorly understood. The dynamic NW-cell interface during cell spreading was examd. through exptl. cell penetration measurements combined with two mech. models based on substrate adhesion force or cell traction forces. Penetration was detd. by comparing the induced tension at a series of given membrane configurations to the crit. membrane failure tension. The adhesion model predicts that penetration occurs within a finite window shortly after initial cell contact and adhesion, while the traction model predicts increasing penetration over a longer period. NW penetration rates detd. from a cobalt ion delivery assay are compared to the predicted results from the two models. In addn., the effects of NW geometry and cell properties are systematically evaluated to identify the key factors for penetration.
64. 64

    Weiland, J. D.; Anderson, D. J.; Humayun, M. S. In Vitro Electrical Properties for Iridium Oxide versus Titanium Nitride Stimulating Electrodes. IEEE Trans. Biomed. Eng. 2002, 49, 1574– 1579,  DOI: 10.1109/TBME.2002.805487

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    In vitro electrical properties for iridium oxide versus titanium nitride stimulating electrodes

    Weiland James D; Anderson David J; Humayun Mark S

    IEEE transactions on bio-medical engineering (2002), 49 (12 Pt 2), 1574-9 ISSN:0018-9294.

    Stimulating electrode materials must be capable of supplying high-density electrical charge to effectively activate neural tissue. Platinum is the most commonly used material for neural stimulation. Two other materials have been considered: iridium oxide and titanium nitride. This study directly compared the electrical characteristics of iridium oxide and titanium nitride by fabricating silicon substrate probes that differed only in the material used to form the electrode. Electrochemical measurements indicated that iridium oxide had lower impedance and a higher charge storage capacity than titanium nitride, suggesting better performance as a stimulating electrode. Direct measurement of the electrode potential in response to a biphasic current pulse confirmed that iridium oxide uses less voltage to transfer the same amount of charge, therefore using less power. The charge injection limit for titanium nitride was 0.87 mC/cm2, contradicting other reports estimating that titanium nitride was capable of injecting 22 mC/cm2. Iridium oxide charge storage was 4 mC/cm2, which is comparable to other published values for iridium oxide. Electrode efficiency will lead to an overall more efficient and effective device.
65. 65

    Janders, M.; Egert, U.; Stelzle, M.; Nisch, W. Novel Thin Film Titanium Nitride Micro-Electrodes with Excellent Charge Transfer Capability for Cell Stimulation and Sensing Applications. In Proceedings of 18th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; IEEE, 1996; pp 245– 247.

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    Lee, K.-Y.; Kim, I.; Kim, S.-E.; Jeong, D.-W.; Kim, J.-J.; Rhim, H.; Ahn, J.-P.; Park, S.-H.; Choi, H.-J. Vertical Nanowire Probes for Intracellular Signaling of Living Cells. Nanoscale Res. Lett. 2014, 9, 56,  DOI: 10.1186/1556-276X-9-56

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    Vertical nanowire probes for intracellular signaling of living cells

    Lee, Ki-Young; Kim, Ilsoo; Kim, So-Eun; Jeong, Du-Won; Kim, Ju-Jin; Rhim, Hyewhon; Ahn, Jae-Pyeong; Park, Seung-Han; Choi, Heon-Jin

    Nanoscale Research Letters (2014), 9 (1), 56/1-56/7, 7 pp.CODEN: NRLAAD; ISSN:1556-276X. (Springer)

    The single living cell action potential was measured in an intracellular mode by using a vertical nanoelectrode. For intracellular interfacing, Si nanowires were vertically grown in a controlled manner, and optimum conditions, such as diam., length, and nanowire d., were detd. by culturing cells on the nanowires. Vertical nanowire probes were then fabricated with a complimentary metal-oxide-semiconductor (CMOS) process including sequential deposition of the passivation and electrode layers on the nanowires, and a subsequent partial etching process. The fabricated nanowire probes had an approx. 60-nm diam. and were intracellular. These probes interfaced with a GH3 cell and measured the spontaneous action potential. It successfully measured the action potential, which rapidly reached a steady state with av. peak amplitude of approx. 10 mV, duration of approx. 140 ms, and period of 0.9 Hz.
67. 67

    Hai, A.; Dormann, A.; Shappir, J.; Yitzchaik, S.; Bartic, C.; Borghs, G.; Langedijk, J. P.; Spira, M. E. Spine-Shaped Gold Protrusions Improve the Adherence and Electrical Coupling of Neurons with the Surface of Micro-Electronic Devices. J. R. Soc. Interface 2009, 6, 1153– 1165,  DOI: 10.1098/rsif.2009.0087

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    Spine-shaped gold protrusions improve the adherence and electrical coupling of neurons with the surface of micro-electronic devices

    Hai, Aviad; Dormann, Ada; Shappir, Joseph; Yitzchaik, Shlomo; Bartic, Carmen; Borghs, Gustaaf; Langedijk, J. P. M.; Spira, Micha E.

    Journal of the Royal Society, Interface (2009), 6 (41), 1153-1165CODEN: JRSICU; ISSN:1742-5689. (Royal Society)

    Interfacing neurons with micro- and nano-electronic devices has been a subject of intense study over the last decade. One of the major problems in assembling efficient neuroelectronic hybrid systems is the weak elec. coupling between the components. This is mainly attributed to the fundamental property of living cells to form and maintain an extracellular cleft between the plasma membrane and any substrate to which they adhere. This cleft shunts the current generated by propagating action potentials and thus reduces the signal-to-noise ratio. Reducing the cleft thickness, and thereby increasing the seal resistance formed between the neurons and the sensing surface, is thus a challenge and could improve the elec. coupling coeff. Using electron microscopic anal. and field potential recordings, we examd. here the use of gold micro-structures that mimic dendritic spines in their shape and dimensions to improve the adhesion and elec. coupling between neurons and micro-electronic devices. We found that neurons cultured on a gold-spine matrix, functionalized by a cysteine-terminated peptide with a no. of RGD repeats, readily engulf the spines, forming tight apposition. The recorded field potentials of cultured Aplysia neurons are significantly larger using gold-spine electrodes in comparison with flat electrodes.
68. 68

    Chiappini, C.; Campagnolo, P.; Almeida, C. S.; Abbassi-Ghadi, N.; Chow, L. W.; Hanna, G. B.; Stevens, M. M. Mapping Local Cytosolic Enzymatic Activity in Human Esophageal Mucosa with Porous Silicon Nanoneedles. Adv. Mater. 2015, 27, 5147– 5152,  DOI: 10.1002/adma.201501304

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    Mapping Local Cytosolic Enzymatic Activity in Human Esophageal Mucosa with Porous Silicon Nanoneedles

    Chiappini, Ciro; Campagnolo, Paola; Almeida, Carina S.; Abbassi-Ghadi, Nima; Chow, Lesley W.; Hanna, George B.; Stevens, Molly M.

    Advanced Materials (Weinheim, Germany) (2015), 27 (35), 5147-5152CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Nanoneedles are developing into versatile nanoscale tools for cell biol. and medical intervention. Here, we present this nanoneedle biosensor that can map the intracellular activity of the cysteine protease cathepsin B (CTSB) both in cell culture and across a large area of bioptic tissue. The sensor discriminates CTSB pos. (+ve) cancer cells from CTSB neg. (-ve) cells in a mixed culture. The nanoneedles also sense the difference in CTSB activity in tissue resected from patients with esophageal cancer.
69. 69

    Tay, A. The Benefits of Going Small: Nanostructures for Mammalian Cell Transfection. ACS Nano 2020, 14, 7714– 7721,  DOI: 10.1021/acsnano.0c04624

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    The Benefits of Going Small: Nanostructures for Mammalian Cell Transfection

    Tay, Andy

    ACS Nano (2020), 14 (7), 7714-7721CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    A review. Nanostructures, with their localized interactions with mammalian cells, can offer better efficiency and lower cell perturbation than conventional viral, biochem., and electroporation transfection techniques. In this Perspective, I describe the different stages of transfection and provide a comparison of transfection techniques based on their mechanisms. Focusing on specific aims of transfection, I also illustrate how recent developments in high-aspect-ratio nanostructures have endowed them with properties that are superior to existing viral, biochem., and electroporation methods as a versatile technique to deliver a variety of cargoes and to interface with different mammalian cell types for biomedical applications. Finally, I describe the challenges assocd. with transfection that need to be overcome to enhance cargo delivery efficiency and clin. translation.
70. 70

    Peng, J.; Garcia, M. A.; Choi, J.-s.; Zhao, L.; Chen, K.-J.; Bernstein, J. R.; Peyda, P.; Hsiao, Y.-S.; Liu, K. W.; Lin, W.-Y. Molecular Recognition Enables Nanosubstrate-Mediated Delivery of Gene-Encapsulated Nanoparticles with High Efficiency. ACS Nano 2014, 8, 4621– 4629,  DOI: 10.1021/nn5003024

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    Molecular Recognition Enables Nanosubstrate-Mediated Delivery of Gene-Encapsulated Nanoparticles with High Efficiency

    Peng, Jinliang; Garcia, Mitch Andre; Choi, Jin-sil; Zhao, Libo; Chen, Kuan-Ju; Bernstein, James R.; Peyda, Parham; Hsiao, Yu-Sheng; Liu, Katherine W.; Lin, Wei-Yu; Pyle, April D.; Wang, Hao; Hou, Shuang; Tseng, Hsian-Rong

    ACS Nano (2014), 8 (5), 4621-4629CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    Substrate-mediated gene delivery is a promising method due to its unique ability to preconc. exogenous genes onto designated substrates. However, many challenges remain to enable continuous and multiround delivery of the gene using the same substrates without depositing payloads and immobilizing cells in each round of delivery. Herein we introduce a gene delivery system, nanosubstrate-mediated delivery (NSMD) platform, based on two functional components with nanoscale features, including (1) DNA⊂SNPs, supramol. nanoparticle (SNP) vectors for gene encapsulation, and (2) Ad-SiNWS, adamantane (Ad)-grafted silicon nanowire substrates. The multivalent mol. recognition between the Ad motifs on Ad-SiNWS and the β-cyclodextrin (CD) motifs on DNA⊂SNPs leads to dynamic assembly and local enrichment of DNA⊂SNPs from the surrounding medium onto Ad-SiNWS. Subsequently, once cells settled on the substrate, DNA⊂SNPs enriched on Ad-SiNWS were introduced through the cell membranes by intimate contact with individual nanowires on Ad-SiNWS, resulting in a highly efficient delivery of exogenous genes. Most importantly, sequential delivery of multiple batches of exogenous genes on the same batch cells settled on Ad-SiNWS was realized by sequential addns. of the corresponding DNA⊂SNPs with equiv. efficiency. Moreover, using the NSMD platform in vivo, cells recruited on s.c. transplanted Ad-SiNWS were also efficiently transfected with exogenous genes loaded into SNPs, validating the in vivo feasibility of this system. We believe that this nanosubstrate-mediated delivery platform will provide a superior system for in vitro and in vivo gene delivery and can be further used for the encapsulation and delivery of other biomols.
71. 71

    Nair, B. G.; Hagiwara, K.; Ueda, M.; Yu, H.-h.; Tseng, H.-R.; Ito, Y. High Density of Aligned Nanowire Treated with Polydopamine for Efficient Gene Silencing by siRNA According to Cell Membrane Perturbation. ACS Appl. Mater. Interfaces 2016, 8, 18693– 18700,  DOI: 10.1021/acsami.6b04913

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    71

    High Density of Aligned Nanowire Treated with Polydopamine for Efficient Gene Silencing by siRNA According to Cell Membrane Perturbation

    Nair, Baiju G.; Hagiwara, Kyoji; Ueda, Motoki; Yu, Hsiao-hua; Tseng, Hsian-Rong; Ito, Yoshihiro

    ACS Applied Materials & Interfaces (2016), 8 (29), 18693-18700CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

    High aspect ratio nanomaterials, such as vertically aligned silicon nanowire (SiNW) substrates, are three-dimensional topol. features for cell manipulations. A high d. of SiNWs significantly affects not only cell adhesion and proliferation but also the delivery of biomols. to cells. Here, we used polydopamine (PD) that simply formed a thin coating on various material surfaces by the action of dopamine as a bioinspired approach. The PD coating not only enhanced cell adhesion, spreading, and growth but also anchored more siRNA by adsorption and provided more surface concn. for substrate-mediated delivery. By comparing plain and SiNW surfaces with the same amt. of loaded siRNA, we quant. found that PD coating efficiently anchored siRNA on the surface, which knocked down the expression of a specific gene by RNA interference. It was also found that the interaction of SiNWs with the cell membrane perturbed the lateral diffusion of lipids in the membrane by fluorescence recovery after photobleaching. The perturbation was considered to induce the effective delivery of siRNA into cells and allow the cells to carry out their biol. functions. These results suggest promising applications of PD-coated, high-d. SiNWs as simple, fast, and versatile platforms for transmembrane delivery of biomols.
72. 72

    Jiang, Y.; Harberts, J.; Assadi, A.; Chen, Y.; Spatz, J. P.; Duan, W.; Nisbet, D. R.; Voelcker, N. H.; Elnathan, R. The Roles of Micro- and Nanoscale Materials in Cell-Engineering Systems. Adv. Mater. 2024, 36, 202410908,  DOI: 10.1002/adma.202410908

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73. 73

    Cao, Y.; Hjort, M.; Chen, H.; Birey, F.; Leal-Ortiz, S. A.; Han, C. M.; Santiago, J. G.; Pasca, S. P.; Wu, J. C.; Melosh, N. A. Nondestructive Nanostraw Intracellular Sampling for Longitudinal Cell Monitoring. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, E1866-E1874,  DOI: 10.1073/pnas.1615375114

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74. 74

    Lin, Z. C.; Xie, C.; Osakada, Y.; Cui, Y.; Cui, B. Iridium Oxide Nanotube Electrodes for Sensitive and Prolonged Intracellular Measurement of Action Potentials. Nat. Commun. 2014, 5, 3206,  DOI: 10.1038/ncomms4206

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    Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials

    Lin Ziliang Carter; Xie Chong; Osakada Yasuko; Cui Bianxiao; Cui Yi

    Nature communications (2014), 5 (), 3206 ISSN:.

    Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry.
75. 75

    Casanova, A.; Bettamin, L.; Blatche, M. C.; Mathieu, F.; Martin, H.; Gonzalez-Dunia, D.; Nicu, L.; Larrieu, G. Nanowire Based Bioprobes for Electrical Monitoring of Electrogenic Cells. J. Phys.: Condens. Matter 2018, 30, 464001,  DOI: 10.1088/1361-648X/aae5aa

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76. 76

    Liu, R.; Lee, J.; Tchoe, Y.; Pre, D.; Bourhis, A. M.; D’Antonio-Chronowska, A.; Robin, G.; Lee, S. H.; Ro, Y. G.; Vatsyayan, R. Ultra-Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks. Adv. Funct. Mater. 2022, 32, 2108378,  DOI: 10.1002/adfm.202108378

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    Ultra-Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks

    Liu, Ren; Lee, Jihwan; Tchoe, Youngbin; Pre, Deborah; Bourhis, Andrew M.; D'Antonio-Chronowska, Agnieszka; Robin, Gaelle; Lee, Sang Heon; Ro, Yun Goo; Vatsyayan, Ritwik; Tonsfeldt, Karen J.; Hossain, Lorraine A.; Phipps, M. Lisa; Yoo, Jinkyoung; Nogan, John; Martinez, Jennifer S.; Frazer, Kelly A.; Bang, Anne G.; Dayeh, Shadi A.

    Advanced Functional Materials (2022), 32 (8), 2108378CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Intracellular access with high spatiotemporal resoln. can enhance the understanding of how neurons or cardiomyocytes regulate and orchestrate network activity and how this activity can be affected with pharmacol. or other interventional modalities. Nanoscale devices often employ electroporation to transiently permeate the cell membrane and record intracellular potentials, which tend to decrease rapidly with time. Here, one reports innovative scalable, vertical, ultrasharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. One reports electrophysiol. recordings that are indicative of intracellular access from 3D tissue-like networks of neurons and cardiomyocytes across recording days and that do not decrease to extracellular amplitudes for the duration of the recording of several minutes. The findings are validated with cross-sectional microscopy, pharmacol., and elec. interventions. The expts. and simulations demonstrate that the individual elec. addressability of nanowires is necessary for high-fidelity intracellular electrophysiol. recordings. This study advances the understanding of and control over high-quality multichannel intracellular recordings and paves the way toward predictive, high-throughput, and low-cost electrophysiol. drug screening platforms.
77. 77

    Luo, Y.; Abidian, M. R.; Ahn, J.-H.; Akinwande, D.; Andrews, A. M.; Antonietti, M.; Bao, Z.; Berggren, M.; Berkey, C. A.; Bettinger, C. J. Technology Roadmap for Flexible Sensors. ACS Nano 2023, 17, 5211– 5295,  DOI: 10.1021/acsnano.2c12606

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    Technology Roadmap for Flexible Sensors

    Luo, Yifei; Abidian, Mohammad Reza; Ahn, Jong-Hyun; Akinwande, Deji; Andrews, Anne M.; Antonietti, Markus; Bao, Zhenan; Berggren, Magnus; Berkey, Christopher A.; Bettinger, Christopher John; Chen, Jun; Chen, Peng; Cheng, Wenlong; Cheng, Xu; Choi, Seon-Jin; Chortos, Alex; Dagdeviren, Canan; Dauskardt, Reinhold H.; Di, Chong-an; Dickey, Michael D.; Duan, Xiangfeng; Facchetti, Antonio; Fan, Zhiyong; Fang, Yin; Feng, Jianyou; Feng, Xue; Gao, Huajian; Gao, Wei; Gong, Xiwen; Guo, Chuan Fei; Guo, Xiaojun; Hartel, Martin C.; He, Zihan; Ho, John S.; Hu, Youfan; Huang, Qiyao; Huang, Yu; Huo, Fengwei; Hussain, Muhammad M.; Javey, Ali; Jeong, Unyong; Jiang, Chen; Jiang, Xingyu; Kang, Jiheong; Karnaushenko, Daniil; Khademhosseini, Ali; Kim, Dae-Hyeong; Kim, Il-Doo; Kireev, Dmitry; Kong, Lingxuan; Lee, Chengkuo; Lee, Nae-Eung; Lee, Pooi See; Lee, Tae-Woo; Li, Fengyu; Li, Jinxing; Liang, Cuiyuan; Lim, Chwee Teck; Lin, Yuanjing; Lipomi, Darren J.; Liu, Jia; Liu, Kai; Liu, Nan; Liu, Ren; Liu, Yuxin; Liu, Yuxuan; Liu, Zhiyuan; Liu, Zhuangjian; Loh, Xian Jun; Lu, Nanshu; Lv, Zhisheng; Magdassi, Shlomo; Malliaras, George G.; Matsuhisa, Naoji; Nathan, Arokia; Niu, Simiao; Pan, Jieming; Pang, Changhyun; Pei, Qibing; Peng, Huisheng; Qi, Dianpeng; Ren, Huaying; Rogers, John A.; Rowe, Aaron; Schmidt, Oliver G.; Sekitani, Tsuyoshi; Seo, Dae-Gyo; Shen, Guozhen; Sheng, Xing; Shi, Qiongfeng; Someya, Takao; Song, Yanlin; Stavrinidou, Eleni; Su, Meng; Sun, Xuemei; Takei, Kuniharu; Tao, Xiao-Ming; Tee, Benjamin C. K.; Thean, Aaron Voon-Yew; Trung, Tran Quang; Wan, Changjin; Wang, Huiliang; Wang, Joseph; Wang, Ming; Wang, Sihong; Wang, Ting; Wang, Zhong Lin; Weiss, Paul S.; Wen, Hanqi; Xu, Sheng; Xu, Tailin; Yan, Hongping; Yan, Xuzhou; Yang, Hui; Yang, Le; Yang, Shuaijian; Yin, Lan; Yu, Cunjiang; Yu, Guihua; Yu, Jing; Yu, Shu-Hong; Yu, Xinge; Zamburg, Evgeny; Zhang, Haixia; Zhang, Xiangyu; Zhang, Xiaosheng; Zhang, Xueji; Zhang, Yihui; Zhang, Yu; Zhao, Siyuan; Zhao, Xuanhe; Zheng, Yuanjin; Zheng, Yu-Qing; Zheng, Zijian; Zhou, Tao; Zhu, Bowen; Zhu, Ming; Zhu, Rong; Zhu, Yangzhi; Zhu, Yong; Zou, Guijin; Chen, Xiaodong

    ACS Nano (2023), 17 (6), 5211-5295CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solns. We first analyze challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biol. interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontech. issues such as business, regulatory, and ethical considerations. Addnl., we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative efforts, scientific breakthroughs can be made sooner and capitalized for the betterment of humanity.
78. 78

    He, F.; Lycke, R.; Ganji, M.; Xie, C.; Luan, L. Ultraflexible Neural Electrodes for Long-Lasting Intracortical Recording. iScience 2020, 23, 101387,  DOI: 10.1016/j.isci.2020.101387

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    Zhao, Z.; Li, X.; He, F.; Wei, X.; Lin, S.; Xie, C. Parallel, Minimally-Invasive Implantation of Ultra-Flexible Neural Electrode Arrays. J. Neural Eng. 2019, 16, 035001,  DOI: 10.1088/1741-2552/ab05b6

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    Luan, L.; Wei, X.; Zhao, Z.; Siegel, J. J.; Potnis, O.; Tuppen, C. A.; Lin, S.; Kazmi, S.; Fowler, R. A.; Holloway, S. Ultraflexible Nanoelectronic Probes Form Reliable, Glial Scar-Free Neural Integration. Sci. Adv. 2017, 3, e1601966,  DOI: 10.1126/sciadv.1601966

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    Ultraflexible nanoelectronic probes form reliable, glial scar-free neural integration

    Luan, Lan; Wei, Xiaoling; Zhao, Zhengtuo; Siegel, Jennifer J.; Potnis, Ojas; Tuppen, Catherine A.; Lin, Shengqing; Kazmi, Shams; Fowler, Robert A.; Holloway, Stewart; Dunn, Andrew K.; Chitwood, Raymond A.; Xie, Chong

    Science Advances (2017), 3 (2), e1601966/1-e1601966/9CODEN: SACDAF; ISSN:2375-2548. (American Association for the Advancement of Science)

    Implanted brain electrodes construct the only means to elec. interface with individual neurons in vivo, but their recording efficacy and biocompatibility pose limitations on scientific and clin. applications. We showed that nanoelectronic thread (NET) electrodes with subcellular dimensions, ultraflexibility, and cellular surgical footprints form reliable, glial scar-free neural integration. We demonstrated that NET electrodes reliably detected and tracked individual units for months; their impedance, noise level, single-unit recording yield, and the signal amplitude remained stable during long-term implantation. In vivo two-photon imaging and postmortem histol. anal. revealed seamless, subcellular integration of NET probes with the local cellular and vasculature networks, featuring fully recovered capillaries with an intact blood-brain barrier and complete absence of chronic neuronal degrdn. and glial scar.
81. 81

    Lycke, R.; Kim, R.; Zolotavin, P.; Montes, J.; Sun, Y.; Koszeghy, A.; Altun, E.; Noble, B.; Yin, R.; He, F. Low-Threshold, High-Resolution, Chronically Stable Intracortical Microstimulation by Ultraflexible Electrodes. Cell Rep. 2023, 42, 112554,  DOI: 10.1016/j.celrep.2023.112554

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82. 82

    Jones, P. D.; Moskalyuk, A.; Barthold, C.; Gutöhrlein, K.; Heusel, G.; Schröppel, B.; Samba, R.; Giugliano, M. Low-Impedance 3D PEDOT: PSS Ultramicroelectrodes. Front. Neurosci. 2020, 14, 405,  DOI: 10.3389/fnins.2020.00405

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    Abbott, J.; Ye, T.; Krenek, K.; Gertner, R. S.; Ban, S.; Kim, Y.; Qin, L.; Wu, W.; Park, H.; Ham, D. A Nanoelectrode Array for Obtaining Intracellular Recordings from Thousands of Connected Neurons. Nat. Biomed. Eng. 2020, 4, 232– 241,  DOI: 10.1038/s41551-019-0455-7

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    A nanoelectrode array for obtaining intracellular recordings from thousands of connected neurons

    Abbott, Jeffrey; Ye, Tianyang; Krenek, Keith; Gertner, Rona S.; Ban, Steven; Kim, Youbin; Qin, Ling; Wu, Wenxuan; Park, Hongkun; Ham, Donhee

    Nature Biomedical Engineering (2020), 4 (2), 232-241CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)

    Current electrophysiol. or optical techniques cannot reliably perform simultaneous intracellular recordings from more than a few tens of neurons. Here we report a nanoelectrode array that can simultaneously obtain intracellular recordings from thousands of connected mammalian neurons in vitro. The array consists of 4,096 platinum-black electrodes with nanoscale roughness fabricated on top of a silicon chip that monolithically integrates 4,096 microscale amplifiers, configurable into pseudocurrent-clamp mode (for concurrent current injection and voltage recording) or into pseudovoltage-clamp mode (for concurrent voltage application and current recording). We used the array in pseudovoltage-clamp mode to measure the effects of drugs on ion-channel currents. In pseudocurrent-clamp mode, the array intracellularly recorded action potentials and postsynaptic potentials from thousands of neurons. In addn., we mapped over 300 excitatory and inhibitory synaptic connections from more than 1,700 neurons that were intracellularly recorded for 19 min. This high-throughput intracellular-recording technol. could benefit functional connectome mapping, electrophysiol. screening and other functional interrogations of neuronal networks.
84. 84

    Sun, L.; Yuan, G.; Gao, L.; Yang, J.; Chhowalla, M.; Gharahcheshmeh, M. H.; Gleason, K. K.; Choi, Y. S.; Hong, B. H.; Liu, Z. Chemical Vapour Deposition. Nat. Rev. Methods Primers 2021, 1, 5,  DOI: 10.1038/s43586-020-00005-y

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    Chemical vapour deposition

    Sun, Luzhao; Yuan, Guowen; Gao, Libo; Yang, Jieun; Chhowalla, Manish; Gharahcheshmeh, Meysam Heydari; Gleason, Karen K.; Choi, Yong Seok; Hong, Byung Hee; Liu, Zhongfan

    Nature Reviews Methods Primers (2021), 1 (1), 5CODEN: NRMPAT; ISSN:2662-8449. (Nature Portfolio)

    A review. Chem. vapor deposition (CVD) is a powerful technol. for producing high-quality solid thin films and coatings. Although widely used in modern industries, it is continuously being developed as it is adapted to new materials. Today, CVD synthesis is being pushed to new heights with the precise manufg. of both inorg. thin films of 2D materials and high-purity polymeric thin films that can be conformally deposited on various substrates. In this Primer, an overview of the CVD technique, including instrument construction, process control, material characterization and reproducibility issues, is provided. By taking graphene, 2D transition metal dichalcogenides (TMDs) and polymeric thin films as typical examples, the best practices for experimentation involving substrate pretreatment, high-temp. growth and post-growth processes are presented. Recent advances and scaling-up challenges are also highlighted. By analyzing current limitations and optimizations, we also provide insight into possible future directions for the method, including reactor design for high-throughput and low-temp. growth of thin films.
85. 85

    Graniel, O.; Weber, M.; Balme, S.; Miele, P.; Bechelany, M. Atomic Layer Deposition for Biosensing Applications. Biosens. Bioelectron. 2018, 122, 147– 159,  DOI: 10.1016/j.bios.2018.09.038

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    Atomic layer deposition for biosensing applications

    Graniel, Octavio; Weber, Matthieu; Balme, Sebastien; Miele, Philippe; Bechelany, Mikhael

    Biosensors & Bioelectronics (2018), 122 (), 147-159CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)

    Atomic layer deposition (ALD) is a thin film deposition technique currently used in various nanofabrication processes for microelectronic applications. The ability to coat high aspect ratio structures with a wide range of materials, the excellent conformality, and the exquisite thickness control have made ALD an essential tool for the fabrication of many devices, including biosensors. This mini-review aims to provide a summary of the different ways ALD has been used to prep. biosensor devices. The materials that have been deposited by ALD, the use of the ALD layers prepd. and the different types of biosensors fabricated are presented. A selected list of studies will be used to illustrate how the ALD route can be implemented to improve the operational performance of biosensors. This work comprehensively shows the benefits of ALD and its application in various facets of biosensing and will help in exploiting the numerous prospects of this emerging and growing field.
86. 86

    Li, P.; Chen, S.; Dai, H.; Yang, Z.; Chen, Z.; Wang, Y.; Chen, Y.; Peng, W.; Shan, W.; Duan, H. Recent Advances in Focused Ion Beam Nanofabrication for Nanostructures and Devices: Fundamentals and Applications. Nanoscale 2021, 13, 1529– 1565,  DOI: 10.1039/D0NR07539F

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    Recent advances in focused ion beam nanofabrication for nanostructures and devices: fundamentals and applications

    Li, Ping; Chen, Siyu; Dai, Houfu; Yang, Zhengmei; Chen, Zhiquan; Wang, Yasi; Chen, Yiqin; Peng, Wenqiang; Shan, Wubin; Duan, Huigao

    Nanoscale (2021), 13 (3), 1529-1565CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

    The past few decades have witnessed growing research interest in developing powerful nanofabrication technologies for three-dimensional (3D) structures and devices to achieve nano-scale and nano-precision manufg. Among the various fabrication techniques, focused ion beam (FIB) nanofabrication has been established as a well-suited and promising technique in nearly all fields of nanotechnol. for the fabrication of 3D nanostructures and devices because of increasing demands from industry and research. In this article, a series of FIB nanofabrication factors related to the fabrication of 3D nanostructures and devices, including mechanisms, instruments, processes, and typical applications of FIB nanofabrication, are systematically summarized and analyzed in detail. Addnl., current challenges and future development trends of FIB nanofabrication in this field are also given. This work intends to provide guidance for practitioners, researchers, or engineers who wish to learn more about the FIB nanofabrication technol. that is driving the revolution in 3D nanostructures and devices.
87. 87

    Kim, J.; Rim, Y. S.; Chen, H.; Cao, H. H.; Nakatsuka, N.; Hinton, H. L.; Zhao, C.; Andrews, A. M.; Yang, Y.; Weiss, P. S. Fabrication of High-Performance Ultrathin In₂O₃ Film Field-Effect Transistors and Biosensors Using Chemical Lift-Off Lithography. ACS Nano 2015, 9, 4572– 4582,  DOI: 10.1021/acsnano.5b01211

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    Fabrication of High-Performance Ultrathin In2O3 Film Field-Effect Transistors and Biosensors Using Chemical Lift-Off Lithography

    Kim, Jaemyung; Rim, You Seung; Chen, Huajun; Cao, Huan H.; Nakatsuka, Nako; Hinton, Hannah L.; Zhao, Chuanzhen; Andrews, Anne M.; Yang, Yang; Weiss, Paul S.

    ACS Nano (2015), 9 (4), 4572-4582CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    The authors demonstrate straightforward fabrication of highly sensitive biosensor arrays based on field-effect transistors, using an efficient high-throughput, large-area patterning process. Chem. lift-off lithog. was used to construct field-effect transistor arrays with high spatial precision suitable for the fabrication of both micrometer- and nanometer-scale devices. Sol-gel processing was used to deposit ultrathin (∼4 nm) In2O3 films as semiconducting channel layers. The aq. sol-gel process produces uniform In2O3 coatings with thicknesses of a few nanometers over large areas through simple spin-coating, and only low-temp. thermal annealing of the coatings is required. The ultrathin In2O3 enables construction of highly sensitive and selective biosensors through immobilization of specific aptamers to the channel surface; the ability to detect subnanomolar concns. of dopamine is demonstrated.
88. 88

    Huff, M. Recent Advances in Reactive Ion Etching and Applications of High-Aspect-Ratio Microfabrication. Micromachines (Basel) 2021, 12, 991,  DOI: 10.3390/mi12080991

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    Hai, A.; Shappir, J.; Spira, M. E. Long-Term, Multisite, Parallel, in-Cell Recording and Stimulation by an Array of Extracellular Microelectrodes. J. Neurophysiol. 2010, 104, 559– 568,  DOI: 10.1152/jn.00265.2010

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    89

    Long-Term, multisite, parallel, in-cell recording and stimulation by an array of extracellular microelectrodes

    Hai, Aviad; Shappir, Joseph; Spira, Micha E.

    Journal of Neurophysiology (2010), 104 (1), 559-568CODEN: JONEA4; ISSN:0022-3077. (American Physiological Society)

    Here we report on the development of a novel neuroelectronic interface consisting of an array of noninvasive gold-mushroom-shaped microelectrodes (gMμEs) that practically provide intracellular recordings and stimulation of many individual neurons, while the electrodes maintain an extracellular position. The development of this interface allows simultaneous, multisite, long-term recordings of action potentials and subthreshold potentials with matching quality and signal-to-noise ratio of conventional intracellular sharp glass microelectrodes or patch electrodes. We refer to the novel approach as "in-cell recording and stimulation by extracellular electrodes" to differentiate it from the classical intracellular recording and stimulation methods. This novel technique is expected to revolutionize the anal. of neuronal networks in relations to learning, information storage and can be used to develop novel drugs as well as high fidelity neural prosthetics and brain-machine systems.
90. 90

    Xie, C.; Lin, Z.; Hanson, L.; Cui, Y.; Cui, B. Intracellular Recording of Action Potentials by Nanopillar Electroporation. Nat. Nanotechnol. 2012, 7, 185– 190,  DOI: 10.1038/nnano.2012.8

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    90

    Intracellular recording of action potentials by nanopillar electroporation

    Xie, Chong; Lin, Ziliang; Hanson, Lindsey; Cui, Yi; Cui, Bianxiao

    Nature Nanotechnology (2012), 7 (3), 185-190CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

    Action potentials have a central role in the nervous system and in many cellular processes, notably those involving ion channels. The accurate measurement of action potentials requires efficient coupling between the cell membrane and the measuring electrodes. Intracellular recording methods such as patch clamping involve measuring the voltage or current across the cell membrane by accessing the cell interior with an electrode, allowing both the amplitude and shape of the action potentials to be recorded faithfully with high signal-to-noise ratios. However, the invasive nature of intracellular methods usually limits the recording time to a few hours, and their complexity makes it difficult to simultaneously record more than a few cells. Extracellular recording methods, such as multielectrode arrays and multitransistor arrays, are noninvasive and allow long-term and multiplexed measurements. However, extracellular recording sacrifices the one-to-one correspondence between the cells and electrodes, and also suffers from significantly reduced signal strength and quality. Extracellular techniques are not, therefore, able to record action potentials with the accuracy needed to explore the properties of ion channels. As a result, the pharmacol. screening of ion-channel drugs is usually performed by low-throughput intracellular recording methods. The use of nanowire transistors, nanotube-coupled transistors and micro gold-spine and related electrodes can significantly improve the signal strength of recorded action potentials. Here, the authors show that vertical nanopillar electrodes can record both the extracellular and intracellular action potentials of cultured cardiomyocytes over a long period of time with excellent signal strength and quality. Moreover, it is possible to repeatedly switch between extracellular and intracellular recording by nanoscale electroporation and resealing processes. Furthermore, vertical nanopillar electrodes can detect subtle changes in action potentials induced by drugs that target ion channels.
91. 91

    Prinz, C. N. Interactions between Semiconductor Nanowires and Living Cells. J. Phys.: Condens. Matter 2015, 27, 233103,  DOI: 10.1088/0953-8984/27/23/233103

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    91

    Interactions between semiconductor nanowires and living cells

    Prinz Christelle N

    Journal of physics. Condensed matter : an Institute of Physics journal (2015), 27 (23), 233103 ISSN:.

    Semiconductor nanowires are increasingly used for biological applications and their small dimensions make them a promising tool for sensing and manipulating cells with minimal perturbation. In order to interface cells with nanowires in a controlled fashion, it is essential to understand the interactions between nanowires and living cells. The present paper reviews current progress in the understanding of these interactions, with knowledge gathered from studies where living cells were interfaced with vertical nanowire arrays. The effect of nanowires on cells is reported in terms of viability, cell-nanowire interface morphology, cell behavior, changes in gene expression as well as cellular stress markers. Unexplored issues and unanswered questions are discussed.
92. 92

    Dipalo, M.; Amin, H.; Lovato, L.; Moia, F.; Caprettini, V.; Messina, G. C.; Tantussi, F.; Berdondini, L.; De Angelis, F. Intracellular and Extracellular Recording of Spontaneous Action Potentials in Mammalian Neurons and Cardiac Cells with 3D Plasmonic Nanoelectrodes. Nano Lett. 2017, 17, 3932– 3939,  DOI: 10.1021/acs.nanolett.7b01523

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    92

    Intracellular and Extracellular Recording of Spontaneous Action Potentials in Mammalian Neurons and Cardiac Cells with 3D Plasmonic Nanoelectrodes

    Dipalo, Michele; Amin, Hayder; Lovato, Laura; Moia, Fabio; Caprettini, Valeria; Messina, Gabriele C.; Tantussi, Francesco; Berdondini, Luca; De Angelis, Francesco

    Nano Letters (2017), 17 (6), 3932-3939CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

    Three-dimensional vertical micro- and nanostructures can enhance the signal quality of multielectrode arrays and promise to become the prime methodol. for the study of large networks of electrogenic cells. So far, access to the intracellular environment has been obtained via spontaneous poration, electroporation, or by surface functionalization of the micro/nanostructures; however, these methods still suffer from some limitations due to their intrinsic characteristics that limit their widespread use. Here, the authors demonstrate the ability to continuously record both extracellular and intracellular-like action potentials at each electrode site in spontaneously active mammalian neurons and HL-1 cardiac-derived cells via the combination of vertical nanoelectrodes with plasmonic optoporation. The authors demonstrate long-term and stable recordings with a very good signal-to-noise ratio. Addnl., plasmonic optoporation does not perturb the spontaneous elec. activity; it permits continuous recording even during the poration process and can regulate extracellular and intracellular contributions by partial cellular poration.
93. 93

    Buch-Månson, N.; Bonde, S.; Bolinsson, J.; Berthing, T.; Nygård, J.; Martinez, K. L. Towards a Better Prediction of Cell Settling on Nanostructure Arrays-Simple Means to Complicated Ends. Adv. Funct. Mater. 2015, 25, 3246– 3255,  DOI: 10.1002/adfm.201500399

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    93

    Towards a Better Prediction of Cell Settling on Nanostructure Arrays - Simple Means to Complicated Ends

    Buch-Manson, Nina; Bonde, Sara; Bolinsson, Jessica; Berthing, Trine; Nygard, Jesper; Martinez, Karen L.

    Advanced Functional Materials (2015), 25 (21), 3246-3255CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Vertical arrays of nanostructures (NSs) are emerging as promising platforms for probing and manipulating live mammalian cells. The broad range of applications requires different types of interfaces, but cell settling on NS arrays is not yet fully controlled and understood. Cells are both seen to deform completely into NS arrays and to stay suspended like tiny fakirs, which have hitherto been explained with differences in NS spacing or d. Here, a better understanding of this phenomenon is provided by using a model that takes into account the extreme membrane deformation needed for a cell to settle into a NS array. In addn. to the NS d., cell settling depends strongly on the dimensions of the single NS, and the settling can be predicted for a given NS array geometry. The predictive power of the model is confirmed by expts. and good agreement with cases from the literature. Furthermore, the influence of cell-related parameters is evaluated theor. and a generic method of tuning cell settling through surface coating is demonstrated exptl. These findings allow a more rational design of NS arrays for the numerous exciting biol. applications where the mode of cell settling is crucial.
94. 94

    Zhu, W.; von dem Bussche, A.; Yi, X.; Qiu, Y.; Wang, Z.; Weston, P.; Hurt, R. H.; Kane, A. B.; Gao, H. Nanomechanical Mechanism for Lipid Bilayer Damage Induced by Carbon Nanotubes Confined in Intracellular Vesicles. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 12374– 12379,  DOI: 10.1073/pnas.1605030113

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    94

    Nanomechanical mechanism for lipid bilayer damage induced by carbon nanotubes confined in intracellular vesicles

    Zhu, Wenpeng; von dem Bussche, Annette; Yi, Xin; Qiu, Yang; Wang, Zhongying; Weston, Paula; Hurt, Robert H.; Kane, Agnes B.; Gao, Huajian

    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (44), 12374-12379CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Understanding the behavior of low-dimensional nanomaterials confined in intracellular vesicles has been limited by the resoln. of bioimaging techniques and the complex nature of the problem. Recent studies report that long, stiff carbon nanotubes are more cytotoxic than flexible varieties, but the mechanistic link between stiffness and cytotoxicity is not understood. Here the authors combine anal. modeling, mol. dynamics simulations, and in vitro intracellular imaging methods to reveal 1D carbon nanotube behavior within intracellular vesicles. The authors show that stiff nanotubes beyond a crit. length are compressed by lysosomal membranes causing persistent tip contact with the inner membrane leaflet, leading to lipid extn., lysosomal permeabilization, release of cathepsin B (a lysosomal protease) into the cytoplasm, and cell death. The precise material parameters needed to activate this unique mech. pathway of nanomaterials interaction with intracellular vesicles were identified through coupled modeling, simulation, and exptl. studies on carbon nanomaterials with wide variation in size, shape, and stiffness, leading to a generalized classification diagram for 1D nanocarbons that distinguishes pathogenic from biocompatible varieties based on a nanomech. buckling criterion. For a wide variety of other 1D material classes (metal, oxide, polymer), this generalized classification diagram shows a crit. threshold in length/width space that represents a transition from biol. soft to stiff, and thus identifies the important subset of all 1D materials with the potential to induce lysosomal permeability by the nanomech. mechanism under investigation.
95. 95

    Lou, H. Y.; Zhao, W.; Li, X.; Duan, L.; Powers, A.; Akamatsu, M.; Santoro, F.; McGuire, A. F.; Cui, Y.; Drubin, D. G.; Cui, B. Membrane Curvature Underlies Actin Reorganization in Response to Nanoscale Surface Topography. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 23143– 23151,  DOI: 10.1073/pnas.1910166116

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    95

    Membrane curvature underlies actin reorganization in response to nanoscale surface topography

    Lou, Hsin-Ya; Zhao, Wenting; Li, Xiao; Duan, Liting; Powers, Alexander; Akamatsu, Matthew; Santoro, Francesca; McGuire, Allister F.; Cui, Yi; Drubin, David G.; Cui, Bianxiao

    Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (46), 23143-23151CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    Surface topog. profoundly influences cell adhesion, differentiation, and stem cell fate control. Numerous studies using a variety of materials demonstrate that nanoscale topogs. change the intracellular organization of actin cytoskeleton and therefore a broad range of cellular dynamics in live cells. However, the underlying mol. mechanism is not well understood, leaving why actin cytoskeleton responds to topog. features unexplained and therefore preventing researchers from predicting optimal topog. features for desired cell behavior. Here we demonstrate that topog.-induced membrane curvature plays a crucial role in modulating intracellular actin organization. By inducing precisely controlled membrane curvatures using engineered vertical nanostructures as topogs., we find that actin fibers form at the sites of nanostructures in a curvature-dependent manner with an upper limit for the diam. of curvature at ∼400 nm. Nanotopog.-induced actin fibers are branched actin nucleated by the Arp2/3 complex and are mediated by a curvature-sensing protein FBP17. Our study reveals that the formation of nanotopog.-induced actin fibers drastically reduces the amt. of stress fibers and mature focal adhesions to result in the reorganization of actin cytoskeleton in the entire cell. These findings establish the membrane curvature as a key linkage between surface topog. and topog.-induced cell signaling and behavior.
96. 96

    Fu, T. M.; Duan, X.; Jiang, Z.; Dai, X.; Xie, P.; Cheng, Z.; Lieber, C. M. Sub-10-nm Intracellular Bioelectronic Probes From Nanowire-Nanotube Heterostructures. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 1259– 1264,  DOI: 10.1073/pnas.1323389111

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    96

    Sub-10-nm intracellular bioelectronic probes from nanowire-nanotube heterostructures

    Fu, Tian-Ming; Duan, Xiaojie; Jiang, Zhe; Dai, Xiaochuan; Xie, Ping; Cheng, Zengguang; Lieber, Charles M.

    Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (4), 1259-1264CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The miniaturization of bioelectronic intracellular probes with a wide dynamic frequency range can open up opportunities to study biol. structures inaccessible by existing methods in a minimally invasive manner. Here, we report the design, fabrication, and demonstration of intracellular bioelectronic devices with probe sizes less than 10 nm. The devices are based on a nanowire-nanotube heterostructure in which a nanowire field-effect transistor detector is synthetically integrated with a nanotube cellular probe. Sub-10-nm nanotube probes were realized by a two-step selective etching approach that reduces the diam. of the nanotube free-end while maintaining a larger diam. at the nanowire detector necessary for mech. strength and elec. sensitivity. Quasi-static water-gate measurements demonstrated selective device response to soln. inside the nanotube, and pulsed measurements together with numerical simulations confirmed the capability to record fast electrophysiol. signals. Systematic studies of the probe bandwidth in different ionic concn. solns. revealed the underlying mechanism governing the time response. In addn., the bandwidth effect of phospholipid coatings, which are important for intracellular recording, was investigated and modeled. The robustness of these sub-10-nm bioelectronics probes for intracellular interrogation was verified by optical imaging and recording the transmembrane resting potential of HL-1 cells. These ultrasmall bioelectronic probes enable direct detection of cellular elec. activity with highest spatial resoln. achieved to date, and with further integration into larger chip arrays could provide a unique platform for ultra-high-resoln. mapping of activity in neural networks and other systems.
97. 97

    Dipalo, M.; Caprettini, V.; Bruno, G.; Caliendo, F.; Garma, L. D.; Melle, G.; Dukhinova, M.; Siciliano, V.; Santoro, F.; De Angelis, F. Membrane Poration Mechanisms at the Cell-Nanostructure Interface. Adv. Biosyst. 2019, 3, e1900148,  DOI: 10.1002/adbi.201900148

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    There is no corresponding record for this reference.
98. 98

    Shokoohimehr, P.; Cepkenovic, B.; Milos, F.; Bednar, J.; Hassani, H.; Maybeck, V.; Offenhausser, A. High-Aspect-Ratio Nanoelectrodes Enable Long-Term Recordings of Neuronal Signals with Subthreshold Resolution. Small 2022, 18, e2200053,  DOI: 10.1002/smll.202200053

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    There is no corresponding record for this reference.
99. 99

    McGuire, A. F.; Santoro, F.; Cui, B. Interfacing Cells with Vertical Nanoscale Devices: Applications and Characterization. Annu. Rev. Anal. Chem. 2018, 11, 101– 126,  DOI: 10.1146/annurev-anchem-061417-125705

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    99

    Interfacing Cells with Vertical Nanoscale Devices: Applications and Characterization

    McGuire Allister F; Santoro Francesca; Cui Bianxiao; Santoro Francesca

    Annual review of analytical chemistry (Palo Alto, Calif.) (2018), 11 (1), 101-126 ISSN:.

    Measurements of the intracellular state of mammalian cells often require probes or molecules to breach the tightly regulated cell membrane. Mammalian cells have been shown to grow well on vertical nanoscale structures in vitro, going out of their way to reach and tightly wrap the structures. A great deal of research has taken advantage of this interaction to bring probes close to the interface or deliver molecules with increased efficiency or ease. In turn, techniques have been developed to characterize this interface. Here, we endeavor to survey this research with an emphasis on the interface as driven by cellular mechanisms.
100. 100

     Higgins, S. G.; Becce, M.; Belessiotis-Richards, A.; Seong, H.; Sero, J. E.; Stevens, M. M. High-Aspect-Ratio Nanostructured Surfaces as Biological Metamaterials. Adv. Mater. 2020, 32, 1903862,  DOI: 10.1002/adma.201903862

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     100

     High-Aspect-Ratio Nanostructured Surfaces as Biological Metamaterials

     Higgins, Stuart G.; Becce, Michele; Belessiotis-Richards, Alexis; Seong, Hyejeong; Sero, Julia E.; Stevens, Molly M.

     Advanced Materials (Weinheim, Germany) (2020), 32 (9), 1903862CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Materials patterned with high-aspect-ratio nanostructures have features on similar length scales to cellular components. These surfaces are an extreme topog. on the cellular level and have become useful tools for perturbing and sensing the cellular environment. Motivation comes from the ability of high-aspect-ratio nanostructures to deliver cargoes into cells and tissues, access the intracellular environment, and control cell behavior. These structures directly perturb cells' ability to sense and respond to external forces, influencing cell fate, and enabling new mechanistic studies. Through careful design of their nanoscale structure, these systems act as biol. metamaterials, eliciting unusual biol. responses. While predominantly used to interface eukaryotic cells, there is growing interest in nonanimal and prokaryotic cell interfacing. Both exptl. and theor. studies have attempted to develop a mechanistic understanding for the obsd. behaviors, predominantly focusing on the cell-nanostructure interface. This review considers how high-aspect-ratio nanostructured surfaces were used to both stimulate and sense biol. systems.
101. 101

     DeWeerdt, S. How to Map the Brain. Nature 2019, 571, S6– S8,  DOI: 10.1038/d41586-019-02208-0

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     There is no corresponding record for this reference.
102. 102

     Azevedo, F. A.; Carvalho, L. R.; Grinberg, L. T.; Farfel, J. M.; Ferretti, R. E.; Leite, R. E.; Filho, W. J.; Lent, R.; Herculano-Houzel, S. Equal Numbers of Neuronal and Nonneuronal Cells Make the Human Brain an Isometrically Scaled-Up Primate Brain. J. Comp. Neurol. 2009, 513, 532– 541,  DOI: 10.1002/cne.21974

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     102

     Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain

     Azevedo Frederico A C; Carvalho Ludmila R B; Grinberg Lea T; Farfel Jose Marcelo; Ferretti Renata E L; Leite Renata E P; Jacob Filho Wilson; Lent Roberto; Herculano-Houzel Suzana

     The Journal of comparative neurology (2009), 513 (5), 532-41 ISSN:.

     The human brain is often considered to be the most cognitively capable among mammalian brains and to be much larger than expected for a mammal of our body size. Although the number of neurons is generally assumed to be a determinant of computational power, and despite the widespread quotes that the human brain contains 100 billion neurons and ten times more glial cells, the absolute number of neurons and glial cells in the human brain remains unknown. Here we determine these numbers by using the isotropic fractionator and compare them with the expected values for a human-sized primate. We find that the adult male human brain contains on average 86.1 +/- 8.1 billion NeuN-positive cells ("neurons") and 84.6 +/- 9.8 billion NeuN-negative ("nonneuronal") cells. With only 19% of all neurons located in the cerebral cortex, greater cortical size (representing 82% of total brain mass) in humans compared with other primates does not reflect an increased relative number of cortical neurons. The ratios between glial cells and neurons in the human brain structures are similar to those found in other primates, and their numbers of cells match those expected for a primate of human proportions. These findings challenge the common view that humans stand out from other primates in their brain composition and indicate that, with regard to numbers of neuronal and nonneuronal cells, the human brain is an isometrically scaled-up primate brain.
103. 103

     Harsch, A.; Calderon, J.; Timmons, R. B.; Gross, G. W. Pulsed Plasma Deposition of Allylamine on Polysiloxane: A Stable Surface for Neuronal Cell Adhesion. J. Neurosci. Methods 2000, 98, 135– 144,  DOI: 10.1016/S0165-0270(00)00196-5

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     103

     Pulsed plasma deposition of allylamine on polysiloxane: a stable surface for neuronal cell adhesion

     Harsch, A.; Calderon, J.; Timmons, R. B.; Gross, G. W.

     Journal of Neuroscience Methods (2000), 98 (2), 135-144CODEN: JNMEDT; ISSN:0165-0270. (Elsevier Science B.V.)

     Allylamine was pulse-plasma polymd. onto a hydrophobic polysiloxane substrate to create cell adhesion surfaces for cell culture that would not require pretreatment with polylysine, could be sterilized via autoclaving, and could be re-used for several culture cycles. We investigated two different plasma deposition protocols at 200 W RF power: (1) a duty cycle of 3 ms on and 5 ms off; and (2) a cycle of 3 ms on and 45 ms off. Control surfaces were unmodified polysiloxane, activated polysiloxane via flaming, and flamed polysiloxane further modified with poly(D-lysine) (PDL). The different surfaces were characterized with XPS anal., water contact angle, and cell adhesion and growth using dissocd. murine embryonic spinal tissue. We found that both the amine content of the 3/45 duty cycle surface and the wettability was higher than that of the 3/5 surface. Also, spinal cord cells were better dispersed 24 h after seeding on the 3/45 surface, suggesting a difference in early adhesion dynamics. However, the networks on the two types of modified surfaces revealed no obvious morphol. differences after 2 wk in vitro. The stability of allylamine-decorated surfaces after autoclaving was high with only minor changes in wettability and nitrogen content. Cell growth on such surfaces after autoclaving was comparable to that found on flamed polysiloxane, freshly modified with PDL. Allylamine surfaces were still usable as cell growth substrates after three autoclaving cycles, 4 wk under warm culture medium, and simple cleaning procedures, indicating the achievement of a long-lasting modification that did not require the repeated use of PDL before each seeding.
104. 104

     Wyart, C.; Ybert, C.; Bourdieu, L.; Herr, C.; Prinz, C.; Chatenay, D. Constrained Synaptic Connectivity in Functional Mammalian Neuronal Networks Grown on Patterned Surfaces. J. Neurosci. Methods 2002, 117, 123– 131,  DOI: 10.1016/S0165-0270(02)00077-8

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     104

     Constrained synaptic connectivity in functional mammalian neuronal networks grown on patterned surfaces

     Wyart Claire; Ybert Christophe; Bourdieu Laurent; Herr Catherine; Prinz Christelle; Chatenay Didier

     Journal of neuroscience methods (2002), 117 (2), 123-31 ISSN:0165-0270.

     The use of ordered neuronal networks in vitro is a promising approach to study the development and the activity of small neuronal assemblies. However, in previous attempts, sufficient growth control and physiological maturation of neurons could not be achieved. Here we describe an original protocol in which polylysine patterns confine the adhesion of cellular bodies to prescribed spots and the neuritic growth to thin lines. Hippocampal neurons in these networks are maintained healthy in serum free medium up to 5 weeks in vitro. Electrophysiology and immunochemistry show that neurons exhibit mature excitatory and inhibitory synapses and calcium imaging reveals spontaneous activity of neurons in isolated networks. We demonstrate that neurons in these geometrical networks form functional synapses preferentially to their first neighbors. We have, therefore, established a simple and robust protocol to constrain both the location of neuronal cell bodies and their pattern of connectivity. Moreover, the long term maintenance of the geometry and the physiology of the networks raises the possibility of new applications for systematic screening of pharmacological agents and for electronic to neuron devices.
105. 105

     Fendler, C.; Denker, C.; Harberts, J.; Bayat, P.; Zierold, R.; Loers, G.; Munzenberg, M.; Blick, R. H. Microscaffolds by Direct Laser Writing for Neurite Guidance Leading to Tailor-Made Neuronal Networks. Adv. Biosyst. 2019, 3, e1800329,  DOI: 10.1002/adbi.201800329

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     There is no corresponding record for this reference.
106. 106

     Harberts, J.; Fendler, C.; Teuber, J.; Siegmund, M.; Silva, A.; Rieck, N.; Wolpert, M.; Zierold, R.; Blick, R. H. Toward Brain-on-a-Chip: Human Induced Pluripotent Stem Cell-Derived Guided Neuronal Networks in Tailor-Made 3D Nanoprinted Microscaffolds. ACS Nano 2020, 14, 13091– 13102,  DOI: 10.1021/acsnano.0c04640

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     106

     Toward Brain-on-a-Chip: Human Induced Pluripotent Stem Cell-Derived Guided Neuronal Networks in Tailor-Made 3D Nanoprinted Microscaffolds

     Harberts, Jann; Fendler, Cornelius; Teuber, Jeremy; Siegmund, Malte; Silva, Aaron; Rieck, Niklas; Wolpert, Merle; Zierold, Robert; Blick, Robert H.

     ACS Nano (2020), 14 (10), 13091-13102CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Brain-on-a-chip (BoC) concepts should consider three-dimensional (3D) scaffolds to mimic the 3D nature of the human brain not accessible by conventional planar cell culturing. Furthermore, the essential key to adequately address drug development for human pathophysiol. diseases of the nervous system, such as Parkinson's or Alzheimer's, is to employ human induced pluripotent stem cell (iPSC)-derived neurons instead of neurons from animal models. To address both issues, the authors present electrophysiol. mature human iPSC-derived neurons cultured in BoC applicable microscaffolds prepd. by direct laser writing. 3D nanoprinted tailor-made elevated cavities interconnected by freestanding microchannels were used to create defined neuronal networks-as a proof of concept-with two-dimensional topol. The neuronal outgrowth in these nonplanar structures was studied, among others, in terms of neurite length, size of continuous networks, and branching behavior using z-stacks prepd. by confocal microscopy and cross-sectional SEM images prepd. by focused ion beam milling. Functionality of the human iPSC-derived neurons was demonstrated with patch clamp measurements in both current- and voltage-clamp mode. Action potentials and spontaneous excitatory postsynaptic currents-fundamental prerequisites for proper network signaling-prove full integrity of these artificial neuronal networks. Considering the network formation occurring within only a few days and the versatile nature of direct laser writing to create even more complex scaffolds for 3D network topologies, the authors believe that the authors' study offers addnl. approaches in human disease research to mimic the complex interconnectivity of the human brain in BoC studies.
107. 107

     Kim, Y. H.; Baek, N. S.; Han, Y. H.; Chung, M.-A.; Jung, S.-D. Enhancement of Neuronal Cell Adhesion by Covalent Binding of Poly-d-Lysine. J. Neurosci. Methods 2011, 202, 38– 44,  DOI: 10.1016/j.jneumeth.2011.08.036

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     107

     Enhancement of neuronal cell adhesion by covalent binding of poly-D-lysine

     Kim, Yong Hee; Baek, Nam Seob; Han, Young Hwan; Chung, Myung-Ae; Jung, Sang-Don

     Journal of Neuroscience Methods (2011), 202 (1), 38-44CODEN: JNMEDT; ISSN:0165-0270. (Elsevier B.V.)

     We have prepd. the poly-D-lysine (PDL) bound surfaces for neuron cell culture by covalent binding between the poly-D-Lysine and substrates and investigated neuronal cell adhesion properties and cell growth morphol. The no. of neuronal cell and the no. of neurite per neuronal cell on PDL bound surfaces was much more than those on PDL coated surfaces and also the neuronal cells on PDL bounded surfaces survived a longer time. On the pattern of covalently bound PDL, neuronal cells and their neurites are confined within the grid line leading to patterned neuronal networks with the long-term survival.
108. 108

     Li, N.; Zhang, Q.; Gao, S.; Song, Q.; Huang, R.; Wang, L.; Liu, L.; Dai, J.; Tang, M.; Cheng, G. Three-Dimensional Graphene Foam as a Biocompatible and Conductive Scaffold for Neural Stem Cells. Sci. Rep. 2013, 3, 1604,  DOI: 10.1038/srep01604

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     108

     Three-dimensional graphene foam as a biocompatible and conductive scaffold for neural stem cells

     Li, Ning; Zhang, Qi; Gao, Song; Song, Qin; Huang, Rong; Wang, Long; Liu, Liwei; Dai, Jianwu; Tang, Mingliang; Cheng, Guosheng

     Scientific Reports (2013), 3 (), 1604, 6 pp.CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     Neural stem cell (NSC) based therapy provides a promising approach for neural regeneration. For the success of NSC clin. application, a scaffold is required to provide 3-dimensional (3D) cell growth microenvironments and appropriate synergistic cell guidance cues. Here, the authors report the first utilization of graphene foam, a 3D porous structure, as a novel scaffold for NSCs in vitro. It was found that 3-dimensional graphene foams (3D-GFs) can not only support NSC growth, but also keep cell at an active proliferation state with upregulation of Ki67 expression than that of 2-dimensional graphene films. Meanwhile, phenotypic anal. indicated that 3D-GFs can enhance the NSC differentiation towards astrocytes and esp. neurons. Furthermore, a good elec. coupling of 3D-GFs with differentiated NSCs for efficient elec. stimulation was obsd. The authors' findings implicate 3D-GFs could offer a powerful platform for NSC research, neural tissue engineering and neural prostheses.
109. 109

     Koitmäe, A.; Harberts, J.; Loers, G.; Müller, M.; Bausch, C. S.; Sonnenberg, D.; Heyn, C.; Zierold, R.; Hansen, W.; Blick, R. H. Approaching Integrated Hybrid Neural Circuits: Axon Guiding on Optically Active Semiconductor Microtube Arrays. Adv. Mater. Interfaces 2016, 3, 1600746,  DOI: 10.1002/admi.201600746

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110. 110

     Huang, Y.; Jiang, Y.; Wu, Q.; Wu, X.; An, X.; Chubykin, A. A.; Cheng, J. X.; Xu, X. M.; Yang, C. Nanoladders Facilitate Directional Axonal Outgrowth and Regeneration. ACS Biomater. Sci. Eng. 2018, 4, 1037– 1045,  DOI: 10.1021/acsbiomaterials.7b00981

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     110

     Nanoladders facilitate directional axonal outgrowth and regeneration

     Huang, Yimin; Jiang, Ying; Wu, Qiuyu; Wu, Xiangbing; An, Xingda; Chubykin, Alexander A.; Cheng, Ji-Xin; Xu, Xiao-Ming; Yang, Chen

     ACS Biomaterials Science & Engineering (2018), 4 (3), 1037-1045CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

     After injuries, axonal regeneration over long distance is challenging due to lack of orientation guidance. Biocompatible scaffolds have been used to mimic the native organization of axons to guide and facilitate axonal regeneration. Those scaffolds are of great importance in achieving functional connections of the nervous system. We have developed a nanoladder scaffold to guide directional outgrowth and facilitate regeneration of axons. The nanoladders, composed of micron-scale stripes and nanoscale protrusions, were fabricated on the glass substrate using photolithog. and reactive ion etching methods. Embryonic neurons cultured on the nanoladder scaffold showed significant neurite elongation and axonal alignment in parallel with the nanoladder direction. Furthermore, the nanoladders promoted axonal regeneration and functional connection between organotypic spinal cord slices over 1 mm apart. Multimodality imaging studies revealed that such neuronal regeneration was supported by directional outgrowth of glial cells along nanoladders in the organotypic spinal cord slice culture as well as in the coculture of glial cells and neurons. These results collectively herald the potential of our nanoladder scaffold in facilitating and guiding neuronal development and functional restoration.
111. 111

     Koitmae, A.; Muller, M.; Bausch, C. S.; Harberts, J.; Hansen, W.; Loers, G.; Blick, R. H. Designer Neural Networks with Embedded Semiconductor Microtube Arrays. Langmuir 2018, 34, 1528– 1534,  DOI: 10.1021/acs.langmuir.7b03311

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112. 112

     Fendler, C.; Harberts, J.; Rafeldt, L.; Loers, G.; Zierold, R.; Blick, R. H. Neurite Guidance and Neuro-Caging on Steps and Grooves in 2.5 Dimensions. Nanoscale Adv. 2020, 2, 5192– 5200,  DOI: 10.1039/D0NA00549E

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113. 113

     Bastiaens, A.; Sabahi-Kaviani, R.; Luttge, R. Nanogrooves for 2D and 3D Microenvironments of SH-SY5Y Cultures in Brain-on-Chip Technology. Front. Neurosci. 2020, 14, 666,  DOI: 10.3389/fnins.2020.00666

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114. 114

     Capasso, A.; Rodrigues, J.; Moschetta, M.; Buonocore, F.; Faggio, G.; Messina, G.; Kim, M. J.; Kwon, J.; Placidi, E.; Benfenati, F.; Bramini, M.; Lee, G. H.; Lisi, N. Interactions between Primary Neurons and Graphene Films with Different Structure and Electrical Conductivity. Adv. Funct. Mater. 2021, 31, 2005300,  DOI: 10.1002/adfm.202005300

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115. 115

     Berthing, T.; Bonde, S.; Sorensen, C. B.; Utko, P.; Nygard, J.; Martinez, K. L. Intact Mammalian Cell Function on Semiconductor Nanowire Arrays: New Perspectives for Cell-Based Biosensing. Small 2011, 7, 640– 647,  DOI: 10.1002/smll.201001642

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116. 116

     Elnathan, R.; Kwiat, M.; Patolsky, F.; Voelcker, N. H. Engineering Vertically Aligned Semiconductor Nanowire Arrays for Applications in the Life Sciences. Nano Today 2014, 9, 172– 196,  DOI: 10.1016/j.nantod.2014.04.001

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     116

     Engineering vertically aligned semiconductor nanowire arrays for applications in the life sciences

     Elnathan, Roey; Kwiat, Moria; Patolsky, Fernando; Voelcker, Nicolas H.

     Nano Today (2014), 9 (2), 172-196CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)

     A review. The interface between nanotechnol. and life sciences is one of the fastest-growing and most promising areas of material science. This review is following a recent shift toward the engineering of vertically aligned (VA) semiconductor nanowire (NW) arrays for the development of next-generation biodevices. The focus of the review is on porous and non-porous silicon and other semiconductor NWs. We will first cover key aspects of VA-NW array fabrication and chem. functionalization. Then we will conc. on the interactions between VA-NW elements and mammalian cells. Specifically, we assess the ability of these nanostructures to influence cellular adhesion, morphol., migration, proliferation, and differentiation. We then address the use of vertically aligned NWs as tools for the delivery of biomol. cargo into mammalian cells. The final sections of the review will be dedicated to examples of vertically aligned silicon nanowire (VA-SiNW) arrays used in drug delivery and for biosensing.
117. 117

     Bonde, S.; Buch-Manson, N.; Rostgaard, K. R.; Andersen, T. K.; Berthing, T.; Martinez, K. L. Exploring Arrays of Vertical One-Dimensional Nanostructures for Cellular Investigations. Nanotechnology 2014, 25, 362001,  DOI: 10.1088/0957-4484/25/36/362001

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     117

     Exploring arrays of vertical one-dimensional nanostructures for cellular investigations

     Bonde, Sara; Buch-Manson, Nina; Rostgaard, Katrine R.; Andersen, Tor Kristian; Berthing, Trine; Martinez, Karen L.

     Nanotechnology (2014), 25 (36), 362001/1-362001/19CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)

     The endeavor of exploiting arrays of vertical one-dimensional (1D) nanostructures (NSs) for cellular applications has recently been experiencing a pronounced surge of activity. The interest is rooted in the intrinsic properties of high-aspect-ratio NSs. With a height comparable to a mammalian cell, and a diam. 100-1000 times smaller, NSs should intuitively reach far into a cell and, due to their small diam., do so without compromising cell health. Single NSs would thus be expedient for measuring and modifying cell response. Further organization of these structures into arrays can provide up-scaled and detailed spatiotemporal information on cell activity, an achievement that would entail a massive leap forward in disease understanding and drug discovery. Numerous proofs-of-principle published recently have expanded the large toolbox that is currently being established in this rapidly advancing field of research. Encouragingly, despite the diversity of NS platforms and exptl. conditions used thus far, general trends and conclusions from combining cells with NSs are beginning to crystallize. This review covers the broad spectrum of NS materials and dimensions used; the obsd. cellular responses with specific focus on adhesion, morphol., viability, proliferation, and migration; compares the different approaches used in the field to provide NSs with the often crucial cytosolic access; covers the progress toward biol. applications; and finally, envisions the future of this technol. By maintaining the impressive rate and quality of recent progress, it is conceivable that the use of vertical 1D NSs may soon be established as a superior choice over other current techniques, with all the further benefits that may entail.
118. 118

     Hanson, L.; Lin, Z. C.; Xie, C.; Cui, Y.; Cui, B. Characterization of the Cell-Nanopillar Interface by Transmission Electron Microscopy. Nano Lett. 2012, 12, 5815– 5820,  DOI: 10.1021/nl303163y

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     118

     Characterization of the Cell-Nanopillar Interface by Transmission Electron Microscopy

     Hanson, Lindsey; Lin, Ziliang Carter; Xie, Chong; Cui, Yi; Cui, Bianxiao

     Nano Letters (2012), 12 (11), 5815-5820CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Vertically aligned nanopillars can serve as excellent elec., optical and mech. platforms for biol. studies. However, revealing the nature of the interface between the cell and the nanopillar is very challenging. In particular, a matter of debate is whether the cell membrane remains intact around the nanopillar. Here the authors present a detailed characterization of the cell-nanopillar interface by TEM. The authors examd. cortical neurons growing on nanopillars with diam. 50-500 nm and heights 0.5-2 μm. On nanopillars <300 nm in diam., the cell membrane wraps around the entirety of the nanopillar without the nanopillar penetrating into the interior of the cell. However, the cell sits on top of arrays of larger, closely spaced nanopillars. Also the membrane-surface gap of both cell bodies and neurites is smaller for nanopillars than for a flat substrate. These results support a tight interaction between the cell membrane and the nanopillars and previous findings of excellent sealing in electrophysiol. recordings using nanopillar electrodes.
119. 119

     Santoro, F.; Zhao, W.; Joubert, L. M.; Duan, L.; Schnitker, J.; van de Burgt, Y.; Lou, H. Y.; Liu, B.; Salleo, A.; Cui, L.; Cui, Y.; Cui, B. Revealing the Cell-Material Interface with Nanometer Resolution by Focused Ion Beam/Scanning Electron Microscopy. ACS Nano 2017, 11, 8320– 8328,  DOI: 10.1021/acsnano.7b03494

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     119

     Revealing the Cell-Material Interface with Nanometer Resolution by Focused Ion Beam/Scanning Electron Microscopy

     Santoro, Francesca; Zhao, Wenting; Joubert, Lydia-Marie; Duan, Liting; Schnitker, Jan; van de Burgt, Yoeri; Lou, Hsin-Ya; Liu, Bofei; Salleo, Alberto; Cui, Lifeng; Cui, Yi; Cui, Bianxiao

     ACS Nano (2017), 11 (8), 8320-8328CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The interface between cells and nonbiol. surfaces regulates cell attachment, chronic tissue responses, and ultimately the success of medical implants or biosensors. Clin. and lab. studies show that topol. features of the surface profoundly influence cellular responses; for example, titanium surfaces with nano- and microtopog. structures enhance osteoblast attachment and host-implant integration as compared to a smooth surface. To understand how cells and tissues respond to different topog. features, it is of crit. importance to directly visualize the cell-material interface at the relevant nanometer length scale. Here, the authors present a method for in situ examn. of the cell-to-material interface at any desired location, based on focused ion beam milling and SEM imaging to resolve the cell membrane-to-material interface with 10 nm resoln. By examg. how cell membranes interact with topog. features such as nanoscale protrusions or invaginations, it was shown that the cell membrane readily deforms inward and wraps around protruding structures, but hardly deforms outward to contour invaginating structures. This asym. membrane response (inward vs. outward deformation) causes the cleft width between the cell membrane and the nanostructure surface to vary by more than an order of magnitude. The authors' results suggest that surface topol. is a crucial consideration for the development of medical implants or biosensors whose performances are strongly influenced by the cell-to-material interface. The authors anticipate that the method can be used to explore the direct interaction of cells/tissue with medical devices such as metal implants in the future.
120. 120

     Shokouhi, A. R.; Chen, Y.; Yoh, H. Z.; Brenker, J.; Alan, T.; Murayama, T.; Suu, K.; Morikawa, Y.; Voelcker, N. H.; Elnathan, R. Engineering Efficient CAR-T Cells via Electroactive Nanoinjection. Adv. Mater. 2023, 35, 2304122,  DOI: 10.1002/adma.202304122

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121. 121

     Harberts, J.; Zierold, R.; Fendler, C.; Koitmäe, A.; Bayat, P.; Fernandez-Cuesta, I.; Loers, G.; Diercks, B.-P.; Fliegert, R.; Guse, A. H.; Ronning, C.; Otnes, G.; Borgström, M.; Blick, R. H. Culturing and Patch Clamping of Jurkat T Cells and Neurons on Al₂O₃ Coated Nanowire Arrays of Altered Morphology. RSC Adv. 2019, 9, 11194– 11201,  DOI: 10.1039/C8RA05320K

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122. 122

     Hällström, W.; Mårtensson, T.; Prinz, C.; Gustavsson, P.; Montelius, L.; Samuelson, L.; Kanje, M. Gallium Phosphide Nanowires as a Substrate for Cultured Neurons. Nano Lett. 2007, 7, 2960– 2965,  DOI: 10.1021/nl070728e

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     122

     Gallium phosphide nanowires as a substrate for cultured neurons

     Hallstrom Waldemar; Martensson Thomas; Prinz Christelle; Gustavsson Per; Montelius Lars; Samuelson Lars; Kanje Martin

     Nano letters (2007), 7 (10), 2960-5 ISSN:1530-6984.

     Dissociated sensory neurons were cultured on epitaxial gallium phosphide (GaP) nanowires grown vertically from a gallium phosphide surface. Substrates covered by 2.5 microm long, 50 nm wide nanowires supported cell adhesion and axonal outgrowth. Cell survival was better on nanowire substrates than on planar control substrates. The cells interacted closely with the nanostructures, and cells penetrated by hundreds of wires were observed as well as wire bending due to forces exerted by the cells.
123. 123

     Xie, C.; Hanson, L.; Xie, W.; Lin, Z.; Cui, B.; Cui, Y. Noninvasive Neuron Pinning With Nanopillar Arrays. Nano Lett. 2010, 10, 4020– 4024,  DOI: 10.1021/nl101950x

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     123

     Noninvasive Neuron Pinning with Nanopillar Arrays

     Xie, Chong; Hanson, Lindsey; Xie, Wenjun; Lin, Ziliang; Cui, Bianxiao; Cui, Yi

     Nano Letters (2010), 10 (10), 4020-4024CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Cell migration in a cultured neuronal network presents an obstacle to selectively measuring the activity of the same neuron over a long period of time. Here we report the use of nanopillar arrays to pin the position of neurons in a noninvasive manner. Vertical nanopillars protruding from the surface serve as geometrically better focal adhesion points for cell attachment than a flat surface. The cell body mobility is significantly reduced from 57.8 μm on a flat surface to 3.9 μm on nanopillars over a 5 day period. Yet, neurons growing on nanopillar arrays show a growth pattern that does not differ in any significant way from that seen on a flat substrate. Notably, while the cell bodies of neurons are efficiently anchored by the nanopillars, the axons and dendrites are free to grow and elongate into the surrounding area to develop a neuronal network, which opens up opportunities for long-term study of the same neurons in connected networks.
124. 124

     Piret, G.; Perez, M. T.; Prinz, C. N. Neurite Outgrowth and Synaptophysin Expression of Postnatal CNS Neurons on GaP Nanowire Arrays in Long-Term Retinal Cell Culture. Biomaterials 2013, 34, 875– 887,  DOI: 10.1016/j.biomaterials.2012.10.042

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     124

     Neurite outgrowth and synaptophysin expression of postnatal CNS neurons on GaP nanowire arrays in long-term retinal cell culture

     Piret, Gaelle; Perez, Maria-Thereza; Prinz, Christelle N.

     Biomaterials (2013), 34 (4), 875-887CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     We have established long-term cultures of postnatal retinal cells on arrays of gallium phosphide nanowires of different geometries. Rod and cone photoreceptors, ganglion cells and bipolar cells survived on the substrates for at least 18 days in vitro. Glial cells were also obsd., but these did not overgrow the neuronal population. On nanowires, neurons extended numerous long and branched neurites that expressed the synaptic vesicle marker synaptophysin. The longest nanowires (4 μm long) allowed a greater attachment and neurite elongation and our anal. suggests that the length of the nanowire per se and/or the adsorption of biomols. on the nanowires may have been important factors regulating the obsd. cell behavior. The study thus shows that CNS neurons are amenable to gallium phosphide nanowires, probably as they create conditions that more closely resemble those encountered in the in vivo environment. These findings suggest that gallium phosphide nanowires may be considered as a material of interest when improving existing or designing the next generation of implantable devices. The features of gallium phosphide nanowires can be precisely controlled, making them suitable for this purpose.
125. 125

     Kang, K.; Park, Y. S.; Park, M.; Jang, M. J.; Kim, S. M.; Lee, J.; Choi, J. Y.; Jung, D. H.; Chang, Y. T.; Yoon, M. H.; Lee, J. S.; Nam, Y.; Choi, I. S. Axon-First Neuritogenesis on Vertical Nanowires. Nano Lett. 2016, 16, 675– 680,  DOI: 10.1021/acs.nanolett.5b04458

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     125

     Axon-First Neuritogenesis on Vertical Nanowires

     Kang, Kyungtae; Park, Yi-Seul; Park, Matthew; Jang, Min Jee; Kim, Seong-Min; Lee, Juno; Choi, Ji Yu; Jung, Da Hee; Chang, Young-Tae; Yoon, Myung-Han; Lee, Jin Seok; Nam, Yoonkey; Choi, Insung S.

     Nano Letters (2016), 16 (1), 675-680CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     In this work, we report that high-d., vertically grown silicon nanowires (vg-SiNWs) direct a new in vitro developmental pathway of primary hippocampal neurons. Neurons on vg-SiNWs formed a single, extremely elongated major neurite earlier than minor neurites, which led to accelerated polarization. Addnl., the development of lamellipodia, which generally occurs on 2D culture coverslips, was absent on vg-SiNWs. The results indicate that surface topog. is an important factor that influences neuronal development and also provide implications for the role of topog. in neuronal development in vivo.
126. 126

     Cortés-Llanos, B.; Rauti, R.; Ayuso-Sacido, Á.; Pérez, L.; Ballerini, L. Impact of Magnetite Nanowires on in Vitro Hippocampal Neural Networks. Biomolecules 2023, 13, 783,  DOI: 10.3390/biom13050783

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127. 127

     Harberts, J.; Siegmund, M.; Hedrich, C.; Kim, W.; Fontcuberta i Morral, A.; Zierold, R.; Blick, R. H. Generation of Human iPSC-Derived Neurons on Nanowire Arrays Featuring Varying Lengths, Pitches, and Diameters. Adv. Mater. Interfaces 2022, 9, 2200806,  DOI: 10.1002/admi.202200806

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128. 128

     Losero, E.; Jagannath, S.; Pezzoli, M.; Goblot, V.; Babashah, H.; Lashuel, H. A.; Galland, C.; Quack, N. Neuronal Growth on High-Aspect-Ratio Diamond Nanopillar Arrays for Biosensing Applications. Sci. Rep. 2023, 13, 5909,  DOI: 10.1038/s41598-023-32235-x

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129. 129

     Tullii, G.; Giona, F.; Lodola, F.; Bonfadini, S.; Bossio, C.; Varo, S.; Desii, A.; Criante, L.; Sala, C.; Pasini, M.; Verpelli, C.; Galeotti, F.; Antognazza, M. R. High-Aspect-Ratio Semiconducting Polymer Pillars for 3D Cell Cultures. ACS Appl. Mater. Interfaces 2019, 11, 28125– 28137,  DOI: 10.1021/acsami.9b08822

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     129

     High-Aspect-Ratio Semiconducting Polymer Pillars for 3D Cell Cultures

     Tullii, Gabriele; Giona, Federica; Lodola, Francesco; Bonfadini, Silvio; Bossio, Caterina; Varo, Simone; Desii, Andrea; Criante, Luigino; Sala, Carlo; Pasini, Mariacecilia; Verpelli, Chiara; Galeotti, Francesco; Antognazza, Maria Rosa

     ACS Applied Materials & Interfaces (2019), 11 (31), 28125-28137CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Hybrid interfaces between living cells and nano/microstructured scaffolds have huge application potential in biotechnol., spanning from regenerative medicine and stem cell therapies to localized drug delivery and from biosensing and tissue engineering to neural computing. However, 3D architectures based on semiconducting polymers, endowed with responsivity to visible light, have never been considered. Here, we apply for the first time a push-coating technique to realize high aspect ratio polymeric pillars, based on polythiophene, showing optimal biocompatibility and allowing for the realization of soft, 3D cell cultures of both primary neurons and cell line models. HEK-293 cells cultured on top of polymer pillars display a remarkable change in the cell morphol. and a sizable enhancement of the membrane capacitance due to the cell membrane thinning in correspondence to the pillars' top surface, without neg. affecting cell proliferation. Electrophysiol. properties and synapse no. of primary neurons are also very well preserved. In perspective, high aspect ratio semiconducting polymer pillars may find interesting applications as soft, photoactive elements for cell activity sensing and modulation.
130. 130

     Harberts, J.; Haferkamp, U.; Haugg, S.; Fendler, C.; Lam, D.; Zierold, R.; Pless, O.; Blick, R. H. Interfacing Human Induced Pluripotent Stem Cell-Derived Neurons With Designed Nanowire Arrays as a Future Platform for Medical Applications. Biomater. Sci. 2020, 8, 2434– 2446,  DOI: 10.1039/D0BM00182A

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     130

     Interfacing human induced pluripotent stem cell-derived neurons with designed nanowire arrays as a future platform for medical applications

     Harberts, Jann; Haferkamp, Undine; Haugg, Stefanie; Fendler, Cornelius; Lam, Dennis; Zierold, Robert; Pless, Ole; Blick, Robert H.

     Biomaterials Science (2020), 8 (9), 2434-2446CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)

     Nanostructured substrates such as nanowire arrays form a powerful tool for building next-generation medical devices. So far, human pluripotent stem cell-derived neurons-a revolutionary tool for studying physiol. function and modeling neurodegenerative diseases-have not been applied to such innovative substrates, due to the highly demanding nature of stem cell quality control and directed differentiation procedures to generate specialized cell types. Our study closes this gap, by presenting electrophysiol. mature human pluripotent stem cell-derived neurons on a set of nanowires in different patterns and growth densities after only four weeks of maturation-thereof 14 to 16 days on the nanowire arrays. While cell viability is maintained on all nanowire substrates, the settling regime of the cells can be controlled and tuned by the nanowire d. from a fakir-like state to a complete nanowire wrapping state. Esp., full electrophysiol. integrity of the neurons independent of the settling regime has been revealed by patch clamp expts. showing characteristic action potentials. Based on these results, our protocol has the potential to open new pathways in stem cell research and regenerative medicine utilizing human stem cell-derived neurons on tailor-made nanostructured substrates.
131. 131

     Harberts, J.; Siegmund, M.; Schnelle, M.; Zhang, T.; Lei, Y.; Yu, L.; Zierold, R.; Blick, R. H. Robust Neuronal Differentiation of Human iPSC-Derived Neural Progenitor Cells Cultured on Densely-Spaced Spiky Silicon Nanowire Arrays. Sci. Rep. 2021, 11, 18819,  DOI: 10.1038/s41598-021-97820-4

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     There is no corresponding record for this reference.
132. 132

     Hallstrom, W.; Lexholm, M.; Suyatin, D. B.; Hammarin, G.; Hessman, D.; Samuelson, L.; Montelius, L.; Kanje, M.; Prinz, C. N. Fifteen-Piconewton Force Detection from Neural Growth Cones Using Nanowire Arrays. Nano Lett. 2010, 10, 782– 787,  DOI: 10.1021/nl902675h

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     132

     Fifteen-Piconewton Force Detection from Neural Growth Cones Using Nanowire Arrays

     Hallstrom, Waldemar; Lexholm, Monica; Suyatin, Dmitry B.; Hammarin, Greger; Hessman, Dan; Samuelson, Lars; Montelius, Lars; Kanje, Martin; Prinz, Christelle N.

     Nano Letters (2010), 10 (3), 782-787CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The authors used epitaxially grown monodisperse nanowire arrays to measure cellular forces with a spatial resoln. of 1 μm. Nerve cells were cultured on the array and cellular forces were calcd. from the displacement of the nanowire tips. The measurements were done in situ on live cells using confocal microscopy. Forces down to 15 pN were measured on neural growth cones, showing that this method can be used to study the fine details of growth-cone dynamics.
133. 133

     Hanson, L.; Zhao, W.; Lou, H. Y.; Lin, Z. C.; Lee, S. W.; Chowdary, P.; Cui, Y.; Cui, B. Vertical Nanopillars for in Situ Probing of Nuclear Mechanics in Adherent Cells. Nat. Nanotechnol. 2015, 10, 554– 562,  DOI: 10.1038/nnano.2015.88

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     133

     Vertical nanopillars for in situ probing of nuclear mechanics in adherent cells

     Hanson, Lindsey; Zhao, Wenting; Lou, Hsin-Ya; Lin, Ziliang Carter; Lee, Seok Woo; Chowdary, Praveen; Cui, Yi; Cui, Bianxiao

     Nature Nanotechnology (2015), 10 (6), 554-562CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     The mech. stability and deformability of the cell nucleus are crucial to many biol. processes, including migration, proliferation and polarization. In vivo, the cell nucleus is frequently subjected to deformation on a variety of length and time scales, but current techniques for studying nuclear mechanics do not provide access to subnuclear deformation in live functioning cells. Here we introduce arrays of vertical nanopillars as a new method for the in situ study of nuclear deformability and the mech. coupling between the cell membrane and the nucleus in live cells. Our measurements show that nanopillar-induced nuclear deformation is detd. by nuclear stiffness, as well as opposing effects from actin and intermediate filaments. Furthermore, the depth, width and curvature of nuclear deformation can be controlled by varying the geometry of the nanopillar array. Overall, vertical nanopillar arrays constitute a novel approach for non-invasive, subcellular perturbation of nuclear mechanics and mechanotransduction in live cells.
134. 134

     Piret, G.; Perez, M. T.; Prinz, C. N. Support of Neuronal Growth Over Glial Growth and Guidance of Optic Nerve Axons by Vertical Nanowire Arrays. ACS Appl. Mater. Interfaces 2015, 7, 18944– 18948,  DOI: 10.1021/acsami.5b03798

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     134

     Support of Neuronal Growth Over Glial Growth and Guidance of Optic Nerve Axons by Vertical Nanowire Arrays

     Piret, Gaelle; Perez, Maria-Thereza; Prinz, Christelle N.

     ACS Applied Materials & Interfaces (2015), 7 (34), 18944-18948CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Neural cultures are very useful in neuroscience, providing simpler and better controlled systems than the in vivo situation. Neural tissue contains two main cell types, neurons and glia, and interactions between these are essential for appropriate neuronal development. In neural cultures, glial cells tend to overgrow neurons, limiting the access to neuronal interrogation. There is therefore a pressing need for improved systems that enable a good sepn. when coculturing neurons and glial cells simultaneously, allowing one to address the neurons unequivocally. Here, the authors used substrates consisting of dense arrays of vertical nanowires intercalated by flat regions to sep. retinal neurons and glial cells in distinct, but neighboring, compartments. The authors also generated a nanowire patterning capable of guiding optic nerve axons. The results will facilitate the design of surfaces aimed at studying and controlling neuronal networks.
135. 135

     Milos, F.; Belu, A.; Mayer, D.; Maybeck, V.; Offenhäusser, A. Polymer Nanopillars Induce Increased Paxillin Adhesion Assembly and Promote Axon Growth in Primary Cortical Neurons. Adv. Biol. 2021, 5, 2000248,  DOI: 10.1002/adbi.202000248

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     135

     Polymer Nanopillars Induce Increased Paxillin Adhesion Assembly and Promote Axon Growth in Primary Cortical Neurons

     Milos, Frano; Belu, Andreea; Mayer, Dirk; Maybeck, Vanessa; Offenhaeusser, Andreas

     Advanced Biology (2021), 5 (2), 2000248CODEN: ABDIKO; ISSN:2701-0198. (Wiley-VCH Verlag GmbH & Co. KGaA)

     The complexity of the extracellular matrix consists of micro- and nanoscale structures that influence neuronal development through contact guidance. Substrates with defined topog. cues mimic the complex extracellular environment and can improve the interface between cells and biomedical devices as well as potentially serve as tissue engineering scaffolds. This study investigates axon development and growth of primary cortical neurons on OrmoComp nanopillars of various dimensions. Neuronal somas and neurites form adhesions and F-actin accumulations around the pillars indicating a close contact to the topog. In addn., higher pillars (400 nm) confine the growing neurites, resulting in greater neurite alignment to the topog. pattern compared to lower pillars (100 nm). A comprehensive anal. of growth cone dynamics during axon development shows that nanopillars induce earlier axon establishment and change the periodicity of growth cone dynamics by promoting elongation. This results in longer axons compared to the flat substrate. Finally, the increase in surface area available for growth cone coupling provided by nanopillar sidewalls is correlated with increased assembly of paxillin-rich point contact adhesions and a redn. in actin retrograde flow rates allowing for accelerated and persistent neurite outgrowth.
136. 136

     Maurizi, E.; Martella, D. A.; Schiroli, D.; Merra, A.; Mustfa, S. A.; Pellegrini, G.; Macaluso, C.; Chiappini, C. Nanoneedles Induce Targeted siRNA Silencing of p16 in the Human Corneal Endothelium. Adv. Sci. 2022, 9, 2203257,  DOI: 10.1002/advs.202203257

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     There is no corresponding record for this reference.
137. 137

     Chen, Y.; Mach, M.; Shokouhi, A.-R.; Yoh, H. Z.; Bishop, D. C.; Murayama, T.; Suu, K.; Morikawa, Y.; Barry, S. C.; Micklethwaite, K. Efficient Non-Viral CAR-T Cell Generation via Silicon-Nanotube-Mediated Transfection. Mater. Today 2023, 63, 8– 17,  DOI: 10.1016/j.mattod.2023.02.009

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     Efficient non-viral CAR-T cell generation via silicon-nanotube-mediated transfection

     Chen, Yaping; Mach, Melanie; Shokouhi, Ali-Reza; Yoh, Hao Zhe; Bishop, David C.; Murayama, Takahide; Suu, Koukou; Morikawa, Yasuhiro; Barry, Simon C.; Micklethwaite, Kenneth; Elnathan, Roey; Voelcker, Nicolas H.

     Materials Today (Oxford, United Kingdom) (2023), 63 (), 8-17CODEN: MTOUAN; ISSN:1369-7021. (Elsevier Ltd.)

     Cell-based immunotherapy such as chimeric antigen receptor (CAR)-T therapy holds great promise in treating cancer and other diseases; but the current viral-based method represents a significant cost and safety hurdle. Here, we show for the first time successful CAR transfection into primary T cells via vertically aligned silicon nanotube (SiNT) arrays. SiNT-mediated transfection achieves comparable or even higher delivery efficiency (20-37%) and expression efficiency (18-24%) to that achieved by electroporation. SEM imaging after focused ion beam milling demonstrated the tight T cell-SiNT interface. The induced membrane invaginations and the proximity between individual SiNTs and the nucleus might enhance endocytic pathways, and enable direct delivery of CAR construct into the nucleus, thus resulting in higher CAR expression efficiency. SiNT-interfacing also results in faster proliferation of T cells compared to cells transfected by electroporation; non-activated T (N_SiNT) cells undergo higher nos. of cell division than pre-activated ones (A_SiNT). By co-culturing with target lymphoma Raji cells, we prove that SiNT-transfected CAR-T cells can suppress Raji cell growth, indicated by significant increase in effector:target (E:T) ratio (by up to 30.7-fold). While SiNTs induce an overall upregulation of cytokine prodn. in T cells, N_SiNT T cells exhibited high increase in secretion of IFNγ and IL-6, and relatively high in TNFα, which could contribute to their enhanced killing ability (∼96% cytotoxicity), demonstrated by their stronger inhibition on target Raji cells through luciferase assay. The results demonstrate the capacity of SiNT-mediated transfection of generating effective anti-lymphoma CAR-T cells. Considering the growing potential of cell-based therapies, we expect that a non-viral nanoinjection platform such as ours will facilitate the full realization of their therapeutic promise.
138. 138

     Yoh, H. Z.; Chen, Y.; Shokouhi, A.-R.; Thissen, H.; Voelcker, N. H.; Elnathan, R. The Influence of Dysfunctional Actin on Polystyrene-Nanotube-Mediated mRNA Nanoinjection into Mammalian Cells. Nanoscale 2023, 15, 7737– 7744,  DOI: 10.1039/D3NR01111A

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139. 139

     Wang, Z.; Wang, H.; Lin, S.; Labib, M.; Ahmed, S.; Das, J.; Angers, S.; Sargent, E. H.; Kelley, S. O. Efficient Delivery of Biological Cargos into Primary Cells by Electrodeposited Nanoneedles via Cell-Cycle-Dependent Endocytosis. Nano Lett. 2023, 23, 5877– 5885,  DOI: 10.1021/acs.nanolett.2c05083

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     139

     Efficient Delivery of Biological Cargos into Primary Cells by Electrodeposited Nanoneedles via Cell-Cycle-Dependent Endocytosis

     Wang, Zongjie; Wang, Hansen; Lin, Sichun; Labib, Mahmoud; Ahmed, Sharif; Das, Jagotamoy; Angers, Stephane; Sargent, Edward H.; Kelley, Shana O.

     Nano Letters (2023), 23 (13), 5877-5885CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Nanoneedles are a useful tool for delivering exogenous biomols. to cells. Although therapeutic applications have been explored, the mechanism regarding how cells interact with nanoneedles remains poorly studied. Here, we present a new approach for the generation of nanoneedles, validated their usefulness in cargo delivery, and studied the underlying genetic modulators during delivery. We fabricated arrays of nanoneedles based on electrodeposition and quantified its efficacy of delivery using fluorescently labeled proteins and siRNAs. Notably, we revealed that our nanoneedles caused the disruption of cell membranes, enhanced the expression of cell-cell junction proteins, and downregulated the expression of transcriptional factors of NFκB pathways. This perturbation trapped most of the cells in G2 phase, in which the cells have the highest endocytosis activities. Taken together, this system provides a new model for the study of interactions between cells and high-aspect-ratio materials.
140. 140

     Chen, Y.; Yoh, H. Z.; Shokouhi, A.-R.; Murayama, T.; Suu, K.; Morikawa, Y.; Voelcker, N. H.; Elnathan, R. Role of Actin Cytoskeleton in Cargo Delivery Mediated by Vertically Aligned Silicon Nanotubes. J. Nanobiotechnol. 2022, 20, 406,  DOI: 10.1186/s12951-022-01618-z

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141. 141

     Kim, W.; Ng, J. K.; Kunitake, M. E.; Conklin, B. R.; Yang, P. Interfacing Silicon Nanowires with Mammalian Cells. J. Am. Chem. Soc. 2007, 129, 7228– 7229,  DOI: 10.1021/ja071456k

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     141

     Interfacing Silicon Nanowires with Mammalian Cells

     Kim, Woong; Ng, Jennifer K.; Kunitake, Miki E.; Conklin, Bruce R.; Yang, Peidong

     Journal of the American Chemical Society (2007), 129 (23), 7228-7229CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

     The authors present the first demonstration of a direct interface of silicon nanowires with mammalian cells such as mouse embryonic stem (mES) cells and human embryonic kidney (HEK 293T) cells without any external force. The cells were cultured on a silicon (Si) substrate with a vertically aligned SiNW array on it. The penetration of the SiNW array into individual cells naturally occurred during the incubation. The cells survived up to several days on the nanowire substrates. The longevity of the cells was highly dependent on the diam. of SiNWs. Furthermore, successful maintenance of cardiac myocytes derived from mES cells on the wire array substrates was obsd., and gene delivery using the SiNW array was demonstrated. The authors' results suggest that the nanowires can be potentially utilized as a powerful tool for studying intra- and intercellular biol. processes.
142. 142

     Elnathan, R.; Delalat, B.; Brodoceanu, D.; Alhmoud, H.; Harding, F. J.; Buehler, K.; Nelson, A.; Isa, L.; Kraus, T.; Voelcker, N. H. Maximizing Transfection Efficiency of Vertically Aligned Silicon Nanowire Arrays. Adv. Funct. Mater. 2015, 25, 7215– 7225,  DOI: 10.1002/adfm.201503465

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     142

     Maximizing Transfection Efficiency of Vertically Aligned Silicon Nanowire Arrays

     Elnathan, Roey; Delalat, Bahman; Brodoceanu, Daniel; Alhmoud, Hashim; Harding, Frances J.; Buehler, Katrin; Nelson, Adrienne; Isa, Lucio; Kraus, Tobias; Voelcker, Nicolas H.

     Advanced Functional Materials (2015), 25 (46), 7215-7225CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Vertically aligned silicon nanowire (VA-SiNW) arrays are emerging as a powerful new tool for gene delivery by means of mech. transfection. In order to utilize this tool efficiently, uncertainties around the required design parameters need to be removed. Here, a combination of nanosphere lithog. and templated metal-assisted wet chem. etching is used to fabricate VA-SiNW arrays with a range of diams., heights, and densities. This fabrication strategy allows identification of crit. parameters of surface topog. and consequently the design of SiNW arrays that deliver plasmid with high transfection efficiency into a diverse range of human cells while maintaining high cell viability. These results illuminate the cell-materials interactions that mediate VA-SiNW transfection and have the potential to transform gene therapy and underpin future treatment modalities.
143. 143

     Liu, R.; Chen, R.; Elthakeb, A. T.; Lee, S. H.; Hinckley, S.; Khraiche, M. L.; Scott, J.; Pre, D.; Hwang, Y.; Tanaka, A.; Ro, Y. G.; Matsushita, A. K.; Dai, X.; Soci, C.; Biesmans, S.; James, A.; Nogan, J.; Jungjohann, K. L.; Pete, D. V.; Webb, D. B.; Zou, Y.; Bang, A. G.; Dayeh, S. A. High Density Individually Addressable Nanowire Arrays Record Intracellular Activity from Primary Rodent and Human Stem Cell Derived Neurons. Nano Lett. 2017, 17, 2757– 2764,  DOI: 10.1021/acs.nanolett.6b04752

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     143

     High Density Individually Addressable Nanowire Arrays Record Intracellular Activity from Primary Rodent and Human Stem Cell Derived Neurons

     Liu, Ren; Chen, Renjie; Elthakeb, Ahmed T.; Lee, Sang Heon; Hinckley, Sandy; Khraiche, Massoud L.; Scott, John; Pre, Deborah; Hwang, Yoontae; Tanaka, Atsunori; Ro, Yun Goo; Matsushita, Albert K.; Dai, Xing; Soci, Cesare; Biesmans, Steven; James, Anthony; Nogan, John; Jungjohann, Katherine L.; Pete, Douglas V.; Webb, Denise B.; Zou, Yimin; Bang, Anne G.; Dayeh, Shadi A.

     Nano Letters (2017), 17 (5), 2757-2764CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The authors report a new hybrid integration scheme that offers for the first time a nanowire-on-lead approach, which enables independent elec. addressability, is scalable, and has superior spatial resoln. in vertical nanowire arrays. The fabrication of these nanowire arrays is demonstrated to be scalable down to submicrometer site-to-site spacing and can be combined with std. integrated circuit fabrication technologies. The authors utilize these arrays to perform electrophysiol. recordings from mouse and rat primary neurons and human induced pluripotent stem cell (hiPSC)-derived neurons, which revealed high signal-to-noise ratios and sensitivity to subthreshold postsynaptic potentials (PSPs). The authors measured elec. activity from rodent neurons from 8 days in vitro (DIV) to 14 DIV and from hiPSC-derived neurons at 6 wk in vitro postculture with signal amplitudes up to 99 mV. Overall, the platform paves the way for longitudinal electrophysiol. expts. on synaptic activity in human iPSC based disease models of neuronal networks, crit. for understanding the mechanisms of neurol. diseases and for developing drugs to treat them.
144. 144

     Parameswaran, R.; Carvalho-de-Souza, J. L.; Jiang, Y.; Burke, M. J.; Zimmerman, J. F.; Koehler, K.; Phillips, A. W.; Yi, J.; Adams, E. J.; Bezanilla, F.; Tian, B. Photoelectrochemical Modulation of Neuronal Activity with Free-Standing Coaxial Silicon Nanowires. Nat. Nanotechnol. 2018, 13, 260– 266,  DOI: 10.1038/s41565-017-0041-7

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     144

     Photoelectrochemical modulation of neuronal activity with free-standing coaxial silicon nanowires

     Parameswaran, Ramya; Carvalho-de-Souza, Joao L.; Jiang, Yuanwen; Burke, Michael J.; Zimmerman, John F.; Koehler, Kelliann; Phillips, Andrew W.; Yi, Jaeseok; Adams, Erin J.; Bezanilla, Francisco; Tian, Bozhi

     Nature Nanotechnology (2018), 13 (3), 260-266CODEN: NNAABX; ISSN:1748-3387. (Nature Research)

     Optical methods for modulating cellular behavior are promising for both fundamental and clin. applications. However, most available methods are either mech. invasive, require genetic manipulation of target cells or cannot provide subcellular specificity. Here, we address all these issues by showing optical neuromodulation with free-standing coaxial p-type/intrinsic/n-type silicon nanowires. We reveal the presence of at. gold on the nanowire surfaces, likely due to gold diffusion during the material growth. To evaluate how surface gold impacts the photoelectrochem. properties of single nanowires, we used modified quartz pipettes from a patch clamp and recorded sustained cathodic photocurrents from single nanowires. We show that these currents can elicit action potentials in primary rat dorsal root ganglion neurons through a primarily at. gold-enhanced photoelectrochem. process.
145. 145

     Liu, Z.; Wen, B.; Cao, L.; Zhang, S.; Lei, Y.; Zhao, G.; Chen, L.; Wang, J.; Shi, Y.; Xu, J.; Pan, X.; Yu, L. Photoelectric Cardiac Pacing by Flexible and Degradable Amorphous Si Radial Junction Stimulators. Adv. Healthc. Mater. 2020, 9, e1901342,  DOI: 10.1002/adhm.201901342

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146. 146

     Verardo, D.; Lindberg, F. W.; Anttu, N.; Niman, C. S.; Lard, M.; Dabkowska, A. P.; Nylander, T.; Mansson, A.; Prinz, C. N.; Linke, H. Nanowires for Biosensing: Lightguiding of Fluorescence as a Function of Diameter and Wavelength. Nano Lett. 2018, 18, 4796– 4802,  DOI: 10.1021/acs.nanolett.8b01360

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     146

     Nanowires for Biosensing: Lightguiding of Fluorescence as a Function of Diameter and Wavelength

     Verardo, Damiano; Lindberg, Frida W.; Anttu, Nicklas; Niman, Cassandra S.; Lard, Mercy; Dabkowska, Aleksandra P.; Nylander, Tommy; Maansson, Alf; Prinz, Christelle N.; Linke, Heiner

     Nano Letters (2018), 18 (8), 4796-4802CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Semiconductor nanowires can act as nanoscaled optical fibers, enabling them to guide and conc. light emitted by surface-bound fluorophores, potentially enhancing the sensitivity of optical biosensing. While parameters such as the nanowire geometry and the fluorophore wavelength can be expected to strongly influence this lightguiding effect, no detailed description of their effect on in-coupling of fluorescent emission is available to date. Here, the authors use confocal imaging to quantify the lightguiding effect in GaP nanowires as a function of nanowire geometry and light wavelength. Using a combination of finite-difference time-domain simulations and anal. approaches, the authors identify the role of multiple waveguide modes for the obsd. lightguiding. The normalized frequency parameter, based on the step-index approxn., predicts the lightguiding ability of the nanowires as a function of diam. and fluorophore wavelength, providing a useful guide for the design of optical biosensors based on nanowires.
147. 147

     Lard, M.; Linke, H.; Prinz, C. N. Biosensing Using Arrays of Vertical Semiconductor Nanowires: Mechanosensing and Biomarker Detection. Nanotechnology 2019, 30, 214003,  DOI: 10.1088/1361-6528/ab0326

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     147

     Biosensing using arrays of vertical semiconductor nanowires: mechanosensing and biomarker detection

     Lard, Mercy; Linke, Heiner; Prinz, Christelle N.

     Nanotechnology (2019), 30 (21), 214003CODEN: NNOTER; ISSN:1361-6528. (IOP Publishing Ltd.)

     A review. Due to their high aspect ratio and increased surface-to-foot-print area, arrays of vertical semiconductor nanowires are used in numerous biol. applications, such as cell transfection and biosensing. Here we focus on two specific valuable biosensing approaches that, so far, have received relatively limited attention in terms of their potential capabilities: cellular mechanosensing and lightguiding-induced enhanced fluorescence detection. Although proposed a decade ago, these two applications for using vertical nanowire arrays have only very recently achieved significant breakthroughs, both in terms of understanding their fundamental phenomena, and in the ease of their implementation. We review the status of the field in these areas and describe significant findings and potential future directions.
148. 148

     Araki, T.; Yoshida, F.; Uemura, T.; Noda, Y.; Yoshimoto, S.; Kaiju, T.; Suzuki, T.; Hamanaka, H.; Baba, K.; Hayakawa, H.; Yabumoto, T.; Mochizuki, H.; Kobayashi, S.; Tanaka, M.; Hirata, M.; Sekitani, T. Long-Term Implantable, Flexible, and Transparent Neural Interface Based on Ag/Au Core-Shell Nanowires. Adv. Healthc. Mater. 2019, 8, e1900130,  DOI: 10.1002/adhm.201900130

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149. 149

     Chen, Y.; Aslanoglou, S.; Gervinskas, G.; Abdelmaksoud, H.; Voelcker, N. H.; Elnathan, R. Cellular Deformations Induced by Conical Silicon Nanowire Arrays Facilitate Gene Delivery. Small 2019, 15, e1904819,  DOI: 10.1002/smll.201904819

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150. 150

     Hansel, C. S.; Crowder, S. W.; Cooper, S.; Gopal, S.; Joao Pardelha da Cruz, M.; de Oliveira Martins, L.; Keller, D.; Rothery, S.; Becce, M.; Cass, A. E. G.; Bakal, C.; Chiappini, C.; Stevens, M. M. Nanoneedle-Mediated Stimulation of Cell Mechanotransduction Machinery. ACS Nano 2019, 13, 2913– 2926,  DOI: 10.1021/acsnano.8b06998

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     150

     Nanoneedle-Mediated Stimulation of Cell Mechanotransduction Machinery

     Hansel, Catherine S.; Crowder, Spencer W.; Cooper, Samuel; Gopal, Sahana; Joao Pardelha da Cruz, Maria; de Oliveira Martins, Leonardo; Keller, Debora; Rothery, Stephen; Becce, Michele; Cass, Anthony E. G.; Bakal, Chris; Chiappini, Ciro; Stevens, Molly M.

     ACS Nano (2019), 13 (3), 2913-2926CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Biomaterial substrates can be engineered to present topog. signals to cells which, through interactions between the material and active components of the cell membrane, regulate key cellular processes and guide cell fate decisions. However, targeting mechanoresponsive elements that reside within the intracellular domain is a concept that has only recently emerged. Here, the authors show that mesoporous silicon nanoneedle arrays interact simultaneously with the cell membrane, cytoskeleton, and nucleus of primary human cells, generating distinct responses at each of these cellular compartments. Specifically, nanoneedles inhibit focal adhesion maturation at the membrane, reduce tension in the cytoskeleton, and lead to remodeling of the nuclear envelope at sites of impingement. The combined changes in actin cytoskeleton assembly, expression and segregation of the nuclear lamina, and localization of Yes-assocd. protein (YAP) correlate differently from what is canonically obsd. upon stimulation at the cell membrane, revealing that biophys. cues directed to the intracellular space can generate heretofore unobserved mechanosensory responses. These findings highlight the ability of nanoneedles to study and direct the phenotype of large cell populations simultaneously, through biophys. interactions with multiple mechanoresponsive components.
151. 151

     Chiappini, C.; De Rosa, E.; Martinez, J. O.; Liu, X.; Steele, J.; Stevens, M. M.; Tasciotti, E. Biodegradable Silicon Nanoneedles Delivering Nucleic Acids Intracellularly Induce Localized in Vivo Neovascularization. Nat. Mater. 2015, 14, 532– 539,  DOI: 10.1038/nmat4249

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     151

     Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localized in vivo neovascularization

     Chiappini, C.; De Rosa, E.; Martinez, J. O.; Liu, X.; Steele, J.; Stevens, M. M.; Tasciotti, E.

     Nature Materials (2015), 14 (5), 532-539CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     The controlled delivery of nucleic acids to selected tissues remains an inefficient process mired by low transfection efficacy, poor scalability because of varying efficiency with cell type and location, and questionable safety as a result of toxicity issues arising from the typical materials and procedures employed. High efficiency and minimal toxicity in vitro has been shown for intracellular delivery of nuclei acids by using nanoneedles, yet extending these characteristics to in vivo delivery has been difficult, as current interfacing strategies rely on complex equipment or active cell internalization through prolonged interfacing. Here, we show that a tunable array of biodegradable nanoneedles fabricated by metal-assisted chem. etching of silicon can access the cytosol to co-deliver DNA and siRNA with an efficiency greater than 90%, and that in vivo the nanoneedles transfect the VEGF-165 gene, inducing sustained neovascularization and a localized sixfold increase in blood perfusion in a target region of the muscle.
152. 152

     Suyatin, D. B.; Wallman, L.; Thelin, J.; Prinz, C. N.; Jörntell, H.; Samuelson, L.; Montelius, L.; Schouenborg, J. Nanowire-Based Electrode for Acute in Vivo Neural Recordings in the Brain. PLoS One 2013, 8, e56673,  DOI: 10.1371/journal.pone.0056673

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     152

     Nanowire-based electrode for acute in vivo neural recordings in the brain

     Suyatin, Dmitry B.; Wallman, Lars; Thelin, Jonas; Prinz, Christelle N.; Joerntell, Henrik; Samuelson, Lars; Montelius, Lars; Schouenborg, Jens

     PLoS One (2013), 8 (2), e56673CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

     We present an electrode, based on structurally controlled nanowires, as a first step towards developing a useful nanostructured device for neurophysiol. measurements in vivo. The sensing part of the electrode is made of a metal film deposited on top of an array of epitaxially grown gallium phosphide nanowires. We achieved the first functional testing of the nanowire-based electrode by performing acute in vivo recordings in the rat cerebral cortex and withstanding multiple brain implantations. Due to the controllable geometry of the nanowires, this type of electrode can be used as a model system for further anal. of the functional properties of nanostructured neuronal interfaces in vivo.
153. 153

     Tang, J.; Qin, N.; Chong, Y.; Diao, Y.; Yiliguma; Wang, Z.; Xue, T.; Jiang, M.; Zhang, J.; Zheng, G. Nanowire Arrays Restore Vision in Blind Mice. Nat. Commun. 2018, 9, 786,  DOI: 10.1038/s41467-018-03212-0

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     153

     Nanowire arrays restore vision in blind mice

     Tang Jing; Qin Nan; Chong Yan; Diao Yupu; Yiliguma; Wang Zhexuan; Jiang Min; Zhang Jiayi; Zheng Gengfeng; Xue Tian

     Nature communications (2018), 9 (1), 786 ISSN:.

     The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 μm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices.
154. 154

     Zhang, A.; Zhao, Y.; You, S. S.; Lieber, C. M. Nanowire Probes Could Drive High-Resolution Brain-Machine Interfaces. Nano Today 2020, 31, 100821,  DOI: 10.1016/j.nantod.2019.100821

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155. 155

     Fairfield, J. A. Nanostructured Materials for Neural Electrical Interfaces. Adv. Funct. Mater. 2018, 28, 1701145,  DOI: 10.1002/adfm.201701145

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156. 156

     VanDersarl, J. J.; Xu, A. M.; Melosh, N. A. Nanostraws for Direct Fluidic Intracellular Access. Nano Lett. 2012, 12, 3881– 3886,  DOI: 10.1021/nl204051v

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     156

     Nanostraws for direct fluidic intracellular access

     VanDersarl Jules J; Xu Alexander M; Melosh Nicholas A

     Nano letters (2012), 12 (8), 3881-6 ISSN:.

     Nanomaterials are promising candidates to improve the delivery efficiency and control of active agents such as DNA or drugs directly into cells. Here we demonstrate cell-culture platforms of nanotemplated "nanostraws" that pierce the cell membrane, providing a permanent fluidic pipeline into the cell for direct cytosolic access. Conventional polymeric track-etch cell culture membranes are alumina coated and etched to produce fields of nanostraws with controllable diameter, thickness, and height. Small molecules and ions were successfully transported into the cytosol with 40 and 70% efficiency, respectively, while GFP plasmids were successfully delivered and expressed. These platforms open the way for active, reproducible delivery of a wide variety of species into cells without endocytosis.
157. 157

     Wang, Y.; Yang, Y.; Yan, L.; Kwok, S. Y.; Li, W.; Wang, Z.; Zhu, X.; Zhu, G.; Zhang, W.; Chen, X.; Shi, P. Poking Cells for Efficient Vector-Free Intracellular Delivery. Nat. Commun. 2014, 5, 4466,  DOI: 10.1038/ncomms5466

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     157

     Poking cells for efficient vector-free intracellular delivery

     Wang, Ying; Yang, Yang; Yan, Li; Kwok, So Ying; Li, Wei; Wang, Zhigang; Zhu, Xiaoyue; Zhu, Guangyu; Zhang, Wenjun; Chen, Xianfeng; Shi, Peng

     Nature Communications (2014), 5 (), 4466CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Techniques for introducing foreign mols. and materials into living cells are of great value in cell biol. research. A major barrier for intracellular delivery is to cross the cell membrane. Here we demonstrate a novel platform utilizing diamond nanoneedle arrays to facilitate efficient vector-free cytosolic delivery. Using our technique, cellular membrane is deformed by an array of nanoneedles with a force on the order of a few nanonewtons. We show that this technique is applicable to deliver a broad range of mols. and materials into different types of cells, including primary neurons in adherent culture. Esp., for delivering plasmid DNAs into neurons, our technique produces at least eightfold improvement (∼45% vs. ∼1-5%) in transfection efficiency with a dramatically shorter exptl. protocol, when compared with the commonly used lipofection approach. It is anticipated that our technique will greatly benefit basic research in cell biol. and also a wide variety of clin. applications.
158. 158

     Chiappini, C.; Martinez, J. O.; De Rosa, E.; Almeida, C. S.; Tasciotti, E.; Stevens, M. M. Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface. ACS Nano 2015, 9, 5500– 5509,  DOI: 10.1021/acsnano.5b01490

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     158

     Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface

     Chiappini, Ciro; Martinez, Jonathan O.; De Rosa, Enrica; Almeida, Carina S.; Tasciotti, Ennio; Stevens, Molly M.

     ACS Nano (2015), 9 (5), 5500-5509CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Nanoneedles display potential in mediating the delivery of drugs and biologicals, as well as intracellular sensing and single-cell stimulation, through direct access to the cell cytoplasm. Nanoneedles enable cytosolic delivery, negotiating the cell membrane and the endolysosomal system, thus overcoming these major obstacles to the efficacy of nanotherapeutics. The low toxicity and minimal invasiveness of nanoneedles have a potential for the sustained nonimmunogenic delivery of payloads in vivo, provided that the development of biocompatible nanoneedles with a simple deployment strategy is achieved. Here we present a mesoporous silicon nanoneedle array that achieves a tight interface with the cell, rapidly negotiating local biol. barriers to grant temporary access to the cytosol with minimal impact on cell viability. The tightness of this interfacing enables both delivery of cell-impermeant quantum dots in vivo and live intracellular sensing of pH. Dissecting the biointerface over time elucidated the dynamics of cell assocn. and nanoneedle biodegrdn., showing rapid interfacing leading to cytosolic payload delivery within less than 30 min in vitro. The rapid and simple application of nanoneedles in vivo to the surface of tissues with different architectures invariably resulted in the localized delivery of quantum dots to the superficial cells and their prolonged retention. This investigation provides an understanding of the dynamics of nanoneedles' biointerface and delivery, outlining a strategy for highly local intracellular delivery of nanoparticles and cell-impermeant payloads within live tissues.
159. 159

     Cao, Y.; Chen, H.; Qiu, R.; Hanna, M.; Ma, E.; Hjort, M.; Zhang, A.; Lewis, R. S.; Wu, J. C.; Melosh, N. A. Universal Intracellular Biomolecule Delivery with Precise Dosage Control. Sci. Adv. 2018, 4, eaat8131,  DOI: 10.1126/sciadv.aat8131

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160. 160

     Gopal, S.; Chiappini, C.; Penders, J.; Leonardo, V.; Seong, H.; Rothery, S.; Korchev, Y.; Shevchuk, A.; Stevens, M. M. Porous Silicon Nanoneedles Modulate Endocytosis to Deliver Biological Payloads. Adv. Mater. 2019, 31, e1806788,  DOI: 10.1002/adma.201806788

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161. 161

     Tay, A.; Melosh, N. Nanostructured Materials for Intracellular Cargo Delivery. Acc. Chem. Res. 2019, 52, 2462– 2471,  DOI: 10.1021/acs.accounts.9b00272

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     Nanostructured Materials for Intracellular Cargo Delivery

     Tay, Andy; Melosh, Nicholas

     Accounts of Chemical Research (2019), 52 (9), 2462-2471CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

     A review. Intracellular cargo delivery is an essential step in many biomedical applications including gene editing and biologics therapy. Examples of cargo include nucleic acids (RNA and DNA), proteins, small biomols., and drugs, which can vary substantially in terms of their sizes, charges, soly., and stability. Viruses have been used traditionally to deliver nucleic acids into cells, but the method suffers from limitations such as small cargo size, safety concerns, and viral genome integration into host cells, all of which complicate therapeutic applications. Com. available techniques using biochems. and bulk electroporation are, in general, poorly compatible with primary cells such as human induced pluripotent stem cells and immune cells, which are increasingly important candidates for adoptive cell therapy.Nanostructures, with dimensions ranging from tens of nanometers to a few micrometers, may play a crit. role in overcoming cellular manipulation and delivery challenges and provide a powerful alternative to conventional techniques. A crit. feature that differentiates nanostructures from viral, biochem., and bulk electroporation techniques is that they interface with cells at a scale measuring ten to hundreds of nanometers in size. This highly local interaction enables application of stronger and more direct stimuli such as mech. force, heat, or elec. fields than would be possible in a bulk treatment. Compared to popular viral, biochem., and bulk electroporation methods, nanostructures were found to minimally perturb cells with cells remaining in good health during postdelivery culture. These advantages have enabled nanostructures such as nanowires and nanotubes to successfully interface with a wide variety of cells, including primary immune cells and cardiomyocytes, for in vitro and in vivo applications.This Account is focused on using nanostructures for cargo delivery into biol. cells. In this Account, we will first outline the historical developments using nanostructures for interfacing with cells. We will highlight how mechanistic understanding of nano-bio interactions has evolved over the last decade and how this improved knowledge has motivated coupling of elec. and magnetic fields to nanostructures to improve delivery outcomes. There will also be an in-depth discussion on the merits of nanostructures in comparison to conventional methods using viruses, biochems., and bulk electroporation. Finally, motivated by our observations on the lack of consistency in reporting key metrics such as efficiency in literature, we suggest a set of metrics for documenting exptl. results with the aim to promote standardization in reporting and ease in comparing. We suggest the use of more sophisticated tools such as RNA transcriptomics for thorough assessment of cell perturbation attributed to intracellular delivery. We hope that this Account can effectively capture the progress of nanostructure-mediated cargo delivery and encourage new innovations.
162. 162

     Fujishiro, A.; Kaneko, H.; Kawashima, T.; Ishida, M.; Kawano, T. In Vivo Neuronal Action Potential Recordings via Three-Dimensional Microscale Needle-Electrode Arrays. Sci. Rep. 2014, 4, 4868,  DOI: 10.1038/srep04868

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     In vivo neuronal action potential recordings via three-dimensional microscale needle-electrode arrays

     Fujishiro, Akifumi; Kaneko, Hidekazu; Kawashima, Takahiro; Ishida, Makoto; Kawano, Takeshi

     Scientific Reports (2014), 4 (), 4868CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     Very fine needle-electrode arrays potentially offer both low invasiveness and high spatial resoln. of electrophysiol. neuronal recordings in vivo. Herein we report the penetrating and recording capabilities of silicon-growth-based three-dimensional microscale-diam. needle-electrodes arrays. The fabricated needles exhibit a circular-cone shape with a 3-μm-diam. tip and a 210-μm length. Due to the microscale diam., our silicon needles are more flexible than other microfabricated silicon needles with larger diams. Coating the microscale-needle-tip with platinum black results in an impedance of ∼600 kΩ in saline with output/input signal amplitude ratios of more than 90% at 40 Hz-10 kHz. The needles can penetrate into the whisker barrel area of a rat's cerebral cortex, and the action potentials recorded from some neurons exhibit peak-to-peak amplitudes of ∼300 μVpp. These results demonstrate the feasibility of in vivo neuronal action potential recordings with a microscale needle-electrode array fabricated using silicon growth technol.
163. 163

     Rincón Montes, V.; Gehlen, J.; Ingebrandt, S.; Mokwa, W.; Walter, P.; Müller, F.; Offenhäusser, A. Development and in Vitro Validation of Flexible Intraretinal Probes. Sci. Rep. 2020, 10, 19836,  DOI: 10.1038/s41598-020-76582-5

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164. 164

     Qing, Q.; Pal, S. K.; Tian, B.; Duan, X.; Timko, B. P.; Cohen-Karni, T.; Murthy, V. N.; Lieber, C. M. Nanowire Transistor Arrays for Mapping Neural Circuits in Acute Brain Slices. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 1882– 1887,  DOI: 10.1073/pnas.0914737107

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     164

     Nanowire transistor arrays for mapping neural circuits in acute brain slices

     Qing, Quan; Pal, Sumon K.; Tian, Bozhi; Duan, Xiaojie; Timko, Brian R.; Cohen-Karni, Tzahi; Murthy, Venkatesh N.; Lieber, Charles M.

     Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (5), 1882-1887, S1882/1-S1882/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Revealing the functional connectivity in natural neuronal networks is central to understanding circuits in the brain. Here, we show that silicon nanowire field-effect transistor (Si NWFET) arrays fabricated on transparent substrates can be reliably interfaced to acute brain slices. NWFET arrays were readily designed to record across a wide range of length scales, while the transparent device chips enabled imaging of individual cell bodies and identification of areas of healthy neurons at both upper and lower tissue surfaces. Simultaneous NWFET and patch clamp studies enabled unambiguous identification of action potential signals, with addnl. features detected at earlier times by the nanodevices. NWFET recording at different positions in the absence and presence of synaptic and ion-channel blockers enabled assignment of these features to presynaptic firing and postsynaptic depolarization from regions either close to somata or abundant in dendritic projections. In all cases, the NWFET signal amplitudes were from 0.3-3 mV. In contrast to conventional multielectrode array measurements, the small active surface of the NWFET devices, ∼0.06 μm2, provides highly localized multiplexed measurements of neuronal activities with demonstrated sub-millisecond temporal resoln. and, significantly, better than 30 prm spatial resoln. In addn., multiplexed mapping with 2D NWFET arrays revealed spatially heterogeneous functional connectivity in the olfactory cortex with a resoln. surpassing substantially previous elec. recording techniques. Our demonstration of simultaneous high temporal and spatial resoln. recording, as well as mapping of functional connectivity, suggest that NWFETs can become a powerful platform for studying neural circuits in the brain.
165. 165

     Timko, B. P.; Cohen-Karni, T.; Qing, Q.; Tian, B.; Lieber, C. M. Design and Implementation of Functional Nanoelectronic Interfaces with Biomolecules, Cells, and Tissue Using Nanowire Device Arrays. IEEE Trans. Nanotechnol. 2010, 9, 269– 280,  DOI: 10.1109/TNANO.2009.2031807

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     Design and Implementation of Functional Nanoelectronic Interfaces With Biomolecules, Cells, and Tissue Using Nanowire Device Arrays

     Timko Brian P; Cohen-Karni Tzahi; Qing Quan; Tian Bozhi; Lieber Charles M

     IEEE transactions on nanotechnology (2010), 9 (3), 269-280 ISSN:1536-125X.

     Nanowire FETs (NWFETs) are promising building blocks for nanoscale bioelectronic interfaces with cells and tissue since they are known to exhibit exquisite sensitivity in the context of chemical and biological detection, and have the potential to form strongly coupled interfaces with cell membranes. We present a general scheme that can be used to assemble NWs with rationally designed composition and geometry on either planar inorganic or biocompatible flexible plastic surfaces. We demonstrate that these devices can be used to measure signals from neurons, cardiomyocytes, and heart tissue. Reported signals are in millivolts range, which are equal to or substantially greater than those recorded with either planar FETs or multielectrode arrays, and demonstrate one unique advantage of NW-based devices. Basic studies showing the effect of device sensitivity and cell/substrate junction quality on signal magnitude are presented. Finally, our demonstrated ability to design high-density arrays of NWFETs enables us to map signal at the subcellular level, a functionality not enabled by conventional microfabricated devices. These advances could have broad applications in high-throughput drug assays, fundamental biophysical studies of cellular function, and development of powerful prosthetics.
166. 166

     Tian, B.; Liu, J.; Dvir, T.; Jin, L.; Tsui, J. H.; Qing, Q.; Suo, Z.; Langer, R.; Kohane, D. S.; Lieber, C. M. Macroporous Nanowire Nanoelectronic Scaffolds for Synthetic Tissues. Nat. Mater. 2012, 11, 986,  DOI: 10.1038/nmat3404

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     Macroporous nanowire nanoelectronic scaffolds for synthetic tissues

     Tian, Bozhi; Liu, Jia; Dvir, Tal; Jin, Lihua; Tsui, Jonathan H.; Qing, Quan; Suo, Zhigang; Langer, Robert; Kohane, Daniel S.; Lieber, Charles M.

     Nature Materials (2012), 11 (11), 986-994CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot elec. probe the physicochem. and biol. microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrixes. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local elec. activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.
167. 167

     Lee, J.-H.; Zhang, A.; You, S. S.; Lieber, C. M. Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons. Nano Lett. 2016, 16, 1509– 1513,  DOI: 10.1021/acs.nanolett.6b00020

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     Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons

     Lee, Jae-Hyun; Zhang, Anqi; You, Siheng Sean; Lieber, Charles M.

     Nano Letters (2016), 16 (2), 1509-1513CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Semiconductor nanowire (NW) devices that can address intracellular electrophysiol. events with high sensitivity and spatial resoln. are emerging as key tools in nanobioelectronics. Intracellular delivery of NWs without compromising cellular integrity and metabolic activity has, however, proven difficult without external mech. forces or elec. pulses. Here, the authors introduce a biomimetic approach in which a cell penetrating peptide, the trans-activating transcriptional activator (TAT) from human immunodeficiency virus 1, is linked to the surface of Si NWs to facilitate spontaneous internalization of NWs into primary neuronal cells. Confocal microscopy imaging studies at fixed time points demonstrate that TAT-conjugated NWs (TAT-NWs) are fully internalized into mouse hippocampal neurons, and quant. image analyses reveal an ∼15% internalization efficiency. In addn., live cell dynamic imaging of NW internalization shows that NW penetration begins within 10-20 min after binding to the membrane and that NWs become fully internalized within 30-40 min. The generality of cell penetrating peptide modification method is further demonstrated by internalization of TAT-NWs into primary dorsal root ganglion (DRG) neurons.
168. 168

     Zhao, Y.; You, S. S.; Zhang, A.; Lee, J.-H.; Huang, J.; Lieber, C. M. Scalable Ultrasmall Three-Dimensional Nanowire Transistor Probes for Intracellular Recording. Nat. Nanotechnol. 2019, 14, 783– 790,  DOI: 10.1038/s41565-019-0478-y

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     168

     Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording

     Zhao, Yunlong; You, Siheng Sean; Zhang, Anqi; Lee, Jae-Hyun; Huang, Jinlin; Lieber, Charles M.

     Nature Nanotechnology (2019), 14 (8), 783-790CODEN: NNAABX; ISSN:1748-3387. (Nature Research)

     New tools for intracellular electrophysiol. that push the limits of spatiotemporal resoln. while reducing invasiveness could provide a deeper understanding of electrogenic cells and their networks in tissues, and push progress towards human-machine interfaces. Although significant advances have been made in developing nanodevices for intracellular probes, current approaches exhibit a trade-off between device scalability and recording amplitude. The authors address this challenge by combining deterministic shape-controlled nanowire transfer with spatially defined semiconductor-to-metal transformation to realize scalable nanowire field-effect transistor probe arrays with controllable tip geometry and sensor size, which enable recording of up to 100 mV intracellular action potentials from primary neurons. Systematic studies on neurons and cardiomyocytes show that controlling device curvature and sensor size is crit. for achieving high-amplitude intracellular recordings. In addn., this device design allows for multiplexed recording from single cells and cell networks and could enable future studies of dynamics in the brain and other tissues.
169. 169

     Neto, J. P.; Costa, A.; Vaz Pinto, J.; Marques-Smith, A.; Costa, J. C.; Martins, R.; Fortunato, E.; Kampff, A. R.; Barquinha, P. Transparent and Flexible Electrocorticography Electrode Arrays Based on Silver Nanowire Networks for Neural Recordings. ACS Appl. Nano Mater. 2021, 4, 5737– 5747,  DOI: 10.1021/acsanm.1c00533

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     169

     Transparent and Flexible Electrocorticography Electrode Arrays Based on Silver Nanowire Networks for Neural Recordings

     Neto, Joana P.; Costa, Adriana; Vaz Pinto, Joana; Marques-Smith, Andre; Costa, Julio C.; Martins, Rodrigo; Fortunato, Elvira; Kampff, Adam R.; Barquinha, Pedro

     ACS Applied Nano Materials (2021), 4 (6), 5737-5747CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)

     This work explored hybrid films of silver nanowires (AgNWs) with indium zinc oxide (IZO) for developing high-performance and low-cost electrocorticog. (ECoG) electrodes. The transparent hybrid films achieved a sheet resistance of 6 Ω/sq, enabling electrodes with a diam. of 500 μm to reach an impedance of 20 kΩ at 1 kHz and a charge storage capacity of 3.2 mC/cm2, an improvement in properties over IZO electrodes, whose performance is on par with classical tin-doped indium oxide (ITO). Characterization of light-induced artifacts was performed, showing that light intensities <14 mW/mm2 elicit min. elec. potential variation, which falls within the magnitude of baseline noise. The validation of the electrodes in vivo was achieved by recording elec. neural activity from the surface of the rat cortex under anesthesia. Moreover, the presence of the hybrid films did not cause the distortion of light during fluorescence microscopy. This study highlighted the capabilities of transparent ECoG electrodes based on AgNWs with IZO. In the end, we leveraged available, yet affordable, techniques and materials to facilitate ease of prodn., creating a tool that is cost-effective and scalable for labs. looking to record neural elec. activity on a large and fast scale with direct visualization of neurons.
170. 170

     Liu, J.; Fu, T. M.; Cheng, Z.; Hong, G.; Zhou, T.; Jin, L.; Duvvuri, M.; Jiang, Z.; Kruskal, P.; Xie, C.; Suo, Z.; Fang, Y.; Lieber, C. M. Syringe-Injectable Electronics. Nat. Nanotechnol. 2015, 10, 629– 636,  DOI: 10.1038/nnano.2015.115

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     Syringe-injectable electronics

     Liu, Jia; Fu, Tian-Ming; Cheng, Zengguang; Hong, Guosong; Zhou, Tao; Jin, Lihua; Duvvuri, Madhavi; Jiang, Zhe; Kruskal, Peter; Xie, Chong; Suo, Zhigang; Fang, Ying; Lieber, Charles M.

     Nature Nanotechnology (2015), 10 (7), 629-636CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     Seamless and minimally invasive three-dimensional interpenetration of electronics within artificial or natural structures could allow for continuous monitoring and manipulation of their properties. Flexible electronics provide a means for conforming electronics to non-planar surfaces, yet targeted delivery of flexible electronics to internal regions remains difficult. Here, we overcome this challenge by demonstrating the syringe injection (and subsequent unfolding) of sub-micrometre-thick, centimetre-scale macroporous mesh electronics through needles with a diam. as small as 100 μm. Our results show that electronic components can be injected into man-made and biol. cavities, as well as dense gels and tissue, with >90% device yield. We demonstrate several applications of syringe-injectable electronics as a general approach for interpenetrating flexible electronics with three-dimensional structures, including (1) monitoring internal mech. strains in polymer cavities, (2) tight integration and low chronic immunoreactivity with several distinct regions of the brain, and (3) in vivo multiplexed neural recording. Moreover, syringe injection enables the delivery of flexible electronics through a rigid shell, the delivery of large-vol. flexible electronics that can fill internal cavities, and co-injection of electronics with other materials into host structures, opening up unique applications for flexible electronics.
171. 171

     Vitale, F.; Vercosa, D. G.; Rodriguez, A. V.; Pamulapati, S. S.; Seibt, F.; Lewis, E.; Yan, J. S.; Badhiwala, K.; Adnan, M.; Royer-Carfagni, G.; Beierlein, M.; Kemere, C.; Pasquali, M.; Robinson, J. T. Fluidic Microactuation of Flexible Electrodes for Neural Recording. Nano Lett. 2018, 18, 326– 335,  DOI: 10.1021/acs.nanolett.7b04184

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     171

     Fluidic Microactuation of Flexible Electrodes for Neural Recording

     Vitale, Flavia; Vercosa, Daniel G.; Rodriguez, Alexander V.; Pamulapati, Sushma Sri; Seibt, Frederik; Lewis, Eric; Yan, J. Stephen; Badhiwala, Krishna; Adnan, Mohammed; Royer-Carfagni, Gianni; Beierlein, Michael; Kemere, Caleb; Pasquali, Matteo; Robinson, Jacob T.

     Nano Letters (2018), 18 (1), 326-335CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Soft and conductive nanomaterials like carbon nanotubes, graphene, and nanowire scaffolds have expanded the family of ultraflexible microelectrodes that can bend and flex with the natural movement of the brain, reduce the inflammatory response, and improve the stability of long-term neural recordings. However, current methods to implant these highly flexible electrodes rely on temporary stiffening agents that temporarily increase the electrode size and stiffness thus aggravating neural damage during implantation, which can lead to cell loss and glial activation that persists even after the stiffening agents are removed or dissolve. A method to deliver thin, ultraflexible electrodes deep into neural tissue without increasing the stiffness or size of the electrodes will enable minimally invasive elec. recordings from within the brain. Specially designed microfluidic devices can apply a tension force to ultraflexible electrodes that prevents buckling without increasing the thickness or stiffness of the electrode during implantation. Addnl., these "fluidic microdrives" allow the authors to precisely actuate the electrode position with micron-scale accuracy. To demonstrate the efficacy of the authors' fluidic microdrives, the authors used them to actuate highly flexible carbon nanotube fiber (CNTf) microelectrodes for electrophysiol. The authors used this approach in three proof-of-concept expts. First, the authors recorded compd. action potentials in a soft model organism, the small cnidarian Hydra. Second, the authors targeted electrodes precisely to the thalamic reticular nucleus in brain slices and recorded spontaneous and optogenetically evoked extracellular action potentials. Finally, the authors inserted electrodes >4 mm deep into the brain of rats and detected spontaneous individual unit activity in both cortical and subcortical regions. Compared to syringe injection, fluidic microdrives do not penetrate the brain and prevent changes in intracranial pressure by diverting fluid away from the implantation site during insertion and actuation. Overall, the fluidic microdrive technol. provides a robust new method to implant and actuate ultraflexible neural electrodes.
172. 172

     Bhandari, R.; Negi, S.; Solzbacher, F. Wafer- Scale Fabrication of Penetrating Neural Microelectrode Arrays. Biomed. Microdevices 2010, 12, 797– 807,  DOI: 10.1007/s10544-010-9434-1

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     Yoo, J.; Kwak, H.; Kwon, J.; Ha, G. E.; Lee, E. H.; Song, S.; Na, J.; Lee, H. J.; Lee, J.; Hwangbo, A.; Cha, E.; Chae, Y.; Cheong, E.; Choi, H. J. Long-term Intracellular Recording of Optogenetically-induced Electrical Activities using Vertical Nanowire Multi Electrode Array. Sci. Rep. 2020, 10, 4279,  DOI: 10.1038/s41598-020-61325-3

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     Long-term Intracellular Recording of Optogenetically-induced Electrical Activities using Vertical Nanowire Multi Electrode Array

     Yoo Jisoo; Kwon Juyoung; Na Jukwan; Lee Hyo-Jung; Lee Jaejun; Cha Eunkyung; Choi Heon-Jin; Kwak Hankyul; Ha Go Eun; Lee Elliot H; Hwangbo Areum; Cheong Eunji; Song Seungwoo; Chae Youngcheol; Cheong Eunji

     Scientific reports (2020), 10 (1), 4279 ISSN:.

     Continuous recording of intracellular activities in single cells is required for deciphering rare, dynamic and heterogeneous cell responses, which are missed by population or brief single-cell recording. Even if the field of intracellular recording is constantly proceeding, several technical challenges are still remained to conquer this important approach. Here, we demonstrate long-term intracellular recording by combining a vertical nanowire multi electrode array (VNMEA) with optogenetic stimulation to minimally disrupt cell survival and functions during intracellular access and measurement. We synthesized small-diameter and high-aspect-ratio silicon nanowires to spontaneously penetrate into single cells, and used light to modulate the cell's responsiveness. The light-induced intra- and extracellular activities of individual optogenetically-modified cells were measured simultaneously, and each cell showed distinctly different measurement characteristics according to the cell-electrode configuration. Intracellular recordings were achieved continuously and reliably without signal interference and attenuation over 24 hours. The integration of two controllable techniques, vertically grown nanowire electrodes and optogenetics, expands the strategies for discovering the mechanisms for crucial physiological and dynamic processes in various types of cells.
174. 174

     Hierlemann, A.; Frey, U.; Hafizovic, S.; Heer, F. Growing Cells Atop Microelectronic Chips: Interfacing Electrogenic Cells in Vitro with CMOS-Based Microelectrode Arrays. Proc. IEEE 2011, 99, 252– 284,  DOI: 10.1109/JPROC.2010.2066532

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     Growing cells atop microelectronic chips: interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays

     Hierlemann, Andreas; Frey, Urs; Hafizovic, Sadik; Heer, Flavio

     Proceedings of the IEEE (2011), 99 (2), 252-284CODEN: IEEPAD; ISSN:0018-9219. (Institute of Electrical and Electronics Engineers)

     A review. Complementary semiconductor-metal-oxide (CMOS) technol. is a very powerful technol. that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielecs. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large no. of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technol. that opens a route to high-spatio-temporal-resoln. and low-noise electrophysiol. recordings from a variety of biol. prepns., such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compds., so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline soln. and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large nos. of tightly spaced microelectrodes and the assocd. circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The resp. dense microelectrode arrays (MEAs) with small pixels enable subcellular-resoln. investigation of regions of interest in, e.g., neurobiol. prepns., and, at the same time, the large no. of electrodes allows for studying the activity of entire neuronal networks. Application areas include neuroscience, as the devices enable fundamental neurophysiol. insights at the cellular and circuit level, as well as medical diagnostics and pharmacol.
175. 175

     Brain Multiple Cores for Cell-Based Assays without Compromises. https://www.3brain.com/products/multiwell/coreplate-tm--multiwell (accessed January 31, 2025).

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     Brain Electrophysiological Signals & Microelectrode Array Principles. https://www.3brain.com/resources/microelectrode-array (accessed December 26, 2023).

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     Berdondini, L.; Imfeld, K.; Maccione, A.; Tedesco, M.; Neukom, S.; Koudelka-Hep, M.; Martinoia, S. Active Pixel Sensor Array for High Spatio-Temporal Resolution Electrophysiological Recordings From Single Cell to Large Scale Neuronal Networks. Lab Chip 2009, 9, 2644– 2651,  DOI: 10.1039/b907394a

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     Active pixel sensor array for high spatio-temporal resolution electrophysiological recordings from single cell to large scale neuronal networks

     Berdondini, Luca; Imfeld, Kilian; Maccione, Alessandro; Tedesco, Mariateresa; Neukom, Simon; Koudelka-Hep, Milena; Martinoia, Sergio

     Lab on a Chip (2009), 9 (18), 2644-2651CODEN: LCAHAM; ISSN:1473-0197. (Royal Society of Chemistry)

     This paper presents a chip-based electrophysiol. platform enabling the study of micro- and macro-circuitry in in-vitro neuronal prepns. The approach is based on a 64 × 64 microelectrode array device providing extracellular electrophysiol. activity recordings with high spatial (21 μm of electrode sepn.) and temporal resoln. (from 0.13 ms for 4096 microelectrodes down to 8 μs for 64 microelectrodes). Applied to in-vitro neuronal prepns., the authors show how this approach enables neuronal signals to be acquired for investigating neuronal activity from single cells and microcircuits to large scale neuronal networks. The main elements of the platform are the metallic microelectrode array (MEA) implemented in Complementary Metal Oxide Semiconductor (CMOS) technol. similar to a light imager, the in-pixel integrated low-noise amplifiers (11 μVrms) and the high-speed random addressing logic. The chip is combined with a real-time acquisition system providing the capability to record at 7.8 kHz/electrode the whole array and to process the acquired signals.
178. 178

     Bakkum, D. J.; Frey, U.; Radivojevic, M.; Russell, T. L.; Muller, J.; Fiscella, M.; Takahashi, H.; Hierlemann, A. Tracking Axonal Action Potential Propagation on a High-Density Microelectrode Array across Hundreds of Sites. Nat. Commun. 2013, 4, 2181,  DOI: 10.1038/ncomms3181

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     Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites

     Bakkum Douglas J; Frey Urs; Radivojevic Milos; Russell Thomas L; Muller Jan; Fiscella Michele; Takahashi Hirokazu; Hierlemann Andreas

     Nature communications (2013), 4 (), 2181 ISSN:.

     Axons are traditionally considered stable transmission cables, but evidence of the regulation of action potential propagation demonstrates that axons may have more important roles. However, their small diameters render intracellular recordings challenging, and low-magnitude extracellular signals are difficult to detect and assign. Better experimental access to axonal function would help to advance this field. Here we report methods to electrically visualize action potential propagation and network topology in cortical neurons grown over custom arrays, which contain 11,011 microelectrodes and are fabricated using complementary metal oxide semiconductor technology. Any neuron lying on the array can be recorded at high spatio-temporal resolution, and simultaneously precisely stimulated with little artifact. We find substantial velocity differences occurring locally within single axons, suggesting that the temporal control of a neuron's output may contribute to neuronal information processing.
179. 179

     Dong, R.; Wang, L.; Hang, C.; Chen, Z.; Liu, X.; Zhong, L.; Qi, J.; Huang, Y.; Liu, S.; Wang, L.; Lu, Y.; Jiang, X. Printed Stretchable Liquid Metal Electrode Arrays for in Vivo Neural Recording. Small 2021, 17, e2006612,  DOI: 10.1002/smll.202006612

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     Bosse, B.; Damle, S.; Akinin, A.; Jing, Y.; Bartsch, D. U.; Cheng, L.; Oesch, N.; Lo, Y. H.; Cauwenberghs, G.; Freeman, W. R. In Vivo Photovoltaic Performance of a Silicon Nanowire Photodiode-Based Retinal Prosthesis. Invest Ophthalmol Vis. Sci. 2018, 59, 5885– 5892,  DOI: 10.1167/iovs.18-24554

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     Wang, Z. L.; Song, J. Piezoelectric Nanogenerators Based on Zinc Oxide Nanowire Arrays. Science 2006, 312, 242– 246,  DOI: 10.1126/science.1124005

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     Piezoelectric Nanogenerators Based on Zinc Oxide Nanowire Arrays

     Wang, Zhong Lin; Song, Jinhui

     Science (Washington, DC, United States) (2006), 312 (5771), 242-246CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     We have converted nanoscale mech. energy into elec. energy by means of piezoelec. zinc oxide nanowire (NW) arrays. The aligned NWs are deflected with a conductive at. force microscope tip in contact mode. The coupling of piezoelec. and semiconducting properties in zinc oxide creates a strain field and charge sepn. across the NW as a result of its bending. The rectifying characteristic of the Schottky barrier formed between the metal tip and the NW leads to elec. current generation. The efficiency of the NW-based piezoelec. power generator is estd. to be 17 to 30%. This approach has the potential of converting mech., vibrational, and/or hydraulic energy into electricity for powering nanodevices.
182. 182

     Rudramurthy, G. R.; Swamy, M. K. Potential Applications of Engineered Nanoparticles in Medicine and Biology: An Update. J. Biol. Inorg. Chem. 2018, 23, 1185– 1204,  DOI: 10.1007/s00775-018-1600-6

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     Potential applications of engineered nanoparticles in medicine and biology: an update

     Rudramurthy, Gudepalya Renukaiah; Swamy, Mallappa Kumara

     JBIC, Journal of Biological Inorganic Chemistry (2018), 23 (8), 1185-1204CODEN: JJBCFA; ISSN:0949-8257. (Springer)

     A review. Abstr.: Nanotechnol. advancements have led to the development of its allied fields, such as nanoparticle synthesis and their applications in the field of biomedicine. Nanotechnol. driven innovations have given a hope to the patients as well as physicians in solving the complex medical problems. Nanoparticles with a size ranging from 0.2 to 100 nm are assocd. with an increased surface to vol. ratio. Moreover, the physico-chem. and biol. properties of nanoparticles can be modified depending on the applications. Different nanoparticles have been documented with a wide range of applications in various fields of medicine and biol. including cancer therapy, drug delivery, tissue engineering, regenerative medicine, biomols. detection, and also as antimicrobial agents. However, the development of stable and effective nanoparticles requires a profound knowledge on both physico-chem. features of nanomaterials and their intended applications. Further, the health risks assocd. with the use of engineered nanoparticles needs a serious attention.
183. 183

     Gorjikhah, F.; Davaran, S.; Salehi, R.; Bakhtiari, M.; Hasanzadeh, A.; Panahi, Y.; Emamverdy, M.; Akbarzadeh, A. Improving ″Lab-on-a-Chip″ Techniques Using Biomedical Nanotechnology: A Review. Artif. Cells Nanomed. Biotechnol. 2016, 44, 1609– 1614,  DOI: 10.3109/21691401.2015.1129619

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184. 184

     Prajapati, S. K.; Malaiya, A.; Kesharwani, P.; Soni, D.; Jain, A. Biomedical Applications and Toxicities of Carbon Nanotubes. Drug Chem. Toxicol. 2022, 45, 435– 450,  DOI: 10.1080/01480545.2019.1709492

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185. 185

     Raphey, V. R.; Henna, T. K.; Nivitha, K. P.; Mufeedha, P.; Sabu, C.; Pramod, K. Advanced Biomedical Applications of Carbon Nanotube. Mater. Sci. Eng., C 2019, 100, 616– 630,  DOI: 10.1016/j.msec.2019.03.043

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     185

     Advanced biomedical applications of carbon nanotube

     Raphey, V. R.; Henna, T. K.; Nivitha, K. P.; Mufeedha, P.; Sabu, Chinnu; Pramod, K.

     Materials Science & Engineering, C: Materials for Biological Applications (2019), 100 (), 616-630CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

     A review. With advances in nanotechnol., the applications of nanomaterial are developing widely and greatly. The characteristic properties of carbon nanotubes (CNTs) make them the most selective candidate for various multi-functional applications. The greater surface area of the CNTs in addn. to the capability to manipulate the surfaces and dimensions has provided greater potential for this nanomaterial. The CNTs possess greater potential for applications in biomedicine due to their vital elec., chem., thermal, and mech. properties. The unique properties of CNT are exploited for numerous applications in the biomedical field. They are useful in both therapeutic and diagnostic applications. They form novel carrier systems which are also capable of site-specific delivery of therapeutic agents. In addn., CNTs are of potential application in biosensing. Many recently reported advanced systems of CNT could be exploited for their immense potential in biomedicine in the future.
186. 186

     Hamada, N.; Sawada, S.; Oshiyama, A. New One-Dimensional Conductors: Graphitic Microtubules. Phys. Rev. Lett. 1992, 68, 1579– 1581,  DOI: 10.1103/PhysRevLett.68.1579

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     New one-dimensional conductors: graphitic microtubules

     Hamada, Noriaki; Sawada, Shinichi; Oshiyama, Atsushi

     Physical Review Letters (1992), 68 (10), 1579-81CODEN: PRLTAO; ISSN:0031-9007.

     On the basis of realistic tight-binding band-structure calcns., we predict that carbon microtubules exhibit striking variations in electronic transport, from metallic to semiconducting with narrow and moderate band gaps, depending on the diam. of the tubule and on the degree of helical arrangement of the carbon hexagons. The origin of this drastic variation in the band structure is explained in terms of the two-dimensional band structure of graphite.
187. 187

     Mintmire, J. W.; Dunlap, B. I.; White, C. T. Are Fullerene Tubules Metallic?. Phys. Rev. Lett. 1992, 68, 631– 634,  DOI: 10.1103/PhysRevLett.68.631

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     Are fullerene tubules metallic?

     Mintmire, J. W.; Dunlap, B. I.; White, C. T.

     Physical Review Letters (1992), 68 (5), 631-4CODEN: PRLTAO; ISSN:0031-9007.

     We have calcd. the electronic structure of a carbon fullerene tubule using a first-principles, self-consistent, all-electron Gaussian-orbital-based local-d.-functional approach. Extending these results to a model contg. an electron-lattice interaction, we est. that the mean-field transition temp. from a Peierls-distorted regime to a high-temp. metallic regime should be well below room temp. Such fullerene tubules should have the advantages (compared to other conjugated carbon systems) of a carrier d. similar to that of metals and zero band gap at room temp.
188. 188

     Ruhunage, C.; Dhawan, V.; Nawarathne, C. P.; Hoque, A.; Cui, X. T.; Alvarez, N. T. Evaluation of Polymer-Coated Carbon Nanotube Flexible Microelectrodes for Biomedical Applications. Bioengineering 2023, 10, 647,  DOI: 10.3390/bioengineering10060647

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189. 189

     Shin, S. R.; Jung, S. M.; Zalabany, M.; Kim, K.; Zorlutuna, P.; Kim, S. B.; Nikkhah, M.; Khabiry, M.; Azize, M.; Kong, J.; Wan, K. T.; Palacios, T.; Dokmeci, M. R.; Bae, H.; Tang, X. S.; Khademhosseini, A. Carbon-Nanotube-Embedded Hydrogel Sheets for Engineering Cardiac Constructs and Bioactuators. ACS Nano 2013, 7, 2369– 80,  DOI: 10.1021/nn305559j

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     189

     Carbon-Nanotube-Embedded Hydrogel Sheets for Engineering Cardiac Constructs and Bioactuators

     Shin, Su Ryon; Jung, Sung Mi; Zalabany, Momen; Kim, Keekyoung; Zorlutuna, Pinar; Kim, Sang bok; Nikkhah, Mehdi; Khabiry, Masoud; Azize, Mohamed; Kong, Jing; Wan, Kai-tak; Palacios, Tomas; Dokmeci, Mehmet R.; Bae, Hojae; Tang, Xiaowu; Khademhosseini, Ali

     ACS Nano (2013), 7 (3), 2369-2380CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     We engineered functional cardiac patches by seeding neonatal rat cardiomyocytes onto carbon nanotube (CNT)-incorporated photo-cross-linkable gelatin methacrylate (GelMA) hydrogels. The resulting cardiac constructs showed excellent mech. integrity and advanced electrophysiol. functions. Specifically, myocardial tissues cultured on 50 μm thick CNT-GelMA showed 3 times higher spontaneous synchronous beating rates and 85% lower excitation threshold, compared to those cultured on pristine GelMA hydrogels. Our results indicate that the elec. conductive and nanofibrous networks formed by CNTs within a porous gelatin framework are the key characteristics of CNT-GelMA leading to improved cardiac cell adhesion, organization, and cell-cell coupling. Centimeter-scale patches were released from glass substrates to form 3D biohybrid actuators, which showed controllable linear cyclic contraction/extension, pumping, and swimming actuations. In addn., we demonstrate for the first time that cardiac tissues cultured on CNT-GelMA resist damage by a model cardiac inhibitor as well as a cytotoxic compd. Therefore, incorporation of CNTs into gelatin, and potentially other biomaterials, could be useful in creating multifunctional cardiac scaffolds for both therapeutic purposes and in vitro studies. These hybrid materials could also be used for neuron and other muscle cells to create tissue constructs with improved organization, electroactivity, and mech. integrity.
190. 190

     Silva, G. A. Neuroscience Nanotechnology: Progress, Opportunities and Challenges. Nat. Rev. Neurosci. 2006, 7, 65– 74,  DOI: 10.1038/nrn1827

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     Neuroscience nanotechnology: progress, opportunities and challenges

     Silva, Gabriel A.

     Nature Reviews Neuroscience (2006), 7 (1), 65-74CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

     A review. Nanotechnologies exploit materials and devices with a functional organization that has been engineered at the nanometer scale. The application of nanotechnol. in cell biol. and physiol. enables targeted interactions at a fundamental mol. level. In neuroscience, this entails specific interactions with neurons and glial cells. Examples of current research include technologies that are designed to better interact with neural cells, advanced mol. imaging technologies, materials and hybrid mols. used in neural regeneration, neuroprotection, and targeted delivery of drugs and small mols. across the blood-brain barrier.
191. 191

     Hanein, Y. Carbon Nanotube Integration into MEMS Devices. Phys. Status Solidi B 2010, 247, 2635– 2640,  DOI: 10.1002/pssb.201000109

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     Shoval, A.; Adams, C.; David-Pur, M.; Shein, M.; Hanein, Y.; Sernagor, E. Carbon Nanotube Electrodes for Effective Interfacing with Retinal Tissue. Front. Neuroeng. 2009, 2, 510,  DOI: 10.3389/neuro.16.004.2009

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193. 193

     Castagnola, E.; Maiolo, L.; Maggiolini, E.; Minotti, A.; Marrani, M.; Maita, F.; Pecora, A.; Angotzi, G. N.; Ansaldo, A.; Boffini, M. PEDOT-CNT-Coated Low-Impedance, Ultra-Flexible, and Brain-Conformable Micro-ECoG Arrays. IEEE Trans. Neural Syst. Rehabil. Eng. 2015, 23, 342– 350,  DOI: 10.1109/TNSRE.2014.2342880

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194. 194

     Castagnola, E.; Biso, M.; Ricci, D. Improvement of Polypyrrole and Carbon Nanotube Co-Deposition Techniques for High Charge-Transfer Electrodes. Phys. Status Solidi B 2009, 246, 2469– 2472,  DOI: 10.1002/pssb.200982283

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195. 195

     Castagnola, E.; Biso, M.; Ricci, D. Controlled Electrochemical Polypyrrole and Carbon Nanotube Co-Deposition onto Platinum Electrodes; In 2009 9th IEEE Conference on Nanotechnology (IEEE-NANO), IEEE: 2009; pp 842– 845.

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196. 196

     Gabay, T.; Ben-David, M.; Kalifa, I.; Sorkin, R.; Abrams, Z. R.; Ben-Jacob, E.; Hanein, Y. Electro- Chemical and Biological Properties of Carbon Nanotube Based Multi-Electrode Arrays. Nanotechnology 2007, 18, 035201,  DOI: 10.1088/0957-4484/18/3/035201

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197. 197

     Bareket-Keren, L.; Hanein, Y. Carbon Nanotube-Based Multi Electrode Arrays for Neuronal Interfacing: Progress and Prospects. Front. Neural Circuits 2013, 6, 122,  DOI: 10.3389/fncir.2012.00122

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198. 198

     Kim, G. H.; Kim, K.; Nam, H.; Shin, K.; Choi, W.; Shin, J. H.; Lim, G. CNT-Au Nanocomposite Deposition on Gold Microelectrodes for Improved Neural Recordings. Sens. Actuators, B 2017, 252, 152– 158,  DOI: 10.1016/j.snb.2017.04.142

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     198

     CNT-Au nanocomposite deposition on gold microelectrodes for improved neural recordings

     Kim, Geon Hwee; Kim, Kanghyun; Nam, Hyoryung; Shin, Kumjae; Choi, Woo Seok; Shin, Jung Hwal; Lim, Geunbae

     Sensors and Actuators, B: Chemical (2017), 252 (), 152-158CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)

     Microelectrode arrays (MEAs) are widely used in neural recordings of cultured neurons and neural tissues. The impedance of neural electrodes is an important factor because it dets. the signal-to-noise ratio (SNR) of the recorded neural signals. Here, we developed a modified technique using CNT-Au nanocomposites (CANs) for MEAs. The impedance of CAN-modified microelectrodes was greatly decreased vs. pure gold microelectrodes due to their large electrochem. surface area (ESA). Importantly, when compared in terms of "impedance with respect to surface area" with previous reports, the value was 8.8 MOum2, which is outstanding. Cultured neurons showed good viability and the SNR (av. SNR = 92) of recorded neural signals with CAN-modified microelectrodes was sufficiently high compared with previous studies. This modified technique will provide a significant advancement in MEA chips and could also be applied to various neural electrodes, such as Si electrodes, multiple site electrodes, and tetrodes.
199. 199

     Baranauskas, G.; Maggiolini, E.; Castagnola, E.; Ansaldo, A.; Mazzoni, A.; Angotzi, G. N.; Vato, A.; Ricci, D.; Panzeri, S.; Fadiga, L. Carbon Nanotube Composite Coating of Neural Microelectrodes Preferentially Improves the Multiunit Signal-to-Noise Ratio. J. Neural Eng. 2011, 8, 066013,  DOI: 10.1088/1741-2560/8/6/066013

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     199

     Carbon nanotube composite coating of neural microelectrodes preferentially improves the multiunit signal-to-noise ratio

     Baranauskas Gytis; Maggiolini Emma; Castagnola Elisa; Ansaldo Alberto; Mazzoni Alberto; Angotzi Gian Nicola; Vato Alessandro; Ricci Davide; Panzeri Stefano; Fadiga Luciano

     Journal of neural engineering (2011), 8 (6), 066013 ISSN:.

     Extracellular metal microelectrodes are widely used to record single neuron activity in vivo. However, their signal-to-noise ratio (SNR) is often far from optimal due to their high impedance value. It has been recently reported that carbon nanotube (CNT) coatings may decrease microelectrode impedance, thus improving their performance. To tease out the different contributions to SNR of CNT-coated microelectrodes we carried out impedance and noise spectroscopy measurements of platinum/tungsten microelectrodes coated with a polypyrrole-CNT composite. Neuronal signals were recorded in vivo from rat cortex by employing tetrodes with two recording sites coated with polypyrrole-CNT and the remaining two left untreated. We found that polypyrrole-CNT coating significantly reduced the microelectrode impedance at all neuronal signal frequencies (from 1 to 10 000 Hz) and induced a significant improvement of the SNR, up to fourfold on average, in the 150-1500 Hz frequency range, largely corresponding to the multiunit frequency band. An equivalent circuit, previously proposed for porous conducting polymer coatings, reproduced the impedance spectra of our coated electrodes but could not explain the frequency dependence of SNR improvement following polypyrrole-CNT coating. This implies that neither the neural signal amplitude, as recorded by a CNT-coated metal microelectrode, nor noise can be fully described by the equivalent circuit model we used here and suggests that a more detailed approach may be needed to better understand the signal propagation at the electrode-solution interface. Finally, the presence of significant noise components that are neither thermal nor electronic makes it difficult to establish a direct relationship between the actual electrode noise and the impedance spectra.
200. 200

     David-Pur, M.; Bareket-Keren, L.; Beit-Yaakov, G.; Raz-Prag, D.; Hanein, Y. All- Carbon-Nanotube Flexible Multi-Electrode Array for Neuronal Recording and Stimulation. Biomed. Microdevices 2014, 16, 43– 53,  DOI: 10.1007/s10544-013-9804-6

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201. 201

     Bendali, A.; Hess, L. H.; Seifert, M.; Forster, V.; Stephan, A. F.; Garrido, J. A.; Picaud, S. Purified Neurons Can Survive on Peptide-Free Graphene Layers. Adv. Healthc. Mater. 2013, 2, 929– 933,  DOI: 10.1002/adhm.201200347

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     Purified Neurons can Survive on Peptide-Free Graphene Layers

     Bendali, Amel; Hess, Lucas H.; Seifert, Max; Forster, Valerie; Stephan, Anne-Fleur; Garrido, Jose A.; Picaud, Serge

     Advanced Healthcare Materials (2013), 2 (7), 929-933CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)

     This article demonstrates the excellent cytocompatibility of graphene, a promising material for novel neural prostheses, by showing that primary retinal ganglion cells can directly survive on its surface without any supporting glial layer or protein coating. In this study, high-quality single layer graphene was prepd. by chem. vapor deposition (CVD) on large samples. The outstanding electronic performance of graphene devices together with its chem. stability, suitable mech. properties, and excellent cytocompatibility - demonstrated in this study-open a highly promising new route for the development of a novel generation of flexible, durable, and highly-sensitive neural prostheses.
202. 202

     Mattson, M. P.; Haddon, R. C.; Rao, A. M. Molecular Functionalization of Carbon Nanotubes and Use as Substrates for Neuronal Growth. J. Mol. Neurosci. 2000, 14, 175– 182,  DOI: 10.1385/JMN:14:3:175

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     Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth

     Mattson, Mark P.; Haddon, Robert C.; Rao, Apparao M.

     Journal of Molecular Neuroscience (2000), 14 (3), 175-182CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)

     Carbon nanotubes are strong, flexible, conduct elec. current, and can be functionalized with different mols., properties that may be useful in basic and applied neuroscience research. We report the first application of carbon nanotube technol. to neuroscience research. Methods were developed for growing embryonic rat-brain neurons on multiwalled carbon nanotubes. On unmodified nanotubes, neurons extend only one or two neurites, which exhibit very few branches. In contrast, neurons grown on nanotubes coated with the bioactive mol. 4-hydroxynonenal elaborate multiple neurites, which exhibit extensive branching. These findings establish the feasibility of using nanotubes as substrates for nerve cell growth and as probes of neuronal function at the nanometer scale.
203. 203

     Lovat, V.; Pantarotto, D.; Lagostena, L.; Cacciari, B.; Grandolfo, M.; Righi, M.; Spalluto, G.; Prato, M.; Ballerini, L. Carbon Nanotube Substrates Boost Neuronal Electrical Signaling. Nano Lett. 2005, 5, 1107– 1110,  DOI: 10.1021/nl050637m

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     203

     Carbon nanotube substrates boost neuronal electrical signaling

     Lovat, Viviana; Pantarotto, Davide; Lagostena, Laura; Cacciari, Barbara; Grandolfo, Micaela; Righi, Massimo; Spalluto, Giampiero; Prato, Maurizio; Ballerini, Laura

     Nano Letters (2005), 5 (6), 1107-1110CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     We demonstrated the possibility of using carbon nanotubes (CNTs) as potential devices able to improve neural signal transfer while supporting dendrite elongation and cell adhesion. The results strongly suggest that the growth of neuronal circuits on a CNT grid was accompanied by a significant increase in network activity. The increase in the efficacy of neural signal transmission may be related to the specific properties of CNT materials, such as the high elec. cond.
204. 204

     Fiorito, S.; Russier, J.; Salemme, A.; Soligo, M.; Manni, L.; Krasnowska, E.; Bonnamy, S.; Flahaut, E.; Serafino, A.; Togna, G. I.; Marlier, L. N. J. L.; Togna, A. R. Switching on Microglia with Electro-Conductive Multi Walled Carbon Nanotubes. Carbon 2018, 129, 572– 584,  DOI: 10.1016/j.carbon.2017.12.069

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     Switching on microglia with electro-conductive multi walled carbon nanotubes

     Fiorito, Silvana; Russier, Julie; Salemme, Adele; Soligo, Marzia; Manni, Luigi; Krasnowska, Ewa; Bonnamy, Sylvie; Flahaut, Emmanuel; Serafino, Annalucia; Togna, Giuseppina Ines; Marlier, Lionel N. J. L.; Togna, Anna Rita

     Carbon (2018), 129 (), 572-584CODEN: CRBNAH; ISSN:0008-6223. (Elsevier Ltd.)

     We explored the mechanisms underlying microglia cell-carbon nanotube interactions in order to investigate whether elec. properties of Carbon-Nanotubes (CNTs) could affect microglia brain cells function and phenotype. We analyzed the effects induced by highly electro-conductive Multi-Walled-Carbon-Nanotubes (α-MWCNTs), on microglia cells from rat brain cortex and compared the results with those obtained with as prepd. not conductive MWCNTs (MWCNTs) and redox-active Double-Walled-Carbon-Nanotubes (DWCNTs). Cell viability and CNT capacity to stimulate the release of nitric oxide (NO), pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory (IL-10, TGF-β1) cytokines and neurotrophic factors (mNGF) were assessed. Electro-conductive MWCNTs, besides not being cytotoxic, were shown to stimulate, at 24 h cell exposure, classical "M1'' microglia activation phenotype, increasing significantly the release of the main pro-inflammatory cytokines. Conversely, after 48 h cell exposure, they induced the transition from classical "M1'' to alternative "M2'' microglia phenotype, supported by anti-inflammatory cytokines and neuroprotective factor mNGF release. The anal. of cell morphol. change, by tubulin and CD-206 + labeling showed that M2 phenotype was much more expressed at 48 h in cells exposed to a-MWCNTs than in untreated cells. Our data suggest that the intrinsic elec. properties of CNTs could be exploited to modulate microglia phenotype and function stimulating microglia anti-inflammatory potential.
205. 205

     Fabbro, A.; Villari, A.; Laishram, J.; Scaini, D.; Toma, F. M.; Turco, A.; Prato, M.; Ballerini, L. Spinal Cord Explants Use Carbon Nanotube Interfaces To Enhance Neurite Outgrowth and To Fortify Synaptic Inputs. ACS Nano 2012, 6, 2041– 2055,  DOI: 10.1021/nn203519r

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     205

     Spinal Cord Explants Use Carbon Nanotube Interfaces To Enhance Neurite Outgrowth and To Fortify Synaptic Inputs

     Fabbro, Alessandra; Villari, Ambra; Laishram, Jummi; Scaini, Denis; Toma, Francesca M.; Turco, Antonio; Prato, Maurizio; Ballerini, Laura

     ACS Nano (2012), 6 (3), 2041-2055CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     New developments in nanotechnol. are increasingly designed to modulate relevant interactions between nanomaterials and neurons, with the aim of exploiting the phys. properties of synthetic materials to tune desired and specific biol. processes. Carbon nanotubes have been applied in several areas of nerve tissue engineering to study cell behavior or to instruct the growth and organization of neural networks. Recent reports show that nanotubes can sustain and promote elec. activity in networks of cultured neurons. However, such results are usually limited to carbon nanotube/neuron hybrids formed on a monolayer of dissocd. brain cells. In the present work, the authors used organotypic spinal slices to model multilayer tissue complexity, and the authors interfaced such spinal segments to carbon nanotube scaffolds for weeks. By immunofluorescence, scanning and transmission electronic microscopy, and at. force microscopy, the authors investigated nerve fiber growth when neuronal processes exit the spinal explant and develop in direct contact to the substrate. By single-cell electrophysiol., the authors investigated the synaptic activity of visually identified ventral interneurons, within the ventral area of the explant, thus synaptically connected, but located remotely, to the substrate/network interface. Here the authors show that spinal cord explants interfaced for weeks to purified carbon nanotube scaffolds expand more neuronal fibers, characterized by different mech. properties and displaying higher growth cones activity. Exploring spontaneous and evoked synaptic activity unmasks an increase in synaptic efficacy in neurons located at as far as 5 cell layers from the cell-substrate interactions.
206. 206

     Fabbro, A.; Prato, M.; Ballerini, L. Carbon Nanotubes in Neuroregeneration and Repair. Adv. Drug Delivery Rev. 2013, 65, 2034– 2044,  DOI: 10.1016/j.addr.2013.07.002

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     206

     Carbon nanotubes in neuroregeneration and repair

     Fabbro, Alessandra; Prato, Maurizio; Ballerini, Laura

     Advanced Drug Delivery Reviews (2013), 65 (15), 2034-2044CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)

     A review. In the last decade, we have experienced an increasing interest and an improved understanding of the application of nanotechnol. to the nervous system. The aim of such studies is that of developing future strategies for tissue repair to promote functional recovery after brain damage. In this framework, carbon nanotube based technologies are emerging as particularly innovative tools due to the outstanding phys. properties of these nanomaterials together with their recently documented ability to interface neuronal circuits, synapses and membranes. This review will discuss the state of the art in carbon nanotube technol. applied to the development of devices able to drive nerve tissue repair; we will highlight the most exciting findings addressing the impact of carbon nanotubes in nerve tissue engineering, focusing in particular on neuronal differentiation, growth and network reconstruction.
207. 207

     Hu, H.; Ni, Y.; Montana, V.; Haddon, R. C.; Parpura, V. Chemically Functionalized Carbon Nanotubes as Substrates for Neuronal Growth. Nano Lett. 2004, 4, 507– 511,  DOI: 10.1021/nl035193d

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     207

     Chemically functionalized carbon nanotubes as substrates for neuronal growth

     Hu, Hui; Ni, Yingchun; Montana, Vedrana; Haddon, Robert C.; Parpura, Vladimir

     Nano Letters (2004), 4 (3), 507-511CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     We report the use of chem. modified carbon nanotubes as a substrate for cultured neurons. The morphol. features of neurons that directly reflect their potential capability in synaptic transmission are characterized. The chem. properties of carbon nanotubes are systematically varied by attaching different functional groups that confer known characteristics to the substrate. By manipulating the charge carried by functionalized carbon nanotubes we are able to control the outgrowth and branching pattern of neuronal processes.
208. 208

     Lichtenstein, M. P.; Carretero, N. M.; Perez, E.; Pulido-Salgado, M.; Moral-Vico, J.; Sola, C.; Casan-Pastor, N.; Sunol, C. Biosafety Assessment of Conducting Nanostructured Materials by Using Co-Cultures of Neurons and Astrocytes. Neurotoxicology 2018, 68, 115– 125,  DOI: 10.1016/j.neuro.2018.07.010

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     Biosafety assessment of conducting nanostructured materials by using co-cultures of neurons and astrocytes

     Lichtenstein, Mathieu P.; Carretero, Nina M.; Perez, Estela; Pulido-Salgado, Marta; Moral-Vico, Javier; Sola, Carme; Casan-Pastor, Nieves; Sunol, Cristina

     NeuroToxicology (2018), 68 (), 115-125CODEN: NRTXDN; ISSN:0161-813X. (Elsevier Inc.)

     Neural electrode implants are made mostly of noble materials. We have synthesized a nanostructured material combining the good electrochem. properties of iridium oxide (IrOx) and carbon-nanotubes (CNT) and the properties of poly(3,4-ethylenedioxythiophene) (PEDOT). IrOx-CNT-PEDOT charge storage capacity was lower than that of IrOx and IrOx-CNT, but higher than that of other PEDOT-contg. hybrids and Pt. Cyclic voltammetry, SEM, XPS and micro-Raman spectroscopy suggest that PEDOT encapsulates IrOx and CNT. In our search for a cell culture platform that could optimize modeling the in vivo environment, we detd. cell viability, neuron and astrocyte functionality and the response of astrocytes to an inflammatory insult by using primary cultures of neurons, of astrocytes and co-cultures of both. The materials tested (based on IrOx, CNT and PEDOT, as well as Pt as a ref.) allowed adhesion and proliferation of astrocytes and full compatibility for neurons grown in co-cultures. Functionality assays show that uptake of glutamate in neuron-astrocyte co-culture was significantly higher than the sum of the uptake in astrocytes and neurons. In co-cultures on IrOx, IrOx-CNT and IrOx-CNT-PEDOT, glutamate was released by a depolarizing stimulus and induced a significant increase in intracellular calcium, supporting the expression of functional NMDA/glutamate receptors. LPS-induced inflammatory response in astrocytes showed a decreased response in NOS2 and COX2 mRNA expression for IrOx-CNT-PEDOT. Results indicate that neuron-astrocyte co-cultures are a reliable model for assessing the biocompatibility and safety of nanostructured materials, evidencing also that hybrid IrOx-CNT-PEDOT nanocomposite materials may offer larger resistance to inflammatory insults.
209. 209

     Shao, H.; Li, T.; Zhu, R.; Xu, X.; Yu, J.; Chen, S.; Song, L.; Ramakrishna, S.; Lei, Z.; Ruan, Y.; He, L. Carbon Nanotube Multilayered Nanocomposites as Multifunctional Substrates for Actuating Neuronal Differentiation and Functions of Neural Stem Cells. Biomaterials 2018, 175, 93– 109,  DOI: 10.1016/j.biomaterials.2018.05.028

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     209

     Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells

     Shao, Han; Li, Tingting; Zhu, Rong; Xu, Xiaoting; Yu, Jiandong; Chen, Shengfeng; Song, Li; Ramakrishna, Seeram; Lei, Zhigang; Ruan, Yiwen; He, Liumin

     Biomaterials (2018), 175 (), 93-109CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Carbon nanotubes (CNTs) have shown potential applications in neuroscience as growth substrates owing to their numerous unique properties. However, a key concern in the fabrication of homogeneous composites is the serious aggregation of CNTs during incorporation into the biomaterial matrix. Moreover, the regulation mechanism of CNT-based substrates on neural differentiation remains unclear. Here, a novel strategy was introduced for the construction of CNT nanocomposites via layer-by-layer assembly of neg. charged multi-walled CNTs and pos. charged poly(dimethyldiallylammonium chloride). Results demonstrated that the CNT-multilayered nanocomposites provided a potent regulatory signal over neural stem cells (NSCs), including cell adhesion, viability, differentiation, neurite outgrowth, and electrophysiol. maturation of NSC-derived neurons. Importantly, the dynamic mol. mechanisms in the NSC differentiation involved the integrin-mediated interactions between NSCs and CNT multilayers, thereby activating focal adhesion kinase, subsequently triggering downstream signaling events to regulate neuronal differentiation and synapse formation. This study provided insights for future applications of CNT-multilayered nanomaterials in neural fields as potent modulators of stem cell behavior.
210. 210

     Su, W. T.; Shih, Y. A. Nanofiber Containing Carbon Nanotubes Enhanced PC12 Cell Proliferation and Neuritogenesis by Electrical Stimulation. Biomed. Mater. Eng. 2015, 26, S189– S195,  DOI: 10.3233/BME-151305

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211. 211

     Fabbro, A.; Bosi, S.; Ballerini, L.; Prato, M. Carbon Nanotubes: Artificial Nanomaterials To Engineer Single Neurons and Neuronal Networks. ACS Chem. Neurosci. 2012, 3, 611– 618,  DOI: 10.1021/cn300048q

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     211

     Carbon Nanotubes: Artificial Nanomaterials to Engineer Single Neurons and Neuronal Networks

     Fabbro, Alessandra; Bosi, Susanna; Ballerini, Laura; Prato, Maurizio

     ACS Chemical Neuroscience (2012), 3 (8), 611-618CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

     A review. In the past decade, nanotechnol. applications to the nervous system have often involved the study and the use of novel nanomaterials to improve the diagnosis and therapy of neurol. diseases. In the field of nanomedicine, carbon nanotubes are evaluated as promising materials for diverse therapeutic and diagnostic applications. Besides, carbon nanotubes are increasingly employed in basic neuroscience approaches, and they have been used in the design of neuronal interfaces or in that of scaffolds promoting neuronal growth in vitro. Ultimately, carbon nanotubes are thought to hold the potential for the development of innovative neurol. implants. In this framework, it is particularly relevant to document the impact of interfacing such materials with nerve cells. Carbon nanotubes were shown, when modified with biol. active compds. or functionalized in order to alter their charge, to affect neurite outgrowth and branching. Notably, purified carbon nanotubes used as scaffolds can promote the formation of nanotube-neuron hybrid networks, able per se to affect neuron integrative abilities, network connectivity, and synaptic plasticity. We focus this review on our work over several years directed to investigate the ability of carbon nanotube platforms in providing a new tool for nongenetic manipulations of neuronal performance and network signaling.
212. 212

     Galvan-Garcia, P.; Keefer, E. W.; Yang, F.; Zhang, M.; Fang, S.; Zakhidov, A. A.; Baughman, R. H.; Romero, M. I. Robust Cell Migration and Neuronal Growth on Pristine Carbon Nanotube Sheets and Yarns. J. Biomater. Sci. Polym. Ed. 2007, 18, 1245– 1261,  DOI: 10.1163/156856207782177891

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     212

     Robust cell migration and neuronal growth on pristine carbon nanotube sheets and yarns

     Galvan-Garcia, Pedro; Keefer, Edward W.; Yang, Fan; Zhang, Mei; Fang, Shaoli; Zakhidov, Anvar A.; Baughman, Ray H.; Romero, Mario I.

     Journal of Biomaterials Science, Polymer Edition (2007), 18 (10), 1245-1261CODEN: JBSEEA; ISSN:0920-5063. (VSP)

     Carbon nanotubes (CNTs) have unique chem. and phys. properties anticipated to enable broad novel biomedical applications. Yet the question concerning their biocompatibility remains controversial. The authors recently reported a method for rapidly prepg. strong, highly elec. conducting sheets and yarns from multiwalled CNTs. The present studies demonstrate that highly oriented 50-nm-thick semi-transparent CNT sheets and yarns, produced with a minimal residual content of catalytic transition materials, support the long-term growth of a variety of cell types ranging from skin fibroblasts and Schwann cells, to postnatal cortical and cerebellar neurons. The authors show that CNT sheets stimulate fibroblast cell migration compared to plastic and glass culture substrates; entice neuronal growth to the level of those achieved on polyornithine-coated glass and can be used for directed cellular growth. These findings have pos. implications for the use of CNTs in applications such as tissue engineering, wound healing, neural interfaces and biosensors.
213. 213

     Malarkey, E. B.; Fisher, K. A.; Bekyarova, E.; Liu, W.; Haddon, R. C.; Parpura, V. Conductive Single-Walled Carbon Nanotube Substrates Modulate Neuronal Growth. Nano Lett. 2009, 9, 264– 268,  DOI: 10.1021/nl802855c

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     213

     Conductive Single-Walled Carbon Nanotube Substrates Modulate Neuronal Growth

     Malarkey, Erik B.; Fisher, Kirk A.; Bekyarova, Elena; Liu, Wei; Haddon, Robert C.; Parpura, Vladimir

     Nano Letters (2009), 9 (1), 264-268CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     We used conductive nanotube films as substrates with which we could systematically vary the conductance to see how this property affects neuronal growth. Here, we show that nanotube substrates in a narrow range of cond. promote the outgrowth of neurites with a decrease in the no. of growth cones as well as an increase in cell body area, while at higher conductance, these effects disappear.
214. 214

     Pampaloni, N. P.; Scaini, D.; Perissinotto, F.; Bosi, S.; Prato, M.; Ballerini, L. Sculpting Neurotransmission during Synaptic Development by 2D Nanostructured Interfaces. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 2521– 2532,  DOI: 10.1016/j.nano.2017.01.020

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215. 215

     Mazzatenta, A.; Giugliano, M.; Campidelli, S.; Gambazzi, L.; Businaro, L.; Markram, H.; Prato, M.; Ballerini, L. Interfacing Neurons with Carbon Nanotubes: Electrical Signal Transfer and Synaptic Stimulation in Cultured Brain Circuits. J. Neurosci. 2007, 27, 6931– 6936,  DOI: 10.1523/JNEUROSCI.1051-07.2007

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     215

     Interfacing neurons with carbon nanotubes: electrical signal transfer and synaptic stimulation in cultured brain circuits

     Mazzatenta, Andrea; Giugliano, Michele; Campidelli, Stephane; Gambazzi, Luca; Businaro, Luca; Markram, Henry; Prato, Maurizio; Ballerini, Laura

     Journal of Neuroscience (2007), 27 (26), 6931-6936CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

     The unique properties of single-wall carbon nanotubes (SWNTs) and the application of nanotechnol. to the nervous system may have a tremendous impact in the future developments of microsystems for neural prosthetics as well as immediate benefits for basic research. Despite increasing interest in neuroscience nanotechnologies, little is known about the elec. interactions between nanomaterials and neurons. We developed an integrated SWNT-neuron system to test whether elec. stimulation delivered via SWNT can induce neuronal signaling. To that aim, hippocampal cells were grown on pure SWNT substrates and patch clamped. We compared neuronal responses to voltage steps delivered either via conductive SWNT substrates or via the patch pipet. Our exptl. results, supported by math. models to describe the elec. interactions occurring in SWNT-neuron hybrid systems, clearly indicate that SWNTs can directly stimulate brain circuit activity.
216. 216

     Fabbro, A.; Cellot, G.; Prato, M.; Ballerini, L. Interfacing Neurons with Carbon Nanotubes: (Re)engineering Neuronal Signaling. Prog. Brain Res. 2011, 194, 241– 252,  DOI: 10.1016/B978-0-444-53815-4.00003-0

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     216

     Interfacing neurons with carbon nanotubes: (re)engineering neuronal signaling

     Fabbro Alessandra; Cellot Giada; Prato Maurizio; Ballerini Laura

     Progress in brain research (2011), 194 (), 241-52 ISSN:.

     Carbon nanotubes (CNTs) are cylindrically shaped nanostructures made by sheets of graphene rolled up to form hollow tubes. Owing to their unique range of thermal, electronic, and structural properties, CNTs have been rapidly developing as a technology platform for biological and medical applications, including those designed to develop novel neuro-implantable devices. Depending on their structure, CNTs combine an incredible strength with an extreme flexibility. Further, these materials exhibit physical and chemical properties which allow them to efficiently conduit electrical current in electrochemical interfaces. CNTs can be organized in scaffolds made up of small fibers or tubes with diameters similar to those of neural processes such as axons and dendrites. Recently, CNT scaffolds have been found to promote growth, differentiation, and survival of neurons and to modify their electrophysiological properties. These features make CNTs an attractive material for the design of nano-bio hybrid systems able to govern cell-specific behaviors in cultured neuronal networks. The leading scope of this short review is to highlight how nanotube scaffolds can impact on neuronal signaling ability. In particular, we will focus on the direct and specific interactions between this synthetic nanomaterial and biological cell membranes, and on the ability of CNTs to improve interfaces developed to record or to stimulate neuronal activity. CNTs hold the potential for the development of innovative nanomaterial-based neurological implants. Therefore, it is particularly relevant to improve our knowledge on the impact on neuronal performance of interfacing nerve cells with CNTs.
217. 217

     Cellot, G.; Cilia, E.; Cipollone, S.; Rancic, V.; Sucapane, A.; Giordani, S.; Gambazzi, L.; Markram, H.; Grandolfo, M.; Scaini, D.; Gelain, F.; Casalis, L.; Prato, M.; Giugliano, M.; Ballerini, L. Carbon Nanotubes Might Improve Neuronal Performance by Favouring Electrical Shortcuts. Nat. Nanotechnol. 2009, 4, 126– 133,  DOI: 10.1038/nnano.2008.374

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     217

     Carbon nanotubes might improve neuronal performance by favouring electrical shortcuts

     Cellot, Giada; Cilia, Emanuele; Cipollone, Sara; Rancic, Vladimir; Sucapane, Antonella; Giordani, Silvia; Gambazzi, Luca; Markram, Henry; Grandolfo, Micaela; Scaini, Denis; Gelain, Fabrizio; Casalis, Loredana; Prato, Maurizio; Giugliano, Michele; Ballerini, Laura

     Nature Nanotechnology (2009), 4 (2), 126-133CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     Carbon nanotubes have been applied in several areas of nerve tissue engineering to probe and augment cell behavior, to label and track subcellular components, and to study the growth and organization of neural networks. Recent reports show that nanotubes can sustain and promote neuronal elec. activity in networks of cultured cells, but the ways in which they affect cellular function are still poorly understood. Here, the authors show, using single-cell electrophysiol. techniques, electron microscopy anal. and theor. modeling, that nanotubes improve the responsiveness of neurons by forming tight contacts with the cell membranes that might favor elec. shortcuts between the proximal and distal compartments of the neuron. The authors propose the 'electrotonic hypothesis' to explain the phys. interactions between the cell and nanotube, and the mechanisms of how carbon nanotubes might affect the collective elec. activity of cultured neuronal networks. These considerations offer a perspective that would allow the authors to predict or engineer interactions between neurons and carbon nanotubes.
218. 218

     Cellot, G.; Toma, F. M.; Kasap Varley, Z.; Laishram, J.; Villari, A.; Quintana, M.; Cipollone, S.; Prato, M.; Ballerini, L. Carbon Nanotube Scaffolds Tune Synaptic Strength in Cultured Neural Circuits: Novel Frontiers in Nanomaterial-Tissue Interactions. J. Neurosci. 2011, 31, 12945– 12953,  DOI: 10.1523/JNEUROSCI.1332-11.2011

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     218

     Carbon nanotube scaffolds tune synaptic strength in cultured neural circuits: novel frontiers in nanomaterial-tissue interactions

     Cellot, Giada; Toma, Francesca Maria; Varley, Zeynep Kasap; Laishram, Jummi; Villari, Ambra; Quintana, Mildred; Cipollone, Sara; Prato, Maurizio; Ballerini, Laura

     Journal of Neuroscience (2011), 31 (36), 12945-12953CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

     A long-term goal of tissue engineering is to exploit the ability of supporting materials to govern cell-specific behaviors. Instructive scaffolds code such information by modulating (via their phys. and chem. features) the interface between cells and materials at the nanoscale. In modern neuroscience, therapeutic regenerative strategies (i.e., brain repair after damage) aim to guide and enhance the intrinsic capacity of the brain to reorganize by promoting plasticity mechanisms in a controlled fashion. Direct and specific interactions between synthetic materials and biol. cell membranes may play a central role in this process. Here, the authors investigate the role of the material's properties alone, in carbon nanotube scaffolds, in constructing the functional building blocks of neural circuits: the synapses. Using electrophysiol. recordings and rat cultured neural networks, the authors describe the ability of a nanoscaled material to promote the formation of synaptic contacts and to modulate their plasticity.
219. 219

     Fabbro, A.; Sucapane, A.; Toma, F. M.; Calura, E.; Rizzetto, L.; Carrieri, C.; Roncaglia, P.; Martinelli, V.; Scaini, D.; Masten, L.; Turco, A.; Gustincich, S.; Prato, M.; Ballerini, L. Adhesion to Carbon Nanotube Conductive Scaffolds Forces Action-Potential Appearance in Immature Rat Spinal Neurons. PLoS One 2013, 8, e73621,  DOI: 10.1371/journal.pone.0073621

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     219

     Adhesion to carbon nanotube conductive scaffolds forces action potential appearance in immature rat spinal neurons

     Fabbro, Alessandra; Sucapane, Antonietta; Toma, Francesca Maria; Calura, Enrica; Rizzetto, Lisa; Carrieri, Claudia; Roncaglia, Paola; Martinelli, Valentina; Scaini, Denis; Masten, Lara; Turco, Antonio; Gustincich, Stefano; Prato, Maurizio; Ballerini, Laura

     PLoS One (2013), 8 (8), e73621CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

     In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiol. and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiol. studies assocd. to gene expression anal. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray expts. suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural regeneration strategies.
220. 220

     Bosi, S.; Ballerini, L.; Prato, M. Carbon Nanotubes in Tissue Engineering. In Making and Exploiting Fullerenes, Graphene, and Carbon Nanotubes; Marcaccio, M., Paolucci, F., Eds.; Springer: Berlin, Heidelberg (Germany), 2013; pp 181– 204.

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221. 221

     Usmani, S.; Aurand, E. R.; Medelin, M.; Fabbro, A.; Scaini, D.; Laishram, J.; Rosselli, F. B.; Ansuini, A.; Zoccolan, D.; Scarselli, M.; Crescenzi, M. D.; Bosi, S.; Prato, M.; Ballerini, L. 3D Meshes of Carbon Nanotubes Guide Functional Reconnection of Segregated Spinal Explants. Sci. Adv. 2016, 2, e1600087,  DOI: 10.1126/sciadv.1600087

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222. 222

     Lee, S. M.; Kim, J. H.; Park, C.; Hwang, J. Y.; Hong, J. S.; Lee, K. H.; Lee, S. H. Self-Adhesive and Capacitive Carbon Nanotube-Based Electrode to Record Electroencephalograph Signals From the Hairy Scalp. IEEE Trans. Biomed. Eng. 2016, 63, 138– 147,  DOI: 10.1109/TBME.2015.2478406

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223. 223

     Hoon Lee, J.; Min Lee, S.; Jin Byeon, H.; Sook Hong, J.; Suk Park, K.; Lee, S. H. CNT/PDMS- Based Canal-Typed Ear Electrodes for Inconspicuous EEG Recording. J. Neural Eng. 2014, 11, 046014,  DOI: 10.1088/1741-2560/11/4/046014

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224. 224

     Peng, H. L.; Liu, J.-Q.; Tian, H.-C.; Xu, B.; Dong, Y.-Z.; Yang, B.; Chen, X.; Yang, C.-S. Flexible Dry Electrode Based on Carbon Nanotube/Polymer Hybrid Micropillars for Biopotential Recording. Sens. Actuators, A 2015, 235, 48– 56,  DOI: 10.1016/j.sna.2015.09.024

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     224

     Flexible dry electrode based on carbon nanotube/polymer hybrid micropillars for biopotential recording

     Peng, Hui-Ling; Liu, Jing-Quan; Tian, Hong-Chang; Xu, Bin; Dong, Yun-Zhao; Yang, Bin; Chen, Xiang; Yang, Chun-Sheng

     Sensors and Actuators, A: Physical (2015), 235 (), 48-56CODEN: SAAPEB; ISSN:0924-4247. (Elsevier B.V.)

     A novel flexible dry electrode based on carbon nanotube (CNT) and polydimethylsiloxane (PDMS) is proposed for recording biopotentials. Because the homogeneous dispersion of CNTs in PDMS is challenge due to the high viscosity of PDMS and aggregation of CNTs, a novel process is developed through addn. of an org. solvent to disentangle CNTs and reduce the viscosity of PDMS. The elec. performance of the composite of CNTs and PDMS as the function of CNT concn. was characterized. The optimized 10 wt% MWCNTs is dispersed in PDMS as the material of flexible dry electrode. In order to apply for long-term, wearable biopotential recording devices, the flexible dry electrode with micropillar array is designed and fabricated by MEMS process. The testing result shows that the skin-electrode contact impedance of the flexible mciropillar electrode is lower an order magnitude than that of the flexible flat electrode without micropillar array structures. Moreover, the contact impedance of this fabricated electrode was stable during two-day continuous testing, which indicates the flexible dry electrode is suitable for long-term measurement. In order to investigate the effect of motion artifact on the ECG signal, ECG signals are recording under two statuses of resting and walking. The ECG signals measured by the fabricated micropillar electrode were good fidelity, and did not degrade because of the motion.
225. 225

     Kumar, S.; Kim, B.-S.; Song, H. An Integrated Approach of CNT Front-End Amplifier towards Spikes Monitoring for Neuro-Prosthetic Diagnosis. BioChip J. 2018, 12, 332– 339,  DOI: 10.1007/s13206-018-2405-y

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226. 226

     Zhang, J.; Liu, X.; Xu, W.; Luo, W.; Li, M.; Chu, F.; Xu, L.; Cao, A.; Guan, J.; Tang, S.; Duan, X. Stretchable Transparent Electrode Arrays for Simultaneous Electrical and Optical Interrogation of Neural Circuits in Vivo. Nano Lett. 2018, 18, 2903– 2911,  DOI: 10.1021/acs.nanolett.8b00087

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     226

     Stretchable Transparent Electrode Arrays for Simultaneous Electrical and Optical Interrogation of Neural Circuits in Vivo

     Zhang, Jing; Liu, Xiaojun; Xu, Wenjing; Luo, Wenhan; Li, Ming; Chu, Fangbing; Xu, Lu; Cao, Anyuan; Guan, Jisong; Tang, Shiming; Duan, Xiaojie

     Nano Letters (2018), 18 (5), 2903-2911CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Recent developments of transparent electrode arrays provide a unique capability for simultaneous optical and elec. interrogation of neural circuits in the brain. However, none of these electrode arrays possess the stretchability highly desired for interfacing with mech. active neural systems, such as the brain under injury, the spinal cord, and the peripheral nervous system (PNS). Here, we report a stretchable transparent electrode array from carbon nanotube (CNT) web-like thin films that retains excellent electrochem. performance and broad-band optical transparency under stretching and is highly durable under cyclic stretching deformation. We show that the CNT electrodes record well-defined neuronal response signals with negligible light-induced artifacts from cortical surfaces under optogenetic stimulation. Simultaneous two-photon calcium imaging through the transparent CNT electrodes from cortical surfaces of GCaMP-expressing mice with epilepsy shows individual activated neurons in brain regions from which the concurrent elec. recording is taken, thus providing complementary cellular information in addn. to the high-temporal-resoln. elec. recording. Notably, the studies on rats show that the CNT electrodes remain operational during and after brain contusion that involves the rapid deformation of both the electrode array and brain tissue. This enables real-time, continuous electrophysiol. monitoring of cortical activity under traumatic brain injury. These results highlight the potential application of the stretchable transparent CNT electrode arrays in combining elec. and optical modalities to study neural circuits, esp. under mech. active conditions, which could potentially provide important new insights into the local circuit dynamics of the spinal cord and PNS as well as the mechanism underlying traumatic injuries of the nervous system.
227. 227

     Abu-Saude, M. J.; Morshed, B. I. Patterned Vertical Carbon Nanotube Dry Electrodes for Impedimetric Sensing and Stimulation. IEEE Sensors J. 2015, 15, 5851– 5858,  DOI: 10.1109/JSEN.2015.2449301

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228. 228

     Shein, M.; Greenbaum, A.; Gabay, T.; Sorkin, R.; David-Pur, M.; Ben-Jacob, E.; Hanein, Y. Engineered Neuronal Circuits Shaped and Interfaced with Carbon Nanotube Microelectrode Arrays. Biomed. Microdevices 2009, 11, 495– 501,  DOI: 10.1007/s10544-008-9255-7

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     Engineered neuronal circuits shaped and interfaced with carbon nanotube microelectrode arrays

     Shein M; Greenbaum A; Gabay T; Sorkin R; David-Pur M; Ben-Jacob E; Hanein Y

     Biomedical microdevices (2009), 11 (2), 495-501 ISSN:.

     Standard micro-fabrication techniques which were originally developed to fabricate semi-conducting electronic devices were inadvertently found to be adequate for bio-chip fabrication suited for applications such as stimulation and recording from neurons in-vitro as well as in-vivo. However, cell adhesion to conventional micro-chips is poor and chemical treatments are needed to facilitate the interaction between the device surface and the cells. Here we present novel carbon nanotube-based electrode arrays composed of cell-alluring carbon nanotube (CNT) islands. These play a double role of anchoring neurons directly and only onto the electrode sites (with no need for chemical treatments) and facilitating high fidelity electrical interfacing-recording and stimulation. This method presents an important step towards building nano-based neurochips of precisely engineered networks. These neurochips can provide unique platform for studying the activity patterns of ordered networks as well as for testing the effects of network damage and methods of network repair.
229. 229

     Su, J. Y.; Zhang, X.; Li, M. N.; Gao, T.; Wang, R.; Chai, X. Y.; Zhang, D. G.; Zhang, X. H.; Sui, X. H. Insulation of Carbon Nanotube Yarn Electrodes for Intrafascicular Neural Stimulation and Recording. 2019 9th International IEEE/EMBS Conference on Neural Engineering (NER) 2019, 815– 818

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230. 230

     Pan, A. I.; Lin, M. H.; Chung, H. W.; Chen, H.; Yeh, S. R.; Chuang, Y. J.; Chang, Y. C.; Yew, T. R. Direct- Growth Carbon Nanotubes on 3D Structural Microelectrodes for Electrophysiological Recording. Analyst 2016, 141, 279– 284,  DOI: 10.1039/C5AN01750E

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231. 231

     Keefer, E. W.; Botterman, B. R.; Romero, M. I.; Rossi, A. F.; Gross, G. W. Carbon Nanotube Coating Improves Neuronal Recordings. Nat. Nanotechnol. 2008, 3, 434– 439,  DOI: 10.1038/nnano.2008.174

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     231

     Carbon nanotube coating improves neuronal recordings

     Keefer, Edward W.; Botterman, Barry R.; Romero, Mario I.; Rossi, Andrew F.; Gross, Guenter W.

     Nature Nanotechnology (2008), 3 (7), 434-439CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     Implanting elec. devices in the nervous system to treat neural diseases is becoming very common. The success of these brain-machine interfaces depends on the electrodes that come into contact with the neural tissue. Here the authors show that conventional tungsten and stainless steel wire electrodes can be coated with carbon nanotubes using electrochem. techniques under ambient conditions. The carbon nanotube coating enhanced both recording and elec. stimulation of neurons in culture, rats and monkeys by decreasing the electrode impedance and increasing charge transfer. Carbon nanotube-coated electrodes are expected to improve current electrophysiol. techniques and to facilitate the development of long-lasting brain-machine interface devices. Coating conventional tungsten and stainless steel electrodes with carbon nanotubes improves their performance in research involving the implantation of elec. devices into the nervous system. The results could have an impact on electrophysiol. and the development of brain-machine interfaces.
232. 232

     Ghane Motlagh, B.; Choueib, M.; Hajhosseini Mesgar, A.; Hasanuzzaman, M.; Sawan, M. Direct Growth of Carbon Nanotubes on New High-Density 3D Pyramid-Shaped Microelectrode Arrays for Brain-Machine Interfaces. Micromachines (Basel) 2016, 7, 163,  DOI: 10.3390/mi7090163

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233. 233

     Burblies, N.; Schulze, J.; Schwarz, H. C.; Kranz, K.; Motz, D.; Vogt, C.; Lenarz, T.; Warnecke, A.; Behrens, P. Coatings of Different Carbon Nanotubes on Platinum Electrodes for Neuronal Devices: Preparation, Cytocompatibility and Interaction with Spiral Ganglion Cells. PLoS One 2016, 11, e0158571,  DOI: 10.1371/journal.pone.0158571

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234. 234

     Tegtmeier, K.; Aliuos, P.; Stieghorst, J.; Schickedanz, M.; Golly, F.; Zernetsch, H.; Glasmacher, B.; Doll, T. Aligned Carbon Nanotube-Liquid Silicone Rubber Conductors and Electrode Surfaces for Stimulating Medical Implants. Phys. Status Solidi, A 2014, 211, 1439– 1447,  DOI: 10.1002/pssa.201330405

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     There is no corresponding record for this reference.
235. 235

     Lee, S.; Yen, S. C.; Sheshadri, S.; Delgado-Martinez, I.; Xue, N.; Xiang, Z.; Thakor, N. V.; Lee, C. Flexible Epineural Strip Electrode for Recording in Fine Nerves. IEEE Trans. Biomed. Eng. 2016, 63, 581– 587,  DOI: 10.1109/TBME.2015.2466442

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     Flexible Epineural Strip Electrode for Recording in Fine Nerves

     Lee Sanghoon; Yen Shih-Cheng; Sheshadri Swathi; Delgado-Martinez Ignacio; Xue Ning; Xiang Zhuolin; Thakor Nitish V; Lee Chengkuo

     IEEE transactions on bio-medical engineering (2016), 63 (3), 581-7 ISSN:.

     This paper demonstrates flexible epineural strip electrodes (FLESE) for recording from small nerves. Small strip-shaped FLESE enables us to easily and closely stick on various sized nerves for less damage in a nerve and optimal recording quality. In addition, in order to enhance the neural interface, the gold electrode contacts were coated with carbon nanotubes, which reduced the impedance of the electrodes. We used the FLESEs to record electrically elicited nerve signals (compound neural action potentials) from the sciatic nerve in rats. Bipolar and differential bipolar configurations for the recording were investigated to optimize the recording configuration of the FLESEs. The successful results from differential bipolar recordings showed that the total length of FLESEs could be further reduced, maintaining the maximum recording ability, which would be beneficial for recording in very fine nerves. Our results demonstrate that new concept of FLESEs could play an important role in electroceuticals in near future.
236. 236

     Lee, S.-J.; Zhu, W.; Nowicki, M.; Lee, G.; Heo, D. N.; Kim, J.; Zuo, Y. Y.; Zhang, L. G. 3D Printing Nano Conductive Multi-Walled Carbon Nanotube Scaffolds for Nerve Regeneration. J. Neural Eng. 2018, 15, 016018,  DOI: 10.1088/1741-2552/aa95a5

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     236

     3D printing nano conductive multi-walled carbon nanotube scaffolds for nerve regeneration

     Lee Se-Jun; Zhu Wei; Nowicki Margaret; Lee Grace; Heo Dong Nyoung; Kim Junghoon; Zuo Yi Y; Zhang Lijie Grace

     Journal of neural engineering (2018), 15 (1), 016018 ISSN:.

     OBJECTIVE: Nanomaterials, such as carbon nanotubes (CNTs), have been introduced to modify the surface properties of scaffolds, thus enhancing the interaction between the neural cells and biomaterials. In addition to superior electrical conductivity, CNTs can provide nanoscale structures similar to those present in the natural neural environment. The primary objective of this study is to investigate the proliferative capability and differential potential of neural stem cells (NSCs) seeded on a CNT incorporated scaffold. APPROACH: Amine functionalized multi-walled carbon nanotubes (MWCNTs) were incorporated with a PEGDA polymer to provide enhanced electrical properties as well as nanofeatures on the surface of the scaffold. A stereolithography 3D printer was employed to fabricate a well-dispersed MWCNT-hydrogel composite neural scaffold with a tunable porous structure. 3D printing allows easy fabrication of complex 3D scaffolds with extremely intricate microarchitectures and controlled porosity. MAIN RESULTS: Our results showed that MWCNT-incorporated scaffolds promoted neural stem cell proliferation and early neuronal differentiation when compared to those scaffolds without the MWCNTs. Furthermore, biphasic pulse stimulation with 500 μA current promoted neuronal maturity quantified through protein expression analysis by quantitative polymerase chain reaction. SIGNIFICANCE: Results of this study demonstrated that an electroconductive MWCNT scaffold, coupled with electrical stimulation, may have a synergistic effect on promoting neurite outgrowth for therapeutic application in nerve regeneration.
237. 237

     Arslantunali, D.; Budak, G.; Hasirci, V. Multiwalled CNT-pHEMA Composite Conduit for Peripheral Nerve Repair. J. Biomed. Mater. Res., Part A 2014, 102, 828– 841,  DOI: 10.1002/jbm.a.34727

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     237

     Multiwalled CNT-pHEMA composite conduit for peripheral nerve repair

     Arslantunali, D.; Budak, G.; Hasirci, V.

     Journal of Biomedical Materials Research, Part A (2014), 102A (3), 828-841CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)

     A nerve conduit is designed to improve peripheral nerve regeneration by providing guidance to the nerve cells. Cond. of such guides is reported to enhance this process. In the current study, a nerve guide was constructed from poly(2-hydroxyethyl methacrylate) (pHEMA), which was loaded with multiwalled carbon nanotubes (mwCNT) to introduce cond. PHEMA hydrogels were designed to have a porous structure to facilitate the transportation of the compds. needed for cell nutrition and growth and also for waste removal. We showed that when loaded with relatively high concns. of mwCNTs (6%, wt./wt. in hydrogels), the pHEMA guide was more conductive and more hydrophobic than pristine pHEMA hydrogel. The mech. properties of the composites were better when they carried mwCNT. Elastic modulus of 6% mwCNT loaded pHEMA was twofold higher (0.32 ± 0.06 MPa) and similar to that of the soft tissues. Elec. cond. was significantly improved (11.4-fold) from 7 × 10-3 Ω-1.cm-1 (pHEMA) to 8.0 × 10-2 Ω-1.cm-1 (6% mwCNT loaded pHEMA). On application of elec. potential, the SHSY5Y neuroblastoma cells seeded on mwCNTs carrying pHEMA maintained their viability, whereas those on pure pHEMA could not, indicating that mwCNT helped conduct electricity and make them more suitable as nerve conduits. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 828-841, 2014.
238. 238

     Lee, J. H.; Lee, J.-Y.; Yang, S. H.; Lee, E.-J.; Kim, H.-W. Carbon Nanotube-Collagen Three-Dimensional Culture of Mesenchymal Stem Cells Promotes Expression of Neural Phenotypes and Secretion of Neurotrophic Factors. Acta Biomater. 2014, 10, 4425– 4436,  DOI: 10.1016/j.actbio.2014.06.023

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     238

     Carbon nanotube-collagen three-dimensional culture of mesenchymal stem cells promotes expression of neural phenotypes and secretion of neurotrophic factors

     Lee, Jae Ho; Lee, Ja-Yeon; Yang, Sung Hee; Lee, Eun-Jung; Kim, Hae-Won

     Acta Biomaterialia (2014), 10 (10), 4425-4436CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

     Microenvironments provided by three-dimensional (3-D) hydrogels mimic native tissue conditions, supplying appropriate phys. cues for regulating stem cell behaviors. Here, we focused on carbon nanotubes (CNTs) dispersed within collagen hydrogels to provide 3-D microenvironmental conditions for mesenchymal stem cells (MSCs) in stimulating biol. functions for neural regeneration. Small concns. of CNTs (0.1-1 wt.%) did not induce toxicity to MSCs, and even improved the proliferative potential of the cells. MSCs cultured within the CNT-collagen hydrogel expressed considerable levels of neural markers, including GAP43 and βIII tubulin proteins by immunostaining as well as GAP43 and synapse I genes by reverse transcriptase polymerase chain reaction (RT-PCR). Of note was that neurotrophic factors, particularly nerve growth factor and brain derived neurotrophic factor, were significantly promoted by the incorporation of CNTs as confirmed by RT-PCR and Western blot anal. A model expt. involving neuritogenesis of PC12 cells influenced by those releasing neurotrophic factors from MSCs cultured within the CNT-collagen hydrogel demonstrated the significant enhancement in neurite outgrowth behaviors. Taken together, collagen hydrogel provides excellent 3-D conditions for MSC growth, and a small incorporation of CNTs within the hydrogel significantly stimulates MSC expression of neural markers and secretion of neurotrophic factors.
239. 239

     Liu, X.; Miller Ii, A. L.; Park, S.; Waletzki, B. E.; Terzic, A.; Yaszemski, M. J.; Lu, L. Covalent Crosslinking of Graphene Oxide and Carbon Nanotube into Hydrogels Enhances Nerve Cell Responses. J. Mater. Chem. B 2016, 4, 6930– 6941,  DOI: 10.1039/C6TB01722C

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     239

     Covalent crosslinking of graphene oxide and carbon nanotube into hydrogels enhances nerve cell responses

     Liu, Xifeng; Miller II, A. Lee; Park, Sungjo; Waletzki, Brian E.; Terzic, Andre; Yaszemski, Michael J.; Lu, Lichun

     Journal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (43), 6930-6941CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

     Healing of nerve injuries is a crit. medical issue. Biodegradable polymeric conduits are a promising therapeutic soln. to provide guidance for axon growth in a given space, thus helping nerve heal. Extensive studies in the past decade reported that conductive materials could effectively increase neurite and axon extension in vitro and nerve regeneration in vivo. In this study, graphene oxide and carbon nanotubes were covalently functionalized with double bonds to obtain crosslinkable graphene oxide acrylate (GOa) sheets and carbon nanotube poly(ethylene glycol) acrylate (CNTpega). An elec. conductive reduced GOa-CNTpega-oligo(polyethylene glycol fumarate) (OPF) hydrogel (rGOa-CNTpega-OPF) was successfully fabricated by chem. crosslinking GOa sheets and CNTpega with OPF chains followed by in situ chem. redn. in L-ascorbic acid soln. SEM and transmission electron microscopy (TEM) imaging showed homogenous distribution of GOa/CNTpega carbon content in the rGOa-CNTpega-OPF composite hydrogel, resulting in a significant increase of elec. cond. compared with neutral OPF without carbon content. Cell studies showed excellent biocompatibility and distinguished PC12 cell proliferation and spreading on the rGOa-CNTpega-OPF composite hydrogel. Fluorescent microscopy imaging demonstrated robustly stimulated neurite development in these cells on a conductive rGOa-CNTpega-OPF composite hydrogel compared with that on neutral OPF hydrogels. These results illustrated a promising potential for the rGOa-CNTpega-OPF composite hydrogel to serve as conduits for neural tissue engineering.
240. 240

     Mounesi Rad, S.; Khorasani, M. T.; Daliri Joupari, M. Preparation of HMWCNT/PLLA Nanocomposite Scaffolds for Application in Nerve Tissue Engineering and Evaluation of Their Physical, Mechanical and Cellular Activity Properties. Polym. Adv. Technol. 2016, 27, 325– 338,  DOI: 10.1002/pat.3644

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     There is no corresponding record for this reference.
241. 241

     Shah, K.; Vasileva, D.; Karadaghy, A.; Zustiak, S. P. Development and Characterization of Polyethylene Glycol-Carbon Nanotube Hydrogel Composite. J. Mater. Chem. B 2015, 3, 7950– 7962,  DOI: 10.1039/C5TB01047K

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     There is no corresponding record for this reference.
242. 242

     Wu, S.; Duan, B.; Lu, A.; Wang, Y.; Ye, Q.; Zhang, L. Biocompatible Chitin/Carbon Nanotubes Composite Hydrogels as Neuronal Growth Substrates. Carbohydr. Polym. 2017, 174, 830– 840,  DOI: 10.1016/j.carbpol.2017.06.101

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     242

     Biocompatible chitin/carbon nanotubes composite hydrogels as neuronal growth substrates

     Wu, Shuangquan; Duan, Bo; Lu, Ang; Wang, Yanfeng; Ye, Qifa; Zhang, Lina

     Carbohydrate Polymers (2017), 174 (), 830-840CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)

     In the past decades, extensive studies have demonstrated that carbon nanotubes (CNTs) could promote cell adhesion, proliferation and differentiation of neuronal cells. However, the potential cytotoxicity in biol. systems severely restricted the utilization of CNTs as substrates for neural growth. In this study, biocompatible chitin/carbon nanotubes (Ch/CNT) composite hydrogels were developed via blending modified CNTs with chitin soln. in 11 wt% NaOH/4 wt% urea aq. system, and subsequently regenerating in ethanol. As the CNTs were dispersed homogeneously in chitin matrix and combined with chitin nanofibers to form a compact and neat Ch/CNT nanofibrous network through intermol. interactions, such as electrostatic interactions, hydrogen bonding and amphiphilic interaction, etc. The tensile strength and elongation at break of the Ch/CNT composite hydrogels were obviously enhanced, and the swelling ratio decreased. In addn., the Ch/CNT hydrogels exhibited good hemocompatibility, biodegrdn. in vitro and biocompatibility without cytotoxicity and neurotoxicity nature to neuronal and Schwann cells (PC12 cells and RSC96 cells). Esp., the Ch/CNT3 composite hydrogels exhibited significant enhancement of the neuronal cell adhesion, proliferation and neurite outgrowth of neuronal cells with a great increase in both the percentage and the length of neurites. Therefore, we provide a simple and efficient approach to construct the novel Ch/CNT hydrogels as neuronal growth substrates for the potential application in nerve regeneration.
243. 243

     Chen, J.; Liu, B.; Gao, X.; Xu, D. A Review of the Interfacial Characteristics of Polymer Nanocomposites Containing Carbon Nanotubes. RSC Adv. 2018, 8, 28048– 28085,  DOI: 10.1039/C8RA04205E

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     243

     A review of the interfacial characteristics of polymer nanocomposites containing carbon nanotubes

     Chen, Junjie; Liu, Baofang; Gao, Xuhui; Xu, Deguang

     RSC Advances (2018), 8 (49), 28048-28085CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)

     This paper provides an overview of recent advances in research on the interfacial characteristics of carbon nanotube-polymer nanocomposites. The state of knowledge about the chem. functionalization of carbon nanotubes as well as the interaction at the interface between the carbon nanotube and the polymer matrix is presented. The primary focus of this paper is on identifying the fundamental relationship between nanocomposite properties and interfacial characteristics. The progress, remaining challenges, and future directions of research are discussed. The latest developments of both microscopy and scattering techniques are reviewed, and their resp. strengths and limitations are briefly discussed. The main methods available for the chem. functionalization of carbon nanotubes are summarized, and particular interest is given to evaluation of their advantages and disadvantages. The crit. issues related to the interaction at the interface are discussed, and the important techniques for improving the properties of carbon nanotube-polymer nanocomposites are introduced. Addnl., the mechanism responsible for the interfacial interaction at the mol. level is briefly described. Furthermore, the mech., elec., and thermal properties of the nanocomposites are discussed sep., and their influencing factors are briefly introduced. Finally, the current challenges and opportunities for efficiently translating the remarkable properties of carbon nanotubes to polymer matrixes are summarized in the hopes of facilitating the development of this emerging area. Potential topics of oncoming focus are highlighted, and several suggestions concerning future research needs are also presented.
244. 244

     He, J.; Wang, X.-M.; Spector, M.; Cui, F.-Z. Scaffolds for Central Nervous System Tissue Engineering. Front. Mater. Sci. 2012, 6, 1– 25,  DOI: 10.1007/s11706-012-0157-5

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245. 245

     Spivey, E. C.; Khaing, Z. Z.; Shear, J. B.; Schmidt, C. E. The Fundamental Role of Subcellular Topography in Peripheral Nerve Repair Therapies. Biomaterials 2012, 33, 4264– 4276,  DOI: 10.1016/j.biomaterials.2012.02.043

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     245

     The fundamental role of subcellular topography in peripheral nerve repair therapies

     Spivey, Eric C.; Khaing, Zin Z.; Shear, Jason B.; Schmidt, Christine E.

     Biomaterials (2012), 33 (17), 4264-4276CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     A review. Clin. evidence suggests that nano- and microtopog. incorporated into scaffolds does not merely improve peripheral nerve regeneration, but is in fact a prerequisite for meaningful restoration of nerve function. Although the biol. mechanisms involved are not fully understood, grafts incorporating phys. guides that mimic microscopic nerve tissue features (e.g., basal laminae) appear to provide a significant advantage over grafts that rely on purely chem. or macroscopic similarities to nerve tissue. Investigators consistently demonstrate the fundamental importance of nano- and micro-scale phys. features for appropriate cell response in a wide range of biol. scenarios. Addnl., recent in vivo research demonstrates that nerve regeneration scaffolds with cell-scale phys. features are more effective than those that rely only on chem. or macro-scale features. Phys. guidance at the cell-scale is esp. important for long (>20 mm) nerve defects, for which the only reliable treatment is the autologous nerve graft. The lack of other available options exposes a clear need for the application of nano- and microfabrication techniques that will allow the next generation of engineered nerve guides to more closely mimic native tissue at those scales. This review examines current research to det. what elements of cell-scale topog. in exptl. scaffolds are most effective at stimulating functional recovery, and then presents an overview of fabrication techniques that could potentially improve future treatment paradigms. Relative advantages and disadvantages of these techniques are discussed, with respect to both clin. adaptation and likely effectiveness. Our intent is to more clearly delineate the remaining obstacles in the development of a next generation nerve guide, particularly for long defects, and offer new perspectives on steering current technologies towards clin. viable solns.
246. 246

     Corey, J. M.; Lin, D. Y.; Mycek, K. B.; Chen, Q.; Samuel, S.; Feldman, E. L.; Martin, D. C. Aligned Electrospun Nanofibers Specify the Direction of Dorsal Root Ganglia Neurite Growth. J. Biomed. Mater. Res., Part A 2007, 83A, 636– 645,  DOI: 10.1002/jbm.a.31285

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     246

     Aligned electrospun nanofibers specify the direction of dorsal root ganglia neurite growth

     Corey, Joseph M.; Lin, David Y.; Mycek, Katherine B.; Chen, Qiaoran; Samuel, Stanley; Feldman, Eva L.; Martin, David C.

     Journal of Biomedical Materials Research, Part A (2007), 83A (3), 636-645CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)

     Nerve injury, a significant cause of disability, may be treated more effectively using nerve guidance channels contg. longitudinally aligned fibers. Aligned, electrospun nanofibers direct the neurite growth of immortalized neural stem cells, demonstrating potential for directing regenerating neurites. However, no study of neurite guidance on these fibers has yet been performed with primary neurons. Here, we examd. neurites from dorsal root ganglia explants on electrospun poly-L-lactate nanofibers of high, intermediate, and random alignment. On aligned fibers, neurites grew radially outward from the ganglia and turned to follow the fibers upon contact. Neurite guidance was robust, with neurites never leaving the fibers to grow on the surrounding cover slip. To compare the alignment of neurites to that of the nanofiber substrates, Fourier methods were used to quantify the alignment. Neurite alignment, however striking, was inferior to fiber alignment on all but the randomly aligned fibers. Neurites on highly aligned substrates were 20 and 16% longer than neurites on random and intermediate fibers, resp. Schwann cells on fibers assumed a very narrow morphol. compared to those on the surrounding coverslip. The robust neurite guidance demonstrated here is a significant step toward the use of aligned, electrospun nanofibers for nerve regeneration.
247. 247

     Park, S. Y.; Kang, B. S.; Hong, S. Improved Neural Differentiation of Human Mesenchymal Stem Cells Interfaced With Carbon Nanotube Scaffolds. Nanomedicine (Lond) 2013, 8, 715– 723,  DOI: 10.2217/nnm.12.143

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248. 248

     Hasanzadeh, E.; Ebrahimi-Barough, S.; Mirzaei, E.; Azami, M.; Tavangar, S. M.; Mahmoodi, N.; Basiri, A.; Ai, J. Preparation of Fibrin Gel Scaffolds Containing MWCNT/PU Nanofibers for Neural Tissue Engineering. J. Biomed. Mater. Res., Part A 2019, 107, 802– 814,  DOI: 10.1002/jbm.a.36596

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     248

     Preparation of fibrin gel scaffolds containing MWCNT/PU nanofibers for neural tissue engineering

     Hasanzadeh, Elham; Ebrahimi-Barough, Somayeh; Mirzaei, Esmaeil; Azami, Mahmoud; Tavangar, Seyed Mohammad; Mahmoodi, Narges; Basiri, Arefeh; Ai, Jafar

     Journal of Biomedical Materials Research, Part A (2019), 107 (4), 802-814CODEN: JBMRCH; ISSN:1549-3296. (John Wiley & Sons, Inc.)

     Compared to the peripheral nervous system, in the central nervous system (CNS) disorders, neurons are less able to regenerate and reconstruct the neural tissue. Tissue engineering is considered as a promising approach for neural regeneration and restoring neurol. function after CNS injuries. Nanofibrous hydrogels have been recently used as three-dimensional (3D) scaffolds for tissue engineering applications. In this kind of composites, hydrogels are incorporated with fibers to enhance their poor mech. properties. Furthermore, introducing meshes within hydrogels can result in composites assocd. with advantages of both components. In the present study, we have prepd. 3D nanofibrous hydrogel scaffolds based on fibrin/polyurethane/multiwall carbon nanotube (fibrin/PU/MWCNT), for application as composite scaffolds for neural tissue engineering. The fabricated fibrin/PU/MWCNT hydrogel scaffolds were characterized and their ability to support cell attachment and viability was assessed in comparison with fibrin hydrogel. SEM (SEM) anal. was performed to examine the microstructural features of scaffolds. The rate of biodegrdn. and rheol. properties of scaffolds were also investigated. After isolation of human endometrial stem cells (hEnSCs), they were cultured into the scaffolds, then their attachment and viability were assessed through SEM anal., MTT assay and DAPI staining. Based on the results, the viability and proliferation of hEnSCs in the fibrin/PU/MWCNT hydrogels were higher than those in fibrin hydrogels. Therefore, our novel fabricated fibrin/PU/MWCNT hydrogel is able to support cell proliferation and can be used as a scaffold to provide an appropriate microenvironment for enhancing cell viability. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.
249. 249

     Bosi, S.; Rauti, R.; Laishram, J.; Turco, A.; Lonardoni, D.; Nieus, T.; Prato, M.; Scaini, D.; Ballerini, L. From 2D to 3D: Novel Nanostructured Scaffolds to Investigate Signalling in Reconstructed Neuronal Networks. Sci. Rep. 2015, 5, 9562,  DOI: 10.1038/srep09562

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     From 2D to 3D: novel nanostructured scaffolds to investigate signalling in reconstructed neuronal networks

     Bosi, Susanna; Rauti, Rossana; Laishram, Jummi; Turco, Antonio; Lonardoni, Davide; Nieus, Thierry; Prato, Maurizio; Scaini, Denis; Ballerini, Laura

     Scientific Reports (2015), 5 (), 9562CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     To recreate in vitro 3D neuronal circuits will ultimately increase the relevance of results from cultured to whole-brain networks and will promote enabling technologies for neuro-engineering applications. Here we fabricate novel elastomeric scaffolds able to instruct 3D growth of living primary neurons. Such systems allow investigating the emerging activity, in terms of calcium signals, of small clusters of neurons as a function of the interplay between the 2D or 3D architectures and network dynamics. We report the ability of 3D geometry to improve functional organization and synchronization in small neuronal assemblies. We propose a math. modeling of network dynamics that supports such a result. Entrapping carbon nanotubes in the scaffolds remarkably boosted synaptic activity, thus allowing for the first time to exploit nanomaterial/cell interfacing in 3D growth support. Our 3D system represents a simple and reliable construct, able to improve the complexity of current tissue culture models.
250. 250

     Roberts, M. J.; Leach, M. K.; Bedewy, M.; Meshot, E. R.; Copic, D.; Corey, J. M.; Hart, A. J. Growth of Primary Motor Neurons on Horizontally Aligned Carbon Nanotube Thin Films and Striped Patterns. J. Neural Eng. 2014, 11, 036013,  DOI: 10.1088/1741-2560/11/3/036013

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251. 251

     Usmani, S.; Franceschi Biagioni, A.; Medelin, M.; Scaini, D.; Casani, R.; Aurand, E. R.; Padro, D.; Egimendia, A.; Ramos Cabrer, P.; Scarselli, M.; De Crescenzi, M.; Prato, M.; Ballerini, L. Functional Rewiring Across Spinal Injuries via Biomimetic Nanofiber Scaffolds. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 25212– 25218,  DOI: 10.1073/pnas.2005708117

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     251

     Functional rewiring across spinal injuries via biomimetic nanofiber scaffolds

     Usmani, Sadaf; Biagioni, Audrey Franceschi; Medelin, Manuela; Scaini, Denis; Casani, Raffaele; Aurand, Emily R.; Padro, Daniel; Egimendia, Ander; Cabrer, Pedro Ramos; Scarselli, Manuela; De Crescenzi, Maurizio; Prato, Maurizio; Ballerini, Laura

     Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (41), 25212-25218CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     The regrowth of severed axons is fundamental to reestablish motor control after spinal-cord injury (SCI). Ongoing efforts to promote axonal regeneration after SCI have involved multiple strategies that have been only partially successful. Our study introduces an artificial carbon-nanotube based scaffold that, once implanted in SCI rats, improves motor function recovery. Confocal microscopy anal. plus fiber tracking by magnetic resonance imaging and neurotracer labeling of long-distance corticospinal axons suggest that recovery might be partly attributable to successful crossing of the lesion site by regenerating fibers. Since manipulating SCI microenvironment properties, such as mech. and elec. ones, may promote biol. responses, we propose this artificial scaffold as a prototype to exploit the physics governing spinal regenerative plasticity.
252. 252

     Cellot, G.; Lagonegro, P.; Tarabella, G.; Scaini, D.; Fabbri, F.; Iannotta, S.; Prato, M.; Salviati, G.; Ballerini, L. PEDOT: PSS Interfaces Support the Development of Neuronal Synaptic Networks with Reduced Neuroglia Response in Vitro. Front. Neurosci. 2016, 9, 521,  DOI: 10.3389/fnins.2015.00521

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253. 253

     Castagnola, E.; Maggiolini, E.; Ceseracciu, L.; Ciarpella, F.; Zucchini, E.; De Faveri, S.; Fadiga, L.; Ricci, D. pHEMA Encapsulated PEDOT-PSS-CNT Microsphere Microelectrodes for Recording Single Unit Activity in the Brain. Front. Neurosci. 2016, 10, 151,  DOI: 10.3389/fnins.2016.00151

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     253

     pHEMA Encapsulated PEDOT-PSS-CNT Microsphere Microelectrodes for Recording Single Unit Activity in the Brain

     Castagnola Elisa; Maggiolini Emma; De Faveri Sara; Ricci Davide; Ceseracciu Luca; Ciarpella Francesca; Zucchini Elena; Fadiga Luciano

     Frontiers in neuroscience (2016), 10 (), 151 ISSN:1662-4548.

     The long-term reliability of neural interfaces and stability of high-quality recordings are still unsolved issues in neuroscience research. High surface area PEDOT-PSS-CNT composites are able to greatly improve the performance of recording and stimulation for traditional intracortical metal microelectrodes by decreasing their impedance and increasing their charge transfer capability. This enhancement significantly reduces the size of the implantable device though preserving excellent electrical performances. On the other hand, the presence of nanomaterials often rises concerns regarding possible health hazards, especially when considering a clinical application of the devices. For this reason, we decided to explore the problem from a new perspective by designing and testing an innovative device based on nanostructured microspheres grown on a thin tether, integrating PEDOT-PSS-CNT nanocomposites with a soft synthetic permanent biocompatible hydrogel. The pHEMA hydrogel preserves the electrochemical performance and high quality recording ability of PEDOT-PSS-CNT coated devices, reduces the mechanical mismatch between soft brain tissue and stiff devices and also avoids direct contact between the neural tissue and the nanocomposite, by acting as a biocompatible protective barrier against potential nanomaterial detachment. Moreover, the spherical shape of the electrode together with the surface area increase provided by the nanocomposite deposited on it, maximize the electrical contact and may improve recording stability over time. These results have a good potential to contribute to fulfill the grand challenge of obtaining stable neural interfaces for long-term applications.
254. 254

     Samba, R.; Fuchsberger, K.; Matiychyn, I.; Epple, S.; Kiesel, L.; Stett, A.; Schuhmann, W.; Stelzle, M. Application of PEDOT-CNT Microelectrodes for Neurotransmitter Sensing. Electroanalysis 2014, 26, 548– 555,  DOI: 10.1002/elan.201300547

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255. 255

     Gerwig, R.; Fuchsberger, K.; Schroeppel, B.; Link, G. S.; Heusel, G.; Kraushaar, U.; Schuhmann, W.; Stett, A.; Stelzle, M. PEDOT-CNT Composite Microelectrodes for Recording and Electrostimulation Applications: Fabrication, Morphology, and Electrical Properties. Front. Neuroeng. 2012, 5, 8,  DOI: 10.3389/fneng.2012.00008

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     255

     PEDOT-CNT composite microelectrodes for recording and electrostimulation applications: fabrication, morphology and electrical properties

     Gerwig, Ramona; Fuchsberger, Kai; Schroeppel, Birgit; Link, Gordon Steve; Heusel, Gerhard; Kraushaar, Udo; Schuhmann, Wolfgang; Stett, Alfred; Stelzle, Martin

     Frontiers in Neuroengineering (2012), 5 (May), 8CODEN: FNREIF; ISSN:1662-6443. (Frontiers Media S.A.)

     Composites of carbon nanotubes and poly(3,4-ethylenedioxythiophene, PEDOT) and layers of PEDOT are deposited onto microelectrodes by electropolymn. of ethylenedioxythiophene in the presence of a suspension of carbon nanotubes and polystyrene sulfonate. Anal. by FIB and SEM demonstrates that CNT-PEDOT composites exhibit a porous morphol. whereas PEDOT layers are more compact. Accordingly, capacitance and charge injection capacity of the composite material exceed those of pure PEDOT layers. In vitro cell culture expts. reveal excellent biocompatibility and adhesion of both PEDOT and PEDOT-CNT electrodes. Signals recorded from heart muscle cells demonstrate the high S/N ratio achievable with these electrodes. Long-term pulsing expts. confirm stability of charge injection capacity. In conclusion, a robust fabrication procedure for composite PEDOT-CNT electrodes is demonstrated and results show that these electrodes are well suited for stimulation and recording in cardiac and neurophysiol. research.
256. 256

     Alegret, N.; Dominguez-Alfaro, A.; Gonzalez-Dominguez, J. M.; Arnaiz, B.; Cossio, U.; Bosi, S.; Vazquez, E.; Ramos-Cabrer, P.; Mecerreyes, D.; Prato, M. Three-Dimensional Conductive Scaffolds as Neural Prostheses Based on Carbon Nanotubes and Polypyrrole. ACS Appl. Mater. Interfaces 2018, 10, 43904– 43914,  DOI: 10.1021/acsami.8b16462

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     256

     Three-Dimensional Conductive Scaffolds as Neural Prostheses Based on Carbon Nanotubes and Polypyrrole

     Alegret, Nuria; Dominguez-Alfaro, Antonio; Gonzalez-Dominguez, Jose M.; Arnaiz, Blanca; Cossio, Unai; Bosi, Susanna; Vazquez, Ester; Ramos-Cabrer, Pedro; Mecerreyes, David; Prato, Maurizio

     ACS Applied Materials & Interfaces (2018), 10 (50), 43904-43914CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Three-dimensional scaffolds for cellular organization need to enjoy a series of specific properties. On the one hand, the morphol., shape and porosity are crit. parameters and eventually related with the mech. properties. On the other hand, elec. cond. is an important asset when dealing with electroactive cells, so it is a desirable property even if the cond. values are not particularly high. Here, we construct three-dimensional (3D) porous and conductive composites, where C8-D1A astrocytic cells were incubated to study their biocompatibility. The manufd. scaffolds are composed exclusively of carbon nanotubes (CNTs), a most promising material to interface with neuronal tissue, and polypyrrole (PPy), a conjugated polymer demonstrated to reduce gliosis, improve adaptability, and increase charge-transfer efficiency in brain-machine interfaces. We developed a new and easy strategy, based on the vapor phase polymn. (VPP) technique, where the monomer vapor is polymd. inside a sucrose sacrificial template contg. CNT and an oxidizing agent. After removing the sucrose template, a 3D porous scaffold was obtained and its phys., chem., and elec. properties were evaluated. The obtained scaffold showed very low d., high and homogeneous porosity, elec. cond., and Young's Modulus similar to the in vivo tissue. Its high biocompatibility was demonstrated even after 6 days of incubation, thus paving the way for the development of new conductive 3D scaffolds potentially useful in the field of electroactive tissues.
257. 257

     Dominguez-Alfaro, A.; Alegret, N.; Arnaiz, B.; Gonzalez-Dominguez, J. M.; Martin-Pacheco, A.; Cossio, U.; Porcarelli, L.; Bosi, S.; Vazquez, E.; Mecerreyes, D.; Prato, M. Tailored Methodology Based on Vapor Phase Polymerization to Manufacture PEDOT/CNT Scaffolds for Tissue Engineering. ACS Biomater. Sci. Eng. 2020, 6, 1269– 1278,  DOI: 10.1021/acsbiomaterials.9b01316

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     257

     Tailored Methodology Based on Vapor Phase Polymerization to Manufacture PEDOT/CNT Scaffolds for Tissue Engineering

     Dominguez-Alfaro, Antonio; Alegret, Nuria; Arnaiz, Blanca; Gonzalez-Dominguez, Jose M.; Martin-Pacheco, Ana; Cossio, Unai; Porcarelli, Luca; Bosi, Susanna; Vazquez, Ester; Mecerreyes, David; Prato, Maurizio

     ACS Biomaterials Science & Engineering (2020), 6 (2), 1269-1278CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

     Three-dimensional (3D) scaffolds with tailored stiffness, porosity, and conductive properties are particularly important in tissue engineering for electroactive cell attachment, proliferation, and vascularization. Carbon nanotubes (CNTs) and poly(3,4-ethylenedioxythiophene) (PEDOT) have been extensively used sep. as neural interfaces showing excellent results. Herein, we combine both the materials and manuf. 3D structures composed exclusively of PEDOT and CNTs using a methodol. based on vapor phase polymn. of PEDOT onto a CNT/sucrose template. Such a strategy presents versatility to produce porous scaffolds, after leaching out the sucrose grains, with different ratios of polymer/CNTs, and controllable and tunable elec. and mech. properties. The resulting 3D structures show Young's modulus typical of soft materials (20-50 kPa), as well as high elec. cond., which may play an important role in electroactive cell growth. The conductive PEDOT/CNT porous scaffolds present high biocompatibility after 3 and 6 days of C8-D1A astrocyte incubation.
258. 258

     Dominguez-Alfaro, A.; Alegret, N.; Arnaiz, B.; Salsamendi, M.; Mecerreyes, D.; Prato, M. Toward Spontaneous Neuronal Differentiation of SH-SY5Y Cells Using Novel Three-Dimensional Electropolymerized Conductive Scaffolds. ACS Appl. Mater. Interfaces 2020, 12, 57330– 57342,  DOI: 10.1021/acsami.0c16645

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     258

     Toward Spontaneous Neuronal Differentiation of SH-SY5Y Cells Using Novel Three-Dimensional Electropolymerized Conductive Scaffolds

     Dominguez-Alfaro, Antonio; Alegret, Nuria; Arnaiz, Blanca; Salsamendi, Maitane; Mecerreyes, David; Prato, Maurizio

     ACS Applied Materials & Interfaces (2020), 12 (51), 57330-57342CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Neuroblastoma-derived SH-SY5Y cells have become an excellent model for nervous system regeneration to treat neurodegenerative disorders. Many approaches achieved a mature population of derived neurons in in vitro plates. However, the importance of the third dimension in tissue regeneration has become indispensable to achieve a potential implant to replace the damaged tissue. Therefore, we have prepd. porous 3D structures composed uniquely of carbon nanotubes (CNT) and poly(3,4-ethylenedioxythiophene) (PEDOT) that show great potential in the tridimensional differentiation of SH-SY5Y cells into mature neurons. The scaffolds were manufd. through electropolymn. by applying 1.2 V in a three-electrode cell using a template of sucrose/CNT as a working electrode. By this method, PEDOT/CNT 3D scaffolds were obtained with homogeneous porosities and high cond. In vitro analyses showed that an excellent biocompatibility of the scaffold and the presence of high amt. of β-tubulin class III and MAP-II target proteins that mainly expresses in neurons, suggesting the differentiation into neuronal cells already after a week of incubation.
259. 259

     Patel, P. R.; Popov, P.; Caldwell, C. M.; Welle, E. J.; Egert, D.; Pettibone, J. R.; Roossien, D. H.; Becker, J. B.; Berke, J. D.; Chestek, C. A. High Density Carbon Fiber Arrays for Chronic Electrophysiology, Fast Scan Cyclic Voltammetry, and Correlative Anatomy. J. Neural Eng. 2020, 17, 056029,  DOI: 10.1088/1741-2552/abb1f6

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260. 260

     Jiman, A. A.; Ratze, D. C.; Welle, E. J.; Patel, P. R.; Richie, J. M.; Bottorff, E. C.; Seymour, J. P.; Chestek, C. A.; Bruns, T. M. Multi-Channel Intraneural Vagus Nerve Recordings with a Novel High-Density Carbon Fiber Microelectrode Array. Sci. Rep. 2020, 10, 15501,  DOI: 10.1038/s41598-020-72512-7

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     260

     Multi-channel intraneural vagus nerve recordings with a novel high-density carbon fiber microelectrode array

     Jiman, Ahmad A.; Ratze, David C.; Welle, Elissa J.; Patel, Paras R.; Richie, Julianna M.; Bottorff, Elizabeth C.; Seymour, John P.; Chestek, Cynthia A.; Bruns, Tim M.

     Scientific Reports (2020), 10 (1), 15501CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)

     Autonomic nerves convey essential neural signals that regulate vital body functions. Recording clearly distinctive physiol. neural signals from autonomic nerves will help develop new treatments for restoring regulatory functions. However, this is very challenging due to the small nature of autonomic nerves and the low-amplitude signals from their small axons. We developed a multi-channel, high-d., intraneural carbon fiber microelectrode array (CFMA) with ultra-small electrodes (8-9μm in diam., 150-250μm in length) for recording physiol. action potentials from small autonomic nerves. In this study, we inserted CFMA with up to 16 recording carbon fibers in the cervical vagus nerve of 22 isoflurane-anesthetized rats. We recorded action potentials with peak-to-peak amplitudes of 15.1-91.7μV and signal-to-noise ratios of 2.0-8.3 on multiple carbon fibers per expt., detd. conduction velocities of some vagal signals in the afferent (0.7-4.4 m/s) and efferent (0.7-8.8 m/s) directions, and monitored firing rate changes in breathing and blood glucose modulated conditions. Overall, these expts. demonstrated that CFMA is a novel interface for in-vivo intraneural action potential recordings. This work is considerable progress towards the comprehensive understanding of physiol. neural signaling in vital regulatory functions controlled by autonomic nerves.
261. 261

     Patel, P. R.; Zhang, H.; Robbins, M. T.; Nofar, J. B.; Marshall, S. P.; Kobylarek, M. J.; Kozai, T. D.; Kotov, N. A.; Chestek, C. A. Chronic in Vivo Stability Assessment of Carbon Fiber Microelectrode Arrays. J. Neural Eng. 2016, 13, 066002,  DOI: 10.1088/1741-2560/13/6/066002

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     261

     Chronic in vivo stability assessment of carbon fiber microelectrode arrays

     Patel Paras R; Zhang Huanan; Robbins Matthew T; Nofar Justin B; Marshall Shaun P; Kobylarek Michael J; Kozai Takashi D Y; Kotov Nicholas A; Chestek Cynthia A

     Journal of neural engineering (2016), 13 (6), 066002 ISSN:.

     OBJECTIVE: Individual carbon fiber microelectrodes can record unit activity in both acute and semi-chronic (∼1 month) implants. Additionally, new methods have been developed to insert a 16 channel array of carbon fiber microelectrodes. Before assessing the in vivo long-term viability of these arrays, accelerated soak tests were carried out to determine the most stable site coating material. Next, a multi-animal, multi-month, chronic implantation study was carried out with carbon fiber microelectrode arrays and silicon electrodes. APPROACH: Carbon fibers were first functionalized with one of two different formulations of PEDOT and subjected to accelerated aging in a heated water bath. After determining the best PEDOT formula to use, carbon fiber arrays were chronically implanted in rat motor cortex. Some rodents were also implanted with a single silicon electrode, while others received both. At the end of the study a subset of animals were perfused and the brain tissue sliced. Tissue sections were stained for astrocytes, microglia, and neurons. The local reactive responses were assessed using qualitative and quantitative methods. MAIN RESULTS: Electrophysiology recordings showed the carbon fibers detecting unit activity for at least 3 months with average amplitudes of ∼200 μV. Histology analysis showed the carbon fiber arrays with a minimal to non-existent glial scarring response with no adverse effects on neuronal density. Silicon electrodes showed large glial scarring that impacted neuronal counts. SIGNIFICANCE: This study has validated the use of carbon fiber microelectrode arrays as a chronic neural recording technology. These electrodes have demonstrated the ability to detect single units with high amplitude over 3 months, and show the potential to record for even longer periods. In addition, the minimal reactive response should hold stable indefinitely, as any response by the immune system may reach a steady state after 12 weeks.
262. 262

     Patel, P. R.; Na, K.; Zhang, H.; Kozai, T. D.; Kotov, N. A.; Yoon, E.; Chestek, C. A. Insertion of Linear 8.4 μm Diameter 16 Channel Carbon Fiber Electrode Arrays for Single Unit Recordings. J. Neural Eng. 2015, 12, 046009,  DOI: 10.1088/1741-2560/12/4/046009

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     262

     Insertion of linear 8.4 μm diameter 16 channel carbon fiber electrode arrays for single unit recordings

     Patel Paras R; Na Kyounghwan; Zhang Huanan; Kozai Takashi D Y; Kotov Nicholas A; Yoon Euisik; Chestek Cynthia A

     Journal of neural engineering (2015), 12 (4), 046009 ISSN:.

     OBJECTIVE: Single carbon fiber electrodes (d = 8.4 μm) insulated with parylene-c and functionalized with PEDOT: pTS have been shown to record single unit activity but manual implantation of these devices with forceps can be difficult. Without an improvement in the insertion method any increase in the channel count by fabricating carbon fiber arrays would be impractical. In this study, we utilize a water soluble coating and structural backbones that allow us to create, implant, and record from fully functionalized arrays of carbon fibers with ∼150 μm pitch. APPROACH: Two approaches were tested for the insertion of carbon fiber arrays. The first method used a poly(ethylene glycol) (PEG) coating that temporarily stiffened the fibers while leaving a small portion at the tip exposed. The small exposed portion (500 μm-1 mm) readily penetrated the brain allowing for an insertion that did not require the handling of each fiber by forceps. The second method involved the fabrication of silicon support structures with individual shanks spaced 150 μm apart. Each shank consisted of a small groove that held an individual carbon fiber. MAIN RESULTS: Our results showed that the PEG coating allowed for the chronic implantation of carbon fiber arrays in five rats with unit activity detected at 31 days post-implant. The silicon support structures recorded single unit activity in three acute rat surgeries. In one of those surgeries a stacked device with three layers of silicon support structures and carbon fibers was built and shown to readily insert into the brain with unit activity on select sites. SIGNIFICANCE: From these studies we have found that carbon fibers spaced at ∼150 μm readily insert into the brain. This greatly increases the recording density of chronic neural probes and paves the way for even higher density devices that have a minimal scarring response.
263. 263

     Zhao, C.; Man, T.; Cao, Y.; Weiss, P. S.; Monbouquette, H. G.; Andrews, A. M. Flexible and Implantable Polyimide Aptamer-Field-Effect Transistor Biosensors. ACS Sens. 2022, 7, 3644– 3653,  DOI: 10.1021/acssensors.2c01909

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     263

     Flexible and Implantable Polyimide Aptamer-Field-Effect Transistor Biosensors

     Zhao, Chuanzhen; Man, Tianxing; Cao, Yan; Weiss, Paul S.; Monbouquette, Harold G.; Andrews, Anne M.

     ACS Sensors (2022), 7 (12), 3644-3653CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)

     Monitoring neurochem. signaling across time scales is crit. to understanding how brains encode and store information. Flexible (vs stiff) devices have been shown to improve in vivo monitoring, particularly over longer times, by reducing tissue damage and immunol. responses. Here, we report our initial steps toward developing flexible and implantable neuroprobes with aptamer-field-effect transistor (FET) biosensors for neurotransmitter monitoring. A high-throughput process was developed to fabricate thin, flexible polyimide probes using microelectromech.-system (MEMS) technologies, where 150 flexible probes were fabricated on each 4 in. Si wafer. Probes were 150μm wide and 7μm thick with two FETs per tip. The bending stiffness was 1.2 x 10-11 N.m2. Semiconductor thin films (3 nm In2O3) were functionalized with DNA aptamers for target recognition, which produces aptamer conformational rearrangements detected via changes in FET conductance. Flexible aptamer-FET neuroprobes detected serotonin at femtomolar concns. in high-ionic strength artificial cerebrospinal fluid. A straightforward implantation process was developed, where microfabricated Si carrier devices assisted with implantation such that flexible neuroprobes detected physiol. relevant serotonin in a tissue-hydrogel brain mimic.
264. 264

     Multichannel Systems. https://www.multichannelsystems.com/ (accessed December 26, 2023).

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     DiFrancesco, M. L.; Colombo, E.; Papaleo, E. D.; Maya-Vetencourt, J. F.; Manfredi, G.; Lanzani, G.; Benfenati, F. A Hybrid P3HT-Graphene Interface for Efficient Photostimulation of Neurons. Carbon 2020, 162, 308– 317,  DOI: 10.1016/j.carbon.2020.02.043

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266. 266

     Pampaloni, N. P.; Lottner, M.; Giugliano, M.; Matruglio, A.; D’Amico, F.; Prato, M.; Garrido, J. A.; Ballerini, L.; Scaini, D. Single-Layer Graphene Modulates Neuronal Communication and Augments Membrane Ion Currents. Nat. Nanotechnol. 2018, 13, 755– 764,  DOI: 10.1038/s41565-018-0163-6

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     Single-layer graphene modulates neuronal communication and augments membrane ion currents

     Pampaloni, Niccolo Paolo; Lottner, Martin; Giugliano, Michele; Matruglio, Alessia; D'Amico, Francesco; Prato, Maurizio; Garrido, Jose Antonio; Ballerini, Laura; Scaini, Denis

     Nature Nanotechnology (2018), 13 (8), 755-764CODEN: NNAABX; ISSN:1748-3387. (Nature Research)

     The use of graphene-based materials to engineer sophisticated biosensing interfaces that can adapt to the central nervous system requires a detailed understanding of how such materials behave in a biol. context. Graphene's peculiar properties can cause various cellular changes, but the underlying mechanisms remain unclear. Here, we show that single-layer graphene increases neuronal firing by altering membrane-assocd. functions in cultured cells. Graphene tunes the distribution of extracellular ions at the interface with neurons, a key regulator of neuronal excitability. The resulting biophys. changes in the membrane include stronger potassium ion currents, with a shift in the fraction of neuronal firing phenotypes from adapting to tonically firing. By using exptl. and theor. approaches, we hypothesize that the graphene-ion interactions that are maximized when single-layer graphene is deposited on elec. insulating substrates are crucial to these effects.
267. 267

     Rastogi, S. K.; Garg, R.; Scopelliti, M. G.; Pinto, B. I.; Hartung, J. E.; Kim, S.; Murphey, C. G.; Johnson, N.; San Roman, D.; Bezanilla, F. Remote Nongenetic Optical Modulation of Neuronal Activity Using Fuzzy Graphene. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 13339– 13349,  DOI: 10.1073/pnas.1919921117

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     267

     Remote nongenetic optical modulation of neuronal activity using fuzzy graphene

     Rastogi, Sahil K.; Garg, Raghav; Scopelliti, Matteo Giuseppe; Pinto, Bernardo I.; Hartung, Jane E.; Kim, Seokhyoung; Murphey, Corban G. E.; Johnson, Nicholas; Roman, Daniel San; Bezanilla, Francisco; Cahoon, James F.; Gold, Michael S.; Chamanzar, Maysam; Cohen-Karni, Tzahi

     Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (24), 13339-13349CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     The ability to modulate cellular electrophysiol. is fundamental to the investigation of development, function, and disease. Currently, there is a need for remote, nongenetic, light-induced control of cellular activity in two-dimensional (2D) and three-dimensional (3D) platforms. Here, we report a breakthrough hybrid nanomaterial for remote, nongenetic, photothermal stimulation of 2D and 3D neural cellular systems. We combine one-dimensional (1D) nanowires (NWs) and 2D graphene flakes grown out-of-plane for highly controlled photothermal stimulation at subcellular precision without the need for genetic modification, with laser energies lower than a hundred nanojoules, one to two orders of magnitude lower than Au-, C-, and Si-based nanomaterials. Photothermal stimulation using NW-templated 3D fuzzy graphene (NT-3DFG) is flexible due to its broadband absorption and does not generate cellular stress. Therefore, it serves as a powerful toolset for studies of cell signaling within and between tissues and can enable therapeutic interventions.
268. 268

     Matino, L.; Mariano, A.; Ausilio, C.; Garg, R.; Cohen-Karni, T.; Santoro, F. Modulation of Early Stage Neuronal Outgrowth through Out-of-Plane Graphene. Nano Lett. 2022, 22, 8633– 8640,  DOI: 10.1021/acs.nanolett.2c03171

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     Aurand, E. R.; Usmani, S.; Medelin, M.; Scaini, D.; Bosi, S.; Rosselli, F. B.; Donato, S.; Tromba, G.; Prato, M.; Ballerini, L. Nanostructures to Engineer 3D Neural-Interfaces: Directing Axonal Navigation toward Successful Bridging of Spinal Segments. Adv. Funct. Matl. 2018, 28, 1700550,  DOI: 10.1002/adfm.201700550

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     Kostarelos, K.; Vincent, M.; Hebert, C.; Garrido, J. A. Graphene in the Design and Engineering of Next-Generation Neural Interfaces. Adv. Matl. 2017, 29, 1700909,  DOI: 10.1002/adma.201700909

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     Kuzum, D.; Takano, H.; Shim, E.; Reed, J. C.; Juul, H.; Richardson, A. G.; De Vries, J.; Bink, H.; Dichter, M. A.; Lucas, T. H. Transparent and Flexible Low Noise Graphene Electrodes for Simultaneous Electrophysiology and Neuroimaging. Nat. Commun. 2014, 5, 5259,  DOI: 10.1038/ncomms6259

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     Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging

     Kuzum, Duygu; Takano, Hajime; Shim, Euijae; Reed, Jason C.; Juul, Halvor; Richardson, Andrew G.; de Vries, Julius; Bink, Hank; Dichter, Marc A.; Lucas, Timothy H.; Coulter, Douglas A.; Cubukcu, Ertugrul; Litt, Brian

     Nature Communications (2014), 5 (), 5259CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Calcium imaging is a versatile exptl. approach capable of resolving single neurons with single-cell spatial resoln. in the brain. Electrophysiol. recordings provide high temporal, but limited spatial resoln., because of the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technol. based on graphene, which enables simultaneous optical imaging and electrophysiol. recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artifacts in the elec. recordings. Graphene electrodes record high-frequency bursting activity and slow synaptic potentials that are hard to resolve by multicellular calcium imaging. This transparent electrode technol. may pave the way for high spatio-temporal resoln. electro-optic mapping of the dynamic neuronal activity.
272. 272

     Xu, B.; Pei, J.; Feng, L.; Zhang, X.-D. Graphene and Graphene-Related Materials as Brain Electrodes. J. Mater. Chem. B 2021, 9, 9485– 9496,  DOI: 10.1039/D1TB01795K

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     Graphene and graphene-related materials as brain electrodes

     Xu, Boyu; Pei, Jiahui; Feng, Liefeng; Zhang, Xiao-Dong

     Journal of Materials Chemistry B: Materials for Biology and Medicine (2021), 9 (46), 9485-9496CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

     A review. Neural electrodes are used for acquiring neuron signals in brain-machine interfaces, and they are crucial for next-generation neuron engineering and related medical applications. Thus, developing flexible, stable and high-resoln. neural electrodes will play an important role in stimulation, acquisition, recording and anal. of signals. Compared with traditional metallic electrodes, electrodes based on graphene and other two-dimensional materials have attracted wide attention in electrophysiol. recording and stimulation due to their excellent phys. properties such as unique flexibility, low resistance, and high optical transparency. In this review, we have reviewed the recent progress of electrodes based on graphene, graphene/polymer compds. and graphene-related materials for neuron signal recording, stimulation, and related optical signal coupling technol., which provides an outlook on the role of electrodes in the nanotechnol.-neuron interface as well as medical diagnosis.
273. 273

     Lu, Y.; Liu, X.; Kuzum, D. Graphene-Based Neurotechnologies for Advanced Neural Interfaces. Curr. Opin. Biomed. Eng. 2018, 6, 138– 147,  DOI: 10.1016/j.cobme.2018.06.001

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274. 274

     Masvidal-Codina, E.; Illa, X.; Dasilva, M.; Calia, A. B.; Dragojević, T.; Vidal-Rosas, E. E.; Prats-Alfonso, E.; Martínez-Aguilar, J.; De la Cruz, J. M.; Garcia-Cortadella, R. High- Resolution Mapping of Infraslow Cortical Brain Activity Enabled by Graphene Microtransistors. Nat. Mater. 2019, 18, 280– 288,  DOI: 10.1038/s41563-018-0249-4

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275. 275

     Calia, A. B.; Masvidal-Codina, E.; Smith, T. M.; Schäfer, N.; Rathore, D.; Rodríguez-Lucas, E.; Illa, X.; Cruz, J. M. D. l.; Corro, E. D.; Prats-Alfonso, E. Full-Bandwidth Electrophysiology of Seizures and Epileptiform Activity Enabled by Flexible Graphene Microtransistor Depth Neural Probes. Nat. Nanotechnol. 2022, 17, 301– 309,  DOI: 10.1038/s41565-021-01041-9

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276. 276

     Garcia-Cortadella, R.; Schafer, N.; Cisneros-Fernandez, J.; Ré, L.; Illa, X.; Schwesig, G.; Moya, A.; Santiago, S.; Guirado, G.; Villa, R. Switchless Multiplexing of Graphene Active Sensor Arrays for Brain Mapping. Nano Lett. 2020, 20, 3528– 3537,  DOI: 10.1021/acs.nanolett.0c00467

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     276

     Switchless Multiplexing of Graphene Active Sensor Arrays for Brain Mapping

     Garcia-Cortadella, Ramon; Schafer, Nathan; Cisneros-Fernandez, Jose; Re, Lucia; Illa, Xavi; Schwesig, Gerrit; Moya, Ana; Santiago, Sara; Guirado, Gonzalo; Villa, Rosa; Sirota, Anton; Serra-Graells, Francesc; Garrido, Jose A.; Guimera-Brunet, Anton

     Nano Letters (2020), 20 (5), 3528-3537CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Sensor arrays used to detect electrophysiol. signals from the brain are paramount in neuroscience. However, the no. of sensors that can be interfaced with macroscopic data acquisition systems currently limits their bandwidth. This bottleneck originates in the fact that, typically, sensors are addressed individually, requiring a connection for each of them. Herein, the authors present the concept of frequency-division multiplexing (FDM) of neural signals by graphene sensors. The authors demonstrate the high performance of graphene transistors as mixers to perform amplitude modulation (AM) of neural signals in situ, which is used to transmit multiple signals through a shared metal line. This technol. eliminates the need for switches, remarkably simplifying the tech. complexity of state-of-the-art multiplexed neural probes. Besides, the scalability of FDM graphene neural probes has been thoroughly evaluated and their sensitivity demonstrated in vivo. Using this technol., the authors envision a new generation of high-count conformal neural probes for high bandwidth brain machine interfaces.
277. 277

     Viana, D.; Walston, S. T.; Masvidal-Codina, E.; Illa, X.; Rodríguez-Meana, B.; Valle, J. d.; Hayward, A.; Dodd, A.; Loret, T.; Prats-Alfonso, E.; Oliva, N. d. l.; Palma, M.; Corro, E. d.; Bernicola, M. d. P.; Rodríguez-Lucas, E.; Gener, T.; Cruz, J. M. d. l.; Torres-Miranda, M.; Duvan, F. T.; Ria, N.; Sperling, J.; Martí-Sánchez, S.; Spadaro, M. C.; Hébert, C.; Savage, S.; Arbiol, J.; Guimerà-Brunet, A.; Puig, M. V.; Yvert, B.; Navarro, X.; Kostarelos, K.; Garrido, J. A. Nanoporous Graphene-Based Thin-Film Microelectrodes for in Vivo High-Resolution Neural Recording and Stimulation. Nat. Nanotechnol. 2024, 19, 514– 523,  DOI: 10.1038/s41565-023-01570-5

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278. 278

     Garcia-Cortadella, R.; Schwesig, G.; Jeschke, C.; Illa, X.; Gray, A. L.; Savage, S.; Stamatidou, E.; Schiessl, I.; Masvidal-Codina, E.; Kostarelos, K. Graphene Active Sensor Arrays for Long-Term and Wireless Mapping of Wide Frequency Band Epicortical Brain Activity. Nat. Commun. 2021, 12, 211,  DOI: 10.1038/s41467-020-20546-w

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     Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity

     Garcia-Cortadella, R.; Schwesig, G.; Jeschke, C.; Illa, X.; Gray, Anna L.; Savage, S.; Stamatidou, E.; Schiessl, I.; Masvidal-Codina, E.; Kostarelos, K.; Guimera-Brunet, A.; Sirota, A.; Garrido, J. A.

     Nature Communications (2021), 12 (1), 211CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)

     Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiol. signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technol. must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-com. headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technol. to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technol., which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.
279. 279

     Ouyang, J. Application of Intrinsically Conducting Polymers in Flexible Electronics. SmartMat 2021, 2, 263– 285,  DOI: 10.1002/smm2.1059

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     Application of intrinsically conducting polymers in flexible electronics

     Ouyang, Jianyong

     SmartMat (2021), 2 (3), 263-285CODEN: SMARFY; ISSN:2688-819X. (John Wiley & Sons, Inc.)

     A review. Intrinsically conducting polymers (ICPs), such as polyacetylene, polyaniline, polypyrrole, polythiophene, and poly(3,4-ethylenedioxythiophene) (PEDOT), can have important application in flexible electronics owing to their unique merits including high cond., high mech. flexibility, low cost, and good biocompatibility. The requirements for their application in flexible electronics include high cond. and appropriate mech. properties. The cond. of some ICPs can be enhanced through a postpolymn. treatment, the so-called "secondary doping". A conducting polymer film with high cond. can be used as flexible electrode and even as flexible transparent electrode of optoelectronic devices. The application of ICPs as stretchable electrode requires high mech. stretchability. The mech. stretchability of ICPs can be improved through blending with a soft polymer or plasticization. Because of their good biocompatibility, ICPs can be modified as dry electrode for biopotential monitoring and neural interface. In addn., ICPs can be used as the active material of strain sensors for healthcare monitoring, and they can be adopted to monitor food processing, such as the fermn., steaming, storage, and refreshing of starch-based food because of the resistance variation caused by the food vol. change. All these applications of ICPs are covered in this review article.
280. 280

     Maziz, A.; Özgür, E.; Bergaud, C.; Uzun, L. Progress in Conducting Polymers for Biointerfacing and Biorecognition Applications. Sens. Actuators Rep. 2021, 3, 100035,  DOI: 10.1016/j.snr.2021.100035

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     Parenti, F.; Tassinari, F.; Libertini, E.; Lanzi, M.; Mucci, A. π-Stacking Signature in NMR Solution Spectra of Thiophene-Based Conjugated Polymers. ACS Omega 2017, 2, 5775– 5784,  DOI: 10.1021/acsomega.7b00943

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     Π-Stacking Signature in NMR Solution Spectra of Thiophene-Based Conjugated Polymers

     Parenti, Francesca; Tassinari, Francesco; Libertini, Emanuela; Lanzi, Massimiliano; Mucci, Adele

     ACS Omega (2017), 2 (9), 5775-5784CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)

     Studies on conjugated polymers seldom report on their NMR characterization in soln. This paper shows how NMR expts., both 1H NMR and routine 2D NMR spectra, can help in gaining a further insight into the aggregation behavior of conjugated polymers and could be used to flank the more employed solid-state NMR and other spectroscopy and microscopy techniques in the understanding of the aggregation processes. NMR spectroscopy allows distinguishing, within the class of poorly-solvatochromic conjugated polymers, those highly prone to form π-stacked aggregates from the ones that have a low tendency towards π- stacking.
282. 282

     Bianchi, M.; De Salvo, A.; Asplund, M.; Carli, S.; Di Lauro, M.; Schulze-Bonhage, A.; Stieglitz, T.; Fadiga, L.; Biscarini, F. Poly(3, 4-ethylenedioxythiophene)-Based Neural Interfaces for Recording and Stimulation: Fundamental Aspects and in Vivo Applications. Adv. Sci. 2022, 9, 2104701,  DOI: 10.1002/advs.202104701

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283. 283

     Zhao, Z.; Spyropoulos, G. D.; Cea, C.; Gelinas, J. N.; Khodagholy, D. Ionic Communication for Implantable Bioelectronics. Sci. Adv. 2022, 8, eabm7851,  DOI: 10.1126/sciadv.abm7851

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     Sheng, H.; Wang, X.; Kong, N.; Xi, W.; Yang, H.; Wu, X.; Wu, K.; Li, C.; Hu, J.; Tang, J. Neural Interfaces by Hydrogels. Extreme Mech. Lett. 2019, 30, 100510,  DOI: 10.1016/j.eml.2019.100510

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     Wang, M.; Mi, G.; Shi, D.; Bassous, N.; Hickey, D.; Webster, T. J. Nanotechnology and nanomaterials for improving neural interfaces. Adv. Funct. Mater. 2018, 28, 1700905,  DOI: 10.1002/adfm.201700905

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     Carrow, J. K.; Gaharwar, A. K. Bioinspired Polymeric Nanocomposites for Regenerative Medicine. Macromol. Chem. Phys. 2015, 216, 248– 264,  DOI: 10.1002/macp.201400427

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     Bioinspired Polymeric Nanocomposites for Regenerative Medicine

     Carrow, James K.; Gaharwar, Akhilesh K.

     Macromolecular Chemistry and Physics (2015), 216 (3), 248-264CODEN: MCHPES; ISSN:1022-1352. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. The design and fabrication of bioinspired nanomaterials for tissue-engineering applications requires a fundamental understanding of the interactions between polymers, nanostructures, and cells. Most biomimetic polymeric nanocomposites consist of two or more types of polymers or of polymers combined with different nanomaterials to obtain composite structures with desired properties. In this Talents & Trends article, the focus is on bioinspired polymeric nanocomposites surrounding three major strategies. Firstly, biomimetic structures composed of a fibrous architecture are discussed. Secondly, the emerging trends in designing complex nanocomposites with multiple functionalities are assessed. Finally, some of the most crit. challenges that come with the design and fabrication are highlighted in bioprinting. Finally, the emerging trends in the field of bioinspired polymeric nanocomposites are highlighted.
287. 287

     Zheng, N.; Fitzpatrick, V.; Cheng, R.; Shi, L.; Kaplan, D. L.; Yang, C. Photoacoustic Carbon Nanotubes Embedded Silk Scaffolds for Neural Stimulation and Regeneration. ACS Nano 2022, 16, 2292– 2305,  DOI: 10.1021/acsnano.1c08491

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     287

     Photoacoustic Carbon Nanotubes Embedded Silk Scaffolds for Neural Stimulation and Regeneration

     Zheng, Nan; Fitzpatrick, Vincent; Cheng, Ran; Shi, Linli; Kaplan, David L.; Yang, Chen

     ACS Nano (2022), 16 (2), 2292-2305CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Neural interfaces using biocompatible scaffolds provide crucial properties, such as cell adhesion, structural support, and mass transport, for the functional repair of nerve injuries and neurodegenerative diseases. Neural stimulation has also been found to be effective in promoting neural regeneration. This work provides a generalized strategy to integrate photoacoustic (PA) neural stimulation into hydrogel scaffolds using a nanocomposite hydrogel approach. Specifically, polyethylene glycol (PEG)-functionalized carbon nanotubes (CNT), highly efficient photoacoustic agents, are embedded into silk fibroin to form biocompatible and soft photoacoustic materials. We show that these photoacoustic functional scaffolds enable nongenetic activation of neurons with a spatial precision defined by the area of light illumination, promoting neuron regeneration. These CNT/silk scaffolds offered reliable and repeatable photoacoustic neural stimulation, and 94% of photoacoustic-stimulated neurons exhibit a fluorescence change larger than 10% in calcium imaging in the light-illuminated area. The on-demand photoacoustic stimulation increased neurite outgrowth by 1.74-fold in a rat dorsal root ganglion model, when compared to the unstimulated group. We also confirmed that promoted neurite outgrowth by photoacoustic stimulation is assocd. with an increased concn. of neurotrophic factor (BDNF). As a multifunctional neural scaffold, CNT/silk scaffolds demonstrated nongenetic PA neural stimulation functions and promoted neurite outgrowth, providing an addnl. method for nonpharmacol. neural regeneration.
288. 288

     Kim, S.; Kwon, Y. W.; Seo, H.; Chung, W. G.; Kim, E.; Park, W.; Song, H.; Lee, D. H.; Lee, J.; Lee, S. Materials and Structural Designs for Neural Interfaces. ACS Appl. Electron. Mater. 2023, 5, 1926– 1946,  DOI: 10.1021/acsaelm.2c01608

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289. 289

     Ledesma, H. A.; Li, X.; Carvalho-de-Souza, J. L.; Wei, W.; Bezanilla, F.; Tian, B. An Atlas of Nano-Enabled Neural Interfaces. Nat. Nanotechnol. 2019, 14, 645– 657,  DOI: 10.1038/s41565-019-0487-x

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290. 290

     Nakielski, P.; Pawłowska, S.; Rinoldi, C.; Ziai, Y.; De Sio, L.; Urbanek, O.; Zembrzycki, K.; Pruchniewski, M.; Lanzi, M.; Salatelli, E. Multifunctional Platform Based on Electrospun Nanofibers and Plasmonic Hydrogel: A Smart Nanostructured Pillow for Near-Infrared Light-Driven Biomedical Applications. ACS Appl. Mater. Interfaces 2020, 12, 54328– 54342,  DOI: 10.1021/acsami.0c13266

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     290

     Multifunctional Platform Based on Electrospun Nanofibers and Plasmonic Hydrogel: A Smart Nanostructured Pillow for Near-Infrared Light-Driven Biomedical Applications

     Nakielski, Pawel; Pawlowska, Sylwia; Rinoldi, Chiara; Ziai, Yasamin; De Sio, Luciano; Urbanek, Olga; Zembrzycki, Krzysztof; Pruchniewski, Michal; Lanzi, Massimiliano; Salatelli, Elisabetta; Calogero, Antonella; Kowalewski, Tomasz A.; Yarin, Alexander L.; Pierini, Filippo

     ACS Applied Materials & Interfaces (2020), 12 (49), 54328-54342CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Multifunctional nanomaterials with the ability to respond to near-IR (NIR) light stimulation are vital for the development of highly efficient biomedical nanoplatforms with a polytherapeutic approach. Inspired by the mesoglea structure of jellyfish bells, a biomimetic multifunctional nanostructured pillow with fast photothermal responsiveness for NIR light-controlled on-demand drug delivery is developed. We fabricate a nanoplatform with several hierarchical levels designed to generate a series of controlled, rapid, and reversible cascade-like structural changes upon NIR light irradn. The mech. contraction of the nanostructured platform, resulting from the increase of temp. to 42°C due to plasmonic hydrogel-light interaction, causes a rapid expulsion of water from the inner structure, passing through an electrospun membrane anchored onto the hydrogel core. The mutual effects of the rise in temp. and water flow stimulate the release of mols. from the nanofibers. To expand the potential applications of the biomimetic platform, the photothermal responsiveness to reach the typical temp. level for performing photothermal therapy (PTT) is designed. The on-demand drug model penetration into pig tissue demonstrates the efficiency of the nanostructured platform in the rapid and controlled release of mols., while the high biocompatibility confirms the pillow potential for biomedical applications based on the NIR light-driven multitherapy strategy.
291. 291

     Rinoldi, C.; Ziai, Y.; Zargarian, S. S.; Nakielski, P.; Zembrzycki, K.; Haghighat Bayan, M. A.; Zakrzewska, A. B.; Fiorelli, R.; Lanzi, M.; Kostrzewska-Ksiezyk, A. In Vivo Chronic Brain Cortex Signal Recording Based on a Soft Conductive Hydrogel Biointerface. ACS Appl. Mater. Interfaces 2023, 15, 6283– 6296,  DOI: 10.1021/acsami.2c17025

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292. 292

     Kumar, R.; Aadil, K. R.; Ranjan, S.; Kumar, V. B. Advances in Nanotechnology and Nanomaterials Based Strategies for Neural Tissue Engineering. J. Drug Delivery Sci. Technol. 2020, 57, 101617,  DOI: 10.1016/j.jddst.2020.101617

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     Advances in nanotechnology and nanomaterials based strategies for neural tissue engineering

     Kumar, Raj; Aadil, Keshaw Ram; Ranjan, Shivendu; Kumar, Vijay Bhooshan

     Journal of Drug Delivery Science and Technology (2020), 57 (), 101617CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)

     A review. Recent development in science and technol. and invention of wonderful nanomaterials by nanotechnol. helps advances in healthcare and treatment. Nerve degeneration, scar tissue formation and loss of communication between neurons and cells are the major issues of nerve injury. Till date it is remain a major challenge the regeneration of nerve tissue at injury site. There are various kinds of nanomaterials-based engineering approaches have been developed and under investigation to prevent or treat nerve injuries. Different nanomaterials are classified into two categories such as inorg. and org. nanomaterials. Inorg. nanomaterials such as metal, alloys, silica, magnetic, upconversion nanoparticles and quantum dots; and org. nanomaterials such as polymeric nanoparticles, nanofibers, carbon-based nanomaterials namely carbon nanotubes and graphene, liposomes, micelles and dendrimers. These are promising nanomaterials with suitable physicochem. properties and hence employed for neural tissue engineering applications. The nanomaterials showed promising results and able to support cells adhesion, proliferation and promote neuronal cell differentiation and enhance regeneration of neuron. Here, in this review we have discussed brief overview of different nanomaterials, their properties, merits and demerit, promising results and progress towards neural tissue engineering applications.
293. 293

     Ziai, Y.; Zargarian, S. S.; Rinoldi, C.; Nakielski, P.; Sola, A.; Lanzi, M.; Truong, Y. B.; Pierini, F. Conducting Polymer-Based Nanostructured Materials for Brain-Machine Interfaces. WIREs Nanomed. Nanobiotechnol. 2023, 15, e1895,  DOI: 10.1002/wnan.1895

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294. 294

     Wang, Z.; Zhang, F.; Vijver, M. G.; Peijnenburg, W. J. Graphene Nanoplatelets and Reduced Graphene Oxide Elevate the Microalgal Cytotoxicity of Nano-Zirconium Oxide. Chemosphere 2021, 276, 130015,  DOI: 10.1016/j.chemosphere.2021.130015

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     294

     Graphene nanoplatelets and reduced graphene oxide elevate the microalgal cytotoxicity of nano-zirconium oxide

     Wang, Zhuang; Zhang, Fan; Vijver, Martina G.; Peijnenburg, Willie J. G. M.

     Chemosphere (2021), 276 (), 130015CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

     Novel products often have a multitude of nanomaterials embedded; likewise within many products graphite-based products are decorated with nano-zirconium oxide (nZrO2) because graphene is an ultrahigh conductive material whereas nZrO2 is for instance fire-retardant. As a consequence, the pristine/isolated nanoparticle has unique beneficial properties but it is no longer the only compd. that needs to be considered in risk assessment. Data on joint toxicol. implications are particularly important for the hazard assessment of multicomponent nanomaterials. Here, we investigated the mechanisms underlying the cytotoxicity induced by the co-occurrence of nZrO2 and two graphene nanomaterials including graphene nanoplatelets (GNPs) and reduced graphene oxide (RGO) to the freshwater algae Chlorella pyrenoidosa. Exposure to GNPs and/or RGO induced enhanced cytotoxicity of nZrO2 to the algae. Intracellular oxidative stress and cellular membrane functional changes in C. pyrenoidosa were the reason for the enhancement of toxicity induced by the binary mixts. of GNPs/RGO and nZrO2. Furthermore, mitochondria-generated ROS played a major role in regulating the treatment-induced cellular response in the algae. Observations of cellular superficial- and ultra-structures indicated that the binary mixts. provoked oxidative damage to the algal cells. RGO increased the cytotoxicity and the extent of cellular oxidative stress to a higher extent than GNPs. These findings provide new insights that are of use in the risk assessment of mixts. of graphene-based carbon nanomaterials and other ENPs, and fit the new ideas on product testing that respects the combination effects.
295. 295

     Saleemi, M. A.; Hosseini Fouladi, M.; Yong, P. V. C.; Chinna, K.; Palanisamy, N. K.; Wong, E. H. Toxicity of Carbon Nanotubes: Molecular Mechanisms, Signaling Cascades, and Remedies in Biomedical Applications. Chem. Res. Toxicol. 2021, 34, 24– 46,  DOI: 10.1021/acs.chemrestox.0c00172

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     295

     Toxicity of Carbon Nanotubes: Molecular Mechanisms, Signaling Cascades, and Remedies in Biomedical Applications

     Saleemi, Mansab Ali; Hosseini Fouladi, Mohammad; Yong, Phelim Voon Chen; Chinna, Karuthan; Palanisamy, Navindra Kumari; Wong, Eng Hwa

     Chemical Research in Toxicology (2021), 34 (1), 24-46CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)

     A review. Carbon nanotubes (CNTs) are the most studied allotropic form of carbon. They can be used in various biomedical applications due to their novel physicochem. properties. In particular, the small size of CNTs, with a large surface area per unit vol., has a considerable impact on their toxicity. Despite of the use of CNTs in various applications, toxicity is a big problem that requires more research. In this Review, we discuss the toxicity of CNTs and the assocd. mechanisms. Physicochem. factors, such as metal impurities, length, size, solubilizing agents, CNTs functionalization, and agglomeration, that may lead to oxidative stress, toxic signaling pathways, and potential ways to control these mechanisms are also discussed. Moreover, with the latest mechanistic evidence described in this review, we expect to give new insights into CNTs' toxicol. effects at the mol. level and provide new clues for the mitigation of harmful effects emerging from exposure to CNTs.
296. 296

     Sung, C.; Jeon, W.; Nam, K. S.; Kim, Y.; Butt, H.; Park, S. Multimaterial and Multifunctional Neural Interfaces: From Surface-Type and Implantable Electrodes to Fiber-Based Devices. J. Mater. Chem. B 2020, 8, 6624– 6666,  DOI: 10.1039/D0TB00872A

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     296

     Multimaterial and multifunctional neural interfaces: from surface-type and implantable electrodes to fiber-based devices

     Sung, Changhoon; Jeon, Woojin; Nam, Kum Seok; Kim, Yeji; Butt, Haider; Park, Seongjun

     Journal of Materials Chemistry B: Materials for Biology and Medicine (2020), 8 (31), 6624-6666CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

     A review. Neural interfaces have enabled significant advancements in neuroscience and paved the way for clin. applications in the diagnosis, treatment, and prevention of neurol. disorders. A variety of device modalities, such as elec., chem. and optical neural interfacing, are required for the comprehensive monitoring and modulation of neural activity. The development of recent devices with multimodal functionalities has been driven by innovations in materials engineering, esp. the utilization of org. soft materials such as polymers, carbon allotropes, and hydrogels. A transition from rigid to soft materials has improved device performance through enhanced biocompatibility and flexibility to realize stable long-term performance. This article provides a comprehensive review of a variety of neural probes ranging from surface-type and implantable electrodes to fiber-based devices. We also highlight the influence of materials on the development of these neural interfaces and their effects on device performance and lifetime.
297. 297

     Li, S.; Ma, L.; Zhou, M.; Li, Y.; Xia, Y.; Fan, X.; Cheng, C.; Luo, H. New Opportunities for Emerging 2D Materials in Bioelectronics and Biosensors. Curr. Opin. Biomed. Eng. 2020, 13, 32– 41,  DOI: 10.1016/j.cobme.2019.08.016

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298. 298

     Chen, F.; Tang, Q.; Ma, T.; Zhu, B.; Wang, L.; He, C.; Luo, X.; Cao, S.; Ma, L.; Cheng, C. Structures, Properties, and Challenges of Emerging 2D Materials in Bioelectronics and Biosensors. InfoMat 2022, 4, e12299,  DOI: 10.1002/inf2.12299

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     Structures, properties, and challenges of emerging 2D materials in bioelectronics and biosensors

     Chen, Fan; Tang, Qing; Ma, Tian; Zhu, Bihui; Wang, Liyun; He, Chao; Luo, Xianglin; Cao, Sujiao; Ma, Lang; Cheng, Chong

     InfoMat (2022), 4 (5), e12299CODEN: INFOHH; ISSN:2567-3165. (John Wiley & Sons Australia, Ltd.)

     Bioelectronics are powerful tools for monitoring and stimulating biol. and biochem. processes, with applications ranging from neural interface simulation to biosensing. The increasing demand for bioelectronics has greatly promoted the development of new nanomaterials as detection platforms. Recently, owing to their ultrathin structures and excellent physicochem. properties, emerging two-dimensional (2D) materials have become one of the most researched areas in the fields of bioelectronics and biosensors. In this timely review, the physicochem. structures of the most representative emerging 2D materials and the design of their nanostructures for engineering high-performance bioelectronic and biosensing devices are presented. We focus on the structural optimization of emerging 2D material-based composites to achieve better regulation for enhancing the performance of bioelectronics. Subsequently, the recent developments of emerging 2D materials in bioelectronics, such as neural interface simulation, biomol./biomarker detection, and skin sensors are discussed thoroughly. Finally, we provide conclusive views on the current challenges and future perspectives on utilizing emerging 2D materials and their composites for bioelectronics and biosensors. This review will offer important guidance in designing and applying emerging 2D materials in bioelectronics, thus further promoting their prospects in a wide biomedical field.
299. 299

     Mariano, A.; Bovio, C. L.; Criscuolo, V.; Santoro, F. Bioinspired Micro- and Nano-Structured Neural Interfaces. Nanotechnology 2022, 33, 492501,  DOI: 10.1088/1361-6528/ac8881

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300. 300

     Zhang, Y.; Chen, L.; Xie, M.; Zhan, Z.; Yang, D.; Cheng, P.; Duan, H.; Ge, Q.; Wang, Z. Ultra-Fast Programmable Human-Machine Interface Enabled by 3D Printed Degradable Conductive Hydrogel. Mater. Today Phys. 2022, 27, 100794,  DOI: 10.1016/j.mtphys.2022.100794

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301. 301

     Tao, Y.; Wei, C.; Liu, J.; Deng, C.; Cai, S.; Xiong, W. Nanostructured Electrically Conductive Hydrogels Obtained via Ultrafast Laser Processing and Self-Assembly. Nanoscale 2019, 11, 9176– 9184,  DOI: 10.1039/C9NR01230C

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302. 302

     Bettucci, O.; Matrone, G. M.; Santoro, F. Conductive Polymer-Based Bioelectronic Platforms Toward Sustainable and Biointegrated Devices: A Journey from Skin to Brain across Human Body Interfaces. Adv. Mater. Technol. 2022, 7, 2100293,  DOI: 10.1002/admt.202100293

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     302

     Conductive Polymer-Based Bioelectronic Platforms toward Sustainable and Biointegrated Devices: A Journey from Skin to Brain across Human Body Interfaces

     Bettucci, Ottavia; Matrone, Giovanni Maria; Santoro, Francesca

     Advanced Materials Technologies (Weinheim, Germany) (2022), 7 (2), 2100293CODEN: AMTDCM; ISSN:2365-709X. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Over the last few years, org. bioelectronics has experienced an exponential growth with applications encompassing platforms for tissue engineering, drug delivery systems, implantable, and wearable sensors. Although reducing the phys. and mech. mismatch with the human tissues allows to increase the coupling efficiency, several challenges are still open in terms of matching biol. curvature, size, and interface stiffness. In this context, the replacement of bulky with more flexible and conformable devices is required, implying the transition from inorg. conventional electronics to org. electronics. Indeed, the advent of org. materials in bioelectronics, due to the indisputable benefits related to biocompatibility, flexibility, and elec. properties, has granted superior coupling properties with human tissues increasing the performances of both sensing and stimulation platforms. In this review the ease of functionalization and patterning of conductive polymers (CPs) will be analyzed as a strategy that enables the fabrication of platforms with high structural flexibility ranging from the macro to the micro/nano-scales, leading to the increase of devices sensitivity. Drawing from the concept of biomimicry, the human body tissues interfaces will be explored through an ideal journey starting from org. platforms for epidermal sensing and stimulation. Then, devices capable of establishing a dynamic coupling with the heart will be reviewed and finally, following the circulatory system and crossing the blood-brain barrier, the brain will be reached and novel sensing and computing implants advances that pave the way to the possibility to emulate as well as to interact with the neural functions will be analyzed.
303. 303

     Qian, S.; Lin, H.-A.; Pan, Q.; Zhang, S.; Zhang, Y.; Geng, Z.; Wu, Q.; He, Y.; Zhu, B. Chemically Revised Conducting Polymers with Inflammation Resistance for Intimate Bioelectronic Electrocoupling. Bioact. Mater. 2023, 26, 24– 51,  DOI: 10.1016/j.bioactmat.2023.02.010

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     Chemically revised conducting polymers with inflammation resistance for intimate bioelectronic electrocoupling

     Qian, Sihao; Lin, Hsing-An; Pan, Qichao; Zhang, Shuhua; Zhang, Yunhua; Geng, Zhi; Wu, Qing; He, Yong; Zhu, Bo

     Bioactive Materials (2023), 26 (), 24-51CODEN: BMIAD4; ISSN:2452-199X. (KeAi Communications Co., Ltd.)

     A review. Conducting polymers offer attractive mixed ionic-electronic cond., tunable interfacial barrier with metal, tissue matchable softness, and versatile chem. functionalization, making them robust to bridge the gap between brain tissue and electronic circuits. This review focuses on chem. revised conducting polymers, combined with their superior and controllable electrochem. performance, to fabricate long-term bioelectronic implants, addressing chronic immune responses, weak neuron attraction, and long-term electrocommunication instability challenges. Moreover, the promising progress of zwitterionic conducting polymers in bioelectronic implants (≥4 wk stable implantation) is highlighted, followed by a comment on their current evolution toward selective neural coupling and reimplantable function. Finally, a crit. forward look at the future of zwitterionic conducting polymers for in vivo bioelectronic devices is provided.
304. 304

     Shur, M.; Fallegger, F.; Pirondini, E.; Roux, A.; Bichat, A.; Barraud, Q.; Courtine, G.; Lacour, S. P. Soft Printable Electrode Coating for Neural Interfaces. ACS Appl. Bio Mater. 2020, 3, 4388– 4397,  DOI: 10.1021/acsabm.0c00401

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     Soft Printable Electrode Coating for Neural Interfaces

     Shur, Michael; Fallegger, Florian; Pirondini, Elvira; Roux, Adrien; Bichat, Arnaud; Barraud, Quentin; Courtine, Gregoire; Lacour, Stephanie P.

     ACS Applied Bio Materials (2020), 3 (7), 4388-4397CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)

     The mech. mismatch between implantable interfaces and neural tissues may be reduced by employing soft polymeric materials. Here, we report on a simple strategy to prep. and pattern a soft electrode coating of neural interfacing devices based on a screen-printable conducting hydrogel. The coating formulation, based on polyacrylamide and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, is suitable to additive manufg. and exhibits excellent adhesion to polydimethylsiloxane, an elastomer commonly used as a substrate in soft neural interfaces. The soft conductive coating displays a tunable elastic modulus in the 10-100 kPa range and electrochem. properties on a par with stiff conductive inks while supporting good neural cell attachment and proliferation in vitro. Next, the soft printable hydrogel is integrated within a 4 x 4 microelectrode array for electrocorticog. with 250μm-diam. contacts. Acute recording of cortical local field potentials and electrochem. characterization preimplantation and postimplantation highlight the stability of the soft org. conductor. The overall robustness of the soft coating and its patterning method provide a promising route for a range of implantable bioelectronic applications.
305. 305

     Azemi, E.; Lagenaur, C. F.; Cui, X. T. The Surface Immobilization of the Neural Adhesion Molecule L1 on Neural Probes and Its Effect on Neuronal Density and Gliosis at the Probe/Tissue Interface. Biomaterials 2011, 32, 681– 692,  DOI: 10.1016/j.biomaterials.2010.09.033

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     The surface immobilization of the neural adhesion molecule L1 on neural probes and its effect on neuronal density and gliosis at the probe/tissue interface

     Azemi Erdrin; Lagenaur Carl F; Cui Xinyan T

     Biomaterials (2011), 32 (3), 681-92 ISSN:.

     Brain tissue inflammatory responses, including neuronal loss and gliosis at the neural electrode/tissue interface, limit the recording stability and longevity of neural probes. The neural adhesion molecule L1 specifically promotes neurite outgrowth and neuronal survival. In this study, we covalently immobilized L1 on the surface of silicon-based neural probes and compared the tissue response between L1 modified and non-modified probes implanted in the rat cortex after 1, 4, and 8 weeks. The effect of L1 on neuronal health and survival, and glial cell reactions were evaluated with immunohistochemistry and quantitative image analysis. Similar to previous findings, persistent glial activation and significant decreases of neuronal and axonal densities were found at the vicinity of the non-modified probes. In contrast, the immediate area (100 μm) around the L1 modified probe showed no loss of neuronal bodies and a significantly increased axonal density relative to background. In this same region, immunohistochemistry analyses show a significantly lower activation of microglia and reaction of astrocytes around the L1 modified probes when compared to the control probes. These improvements in tissue reaction induced by the L1 coating are likely to lead to improved functionality of the implanted neural electrodes during chronic recordings.
306. 306

     Martinez, M. V.; Abel, S. B.; Rivero, R.; Miras, M. C.; Rivarola, C. R.; Barbero, C. A. Polymeric Nanocomposites Made of a Conductive Polymer and a Thermosensitive Hydrogel: Strong Effect of the Preparation Procedure on the Properties. Polymer 2015, 78, 94– 103,  DOI: 10.1016/j.polymer.2015.09.054

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     Polymeric nanocomposites made of a conductive polymer and a thermosensitive hydrogel: Strong effect of the preparation procedure on the properties

     Martinez, M. V.; Bongiovanni Abel, S.; Rivero, R.; Miras, M. C.; Rivarola, C. R.; Barbero, C. A.

     Polymer (2015), 78 (), 94-103CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)

     Nanocomposites are made by loading a conductive polymer (polyaniline, PANI) inside a thermosensitive hydrogel matrix (poly(N-isopropylacrylamide)-co-(2-acrylamido-2-methylpropane sulfonic acid), HG). The composites were obtained by two loading methods: (1) in-situ polymn. of aniline inside the hydrogel matrix (ISP) and (2) by swelling of hydrogel in a true soln. (SIS) of PANI (base) in N-methylpyrrolidone. Even though the composites have similar chem. compn., scanning electronic microscopy (SEM) shows different morphologies for each material obtained. ISP produces a material with segregated nanodomains of PANI inside HG, building a true nanocomposite (NC). On the other hand, SIS seems to create a semi-interpenetrated (semi-IPN) network of PANI inside the HG. The swelling capacity and vol. phase transition temp. (VPTT) of composites are also affected by the loading methods. The segregated nanodomains of PANI in the NC do not affect the thermosensitivity of HG, while the PANI chains are directly interacting with the HG chains in the semi-IPN, affecting the VPTT. The swelling capacity of NC is of %Sweq = 6500 while the semi-IPN is of %Sweq = 8600. Both of them are lower than the one of pure HG (%Sweq = 11,000). The elastic module of both materials is higher than HG. The states of water analyzed by DSC show a high hydrophobic character inside the composite. The amt. of water interacting with HG chains decreases with the presence of PANI. Both composites show electronic cond. which changes when pressure is applied on them. However the NC shows a larger gauge factor. Such property could be applied in a pressure sensor. Addnl., the thermal sensitivity of the matrix is coupled with the electronic cond. of PANI, allowing to build an elec. switch controlled by the temp.
307. 307

     Hu, X.; Feng, L.; Xie, A.; Wei, W.; Wang, S.; Zhang, J.; Dong, W. Synthesis and Characterization of a Novel Hydrogel: Salecan/Polyacrylamide Semi-IPN Hydrogel with a Desirable Pore Structure. J. Mater. Chem. B 2014, 2, 3646– 3658,  DOI: 10.1039/c3tb21711f

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     Synthesis and characterization of a novel hydrogel: salecan/polyacrylamide semi-IPN hydrogel with a desirable pore structure

     Hu, Xinyu; Feng, Liandong; Xie, Aming; Wei, Wei; Wang, Shiming; Zhang, Jianfa; Dong, Wei

     Journal of Materials Chemistry B: Materials for Biology and Medicine (2014), 2 (23), 3646-3658CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

     Salecan is a novel water-sol. β-glucan produced by a salt-tolerant strain Agrobacterium sp. ZX09 which was isolated from a soil sample in our lab. and the 16S rDNA sequence of this novel strain was deposited in the GenBank database under the accession no. GU810841. Salecan has excellent physicochem. properties and can be used in industries such as food and medicine. In this paper, novel semi-interpenetrating polymer network (semi-IPN) hydrogels based on salecan and polyacrylamide (PAAm) were synthesized by radical polymn./cryopolymn. and semi-IPN techniques. The resulting hydrogels with different salecan/PAAm compn. ratios and prepn. temps. were characterized using FTIR, XRD, TGA and SEM measurements. The semi-IPNs exhibited a homogeneous porous architecture with a tunable pore size in a very broad range of 5-150 μm. Furthermore, swelling behaviors of the hydrogels were also studied to investigate the response properties of the hydrogels. The hydrogels obtained at subzero temp. can attain the equil. state in water within 260 s. Mech. measurements showed that all semi-IPNs possessed good mech. properties. In vitro degrdn. was also studied in PBS soln. Cytotoxicity results suggested that semi-IPN hydrogels were non-toxic to COS-7 cells. A cell culture expt. performed using COS-7 cells revealed their appropriateness for cell adhesion. Together, these results make salecan/PAAm semi-IPNs promising materials for biomedical applications.
308. 308

     Rinoldi, C.; Lanzi, M.; Fiorelli, R.; Nakielski, P.; Zembrzycki, K.; Kowalewski, T.; Urbanek, O.; Grippo, V.; Jezierska-Woźniak, K.; Maksymowicz, W. Three- Dimensional Printable Conductive Semi-Interpenetrating Polymer Network Hydrogel for Neural Tissue Applications. Biomacromolecules 2021, 22, 3084– 3098,  DOI: 10.1021/acs.biomac.1c00524

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     308

     Three-Dimensional Printable Conductive Semi-Interpenetrating Polymer Network Hydrogel for Neural Tissue Applications

     Rinoldi, Chiara; Lanzi, Massimiliano; Fiorelli, Roberto; Nakielski, Pawel; Zembrzycki, Krzysztof; Kowalewski, Tomasz; Urbanek, Olga; Grippo, Valentina; Jezierska-Wozniak, Katarzyna; Maksymowicz, Wojciech; Camposeo, Andrea; Bilewicz, Renata; Pisignano, Dario; Sanai, Nader; Pierini, Filippo

     Biomacromolecules (2021), 22 (7), 3084-3098CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

     Intrinsically conducting polymers (ICPs) are widely used to fabricate biomaterials; their application in neural tissue engineering, however, is severely limited because of their hydrophobicity and insufficient mech. properties. For these reasons, soft conductive polymer hydrogels (CPHs) are recently developed, resulting in a water-based system with tissue-like mech., biol., and elec. properties. The strategy of incorporating ICPs as a conductive component into CPHs is recently explored by synthesizing the hydrogel around ICP chains, thus forming a semi-interpenetrating polymer network (semi-IPN). In this work, a novel conductive semi-IPN hydrogel is designed and synthesized. The hybrid hydrogel is based on a poly(N-isopropylacrylamide-co-N-isopropylmethacrylamide) hydrogel where polythiophene is introduced as an ICP to provide the system with good elec. properties. The fabrication of the hybrid hydrogel in an aq. medium is made possible by modifying and synthesizing the monomers of polythiophene to ensure water soly. The morphol., chem., thermal, elec., electrochem., and mech. properties of semi-IPNs were fully investigated. Addnl., the biol. response of neural progenitor cells and mesenchymal stem cells in contact with the conductive semi-IPN was evaluated in terms of neural differentiation and proliferation. Lastly, the potential of the hydrogel soln. as a 3D printing ink was evaluated through the 3D laser printing method. The presented results revealed that the proposed 3D printable conductive semi-IPN system is a good candidate as a scaffold for neural tissue applications.
309. 309

     Santhanam, S.; Feig, V. R.; McConnell, K. W.; Song, S.; Gardner, E. E.; Patel, J. J.; Shan, D.; Bao, Z.; George, P. M. Controlling the Stem Cell Environment via Conducting Polymer Hydrogels to Enhance Therapeutic Potential. Adv. Mater. Technol. 2023, 8, 2201724,  DOI: 10.1002/admt.202201724

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310. 310

     Rebelo, A.; Liu, Y.; Liu, C.; Schäfer, K.-H.; Saumer, M.; Yang, G. Poly(4-vinylaniline)/polyaniline Bilayer Functionalized Bacterial Cellulose Membranes as Bioelectronics Interfaces. Carbohydr. Polym. 2019, 204, 190– 201,  DOI: 10.1016/j.carbpol.2018.10.017

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311. 311

     Dong, M.; Shi, B.; Liu, D.; Liu, J.-H.; Zhao, D.; Yu, Z.-H.; Shen, X.-Q.; Gan, J.-M.; Shi, B.-L.; Qiu, Y. Conductive Hydrogel for a Photothermal-Responsive Stretchable Artificial Nerve and Coalescing with a Damaged Peripheral Nerve. ACS Nano 2020, 14, 16565– 16575,  DOI: 10.1021/acsnano.0c05197

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     311

     Conductive Hydrogel for a Photothermal-Responsive Stretchable Artificial Nerve and Coalescing with a Damaged Peripheral Nerve

     Dong, Mei; Shi, Bo; Liu, Dun; Liu, Jia-Hao; Zhao, Di; Yu, Zheng-Hang; Shen, Xiao-Quan; Gan, Jia-Min; Shi, Ben-long; Qiu, Yong; Wang, Chang-Chun; Zhu, Ze-Zhang; Shen, Qun-Dong

     ACS Nano (2020), 14 (12), 16565-16575CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Modern development of flexible electronics has made use of bioelectronic materials as artificial tissue in vivo. As hydrogels are more similar to nerve tissue, functional hydrogels have become a promising candidate for bioelectronics. Meanwhile, interfacing functional hydrogels and living tissues is at the forefront of bioelectronics. The peripheral nerve injury often leads to paralysis, chronic pain, neurol. disorders, and even disability, because it has affected the bioelec. signal transmission between the brain and the rest of body. Here, a kind of light-stimuli-responsive and stretchable conducting polymer hydrogel (CPH) is developed to explore artificial nerve. The cond. of CPH can be enhanced when illuminated by near-IR light, which can promote the conduction of the bioelec. signal. When CPH is mech. elongated, it still has high durability of cond. and, thus, can accommodate unexpected strain of nerve tissues in motion. Thereby, CPH can better serve as an implant of the serious peripheral nerve injury in vivo, esp. in the case that the length of the missing nerve exceeds 10 mm.
312. 312

     George, P. M.; Lyckman, A. W.; LaVan, D. A.; Hegde, A.; Leung, Y.; Avasare, R.; Testa, C.; Alexander, P. M.; Langer, R.; Sur, M. Fabrication and Biocompatibility of Polypyrrole Implants Suitable for Neural Prosthetics. Biomaterials 2005, 26, 3511– 3519,  DOI: 10.1016/j.biomaterials.2004.09.037

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     Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics

     George, Paul M.; Lyckman, Alvin W.; LaVan, David A.; Hegde, Anita; Leung, Yuika; Avasare, Rupali; Testa, Chris; Alexander, Phillip M.; Langer, Robert; Sur, Mriganka

     Biomaterials (2005), 26 (17), 3511-3519CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Finding a conductive substrate that promotes neural interactions is an essential step for advancing neural interfaces. The biocompatibility and conductive properties of polypyrrole (PPy) make it an attractive substrate for neural scaffolds, electrodes, and devices. Stand-alone polymer implants also provide the addnl. advantages of flexibility and biodegradability. To examine PPy biocompatibility, dissocd. primary cerebral cortical cells were cultured on PPy samples that had been doped with polystyrene-sulfonate (PSS) or sodium dodecylbenzenesulfonate (NaDBS). Various conditions were used for electrodeposition to produce different surface properties. Neural networks grew on all of the PPy surfaces. PPy implants, consisting of the same dopants and conditions, were surgically implanted in the cerebral cortex of the rat. The results were compared to stab wounds and Teflon implants of the same size. Quantification of the intensity and extent of gliosis at 3- and 6-wk time points demonstrated that all versions of PPy were at least as biocompatible as Teflon and in fact performed better in most cases. In all of the PPy implant cases, neurons and glial cells enveloped the implant. In several cases, neural tissue was present in the lumen of the implants, allowing contact of the brain parenchyma through the implants.
313. 313

     Tian, F.; Yu, J.; Wang, W.; Zhao, D.; Cao, J.; Zhao, Q.; Wang, F.; Yang, H.; Wu, Z.; Xu, J. Design of Adhesive Conducting PEDOT-MeOH: PSS/PDA Neural Interface via Electropolymerization for Ultrasmall Implantable Neural Microelectrodes. J. Colloid Interface Sci. 2023, 638, 339– 348,  DOI: 10.1016/j.jcis.2023.01.146

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314. 314

     Liang, Y.; Offenhäusser, A.; Ingebrandt, S.; Mayer, D. PEDOT: PSS- BasedBioelectronic Devices for Recording and Modulation of Electrophysiological and Biochemical Cell Signals. Adv. Healthc. Mater. 2021, 10, 2100061,  DOI: 10.1002/adhm.202100061

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     Li, J.; Zeng, H.; Zeng, Z.; Zeng, Y.; Xie, T. Promising Graphene-Based Nanomaterials and Their Biomedical Applications and Potential Risks: A Comprehensive Review. ACS Biomater. Sci. Eng. 2021, 7, 5363– 5396,  DOI: 10.1021/acsbiomaterials.1c00875

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     315

     Promising Graphene-Based Nanomaterials and Their Biomedical Applications and Potential Risks: A Comprehensive Review

     Li, Jie; Zeng, Huamin; Zeng, Zhaowu; Zeng, Yiying; Xie, Tian

     ACS Biomaterials Science & Engineering (2021), 7 (12), 5363-5396CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

     A review. Graphene-based nanomaterials (GBNs) have been the subject of research focus in the scientific community because of their excellent phys., chem., elec., mech., thermal, and optical properties. Several studies have been conducted on GBNs, and they have provided a detailed review and summary of various applications. However, comprehensive comments on biomedical applications and potential risks and strategies to reduce toxicity are limited. In this review, we systematically summarized the following aspects of GBNs in order to fill the gaps: (1) the history, synthesis methods, structural characteristics, and surface modification; (2) the latest advances in biomedical applications (including drug/gene delivery, biosensors, bioimaging, tissue engineering, phototherapy, and antibacterial activity); and (3) biocompatibility, potential risks (toxicity in vivo/vitro and effects on human health and the environment), and strategies to reduce toxicity. Moreover, we have analyzed the challenges to be overcome in order to enhance application of GBNs in the biomedical field.
316. 316

     Hu, X.; Zhou, Q. Health and Ecosystem Risks of Graphene. Chem. Rev. 2013, 113, 3815– 3835,  DOI: 10.1021/cr300045n

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     Health and Ecosystem Risks of Graphene

     Hu, Xiangang; Zhou, Qixing

     Chemical Reviews (Washington, DC, United States) (2013), 113 (5), 3815-3835CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Herein, this review focuses on the unique properties of graphene and the related challenges. The distinct properties of graphene are discussed, including size/shape, edge, nanohole, π-π-stacking, surface charge, cond., hydrophilicity/ hydrophobicity, and functionalization, which significantly affect the environmental fate and bioresponses of graphene. Importantly, these physiochem. parameters are interdependent and are discussed at the end of this section.
317. 317

     Lanzi, M.; Pierini, F. Effect of Electron-Acceptor Content on the Efficiency of Regioregular Double-Cable Thiophene Copolymers in Single-Material Organic Solar Cells. ACS Omega 2019, 4, 19863– 19874,  DOI: 10.1021/acsomega.9b02790

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     317

     Effect of Electron-Acceptor Content on the Efficiency of Regioregular Double-Cable Thiophene Copolymers in Single-Material Organic Solar Cells

     Lanzi, Massimiliano; Pierini, Filippo

     ACS Omega (2019), 4 (22), 19863-19874CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)

     Three regioregular thiophenic copolymers, characterized by a bromine atom or a C60-fullerene group at different molar ratios at the end of a decamethylenic plastifying side chain, have been successfully synthesized using a straightforward postpolymn. functionalization procedure based on a Grignard coupling reaction. Owing to their good soly. in common org. solvents, the products were fully characterized using chromatog., spectroscopic, thermal, and morphol. techniques and used as single materials in the photoactive layers of org. solar cells. The photoconversion efficiencies obtained with copolymers were compared with those of a ref. cell prepd. using a phys. blend of the precursor homopolymer and [6,6]-phenyl-C61-butyric acid Me ester. The best results were obtained with COP2, the copolymer with a 21% molar content of C60-functionalized side chains. The use of the double-cable polymer made possible an enhanced control on the nanomorphol. of the active blend, thus reducing phase-segregation phenomena as well as the macroscale sepn. between the electron-acceptor and -donor components, yielding a power conversion efficiency higher than that of the ref. cell (4.05 vs 3.68%). Moreover, the presence of the halogen group was exploited for the photo-crosslinking of the active layer immediately after the thermal annealing procedure. The cross-linked samples showed an increased stability over time, leading to good efficiencies even after 120 h of accelerated aging: this was a key feature for the widespread practical applicability of the prepd. devices.
318. 318

     Zakrzewska, A.; Zargarian, S. S.; Rinoldi, C.; Gradys, A.; Jarza̧bek, D.; Zanoni, M.; Gualandi, C.; Lanzi, M.; Pierini, F. Electrospun Poly(vinyl alcohol)-Based Conductive Semi-Interpenetrating Polymer Network Fibrous Hydrogel: A Toolbox for Optimal Cross-Linking. ACS Mater. Au 2023, 3, 464– 482,  DOI: 10.1021/acsmaterialsau.3c00025

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319. 319

     Kim, Y.; Park, C.; Im, S.; Kim, J. H. Design of Intrinsically Stretchable and Highly Conductive Polymers for Fully Stretchable Electrochromic Devices. Sci. Rep. 2020, 10, 16488,  DOI: 10.1038/s41598-020-73259-x

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     Design of intrinsically stretchable and highly conductive polymers for fully stretchable electrochromic devices

     Kim, Youngno; Park, Chanil; Im, Soeun; Kim, Jung Hyun

     Scientific Reports (2020), 10 (1), 16488CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)

     Stretchable materials are essential for next generation wearable and stretchable electronic devices. Intrinsically stretchable and highly conductive polymers (termed ISHCP) are designed with semi interpenetrating polymer networks (semi-IPN) that enable polymers to be simultaneously applied to transparent electrodes and electrochromic materials. Through a facile method of acid-catalyzed polymer condensation reaction, optimized ISHCP films show the highest elec. cond., 1406 S/cm, at a 20% stretched state. Without the blending of any other elastomeric matrix, ISHCP maintains its initial elec. properties under a cyclic stretch-release of over 50% strain. A fully stretchable electrochromic device based on ISHCP is fabricated and shows a performance of 47.7% ΔT and high coloration efficiency of 434.1 cm2/C at 590 nm. The device remains at 45.2% ΔT after 50% strain stretching. A simple patterned electrolyte layer on a stretchable electrochromic device is also realized. The fabricated device, consisting of all-plastic, can be applied by a soln. process for large scale prodn. The ISHCP reveals its potential application in stretchable electrochromic devices and satisfies the requirements for next-generation stretchable electronics.
320. 320

     Zinno, C.; Cedrola, I.; Giannotti, A.; Riva, E. R.; Micera, S. Development of a 3D Printing Strategy for Completely Polymeric Neural Interfaces Fabrication. In 2023 11th International IEEE/EMBS Conference on Neural Engineering (NER), IEEE: 2023; pp 1– 4.

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321. 321

     Bagheri, B.; Zarrintaj, P.; Surwase, S. S.; Baheiraei, N.; Saeb, M. R.; Mozafari, M.; Kim, Y. C.; Park, O. O. Self-Gelling Electroactive Hydrogels Based on Chitosan-Aniline Oligomers/Agarose for Neural Tissue Engineering with On-Demand Drug Release. Coll. Surf., B 2019, 184, 110549,  DOI: 10.1016/j.colsurfb.2019.110549

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     Kleber, C.; Bruns, M.; Lienkamp, K.; Rühe, J.; Asplund, M. An Interpenetrating, Microstructurable and Covalently Attached Conducting Polymer Hydrogel for Neural Interfaces. Acta Biomater. 2017, 58, 365– 375,  DOI: 10.1016/j.actbio.2017.05.056

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     322

     An interpenetrating, microstructurable and covalently attached conducting polymer hydrogel for neural interfaces

     Kleber, Carolin; Bruns, Michael; Lienkamp, Karen; Ruehe, Juergen; Asplund, Maria

     Acta Biomaterialia (2017), 58 (), 365-375CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

     This study presents a new conducting polymer hydrogel (CPH) system, consisting of the synthetic hydrogel P(DMAA-co-5%MABP-co-2,5%SSNa) and the conducting polymer (CP) poly(3,4-ethylenedioxythiophene) (PEDOT), intended as coating material for neural interfaces. The composite material can be covalently attached to the surface electrode, can be patterned by a photolithog. process to influence selected electrode sites only and forms an interpenetrating network. The hybrid material was characterized using cyclic voltammetry (CV), impedance spectroscopy (EIS) and XPS, which confirmed a homogeneous distribution of PEDOT throughout all CPH layers. The CPH exhibited a 2,5 times higher charge storage capacity (CSC) and a reduced impedance when compared to the bare hydrogel. Electrochem. stability was proven over at least 1000 redox cycles. Non-toxicity was confirmed using an elution toxicity test together with a neuroblastoma cell-line. The described material shows great promise for surface modification of neural probes making it possible to combine the beneficial properties of the hydrogel with the excellent electronic properties necessary for high quality neural microelectrodes. Conductive polymer hydrogels have emerged as a promising new class of materials to functionalize electrode surfaces for enhanced neural interfaces and drug delivery. Common weaknesses of such systems are delamination from the connection surface, and the lack of suitable patterning methods for confining the gel to the selected electrode site. Various studies have reported on conductive polymer hydrogels addressing one of these challenges. In this study we present a new composite material which offers, for the first time, the unique combination of properties: it can be covalently attached to the substrate, forms an interpenetrating network, shows excellent elec. properties and can be patterned via UV-irradn. through a structured mask.
323. 323

     Bansal, M.; Raos, B.; Aqrawe, Z.; Wu, Z.; Svirskis, D. An Interpenetrating and Patternable Conducting Polymer Hydrogel for Electrically Stimulated Release of Glutamate. Acta Biomater. 2022, 137, 124– 135,  DOI: 10.1016/j.actbio.2021.10.010

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     323

     An interpenetrating and patternable conducting polymer hydrogel for electrically stimulated release of glutamate

     Bansal, Mahima; Raos, Brad; Aqrawe, Zaid; Wu, Zimei; Svirskis, Darren

     Acta Biomaterialia (2022), 137 (), 124-135CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

     Recent advances in drug delivery have made it possible to release bioactive agents from neural implants specifically to local tissues. Conducting polymer coatings have been explored as a delivery platform in bioelectronics, however, their utility is restricted by their limited loading capacity and stability. This study presents the fabrication of a stable conducting polymer hydrogel (CPH), comprising the hydrogel gelatin methacrylate (GelMA), and conducting polymer polypyrrole (PPy) for the elec. controlled delivery of glutamate (Glu). The hybrid GelMA/PPy/Glu can be photolithog. patterned and covalently bonded to an electrode. Fourier-transform IR (FTIR) anal. confirmed the interpenetrating nature of PPy through the GelMA hydrogels. Electrochem. polymn. of PPy/Glu through the GelMA hydrogels resulted in a significant increase in the charge storage capacity as detd. by cyclic voltammetry (CV). Long-term electrochem. and mech. stability was demonstrated over 1000 CV cycles and exts. of the materials were cytocompatible with SH-SY5Y neuroblastoma cell lines. Release of Glu from the CPH was responsive to elec. stimulation with almost five times the amt. of Glu released upon const. redn. (-0.6 V) compared to when no stimulus was applied. Notably, GelMA/PPy/Glu was able to deliver almost 14 times higher amts. of Glu compared to conventional PPy/Glu films. The described CPH coatings are well suited in implantable drug delivery applications and compared to conducting polymer films can deliver higher quantities of drug in response to mild elec. stimulus.
324. 324

     Zeng, Q.; Huang, Z. Challenges and Opportunities of Implantable Neural Interfaces: From Material, Electrochemical and Biological Perspectives. Adv. Funct. Mater. 2023, 33, 2301223,  DOI: 10.1002/adfm.202301223

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     324

     Challenges and Opportunities of Implantable Neural Interfaces: From Material, Electrochemical and Biological Perspectives

     Zeng, Qi; Huang, Zhaoling

     Advanced Functional Materials (2023), 33 (32), 2301223CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. The desirable implantable neural interfaces can accurately record bioelec. signals from neurons and regulate neural activities with high spatial/time resoln., facilitating the understanding of neuronal functions and dynamics. However, the electrochem. performance (impedance, charge storage/injection capacity) is limited with the miniaturization and integration of neural electrodes. The "crosstalk" caused by the uneven distribution of elctric field leads to lower elec. stimulation/recording efficiency. The mismatch between stiff electrodes and soft tissues exacerbates the inflammatory responses, thus weakening the transmission of signals. Though remarkable breakthroughs have been made through the incorporation of optimizing electrode design and functionalized nanomaterials, the chronic stability, and long-term activity in vivo of the neural electrodes still need further development. In this review, the neural interface challenges mainly on electrochem. and biol. are discussed, followed by summarizing typical electrode optimization technologies and exploring recent advances in the application of nanomaterials, based on traditional metallic materials, emerging 2D materials, conducting polymer hydrogels, etc., for enhancing neural interfaces. The strategies for improving the durability including enhanced adhesion and minimized inflammatory response, are also summarized. The promising directions are finally presented to provide enlightenment for high-performance neural interfaces in future, which will promote profound progress in neuroscience research.
325. 325

     Goding, J.; Gilmour, A.; Martens, P.; Poole-Warren, L.; Green, R. Interpenetrating Conducting Hydrogel Materials for Neural Interfacing Electrodes. Adv. Healthc. Mater. 2017, 6, 1601177,  DOI: 10.1002/adhm.201601177

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326. 326

     Yang, M.; Chen, P.; Qu, X.; Zhang, F.; Ning, S.; Ma, L.; Yang, K.; Su, Y.; Zang, J.; Jiang, W. Robust Neural Interfaces with Photopatternable, Bioadhesive, and Highly Conductive Hydrogels for Stable Chronic Neuromodulation. ACS Nano 2023, 17, 885– 895,  DOI: 10.1021/acsnano.2c04606

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     326

     Robust Neural Interfaces with Photopatternable, Bioadhesive, and Highly Conductive Hydrogels for Stable Chronic Neuromodulation

     Yang, Ming; Chen, Ping; Qu, Xinyu; Zhang, Fuchi; Ning, Shan; Ma, Li; Yang, Kun; Su, Yuming; Zang, Jianfeng; Jiang, Wei; Yu, Ting; Dong, Xiaochen; Luo, Zhiqiang

     ACS Nano (2023), 17 (2), 885-895CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     A robust neural interface with intimate elec. coupling between neural electrodes and neural tissues is crit. for stable chronic neuromodulation. The development of bioadhesive hydrogel neural electrodes is a potential approach for tightly fixing the neural electrodes on the epineurium surface to construct a robust neural interface. Herein, we construct a photopatternable, antifouling, conductive (~ 6 S cm-1), bioadhesive (interfacial toughness ~ 100 J m-2), soft, and elastic (~ 290% strain, Young's modulus of 7.25 kPa) hydrogel to establish a robust neural interface for bioelectronics. The UV-sensitive zwitterionic monomer can facilitate the formation of an electrostatic-assembled conductive polymer PEDOT:PSS network, and it can be further photo-crosslinked into elastic polymer network. Such a semi-interpenetrating network endows the hydrogel electrodes with good cond. Esp., the photopatternable feature enables the facile microfabrication processes of multifunctional hydrogel (MH) interface with a characteristic size of 50μm. The MH neural electrodes, which show improved performance of impedance, charge storage capacity, and charge injection capability, can produce effective elec. stimulation with high c.d. (1 mA cm-2) at ultralow voltages (±25 mV). The MH interface could realize high-efficient elec. communication at the chronic neural interface for stable recording and stimulation of a sciatic nerve in the rat model.
327. 327

     Huang, X.; Chen, C.; Ma, X.; Zhu, T.; Ma, W.; Jin, Q.; Du, R.; Cai, Y.; Zhang, M.; Kong, D. In Situ Forming Dual-Conductive Hydrogels Enable Conformal, Self-Adhesive and Antibacterial Epidermal Electrodes. Adv. Funct. Mater. 2023, 33, 2302846,  DOI: 10.1002/adfm.202302846

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     327

     In Situ Forming Dual-Conductive Hydrogels Enable Conformal, Self-Adhesive and Antibacterial Epidermal Electrodes

     Huang, Xinxin; Chen, Canwen; Ma, Xiaohui; Zhu, Tangsong; Ma, Wencan; Jin, Qi; Du, Ruichun; Cai, Yifeng; Zhang, Menghu; Kong, Desheng; Wang, Minyan; Ren, Jian'an; Zhang, Qiuhong; Jia, Xudong

     Advanced Functional Materials (2023), 33 (38), 2302846CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Conductive hydrogels (CHs) are regarded as one of the most promising materials for bioelectronic devices on human-machine interfaces (HMIs). However, conventional CHs cannot conform well with complex skin surfaces, such as hairy or wrinkled skin, due to pre-formation and insufficient adhesion; they also usually lack antibacterial abilities and require tissue-harm and time-consuming prepn. (e.g., heating or UV irradn.), which limits their practical application on HMIs. Herein, an in situ forming CH is proposed by taking advantage of the PEDOT:PSS-promoted self-polymn. of zwitterionic [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) (SBMA). The hydrogel is formed spontaneously after injection of the precursor soln. onto the desired location without any addnl. treatments. The as-prepd. hydrogel possesses excellent elasticity (elastic recovery >96%), desirable adhesive strength (≈6.5 kPa), biocompatibility, and intrinsically antibacterial properties. Without apparent heat release (<5°C) during gelation, the hydrogel can form in situ on skin. Addnl., the obtained hydrogel can establish tight contact with skin, forming highly conformal interfaces on hairy skin surfaces and irregular wounds. Finally, the in situ forming hydrogels are applied as conformal epidermal electrodes to record stable and reliable surface electromyogram signals from hairy skin (with high signal-to-noise ratio, SNR ≈ 32 dB) and accelerate diabetic wound healing under elec. stimulation.
328. 328

     Anderson, C. L.; Zhang, T.; Qi, M.; Chen, Z.; Yang, C.; Teat, S. J.; Settineri, N. S.; Dailing, E. A.; Garzón-Ruiz, A.; Navarro, A. Exceptional Electron-Rich Heteroaromatic Pentacycle for Ultralow Band Gap Conjugated Polymers and Photothermal Therapy. J. Am. Chem. Soc. 2023, 145, 5474– 5485,  DOI: 10.1021/jacs.3c00036

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     328

     Exceptional Electron-Rich Heteroaromatic Pentacycle for Ultralow Band Gap Conjugated Polymers and Photothermal Therapy

     Anderson, Christopher L.; Zhang, Tong; Qi, Miao; Chen, Ziman; Yang, Chongqing; Teat, Simon J.; Settineri, Nicholas S.; Dailing, Eric A.; Garzon-Ruiz, Andres; Navarro, Amparo; Lv, Yongqin; Liu, Yi

     Journal of the American Chemical Society (2023), 145 (9), 5474-5485CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

     Stable redox-active conjugated mols. with exceptional electron-donating abilities are key components for the design and synthesis of ultralow band gap conjugated polymers. While hallmark electron-rich examples such as pentacene derivs. have been thoroughly explored, their poor air stability has hampered their broad incorporation into conjugated polymers for practical applications. Herein, we describe the synthesis of the electron-rich, fused pentacyclic pyrazino[2,3-b:5,6-b']diindolizine (PDIz) motif and detail its optical and redox behavior. The PDIz ring system exhibits a lower oxidn. potential and a reduced optical band gap than the isoelectronic pentacene while retaining greater air stability in both soln. and the solid state. The enhanced stability and electron d., together with readily installed solubilizing groups and polymn. handles, allow for the use of the PDIz motif in the synthesis of a series of conjugated polymers with band gaps as small as 0.71 eV. The tunable absorbance throughout the biol. relevant near-IR I and II regions enables the use of these PDIz-based polymers as efficient photothermal therapeutic reagents for laser ablation of cancer cells.
329. 329

     Sun, J.; Wu, X.; Xiao, J.; Zhang, Y.; Ding, J.; Jiang, J.; Chen, Z.; Liu, X.; Wei, D.; Zhou, L. Hydrogel-Integrated Multimodal Response as a Wearable and Implantable Bidirectional Interface for Biosensor and Therapeutic Electrostimulation. ACS Appl. Mater. Interfaces 2023, 15, 5897– 5909,  DOI: 10.1021/acsami.2c20057

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     329

     Hydrogel-Integrated Multimodal Response as a Wearable and Implantable Bidirectional Interface for Biosensor and Therapeutic Electrostimulation

     Sun, Jing; Wu, Xiaoyang; Xiao, Jiamei; Zhang, Yusheng; Ding, Jie; Jiang, Ji; Chen, Zhihong; Liu, Xiaoyin; Wei, Dan; Zhou, Liangxue; Fan, Hongsong

     ACS Applied Materials & Interfaces (2023), 15 (4), 5897-5909CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     A hydrogel that fuses long-term biol. integration, multimodal responsiveness, and therapeutic functions has received increasing interest as a wearable and implantable sensor but still faces great challenges as an all-in-one sensor by itself. Multiple bonding with stimuli response in a biocompatible hydrogel lights up the field of soft hydrogel interfaces suitable for both wearable and implantable applications. Given that, we proposed a strategy of combining chem. crosslinking and stimuli-responsive phys. interactions to construct a biocompatible multifunctional hydrogel. In this hydrogel system, ureidopyrimidinone/tyramine (Upy/Tyr) difunctionalization of gelatin provides abundant dynamic phys. interactions and stable covalent crosslinking; meanwhile, Tyr-doped poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) acts as a conductive filler to establish elec. percolation networks through enzymic chem. crosslinking. Thus, the hydrogel is characterized with improved cond., conformal biointegration features (i.e., high stretchability, rapid self-healing, and excellent tissue adhesion), and multistimuli-responsive cond. (i.e., temp. and urea). On the basis of these excellent performances, the prepd. multifunctional hydrogel enables multimodal wearable sensing integration that can simultaneously track both physicochem. and electrophysiol. attributes (i.e., motion, temp., and urea), providing a more comprehensive monitoring of human health than current wearable monitors. In addn., the electroactive hydrogel here can serve as a bidirectional neural interface for both neural recording and therapeutic electrostimulation, bringing more opportunities for nonsurgical diagnosis and treatment of diseases.
330. 330

     Ziai, Y.; Petronella, F.; Rinoldi, C.; Nakielski, P.; Zakrzewska, A.; Kowalewski, T. A.; Augustyniak, W.; Li, X.; Calogero, A.; Sabała, I. Chameleon-Inspired Multifunctional Plasmonic Nanoplatforms for Biosensing Applications. NPG Asia Mater. 2022, 14, 18,  DOI: 10.1038/s41427-022-00365-9

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     Chameleon-inspired multifunctional plasmonic nanoplatforms for biosensing applications

     Ziai, Yasamin; Petronella, Francesca; Rinoldi, Chiara; Nakielski, Pawel; Zakrzewska, Anna; Kowalewski, Tomasz A.; Augustyniak, Weronika; Li, Xiaoran; Calogero, Antonella; Sabala, Izabela; Ding, Bin; De Sio, Luciano; Pierini, Filippo

     NPG Asia Materials (2022), 14 (1), 18CODEN: NAMPCE; ISSN:1884-4057. (Nature Portfolio)

     One of the most fascinating areas in the field of smart biopolymers is biomol. sensing. Accordingly, multifunctional biomimetic, biocompatible, and stimuli-responsive materials based on hydrogels have attracted much interest. Within this framework, the design of nanostructured materials that do not require any external energy source is beneficial for developing a platform for sensing glucose in body fluids. In this article, we report the realization and application of an innovative platform consisting of two outer layers of a nanocomposite plasmonic hydrogel plus one inner layer of electrospun mat fabricated by electrospinning, where the outer layers exploit photoinitiated free radical polymn., obtaining a compact and stable device. Inspired by the exceptional features of chameleon skin, plasmonic silver nanocubes are embedded into a poly(N-isopropylacrylamide)-based hydrogel network to obtain enhanced thermoresponsive and antibacterial properties. The introduction of an electrospun mat creates a compatible environment for the homogeneous hydrogel coating while imparting excellent mech. and structural properties to the final system. Chem., morphol., and optical characterizations were performed to investigate the structure of the layers and the multifunctional platform. The synergetic effect of the nanostructured systems photothermal responsivity and antibacterial properties was evaluated. The sensing features assocd. with the optical properties of silver nanocubes revealed that the proposed multifunctional system is a promising candidate for glucose-sensing applications.
331. 331

     Renz, A. F; Reichmuth, A. M; Stauffer, F.; Thompson-Steckel, G.; Voros, J. A Inspired Multifunctional Plasmonic Nanoplatforms for Biosensing Applications. J. Neural Eng. 2018, 15, 061001,  DOI: 10.1088/1741-2552/aae0c2

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332. 332

     Joseph, K.; Kirsch, M.; Johnston, M.; Münkel, C.; Stieglitz, T.; Haas, C. A.; Hofmann, U. G. Transcriptional Characterization of the Glial Response Due to Chronic Neural Implantation of Flexible Microprobes. Biomaterials 2021, 279, 121230,  DOI: 10.1016/j.biomaterials.2021.121230

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333. 333

     Thompson, C. H.; Evans, B. M.; Zhao, D. X.; Purcell, E. K. Spatiotemporal Expression of RNA-Seq Identified Proteins at the Electrode Interface. Acta Biomater. 2023, 164, 209– 222,  DOI: 10.1016/j.actbio.2023.04.028

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334. 334

     Whitsitt, Q. A.; Patel, B.; Hunt, B.; Purcell, E. K. A Spatial Transcriptomics Study of the Brain-Electrode Interface in Rat Motor Cortex. bioRxiv 2021, 471147,  DOI: 10.1101/2021.12.03.471147

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335. 335

     Thompson, C. H.; Saxena, A.; Heelan, N.; Salatino, J.; Purcell, E. K. Spatiotemporal Patterns of Gene Expression around Implanted Silicon Electrode Arrays. J. Neural Eng. 2021, 18, 045005,  DOI: 10.1088/1741-2552/abf2e6

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336. 336

     Luan, L.; Yin, R.; Zhu, H.; Xie, C. Emerging Penetrating Neural Electrodes: In Pursuit of Large Scale and Longevity. Annu. Rev. Biomed. Eng. 2023, 25, 185– 205,  DOI: 10.1146/annurev-bioeng-090622-050507

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     There is no corresponding record for this reference.
337. 337

     Thanawala, S.; Palyvoda, O.; Georgiev, D. G.; Khan, S. P.; Al-Homoudi, I. A.; Newaz, G.; Auner, G. A Neural Cell Culture Study on Thin Film Electrode Materials. J. Mater. Sci. Mater. Med. 2007, 18, 1745– 1752,  DOI: 10.1007/s10856-007-3054-1

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     337

     A neural cell culture study on thin film electrode materials

     Thanawala, Sachin; Palyvoda, Olena; Georgiev, Daniel G.; Khan, Saida P.; Al-Homoudi, Ibrahim A.; Newaz, Golam; Auner, Gregory

     Journal of Materials Science: Materials in Medicine (2007), 18 (9), 1745-1752CODEN: JSMMEL; ISSN:0957-4530. (Springer)

     Functional neural stimulation requires good interface between the neural cells and the electrode surfaces. In order to study the effect of electrode materials and surface structure on cell adhesion and biocompatibility, we cultured cortical neurons on thin films of platinum and iridium oxide. We used both flat, as-deposited and laser micro-structured films. The laser micro-structuring consisted of creating regular arrays of micro-bumps or holes with diams. of 4-5 μm and height of about 1.5 μm. The micro-bumps were fabricated onto platinum and iridium film surfaces deposited on borosilicate glass substrates, using mask-projection irradn. with single nano-second pulses from a KrF excimer laser (λ = 248 nm). Amorphous and cryst. (deposited at 250°) IrO2 films were deposited onto the laser micro-structured iridium films by pulsed-DC reactive sputtering to obtain micro-structured IrO2 films. Cortical neurons isolated from rat embryo brain were cultured onto these film surfaces. Our results indicate that flat and micro-structured film surfaces are biocompatible and non-toxic for neural cell growth. The use of poly-d-lysine as a mediator for cell adhesion onto the thin film surfaces is also discussed.
338. 338

     Liu, S.; Zhao, Y.; Hao, W.; Zhang, X.-D.; Ming, D. Micro- and Nanotechnology for Neural Electrode-Tissue Interfaces. Biosens. Bioelectron. 2020, 170, 112645,  DOI: 10.1016/j.bios.2020.112645

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     338

     Micro- and nanotechnology for neural electrode-tissue interfaces

     Liu, Shuangjie; Zhao, Yue; Hao, Wenting; Zhang, Xiao-Dong; Ming, Dong

     Biosensors & Bioelectronics (2020), 170 (), 112645CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)

     A review. Implantable neural electrodes can record and regulate neural activities with high spatial resoln. of single-neuron and high time resoln. of sub-millisecond, which are the most extensive window in neuroscience research. However, the mech. mismatch between conventional stiff electrodes and soft neural tissue can lead to inflammatory responses and degrdn. of signals in chronic recordings. Although remarkable breakthroughs have been made in sensing and regulation of neural signals, the long-term stability and chronic inflammatory response of the neural electrode-tissue interfaces still needs further development. In this review, we focus on the latest developments for the optimization of neural electrode-tissue interfaces, including electrode materials (graphene fiber-based and CNT fiber-based), electrode structures (flexible electrodes), nano-coatings and hydrogel-based neural interfaces. The parameters of impedance, charge injection limit, signal-to-noise ratio and neuron lost zone are used to evaluate the electrochem. performance of the devices, the recording performance of biosignals and the stability of the neural interfaces, resp. These optimization methods can effectively improve the long-term stability and the chronic inflammatory response of neural interfaces during the recording and modulation of biosignals.
339. 339

     Parak, W. J.; George, M.; Gaub, H. E.; Böhm, S.; Lorke, A. The Field-Effect-Addressable Potentiometric Sensor/Stimulator (FAPS) - A New Concept for a Surface Potential Sensor and Stimulator with Spatial Resolution. Sens. Actuators, B 1999, 58, 497– 504,  DOI: 10.1016/S0925-4005(99)00129-X

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     339

     The field-effect-addressable potentiometric sensor/stimulator (FAPS)-a new concept for a surface potential sensor and stimulator with spatial resolution

     Parak, W. J.; George, M.; Gaub, H. E.; Bohm, S.; Lorke, A.

     Sensors and Actuators, B: Chemical (1999), 58 (1-3), 497-504CODEN: SABCEB; ISSN:0925-4005. (Elsevier Science S.A.)

     We propose a new concept for a surface potential detector with high spatial resoln. and large no. of addressable points. The so-called field-effect-addressable potentiometric sensor/stimulator (FAPS) uses the ability to control the resistance of FET-channels in semiconductor films with elec. potentials. Making use of a grid-structure of perpendicular FET-channels and gate electrodes located below the FET-channels, it is possible to tune a single intersection into max. sensitivity to elec. potentials located above the FET-channel. By covering the surface above the FET-channels of a GaAs based FAPS with less than 100 nm PMMA, a bio-compatible interface could be created. This suggests the ability to record extracellular potentials and apply extracellular stimuli to elec. excitable cells adherent to the FAPS surface.
340. 340

     Kirchner, C.; George, M.; Stein, B.; Parak, W. J.; Gaub, H. E.; Seitz, M. Corrosion Protection and Long-Term Chemical Functionalization of Gallium Arsenide in Aqueous Environment. Adv. Funct. Mater. 2002, 12, 266– 276,  DOI: 10.1002/1616-3028(20020418)12:4<266::AID-ADFM266>3.0.CO;2-U

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     340

     Corrosion protection and long-term chemical functionalization of gallium arsenide in an aqueous environment

     Kirchner, Christian; George, Michael; Stein, Bernhard; Parak, Wolfgang J.; Gaub, Hermann E.; Seitz, Markus

     Advanced Functional Materials (2002), 12 (4), 266-276CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH)

     The chem. instability of the gallium arsenide surface poses a serious limitation to its use under ambient conditions, such as in air or aq. soln. It is shown that both bare GaAs and GaAs coated with self-assembled monolayers of org. alkanethiols are continuously etched in aq. environments, which limits their use as biosensor devices in physiol. environments. A corrosion protection material having long-term stability ("chem. passivation") and biocompatibility ("biol. passivation") with the GaAs surface was found to be interfacial layers of polymd. org. mercaptosilanes a few tens of nanometers thick. The mercaptosilanes not only provided a nearly perfect corrosion protection of GaAs in water, but they also have the potential to introduce chem. groups that allow easy, further surface functionalization. Characterization of the interfacial polymer layer and its protective role was done by at. force microscopy (AFM), ellipsometry, contact angle measurements, and at. absorption spectroscopy (AAS). The interfacial polymer layers fully suppressed the release of arsenic into the electrolyte buffer and also provided an adhesion-promoting interface, which allowed the cultivation of elec. excitable cells, normal rat kidney (NRK) fibroblasts, on GaAs. The elec. performance of GaAs and GaAs/InGaAs heterostructures in water was monitored via cyclic voltammetry and the IU characteristics of field-effect channels. GaAs was significantly stabilized by the insulating polymeric surface coatings, even under moderate electrochem. loads. These findings are promising for, e.g., the implementation of GaAs technol. in future cell-semiconductor hybrids.
341. 341

     Parak, W. J.; George, M.; Kudera, M.; Gaub, H. E.; Behrends, J. C. Effects of Semiconductor Substrate and Glia-Free Culture on the Development of Voltage Dependent Currents in Rat Striatal Neurones. Eur. Biophys. J. 2001, 29, 607– 620,  DOI: 10.1007/s002490000109

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342. 342

     Slaughter, G. E.; Bieberich, E.; Wnek, G. E.; Wynne, K. J.; Guiseppi-Elie, A. Improving Neuron-to-Electrode Surface Attachment via Alkanethiol Self-Assembly: An Alternating Current Impedance Study. Langmuir 2004, 20, 7189– 7200,  DOI: 10.1021/la049192s

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     342

     Improving Neuron-to-Electrode Surface Attachment via Alkanethiol Self-Assembly: An Alternating Current Impedance Study

     Slaughter, Gymama E.; Bieberich, Erhard; Wnek, Gary E.; Wynne, Kenneth J.; Guiseppi-Elie, Anthony

     Langmuir (2004), 20 (17), 7189-7200CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)

     In this work, the ω-amine alkanethiols, cysteamine (CA) and 11-amino-1-undecanethiol (11-AUT), were chemisorbed as self-assembled monolayers (SAMs) onto 250-μm gold microelectrodes that were microlithog. fabricated within eight-well cell culture plates and investigated as a means to improve neuron-to-electrode surface attachment (NESA). Dynamic contact angle (DCA) measurements showed similar advancing, θa (69° and 65°), but contrasting receding contact angles, θr (9 and 30°) for CA- and 11-AUT-SAMs, resp. The corresponding hysteresis (Δθar = 60 and 35°, resp.) indicates the CA-SAM displays greater amphiphilic character than the 11-AUT-SAM. A portion of the greater Δθar for CA-SAMs may arise from surface heterogeneity, as compared to sputter-deposited gold and 11-AUT-SAMs. Tapping mode at. force microscopy (AFM) confirmed a 6% increase (CA-SAM) and a 22% decrease (11-AUT-SAM) in surface roughness when compared to clean but unmodified, sputter-deposited gold. The extracellular matrix cell adhesion proteins, collagen, fibronectin, and laminin, were covalently coupled to the aminoalkanethiol-decorated gold electrodes via acid-amine heterobifunctional crosslinking. Using fluorescein isothiocyanate-tagged laminin, confocal fluorescence microscopy of both CA- and 11-AUT-SAM-modified and unmodified gold microelectrodes confirmed coupling of the protein to the electrode and was readily distinguishable from nonspecifically adsorbed protein. DCA measurements of laminin physisorbed directly onto gold or covalently immobilized via CA- or 11-AUT-SAM had similar advancing (∼63-65°) and receding (∼7-9°) contact angles. Tapping mode AFM of these protein-bearing surfaces likewise showed dimerized protein aggregates of similar surface roughness. PC-12 cells cultured to confluence on both unmodified and SAM-modified, protein-derivatized gold microelectrodes were examd. by a.c. impedance (50 mV p-t-p at 4 kHz). CA- and 11-AUT-SAM-modified surfaces when serving as a foundation or covalently immobilized adhesion proteins produced highly stable and reproducible temporal impedance responses. On the basis of the magnitude and the reproducibility of the impedance responses, the CA-SAM-modified surfaces were identified as being best suited for optimal neuron-to-electrode contact with laminin. Laminin performed best when compared to collagen and fibronectin. Covalent immobilization of the adhesion-promoting proteins results in enhanced NESA by tightly anchoring cells to the electrode.
343. 343

     Parashar, K.; Prajapati, D.; McIntyre, R.; Kandasubramanian, B. Advancements in Biological Neural Interfaces Using Conducting Polymers: A Review. Ind. Eng. Chem. Res. 2020, 59, 9707– 9718,  DOI: 10.1021/acs.iecr.0c00174

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     343

     Advancements in Biological Neural Interfaces Using Conducting Polymers: A Review

     Parashar, Kashish; Prajapati, Deepak; McIntyre, Robin; Kandasubramanian, Balasubramanian

     Industrial & Engineering Chemistry Research (2020), 59 (21), 9707-9718CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)

     A review. Neural interfacing machines are interfacial devices that restores the purpose of the nervous system lost because of any disease or injury. In the current scenario, conventional metal-based electrodes are employed for neural interfacing; however, the challenge faced with these electrodes is signal degeneration, because of filling of the liq. gap (i.e., in extra systemic implants) between target tissue and electrode. Thus, this problem aroused a novel idea to use conducting polymers (CPs), because it provides excellent elec. cond. for signal transduction, along with biocompatibility with human body. Implanted metal electrodes generate an immunol. response in the human body and attempts to eradicate them by treating them as a foreign material. CPs are generally biocompatible with the bodies' immune system and does not induce any significant long-term neg. effect in vivo and are much preferred and reliable over the conventional techniques, because of its high surface area, which promotes a good conductance with target tissues by reducing impedance and, hence, enhances the recording and simulation applications of various neural processes. Thus, this Review intends to study several neural interfacing applications by using polypyrrole and PEDOT as primary CPs, with brief explanation of their prepn. and conductance mechanisms, and then focuses on neural implanting, interfacing behaviors, and superiority over other materials. Novel designing and applications of cochlear implants, bionic eyes, and brain-machine interfering are hereby reviewed.
344. 344

     Leal, J.; Jedrusik, N.; Shaner, S.; Boehler, C.; Asplund, M. SIROF Stabilized PEDOT/PSS Allows Biocompatible and Reversible Direct Current Stimulation Capable of Driving Electrotaxis in Cells. Biomaterials 2021, 275, 120949,  DOI: 10.1016/j.biomaterials.2021.120949

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345. 345

     Vomero, M.; Ciarpella, F.; Kirsch, M.; Fadiga, L.; Stieglitz, T.; Asplund, M. Bioelectronics Meets the Brain: Establishing Biostability of Multi-Layered Polyimide-Based Intracortical Implants. Cell Press 2021, In Review. DOI: 10.2139/ssrn.3832145

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346. 346

     Boehler, C.; Kleber, C.; Martini, N.; Xie, Y.; Dryg, I.; Stieglitz, T.; Hofmann, U.; Asplund, M. Actively Controlled Release of Dexamethasone from Neural Microelectrodes in a Chronic in Vivo Study. Biomaterials 2017, 129, 176– 187,  DOI: 10.1016/j.biomaterials.2017.03.019

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     346

     Actively controlled release of Dexamethasone from neural microelectrodes in a chronic in vivo study

     Boehler, C.; Kleber, C.; Martini, N.; Xie, Y.; Dryg, I.; Stieglitz, T.; Hofmann, U. G.; Asplund, M.

     Biomaterials (2017), 129 (), 176-187CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Stable interconnection to neurons in vivo over long time-periods is crit. for the success of future advanced neuroelectronic applications. The inevitable foreign body reaction towards implanted materials challenges the stability and an active intervention strategy would be desirable to treat inflammation locally. Here, we investigate whether controlled release of the anti-inflammatory drug Dexamethasone from flexible neural microelectrodes in the rat hippocampus has an impact on probe-tissue integration over 12 wk of implantation. The drug was stored in a conducting polymer coating (PEDOT/Dex), selectively deposited on the electrode sites of neural probes, and released on weekly basis by applying a cyclic voltammetry signal in three electrode configuration in fully awake animals. Dex-functionalized probes provided stable recordings and impedance characteristics over the entire chronic study. Histol. evaluation after 12 wk of implantation revealed an overall low degree of inflammation around all flexible probes whereas electrodes exposed to active drug release protocols did have neurons closer to the electrode sites compared to controls. The combination of flexible probe technol. with anti-inflammatory coatings accordingly offers a promising approach for enabling long-term stable neural interfaces.
347. 347

     Vomero, M.; Castagnola, E.; Ciarpella, F.; Maggiolini, E.; Goshi, N.; Zucchini, E.; Carli, S.; Fadiga, L.; Kassegne, S.; Ricci, D. Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low-Noise Recording of Brain Activity. Sci. Rep. 2017, 7, 40332,  DOI: 10.1038/srep40332

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     347

     Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low-Noise Recording of Brain Activity

     Vomero, Maria; Castagnola, Elisa; Ciarpella, Francesca; Maggiolini, Emma; Goshi, Noah; Zucchini, Elena; Carli, Stefano; Fadiga, Luciano; Kassegne, Sam; Ricci, Davide

     Scientific Reports (2017), 7 (), 40332CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     We report on the superior electrochem. properties, in-vivo performance and long term stability under elec. stimulation of a new electrode material fabricated from lithog. patterned glassy carbon. For a direct comparison with conventional metal electrodes, similar ultra-flexible, micro-electrocorticog. (μ-ECoG) arrays with platinum (Pt) or glassy carbon (GC) electrodes were manufd. The GC microelectrodes have more than 70% wider electrochem. window and 70% higher CTC (charge transfer capacity) than Pt microelectrodes of similar geometry. Moreover, we demonstrate that the GC microelectrodes can withstand at least 5 million pulses at 0.45 mC/cm2 charge d. with less than 7.5% impedance change, while the Pt microelectrodes delaminated after 1 million pulses. Addnl., poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) was selectively electrodeposited on both sets of devices to specifically reduce their impedances for smaller diams. (<60μm). We obsd. that PEDOT-PSS adhered significantly better to GC than Pt, and allowed drastic redn. of electrode size while maintaining same amt. of delivered current. The electrode arrays biocompatibility was demonstrated through in-vitro cell viability expts., while acute in vivo characterization was performed in rats and showed that GC microelectrode arrays recorded somatosensory evoked potentials (SEP) with an almost twice SNR (signal-to-noise ratio) when compared to the Pt ones.
348. 348

     Singh, Y. S.; Sawarynski, L. E.; Michael, H. M.; Ferrell, R. E.; Murphey-Corb, M. A.; Swain, G. M.; Patel, B. A.; Andrews, A. M. Boron- Doped Diamond Microelectrodes Reveal Reduced Serotonin Uptake Rates in Lymphocytes From Adult Rhesus Monkeys Carrying the Short Allele of the 5-HTTLPR. ACS Chem. Neurosci. 2010, 1, 49– 64,  DOI: 10.1021/cn900012y

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     348

     Boron-Doped Diamond Microelectrodes Reveal Reduced Serotonin Uptake Rates in Lymphocytes from Adult Rhesus Monkeys Carrying the Short Allele of the 5-HTTLPR

     Singh, Yogesh S.; Sawarynski, Lauren E.; Michael, Heather M.; Ferrell, Robert E.; Murphey-Corb, Michael A.; Swain, Greg M.; Patel, Bhavik A.; Andrews, Anne M.

     ACS Chemical Neuroscience (2010), 1 (1), 49-64CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

     Uptake resolved by high-speed chronoamperometry on a second-by-second basis has revealed important differences in brain serotonin transporter function assocd. with genetic variability. Here, we use chronoamperometry to investigate variations in serotonin transport in primary lymphocytes assocd. with the rhesus serotonin transporter gene-linked polymorphism (rh5-HTTLPR), a promoter polymorphism whose orthologs occur only in higher order primates including humans. Serotonin clearance by lymphocytes is Na+-dependent and inhibited by the serotonin-selective reuptake inhibitor paroxetine (Paxil), indicative of active uptake by serotonin transporters. Moreover, redns. in serotonin uptake rates are evident in lymphocytes from monkeys with one or two copies of the short 's' allele of the rh5-HTTLPR (s/s < s/l < l/l). These findings illustrate that rh5-HTTLPR-related alterations in serotonin uptake are present during adulthood in peripheral blood cells natively expressing serotonin transporters. Moreover, they suggest that lymphocytes can be used as peripheral biomarkers for investigating genetic or pharmacol. alterations in serotonin transporter function. Use of boron-doped diamond microelectrodes for measuring serotonin uptake, in contrast to carbon fiber microelectrodes used previously in the brain, enabled these high-sensitivity and high-resoln. measurements. Boron-doped diamond microelectrodes show excellent signal-to-noise and signal-to-background ratios due mainly to low background currents and are highly resistant to fouling when exposed to lymphocytes or high concns. of serotonin.
349. 349

     Luo, X.; Weaver, C. L.; Zhou, D. D.; Greenberg, R.; Cui, X. T. Highly Stable Carbon Nanotube Doped Poly(3,4-ethylenedioxythiophene) for Chronic Neural Stimulation. Biomaterials 2011, 32, 5551– 5557,  DOI: 10.1016/j.biomaterials.2011.04.051

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     349

     Highly stable carbon nanotube doped poly(3,4-ethylenedioxythiophene) for chronic neural stimulation

     Luo, Xiliang; Weaver, Cassandra L.; Zhou, David D.; Greenberg, Robert; Cui, Xinyan T.

     Biomaterials (2011), 32 (24), 5551-5557CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     The function and longevity of implantable microelectrodes for chronic neural stimulation depends heavily on the electrode materials, which need to present high charge injection capability and high stability. While conducting polymers were coated on neural microelectrodes and shown promising properties for chronic stimulation, their practical applications were limited due to unsatisfying stability. Here, poly(3,4-ethylenedioxythiophene) (PEDOT) doped with pure carbon nanotubes (CNTs) was electrochem. deposited on Pt microelectrodes to evaluate its properties for chronic stimulation. The PEDOT/CNT coated microelectrodes demonstrated much lower impedance than the bare Pt, and the PEDOT/CNT film exhibited excellent stability. For both acute and chronic stimulation tests, there is no significant increase in the impedance of the PEDOT/CNT coated microelectrodes, and none of the PEDOT/CNT films show any cracks or delamination, which were the limitation for many conducting polymer coatings on neural electrodes. The charge injection limit of the Pt microelectrode was significantly increased to 2.5 mC/cm2 with the PEDOT/CNT coating. Further in vitro expts. also showed that the PEDOT/CNT coatings are non-toxic and support the growth of neurons. It is expected that this highly stable PEDOT/CNT composite may serve as excellent new material for neural electrodes.
350. 350

     Zhao, S.; Liu, X.; Xu, Z.; Ren, H.; Deng, B.; Tang, M.; Lu, L.; Fu, X.; Peng, H.; Liu, Z.; Duan, X. Graphene Encapsulated Copper Microwires as Highly MRI Compatible Neural Electrodes. Nano Lett. 2016, 16, 7731– 7738,  DOI: 10.1021/acs.nanolett.6b03829

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     350

     Graphene Encapsulated Copper Microwires as Highly MRI Compatible Neural Electrodes

     Zhao, Siyuan; Liu, Xiaojun; Xu, Zheng; Ren, Huaying; Deng, Bing; Tang, Miao; Lu, Linlin; Fu, Xuefeng; Peng, Hailin; Liu, Zhongfan; Duan, Xiaojie

     Nano Letters (2016), 16 (12), 7731-7738CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Magnetic resonance imaging (MRI) compatible neural electrodes are important for combining high-resoln. electrophysiol. measurements with more global MRI mapping of brain activity, which is crit. for fundamental neuroscience studies, as well as clin. evaluation and monitoring. Copper is a favorable material to use in MRI because it has magnetic susceptibility close to water and tissues. However, the cytotoxicity of copper precludes its direct implantation for neural recording. Here, we overcome this limitation by developing a graphene encapsulated copper (G-Cu) microelectrode. The toxicity of copper is largely eliminated, as evidenced by the in-vitro cell tests and in-vivo histol. studies. Local field potentials and single-unit spikes are recorded from rodent brains with the G-Cu microelectrodes. Notably, the G-Cu microelectrodes show no image artifacts in a 7.0 T MRI scanner, indicating minimal magnetic field distortion in their vicinity. This high MRI compatibility of our G-Cu probes would open up new opportunities for fundamental brain activity studies and clin. applications requiring continuous MRI and electrophysiol. recordings.
351. 351

     Wadhwa, R.; Lagenaur, C. F.; Cui, X. T. Electrochemically Controlled Release of Dexamethasone From Conducting Polymer Polypyrrole Coated Electrode. J. Controlled Release 2006, 110, 531– 541,  DOI: 10.1016/j.jconrel.2005.10.027

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     351

     Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode

     Wadhwa, Reecha; Lagenaur, Carl F.; Cui, Xinyan Tracy

     Journal of Controlled Release (2006), 110 (3), 531-541CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

     Chronic recordings from micromachined neural electrode arrays often fail a few weeks after implantation primarily due to the formation of an astro-glial sheath around the implant. We propose a drug delivery system, from conducting polymer (CP) coatings on the electrode sites, to modulate the inflammatory implant-host tissue reaction. In this study, polypyrrole (PPy) based coatings for elec. controlled and local delivery of the ionic form of an anti-inflammatory drug, dexamethasone (Dex), was investigated. The drug was incorporated in PPy via electropolymn. of pyrrole and released in PBS using cyclic voltammetry (CV). FTIR anal. of the surface showed the presence of Dex and polypyrrole on the coated electrode. The thickness of the coated film was estd. to be ∼50 nm by ellipsometry. We are able to release 0.5 μg/cm2 Dex in 1 CV cycle and a total of almost 16 μg/cm2 Dex after 30 CV cycles. In vitro studies and immunocytochem. on murine glial cells suggest that the released drug lowers the count of reactive astrocytes to the same extent as the added drug. In addn., the released drug is not toxic to neurons as seen by healthy neuronal viability in the released drug treated cells.
352. 352

     Boehler, C.; Vieira, D. M.; Egert, U.; Asplund, M. NanoPt─A Nanostructured Electrode Coating for Neural Recording and Microstimulation. ACS Appl. Mater. Interfaces 2020, 12, 14855– 14865,  DOI: 10.1021/acsami.9b22798

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     Rivera_Gil, P.; Yang, F.; Thomas, H.; Li, L.; Terfort, A.; Parak, W. J. Development of an Assay Based on Cell Counting with Quantum Dot Labels for Comparing Cell Adhesion Within Cocultures. Nano Today 2011, 6, 20– 27,  DOI: 10.1016/j.nantod.2010.12.006

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354. 354

     Rupprecht, P.; Lewis, C. M.; Helmchen, F. Centripetal Integration of Past Events by Hippocampal Astrocytes. bioRxiv , August 17, 2022, 504030. DOI: 10.1101/2022.08.16.504030 .

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     Li, D.; Agulhon, C.; Schmidt, E.; Oheim, M.; Ropert, N. New Tools for Investigating Astrocyte-to-Neuron Communication. Front. Cell. Neurosci. 2013, 7, 193,  DOI: 10.3389/fncel.2013.00193

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356. 356

     Chowdhury, H. H.; Cerqueira, S. R.; Sousa, N.; Oliveira, J. M.; Reis, R. L.; Zorec, R. The Uptake, Retention and Clearance of Drug-Loaded Dendrimer Nanoparticles in Astrocytes-Electrophysiological Quantification. Biomater. Sci. 2018, 6, 388– 397,  DOI: 10.1039/C7BM00886D

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357. 357

     Zhang, N.; Lin, J.; Chew, S. Y. Neural Cell Membrane-Coated Nanoparticles for Targeted and Enhanced Uptake by Central Nervous System Cells. ACS Appl. Mater. Interfaces 2021, 13, 55840– 55850,  DOI: 10.1021/acsami.1c16543

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     357

     Neural Cell Membrane-Coated Nanoparticles for Targeted and Enhanced Uptake by Central Nervous System Cells

     Zhang, Na; Lin, Junquan; Chew, Sing Yian

     ACS Applied Materials & Interfaces (2021), 13 (47), 55840-55850CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Targeted drug delivery to specific neural cells within the central nervous system (CNS) plays important roles in treating neurol. disorders, such as neurodegenerative (e.g., targeting neurons) and demyelinating diseases [e.g., targeting oligodendrocytes (OLs)]. However, the presence of many other cell types within the CNS, such as microglial and astrocytes, may lead to nonspecific uptake and subsequent side effects. As such, exploring an effective and targeted drug delivery system is of great necessity. Synthetic micro-/nanoparticles that have been coated with biol. derived cellular membranes have emerged as a new class of drug delivery vehicles. However, the use of neural cell-derived membrane coatings remains unexplored. Here, we utilized this technique and demonstrated the efficacy of targeted delivery by using four types of cell membranes that were derived from the CNS, namely, microglial, astrocytes, oligodendrocyte progenitor cells (OPCs), and cortical neurons. A successful cell membrane coating over poly(ε-caprolactone) nanoparticles (NPs) was confirmed using dynamic light scattering, zeta potential measurements, and transmission electron microscopy. Subsequently, an extensive screening of these cell membrane-coated NPs was carried out on various CNS cells. Results suggested that microglial and OLs were the most sensitive cell types toward cell membrane-coated NPs. Specifically, cell membrane-coated NPs significantly enhanced the uptake efficiency of OLs (p < 0.001). Addnl., a temporal uptake study indicated that the OLs took up microglial membrane-coated NPs (DPP-PCL-M Mem) most efficiently. Besides that, coating the NPs with four types of the CNS cell membrane did not result in obvious specific uptake in microglial but reduced the activation of microglial, esp. for DPP-PCL-M Mem (p < 0.01). Taken together, DPP-PCL-M Mem were uptaken most efficiently in OLs and did not induce significant microglial activation and may be most suitable for CNS drug delivery applications.
358. 358

     Gong, J.-Y.; Holt, M. G.; Hoet, P. H.; Ghosh, M. Neurotoxicity of Four Frequently Used Nanoparticles: A Systematic Review to Reveal the Missing Data. Arch. Toxicol. 2022, 96, 1141– 1212,  DOI: 10.1007/s00204-022-03233-1

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359. 359

     Shin, H. J.; Lee, K. Y.; Kwon, K.; Kwon, O.-Y.; Kim, D. W. Development of PLGA Nanoparticles for Astrocyte-specific Delivery of Gene Therapy: A Review. J. Life Sci. 2021, 31, 849– 855,  DOI: 10.5352/JLS.2021.31.9.849

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360. 360

     Porkoláb, G.; Mészáros, M.; Tóth, A.; Szecskó, A.; Harazin, A.; Szegletes, Z.; Ferenc, G.; Blastyák, A.; Mátés, L.; Rákhely, G. Combination of Alanine and Glutathione as Targeting Ligands of Nanoparticles Enhances Cargo Delivery into the Cells of the Neurovascular Unit. Pharmaceutics 2020, 12, 635,  DOI: 10.3390/pharmaceutics12070635

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     360

     Combination of alanine and glutathione as targeting ligands of nanoparticles enhances cargo delivery into the cells of the neurovascular unit

     Porkolab, Gergo; Meszaros, Maria; Toth, Andras; Szecsko, Aniko; Harazin, Andras; Szegletes, Zsolt; Ferenc, Gyoergyi; Blastyak, Andras; Mates, Lajos; Rakhely, Gabor; Deli, Maria A.; Veszelka, Szilvia

     Pharmaceutics (2020), 12 (7), 635CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)

     Inefficient drug delivery across the blood-brain barrier (BBB) and into target cells in the brain hinders the treatment of neurol. diseases. One strategy to increase the brain penetration of drugs is to use vesicular nanoparticles functionalized with multiple ligands of BBB transporters as vehicles. Once within the brain, however, drugs must also be able to reach their therapeutic targets in the different cell types. It is, therefore, favorable if such nanocarriers are designed that can deliver their cargo not only to brain endothelial cells, but to other cell types as well. Here, we show that alanine-glutathione dual-targeting of niosomes enhances the delivery of a large protein cargo into cultured cells of the neurovascular unit, namely brain endothelial cells, pericytes, astrocytes and neurons. Furthermore, using metabolic and endocytic inhibitors, we show that the cellular uptake of niosomes is energy-dependent and is partially mediated by endocytosis. Finally, we demonstate the ability of our targeted nanovesicles to deliver their cargo into astroglial cells after crossing the BBB in vitro. These data indicate that dual-labeling of nanoparticles with alanine and glutathione can potentially be exploited to deliver drugs, even biopharmacons, across the BBB and into multiple cell types in the brain.
361. 361

     Papa, S.; Veneruso, V.; Mauri, E.; Cremonesi, G.; Mingaj, X.; Mariani, A.; De Paola, M.; Rossetti, A.; Sacchetti, A.; Rossi, F. Functionalized Nanogel for Treating Activated Astrocytes in Spinal Cord Injury. J. Controlled Release 2021, 330, 218– 228,  DOI: 10.1016/j.jconrel.2020.12.006

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     Functionalized nanogel for treating activated astrocytes in spinal cord injury

     Papa, Simonetta; Veneruso, Valeria; Mauri, Emanuele; Cremonesi, Giada; Mingaj, Xhuljana; Mariani, Alessandro; De Paola, Massimiliano; Rossetti, Arianna; Sacchetti, Alessandro; Rossi, Filippo; Forloni, Gianluigi; Veglianese, Pietro

     Journal of Controlled Release (2021), 330 (), 218-228CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

     Astrogliosis has a unique reaction during spinal cord damage, with helpful or adverse impacts on recovery. There is consequently a pressing need for treatment to target activated astrocytes and their unsafe response after injury to ensure some preservative effect during the progressive damage. We specifically developed and characterized a functionalized nanogel-based nanovector in vitro and in vivo, demonstrating its selectivity towards astrocytes, and limited uptake by macrophages when functionalized with both NH2 and Cy5 groups. In vitro expts. showed that the internalization was mediated by a clathrin-dependent endocytic pathway. After internalization into the cytoplasm of astrocytes, nanogels undergo lysosomal degrdn. and release compds. with potential therapeutic efficacy.
362. 362

     Wald, G. Molecular Basis of Visual Excitation. Science 1968, 162, 230– 239,  DOI: 10.1126/science.162.3850.230

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     Molecular basis of visual excitation

     Wald, George

     Science (Washington, DC, United States) (1968), 162 (3850), 230-9CODEN: SCIEAS; ISSN:0036-8075.

     In a lecture given at the time of the Nobel prize acceptance, the mol. architecture of retinol1, retinol2, retinal1, and retinal2, as well as their all-trans, 9-cis, and 11-cis-isomers was presented. The rhodopsin system and the isomerization cycle were reviewed followed by a discussion of color vision pigments and color blindness. Some of the most significant aspects of the photoreceptor process come from its being laid out in 2 dimensions: on the mol. level, in a 2-dimensional array of oriented mols., the membranes that comprise the photoreceptor organelles; and on the cellular level, in the single layer of receptor cells that composes the retinal mosaic. 76 references.
363. 363

     Zabelskii, D.; Dmitrieva, N.; Volkov, O.; Shevchenko, V.; Kovalev, K.; Balandin, T.; Soloviov, D.; Astashkin, R.; Zinovev, E.; Alekseev, A. Structure-Based Insights into Evolution of Rhodopsins. Commun. Biol. 2021, 4, 821,  DOI: 10.1038/s42003-021-02326-4

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364. 364

     Gerrard, E.; Mutt, E.; Nagata, T.; Koyanagi, M.; Flock, T.; Lesca, E.; Schertler, G. F.; Terakita, A.; Deupi, X.; Lucas, R. J. Convergent Evolution of Tertiary Structure in Rhodopsin Visual Proteins from Vertebrates and Box Jellyfish. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, 6201– 6206,  DOI: 10.1073/pnas.1721333115

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     Oesterhelt, D.; Stoeckenius, W. Rhodopsin-Like Protein from the Purple Membrane of Halobacterium halobium. Nat. New Biol. 1971, 233, 149– 152,  DOI: 10.1038/newbio233149a0

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     Rhodopsin-like protein from the purple membrane of Halobacterium halobium

     Oesterhelt, Dieter; Stoeckenius, Walther

     Nature (London), New Biology (1971), 233 (39), 149-52CODEN: NNBYA7; ISSN:0369-4887.

     A retinal-protein complex, similar to that found in the retinas of higher animals, was isolated from the purple membrane of H. halobium. The retinal seemed to be bound to a lysine residue in a purple-membrane protein with a mol. wt. of 26,000. The retinal moiety further interacted with the protein, so that its absorption max. was shifted towards a longer wavelength. The Schiff base of the intact complex was inaccessible to BH4- and NH2OH. When the complex was bleached by cetyltrimethyl-ammonium bromide, it became accessible to the above reagents and was either irreversibly bound to the protein or retinal oxime could be extd. It is suggested that the purple membrane may function as a photoreceptor, and the name bacteriorhodopsin is proposed for the purple membrane protein.
366. 366

     Nagel, G.; Ollig, D.; Fuhrmann, M.; Kateriya, S.; Musti, A. M.; Bamberg, E.; Hegemann, P. Channelrhodopsin-1: A Light-Gated Proton Channel in Green Algae. Science 2002, 296, 2395– 2398,  DOI: 10.1126/science.1072068

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     Channelrhodopsin-1: a light-gated proton channel in green algae

     Nagel, Georg; Ollig, Doris; Fuhrmann, Markus; Kateriya, Suneel; Musti, Anna Maria; Bamberg, Ernst; Hegemann, Peter

     Science (Washington, DC, United States) (2002), 296 (5577), 2395-2398CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Phototaxis and photophobic responses of green algae are mediated by rhodopsins with microbial-type chromophores. We report a complementary DNA sequence in the green alga Chlamydomonas reinhardtii that encodes a microbial opsin-related protein, which we term Channelopsin-1. The hydrophobic core region of the protein shows homol. to the light-activated proton pump bacteriorhodopsin. Expression of Channelopsin-1, or only the hydrophobic core, in Xenopus laevis oocytes in the presence of all-trans retinal produces a light-gated conductance that shows characteristics of a channel selectively permeable for protons. We suggest that Channelrhodopsins are involved in phototaxis of green algae.
367. 367

     Crandall, K. A.; Hillis, D. M. Rhodopsin Evolution in the Dark. Nature 1997, 387, 667– 668,  DOI: 10.1038/42628

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     Deisseroth, K.; Hegemann, P. The Form and Function of Channelrhodopsin. Science 2017, 357 (6356), aan5544,  DOI: 10.1126/science.aan5544

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     Zhang, F.; Vierock, J.; Yizhar, O.; Fenno, L. E.; Tsunoda, S.; Kianianmomeni, A.; Prigge, M.; Berndt, A.; Cushman, J.; Polle, J.; Magnuson, J.; Hegemann, P.; Deisseroth, K. The Microbial Opsin Family of Optogenetic Tools. Cell 2011, 147, 1446– 1457,  DOI: 10.1016/j.cell.2011.12.004

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     369

     The Microbial Opsin Family of Optogenetic Tools

     Zhang, Feng; Vierock, Johannes; Yizhar, Ofer; Fenno, Lief E.; Tsunoda, Satoshi; Kianianmomeni, Arash; Prigge, Matthias; Berndt, Andre; Cushman, John; Polle, Juergen; Magnuson, Jon; Hegemann, Peter; Deisseroth, Karl

     Cell (Cambridge, MA, United States) (2011), 147 (7), 1446-1457CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

     A review. The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by mol. engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of mol. engineering and genomic discovery for the utilization and understanding of these remarkable mol. machines.
370. 370

     Berndt, A.; Lee, S. Y.; Wietek, J.; Ramakrishnan, C.; Steinberg, E. E.; Rashid, A. J.; Kim, H.; Park, S.; Santoro, A.; Frankland, P. W.; Iyer, S. M.; Pak, S.; Ährlund-Richter, S.; Delp, S. L.; Malenka, R. C.; Josselyn, S. A.; Carlén, M.; Hegemann, P.; Deisseroth, K. Structural Foundations of Optogenetics: Determinants of Channelrhodopsin Ion Selectivity. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, 822– 829,  DOI: 10.1073/pnas.1523341113

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     Boyden, E. S.; Zhang, F.; Bamberg, E.; Nagel, G.; Deisseroth, K. Millisecond- Timescale, Genetically Targeted Optical Control of Neural Activity. Nat. Neurosci. 2005, 8, 1263– 1268,  DOI: 10.1038/nn1525

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     Millisecond-timescale, genetically targeted optical control of neural activity

     Boyden, Edward S.; Zhang, Feng; Bamberg, Ernst; Nagel, Georg; Deisseroth, Karl

     Nature Neuroscience (2005), 8 (9), 1263-1268CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

     Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technol. allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.
372. 372

     Emiliani, V.; Entcheva, E.; Hedrich, R.; Hegemann, P.; Konrad, K. R.; Lüscher, C.; Mahn, M.; Pan, Z.-H.; Sims, R. R.; Vierock, J.; Yizhar, O. Optogenetics for Light Control of Biological Systems. Nat. Rev. Methods Primers 2022, 2, 55,  DOI: 10.1038/s43586-022-00136-4

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     Joshi, J.; Rubart, M.; Zhu, W. Optogenetics: Background, Methodological Advances and Potential Applications for Cardiovascular Research and Medicine. Front. Bioeng. Biotechnol. 2020, 7, 466,  DOI: 10.3389/fbioe.2019.00466

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374. 374

     Sahel, J. A.; Boulanger-Scemama, E.; Pagot, C.; Arleo, A.; Galluppi, F.; Martel, J. N.; Esposti, S. D.; Delaux, A.; de Saint Aubert, J. B.; de Montleau, C.; Gutman, E.; Audo, I.; Duebel, J.; Picaud, S.; Dalkara, D.; Blouin, L.; Taiel, M.; Roska, B. Partial Recovery of Visual Function in a Blind Patient After Optogenetic Therapy. Nat. Med. 2021, 27, 1223– 1229,  DOI: 10.1038/s41591-021-01351-4

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     374

     Partial recovery of visual function in a blind patient after optogenetic therapy

     Sahel, Jose-Alain; Boulanger-Scemama, Elise; Pagot, Chloe; Arleo, Angelo; Galluppi, Francesco; Martel, Joseph N.; Esposti, Simona Degli; Delaux, Alexandre; de Saint Aubert, Jean-Baptiste; de Montleau, Caroline; Gutman, Emmanuel; Audo, Isabelle; Duebel, Jens; Picaud, Serge; Dalkara, Deniz; Blouin, Laure; Taiel, Magali; Roska, Botond

     Nature Medicine (New York, NY, United States) (2021), 27 (7), 1223-1229CODEN: NAMEFI; ISSN:1078-8956. (Nature Portfolio)

     Abstr.: Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurol. diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-assocd. viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalog. recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.
375. 375

     Bamberg, E.; Gärtner, W.; Trauner, D. Introduction: Optogenetics and Photopharmacology. Chem. Rev. 2018, 118, 10627– 10628,  DOI: 10.1021/acs.chemrev.8b00483

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     Klapper, S. D.; Swiersy, A.; Bamberg, E.; Busskamp, V. Biophysical Properties of Optogenetic Tools and Their Application for Vision Restoration Approaches. Front. Sys. Neurosci. 2016, 10, 74,  DOI: 10.3389/fnsys.2016.00074

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377. 377

     Adamantidis, A.; Arber, S.; Bains, J. S.; Bamberg, E.; Bonci, A.; Buzsáki, G.; Cardin, J. A.; Costa, R. M.; Dan, Y.; Goda, Y. Optogenetics: 10 years after ChR2 in Neurons─Views from the Community. Nat. Neurosci. 2015, 18, 1202– 1212,  DOI: 10.1038/nn.4106

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     Rost, B. R.; Schneider-Warme, F.; Schmitz, D.; Hegemann, P. Optogenetic Tools for Subcellular Applications in Neuroscience. Neuron 2017, 96, 572– 603,  DOI: 10.1016/j.neuron.2017.09.047

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     378

     Optogenetic Tools for Subcellular Applications in Neuroscience

     Rost, Benjamin R.; Schneider-Warme, Franziska; Schmitz, Dietmar; Hegemann, Peter

     Neuron (2017), 96 (3), 572-603CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     The ability to study cellular physiol. using photosensitive, genetically encoded mols. has profoundly transformed neuroscience. The modern optogenetic toolbox includes fluorescent sensors to visualize signaling events in living cells and optogenetic actuators enabling manipulation of numerous cellular activities. Most optogenetic tools are not targeted to specific subcellular compartments but are localized with limited discrimination throughout the cell. Therefore, optogenetic activation often does not reflect context-dependent effects of highly localized intracellular signaling events. Subcellular targeting is required to achieve more specific optogenetic readouts and photomanipulation. Here we first provide a detailed overview of the available optogenetic tools with a focus on optogenetic actuators. Second, we review established strategies for targeting these tools to specific subcellular compartments. Finally, we discuss useful tools and targeting strategies that are currently missing from the optogenetics repertoire and provide suggestions for novel subcellular optogenetic applications.
379. 379

     Chernov, K. G.; Redchuk, T. A.; Omelina, E. S.; Verkhusha, V. V. Near- Infrared Fluorescent Proteins, Biosensors, and Optogenetic Tools Engineered from Phytochromes. Chem. Rev. 2017, 117, 6423– 6446,  DOI: 10.1021/acs.chemrev.6b00700

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     379

     Near-Infrared Fluorescent Proteins, Biosensors, and Optogenetic Tools Engineered from Phytochromes

     Chernov, Konstantin G.; Redchuk, Taras A.; Omelina, Evgeniya S.; Verkhusha, Vladislav V.

     Chemical Reviews (Washington, DC, United States) (2017), 117 (9), 6423-6446CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Phytochrome photoreceptors absorb far-red and near-IR (NIR) light and regulate light responses in plants, fungi and bacteria. Their multidomain structure and autocatalytic incorporation of linear tetrapyrrole chromophores make phytochromes attractive mol. templates for the development of light-sensing probes. A subclass of bacterial phytochromes (BphPs) utilizes heme-derived biliverdin tetrapyrrole, which is ubiquitous in mammalian tissues, as a chromophore. Because biliverdin possesses the largest electron conjugated chromophore system among linear tetrapyrroles, BphPs exhibit the most NIR-shifted spectra that reside within the NIR tissue transparency window. Here we analyze phytochrome structure and photochem. to describe the mol. mechanisms by which they function. We then present strategies to engineer BphP-based NIR fluorescent proteins and review their properties and applications in modern imaging technologies. We next summarize designs of reporters and biosensors and describe their use in the detection of protein-protein interactions, proteolytic activities and posttranslational modifications. Finally, we provide an overview of optogenetic tools developed from phytochromes and describe their use in light-controlled cell signaling, gene expression and protein localization. Our review provides guidelines for the selection of NIR probes and tools for noninvasive imaging, sensing and light manipulation applications, specifically focusing on the probes developed for use in mammalian cells and in vivo.
380. 380

     Hososhima, S.; Yuasa, H.; Ishizuka, T.; Hoque, M. R.; Yamashita, T.; Yamanaka, A.; Sugano, E.; Tomita, H.; Yawo, H. Near-Infrared (NIR) Up-Conversion Optogenetics. Sci. Rep. 2015, 5, 16533,  DOI: 10.1038/srep16533

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     Near-infrared (NIR) up-conversion optogenetics

     Hososhima, Shoko; Yuasa, Hideya; Ishizuka, Toru; Hoque, Mohammad Razuanul; Yamashita, Takayuki; Yamanaka, Akihiro; Sugano, Eriko; Tomita, Hiroshi; Yawo, Hiromu

     Scientific Reports (2015), 5 (), 16533CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     Non-invasive remote control technologies designed to manipulate neural functions have been long-awaited for the comprehensive and quant. understanding of neuronal network in the brain as well as for the therapy of neurol. disorders. Recently, it has become possible for the neuronal activity to be optically manipulated using biol. photo-reactive mols. such as channelrhodopsin (ChR)-2. However, ChR2 and its relatives are mostly reactive to visible light, which does not effectively penetrate through biol. tissues. In contrast, near-IR (NIR) light (650-1450 nm) penetrates deep into the tissues because biol. systems are almost transparent to light within this so-called 'imaging window'. Here we used lanthanide nanoparticles (LNPs), composed of rare-earth elements, as luminous bodies to activate ChRs since they absorb low-energy NIR light to emit high-energy visible light (up-conversion). Here, we created a new type of optogenetic system which consists of the donor LNPs and the acceptor ChRs. The NIR laser irradn. emitted visible light from LNPs, then induced the photo-reactive responses in the near-by cells that expressed ChRs. However, there remains room for large improvements in the energy efficiency of the LNP-ChR system.
381. 381

     Bi, A.; Cui, J.; Ma, Y.-P.; Olshevskaya, E.; Pu, M.; Dizhoor, A. M.; Pan, Z.-H. Ectopic Expression of a Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration. Neuron 2006, 50, 23– 33,  DOI: 10.1016/j.neuron.2006.02.026

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     381

     Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration

     Bi, Anding; Cui, Jinjuan; Ma, Yu-Ping; Olshevskaya, Elena; Pu, Mingliang; Dizhoor, Alexander M.; Pan, Zhuo-Hua

     Neuron (2006), 50 (1), 23-33CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     The death of photoreceptor cells caused by retinal degenerative diseases often results in a complete loss of retinal responses to light. We explore the feasibility of converting inner retinal neurons to photosensitive cells as a possible strategy for imparting light sensitivity to retinas lacking rods and cones. Using delivery by an adeno-assocd. viral vector, here, we show that long-term expression of a microbial-type rhodopsin, channelrhodopsin-2 (ChR2), can be achieved in rodent inner retinal neurons in vivo. Furthermore, we demonstrate that expression of ChR2 in surviving inner retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex. Thus, expression of microbial-type channelrhodopsins, such as ChR2, in surviving inner retinal neurons is a potential strategy for the restoration of vision after rod and cone degeneration.
382. 382

     Efimov, A. I.; Hibberd, T. J.; Wang, Y.; Wu, M.; Zhang, K.; Ting, K.; Madhvapathy, S.; Lee, M.-K.; Kim, J.; Kang, J. Remote Optogenetic Control of the Enteric Nervous System and Brain-Gut Axis in Freely-Behaving Mice Enabled by a Wireless, Battery-Free Optoelectronic Device. Biosens. Bioelectron. 2024, 258, 116298,  DOI: 10.1016/j.bios.2024.116298

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383. 383

     Losi, A.; Gardner, K. H.; Möglich, A. Blue-Light Receptors for Optogenetics. Chem. Rev. 2018, 118, 10659– 10709,  DOI: 10.1021/acs.chemrev.8b00163

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     383

     Blue-Light Receptors for Optogenetics

     Losi, Aba; Gardner, Kevin H.; Moglich, Andreas

     Chemical Reviews (Washington, DC, United States) (2018), 118 (21), 10659-10709CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Sensory photoreceptors underpin light-dependent adaptations of organismal physiol., development, and behavior in nature. Adapted for optogenetics, sensory photoreceptors become genetically encoded actuators and reporters to enable the noninvasive, spatiotemporally accurate and reversible control by light of cellular processes. Rooted in a mechanistic understanding of natural photoreceptors, artificial photoreceptors with customized light-gated function have been engineered that greatly expand the scope of optogenetics beyond the original application of light-controlled ion flow. As we survey presently, UV/blue-light-sensitive photoreceptors have particularly allowed optogenetics to transcend its initial neuroscience applications by unlocking numerous addnl. cellular processes and parameters for optogenetic intervention, including gene expression, DNA recombination, subcellular localization, cytoskeleton dynamics, intracellular protein stability, signal transduction cascades, apoptosis, and enzyme activity. The engineering of novel photoreceptors benefits from powerful and reusable design strategies, most importantly light-dependent protein assocn. and (un)folding reactions. Addnl., modified versions of these same sensory photoreceptors serve as fluorescent proteins and generators of singlet oxygen, thereby further enriching the optogenetic toolkit. The available and upcoming UV/blue-light-sensitive actuators and reporters enable the detailed and quant. interrogation of cellular signal networks and processes in increasingly more precise and illuminating manners.
384. 384

     Verkhratsky, A.; Nedergaard, M. Physiology of Astroglia. Physiol. Rev. 2018, 98, 239– 389,  DOI: 10.1152/physrev.00042.2016

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     384

     Physiology of astroglia

     Verkhratsky, Alexei; Nedergaard, Maiken

     Physiological Reviews (2018), 98 (1), 239-389CODEN: PHREA7; ISSN:1522-1210. (American Physiological Society)

     Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphol. appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from mol. to the whole organ.
385. 385

     Lim, D.; Semyanov, A.; Genazzani, A.; Verkhratsky, A. Calcium Signaling in Neuroglia. Int. Rev. Cell Mol. Biol. 2021, 362, 1– 53,  DOI: 10.1016/bs.ircmb.2021.01.003

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386. 386

     Airan, R. D.; Thompson, K. R.; Fenno, L. E.; Bernstein, H.; Deisseroth, K. Temporally Precise in Vivo Control of Intracellular Signalling. Nature 2009, 458, 1025– 1029,  DOI: 10.1038/nature07926

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     386

     Temporally precise in vivo control of intracellular signalling

     Airan, Raag D.; Thompson, Kimberly R.; Fenno, Lief E.; Bernstein, Hannah; Deisseroth, Karl

     Nature (London, United Kingdom) (2009), 458 (7241), 1025-1029CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     In the study of complex mammalian behaviors, technol. limitations have prevented spatiotemporally precise control over intracellular signaling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochem. signaling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signaling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochem. signaling in behaving mammals, in a targetable and temporally precise manner.
387. 387

     Iwai, Y.; Ozawa, K.; Yahagi, K.; Mishima, T.; Akther, S.; Vo, C. T.; Lee, A. B.; Tanaka, M.; Itohara, S.; Hirase, H. Transient Astrocytic GQ Signaling Underlies Remote Memory Enhancement. Front. Neural Circuits 2021, 15, 658343,  DOI: 10.3389/fncir.2021.658343

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388. 388

     Figueiredo, M.; Lane, S.; Tang, F.; Liu, B.; Hewinson, J.; Marina, N.; Kasymov, V.; Souslova, E.; Chudakov, D.; Gourine, A. Optogenetic Experimentation on Astrocytes. Exp. Physiol. 2011, 96, 40– 50,  DOI: 10.1113/expphysiol.2010.052597

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     388

     Optogenetic experimentation on astrocytes

     Figueiredo M; Lane S; Tang F; Liu B H; Hewinson J; Marina N; Kasymov V; Souslova E A; Chudakov D M; Gourine A V; Teschemacher A G; Kasparov S

     Experimental physiology (2011), 96 (1), 40-50 ISSN:.

     We briefly review the current literature where optogenetics has been used to study various aspects of astrocyte physiology in vitro and in vivo. This includes both genetically engineered Ca(2+) sensors and effector proteins, such as channelrhodopsin. We demonstrate how the ability to target astrocytes with cell-specific viral vectors to express optogenetic constructs helped to unravel some previously unsuspected roles of these inconspicuous cells.
389. 389

     Lohr, C. Role of P2Y Receptors in Astrocyte Physiology and Pathophysiology. Neuropharmacology 2023, 223, 109311,  DOI: 10.1016/j.neuropharm.2022.109311

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     389

     Role of P2Y receptors in astrocyte physiology and pathophysiology

     Lohr, Christian

     Neuropharmacology (2023), 223 (), 109311CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

     A review. Astrocytes are active constituents of the brain that manage ion homeostasis and metabolic support of neurons and directly tune synaptic transmission and plasticity. Astrocytes express all known P2Y receptors. These regulate a multitude of physiol. functions such as cell proliferation, Ca2+ signalling, gliotransmitter release and neurovascular coupling. In addn., P2Y receptors are fundamental in the transition of astrocytes into reactive astrocytes, as occurring in many brain disorders such as neurodegenerative diseases, neuroinflammation and epilepsy. This review summarizes the current literature addressing the function of P2Y receptors in astrocytes in the healthy brain as well as in brain diseases.
390. 390

     Oliveira, J. F.; Sardinha, V. M.; Guerra-Gomes, S.; Araque, A.; Sousa, N. Do Stars Govern Our Actions? Astrocyte Involvement in Rodent Behavior. Trends Neurosci. 2015, 38, 535– 549,  DOI: 10.1016/j.tins.2015.07.006

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391. 391

     Henneberger, C.; Papouin, T.; Oliet, S. H.; Rusakov, D. A. Long- Term Potentiation Depends on Release of d-Serine from Astrocytes. Nature 2010, 463, 232– 236,  DOI: 10.1038/nature08673

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392. 392

     Lohr, C.; Beiersdorfer, A.; Fischer, T.; Hirnet, D.; Rotermund, N.; Sauer, J.; Schulz, K.; Gee, C. E. Using Genetically Encoded Calcium Indicators to Study Astrocyte Physiology: A Field Guide. Front. Cell. Neurosci. 2021, 15, 690147,  DOI: 10.3389/fncel.2021.690147

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393. 393

     Semyanov, A.; Henneberger, C.; Agarwal, A. Making Sense of Astrocytic Calcium Signals─from Acquisition to Interpretation. Nat. Rev. Neurosci. 2020, 21, 551– 564,  DOI: 10.1038/s41583-020-0361-8

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394. 394

     Li, P.; Rial, D.; Canas, P. M.; Yoo, J.-H.; Li, W.; Zhou, X.; Wang, Y.; van Westen, G. J.; Payen, M.-P.; Augusto, E. Optogenetic Activation of Intracellular Adenosine A2A Receptor Signaling in the Hippocampus Is Sufficient to Trigger CREB Phosphorylation and Impair Memory. Mol. Psychiatry 2015, 20, 1339– 1349,  DOI: 10.1038/mp.2014.182

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     394

     Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory

     Li, P.; Rial, D.; Canas, P. M.; Yoo, J.-H.; Li, W.; Zhou, X.; Wang, Y.; van Westen, G. J. P.; Payen, M.-P.; Augusto, E.; Goncalves, N.; Tome, A. R.; Li, Z.; Wu, Z.; Hou, X.; Zhou, Y.; PiJzerman, Ad; Boyden, E. S.; Cunha, R. A.; Qu, J.; Chen, J.-F.

     Molecular Psychiatry (2015), 20 (11), 1339-1349CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)

     Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiol. relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
395. 395

     Nikolaev, V. O.; Bunemann, M.; Hein, L.; Hannawacker, A.; Lohse, M. J. Novel Single Chain cAMP Sensors for Receptor-Induced Signal Propagation. J. Biol. Chem. 2004, 279, 37215– 37218,  DOI: 10.1074/jbc.C400302200

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     395

     Novel Single Chain cAMP Sensors for Receptor-induced Signal Propagation

     Nikolaev, Viacheslav O.; Buenemann, Moritz; Hein, Lutz; Hannawacker, Annette; Lohse, Martin J.

     Journal of Biological Chemistry (2004), 279 (36), 37215-37218CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     CAMP is a universal second messenger of many G-protein-coupled receptors and regulates a wide variety of cellular events. CAMP exerts its effects via cAMP-dependent protein kinase (PKA), cAMP-gated ion channels, and two isoforms of exchange protein directly activated by cAMP (Epac). Here we report the development of novel fluorescent indicators for cAMP based on the cAMP-binding domains of Epac and PKA. Fluorescence resonance energy transfer between variants of green fluorescent protein (enhanced cyan fluorescent protein and enhanced yellow fluorescent protein) fused directly to the cAMP-binding domains was used to analyze spatial and temporal aspects of cAMP-signaling in different cells. In contrast to previously developed PKA-based indicators, these probes are comprised of only a single binding site lacking cooperativity, catalytic properties, and interactions with other proteins and thereby allow us to easily image free intracellular cAMP and rapid signaling events. Rapid β-adrenergic receptor-induced cAMP signals were obsd. to travel with high speed (≈40 μm/s) throughout the entire cell body of hippocampal neurons and peritoneal macrophages. The developed indicators could be ubiquitously applied to studying cAMP, its physiol. role and spatio-temporal regulation.
396. 396

     Odaka, H.; Arai, S.; Inoue, T.; Kitaguchi, T. Genetically-Encoded Yellow Fluorescent cAMP Indicator with an Expanded Dynamic Range for Dual-Color Imaging. PLoS One 2014, 9, e100252,  DOI: 10.1371/journal.pone.0100252

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397. 397

     Stierl, M.; Stumpf, P.; Udwari, D.; Gueta, R.; Hagedorn, R.; Losi, A.; Gärtner, W.; Petereit, L.; Efetova, M.; Schwarzel, M. Light Modulation of Cellular cAMP by a Small Bacterial Photoactivated Adenylyl Cyclase, bPAC, of the Soil Bacterium Beggiatoa. J. Biol. Chem. 2011, 286, 1181– 1188,  DOI: 10.1074/jbc.M110.185496

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     397

     Light Modulation of Cellular cAMP by a Small Bacterial Photoactivated Adenylyl Cyclase, bPAC, of the Soil Bacterium Beggiatoa

     Stierl, Manuela; Stumpf, Patrick; Udwari, Daniel; Gueta, Ronnie; Hagedorn, Rolf; Losi, Aba; Gaertner, Wolfgang; Petereit, Linda; Efetova, Marina; Schwarzel, Martin; Oertner, Thomas G.; Nagel, Georg; Hegemann, Peter

     Journal of Biological Chemistry (2011), 286 (2), 1181-1188CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

     The recent success of channelrhodopsin (ChR) in optogenetics has generated increasing interest in enzymes that are directly activated by light. We have identified in the genome of the bacterium Beggiatoa a DNA sequence encoding an adenylyl cyclase directly linked to a BLUF (blue light receptor using FAD) type light sensor domain. In Escherichia coli and Xenopus oocytes, this photoactivated adenylyl cyclase (bPAC) showed cyclase activity that is low in darkness but increased 300-fold in the light. This enzymic activity decays thermally within 20 s in parallel with the red-shifted BLUF photointermediate. BPAC is efficiently expressed in pyramidal neurons, and in combination with cyclic nucleotide-gated channels, causes efficient light-induced depolarization. In the Drosophila central nervous system, bPAC mediates light-dependent cAMP increases and behavioral changes in freely moving animals. BPAC seems a perfect optogenetic tool for light modulation of cAMP in neuronal cells and tissues and for studying cAMP-dependent processes in live animals.
398. 398

     Yang, S.; Constantin, O. M.; Sachidanandan, D.; Hofmann, H.; Kunz, T. C.; Kozjak-Pavlovic, V.; Oertner, T. G.; Nagel, G.; Kittel, R. J.; Gee, C. E. PACmn for Improved Optogenetic Control of Intracellular cAMP. BMC Biol. 2021, 19, 227,  DOI: 10.1186/s12915-021-01151-9

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     There is no corresponding record for this reference.
399. 399

     Oe, Y.; Wang, X.; Patriarchi, T.; Konno, A.; Ozawa, K.; Yahagi, K.; Hirai, H.; Tsuboi, T.; Kitaguchi, T.; Tian, L. Distinct Temporal Integration of Noradrenaline Signaling by Astrocytic Second Messengers During Vigilance. Nat. Commun. 2020, 11, 471,  DOI: 10.1038/s41467-020-14378-x

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400. 400

     Zhou, Z.; Okamoto, K.; Onodera, J.; Hiragi, T.; Andoh, M.; Ikawa, M.; Tanaka, K. F.; Ikegaya, Y.; Koyama, R. Astrocytic cAMP Modulates Memory via Synaptic Plasticity. Proc. Natl. Acad. Sci. U. S. A. 2021, 118, e2016584118,  DOI: 10.1073/pnas.2016584118

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     400

     Astrocytic cAMP modulates memory via synaptic plasticity

     Zhou, Zhiwen; Okamoto, Kazuki; Onodera, Junya; Hiragi, Toshimitsu; Andoh, Megumi; Ikawa, Masahito; Tanaka, Kenji F.; Ikegaya, Yuji; Koyama, Ryuta

     Proceedings of the National Academy of Sciences of the United States of America (2021), 118 (3), e2016584118CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial-neuronal interactions remains largely unknown. Here, we show that an increase in astrocytic cAMP is sufficient to induce synaptic plasticity and modulate memory. We developed a method to increase astrocytic cAMP levels in vivo using photoactivated adenylyl cyclase and found that increased cAMP in hippocampal astrocytes at different time points facilitated memory formation but interrupted memory retention via NMDA receptor-dependent plasticity. Furthermore, we found that the cAMP-induced modulation of memory was mediated by the astrocyte-neuron lactate shuttle. Thus, our study unveils a role of astrocytic cAMP in brain function by providing a tool to modulate astrocytic cAMP in vivo.
401. 401

     Zhuo, J.; Weidrick, C. E.; Liu, Y.; Moffitt, M. A.; Jansen, E. D.; Chiel, H. J.; Jenkins, M. W. Selective Infrared Neural Inhibition Can Be Reproduced by Resistive Heating. Neuromodulation: Technol. Neural Interface 2023, 26, 1757– 1771,  DOI: 10.1016/j.neurom.2022.12.004

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     There is no corresponding record for this reference.
402. 402

     Szallasi, A.; Nilsson, S.; Farkas-Szallasi, T.; Blumberg, P. M.; Hökfelt, T.; Lundberg, J. M. Vanilloid (Capsaicin) Receptors in the Rat: Distribution in the Brain, Regional Differences in the Spinal Cord, Axonal Transport to the Periphery, and Depletion by Systemic Vanilloid Treatment. Brain Res. 1995, 703, 175– 183,  DOI: 10.1016/0006-8993(95)01094-7

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     402

     Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional differences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment

     Szallasi, Arpad; Nilsson, Siv; Farkas-Szallasi, Tunde; Blumberg, Peter M.; Hoekfelt, Tomas; Lundberg, Jan M.

     Brain Research (1995), 703 (1,2), 175-83CODEN: BRREAP; ISSN:0006-8993. (Elsevier)

     Vanilloid (capsaicin) receptors were visualized by [3H]resiniferatoxin (RTX) autoradiog. in the brain of newborn as well as adult (both control and colchicine-treated) rats. Specific labeling was seen in the brain stem only, in the nucleus of the solitary tract extending into the area postrema and the spinal sensory nucleus of the trigeminal nerve. Also, a strong signal was seen in the dorsal horn, dorsal root, trigeminal and nodose ganglia. Membranes obtained from the cervical, thoracic, and lumbar segments of the spinal cord showed similar affinities for RTX and likewise for capsaicin and capsazepine; maximal receptor d. was similar in the cervical and thoracic segments (approx. 70 fmol/mg protein) but was twice as high in the lumbar segment. 24 h after ligation of the vagal or the sciatic nerves, a strong accumulation of specific RTX binding sites was obsd. mainly proximal to the ligature, implying intraaxonal receptor transport from the nodose and dorsal root ganglia, resp., to the periphery. Systemic (s.c.) vanilloid treatment depleted specific [3H]RTX binding sites from the brain stem, the sensory (dorsal root as well as trigeminal) ganglia, and the spinal cord. RTX was approx. 200-fold more potent than capsaicin for eliminating vanilloid receptors from the spinal cord. The present results suggest a discrete expression of vanilloid receptors in the brain stem (sensory nuclei); although intrinsic vanilloid receptor-expressing neurons are thought to exist in the rat brain, they remain undetected by the present [3H]RTX autoradiog. methodol.
403. 403

     Chen, R.; Romero, G.; Christiansen, M. G.; Mohr, A.; Anikeeva, P. Wireless Magnetothermal Deep Brain Stimulation. Science 2015, 347, 1477– 1480,  DOI: 10.1126/science.1261821

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     403

     Wireless magnetothermal deep brain stimulation

     Chen, Ritchie; Romero, Gabriela; Christiansen, Michael G.; Mohr, Alan; Anikeeva, Polina

     Science (Washington, DC, United States) (2015), 347 (6229), 1477-1480CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Wireless deep brain stimulation of well-defined neuronal populations could facilitate the study of intact brain circuits and the treatment of neurol. disorders. Here, we demonstrate minimally invasive and remote neural excitation through the activation of the heat-sensitive capsaicin receptor TRPV1 by magnetic nanoparticles. When exposed to alternating magnetic fields, the nanoparticles dissipate heat generated by hysteresis, triggering widespread and reversible firing of TRPV1+ neurons. Wireless magnetothermal stimulation in the ventral tegmental area of mice evoked excitation in subpopulations of neurons in the targeted brain region and in structures receiving excitatory projections. The nanoparticles persisted in the brain for over a month, allowing for chronic stimulation without the need for implants and connectors.
404. 404

     Takaishi, M.; Uchida, K.; Suzuki, Y.; Matsui, H.; Shimada, T.; Fujita, F.; Tominaga, M. Reciprocal Effects of Capsaicin and Menthol on Thermosensation through Regulated Activities of TRPV1 and TRPM8. J. Physiol. Sci. 2016, 66, 143– 155,  DOI: 10.1007/s12576-015-0427-y

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     404

     Reciprocal effects of capsaicin and menthol on thermosensation through regulated activities of TRPV1 and TRPM8

     Takaishi, Masayuki; Uchida, Kunitoshi; Suzuki, Yoshiro; Matsui, Hiroshi; Shimada, Tadashi; Fujita, Fumitaka; Tominaga, Makoto

     Journal of Physiological Sciences (2016), 66 (2), 143-155CODEN: JPSOE2; ISSN:1880-6546. (Springer Japan)

     Transient receptor potential vanilloid 1 (TRPV1) is activated by elevated temp. (>42°), and it has been reported that cold temp. decreases capsaicin-induced TRPV1 activity. In contrast, transient receptor potential melastatin 8 (TRPM8) is activated by low temps. and menthol, and heat stimulation suppresses menthol-evoked TRPM8 currents. These findings suggest that the effects of specific agents on TRPV1 and TRPM8 channels are intricately interrelated. We examd. the effects of menthol on human (h)TRPV1 and of capsaicin on hTRPM8. hTRPV1 currents activated by heat and capsaicin were inhibited by menthol, whereas hTRPM8 currents activated by cold and menthol were similarly inhibited by capsaicin. An in vivo sensory irritation test showed that menthol conferred an analgesic effect on the sensory irritation evoked by a capsaicin analog. These results indicate that in our study the agonists of TRPV1 and TRPM8 interacted with both of these channels and suggest that the anti-nociceptive effects of menthol can be partially explained by this phenomenon.
405. 405

     Bernstein, J. G.; Garrity, P. A.; Boyden, E. S. Optogenetics and Thermogenetics: Technologies for Controlling the Activity of Targeted Cells within Intact Neural Circuits. Curr. Opin. Neurobiol. 2012, 22, 61– 71,  DOI: 10.1016/j.conb.2011.10.023

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     405

     Optogenetics and thermogenetics: technologies for controlling the activity of targeted cells within intact neural circuits

     Bernstein, Jacob G.; Garrity, Paul A.; Boyden, Edward S.

     Current Opinion in Neurobiology (2012), 22 (1), 61-71CODEN: COPUEN; ISSN:0959-4388. (Elsevier Ltd.)

     In recent years, interest has grown in the ability to manipulate, in a temporally precise fashion, the elec. activity of specific neurons embedded within densely wired brain circuits, in order to reveal how specific neurons subserve behaviors and neural computations, and to open up new horizons on the clin. treatment of brain disorders. Technologies that enable temporally precise control of elec. activity of specific neurons, and not these neurons' neighbors - whose cell bodies or processes might be just tens to hundreds of nanometers away - must involve two components. First, they require as a trigger a transient pulse of energy that supports the temporal precision of the control. Second, they require a mol. sensitizer that can be expressed in specific neurons and which renders those neurons specifically responsive to the triggering energy delivered. Optogenetic tools, such as microbial opsins, can be used to activate or silence neural activity with brief pulses of light. Thermogenetic tools, such as thermosensitive TRP channels, can be used to drive neural activity downstream of increases or decreases in temp. We here discuss the principles underlying the operation of these two recently developed, but widely used, toolboxes, as well as the directions being taken in the use and improvement of these toolboxes.
406. 406

     Huang, H.; Delikanli, S.; Zeng, H.; Ferkey, D. M.; Pralle, A. Remote Control of Ion Channels and Neurons Through Magnetic-Field Heating of Nanoparticles. Nat. Nanotechnol. 2010, 5, 602– 606,  DOI: 10.1038/nnano.2010.125

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     406

     Remote control of ion channels and neurons through magnetic-field heating of nanoparticles

     Huang, Heng; Delikanli, Savas; Zeng, Hao; Ferkey, Denise M.; Pralle, Arnd

     Nature Nanotechnology (2010), 5 (8), 602-606CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     Recently, optical stimulation has begun to unravel the neuronal processing that controls certain animal behaviors. However, optical approaches are limited by the inability of visible light to penetrate deep into tissues. Here, the authors show an approach based on radio-frequency magnetic-field heating of nanoparticles to remotely activate temp.-sensitive cation channels in cells. Superparamagnetic ferrite nanoparticles were targeted to specific proteins on the plasma membrane of cells expressing TRPV1, and heated by a radio-frequency magnetic field. Using fluorophores as mol. thermometers, the authors show that the induced temp. increase is highly localized. Thermal activation of the channels triggers action potentials in cultured neurons without observable toxic effects. This approach can be adapted to stimulate other cell types and, moreover, may be used to remotely manipulate other cellular machinery for novel therapeutics.
407. 407

     Munshi, R.; Qadri, S. M.; Zhang, Q.; Rubio, I. C.; Pino, P. d.; Pralle, A. Magnetothermal genetic deep brain stimulation of motor behaviors in awake, freely moving mice. eLife 2017, 6, e27069,  DOI: 10.7554/eLife.27069

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     407

     Magnetothermal genetic deep brain stimulation of motor behaviors in awake, freely moving mice

     Munshi, Rahul; Qadri, Shahnaz M.; Zhang, Qian; Rubio, Idoia Castellanos; del Pino, Pablo; Pralle, Arnd

     eLife (2017), 6 (), e27069/1-e27069/26CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)

     Establishing how neurocircuit activation causes particular behaviors requires modulating the activity of specific neurons. Here, we demonstrate that magnetothermal genetic stimulation provides tetherless deep brain activation sufficient to evoke motor behavior in awake mice. The approach uses alternating magnetic fields to heat superparamagnetic nanoparticles on the neuronal membrane. Neurons, heat-sensitized by expressing TRPV1 are activated with magnetic field application. Magnetothermal genetic stimulation in the motor cortex evoked ambulation, deep brain stimulation in the striatum caused rotation around the body-axis, and stimulation near the ridge between ventral and dorsal striatum caused freezing-of-gait. The duration of the behavior correlated tightly with field application. This approach provides genetically and spatially targetable, repeatable and temporarily precise activation of deep-brain circuits without the need for surgical implantation of any device.
408. 408

     Coste, B.; Mathur, J.; Schmidt, M.; Earley, T. J.; Ranade, S.; Petrus, M. J.; Dubin, A. E.; Patapoutian, A. Piezo1 and Piezo2 are Essential Components of Distinct Mechanically Activated Cation Channels. Science 2010, 330, 55– 60,  DOI: 10.1126/science.1193270

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     408

     Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels

     Coste, Bertrand; Mathur, Jayanti; Schmidt, Manuela; Earley, Taryn J.; Ranade, Sanjeev; Petrus, Matt J.; Dubin, Adrienne E.; Patapoutian, Ardem

     Science (Washington, DC, United States) (2010), 330 (6000), 55-60CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Mech. stimuli drive many physiol. processes, including touch and pain sensation, hearing, and blood pressure regulation. Mech. activated (MA) cation channel activities have been recorded in many cells, but the responsible mols. have not been identified. We characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. We propose that Piezos are components of MA cation channels.
409. 409

     Kefauver, J.; Ward, A.; Patapoutian, A. Discoveries in Structure and Physiology of Mechanically Activated Ion Channels. Nature 2020, 587, 567– 576,  DOI: 10.1038/s41586-020-2933-1

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     409

     Discoveries in structure and physiology of mechanically activated ion channels

     Kefauver, J. M.; Ward, A. B.; Patapoutian, A.

     Nature (London, United Kingdom) (2020), 587 (7835), 567-576CODEN: NATUAS; ISSN:0028-0836. (Nature Research)

     A review. The ability to sense phys. forces is conserved across all organisms. Cells convert mech. stimuli into elec. or chem. signals via mech. activated ion channels. In recent years, the identification of new families of mechanosensitive ion channels-such as PIEZO and OSCA/TMEM63 channels-along with surprising insights into well-studied mechanosensitive channels have driven further developments in the mechanotransduction field. Several well-characterized mechanosensory roles such as touch, blood-pressure sensing and hearing are now linked with primary mechanotransducers. Unanticipated roles of mech. force sensing continue to be uncovered. Furthermore, high-resoln. structures representative of nearly every family of mech. activated channel described so far have underscored their diversity while advancing the authors' understanding of the biophys. mechanisms of pressure sensing. Here the authors summarize recent discoveries in the physiol. and structures of known mech. activated ion channel families and discuss their implications for understanding the mechanisms of mech. force sensing.
410. 410

     Haswell, E. S.; Phillips, R.; Rees, D. C. Mechanosensitive Channels: What Can They Do and How Do They Do It?. Structure 2011, 19, 1356– 1369,  DOI: 10.1016/j.str.2011.09.005

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     410

     Mechanosensitive channels: What can they do and how do they do it?

     Haswell, Elizabeth S.; Phillips, Rob; Rees, Douglas C.

     Structure (Cambridge, MA, United States) (2011), 19 (10), 1356-1369CODEN: STRUE6; ISSN:0969-2126. (Cell Press)

     A review. While mechanobiol. processes employ diverse mechanisms, at their heart are force-induced perturbations in the structure and dynamics of mols. capable of triggering subsequent events. Among the best characterized force-sensing systems are bacterial mechanosensitive channels. These channels reflect an intimate coupling of protein conformation with the mechanics of the surrounding membrane; the membrane serves as an adaptable sensor that responds to an input of applied force and converts it into an output signal, interpreted for the cell by mechanosensitive channels. The cell can exploit this information in a no. of ways: ensuring cellular viability in the presence of osmotic stress and perhaps also serving as a signal transducer for membrane tension or other functions. Here, the authors focus on bacterial mechanosensitive channels of large (MscL) and small (MscS) conductance and their eukaryotic homologs, with an emphasis on the outstanding issues surrounding the function and mechanism of this fascinating class of mols.
411. 411

     Cadoni, S.; Demené, C.; Alcala, I.; Provansal, M.; Nguyen, D.; Nelidova, D.; Labernède, G.; Lubetzki, J.; Goulet, R.; Burban, E. Ectopic Expression of a Mechanosensitive Channel Confers Spatiotemporal Resolution to Ultrasound Stimulations of Neurons for Visual Restoration. Nat. Nanotechnol. 2023, 18, 667– 676,  DOI: 10.1038/s41565-023-01359-6

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     411

     Ectopic expression of a mechanosensitive channel confers spatiotemporal resolution to ultrasound stimulations of neurons for visual restoration

     Cadoni, Sara; Demene, Charlie; Alcala, Ignacio; Provansal, Matthieu; Nguyen, Diep; Nelidova, Dasha; Labernede, Guillaume; Lubetzki, Jules; Goulet, Ruben; Burban, Emma; Degardin, Julie; Simonutti, Manuel; Gauvain, Gregory; Arcizet, Fabrice; Marre, Olivier; Dalkara, Deniz; Roska, Botond; Sahel, Jose Alain; Tanter, Mickael; Picaud, Serge

     Nature Nanotechnology (2023), 18 (6), 667-676CODEN: NNAABX; ISSN:1748-3387. (Nature Portfolio)

     Abstr.: Remote and precisely controlled activation of the brain is a fundamental challenge in the development of brain-machine interfaces for neurol. treatments. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain, esp. after expressing ultrasound-sensitive proteins. But so far, no study has described an ultrasound-mediated activation strategy whose spatiotemporal resoln. and acoustic intensity are compatible with the mandatory needs of brain-machine interfaces, particularly for visual restoration. Here we combined the expression of large-conductance mechanosensitive ion channels with uncustomary high-frequency ultrasonic stimulation to activate retinal or cortical neurons over millisecond durations at a spatiotemporal resoln. and acoustic energy deposit compatible with vision restoration. The in vivo sonogenetic activation of the visual cortex generated a behavior assocd. with light perception. Our findings demonstrate that sonogenetics can deliver millisecond pattern presentations via an approach less invasive than current brain-machine interfaces for visual restoration.
412. 412

     Kireev, D.; Shokoohimehr, P.; Ernst, M.; Montes, V. R.; Srikantharajah, K.; Maybeck, V.; Wolfrum, B.; Offenhäusser, A. Fabrication of Ultrathin and Flexible Graphene-Based Devices for in Vivo Neuroprosthetics. MRS Adv. 2018, 3, 1621– 1627,  DOI: 10.1557/adv.2018.94

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413. 413

     Fu, X.; Li, G.; Niu, Y.; Xu, J.; Wang, P.; Zhou, Z.; Ye, Z.; Liu, X.; Xu, Z.; Yang, Z. Carbon-Based Fiber Materials as Implantable Depth Neural Electrodes. Front. Neurosci. 2021, 15, 771980,  DOI: 10.3389/fnins.2021.771980

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414. 414

     Lu, L.; Fu, X.; Liew, Y.; Zhang, Y.; Zhao, S.; Xu, Z.; Zhao, J.; Li, D.; Li, Q.; Stanley, G. B. Soft and MRI Compatible Neural Electrodes from Carbon Nanotube Fibers. Nano Lett. 2019, 19, 1577– 1586,  DOI: 10.1021/acs.nanolett.8b04456

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     414

     Soft and MRI Compatible Neural Electrodes from Carbon Nanotube Fibers

     Lu, Linlin; Fu, Xuefeng; Liew, Yijuin; Zhang, Yongyi; Zhao, Siyuan; Xu, Zheng; Zhao, Jingna; Li, Da; Li, Qingwen; Stanley, Garrett B.; Duan, Xiaojie

     Nano Letters (2019), 19 (3), 1577-1586CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Soft and magnetic resonance imaging (MRI) compatible neural electrodes enable stable chronic electrophysiol. measurements and anatomical or functional MRI studies of the entire brain without electrode interference with MRI images. These properties are important for many studies, ranging from a fundamental neurophysiol. study of functional MRI signals to a chronic neuromodulatory effect investigation of therapeutic deep brain stimulation. Here we develop soft and MRI compatible neural electrodes using carbon nanotube (CNT) fibers with a diam. from 20 μm down to 5 μm. The CNT fiber electrodes demonstrate excellent interfacial electrochem. properties and greatly reduced MRI artifacts than PtIr electrodes under a 7.0 T MRI scanner. With a shuttle-assisted implantation strategy, we show that the soft CNT fiber electrodes can precisely target specific brain regions and record high-quality single-unit neural signals. Significantly, they are capable of continuously detecting and isolating single neuronal units from rats for up to 4-5 mo without electrode repositioning, with greatly reduced brain inflammatory responses as compared to their stiff metal counterparts. In addn., we show that due to their high tensile strength, the CNT fiber electrodes can be retracted controllably postinsertion, which provides an effective and convenient way to do multidepth recording or potentially selecting cells with particular response properties. The chronic recording stability and MRI compatibility, together with their small size, provide the CNT fiber electrodes unique research capabilities for both basic and applied neuroscience studies.
415. 415

     Zhang, Y.; Yang, D.; Nie, J.; Dai, J.; Wu, H.; Zheng, J. C.; Zhang, F.; Fang, Y. Transcranial Nongenetic Neuromodulation via Bioinspired Vesicle-Enabled Precise NIR-II Optical Stimulation. Adv. Mater. 2023, 35, 2208601,  DOI: 10.1002/adma.202208601

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416. 416

     Nie, J.; Zhang, Y.; Wang, B.; Wu, H.; Chang, Z.; Ren, Q.; Zheng, J. C.; Zhao, D.; Fang, Y. Transcranial NIR Neuromodulation via Multifunctional Nano-Optical Electrodes for Relieving Depressive Symptoms. Adv. Funct. Mater. 2024, 34, 2470262,  DOI: 10.1002/adfm.202405832

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     There is no corresponding record for this reference.
417. 417

     Ren, Q.; Wu, H.; Zhang, Y.; Dai, J.; Chang, Z.; Nie, J.; Wang, B.; Fang, Y. Neuroprotection for Epilepsy Therapy via Rationally Designed Multifunctional Nanotransducer. ACS Nano 2024, 18, 16853– 16866,  DOI: 10.1021/acsnano.4c02546

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418. 418

     Parak, W. J.; Hofmann, U. G.; Gaub, H. E.; Owicki, J. C. Lateral Resolution of Light Addressable Potentiometric Sensors: An Experimental and Theoretical Investigation. Sens. Actuators, A 1997, 63, 47– 57,  DOI: 10.1016/S0924-4247(97)80428-1

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     418

     Lateral resolution of light-addressable potentiometric sensors: an experimental and theoretical investigation

     Parak, Wolfgang J.; Hofmann, Ulrich G.; Gaub, Hermann E.; Owicki, John C.

     Sensors and Actuators, A: Physical (1997), 63 (1), 47-57CODEN: SAAPEB; ISSN:0924-4247. (Elsevier)

     The surface potential of semiconductor devices in contact with electrolyte solns. is an important part of signal transduction for a variety of bioanal. devices. Here we have investigated the lateral resoln. at which the surface potential may be measured with a semiconductor-based device, a light-addressable potentiometric sensor (LAPS). We have first established an exptl. setup where a permanent charge pattern is generated in the oxide-nitride interface of an n-doped silicon wafer by UV irradn. Using a laser beam to interrogate the LAPS, the charge pattern can be detected by measuring the local photocurrent at a resoln. of better than 100 μm. A theor. model based on the diffusion and recombination of photogenerated minority charge carriers has been developed and solved anal.; it is consistent with expt. For Beer-Lambert law absorption of a sufficiently narrow beam of interrogating light, according to the theory the lateral resoln. depends on the relative sizes of the penetration depth of the light, d, and the recombination-diffusion length of the carriers, L. When d«L, the resoln. is (2Ld)1/2; when L»d, it is (2L2)1/2.
419. 419

     George, M.; Parak, W. J.; Gerhardt, I.; Moritz, W.; Kaesen, F.; Geiger, H.; Eisele, I.; Gaub, H. E. Investigation of the Spatial Resolution of the Light-Addressable Potentiometric Sensor (LAPS). Sens. Actuators, A 2000, 86, 187– 196,  DOI: 10.1016/S0924-4247(00)00455-6

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420. 420

     Parak, W. J.; George, M.; Domke, J.; Radmacher, M.; Gaub, H. E.; Behrends, J. C.; Denyer, M. C. Can the Light-Addressable Potentiometric Sensor (LAPS) Detect Extracellular Potentials of Cardiac Myocytes?. IEEE Trans. Biomed. Eng. 2000, 47, 1106– 1113,  DOI: 10.1109/10.855939

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     420

     Can the light-addressable potentiometric sensor (LAPS) detect extracellular potentials of cardiac myocytes?

     Parak W J; George M; Domke J; Radmacher M; Behrends J C; Denyer M C; Gaub H E

     IEEE transactions on bio-medical engineering (2000), 47 (8), 1106-13 ISSN:0018-9294.

     The light-addressable potentiometric sensor (LAPS) measures localized photo-induced currents from a silicon wafer, which are dependent on the local surface potential and on the intensity of the light pointer. In this study the ability of the LAPS to record extracellular potentials of adherent cells was investigated. Time dependent LAPS photocurrent signals that correlated in time with contractions were recorded from beating cardiac myocytes cultured on LAPS surfaces. Signals could be recorded both when the LAPS was biased to working points where the photocurrent was maximally sensitive to potential changes and when it was biased to working points where the photocurrent was insensitive to changes in surface potential. Therefore, signals could not be predominantly created by changes in extracellular potential and might be related to mechanical contractions. One possible explanation might be, that the cell-induced modulation of photocurrents arose as a result of cell shape changes. Such alterations in cell shape might have focused and defocused the light pointer and, thus, modulated its intensity. To further test this hypothesis, height changes of beating cardiac myocytes were measured with an atomic force microscope (AFM). They were found to match well with signals derived from LAPS measurements. Therefore, it can be concluded, that LAPS signals were mainly determined by the periodic changes in shape of beating heart cells, and this interference precludes the measurements of extracellular electrophysiological potentials from these cells.
421. 421

     Stein, B.; George, M.; Gaub, H. E.; Behrends, J. C.; Parak, W. J. Spatially Resolved Monitoring of the Cellular Metabolic Activity with a Semiconductor-Based Biosensor. Biosens. Bioelectron. 2003, 18, 31– 41,  DOI: 10.1016/S0956-5663(02)00109-4

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422. 422

     Stein, B.; George, M.; Parak, W. J.; Gaub, H. E. Extracellular Measurements of Averaged Ionic Currents with the Light-Addressable Potentiometric Sensor (LAPS). Sens. Actuators, B 2004, 98, 299– 304,  DOI: 10.1016/j.snb.2003.10.034

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     422

     Extracellular measurements of averaged ionic currents with the light-addressable potentiometric sensor (LAPS)

     Stein, B.; George, M.; Gaub, H. E.; Parak, W. J.

     Sensors and Actuators, B: Chemical (2004), 98 (2-3), 299-304CODEN: SABCEB; ISSN:0925-4005. (Elsevier Science B.V.)

     The light-addressable potentiometric sensor (LAPS) is a silicon-based detector which allows for measuring the elec. potential distribution along its surface. The point of measurement is detd. by illumination with a pulsed light source, and therefore the surface potential distribution can be measured spatially resolved by raster scanning a light-pointer along the surface. In this study elec. excitable neuronal cells (N1-E115 cell line) were grown on top of the surface of the LAPS. Individual cells were elec. stimulated using a patch clamp pipet. The light-pointer was focused on the stimulated cell and the elec. potential of the silicon surface below the stimulated cell was recorded with the LAPS. Averaged extracellularly recorded signals were found to correspond with the intracellularly recorded patch clamp signals. Although it was possible to record averaged ionic currents of individual cells with the LAPS technique, the low signal-to-noise ratio so far hampers practical applications.
423. 423

     Stoll, C.; Kudera, S.; Parak, W. J.; Lisdat, F. Quantum Dots on Gold: Electrodes For Photoswitchable Cytochrome c Electrochemistry. Small 2006, 2, 741– 743,  DOI: 10.1002/smll.200500441

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     423

     Quantum dots on gold: electrodes for photoswitchable cytochrome c electrochemistry

     Stoll, Christian; Kudera, Stefan; Parak, Wolfgang J.; Lisdat, Fred

     Small (2006), 2 (6), 741-743CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A photoswitchable arrangement for direct electrochem. of the redox protein cytochrome c can result from the application of CdSe/ZnS quantum dots on Au electrodes. On/off responses can be realized through photoexcitation of the quantum dots. Electrode illumination resulted in stepwise heterogeneous electron transfer from the electrode via the semiconductor particles to the heme proteins (see figure).
424. 424

     Brongersma, M. L.; Halas, N. J.; Nordlander, P. Plasmon-Induced Hot Carrier Science and Technology. Nat. Nanotechnol. 2015, 10, 25– 34,  DOI: 10.1038/nnano.2014.311

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     424

     Plasmon-induced hot carrier science and technology

     Brongersma, Mark L.; Halas, Naomi J.; Nordlander, Peter

     Nature Nanotechnology (2015), 10 (1), 25-34CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     A review. The discovery of the photoelec. effect by Heinrich Hertz in 1887 set the foundation for over 125 years of hot carrier science and technol. In the early 1900s it played a crit. role in the development of quantum mechanics, but even today the unique properties of these energetic, hot carriers offer new and exciting opportunities for fundamental research and applications. Measurement of the kinetic energy and momentum of photoejected hot electrons can provide valuable information on the electronic structure of materials. The heat generated by hot carriers can be harvested to drive a wide range of phys. and chem. processes. Their kinetic energy can be used to harvest solar energy or create sensitive photodetectors and spectrometers. Photoejected charges can also be used to elec. dope two-dimensional materials. Plasmon excitations in metallic nanostructures can be engineered to enhance and provide valuable control over the emission of hot carriers. This Review discusses recent advances in the understanding and application of plasmon-induced hot carrier generation and highlights some of the exciting new directions for the field.
425. 425

     Zhao, S.; Caruso, F.; Dähne, L.; Decher, G.; Geest, B. G. D.; Fan, J.; Feliu, N.; Gogotsi, Y.; Hammond, P. T.; Hersam, M. C.; Khademhosseini, A.; Kotov, N.; Leporatti, S.; Li, Y.; Lisdat, F.; Liz-Marzán, L. M.; Moya, S.; Mulvaney, P.; Rogach, A. L.; Roy, S.; Shchukin, D. G.; Skirtach, A. G.; Stevens, M. M.; Sukhorukov, G. B.; Weiss, P. S.; Yue, Z.; Zhu, D.; Parak, W. J. The Future of Layer-by-Layer Assembly: A Tribute to ACS Nano Associate Editor Helmuth Möhwald. ACS Nano 2019, 13, 6151– 6169,  DOI: 10.1021/acsnano.9b03326

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     425

     The Future of Layer-by-Layer Assembly: A Tribute to ACS Nano Associate Editor Helmuth M.ovrddot.ohwald

     Zhao, Shuang; Caruso, Frank; Daehne, Lars; Decher, Gero; De Geest, Bruno G.; Fan, Jinchen; Feliu, Neus; Gogotsi, Yury; Hammond, Paula T.; Hersam, Mark C.; Khademhosseini, Ali; Kotov, Nicholas; Leporatti, Stefano; Li, Yan; Lisdat, Fred; Liz-Marzan, Luis M.; Moya, Sergio; Mulvaney, Paul; Rogach, Andrey L.; Roy, Sathi; Shchukin, Dmitry G.; Skirtach, Andre G.; Stevens, Molly M.; Sukhorukov, Gleb B.; Weiss, Paul S.; Yue, Zhao; Zhu, Dingcheng; Parak, Wolfgang J.

     ACS Nano (2019), 13 (6), 6151-6169CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Layer-by-layer (LbL) assembly is a widely used tool for engineering materials and coatings. In this Perspective, dedicated to the memory of ACS Nano assoc. editor Prof. Dr. Helmuth Mohwald, we discuss the developments and applications that are to come in LbL assembly, focusing on coatings, bulk materials, membranes, nanocomposites, and delivery vehicles.
426. 426

     Pappas, T. C.; Wickramanyake, W. M. S.; Jan, E.; Motamedi, M.; Brodwick, M.; Kotov, N. A. Nanoscale Engineering of a Cellular Interface with Semiconductor Nanoparticle Films for Photoelectric Stimulation of Neurons. Nano Lett. 2007, 7, 513– 519,  DOI: 10.1021/nl062513v

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     426

     Nanoscale Engineering of a Cellular Interface with Semiconductor Nanoparticle Films for Photoelectric Stimulation of Neurons

     Pappas, Todd C.; Wickramanyake, W. M. Shan; Jan, Edward; Motamedi, Massoud; Brodwick, Malcolm; Kotov, Nicholas A.

     Nano Letters (2007), 7 (2), 513-519CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The remarkable optical and elec. properties of nanostructured materials are considered now as a source for a variety of biomaterials, biosensing, and cell interface applications. In this study, the authors report the first example of hybrid bionanodevice where absorption of light by thin films of quantum confined semiconductor nanoparticles of HgTe produced by the layer-by-layer assembly stimulate adherent neural cells via a sequence of photochem. and charge-transfer reactions. The authors also demonstrate an example of nanoscale engineering of the material driven by biol. functionalities.
427. 427

     Lugo, K.; Miao, X.; Rieke, F.; Lin, L. Y. Remote Switching of Cellular Activity and Cell Signaling Using Light in Conjunction with Quantum Dots. Biomed. Opt. Express 2012, 3, 447– 454,  DOI: 10.1364/BOE.3.000447

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     427

     Remote switching of cellular activity and cell signaling using light in conjunction with quantum dots

     Lugo, Katherine; Miao, Xiaoyu; Rieke, Fred; Lin, Lih Y.

     Biomedical Optics Express (2012), 3 (3), 447-454CODEN: BOEICL; ISSN:2156-7085. (Optical Society of America)

     Stimulating cells by using light is a non-invasive technique that provides flexibility in probing different locations while minimizing unintended effects on the system. We propose a new way to make cells photosensitive without using genetic or chem. manipulation, which alters natural cells, in conjunction with Quantum Dots (QDs). Remote switching of cellular activity by optical QD excitation is demonstrated by integrating QDs with cells: CdTe QD films with prostate cancer (LnCap) cells, and CdSe QD films and probes with cortical neurons. Changes in membrane potential and ionic currents are recorded by using the patch-clamp method. Upon excitation, the ion channels in the cell membrane were activated, resulting in hyperpolarization or depolarization of the cell.
428. 428

     Derfus, A. M.; Chan, W. C. W.; Bhatia, S. N. Probing the Cytotoxicity of Semiconductor Quantum Dots. Nano Lett. 2004, 4, 11– 18,  DOI: 10.1021/nl0347334

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     428

     Probing the Cytotoxicity of Semiconductor Quantum Dots

     Derfus, Austin M.; Chan, Warren C. W.; Bhatia, Sangeeta N.

     Nano Letters (2004), 4 (1), 11-18CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     With their bright, photostable fluorescence, semiconductor quantum dots (QDs) show promise as alternatives to org. dyes for biol. labeling. Questions about their potential cytotoxicity, however, remain unanswered. While cytotoxicity of bulk cadmium selenide (CdSe) is well documented, a no. of groups have suggested that CdSe QDs are cytocompatible, at least with some immortalized cell lines. Using primary hepatocytes as a liver model, we found that CdSe-core QDs were indeed acutely toxic under certain conditions. Specifically, we found that the cytotoxicity of QDs was modulated by processing parameters during synthesis, exposure to UV light, and surface coatings. Our data further suggest that cytotoxicity correlates with the liberation of free Cd2+ ions due to deterioration of the CdSe lattice. When appropriately coated, CdSe-core QDs can be rendered nontoxic and used to track cell migration and reorganization in vitro. Our results provide information for design criteria for the use of QDs in vitro and esp. in vivo, where deterioration over time may occur.
429. 429

     Kirchner, C.; Liedl, T.; Kudera, S.; Pellegrino, T.; Muñoz Javier, A.; Gaub, H. E.; Stölzle, S.; Fertig, N.; Parak, W. J. Cytotoxicity of Colloidal CdSe and CdSe/ZnS Nanoparticles. Nano Lett. 2005, 5, 331– 338,  DOI: 10.1021/nl047996m

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     429

     Cytotoxicity of Colloidal CdSe and CdSe/ZnS Nanoparticles

     Kirchner, Christian; Liedl, Tim; Kudera, Stefan; Pellegrino, Teresa; Javier, Almudena Munoz; Gaub, Hermann E.; Stoelzle, Sonja; Fertig, N.; Parak, Wolfgang J.

     Nano Letters (2005), 5 (2), 331-338CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Cytotoxicity of CdSe and CdSe/ZnS nanoparticles has been investigated for different surface modifications such as coating with mercaptopropionic acid, silanization, and polymer coating. For all cases, quant. values for the onset of cytotoxic effects in serum-free culture media are given. These values are correlated with microscope images in which the uptake of the particles by the cells has been investigated. Our data suggest that in addn. to the release of toxic Cd2+ ions from the particles also their surface chem., in particular their stability toward aggregation, plays an important role for cytotoxic effects. Addnl. patch clamp expts. investigate effects of the particles on currents through ion channels.
430. 430

     Brunetti, V.; Chibli, H.; Fiammengo, R.; Galeone, A.; Malvindi, M. A.; Vecchio, G.; Cingolani, R.; Nadeau, J. L.; Pompa, P. P. InP/ZnS as a Safer Alternative to CdSe/ZnS Core/Shell Quantum Dots: In Vitro and in Vivo Toxicity Assessment. Nanoscale 2013, 5, 307– 317,  DOI: 10.1039/C2NR33024E

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     430

     InP/ZnS as a safer alternative to CdSe/ZnS core/shell quantum dots: in vitro and in vivo toxicity assessment

     Brunetti, Virgilio; Chibli, Hicham; Fiammengo, Roberto; Galeone, Antonio; Malvindi, Maria Ada; Vecchio, Giuseppe; Cingolani, Roberto; Nadeau, Jay L.; Pompa, Pier Paolo

     Nanoscale (2013), 5 (1), 307-317CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     We show that water sol. InP/ZnS core/shell QDs are a safer alternative to CdSe/ZnS QDs for biol. applications, by comparing their toxicity in vitro (cell culture) and in vivo (animal model Drosophila). By choosing QDs with comparable phys. and chem. properties, we find that cellular uptake and localization are practically identical for these two nanomaterials. Toxicity of CdSe/ZnS QDs appears to be related to the release of poisonous Cd2+ ions and indeed we show that there is leaching of Cd2+ ions from the particle core despite the two-layer ZnS shell. Since an almost identical amt. of In(III) ions is obsd. to leach from the core of InP/ZnS QDs, their very low toxicity as revealed in this study hints at a much lower intrinsic toxicity of indium compared to cadmium.
431. 431

     Bahmani Jalali, H.; Mohammadi Aria, M.; Dikbas, U. M.; Sadeghi, S.; Ganesh Kumar, B.; Sahin, M.; Kavakli, I. H.; Ow-Yang, C. W.; Nizamoglu, S. Effective Neural Photostimulation Using Indium-Based Type-II Quantum Dots. ACS Nano 2018, 12, 8104– 8114,  DOI: 10.1021/acsnano.8b02976

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     431

     Effective Neural Photostimulation Using Indium-Based Type-II Quantum Dots

     Bahmani Jalali, Houman; Mohammadi Aria, Mohammad; Dikbas, Ugur Meric; Sadeghi, Sadra; Ganesh Kumar, Baskaran; Sahin, Mehmet; Kavakli, Ibrahim Halil; Ow-Yang, Cleva W.; Nizamoglu, Sedat

     ACS Nano (2018), 12 (8), 8104-8114CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Light-induced stimulation of neurons via photoactive surfaces offers rich opportunities for the development of therapeutic methods and high-resoln. retinal prosthetic devices. Quantum dots serve as an attractive building block for such surfaces, as they can be easily functionalized to match the biocompatibility and charge transport requirements of cell stimulation. Although indium-based colloidal quantum dots with type-I band alignment have attracted significant attention as a nontoxic alternative to cadmium-based ones, little attention has been paid to their photovoltaic potential as type-II heterostructures. Herein, we demonstrate type-II indium phosphide/zinc oxide core/shell quantum dots that are incorporated into a photoelectrode structure for neural photostimulation. This induces a hyperpolarizing bioelec. current that triggers the firing of a single neural cell at 4 μW mm-2, 26-fold lower than the ocular safety limit for continuous exposure to visible light. These findings show that nanomaterials can induce a biocompatible and effective biol. junction and can introduce a route in the use of quantum dots in photoelectrode architectures for artificial retinal prostheses.
432. 432

     Bahmani Jalali, H.; Karatum, O.; Melikov, R.; Dikbas, U. M.; Sadeghi, S.; Yildiz, E.; Dogru, I. B.; Ozgun Eren, G.; Ergun, C.; Sahin, A. Biocompatible Quantum Funnels for Neural Photostimulation. Nano Lett. 2019, 19, 5975– 5981,  DOI: 10.1021/acs.nanolett.9b01697

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     432

     Biocompatible Quantum Funnels for Neural Photostimulation

     Bahmani Jalali, Houman; Karatum, Onuralp; Melikov, Rustamzhon; Dikbas, Ugur Meric; Sadeghi, Sadra; Yildiz, Erdost; Dogru, Itir Bakis; Ozgun Eren, Guncem; Ergun, Cagla; Sahin, Afsun; Kavakli, Ibrahim Halil; Nizamoglu, Sedat

     Nano Letters (2019), 19 (9), 5975-5981CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Neural photostimulation has high potential to understand the working principles of complex neural networks and develop novel therapeutic methods for neurol. disorders. A key issue in the light-induced cell stimulation is the efficient conversion of light to bioelec. stimuli. In photosynthetic systems developed in millions of years by nature, the absorbed energy by the photoabsorbers is transported via nonradiative energy transfer to the reaction centers. Inspired by these systems, neural interfaces based on biocompatible quantum funnels are developed that direct the photogenerated charge carriers toward the bionanojunction for effective photostimulation. Funnels are constructed with indium-based rainbow quantum dots that are assembled in a graded energy profile. Implementation of a quantum funnel enhances the generated photoelectrochem. current 215% per unit absorbance in comparison with ungraded energy profile in a wireless and free-standing mode and facilitates optical neuromodulation of a single cell. This study indicates that the control of charge transport at nanoscale can lead to unconventional and effective neural interfaces.
433. 433

     Bareket, L.; Waiskopf, N.; Rand, D.; Lubin, G.; David-Pur, M.; Ben-Dov, J.; Roy, S.; Eleftheriou, C.; Sernagor, E.; Cheshnovsky, O. Semiconductor Nanorod-Carbon Nanotube Biomimetic Films for Wire-Free Photostimulation of Blind Retinas. Nano Lett. 2014, 14, 6685– 6692,  DOI: 10.1021/nl5034304

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     433

     Semiconductor Nanorod-Carbon Nanotube Biomimetic Films for Wire-Free Photostimulation of Blind Retinas

     Bareket, Lilach; Waiskopf, Nir; Rand, David; Lubin, Gur; David-Pur, Moshe; Ben-Dov, Jacob; Roy, Soumyendu; Eleftheriou, Cyril; Sernagor, Evelyne; Cheshnovsky, Ori; Banin, Uri; Hanein, Yael

     Nano Letters (2014), 14 (11), 6685-6692CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     We report the development of a semiconductor nanorod-carbon nanotube based platform for wire-free, light induced retina stimulation. A plasma polymd. acrylic acid midlayer was used to achieve covalent conjugation of semiconductor nanorods directly onto neuro-adhesive, three-dimensional carbon nanotube surfaces. Photocurrent, photovoltage, and fluorescence lifetime measurements validate efficient charge transfer between the nanorods and the carbon nanotube films. Successful stimulation of a light-insensitive chick retina suggests the potential use of this novel platform in future artificial retina applications.
434. 434

     Kim, T.; Kim, H. J.; Choi, W.; Lee, Y. M.; Pyo, J. H.; Lee, J.; Kim, J.; Kim, J.; Kim, J.-H.; Kim, C. Deep Brain Stimulation by Blood-Brain-Barrier-Crossing Piezoelectric Nanoparticles Generating Current and Nitric Oxide under Focused Ultrasound. Nat. Biomed. Eng. 2023, 7, 149– 163,  DOI: 10.1038/s41551-022-00965-4

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     434

     Deep brain stimulation by blood-brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound

     Kim, Taejeong; Kim, Hyun Jin; Choi, Wonseok; Lee, Yeong Mi; Pyo, Jung Hyun; Lee, Junseok; Kim, Jeesu; Kim, Jihoon; Kim, Joung-Hun; Kim, Chulhong; Kim, Won Jong

     Nature Biomedical Engineering (2023), 7 (2), 149-163CODEN: NBEAB3; ISSN:2157-846X. (Nature Portfolio)

     Deep brain stimulation via implanted electrodes can alleviate neuronal disorders. However, its applicability is constrained by side effects resulting from the insertion of electrodes into the brain. Here, we show that systemically administered piezoelec. nanoparticles producing nitric oxide and generating d.c. under high-intensity focused ultrasound can be used to stimulate deep tissue in the brain. The release of nitric oxide temporarily disrupted tight junctions in the blood-brain barrier, allowing for the accumulation of the nanoparticles into brain parenchyma, and the piezoelec. induced output current stimulated the release of dopamine by dopaminergic neuron-like cells. In a mouse model of Parkinson's disease, the ultrasound-responsive nanoparticles alleviated the symptoms of the disease without causing overt toxicity. The strategy may inspire the development of other minimally invasive therapies for neurodegenerative diseases.
435. 435

     Fan, C.-H.; Tsai, H.-C.; Tsai, Y.-S.; Wang, H.-C.; Lin, Y.-C.; Chiang, P.-H.; Wu, N.; Chou, M.-H.; Ho, Y.-J.; Lin, Z.-H. Selective Activation of Cells by Piezoelectric Molybdenum Disulfide Nanosheets with Focused Ultrasound. ACS Nano 2023, 17, 9140– 9154,  DOI: 10.1021/acsnano.2c12438

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436. 436

     Cassidy, P. J.; Radda, G. K. Molecular Imaging Perspectives. J. R. Soc. Interface 2005, 2, 133– 144,  DOI: 10.1098/rsif.2005.0040

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     436

     Molecular imaging perspectives

     Cassidy, Paul J.; Radda, George K.

     Journal of the Royal Society, Interface (2005), 2 (3), 133-144CODEN: JRSICU; ISSN:1742-5689. (Royal Society)

     A review. Mol. imaging is an emerging technol. at the life science/phys. science interface which is set to revolutionize our understanding and treatment of disease. The tools of mol. imaging are the imaging modalities and their corresponding contrast agents. These facilitate interaction with a biol. target at a mol. level in a no. of ways. The diverse nature of mol. imaging requires knowledge from both the life and phys. sciences for its successful development and implementation. The aim of this review is to introduce the subject of mol. imaging from both life science and phys. science perspectives. However, we will restrict our coverage to the prominent in vivo mol. imaging modalities of magnetic resonance imaging, optical imaging and nuclear imaging. The phys. basis of these imaging modalities, the use of contrast agents and the imaging parameters of sensitivity, temporal resoln. and spatial resoln. are described. Then, the specificity of contrast agents for targeting and sensing mol. events, and some applications of mol. imaging in biol. and medicine are given. Finally, the diverse nature of mol. imaging and its reliance on interdisciplinary collaboration is discussed.
437. 437

     Reinhardt, C. J.; Chan, J. Development of Photoacoustic Probes for in Vivo Molecular Imaging. Biochemistry 2018, 57, 194– 199,  DOI: 10.1021/acs.biochem.7b00888

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     437

     Development of Photoacoustic Probes for in Vivo Molecular Imaging

     Reinhardt, Christopher J.; Chan, Jefferson

     Biochemistry (2018), 57 (2), 194-199CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

     A review. Photoacoustic (PA) imaging is an emerging, non-invasive imaging modality that encompasses attributes of both optical and ultrasound imaging. Because of the combination of optical excitation and acoustic detection, PA imaging enables high contrast and high resoln. within deep tissue (centimeter depths). Recent advances in PA probe development have allowed for stimulus-responsive imaging in a variety of biol. models with implications for basic, translational, and clin. sciences. This perspective highlights recent progress in the development of PA probes and their application to live-animal mol. imaging.
438. 438

     Meneghetti, M.; Kaur, J.; Sui, K.; Sørensen, J. F.; Berg, R. W.; Markos, C. Soft Monolithic Infrared Neural Interface for Simultaneous Neurostimulation and Electrophysiology. Light Sci. Appl. 2023, 12, 127,  DOI: 10.1038/s41377-023-01164-9

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439. 439

     Coventry, B. S.; Lawlor, G. L.; Bagnati, C. B.; Krogmeier, C.; Bartlett, E. L. Characterization and Closed-Loop Control of Infrared Thalamocortical Stimulation Produces Spatially Constrained Single-Unit Responses. PNAS Nexus 2024, 3, pgae082,  DOI: 10.1093/pnasnexus/pgae082

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     There is no corresponding record for this reference.
440. 440

     Yu, N.; Huang, L.; Zhou, Y.; Xue, T.; Chen, Z.; Han, G. Near-Infrared-Light Activatable Nanoparticles for Deep-Tissue-Penetrating Wireless Optogenetics. Adv. Healthc. Mater. 2019, 8, 1801132,  DOI: 10.1002/adhm.201801132

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441. 441

     Mager, T.; Lopez de la Morena, D.; Senn, V.; Schlotte, J.; D'Errico, A.; Feldbauer, K.; Wrobel, C.; Jung, S.; Bodensiek, K.; Rankovic, V. High Frequency Neural Spiking and Auditory Signaling by Ultrafast Red-Shifted Optogenetics. Nat. Commun. 2018, 9, 1750,  DOI: 10.1038/s41467-018-04146-3

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     441

     High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics

     Mager Thomas; Schlotte Johannes; D Errico Anna; Feldbauer Katrin; Wood Phillip G; Bamberg Ernst; Lopez de la Morena David; Wrobel Christian; Jung Sangyong; Bodensiek Kai; Rankovic Vladan; Browne Lorcan; Huet Antoine; Moser Tobias; Lopez de la Morena David; Moser Tobias; Senn Verena; Letzkus Johannes J; Senn Verena; Schlotte Johannes; D Errico Anna; Feldbauer Katrin; Jung Sangyong; Rankovic Vladan; Browne Lorcan; Huet Antoine; Moser Tobias; Browne Lorcan; Juttner Josephine

     Nature communications (2018), 9 (1), 1750 ISSN:.

     Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast neural photoactivation over the whole range of the visible spectrum. We focus our functional analysis on the fast-switching, red light-activated Chrimson variants, because red light has lower light scattering and marginal phototoxicity in tissues. We show paradigmatically for neurons of the cerebral cortex and the auditory nerve that the fast Chrimson mutants enable neural stimulation with firing frequencies of several hundred Hz. They drive spiking at high rates and temporal fidelity with low thresholds for stimulus intensity and duration. Optical cochlear implants restore auditory nerve activity in deaf mice. This demonstrates that the mutants facilitate neuroscience research and future medical applications such as hearing restoration.
442. 442

     Klapoetke, N. C.; Murata, Y.; Kim, S. S.; Pulver, S. R.; Birdsey-Benson, A.; Cho, Y. K.; Morimoto, T. K.; Chuong, A. S.; Carpenter, E. J.; Tian, Z. Independent Optical Excitation of Distinct Neural Populations. Nat. Methods 2014, 11, 338– 346,  DOI: 10.1038/nmeth.2836

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     442

     Independent optical excitation of distinct neural populations

     Klapoetke, Nathan C.; Murata, Yasunobu; Kim, Sung Soo; Pulver, Stefan R.; Birdsey-Benson, Amanda; Cho, Yong Ku; Morimoto, Tania K.; Chuong, Amy S.; Carpenter, Eric J.; Tian, Zhijian; Wang, Jun; Xie, Yinlong; Yan, Zhixiang; Zhang, Yong; Chow, Brian Y.; Surek, Barbara; Melkonian, Michael; Jayaraman, Vivek; Constantine-Paton, Martha; Wong, Gane Ka-Shu; Boyden, Edward S.

     Nature Methods (2014), 11 (3), 338-346CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)

     Optogenetic tools enable examn. of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiol. characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable expts. in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
443. 443

     Prakash, R.; Yizhar, O.; Grewe, B.; Ramakrishnan, C.; Wang, N.; Goshen, I.; Packer, A. M.; Peterka, D. S.; Yuste, R.; Schnitzer, M. J. Two-Photon Optogenetic Toolbox for Fast Inhibition, Excitation and Bistable Modulation. Nat. Methods 2012, 9, 1171– 1179,  DOI: 10.1038/nmeth.2215

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     443

     Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation

     Prakash, Rohit; Yizhar, Ofer; Grewe, Benjamin; Ramakrishnan, Charu; Wang, Nancy; Goshen, Inbal; Packer, Adam M.; Peterka, Darcy S.; Yuste, Rafael; Schnitzer, Mark J.; Deisseroth, Karl

     Nature Methods (2012), 9 (12), 1171-1179CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)

     Optogenetics with microbial opsin genes has enabled high-speed control of genetically specified cell populations in intact tissue. However, it remains a challenge to independently control subsets of cells within the genetically targeted population. Although spatially precise excitation of target mols. can be achieved using two-photon laser-scanning microscopy (TPLSM) hardware, the integration of two-photon excitation with optogenetics has thus far required specialized equipment or scanning and has not yet been widely adopted. Here we take a complementary approach, developing opsins with custom kinetic, expression and spectral properties uniquely suited to scan times typical of the raster approach that is ubiquitous in TPLSM labs. We use a range of culture, slice and mammalian in vivo prepns. to demonstrate the versatility of this toolbox, and we quant. map parameter space for fast excitation, inhibition and bistable control. Together these advances may help enable broad adoption of integrated optogenetic and TPLSM technologies across exptl. fields and systems.
444. 444

     Schmidt, E.; Oheim, M. Infrared Excitation Induces Heating and Calcium Microdomain Hyperactivity in Cortical Astrocytes. Biophys. J. 2020, 119, 2153– 2165,  DOI: 10.1016/j.bpj.2020.10.027

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445. 445

     Picot, A.; Dominguez, S.; Liu, C.; Chen, I.-W.; Tanese, D.; Ronzitti, E.; Berto, P.; Papagiakoumou, E.; Oron, D.; Tessier, G. Temperature Rise Under Two-Photon Optogenetic Brain Stimulation. Cell Rep. 2018, 24, 1243– 1253,  DOI: 10.1016/j.celrep.2018.06.119

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446. 446

     Hemmer, E.; Benayas, A.; Légaré, F.; Vetrone, F. Exploiting the Biological Windows: Current Perspectives on Fluorescent Bioprobes Emitting above 1000 nm. Nanoscale Horiz. 2016, 1, 168– 184,  DOI: 10.1039/C5NH00073D

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     446

     Exploiting the biological windows: current perspectives on fluorescent bioprobes emitting above 1000 nm

     Hemmer, Eva; Benayas, Antonio; Legare, Francois; Vetrone, Fiorenzo

     Nanoscale Horizons (2016), 1 (3), 168-184CODEN: NHAOAW; ISSN:2055-6764. (Royal Society of Chemistry)

     With the goal of developing more accurate, efficient, non-invasive and fast diagnostic tools, the use of near-IR (NIR) light in the range of the second and third biol. windows (NIR-II: 1000-1350 nm, NIR-III: 1550-1870 nm) is growing remarkably as it provides the advantages of deeper penetration depth into biol. tissues, better image contrast, reduced phototoxicity and photobleaching. Consequently, NIR-based bioimaging has become a quickly emerging field and manifold new NIR-emitting bioprobes have been reported. Classes of materials suggested as potential probes for NIR-to-NIR bioimaging (using NIR light for the excitation and emission) are quite diverse. These include rare-earth based nanoparticles, Group-IV nanostructures (single-walled carbon nanotubes, carbon nanoparticles and more recently Si- or Ge-based nanostructures) as well as Ag, In and Pb chalcogenide quantum dots. This review summarizes and discusses current trends, material merits, and latest developments in NIR-to-NIR bioimaging taking advantage of the region above 1000 nm (i.e. the second and third biol. windows). Further consideration will be given to upcoming probe materials emitting in the NIR-I region (700-950 nm), thus do not possess emissions in these two windows, but have high expectations. Overall, the focus is placed on recent discussions concerning the optimal choice of excitation and emission wavelengths for deep-tissue high-resoln. optical bioimaging and on fluorescent bioprobes that have successfully been implemented in in vitro and in vivo applications.
447. 447

     Kim, D.; Lee, N.; Park, Y. I.; Hyeon, T. Recent Advances in Inorganic Nanoparticle-Based NIR Luminescence Imaging: Semiconductor Nanoparticles and Lanthanide Nanoparticles. Bioconjugate Chem. 2017, 28, 115– 123,  DOI: 10.1021/acs.bioconjchem.6b00654

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     447

     Recent Advances in Inorganic Nanoparticle-Based NIR Luminescence Imaging: Semiconductor Nanoparticles and Lanthanide Nanoparticles

     Kim, Dokyoon; Lee, Nohyun; Park, Yong Il; Hyeon, Taeghwan

     Bioconjugate Chemistry (2017), 28 (1), 115-123CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

     A review. Several types of nanoparticle-based imaging probes have been developed to replace conventional luminescent probes. For luminescence imaging, near-IR (NIR) probes are useful in that they allow deep tissue penetration and high spatial resoln. as a result of reduced light absorption/scattering and negligible autofluorescence in biol. media. They rely on either an anti-Stokes or a Stokes shift process to generate luminescence. For example, transition metal-doped semiconductor nanoparticles and lanthanide-doped inorg. nanoparticles have been demonstrated as anti-Stokes shift-based agents that absorb NIR light through two- or three-photon absorption process and upconversion process, resp. On the other hand, quantum dots (QDs) and lanthanide-doped nanoparticles that emit in NIR-II range (∼1000 to ∼1350 nm) were suggested as promising Stokes shift-based imaging agents. In this topical review, the authors summarize and discuss the recent progress in the development of inorg. nanoparticle-based luminescence imaging probes working in NIR range.
448. 448

     Tao, Z.; Hong, G.; Shinji, C.; Chen, C.; Diao, S.; Antaris, A. L.; Zhang, B.; Zou, Y.; Dai, H. Biological Imaging Using Nanoparticles of Small Organic Molecules with Fluorescence Emission at Wavelengths Longer than 1000 nm. Angew. Chem., Int. Ed. 2013, 52, 13002– 13006,  DOI: 10.1002/anie.201307346

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     448

     Biological Imaging Using Nanoparticles of Small Organic Molecules with Fluorescence Emission at Wavelengths Longer than 1000 nm

     Tao, Zhimin; Hong, Guosong; Shinji, Chihiro; Chen, Changxin; Diao, Shuo; Antaris, Alexander L.; Zhang, Bo; Zou, Yingping; Dai, Hongjie

     Angewandte Chemie, International Edition (2013), 52 (49), 13002-13006CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A hydrophobic org. mol. that fluoresces in the near-IR II (NIR-II) region was made water-sol. and biocompatible by its embedment in a polymer nanoparticle, which was then coated with hydrophilic poly(ethylene glycol) chains. The resulting nanoparticles exhibit bright fluorescence in the NIR-II window and high photostability in aq. media and were used for in vivo imaging in mice.
449. 449

     Huang, K.; Dou, Q.; Loh, X. J. Nanomaterial Mediated Optogenetics: Opportunities and Challenges. RSC Adv. 2016, 6, 60896– 60906,  DOI: 10.1039/C6RA11289G

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     449

     Nanomaterial mediated optogenetics: opportunities and challenges

     Huang, Kai; Dou, Qingqing; Loh, Xian Jun

     RSC Advances (2016), 6 (65), 60896-60906CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)

     Optogenetics is a promising neuronal modulation strategy in neuroscience, which enables real-time neuromodulation in free-moving animals with high spatiotemporal control. However, it still suffers from several disadvantages, including low penetration of excitation light and the invasiveness of the insertion of the light delivery system. The incorporation of nanomaterials with different properties into optogenetics may bring new opportunities to solve the problems encountered in optogenetics, from the delivery/expression of the optogene to the stimulation/inhibition and follow-up sensing of neural activity. The challenges of nanomaterial-mediated optogenetics are also discussed. This review elaborates on the feasibility of incorporating nanomaterials into optogenetics and analyzes the benefits of nanomaterial-mediated optogenetics.
450. 450

     Sardoiwala, M. N.; Srivastava, A. K.; Karmakar, S.; Roy Choudhury, S. Nanostructure Endows Neurotherapeutic Potential in Optogenetics: Current Development and Future Prospects. ACS Chem. Neurosci. 2019, 10, 3375– 3385,  DOI: 10.1021/acschemneuro.9b00246

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451. 451

     Haase, M.; Schäfer, H. Upconverting Nanoparticles. Angew. Chem., Int. Ed. 2011, 50, 5808– 5829,  DOI: 10.1002/anie.201005159

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     Upconverting Nanoparticles

     Haase, Markus; Schaefer, Helmut

     Angewandte Chemie, International Edition (2011), 50 (26), 5808-5829CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Upconversion (UC) refers to nonlinear optical processes in which the sequential absorption of two or more photons leads to the emission of light at shorter wavelength than the excitation wavelength (anti-Stokes type emission). In contrast to other emission processes based on multiphoton absorption, upconversion can be efficiently excited even at low excitation densities. The most efficient UC mechanisms are present in solid-state materials doped with rare-earth ions. The development of nanocrystal research has evoked increasing interest in the development of synthesis routes which allow the synthesis of highly efficient, small UC particles with narrow size distribution able to form transparent solns. in a wide range of solvents. Meanwhile, high-quality UC nanocrystals can be routinely synthesized and their soly., particle size, crystallog. phase, optical properties and shape can be controlled. In recent years, these particles have been discussed as promising alternatives to org. fluorophosphors and quantum dots in the field of medical imaging.
452. 452

     Chen, G.; Ågren, H.; Ohulchanskyy, T. Y.; Prasad, P. N. Light Upconverting Core-Shell Nanostructures: Nanophotonic Control for Emerging Applications. Chem. Soc. Rev. 2015, 44, 1680– 1713,  DOI: 10.1039/C4CS00170B

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     452

     Light upconverting core-shell nanostructures: nanophotonic control for emerging applications

     Chen, Guanying; Agren, Hans; Ohulchanskyy, Tymish Y.; Prasad, Paras N.

     Chemical Society Reviews (2015), 44 (6), 1680-1713CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. Light upconverting nanostructures employing lanthanide ions constitute an emerging research field recognized with wide ramifications and impact in many areas ranging from healthcare, to energy and, to security. The core-shell design of these nanostructures allows us to deliberately introduce a hierarchy of electronic energy states, thus providing unprecedented opportunities to manipulate the electronic excitation, energy transfer and upconverted emissions. The core-shell morphol. also causes the suppression of quenching mechanisms to produce efficient upconversion emission for biophotonic and photonic applications. Using hierarchical architect, whereby each shell layer can be defined to have a specific feature, the electronic structure as well as the physiochem. structure of the upconverting nanomaterials can be tuned to couple other electronic states on the surface such as excitations of org. dye mols. or localized surface plasmons from metallic nanostructures, or to introduce a broad range of imaging or therapeutic modalities into a single conduct. In this review, we summarize the key aspects of nanophotonic control of the light upconverting nanoparticles through governed design and prepn. of hierarchical shells in the core-shell nanostructures, and review their emerging applications in the biomedical field, solar energy conversion, as well as security encoding.
453. 453

     Wiesholler, L. M.; Frenzel, F.; Grauel, B.; Würth, C.; Resch-Genger, U.; Hirsch, T. Yb, Nd, Er-Doped Upconversion Nanoparticles: 980 nm versus 808 nm Excitation. Nanoscale 2019, 11, 13440– 13449,  DOI: 10.1039/C9NR03127H

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     453

     Yb,Nd,Er-doped upconversion nanoparticles: 980 nm versus 808 nm excitation

     Wiesholler, Lisa M.; Frenzel, Florian; Grauel, Bettina; Wuerth, Christian; Resch-Genger, Ute; Hirsch, Thomas

     Nanoscale (2019), 11 (28), 13440-13449CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Yb,Nd,Er-doped upconversion nanoparticles (UCNPs) have attracted considerable interest as luminescent reporters for bioimaging, sensing, energy conversion/shaping, and anticounterfeiting due to their capability to convert multiple near-IR (NIR) photons into shorter wavelength UV, visible or NIR luminescence by successive absorption of two or more NIR photons. This enables optical measurements in complex media with very little background and high penetration depths for bioimaging. The use of Nd3+ as substitute for the commonly employed sensitizer Yb3+ or in combination with Yb3+ shifts the excitation wavelength from about 980 nm, where the absorption of water can weaken upconversion luminescence, to about 800 nm, and laser-induced local overheating effects in cells, tissue, and live animal studies can be minimized. To systematically investigate the potential of Nd3+ doping, we assessed the performance of a set of similarly sized Yb3+,Nd3+,Er3+-doped core- and core-shell UCNPs of different particle architecture in water at broadly varied excitation power densities (P) with steady state and time-resolved fluorometry for excitation at 980 nm and 808 nm. As a measure for UCNPs performance, the P-dependent upconversion quantum yield (ΦUC) and its satn. behavior were used as well as particle brightness (BUC). Based upon spectroscopic measurements at both excitation wavelengths in water and in a lipid phantom and BUC-based calcns. of signal size at different penetration depths, conditions under which excitation at 808 nm is advantageous are derived and parameters for the further optimization of triple-doped UCNPs are given.
454. 454

     Auzel, F. Upconversion and Anti-Stokes Processes with f and d Ions in Solids. Chem. Rev. 2004, 104, 139– 174,  DOI: 10.1021/cr020357g

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     454

     Upconversion and Anti-Stokes Processes with f and d Ions in Solids

     Auzel, Francois

     Chemical Reviews (Washington, DC, United States) (2004), 104 (1), 139-173CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Topics include: role of energy diffusion in up and down-conversion in energy transfers between rare earth ions; upconversion in a single-ion level description for APTE (i.e., energy transfer upconversion) or excited state absorption (ESA) and in a pair-level one; upconversion studies in lanthanide and actinide ion-doped solids and transition-metal ion-doped solids with APTE and ESA processes; cross-relaxation and the photon avalanche effect; APTE for display and IR detection; APTE and ESA pumped lasers; perspective and future advances in upconversion UV-tunable lasers, in IR imaging, bistability, hot emission and avalanche like codoped systems, and biol. applications.
455. 455

     Wu, X.; Chen, G.; Shen, J.; Li, Z.; Zhang, Y.; Han, G. Upconversion Nanoparticles: A Versatile Solution to Multiscale Biological Imaging. Bioconjugate Chem. 2015, 26, 166– 175,  DOI: 10.1021/bc5003967

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     455

     Upconversion Nanoparticles: A Versatile Solution to Multiscale Biological Imaging

     Wu, Xiang; Chen, Guanying; Shen, Jie; Li, Zhanjun; Zhang, Yuanwei; Han, Gang

     Bioconjugate Chemistry (2015), 26 (2), 166-175CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

     A review. Lanthanide-doped photon upconverting nanomaterials are emerging as a new class of imaging contrast agents, providing numerous unprecedented possibilities in the realm of biomedical imaging. Because of their ability to convert long-wavelength near-IR excitation radiation into shorter-wavelength emissions, these nanomaterials are able to produce assets of low imaging background, large anti-Stokes shift, as well as high optical penetration depth of light for deep tissue optical imaging or light-activated drug release and therapy. The aim of this review is to line up some issues assocd. with conventional fluorescent probes, and to address the recent advances of upconverting nanoparticles (UCNPs) as a soln. to multiscale biol. imaging applications.
456. 456

     Xu, C. T.; Zhan, Q.; Liu, H.; Somesfalean, G.; Qian, J.; He, S.; Andersson-Engels, S. Upconverting Nanoparticles for Pre-Clinical Diffuse Optical Imaging, Microscopy and Sensing: Current Trends and Future Challenges. Laser Photonics Rev. 2013, 7, 663– 697,  DOI: 10.1002/lpor.201200052

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     456

     Upconverting nanoparticles for pre-clinical diffuse optical imaging, microscopy and sensing: Current trends and future challenges

     Xu, Can T.; Zhan, Qiuqiang; Liu, Haichun; Somesfalean, Gabriel; Qian, Jun; He, Sailing; Andersson-Engels, Stefan

     Laser & Photonics Reviews (2013), 7 (5), 663-697CODEN: LPRAB8; ISSN:1863-8880. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Upconverting nanoparticles (UCNPs) are a class of recently developed luminescent biomarkers that - in several aspects - are superior to org. dyes and quantum dots. UCNPs can emit spectrally narrow anti-Stokes shifted light with quantum yields which greatly exceed those of two-photon dyes for fluence rates relevant for deep tissue imaging. Compared with conventionally used Stokes-shifting fluorophores, UCNP-based imaging systems can acquire completely autofluorescence-free data with superb contrast. For diffuse optical imaging, the multi-photon process involved in the upconversion process can be used to obtain images with unprecedented resoln. These unique properties make UCNPs extremely attractive in the field of biophotonics. UCNPs have already been applied in microscopy, small-animal imaging, multi-modal imaging, highly sensitive bioassays, temp. sensing and photodynamic therapy. In this review, the current state-of-the-art UCNPs and their applications for diffuse imaging, microscopy and sensing targeted towards solving essential biol. issues are discussed.
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     Wang, H. Q.; Batentschuk, M.; Osvet, A.; Pinna, L.; Brabec, C. J. Rare-Earth Ion Doped Up-Conversion Materials for Photovoltaic Applications. Adv. Mater. 2011, 23, 2675– 2680,  DOI: 10.1002/adma.201100511

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     Rare-Earth Ion Doped Up-Conversion Materials for Photovoltaic Applications

     Wang, Hai-Qiao; Batentschuk, Miroslaw; Osvet, Andres; Pinna, Luigi; Brabec, Christoph J.

     Advanced Materials (Weinheim, Germany) (2011), 23 (22-23), 2675-2680CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review of recent progress in the development of rare-earth-ion-doped up-conversion materials for solar cell applications. With the aim of utilizing the IR region of solar radiation to improve solar cell performance, significant progress, including theor. anal. and exptl. achievement, has been made in the field of up-conversion for photovoltaic applications. In addn., new trends for rare-earth-ion-doped phosphors are briefly discussed, among them trivalent rare-earth-ion-doped up-conversion materials for org. solar cell applications.
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     Gnach, A.; Bednarkiewicz, A. Lanthanide-Doped Up-Converting Nanoparticles: Merits and Challenges. Nano Today 2012, 7, 532– 563,  DOI: 10.1016/j.nantod.2012.10.006

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     Lanthanide-doped up-converting nanoparticles: Merits and challenges

     Gnach, Anna; Bednarkiewicz, Artur

     Nano Today (2012), 7 (6), 532-563CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)

     A review. Summary: Due to exceptional photo-phys. properties, up-converting nanoparticles (UCNPs) are promising and advantageous alternative to conventional fluorescent labels used in many bio-medical applications. The first part of this review aims at presenting these properties as well as the current state-of-the-art in the up-conversion enhancement, NPs surface functionalization and bioconjugation. In the second part of the paper, the applications of UCNPs and currently available detection instrumentation are discussed in the view of the distinctive properties of these markers. Because the growing widespread use of the biofunctionalized NPs, scarce instrumentation for up-conversion detection is reviewed. Finally, the challenges and future perspectives of the UCNPs are discussed.
459. 459

     Wang, F.; Liu, X. Recent Advances in the Chemistry of Lanthanide-Doped Upconversion Nanocrystals. Chem. Soc. Rev. 2009, 38, 976– 989,  DOI: 10.1039/b809132n

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     Recent advances in the chemistry of lanthanide-doped upconversion nanocrystals

     Wang, Feng; Liu, Xiaogang

     Chemical Society Reviews (2009), 38 (4), 976-989CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. Lanthanide ions exhibit unique luminescent properties, including the ability to convert near IR long-wavelength excitation radiation into shorter visible wavelengths through a process known as photon upconversion. In recent years lanthanide-doped upconversion nanocrystals were developed as a new class of luminescent optical labels that have become promising alternatives to org. fluorophores and quantum dots for applications in biol. assays and medical imaging. These techniques offer low autofluorescence background, large anti-Stokes shifts, sharp emission bandwidths, high resistance to photobleaching, and high penetration depth and temporal resoln. Such techniques also show potential for improving the selectivity and sensitivity of conventional methods. They also pave the way for high throughput screening and miniaturization. This tutorial review focuses on the recent development of various synthetic approaches and possibilities for chem. tuning of upconversion properties, as well as giving an overview of biol. applications of these luminescent nanocrystals.
460. 460

     Goldschmidt, J. C.; Fischer, S. Upconversion for Photovoltaics - A Review of Materials, Devices and Concepts for Performance Enhancement. Adv. Opt. Mater. 2015, 3, 510– 535,  DOI: 10.1002/adom.201500024

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     Upconversion for Photovoltaics - a Review of Materials, Devices and Concepts for Performance Enhancement

     Goldschmidt, Jan Christoph; Fischer, Stefan

     Advanced Optical Materials (2015), 3 (4), 510-535CODEN: AOMDAX; ISSN:2195-1071. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Upconversion of low-energy photons into high-energy photons increases the efficiency of photovoltaic devices by converting photons with energies below the absorption threshold of the solar cell into photons that can be utilized. In this review, an overview is provided of quant. studies of the upconversion quantum yield of upconverter materials, and of the achieved efficiency enhancements in upconverting solar cell devices. Different materials and devices are compared based on well-defined figures-of-merit and the challenges to their accurate measurement are discussed. Internal upconversion quantum yields above 13% have been reported both for Er3+-based materials as well as for org. upconverters, using irradiance values below 0.4 W cm-2. On the upconverting solar cell device level, relative enhancements of the solar cells' short-circuit currents by up to 0.55% have been achieved. These values document progress by orders of magnitude achieved in the last years. However, they also show that the field of upconversion needs further development to become a relevant technol. option in photovoltaics. Different options regarding how upconversion performance can be increased further in the future are outlined.
461. 461

     Zheng, W.; Huang, P.; Tu, D.; Ma, E.; Zhu, H.; Chen, X. Lanthanide-Doped Upconversion Nano-Bioprobes: Electronic Structures, Optical Properties, and Biodetection. Chem. Soc. Rev. 2015, 44, 1379– 1415,  DOI: 10.1039/C4CS00178H

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     Lanthanide-doped upconversion nano-bioprobes: electronic structures, optical properties, and biodetection

     Zheng, Wei; Huang, Ping; Tu, Datao; Ma, En; Zhu, Haomiao; Chen, Xueyuan

     Chemical Society Reviews (2015), 44 (6), 1379-1415CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. Lanthanide-doped upconversion nanoparticles (UCNPs) have attracted considerable interest due to their superior physicochem. features, such as large anti-Stokes shifts, low autofluorescence background, low toxicity and high penetration depth, which make them extremely suitable for use as alternatives to conventional downshifting luminescence bioprobes like org. dyes and quantum dots for various biol. applications. A fundamental understanding of the photophysics of lanthanide-doped UCNPs is of vital importance for discovering novel optical properties and exploring their new applications. In this review, we focus on the most recent advances in the development of lanthanide-doped UCNPs as potential luminescent nano-bioprobes by means of our customized lanthanide photophysics measurement platforms specially designed for upconversion luminescence, which covers from their fundamental photophysics to bioapplications, including electronic structures (energy levels and local site symmetry of emitters), excited-state dynamics, optical property designing, and their promising applications for in vitro biodetection of tumor markers. Some future prospects and efforts towards this rapidly growing field are also envisioned.
462. 462

     Zhou, B.; Shi, B.; Jin, D.; Liu, X. Controlling Upconversion Nanocrystals for Emerging Applications. Nat. Nanotechnol. 2015, 10, 924– 936,  DOI: 10.1038/nnano.2015.251

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     Controlling upconversion nanocrystals for emerging applications

     Zhou, Bo; Shi, Bingyang; Jin, Dayong; Liu, Xiaogang

     Nature Nanotechnology (2015), 10 (11), 924-936CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     A review. Lanthanide-doped upconversion nanocrystals enable anti-Stokes emission with pump intensities several orders of magnitude lower than required by conventional nonlinear optical techniques. Their exceptional properties, large anti-Stokes shifts, sharp emission spectra and long excited-state lifetimes, led to a diversity of applications. Here, the authors review upconversion nanocrystals from the perspective of fundamental concepts and examine the tech. challenges in relation to emission color tuning and luminescence enhancement. In particular, the authors highlight the advances in functionalization strategies that enable the broad utility of upconversion nanocrystals for multimodal imaging, cancer therapy, volumetric displays and photonics.
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     Gorris, H. H.; Wolfbeis, O. S. Photon-Upconverting Nanoparticles for Optical Encoding and Multiplexing of Cells, Biomolecules, and Microspheres. Angew. Chem., Int. Ed. 2013, 52, 3584– 3600,  DOI: 10.1002/anie.201208196

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     Photon-Upconverting Nanoparticles for Optical Encoding and Multiplexing of Cells, Biomolecules, and Microspheres

     Gorris, Hans H.; Wolfbeis, Otto S.

     Angewandte Chemie, International Edition (2013), 52 (13), 3584-3600CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Photon-upconverting nanoparticles (UCNPs) are lanthanide-doped nanocrystals that emit visible light under near-IR excitation (anti-Stokes emission). This unique optical property precludes background fluorescence and light scattering from biol. materials. The emission of multiple and narrow emission lines is an addnl. hallmark of UCNPs that opens up new avenues for optical encoding. Distinct emission signatures can be obtained if the multiple emission of UCNPs is tuned by their dopant compn. or by surface modification with dyes. Tuning the intensity of only one of the multiple emission lines and using another one as a const. ref. signal enables the design of ratiometric codes that are resistant to fluctuations in abs. signal intensities. Combining several UCNPs each displaying a distinct set of emission lines expands the coding capacity exponentially and lays the foundation for highly multiplexed analyte detection. This Review highlights the potential of UCNPs for labeling and encoding biomols., microspheres, and even whole cells.
464. 464

     Resch-Genger, U.; Gorris, H. H. Perspectives and Challenges of Photon-Upconversion Nanoparticles-Part I: Routes to Brighter Particles and Quantitative Spectroscopic Studies. Anal. Bioanal. Chem. 2017, 409, 5855– 5874,  DOI: 10.1007/s00216-017-0499-z

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     Perspectives and challenges of photon-upconversion nanoparticles - Part I: routes to brighter particles and quantitative spectroscopic studies

     Resch-Genger, Ute; Gorris, Hans H.

     Analytical and Bioanalytical Chemistry (2017), 409 (25), 5855-5874CODEN: ABCNBP; ISSN:1618-2642. (Springer)

     A review on the recent developments in the design, synthesis, optical-spectroscopic characterization, and application of lanthanide-doped photon-upconversion nanoparticles (UCNPs) with the special focus on bioanal. and life sciences.
465. 465

     Skripka, A.; Marin, R.; Benayas, A.; Canton, P.; Hemmer, E.; Vetrone, F. Covering the Optical Spectrum through Collective Rare-Earth Doping of NaGdF₄ Nanoparticles: 806 and 980 nm Excitation Routes. Phys. Chem. Chem. Phys. 2017, 19, 11825– 11834,  DOI: 10.1039/C7CP01167A

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     Covering the optical spectrum through collective rare-earth doping of NaGdF4 nanoparticles: 806 and 980 nm excitation routes

     Skripka, A.; Marin, R.; Benayas, A.; Canton, P.; Hemmer, E.; Vetrone, F.

     Physical Chemistry Chemical Physics (2017), 19 (19), 11825-11834CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)

     Today, at the frontier of biomedical research, the need was clearly established for integrating disease detection and therapeutic function in 1 single theranostic system. Light-emitting nanoparticles are being intensively studied to fulfil this demand, by continuously developing nanoparticle systems simultaneously emitting in both the UV/visible (light-triggered release and activation of drugs) and the near-IR (imaging and tracking) spectral regions. Rare-earth (RE) doped nanoparticles (RENPs) were synthesized via a thermal decompn. process and spectroscopically studied as potential candidates as all-in-one optical imaging, diagnostic and therapeutic agents. These core/shell/shell nanoparticles (NaGdF4:Er3+,Ho3+,Yb3+/NaGdF4:Nd3+,Yb3+/NaGdF4) are optically excited by heating-free 806 nm light that, aside from minimizing the local thermal load, also allows to obtain a deeper sub-tissue penetration with respect to the still widely used 980 nm light. Also, these H2O-dispersed nanoplatforms offer interesting assets as triggers/probes for biomedical applications, by virtue of a plethora of emission bands (spanning the 380-1600 nm range). The results pave the way to use these RENPs for UV/visible-triggered photodynamic therapy/drug release, while simultaneously tracking the nanoparticle biodistribution and monitoring their therapeutic action through the near-IR signal that overlaps with biol. transparency windows.
466. 466

     Cortelletti, P.; Skripka, A.; Facciotti, C.; Pedroni, M.; Caputo, G.; Pinna, N.; Quintanilla, M.; Benayas, A.; Vetrone, F.; Speghini, A. Tuning the Sensitivity of Lanthanide-Activated NIR Nanothermometers in the Biological Windows. Nanoscale 2018, 10, 2568– 2576,  DOI: 10.1039/C7NR06141B

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     Tuning the sensitivity of lanthanide-activated NIR nanothermometers in the biological windows

     Cortelletti, P.; Skripka, A.; Facciotti, C.; Pedroni, M.; Caputo, G.; Pinna, N.; Quintanilla, M.; Benayas, A.; Vetrone, F.; Speghini, A.

     Nanoscale (2018), 10 (5), 2568-2576CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Lanthanide-activated SrF2 nanoparticles with a multishell architecture were investigated as optical thermometers in the biol. windows. A ratiometric approach based on the relative changes in the intensities of different lanthanide (Nd3+ and Yb3+) NIR emissions was applied to investigate the thermometric properties of the nanoparticles. It was found that an appropriate doping with Er3+ ions can increase the thermometric properties of the Nd3+-Yb3+ coupled systems. In addn., a core contg. Yb3+ and Tm3+ can generate light in the visible and UV regions upon near-IR (NIR) laser excitation at 980 nm. The multishell structure combined with the rational choice of dopants proves to be particularly important to control and enhance the performance of nanoparticles as NIR nanothermometers.
467. 467

     Rocha, U.; Jacinto da Silva, C.; Ferreira Silva, W.; Guedes, I.; Benayas, A.; Martínez Maestro, L.; Acosta Elias, M.; Bovero, E.; van Veggel, F. C. J. M.; García Solé, J. A.; Jaque, D. Subtissue Thermal Sensing Based on Neodymium-Doped LaF₃ Nanoparticles. ACS Nano 2013, 7, 1188– 1199,  DOI: 10.1021/nn304373q

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     Subtissue Thermal Sensing Based on Neodymium-Doped LaF3 Nanoparticles

     Rocha, Ueslen; Jacinto da Silva, Carlos; Ferreira Silva, Wagner; Guedes, Ilde; Benayas, Antonio; Martinez Maestro, Laura; Acosta Elias, Monica; Bovero, Enrico; van Veggel, Frank C. J. M.; Garcia Sole, Jose Antonio; Jaque, Daniel

     ACS Nano (2013), 7 (2), 1188-1199CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The authors report the multifunctional character of Nd-doped LaF3 core/shell nanoparticles. Because of the spectral overlap of the Nd emission bands with the transparency windows of human tissues, these nanoparticles emerge as relevant subtissue optical probes. For Nd contents optimizing the luminescence brightness of Nd3+:LaF3 nanoparticles, subtissue penetration depths of several millimeters were demonstrated. At the same time, the IR emission bands of Nd3+:LaF3 nanoparticles show a remarkable thermal sensitivity, so that they can be advantageously used as luminescent nanothermometers for subtissue thermal sensing. This possibility was demonstrated in this work: Nd3+:LaF3 nanoparticles were used to provide optical control over subtissue temp. in a single-beam plasmonic-mediated heating expt. In this expt., Au nanorods are used as nanoheaters while thermal reading is performed by the Nd3+:LaF3 nanoparticles. The possibility of a real single-beam-controlled subtissue hyperthermia process is, therefore, pointed out.
468. 468

     Wang, Y.-F.; Liu, G.-Y.; Sun, L.-D.; Xiao, J.-W.; Zhou, J.-C.; Yan, C.-H. Nd³⁺-Sensitized Upconversion Nanophosphors: Efficient in Vivo Bioimaging Probes with Minimized Heating Effect. ACS Nano 2013, 7, 7200– 7206,  DOI: 10.1021/nn402601d

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     Nd3+-Sensitized Upconversion Nanophosphors: Efficient In Vivo Bioimaging Probes with Minimized Heating Effect

     Wang, Ye-Fu; Liu, Gao-Yuan; Sun, Ling-Dong; Xiao, Jia-Wen; Zhou, Jia-Cai; Yan, Chun-Hua

     ACS Nano (2013), 7 (8), 7200-7206CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Upconversion (UC) process in lanthanide-doped nanomaterials has attracted great research interest for its extensive biol. applications in vitro and in vivo, benefiting from the high tissue penetration depth of near-IR excitation light and low autofluorescence background. However, the 980 nm laser, typically used to trigger the Yb3+-sensitized UC process, is strongly absorbed by water in biol. structures and could cause severe overheating effect. In this article, we report the extension of the UC excitation spectrum to shorter wavelengths, where water has lower absorption. This is realized by further introducing Nd3+ as the sensitizer and by building a core/shell structure to ensure successive Nd3+→Yb3+→activator energy transfer. The efficacy of this Nd3+-sensitized UC process is demonstrated in in vivo imaging, and the results confirmed that the laser-induced local overheating effect is greatly minimized.
469. 469

     Liu, T.-M.; Conde, J.; Lipiński, T.; Bednarkiewicz, A.; Huang, C.-C. Revisiting the Classification of NIR-Absorbing/Emitting Nanomaterials for in Vivo Bioapplications. NPG Asia Mater. 2016, 8, e295,  DOI: 10.1038/am.2016.106

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     Revisiting the classification of NIR-absorbing/emitting nanomaterials for in vivo bioapplications

     Liu, Tzu-Ming; Conde, Joao; Lipinski, Tomasz; Bednarkiewicz, Artur; Huang, Chih-Chia

     NPG Asia Materials (2016), 8 (8), e295CODEN: NAMPCE; ISSN:1884-4057. (Nature Publishing Group)

     With the development of nonlinear optics and new imaging methods, near-IR (NIR) light can excite contrast agents to probe biol. specimens both functionally and structurally with a deeper imaging depth and a higher spatial resoln. than linear optical approaches. There is considerable and growing interest in how biol. specimens respond to NIR light. Moreover, the visible absorption band of most functional nanomaterials becomes NIR-excitable through multiphoton processes, thus allowing multifunctional imaging and combined therapy with noble metal and magnetic nanoparticles both in vitro and in vivo. A groundbreaking example is the use of different laser techniques to excite single-type NIR-absorbing/emitting nanomaterials to produce multiphoton emission by femtosecond lasers using either a remote control system for photodynamic therapy or photo-induced chem. bond dissocn. These techniques provided superior anatomical resoln. and detection sensitivity for in vivo tumor-targeted imaging than those offered by conventional methods. Here we summarize the most recent progress in the development of smart NIR-absorbing/emitting nanomaterials for in vivo bioapplications.
470. 470

     Pliss, A.; Ohulchanskyy, T. Y.; Chen, G.; Damasco, J.; Bass, C. E.; Prasad, P. N. Subcellular Optogenetics Enacted by Targeted Nanotransformers of Near-Infrared Light. ACS Photonics 2017, 4, 806– 814,  DOI: 10.1021/acsphotonics.6b00475

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     Subcellular Optogenetics Enacted by Targeted Nanotransformers of Near-Infrared Light

     Pliss, Artem; Ohulchanskyy, Tymish Y.; Chen, Guanying; Damasco, Jossana; Bass, Caroline E.; Prasad, Paras N.

     ACS Photonics (2017), 4 (4), 806-814CODEN: APCHD5; ISSN:2330-4022. (American Chemical Society)

     Light activation of photo-switchable mols. enables control over physicochem. processes with high spatiotemporal precision, offering revolutionizing potential in multiple areas of contemporary biomedicine. Yet, application of this technol. in live organisms remains severely limited due to the reliance on visible light that has poor penetration in biol. tissues. Herein, the authors introduce highly efficient upconversion nanoparticles (UCNPs) as photon nanotransformers that intracellularly convert tissue-penetrating near IR light into visible light required for photo-activation. The core/shell nanoparticles described here are about six times brighter in the blue range than the canonical hexagonal (NaYF4:Yb3+30%/Tm3+0.5%)/ NaYF4 core/shell UCNPs with record efficiency. An application of such efficient photon nanotransformers can significantly advance optogenetics technol., wherein the signaling of genetically modified neurons is controlled through interaction of visible light with optogenetic proteins inserted into the cell membranes. The authors' photon nanotransformers, targeted to cultured cells, enable optogenetic activation with incident near-IR light. The resulting membrane potential modulation by ion channel activity is probed by Ca2+ sensitive dye. In contrast to conventional optogenetic approaches involving unselective activation of optogenetic proteins in the cellular vol. with incident light irradn., the upconverted light generated in situ by intracellular UCNPs, activates the optogenetic proteins in close vicinity of the nanoparticles, thus providing a high subcellular precision of photoactivation.
471. 471

     Chen, S.; Weitemier, A. Z.; Zeng, X.; He, L.; Wang, X.; Tao, Y.; Huang, A. J. Y.; Hashimotodani, Y.; Kano, M.; Iwasaki, H.; Parajuli, L. K.; Okabe, S.; Teh, D. B. L.; All, A. H.; Tsutsui-Kimura, I.; Tanaka, K. F.; Liu, X.; McHugh, T. J. Near-Infrared Deep Brain Stimulation via Upconversion Nanoparticle Mediated Optogenetics. Science 2018, 359, 679– 684,  DOI: 10.1126/science.aaq1144

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     Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics

     Chen, Shuo; Weitemier, Adam Z.; Zeng, Xiao; He, Linmeng; Wang, Xiyu; Tao, Yanqiu; Huang, Arthur J. Y.; Hashimotodani, Yuki; Kano, Masanobu; Iwasaki, Hirohide; Parajuli, Laxmi Kumar; Okabe, Shigeo; Teh, Daniel B. Loong; All, Angelo H.; Tsutsui-Kimura, Iku; Tanaka, Kenji F.; Liu, Xiaogang; McHugh, Thomas J.

     Science (Washington, DC, United States) (2018), 359 (6376), 679-684CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Optogenetics has revolutionized the exptl. interrogation of neural circuits and holds promise for the treatment of neurol. disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-IR (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technol. will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.
472. 472

     Yi, Z.; Luo, Z.; Qin, X.; Chen, Q.; Liu, X. Lanthanide-Activated Nanoparticles: A Toolbox for Bioimaging, Therapeutics, and Neuromodulation. Acc. Chem. Res. 2020, 53, 2692– 2704,  DOI: 10.1021/acs.accounts.0c00513

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     Lanthanide-Activated Nanoparticles: A Toolbox for Bioimaging, Therapeutics, and Neuromodulation

     Yi, Zhigao; Luo, Zichao; Qin, Xian; Chen, Qiushui; Liu, Xiaogang

     Accounts of Chemical Research (2020), 53 (11), 2692-2704CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

     Conspectus: Owing to their unique features, the past decade has witnessed rapid developments of lanthanide-activated nanoparticles for biol. applications. These include highly tunable upconverting and downshifting photoluminescence when illuminated in deep tissue, excellent photostability against blinking and bleaching effects, biocompatibility through versatile surface modification, and ease of achieving multifunctionality, as well as satisfactory signal output. These attributes make lanthanide-doped nanoparticles an ideal toolbox for advanced bioimaging and next-generation therapeutics. The interest in lanthanide-doped nanoparticles for biomedical research arises from their unique optical properties in response to deep-tissue-penetrable light sources. Upon near-IR irradn., these nanoparticles with properly doped emitters display photon upconversion with large anti-Stokes shifts and broad-spectrum tunability from the UV to the visible. It is also possible to achieve orthogonal photoluminescence with variations in wavelength and lifetime. Coupled with surface ligands, dyes, biomols., or other types of functional nanomaterials, lanthanide-doped nanoparticles offer new opportunities for applications in bioimaging, advanced oncotherapy, and neuromodulation. Given the possibility of locating downshifting luminescence at "biol. transmission windows", exquisite design of lanthanide-doped nanoparticles also enables deep-tissue imaging with high spatial resoln. In addn., these nanoparticles can respond to high-energy photons, such as X-rays, to trigger nonradioactive and radiative pathways, making it possible to develop high-sensitivity X-ray detectors. Precise control of paramagnetic lanthanide ions in nanocrystal lattices also provides advanced materials for high-performance magnetic resonance imaging in medical diagnostics and biomedical research. Full consideration of fundamental attributes of lanthanide-doped nanoparticles will facilitate the design of multifunctional and sensitive probes and improve diagnostic and therapeutic outcomes. In this Account, we categorize various lanthanide-activation strategies into three modes: near-IR excitation, X-ray irradn., and magnetic field stimulation. We introduce energy manipulations in upconverting, downshifting, and persistence luminescence in spectral and time domains and discuss how they can be applied in biol. practices. We assess general design principles for lanthanide-activated nanosystems with multiple modalities of bioimaging, oncotherapy, and neuromodulation. We also review the current state-of-the-art in the field of lanthanide-based theranostic nanoplatforms, with particular emphasis on energy conversion and nano-/biointerfacing as well as emerging bioapplications. In this context, we also highlight recent advances in controlling optical properties of nanoplatforms for single- or multimodal bioimaging, stimulus-responsive phototherapy, and optogenetics. Finally, we discuss future opportunities and challenges of this exciting research field.
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     Liu, X.; Yan, C. H.; Capobianco, J. A. Photon Upconversion Nanomaterials. Chem. Soc. Rev. 2015, 44, 1299– 301,  DOI: 10.1039/C5CS90009C

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     Photon upconversion nanomaterials

     Liu, Xiaogang; Yan, Chun-Hua; Capobianco, John A.

     Chemical Society Reviews (2015), 44 (6), 1299-1301CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     In this paper, the fundamental principles, synthetic strategies, materials characterization, broad applications of photon upconversion nanomaterials were discussed.
474. 474

     Ao, Y.; Zeng, K.; Yu, B.; Miao, Y.; Hung, W.; Yu, Z.; Xue, Y.; Tan, T. T. Y.; Xu, T.; Zhen, M. An Upconversion Nanoparticle Enables Near Infrared-Optogenetic Manipulation of the Caenorhabditis elegans Motor Circuit. ACS Nano 2019, 13, 3373– 3386,  DOI: 10.1021/acsnano.8b09270

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     An Upconversion Nanoparticle Enables Near Infrared-Optogenetic Manipulation of the Caenorhabditis elegans Motor Circuit

     Ao, Yanxiao; Zeng, Kanghua; Yu, Bin; Miao, Yu; Hung, Wesley; Yu, Zhongzheng; Xue, Yanhong; Tan, Timothy Thatt Yang; Xu, Tao; Zhen, Mei; Yang, Xiangliang; Zhang, Yan; Gao, Shangbang

     ACS Nano (2019), 13 (3), 3373-3386CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Near-IR (NIR) light penetrates tissue deeply, but its application to motor behavior stimulation has been limited by the lack of known genetic NIR light-responsive sensors. We designed and synthesized a Yb3+/Er3+/Ca2+-based lanthanide-doped upconversion nanoparticle (UCNP) that effectively converts 808 nm NIR light to green light emission. This UCNP is compatible with Chrimson, a cation channel activated by green light; as such, it can be used in the optogenetic manipulation of the motor behaviors of Caenorhabditis elegans. We show that this UCNP effectively activates Chrimson-expressing, inhibitory GABAergic motor neurons, leading to reduced action potential firing in the body wall muscle and resulting in locomotion inhibition. The UCNP also activates the excitatory glutamatergic DVC interneuron, leading to potentiated muscle action potential bursts and active reversal locomotion. Moreover, this UCNP exhibits negligible toxicity in neural development, growth, and reprodn., and the NIR energy required to elicit these behavioral and physiol. responses does not activate the animal's temp. response. This study shows that UCNP provides a useful integrated optogenetic toolset, which may have wide applications in other exptl. systems.
475. 475

     All, A. H.; Zeng, X.; Teh, D. B. L.; Yi, Z.; Prasad, A.; Ishizuka, T.; Thakor, N.; Hiromu, Y.; Liu, X. Expanding the Toolbox of Upconversion Nanoparticles for in Vivo Optogenetics and Neuromodulation. Adv. Mater. 2019, 31, 1803474,  DOI: 10.1002/adma.201803474

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     475

     Expanding the Toolbox of Upconversion Nanoparticles for In Vivo Optogenetics and Neuromodulation

     All, Angelo Homayoun; Zeng, Xiao; Teh, Daniel Boon Loong; Yi, Zhigao; Prasad, Ankshita; Ishizuka, Toru; Thakor, Nitish; Hiromu, Yawo; Liu, Xiaogang

     Advanced Materials (Weinheim, Germany) (2019), 31 (41), 1803474CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Optogenetics is an optical technique that exploits visible light for selective neuromodulation with spatio-temporal precision. Despite enormous effort, the effective stimulation of targeted neurons, which are located in deeper structures of the nervous system, by visible light, remains a tech. challenge. Compared to visible light, near-IR illumination offers a higher depth of tissue penetration owing to a lower degree of light attenuation. Herein, an overview of advances in developing new modalities for neural circuitry modulation utilizing upconversion-nanoparticle-mediated optogenetics is presented. These developments have led to minimally invasive optical stimulation and inhibition of neurons with substantially improved selectivity, sensitivity, and spatial resoln. The focus is to provide a comprehensive review of the mechanistic basis for evaluating upconversion parameters, which will be useful in designing, executing, and reporting optogenetic expts.
476. 476

     Lin, X.; Wang, Y.; Chen, X.; Yang, R.; Wang, Z.; Feng, J.; Wang, H.; Lai, K. W. C.; He, J.; Wang, F.; Shi, P. Multiplexed Optogenetic Stimulation of Neurons with Spectrum-Selective Upconversion Nanoparticles. Adv. Healthc. Mater. 2017, 6, 1700446,  DOI: 10.1002/adhm.201700446

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     There is no corresponding record for this reference.
477. 477

     Zheng, B.; Wang, H.; Pan, H.; Liang, C.; Ji, W.; Zhao, L.; Chen, H.; Gong, X.; Wu, X.; Chang, J. Near-Infrared Light Triggered Upconversion Optogenetic Nanosystem for Cancer Therapy. ACS Nano 2017, 11, 11898– 11907,  DOI: 10.1021/acsnano.7b06395

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     477

     Near-Infrared Light Triggered Upconversion Optogenetic Nanosystem for Cancer Therapy

     Zheng, Bin; Wang, Hanjie; Pan, Huizhuo; Liang, Chao; Ji, Wanying; Zhao, Li; Chen, Hongbin; Gong, Xiaoqun; Wu, Xiaoli; Chang, Jin

     ACS Nano (2017), 11 (12), 11898-11907CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     In vivo the application of optogenetic manipulation in deep tissue is seriously obstructed by the limited penetration depth of visible light that is continually applied to activate a photoactuator. Herein, we designed a versatile upconversion optogenetic nanosystem based on a blue-light-mediated heterodimerization module and rare-earth upconversion nanoparticles (UCNs). The UCNs worked as a nanotransducer to convert external deep-tissue-penetrating near-IR (NIR) light to local blue light to noninvasively activate photoreceptors for optogenetic manipulation in vivo. In this, we demonstrated that deeply penetrating NIR light could be used to control the apoptotic signaling pathway of cancer cells in both mammalian cells and mice by UCNs. We believe that this interesting NIR-light-responsive upconversion optogenetic nanotechnol. has significant application potentials for both basic research and clin. applications in vivo.
478. 478

     Hao, Y.; Du, T.; Pang, G.; Li, J.; Pan, H.; Zhang, Y.; Wang, L.; Chang, J.; Zhou, E.-m.; Wang, H. Spatiotemporal Regulation of Ubiquitin-Mediated Protein Degradation via Upconversion Optogenetic Nanosystem. Nano Res. 2020, 13, 3253– 3260,  DOI: 10.1007/s12274-020-2998-z

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     There is no corresponding record for this reference.
479. 479

     Zhang, Y.; Wiesholler, L. M.; Rabie, H.; Jiang, P.; Lai, J.; Hirsch, T.; Lee, K.-B. Remote Control of Neural Stem Cell Fate Using NIR-Responsive Photoswitching Upconversion Nanoparticle Constructs. ACS Appl. Mater. Interfaces 2020, 12, 40031– 40041,  DOI: 10.1021/acsami.0c10145

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     479

     Remote Control of Neural Stem Cell Fate Using NIR-Responsive Photoswitching Upconversion Nanoparticle Constructs

     Zhang, Yixiao; Wiesholler, Lisa M.; Rabie, Hudifah; Jiang, Pengfei; Lai, Jinping; Hirsch, Thomas; Lee, Ki-Bum

     ACS Applied Materials & Interfaces (2020), 12 (36), 40031-40041CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Light-mediated remote control of stem cell fate, such as proliferation, differentiation, and migration, can bring a significant impact on stem cell biol. and regenerative medicine. Current UV/vis-mediated control approaches are limited in terms of nonspecific absorption, poor tissue penetration, and phototoxicity. Upconversion nanoparticle (UCNP)-based near-IR (NIR)-mediated control systems have gained increasing attention for vast applications with minimal nonspecific absorption, good penetration depth, and minimal phototoxicity from NIR excitations. Specifically, 808 nm NIR-responsive upconversion nanomaterials have shown clear advantages for biomedical applications owing to diminished heating effects and better tissue penetration. Herein, a novel 808 nm NIR-mediated control method for stem cell differentiation has been developed using multishell UCNPs, which are optimized for up-converting 808 nm NIR light to UV emission. The locally generated UV emissions further toggle photoswitching polymer capping ligands to achieve spatiotemporally controlled small-mol. release. More specifically, with 808 nm NIR excitation, stem cell differentiation factors can be released to guide neural stem cell (NSC) differentiation in a highly controlled manner. Given the challenges in stem cell behavior control, the developed 808 nm NIR-responsive UCNP-based approach to control stem cell differentiation can represent a new tool for studying single-mol. roles in stem cell and developmental biol.
480. 480

     Lin, X.; Chen, X.; Zhang, W.; Sun, T.; Fang, P.; Liao, Q.; Chen, X.; He, J.; Liu, M.; Wang, F. Core-Shell-Shell Upconversion Nanoparticles with Enhanced Emission for Wireless Optogenetic Inhibition. Nano Lett. 2018, 18, 948– 956,  DOI: 10.1021/acs.nanolett.7b04339

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     480

     Core-Shell-Shell Upconversion Nanoparticles with Enhanced Emission for Wireless Optogenetic Inhibition

     Lin, Xudong; Chen, Xian; Zhang, Wenchong; Sun, Tianying; Fang, Peilin; Liao, Qinghai; Chen, Xi; He, Jufang; Liu, Ming; Wang, Feng; Shi, Peng

     Nano Letters (2018), 18 (2), 948-956CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Recent advances in upconversion technol. have enabled optogenetic neural stimulation using remotely applied optical signals, but limited success was demonstrated for neural inhibition by using this method, primarily due to the much higher optical power and more red-shifted excitation spectrum that are required to work with the appropriate inhibitory opsin proteins. To overcome these limitations, core-shell-shell upconversion nanoparticles (UCNPs) with a hexagonal phase are synthesized to optimize the doping contents of Yb3+ and to mitigate Yb-assocd. concn. quenching. Such UCNPs' emission contains an almost 3-fold enhanced peak around 540-570 nm, matching the excitation spectrum of a commonly used inhibitory opsin protein, halorhodopsin. The enhanced UCNPs are used as optical transducers to develop a fully implantable upconversion-based device for in vivo tetherless optogenetic inhibition, which is actuated by near-IR (NIR) light irradn. without any electronics. When the device is implanted into targeted sites deep in the rat brain, the elec. activity of the neurons is reliably inhibited with NIR irradn. and restores to normal level upon switching off the NIR light. The system is further used to perform tetherless unilateral inhibition of the secondary motor cortex in behaving mice, achieving control of their motor functions. This study provides an important and useful supplement to the upconversion-based optogenetic toolset, which is beneficial for both basic and translational neuroscience studies.
481. 481

     Wu, X.; Zhang, Y.; Takle, K.; Bilsel, O.; Li, Z.; Lee, H.; Zhang, Z.; Li, D.; Fan, W.; Duan, C. Dye-Sensitized Core/Active Shell Upconversion Nanoparticles for Optogenetics and Bioimaging Applications. ACS Nano 2016, 10, 1060– 1066,  DOI: 10.1021/acsnano.5b06383

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     481

     Dye-Sensitized Core/Active Shell Upconversion Nanoparticles for Optogenetics and Bioimaging Applications

     Wu, Xiang; Zhang, Yuanwei; Takle, Kendra; Bilsel, Osman; Li, Zhanjun; Lee, Hyungseok; Zhang, Zijiao; Li, Dongsheng; Fan, Wei; Duan, Chunying; Chan, Emory M.; Lois, Carlos; Xiang, Yang; Han, Gang

     ACS Nano (2016), 10 (1), 1060-1066CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Near-IR (NIR) dye-sensitized upconversion nanoparticles (UCNPs) can broaden the absorption range and boost upconversion efficiency of UCNPs. Here, we achieved significantly enhanced upconversion luminescence in dye-sensitized core/active shell UCNPs via the doping of ytterbium ions (Yb3+) in the UCNP shell, which bridged the energy transfer from the dye to the UCNP core. As a result, we synergized the two most practical upconversion booster effectors (dye-sensitizing and core/shell enhancement) to amplify upconversion efficiency. We demonstrated two biomedical applications using these UCNPs. By using dye-sensitized core/active shell UCNP embedded poly(Me methacrylate) polymer implantable systems, we successfully shifted the optogenetic neuron excitation window to a biocompatible and deep tissue penetrable 800 nm wavelength. Furthermore, UCNPs were water-solubilized with Pluronic F127 with high upconversion efficiency and can be imaged in a mouse model.
482. 482

     Wang, Y.; Lin, X.; Chen, X.; Chen, X.; Xu, Z.; Zhang, W.; Liao, Q.; Duan, X.; Wang, X.; Liu, M.; Wang, F.; He, J.; Shi, P. Tetherless Near-Infrared Control of Brain Activity in Behaving Animals Using Fully Implantable Upconversion Microdevices. Biomaterials 2017, 142, 136– 148,  DOI: 10.1016/j.biomaterials.2017.07.017

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     482

     Tetherless near-infrared control of brain activity in behaving animals using fully implantable upconversion microdevices

     Wang, Ying; Lin, Xudong; Chen, Xi; Chen, Xian; Xu, Zhen; Zhang, Wenchong; Liao, Qinghai; Duan, Xin; Wang, Xin; Liu, Ming; Wang, Feng; He, Jufang; Shi, Peng

     Biomaterials (2017), 142 (), 136-148CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Many nanomaterials can be used as sensors or transducers in biomedical research and they form the essential components of transformative novel biotechnologies. In this study, we present an all-optical method for tetherless remote control of neural activity using fully implantable micro-devices based on upconversion technol. Upconversion nanoparticles (UCNPs) were used as transducers to convert near-IR (NIR) energy to visible light to stimulate neurons expressing different opsin proteins. In our setup, UCNPs were packaged in a glass micro-optrode to form an implantable device with superb long-term biocompatibility. We showed that remotely applied NIR illumination is able to reliably trigger spiking activity in rat brains. In combination with a robotic laser projection system, the upconversion-based tetherless neural stimulation technique was implemented to modulate brain activity in various regions, including the striatum, ventral tegmental area, and visual cortex. Using this system, we were able to achieve behavioral conditioning in freely moving animals. Notably, our microscale device was at least one order of magnitude smaller in size (∼100 μm in diam.) and two orders of magnitude lighter in wt. (less than 1 mg) than existing wireless optogenetic devices based on light-emitting diodes. This feature allows simultaneous implantation of multiple UCNP-optrodes to achieve modulation of brain function to control complex animal behavior. We believe that this technol. not only represents a novel practical application of upconversion nanomaterials, but also opens up new possibilities for remote control of neural activity in the brains of behaving animals.
483. 483

     Zhao, J.; Ellis-Davies, G. C. R. Intracellular Photoswitchable Neuropharmacology Driven by Luminescence from Upconverting Nanoparticles. Chem. Commun. 2020, 56, 9445– 9448,  DOI: 10.1039/D0CC03956J

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484. 484

     Ma, Y.; Bao, J.; Zhang, Y.; Li, Z.; Zhou, X.; Wan, C.; Huang, L.; Zhao, Y.; Han, G.; Xue, T. Mammalian Near-Infrared Image Vision through Injectable and Self-Powered Retinal Nanoantennae. Cell 2019, 177, 243– 255,  DOI: 10.1016/j.cell.2019.01.038

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     484

     Mammalian Near-Infrared Image Vision through Injectable and Self-Powered Retinal Nanoantennae

     Ma, Yuqian; Bao, Jin; Zhang, Yuanwei; Li, Zhanjun; Zhou, Xiangyu; Wan, Changlin; Huang, Ling; Zhao, Yang; Han, Gang; Xue, Tian

     Cell (Cambridge, MA, United States) (2019), 177 (2), 243-255.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

     Mammals cannot see light over 700 nm in wavelength. This limitation is due to the phys. thermodn. properties of the photon-detecting opsins. However, the detection of naturally invisible near-IR (NIR) light is a desirable ability. To break this limitation, we developed ocular injectable photoreceptor-binding upconversion nanoparticles (pbUCNPs). These nanoparticles anchored on retinal photoreceptors as miniature NIR light transducers to create NIR light image vision with negligible side effects. Based on single-photoreceptor recordings, electroretinograms, cortical recordings, and visual behavioral tests, we demonstrated that mice with these nanoantennae could not only perceive NIR light, but also see NIR light patterns. Excitingly, the injected mice were also able to differentiate sophisticated NIR shape patterns. Moreover, the NIR light pattern vision was ambient-daylight compatible and existed in parallel with native daylight vision. This new method will provide unmatched opportunities for a wide variety of emerging bio-integrated nanodevice designs and applications.
485. 485

     Wang, Y.; Xie, K.; Yue, H.; Chen, X.; Luo, X.; Liao, Q.; Liu, M.; Wang, F.; Shi, P. Flexible and Fully Implantable Upconversion Device for Wireless Optogenetic Stimulation of the Spinal Cord in Behaving Animals. Nanoscale 2020, 12, 2406– 2414,  DOI: 10.1039/C9NR07583F

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486. 486

     Feliu, N.; Neher, E.; Parak, W. J. Toward an Optically Controlled Brain - Noninvasive Deep Brain Stimulation Can Be Achieved by Optical Triggers. Science 2018, 359, 633– 634,  DOI: 10.1126/science.aar7379

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487. 487

     Feliu, N.; Docter, D.; Heine, M.; del Pino, P.; Ashraf, S.; Kolosnjaj-Tabi, J.; Macchiarini, P.; Nielsen, P.; Alloyeau, D.; Gazeau, F.; Stauber, R. H.; Parak, W. J. In Vivo Degeneration and the Fate of Inorganic Nanoparticles. Chem. Soc. Rev. 2016, 45, 2440– 2457,  DOI: 10.1039/C5CS00699F

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     487

     In vivo degeneration and the fate of inorganic nanoparticles

     Feliu, Neus; Docter, Dominic; Heine, Markus; del Pino, Pablo; Ashraf, Sumaira; Kolosnjaj-Tabi, Jelena; Macchiarini, Paolo; Nielsen, Peter; Alloyeau, Damien; Gazeau, Florence; Stauber, Roland H.; Parak, Wolfgang J.

     Chemical Society Reviews (2016), 45 (9), 2440-2457CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. What happens to inorg. nanoparticles (NPs), such as plasmonic gold or silver, superparamagnetic iron oxide, or fluorescent quantum dot NPs after they have been administrated to a living being. This review discusses the integrity, biodistribution, and fate of NPs after in vivo administration. The hybrid nature of the NPs is described, conceptually divided into the inorg. core, the engineered surface coating comprising of the ligand shell and optionally also bio-conjugates, and the corona of adsorbed biol. mols. Empirical evidence shows that all of these three compds. may degrade individually in vivo and can drastically modify the life cycle and biodistribution of the whole heterostructure. Thus, the NPs may be decompd. into different parts, whose biodistribution and fate would need to be analyzed individually. Multiple labeling and quantification strategies for such a purpose will be discussed. All reviewed data indicate that NPs in vivo should no longer be considered as homogeneous entities, but should be seen as inorg./org./biol. nano-hybrids with complex and intricately linked distribution and degrdn. pathways.
488. 488

     Poon, W.; Zhang, Y.-N.; Ouyang, B.; Kingston, B. R.; Wu, J. L. Y.; Wilhelm, S.; Chan, W. C. W. Elimination Pathways of Nanoparticles. ACS Nano 2019, 13, 5785– 5798,  DOI: 10.1021/acsnano.9b01383

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     488

     Elimination Pathways of Nanoparticles

     Poon, Wilson; Zhang, Yi-Nan; Ouyang, Ben; Kingston, Benjamin R.; Wu, Jamie L. Y.; Wilhelm, Stefan; Chan, Warren C. W.

     ACS Nano (2019), 13 (5), 5785-5798CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Understanding how nanoparticles are eliminated from the body is required for their successful clin. translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally. A proposed pathway for these nanoparticles is hepatobiliary elimination, but their transport has not been well-studied. Here, we explored the barriers that detd. the elimination of nanoparticles through the hepatobiliary route. The route of hepatobiliary elimination is usually through the following pathway: (1) liver sinusoid, (2) space of Disse, (3) hepatocytes, (4) bile ducts, (5) intestines, and (6) out of the body. We discovered that the interaction of nanoparticles with liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) dets. the elimination fate. Each step in the route contains cells that can sequester and chem. or phys. alter the nanoparticles, which influences their fecal elimination. We showed that the removal of Kupffer cells increased fecal elimination by >10 times. Combining our results with those of prior studies, we can start to build a systematic view of nanoparticle elimination pathways as it relates to particle size and other design parameters. This is crit. to engineering medically useful and translatable nanotechnologies.
489. 489

     Wilhelm, S.; Tavares, A. J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H. F.; Chan, W. C. W. Analysis of Nanoparticle Delivery to Tumours. Nat. Rev. Mater. 2016, 1, 16014,  DOI: 10.1038/natrevmats.2016.14

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     489

     Analysis of nanoparticle delivery to tumours

     Wilhelm, Stefan; Tavares, Anthony J.; Dai, Qin; Ohta, Seiichi; Audet, Julie; Dvorak, Harold F.; Chan, Warren C. W.

     Nature Reviews Materials (2016), 1 (5), 16014CODEN: NRMADL; ISSN:2058-8437. (Nature Publishing Group)

     Targeting nanoparticles to malignant tissues for improved diagnosis and therapy is a popular concept. However, after surveying the literature from the past 10 years, only 0.7% (median) of the administered nanoparticle dose is found to be delivered to a solid tumor. This has neg. consequences on the translation of nanotechnol. for human use with respect to manufg., cost, toxicity, and imaging and therapeutic efficacy. In this article, we conduct a multivariate anal. on the compiled data to reveal the contributions of nanoparticle physicochem. parameters, tumor models and cancer types on the low delivery efficiency. We explore the potential causes of the poor delivery efficiency from the perspectives of tumor biol. (intercellular vs. transcellular transport, enhanced permeability and retention effect, and physicochem.-dependent nanoparticle transport through the tumor stroma) as well as competing organs (mononuclear phagocytic and renal systems) and present a 30-yr research strategy to overcome this fundamental limitation. Solving the nanoparticle delivery problem will accelerate the clin. translation of nanomedicine.
490. 490

     Montenegro, J.-M.; Grazu, V.; Sukhanova, A.; Agarwal, S.; de la Fuente, J. M.; Nabiev, I.; Greiner, A.; Parak, W. J. Controlled Antibody/(Bio-) Conjugation of Inorganic Nanoparticles for Targeted Delivery. Adv. Drug Delivery Rev. 2013, 65, 677– 688,  DOI: 10.1016/j.addr.2012.12.003

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     490

     Controlled antibody/(bio-) conjugation of inorganic nanoparticles for targeted delivery

     Montenegro, Jose-Maria; Grazu, Valeria; Sukhanova, Alyona; Agarwal, Seema; de la Fuente, Jesus M.; Nabiev, Igor; Greiner, Andreas; Parak, Wolfgang J.

     Advanced Drug Delivery Reviews (2013), 65 (5), 677-688CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)

     A review. Arguably targeting is one of the biggest problems for controlled drug delivery. In the case that drugs can be directed with high efficiency to the target tissue, side effects of medication are drastically reduced. Colloidal inorg. nanoparticles (NPs) were proposed and described in the last 10 years as new platforms for in vivo delivery. However, though NPs can introduce plentiful functional properties (such as controlled destruction of tissue by local heating or local generation of free radicals), targeting remains an issue of intense research efforts. While passive targeting of NPs was reported (the so-called enhanced permeation and retention, EPR effect), still improved active targeting would be highly desirable. One classical approach for active targeting is mediated by mol. recognition via capture mols., i.e. antibodies (Abs) specific for the target. In order to apply this strategy for NPs, they need to be conjugated with Abs against specific biomarkers. Though many approaches were reported in this direction, the controlled bioconjugation of NPs is still a challenge. In this article the strategies of controlled bioconjugation of NPs will be reviewed giving particular emphasis to the following questions: (1) how can the no. of capture mols. per NP be precisely adjusted, and (2) how can the Abs be attached to NP surfaces in an oriented way. Soln. of both questions is a cornerstone in controlled targeting of the inorg. NPs bioconjugates.
491. 491

     Joshi, T.; Mamat, C.; Stephan, H. Contemporary Synthesis of Ultrasmall (sub-10 nm) Upconverting Nanomaterials. ChemistryOpen 2020, 9, 703– 712,  DOI: 10.1002/open.202000073

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492. 492

     Zeng, X.; Chen, S.; Weitemier, A.; Han, S.; Blasiak, A.; Prasad, A.; Zheng, K.; Yi, Z.; Luo, B.; Yang, I. H.; Thakor, N.; Chai, C.; Lim, K. L.; McHugh, T. J.; All, A. H.; Liu, X. Visualization of Intra-neuronal Motor Protein Transport through Upconversion Microscopy. Angew. Chem., Int. Ed. Engl. 2019, 58 (27), 9262– 9268,  DOI: 10.1002/anie.201904208

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493. 493

     Liu, Y.; Lu, Y.; Yang, X.; Zheng, X.; Wen, S.; Wang, F.; Vidal, X.; Zhao, J.; Liu, D.; Zhou, Z. Amplified Stimulated Emission in Upconversion Nanoparticles for Super-Resolution Nanoscopy. Nature 2017, 543, 229– 233,  DOI: 10.1038/nature21366

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     493

     Amplified stimulated emission in upconversion nanoparticles for super-resolution nanoscopy

     Liu, Yujia; Lu, Yiqing; Yang, Xusan; Zheng, Xianlin; Wen, Shihui; Wang, Fan; Vidal, Xavier; Zhao, Jiangbo; Liu, Deming; Zhou, Zhiguang; Ma, Chenshuo; Zhou, Jiajia; Piper, James A.; Xi, Peng; Jin, Dayong

     Nature (London, United Kingdom) (2017), 543 (7644), 229-233CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     UCNPs doped with high concns. of Tm ions (Tm3+), excited at λ = 980 nm, can readily establish a population inversion on their intermediate metastable 3H4 level: the reduced inter-emitter distance at high Tm3+ doping concn. leads to intense cross-relaxation, inducing a photon-avalanche-like effect that rapidly populates the metastable 3H4 level, resulting in population inversion relative to the 3H6 ground level within a single nanoparticle. Illumination by a laser at 808 nm, matching the upconversion band of the 3H4 → 3H6 transition, can trigger amplified stimulated emission to discharge the 3H4 intermediate level, so that the upconversion pathway to generate blue luminescence can be optically inhibited. These properties were harnessed to realize low-power super-resoln. stimulated emission depletion (STED) microscopy and achieve nm-scale optical resoln. (nanoscopy), imaging single UCNPs; the resoln. is 28 nm, i.e., 1/36th of the wavelength. These engineered nanocrystals offer satn. intensity two orders of magnitude lower than those of fluorescent probes currently employed in stimulated emission depletion microscopy, suggesting a new way of alleviating the square-root law that typically limits the resoln. that can be practically achieved by such techniques.
494. 494

     Oliveira, H.; Bednarkiewicz, A.; Falk, A.; Fröhlich, E.; Lisjak, D.; Prina-Mello, A.; Resch, S.; Schimpel, C.; Vrček, I. V.; Wysokińska, E. Critical Considerations on the Clinical Translation of Upconversion Nanoparticles (UCNPs): Recommendations from the European Upconversion Network (COST Action CM1403). Adv. Healthc. Mater. 2019, 8, 1801233,  DOI: 10.1002/adhm.201801233

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     494

     Critical Considerations on the Clinical Translation of Upconversion Nanoparticles (UCNPs): Recommendations from the European Upconversion Network (COST Action CM1403)

     Oliveira, Helena; Bednarkiewicz, Artur; Falk, Andreas; Froehlich, Eleonore; Lisjak, Darja; Prina-Mello, Adriele; Resch, Susanne; Schimpel, Christa; Vrcek, Ivana Vinkovic; Wysokinska, Edyta; Gorris, Hans H.

     Advanced Healthcare Materials (2019), 8 (1), 1801233CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)

     The unique photoluminescent properties of upconversion nanoparticles (UCNPs) have attracted worldwide research interest and inspired many bioanal. applications. The anti-Stokes emission with long luminescence lifetimes, narrow and multiple absorption and emission bands, and excellent photostability enable background-free and multiplexed detection in deep tissues. So far, however, in vitro and in vivo applications of UCNPs are restricted to the lab. use due to safety concerns. Possible harmful effects may originate from the chem. compn. but also from the small size of UCNPs. Potential end users must rely on well-founded safety data. Thus, a risk to benefit assessment of the envisioned combined therapeutic and diagnostic ("theranostic") applications is fundamentally important to bridge the translational gap between lab. and clinics. The COST Action CM1403 "The European Upconversion Network-From the Design of Photon-Upconverting Nanomaterials to Biomedical Applications" integrates research on UCNPs ranging from fundamental materials synthesis and research, detection instrumentation, biofunctionalization, and bioassay development to toxicity testing. Such an interdisciplinary approach is necessary for a better and safer theranostic use of UCNPs. Here, the status of nanotoxicity research on UCNPs is compared to other nanomaterials, and routes for the translation of UCNPs into clin. applications are delineated.
495. 495

     Gnach, A.; Lipinski, T.; Bednarkiewicz, A.; Rybka, J.; Capobianco, J. A. Upconverting Nanoparticles: Assessing the Toxicity. Chem. Soc. Rev. 2015, 44, 1561– 1584,  DOI: 10.1039/C4CS00177J

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     495

     Upconverting nanoparticles: assessing the toxicity

     Gnach, Anna; Lipinski, Tomasz; Bednarkiewicz, Artur; Rybka, Jacek; Capobianco, John A.

     Chemical Society Reviews (2015), 44 (6), 1561-1584CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. Lanthanide doped nanoparticles (Ln:NPs) hold promise as novel luminescent probes for numerous applications in nanobiophotonics. Despite excellent photostability, narrowband photoluminescence, efficient anti-Stokes emission and long luminescence lifetimes, which are needed to meet the requirements of multiplexed and background free detection at prolonged observation times, concern about their toxicity is still an issue for both in vivo and in vitro applications. Similar to other chems. or pharmaceuticals, the very same properties that are desirable and potentially useful from a biomedical perspective can also give rise to unexpected and hazardous toxicities. In engineered bionanomaterials, the potentially harmful effects may originate not only from their chem. compn. but also from their small size. The latter property enables the nanoparticles to bypass the biol. barriers, thus allowing deep tissue penetration and the accumulation of the nanoparticles in a no. of organs. In addn., nanoparticles are known to possess high surface chem. reactivity as well as a large surface-to-vol. ratio, which may seriously affect their biocompatibility. Herein we survey the underlying mechanisms of nanotoxicity and provide an overview on the nanotoxicity of lanthanides and of upconverting nanoparticles.
496. 496

     Dukhno, O.; Przybilla, F.; Muhr, V.; Buchner, M.; Hirsch, T.; Mély, Y. Time-Dependent Luminescence Loss for Individual Upconversion Nanoparticles upon Dilution in Aqueous Solution. Nanoscale 2018, 10, 15904– 15910,  DOI: 10.1039/C8NR03892A

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     496

     Time-dependent luminescence loss for individual upconversion nanoparticles upon dilution in aqueous solution

     Dukhno, Oleksii; Przybilla, Frederic; Muhr, Verena; Buchner, Markus; Hirsch, Thomas; Mely, Yves

     Nanoscale (2018), 10 (34), 15904-15910CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Single-particle luminescence microscopy is a powerful method to ext. information on biol. systems that is not accessible by ensemble-level methods. Upconversion nanoparticles (UCNPs) are a particularly promising luminophore for single-particle microscopy as they provide stable, non-blinking luminescence and allow the avoidance of biol. autofluorescence by their anti-Stokes emission. Recently, ensemble measurements of dild. aq. dispersions of UCNPs have shown the instability of luminescence over time due to particle dissoln.-related effects. This can be esp. detrimental for single-particle expts. However, this effect has never been estd. at the individual particle level. Here, the luminescence response of individual UCNPs under aq. conditions is investigated by quant. wide-field microscopy. The particles exhibit a rapid luminescence loss, accompanied by large changes in spectral response, leading to a considerable heterogeneity in their luminescence and band intensity ratio. Moreover, the dissoln.-caused intensity loss is not correlated with the initial particle intensity or band ratio, which makes it virtually unpredictable. These effects and the subsequent development of their heterogeneity can be largely slowed down by adding millimolar concns. of sodium fluoride in buffer. As a consequence, the presented data indicate that microscopy expts. employing UCNPs in an aq. environment should be performed under conditions that carefully prevent these effects.
497. 497

     Andresen, E.; Würth, C.; Prinz, C.; Michaelis, M.; Resch-Genger, U. Time-Resolved Luminescence Spectroscopy for Monitoring the Stability and Dissolution Behaviour of Upconverting Nanocrystals with Different Surface Coatings. Nanoscale 2020, 12, 12589– 12601,  DOI: 10.1039/D0NR02931A

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498. 498

     Saleh, M. I.; Rühle, B.; Wang, S.; Radnik, J.; You, Y.; Resch-Genger, U. Assessing the Protective Effects of Different Surface Coatings on NaYF₄: Yb³⁺, Er³⁺ Upconverting Nanoparticles in Buffer and DMEM. Sci. Rep. 2020, 10, 19318,  DOI: 10.1038/s41598-020-76116-z

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499. 499

     Pombo Garcia, K.; Zarschler, K.; Barbaro, L.; Barreto, J. A.; O’Malley, W.; Spiccia, L.; Stephan, H.; Graham, B. Zwitterionic-Coated “Stealth” Nanoparticles for Biomedical Applications: Recent Advances in Countering Biomolecular Corona Formation and Uptake by the Mononuclear Phagocyte System. Small 2014, 10, 2516– 2529,  DOI: 10.1002/smll.201303540

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     499

     Zwitterionic-coated "stealth" nanoparticles for biomedical applications: recent advances in countering biomolecular corona formation and uptake by the mononuclear phagocyte system

     Pombo Garcia Karina; Zarschler Kristof; Barbaro Lisa; Barreto Jose A; O'Malley William; Spiccia Leone; Stephan Holger; Graham Bim

     Small (Weinheim an der Bergstrasse, Germany) (2014), 10 (13), 2516-29 ISSN:.

     Nanoparticles represent highly promising platforms for the development of imaging and therapeutic agents, including those that can either be detected via more than one imaging technique (multi-modal imaging agents) or used for both diagnosis and therapy (theranostics). A major obstacle to their medical application and translation to the clinic, however, is the fact that many accumulate in the liver and spleen as a result of opsonization and scavenging by the mononuclear phagocyte system. This focused review summarizes recent efforts to develop zwitterionic-coatings to counter this issue and render nanoparticles more biocompatible. Such coatings have been found to greatly reduce the rate and/or extent of non-specific adsorption of proteins and lipids to the nanoparticle surface, thereby inhibiting production of the "biomolecular corona" that is proposed to be a universal feature of nanoparticles within a biological environment. Additionally, in vivo studies have demonstrated that larger-sized nanoparticles with a zwitterionic coating have extended circulatory lifetimes, while those with hydrodynamic diameters of ≤5 nm exhibit small-molecule-like pharmacokinetics, remaining sufficiently small to pass through the fenestrae and slit pores during glomerular filtration within the kidneys, and enabling efficient excretion via the urine. The larger particles represent ideal candidates for use as blood pool imaging agents, whilst the small ones provide a highly promising platform for the future development of theranostics with reduced side effect profiles and superior dose delivery and image contrast capabilities.
500. 500

     Wilhelm, S.; Kaiser, M.; Wuerth, C.; Heiland, J.; Carrillo-Carrion, C.; Muhr, V.; Wolfbeis, O. S.; Parak, W. J.; Resch-Genger, U.; Hirsch, T. Water Dispersible Upconverting Nanoparticles: Effects of Surface Modification on Their Luminescence and Colloidal Stability. Nanoscale 2015, 7, 1403– 1410,  DOI: 10.1039/C4NR05954A

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     500

     Water dispersible upconverting nanoparticles: effects of surface modification on their luminescence and colloidal stability

     Wilhelm, Stefan; Kaiser, Martin; Wuerth, Christian; Heiland, Josef; Carrillo-Carrion, Carolina; Muhr, Verena; Wolfbeis, Otto S.; Parak, Wolfgang J.; Resch-Genger, Ute; Hirsch, Thomas

     Nanoscale (2015), 7 (4), 1403-1410CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     We present a systematic study on the effect of surface ligands on the luminescence properties and colloidal stability of β-NaYF4:Yb3+,Er3+ upconversion nanoparticles (UCNPs), comparing nine different surface coatings to render these UCNPs water-dispersible and bioconjugatable. A prerequisite for this study was a large-scale synthetic method that yields ∼2 g per batch of monodisperse oleate-capped UCNPs providing identical core particles. These ∼23 nm sized UCNPs display an upconversion quantum yield of ∼0.35% when dispersed in cyclohexane and excited with a power d. of 150 W cm-2, underlining their high quality. A comparison of the colloidal stability and luminescence properties of these UCNPs, subsequently surface modified with ligand exchange or encapsulation protocols, revealed that the ratio of the green (545 nm) and red (658 nm) emission bands detd. at a const. excitation power d. clearly depends on the surface chem. Modifications relying on the deposition of addnl. (amphiphilic) layer coatings, where the initial oleate coating is retained, show reduced non-radiative quenching by water as compared to UCNPs that are rendered water-dispersible via ligand exchange. Moreover, we could demonstrate that the brightness of the upconversion luminescence of the UCNPs is strongly affected by the type of surface modification, i.e., ligand exchange or encapsulation, yet hardly by the chem. nature of the ligand.
501. 501

     Nsubuga, A.; Zarschler, K.; Sgarzi, M.; Graham, B.; Stephan, H.; Joshi, T. Towards Utilising Photocrosslinking of Polydiacetylenes for the Preparation of “Stealth” Upconverting Nanoparticles. Angew. Chem. 2018, 130, 16268– 16272,  DOI: 10.1002/ange.201811003

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502. 502

     Märkl, S.; Schroter, A.; Hirsch, T. Small and Bright Water-Protected Upconversion Nanoparticles with Long-Time Stability in Complex, Aqueous Media by Phospholipid Membrane Coating. Nano Lett. 2020, 20, 8620– 8625,  DOI: 10.1021/acs.nanolett.0c03327

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503. 503

     Young, A. T.; Cornwell, N.; Daniele, M. A. Neuro-Nano Interfaces: Utilizing Nano-Coatings and Nanoparticles to Enable Next-Generation Electrophysiological Recording, Neural Stimulation, and Biochemical Modulation. Adv. Funct. Mater. 2018, 28, 1700239,  DOI: 10.1002/adfm.201700239

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504. 504

     Qi, Y.; Wei, S.; Xin, T.; Huang, C.; Pu, Y.; Ma, J.; Zhang, C.; Liu, Y.; Lynch, I.; Liu, S. Passage of Exogeneous Fine Particles from the Lung into the Brain in Humans and Animals. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2117083119,  DOI: 10.1073/pnas.2117083119

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     504

     Passage of exogeneous fine particles from the lung into the brain in humans and animals

     Qi, Yu; Wei, Shuting; Xin, Tao; Huang, Chuanjiang; Pu, Yichen; Ma, Jinzhu; Zhang, Changbin; Liu, Yajun; Lynch, Iseult; Liu, Sijin

     Proceedings of the National Academy of Sciences of the United States of America (2022), 119 (26), e2117083119CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     There are still significant knowledge gaps in understanding the intrusion and retention of exogeneous particles into the central nervous system (CNS). Here, we uncovered various exogeneous fine particles in human cerebrospinal fluids (CSFs) and identified the ambient environmental or occupational exposure sources of these particles, including commonly found particles (e.g., Fe- and Ca-contg. ones) and other compns. that have not been reported previously (such as malayaite and anatase TiO2), by mapping their chem. and structural fingerprints. Furthermore, using mouse and in vitro models, we unveiled a possible translocation pathway of various inhaled fine particles from the lung to the brain through blood circulation (via dedicated biodistribution and mechanistic studies). Importantly, with the aid of isotope labeling, we obtained the retention kinetics of inhaled fine particles in mice, indicating a much slower clearance rate of localized exogenous particles from the brain than from other main metabolic organs. Collectively, our results provide a piece of evidence on the intrusion of exogeneous particles into the CNS and support the assocn. between the inhalation of exogenous particles and their transport into the brain tissues. This work thus provides addnl. insights for the continued investigation of the adverse effects of air pollution on the brain.
505. 505

     Gregori, M.; Bertani, D.; Cazzaniga, E.; Orlando, A.; Mauri, M.; Bianchi, A.; Re, F.; Sesana, S.; Minniti, S.; Francolini, M.; Cagnotto, A.; Salmona, M.; Nardo, L.; Salerno, D.; Mantegazza, F.; Masserini, M.; Simonutti, R. Investigation of Functionalized Poly(N,N-dimethylacrylamide)-block-polystyrene Nanoparticles As Novel Drug Delivery System to Overcome the Blood-Brain Barrier in Vitro. Macromol. Biosci. 2015, 15, 1687– 97,  DOI: 10.1002/mabi.201500172

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506. 506

     Kreuter, J.; Shamenkov, D.; Petrov, V.; Ramge, P.; Cychutek, K.; Koch-Brandt, C.; Alyautdin, R. Apolipoprotein-Mediated Transport of Nanoparticle-Bound Drugs across the Blood-Brain Barrier. J. Drug Targeting 2002, 10, 317– 325,  DOI: 10.1080/10611860290031877

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     Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier

     Kreuter, Jorg; Shamenkov, Dmitry; Petrov, Valery; Ramge, Peter; Cychutek, Klaus; Koch-Brandt, Claudia; Alyautdin, Renad

     Journal of Drug Targeting (2002), 10 (4), 317-325CODEN: JDTAEH; ISSN:1061-186X. (Taylor & Francis Ltd.)

     Recent studies have shown that drugs that are normally unable to cross the blood-brain barrier (BBB) following i.v. injection can be transported across this barrier by binding to poly(Bu cyanoacrylate) nanoparticles and coating with polysorbate 80. However, the mechanism of this transport so far was not known. In the present paper, the possible involvement of apolipoproteins in the transport of nanoparticle-bound drugs into the brain is investigated. Poly(Bu cyanoacrylate) nanoparticles loaded with the hexapeptide dalargin were coated with the apolipoproteins AII, B, CII, E, or J without or after precoating with polysorbate 80. In addn., loperamide-loaded nanoparticles were coated with apolipoprotein E alone or again after precoating with polysorbate 80. After i.v. injection to ICR mice the antinociceptive threshold was measured by the tail flick test. Furthermore, the antinociceptive threshold of polysorbate 80-coated dalargin-loaded nanoparticles was detd. in ApoEtm1Unc and C57BL/6J mice. The results show that only dalargin or loperamide-loaded nanoparticles coated with polysorbate 80 and/or with apolipoprotein B or E were able to achieve an antinociceptive effect. This effect was significantly higher after polysorbate-precoating and apolipoprotein B or E-overcoating. With the apolipoprotein E-deficient ApoEtm1Unc mice the antinociceptive effect was considerably reduced in comparison to the C57BL/6J mice. These results suggest that apolipoproteins B and E are involved in the mediation of the transport of drugs bound to poly(Bu cyanoacrylate) nanoparticles across the BBB. Polysorbate 80-coated nanoparticles adsorb these apolipoproteins from the blood after injection and thus seem to mimic lipoprotein particles that could be taken up by the brain capillary endothelial cells via receptor-mediated endocytosis. Bound drugs then may be further transported into the brain by diffusion following release within the endothelial cells or, alternatively, by transcytosis.
507. 507

     Qiao, R.; Jia, Q.; Hüwel, S.; Xia, R.; Liu, T.; Gao, F.; Galla, H.-J.; Gao, M. Receptor-Mediated Delivery of Magnetic Nanoparticles across the Blood-Brain Barrier. ACS Nano 2012, 6, 3304– 3310,  DOI: 10.1021/nn300240p

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     507

     Receptor-Mediated Delivery of Magnetic Nanoparticles across the Blood-Brain Barrier

     Qiao, Ruirui; Jia, Qiaojuan; Huwel, Sabine; Xia, Rui; Liu, Ting; Gao, Fabao; Galla, Hans-Joachim; Gao, Mingyuan

     ACS Nano (2012), 6 (4), 3304-3310CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     A brain delivery probe was prepd. by covalently conjugating lactoferrin (Lf) to a poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticle in order to facilitate the transport of the nanoparticles across the blood-brain barrier (BBB) by receptor-mediated transcytosis via the Lf receptor present on cerebral endothelial cells. The efficacy of the Fe3O4-Lf conjugate to cross the BBB was evaluated in vitro using a cell culture model for the blood-brain barrier as well as in vivo in SD rats. For an in vitro expt., a well-established porcine BBB model was used based on the primary culture of cerebral capillary endothelial cells grown on filter supports, thus allowing one to follow the transfer of nanoparticles from the apical (blood) to the basolateral (brain) side. For in vivo expts., SD rats were used as animal model to detect the passage of the nanoparticles through the BBB by MRI techniques. The results of both in vitro and in vivo expts. revealed that the Fe3O4-Lf probe exhibited an enhanced ability to cross the BBB in comparison to the PEG-coated Fe3O4 nanoparticles and further suggested that the Lf-receptor-mediated transcytosis was an effective measure for delivering the nanoparticles across the BBB.
508. 508

     Ulbrich, K.; Knobloch, T.; Kreuter, J. Targeting the Insulin Receptor: Nanoparticles for Drug Delivery across the Blood-Brain Barrier (BBB). J. Drug Targeting 2011, 19, 125– 132,  DOI: 10.3109/10611861003734001

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     508

     Targeting the insulin receptor: nanoparticles for drug delivery across the blood-brain barrier (BBB)

     Ulbrich, Karsten; Knobloch, Thomas; Kreuter, Joerg

     Journal of Drug Targeting (2011), 19 (2), 125-132CODEN: JDTAEH; ISSN:1061-186X. (Informa Healthcare)

     Human serum albumin (HSA) nanoparticles (NP) were prepd. by desolvation. Insulin or an anti-insulin receptor monoclonal antibody (29B4) were covalently coupled to the HSA NP, using the NHS-PEG-MAL-5000 crosslinker. Loperamide-loaded HSA NP with covalently bound insulin or the 29B4 antibodies induced significant antinociceptive effects in the tail-flick test in ICR (CD-1) mice after i.v. injection, demonstrating that insulin or these antibodies covalently coupled to HSA NP are able to transport loperamide across the blood-brain barrier (BBB) which it normally is unable to cross. Control loperamide-loaded HSA NP with IgG antibodies yielded only marginal effects. The loperamide transport across the BBB using the NP with covalently attached insulin could be totally inhibited by the pretreatment with the antibody 29B4.
509. 509

     Werner, C.; Sauer, M.; Geis, C. Super-Resolving Microscopy in Neuroscience. Chem. Rev. 2021, 121, 11971– 12015,  DOI: 10.1021/acs.chemrev.0c01174

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     509

     Super-resolving Microscopy in Neuroscience

     Werner, Christian; Sauer, Markus; Geis, Christian

     Chemical Reviews (Washington, DC, United States) (2021), 121 (19), 11971-12015CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Fluorescence imaging techniques play a pivotal role in our understanding of the nervous system. The emergence of various super-resoln. microscopy methods and specialized fluorescent probes enables direct insight into neuronal structure and protein arrangements in cellular subcompartments with so far unmatched resoln. Super-resolving visualization techniques in neurons unveil a novel understanding of cytoskeletal compn., distribution, motility, and signaling of membrane proteins, subsynaptic structure and function, and neuron-glia interaction. Well-defined mol. targets in autoimmune and neurodegenerative disease models provide excellent starting points for in-depth investigation of disease pathophysiol. using novel and innovative imaging methodol. Application of super-resoln. microscopy in human brain samples and for testing clin. biomarkers is still in its infancy but opens new opportunities for translational research in neurol. and neuroscience. In this review, we describe how super-resolving microscopy has improved our understanding of neuronal and brain function and dysfunction in the last two decades.
510. 510

     Paviolo, C.; Thompson, A. C.; Yong, J.; Brown, W. G.; Stoddart, P. R. Nanoparticle-Enhanced Infrared Neural Stimulation. J. Neural Eng. 2014, 11, 065002,  DOI: 10.1088/1741-2560/11/6/065002

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511. 511

     Nakatsuji, H.; Numata, T.; Morone, N.; Kaneko, S.; Mori, Y.; Imahori, H.; Murakami, T. Thermosensitive Ion Channel Activation in Single Neuronal Cells by Using Surface-Engineered Plasmonic Nanoparticles. Angew. Chem., Int. Ed. 2015, 54, 11725– 11729,  DOI: 10.1002/anie.201505534

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     511

     Thermosensitive ion channel activation in single neuronal cells by using surface-engineered plasmonic nanoparticles

     Nakatsuji, Hirotaka; Numata, Tomohiro; Morone, Nobuhiro; Kaneko, Shuji; Mori, Yasuo; Imahori, Hiroshi; Murakami, Tatsuya

     Angewandte Chemie, International Edition (2015), 54 (40), 11725-11729CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Controlling cell functions using external photoresponsive nanomaterials has enormous potential for the development of cell-engineering technologies and intractable disease therapies, but the former currently requires genetic modification of the target cells. We present a method using plasma-membrane-targeted gold nanorods (pm-AuNRs) prepd. with a cationic protein/lipid complex to activate a thermosensitive cation channel, TRPV1, in intact neuronal cells. Highly localized photothermal heat generation mediated by the pm-AuNRs induced Ca2+ influx solely by TRPV1 activation. In contrast, the use of previously reported cationic AuNRs that are coated with a conventional synthetic polymer also led to photoinduced Ca2+ influx, but this influx resulted from membrane damage. Our method provides an optogenetic platform without the need for prior genetic engineering of the target cells and might be useful for novel TRPV1-targeted phototherapeutic approaches.
512. 512

     Cheong, J.; Yu, H.; Lee, C. Y.; Lee, J.-u.; Choi, H.-J.; Lee, J.-H.; Lee, H.; Cheon, J. Fast Detection of SARS-CoV-2 RNA via the Integration of Plasmonic Thermocycling and Fluorescence Detection in a Portable Device. Nat. Biomed. Eng. 2020, 4, 1159– 1167,  DOI: 10.1038/s41551-020-00654-0

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     512

     Fast detection of SARS-CoV-2 RNA via the integration of plasmonic thermocycling and fluorescence detection in a portable device

     Cheong, Jiyong; Yu, Hojeong; Lee, Chang Yeol; Lee, Jung-uk; Choi, Hyun-Jung; Lee, Jae-Hyun; Lee, Hakho; Cheon, Jinwoo

     Nature Biomedical Engineering (2020), 4 (12), 1159-1167CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)

     The diagnosis of severe acute respiratory syndrome 2 (SARS-CoV-2) infection by quant. PCR with reverse transcription (RT-qPCR) typically involves bulky instrumentation in centralized labs. and an assay time of 1-2 h. Here, we show that SARS-CoV-2 RNA can be detected in 17 min via a portable device integrating reverse transcription, fast thermocycling (via plasmonic heating through magneto-plasmonic nanoparticles) and in situ fluorescence detection following magnetic clearance of the nanoparticles. The device correctly classified all nasopharyngeal, oropharyngeal and sputum samples from 75 patients with COVID-19 and 75 healthy controls, with good concordance in fluorescence intensity with std. RT-qPCR (Pearson coeffs. > 0.7 for the N1, N2 and RPP30 genes). Fast, portable and automated nucleic acid detection should facilitate testing at the point of care.
513. 513

     Gao, W.; Sun, Y.; Cai, M.; Zhao, Y.; Cao, W.; Liu, Z.; Cui, G.; Tang, B. Copper Sulfide Nanoparticles as a Photothermal Switch for TRPV1 Signaling to Attenuate Atherosclerosis. Nat. Commun. 2018, 9, 231,  DOI: 10.1038/s41467-017-02657-z

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     513

     Copper sulfide nanoparticles as a photothermal switch for TRPV1 signaling to attenuate atherosclerosis

     Gao Wen; Sun Yuhui; Zhao Yujie; Cao Wenhua; Liu Zhenhua; Cui Guanwei; Tang Bo; Cai Michelle

     Nature communications (2018), 9 (1), 231 ISSN:.

     Atherosclerosis is characterized by the accumulation of lipids within the arterial wall. Although activation of TRPV1 cation channels by capsaicin may reduce lipid storage and the formation of atherosclerotic lesions, a clinical use for capsaicin has been limited by its chronic toxicity. Here we show that coupling of copper sulfide (CuS) nanoparticles to antibodies targeting TRPV1 act as a photothermal switch for TRPV1 signaling in vascular smooth muscle cells (VSMCs) using near-infrared light. Upon irradiation, local increases of temperature open thermo-sensitive TRPV1 channels and cause Ca(2+) influx. The increase in intracellular Ca(2+) activates autophagy and impedes foam cell formation in VSMCs treated with oxidized low-density lipoprotein. In vivo, CuS-TRPV1 allows photoacoustic imaging of the cardiac vasculature and reduces lipid storage and plaque formation in ApoE(-)/(-) mice fed a high-fat diet, with no obvious long-term toxicity. Together, this suggests CuS-TRPV1 may represent a therapeutic tool to locally and temporally attenuate atherosclerosis.
514. 514

     Kaplan, L.; Chow, B. W.; Gu, C. Neuronal Regulation of the Blood-Brain Barrier and Neurovascular Coupling. Nat. Rev. Neurosci. 2020, 21, 416– 432,  DOI: 10.1038/s41583-020-0322-2

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515. 515

     Podgorski, K.; Ranganathan, G. Brain Heating Induced by Near-Infrared Lasers During Multiphoton Microscopy. J. Neurophysiol. 2016, 116, 1012– 1023,  DOI: 10.1152/jn.00275.2016

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     Brain heating induced by near-infrared lasers during multiphoton microscopy

     Podgorski, Kaspar; Ranganathan, Gayathri

     Journal of Neurophysiology (2016), 116 (3), 1012-1023CODEN: JONEA4; ISSN:0022-3077. (American Physiological Society)

     Two-photon imaging and optogenetic stimulation rely on high illumination powers, particularly for state-of-the-art applications that target deeper structures, achieve faster measurements, or probe larger brain areas. However, little information is available on heating and resulting damage induced by high-power illumination in the brain. In the current study we used thermocouple probes and quantum dot nanothermometers to measure temp. changes induced by two-photon microscopy in the neocortex of awake and anesthetized mice. We characterized heating as a function of wavelength, exposure time, and distance from the center of illumination. Although total power is highest near the surface of the brain, heating was most severe hundreds of micrometers below the focal plane, due to heat dissipation through the cranial window. Continuous illumination of a 1-mm2 area produced a peak temp. increase of ∼1.8°C/100 mW. Continuous illumination with powers above 250 mW induced lasting damage, detected with immunohistochem. against Iba1, glial fibrillary acidic protein, heat shock proteins, and activated caspase-3. Higher powers were usable in expts. with limited duty ratios, suggesting an approach to mitigate damage in high-power microscopy expts.
516. 516

     Liu, Y.; Bhattarai, P.; Dai, Z.; Chen, X. Photothermal Therapy and Photoacoustic Imaging via Nanotheranostics in Fighting Cancer. Chem. Soc. Rev. 2019, 48, 2053– 2108,  DOI: 10.1039/C8CS00618K

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     516

     Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer

     Liu, Yijing; Bhattarai, Pravin; Dai, Zhifei; Chen, Xiaoyuan

     Chemical Society Reviews (2019), 48 (7), 2053-2108CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, resp. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumor accumulation have been thoroughly studied to improve the pre-clin. efficiency of PAI and PTT. In this review, we first summarize the development of inorg. and org. nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumors. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, esp. regarding their clin. translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.
517. 517

     Rodriguez-Fernandez, J.; Perez-Juste, J.; Mulvaney, P.; Liz-Marzan, L. M. Spatially- Directed Oxidation of Gold Nanoparticles by Au(III)-CTAB Complexes. J. Phys. Chem. B 2005, 109, 14257– 14261,  DOI: 10.1021/jp052516g

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     Spatially-Directed Oxidation of Gold Nanoparticles by Au(III)-CTAB Complexes

     Rodriguez-Fernandez, Jessica; Perez-Juste, Jorge; Mulvaney, Paul; Liz-Marzan, Luis M.

     Journal of Physical Chemistry B (2005), 109 (30), 14257-14261CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)

     Gold nanoparticles are readily oxidized by Au(III) in the presence of cetyl-trimethylammonium bromide (CTAB). Oxidn. occurs preferentially at surface sites with higher curvature. Conversely, oxidn. with cyanide ions in the absence of CTAB leads to uniform oxidn. over the whole surface. Examples of the spatially directed oxidn. are provided using large, irregular spheres, nanocubes, and nanorods. We conclude that the mechanism of oxidn. depends on whether the oxidant is attached to CTAB micelles. The CTAB micelles approach the nanoparticles preferentially at the tips, leading to spatially directed oxidn.
518. 518

     Prisner, L.; Witthöft, P.; Nguyen, L. V. N.; Tsangas, T.; Gefken, T.; Klaus, F.; Strelow, C.; Kipp, T.; Mews, A. Monitoring the Death of Single BaF3 cells under Plasmonic Photothermal Heating Induced by Ultrasmall Gold Nanorods. J. Mater. Chem. B 2019, 7, 3582– 3589,  DOI: 10.1039/C8TB03135E

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     518

     Monitoring the death of single BaF3 cells under plasmonic photothermal heating induced by ultrasmall gold nanorods

     Prisner, Lisa; Witthoeft, Phillip; Nguyen, Lan Vi Ngoc; Tsangas, Thomas; Gefken, Tobias; Klaus, Florentine; Strelow, Christian; Kipp, Tobias; Mews, Alf

     Journal of Materials Chemistry B: Materials for Biology and Medicine (2019), 7 (22), 3582-3589CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)

     Gold nanorods are very suitable as energy converters for plasmonic photothermal therapy (PPTT) applications. These particles can be accumulated on cells by targeted or non-targeted delivery and subsequently internalized by the cells. Upon photoexcitation, the plasmonic particles create heat that can trigger cell-death mechanisms that are still not fully understood. Here, we used ultrasmall plasmonic gold nanorods, either non-targeted or targeted by functionalization with the aptamer AIR-3A. This aptamer specifically binds to the Interleukin-6 receptor expressed on the investigated BaF3 cell line. After photoexcitation of only individual cells, we monitored and investigated the evolution of cell death in real time on the single-cell level by tracking the temporal development of both the morphol. and the absorbance of the cell, which changed due to the uptake of the dye trypan blue. We obsd. a swelling of the cell during the first few minutes, followed by a subsequent staining due to loss of membrane integrity, before cellular lysis took place. As the most notable difference between the use of targeted and non-targeted gold nanorods, the trypan blue staining period was considerably shorter when the targeted gold nanorods were used. Morphol. changes of the cell after irradn. strongly suggest that necrosis is induced. The temporal delay between the start of the necrotic process and the beginning of cell staining indicates that the cell damage initially occurs in the inner cell compartments before the cell membrane is affected.
519. 519

     Urban, P.; Kirchner, S. R.; Muhlbauer, C.; Lohmuller, T.; Feldmann, J. Reversible Control of Current Across Lipid Membranes by Local Heating. Sci. Rep. 2016, 6, 22686,  DOI: 10.1038/srep22686

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     519

     Reversible control of current across lipid membranes by local heating

     Urban, Patrick; Kirchner, Silke R.; Muehlbauer, Christian; Lohmueller, Theobald; Feldmann, Jochen

     Scientific Reports (2016), 6 (), 22686CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     Lipid membranes are almost impermeable for charged mols. and ions that can pass the membrane barrier only with the help of specialized transport proteins. Here, we report how temp. manipulation at the nanoscale can be employed to reversibly control the elec. resistance and the amt. of current that flows through a bilayer membrane with pA resoln. For this expt., heating is achieved by irradiating gold nanoparticles that are attached to the bilayer membrane with laser light at their plasmon resonance frequency. We found that controlling the temp. on the nanoscale renders it possible to reproducibly regulate the current across a phospholipid membrane and the membrane of living cells in absence of any ion channels.
520. 520

     Wu, X.; Jiang, Y.; Rommelfanger, N. J.; Yang, F.; Zhou, Q.; Yin, R.; Liu, J.; Cai, S.; Ren, W.; Shin, A. Tether-Free Photothermal Deep-Brain Stimulation in Freely Behaving Mice via Wide-Field Illumination in the Near-Infrared-II Window. Nat. Biomed. Eng. 2022, 6, 754– 770,  DOI: 10.1038/s41551-022-00862-w

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     520

     Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window

     Wu, Xiang; Jiang, Yuyan; Rommelfanger, Nicholas J.; Yang, Fan; Zhou, Qi; Yin, Rongkang; Liu, Junlang; Cai, Sa; Ren, Wei; Shin, Andrew; Ong, Kyrstyn S.; Pu, Kanyi; Hong, Guosong

     Nature Biomedical Engineering (2022), 6 (6), 754-770CODEN: NBEAB3; ISSN:2157-846X. (Nature Portfolio)

     Neural circuitry is typically modulated via invasive brain implants and tethered optical fibers in restrained animals. Here we show that wide-field illumination in the second near-IR spectral window (NIR-II) enables implant-and-tether-free deep-brain stimulation in freely behaving mice with stereotactically injected macromol. photothermal transducers activating neurons ectopically expressing the temp.-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1). The macromol. transducers, ∼40 nm in size and consisting of a semiconducting polymer core and an amphiphilic polymer shell, have a photothermal conversion efficiency of 71at 1,064 nm, the wavelength at which light attenuation by brain tissue is minimized (within the 400-1,800 nm spectral window). TRPV1-expressing neurons in the hippocampus, motor cortex and ventral tegmental area of mice can be activated with minimal thermal damage on wide-field NIR-II illumination from a light source placed at distances higher than 50 cm above the animal's head and at an incident power d. of 10 mW mm-2. Deep-brain stimulation via wide-field NIR-II illumination may open up opportunities for social behavioral studies in small animals.
521. 521

     Baffou, G.; Quidant, R. Thermo-Plasmonics: Using Metallic Nanostructures as Nano-Sources of Heat. Laser Photonics Rev. 2013, 7, 171– 187,  DOI: 10.1002/lpor.201200003

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     521

     Thermo-plasmonics: using metallic nanostructures as nano-sources of heat

     Baffou, Guillaume; Quidant, Romain

     Laser & Photonics Reviews (2013), 7 (2), 171-187CODEN: LPRAB8; ISSN:1863-8880. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Recent years have seen a growing interest in using metal nanostructures to control temp. on the nanoscale. Under illumination at its plasmonic resonance, a metal nanoparticle features enhanced light absorption, turning it into an ideal nano-source of heat, remotely controllable using light. Such a powerful and flexible photothermal scheme is the basis of thermo-plasmonics. Here, the recent progress of this emerging and fast-growing field is reviewed. First, the physics of heat generation in metal nanoparticles is described, under both continuous and pulsed illumination. The second part is dedicated to numerical and exptl. methods that have been developed to further understand and engineer plasmonic-assisted heating processes on the nanoscale. Finally, some of the most recent applications based on the heat generated by gold nanoparticles are surveyed, namely photothermal cancer therapy, nano-surgery, drug delivery, photothermal imaging, protein tracking, photoacoustic imaging, nano-chem. and optofluidics.
522. 522

     Boulais, E.; Lachaine, R.; Meunier, M. Plasma Mediated Off-Resonance Plasmonic Enhanced Ultrafast Laser-Induced Nanocavitation. Nano Lett. 2012, 12, 4763– 4769,  DOI: 10.1021/nl302200w

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     522

     Plasma Mediated off-Resonance Plasmonic Enhanced Ultrafast Laser-Induced Nanocavitation

     Boulais, Etienne; Lachaine, Remi; Meunier, Michel

     Nano Letters (2012), 12 (9), 4763-4769CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The generation of nanobubbles around plasmonic nanostructures is an efficient approach for imaging and therapy, esp. in the field of cancer research. A novel method using IR fs laser that generates ∼800 nm bubbles around off-resonance Au nanospheres using 200 mJ/cm2 45 fs pulses is shown. Exptl. and theor. work demonstrate that the nanobubble formation results from the generation of a nanoscale plasma around the particle due to the enhanced near-field rather than from the heating of the particle. Energy absorbed in the nanoplasma is indeed >11 times the energy absorbed in the particle. When compared to the usual approach that uses ns laser to induce the extreme heating of in-resonance nanoparticles to initiate bubble formation, the off-resonance fs technique brings many advantages, including avoiding the particles fragmentation, working in the optical window of biol. material, and using the deposited energy more efficiently.
523. 523

     Baffou, G.; Rigneault, H. Femtosecond-Pulsed Optical Heating of Gold Nanoparticles. Phys. Rev. B 2011, 84, 035415,  DOI: 10.1103/PhysRevB.84.035415

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     523

     Femtosecond-pulsed optical heating of gold nanoparticles

     Baffou, Guillaume; Rigneault, Herve

     Physical Review B: Condensed Matter and Materials Physics (2011), 84 (3), 035415/1-035415/13CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)

     The authors study theor. and numerically the thermodn. of Au nanoparticles immersed in H2O and illuminated by a femtosecond-pulsed laser at their plasmonic resonance. The spatiotemporal evolution of the temp. profile inside and outside is computed using a numerical framework based on a Runge-Kutta algorithm of the 4th order. The aim is to provide a comprehensive description of the physics of heat release of plasmonic nanoparticles under pulsed illumination, along with a simple and powerful numerical algorithm. In particular, the authors study the amplitude of the initial instantaneous temp. increase, the phys. differences between pulsed and continuous-wave illuminations, the time scales governing the heat release into the surroundings, the spatial extension of the temp. distribution in the surrounding medium, the influence of a finite thermal cond. of the Au/H2O interface, the influence of the pulse repetition rate of the laser, the validity of the uniform temp. approxn. in the metal nanoparticle, and the optimum nanoparticle size (∼40 nm) to achieve a max. temp. increase.
524. 524

     Cesare, P.; Moriondo, A.; Vellani, V.; McNaughton, P. A. Ion Channels Gated by Heat. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 7658– 7663,  DOI: 10.1073/pnas.96.14.7658

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     524

     Ion channels gated by heat

     Cesare, P.; Moriondo, A.; Vellani, V.; McNaughton, P. A.

     Proceedings of the National Academy of Sciences of the United States of America (1999), 96 (14), 7658-7663CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     A review with 32 refs. All animals need to sense temp. to avoid hostile environments and to regulate their internal homeostasis. A particularly obvious example is that animals need to avoid damagingly hot stimuli. The mechanisms by which temp. is sensed have until recently been mysterious, but in the last couple of years, we have begun to understand how noxious thermal stimuli are detected by sensory neurons. Heat has been found to open a nonselective cation channel in primary sensory neurons, probably by a direct action. In a sep. study, an ion channel gated by capsaicin, the active ingredient of chili peppers, was cloned from sensory neurons. This channel (vanilloid receptor subtype 1, VR1) is gated by heat in a manner similar to the native heat-activated channel, and our current best guess is that this channel is the mol. substrate for the detection of painful heat. Both the heat channel and VR1 are modulated in interesting ways. The response of the heat channel is potentiated by phosphorylation by protein kinase C, whereas VR1 is potentiated by externally applied protons. Protein kinase C is known to be activated by a variety of inflammatory mediators, including bradykinin, whereas extracellular acidification is characteristically produced by anoxia and inflammation. Both modulatory pathways are likely, therefore, to have important physiol. correlates in terms of the enhanced pain (hyperalgesia) produced by tissue damage and inflammation. Future work should focus on establishing, in mol. terms, how a single ion channel can detect heat and how the detection threshold can be modulated by hyperalgesic stimuli.
525. 525

     Ebtehaj, Z.; Malekmohammad, M.; Hatef, A.; Soltanolkotabi, M. Direct and Plasmonic Nanoparticle-Mediated Infrared Neural Stimulation: Comprehensive Computational Modeling and Validation. Adv. Theor. Simul. 2021, 4, 2000214,  DOI: 10.1002/adts.202000214

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526. 526

     Li, P.; Gu, M.; Xu, H. Lysosomal Ion Channels as Decoders of Cellular Signals. Trends Biochem. Sci. 2019, 44, 110– 124,  DOI: 10.1016/j.tibs.2018.10.006

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     526

     Lysosomal Ion Channels as Decoders of Cellular Signals

     Li, Ping; Gu, Mingxue; Xu, Haoxing

     Trends in Biochemical Sciences (2019), 44 (2), 110-124CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)

     A review. Lysosomes, the degrdn. center of the cell, are filled with acidic hydrolases. Lysosomes generate nutrient-sensitive signals to regulate the import of H+, hydrolases, and endocytic and autophagic cargos, as well as the export of their degrdn. products (catabolites). In response to environmental and cellular signals, lysosomes change their positioning, no., morphol., size, compn., and activity within minutes to hours to meet the changing cellular needs. Ion channels in the lysosome are essential transducers that mediate signal-initiated Ca2+/Fe2+/Zn2+ release and H+/Na+/K+-dependent changes of membrane potential across the perimeter membrane. Dysregulation of lysosomal ion flux impairs lysosome movement, membrane trafficking, nutrient sensing, membrane repair, organelle membrane contact, and lysosome biogenesis and adaptation. Hence, activation and inhibition of lysosomal channels by synthetic modulators may tune lysosome function to maintain cellular health and promote cellular clearance in lysosome storage disorders.
527. 527

     Hermann, J.; Bender, M.; Schumacher, D.; Woo, M. S.; Shaposhnykov, A.; Rosenkranz, S. C.; Kuryshev, V.; Meier, C.; Guse, A. H.; Friese, M. A.; Freichel, M.; Tsvilovskyy, V. Contribution of NAADP to Glutamate-Evoked Changes in Ca²⁺ Homeostasis in Mouse Hippocampal Neurons. Front. Cell. Dev. Biol. 2020, 8, 496,  DOI: 10.3389/fcell.2020.00496

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     There is no corresponding record for this reference.
528. 528

     Zhu, D.; Feng, L.; Feliu, N.; Guse, A. H.; Parak, W. J. Stimulation of Local Cytosolic Calcium Release by Photothermal Heating for Studying Intra- and Inter-Cellular Calcium Waves. Adv. Mater. 2021, 33, 2008261,  DOI: 10.1002/adma.202008261

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529. 529

     Lee, D.; Hong, J. H. Physiological Application of Nanoparticles in Calcium-Related Proteins and Channels. Nanomedicine 2019, 14, 2479– 2486,  DOI: 10.2217/nnm-2019-0004

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530. 530

     Li, E. S.; Saha, M. S. Optimizing Calcium Detection Methods in Animal Systems: A Sandbox for Synthetic Biology. Biomolecules 2021, 11, 343,  DOI: 10.3390/biom11030343

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531. 531

     Pinto, B. I.; Bassetto, C. A. Z.; Bezanilla, F. Optocapacitance: Physical Basis and Its Application. Biophys. Rev. 2022, 14, 569– 577,  DOI: 10.1007/s12551-022-00943-9

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532. 532

     Jiang, Y.; Carvalho-de-Souza, J. L.; Wong, R. C. S.; Luo, Z.; Isheim, D.; Zuo, X.; Nicholls, A. W.; Jung, I. W.; Yue, J.; Liu, D.-J.; Wang, Y.; De Andrade, V.; Xiao, X.; Navrazhnykh, L.; Weiss, D. E.; Wu, X.; Seidman, D. N.; Bezanilla, F.; Tian, B. Heterogeneous Silicon Mesostructures for Lipid-Supported Bioelectric Interfaces. Nat. Mater. 2016, 15, 1023,  DOI: 10.1038/nmat4673

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     532

     Heterogeneous silicon mesostructures for lipid-supported bioelectric interfaces

     Jiang, Yuanwen; Carvalho-de-Souza, Joao L.; Wong, Raymond C. S.; Luo, Zhiqiang; Isheim, Dieter; Zuo, Xiaobing; Nicholls, Alan W.; Jung, Il Woong; Yue, Jiping; Liu, Di-Jia; Wang, Yucai; De Andrade, Vincent; Xiao, Xianghui; Navrazhnykh, Luizetta; Weiss, Dara E.; Wu, Xiaoyang; Seidman, David N.; Bezanilla, Francisco; Tian, Bozhi

     Nature Materials (2016), 15 (9), 1023-1030CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     Silicon-based materials have widespread application as biophys. tools and biomedical devices. Here the authors introduce a biocompatible and degradable mesostructured form of silicon with multi-scale structural and chem. heterogeneities. The material was synthesized using mesoporous silica as a template through a CVD process. It has an amorphous at. structure, an ordered nanowire-based framework and random submicrometer voids, and shows an av. Young's modulus that is 2-3 orders of magnitude smaller than that of single-cryst. silicon. In addn., the authors used the heterogeneous silicon mesostructures to design a lipid-bilayer-supported bioelec. interface that is remotely controlled and temporally transient, and that permits non-genetic and subcellular optical modulation of the electrophysiol. dynamics in single dorsal root ganglia neurons. The authors' findings suggest that the biomimetic expansion of silicon into heterogeneous and deformable forms can open up opportunities in extracellular biomaterial or bioelec. systems.
533. 533

     Jiang, Y.; Li, X.; Liu, B.; Yi, J.; Fang, Y.; Shi, F.; Gao, X.; Sudzilovsky, E.; Parameswaran, R.; Koehler, K. Rational Design of Silicon Structures for Optically Controlled Multiscale Biointerfaces. Nat. Biomed. Eng. 2018, 2, 508– 521,  DOI: 10.1038/s41551-018-0230-1

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     533

     Rational design of silicon structures for optically controlled multiscale biointerfaces

     Jiang, Yuanwen; Li, Xiaojian; Liu, Bing; Yi, Jaeseok; Fang, Yin; Shi, Fengyuan; Gao, Xiang; Sudzilovsky, Edward; Parameswaran, Ramya; Koehler, Kelliann; Nair, Vishnu; Yue, Jiping; Guo, KuangHua; Tsai, Hsiu-Ming; Freyermuth, George; Wong, Raymond C. S.; Kao, Chien-Min; Chen, Chin-Tu; Nicholls, Alan W.; Wu, Xiaoyang; Shepherd, Gordon M. G.; Tian, Bozhi

     Nature Biomedical Engineering (2018), 2 (7), 508-521CODEN: NBEAB3; ISSN:2157-846X. (Nature Research)

     Silicon-based materials have been widely used in biol. applications. However, remotely controlled and interconnect-free silicon configurations have been rarely explored, because of limited fundamental understanding of the complex physicochem. processes that occur at interfaces between silicon and biol. materials. Here, we describe rational design principles, guided by biol., for establishing intracellular, intercellular and extracellular silicon-based interfaces, where the silicon and the biol. targets have matched properties. We focused on light-induced processes at these interfaces, and developed a set of matrixes to quantify and differentiate the capacitive, Faradaic and thermal outputs from about 30 different silicon materials in saline. We show that these interfaces are useful for the light-controlled non-genetic modulation of intracellular calcium dynamics, of cytoskeletal structures and transport, of cellular excitability, of neurotransmitter release from brain slices and of brain activity in vivo.
534. 534

     Wang, Y.; Garg, R.; Cohen-Karni, D.; Cohen-Karni, T. Neural Modulation with Photothermally Active Nanomaterials. Nat. Rev. Bioeng. 2023, 1, 193– 207,  DOI: 10.1038/s44222-023-00022-y

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535. 535

     Wang, Y.; Garg, R.; Hartung, J. E.; Goad, A.; Patel, D. A.; Vitale, F.; Gold, M. S.; Gogotsi, Y.; Cohen-Karni, T. Ti₃C₂T_x MXene Flakes for Optical Control of Neuronal Electrical Activity. ACS Nano 2021, 15, 14662– 14671,  DOI: 10.1021/acsnano.1c04431

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     535

     Ti3C2Tx MXene Flakes for Optical Control of Neuronal Electrical Activity

     Wang, Yingqiao; Garg, Raghav; Hartung, Jane E.; Goad, Adam; Patel, Dipna A.; Vitale, Flavia; Gold, Michael S.; Gogotsi, Yury; Cohen-Karni, Tzahi

     ACS Nano (2021), 15 (9), 14662-14671CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Understanding cellular elec. communications in both health and disease necessitates precise subcellular electrophysiol. modulation. Nanomaterial-assisted photothermal stimulation was demonstrated to modulate cellular activity with high spatiotemporal resoln. Ideal candidates for such an application are expected to have high absorbance at the near-IR window, high photothermal conversion efficiency, and straightforward scale-up of prodn. to allow future translation. Here, we demonstrate two-dimensional Ti3C2Tx (MXene) as an outstanding candidate for remote, nongenetic, optical modulation of neuronal elec. activity with high spatiotemporal resoln. Ti3C2Tx's photothermal response measured at the single-flake level resulted in local temp. rises of 2.31 ± 0.03 and 3.30 ± 0.02 K for 635 and 808 nm laser pulses (1 ms, 10 mW), resp. Dorsal root ganglion (DRG) neurons incubated with Ti3C2Tx film (25μg/cm2) or Ti3C2Tx flake dispersion (100μg/mL) for 6 days did not show a detectable influence on cellular viability, indicating that Ti3C2Tx is noncytotoxic. DRG neurons were photothermally stimulated using Ti3C2Tx films and flakes with as low as tens of microjoules per pulse incident energy (635 nm, 2μJ for film, 18μJ for flake) with subcellular targeting resoln. Ti3C2Tx's straightforward and large-scale synthesis allows translation of the reported photothermal stimulation approach in multiple scales, thus presenting a powerful tool for modulating electrophysiol. from single-cell to additive manufg. of engineered tissues.
536. 536

     Xu, J.; Jarocha, L. E.; Zollitsch, T.; Konowalczyk, M.; Henbest, K. B.; Richert, S.; Golesworthy, M. J.; Schmidt, J.; Dejean, V.; Sowood, D. J. C.; Bassetto, M.; Luo, J.; Walton, J. R.; Fleming, J.; Wei, Y.; Pitcher, T. L.; Moise, G.; Herrmann, M.; Yin, H.; Wu, H.; Bartolke, R.; Kasehagen, S. J.; Horst, S.; Dautaj, G.; Murton, P. D. F.; Gehrckens, A. S.; Chelliah, Y.; Takahashi, J. S.; Koch, K. W.; Weber, S.; Solov’yov, I. A.; Xie, C.; Mackenzie, S. R.; Timmel, C. R.; Mouritsen, H.; Hore, P. J. Magnetic Sensitivity of Cryptochrome 4 from a Migratory Songbird. Nature 2021, 594, 535– 540,  DOI: 10.1038/s41586-021-03618-9

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     536

     Magnetic sensitivity of cryptochrome 4 from a migratory songbird

     Xu, Jingjing; Jarocha, Lauren E.; Zollitsch, Tilo; Konowalczyk, Marcin; Henbest, Kevin B.; Richert, Sabine; Golesworthy, Matthew J.; Schmidt, Jessica; Dejean, Victoire; Sowood, Daniel J. C.; Bassetto, Marco; Luo, Jiate; Walton, Jessica R.; Fleming, Jessica; Wei, Yujing; Pitcher, Tommy L.; Moise, Gabriel; Herrmann, Maike; Yin, Hang; Wu, Haijia; Bartoelke, Rabea; Kaesehagen, Stefanie J.; Horst, Simon; Dautaj, Glen; Murton, Patrick D. F.; Gehrckens, Angela S.; Chelliah, Yogarany; Takahashi, Joseph S.; Koch, Karl-Wilhelm; Weber, Stefan; Solov'yov, Ilia A.; Xie, Can; Mackenzie, Stuart R.; Timmel, Christiane R.; Mouritsen, Henrik; Hore, P. J.

     Nature (London, United Kingdom) (2021), 594 (7864), 535-540CODEN: NATUAS; ISSN:0028-0836. (Nature Portfolio)

     Abstr.: Night-migratory songbirds are remarkably proficient navigators1. Flying alone and often over great distances, they use various directional cues including, crucially, a light-dependent magnetic compass2,3. The mechanism of this compass has been suggested to rely on the quantum spin dynamics of photoinduced radical pairs in cryptochrome flavoproteins located in the retinas of the birds4-7. Here we show that the photochem. of cryptochrome 4 (CRY4) from the night-migratory European robin (Erithacus rubecula) is magnetically sensitive in vitro, and more so than CRY4 from two non-migratory bird species, chicken (Gallus gallus) and pigeon (Columba livia). Site-specific mutations of ErCRY4 reveal the roles of four successive flavin-tryptophan radical pairs in generating magnetic field effects and in stabilizing potential signalling states in a way that could enable sensing and signalling functions to be independently optimized in night-migratory birds.
537. 537

     Clapham, D. E.; Runnels, L. W.; Strübing, C. The TRP Ion Channel Family. Nat. Rev. Neurosci. 2001, 2, 387– 396,  DOI: 10.1038/35077544

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     537

     The TRP ion channel family

     Clapham, David E.; Runnels, Loren W.; Strubing, Carsten

     Nature Reviews Neuroscience (2001), 2 (6), 387-396CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

     A review with 70 refs. Mammalian homologs of the Drosophila transient receptor potential (TRP) channel gene encode a family of at least 20 ion channel proteins. They are widely distributed in mammalian tissues, but their specific physiol. functions are largely unknown. A common theme that links the TRP channels is their activation or modulation by phosphatidylinositol signal transduction pathways. The channel subunits have six transmembrane domains that most probably assemble into tetramers to form non-selective cationic channels, which allow for the influx of calcium ions into cells. Three subgroups comprise the TRP channel family; the best understood of these mediates responses to painful stimuli. Other proposed functions include repletion of intracellular calcium stores, receptor-mediated excitation and modulation of the cell cycle.
538. 538

     Tominaga, M.; Caterina, M. J. Thermosensation and Pain. J. Neurobiol. 2004, 61, 3– 12,  DOI: 10.1002/neu.20079

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     538

     Thermosensation and pain

     Tominaga Makoto; Caterina Michael J

     Journal of neurobiology (2004), 61 (1), 3-12 ISSN:0022-3034.

     We feel a wide range of temperatures spanning from cold to heat. Within this range, temperatures over about 43 degrees C and below about 15 degrees C evoke not only a thermal sensation, but also a feeling of pain. In mammals, six thermosensitive ion channels have been reported, all of which belong to the TRP (transient receptor potential) superfamily. These include TRPV1 (VR1), TRPV2 (VRL-1), TRPV3, TRPV4, TRPM8 (CMR1), and TRPA1 (ANKTM1). These channels exhibit distinct thermal activation thresholds (>43 degrees C for TRPV1, >52 degrees C for TRPV2, > approximately 34-38 degrees C for TRPV3, > approximately 27-35 degrees C for TRPV4, < approximately 25-28 degrees C for TRPM8 and <17 degrees C for TRPA1), and are expressed in primary sensory neurons as well as other tissues. The involvement of TRPV1 in thermal nociception has been demonstrated by multiple methods, including the analysis of TRPV1-deficient mice. TRPV2, TRPM8, and TRPA1 are also very likely to be involved in thermal nociception, because their activation thresholds are within the noxious range of temperatures.
539. 539

     Montell, C. The TRP Superfamily of Cation Channels. Sci. Signaling 2005, 2005, re3,  DOI: 10.1126/stke.2722005re3

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540. 540

     Yao, J.; Liu, B.; Qin, F. Rapid Temperature Jump by Infrared Diode Laser Irradiation for Patch-Clamp Studies. Biophys. J. 2009, 96, 3611– 3619,  DOI: 10.1016/j.bpj.2009.02.016

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     540

     Rapid temperature jump by infrared diode laser irradiation for patch-clamp studies

     Yao, Jing; Liu, Beiying; Qin, Feng

     Biophysical Journal (2009), 96 (9), 3611-3619CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

     Several thermal TRP ion channels have recently been identified. These channels are directly gated by temp., but the mechanisms have remained elusive. Studies of their temp. gating have been impeded by lack of methods for rapid alteration of temp. in live cells. As a result, only measurements of steady-state properties have been possible. To solve the problem, we have developed an optical approach that uses recently available IR diode lasers as heat sources. By restricting laser irradn. around a single cell, our approach can produce const. temp. jumps over 50°C in submilliseconds. Expts. with several heat-gated ion channels (TRPV1-3) show its applicability for rapid temp. perturbation in both single cells and membrane patches. Compared with other laser heating approaches such as those by Raman-shifting of the Nd:YAG fundamentals, our approach has the advantage of being cost effective and applicable to live cells while providing an adequate resoln. for time-resolved detection of channel activation.
541. 541

     Albert, E.; Bec, J. M.; Desmadryl, G.; Chekroud, K.; Travo, C.; Gaboyard, S.; Bardin, F.; Marc, I.; Dumas, M.; Lenaers, G. TRPV4 Channels Mediate the Infrared Laser-Evoked Response in Sensory Neurons. J. Neurophysiol. 2012, 107, 3227– 3234,  DOI: 10.1152/jn.00424.2011

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     541

     TRPV4 channels mediate the infrared laser-evoked response in sensory neurons

     Albert, E. S.; Bec, J. M.; Desmadryl, G.; Chekroud, K.; Travo, C.; Gaboyard, S.; Bardin, F.; Mare, I.; Dumas, M.; Lenaers, G.; Hamel, C.; Muller, A.; Chabbert, C.

     Journal of Neurophysiology (2012), 107 (6), 3227-3234CODEN: JONEA4; ISSN:0022-3077. (American Physiological Society)

     IR laser irradn. has been established as an appropriate stimulus for primary sensory neurons under conditions where sensory receptor cells are impaired or lost. Yet, development of clin. applications has been impeded by lack of information about the mol. mechanisms underlying the laser-induced neural response. Here, we directly address this question through pharmacol. characterization of the biol. response evoked by midinfrared irradn. of isolated retinal and vestibular ganglion cells from rodents. Whole cell patch-clamp recordings reveal that both voltage-gated calcium and sodium channels contribute to the laser-evoked neuronal voltage variations (LEVV). In addn., selective blockade of the LEVV by micromolar concns. of ruthenium red and RN 1734 identifies thermosensitive transient receptor potential vanilloid channels as the primary effectors of the chain reaction triggered by midinfrared laser irradn. These results have the potential to facilitate greatly the design of future prosthetic devices aimed at restoring neurosensory capacities in disabled patients.
542. 542

     Storozhuk, M. V.; Moroz, O. F.; Zholos, A. V. Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems. BioMed. Res. Int. 2019, 2019, 5806321,  DOI: 10.1155/2019/5806321

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     542

     Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems

     Storozhuk Maksim V; Zholos Alexander V; Moroz Olesia F; Zholos Alexander V

     BioMed research international (2019), 2019 (), 5806321 ISSN:.

     TRPV1 has been originally cloned as the heat and capsaicin receptor implicated in acute pain signalling, while further research has shifted the focus to its importance in chronic pain caused by inflammation and associated with this TRPV1 sensitization. However, accumulating evidence suggests that, apart from pain signalling, TRPV1 subserves many other unrelated to nociception functions in the nervous system. In the brain, TRPV1 can modulate synaptic transmission via both pre- and postsynaptic mechanisms and there is a functional crosstalk between GABA receptors and TRPV1. Other fundamental processes include TRPV1 role in plasticity, microglia-to-neuron communication, and brain development. Moreover, TRPV1 is widely expressed in the peripheral tissues, including the vasculature, gastrointestinal tract, urinary bladder, epithelial cells, and the cells of the immune system. TRPV1 can be activated by a large array of physical (heat, mechanical stimuli) and chemical factors (e.g., protons, capsaicin, resiniferatoxin, and endogenous ligands, such as endovanilloids). This causes two general cell effects, membrane depolarization and calcium influx, thus triggering depending on the cell-type diverse functional responses ranging from neuronal excitation to secretion and smooth muscle contraction. Here, we review recent research on the diverse TRPV1 functions with focus on the brain, vasculature, and some visceral systems as the basis of our better understanding of TRPV1 role in different human disorders.
543. 543

     Tóth, A.; Boczán, J.; Kedei, N.; Lizanecz, E.; Bagi, Z.; Papp, Z.; Édes, I.; Csiba, L.; Blumberg, P. M. Expression and Distribution of Vanilloid Receptor 1 (TRPV1) in the Adult Rat Brain. Mol. Brain Res. 2005, 135, 162– 168,  DOI: 10.1016/j.molbrainres.2004.12.003

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     543

     Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain

     Toth, Attila; Boczan, Judit; Kedei, Noemi; Lizanecz, Erzsebet; Bagi, Zsolt; Papp, Zoltan; Edes, Istvan; Csiba, Laszlo; Blumberg, Peter M.

     Molecular Brain Research (2005), 135 (1-2), 162-168CODEN: MBREE4; ISSN:0169-328X. (Elsevier B.V.)

     The vanilloid receptor (TRPV1 or VR1) is a mol. integrator of various painful stimuli, including capsaicin, acid, and high temp. It can also be activated by endogenous ligands, like the cannabinoid 1 receptor (CB1) agonist anandamide. TRPV1 is well characterized at the terminals of sensory nerves involved in the pain pathway. There is also evidence that TRPV1 is expressed in the brain but little is known about its function. Here, using com. available specific antibodies to investigate the localization of TRPV1 in the brain of the rat, the authors report that TRPV1 was expressed in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. Immunohistochem. analyses showed high expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. To address the question of subcellular localization, immunoelectron-microscopy was used. TRPV1-like staining was detected in the synapses (mostly, but not exclusively in post-synaptic dendritic spines), on the end feet of astrocytes and in pericytes. In summary, TRPV1 expression shows wide distribution in the brain of the rat, being found in astrocytes and pericytes as well as in neurons. Its localization is consistent with multiple functions within the central nervous system, including the regulation of brain vasculature.
544. 544

     Cavanaugh, D. J.; Chesler, A. T.; Jackson, A. C.; Sigal, Y. M.; Yamanaka, H.; Grant, R.; O’Donnell, D.; Nicoll, R. A.; Shah, N. M.; Julius, D. Trpv1 Reporter Mice Reveal Highly Restricted Brain Distribution and Functional Expression in Arteriolar Smooth Muscle Cells. J. Neurosci. 2011, 31, 5067– 5077,  DOI: 10.1523/JNEUROSCI.6451-10.2011

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     544

     Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells

     Cavanaugh, Daniel J.; Chesler, Alexander T.; Jackson, Alexander C.; Sigal, Yaron M.; Yamanaka, Hiroki; Grant, Rebecca; O'Donnell, Dajan; Nicoll, Roger A.; Shah, Nirao M.; Julius, David; Basbaum, Allan I.

     Journal of Neuroscience (2011), 31 (13), 5067-5077CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

     The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiol. responses to capsaicin, here we genetically modified the Trpv1 locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, including in situ hybridization, calcium imaging, and electrophysiol. recordings. Addnl. in situ hybridization expts. in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.
545. 545

     Munshi, R.; Qadri, S. M.; Pralle, A. Transient Magnetothermal Neuronal Silencing Using the Chloride Channel Anoctamin 1 (TMEM16A). Front. Neurosci. 2018, 12, 560,  DOI: 10.3389/fnins.2018.00560

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546. 546

     Lee, J. H.; Jang, J. T.; Choi, J. S.; Moon, S. H.; Noh, S. H.; Kim, J. W.; Kim, J. G.; Kim, I. S.; Park, K. I.; Cheon, J. Exchange-Coupled Magnetic Nanoparticles for Efficient Heat Induction. Nat. Nanotechnol. 2011, 6, 418– 422,  DOI: 10.1038/nnano.2011.95

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     546

     Exchange-coupled magnetic nanoparticles for efficient heat induction

     Lee, Jae-Hyun; Jang, Jung-tak; Choi, Jin-sil; Moon, Seung Ho; Noh, Seung-hyun; Kim, Ji-wook; Kim, Jin-Gyu; Kim, Il-Sun; Park, Kook In; Cheon, Jinwoo

     Nature Nanotechnology (2011), 6 (7), 418-422CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     The conversion of electromagnetic energy into heat by nanoparticles has the potential to be a powerful, non-invasive technique for biotechnol. applications such as drug release, disease treatment and remote control of single cell functions, but poor conversion efficiencies have hindered practical applications so far. In this Letter, we demonstrate a significant increase in the efficiency of magnetic thermal induction by nanoparticles. We take advantage of the exchange coupling between a magnetically hard core and magnetically soft shell to tune the magnetic properties of the nanoparticle and maximize the specific loss power, which is a gauge of the conversion efficiency. The optimized core-shell magnetic nanoparticles have specific loss power values that are an order of magnitude larger than conventional iron-oxide nanoparticles. We also perform an antitumor study in mice, and find that the therapeutic efficacy of these nanoparticles is superior to that of a common anticancer drug.
547. 547

     Chen, R.; Christiansen, M. G.; Anikeeva, P. Maximizing Hysteretic Losses in Magnetic Ferrite Nanoparticles via Model-Driven Synthesis and Materials Optimization. ACS Nano 2013, 7, 8990– 9000,  DOI: 10.1021/nn4035266

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     547

     Maximizing Hysteretic Losses in Magnetic Ferrite Nanoparticles via Model-Driven Synthesis and Materials Optimization

     Chen, Ritchie; Christiansen, Michael G.; Anikeeva, Polina

     ACS Nano (2013), 7 (10), 8990-9000CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     This article develops a set of design guidelines for maximizing heat dissipation characteristics of magnetic ferrite MFe2O4 (M = Mn, Fe, Co) nanoparticles in alternating magnetic fields. Using magnetic and structural nanoparticle characterization, the authors identify key synthetic parameters in the thermal decompn. of organometallic precursors that yield optimized magnetic nanoparticles over a wide range of sizes and compns. The developed synthetic procedures allow for gram-scale prodn. of magnetic nanoparticles stable in physiol. buffer for several months. The authors' magnetic nanoparticles display some of the highest heat dissipation rates, which are in qual. agreement with the trends predicted by a dynamic hysteresis model of coherent magnetization reversal in single domain magnetic particles. By combining phys. simulations with robust scalable synthesis and materials characterization techniques, this work provides a pathway to a model-driven design of magnetic nanoparticles tailored to a variety of biomedical applications ranging from cancer hyperthermia to remote control of gene expression.
548. 548

     Zhang, Q.; Castellanos-Rubio, I.; Munshi, R.; Orue, I.; Pelaz, B.; Gries, K. I.; Parak, W. J.; del Pino, P.; Pralle, A. Model Driven Optimization of Magnetic Anisotropy of Exchange-Coupled Core-Shell Ferrite Nanoparticles for Maximal Hysteretic Loss. Chem. Mater. 2015, 27, 7380– 7387,  DOI: 10.1021/acs.chemmater.5b03261

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     548

     Model Driven Optimization of Magnetic Anisotropy of Exchange-Coupled Core-Shell Ferrite Nanoparticles for Maximal Hysteretic Loss

     Zhang, Qian; Castellanos-Rubio, Idoia; Munshi, Rahul; Orue, Inaki; Pelaz, Beatriz; Gries, Katharina Ines; Parak, Wolfgang J.; del Pino, Pablo; Pralle, Arnd

     Chemistry of Materials (2015), 27 (21), 7380-7387CODEN: CMATEX; ISSN:0897-4756. (American Chemical Society)

     This study provides a guide to maximizing hysteretic loss by matching the design and synthesis of superparamagnetic nanoparticles to the desired hyperthermia application. The maximal heat release from magnetic nanoparticles to the environment depends on intrinsic properties of magnetic nanoparticles (e.g., size, magnetization, and magnetic anisotropy) and extrinsic properties of the applied fields (e.g., frequency and field strength). Often, the biomedical hyperthermia application limits flexibility in settings of many parameters (e.g., nanoparticle size and mobility, field strength, and frequency). Core-shell nanoparticles combining a soft (Mn ferrite) and a hard (Co ferrite) magnetic material form a system in which the effective magnetic anisotropy can be easily tuned independently of the nanoparticle size. A theor. framework to include the crystal anisotropy contribution of the Co ferrite phase to the nanoparticle's total anisotropy is developed. This framework predicts the hysteretic heating loss correctly when including nonlinear effects in an effective susceptibility. Hence, the authors provide a guide on how to characterize the magnetic anisotropy of core-shell magnetic nanoparticles, model the expected heat loss, and thereby synthesize tuned nanoparticles for a particular biomedical application.
549. 549

     Meister, M. Physical Limits to Magnetogenetics. eLife 2016, 5, e17210,  DOI: 10.7554/eLife.17210

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     549

     Physical limits to magnetogenetics

     Meister, Markus

     eLife (2016), 5 (), e17210/1-e17210/14CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)

     This is an anal. of how magnetic fields affect biol. mols. and cells. It was prompted by a series of prominent reports regarding magnetism in biol. systems. The first claims to have identified a protein complex that acts like a compass needle to guide magnetic orientation in animals (Qin et al., 2016). Two other articles report magnetic control of membrane conductance by attaching ferritin to an ion channel protein and then tugging the ferritin or heating it with a magnetic field (Stanley et al., 2015; Wheeler et al., 2016). Here I argue that these claims conflict with basic laws of physics. The discrepancies are large: from 5 to 10 log units. If the reported phenomena do in fact occur, they must have causes entirely different from the ones proposed by the authors. The paramagnetic nature of protein complexes is found to seriously limit their utility for engineering magnetically sensitive cells.
550. 550

     Davis, H. C.; Kang, S.; Lee, J.-H.; Shin, T.-H.; Putterman, H.; Cheon, J.; Shapiro, M. G. Nanoscale Heat Transfer from Magnetic Nanoparticles and Ferritin in an Alternating Magnetic Field. Biophys. J. 2020, 118, 1502– 1510,  DOI: 10.1016/j.bpj.2020.01.028

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551. 551

     Riedinger, A.; Guardia, P.; Curcio, A.; Garcia, M. A.; Cingolani, R.; Manna, L.; Pellegrino, T. Subnanometer Local Temperature Probing and Remotely Controlled Drug Release Based on Azo-Functionalized Iron Oxide Nanoparticles. Nano Lett. 2013, 13, 2399– 2406,  DOI: 10.1021/nl400188q

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     551

     Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles

     Riedinger, Andreas; Guardia, Pablo; Curcio, Alberto; Garcia, Miguel A.; Cingolani, Roberto; Manna, Liberato; Pellegrino, Teresa

     Nano Letters (2013), 13 (6), 2399-2406CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Local heating can be produced by iron oxide nanoparticles (IONPs) when exposed to an alternating magnetic field (AMF). To measure the temp. profile at the nanoparticle surface with a subnanometer resoln., here we present a mol. temp. probe based on the thermal decompn. of a thermo-sensitive mol., namely, azobis[N-(2-carboxyethyl)-2-methylpropionamidine]. Fluoresceineamine (FA) was bound to the azo mol. at the IONP surface functionalized with poly(ethylene glycol) (PEG) spacers of different mol. wts. Significant local heating, with a temp. increase up to 45°, was found at distances below 0.5 nm from the surface of the nanoparticle, which decays exponentially with increasing distance. Furthermore, the temp. increase was found to scale linearly with the applied field at all distances. We implemented these findings in an AMF-triggered drug release system in which doxorubicin was covalently linked at different distances from the IONP surface bearing the same thermo-labile azo mol. We demonstrated the AMF triggered distance-dependent release of the drug in a cytotoxicity assay on KB cancer cells.
552. 552

     Bailey, C. H.; Kandel, E. R.; Harris, K. M. Structural Components of Synaptic Plasticity and Memory Consolidation. Cold Spring Harbor Perspect. Biol. 2015, 7, a021758,  DOI: 10.1101/cshperspect.a021758

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553. 553

     Josselyn, S. A.; Tonegawa, S. Memory Engrams: Recalling the Past and Imagining the Future. Science 2020, 367, eaaw4325,  DOI: 10.1126/science.aaw4325

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554. 554

     Ashmore, J. Cochlear Outer Hair Cell Motility. Physiol. Rev. 2008, 88, 173– 210,  DOI: 10.1152/physrev.00044.2006

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555. 555

     Kim, J.-w.; Lee, J.-H.; Ma, J.-H.; Chung, E.; Choi, H.; Bok, J.; Cheon, J. Magnetic Force Nanoprobe for Direct Observation of Audio Frequency Tonotopy of Hair Cells. Nano Lett. 2016, 16, 3885– 3891,  DOI: 10.1021/acs.nanolett.6b01392

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556. 556

     Lee, J.-H.; Kim, J.-w.; Levy, M.; Kao, A.; Noh, S.-h.; Bozovic, D.; Cheon, J. Magnetic Nanoparticles for Ultrafast Mechanical Control of Inner Ear Hair Cells. ACS Nano 2014, 8, 6590– 6598,  DOI: 10.1021/nn5020616

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     556

     Magnetic Nanoparticles for Ultrafast Mechanical Control of Inner Ear Hair Cells

     Lee, Jae-Hyun; Kim, Ji-wook; Levy, Michael; Kao, Albert; Noh, Seung-hyun; Bozovic, Dolores; Cheon, Jinwoo

     ACS Nano (2014), 8 (7), 6590-6598CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The authors introduce cubic magnetic nanoparticles as an effective tool for precise and ultrafast control of mechanosensitive cells. The temporal resoln. of the authors' system is ∼1000 times faster than previously used magnetic switches and is comparable to the current state-of-the-art optogenetic tools. The use of a magnetism-gated switch reported here can address the key challenges of studying mechanotransduction in biol. systems. The cube-shaped magnetic nanoparticles are designed to bind to components of cellular membranes and can be controlled with an electromagnet to exert pico-Newtons of mech. force on the cells. The cubic nanoparticles can thus be used for noncontact mech. control of the position of the stereocilia of an inner ear hair cell, yielding displacements of tens of nanometers, with sub-millisecond temporal resoln. Also such mech. stimulus leads to the influx of ions into the hair cell. The authors' study demonstrates that a magnetic switch can yield ultrafast temporal resoln., and has capabilities for remote manipulation and biol. specificity, and that such magnetic system can be used for the study of mechanotransduction processes of a wide range of sensory systems.
557. 557

     Jia, Y.; Zhao, Y.; Kusakizako, T.; Wang, Y.; Pan, C.; Zhang, Y.; Nureki, O.; Hattori, M.; Yan, Z. TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels. Neuron 2020, 105, 310– 321,  DOI: 10.1016/j.neuron.2019.10.017

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558. 558

     Wu, J.; Lewis, A. H.; Grandl, J. Touch, Tension, and Transduction-the Function and Regulation of Piezo Ion Channels. Trends Biochem. Sci. 2017, 42, 57– 71,  DOI: 10.1016/j.tibs.2016.09.004

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559. 559

     Wheeler, M. A.; Smith, C. J.; Ottolini, M.; Barker, B. S.; Purohit, A. M.; Grippo, R. M.; Gaykema, R. P.; Spano, A. J.; Beenhakker, M. P.; Kucenas, S. Genetically Targeted Magnetic Control of the Nervous System. Nat. Neurosci. 2016, 19, 756– 761,  DOI: 10.1038/nn.4265

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     559

     Genetically targeted magnetic control of the nervous system

     Wheeler, Michael A.; Smith, Cody J.; Ottolini, Matteo; Barker, Bryan S.; Purohit, Aarti M.; Grippo, Ryan M.; Gaykema, Ronald P.; Spano, Anthony J.; Beenhakker, Mark P.; Kucenas, Sarah; Patel, Manoj K.; Deppmann, Christopher D.; Guler, Ali D.

     Nature Neuroscience (2016), 19 (5), 756-761CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

     Optogenetic and chemogenetic actuators are crit. for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or slow on/off kinetics. We have overcome these disadvantages by synthesizing a single-component, magnetically sensitive actuator, "Magneto," comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin. We validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiol. recordings in brain slices, in vivo electrophysiol. recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together our results present Magneto as an actuator capable of remotely controlling circuits assocd. with complex animal behaviors.
560. 560

     Wang, G.; Zhang, P.; Mendu, S. K.; Wang, Y.; Zhang, Y.; Kang, X.; Desai, B. N.; Zhu, J. J. Revaluation of Magnetic Properties of Magneto. Nat. Neurosci. 2020, 23, 1047– 1050,  DOI: 10.1038/s41593-019-0473-5

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561. 561

     Kole, K.; Zhang, Y.; Jansen, E. J.; Brouns, T.; Bijlsma, A.; Calcini, N.; Yan, X.; Lantyer, A. d. S.; Celikel, T. Assessing the Utility of Magneto to Control Neuronal Excitability in the Somatosensory Cortex. Nat. Neurosci. 2020, 23, 1044– 1046,  DOI: 10.1038/s41593-019-0474-4

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562. 562

     Xu, F.-X.; Zhou, L.; Wang, X.-T.; Jia, F.; Ma, K.-Y.; Wang, N.; Lin, L.; Xu, F.-Q.; Shen, Y. Magneto Is Ineffective in Controlling Electrical Properties of Cerebellar Purkinje Cells. Nat. Neurosci. 2020, 23, 1041– 1043,  DOI: 10.1038/s41593-019-0475-3

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     562

     Magneto is ineffective in controlling electrical properties of cerebellar Purkinje cells

     Xu, Fang-Xiao; Zhou, Lin; Wang, Xin-Tai; Jia, Fan; Ma, Kuang-Yi; Wang, Na; Lin, Li; Xu, Fu-Qiang; Shen, Ying

     Nature Neuroscience (2020), 23 (9), 1041-1043CODEN: NANEFN; ISSN:1097-6256. (Nature Research)

     It was recently reported that a magnetic actuator, Magneto, can control neuronal firings at magnetic strength as low as 50 mT (ref. 1), offering an exciting non-invasive approach to manipulating neuronal activity in a variety of research and clin. applications. We investigated whether Magneto can be used to manipulate elec. properties of Purkinje cells in the cerebellum, which play crit. roles in motor learning and emotional behaviors2. Surprisingly, we found that the application of a magnetic field did not change any elec. properties of Purkinje cells expressing Magneto, raising serious doubt about the previous claim that Magneto can readily be used as a magnetic actuator1.
563. 563

     Gregurec, D.; Senko, A. W.; Chuvilin, A.; Reddy, P. D.; Sankararaman, A.; Rosenfeld, D.; Chiang, P.-H.; Garcia, F.; Tafel, I.; Varnavides, G. Magnetic Vortex Nanodiscs Enable Remote Magnetomechanical Neural Stimulation. ACS Nano 2020, 14, 8036– 8045,  DOI: 10.1021/acsnano.0c00562

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     563

     Magnetic Vortex Nanodiscs Enable Remote Magnetomechanical Neural Stimulation

     Gregurec, Danijela; Senko, Alexander W.; Chuvilin, Andrey; Reddy, Pooja D.; Sankararaman, Ashwin; Rosenfeld, Dekel; Chiang, Po-Han; Garcia, Francisco; Tafel, Ian; Varnavides, Georgios; Ciocan, Eugenia; Anikeeva, Polina

     ACS Nano (2020), 14 (7), 8036-8045CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Magnetic nanomaterials in magnetic fields can serve as versatile transducers for remote interrogation of cell functions. The authors leveraged the transition from vortex to in-plane magnetization in Fe oxide nanodiscs to modulate the activity of mechanosensory cells. When a vortex configuration of spins is present in magnetic nanomaterials, it enables rapid control over their magnetization direction and magnitude. The vortex configuration manifests in near zero net magnetic moment in the absence of a magnetic field, affording greater colloidal stability of magnetic nanomaterials in suspensions. Together, these properties invite the application of magnetic vortex particles as transducers of externally applied minimally invasive magnetic stimuli in biol. systems. Using magnetic modeling and electron holog., the authors predict and exptl. demonstrate magnetic vortex states in an array of colloidally synthesized magnetite nanodiscs 98-226 nm in diam. The magnetic nanodiscs applied as transducers of torque for remote control of mechanosensory neurons demonstrated the ability to trigger Ca2+ influx in weak (≤28 mT), slowly varying (≤5 Hz) magnetic fields. The extent of cellular response was detd. by the magnetic nanodisc vol. and magnetic field conditions. Magnetomech. activation of a mechanosensitive cation channel TRPV4 (transient receptor potential vanilloid family member 4) exogenously expressed in the nonmechanosensitive HEK293 cells corroborated that the stimulation is mediated by mechanosensitive ion channels. With their large magnetic torques and colloidal stability, magnetic vortex particles may facilitate basic studies of mechanoreception and its applications to control electroactive cells with remote magnetic stimuli.
564. 564

     Shin, W.; Jeong, S.; Lee, J.-u.; Jeong, S. Y.; Shin, J.; Kim, H. H.; Cheon, J.; Lee, J.-H. Magnetogenetics with Piezo1Mechanosensitive Ion Channel for CRISPR Gene Editing. Nano Lett. 2022, 22, 7415– 7422,  DOI: 10.1021/acs.nanolett.2c02314

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565. 565

     Lee, J. U.; Shin, W.; Lim, Y.; Kim, J.; Kim, W. R.; Kim, H.; Lee, J. H.; Cheon, J. Non-Contact Long-Range Magnetic Stimulation of Mechanosensitive Ion Channels in Freely Moving Animals. Nat. Mater. 2021, 20, 1029– 1036,  DOI: 10.1038/s41563-020-00896-y

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     565

     Non-contact long-range magnetic stimulation of mechanosensitive ion channels in freely moving animals

     Lee, Jung-uk; Shin, Wookjin; Lim, Yongjun; Kim, Jungsil; Kim, Woon Ryoung; Kim, Heehun; Lee, Jae-Hyun; Cheon, Jinwoo

     Nature Materials (2021), 20 (7), 1029-1036CODEN: NMAACR; ISSN:1476-1122. (Nature Portfolio)

     Among phys. stimulation modalities, magnetism has clear advantages, such as deep penetration and untethered interventions in biol. subjects. However, some of the working principles and effectiveness of existing magnetic neurostimulation approaches have been challenged, leaving questions to be answered. Here we introduce m-Torquer, a magnetic toolkit that mimics magnetoreception in nature. It comprises a nanoscale magnetic torque actuator and a circular magnet array, which deliver piconewton-scale forces to cells over a working range of ∼70 cm. With m-Torquer, stimulation of neurons expressing bona fide mechanosensitive ion channel Piezo1 enables consistent and reproducible neuromodulation in freely moving mice. With its long working distance and cellular targeting capability, m-Torquer provides versatility in its use, which can range from single cells to in vivo systems, with the potential application in large animals such as primates.
566. 566

     Kozielski, K. L.; Jahanshahi, A.; Gilbert, H. B.; Yu, Y.; Erin, Ö.; Francisco, D.; Alosaimi, F.; Temel, Y.; Sitti, M. Nonresonant Powering of Injectable Nanoelectrodes Enables Wireless Deep Brain Stimulation in Freely Moving Mice. Sci. Adv. 2021, 7, eabc4189,  DOI: 10.1126/sciadv.abc4189

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567. 567

     Choi, S.-H.; Shin, J.; Park, C.; Lee, J.-u.; Lee, J.; Ambo, Y.; Shin, W.; Yu, R.; Kim, J.-Y.; Lah, J. D.; Shin, D.; Kim, G.; Noh, K.; Koh, W.; Lee, C. J.; Lee, J.-H.; Kwak, M.; Cheon, J. In Vivo Magnetogenetics for Cell-Type-Specific Targeting and Modulation of Brain Circuits. Nat. Nanotechnol. 2024, 19, 1333– 1343,  DOI: 10.1038/s41565-024-01694-2

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     There is no corresponding record for this reference.
568. 568

     Jiang, Y.; Huang, Y.; Luo, X.; Wu, J.; Zong, H.; Shi, L.; Cheng, R.; Zhu, Y.; Jiang, S.; Lan, L.; Jia, X.; Mei, J.; Man, H.-Y.; Cheng, J.-X.; Yang, C. Neural Stimulation in Vitro and in Vivo by Photoacoustic Nanotransducers. Matter 2021, 4, 654– 674,  DOI: 10.1016/j.matt.2020.11.019

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     568

     Neural Stimulation In Vitro and In Vivo by Photoacoustic Nanotransducers

     Jiang, Ying; Huang, Yimin; Luo, Xuyi; Wu, Jiayingzi; Zong, Haonan; Shi, Linli; Cheng, Ran; Zhu, Yifan; Jiang, Shan; Lan, Lu; Jia, Xiaoting; Mei, Jianguo; Man, Heng-Ye; Cheng, Ji-Xin; Yang, Chen

     Matter (2021), 4 (2), 654-674CODEN: MATTCG; ISSN:2590-2385. (Elsevier Inc.)

     Neuromodulation is an invaluable approach for the study of neural circuits and clin. treatment of neurol. diseases. Here, we report semiconducting polymer nanoparticles based photoacoustic nanotransducers (PANs) for neural stimulation in vitro and in vivo. Our PANs strongly absorb the nanosecond pulsed laser in the near-IR second window (NIR-II) and generate localized acoustic waves. PANs are shown to be surface modified and selectively bind onto neurons. PAN-mediated activation of primary neurons in vitro is achieved with ten 3-ns laser pulses at 1,030 nm over a 3-ms duration. In vivo neural modulation of mouse brain activities and motor activities is demonstrated by PANs directly injected into brain cortex. With submillimeter spatial resoln. and negligible heat deposition, PAN stimulation is a new non-genetic method for precise control of neuronal activities, opening up potentials in non-invasive brain modulation.
569. 569

     Brinker, M.; Dittrich, G.; Richert, C.; Lakner, P.; Krekeler, T.; Keller, T. F.; Huber, N.; Huber, P. Giant Electrochemical Actuation in a Nanoporous Silicon-Polypyrrole Hybrid Material. Sci. Adv. 2020, 6, eaba1483,  DOI: 10.1126/sciadv.aba1483

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570. 570

     Jiang, Y.; Lee, H. J.; Lan, L.; Tseng, H. A.; Yang, C.; Man, H. Y.; Han, X.; Cheng, J. X. Optoacoustic Brain Stimulation at Submillimeter Spatial Precision. Nat. Commun. 2020, 11, 881,  DOI: 10.1038/s41467-020-14706-1

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     570

     Optoacoustic brain stimulation at submillimeter spatial precision

     Jiang, Ying; Lee, Hyeon Jeong; Lan, Lu; Tseng, Hua-an; Yang, Chen; Man, Heng-Ye; Han, Xue; Cheng, Ji-Xin

     Nature Communications (2020), 11 (1), 881CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)

     Abstr.: Low-intensity ultrasound is an emerging modality for neuromodulation. Yet, transcranial neuromodulation using low-frequency piezo-based transducers offers poor spatial confinement of excitation vol., often bigger than a few millimeters in diam. In addn., the bulky size limits their implementation in a wearable setting and prevents integration with other exptl. modalities. Here, we report spatially confined optoacoustic neural stimulation through a miniaturized Fiber-Optoacoustic Converter (FOC). The FOC has a diam. of 600 μm and generates omnidirectional ultrasound wave locally at the fiber tip through the optoacoustic effect. We show that the acoustic wave generated by FOC can directly activate individual cultured neurons and generate intracellular Ca2+ transients. The FOC activates neurons within a radius of 500 μm around the fiber tip, delivering superior spatial resoln. over conventional piezo-based low-frequency transducers. Finally, we demonstrate direct and spatially confined neural stimulation of mouse brain and modulation of motor activity in vivo.
571. 571

     Tyler, W. J.; Lani, S. W.; Hwang, G. M. Ultrasonic Modulation of Neural Circuit Activity. Curr. Opin. Neurobiol. 2018, 50, 222– 231,  DOI: 10.1016/j.conb.2018.04.011

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     571

     Ultrasonic modulation of neural circuit activity

     Tyler, William J.; Lani, Shane W.; Hwang, Grace M.

     Current Opinion in Neurobiology (2018), 50 (), 222-231CODEN: COPUEN; ISSN:0959-4388. (Elsevier Ltd.)

     Ultrasound (US) is recognized for its use in medical imaging as a diagnostic tool. As an acoustic energy source, US has become increasingly appreciated over the past decade for its ability to non-invasively modulate cellular activity including neuronal activity. Data obtained from a host of exptl. models has shown that low-intensity US can reversibly modulate the physiol. activity of neurons in peripheral nerves, spinal cord, and intact brain circuits. Exptl. evidence indicates that acoustic pressures exerted by US act, in part, on mechanosensitive ion channels to modulate activity. While the precise mechanisms of action enabling US to both stimulate and suppress neuronal activity remain to be clarified, there are several advantages conferred by the physics of US that make it an appealing option for neuromodulation. For example, it can be focused with millimeter spatial resolns. through skull bone to deep-brain regions. By increasing our engineering capability to leverage such phys. advantages while growing our understanding of how US affects neuronal function, the development of a new generation of non-invasive neurotechnol. can be developed using ultrasonic methods.
572. 572

     Tufail, Y.; Yoshihiro, A.; Pati, S.; Li, M. M.; Tyler, W. J. Ultrasonic Neuromodulation by Brain Stimulation with Transcranial Ultrasound. Nat. Protoc. 2011, 6, 1453– 1470,  DOI: 10.1038/nprot.2011.371

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     572

     Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound

     Tufail, Yusuf; Yoshihiro, Anna; Pati, Sandipan; Li, Monica M.; Tyler, William J.

     Nature Protocols (2011), 6 (9), 1453-1470CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

     Brain stimulation methods are indispensable to the study of brain function. They have also proven effective for treating some neurol. disorders. Historically used for medical imaging, ultrasound (US) has recently been shown to be capable of noninvasively stimulating brain activity. Here we provide a general protocol for the stimulation of intact mouse brain circuits using transcranial US, and, using a traditional mouse model of epilepsy, we describe how to use transcranial US to disrupt electrog. seizure activity. The advantages of US for brain stimulation are that it does not necessitate surgery or genetic alteration, but it confers spatial resolns. superior to other noninvasive methods such as transcranial magnetic stimulation. With a basic working knowledge of electrophysiol., and after an initial setup, ultrasonic neuromodulation (UNMOD) can be implemented in less than 1 h. Using the general protocol that we describe, UNMOD can be readily adapted to support a broad range of studies on brain circuit function and dysfunction.
573. 573

     Koshida, N.; Nakamura, T. Emerging Functions of Nanostructured Porous Silicon-With a Focus on the Emissive Properties of Photons, Electrons, and Ultrasound. Front. Chem. 2019, 7, 273,  DOI: 10.3389/fchem.2019.00273

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574. 574

     Brinker, M.; Huber, P. Wafer-Scale Electroactive Nanoporous Silicon: Large and Fully Reversible Electrochemo-Mechanical Actuation in Aqueous Electrolytes. Adv. Mater. 2022, 34, 2105923,  DOI: 10.1002/adma.202105923

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     There is no corresponding record for this reference.
575. 575

     Nag, O. K.; Muroski, M. E.; Hastman, D. A.; Almeida, B.; Medintz, I. L.; Huston, A. L.; Delehanty, J. B. Nanoparticle- Mediated Visualization and Control of Cellular Membrane Potential: Strategies, Progress, and Remaining Issues. ACS Nano 2020, 14, 2659– 2677,  DOI: 10.1021/acsnano.9b10163

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576. 576

     Efros, A. L.; Delehanty, J. B.; Huston, A. L.; Medintz, I. L.; Barbic, M.; Harris, T. D. Evaluating the Potential of Using Quantum Dots for Monitoring Electrical Signals in Neurons. Nat. Nanotechnol. 2018, 13, 278– 288,  DOI: 10.1038/s41565-018-0107-1

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     576

     Evaluating the potential of using quantum dots for monitoring electrical signals in neurons

     Efros, Alexander L.; Delehanty, James B.; Huston, Alan L.; Medintz, Igor L.; Barbic, Mladen; Harris, Timothy D.

     Nature Nanotechnology (2018), 13 (4), 278-288CODEN: NNAABX; ISSN:1748-3387. (Nature Research)

     A review. Success in the projects aimed at providing an advanced understanding of the brain is directly predicated on making crit. advances in nanotechnol. This Perspective addresses the unique interface of neuroscience and nanomaterials by considering the foundational problem of sensing neuron membrane voltage and offers a potential soln. that may be facilitated by a prototypical nanomaterial. Despite substantial improvements, the visualization of instantaneous voltage changes within individual neurons, whether in cell culture or in vivo, at both the single-cell and network level at high speed remains complex and problematic. The unique properties of semiconductor quantum dots (QDs) have made them powerful fluorophores for bioimaging. What is not widely appreciated, however, is that QD photoluminescence is exquisitely sensitive to proximal elec. fields. This property should be suitable for sensing voltage changes that occur in the active neuronal membrane. Here, we examine the potential role of QDs in addressing the important challenge of real-time optical voltage imaging.
577. 577

     Thorn, K. Genetically Encoded Fluorescent Tags. Mol. Biol. Cell 2017, 28, 848– 857,  DOI: 10.1091/mbc.e16-07-0504

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     577

     Genetically encoded fluorescent tags

     Thorn, Kurt

     Molecular Biology of the Cell (2017), 28 (7), 848-857CODEN: MBCEEV; ISSN:1939-4586. (American Society for Cell Biology)

     Genetically encoded fluorescent tags are protein sequences that can be fused to a protein of interest to render it fluorescent. These tags have revolutionized cell biol. by allowing nearly any protein to be imaged by light microscopy at submicrometer spatial resoln. and subsecond time resoln. in a live cell or organism. They can also be used to measure protein abundance in thousands to millions of cells using flow cytometry. Here I provide an introduction to the different genetic tags available, including both intrinsically fluorescent proteins and proteins that derive their fluorescence from binding of either endogenous or exogenous fluorophores. I discuss their optical and biol. properties and guidelines for choosing appropriate tags for an expt. Tools for tagging nucleic acid sequences and reporter mols. that detect the presence of different biomols. are also briefly discussed.
578. 578

     Park, K.; Weiss, S. Design Rules for Membrane-Embedded Voltage-Sensing Nanoparticles. Biophys. J. 2017, 112, 703– 713,  DOI: 10.1016/j.bpj.2016.12.047

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     578

     Design Rules for Membrane-Embedded Voltage-Sensing Nanoparticles

     Park, Kyoungwon; Weiss, Shimon

     Biophysical Journal (2017), 112 (4), 703-713CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)

     Voltage-sensing dyes and voltage-sensing fluorescence proteins have been continually improved and as a result provided a wealth of insights into neuronal circuits. Further improvements in voltage-sensing dyes and voltage-sensing fluorescence proteins are needed, however, for routine detection of single action potentials across a large no. of individual neurons in a large field-of-view of a live mammalian brain. However, recent expts. and calcns. suggest that semiconducting nanoparticles could act as efficient voltage sensors, suitable for the above-mentioned task. This study presents quantum mech. calcns., including Auger recombination rates, of the quantum-confined Stark effect in membrane-embedded semiconducting nanoparticles, examines their possible utility as membrane voltage sensors, and provide design rules for their structure and compn.
579. 579

     Rowland, C. E.; Susumu, K.; Stewart, M. H.; Oh, E.; Mäkinen, A. J.; O’Shaughnessy, T. J.; Kushto, G.; Wolak, M. A.; Erickson, J. S.; L Efros, A.; Huston, A. L.; Delehanty, J. B. Electric Field Modulation of Semiconductor Quantum Dot Photoluminescence: Insights Into the Design of Robust Voltage-Sensitive Cellular Imaging Probes. Nano Lett. 2015, 15, 6848– 6854,  DOI: 10.1021/acs.nanolett.5b02725

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     579

     Electric Field Modulation of Semiconductor Quantum Dot Photoluminescence: Insights Into the Design of Robust Voltage-Sensitive Cellular Imaging Probes

     Rowland, Clare E.; Susumu, Kimihiro; Stewart, Michael H.; Oh, Eunkeu; Makinen, Antti J.; O'Shaughnessy, Thomas J.; Kushto, Gary; Wolak, Mason A.; Erickson, Jeffrey S.; Efros, Alexander L.; Huston, Alan L.; Delehanty, James B.

     Nano Letters (2015), 15 (10), 6848-6854CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The intrinsic properties of quantum dots (QDs) and the growing ability to interface them controllably with living cells has far-reaching potential applications in probing cellular processes such as membrane action potential. It was shown that an elec. field typical of those found in neuronal membranes results in suppression of the QD photoluminescence (PL) and, for the first time, that QD PL is able to track the action potential profile of a firing neuron with millisecond time resoln. This effect is connected with elec.-field-driven QD ionization and consequent QD PL quenching, in contradiction with conventional wisdom that suppression of the QD PL is attributable to the quantum confined Stark effect.
580. 580

     Marshall, J. D.; Schnitzer, M. J. Optical Strategies for Sensing Neuronal Voltage Using Quantum Dots and Other Semiconductor Nanocrystals. ACS Nano 2013, 7, 4601– 4609,  DOI: 10.1021/nn401410k

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     580

     Optical Strategies for Sensing Neuronal Voltage Using Quantum Dots and Other Semiconductor Nanocrystals

     Marshall, Jesse D.; Schnitzer, Mark J.

     ACS Nano (2013), 7 (5), 4601-4609CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Biophysicists have long sought optical methods capable of reporting the electrophysiol. dynamics of large-scale neural networks with millisecond-scale temporal resoln. Existing fluorescent sensors of cell membrane voltage can report action potentials in individual cultured neurons, but limitations in brightness and dynamic range of both synthetic org. and genetically encoded voltage sensors have prevented concurrent monitoring of spiking activity across large populations of individual neurons. Here we propose a novel, inorg. class of fluorescent voltage sensors: semiconductor nanoparticles, such as ultrabright quantum dots (qdots). Our calcns. revealed that transmembrane elec. fields characteristic of neuronal spiking (∼10 mV/nm) modulate a qdot's electronic structure and can induce ∼5% changes in its fluorescence intensity and ∼1 nm shifts in its emission wavelength, depending on the qdot's size, compn., and dielec. environment. Moreover, tailored qdot sensors composed of two different materials can exhibit substantial (∼30%) changes in fluorescence intensity during neuronal spiking. Using signal detection theory, we show that conventional qdots should be capable of reporting voltage dynamics with millisecond precision across several tens or more individual neurons over a range of optical and neurophysiol. conditions. These results unveil promising avenues for imaging spiking dynamics in neural networks and merit in-depth exptl. investigation.
581. 581

     Nag, O. K.; Stewart, M. H.; Deschamps, J. R.; Susumu, K.; Oh, E.; Tsytsarev, V.; Tang, Q.; Efros, A. L.; Vaxenburg, R.; Black, B. J.; Chen, Y.; O’Shaughnessy, T. J.; North, S. H.; Field, L. D.; Dawson, P. E.; Pancrazio, J. J.; Medintz, I. L.; Chen, Y.; Erzurumlu, R. S.; Huston, A. L.; Delehanty, J. B. Quantum Dot-Peptide-Fullerene Bioconjugates for Visualization of in Vitro and in Vivo Cellular Membrane Potential. ACS Nano 2017, 11, 5598– 5613,  DOI: 10.1021/acsnano.7b00954

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     581

     Quantum Dot-Peptide-Fullerene Bioconjugates for Visualization of in Vitro and in Vivo Cellular Membrane Potential

     Nag, Okhil K.; Stewart, Michael H.; Deschamps, Jeffrey R.; Susumu, Kimihiro; Oh, Eunkeu; Tystsarev, Vassiliy; Tang, Qinggong; Efros, Alexander L.; Vaxenburg, Roman; Black, Bryan J.; Chen, YungChia; O'Shaughnessy, Thomas J.; North, Stella H.; Field, Lauren D.; Dawson, Philip E.; Pancrazio, Joseph J.; Medintz, Igor L.; Chen, Yu; Erzurumlu, Reha S.; Huston, Alan L.; Delehanty, James B.

     ACS Nano (2017), 11 (6), 5598-5613CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The authors report the development of a quantum dot (QD)-peptide-fullerene (C60) electron transfer (ET)-based nanobioconjugate for the visualization of membrane potential in living cells. The bioconjugate is composed of (1) a central QD electron donor, (2) a membrane-inserting peptidyl linker, and (3) a C60 electron acceptor. The photoexcited QD donor engages in ET with the C60 acceptor, resulting in quenching of QD photoluminescence (PL) that tracks pos. with the no. of C60 moieties arrayed around the QD. The nature of the QD-capping ligand also modulates the quenching efficiency; a neutral ligand coating facilitates greater QD quenching than a neg. charged carboxylated ligand. Steady-state photophys. characterization confirms an ET-driven process between the donor-acceptor pair. When introduced to cells, the amphiphilic QD-peptide-C60 bioconjugate labels the plasma membrane by insertion of the peptide-C60 portion into the hydrophobic bilayer, while the hydrophilic QD sits on the exofacial side of the membrane. Depolarization of cellular membrane potential augments the ET process, which is manifested as further quenching of QD PL. The authors demonstrate in HeLa cells, PC12 cells, and primary cortical neurons significant QD PL quenching (ΔF/F0 of 2-20% depending on the QD-C60 sepn. distance) in response to membrane depolarization with KCl. Further, the authors show the ability to use the QD-peptide-C60 probe in combination with conventional voltage-sensitive dyes (VSDs) for simultaneous two-channel imaging of membrane potential. In in vivo imaging of cortical elec. stimulation, the optical response of the optimal QD-peptide-C60 configuration exhibits temporal responsivity to elec. stimulation similar to that of VSDs. Notably, however, the QD-peptide-C60 construct displays 20-40-fold greater ΔF/F0 than VSDs. The tractable nature of the QD-peptide-C60 system offers the advantages of ease of assembly, large ΔF/F0, enhanced photostability, and high throughput without the need for complicated org. synthesis or genetic engineering, resp., that is required of traditional VSDs and fluorescent protein constructs.
582. 582

     Chen, G.; Zhang, Y.; Peng, Z.; Huang, D.; Li, C.; Wang, Q. Glutathione-Capped Quantum Dots for Plasma Membrane Labeling and Membrane Potential Imaging. Nano Res. 2019, 12, 1321– 1326,  DOI: 10.1007/s12274-019-2283-1

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     582

     Glutathione-capped quantum dots for plasma membrane labeling and membrane potential imaging

     Chen, Guangcun; Zhang, Yejun; Peng, Zhao; Huang, Dehua; Li, Chunyan; Wang, Qiangbin

     Nano Research (2019), 12 (6), 1321-1326CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)

     The plasma membrane of cells is a crucial biol. membrane that involved in a variety of cellular processes including cell signaling transduction through membrane elec. activity. Recently, monitoring membrane elec. activity using fluorescence imaging has attracted numerous attentions for its potential applications in evaluating how the nervous system works. However, the development of ideal fluorescent voltage-sensitive probes with both high membrane labeling efficiency and voltage sensitivity is still retain a big challenge. Herein, glutathione-capped CdSe@ZnS quantum dots (CdSe@ZnS-GSH QDs) with a size of 2.5 nm and an emission peak at 520 nm are synthesized using a facile ligand exchange method for plasma membrane labeling and membrane potential imaging. The as-synthesized CdSe@ZnS-GSH QDs can effectively label cell membrane at neutral pH within 30 min and exhibit excellent optical stability in continuous imaging for up to 60 min. With the test concn. up to 200 nM, CdSe@ZnS-GSH QDs show high biocompatibility to cells and do not affect cell proliferation, disturb cell membrane integrity or cause apoptosis and necrosis of cells. This study offers a facile strategy for labeling plasma membrane and monitoring the membrane potential of cells and will hold great potential in the research of signaling within intact neuronal circuits. [Figure not available: see fulltext.].
583. 583

     Clapp, A. R.; Pons, T.; Medintz, I. L.; Delehanty, J. B.; Melinger, J. S.; Tiefenbrunn, T.; Dawson, P. E.; Fisher, B. R.; O’Rourke, B.; Mattoussi, H. Two-Photon Excitation of Quantum-Dot-Based Fluorescence Resonance Energy Transfer and Its Applications. Adv. Mater. 2007, 19, 1921– 1926,  DOI: 10.1002/adma.200602036

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     583

     Two-photon excitation of quantum-dot-based fluorescence resonance energy transfer and its applications

     Clapp, Aaron R.; Pons, Thomas; Medintz, Igor L.; Delehanty, James B.; Melinger, Joseph S.; Tiefenbrunn, Theresa; Dawson, Philip E.; Fisher, Brent R.; O'Rourke, Brian; Mattoussi, Hedi

     Advanced Materials (Weinheim, Germany) (2007), 19 (15), 1921-1926CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Nonradiative fluorescence resonance energy transfer (FRET) between a luminescent quantum dot (QD) donor and a proximal dye brought in close proximity of the QD surface via conjugation with a dye-labeled peptide (or a protein) is shown. The system is excited with near IR irradn. (well below the absorption band of the QD), via a fast two-photon process, which produces a FRET signal with very low background contribution due to a substantially reduced nonlinear direct excitation of the dye.
584. 584

     Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke, R.; Nann, T. Quantum Dots versus Organic Dyes as Fluorescent Labels. Nat. Methods 2008, 5, 763,  DOI: 10.1038/nmeth.1248

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     584

     Quantum dots versus organic dyes as fluorescent labels

     Resch-Genger, Ute; Grabolle, Markus; Cavaliere-Jaricot, Sara; Nitschke, Roland; Nann, Thomas

     Nature Methods (2008), 5 (9), 763-775CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)

     A review. Suitable labels are at the core of luminescence and fluorescence imaging and sensing. One of the most exciting, yet also controversial, advances in label technol. is the emerging development of quantum dots (QDs) - inorg. nanocrystals with unique optical and chem. properties but complicated surface chem. - as in vitro and in vivo fluorophores. Here the authors compare and evaluate the differences in physicochem. properties of common fluorescent labels, focusing on traditional org. dyes and QDs. The authors' aim is to provide a better understanding of the advantages and limitations of both classes of chromophores, to facilitate label choice and to address future challenges in the rational design and manipulation of QD labels.
585. 585

     Park, K.; Deutsch, Z.; Li, J. J.; Oron, D.; Weiss, S. Single Molecule Quantum-Confined Stark Effect Measurements of Semiconductor Nanoparticles at Room Temperature. ACS Nano 2012, 6, 10013– 10023,  DOI: 10.1021/nn303719m

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     585

     Single Molecule Quantum-Confined Stark Effect Measurements of Semiconductor Nanoparticles at Room Temperature

     Park, KyoungWon; Deutsch, Zvicka; Li, J. Jack; Oron, Dan; Weiss, Shimon

     ACS Nano (2012), 6 (11), 10013-10023CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The authors measured the quantum-confined Stark effect (QCSE) of several types of fluorescent colloidal semiconductor quantum dots and nanorods at the single mol. level at room temp. These measurements demonstrate the possible utility of these nanoparticles for local elec. field (voltage) sensing on the nanoscale. Charge sepn. across one (or more) heterostructure interface(s) with type-II band alignment (and the assocd. induced dipole) is crucial for an enhanced QCSE. To further gain insight into the exptl. results, the authors numerically solved the Schroedinger and Poisson equations under SCF approxn., including dielec. inhomogeneities. Both calcns. and probably the degree of initial charge sepn. (and the assocd. exciton binding energy) dets. the magnitude of the QCSE in these structures.
586. 586

     Caglar, M.; Pandya, R.; Xiao, J.; Foster, S. K.; Divitini, G.; Chen, R. Y.; Greenham, N. C.; Franze, K.; Rao, A.; Keyser, U. F. All-Optical Detection of Neuronal Membrane Depolarization in Live Cells Using Colloidal Quantum Dots. Nano Lett. 2019, 19, 8539– 8549,  DOI: 10.1021/acs.nanolett.9b03026

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     586

     All-Optical Detection of Neuronal Membrane Depolarization in Live Cells Using Colloidal Quantum Dots

     Caglar, Mustafa; Pandya, Raj; Xiao, James; Foster, Sarah K.; Divitini, Giorgio; Chen, Richard Y. S.; Greenham, Neil C.; Franze, Kristian; Rao, Akshay; Keyser, Ulrich F.

     Nano Letters (2019), 19 (12), 8539-8549CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Luminescent semiconductor quantum dots (QDs) have recently been suggested as novel probes for imaging and sensing cell membrane voltages. However, a key bottleneck for their development is a lack of techniques to assess QD responses to voltages generated in the aq. electrolytic environments typical of biol. systems. Even more generally, there have been relatively few efforts to assess the response of QDs to voltage changes in live cells. Here, the authors develop a platform for monitoring the photoluminescence (PL) response of QDs under AC and DC voltage changes within aq. ionic environments. The authors evaluate both traditional CdSe/CdS and more biol. compatible InP/ZnS QDs at a range of ion concns. to establish their PL/voltage characteristics on chip. Wide-field, few-particle PL measurements with neuronal cells show the QDs can be used to track local voltage changes with greater sensitivity (ΔPL up to twice as large) than state-of-the-art calcium imaging dyes, making them particularly appealing for tracking sub-threshold events. Addnl. physiol. observation studies showed that while CdSe/CdS dots have greater PL responses on membrane depolarization, their lower cytotoxicity makes InP/ZnS far more suitable for voltage sensing in living systems. The results provide a methodol. for the rational development of QD voltage sensors and highlight their potential for imaging changes in cell membrane voltage.
587. 587

     Bar-Elli, O.; Steinitz, D.; Yang, G.; Tenne, R.; Ludwig, A.; Kuo, Y.; Triller, A.; Weiss, S.; Oron, D. Rapid Voltage Sensing with Single Nanorods via the Quantum Confined Stark Effect. ACS Photonics 2018, 5, 2860– 2867,  DOI: 10.1021/acsphotonics.8b00206

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     587

     Rapid Voltage Sensing with Single Nanorods via the Quantum Confined Stark Effect

     Bar-Elli, Omri; Steinitz, Dan; Yang, Gaoling; Tenne, Ron; Ludwig, Anastasia; Kuo, Yung; Triller, Antoine; Weiss, Shimon; Oron, Dan

     ACS Photonics (2018), 5 (7), 2860-2867CODEN: APCHD5; ISSN:2330-4022. (American Chemical Society)

     Properly designed colloidal semiconductor quantum dots (QDs) have already been shown to exhibit high sensitivity to external elec. fields via the quantum confined Stark effect (QCSE). Yet, detection of the characteristic spectral shifts assocd. with the effect of the QCSE has traditionally been painstakingly slow, dramatically limiting the sensitivity of these QD sensors to fast transients. We exptl. demonstrate a new detection scheme designed to achieve shot-noise-limited sensitivity to emission wavelength shifts in QDs, showing feasibility for their use as local elec. field sensors on the millisecond time scale. This regime of operation is already potentially suitable for detection of single action potentials in neurons at a high spatial resoln.
588. 588

     Kuo, Y.; Li, J.; Michalet, X.; Chizhik, A.; Meir, N.; Bar-Elli, O.; Chan, E.; Oron, D.; Enderlein, J.; Weiss, S. Characterizing the Quantum-Confined Stark Effect in Semiconductor Quantum Dots and Nanorods for Single-Molecule Electrophysiology. ACS Photonics 2018, 5, 4788– 4800,  DOI: 10.1021/acsphotonics.8b00617

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     588

     Characterizing the Quantum-Confined Stark Effect in Semiconductor Quantum Dots and Nanorods for Single-Molecule Electrophysiology

     Kuo, Yung; Li, Jack; Michalet, Xavier; Chizhik, Alexey; Meir, Noga; Bar-Elli, Omri; Chan, Emory; Oron, Dan; Enderlein, Joerg; Weiss, Shimon

     ACS Photonics (2018), 5 (12), 4788-4800CODEN: APCHD5; ISSN:2330-4022. (American Chemical Society)

     We optimized the performance of quantum-confined Stark effect (QCSE)-based voltage nanosensors. A high-throughput approach for single-particle QCSE characterization was developed and utilized to screen a library of such nanosensors. Type-II ZnSe/CdS-seeded nanorods were found to have the best performance among the different nanosensors evaluated in this work. The degree of correlation between intensity changes and spectral changes of the exciton's emission under an applied field was characterized. An upper limit for the temporal response of individual ZnSe/CdS nanorods to voltage modulation was characterized by high-throughput, high temporal resoln. intensity measurements using a novel photon-counting camera. The measured 3.5 μs response time is limited by the voltage modulation electronics and represents ∼30 times higher bandwidth than needed for recording an action potential in a neuron.
589. 589

     Park, K.; Kuo, Y.; Shvadchak, V.; Ingargiola, A.; Dai, X.; Hsiung, L.; Kim, W.; Zhou, Z. H.; Zou, P.; Levine, A. J. Membrane Insertion of─and Membrane Potential Sensing by─Semiconductor Voltage Nanosensors: Feasibility Demonstration. Sci. Adv. 2018, 4, e1601453,  DOI: 10.1126/sciadv.1601453

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590. 590

     Tsytsarev, V.; Premachandra, K.; Takeshita, D.; Bahar, S. Imaging Cortical Electrical Stimulation in Vivo: Fast Intrinsic Optical Signal versus Voltage-Sensitive Dyes. Opt. Lett. 2008, 33, 1032– 1034,  DOI: 10.1364/OL.33.001032

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591. 591

     Europeans Chemicals Agency. REACH Registration data Substance Infocard Cadmium. https://echa.europa.eu/de/substance-information/-/substanceinfo/100.028.320 (accessed June 18, 2024).

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592. 592

     Ludwig, A.; Serna, P.; Morgenstein, L.; Yang, G.; Bar-Elli, O.; Ortiz, G.; Miller, E.; Oron, D.; Grupi, A.; Weiss, S. Development of Lipid-Coated Semiconductor Nanosensors for Recording of Membrane Potential in Neurons. ACS Photonics 2020, 7, 1141– 1152,  DOI: 10.1021/acsphotonics.9b01558

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     Development of Lipid-Coated Semiconductor Nanosensors for Recording of Membrane Potential in Neurons

     Ludwig, Anastasia; Serna, Pablo; Morgenstein, Lion; Yang, Gaoling; Bar-Elli, Omri; Ortiz, Gloria; Miller, Evan; Oron, Dan; Grupi, Asaf; Weiss, Shimon; Triller, Antoine

     ACS Photonics (2020), 7 (5), 1141-1152CODEN: APCHD5; ISSN:2330-4022. (American Chemical Society)

     In the past decade, optical imaging methods have significantly improved the understanding of the information processing principles in the brain. Although many promising tools have been designed, sensors of membrane potential are lagging behind the rest. Semiconductor nanoparticles are an attractive alternative to classical voltage indicators, such as voltage-sensitive dyes and proteins. Such nanoparticles exhibit high sensitivity to external elec. fields via the quantum-confined Stark effect. Here the authors report the development of semiconductor voltage-sensitive nanorods (vsNRs) that self-insert into the neuronal membrane. To facilitate interaction of the nanorods with the membrane, the authors functionalized their surface with the lipid mixt. derived from brain ext. The authors describe a workflow to detect and process the photoluminescent signal of vsNRs after wide-field time-lapse recordings. The authors also present data indicating that vsNRs are feasible for sensing membrane potential in neurons at a single-particle level. This shows the potential of vsNRs for the detection of neuronal activity with unprecedentedly high spatial and temporal resoln.
593. 593

     Lütcke, H.; Gerhard, F.; Zenke, F.; Gerstner, W.; Helmchen, F. Inference of Neuronal Network Spike Dynamics and Topology from Calcium Imaging Data. Front. Neural Circuits 2013, 7, 201,  DOI: 10.3389/fncir.2013.00201

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     Ledochowitsch, P.; Huang, L.; Knoblich, U.; Oliver, M.; Lecoq, J.; Reid, C.; Li, L.; Zeng, H.; Koch, C.; Waters, J. On the Correspondence of Electrical and Optical Physiology in in Vivo Population-Scale Two-Photon Calcium Imaging. bioRxiv , October 11, 2019, 800102. DOI: 10.1101/800102 .

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     Oheim, M.; Kirchhoff, F.; Stühmer, W. Calcium Microdomains in Regulated Exocytosis. Cell Calcium 2006, 40, 423– 439,  DOI: 10.1016/j.ceca.2006.08.007

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     Shuai, J.; Parker, I. Optical Single-Channel Recording by Imaging Ca²⁺ Flux through Individual Ion Channels: Theoretical Considerations and Limits to Resolution. Cell Calcium 2005, 37, 283– 299,  DOI: 10.1016/j.ceca.2004.10.008

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     Kohlhaas, M.; Maack, C. Calcium Release Microdomains and Mitochondria. Cardiovasc. Res. 2013, 98, 259– 268,  DOI: 10.1093/cvr/cvt032

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     Calcium release microdomains and mitochondria

     Kohlhaas, Michael; Maack, Christoph

     Cardiovascular Research (2013), 98 (2), 259-268CODEN: CVREAU; ISSN:0008-6363. (Oxford University Press)

     A review. The processes of excitation-contraction (EC) coupling consume large amts. of energy that need to be replenished by oxidative phosphorylation in the mitochondria. Since Ca2+ activates key enzymes of the Krebs cycle in the mitochondrial matrix, it is important to understand the mechanisms and kinetics of mitochondrial Ca2+ uptake to delineate how in cardiac myocytes, energy supply is efficiently matched to demand. In recent years, the identification of various proteins involved in mitochondrial Ca2+ signalling and the tethering of mitochondria to the sarcoplasmic reticulum (SR) has considerably advanced the field and supported the concept of a mitochondrial Ca2+ microdomain, in which Ca2+ concns. are high enough to overcome the low Ca2+ affinity of the principal mitochondrial Ca2+ uptake mechanism, the Ca2+ uniporter. Furthermore, defects in EC coupling that occur in heart failure disrupt SR-mitochondrial Ca2+ crosstalk and may cause energetic deficit and oxidative stress, both factors that are thought to be causally involved in the initiation and progression of the disease.
598. 598

     Berridge, M. J. Calcium Microdomains: Organization and Function. Cell Calcium 2006, 40, 405– 412,  DOI: 10.1016/j.ceca.2006.09.002

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599. 599

     Becherer, U.; Moser, T.; Stühmer, W.; Oheim, M. Calcium Regulates Exocytosis at the Level of Single Vesicles. Nat. Neurosci. 2003, 6, 846– 853,  DOI: 10.1038/nn1087

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     Calcium regulates exocytosis at the level of single vesicles

     Becherer, Ute; Moser, Tobias; Stuehmer, Walter; Oheim, Martin

     Nature Neuroscience (2003), 6 (8), 846-853CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

     Ca2+ microdomains that form during the opening of voltage-gated Ca2+ channels have been implicated in regulating the kinetics of hormone and transmitter release. Direct assessment of the interaction between a single Ca2+ microdomain and a single secretory vesicle has been impossible because of tech. limitations. Using evanescent field imaging of near-membrane micromolar Ca2+ concn. ([Ca2+]) and fluorescently labeled vesicles, we have obsd. exocytosis of individual chromaffin dense-core vesicles that was triggered by Ca2+ microdomains. Ca2+ microdomains selectively triggered the release of vesicles that were docked within 300 nm. Not all vesicles exposed to a Ca2+ microdomain were released, indicating that some vesicles are docked but are not ready for release. In addn. to its established role as a trigger for release, elevated near-membrane [Ca2+] reduced the distance between docked vesicles and Ca2+ entry sites. Our results suggest a new mechanism for stimulation-dependent facilitation of exocytosis, whereby vesicles are moved closer to Ca2+ entry sites, thereby increasing a Ca2+ microdomain's efficacy to trigger vesicle fusion.
600. 600

     Demuro, A.; Parker, I. Imaging Single-Channel Calcium Microdomains. Cell Calcium 2006, 40, 413– 422,  DOI: 10.1016/j.ceca.2006.08.006

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     Zamaleeva, A. I.; Collot, M.; Bahembera, E.; Tisseyre, C.; Rostaing, P.; Yakovlev, A. V.; Oheim, M.; De Waard, M.; Mallet, J.-M.; Feltz, A. Cell-Penetrating Nanobiosensors for Pointillistic Intracellular Ca²⁺-Transient Detection. Nano Lett. 2014, 14, 2994– 3001,  DOI: 10.1021/nl500733g

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     601

     Cell-Penetrating Nanobiosensors for Pointillistic Intracellular Ca2+-Transient Detection

     Zamaleeva, Alsu I.; Collot, Mayeul; Bahembera, Eloi; Tisseyre, Celine; Rostaing, Philippe; Yakovlev, Aleksey V.; Oheim, Martin; de Waard, Michel; Mallet, Jean-Maurice; Feltz, Anne

     Nano Letters (2014), 14 (6), 2994-3001CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     Small-mol. chem. calcium (Ca2+) indicators are invaluable tools for studying intracellular signaling pathways but have severe shortcomings for detecting local Ca2+ entry. Nanobiosensors incorporating functionalized quantum dots (QDs) have emerged as promising alternatives but their intracellular use remains a major challenge. The authors designed cell-penetrating FRET-based Ca2+ nanobiosensors for the detection of local Ca2+ concn. transients, using com. available CANdot565QD as a donor and CaRuby, a custom red-emitting Ca2+ indicator, as an acceptor. With Ca2+-binding affinities covering the range of 3-20 μM, the authors' CaRubies allow building sensors with a scalable affinity for detecting intracellular Ca2+ transients at various concns. To facilitate their cytoplasmic delivery, QDs were further functionalized with a small cell-penetrating peptide (CPP) derived from hadrucalcin (HadUF1-11: H11), a ryanodine receptor-directed scorpion toxin identified within the venom of Hadrurus gertschi. Efficient internalization of QDs doubly functionalized with PEG5-CaRuby and H11 (in a molar ratio of 1:10:10, resp.) is demonstrated. In BHK cells expressing a N-methyl-D-aspartate receptor (NMDAR) construct, these nanobiosensors report rapid intracellular near-membrane Ca2+ transients following agonist application when imaged by TIRF microscopy. The authors' work presents the elaboration of cell-penetrating FRET-based nanobiosensors and validates their function for detection of intracellular Ca2+ transients.
602. 602

     Yakovlev, A. V.; Zhang, F.; Zulqurnain, A.; Azhar-Zahoor, A.; Luccardini, C.; Gaillard, S.; Mallet, J. M.; Tauc, P.; Brochon, J. C.; Parak, W. J.; Feltz, A.; Oheim, M. Wrapping Nanocrystals with an Amphiphilic Polymer Preloaded with Fixed Amounts of Fluorophore Generates FRET-Based Nanoprobes with a Controlled Donor/Acceptor Ratio. Langmuir 2009, 25, 3232– 3239,  DOI: 10.1021/la8038347

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     602

     Wrapping Nanocrystals with an Amphiphilic Polymer Preloaded with Fixed Amounts of Fluorophore Generates FRET-Based Nanoprobes with a Controlled Donor/Acceptor Ratio

     Yakovlev, Aleksey V.; Zhang, Feng; Zulqurnain, Ali; Azhar-Zahoor, Abbasi; Luccardini, Camilla; Gaillard, Stephane; Mallet, Jean-Maurice; Tauc, Patrick; Brochon, Jean-Claude; Parak, Wolfgang J.; Feltz, Anne; Oheim, Martin

     Langmuir (2009), 25 (5), 3232-3239CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)

     Colloidal nanocrystal (NC) donors wrapped with a polymer coating including multiple org. acceptor mols. are promising scaffolds for fluorescence resonance energy transfer (FRET)-based nanobiosensors. Over other self-assembling donor-acceptor configurations, the authors' preloaded polymers have the virtue of producing compact assemblies with a fixed donor/acceptor distance. This property, together with the possibility of stoichiometric polymer loading, allowed the authors to directly address how the FRET efficiency depended on the donor/acceptor. At the population level, nanoprobes based on com. as well as custom CdSe/ZnS donors displayed the expected dose-dependent rise in transfer efficiency, satg. from about five ATTO dyes/NC. However, for a given acceptor concn., both the intensity and lifetime of single-pair FRET data revealed a large dispersion of transfer efficiencies, highlighting an important heterogeneity among nominally identical FRET-based nanoprobes. Rigorous quality check during synthesis and shell assembly as well as postsynthesis sorting and purifn. are required to make hybrid semiconductor-org. nanoprobes a robust and viable alternative to org. or genetically encoded nanobiosensors.
603. 603

     Zhang, F.; Ali, Z.; Amin, F.; Feltz, A.; Oheim, M.; Parak, W. J. Ion and pH Sensing with Colloidal Nanoparticles: Influence of Surface Charge on Sensing and Colloidal Properties. ChemPhysChem 2010, 11, 730– 735,  DOI: 10.1002/cphc.200900849

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     603

     Ion and pH Sensing with Colloidal Nanoparticles: Influence of Surface Charge on Sensing and Colloidal Properties

     Zhang, Feng; Ali, Zulqurnain; Amin, Faheem; Feltz, Anne; Oheim, Martin; Parak, Wolfgang J.

     ChemPhysChem (2010), 11 (3), 730-735CODEN: CPCHFT; ISSN:1439-4235. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Ion sensors based on colloidal nanoparticles (NPs), either as actively ion-sensing NPs or as nanoscale carrier systems for org. ion-sensing fluorescent chelators typically require a charged surface to be colloidally stable. This surface charge significantly impacts the ion binding and affects the read-out. Sensor read-out should be thus not detd. by the bulk ion concn., but by the local ion concn. in the nano-environment of the NP surface. The authors present a conclusive model corroborated by exptl. data that reproduces the strong distance-dependence of the effect. The exptl. data are based on the capability of tuning the distance of a pH-sensitive fluorophore to the surface of NPs in the nanometer (nm) range. This in turn allows for modification of the effective acid dissocn. const. value (its logarithmic form, pKa) of analyte-sensitive fluorophores by tuning their distance to the underlying colloidal NPs.
604. 604

     Prasuhn, D. E.; Feltz, A.; Blanco-Canosa, J. B.; Susumu, K.; Stewart, M. H.; Mei, B. C.; Yakovlev, A. V.; Loukou, C.; Mallet, J. M.; Oheim, M.; Dawson, P. E.; Medintz, I. L. Quantum Dot Peptide Biosensors for Monitoring Caspase 3 Proteolysis and Calcium Ions. ACS Nano 2010, 4, 7726– 7726,  DOI: 10.1021/nn102986a

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     Quantum Dot Peptide Biosensors for Monitoring Caspase 3 Proteolysis and Calcium Ions. [Erratum to document cited in CA153:475136]

     Prasuhn, Duane E.; Feltz, Anne; Blanco-Canosa, Juan B.; Susumu, Kimihiro; Stewart, Michael H.; Mei, Bing-C.; Yakovlev, Aleksey V.; Loukou, Christina; Mallet, Jean-Maurice; Oheim, Martin; Dawson, Philip E.; Medintz, Igor L.

     ACS Nano (2010), 4 (12), 7726CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     On page 5487, in the original version of this paper, the eighth author's name was misspelled as Loukov. The correct spelling is Loukou.
605. 605

     Edwards, F. A.; Konnerth, A.; Sakmann, B.; Takahashi, T. A Thin Slice Preparation for Patch Clamp Recordings from Neurones of the Mammalian Central Nervous System. Pflugers Arch. 1989, 414, 600– 612,  DOI: 10.1007/BF00580998

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606. 606

     Chow, R. H.; von Rüden, L.; Neher, E. Delay in Vesicle Fusion Revealed by Electrochemical Monitoring of Single Secretory Events in Adrenal Chromaffin Cells. Nature 1992, 356, 60– 63,  DOI: 10.1038/356060a0

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     Delay in vesicle fusion revealed by electrochemical monitoring of single secretory events in adrenal chromaffin cells

     Chow, Robert H.; Von Rueden, Ludolf; Neher, Erwin

     Nature (London, United Kingdom) (1992), 356 (6364), 60-3CODEN: NATUAS; ISSN:0028-0836.

     Under voltage-clamp conditions, stochastically occurring signals can be recorded from adrenal chromaffin cells using a carbon-fiber electrode as an electrochem. detector. These signals obey statistics characteristic for quantal release; however, in contrast to neuronal transmitter release, secretion occurs with a delay after short step depolarizations. Furthermore, a pedestal or foot was identified at the onset of unitary events which may represent the slow leak of catecholamine mols. out of a narrow fusion pore before the pore dilates for complete exocytosis.
607. 607

     Alvarez de Toledo, G.; Fernández-Chacón, R.; Fernández, J. M. Release of Secretory Products during Transient Vesicle Fusion. Nature 1993, 363, 554– 558,  DOI: 10.1038/363554a0

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     Release of secretory products during transient vesicle fusion

     Alvarez de Toledo, G.; Fernandez-Chacon, R.; Fernandez, J. M.

     Nature (London, United Kingdom) (1993), 363 (6429), 554-8CODEN: NATUAS; ISSN:0028-0836.

     Patch-clamp measurements of the activity of single exocytotic fusion pores in beige mouse mast cells were combined with the electrochem. detection of serotonin released during the exocytotic events. The authors report here that on fusion pore opening there is a small release of serotonin which is directly proportional to the pore conductance. Also, a significant release occurs during transient fusion events. These results demonstrate release of a neurotransmitter from a secretory vesicle that did not undergo complete fusion.
608. 608

     Travis, E. R.; Wightman, R. M. Spatio-Temporal Resolution of Exocytosis from Individual Cells. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 77– 103,  DOI: 10.1146/annurev.biophys.27.1.77

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     Spatio-temporal resolution of exocytosis from individual cells

     Travis, Eric R.; Wightman, R. Mark

     Annual Review of Biophysics and Biomolecular Structure (1998), 27 (), 77-103CODEN: ABBSE4; ISSN:1056-8700. (Annual Reviews Inc.)

     A review with 96 refs. Biophys. events involved in late stages of exocytosis occur at highly localized areas of cells on millisecond and sub-millisecond time scales. Thus, methodologies with high spatio-temporal resoln. are required to achieve measurements at individual secretory cells. Much has been learned about the mechanisms and kinetics of vesicular release through anal. with the carbon fiber microelectrode techniques amperometry and cyclic voltammetry. Coupling of these techniques with other methods such as patch-clamp continues to reveal details of the secretion process. It is now clear that extrusion of the vesicular contents is a more complex process than previously believed. Vesicle-cell fusion, revealed by cell capacitance measurements, is temporally dissocd. from secretion measured amperometrically. The stability imparted by interaction and assocn. of vesicle contents at rest results in a rate-limiting extrusion process after full fusion. Furthermore, the presence of partial fusion events and the occurrence of non-quantized release have been revealed with electrochem. tools.
609. 609

     Huang, M.; Delacruz, J. B.; Ruelas, J. C.; Rathore, S. S.; Lindau, M. Surface-Modified CMOS IC Electrochemical Sensor Array Targeting Single Chromaffin Cells for Highly Parallel Amperometry Measurements. Pflugers Arch. 2018, 470, 113– 123,  DOI: 10.1007/s00424-017-2067-y

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     Movassaghi, C. S.; Perrotta, K. A.; Yang, H.; Iyer, R.; Cheng, X.; Dagher, M.; Fillol, M. A.; Andrews, A. M. Simultaneous Serotonin and Dopamine Monitoring Across Timescales by Rapid Pulse Voltammetry with Partial Least Squares Regression. Anal. Bioanal. Chem. 2021, 413, 6747– 6767,  DOI: 10.1007/s00216-021-03665-1

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     610

     Simultaneous serotonin and dopamine monitoring across timescales by rapid pulse voltammetry with partial least squares regression

     Movassaghi, Cameron S.; Perrotta, Katie A.; Yang, Hongyan; Iyer, Rahul; Cheng, Xinyi; Dagher, Merel; Fillol, Miguel Alcaniz; Andrews, Anne M.

     Analytical and Bioanalytical Chemistry (2021), 413 (27), 6747-6767CODEN: ABCNBP; ISSN:1618-2642. (Springer)

     Many voltammetry methods have been developed to monitor brain extracellular dopamine levels. Fewer approaches have been successful in detecting serotonin in vivo. No voltammetric techniques are currently available to monitor both neurotransmitters simultaneously across timescales, even though they play integrated roles in modulating behavior. We provide proof-of-concept for rapid pulse voltammetry coupled with partial least squares regression (RPV-PLSR), an approach adapted from multi-electrode systems (i.e., electronic tongues) used to identify multiple components in complex environments. We exploited small differences in analyte redox profiles to select pulse steps for RPV waveforms. Using an intentionally designed pulse strategy combined with custom instrumentation and anal. software, we monitored basal and stimulated levels of dopamine and serotonin. In addn. to faradaic currents, capacitive currents were important factors in analyte identification arguing against background subtraction. Compared to fast-scan cyclic voltammetry-principal components regression (FSCV-PCR), RPV-PLSR better differentiated and quantified basal and stimulated dopamine and serotonin assocd. with striatal recording electrode position, optical stimulation frequency, and serotonin reuptake inhibition. The RPV-PLSR approach can be generalized to other electrochem. active neurotransmitters and provides a feedback pipeline for future optimization of multi-analyte, fit-for-purpose waveforms and machine learning approaches to data anal.
611. 611

     Movassaghi, C. S.; Alcañiz Fillol, M.; Kishida, K. T.; McCarty, G.; Sombers, L. A.; Wassum, K. M.; Andrews, A. M. Maximizing Electrochemical Information: A Perspective on Background-Inclusive Fast Voltammetry. Anal. Chem. 2024, 96, 6097– 6105,  DOI: 10.1021/acs.analchem.3c04938

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     Madhurantakam, S.; Karnam, J. B.; Brabazon, D.; Takai, M.; Ahad, I. U.; Balaguru Rayappan, J. B.; Krishnan, U. M. ″Nano″: An Emerging Avenue in Electrochemical Detection of Neurotransmitters. ACS Chem. Neurosci. 2020, 11, 4024– 4047,  DOI: 10.1021/acschemneuro.0c00355

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     612

     "Nano": An Emerging Avenue in Electrochemical Detection of Neurotransmitters

     Madhurantakam, Sasya; Karnam, Jayanth Babu; Brabazon, Dermot; Takai, Madoka; Ahad, Inam Ul; Balaguru Rayappan, John Bosco; Krishnan, Uma Maheswari

     ACS Chemical Neuroscience (2020), 11 (24), 4024-4047CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

     A review. The growing importance of nanomaterials toward the detection of neurotransmitter mols. has been chronicled in this review. Neurotransmitters (NTs) are chems. that serve as messengers in synaptic transmission and are key players in brain functions. Abnormal levels of NTs are assocd. with numerous psychotic and neurodegenerative diseases. Therefore, their sensitive and robust detection is of great significance in clin. diagnostics. For more than three decades, electrochem. sensors have made a mark toward clin. detection of NTs. The superiority of these electrochem. sensors lies in their ability to enable sensitive, simple, rapid and selective detn. of analyte mols. while remaining relatively inexpensive. Addnl., these sensors are capable of being integrated in robust, portable and miniaturized devices to establish point-of-care diagnostic platforms. Nanomaterials have emerged as promising materials with significant implications for electrochem. sensing due to their inherent capability to achieve high surface coverage, superior sensitivity, and rapid response in addn. to simple device architecture and miniaturization. Considering the enormous significance of the levels of NTs in the biol. systems and the advances in sensing ushered in with the integration of nanotechnol. in electrochem., the anal. of NTs by employing nanomaterials as interface materials in various matrixes has emerged as an active area of research. This review explores the advancements made in the field of electrochem. sensors for the sensitive and selective detn. of NTs which have been described in the past the two decades with a distinctive focus on extremely innovative attributes introduced by nanotechnol.
613. 613

     Fuller, C. W.; Padayatti, P. S.; Abderrahim, H.; Adamiak, L.; Alagar, N.; Ananthapadmanabhan, N.; Baek, J.; Chinni, S.; Choi, C.; Delaney, K. J. Molecular Electronics Sensors on a Scalable Semiconductor Chip: A Platform for Single-Molecule Measurement of Binding Kinetics and Enzyme Activity. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2112812119,  DOI: 10.1073/pnas.2112812119

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     613

     Molecular electronics sensors on a scalable semiconductor chip: a platform for single-molecule measurement of binding kinetics and enzyme activity

     Fuller, Carl W.; Padayatti, Pius S.; Abderrahim, Hadi; Adamiak, Lisa; Alagar, Nolan; Ananthapadmanabhan, Nagaraj; Baek, Jihye; Chinni, Sarat; Choi, Chulmin; Delaney, Kevin J.; Dubielzig, Rich; Frkanec, Julie; Garcia, Chris; Gardner, Calvin; Gebhardt, Daniel; Geiser, Tim; Gutierrez, Zachariah; Hall, Drew A.; Hodges, Andrew P.; Hou, Guangyuan; Jain, Sonal; Jones, Teresa; Lobaton, Raymond; Majzik, Zsolt; Marte, Allen; Mohan, Prateek; Mola, Paul, II; Mudondo, Paul; Mullinix, James; Nguyen, Thuan; Ollinger, Frederick; Orr, Sarah; Ouyang, Yuxuan; Pan, Paul; Park, Namseok; Porras, David; Prabhu, Keshav; Reese, Cassandra; Ruel, Travers; Sauerbrey, Trevor; Sawyer, Jaymie R.; Sinha, Prem; Tu, Jacky; Venkatesh, A. G.; VijayKumar, Sushmitha; Le Zheng; Jin, Sungho; Tour, James M.; Church, George M.; Mola, Paul W.; Merriman, Barry

     Proceedings of the National Academy of Sciences of the United States of America (2022), 119 (5), e2112812119CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     For nearly 50 years, the vision of using single mols. in circuits has been seen as providing the ultimate miniaturization of electronic chips. An advanced example of such a mol. electronics chip is presented here, with the important distinction that the mol. circuit elements play the role of general-purpose single-mol. sensors. The device consists of a semiconductor chip with a scalable array architecture. Each array element contains a synthetic mol. wire assembled to span nanoelectrodes in a current monitoring circuit. A central conjugation site is used to attach a single probe mol. that defines the target of the sensor. The chip digitizes the resulting picoamp-scale current-vs.-time readout from each sensor element of the array at a rate of 1,000 frames per s. This provides detailed elec. signatures of the single-mol. interactions between the probe and targets present in a soln.-phase test sample. This platform is used to measure the interaction kinetics of single mols., without the use of labels, in a massively parallel fashion. To demonstrate broad applicability, examples are shown for probe mol. binding, including DNA oligos, aptamers, antibodies, and antigens, and the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR/Cas enzyme binding a target DNA, and a DNA polymerase enzyme incorporating nucleotides as it copies a DNA template. All of these applications are accomplished with high sensitivity and resoln., on a manufacturable, scalable, all-electronic semiconductor chip device, thereby bringing the power of modern chips to these diverse areas of biosensing.
614. 614

     Nakatsuka, N.; Yang, K.-A.; Abendroth, J. M.; Cheung, K. M.; Xu, X.; Yang, H.; Zhao, C.; Zhu, B.; Rim, Y. S.; Yang, Y.; Weiss, P. S.; Stojanović, M.; Andrews, A. M. Aptamer-Field-Effect Transistors Overcome Debye Length Limitations for Small-Molecule Sensing. Science 2018, 362, 319– 324,  DOI: 10.1126/science.aao6750

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     614

     Aptamer-field-effect transistors overcome Debye length limitations for small-molecule sensing

     Nakatsuka, Nako; Yang, Kyung-Ae; Abendroth, John M.; Cheung, Kevin M.; Xu, Xiaobin; Yang, Hongyan; Zhao, Chuanzhen; Zhu, Bowen; Rim, You Seung; Yang, Yang; Weiss, Paul S.; Stojanovic, Milan N.; Andrews, Anne M.

     Science (Washington, DC, United States) (2018), 362 (6412), 319-324CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Detection of analytes by means of field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the elec. double layer (the "Debye length" limitation). We detected small mols. under physiol. high-ionic strength conditions by modifying printed ultrathin metal-oxide field-effect transistor arrays with deoxyribonucleotide aptamers selected to bind their targets adaptively. Target-induced conformational changes of neg. charged aptamer phosphodiester backbones in close proximity to semiconductor channels gated conductance in physiol. buffers, resulting in highly sensitive detection. Sensing of charged and electroneutral targets (serotonin, dopamine, glucose, and sphingosine-1-phosphate) was enabled by specifically isolated aptameric stem-loop receptors.
615. 615

     Yang, K.; Mitchell, N. M.; Banerjee, S.; Cheng, Z.; Taylor, S.; Kostic, A. M.; Wong, I.; Sajjath, S.; Zhang, Y.; Stevens, J.; Mohan, S.; Landry, D. W.; Worgall, T. S.; Andrews, A. M.; Stojanovic, M. N. A Functional Group-Guided Approach to Aptamers for Small Molecules. Science 2023, 380, 942– 948,  DOI: 10.1126/science.abn9859

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     615

     A functional group-guided approach to aptamers for small molecules

     Yang, Kyungae; Mitchell, Noelle M.; Banerjee, Saswata; Cheng, Zhenzhuang; Taylor, Steven; Kostic, Aleksandra M.; Wong, Isabel; Sajjath, Sairaj; Zhang, Yameng; Stevens, Jacob; Mohan, Sumit; Landry, Donald W.; Worgall, Tilla S.; Andrews, Anne M.; Stojanovic, Milan N.

     Science (Washington, DC, United States) (2023), 380 (6648), 942-948CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)

     Aptameric receptors are important biosensor components, yet our ability to identify them depends on the target structures. We analyzed the contributions of individual functional groups on small mols. to binding within 27 target-aptamer pairs, identifying potential hindrances to receptor isolation-for example, neg. cooperativity between sterically hindered functional groups. To increase the probability of aptamer isolation for important targets, such as leucine and voriconazole, for which multiple previous selection attempts failed, we designed tailored strategies focused on overcoming individual structural barriers to successful selections. This approach enables us to move beyond standardized protocols into functional group-guided searches, relying on sequences common to receptors for targets and their analogs to serve as anchors in regions of vast oligonucleotide spaces wherein useful reagents are likely to be found.
616. 616

     Liao, W.-S.; Cheunkar, S.; Cao, H. H.; Bednar, H. R.; Weiss, P. S.; Andrews, A. M. Subtractive Patterning via Chemical Lift-Off Lithography. Science 2012, 337, 1517– 1521,  DOI: 10.1126/science.1221774

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     616

     Subtractive Patterning via Chemical Lift-Off Lithography

     Liao, Wei-Ssu; Cheunkar, Sarawut; Cao, Huan H.; Bednar, Heidi R.; Weiss, Paul S.; Andrews, Anne M.

     Science (Washington, DC, United States) (2012), 337 (6101), 1517-1521CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Conventional soft-lithog. methods involving the transfer of mol. "inks" from polymeric stamps to substrates often encounter micrometer-scale resoln. limits due to diffusion of the transferred mols. during printing. The authors report a "subtractive" stamping process in which silicone rubber stamps, activated by oxygen plasma, selectively remove hydroxyl-terminated alkanethiols from self-assembled monolayers (SAMs) on gold surfaces with high pattern fidelity. The covalent interactions formed at the stamp-substrate interface are sufficiently strong to remove not only alkanethiol mols. but also gold atoms from the substrate. A variety of high-resoln. patterned features were fabricated, and stamps were cleaned and reused many times without feature deterioration. The remaining SAM acted as a resist for etching exposed gold features. Monolayer backfilling into the lift-off areas enabled patterned protein capture, and 40-nm chem. patterns were achieved.
617. 617

     Zhao, C.; Cheung, K. M.; Huang, I.-W.; Yang, H.; Nakatsuka, N.; Liu, W.; Cao, Y.; Man, T.; Weiss, P. S.; Monbouquette, H. G.; Andrews, A. M. Implantable Aptamer-Field-Effect Transistor Neuroprobes for in Vivo Neurotransmitter Monitoring. Sci. Adv. 2021, 7, eabj7422,  DOI: 10.1126/sciadv.abj7422

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618. 618

     Liu, Q.; Zhao, C.; Chen, M.; Liu, Y.; Zhao, Z.; Wu, F.; Li, Z.; Weiss, P. S.; Andrews, A. M.; Zhou, C. Flexible Multiplexed In₂O₃ Nanoribbon Aptamer-Field-Effect Transistors for Biosensing. iScience 2020, 23, 101469,  DOI: 10.1016/j.isci.2020.101469

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     618

     Flexible Multiplexed In2O3 Nanoribbon Aptamer-Field-Effect Transistors for Biosensing

     Liu, Qingzhou; Zhao, Chuanzhen; Chen, Mingrui; Liu, Yihang; Zhao, Zhiyuan; Wu, Fanqi; Li, Zhen; Weiss, Paul S.; Andrews, Anne M.; Zhou, Chongwu

     iScience (2020), 23 (9), 101469CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)

     Flexible sensors are essential for advancing implantable and wearable bioelectronics toward monitoring chem. signals within and on the body. Developing biosensors for monitoring multiple neurotransmitters in real time represents a key in vivo application that will increase understanding of information encoded in brain neurochem. fluxes. Here, arrays of devices having multiple In2O3nanoribbon field-effect transistors (FETs) were fabricated on 1.4-μm-thick polyethylene terephthalate (PET) substrates using shadow mask patterning techniques. Thin PET-FET devices withstood crumpling and bending such that stable transistor performance with high mobility was maintained over >100 bending cycles. Real-time detection of the small-mol. neurotransmitters serotonin and dopamine was achieved by immobilizing recently identified high-affinity nucleic-acid aptamers on individual In2O3nanoribbon devices. Limits of detection were 10 fM for serotonin and dopamine with detection ranges spanning eight orders of magnitude. Simultaneous sensing of temp., pH, serotonin, and dopamine enabled integration of physiol. and neurochem. data from individual bioelectronic devices.
619. 619

     Wang, B.; Zhao, C.; Wang, Z.; Yang, K.-A.; Cheng, X.; Liu, W.; Yu, W.; Lin, S.; Zhao, Y.; Cheung, K. M. Wearable Aptamer-Field-Effect Transistor Sensing System for Noninvasive Cortisol Monitoring. Sci. Adv. 2022, 8, eabk0967,  DOI: 10.1126/sciadv.abk0967

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     There is no corresponding record for this reference.
620. 620

     Cheung, K. M.; Yang, K.-A.; Nakatsuka, N.; Zhao, C.; Ye, M.; Jung, M. E.; Yang, H.; Weiss, P. S.; Stojanovic, M. N.; Andrews, A. M. Phenylalanine Monitoring via Aptamer-Field-Effect Transistor Sensors. ACS Sens. 2019, 4, 3308– 3317,  DOI: 10.1021/acssensors.9b01963

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     620

     Phenylalanine Monitoring via Aptamer-Field-Effect Transistor Sensors

     Cheung, Kevin M.; Yang, Kyung-Ae; Nakatsuka, Nako; Zhao, Chuanzhen; Ye, Mao; Jung, Michael E.; Yang, Hongyan; Weiss, Paul S.; Stojanovic, Milan N.; Andrews, Anne M.

     ACS Sensors (2019), 4 (12), 3308-3317CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)

     Detn. of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine accumulates and persists at levels that alter brain development and cause permanent neurol. damage and cognitive dysfunction. Recent approaches for treating phenylketonuria focus on injectable medications that efficiently break down phenylalanine but sometimes result in detrimentally low phenylalanine levels. We have identified new DNA aptamers for phenylalanine in two formats, initially as fluorescent sensors and then, incorporated with field-effect transistors (FETs). Aptamer-FET sensors detected phenylalanine over a wide range of concns. (fM to mM). para-Chlorophenylalanine, which inhibits the enzyme that converts phenylalanine to tyrosine, was used to induce hyperphenylalaninemia during brain development in mice. Aptamer-FET sensors were specific for phenylalanine vs. para-chlorophenylalanine and differentiated changes in mouse serum phenylalanine at levels expected in patients. Aptamer-FETs can be used to investigate models of hyperphenylalanemia in the presence of structurally related enzyme inhibitors, as well as naturally occurring amino acids. Nucleic acid-based receptors that discriminate phenylalanine analogs, some that differ by a single substituent, indicate a refined ability to identify aptamers with binding pockets tailored for high affinity and specificity. Aptamers of this type integrated into FETs enable rapid, electronic, label-free phenylalanine sensing.
621. 621

     Cheung, K. M.; Abendroth, J. M.; Nakatsuka, N.; Zhu, B.; Yang, Y.; Andrews, A. M.; Weiss, P. S. Detecting DNA and RNA and Differentiating Single-Nucleotide Variations via Field-Effect Transistors. Nano Lett. 2020, 20, 5982– 5990,  DOI: 10.1021/acs.nanolett.0c01971

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     621

     Detecting DNA and RNA and Differentiating Single-Nucleotide Variations via Field-Effect Transistors

     Cheung, Kevin M.; Abendroth, John M.; Nakatsuka, Nako; Zhu, Bowen; Yang, Yang; Andrews, Anne M.; Weiss, Paul S.

     Nano Letters (2020), 20 (8), 5982-5990CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The authors detect short oligonucleotides and distinguish between sequences that differ by a single base, using label-free, electronic field-effect transistors (FETs). The authors' sensing platform uses ultrathin-film indium oxide FETs chem. functionalized with single-stranded DNA (ssDNA). The ssDNA-functionalized semiconducting channels in FETs detect fully complementary DNA sequences and differentiate these sequences from those having different types and locations of single base-pair mismatches. Changes in charge assocd. with surface-bound ssDNA vs. double-stranded DNA (dsDNA) alter FET channel conductance to enable detection due to differences in DNA duplex stability. The authors illustrate the capability of ssDNA-FETs to detect complementary RNA sequences and to distinguish from RNA sequences with single nucleotide variations. The development and implementation of electronic biosensors that rapidly and sensitively detect and differentiate oligonucleotides present new opportunities in the fields of disease diagnostics and precision medicine.
622. 622

     Nakatsuka, N.; Heard, K. J.; Faillétaz, A.; Momotenko, D.; Vörös, J.; Gage, F. H.; Vadodaria, K. C. Sensing Serotonin Secreted from Human Serotonergic Neurons Using Aptamer-Modified Nanopipettes. Mol. Psychiatry 2021, 26, 2753– 2763,  DOI: 10.1038/s41380-021-01066-5

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     622

     Sensing serotonin secreted from human serotonergic neurons using aptamer-modified nanopipettes

     Nakatsuka, Nako; Heard, Kelly J.; Failletaz, Alix; Momotenko, Dmitry; Voros, Janos; Gage, Fred H.; Vadodaria, Krishna C.

     Molecular Psychiatry (2021), 26 (7), 2753-2763CODEN: MOPSFQ; ISSN:1359-4184. (Nature Portfolio)

     The serotonergic system in the human brain modulates several physiol. processes, and altered serotonergic neurotransmission has been implicated in the neuropathol. of several psychiatric disorders. The study of serotonergic neurotransmission in psychiatry has long been restricted to animal models, but advances in cell reprogramming technol. have enabled the generation of serotonergic neurons from patient-induced pluripotent stem cells (iPSCs). While iPSC-derived human serotonergic neurons offer the possibility to study serotonin (5-HT) release and uptake, particularly by 5-HT-modulating drugs such as selective serotonin reuptake inhibitors (SSRIs), a major limitation is the inability to reliably quantify 5-HT secreted from neurons in vitro. Herein, we address this tech. gap via a novel sensing technol. that couples 5-HT-specific DNA aptamers into nanopores (glass nanopipettes) with orifices of ∼10 nm to detect 5-HT in complex neuronal culture medium with higher selectivity, sensitivity, and stability than existing methods. The 5-HT aptamers undergo conformational rearrangement upon target capture and serve as gatekeepers of ionic flux through the nanopipette opening. We generated human serotonergic neurons in vitro and detected secreted 5-HT using aptamer-coated nanopipettes in a low nanomolar range, with the possibility of detecting significantly lower (picomolar) concns. Furthermore, as a proof of concept, we treated human serotonergic neurons in vitro with the SSRI citalopram and detected a significant increase in extracellular 5-HT using the aptamer-modified nanopipettes. We demonstrate the utility of such methods for 5-HT detection, raising the possibility of fast quantification of neurotransmitters secreted from patient-derived live neuronal cells.
623. 623

     Patriarchi, T.; Cho, J. R.; Merten, K.; Howe, M. W.; Marley, A.; Xiong, W. H.; Folk, R. W.; Broussard, G. J.; Liang, R.; Jang, M. J.; Zhong, H.; Dombeck, D.; von Zastrow, M.; Nimmerjahn, A.; Gradinaru, V.; Williams, J. T.; Tian, L. Ultrafast Neuronal Imaging of Dopamine Dynamics with Designed Genetically Encoded Sensors. Science 2018, 360, eaat4422,  DOI: 10.1126/science.aat4422

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     There is no corresponding record for this reference.
624. 624

     Ackermann, J.; Metternich, J. T.; Herbertz, S.; Kruss, S. Biosensing with Fluorescent Carbon Nanotubes. Angew. Chem., Int. Ed. 2022, 61, e202112372,  DOI: 10.1002/anie.202112372

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     624

     Biosensing with Fluorescent Carbon Nanotubes

     Ackermann, Julia; Metternich, Justus T.; Herbertz, Svenja; Kruss, Sebastian

     Angewandte Chemie, International Edition (2022), 61 (18), e202112372CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Biosensors are powerful tools for modern basic research and biomedical diagnostics. Their development requires substantial input from the chem. sciences. Sensors or probes with an optical readout, such as fluorescence, offer rapid, minimally invasive sensing of analytes with high spatial and temporal resoln. The near-IR (NIR) region is beneficial because of the reduced background and scattering of biol. samples (tissue transparency window) in this range. In this context, single-walled carbon nanotubes (SWCNTs) have emerged as versatile NIR fluorescent building blocks for biosensors. Here, we provide an overview of advances in SWCNT-based NIR fluorescent mol. sensors. We focus on chem. design strategies for diverse analytes and summarize insights into the photophysics and mol. recognition. Furthermore, different application areas are discussed-from chem. imaging of cellular systems and diagnostics to in vivo applications and perspectives for the future.
625. 625

     Kruss, S.; Salem, D. P.; Vuković, L.; Lima, B.; Vander Ende, E.; Boyden, E. S.; Strano, M. S. High-Resolution Imaging of Cellular Dopamine Efflux Using a Fluorescent Nanosensor Array. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 1789– 1794,  DOI: 10.1073/pnas.1613541114

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     625

     High-resolution imaging of cellular dopamine efflux using a fluorescent nanosensor array

     Kruss, Sebastian; Salem, Daniel P.; Vukovic, Lela; Lima, Barbara; Vander Ende, Emma; Boyden, Edward S.; Strano, Michael S.

     Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (8), 1789-1794CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Intercellular communication via chem. signaling proceeds with both spatial and temporal components, but anal. tools, such as microfabricated electrodes, have been limited to just a few probes per cell. In this work, the authors use a nonphotobleaching fluorescent nanosensor array based on single-walled carbon nanotubes (SWCNTs) rendered selective to dopamine to study its release from PC12 neuroprogenitor cells at a resoln. exceeding 20,000 sensors per cell. This allows the spatial and temporal dynamics of dopamine release, following K+ stimulation, to be measured at exceedingly high resoln. The authors observe localized, unlabeled release sites of dopamine spanning 100 ms to seconds that correlate with protrusions but not predominately the pos. curvature assocd. with the tips of cellular protrusions as intuitively expected. The results illustrate how directionality of chem. signaling is shaped by membrane morphol., and highlight the advantages of nanosensor arrays that can provide high spatial and temporal resoln. of chem. signaling.
626. 626

     Beyene, A. G.; Delevich, K.; del Bonis-O’Donnell, J. T.; Piekarski, D. J.; Lin, W. C.; Thomas, A. W.; Yang, S. J.; Kosillo, P.; Yang, D.; Prounis, G. S.; Wilbrecht, L.; Landry, M. P. Imaging Striatal Dopamine Release Using a Nongenetically Encoded Near Infrared Fluorescent Catecholamine Nanosensor. Sci. Adv. 2019, 5, eaaw3108,  DOI: 10.1126/sciadv.aaw3108

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     There is no corresponding record for this reference.
627. 627

     Elizarova, S.; Chouaib, A. A.; Shaib, A.; Hill, B.; Mann, F.; Brose, N.; Kruss, S.; Daniel, J. A. A Fluorescent Nanosensor Paint Detects Dopamine Release at Axonal Varicosities with High Spatiotemporal Resolution. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2202842119,  DOI: 10.1073/pnas.2202842119

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     There is no corresponding record for this reference.
628. 628

     Xia, J.; Yang, H.; Mu, M.; Micovic, N.; Poskanzer, K. E.; Monaghan, J. R.; Clark, H. A. Imaging in Vivo Acetylcholine Release in the Peripheral Nervous System with a Fluorescent Nanosensor. Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2023807118,  DOI: 10.1073/pnas.2023807118

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     There is no corresponding record for this reference.
629. 629

     Dresselhaus, M. S.; Dresselhaus, G.; Charlier, J. C.; Hernández, E. Electronic, Thermal and Mechanical Properties of Carbon Nanotubes. Philos. Trans. A 2004, 362, 2065– 2098,  DOI: 10.1098/rsta.2004.1430

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     629

     Electronic, thermal and mechanical properties of carbon nanotubes

     Dresselhaus, M. S.; Dresselhaus, G.; Charlier, J. C.; Hernandez, E.

     Philosophical Transactions of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences (2004), 362 (1823), 2065-2098CODEN: PTRMAD; ISSN:1364-503X. (Royal Society)

     A review of the electronic, thermal and mech. properties of nanotubes is presented, with particular ref. to properties that differ from those of the bulk counterparts and to potential applications that might result from the special structure and properties of nanotubes. Both exptl. and theor. aspects of these topics are reviewed.
630. 630

     O’Connell, M. J.; Bachilo, S. M.; Huffman, C. B.; Moore, V. C.; Strano, M. S.; Haroz, E. H.; Rialon, K. L.; Boul, P. J.; Noon, W. H.; Kittrell, C.; Ma, J.; Hauge, R. H.; Weisman, R. B.; Smalley, R. E. Band Gap Fluorescence from Individual Single-Walled Carbon Nanotubes. Science 2002, 297, 593– 596,  DOI: 10.1126/science.1072631

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     630

     Band gap fluorescence from individual single-walled carbon nanotubes

     O'Connell, Michael J.; Bachilo, Sergei M.; Huffman, Chad B.; Moore, Valerie C.; Strano, Michael S.; Haroz, Erik H.; Rialon, Kristy L.; Boul, Peter J.; Noon, William H.; Kittrell, Carter; Ma, Jianpeng; Hauge, Robert H.; Weisman, R. Bruce; Smalley, Richard E.

     Science (Washington, DC, United States) (2002), 297 (5581), 593-596CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Fluorescence has been obsd. directly across the band gap of semiconducting carbon nanotubes. We obtained individual nanotubes, each encased in a cylindrical micelle, by ultrasonically agitating an aq. dispersion of raw single-walled carbon nanotubes in sodium dodecyl sulfate and then centrifuging to remove tube bundles, ropes, and residual catalyst. Aggregation of nanotubes into bundles otherwise quenches the fluorescence through interactions with metallic tubes and substantially broadens the absorption spectra. At pH less than 5, the absorption and emission spectra of individual nanotubes show evidence of band gap-selective protonation of the side walls of the tube. This protonation is readily reversed by treatment with base or UV light.
631. 631

     Coleman, J. N. Liquid-Phase Exfoliation of Nanotubes and Graphene. Adv. Funct. Mater. 2009, 19, 3680– 3695,  DOI: 10.1002/adfm.200901640

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     631

     Liquid-phase exfoliation of nanotubes and graphene

     Coleman, Jonathan N.

     Advanced Functional Materials (2009), 19 (23), 3680-3695CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. Many applications of carbon nanotubes require the exfoliation of the nanotubes to give individual tubes in the liq. phase. This requires the dispersion, exfoliation, and stabilization of nanotubes in a variety of liqs. In this paper recent work in this area is reviewed, focusing on results from the author's group. It begins by reviewing stabilization mechanisms before exploring research into the exfoliation of nanotubes in solvents, by surfactants or biomols. and by covalent attachment of mols. The concn. dependence of the degree of exfoliation in each case will be highlighted. In addn. research into the dispersion mechanism for each dispersant type is discussed. Most importantly, dispersion quality metrics for all dispersants are compared. From this anal., it is concluded that functionalized nanotubes can be exfoliated to the greatest degree. Finally, the extension of this work to the liq. phase exfoliation of graphite to give graphene is reviewed.
632. 632

     Bisker, G.; Dong, J.; Park, H. D.; Iverson, N. M.; Ahn, J.; Nelson, J. T.; Landry, M. P.; Kruss, S.; Strano, M. S. Protein-Targeted Corona Phase Molecular Recognition. Nat. Commun. 2016, 7, 10241,  DOI: 10.1038/ncomms10241

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     632

     Protein-targeted corona phase molecular recognition

     Bisker, Gili; Dong, Juyao; Park, Hoyoung D.; Iverson, Nicole M.; Ahn, Jiyoung; Nelson, Justin T.; Landry, Markita P.; Kruss, Sebastian; Strano, Michael S.

     Nature Communications (2016), 7 (), 10241CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Corona phase mol. recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromol. analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single-walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at satn. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clin. relevant fibrinogen concns. in the human blood. These results open new avenues for synthetic, non-biol. antibody analogs that recognize biol. macromols., and hold great promise for medical and clin. applications.
633. 633

     Bisker, G.; Bakh, N. A.; Lee, M. A.; Ahn, J.; Park, M.; O’Connell, E. B.; Iverson, N. M.; Strano, M. S. Insulin Detection Using a Corona Phase Molecular Recognition Site on Single-Walled Carbon Nanotubes. ACS Sens. 2018, 3, 367– 377,  DOI: 10.1021/acssensors.7b00788

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     633

     Insulin Detection Using a Corona Phase Molecular Recognition Site on Single-Walled Carbon Nanotubes

     Bisker, Gili; Bakh, Naveed A.; Lee, Michael A.; Ahn, Jiyoung; Park, Minkyung; O'Connell, Ellen B.; Iverson, Nicole M.; Strano, Michael S.

     ACS Sensors (2018), 3 (2), 367-377CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)

     Corona phase mol. recognition (CoPhMoRe) is a technique whereby an external, adsorbed phase around a colloidal nanoparticle is selected such that its mol. conformation or interaction recognizes a specific target analyte. In this work, we employ a high-throughput screening of a library of poly(ethylene glycol) (PEG)-conjugated lipids adsorbed onto near-IR fluorescent single-walled carbon nanotubes to discover a corona phase selective for insulin. We find that a C16-PEG(2000 Da)-ceramide causes a 62% fluorescent intensity decrease of the (10,2) chirality nanotube in the presence of 20μg/mL insulin. The insulin protein has no prior affinity toward the C16-PEG(2000 Da)-ceramide mols. in free soln., verified by isothermal titrn. calorimetry, and the interaction occurs only upon their adsorption onto the single-walled carbon nanotube scaffolds. Testing a panel of proteins originating from human blood as well as short 7 amino acid fragments of the insulin peptide rules out nonselective recognition mechanisms such as mol. wt., isoelec. point, and hydrophobicity-based detection. Interestingly, longer fragments of isolated α- and β-peptide chains of insulin are detected by the construct, albeit with lower affinity compared to that of the intact insulin protein, suggesting that the construct recognizes insulin in its native form and conformation. Finally, the insulin recognition and the quantification of its soln. concn. were demonstrated both in buffer and in blood serum, showing that the CoPhMoRe construct works in this complex environment despite the presence of potential nonspecific adsorption. Our results further motivate the search for nonbiol. synthetic recognition sites and open up a new path for continuous insulin monitoring in vivo with the hope of improving glycemic control in closed-loop artificial pancreas systems.
634. 634

     Zhang, J.; Landry, M. P.; Barone, P. W.; Kim, J. H.; Lin, S.; Ulissi, Z. W.; Lin, D.; Mu, B.; Boghossian, A. A.; Hilmer, A. J.; Rwei, A.; Hinckley, A. C.; Kruss, S.; Shandell, M. A.; Nair, N.; Blake, S.; Sen, F.; Sen, S.; Croy, R. G.; Li, D.; Yum, K.; Ahn, J. H.; Jin, H.; Heller, D. A.; Essigmann, J. M.; Blankschtein, D.; Strano, M. S. Molecular Recognition Using Corona Phase Complexes Made of Synthetic Polymers Adsorbed on Carbon Nanotubes. Nat. Nanotechnol. 2013, 8, 959– 968,  DOI: 10.1038/nnano.2013.236

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     634

     Molecular recognition using corona phase complexes made of synthetic polymers adsorbed on carbon nanotubes

     Zhang, Jingqing; Landry, Markita P.; Barone, Paul W.; Kim, Jong-Ho; Lin, Shangchao; Ulissi, Zachary W.; Lin, Dahua; Mu, Bin; Boghossian, Ardemis A.; Hilmer, Andrew J.; Rwei, Alina; Hinckley, Allison C.; Kruss, Sebastian; Shandell, Mia A.; Nair, Nitish; Blake, Steven; Sen, Fatih; Sen, Selda; Croy, Robert G.; Li, Deyu; Yum, Kyungsuk; Ahn, Jin-Ho; Jin, Hong; Heller, Daniel A.; Essigmann, John M.; Blankschtein, Daniel; Strano, Michael S.

     Nature Nanotechnology (2013), 8 (12), 959-968CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     Understanding mol. recognition is of fundamental importance in applications such as therapeutics, chem. catalysis and sensor design. The most common recognition motifs involve biol. macromols. such as antibodies and aptamers. The key to biorecognition consists of a unique three-dimensional structure formed by a folded and constrained bioheteropolymer that creates a binding pocket, or an interface, able to recognize a specific mol. Here, we show that synthetic heteropolymers, once constrained onto a single-walled carbon nanotube by chem. adsorption, also form a new corona phase that exhibits highly selective recognition for specific mols. To prove the generality of this phenomenon, we report three examples of heteropolymer-nanotube recognition complexes for riboflavin, L-thyroxine and oestradiol. In each case, the recognition was predicted using a two-dimensional thermodn. model of surface interactions in which the dissocn. consts. can be tuned by perturbing the chem. structure of the heteropolymer. Moreover, these complexes can be used as new types of spatiotemporal sensors based on modulation of the carbon nanotube photoemission in the near-IR, as we show by tracking riboflavin diffusion in murine macrophages.
635. 635

     Kruss, S.; Landry, M. P.; Vander Ende, E.; Lima, B. M.; Reuel, N. F.; Zhang, J.; Nelson, J.; Mu, B.; Hilmer, A.; Strano, M. Neurotransmitter Detection Using Corona Phase Molecular Recognition on Fluorescent Single-Walled Carbon Nanotube Sensors. J. Am. Chem. Soc. 2014, 136, 713– 724,  DOI: 10.1021/ja410433b

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     635

     Neurotransmitter Detection Using Corona Phase Molecular Recognition on Fluorescent Single-Walled Carbon Nanotube Sensors

     Kruss, Sebastian; Landry, Markita P.; Vander Ende, Emma; Lima, Barbara M. A.; Reuel, Nigel F.; Zhang, Jingqing; Nelson, Justin; Mu, Bin; Hilmer, Andrew; Strano, Michael

     Journal of the American Chemical Society (2014), 136 (2), 713-724CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

     Temporal and spatial changes in neurotransmitter concns. are central to information processing in neural networks. Therefore, biosensors for neurotransmitters are essential tools for neuroscience. The authors applied a new technique, corona phase mol. recognition (CoPhMoRe), to identify adsorbed polymer phases on fluorescent single-walled carbon nanotubes (SWCNTs) that allow for the selective detection of specific neurotransmitters, including dopamine. The authors functionalized and suspended SWCNTs with a library of different polymers (n = 30) contg. phospholipids, nucleic acids, and amphiphilic polymers to study how neurotransmitters modulate the resulting band gap, near-IR (nIR) fluorescence of the SWCNT. The authors identified several corona phases that enable the selective detection of neurotransmitters. Catecholamines such as dopamine increased the fluorescence of specific single-stranded DNA- and RNA-wrapped SWCNTs by 58-80% upon addn. of 100 μM dopamine depending on the SWCNT chirality (n,m). In soln., the limit of detection was 11 nM [Kd = 433 nM for (GT)15 DNA-wrapped SWCNTs]. Mechanistic studies revealed that this turn-on response is due to an increase in fluorescence quantum yield and not covalent modification of the SWCNT or scavenging of reactive oxygen species. When immobilized on a surface, the fluorescence intensity of a single DNA- or RNA-wrapped SWCNT is enhanced by a factor of up to 5.39±1.44, whereby fluorescence signals are reversible. The authors' findings indicate that certain DNA/RNA coronae act as conformational switches on SWCNTs, which reversibly modulate the SWCNT fluorescence. These findings suggest that the authors' polymer-SWCNT constructs can act as fluorescent neurotransmitter sensors in the tissue-compatible nIR optical window, which may find applications in neuroscience.
636. 636

     Jeong, S.; Yang, D.; Beyene, A. G.; Del Bonis-O’Donnell, J. T.; Gest, A. M. M.; Navarro, N.; Sun, X.; Landry, M. P. High-Throughput Evolution of Near-Infrared Serotonin Nanosensors. Sci. Adv. 2019, 5, eaay3771,  DOI: 10.1126/sciadv.aay3771

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637. 637

     Liu, C.; Goel, P.; Kaeser, P. S. Spatial and Temporal Scales of Dopamine Transmission. Nat. Rev. Neurosci. 2021, 22, 345– 358,  DOI: 10.1038/s41583-021-00455-7

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     637

     Spatial and temporal scales of dopamine transmission

     Liu, Changliang; Goel, Pragya; Kaeser, Pascal S.

     Nature Reviews Neuroscience (2021), 22 (6), 345-358CODEN: NRNAAN; ISSN:1471-003X. (Nature Portfolio)

     A review. Abstr.: Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signaling. Neuromodulators are vol. transmitters, with release followed by diffusion for widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signaling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signaling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization that is often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signaling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.
638. 638

     Yang, S. J.; Del Bonis-O’Donnell, J. T.; Beyene, A. G.; Landry, M. P. Near-Infrared Catecholamine Nanosensors for High Spatiotemporal Dopamine Imaging. Nat. Protoc. 2021, 16, 3026– 3048,  DOI: 10.1038/s41596-021-00530-4

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     638

     Near-infrared catecholamine nanosensors for high spatiotemporal dopamine imaging

     Yang, Sarah J.; Del Bonis-O'Donnell, Jackson Travis; Beyene, Abraham G.; Landry, Markita P.

     Nature Protocols (2021), 16 (6), 3026-3048CODEN: NPARDW; ISSN:1750-2799. (Nature Portfolio)

     Dopamine neuromodulation of neural synapses is a process implicated in a no. of crit. brain functions and diseases. Development of protocols to visualize this dynamic neurochem. process is essential to understanding how dopamine modulates brain function. We have developed a non-genetically encoded, near-IR (nIR) catecholamine nanosensor (nIRCat) capable of identifying ∼2-μm dopamine release hotspots in dorsal striatal brain slices. nIRCat is readily synthesized through sonication of single walled carbon nanotubes with DNA oligos, can be readily introduced into both genetically tractable and intractable organisms and is compatible with a no. of dopamine receptor agonists and antagonists. Here we describe the synthesis, characterization and implementation of nIRCat in acute mouse brain slices. We demonstrate how nIRCat can be used to image elec. or optogenetically stimulated dopamine release, and how these procedures can be leveraged to study the effects of dopamine receptor pharmacol. In addn., we provide suggestions for building or adapting wide-field microscopy to be compatible with nIRCat nIR fluorescence imaging. We discuss strategies for analyzing nIR video data to identify dopamine release hotspots and quantify their kinetics. This protocol can be adapted and implemented for imaging other neuromodulators by using probes of this class and can be used in a broad range of species without genetic manipulation. The synthesis and characterization protocols for nIRCat take ∼5 h, and the prepn. and fluorescence imaging of live brain slices by using nIRCats require ∼6 h.
639. 639

     Godin, A. G.; Varela, J. A.; Gao, Z.; Danne, N.; Dupuis, J. P.; Lounis, B.; Groc, L.; Cognet, L. Single-Nanotube Tracking Reveals the Nanoscale Organization of the Extracellular Space in the Live Brain. Nat. Nanotechnol. 2017, 12, 238– 243,  DOI: 10.1038/nnano.2016.248

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     639

     Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

     Godin, Antoine G.; Varela, Juan A.; Gao, Zhenghong; Danne, Noemie; Dupuis, Julien P.; Lounis, Brahim; Groc, Laurent; Cognet, Laurent

     Nature Nanotechnology (2017), 12 (3), 238-243CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)

     The brain is a dynamic structure with the extracellular space (ECS) taking up almost a quarter of its vol. Signaling mols., neurotransmitters and nutrients transit via the ECS, which constitutes a key microenvironment for cellular communication and the clearance of toxic metabolites. The spatial organization of the ECS varies during sleep, development and aging and is probably altered in neuropsychiatric and degenerative diseases, as inferred from electron microscopy and macroscopic biophys. studies. Here the authors show an approach to directly observe the local ECS structures and rheol. in brain tissue using super-resoln. imaging. The authors inject single-walled carbon nanotubes into rat cerebroventricles and follow the near-IR emission of individual nanotubes as they diffuse inside the ECS for tens of minutes in acute slices. Because of the interplay between the nanotube geometry and the ECS local environment, the authors can ext. information about the dimensions and local viscosity of the ECS. A striking diversity of ECS dimensions down to 40 nm and of local viscosity values were found. Moreover, by chem. altering the extracellular matrix of the brains of live animals before nanotube injection, the authors reveal that the rheol. properties of the ECS are affected, but these alterations are local and inhomogeneous at the nanoscale.
640. 640

     McCann, C. M.; Lichtman, J. W. In Vivo Imaging of Presynaptic Terminals and Postsynaptic Sites in the Mouse Submandibular Ganglion. Dev. Neurobiol. 2008, 68, 760– 770,  DOI: 10.1002/dneu.20621

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     There is no corresponding record for this reference.
641. 641

     Langer, J.; Jimenez de Aberasturi, D.; Aizpurua, J.; Alvarez-Puebla, R. A.; Auguié, B.; Baumberg, J. J.; Bazan, G. C.; Bell, S. E. J.; Boisen, A.; Brolo, A. G.; Choo, J.; Cialla-May, D.; Deckert, V.; Fabris, L.; Faulds, K.; García de Abajo, F. J.; Goodacre, R.; Graham, D.; Haes, A. J.; Haynes, C. L.; Huck, C.; Itoh, T.; Käll, M.; Kneipp, J.; Kotov, N. A.; Kuang, H.; Le Ru, E. C.; Lee, H. K.; Li, J.-F.; Ling, X. Y.; Maier, S. A.; Mayerhöfer, T.; Moskovits, M.; Murakoshi, K.; Nam, J.-M.; Nie, S.; Ozaki, Y.; Pastoriza-Santos, I.; Perez-Juste, J.; Popp, J.; Pucci, A.; Reich, S.; Ren, B.; Schatz, G. C.; Shegai, T.; Schlücker, S.; Tay, L.-L.; Thomas, K. G.; Tian, Z.-Q.; Van Duyne, R. P.; Vo-Dinh, T.; Wang, Y.; Willets, K. A.; Xu, C.; Xu, H.; Xu, Y.; Yamamoto, Y. S.; Zhao, B.; Liz-Marzán, L. M. Present and Future of Surface-Enhanced Raman Scattering. ACS Nano 2020, 14, 28– 117,  DOI: 10.1021/acsnano.9b04224

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     641

     Present and Future of Surface-Enhanced Raman Scattering

     Langer, Judith; Jimenez de Aberasturi, Dorleta; Aizpurua, Javier; Alvarez-Puebla, Ramon A.; Auguie, Baptiste; Baumberg, Jeremy J.; Bazan, Guillermo C.; Bell, Steven E. J.; Boisen, Anja; Brolo, Alexandre G.; Choo, Jaebum; Cialla-May, Dana; Deckert, Volker; Fabris, Laura; Faulds, Karen; Garcia de Abajo, F. Javier; Goodacre, Royston; Graham, Duncan; Haes, Amanda J.; Haynes, Christy L.; Huck, Christian; Itoh, Tamitake; Kall, Mikael; Kneipp, Janina; Kotov, Nicholas A.; Kuang, Hua; Le Ru, Eric C.; Lee, Hiang Kwee; Li, Jian-Feng; Ling, Xing Yi; Maier, Stefan A.; Mayerhofer, Thomas; Moskovits, Martin; Murakoshi, Kei; Nam, Jwa-Min; Nie, Shuming; Ozaki, Yukihiro; Pastoriza-Santos, Isabel; Perez-Juste, Jorge; Popp, Juergen; Pucci, Annemarie; Reich, Stephanie; Ren, Bin; Schatz, George C.; Shegai, Timur; Schlucker, Sebastian; Tay, Li-Lin; Thomas, K. George; Tian, Zhong-Qun; Van Duyne, Richard P.; Vo-Dinh, Tuan; Wang, Yue; Willets, Katherine A.; Xu, Chuanlai; Xu, Hongxing; Xu, Yikai; Yamamoto, Yuko S.; Zhao, Bing; Liz-Marzan, Luis M.

     ACS Nano (2020), 14 (1), 28-117CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     A review. The discovery of the enhancement of Raman scattering by mols. adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and anal. techniques. Significant exptl. and theor. effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technol., but addnl. efforts are still needed before it can be routinely used anal. and in com. products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technol. development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the prepn. of this article.
642. 642

     Lee, W.; Kang, B. H.; Yang, H.; Park, M.; Kwak, J. H.; Chung, T.; Jeong, Y.; Kim, B. K.; Jeong, K. H. Spread Spectrum SERS Allows Label-Free Detection of Attomolar Neurotransmitters. Nat. Commun. 2021, 12, 159,  DOI: 10.1038/s41467-020-20413-8

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     642

     Spread spectrum SERS allows label-free detection of attomolar neurotransmitters

     Lee, Wonkyoung; Kang, Byoung-Hoon; Yang, Hyunwoo; Park, Moonseong; Kwak, Ji Hyun; Chung, Taerin; Jeong, Yong; Kim, Bong Kyu; Jeong, Ki-Hun

     Nature Communications (2021), 12 (1), 159CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)

     Abstr.: The quant. label-free detection of neurotransmitters provides crit. clues in understanding neurol. functions or disorders. However, the identification of neurotransmitters remains challenging for surface-enhanced Raman spectroscopy (SERS) due to the presence of noise. Here, we report spread spectrum SERS (ss-SERS) detection for the rapid quantification of neurotransmitters at the attomolar level by encoding excited light and decoding SERS signals with peak autocorrelation and near-zero cross-correlation. Compared to conventional SERS measurements, the exptl. result of ss-SERS shows an exceptional improvement in the signal-to-noise ratio of more than three orders of magnitude, thus achieving a high temporal resoln. of over one hundred times. The ss-SERS measurement further allows the attomolar SERS detection of dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and glutamate without Raman reporters. This approach opens up opportunities not only for investigating the early diagnostics of neurol. disorders or highly sensitive biomedical SERS applications but also for developing low-cost spectroscopic biosensing applications.
643. 643

     Farah, A. A.; Bravo-Vasquez, J. P.; Alvarez-Puebla, R. A.; Cho, J. Y.; Fenniri, H. Robust Au-PEG/PS Microbeads as Optically Stable Platforms for SERS. Small 2009, 5, 1283– 1286,  DOI: 10.1002/smll.200801398

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     There is no corresponding record for this reference.
644. 644

     López-Puente, V.; Abalde-Cela, S.; Angelomé, P. C.; Alvarez-Puebla, R. A.; Liz-Marzán, L. M. Plasmonic Mesoporous Composites as Molecular Sieves for SERS Detection. J. Phys. Chem. Lett. 2013, 4, 2715– 2720,  DOI: 10.1021/jz4014085

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     644

     Plasmonic Mesoporous Composites as Molecular Sieves for SERS Detection

     Lopez-Puente, Vanesa; Abalde-Cela, Sara; Angelome, Paula C.; Alvarez-Puebla, Ramon A.; Liz-Marzan, Luis M.

     Journal of Physical Chemistry Letters (2013), 4 (16), 2715-2720CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)

     Application of surface-enhanced Raman scattering (SERS) spectroscopy to the ultrasensitive anal. of small mols. in biol. samples is complicated by signal contamination by ubiquitous macromols. such as proteins, nucleic acids, or lipids. The authors present a proof-of-concept study of the application of composite films comprising branched gold nanoparticles embedded in mesoporous thin films, which act as mol. sieves. The inorg. mesoporous layer only allows the diffusion of small mols. toward the plasmonic particles while preventing the contact of macromols. in soln. with the optical sensor.
645. 645

     Silwal, A. P.; Yadav, R.; Sprague, J. E.; Lu, H. P. Raman Spectroscopic Signature Markers of Dopamine-Human Dopamine Transporter Interaction in Living Cells. ACS Chem. Neurosci. 2017, 8, 1510– 1518,  DOI: 10.1021/acschemneuro.7b00048

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     645

     Raman Spectroscopic Signature Markers of Dopamine-Human Dopamine Transporter Interaction in Living Cells

     Silwal, Achut P.; Yadav, Rajeev; Sprague, Jon E.; Lu, H. Peter

     ACS Chemical Neuroscience (2017), 8 (7), 1510-1518CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

     Dopamine (DA) controls many psychol. and behavioral activities in the central nervous system (CNS) through interactions with the human dopamine transporter (hDAT) and dopamine receptors. The roles of DA in the function of the CNS are affected by the targeted binding of drugs to hDAT; thus, hDAT plays a crit. role in neurophysiol. and neuropathophysiol. An effective exptl. method is necessary to study the DA-hDAT interaction and effects of variety of drugs like psychostimulants and anti-depressants that are dependent on this interaction. In searching for obtaining and identifying the Raman spectral signatures, the authors have used surface enhanced Raman scattering (SERS) spectroscopy to record SERS spectrum from DA, Human Embryonic Kidney 293 cells (HEK293), hDAT-HEK293, DA-HEK293, and DA-hDAT-HEK293. The authors have demonstrated a specific 2D-distribution SERS spectral anal. approach to analyze DA-hDAT interaction. The authors' study shows that the Raman modes at 807, 839, 1076, 1090, 1538, and 1665 cm-1 are related to DA-hDAT interaction, where Raman shift at 807 and 1076 cm-1 are the signature marker for bound state of DA to probe DA-hDAT interaction. On the basis of d. function theory (DFT) calcn., Raman shift of bound state of DA at 807 cm-1 is related to combination of bending modes α(C3-O10-H21), α(C2-O11-H22), α(C7-C8-H18), α(C6-C4-H13), α(C7-C8-H19), α(C7-C8-N9), and Raman shift at 1076 cm-1 is related to combination of bending modes α(H19-N9-C8), γ(N9-H19), γ(C8-H19), γ(N9-H20), γ(C8-H18), and α(C7-C8-H18). These findings demonstrate that protein-ligand interactions can be confirmed by probing change in Raman shift of ligand mols., which could be crucial to understanding mol. interactions between neurotransmitters and their receptors or transporters.
646. 646

     Choi, J. H.; Kim, T. H.; El-Said, W. A.; Lee, J. H.; Yang, L.; Conley, B.; Choi, J. W.; Lee, K. B. In Situ Detection of Neurotransmitters from Stem Cell-Derived Neural Interface at the Single-Cell Level via Graphene-Hybrid SERS Nanobiosensing. Nano Lett. 2020, 20, 7670– 7679,  DOI: 10.1021/acs.nanolett.0c03205

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     646

     In Situ Detection of Neurotransmitters from Stem Cell-Derived Neural Interface at the Single-Cell Level via Graphene-Hybrid SERS Nanobiosensing

     Choi, Jin-Ha; Kim, Tae-Hyung; El-said, Waleed Ahmed; Lee, Jin-Ho; Yang, Letao; Conley, Brian; Choi, Jeong-Woo; Lee, Ki-Bum

     Nano Letters (2020), 20 (10), 7670-7679CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     In situ quant. measurements of neurotransmitter activities can provide useful insights into the underlying mechanisms of stem cell differentiation, the formation of neuronal networks, and neurodegenerative diseases. Currently, neurotransmitter detection methods suffer from poor spatial resoln., nonspecific detection, and a lack of in situ anal. To address this challenge, herein, the authors first developed a graphene oxide (GO)-hybrid nanosurface-enhanced Raman scattering (SERS) array to detect dopamine (DA) in a selective and sensitive manner. Using the GO-hybrid nano-SERS array, the authors successfully measured a wide range of DA concns. (10-4 to 10-9 M) rapidly and reliably. Moreover, the measurement of DA from differentiating neural stem cells applies to the characterization of neuronal differentiation. Given the challenges of in situ detection of neurotransmitters at the single-cell level, the authors' developed SERS-based detection method can represent a unique tool for studying single-cell signaling pathways assocd. with DA, or other neurotransmitters, and their roles in neurol. processes.
647. 647

     Wang, W.; Zhao, F.; Li, M.; Zhang, C.; Shao, Y.; Tian, Y. A SERS Optophysiological Probe for the Real-Time Mapping and Simultaneous Determination of the Carbonate Concentration and pH Value in a Live Mouse Brain. Angew. Chem., Int. Ed. 2019, 58, 5256– 5260,  DOI: 10.1002/anie.201814286

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     647

     A SERS Optophysiological Probe for the Real-Time Mapping and Simultaneous Determination of the Carbonate Concentration and pH Value in a Live Mouse Brain

     Wang, Weikang; Zhao, Fan; Li, Mingzhi; Zhang, Chuanping; Shao, Yuanhua; Tian, Yang

     Angewandte Chemie, International Edition (2019), 58 (16), 5256-5260CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

     To have a profound understanding of the physiol. and pathol. processes in a brain, both chem. and elec. signals need to be recorded, but this is still very challenging. Herein, micrometer- to nanometer-sized SERS optophysiol. probes were created to det. both the CO32- concn. and the pH in live brains and neurons because both species play important roles in regulating the acid-base balance in the brain. A ratiometric SERS microarray of eight microprobes with tip sizes of 5 μm was established and used for the first time for real-time mapping and simultaneous quantification of CO32- and pH in a live brain. Both the CO32- concn. and the pH value dramatically decreased under ischemic conditions. The present SERS technique can be combined with electrophysiol. without cross-talk to record both elec. and chem. signals in brains. To deepen the authors' understanding of the mechanism of ischemia on the single-cell level, a SERS nanoprobe with a tip size of 200 nm was developed for use in a single neuron.
648. 648

     Reichel, D.; Sagong, B.; Teh, J.; Zhang, Y.; Wagner, S.; Wang, H.; Chung, L. W.; Butte, P.; Black, K. L.; Yu, J. S. Near Infrared Fluorescent Nanoplatform for Targeted Intraoperative Resection and Chemotherapeutic Treatment of Glioblastoma. ACS Nano 2020, 14, 8392– 8408,  DOI: 10.1021/acsnano.0c02509

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     648

     Near Infrared Fluorescent Nanoplatform for Targeted Intraoperative Resection and Chemotherapeutic Treatment of Glioblastoma

     Reichel, Derek; Sagong, Bien; Teh, James; Zhang, Yi; Wagner, Shawn; Wang, Hongqiang; Chung, Leland W. K.; Butte, Pramod; Black, Keith L.; Yu, John; Perez, J. Manuel

     ACS Nano (2020), 14 (7), 8392-8408CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Despite significant efforts to improve glioblastoma multiforme (GBM) treatment, GBM remains one of the most lethal cancers. Effective GBM treatments require sensitive intraoperative tumor visualization and effective postoperative chemotherapeutic delivery. Unfortunately, the diffusive and infiltrating nature of GBM limits the detection of GBM tumors, and current intraoperative visualization methods limit complete tumor resection. In addn., although chemotherapy is often used to eliminate any cancerous tissue remaining after surgery, most chemotherapeutic drugs do not effectively cross the brain-blood barrier (BBB) or enter GBM tumors. As a result, GBM has limited treatment options with high recurrence rates, and methods that improve its complete visualization during surgery and treatment are needed. Herein, we report a fluorescent nanoparticle platform for the near-IR fluorescence (NIRF)-based tumor boundary visualization and image-guided drug delivery into GBM tumors. Our nanoplatform is based on ferumoxytol (FMX), an FDA-approved magnetic resonance imaging-sensitive superparamagnetic iron oxide nanoparticle, which is conjugated with heptamethine cyanine (HMC), a NIRF ligand that specifically targets the org. anion transporter polypeptides that are overexpressed in GBM. We have shown that HMC-FMX nanoparticles cross the BBB and selectively accumulate in the tumor using orthotopic GBM mouse models, enabling NIRF-based visualization of infiltrating tumor tissue. In addn., HMC-FMX can encapsulate chemotherapeutic drugs, such as paclitaxel or cisplatin, and deliver these agents into GBM tumors, reducing tumor size and increasing survival. Taken together, these observations indicate that HMC-FMX is a promising nanoprobe for GBM surgical visualization and drug delivery.
649. 649

     Guo, X.; Deng, G.; Liu, J.; Zou, P.; Du, F.; Liu, F.; Chen, A. T.; Hu, R.; Li, M.; Zhang, S. Thrombin-Responsive, Brain-Targeting Nanoparticles for Improved Stroke Therapy. ACS Nano 2018, 12, 8723– 8732,  DOI: 10.1021/acsnano.8b04787

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     649

     Thrombin-Responsive, Brain-Targeting Nanoparticles for Improved Stroke Therapy

     Guo, Xing; Deng, Gang; Liu, Jun; Zou, Pan; Du, Fengyi; Liu, Fuyao; Chen, Ann T.; Hu, Rui; Li, Miao; Zhang, Shenqi; Tang, Zhishu; Han, Liang; Liu, Jie; Sheth, Kevin N.; Chen, Qianxue; Gou, Xingchun; Zhou, Jiangbing

     ACS Nano (2018), 12 (8), 8723-8732CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Current treatments for ischemic stroke are insufficient. The lack of effective pharmacol. approaches can be mainly attributed to the difficulty in overcoming the blood-brain barrier. Here, we report a simple strategy to synthesize protease-responsive, brain-targeting nanoparticles for the improved treatment of stroke. The resulting nanoparticles respond to proteases enriched in the ischemic microenvironment, including thrombin or matrix metalloproteinase-9, by shrinking or expanding their size. Targeted delivery was achieved using surface conjugation of ligands that bind to proteins that were identified to enrich in the ischemic brain using protein arrays. By screening a variety of formulations, we found that AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) exhibited the greatest delivery efficiency. The brain targeting effect is mainly mediated by AMD3100, which interacts with CXCR4 that is enriched in the ischemic brain tissue. We showed that ASNPs significantly enhanced the efficacy of glyburide, a promising stroke therapeutic drug whose efficacy is limited by its toxicity. Due to their high efficiency in penetrating the ischemic brain and low toxicity, we anticipate that ASNPs have the potential to be translated into clin. applications for the improved treatment of stroke patients.
650. 650

     Lunov, O.; Syrovets, T.; Loos, C.; Beil, J.; Delacher, M.; Tron, K.; Nienhaus, G. U.; Musyanovych, A.; Mailander, V.; Landfester, K. Differential Uptake of Functionalized Polystyrene Nanoparticles by Human Macrophages and a Monocytic Cell Line. ACS Nano 2011, 5, 1657– 1669,  DOI: 10.1021/nn2000756

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     650

     Differential Uptake of Functionalized Polystyrene Nanoparticles by Human Macrophages and a Monocytic Cell Line

     Lunov, Oleg; Syrovets, Tatiana; Loos, Cornelia; Beil, Johanna; Delacher, Michael; Tron, Kyrylo; Nienhaus, G. Ulrich; Musyanovych, Anna; Mailander, Volker; Landfester, Katharina; Simmet, Thomas

     ACS Nano (2011), 5 (3), 1657-1669CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Tumor cell lines are often used as models for the study of nanoparticle-cell interactions. Here we demonstrate that carboxy (PS-COOH) and amino functionalized (PS-NH2) polystyrene nanoparticles of ∼ 100 nm in diam. are internalized by human macrophages, by undifferentiated and by PMA-differentiated monocytic THP-1 cells via diverse mechanisms. The uptake mechanisms also differed for all cell types and particles when analyzed either in buffer or in medium contg. human serum. Macrophages internalized ∼4 times more PS-COOH than THP-1 cells, when analyzed in serum-contg. medium. By contrast, in either medium, THP-1 cells internalized PS-NH2 more rapidly than macrophages. Using pharmacol. and antisense in vitro knockdown approaches, we showed that, in the presence of serum, the specific interaction between the CD64 receptor and the particles dets. the macrophage uptake of particles by phagocytosis, whereas particle internalization in THP-1 cells occurred via dynamin II-dependent endocytosis. PMA-differentiated THP-1 cells differed in their uptake mechanism from macrophages and undifferentiated THP-1 cells by internalizing the particles via macropinocytosis. In line with our in vitro data, more i.v. applied PS-COOH particles accumulated in the liver, where macrophages of the reticuloendothelial system reside. By contrast, PS-NH2 particles were preferentially targeted to tumor xenografts grown on the chorioallantoic membrane of fertilized chicken eggs. These data show that the amt. of internalized nanoparticles, the uptake kinetics, and its mechanism may differ considerably between primary cells and a related tumor cell line, whether differentiated or not, and that particle uptake by these cells is critically dependent on particle opsonization by serum proteins.
651. 651

     Schottler, S.; Becker, G.; Winzen, S.; Steinbach, T.; Mohr, K.; Landfester, K.; Mailander, V.; Wurm, F. R. Protein Adsorption Is Required for Stealth Effect of Poly(ethylene glycol)- and Poly(phosphoester)-Coated Nanocarriers. Nat. Nanotechnol. 2016, 11, 372– 377,  DOI: 10.1038/nnano.2015.330

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     651

     Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers

     Schottler Susanne; Becker Greta; Winzen Svenja; Steinbach Tobias; Mohr Kristin; Landfester Katharina; Mailander Volker; Wurm Frederik R; Schottler Susanne; Mailander Volker

     Nature nanotechnology (2016), 11 (4), 372-7 ISSN:.

     The current gold standard to reduce non-specific cellular uptake of drug delivery vehicles is by covalent attachment of poly(ethylene glycol) (PEG). It is thought that PEG can reduce protein adsorption and thereby confer a stealth effect. Here, we show that polystyrene nanocarriers that have been modified with PEG or poly(ethyl ethylene phosphate) (PEEP) and exposed to plasma proteins exhibit a low cellular uptake, whereas those not exposed to plasma proteins show high non-specific uptake. Mass spectrometric analysis revealed that exposed nanocarriers formed a protein corona that contains an abundance of clusterin proteins (also known as apolipoprotein J). When the polymer-modified nanocarriers were incubated with clusterin, non-specific cellular uptake could be reduced. Our results show that in addition to reducing protein adsorption, PEG, and now PEEPs, can affect the composition of the protein corona that forms around nanocarriers, and the presence of distinct proteins is necessary to prevent non-specific cellular uptake.
652. 652

     Suk, J. S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L. M. PEGylation as a Strategy for Improving Nanoparticle-Based Drug and Gene Delivery. Adv. Drug Delivery Rev. 2016, 99, 28– 51,  DOI: 10.1016/j.addr.2015.09.012

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     652

     PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

     Suk, Jung Soo; Xu, Qingguo; Kim, Namho; Hanes, Justin; Ensign, Laura M.

     Advanced Drug Delivery Reviews (2016), 99 (Part_A), 28-51CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)

     Coating the surface of nanoparticles with polyethylene glycol (PEG), or "PEGylation", is a commonly used approach for improving the efficiency of drug and gene delivery to target cells and tissues. Building from the success of PEGylating proteins to improve systemic circulation time and decrease immunogenicity, the impact of PEG coatings on the fate of systemically administered nanoparticle formulations has, and continues to be, widely studied. PEG coatings on nanoparticles shield the surface from aggregation, opsonization, and phagocytosis, prolonging systemic circulation time. Here, we briefly describe the history of the development of PEGylated nanoparticle formulations for systemic administration, including how factors such as PEG mol. wt., PEG surface d., nanoparticle core properties, and repeated administration impact circulation time. A less frequently discussed topic, we then describe how PEG coatings on nanoparticles have also been utilized for overcoming various biol. barriers to efficient drug and gene delivery assocd. with other modes of administration, ranging from gastrointestinal to ocular. Finally, we describe both methods for PEGylating nanoparticles and methods for characterizing PEG surface d., a key factor in the effectiveness of the PEG surface coating for improving drug and gene delivery.
653. 653

     Partikel, K.; Korte, R.; Stein, N. C.; Mulac, D.; Herrmann, F. C.; Humpf, H.-U.; Langer, K. Effect of Nanoparticle Size and PEGylation on the Protein Corona of PLGA Nanoparticles. Eur. J. Pharm. Biopharm. 2019, 141, 70– 80,  DOI: 10.1016/j.ejpb.2019.05.006

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     653

     Effect of nanoparticle size and PEGylation on the protein corona of PLGA nanoparticles

     Partikel, Katrin; Korte, Robin; Stein, Nora C.; Mulac, Dennis; Herrmann, Fabian C.; Humpf, Hans-Ulrich; Langer, Klaus

     European Journal of Pharmaceutics and Biopharmaceutics (2019), 141 (), 70-80CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)

     Upon i.v. administration of nanoparticles (NP) into the bloodstream, proteins bind rapidly on their surface resulting in a formation of a so-called Protein Corona. These proteins are strongly attached to the NP surface and provide a new biol. identity which is crucial for the reaction at the nano-biointerface. The structure and compn. of the protein corona is greatly detd. by the physico-chem. properties of the NP and the characteristics of the biol. environment. The overall objective of this study was to characterize the role of NP size/surface curvature and PEGylation on the formation of the protein corona. Therefore, we prepd. NP in a size of 100 and 200 nm using the biodegradable polymers poly(DL-lactide-co-glycolide) (PLGA) and poly(DL-lactide-co-glycolide)-co-polyethylene glycol diblock (PLGA-PEG) and subsequently incubated them with fetal bovine serum (FBS) to induce the formation of a protein corona. After removal of unbound protein, we employed different anal. approaches to study the corona in detail. Sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) was performed to gain a first impression about amt. and compn. of the corona proteins. Identification was carried out after tryptic in-soln. digestion and liq. chromatog.-mass spectrometry/mass spectrometry (LC-MS/MS). In addn., we successfully established the Bradford protein assay as a suitable colorimetric method to quantify total adsorbed protein amt. after alk. hydrolysis of PLGA based NP. Our results revealed that protein adsorption on PLGA- and PLGA-PEG-NP didnt depend on NP size within the range of 100 and 200 nm. PEGylation led to a significant reduced amt. of bound proteins. The depletion of proteins which are involved in immune response was remarkable and indicated a prolonged circulation time in body.
654. 654

     Lipka, M.; Semmler-Behnke, M.; Sperling, R. A.; Wenk, A.; Takenaka, S.; Schleh, C.; Kissel, T.; Parak, W. J.; Kreyling, W. G. Biodistribution of PEG-Modified Gold Nanoparticles Following Intratracheal Instillation and Intravenous Injection. Biomaterials 2010, 31, 6574– 6581,  DOI: 10.1016/j.biomaterials.2010.05.009

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     654

     Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection

     Lipka, Jens; Semmler-Behnke, Manuela; Sperling, Ralph A.; Wenk, Alexander; Takenaka, Shinji; Schleh, Carsten; Kissel, Thomas; Parak, Wolfgang J.; Kreyling, Wolfgang G.

     Biomaterials (2010), 31 (25), 6574-6581CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Besides toxicity tests, biokinetic studies are a fundamental part of investigations to evaluate a safe and sustainable use of nanoparticles. Today, gold nanoparticles (Au NPs) are known to be a versatile tool in different areas such as science, engineering or medicine. In this study, we investigated the biokinetics after i.v. and intratracheal applications of poly(ethylene glycol) (PEG) modified Au NPs compared to plain Au NPs. Radioactive-labeled Au NPs of 5 nm inorg. core diam. were applied to rats and the NP content in tissues, organs and excretion were quantified after 1-h and 24-h. After i.v. injection, a prolonged blood circulation time was detd. for Au NPs with 10 kDa PEG chains. Non-PEGylated Au NPs and 750 Da PEG Au NPs accumulated mostly in liver and spleen. After intratracheal application the majority of all three types of applied NPs stayed in the lungs: the total translocation towards the circulation did not differ considerably after PEGylation of the Au NPs. However, a prolonged retention time in the circulation was detected for the small fraction of translocated 10 kDa PEG Au NPs, too.
655. 655

     Sun, C.; Ding, Y.; Zhou, L.; Shi, D.; Sun, L.; Webster, T. J.; Shen, Y. Noninvasive Nanoparticle Strategies for Brain Tumor Targeting. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 2605– 2621,  DOI: 10.1016/j.nano.2017.07.009

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     There is no corresponding record for this reference.
656. 656

     Bony, B. A.; Tarudji, A. W.; Miller, H. A.; Gowrikumar, S.; Roy, S.; Curtis, E. T.; Gee, C. C.; Vecchio, A.; Dhawan, P.; Kievit, F. M. Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier. ACS Nano 2021, 15, 18520– 18531,  DOI: 10.1021/acsnano.1c08432

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     656

     Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier

     Bony, Badrul Alam; Tarudji, Aria W.; Miller, Hunter A.; Gowrikumar, Saiprasad; Roy, Sourav; Curtis, Evan T.; Gee, Connor C.; Vecchio, Alex; Dhawan, Punita; Kievit, Forrest M.

     ACS Nano (2021), 15 (11), 18520-18531CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Aging-induced alterations to the blood-brain barrier (BBB) are increasingly being seen as a primary event in chronic progressive neurol. disorders that lead to cognitive decline. With the goal of increasing delivery into the brain in hopes of effectively treating these diseases, a large focus has been placed on developing BBB permeable materials. However, these strategies have suffered from a lack of specificity toward regions of disease progression. Here, we report on the development of a nanoparticle (C1C2-NP) that targets regions of increased claudin-1 expression that reduces BBB integrity. Using dynamic contrast enhanced magnetic resonance imaging, we find that C1C2-NP accumulation and retention is significantly increased in brains from 12 mo-old mice as compared to nontargeted NPs and brains from 2 mo-old mice. Furthermore, we find C1C2-NP accumulation in brain endothelial cells with high claudin-1 expression, suggesting target-specific binding of the NPs, which was validated through fluorescence imaging, in vitro testing, and biophys. analyses. Our results further suggest a role of claudin-1 in reducing BBB integrity during aging and show altered expression of claudin-1 can be actively targeted with NPs. These findings could help develop strategies for longitudinal monitoring of tight junction protein expression changes during aging as well as be used as a delivery strategy for site-specific delivery of therapeutics at these early stages of disease development.
657. 657

     Lingineni, K.; Belekar, V.; Tangadpalliwar, S. R.; Garg, P. The Role of Multidrug Resistance Protein (MRP-1) as an Active Efflux Transporter on Blood-Brain Barrier (BBB) Permeability. Mol. Diversity 2017, 21, 355– 365,  DOI: 10.1007/s11030-016-9715-6

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658. 658

     Pardridge, W. M. Kinetics of Blood-Brain Barrier Transport of Monoclonal Antibodies Targeting the Insulin Receptor and the Transferrin Receptor. Pharmaceuticals 2022, 15, 3,  DOI: 10.3390/ph15010003

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659. 659

     Sandbhor, P.; Goda, J.; Mohanty, B.; Chaudhari, P.; Dutt, S.; Banerjee, R. Non-Invasive Transferrin Targeted Nanovesicles Sensitize Resistant Glioblastoma Multiforme Tumors and Improve Survival in Orthotopic Mouse Models. Nanoscale 2021, 14, 108– 126,  DOI: 10.1039/D1NR05460K

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660. 660

     Wei, Y.; Sun, Y.; Wei, J.; Qiu, X.; Meng, F.; Storm, G.; Zhong, Z. Selective Transferrin Coating as a Facile Strategy to Fabricate BBB-Permeable and Targeted Vesicles for Potent RNAi Therapy of Brain Metastatic Breast Cancer in Vivo. J. Controlled Release 2021, 337, 521– 529,  DOI: 10.1016/j.jconrel.2021.07.048

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     660

     Selective transferrin coating as a facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo

     Wei, Yaohua; Sun, Yinping; Wei, Jingjing; Qiu, Xinyun; Meng, Fenghua; Storm, Gert; Zhong, Zhiyuan

     Journal of Controlled Release (2021), 337 (), 521-529CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

     Brain metastases are a most disturbing situation for breast cancer patients as there is basically no adequate treatment available. Any potential drug formulation has to be able to cross the blood-brain barrier (BBB) and specific to metastatic brain tumors without causing unacceptable adverse effects. Here, we developed transferrin-functionalized chimeric polymersomes carrying siRNA against polo-like kinase 1 (Tf@TBP-CPs-siPLK1) for treating brain metastatic MDA-MB 231 triple neg. breast cancer (TNBC) xenografts in mice. To facilitate the loading of siPLK1, chimaeric polymersomes (CPs) were designed with spermine in the watery core and transferrin-binding peptide (TBP) at the surface, enabling attachment of transferrin after the siRNA loading step and thereby circumventing interference of transferrin with siRNA loading. Tf@TBP-CPs-siPLK1 encapsulating 3.8 wt% siRNA had a mean size of about 50 nm and a neutral zeta potential in phosphate buffer (PB). By virtue of the presence of transferrin, Tf@TBP-CPs demonstrated greatly (ca. 5-fold) enhanced internalization in MDA-MB 231 cells and transcytosis in the endothelial (bEnd.3) monolayer model in vitro as well as markedly improved accumulation in the orthotopically xenografted MDA-MB 231 tumor in the brain in vivo compared with control CPs lacking transferrin, supporting that transferrin mediates efficient BBB penetration and high specificity towards MDA-MB 231 cells. As a result, Tf@TBP-CPs-siPLK1 effectively inhibited tumor progression and prolonged the lifespan of the mice significantly. Selective transferrin coating appears to be a particularly facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer.
661. 661

     Al-Ahmady, Z. S.; Dickie, B. R.; Aldred, I.; Jasim, D. A.; Barrington, J.; Haley, M. J.; Lemarchand, E.; Coutts, G.; Kaur, S.; Bates, J.; Curran, S.; Goddard, R.; Walker, M.; Parry-jones, A.; Kostarelos, K.; Allan, S. M. Selective Brain Entry of Lipid Nanoparticles in Haemorrhagic Stroke Is Linked to Biphasic Blood-Brain Barrier Disruption. Theranostics 2022, 12, 4477– 4497,  DOI: 10.7150/thno.72167

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662. 662

     Sokolova, V.; Nzou, G.; van der Meer, S. B.; Ruks, T.; Heggen, M.; Loza, K.; Hagemann, N.; Murke, F.; Giebel, B.; Hermann, D. M.; Atala, A. J.; Epple, M. Ultrasmall Gold Nanoparticles (2 nm) Can Penetrate and Enter Cell Nuclei in an in Vitro 3D Brain Spheroid Model. Acta Biomater. 2020, 111, 349– 362,  DOI: 10.1016/j.actbio.2020.04.023

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     662

     Ultrasmall gold nanoparticles (2 nm) can penetrate and enter cell nuclei in an in vitro 3D brain spheroid model

     Sokolova, Viktoriya; Nzou, Goodwell; van der Meer, Selina B.; Ruks, Tatjana; Heggen, Marc; Loza, Kateryna; Hagemann, Nina; Murke, Florian; Giebel, Bernd; Hermann, Dirk M.; Atala, Anthony J.; Epple, Matthias

     Acta Biomaterialia (2020), 111 (), 349-362CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)

     The neurovascular unit (NVU) is a complex functional and anatomical structure composed of endothelial cells and their blood-brain barrier (BBB) forming tight junctions. It represents an efficient barrier for mols. and drugs. However, it also prevents a targeted transport for the treatment of cerebral diseases. The uptake of ultrasmall nanoparticles as potential drug delivery agents was studied in a three-dimensional co-culture cell model (3D spheroid) composed of primary human cells (astrocytes, pericytes, endothelial cells). Multicellular 3D spheroids show reproducible NVU features and functions. The spheroid core is composed mainly of astrocytes, covered with pericytes, while brain endothelial cells form the surface layer, establishing the NVU that regulates the transport of mols. After 120 h cultivation, the cells self-assemble into a 350μm spheroid as shown by confocal laser scanning microscopy. The passage of different types of fluorescent ultrasmall gold nanoparticles (core diam. 2 nm) both into the spheroid and into three constituting cell types was studied by confocal laser scanning microscopy. Three kinds of covalently fluorophore-conjugated gold nanoparticles were used: One with fluorescein (FAM), one with Cy3, and one with the peptide CGGpTPAAK-5,6-FAM-NH2. In 2D cell co-culture expts., it was found that all three kinds of nanoparticles readily entered all three cell types. FAM- and Cy3-labeled nanoparticles were able to enter the cell nucleus as well. The three dissolved dyes alone were not taken up by any cell type. A similar situation evolved with 3D spheroids: The three kinds of nanoparticles entered the spheroid, but the dissolved dyes did not. The presence of a functional blood-brain barrier was demonstrated by adding histamine to the spheroids. In that case, the blood-brain barrier opened, and dissolved dyes like a FITC-labeled antibody and FITC alone entered the spheroid. In summary, our results qualify ultrasmall gold nanoparticles as suitable carriers for imaging or drug delivery into brain cells (sometimes including the nucleus), brain cell spheroids, and probably also into the brain.3D brain spheroid model and its permeability by ultrasmall gold nanoparticles. We demonstrate that ultrasmall gold nanoparticles can easily penetrate the constituting cells and sometimes even enter the cell nucleus. They can also enter the interior of the blood-brain barrier model. In contrast, small mols. like fluorescing dyes are not able to do that. Thus, ultrasmall gold nanoparticles can serve as carriers of drugs or for imaging inside the brain.
663. 663

     Sokolova, V.; Mekky, G.; van der Meer, S. B.; Seeds, M. C.; Atala, A. J.; Epple, M. Transport of Ultrasmall Gold Nanoparticles (2 nm) across the Blood-Brain Barrier in a Six-Cell Brain Spheroid Model. Sci. Rep. 2020, 10, 18033,  DOI: 10.1038/s41598-020-75125-2

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     663

     Transport of ultrasmall gold nanoparticles (2 nm) across the blood-brain barrier in a six-cell brain spheroid model

     Sokolova, Viktoriya; Mekky, Gehad; van der Meer, Selina Beatrice; Seeds, Michael C.; Atala, Anthony J.; Epple, Matthias

     Scientific Reports (2020), 10 (1), 18033CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)

     The blood-brain barrier (BBB) is an efficient barrier for mols. and drugs. Multicellular 3D spheroids display reproducible BBB features and functions. The spheroids used here were composed of six brain cell types: Astrocytes, pericytes, endothelial cells, microglia cells, oligodendrocytes, and neurons. They form an in vitro BBB that regulates the transport of compds. into the spheroid. The penetration of fluorescent ultrasmall gold nanoparticles (core diam. 2 nm; hydrodynamic diam. 3-4 nm) across the BBB was studied as a function of time by confocal laser scanning microscopy, with the dissolved fluorescent dye (FAM-alkyne) as a control. The nanoparticles readily entered the interior of the spheroid, whereas the dissolved dye alone did not penetrate the BBB. We present a model that is based on a time-dependent opening of the BBB for nanoparticles, followed by a rapid diffusion into the center of the spheroid. After the spheroids underwent hypoxia (0.1% O2; 24 h), the BBB was more permeable, permitting the uptake of more nanoparticles and also of dissolved dye mols. Together with our previous observations that such nanoparticles can easily enter cells and even the cell nucleus, these data provide evidence that ultrasmall nanoparticle can cross the blood brain barrier.
664. 664

     Koffie, R. M.; Farrar, C. T.; Saidi, L.-J.; William, C. M.; Hyman, B. T.; Spires-Jones, T. L. Nanoparticles Enhance Brain Delivery of Blood-Brain Barrier-Impermeable Probes for in Vivo Optical and Magnetic Resonance Imaging. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 18837– 18842,  DOI: 10.1073/pnas.1111405108

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     664

     Nanoparticles enhance brain delivery of blood-brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging

     Koffie, Robert M.; Farrar, Christian T.; Saidi, Laiq-Jan; William, Christopher M.; Hyman, Bradley T.; Spires-Jones, Tara L.

     Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (46), 18837-18842, S18837/1-S18837/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Several imaging modalities are suitable for in vivo mol. neuroimaging, but the blood-brain barrier (BBB) limits their utility by preventing brain delivery of most targeted mol. probes. We prepd. biodegradable nanocarrier systems made up of poly(Bu cyanoacrylate) dextran polymers coated with polysorbate 80 (PBCA nanoparticles) to deliver BBB-impermeable mol. imaging probes into the brain for targeted mol. neuroimaging. We demonstrate that PBCA nanoparticles allow in.vivo targeting of BBB-impermeable contrast agents and staining reagents for electron microscopy, optical imaging (multiphoton), and whole brain magnetic resonance imaging (MRI), facilitating mol. studies ranging from individual synapses to the entire brain. PBCA nanoparticles can deliver BBB-impermeable targeted fluorophores of a wide range of sizes: from 500-Da targeted polar mols. to 150,000-Da tagged Igs into the brain of living mice. The utility of this approach is demonstrated by (i) development of a "Nissl stain" contrast agent for cellular imaging, (ii) visualization of amyloid plaques in vivo in a mouse model of Alzheimer's disease using (traditionally) non-BBB-permeable reagents that detect plaques, and (iii) delivery of gadolinium-based contrast agents into the brain of mice for in vivo whole brain MRI. Four-dimensional real-time two-photon and MR imaging reveal that brain penetration of PBCA nanoparticles occurs rapidly with a time const. of ∼18 min. PBCA nanoparticles do not induce nonspecific BBB disruption, but collaborate with plasma apolipoprotein E to facilitate BBB crossing. Collectively, these findings highlight the potential of using biodegradable nanocarrier systems to deliver BBB-impermeable targeted mol. probes into the brain for diagnostic neuroimaging.
665. 665

     Wohlfart, S.; Khalansky, A. S.; Gelperina, S.; Begley, D.; Kreuter, J. Kinetics of Transport of Doxorubicin Bound to Nanoparticles across the Blood-Brain Barrier. J. Controlled Release 2011, 154, 103– 107,  DOI: 10.1016/j.jconrel.2011.05.010

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666. 666

     Zhang, Z.; Guan, J.; Jiang, Z.; Yang, Y.; Liu, J.; Hua, W.; Mao, Y.; Li, C.; Lu, W.; Qian, J. Brain-Targeted Drug Delivery by Manipulating Protein Corona Functions. Nat. Commun. 2019, 10, 3561,  DOI: 10.1038/s41467-019-11593-z

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     666

     Brain-targeted drug delivery by manipulating protein corona functions

     Zhang Zui; Guan Juan; Jiang Zhuxuan; Yang Yang; Zhan Changyou; Zhang Zui; Li Cheng; Lu Weiyue; Qian Jun; Zhan Changyou; Liu Jican; Hua Wei; Mao Ying

     Nature communications (2019), 10 (1), 3561 ISSN:.

     Protein corona presents a major obstacle to bench-to-bedside translation of targeted drug delivery systems, severely affecting targeting yields and directing unfavorable biodistribution. Corona-mediated targeting provides a new impetus for specific drug delivery by precisely manipulating interaction modes of functional plasma proteins on nano-surface. Here bio-inspired liposomes (SP-sLip) were developed by modifying liposomal surface with a short nontoxic peptide derived from Aβ1-42 that specifically interacts with the lipid-binding domain of exchangeable apolipoproteins. SP-sLip absorb plasma apolipoproteins A1, E and J, consequently exposing receptor-binding domain of apolipoproteins to achieve brain-targeted delivery. Doxorubicin loaded SP-sLip (SP-sLip/DOX) show significant enhancement of brain distribution and anti-brain cancer effect in comparison to doxorubicin loaded plain liposomes. SP-sLip preserve functions of the absorbed human plasma ApoE, and the corona-mediated targeting strategy works in SP modified PLGA nanoparticles. The present study may pave a new avenue to facilitate clinical translation of targeted drug delivery systems.
667. 667

     Rabanel, J.-M.; Piec, P.-A.; Landri, S.; Patten, S. A.; Ramassamy, C. Transport of PEGylated-PLA Nanoparticles across a Blood Brain Barrier Model, Entry into Neuronal Cells and in Vivo Brain Bioavailability. J. Controlled Release 2020, 328, 679– 695,  DOI: 10.1016/j.jconrel.2020.09.042

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     667

     Transport of PEGylated-PLA nanoparticles across a blood brain barrier model, entry into neuronal cells and in vivo brain bioavailability

     Rabanel, Jean-Michel; Piec, Pierre-Alexandre; Landri, Sarra; Patten, Shunmoogum A.; Ramassamy, Charles

     Journal of Controlled Release (2020), 328 (), 679-695CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

     Treatments of neurodegenerative diseases (NDDs) are severely hampered by the presence of the blood-brain barrier (BBB) precluding efficient brain drug delivery. The development of drug nanocarriers aims at increasing the brain therapeutic index would represent a real progress in brain disease management. PEGylated polyester nanoparticles (NPs) are intensively tested in clin. trials for improved drug delivery. Our working hypothesis was that some surface parameters and size of NPs could favor their penetration across the BBB and their neuronal uptake. Polymeric material PEG-b-PLA diblocks were synthesized by ring opening polymn. (ROP) with PEG2000 or PEG5000. A library of polymeric PEG-b-PLA diblocks NPs with different physicochem. properties was produced. The toxicity, endocytosis and transcytosis through the brain microvascular endothelial cells were monitored as well as the neuronal cells uptake. In vivo assays on a zebrafish model showed that the kinetic of NPs in circulation is dependent on PEG coating properties. In vivo findings also showed a low but similar translocation of PEG-b-PLA diblocks NPs to the CNS, regardless of their properties. In conclusion, modulation of surface PEG chain length and NPs size impact the endocytosis rate of NPs but have little influence on cell barriers translocation; while in vivo biodistribution is influenced by surface PEG chain d.
668. 668

     Cox, A.; Andreozzi, P.; Dal Magro, R.; Fiordaliso, F.; Corbelli, A.; Talamini, L.; Chinello, C.; Raimondo, F.; Magni, F.; Tringali, M. Evolution of Nanoparticle Protein Corona across the Blood-Brain Barrier. ACS Nano 2018, 12, 7292– 7300,  DOI: 10.1021/acsnano.8b03500

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     668

     Evolution of Nanoparticle Protein Corona across the Blood-Brain Barrier

     Cox, Alysia; Andreozzi, Patrizia; Dal Magro, Roberta; Fiordaliso, Fabio; Corbelli, Alessandro; Talamini, Laura; Chinello, Clizia; Raimondo, Francesca; Magni, Fulvio; Tringali, Maria; Krol, Silke; Jacob Silva, Paulo; Stellacci, Francesco; Masserini, Massimo; Re, Francesca

     ACS Nano (2018), 12 (7), 7292-7300CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Engineered nanoparticles offer the chance to improve drug transport and delivery through biol. barriers, exploiting the possibility to leave the blood circulation and traverse the endothelial vascular bed, blood-brain barrier (BBB) included, to reach their target. It is known that nanoparticles gather mols. on their surface upon contact with biol. fluids, forming the "protein corona", which can affect their fate and therapeutic/diagnostic performance, yet no information on the corona's evolution across the barrier has been gathered so far. Using a cellular model of the BBB and gold nanoparticles, we show that the compn. of the corona undergoes dramatic quant. and qual. mol. modifications during passage from the "blood" to the "brain" side, while it is stable once beyond the BBB. Thus, we demonstrate that the nanoparticle corona dynamically and drastically evolves upon crossing the BBB and that its initial compn. is not predictive of nanoparticle fate and performance once beyond the barrier at the target organ.
669. 669

     Shin, D. W.; Fan, J.; Luu, E.; Khalid, W.; Xia, Y.; Khadka, N.; Bikson, M.; Fu, B. M. In Vivo Modulation of the Blood-Brain Barrier Permeability by Transcranial Direct Current Stimulation (tDCS). Ann. Biomed. Eng. 2020, 48, 1256– 1270,  DOI: 10.1007/s10439-020-02447-7

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     Rapoport, S. I. Osmotic Opening of the Blood-Brain Barrier: Principles, Mechanism, and Therapeutic Applications. Cell. Mol. Neurobiol. 2000, 20, 217– 230,  DOI: 10.1023/A:1007049806660

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     Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications

     Rapoport S I

     Cellular and molecular neurobiology (2000), 20 (2), 217-30 ISSN:0272-4340.

     1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.
671. 671

     Tabatabaei, S. N.; Girouard, H.; Carret, A.-S.; Martel, S. Remote c Ontrol of the Permeability of the Blood-Brain Barrier by Magnetic Heating of Nanoparticles: A Proof of Concept for Brain Drug Delivery. J. Controlled Release 2015, 206, 49– 57,  DOI: 10.1016/j.jconrel.2015.02.027

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     Johansson, B.; Li, C.-L.; Olsson, Y.; Klatzo, I. The Effect of Acute Arterial Hypertension on the Blood-Brain Barrier to Protein Tracers. Acta Neuropathol. 1970, 16, 117– 124,  DOI: 10.1007/BF00687666

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673. 673

     Johansson, B.; Linder, L. Do Nitrous Oxide and Lidocaine Modify the Blood Brain Barrier in Acute Hypertension in the Rat?. Acta Anaesthesiol. Scand. 1980, 24, 65– 68,  DOI: 10.1111/j.1399-6576.1980.tb01507.x

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     Bär, S.; Buchholz, O.; Münkel, C.; Schlett, P.; Levan, P.; von Elverfeldt, D.; Hofmann, U. G. Thermal Threshold for Localized Blood-Brain-Barrier Disruption. arXiv , June 15, 2023, 2306.09214, ver. 1 DOI: 10.48550/arXiv.2306.09214 .

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     Buchholz, O.; Sajjamark, K.; Franke, J.; Wei, H.; Behrends, A.; Munkel, C.; Gruttner, C.; Levan, P.; von Elverfeldt, D.; Graeser, M.; Buzug, T.; Bar, S.; Hofmann, U. G. In Situ Theranostic Platform Uniting Highly Localized Magnetic Fluid Hyperthermia, Magnetic Particle Imaging, and Thermometry in 3D. Theranostics 2024, 14, 324– 340,  DOI: 10.7150/thno.86759

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676. 676

     Gunaydin, L. A.; Grosenick, L.; Finkelstein, J. C.; Kauvar, I. V.; Fenno, L. E.; Adhikari, A.; Lammel, S.; Mirzabekov, J. J.; Airan, R. D.; Zalocusky, K. A.; Tye, K. M.; Anikeeva, P.; Malenka, R. C.; Deisseroth, K. Natural Neural Projection Dynamics Underlying Social Behavior. Cell 2014, 157, 1535– 1551,  DOI: 10.1016/j.cell.2014.05.017

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     676

     Natural Neural Projection Dynamics Underlying Social Behavior

     Gunaydin, Lisa A.; Grosenick, Logan; Finkelstein, Joel C.; Kauvar, Isaac V.; Fenno, Lief E.; Adhikari, Avishek; Lammel, Stephan; Mirzabekov, Julie J.; Airan, Raag D.; Zalocusky, Kelly A.; Tye, Kay M.; Anikeeva, Polina; Malenka, Robert C.; Deisseroth, Karl

     Cell (Cambridge, MA, United States) (2014), 157 (7), 1535-1551CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

     Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacol. studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodol., termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.
677. 677

     Beier, K. T.; Saunders, A.; Oldenburg, I. A.; Miyamichi, K.; Akhtar, N.; Luo, L.; Whelan, S. P.; Sabatini, B.; Cepko, C. L. Anterograde or Retrograde Transsynaptic Labeling of CNS Neurons with Vesicular Stomatitis Virus Vectors. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 15414– 15419,  DOI: 10.1073/pnas.1110854108

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     Ojima, K.; Shiraiwa, K.; Soga, K.; Doura, T.; Takato, M.; Komatsu, K.; Yuzaki, M.; Hamachi, I.; Kiyonaka, S. Ligand-Directed Two-Step Labeling to Quantify Neuronal Glutamate Receptor Trafficking. Nat. Commun. 2021, 12, 831,  DOI: 10.1038/s41467-021-21082-x

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     Ligand-directed two-step labeling to quantify neuronal glutamate receptor trafficking

     Ojima, Kento; Shiraiwa, Kazuki; Soga, Kyohei; Doura, Tomohiro; Takato, Mikiko; Komatsu, Kazuhiro; Yuzaki, Michisuke; Hamachi, Itaru; Kiyonaka, Shigeki

     Nature Communications (2021), 12 (1), 831CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)

     The regulation of glutamate receptor localization is crit. for development and synaptic plasticity in the central nervous system. Conventional biochem. and mol. biol. approaches have been widely used to analyze glutamate receptor trafficking, esp. for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors (AMPARs). However, conflicting findings have been reported because of a lack of useful tools for analyzing endogenous AMPARs. Here, we develop a method for the rapid and selective labeling of AMPARs with chem. probes, by combining affinity-based protein labeling and bioorthogonal click chem. under physiol. temp. in culture medium. This method allows us to quantify AMPAR distribution and trafficking, which reveals some unique features of AMPARs, such as a long lifetime and a rapid recycling in neurons. This method is also successfully expanded to selectively label N-methyl-D-aspartate-type glutamate receptors. Thus, bioorthogonal two-step labeling may be a versatile tool for investigating the physiol. and pathophysiol. roles of glutamate receptors in neurons.
679. 679

     Stefanick, J. F.; Omstead, D. T.; Kiziltepe, T.; Bilgicer, B. Dual-Receptor Targeted Strategy in Nanoparticle Design Achieves Tumor Cell Selectivity through Cooperativity. Nanoscale 2019, 11, 4414– 4427,  DOI: 10.1039/C8NR09431D

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     Dual-receptor targeted strategy in nanoparticle design achieves tumor cell selectivity through cooperativity

     Stefanick, Jared Francis; Omstead, David Thomas; Kiziltepe, Tanyel; Bilgicer, Basar

     Nanoscale (2019), 11 (10), 4414-4427CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Here, we demonstrated that the selectivity of peptide-targeted liposomes for their target cells can be significantly enhanced by employing a dual-receptor targeted approach to simultaneously target multiple tumor cell surface receptors. We evaluated this strategy in a multiple myeloma disease model where the liposomes were functionalized with two distinct peptide antagonists to target VLA-4 and LPAM-1, two receptors with increasing relevance in multiple myeloma. Through control of the liposomal formulation and valency of each targeting peptide, we identified that the optimal dual-receptor targeted liposome consisted of a peptide d. of 0.75% VLA4pep and 1% LPAM1pep, resulting in an 8-fold and 12-fold increased cellular uptake over VLA-4 and LPAM-1 single targeted liposomes resp. This formulation resulted in a cooperative ratio of 4.3 and enhanced uptake for myeloma cells that simultaneously express both VLA-4 and LPAM-1 receptors, but displayed no increase in uptake for cells that express only one or neither of the receptors, resulting in a 28-fold selectivity of the dual-targeted liposomes for cells displaying both targeted receptors over cells displaying neither receptor. These results demonstrated that through refined design and well-characterized nanoparticle formulations, dual-receptor targeted liposomes have the potential to improve cancer therapy by providing enhanced selectivity over conventional single-receptor targeted approaches.
680. 680

     Pegard, N. C.; Mardinly, A. R.; Oldenburg, I. A.; Sridharan, S.; Waller, L.; Adesnik, H. Three-Dimensional Scanless Holographic Optogenetics with Temporal Focusing (3D-SHOT). Nat. Commun. 2017, 8, 1228,  DOI: 10.1038/s41467-017-01031-3

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     Hubrecht, R. C.; Carter, E. The 3Rs and Humane Experimental Technique: Implementing Change. Animals 2019, 9, 754,  DOI: 10.3390/ani9100754

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     Inoue, M. Genetically Encoded Calcium Indicators to Probe Complex Brain Circuit Dynamics in Vivo. Neurosci. Res. 2021, 169, 2– 8,  DOI: 10.1016/j.neures.2020.05.013

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     Genetically encoded calcium indicators to probe complex brain circuit dynamics in vivo

     Inoue, Masatoshi

     Neuroscience Research (Shannon, Ireland) (2021), 169 (), 2-8CODEN: NERADN; ISSN:0168-0102. (Elsevier Ireland Ltd.)

     A review. Over the past two decades, genetically encoded calcium indicators (GECIs) have been used extensively to report intracellular calcium (Ca2+) dynamics in order to readout neuronal and network activity in living tissue. Single wavelength GECIs, such as GCaMP, have been widely adapted due to advances in dynamic range, sensitivity, and kinetics. Addnl., recent efforts in protein engineering have expanded the GECI color palette to enable direct optical interrogation of more complex circuit dynamics. Here, I discuss the engineering, application, and future directions of the most recently developed GECIs for in vivo neuroscience research.
683. 683

     Khadria, A. Tools to Measure Membrane Potential of Neurons. Biomed. J. 2022, 45, 749,  DOI: 10.1016/j.bj.2022.05.007

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     683

     Tools to measure membrane potential of neurons

     Khadria Anjul

     Biomedical journal (2022), 45 (5), 749-762 ISSN:.

     The brain is the most unexplored part of our body. The lack of sufficient tools has hindered our understanding of the brain and the associated diseases. The study of neurons and the neuronal network will help elucidate how the brain functions and related disorders. Over the last few decades, an increasing number of techniques have been reported to study neurons and neuronal communication in vitro, ex vivo, and in vivo. These methods have pushed the boundaries of neuroscience and elucidated more information than ever before; however, much more requires to be done to understand the brain in its entirety. In this review article, I discuss the principles and the advantages and disadvantages of the classical electrode-based recording techniques and the optical imaging-based methods, which have aided neuroscientists in understanding neuronal communication.
684. 684

     Kannan, M.; Vasan, G.; Pieribone, V. A. Optimizing Strategies for Developing Genetically Encoded Voltage Indicators. Front. Cell. Neurosci. 2019, 13, 53,  DOI: 10.3389/fncel.2019.00053

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685. 685

     Looger, L. L.; Griesbeck, O. Genetically Encoded Neural Activity Indicators. Curr. Opin. Neurobiol. 2012, 22, 18– 23,  DOI: 10.1016/j.conb.2011.10.024

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     685

     Genetically encoded neural activity indicators

     Looger, Loren L.; Griesbeck, Oliver

     Current Opinion in Neurobiology (2012), 22 (1), 18-23CODEN: COPUEN; ISSN:0959-4388. (Elsevier Ltd.)

     Recording activity from identified populations of neurons is a central goal of neuroscience. Changes in membrane depolarization, particularly action potentials, are the most important features of neural physiol. to ext., although ions, neurotransmitters, neuromodulators, second messengers, and the activation state of specific proteins are also crucial. Modern fluorescence microscopy provides the basis for such activity mapping, through multi-photon imaging and other optical schemes. Probes remain the rate-limiting step for progress in this field: they should be bright and photostable, and ideally come in multiple colors. Only protein-based reagents permit chronic imaging from genetically specified cells. Here we review recent progress in the design, optimization and deployment of genetically encoded indicators for calcium ions (a proxy for action potentials), membrane potential, and neurotransmitters. We highlight seminal expts., and present an outlook for future progress.
686. 686

     Sabatini, B. L.; Tian, L. Imaging Neurotransmitter and Neuromodulator Dynamics in Vivo with Genetically Encoded Indicators. Neuron 2020, 108, 17– 32,  DOI: 10.1016/j.neuron.2020.09.036

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     686

     Imaging Neurotransmitter and Neuromodulator Dynamics In Vivo with Genetically Encoded Indicators

     Sabatini, Bernardo L.; Tian, Lin

     Neuron (2020), 108 (1), 17-32CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     The actions of neuromodulation are thought to mediate the ability of the mammalian brain to dynamically adjust its functional state in response to changes in the environment. Altered neurotransmitter (NT) and neuromodulator (NM) signaling is central to the pathogenesis or treatment of many human neurol. and psychiatric disorders, including Parkinson's disease, schizophrenia, depression, and addiction. To reveal the precise mechanisms by which these neurochems. regulate healthy and diseased neural circuitry, one needs to measure their spatiotemporal dynamics in the living brain with great precision. Here, we discuss recent development, optimization, and applications of optical approaches to measure the spatial and temporal profiles of NT and NM release in the brain using genetically encoded sensors for in vivo studies.
687. 687

     Gee, C. E.; Ohmert, I.; Wiegert, J. S.; Oertner, T. G. Preparation of Slice Cultures from Rodent Hippocampus; Cold Spring Harbor Laboratory Press, 2017.

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688. 688

     Stoppini, L.; Buchs, P.-A.; Muller, D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 1991, 37, 173– 182,  DOI: 10.1016/0165-0270(91)90128-M

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     688

     A simple method for organotypic cultures of nervous tissue

     Stoppini L; Buchs P A; Muller D

     Journal of neuroscience methods (1991), 37 (2), 173-82 ISSN:0165-0270.

     Hippocampal slices prepared from 2-23-day-old neonates were maintained in culture at the interface between air and a culture medium. They were placed on a sterile, transparent and porous membrane and kept in petri dishes in an incubator. No plasma clot or roller drum were used. This method yields thin slices which remain 1-4 cell layers thick and are characterized by a well preserved organotypic organization. Pyramidal neurons labelled by extra- and intracellular application of horse radish peroxidase resemble by the organization and complexity of their dendritic processes those observed in situ at a comparable developmental stage. Excitatory and inhibitory synaptic potentials can easily be analysed using extra- or intracellular recording techniques. After a few days in culture, long-term potentiation of synaptic responses can reproducibly be induced. Evidence for a sprouting response during the first days in culture or following sections is illustrated. This technique may represent an interesting alternative to roller tube cultures for studies of the developmental changes occurring during the first days or weeks in culture.
689. 689

     De Simoni, A.; Griesinger, C. B.; Edwards, F. A. Development of Rat CA1 Neurones in Acute versus Organotypic Slices: Role of Experience in Synaptic Morphology and Activity. J. Physiol. 2003, 550, 135– 147,  DOI: 10.1113/jphysiol.2003.039099

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     689

     Development of rat CA1 neurones in acute versus organotypic slices: Role of experience in synaptic morphology and activity

     De Simoni, Anna; Griesinger, Claudius B.; Edwards, Frances A.

     Journal of Physiology (Cambridge, United Kingdom) (2003), 550 (1), 135-147CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)

     Despite their wide use, the physiol. relevance of organotypic slices remains controversial. Such cultures are prepd. at 5 days postnatal. Although some local circuitry remains intact, they develop subsequently in isolation from the animal and hence without plasticity due to experience. Development of synaptic connectivity and morphol. might be expected to proceed differently under these conditions than in a behaving animal. To address these questions, patch-clamp techniques and confocal microscopy were used in the CA1 region of the rat hippocampus to compare acute slices from the third postnatal week with various stages of organotypic slices. Acute slices prepd. at postnatal days (P) 14, 17 and 21 were found to be developmentally equiv. to organotypic slices cultured for 1, 2 and 3 wk, resp., in terms of development of synaptic transmission and dendritic morphol. The frequency of inhibitory and excitatory miniature synaptic currents increased in parallel. Development of dendritic length and primary branching as well as spine d. and proportions of different spine types were also similar in both prepns., at these corresponding stages. The most notable difference between organotypic and acute slices was a four- to five-fold increase in the abs. frequency of glutamatergic (but not GABAergic) miniature postsynaptic currents in organotypic slices. This was probably related to an increase in complexity of higher order dendritic branching in organotypic slices, as measured by fractal anal., resulting in an increased total synapse no. Both increased excitatory miniature synaptic current frequency and dendritic complexity were already established during the first week in culture. The level of complexity then stayed const. in both prepns. over subsequent stages, with synaptic frequency increasing in parallel. Thus, although connectivity was greater in organotypic slices, once this was established, development continued in both prepns. at a remarkably similar rate. We conclude that, for the parameters studied, changes seem to be preprogrammed by 5 days and their subsequent development is largely independent of environment.
690. 690

     Berndt, A.; Schoenenberger, P.; Mattis, J.; Tye, K. M.; Deisseroth, K.; Hegemann, P.; Oertner, T. G. High-Efficiency Channelrhodopsins for Fast Neuronal Stimulation at Low Light Levels. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 7595– 7600,  DOI: 10.1073/pnas.1017210108

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     690

     High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels

     Berndt, Andre; Schoenenberger, Philipp; Mattis, Joanna; Tye, Kay M.; Deisseroth, Karl; Hegemann, Peter; Oertner, Thomas G.

     Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (18), 7595-7600, S7595/1-S7595/3CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Channelrhodopsin-2 (ChR2) has become an indispensable tool in neuro-science, allowing precise induction of action potentials with short light pulses. A limiting factor for many optophysiol. expts. is the relatively small photocurrent induced by ChR2. We screened a large no. of ChR2 point mutants and discovered a dramatic increase in photocurrent amplitude after threonine-to-cysteine substitution at position 159. When we tested the T159C mutant in hippocampal pyramidal neurons, action potentials could be induced at very low light intensities, where currently available channelrhodopsins were unable to drive spiking. Biophys. characterization revealed that the kinetics of most ChR2 variants slows down considerably at depolarized membrane potentials. We show that the recently published E123T substitution abolishes this voltage sensitivity and speeds up channel kinetics. When we combined T159C with E123T, the resulting double mutant delivered fast photocurrents with large amplitudes and increased the precision of single action potential induction over a broad range of frequencies, suggesting it may become the std. for light- controlled activation of neurons.
691. 691

     Wietek, J.; Beltramo, R.; Scanziani, M.; Hegemann, P.; Oertner, T. G.; Wiegert, J. S. An Improved Chloride-Conducting Channelrhodopsin for Light-Induced Inhibition of Neuronal Activity in Vivo. Sci. Rep. 2015, 5, 14807,  DOI: 10.1038/srep14807

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     Ji, J.; Moquin, A.; Bertorelle, F.; Chang, P. KY.; Antoine, R.; Luo, J.; Mckinney, R. A.; Maysinger, D. Organotypic and Primary Neural Cultures as Models to Assess Effects of Different Gold Nanostructures on Glia and Neurons. Nanotoxicology 2019, 13, 285– 304,  DOI: 10.1080/17435390.2018.1543468

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     Wiegert, J. S.; Gee, C. E.; Oertner, T. G. Stimulating Neurons with Heterologously Expressed Light-Gated Ion Channels; Cold Spring Harbor Laboratory Press, 2017.

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     Holbro, N.; Grunditz, Å.; Oertner, T. G. Differential Distribution of Endoplasmic Reticulum Controls Metabotropic Signaling and Plasticity at Hippocampal Synapses. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 15055– 15060,  DOI: 10.1073/pnas.0905110106

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     Wiegert, J. S.; Oertner, T. G. Long-Term Depression Triggers the Selective Elimination of Weakly Integrated Synapses. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, E4510– E4519,  DOI: 10.1073/pnas.1315926110

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     Anisimova, M.; van Bommel, B.; Wang, R.; Mikhaylova, M.; Wiegert, J. S.; Oertner, T. G.; Gee, C. E. Spike-Timing-Dependent Plasticity Rewards Synchrony Rather Than Causality. Cereb Cortex 2022, 33, 23– 34,  DOI: 10.1093/cercor/bhac050

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     Bi, G.-q. B.; Poo, M.-m. Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type. J. Neurosci. 1998, 18, 10464– 10472,  DOI: 10.1523/JNEUROSCI.18-24-10464.1998

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     697

     Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type

     Bi, Guo-Qiang; Poo, Mu-Ming

     Journal of Neuroscience (1998), 18 (24), 10464-10472CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)

     In cultures of dissocd. rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking detd. the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 ms after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 ms before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quant. consideration of spike timing that reflects the narrow and asym. window for the induction of synaptic modification.
698. 698

     Perez-Alvarez, A.; Fearey, B. C.; O’Toole, R. J.; Yang, W.; Arganda-Carreras, I.; Lamothe-Molina, P. J.; Moeyaert, B.; Mohr, M. A.; Panzera, L. C.; Schulze, C.; Schreiter, E. R.; Wiegert, J. S.; Gee, C. E.; Hoppa, M. B.; Oertner, T. G. Freeze-Frame Imaging of Synaptic Activity Using SynTagMA. Nat. Commun. 2020, 11, 2464,  DOI: 10.1038/s41467-020-16315-4

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     Laprell, L.; Schulze, C.; Brehme, M. L.; Oertner, T. G. The Role of Microglia Membrane Potential in Chemotaxis. J. Neuroinflammation 2021, 18, 21,  DOI: 10.1186/s12974-020-02048-0

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700. 700

     Ravi, V. M.; Will, P.; Kueckelhaus, J.; Sun, N.; Joseph, K.; Salié, H.; Vollmer, L.; Kuliesiute, U.; von Ehr, J.; Benotmane, J. K. Spatially Resolved Multi-Omics Deciphers Bidirectional Tumor-Host Interdependence in Glioblastoma. Cancer Cell 2022, 40, 639– 655,  DOI: 10.1016/j.ccell.2022.05.009

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     700

     Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma

     Ravi, Vidhya M.; Will, Paulina; Kueckelhaus, Jan; Sun, Na; Joseph, Kevin; Salie, Henrike; Vollmer, Lea; Kuliesiute, Ugne; von Ehr, Jasmin; Benotmane, Jasim K.; Neidert, Nicolas; Follo, Marie; Scherer, Florian; Goeldner, Jonathan M.; Behringer, Simon P.; Franco, Pamela; Khiat, Mohammed; Zhang, Junyi; Hofmann, Ulrich G.; Fung, Christian; Ricklefs, Franz L.; Lamszus, Katrin; Boerries, Melanie; Ku, Manching; Beck, Juergen; Sankowski, Roman; Schwabenland, Marius; Prinz, Marco; Schueller, Ulrich; Killmer, Saskia; Bengsch, Bertram; Walch, Axel K.; Delev, Daniel; Schnell, Oliver; Heiland, Dieter Henrik

     Cancer Cell (2022), 40 (6), 639-655.e13CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)

     Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-no. alterations emphasizes a spatially cohesive organization of subclones assocd. with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.
701. 701

     Ravi, V. M.; Will, P.; Kueckelhaus, J.; Sun, N.; Joseph, K.; Salié, H.; Ehr, J. v.; Vollmer, L.; Benotmane, J. K.; Neidert, N. Spatiotemporal Heterogeneity of Glioblastoma Is Dictated by Microenvironmental Interference. bioRxiv , February 17, 2021, 431475.

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     Nzou, G.; Wicks, R. T.; Wicks, E. E.; Seale, S. A.; Sane, C. H.; Chen, A.; Murphy, S. V.; Jackson, J. D.; Atala, A. J. Human Cortex Spheroid with a Functional Blood Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling. Sci. Rep. 2018, 8, 7413,  DOI: 10.1038/s41598-018-25603-5

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     702

     Human Cortex Spheroid with a Functional Blood Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling

     Nzou Goodwell; Wicks R T; Wicks E E; Seale S A; Sane C H; Chen A; Murphy S V; Jackson J D; Atala A J; Wicks R T

     Scientific reports (2018), 8 (1), 7413 ISSN:.

     The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex. To date, most in vitro BBB models utilize endothelial cells, pericytes and astrocytes. We report a 3D spheroid model of the BBB comprising all major cell types, including neurons, microglia and oligodendrocytes, to recapitulate more closely normal human brain tissue. Spheroids show expression of tight junctions, adherens junctions, adherens junction-associated proteins and cell specific markers. Functional assessment using MPTP, MPP+ and mercury chloride indicate charge selectivity through the barrier. Junctional protein distribution was altered under hypoxic conditions. Our spheroid model may have potential applications in drug discovery, disease modeling, neurotoxicity and cytotoxicity testing.
703. 703

     Chatzinikolaidou, M. Cell Spheroids: The New Frontiers in in Vitro Models for Cancer Drug Validation. Drug Discovery Today 2016, 21, 1553– 1560,  DOI: 10.1016/j.drudis.2016.06.024

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     703

     Cell spheroids: the new frontiers in in vitro models for cancer drug validation

     Chatzinikolaidou, Maria

     Drug Discovery Today (2016), 21 (9), 1553-1560CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)

     During the past decades, evaluation of anticancer drugs utilizing 2D cell cultures has been in common usage. In contrast to 2D cell cultures however, which lack many characteristics of the complex in vivo situation, 3D cell or tissue culture systems, such as cellular spheroids, better mimic the crucial tumor tissue properties and the microenvironment, and are thus more appropriate for the evaluation of pharmaceutical candidates. Taking the characteristics of the tumor microenvironment into consideration, crucial aspects and recent advances related to cell spheroids in the validation of anticancer drugs are discussed here.
704. 704

     Saraiva, C.; Praca, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-Mediated Brain Drug Delivery: Overcoming Blood-Brain Barrier to Treat Neurodegenerative Diseases. J. Controlled Release 2016, 235, 34– 47,  DOI: 10.1016/j.jconrel.2016.05.044

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     704

     Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases

     Saraiva, Claudia; Praca, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

     Journal of Controlled Release (2016), 235 (), 34-47CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

     The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and mol. movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuro inflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate mols. with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB compn. and characteristics and how these features are altered in pathol., namely in stroke, AD and PD. Addnl., factors influencing an efficient i.v. delivery of polymeric and inorg. NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.
705. 705

     Pandey, P. K.; Sharma, A. K.; Gupta, U. Blood Brain Barrier: An Overview on Strategies in Drug Delivery, Realistic in Vitro Modeling and in Vivo Live Tracking. Tissue Barriers 2016, 4, e1129476,  DOI: 10.1080/21688370.2015.1129476

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706. 706

     Nzou, G.; Seeds, M. C.; Wicks, R. T.; Atala, A. J. Fundamental Neurovascular Components for the Development of Complex and Dynamic in Vitro Brain Equivalent Models. J. Alzheimer’s Neurodegener. Dis. 2019, 5, 021,  DOI: 10.24966/AND-9608/100021

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707. 707

     Bergmann, S.; Lawler, S. E.; Qu, Y.; Fadzen, C. M.; Wolfe, J. M.; Regan, M. S.; Pentelute, B. L.; Agar, N. Y. R.; Cho, C. F. Blood-Brain-Barrier Organoids for Investigating the Permeability of CNS Therapeutics. Nat. Protoc. 2018, 13, 2827– 2843,  DOI: 10.1038/s41596-018-0066-x

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     707

     Blood-brain-barrier organoids for investigating the permeability of CNS therapeutics

     Bergmann, Sonja; Lawler, Sean E.; Qu, Yuan; Fadzen, Colin M.; Wolfe, Justin M.; Regan, Michael S.; Pentelute, Bradley L.; Agar, Nathalie Y. R.; Cho, Choi-Fong

     Nature Protocols (2018), 13 (12), 2827-2843CODEN: NPARDW; ISSN:1750-2799. (Nature Research)

     In vitro models of the blood-brain barrier (BBB) are crit. tools for the study of BBB transport and the development of drugs that can reach the CNS. Brain endothelial cells grown in culture are often used to model the BBB; however, it is challenging to maintain reproducible BBB properties and function. 'BBB organoids' are obtained following coculture of endothelial cells, pericytes and astrocytes under low-adhesion conditions. These organoids reproduce many features of the BBB, including the expression of tight junctions, mol. transporters and drug efflux pumps, and hence can be used to model drug transport across the BBB. This protocol provides a comprehensive description of the techniques required to culture and maintain BBB organoids. We also describe two sep. detection approaches that can be used to analyze drug penetration into the organoids: confocal fluorescence microscopy and mass spectrometry imaging. Using our protocol, BBB organoids can be established within 2-3 d. An addnl. day is required to analyze drug permeability. The BBB organoid platform represents an accurate, versatile and cost-effective in vitro tool. It can easily be scaled to a high-throughput format, offering a tool for BBB modeling that could accelerate therapeutic discovery for the treatment of various neuropathologies.
708. 708

     Helms, H. C.; Abbott, N. J.; Burek, M.; Cecchelli, R.; Couraud, P. O.; Deli, M. A.; Forster, C.; Galla, H. J.; Romero, I. A.; Shusta, E. V.; Stebbins, M. J.; Vandenhaute, E.; Weksler, B.; Brodin, B. In Vitro Models of the Blood-Brain Barrier: An Overview of Commonly Used Brain Endothelial Cell Culture Models and Guidelines for Their Use. J. Cereb. Blood Flow Metab. 2016, 36, 862– 90,  DOI: 10.1177/0271678X16630991

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     708

     In vitro models of the blood-brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use

     Helms, Hans C.; Abbott, N. Joan; Burek, Malgorzata; Cecchelli, Romeo; Couraud, Pierre-Olivier; Deli, Maria A.; Foerster, Carola; Galla, Hans J.; Romero, Ignacio A.; Shusta, Eric V.; Stebbins, Matthew J.; Vandenhaute, Elodie; Weksler, Babette; Brodin, Birger

     Journal of Cerebral Blood Flow & Metabolism (2016), 36 (5), 862-890CODEN: JCBMDN; ISSN:0271-678X. (Sage Publications)

     A review. The endothelial cells lining the brain capillaries sep. the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biol. and pathophysiol. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of wellestablished blood-brain barrier characteristics. As an ideal cell culture model of the blood-brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.
709. 709

     Cho, C. F.; Wolfe, J. M.; Fadzen, C. M.; Calligaris, D.; Hornburg, K.; Chiocca, E. A.; Agar, N. Y. R.; Pentelute, B. L.; Lawler, S. E. Models of the Blood-Brain Barrier: An Overview of Commonly Used Brain Endothelial Cell Culture Models and Guidelines for Their Use. Nat. Commun. 2017, 8, 15623,  DOI: 10.1038/ncomms15623

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710. 710

     Lu, H.; Stenzel, M. H. Multicellular Tumor Spheroids (MCTS) as a 3D in Vitro Evaluation Tool of Nanoparticles. Small 2018, 14, e1702858,  DOI: 10.1002/smll.201702858

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711. 711

     Leite, P. E. C.; Pereira, M. R.; Harris, G.; Pamies, D.; Dos Santos, L. M. G.; Granjeiro, J. M.; Hogberg, H. T.; Hartung, T.; Smirnova, L. Suitability of 3D Human Brain Spheroid Models to Distinguish Toxic Effects of Gold and Poly-Lactic Acid Nanoparticles to Assess Biocompatibility for Brain Drug Delivery. Part. Fibre Toxicol. 2019, 16, 22,  DOI: 10.1186/s12989-019-0307-3

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     711

     Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery

     Leite Paulo Emilio Correa; Granjeiro Jose Mauro; Pereira Mariana Rodrigues; Harris Georgina; Pamies David; Hogberg Helena T; Hartung Thomas; Smirnova Lena; Pamies David; Dos Santos Lisia Maria Gobbo; Granjeiro Jose Mauro; Hartung Thomas

     Particle and fibre toxicology (2019), 16 (1), 22 ISSN:.

     BACKGROUND: The blood brain barrier (BBB) is the bottleneck of brain-targeted drug development. Due to their physico-chemical properties, nanoparticles (NP) can cross the BBB and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brain disorders. In vitro systems and animal models have demonstrated that some NP types promote neurotoxic effects such as neuroinflammation and neurodegeneration in the CNS. Thus, risk assessment of the NP is required, but current 2D cell cultures fail to mimic complex in vivo cellular interactions, while animal models do not necessarily reflect human effects due to physiological and species differences. RESULTS: We evaluated the suitability of in vitro models that mimic the human CNS physiology, studying the effects of metallic gold NP (AuNP) functionalized with sodium citrate (Au-SC), or polyethylene glycol (Au-PEG), and polymeric polylactic acid NP (PLA-NP). Two different 3D neural models were used (i) human dopaminergic neurons differentiated from the LUHMES cell line (3D LUHMES) and (ii) human iPSC-derived brain spheroids (BrainSpheres). We evaluated NP uptake, mitochondrial membrane potential, viability, morphology, secretion of cytokines, chemokines and growth factors, and expression of genes related to ROS regulation after 24 and 72 h exposures. NP were efficiently taken up by spheroids, especially when PEGylated and in presence of glia. AuNP, especially PEGylated AuNP, effected mitochondria and anti-oxidative defense. PLA-NP were slightly cytotoxic to 3D LUHMES with no effects to BrainSpheres. CONCLUSIONS: 3D brain models, both monocellular and multicellular are useful in studying NP neurotoxicity and can help identify how specific cell types of CNS are affected by NP.
712. 712

     Nzou, G.; Wicks, R. T.; VanOstrand, N. R.; Mekky, G. A.; Seale, S. A.; El-Taibany, A.; Wicks, E. E.; Nechtman, C. M.; Marrotte, E. J.; Makani, V. S.; Murphy, S. V.; Seeds, M. C.; Jackson, J. D.; Atala, A. J. Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction. Sci. Rep. 2020, 10, 9766,  DOI: 10.1038/s41598-020-66487-8

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713. 713

     Chlebanowska, P.; Tejchman, A.; Sulkowski, M.; Skrzypek, K.; Majka, M. Use of 3D Organoids as a Model to Study Idiopathic Form of Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 694,  DOI: 10.3390/ijms21030694

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714. 714

     Chhibber, T.; Bagchi, S.; Lahooti, B.; Verma, A.; Al-Ahmad, A.; Paul, M. K.; Pendyala, G.; Jayant, R. D. CNS Organoids: An Innovative Tool for Neurological Disease Modeling and Drug Neurotoxicity Screening. Drug Discovery Today 2020, 25, 456– 465,  DOI: 10.1016/j.drudis.2019.11.010

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715. 715

     Cheah, P.-S.; Mason, J. O.; Ling, K. H. Challenges and Future Perspectives for 3D Cerebral Organoids as a Model for Complex Brain Disorders. Neurosci. Res. Notes 2019, 2, 1– 6,  DOI: 10.31117/neuroscirn.v2i1.28

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716. 716

     Rakotoson, I.; Delhomme, B.; Djian, P.; Deeg, A.; Brunstein, M.; Seebacher, C.; Uhl, R.; Ricard, C.; Oheim, M. Fast 3-D Imaging of Brain Organoids with a New Single-Objective Planar-Illumination Two-Photon Microscope. Front. Neuroanat. 2019, 13, 77,  DOI: 10.3389/fnana.2019.00077

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     716

     Fast 3-D imaging of brain organoids with a new single-objective planar-illumination two-photon microscope

     Rakotoson, Irina; Delhomme, Brigitte; Djian, Philippe; Deeg, Andreas; Brunstein, Maia; Seebacher, Christian; Uhl, Rainer; Ricard, Clement; Oheim, Martin

     Frontiers in Neuroanatomy (2019), 13 (), 77CODEN: FNREB8; ISSN:1662-5129. (Frontiers Media S.A.)

     Human inducible pluripotent stem cells (hiPSCs) hold a large potential for disease modeling. hiPSC-derived human astrocyte and neuronal cultures permit investigations of neural signaling pathways with subcellular resoln. Combinatorial cultures, and three-dimensional (3-D) embryonic bodies (EBs) enlarge the scope of investigations to multi-cellular phenomena. The highest level of complexity, brain organoids that-in many aspects-recapitulate anatomical and functional features of the developing brain permit the study of developmental and morphol. aspects of human disease. An ideal microscope for 3-D tissue imaging at these different scales would combine features from both confocal laser-scanning and light-sheet microscopes: a micrometric optical sectioning capacity and sub-micrometric spatial resoln., a large field of view and high frame rate, and a low degree of invasiveness, i.e., ideally, a better photon efficiency than that of a confocal microscope. In the present work, we describe such an instrument that uses planar two-photon (2P) excitation. Its particularity is that-unlike two- or three-lens light-sheet microscopes-it uses a single, low-magnification, high-numerical aperture objective for the generation and scanning of a virtual light sheet. The microscope builds on a modified Nipkow-Petr´an spinning-disk scheme for achieving wide-field excitation. ♂ However, unlike the Yokogawa design that uses a tandem disk, our concept combines micro lenses, dichroic mirrors and detection pinholes on a single disk. This new design, advantageous for 2P excitation, circumvents problems arising with the tandem disk from the large wavelength difference between the IR excitation light and visible fluorescence. 2P fluorescence excited by the light sheet is collected with the same objective and imaged onto a fast sCMOS camera. We demonstrate 3-D imaging of TO-PRO3-stained EBs and of brain organoids, uncleared and after rapid partial transparisation with triethanolamine formamide (RTF) and we compare the performance of our instrument to that of a confocal laser-scanning microscope (CLSM) having a similar numerical aperture. Our large-field 2P-spinning disk microscope permits one order of magnitude faster imaging, affords less photobleaching and permits better depth penetration than a confocal microscope with similar spatial resoln.
717. 717

     Abbott, N. J. Inflammatory Mediators and Modulation of Blood-Brain Barrier Permeability. Cell. Mol. Neurobiol. 2000, 20, 131– 147,  DOI: 10.1023/A:1007074420772

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     Inflammatory mediators and modulation of blood-brain barrier permeability

     Abbott N J

     Cellular and molecular neurobiology (2000), 20 (2), 131-47 ISSN:0272-4340.

     1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
718. 718

     Ju, F.; Ran, Y.; Zhu, L.; Cheng, X.; Gao, H.; Xi, X.; Yang, Z.; Zhang, S. Increased BBB Permeability Enhances Activation of Microglia and Exacerbates Loss of Dendritic Spines After Transient Global Cerebral Ischemia. Front. Cell. Neurosci. 2018, 12, 236,  DOI: 10.3389/fncel.2018.00236

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     718

     Increased BBB permeability enhances activation of microglia and exacerbates loss of dendritic spines after transient global cerebral ischemia

     Ju, Furong; Ran, Yanli; Zhu, Lirui; Cheng, Xiaofeng; Gao, Hao; Xi, Xiaoxia; Yang, Zhanli; Zhang, Shengxiang

     Frontiers in Cellular Neuroscience (2018), 12 (), 236/1-236/14CODEN: FCNRAH; ISSN:1662-5102. (Frontiers Media S.A.)

     Ischemic stroke can induce rapid disruption of blood-brain barrier (BBB). It has been suggested that increased BBB permeability can affect the pathol. progression of ischemic tissue. However, the impact of increased BBB permeability on microglial activation and synaptic structures following reperfusion after ischemia remains unclear. In this study, we investigated microglial activation, dendritic damage and plasticity of dendritic spines after increasing BBB permeability following transient global cerebral ischemia in the somatosensory cortices in mice. Bilateral common carotid artery ligation (BCAL) was used to induce transient global cerebral ischemia. Mannitol was used to increase the BBB permeability. Intravital two-photon imaging was performed to image the dendritic structures and BBB extravasation. Microglial morphol. was quantitated using a skeletonization anal. method. To evaluate inflammation of cerebral cortex, the mRNA expression levels of integrin alpha M (CD11b), CD68, chemokine (C-X-C motif) ligand 10 (IP10) and tumor necrosis factor alpha (TNF-α) were measured by fluorescent quant. PCR. Intravital two-photon imaging revealed that mannitol caused a drastic increase in BBB extravasation during reperfusion after transient global ischemia. Increased BBB permeability induced by mannitol had no significant effect on inflammation and dendritic spines in healthy mice but triggered a marked de-ramification of microglia; importantly, in ischemic animals, mannitol accelerated de-ramification of microglia and aggravated inflammation at 3 h but not at 3 days following reperfusion after ischemia. Although mannitol did not cause significant change in the percentage of blebbed dendrites and did not affect the reversible recovery of the dendritic structures, excessive extravasation was accompanied with significant decrease in spine formation and increase in spine elimination during reperfusion in ischemic mice. These findings suggest that increased BBB permeability induced by mannitol can lead to acute activation of microglia and cause excessive loss of dendritic spines after transient global cerebral ischemia.
719. 719

     Li, T. L.; Liu, Y.; Forro, C.; Yang, X.; Beker, L.; Bao, Z.; Cui, B.; Paşca, S. P. Stretchable Mesh Microelectronics for the Biointegration and Stimulation of Human Neural Organoids. Biomaterials 2022, 290, 121825,  DOI: 10.1016/j.biomaterials.2022.121825

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     719

     Stretchable mesh microelectronics for the biointegration and stimulation of human neural organoids

     Li, Thomas L.; Liu, Yuxin; Forro, Csaba; Yang, Xiao; Beker, Levent; Bao, Zhenan; Cui, Bianxiao; Pasca, Sergiu P.

     Biomaterials (2022), 290 (), 121825CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Advances in tridimensional (3D) culture approaches have led to the generation of organoids that recapitulate cellular and physiol. features of domains of the human nervous system. Although microelectrodes have been developed for long-term electrophysiol. interfaces with neural tissue, studies of long-term interfaces between microelectrodes and free-floating organoids remain limited. In this study, we report a stretchable, soft mesh electrode system that establishes an intimate in vitro elec. interface with human neurons in 3D organoids. Our mesh is constructed with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) based elec. conductive hydrogel electrode arrays and elastomeric poly(styrene-ethylene-butylene-styrene) (SEBS) as the substrate and encapsulation materials. This mesh electrode can maintain a stable electrochem. impedance in buffer soln. under 50% compressive and 50% tensile strain. We have successfully cultured pluripotent stem cell-derived human cortical organoids (hCO) on this polymeric mesh for more than 3 mo and demonstrated that organoids readily integrate with the mesh. Using simultaneous stimulation and calcium imaging, we show that elec. stimulation through the mesh can elicit intensity-dependent calcium signals comparable to stimulation from a bipolar stereotrode. This platform may serve as a tool for monitoring and modulating the elec. activity of in vitro models of neuropsychiatric diseases.
720. 720

     Huang, Q.; Tang, B.; Romero, J. C.; Yang, Y.; Elsayed, S. K.; Pahapale, G.; Lee, T.-J.; Morales Pantoja, I. E.; Han, F.; Berlinicke, C. Shell Microelectrode Arrays (MEAs) for Brain Organoids. Sci. Adv. 2022, 8, eabq5031,  DOI: 10.1126/sciadv.abq5031

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721. 721

     Le Floch, P.; Li, Q.; Lin, Z.; Zhao, S.; Liu, R.; Tasnim, K.; Jiang, H.; Liu, J. Stretchable Mesh Nanoelectronics for 3D Single-Cell Chronic Electrophysiology from Developing Brain Organoids. Adv. Mater. 2022, 34, 2106829,  DOI: 10.1002/adma.202106829

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     721

     Stretchable mesh nanoelectronics for 3D single-cell chronic electrophysiology from developing brain organoids

     Le Floch, Paul; Li, Qiang; Lin, Zuwan; Zhao, Siyuan; Liu, Ren; Tasnim, Kazi; Jiang, Han; Liu, Jia

     Advanced Materials (Weinheim, Germany) (2022), 34 (11), 2106829CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Human induced pluripotent stem cell derived brain organoids have shown great potential for studies of human brain development and neurol. disorders. However, quantifying the evolution of the elec. properties of brain organoids during development is currently limited by the measurement techniques, which cannot provide long-term stable 3D bioelec. interfaces with developing brain organoids. Here, a cyborg brain organoid platform is reported, in which "tissue-like" stretchable mesh nanoelectronics are designed to match the mech. properties of brain organoids and to be folded by the organogenetic process of progenitor or stem cells, distributing stretchable electrode arrays across the 3D organoids. The tissue-wide integrated stretchable electrode arrays show no interruption to brain organoid development, adapt to the vol. and morphol. changes during brain organoid organogenesis, and provide long-term stable elec. contacts with neurons within brain organoids during development. The seamless and noninvasive coupling of electrodes to neurons enables long-term stable, continuous recording and captures the emergence of single-cell action potentials from early-stage brain organoid development.
722. 722

     Kalmykov, A.; Huang, C.; Bliley, J.; Shiwarski, D.; Tashman, J.; Abdullah, A.; Rastogi, S. K.; Shukla, S.; Mataev, E.; Feinberg, A. W. Organ-on-e-Chip: Three-Dimensional Self-Rolled Biosensor Array for Electrical Interrogations of Human Electrogenic Spheroids. Sci. Adv. 2019, 5, eaax0729,  DOI: 10.1126/sciadv.aax0729

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723. 723

     Darrigues, E.; Nima, Z. A.; Griffin, R. J.; Anderson, J. M.; Biris, A. S.; Rodriguez, A. 3D Cultures for Modeling Nanomaterial-Based Photothermal Therapy. Nanoscale Horiz. 2020, 5, 400– 430,  DOI: 10.1039/C9NH00628A

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     De Simone, U.; Roccio, M.; Gribaldo, L.; Spinillo, A.; Caloni, F.; Coccini, T. Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure. Int. J. Mol. Sci. 2018, 19, 1993,  DOI: 10.3390/ijms19071993

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725. 725

     Marino, A.; Camponovo, A.; Degl’Innocenti, A.; Bartolucci, M.; Tapeinos, C.; Martinelli, C.; De Pasquale, D.; Santoro, F.; Mollo, V.; Arai, S.; Suzuki, M.; Harada, Y.; Petretto, A.; Ciofani, G. Multifunctional Temozolomide-Loaded Lipid Superparamagnetic Nanovectors: Dual Targeting and Disintegration of Glioblastoma Spheroids by Synergic Chemotherapy and Hyperthermia Treatment. Nanoscale 2019, 11, 21227– 21248,  DOI: 10.1039/C9NR07976A

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     725

     Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment

     Marino, Attilio; Camponovo, Alice; Degl'Innocenti, Andrea; Bartolucci, Martina; Tapeinos, Christos; Martinelli, Chiara; De Pasquale, Daniele; Santoro, Francesca; Mollo, Valentina; Arai, Satoshi; Suzuki, Madoka; Harada, Yoshie; Petretto, Andrea; Ciofani, Gianni

     Nanoscale (2019), 11 (44), 21227-21248CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

     Aiming at finding new solns. for fighting glioblastoma multiforme, one of the most aggressive and lethal human cancer, here an in vitro validation of multifunctional nanovectors for drug delivery and hyperthermia therapy is proposed. Hybrid magnetic lipid nanoparticles have been fully characterized and tested on a multi-cellular complex model resembling the tumor microenvironment. Investigations of cancer therapy based on a phys. approach (namely hyperthermia) and on a pharmaceutical approach (by exploiting the chemotherapeutic drug temozolomide) have been extensively carried out, by evaluating its antiproliferative and pro-apoptotic effects on 3D models of glioblastoma multiforme. A systematic study of transcytosis and endocytosis mechanisms has been moreover performed with multiple complimentary investigations, besides a detailed description of local temp. increments following hyperthermia application. Finally, an in-depth proteomic anal. corroborated the obtained findings, which can be summarized in the prepn. of a versatile, multifunctional, and effective nanoplatform able to overcome the blood-brain barrier and to induce powerful anti-cancer effects on in vitro complex models.
726. 726

     Arvanitis, C. D.; Ferraro, G. B.; Jain, R. K. The Blood-Brain Barrier and Blood-Tumour Barrier in Brain Tumours and Metastases. Nat. Rev. Cancer 2020, 20, 26– 41,  DOI: 10.1038/s41568-019-0205-x

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     The blood-brain barrier and blood-tumour barrier in brain tumours and metastases

     Arvanitis, Costas D.; Ferraro, Gino B.; Jain, Rakesh K.

     Nature Reviews Cancer (2020), 20 (1), 26-41CODEN: NRCAC4; ISSN:1474-175X. (Nature Research)

     For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumors as well as brain metastases. In this Review, we highlight the cellular and mol. components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumors are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumor barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of mols. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging mol., cellular and phys. strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biol. approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
727. 727

     Khaitan, D.; Reddy, P. L.; Ningaraj, N. Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges. Curr. Clin. Pharmacol. 2018, 13, 110– 119,  DOI: 10.2174/1574884713666180412150153

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     727

     Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges

     Khaitan, Divya; Reddy, Polluru L.; Ningaraj, Nagendra

     Current Clinical Pharmacology (2018), 13 (2), 110-119CODEN: CCPUC5; ISSN:1574-8847. (Bentham Science Publishers Ltd.)

     A review. This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized mols. and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addn., we discussed multimeric mol. therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors. In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells. This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clin. developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.
728. 728

     Tang, W.; Fan, W.; Lau, J.; Deng, L.; Shen, Z.; Chen, X. Emerging Blood-Brain-Barrier-Crossing Nanotechnology for Brain Cancer Theranostics. Chem. Soc. Rev. 2019, 48, 2967– 3014,  DOI: 10.1039/C8CS00805A

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     Emerging blood-brain-barrier-crossing nanotechnology for brain cancer theranostics

     Tang, Wei; Fan, Wenpei; Lau, Joseph; Deng, Liming; Shen, Zheyu; Chen, Xiaoyuan

     Chemical Society Reviews (2019), 48 (11), 2967-3014CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     Brain cancer, esp. the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 mo. Drug delivery to the brain is significantly hindered by the existence of the blood-brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnol. have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumors. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnol., with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumor accumulation, precise tumor imaging, and significant tumor inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnol. in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.
729. 729

     Jafari, B.; Pourseif, M. M.; Barar, J.; Rafi, M. A.; Omidi, Y. Peptide-Mediated Drug Delivery across the Blood-Brain Barrier for Targeting Brain Tumors. Expert Opin. Drug Delivery 2019, 16, 583– 605,  DOI: 10.1080/17425247.2019.1614911

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     Peptide-mediated drug delivery across the blood-brain barrier for targeting brain tumors

     Jafari, Behzad; Pourseif, Mohammad M.; Barar, Jaleh; Rafi, Mohammad A.; Omidi, Yadollah

     Expert Opinion on Drug Delivery (2019), 16 (6), 583-605CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)

     : Transportation of the nutrients and other substances from the blood to the brain is selectively controlled by the brain capillary endothelial cells that form a restrictive barrier, so-called blood-brain barrier (BBB). Currently, there is no unimpeachable approach to overcome the BBB obstructiveness because the existing options are either invasive or ineffective.: This review delineates the biol. impacts of BBB on brain drug delivery and targeting. The nanoscaled multifunctional shuttles armed with the targeting entities (e.g., antibodies and peptides) are discussed. Important insights are remarked into the combinatorial screening methodologies used for the identification of de novo peptides capable of crossing BBB and targeting the brain.: Depending on the physicochem. properties of small mols. and macromols., they may cross the BBB and get into the brain either through passive diffusion or active/facilitated transportation and transcytosis in a very selectively controlled manner. Phage-derived shuttle peptides can specifically be selected against BBB endocytic machinery and used in engineering novel peptide-drug conjugates (PDCs). Nanoscaled multitargeting delivery systems encompassing PDCs can overcome the BBB obstructiveness and deliver drugs specifically to diseased cells in the brain with trivial side effects.
730. 730

     Noël, X.; Bechara, A. Bridging the Gap between the Lab and the Clinic: Psychopathology’s Grand Challenge. Front. Psychol. 2016, 7, 1752,  DOI: 10.3389/fpsyg.2016.01752

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     Sirota, A.; Montgomery, S.; Fujisawa, S.; Isomura, Y.; Zugaro, M.; Buzsáki, G. Entrainment of Neocortical Neurons and Gamma Oscillations by the Hippocampal Theta Rhythm. Neuron 2008, 60, 683– 697,  DOI: 10.1016/j.neuron.2008.09.014

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     Patrono, E.; Hrůzova, K.; Svoboda, J.; Stuchlík, A. The Role of Optogenetic Stimulations of Parvalbumin-Positive Interneurons in the Prefrontal Cortex and the Ventral Hippocampus on an Acute MK-801 Model of Schizophrenia-Like Cognitive Inflexibility. Schizophr. Res. 2023, 252, 198– 205,  DOI: 10.1016/j.schres.2022.12.047

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     Szczurowska, E.; Ahuja, N.; Jiruška, P.; Kelemen, E.; Stuchlík, A. Impairment of Neural Coordination in Hippocampal Neuronal Ensembles after a Psychotomimetic Dose of Dizocilpine. Prog. Neuro-Psychopharmacol. 2018, 81, 275– 283,  DOI: 10.1016/j.pnpbp.2017.09.013

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     Brofiga, M.; Pisano, M.; Tedesco, M.; Boccaccio, A.; Massobrio, P. Functional Inhibitory Connections Modulate the Electrophysiological Activity Patterns of Cortical-Hippocampal Ensembles. Cerebr. Cortex 2022, 32, 1866– 1881,  DOI: 10.1093/cercor/bhab318

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     Callegari, F.; Brofiga, M.; Poggio, F.; Massobrio, P. Stimulus-Evoked Activity Modulation of in Vitro Engineered Cortical and Hippocampal Networks. Micromachines 2022, 13, 1212,  DOI: 10.3390/mi13081212

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     Brofiga, M.; Massobrio, P. Brain-on-a-Chip: Dream or Reality?. Front. Neurosci. 2022, 16, 837623,  DOI: 10.3389/fnins.2022.837623

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     Amirifar, L.; Shamloo, A.; Nasiri, R.; de Barros, N. R.; Wang, Z. Z.; Unluturk, B. D.; Libanori, A.; Ievglevskyi, O.; Diltemiz, S. E.; Sances, S. Brain-on-a-Chip: Recent Advances in Design and Techniques for Microfluidic Models of the Brain in Health and Disease. Biomaterials 2022, 285, 121531,  DOI: 10.1016/j.biomaterials.2022.121531

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     737

     Brain-on-a-chip: Recent advances in design and techniques for microfluidic models of the brain in health and disease

     Amirifar, Leyla; Shamloo, Amir; Nasiri, Rohollah; de Barros, Natan Roberto; Wang, Ze Zhong; Unluturk, Bige Deniz; Libanori, Alberto; Ievglevskyi, Oleksandr; Diltemiz, Sibel Emir; Sances, Samuel; Balasingham, Ilangko; Seidlits, Stephanie K.; Ashammakhi, Nureddin

     Biomaterials (2022), 285 (), 121531CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     A review. Recent advances in biomaterials, microfabrication, microfluidics, and cell biol. have led to the development of organ-on-a-chip devices that can reproduce key functions of various organs. Such platforms promise to provide novel insights into various physiol. events, including mechanisms of disease, and evaluate the effects of external interventions, such as drug administration. The neuroscience field is expected to benefit greatly from these innovative tools. Conventional ex vivo studies of the nervous system have been limited by the inability of cell culture to adequately mimic in vivo physiol. While animal models can be used, their relevance to human physiol. is uncertain and their use is laborious and assocd. with ethical issues. To date, organ-on-a-chip systems have been developed to model different tissue components of the brain, including brain regions with specific functions and the blood brain barrier, both in normal and pathophysiol. conditions. While the field is still in its infancy, it is expected to have major impact on studies of neurophysiol., pathol. and neuropharmacol. in future. Here, we review advances made and limitations faced in an effort to stimulate development of the next generation of brain-on-a-chip devices.
738. 738

     Dai, M.; Xiao, G.; Shao, M.; Zhang, Y. S. The Synergy between Deep Learning and Organs-on-Chips for High-Throughput Drug Screening: A Review. Biosensors 2023, 13, 389,  DOI: 10.3390/bios13030389

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739. 739

     Kamudzandu, M.; Köse-Dunn, M.; Evans, M. G.; Fricker, R. A.; Roach, P. A Micro-Fabricated in Vitro Complex Neuronal Circuit Platform. Biomed. Phys. Eng. Express 2019, 5, 045016,  DOI: 10.1088/2057-1976/ab2307

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740. 740

     Nikolakopoulou, P.; Rauti, R.; Voulgaris, D.; Shlomy, I.; Maoz, B. M.; Herland, A. Recent Progress in Translational Engineered in Vitro Models of the Central Nervous System. Brain 2020, 143, 3181– 3213,  DOI: 10.1093/brain/awaa268

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     740

     Recent progress in translational engineered in vitro models of the central nervous system

     Nikolakopoulou Polyxeni; Herland Anna; Rauti Rossana; Shlomy Iftach; Maoz Ben M; Voulgaris Dimitrios; Herland Anna; Maoz Ben M; Maoz Ben M

     Brain : a journal of neurology (2020), 143 (11), 3181-3213 ISSN:.

     The complexity of the human brain poses a substantial challenge for the development of models of the CNS. Current animal models lack many essential human characteristics (in addition to raising operational challenges and ethical concerns), and conventional in vitro models, in turn, are limited in their capacity to provide information regarding many functional and systemic responses. Indeed, these challenges may underlie the notoriously low success rates of CNS drug development efforts. During the past 5 years, there has been a leap in the complexity and functionality of in vitro systems of the CNS, which have the potential to overcome many of the limitations of traditional model systems. The availability of human-derived induced pluripotent stem cell technology has further increased the translational potential of these systems. Yet, the adoption of state-of-the-art in vitro platforms within the CNS research community is limited. This may be attributable to the high costs or the immaturity of the systems. Nevertheless, the costs of fabrication have decreased, and there are tremendous ongoing efforts to improve the quality of cell differentiation. Herein, we aim to raise awareness of the capabilities and accessibility of advanced in vitro CNS technologies. We provide an overview of some of the main recent developments (since 2015) in in vitro CNS models. In particular, we focus on engineered in vitro models based on cell culture systems combined with microfluidic platforms (e.g. 'organ-on-a-chip' systems). We delve into the fundamental principles underlying these systems and review several applications of these platforms for the study of the CNS in health and disease. Our discussion further addresses the challenges that hinder the implementation of advanced in vitro platforms in personalized medicine or in large-scale industrial settings, and outlines the existing differentiation protocols and industrial cell sources. We conclude by providing practical guidelines for laboratories that are considering adopting organ-on-a-chip technologies.
741. 741

     Tessier-Lavigne, M.; Goodman, C. S. The Molecular Biology of Axon Guidance. Science 1996, 274, 1123– 1133,  DOI: 10.1126/science.274.5290.1123

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     741

     The molecular biology of axon guidance

     Tessier-Lavigne, Marc; Goodman, Corey S.

     Science (Washington, D. C.) (1996), 274 (5290), 1123-1133CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     A review, with 121 refs. Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and mols. that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
742. 742

     Luo, B.; Tiwari, A. P.; Chen, N.; Ramakrishna, S.; Yang, I. H. Development of an Axon-Guiding Aligned Nanofiber-Integrated Compartmentalized Microfluidic Neuron Culture System. ACS Appl. Bio Mater. 2021, 4, 8424– 8432,  DOI: 10.1021/acsabm.1c00960

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     742

     Development of an Axon-Guiding Aligned Nanofiber-Integrated Compartmentalized Microfluidic Neuron Culture System

     Luo, Baiwen; Tiwari, Arjun Prasad; Chen, Nuan; Ramakrishna, Seeram; Yang, In Hong

     ACS Applied Bio Materials (2021), 4 (12), 8424-8432CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)

     Microfluidic-based neuron cell culture systems have recently gained a lot of attention due to their efficiency in supporting the spatial and temporal control of cellular microenvironments. However, the lack of axon guidance is the key limitation in current culture systems. To combat this, we have developed electrospun aligned nanofiber-integrated compartmentalized microfluidic neuron culture systems (NIMSs), where the nanofibers have enabled axonal guidance and stability. The resulting platform significantly improved axon alignment, length, and stability for both rat primary embryonic motor neurons (MNs) and dorsal root ganglia (DRG) neurons compared to the conventional glass-based microfluidic systems (GMSs). The results showed that axonal growth covered more than two times the area on the axonal chamber of NIMSs compared to the area covered for GMSs. Overall, this platform can be used as a valuable tool for fundamental neuroscience research, drug screening, and biomaterial testing.
743. 743

     Virlogeux, A.; Moutaux, E.; Christaller, W.; Genoux, A.; Bruyere, J.; Fino, E.; Charlot, B.; Cazorla, M.; Saudou, F. Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease. Cell Rep. 2018, 22, 110– 122,  DOI: 10.1016/j.celrep.2017.12.013

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     743

     Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington's Disease

     Virlogeux, Amandine; Moutaux, Eve; Christaller, Wilhelm; Genoux, Aurelie; Bruyere, Julie; Fino, Elodie; Charlot, Benoit; Cazorla, Maxime; Saudou, Frederic

     Cell Reports (2018), 22 (1), 110-122CODEN: CREED8; ISSN:2211-1247. (Cell Press)

     Huntington's disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease is unclear due to difficulties performing early subcellular investigations in vivo. Here, we have developed an on-a-chip approach to reconstitute an HD corticostriatal network in vitro, using microfluidic devices compatible with subcellular resoln. We obsd. major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling, that correlate with altered global synchrony of the network. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit. This highlights an important wt. for the presynaptic compartment in HD that has to be considered for future therapies. This disease-on-a-chip microfluidic platform is thus a physiol. relevant in vitro system for investigating pathogenic mechanisms and for identifying drugs.
744. 744

     Dauth, S.; Maoz, B. M.; Sheehy, S. P.; Hemphill, M. A.; Murty, T.; Macedonia, M. K.; Greer, A. M.; Budnik, B.; Parker, K. K. Neurons Derived from Different Brain Regions Are Inherently Different in Vitro: A Novel Multiregional Brain-on-a-Chip. J. Neurophysiol. 2017, 117, 1320– 1341,  DOI: 10.1152/jn.00575.2016

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     744

     Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip

     Dauth, Stephanie; Maoz, Ben M.; Sheehy, Sean P.; Hemphill, Matthew A.; Murty, Tara; Macedonia, Mary Kate; Greer, Angie M.; Budnik, Bogdan; Parker, Kevin Kit

     Journal of Neurophysiology (2017), 117 (3), 1320-1341CODEN: JONEA4; ISSN:0022-3077. (American Physiological Society)

     Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiol., potential neurotoxic effects of chems., and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell compn., protein expression, metab., and elec. activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and obsd. a redn. of overall firing activity, as well as altered amts. of astrocytes and specific neuronal cell types compared with sep. cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas sep. while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features. NEW AND NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections.
745. 745

     Taylor, A. M.; Blurton-Jones, M.; Rhee, S. W.; Cribbs, D. H.; Cotman, C. W.; Jeon, N. L. A Microfluidic Culture Platform for CNS Axonal Injury, Regeneration and Transport. Nat. Methods 2005, 2, 599– 605,  DOI: 10.1038/nmeth777

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     745

     A microfluidic culture platform for CNS axonal injury, regeneration and transport

     Taylor, Anne M.; Blurton-Jones, Mathew; Rhee, Seog Woo; Cribbs, David H.; Cotman, Carl W.; Jeon, Noo Li

     Nature Methods (2005), 2 (8), 599-605CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)

     Investigation of axonal biol. in the central nervous system (CNS) is hindered by a lack of an appropriate in vitro method to probe axons independently from cell bodies. Here the authors describe a microfluidic culture platform that polarizes the growth of CNS axons into a fluidically isolated environment without the use of targeting neurotrophins. In addn. to its compatibility with live cell imaging, the platform can be used to (i) isolate CNS axons without somata or dendrites, facilitating biochem. analyses of pure axonal fractions and (ii) localize phys. and chem. treatments to axons or somata. The authors report the first evidence that presynaptic (Syp) but not postsynaptic (Camk2a) mRNA is localized to developing rat cortical and hippocampal axons. The platform also serves as a straightforward, reproducible method to model CNS axonal injury and regeneration. The results presented here demonstrate several exptl. paradigms using the microfluidic platform, which can greatly facilitate future studies in axonal biol.
746. 746

     Podbiel, D.; Laermer, F.; Zengerle, R.; Hoffmann, J. Fusing MEMS Technology with Lab-on-Chip: Nanoliter-Scale Silicon Microcavity Arrays for Digital DNA Quantification and Multiplex Testing. Microsyst. Nanoeng. 2020, 6, 82,  DOI: 10.1038/s41378-020-00187-1

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     746

     Fusing MEMS technology with lab-on-chip: nanoliter-scale silicon microcavity arrays for digital DNA quantification and multiplex testing

     Podbiel, Daniel; Laermer, Franz; Zengerle, Roland; Hoffmann, Jochen

     Microsystems & Nanoengineering (2020), 6 (1), 82CODEN: MNIACT; ISSN:2055-7434. (Nature Research)

     Abstr.: We report on the development of a microfluidic multiplexing technol. for highly parallelized sample anal. via quant. polymerase chain reaction (PCR) in an array of 96 nL-scale microcavities made from silicon. This PCR array technol. features fully automatable aliquoting microfluidics, a robust sample compartmentalization up to temps. of 95 °C, and an application-specific prestorage of reagents within the 25 nl microcavities. The here presented hybrid silicon-polymer microfluidic chip allows both a rapid thermal cycling of the liq. compartments and a real-time fluorescence read-out for a tracking of the individual amplification reactions taking place inside the microcavities. We demonstrate that the technol. provides very low reagent carryover of prestored reagents < 6 x 10-2 and a cross talk rate < 1 x 10-3 per PCR cycle, which facilitate a multi-targeted sample anal. via geometric multiplexing. Furthermore, we apply this PCR array technol. to introduce a novel digital PCR-based DNA quantification method: by taking the assay-specific amplification characteristics like the limit of detection into account, the method allows for an abs. gene target quantification by means of a statistical anal. of the amplification results.
747. 747

     Zhao, E. T.; Hull, J. M.; Mintz Hemed, N.; Uluşan, H.; Bartram, J.; Zhang, A.; Wang, P.; Pham, A.; Ronchi, S.; Huguenard, J. R. A CMOS-Based Highly Scalable Flexible Neural Electrode Interface. Sci. Adv. 2023, 9, eadf9524,  DOI: 10.1126/sciadv.adf9524

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748. 748

     Fernandez-Cuesta, I.; Llobera, A.; Ramos-Payán, M. Optofluidic Systems Enabling Detection in Real Samples: A Review. Anal. Chim. Acta 2022, 1192, 339307,  DOI: 10.1016/j.aca.2021.339307

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749. 749

     Wang, P.; Wu, E. G.; Uluşan, H.; Phillips, A. J.; Hays, M. R.; Kling, A.; Zhao, E. T.; Madugula, S.; Vilkhu, R. S.; Vasireddy, P. K.; Hierlemann, A.; Hong, G.; Chichilnisky, E. J.; Melosh, N. A. Direct-Print Three-Dimensional Electrodes for Large-Scale, High-Density, and Customizable Neural Interfaces. bioRxiv , June 2, 2023, 542925. DOI: 10.1101/2023.05.30.542925 .

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750. 750

     Katt, M. E.; Shusta, E. V. In Vitro Models of the Blood-Brain Barrier: Building in Physiological Complexity. Curr. Opin. Chem. Eng. 2020, 30, 42– 52,  DOI: 10.1016/j.coche.2020.07.002

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     750

     In vitro Models of the Blood-Brain Barrier: Building in physiological complexity

     Katt Moriah E; Shusta Eric V; Shusta Eric V

     Current opinion in chemical engineering (2020), 30 (), 42-52 ISSN:2211-3398.

     Development of brain therapeutics is significantly hampered by the presence of the blood-brain barrier (BBB). Classical transwell models are able to recapitulate many important aspects of drug transport across the BBB, but are not completely predictive of in vivo brain uptake. Species differences further complicate translation of experimental therapeutics from the benchtop to the clinic. Human BBB models offer some solutions to this problem, and by increasing device complexity both in terms of multicellularity, flow and physical architecture, physiological models of the BBB have been developed that can more faithfully model different aspects of transport and homeostasis BBB. Using these models, it may be possible to improve the predictive capacity in benchmarking candidate therapeutics, and to identify new druggable targets by studying multicellular interactions.
751. 751

     Huber, P.; Karim, A.; Zvonkina, I.; Lee, S.-W.; Kim, J.-W.; Roper, D. K.; Li, W. J.; Gang, O. Nanomedicine 1. In Soft Matter and Biomaterials on the Nanoscale, Vol. 4; World Scientific: 2020.

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752. 752

     Kotov, N. A.; Winter, J. O.; Clements, I. P.; Jan, E.; Timko, B. P.; Campidelli, S.; Pathak, S.; Mazzatenta, A.; Lieber, C. M.; Prato, M.; Bellamkonda, R. V.; Silva, G. A.; Kam, N. W. S.; Patolsky, F.; Ballerini, L. Nanomaterials for Neural Interfaces. Adv. Mater. 2009, 21, 3970– 4004,  DOI: 10.1002/adma.200801984

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     752

     Nanomaterials for Neural Interfaces

     Kotov, Nicholas A.; Winter, Jessica O.; Clements, Isaac P.; Jan, Edward; Timko, Brian P.; Campidelli, Stephane; Pathak, Smita; Mazzatenta, Andrea; Lieber, Charles M.; Prato, Maurizio; Bellamkonda, Ravi V.; Silva, Gabriel A.; Kam, Nadine Wong Shi; Patolsky, Fernando; Ballerini, Laura

     Advanced Materials (Weinheim, Germany) (2009), 21 (40), 3970-4004CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     This review focuses on the application of nanomaterials for neural interfacing. The junction between nanotechnol. and neural tissues can be particularly worthy of scientific attention for several reasons: (i) Neural cells are electroactive, and the electronic properties of nanostructures can be tailored to match the charge transport requirements of elec. cellular interfacing. (ii) The unique mech. and chem. properties of nanomaterials are crit. for integration with neural tissue as long-term implants. (iii) Solns. to many crit. problems in neural biol./medicine are limited by the availability of specialized materials. (iv) Neuronal stimulation is needed for a variety of common and severe health problems. This confluence of need, accumulated expertise, and potential impact on the well-being of people suggests the potential of nanomaterials to revolutionize the field of neural interfacing. In this review, we begin with foundational topics, such as the current status of neural electrode (NE) technol., the key challenges facing the practical utilization of NEs, and the potential advantages of nanostructures as components of chronic implants. After that the detailed account of toxicol. and biocompatibility of nanomaterials in respect to neural tissues is given. Next, we cover a variety of specific applications of nanoengineered devices, including drug delivery, imaging, topog. patterning, electrode design, nanoscale transistors for high-resoln. neural interfacing, and photoactivated interfaces. We also critically evaluate the specific properties of particular nanomaterials-including nanoparticles, nanowires, and carbon nanotubes-that can be taken advantage of in neuroprosthetic devices. The most promising future areas of research and practical device engineering are discussed as a conclusion to the review.
753. 753

     Wellman, S. M.; Eles, J. R.; Ludwig, K. A.; Seymour, J. P.; Michelson, N. J.; McFadden, W. E.; Vazquez, A. L.; Kozai, T. D. Y. A Materials Roadmap to Functional Neural Interface Design. Adv. Funct. Mater. 2018, 28, 1701269,  DOI: 10.1002/adfm.201701269

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754. 754

     Erlebacher, J.; Aziz, M. J.; Karma, A.; Dimitrov, N.; Sieradzki, K. Evolution of Nanoporosity in Dealloying. Nature 2001, 410, 450– 453,  DOI: 10.1038/35068529

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     754

     Evolution of nanoporosity in dealloying

     Erlebacher, Jonah; Aziz, Michael J.; Karma, Alain; Dimitrov, Nikolay; Sleradzki, Karl

     Nature (London, United Kingdom) (2001), 410 (6827), 450-453CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     Dealloying is a common corrosion process during which an alloy is 'parted' by the selective dissoln. of the most electro-chem. active of its elements. This process results in the formation of a nanoporous sponge composed almost entirely of the more noble alloy constituents. Although considerable attention has been devoted to the morphol. aspects of the dealloying process, its underlying phys. mechanism has remained unclear. Here we propose a continuum model that is fully consistent with expts. and theor. simulations of alloy dissoln., and demonstrate that nanoporosity in metals is due to an intrinsic dynamical pattern formation process. That is, pores form because the more noble atoms are chem. driven to aggregate into two-dimensional clusters by a phase sepn. process (spinodal decompn.) at the solid-electrolyte interface, and the surface area continuously increases owing to etching. Together, these processes evolve porosity with a characteristic length scale predicted by our continuum model. We expect that chem. tailored nanoporous gold made by dealloying Ag-Au should be suitable for sensor applications, particularly in a biomaterials context.
755. 755

     Seker, E.; Berdichevsky, Y.; Begley, M. R.; Reed, M. L.; Staley, K. J.; Yarmush, M. L. The Fabrication of Low-Impedance Nanoporous Gold Multiple-Electrode Arrays for Neural Electrophysiology Studies. Nanotechnology 2010, 21, 125504,  DOI: 10.1088/0957-4484/21/12/125504

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     755

     The fabrication of low-impedance nanoporous gold multiple-electrode arrays for neural electrophysiology studies

     Seker, Erkin; Berdichevsky, Yevgeny; Begley, Matthew R.; Reed, Michael L.; Staley, Kevin J.; Yarmush, Martin L.

     Nanotechnology (2010), 21 (12), 125504/1-125504/7CODEN: NNOTER; ISSN:1361-6528. (Institute of Physics Publishing)

     Neural electrodes are essential tools for the study of the nervous system and related diseases. Low electrode impedance is a figure of merit for sensitive detection of neural elec. activity and numerous studies have aimed to reduce impedance. Unfortunately, most of these efforts have been tethered by a combination of poor functional coating adhesion, complicated fabrication techniques, and poor fabrication repeatability. We address these issues with a facile method for reliably producing multiple-electrode arrays with low impedance by patterning highly adherent nanoporous gold films using conventional microfabrication techniques. The high surface area-to-vol. ratio of self-assembled nanoporous gold results in a more than 25-fold improvement in the electrode-electrolyte impedance, where at 1 kHz, 850 kΩ impedance for conventional Au electrodes is reduced to 30 kΩ for nanoporous gold electrodes. Low impedance provides a superior signal-to-noise ratio for detection of neural activity in noisy environments. We systematically studied the effect of film morphol. on electrode impedance and successfully recorded field potentials from rat hippocampal slices. Here, we present our fabrication approach, the relationship between film morphol. and impedance, and field potential recordings.
756. 756

     Daggumati, P.; Matharu, Z.; Wang, L.; Seker, E. Biofouling-Resilient Nanoporous Gold Electrodes for DNA Sensing. Anal. Chem. 2015, 87, 8618– 8622,  DOI: 10.1021/acs.analchem.5b02969

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     756

     Biofouling-resilient nanoporous gold electrodes for DNA sensing

     Daggumati, Pallavi; Matharu, Zimple; Wang, Ling; Seker, Erkin

     Analytical Chemistry (Washington, DC, United States) (2015), 87 (17), 8618-8622CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

     Electrochem. nucleic acid sensors are promising tools for point-of-care diagnostic platforms with their facile integration with electronics and scalability. However, nucleic acid detection in complex biol. fluids is challenging as biomols. nonspecifically adsorb on the electrode surface and adversely affect the sensor performance by obscuring the transport of analytes and redox species to the electrode. We report that nanoporous gold (np-Au) electrodes, prepd. by a microfabrication-compatible self-assembly process and functionalized with DNA probes, enabled detection of target DNA mols. (10-200 nM) in physiol. relevant complex media (bovine serum albumin and fetal bovine serum). In contrast, the sensor performance was compromised for planar gold electrodes in the same conditions. Hybridization efficiency decreased by 10% for np-Au with coarser pores revealing a pore-size dependence of sensor performance in biofouling conditions. This nanostructure-dependent functionality in complex media suggests that the pores with the optimal size and geometry act as sieves for blocking the biomols. from inhibiting the surfaces within the porous vol. while allowing the transport of nucleic acid analytes and redox mols.
757. 757

     Patel, J.; Radhakrishnan, L.; Zhao, B.; Uppalapati, B.; Daniels, R. C.; Ward, K. R.; Collinson, M. M. Electrochemical Properties of Nanostructured Porous Gold Electrodes in Biofouling Solutions. Anal. Chem. 2013, 85, 11610– 11618,  DOI: 10.1021/ac403013r

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     757

     Electrochemical Properties of Nanostructured Porous Gold Electrodes in Biofouling Solutions

     Patel, Jay; Radhakrishnan, Logudurai; Zhao, Bo; Uppalapati, Badharinadh; Daniels, Rodney C.; Ward, Kevin R.; Collinson, Maryanne M.

     Analytical Chemistry (Washington, DC, United States) (2013), 85 (23), 11610-11618CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

     The effect of electrode porosity on the electrochem. response of redox active mols. (K ferricyanide, Ru-(III) hexammine, and ferrocenemethanol) in the presence of bovine serum albumin or fibrinogen was studied at macroporous (pore diam.: 1200 nm), hierarchical (1200/60 nm), and nanoporous (<50 nm) Au. These electrodes were prepd. using std. templating or dealloying techniques, and cyclic voltammetry (CV) was used to evaluate the effect of protein adsorption on the electron transfer of the diffusing redox probes. Following exposure to albumin (or fibrinogen) under near neutral pH conditions, planar Au electrodes showed an immediate redn. in faradaic peak current and increase in peak splitting for K ferricyanide. The rate at which the CV curves changed was highly dependent on the morphol. of the electrode. For example, the time required for the faradaic current to drop to 1/2 of its original value was 3, 12, and 38 min for planar Au, macroporous Au, and hierarchical Au, resp. Remarkably, for nanoporous Au, only a few percent drop in the peak faradaic current was obsd. after an hour in soln. A similar suppression in the voltammetry at planar Au was also noted for Ru hexammine at pH 3 after exposure to albumin for several hours. At nanoporous Au, no significant loss in response was obsd. The order of performance of the electrodes as judged by their ability to efficiently transfer electrons in the presence of biofouling agents tracked porosity with the electrode having the smallest pore size and largest surface area, providing near ideal results. Nanoporous Au electrodes when immersed in serum or heparinized blood contg. K ferricyanide showed ideal voltammetry while significant fouling was evident in the electrochem. response at planar Au. The small nanopores in this 3-dimensional open framework are believed to restrict the transport of large biomols., thus minimizing passivation of the inner surfaces while permitting access to small redox probes to efficiently exchange electrons.
758. 758

     Chapman, C. A. R.; Wang, L.; Chen, H.; Garrison, J.; Lein, P. J.; Seker, E. Nanoporous Gold Biointerfaces: Modifying Nanostructure to Control Neural Cell Coverage and Enhance Electrophysiological Recording Performance. Adv. Funct. Mater. 2017, 27, 1604631,  DOI: 10.1002/adfm.201604631

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759. 759

     Sánchez, G.; Dalchiele, E.; Bologna Alles, A. Electrical Characterization of Titanium Nitride Surfaces for Pacing Electrodes. J. Mater. Sci. 2006, 41, 3241– 3247,  DOI: 10.1007/s10853-005-5477-8

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760. 760

     Abend, A.; Steele, C.; Schmidt, S.; Frank, R.; Jahnke, H.-G.; Zink, M. Neuronal and Glial Cell Co-Culture Organization and Impedance Spectroscopy on Nanocolumnar TiN Films for Lab-on-a-Chip Devices. Biomater. Sci. 2022, 10, 5719– 5730,  DOI: 10.1039/D2BM01066F

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761. 761

     Kim, Y. H.; Koo, H.; Kim, M. S.; Jung, S.-D. Iridium Oxide on Indium-Tin Oxide Nanowires: An All Metal Oxide Heterostructured Multi-Electrode Array for Neuronal Interfacing. Sens. Actuators, B 2018, 273, 718– 725,  DOI: 10.1016/j.snb.2018.06.045

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     761

     Iridium oxide on indium-tin oxide nanowires: An all metal oxide heterostructured multi-electrode array for neuronal interfacing

     Kim, Yong Hee; Koo, Ho; Kim, Min Sun; Jung, Sang-Don

     Sensors and Actuators, B: Chemical (2018), 273 (), 718-725CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)

     All metal oxide heterostructured multielectrode arrays consisting of indium-tin oxide nanowires (ITO NWs) and an iridium oxide (IrOx) layer were fabricated. The needle-type ITO NWs were grown on an ITO electrode using a radio frequency magnetron sputtering technique followed by electrodeposition of an IrOx layer. The major advantage of this fabrication technique is in its simplicity because it does not require templates and seed layers to grow the ITO NWs. A transmission electron microscope found the IrOx to be uniformly electrodeposited over the surface of the ITO NW. After the electrodeposition process, the charge storage capacitance (CSC) of the ITO NW electrode increased from 0.09 to 4.25mCcm-2, and the IrOx/ITO NW electrode exhibited a charge injection limit of 1.9mCcm-2 and CSC utilization efficiency of approx. 45%. The stimulation performance of the IrOx/ITO NW electrode was confirmed using rat hippocampal slices, which exhibited a higher neg. peak amplitude in the field excitatory postsynaptic potential when stimulated by a single pulse, and more effectively induced long-term potentiation via a theta burst stimulation compared with an ITO NW electrode. These results indicate that the synergetic combination of ITO NWs and a very thin IrOx layer enhanced the performance of the stimulus.
762. 762

     Chen, C.; Ruan, S.; Bai, X.; Lin, C.; Xie, C.; Lee, I.-S. Patterned Iridium Oxide Film as Neural Electrode Interface: Biocompatibility and Improved Neurite Outgrowth with Electrical Stimulation. Mater. Sci. Eng., C 2019, 103, 109865,  DOI: 10.1016/j.msec.2019.109865

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     762

     Patterned iridium oxide film as neural electrode interface: Biocompatibility and improved neurite outgrowth with electrical stimulation

     Chen, Cen; Ruan, Shichao; Bai, Xue; Lin, Chenming; Xie, Chungang; Lee, In-Seop

     Materials Science & Engineering, C: Materials for Biological Applications (2019), 103 (), 109865CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

     Iridium (Ir) thin film was deposited on patterned titanium substrate by direct-current (DC) magnetron sputtering, and then activated in sulfuric acid (H2SO4) through repetitive potential sweeps to form iridium oxide (IrOx) as neural electrode interface. The resultant IrOx film showed a porous and open morphol. with aligned microstructure, exhibited superior electrochem. performance and excellent stability. The IrOx film supported neural stem cells (NSCs) attachment, proliferation and improved processes without causing toxicity. The patterned IrOx films offered a unique system to investigate the synergistic effects of topog. cue and elec. stimulation on neurite outgrowth. Elec. stimulation, when applied through patterned IrOx films, was found to further increase the neurite extension of neuron-like cells and significantly reorient the neurite alignment towards to the direction of stimulation. These results indicate that IrOx film, as electrode-tissue interface is highly stable and biocompatible with excellent electrochem. properties.
763. 763

     Yamagiwa, S.; Fujishiro, A.; Sawahata, H.; Numano, R.; Ishida, M.; Kawano, T. Layer-by-Layer Assembled Nanorough Iridium-Oxide/Platinum-Black for Low-Voltage Microscale Electrode Neurostimulation. Sens. Actuators, B 2015, 206, 205– 211,  DOI: 10.1016/j.snb.2014.09.048

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     763

     Layer-by-layer assembled nanorough iridium-oxide/platinum-black for low-voltage microscale electrode neurostimulation

     Yamagiwa, Shota; Fujishiro, Akifumi; Sawahata, Hirohito; Numano, Rika; Ishida, Makoto; Kawano, Takeshi

     Sensors and Actuators, B: Chemical (2015), 206 (), 205-211CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)

     Elec. neural stimulating electrodes play an important role in medical applications and improving health/medical conditions. However, size redn. for low-invasive electrodes creates issues with high electrolyte/electrode interfacial impedance and low charge-injection characteristics, which makes it impossible to stimulate neurons/cells. To overcome these limitations, we propose an electrode material for low-voltage microscale electrode neurostimulation that combines the advantages of low impedance of iridium oxide (IrOx) with the enhanced surface area of platinum black (Pt-black). Based on a simple, rapid, low-temp. electroplating process, herein a low impedance and high charge-injection electrode is fabricated by a layer-by-layer assembly of IrOx/Pt-black with nanoscale roughness. The assembled nanorough-IrOx/Pt-black electrode has an impedance of 32 Ω cm2 at 1 kHz and a charge-injection delivery capacity (QCDC) of 46.7 mC cm-2, which are 0.5 and 2.4 times the values for the same-sized IrOx/flat-Pt electrode, resp. The stimulation capability of the nanorough-IrOx/Pt-black plated microelectrode is confirmed by in vivo stimulations of the sciatic nerve of a mouse. The threshold voltages of 8-μm-diam. and 11-μm-diam. electrodes are 700 mV and 300 mV, resp. However, increasing the diam. of high QCDC nanorough-IrOx/Pt-black can further reduce the stimulation voltage. Consequently, nanorough-IrOx/Pt-black is applicable to low-voltage microscale electrode neurostimulations for powerful in vivo/in vitro electrophysiol. measurements.
764. 764

     Kim, Y. H.; Kim, G. H.; Kim, M. S.; Jung, S. D. Iridium Oxide-Electrodeposited Nanoporous Gold Multielectrode Array with Enhanced Stimulus Efficacy. Nano Lett. 2016, 16, 7163– 7168,  DOI: 10.1021/acs.nanolett.6b03473

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765. 765

     Ganji, M.; Paulk, A. C.; Yang, J. C.; Vahidi, N. W.; Lee, S. H.; Liu, R.; Hossain, L.; Arneodo, E. M.; Thunemann, M.; Shigyo, M.; Tanaka, A.; Ryu, S. B.; Lee, S. W.; Tchoe, Y.; Marsala, M.; Devor, A.; Cleary, D. R.; Martin, J. R.; Oh, H.; Gilja, V.; Gentner, T. Q.; Fried, S. I.; Halgren, E.; Cash, S. S.; Dayeh, S. A. Selective Formation of Porous Pt Nanorods for Highly Electrochemically Efficient Neural Electrode Interfaces. Nano Lett. 2019, 19, 6244– 6254,  DOI: 10.1021/acs.nanolett.9b02296

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     765

     Selective Formation of Porous Pt Nanorods for Highly Electrochemically Efficient Neural Electrode Interfaces

     Ganji, Mehran; Paulk, Angelique C.; Yang, Jimmy C.; Vahidi, Nasim W.; Lee, Sang Heon; Liu, Ren; Hossain, Lorraine; Arneodo, Ezequiel M.; Thunemann, Martin; Shigyo, Michiko; Tanaka, Atsunori; Ryu, Sang Baek; Lee, Seung Woo; Tchoe, Youngbin; Marsala, Martin; Devor, Anna; Cleary, Daniel R.; Martin, Joel R.; Oh, Hongseok; Gilja, Vikash; Gentner, Timothy Q.; Fried, Shelley I.; Halgren, Eric; Cash, Sydney S.; Dayeh, Shadi A.

     Nano Letters (2019), 19 (9), 6244-6254CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)

     The enhanced electrochem. activity of nanostructured materials is readily exploited in energy devices, but their utility in scalable and human-compatible implantable neural interfaces can significantly advance the performance of clin. and research electrodes. We utilize low-temp. selective dealloying to develop scalable and biocompatible one-dimensional platinum nanorod (PtNR) arrays that exhibit superb electrochem. properties at various length scales, stability, and biocompatibility for high performance neurotechnologies. PtNR arrays record brain activity with cellular resoln. from the cortical surfaces in birds and nonhuman primates. Significantly, strong modulation of surface recorded single unit activity by auditory stimuli is demonstrated in European Starling birds as well as the modulation of local field potentials in the visual cortex by light stimuli in a nonhuman primate and responses to elec. stimulation in mice. PtNRs record behaviorally and physiol. relevant neuronal dynamics from the surface of the brain with high spatiotemporal resoln., which paves the way for less invasive brain-machine interfaces.
766. 766

     Seker, E.; Berdichevsky, Y.; Staley, K. J.; Yarmush, M. L. Microfabrication-Compatible Nanoporous Gold Foams as Biomaterials for Drug Delivery. Adv. Healthc. Mater. 2012, 1, 172– 176,  DOI: 10.1002/adhm.201200002

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     766

     Microfabrication-compatible nanoporous gold foams as biomaterials for drug delivery

     Seker, Erkin; Berdichevsky, Yevgeny; Staley, Kevin J.; Yarmush, Martin L.

     Advanced Healthcare Materials (2012), 1 (2), 172-176CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Nanoporous gold is a promising material for multi-functional bio-interfaces with its well-characterized surface chem., compatibility with conventional micropatterning techniques, elec. cond., and high effective surface-area for mol. release. This paper demonstrates its biocompatibility and capability for drug release to modulate cellular response.
767. 767

     Li, Z.; Polat, O.; Seker, E. Voltage-Gated Closed-Loop Control of Small-Molecule Release from Alumina-Coated Nanoporous Gold Thin Film Electrodes. Adv. Funct. Mater. 2018, 28, 1801292,  DOI: 10.1002/adfm.201801292

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768. 768

     Isaksson, J.; Kjäll, P.; Nilsson, D.; Robinson, N.; Berggren, M.; Richter-Dahlfors, A. Electronic Control of Ca²⁺ Signalling in Neuronal Cells Using an Organic Electronic Ion Pump. Nat. Mater. 2007, 6, 673– 679,  DOI: 10.1038/nmat1963

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     768

     Electronic control of Ca2+ signaling in neuronal cells using an organic electronic ion pump

     Isaksson, Joakim; Kjaell, Peter; Nilsson, David; Robinson, Nathaniel; Berggren, Magnus; Richter-Dahlfors, Agneta

     Nature Materials (2007), 6 (9), 673-679CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     Cells and tissues use finely regulated ion fluxes for their intra- and intercellular communication. Technologies providing spatial and temporal control for studies of such fluxes are however, limited. We have developed an electrophoretic ion pump made of poly(3,4-ethylenedioxythiophene) doped with poly(styrene sulfonate) (PEDOT:PSS) to mediate electronic control of the ion homeostasis in neurons. Ion delivery from a source reservoir to a receiving electrolyte via a PEDOT:PSS thin-film channel was achieved by electronic addressing. Ions are delivered in high quantities at an assocd. on/off ratio exceeding 300. This induces physiol. signaling events that can be recorded at the single-cell level. Furthermore, miniaturization of the device to a 50-μm-wide channel allows for stimulation of individual cells. As this technol. platform allows for electronic control of ion signaling in individual cells with proper spatial and temporal resoln., it will be useful in further studies of communication in biol. systems.
769. 769

     Tybrandt, K.; Larsson, K. C.; Kurup, S.; Simon, D. T.; Kjäll, P.; Isaksson, J.; Sandberg, M.; Jager, E. W.; Richter-Dahlfors, A.; Berggren, M. Translating Electronic Currents to Precise Acetylcholine-Induced Neuronal Signaling Using an Organic Electrophoretic Delivery Device. Adv. Mater. 2009, 21, 4442– 4446,  DOI: 10.1002/adma.200900187

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     769

     Translating Electronic Currents to Precise Acetylcholine-Induced Neuronal Signaling Using an Organic Electrophoretic Delivery Device

     Tybrandt, Klas; Larsson, Karin C.; Kurup, Sindhulakshmi; Simon, Daniel T.; Kjaell, Peter; Isaksson, Joakim; Sandberg, Mats; Jager, Edwin W. H.; Richter-Dahlfors, Agneta; Berggren, Magnus

     Advanced Materials (Weinheim, Germany) (2009), 21 (44), 4442-4446CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     The authors report on development of the Org. Electronic Ion Pump (OEIP) which has yielded (i) expansion of the transport repertoire from metal cations to biomols., demonstrated by the neurotransmitter acetylcholine (ACh); (ii) miniaturized outlets down to 10 Rm channels, that is equal to or smaller than the size of individual neuronal cells; and (iii) a redn. of the delay time of delivery, from minutes to seconds, by incorporating a preloading circuit which also minimized undesired delivery of residual ions. The above achievements result in exact correlation between the addressing signal and the delivery rate of ACh, enabling stimulation of single 5H-SYSY neuroblastoma cells via local [ACh] in the range of micromolars. Monitoring the induced Ca2+ responses, the authors also demonstrate the electronic regulation of dynamic parameters, for example amplitude and frequency, and there by the potential of this device to be used for further exploration of spatiotemporal patterning of cell signaling systems. Ach's pos. charge across the range of physiol. pH suggests that the chem. of ACh would be compatible with the conducting polymer poly(3,4-ethylenedioxythiophene) doped with the polyanion poly(styrenesulfonate) (PEDOT:PSS). The principal device structure of the new 10 bm-OEIP consists of three electrochem. active PEDOT:PSS electrodes and an SU-8 encapsulation incorporating openings for source (S), target (T) and waste (W) electrolytes.
770. 770

     Arbring Sjöström, T.; Berggren, M.; Gabrielsson, E. O.; Janson, P.; Poxson, D. J.; Seitanidou, M.; Simon, D. T. Iontronics: A Decade of Iontronic Delivery Devices. Adv. Mater. Technol. 2018, 3, 1870018,  DOI: 10.1002/admt.201700360

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771. 771

     Seitanidou, M.; Sygletou, M.; Savva, K.; Berggren, M.; Stratakis, E.; Simon, D. T. Graphene-Enabled Electrophoretic Ion Pump Delivery Devices. Adv. Mater. Interfaces 2022, 9, 2102507,  DOI: 10.1002/admi.202102507

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772. 772

     Jakešová, M.; Sjöström, T. A.; Đerek, V.; Poxson, D.; Berggren, M.; Głowacki, E. D.; Simon, D. T. Wireless Organic Electronic Ion Pumps Driven by Photovoltaics. npj Flexible Electron. 2019, 3, 14,  DOI: 10.1038/s41528-019-0060-6

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773. 773

     Xue, Y.; Markmann, J.; Duan, H.; Weissmuller, J.; Huber, P. Switchable Imbibition in Nanoporous Gold. Nat. Commun. 2014, 5, 4237,  DOI: 10.1038/ncomms5237

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     773

     Switchable imbibition in nanoporous gold

     Xue, Yahui; Markmann, Juergen; Duan, Huiling; Weissmueller, Joerg; Huber, Patrick

     Nature Communications (2014), 5 (), 4237CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Spontaneous imbibition enables the elegant propelling of nano-flows because of the dominance of capillarity at small length scales. The imbibition kinetics are, however, solely detd. by the static host geometry, the capillarity, and the fluidity of the imbibed liq. This makes active control particularly challenging. Here we show for aq. electrolyte imbibition in nanoporous gold that the fluid flow can be reversibly switched on and off through elec. potential control of the solid-liq. interfacial tension, i.e., we can accelerate the imbibition front, stop it, and have it proceed at will. Simultaneous measurements of the mass flux and the elec. current allow us to document simple scaling laws for the imbibition kinetics, and to explore the charge transport in the metallic nanopores. Our findings demonstrate that the high elec. cond. along with the pathways for fluid/ionic transport render nanoporous gold a versatile, accurately controllable electrocapillary pump and flow sensor for minute amts. of liqs. with exceptionally low operating voltages.
774. 774

     Palanisamy, B.; Goshi, N.; Seker, E. Chemically-Gated and Sustained Molecular Transport through Nanoporous Gold Thin Films in Biofouling Conditions. Nanomaterials (Basel) 2021, 11, 498,  DOI: 10.3390/nano11020498

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775. 775

     Coffer, J. Porous Silicon and Tissue Engineering Scaffolds. In Handbook of Porous Silicon; Canham, L., Ed.; Springer, 2018.

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776. 776

     Tieu, T.; Alba, M.; Elnathan, R.; Cifuentes-Rius, A.; Voelcker, N. H. Advances in Porous Silicon-Based Nanomaterials for Diagnostic and Therapeutic Applications. Adv. Ther. 2019, 2, 1800095,  DOI: 10.1002/adtp.201800095

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777. 777

     Tzur-Balter, A.; Shatsberg, Z.; Beckerman, M.; Segal, E.; Artzi, N. Mechanism of Erosion of Nanostructured Porous Silicon Drug Carriers in Neoplastic Tissues. Nat. Commun. 2015, 6, 6208,  DOI: 10.1038/ncomms7208

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     777

     Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues

     Tzur-Balter, Adi; Shatsberg, Zohar; Beckerman, Margarita; Segal, Ester; Artzi, Natalie

     Nature Communications (2015), 6 (), 6208CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degrdn. of PSi under (pre)clin. relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degrdn. in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumor vicinity that oxidize the silicon scaffold and catalyze its degrdn. We further show that PSi degrdn. in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-contg. media are used, resp. Our work demonstrates that understanding the governing mechanisms assocd. with specific tissue microenvironment permits predictive material performance.
778. 778

     Yuryev, M.; Ferreira, M. P.; Balasubramanian, V.; Correia, A. M.; Mäkilä, E. M.; Jokinen, V.; Andriichuk, L.; Kemell, M.; Salonen, J. J.; Hirvonen, J. T.; Santos, H. A.; Rivera, C. Active Diffusion of Nanoparticles of Maternal Origin within the Embryonic Brain. Nanomedicine (Lond) 2016, 11, 2471– 2481,  DOI: 10.2217/nnm-2016-0207

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779. 779

     Prominski, A.; Shi, J.; Li, P.; Yue, J.; Lin, Y.; Park, J.; Tian, B.; Rotenberg, M. Y. Porosity-Based Heterojunctions Enable Leadless Optoelectronic Modulation of Tissues. Nat. Mater. 2022, 21, 647– 655,  DOI: 10.1038/s41563-022-01249-7

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780. 780

     Thelen, M.; Bochud, N.; Brinker, M.; Prada, C.; Huber, P. Laser-Excited Elastic Guided Waves Reveal the Complex Mechanics of Nanoporous Silicon. Nat. Commun. 2021, 12, 3597,  DOI: 10.1038/s41467-021-23398-0

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781. 781

     Canham, L. Handbook of Porous Silicon. 2nd ed.; Springer, 2018.

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782. 782

     Sailor, M. J. Porous Silicon in Practice - Preparation, Characterization and Applications; Wiley-VCH: Weinheim, 2011; p 250.

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783. 783

     Cencha, L. G.; Dittrich, G.; Huber, P.; Berli, C. L. A.; Urteaga, R. Precursor Film Spreading during Liquid Imbibition in Nanoporous Photonic Crystals. Phys. Rev. Lett. 2020, 125, 234502,  DOI: 10.1103/PhysRevLett.125.234502

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     783

     Precursor Film Spreading during Liquid Imbibition in Nanoporous Photonic Crystals

     Cencha, Luisa G.; Dittrich, Guido; Huber, Patrick; Berli, Claudio L. A.; Urteaga, Raul

     Physical Review Letters (2020), 125 (23), 234502CODEN: PRLTAO; ISSN:1079-7114. (American Physical Society)

     When a macroscopic droplet spreads, a thin precursor film of liq. moves ahead of the advancing liq.-solid-vapor contact line. Whereas this phenomenon has been explored extensively for planar solid substrates, its presence in nanostructured geometries has barely been studied so far, despite its importance for many natural and technol. fluid transport processes. Here we use porous photonic crystals in silicon to resolve by light interferometry capillarity-driven spreading of liq. fronts in pores of few nanometers in radius. Upon spatiotemporal rescaling the fluid profiles collapse on master curves indicating that all imbibition fronts follow a square-root-of-time broadening dynamics. For the simple liq. (glycerol) a sharp front with a widening typical of Lucas-Washburn capillary-rise dynamics in a medium with pore-size distribution occurs. By contrast, for a polymer (PDMS) a precursor film moving ahead of the main menisci entirely alters the nature of the nanoscale transport, in agreement with predictions of computer simulations.
784. 784

     Coluccio, M. L.; Onesto, V.; Marinaro, G.; Dell’Apa, M.; De Vitis, S.; Imbrogno, A.; Tirinato, L.; Perozziello, G.; Di Fabrizio, E.; Candeloro, P.; Malara, N.; Gentile, F. Cell Theranostics on Mesoporous Silicon Substrates. Pharmaceutics 2020, 12, 481,  DOI: 10.3390/pharmaceutics12050481

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785. 785

     Huber, P. Soft Matter in Hard Confinement: Phase Transition Thermodynamics, Structure, Texture, Diffusion and Flow in Nanoporous Media. J. Phys.: Condens. Matter 2015, 27, 103102,  DOI: 10.1088/0953-8984/27/10/103102

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     785

     Soft matter in hard confinement: phase transition thermodynamics, structure, texture, diffusion and flow in nanoporous media

     Huber, Patrick

     Journal of Physics: Condensed Matter (2015), 27 (10), 103102/1-103102/43CODEN: JCOMEL; ISSN:0953-8984. (IOP Publishing Ltd.)

     A review. Spatial confinement in nanoporous media affects the structure, thermodn. and mobility of mol. soft matter often markedly. This article reviews thermodn. equil. phenomena, such as physisorption, capillary condensation, crystn., self-diffusion, and structural phase transitions as well as selected aspects of the emerging field of spatially confined, non-equil. physics, i.e. the rheol. of liqs., capillarity-driven flow phenomena, and imbibition front broadening in nanoporous materials. The observations in the nanoscale systems are related to the corresponding bulk phenomenologies. The complexity of the confined mol. species is varied from simple building blocks, like noble gas atoms, normal alkanes and alcs. to liq. crystals, polymers, ionic liqs., proteins and water. Mostly, expts. with mesoporous solids of alumina, gold, carbon, silica, and silicon with pore diams. ranging from a few up to 50 nm are presented. The obsd. peculiarities of nanopore-confined condensed matter are also discussed with regard to applications. A particular emphasis is put on texture formation upon crystn. in nanoporous media, a topic both of high fundamental interest and of increasing nanotechnol. importance, e.g. for the synthesis of org./inorg. hybrid materials by melt infiltration, the usage of nanoporous solids in crystal nucleation or in template-assisted electrochem. deposition of nanostructures.
786. 786

     Huber, P.; Karim, A.; Zvonkina, I.; Lee, S.-W.; Kim, J.-W.; Roper, D. K.; Li, W. J.; Gang, O. Soft Matter and Biomaterials on the Nanoscale, Vol. 1; World Scientific: 2020.

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787. 787

     Park, J. H.; Gu, L.; von Maltzahn, G.; Ruoslahti, E.; Bhatia, S. N.; Sailor, M. J. Biodegradable Luminescent Porous Silicon Nanoparticles for in Vivo Applications. Nat. Mater. 2009, 8, 331– 336,  DOI: 10.1038/nmat2398

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     787

     Biodegradable luminescent porous silicon nanoparticles for in vivo applications

     Park, Ji-Ho; Gu, Luo; von Maltzahn, Geoffrey; Ruoslahti, Erkki; Bhatia, Sangeeta N.; Sailor, Michael J.

     Nature Materials (2009), 8 (4), 331-336CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     Nanomaterials that can circulate in the body hold great potential to diagnose and treat disease. For such applications, it is important that the nanomaterials be harmlessly eliminated from the body in a reasonable period of time after they carry out their diagnostic or therapeutic function. Despite efforts to improve their targeting efficiency, significant quantities of systemically administered nanomaterials are cleared by the mononuclear phagocytic system before finding their targets, increasing the likelihood of unintended acute or chronic toxicity. However, there has been little effort to engineer the self-destruction of errant nanoparticles into non-toxic, systemically eliminated products. Here, we present luminescent porous silicon nanoparticles (LPSiNPs) that can carry a drug payload and of which the intrinsic near-IR photoluminescence enables monitoring of both accumulation and degrdn. in vivo. Furthermore, in contrast to most optically active nanomaterials (carbon nanotubes, gold nanoparticles and quantum dots), LPSiNPs self-destruct in a mouse model into renally cleared components in a relatively short period of time with no evidence of toxicity. As a preliminary in vivo application, we demonstrate tumor imaging using dextran-coated LPSiNPs (D-LPSiNPs). These results demonstrate a new type of multifunctional nanostructure with a low-toxicity degrdn. pathway for in vivo applications.
788. 788

     Gu, L.; Hall, D. J.; Qin, Z.; Anglin, E.; Joo, J.; Mooney, D. J.; Howell, S. B.; Sailor, M. J. In Vivo Time-Gated Fluorescence Imaging with Biodegradable Luminescent Porous Silicon Nanoparticles. Nat. Commun. 2013, 4, 2326,  DOI: 10.1038/ncomms3326

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     788

     In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles

     Gu Luo; Hall David J; Qin Zhengtao; Anglin Emily; Joo Jinmyoung; Mooney David J; Howell Stephen B; Sailor Michael J

     Nature communications (2013), 4 (), 2326 ISSN:.

     Fluorescence imaging is one of the most versatile and widely used visualization methods in biomedical research. However, tissue autofluorescence is a major obstacle confounding interpretation of in vivo fluorescence images. The unusually long emission lifetime (5-13 μs) of photoluminescent porous silicon nanoparticles can allow the time-gated imaging of tissues in vivo, completely eliminating shorter-lived (<10 ns) emission signals from organic chromophores or tissue autofluorescence. Here using a conventional animal imaging system not optimized for such long-lived excited states, we demonstrate improvement of signal to background contrast ratio by >50-fold in vitro and by >20-fold in vivo when imaging porous silicon nanoparticles. Time-gated imaging of porous silicon nanoparticles accumulated in a human ovarian cancer xenograft following intravenous injection is demonstrated in a live mouse. The potential for multiplexing of images in the time domain by using separate porous silicon nanoparticles engineered with different excited state lifetimes is discussed.
789. 789

     Joo, J.; Liu, X.; Kotamraju, V. R.; Ruoslahti, E.; Nam, Y.; Sailor, M. J. Gated Luminescence Imaging of Silicon Nanoparticles. ACS Nano 2015, 9, 6233– 6241,  DOI: 10.1021/acsnano.5b01594

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     789

     Gated Luminescence Imaging of Silicon Nanoparticles

     Joo, Jinmyoung; Liu, Xiangyou; Kotamraju, Venkata Ramana; Ruoslahti, Erkki; Nam, Yoonkey; Sailor, Michael J.

     ACS Nano (2015), 9 (6), 6233-6241CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     The luminescence lifetime of nanocryst. silicon is typically on the order of microseconds, significantly longer than the nanosecond lifetimes exhibited by fluorescent mols. naturally present in cells and tissues. Time-gated imaging, where the image is acquired at a time after termination of an excitation pulse, allows discrimination of a silicon nanoparticle probe from these endogenous signals. Because of the microsecond time scale for silicon emission, time-gated imaging is relatively simple to implement for this biocompatible and nontoxic probe. Here a time-gated system with ∼10 ns resoln. is described, using an intensified CCD camera and pulsed LED or laser excitation sources. The method is demonstrated by tracking the fate of mesoporous silicon nanoparticles contg. the tumor-targeting peptide iRGD, administered by retro-orbital injection into live mice. Imaging of such systemically administered nanoparticles in vivo is particularly challenging because of the low concn. of probe in the targeted tissues and relatively high background signals from tissue autofluorescence. Contrast improvements of >100-fold (relative to steady-state imaging) is demonstrated in the targeted tissues.
790. 790

     Kang, J.; Kim, D.; Wang, J.; Han, Y.; Zuidema, J. M.; Hariri, A.; Park, J. H.; Jokerst, J. V.; Sailor, M. J. Enhanced Performance of a Molecular Photoacoustic Imaging Agent by Encapsulation in Mesoporous Silicon Nanoparticles. Adv. Mater. 2018, 30, e1800512,  DOI: 10.1002/adma.201800512

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791. 791

     Rosenberg, M.; Zilony, N.; Shefi, O.; Segal, E. Designing Porous Silicon Films as Carriers of Nerve Growth Factor. J. Vis. Exp. 2019, 143, e58982,  DOI: 10.3791/58982-v

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792. 792

     Zilony-Hanin, N.; Rosenberg, M.; Richman, M.; Yehuda, R.; Schori, H.; Motiei, M.; Rahimipour, S.; Groisman, A.; Segal, E.; Shefi, O. Neuroprotective Effect of Nerve Growth Factor Loaded in Porous Silicon Nanostructures in an Alzheimer’s Disease Model and Potential Delivery to the Brain. Small 2019, 15, e1904203,  DOI: 10.1002/smll.201904203

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     792

     Neuroprotective effect of nerve growth factor loaded in porous silicon nanostructures in an Alzheimer's disease model and potential delivery to the brain

     Zilony-Hanin, Neta; Rosenberg, Michal; Richman, Michal; Yehuda, Ronen; Schori, Hadas; Motiei, Menachem; Rahimipour, Shai; Groisman, Alexander; Segal, Ester; Shefi, Orit

     Small (2019), 15 (45), 1904203CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Nerve growth factor (NGF) plays a vital role in reducing the loss of cholinergic neurons in Alzheimer's disease (AD). However, its delivery to the brain remains a challenge. Herein, NGF is loaded into degradable oxidized porous silicon (PSiO2) carriers, which are designed to carry and continuously release the protein over a 1 mo period. The released NGF exhibits a substantial neuroprotective effect in differentiated rat pheochromocytoma PC12 cells against amyloid-beta (Aβ)-induced cytotoxicity, which is assocd. with Alzheimer's disease. Next, two potential localized administration routes of the porous carriers into murine brain are investigated: implantation of PSiO2 chips above the dura mater, and biolistic bombardment of PSiO2 microparticles through an opening in the skull using a pneumatic gene gun. The PSiO2-implanted mice are monitored for a period of 8 wk and no inflammation or adverse effects are obsd. Subsequently, a successful biolistic delivery of these highly porous microparticles into a live-mouse brain is demonstrated for the first time. The bombarded microparticles are obsd. to penetrate the brain and reach a depth of 150 μm. These results pave the way for using degradable PSiO2 carriers as potential localized delivery systems for NGF to the brain.
793. 793

     Balasubramanian, V.; Domanskyi, A.; Renko, J. M.; Sarparanta, M.; Wang, C. F.; Correia, A.; Makila, E.; Alanen, O. S.; Salonen, J.; Airaksinen, A. J.; Tuominen, R.; Hirvonen, J.; Airavaara, M.; Santos, H. A. Engineered Antibody-Functionalized Porous Silicon Nanoparticles for Therapeutic Targeting of Pro-Survival Pathway in Endogenous Neuroblasts after Stroke. Biomaterials 2020, 227, 119556,  DOI: 10.1016/j.biomaterials.2019.119556

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     793

     Engineered antibody-functionalized porous silicon nanoparticles for therapeutic targeting of pro-survival pathway in endogenous neuroblasts after stroke

     Balasubramanian, Vimalkumar; Domanskyi, Andrii; Renko, Juho-Matti; Sarparanta, Mirkka; Wang, Chang-Fang; Correia, Alexandra; Makila, Ermei; Alanen, Osku S.; Salonen, Jarno; Airaksinen, Anu J.; Tuominen, Raimo; Hirvonen, Jouni; Airavaara, Mikko; Santos, Helder A.

     Biomaterials (2020), 227 (), 119556CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     Generation of new neurons by utilizing the regenerative potential of adult neural stem cells (NSCs) and neuroblasts is an emerging therapeutic strategy to treat various neurodegenerative diseases, including neuronal loss after stroke. Committed to neuronal lineages, neuroblasts are differentiated from NSCs and have a lower proliferation rate. In stroke the proliferation of the neuroblasts in the neurogenic areas is increased, but the limiting factor for regeneration is the poor survival of migrating neuroblasts. Survival of neuroblasts can be promoted by small mols.; however, new drug delivery methods are needed to specifically target these cells. Herein, to achieve specific targeting, we have engineered biofunctionalized porous silicon nanoparticles (PSi NPs) conjugated with a specific antibody against polysialylated neural cell adhesion mol. (PSA-NCAM). The PSi NPs loaded with a small mol. drug, SC-79, were able to increase the activity of the Akt signaling pathway in doublecortin pos. neuroblasts both in cultured cells and in vivo in the rat brain. This study opens up new possibilities to target drug effects to migrating neuroblasts and facilitate differentiation, maturation and survival of developing neurons. The conjugated PSi NPs are a novel tool for future studies to develop new therapeutic strategies aiming at regenerating functional neurocircuitry after stoke.
794. 794

     Balasubramanian, V. Brain Power. Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2107022118,  DOI: 10.1073/pnas.2107022118

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     Nagarajan, N.; Stevens, C. F. How Does the Speed of Thought Compare for Brains and Digital Computers?. Curr. Biol. 2008, 18, R756– R758,  DOI: 10.1016/j.cub.2008.06.043

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796. 796

     Zarrintaj, P.; Saeb, M. R.; Stadler, F. J.; Yazdi, M. K.; Nezhad, M. N.; Mohebbi, S.; Seidi, F.; Ganjali, M. R.; Mozafari, M. Human Organs-on-Chips: A Review of the State-of-the-Art, Current Prospects, and Future Challenges. Adv. Biol. 2022, 6, 2000526,  DOI: 10.1002/adbi.202000526

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797. 797

     Wu, Q.; Liu, J.; Wang, X.; Feng, L.; Wu, J.; Zhu, X.; Wen, W.; Gong, X. Organ-on-a-Chip: Recent Breakthroughs and Future Prospects. Biomed. Eng. OnLine 2020, 19, 9,  DOI: 10.1186/s12938-020-0752-0

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     Organ-on-a-chip: recent breakthroughs and future prospects

     Wu Qirui; Liu Jinfeng; Wang Xiaohong; Feng Lingyan; Wu Jinbo; Wen Weijia; Gong Xiuqing; Zhu Xiaoli

     Biomedical engineering online (2020), 19 (1), 9 ISSN:.

     The organ-on-a-chip (OOAC) is in the list of top 10 emerging technologies and refers to a physiological organ biomimetic system built on a microfluidic chip. Through a combination of cell biology, engineering, and biomaterial technology, the microenvironment of the chip simulates that of the organ in terms of tissue interfaces and mechanical stimulation. This reflects the structural and functional characteristics of human tissue and can predict response to an array of stimuli including drug responses and environmental effects. OOAC has broad applications in precision medicine and biological defense strategies. Here, we introduce the concepts of OOAC and review its application to the construction of physiological models, drug development, and toxicology from the perspective of different organs. We further discuss existing challenges and provide future perspectives for its application.
798. 798

     Shahrubudin, N.; Lee, T. C.; Ramlan, R. An Overview on 3D Printing Technology: Technological, Materials, and Applications. Procedia Manuf. 2019, 35, 1286– 1296,  DOI: 10.1016/j.promfg.2019.06.089

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799. 799

     Tack, P.; Victor, J.; Gemmel, P.; Annemans, L. 3D-Printing Techniques in a Medical Setting: A Systematic Literature Review. Biomed. Eng. OnLine 2016, 15, 115,  DOI: 10.1186/s12938-016-0236-4

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     799

     3D-printing techniques in a medical setting: a systematic literature review

     Tack Philip; Annemans Lieven; Victor Jan; Gemmel Paul

     Biomedical engineering online (2016), 15 (1), 115 ISSN:.

     BACKGROUND: Three-dimensional (3D) printing has numerous applications and has gained much interest in the medical world. The constantly improving quality of 3D-printing applications has contributed to their increased use on patients. This paper summarizes the literature on surgical 3D-printing applications used on patients, with a focus on reported clinical and economic outcomes. METHODS: Three major literature databases were screened for case series (more than three cases described in the same study) and trials of surgical applications of 3D printing in humans. RESULTS: 227 surgical papers were analyzed and summarized using an evidence table. The papers described the use of 3D printing for surgical guides, anatomical models, and custom implants. 3D printing is used in multiple surgical domains, such as orthopedics, maxillofacial surgery, cranial surgery, and spinal surgery. In general, the advantages of 3D-printed parts are said to include reduced surgical time, improved medical outcome, and decreased radiation exposure. The costs of printing and additional scans generally increase the overall cost of the procedure. CONCLUSION: 3D printing is well integrated in surgical practice and research. Applications vary from anatomical models mainly intended for surgical planning to surgical guides and implants. Our research suggests that there are several advantages to 3D-printed applications, but that further research is needed to determine whether the increased intervention costs can be balanced with the observable advantages of this new technology. There is a need for a formal cost-effectiveness analysis.
800. 800

     Huang, Z.; Chi-Pong Tsui, G.; Deng, Y.; Tang, C.-Y. Two-Photon Polymerization Nanolithography Technology for Fabrication of Stimulus-Responsive Micro/Nano-Structures for Biomedical Applications. Nanotechnol. Rev. 2020, 9, 1118– 1136,  DOI: 10.1515/ntrev-2020-0073

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801. 801

     Harinarayana, V.; Shin, Y. Two-Photon Lithography for Three-Dimensional Fabrication in Micro/Nanoscale Regime: A Comprehensive Review. Opt. Laser Technol. 2021, 142, 107180,  DOI: 10.1016/j.optlastec.2021.107180

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     Two-photon lithography for three-dimensional fabrication in micro/nanoscale regime: A comprehensive review

     Harinarayana, V.; Shin, Y. C.

     Optics & Laser Technology (2021), 142 (), 107180CODEN: OLTCAS; ISSN:0030-3992. (Elsevier Ltd.)

     A review. With the advent of femtosecond lasers in the early 1990s, ultrafast laser processing has proven to be an imperative tool for micro/nano machining. Two-photon lithog. (TPL) is one such unique microfabrication technique exploiting the nonlinear dependency of the polymn. rate on the irradiating light intensity to produce true three-dimensional structures with feature sizes beyond the diffraction limit. This characteristic has revolutionized laser material processing for the fabrication of micro and nanostructures. In this paper, an overview of TPL including its working principle, exptl. setup, and materials is presented. Then, the effect of resoln. with a focus on techniques adopted to improve the final resoln. of the structures is covered. Insights to improve throughput and speed of fabrication to pave a way for industrialization of this technique are provided. Finally, TPL for microfabrication of structures with the emphasis on metamaterials is thoroughly reviewed and presented.
802. 802

     Bernardeschi, I.; Ilyas, M.; Beccai, L. A Review on Active 3D Microstructures via Direct Laser Lithography. Adv. Intell. Syst. 2021, 3, 2100051,  DOI: 10.1002/aisy.202100051

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803. 803

     Selimis, A.; Mironov, V.; Farsari, M. Direct Laser Writing: Principles and Materials for Scaffold 3D Printing. Microelectron. Eng. 2015, 132, 83– 89,  DOI: 10.1016/j.mee.2014.10.001

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     Direct laser writing: Principles and materials for scaffold 3D printing

     Selimis, Alexandros; Mironov, Vladimir; Farsari, Maria

     Microelectronic Engineering (2015), 132 (), 83-89CODEN: MIENEF; ISSN:0167-9317. (Elsevier B.V.)

     A review. For a great variety of research fields extending from photonics to tissue engineering applications, the requests for the construction of three-dimensional structures with high resoln. grow more and more imperative. Towards this aim, the direct laser writing technique by multi-photon polymn., due to its unique properties and characteristics, has proven to be an indispensable tool to high accuracy structuring and has been put on the map as an emerging technol. for scaffold 3D printing. In the present review, the basic principles of multi-photon polymn. are presented, the exptl. set-up requirements are described and the employed materials demands are thoroughly mentioned as well as the most representative examples of the recent developments in the field.
804. 804

     Bausch, C. S.; Koitmäe, A.; Stava, E.; Price, A.; Resto, P. J.; Huang, Y.; Sonnenberg, D.; Stark, Y.; Heyn, C.; Williams, J. C.; Dent, E. W.; Blick, R. H. Guided Neuronal Growth on Arrays of Biofunctionalized GaAs/InGaAs Semiconductor Microtubes. Appl. Phys. Lett. 2013, 103, 173705,  DOI: 10.1063/1.4826885

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     804

     Guided neuronal growth on arrays of biofunctionalized GaAs/InGaAs semiconductor microtubes

     Bausch, Cornelius S.; Koitmaee, Aune; Stava, Eric; Price, Amanda; Resto, Pedro J.; Huang, Yu; Sonnenberg, David; Stark, Yuliya; Heyn, Christian; Williams, Justin C.; Dent, Erik W.; Blick, Robert H.

     Applied Physics Letters (2013), 103 (17), 173705/1-173705/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)

     We demonstrate embedded growth of cortical mouse neurons in dense arrays of semiconductor microtubes. The microtubes, fabricated from a strained GaAs/InGaAs heterostructure, guide axon growth through them and potentially enable elec. and optical probing of propagating action potentials. The coaxial nature of the microtubes-similar to myelin-is expected to enhance the signal transduction along the axon. We present a technique of suppressing arsenic toxicity and prove the success of this technique by overgrowing neuronal mouse cells. (c) 2013 American Institute of Physics.
805. 805

     Marino, A.; Ciofani, G.; Filippeschi, C.; Pellegrino, M.; Pellegrini, M.; Orsini, P.; Pasqualetti, M.; Mattoli, V.; Mazzolai, B. Two-Photon Polymerization of Sub-Micrometric Patterned Surfaces: Investigation of Cell-Substrate Interactions and Improved Differentiation of Neuron-Like Cells. ACS Appl. Mater. Interfaces 2013, 5, 13012– 13021,  DOI: 10.1021/am403895k

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     805

     Two-Photon Polymerization of Sub-micrometric Patterned Surfaces: Investigation of Cell-Substrate Interactions and Improved Differentiation of Neuron-like Cells

     Marino, Attilio; Ciofani, Gianni; Filippeschi, Carlo; Pellegrino, Mario; Pellegrini, Monica; Orsini, Paolo; Pasqualetti, Massimo; Mattoli, Virgilio; Mazzolai, Barbara

     ACS Applied Materials & Interfaces (2013), 5 (24), 13012-13021CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Direct Laser Writing (DLW) is an innovative tool that allows the photofabrication of high resoln. 3D structures, which can be successfully exploited for the study of the phys. interactions between cells and substrates. In this work, we focused our attention on the topog. effects of submicrometric patterned surfaces fabricated via DLW on neuronal cell behavior. In particular, we designed, prepd., and characterized substrates based on aligned ridges for the promotion of axonal outgrowth and guidance. We demonstrated that both rat PC12 neuron-like cells and human SH-SY5Y derived neurons differentiate on parallel 2.5 μm spaced submicrometric ridges, being characterized by strongly aligned and significantly longer neurites with respect to those differentiated on flat control substrates, or on more spaced (5 and 10 μm) ridges. Furthermore, we detected an increased mol. differentiation toward neurons of the SH-SY5Y cells when grown on the submicrometric patterned substrates. Finally, we obsd. that the axons can exert forces able of bending the ridges, and we indirectly estd. the order of magnitude of these forces thanks to scanning probe techniques. Collectively, we showed as submicrometric structures fabricated by DLW can be used as a useful tool for the study of the axon mechanobiol.
806. 806

     Fan, Y.; Cui, F.; Hou, S.; Xu, Q.; Chen, L.; Lee, I.-S. Culture of Neural Cells on Silicon Wafers with Nano-Scale Surface Topograph. J. Neurosci. Methods 2002, 120, 17– 23,  DOI: 10.1016/S0165-0270(02)00181-4

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     Culture of neural cells on silicon wafers with nano-scale surface topograph

     Fan, Y. W.; Cui, F. Z.; Hou, S. P.; Xu, Q. Y.; Chen, L. N.; Lee, I.-S.

     Journal of Neuroscience Methods (2002), 120 (1), 17-23CODEN: JNMEDT; ISSN:0165-0270. (Elsevier Science B.V.)

     The adherence and viability of central neural cells (substantia nigra) on a thin layer of SiO2 on Si wafers with different surface roughness were investigated. Variable roughness of the Si wafer surface was achieved by etching. The nano-scale surface topog. was evaluated by at. force microscopy. The adherence and subsequent viability of the cells on the wafer were examd. by SEM and fluorescence immunostaining of tyrosine hydroxylase (TH). It is found that the surface roughness significantly affected cell adhesion and viability. Cells survived for over 5 days with normal morphol. and expressed neuronal TH when grown on surfaces with an av. roughness (Ra) ranging from 20 to 50 nm. However, cell adherence was adversely affected when surfaces with Ra less than 10 nm and rough surfaces with Ra above 70 nm were used as the substrate. Such a simple prepn. procedure may provide a suitable interface surface for silicon-based devices and neurons or other living tissues.
807. 807

     Kaehr, B.; Allen, R.; Javier, D. J.; Currie, J.; Shear, J. B. Guiding Neuronal Development with in Situ Microfabrication. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 16104– 16108,  DOI: 10.1073/pnas.0407204101

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     807

     Guiding neuronal development with in situ microfabrication

     Kaehr, Bryan; Allen, Richard; Javier, David J.; Currie, John; Shear, Jason B.

     Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (46), 16104-16108CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     We report the ability to modify microscopic 3D topogs. within dissocd. cultures, providing a means to alter the development of neurons as they extend neurites and establish interconnections. In this approach, multiphoton excitation is used to focally excite noncytotoxic photosensitizers that promote protein crosslinking, such as BSA, into matrixes having feature sizes ≥250 nm. Barriers, growth lanes, and pinning structures comprised of crosslinked proteins are fabricated under conditions that do not compromise the viability of neurons both on short time scales and over periods of days. In addn., the ability to fabricate functional microstructures from crosslinked avidin enables submicrometer localization of controllable quantities of biotinylated ligands, such as indicators and biol. effectors. Feasibility is demonstrated for using in situ microfabrication to guide the contact position of cortical neurons with micrometer accuracy, opening the possibility for engineering well defined sets of synaptic interactions.
808. 808

     Renault, R.; Durand, J.-B.; Viovy, J.-L.; Villard, C. Asymmetric Axonal Edge Guidance: A New Paradigm for Building Oriented Neuronal Networks. Lab Chip 2016, 16, 2188– 2191,  DOI: 10.1039/C6LC00479B

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     Asymmetric axonal edge guidance: a new paradigm for building oriented neuronal networks

     Renault, Renaud; Durand, Jean-Baptiste; Viovy, Jean-Louis; Villard, Catherine

     Lab on a Chip (2016), 16 (12), 2188-2191CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)

     We present a novel kind of directional axon guides for brain-on-a-chip applications. Contrarily to previous works, the directionality in our design is created by rerouting axons growing in the unwanted direction back to their original compartment while leaving the other growth direction unaffected. This design yields state-of-the-art levels of directionality without the disadvantages of previously reported technologies.
809. 809

     Li, W.; Tang, Q. Y.; Jadhav, A. D.; Narang, A.; Qian, W. X.; Shi, P.; Pang, S. W. Large-Scale Topographical Screen for Investigation of Physical Neural-Guidance Cues. Sci. Rep. 2015, 5, 8644,  DOI: 10.1038/srep08644

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     Large-scale Topographical Screen for Investigation of Physical Neural-Guidance Cues

     Li, Wei; Tang, Qing Yuan; Jadhav, Amol D.; Narang, Ankit; Qian, Wei Xian; Shi, Peng; Pang, Stella W.

     Scientific Reports (2015), 5 (), 8644CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

     A combinatorial approach was used to present primary neurons with a large library of topog. features in the form of micropatterned substrate for high-throughput screening of phys. neural-guidance cues that can effectively promote different aspects of neuronal development, including axon and dendritic outgrowth. Notably, the neuronal-guidance capability of specific features was automatically identified using a customized image processing software, thus significantly increasing the screening throughput with minimal subjective bias. Our results indicate that the anisotropic topogs. promote axonal and in some cases dendritic extension relative to the isotropic topogs., while dendritic branching showed preference to plain substrates over the microscale features. The results from this work can be readily applied towards engineering novel biomaterials with precise surface topog. that can serve as guidance conduits for neuro-regenerative applications. This novel topog. screening strategy combined with the automated processing capability can also be used for high-throughput screening of chem. or genetic regulatory factors in primary neurons.
810. 810

     Tuft, B. W.; Xu, L.; White, S. P.; Seline, A. E.; Erwood, A. M.; Hansen, M. R.; Guymon, C. A. Neural Pathfinding on Uni- and Multidirectional Photopolymerized Micropatterns. ACS Appl. Mater. Interfaces 2014, 6, 11265– 11276,  DOI: 10.1021/am501622a

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     Neural Pathfinding on Uni- and Multidirectional Photopolymerized Micropatterns

     Tuft, Bradley W.; Xu, Linjing; White, Scott P.; Seline, Alison E.; Erwood, Andrew M.; Hansen, Marlan R.; Guymon, C. Allan

     ACS Applied Materials & Interfaces (2014), 6 (14), 11265-11276CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     Overcoming signal resoln. barriers of neural prostheses, such as the com. available cochlear impant (CI) or the developing retinal implant, will likely require spatial control of regenerative neural elements. To rationally design materials that direct nerve growth, it is first necessary to det. pathfinding behavior of de novo neurite growth from prosthesis-relevant cells such as spiral ganglion neurons (SGNs) in the inner ear. Accordingly, in this work, repeating 90° turns were fabricated as multidirectional micropatterns to det. SGN neurite turning capability and pathfinding. Unidirectional micropatterns and unpatterned substrates are used as comparisons. Spiral ganglion Schwann cell alignment (SGSC) is also examd. on each surface type. Micropatterns are fabricated using the spatial reaction control inherent to photopolymn. with photomasks that have either parallel line spacing gratings for unidirectional patterns or repeating 90° angle steps for multidirectional patterns. Feature depth is controlled by modulating UV exposure time by shuttering the light source at given time increments. Substrate topog. is characterized by white light interferometry and SEM. Both pattern types exhibit features that are 25 μm in width and 7.4 ± 0.7 μm in depth. SGN neurites orient randomly on unpatterned photopolymer controls, align and consistently track unidirectional patterns, and are substantially influenced by, but do not consistently track, multidirectional turning cues. Neurite lengths are 20% shorter on multidirectional substrates compared to unidirectional patterns while neurite branching and microfeature crossing events are significantly higher. For both pattern types, the majority of the neurite length is located in depressed surface features. Developing methods to understand neural pathfinding and to guide de novo neurite growth to specific stimulatory elements will enable design of innovative biomaterials that improve functional outcomes of devices that interface with the nervous system.
811. 811

     Tooker, A.; Meng, E.; Erickson, J.; Tai, Y.-C.; Pine, J. Development of Biocompatible Parylene Neurocages. In The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; IEEE, 2004; pp 2542– 2545.

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     Goldner, J. S.; Bruder, J. M.; Li, G.; Gazzola, D.; Hoffman-Kim, D. Neurite Bridging across Micropatterned Grooves. Biomaterials 2006, 27, 460– 472,  DOI: 10.1016/j.biomaterials.2005.06.035

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     Neurite bridging across micropatterned grooves

     Goldner, Joshua S.; Bruder, Jan M.; Li, Grace; Gazzola, Daniele; Hoffman-Kim, Diane

     Biomaterials (2006), 27 (3), 460-472CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

     After injury, regenerating axons must navigate complex, three-dimensional (3D) microenvironments. Topog. guidance of neurite outgrowth has been demonstrated in vitro with culture substrates that contain micropatterned features on the nanometer-micron scale. In this study we report the ability of microfabricated biomaterials to support neurite extension across micropatterned grooves with feature sizes on the order of tens of microns, sizes relevant to the design of biomaterials and tissue engineering scaffolds. Neonatal rat dorsal root ganglion (DRG) neurons were cultured on grooved substrates of poly(di-Me siloxane) coated with poly-L-lysine and laminin. Here we describe an unusual capability of a subpopulation of DRG neurons to extend neurites that spanned across the grooves, with no underlying solid support. Multiple parameters influenced the formation of bridging neurites, with the highest nos. of bridges obsd. under the following exptl. conditions: cell d. of 125,000 cells per sample, groove depth of 50 μm, groove width of 30 μm, and plateau width of 200 μm. Bridges were formed as neurites extended from a neuron in a groove, contacted adjacent plateaus, pulled the neuron up to become suspended over the groove, and the soma translocated to the plateau. These studies are of interest to understanding cytoskeletal dynamics and designing biomaterials for 3D axon guidance.
813. 813

     Turunen, S.; Käpylä, E.; Lähteenmäki, M.; Ylä-Outinen, L.; Narkilahti, S.; Kellomäki, M. Direct Laser Writing of Microstructures for the Growth Guidance of Human Pluripotent Stem Cell Derived Neuronal Cells. Opt. Lasers Eng. 2014, 55, 197– 204,  DOI: 10.1016/j.optlaseng.2013.11.003

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814. 814

     Amin, H.; Dipalo, M.; De Angelis, F.; Berdondini, L. Biofunctionalized 3D Nanopillar Arrays Fostering Cell Guidance and Promoting Synapse Stability and Neuronal Activity in Networks. ACS Appl. Mater. Interfaces 2018, 10, 15207– 15215,  DOI: 10.1021/acsami.8b00387

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     814

     Biofunctionalized 3D Nanopillar Arrays Fostering Cell Guidance and Promoting Synapse Stability and Neuronal Activity in Networks

     Amin, Hayder; Dipalo, Michele; De Angelis, Francesco; Berdondini, Luca

     ACS Applied Materials & Interfaces (2018), 10 (17), 15207-15215CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

     A controlled geometry of in vitro neuronal networks allows investigation of the cellular mechanisms that underlie neuron-to-neuron and neuron-extracellular matrix interactions, which are essential to biomedical research. Herein, we report a selective guidance of primary hippocampal neurons by using arrays of three-dimensional vertical nanopillars (NPs) functionalized with a specific adhesion-promoting mol.-poly-DL-ornithine (PDLO). We show that 90% of neuronal cells are guided exclusively on the combinatorial PDLO/NP substrate. Moreover, we demonstrate the influence of the interplay between nanostructures and neurons on synapse formation and maturation, resulting in increased expression of postsynaptic d.-95 protein and enhanced network cellular activity conferred by the endogenous c-fos expression. Successful guidance to foster synapse stability and cellular activity on multilevel cues of surface topog. and chem. functionalization suggests the potential to devise technologies to control neuronal growth on nanostructures for tissue engineering, neuroprostheses, and drug development.
815. 815

     Park, M.; Oh, E.; Seo, J.; Kim, M. H.; Cho, H.; Choi, J. Y.; Lee, H.; Choi, I. S. Control over Neurite Directionality and Neurite Elongation on Anisotropic Micropillar Arrays. Small 2016, 12, 1148– 1152,  DOI: 10.1002/smll.201501896

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     Control over Neurite Directionality and Neurite Elongation on Anisotropic Micropillar Arrays

     Park, Matthew; Oh, Eunkyul; Seo, Jeongyeon; Kim, Mi-Hee; Cho, Hyeoncheol; Choi, Ji Yu; Lee, Haiwon; Choi, Insung S.

     Small (2016), 12 (9), 1148-1152CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Controlled neurite directionality in primary hippocampal neurons was demonstrated using interrupted anisotropic pillar array substrates without the use of any biochem. patterns.
816. 816

     Micholt, L.; Gärtner, A.; Prodanov, D.; Braeken, D.; Dotti, C. G.; Bartic, C. Substrate Topography Determines Neuronal Polarization and Growth in Vitro. PLoS 2013, 8, e66170,  DOI: 10.1371/journal.pone.0066170

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817. 817

     Kwiat, M.; Elnathan, R.; Pevzner, A.; Peretz, A.; Barak, B.; Peretz, H.; Ducobni, T.; Stein, D.; Mittelman, L.; Ashery, U. Highly Ordered Large-Scale Neuronal Networks of Individual Cells-Toward Single Cell to 3D Nanowire Intracellular Interfaces. ACS Appl. Mater. Interfaces 2012, 4, 3542– 3549,  DOI: 10.1021/am300602e

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     Yu, M.; Huang, Y.; Ballweg, J.; Shin, H.; Huang, M.; Savage, D. E.; Lagally, M. G.; Dent, E. W.; Blick, R. H.; Williams, J. C. Semiconductor Nanomembrane Tubes: Three-Dimensional Confinement for Controlled Neurite Outgrowth. ACS Nano 2011, 5, 2447– 2457,  DOI: 10.1021/nn103618d

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     Semiconductor nanomembrane tubes: The three-dimensional confinement for controlled neurite outgrowth

     Yu, Minrui; Huang, Yu; Ballweg, Jason; Shin, Hyuncheol; Huang, Minghuang; Savage, Donald E.; Lagally, Max G.; Dent, Erik W.; Blick, Robert H.; Williams, Justin C.

     ACS Nano (2011), 5 (4), 2447-2457CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     In many neural culture studies, neurite migration on a flat, open surface does not reflect the three-dimensional (3D) microenvironment in vivo. With that in mind, we fabricated arrays of semiconductor tubes using strained silicon (Si) and germanium (Ge) nanomembranes and employed them as a cell culture substrate for primary cortical neurons. Our expts. show that the SiGe substrate and the tube fabrication process are biol. viable for neuron cells. We also observe that neurons are attracted by the tube topog., even in the absence of adhesion factors, and can be guided to pass through the tubes during outgrowth. Coupled with selective seeding of individual neurons close to the tube opening, growth within a tube can be limited to a single axon. Furthermore, the tube feature resembles the natural myelin, both phys. and elec., and it is possible to control the tube diam. to be close to that of an axon, providing a confined 3D contact with the axon membrane and potentially insulating it from the extracellular soln.
819. 819

     Larramendy, F.; Yoshida, S.; Fekete, Z.; Serien, D.; Takeuchi, S.; Paul, O. Stackable Octahedron-Based Photoresist Scaffold by Direct Laser Writing for Controlled Three-Dimensional Cell Networks. In 2015 Transducers-2015 18th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS); IEEE, 2015; pp 642– 645.

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     Fendler, C. From 2D to 3D - Neurite Guiding Scaffolds for Designer Neuronal Networks; Ph.D. Dissertation, Universität Hamburg, 2019.

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     Ruggiero, A.; Criscuolo, V.; Grasselli, S.; Bruno, U.; Ausilio, C.; Bovio, C. L.; Bettucci, O.; Santoro, F. Two-Photon Polymerization Lithography Enabling the Fabrication of PEDOT: PSS 3D Structures for Bioelectronic Applications. Chem. Commun. 2022, 58, 9790– 9793,  DOI: 10.1039/D2CC03152C

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     Buchmann, S.; Enrico, A.; Holzreuter, M. A.; Reid, M.; Zeglio, E.; Niklaus, F.; Stemme, G.; Herland, A. Probabilistic Cell Seeding and Non-Autofluorescent 3D-Printed Structures as Scalable Approach for Multi-Level Co-Culture Modeling. Mater. Today Bio 2023, 21, 100706,  DOI: 10.1016/j.mtbio.2023.100706

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     Jarosiewicz, B.; Sarma, A. A.; Bacher, D.; Masse, N. Y.; Simeral, J. D.; Sorice, B.; Oakley, E. M.; Blabe, C.; Pandarinath, C.; Gilja, V. Virtual Typing by People with Tetraplegia Using a Self-Calibrating Intracortical Brain-Computer Interface. Sci. Transl. Med. 2015, 7, 313ra179,  DOI: 10.1126/scitranslmed.aac7328

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     Musk, E. An Integrated Brain-Machine Interface Platform with Thousands of Channels. J. Med. Internet Res. 2019, 21, e16194,  DOI: 10.2196/16194

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     Schwartz, A. B. Cortical Neural Prosthetics. Annu. Rev. Neurosci. 2004, 27, 487– 507,  DOI: 10.1146/annurev.neuro.27.070203.144233

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     Cortical neural prosthetics

     Schwartz, Andrew B.

     Annual Review of Neuroscience (2004), 27 (), 487-507CODEN: ARNSD5; ISSN:0147-006X. (Annual Reviews Inc.)

     Control of prostheses using cortical signals is based on three elements: chronic microelectrode arrays, extn. algorithms, and prosthetic effectors. Arrays of microelectrodes are permanently implanted in cerebral cortex. These arrays must record populations of single- and multiunit activity indefinitely. Information contg. position and velocity correlates of animate movement needs to be extd. continuously in real time from the recorded activity. Prosthetic arms, the current effectors used in this work, need to have the agility and configuration of natural arms. Demonstrations using closed-loop control show that subjects change their neural activity to improve performance with these devices. Adaptive-learning algorithms that capitalize on these improvements show that this technol. has the capability of restoring much of the arm movement lost with immobilizing deficits.
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     Shannon, C. E. Communication in the Presence of Noise. Proc. IRE 1949, 37, 10– 21,  DOI: 10.1109/JRPROC.1949.232969

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     Wolpaw, J. R.; Birbaumer, N.; McFarland, D. J.; Pfurtscheller, G.; Vaughan, T. M. Brain-Computer Interfaces for Communication and Control. Clin. Neurophysiol. 2002, 113, 767– 791,  DOI: 10.1016/S1388-2457(02)00057-3

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     Brain-computer interfaces for communication and control

     Wolpaw Jonathan R; Birbaumer Niels; McFarland Dennis J; Pfurtscheller Gert; Vaughan Theresa M

     Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology (2002), 113 (6), 767-91 ISSN:1388-2457.

     For many years people have speculated that electroencephalographic activity or other electrophysiological measures of brain function might provide a new non-muscular channel for sending messages and commands to the external world - a brain-computer interface (BCI). Over the past 15 years, productive BCI research programs have arisen. Encouraged by new understanding of brain function, by the advent of powerful low-cost computer equipment, and by growing recognition of the needs and potentials of people with disabilities, these programs concentrate on developing new augmentative communication and control technology for those with severe neuromuscular disorders, such as amyotrophic lateral sclerosis, brainstem stroke, and spinal cord injury. The immediate goal is to provide these users, who may be completely paralyzed, or 'locked in', with basic communication capabilities so that they can express their wishes to caregivers or even operate word processing programs or neuroprostheses. Present-day BCIs determine the intent of the user from a variety of different electrophysiological signals. These signals include slow cortical potentials, P300 potentials, and mu or beta rhythms recorded from the scalp, and cortical neuronal activity recorded by implanted electrodes. They are translated in real-time into commands that operate a computer display or other device. Successful operation requires that the user encode commands in these signals and that the BCI derive the commands from the signals. Thus, the user and the BCI system need to adapt to each other both initially and continually so as to ensure stable performance. Current BCIs have maximum information transfer rates up to 10-25bits/min. This limited capacity can be valuable for people whose severe disabilities prevent them from using conventional augmentative communication methods. At the same time, many possible applications of BCI technology, such as neuroprosthesis control, may require higher information transfer rates. Future progress will depend on: recognition that BCI research and development is an interdisciplinary problem, involving neurobiology, psychology, engineering, mathematics, and computer science; identification of those signals, whether evoked potentials, spontaneous rhythms, or neuronal firing rates, that users are best able to control independent of activity in conventional motor output pathways; development of training methods for helping users to gain and maintain that control; delineation of the best algorithms for translating these signals into device commands; attention to the identification and elimination of artifacts such as electromyographic and electro-oculographic activity; adoption of precise and objective procedures for evaluating BCI performance; recognition of the need for long-term as well as short-term assessment of BCI performance; identification of appropriate BCI applications and appropriate matching of applications and users; and attention to factors that affect user acceptance of augmentative technology, including ease of use, cosmesis, and provision of those communication and control capacities that are most important to the user. Development of BCI technology will also benefit from greater emphasis on peer-reviewed research publications and avoidance of the hyperbolic and often misleading media attention that tends to generate unrealistic expectations in the public and skepticism in other researchers. With adequate recognition and effective engagement of all these issues, BCI systems could eventually provide an important new communication and control option for those with motor disabilities and might also give those without disabilities a supplementary control channel or a control channel useful in special circumstances.
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     Pfurtscheller, G.; Flotzinger, D.; Kalcher, J. Brain-Computer Interface─a New Communication Device for Handicapped Persons. J. Microcomp. Appl. 1993, 16, 293– 299,  DOI: 10.1006/jmca.1993.1030

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     von Lühmann, A.; Wabnitz, H.; Sander, T.; Müller, K.-R. M3BA: A Mobile, Modular, Multimodal Biosignal Acquisition Architecture for Miniaturized EEG-NIRS-Based Hybrid BCI and Monitoring. IEEE Trans. Biomed. Eng. 2017, 64, 1199– 1210,  DOI: 10.1109/TBME.2016.2594127

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     Almajidy, R. K.; Mankodiya, K.; Abtahi, M.; Hofmann, U. G. A Newcomer’s Guide to Functional Near Infrared Spectroscopy Experiments. IEEE Rev. Biomed. Eng. 2020, 13, 292– 308,  DOI: 10.1109/RBME.2019.2944351

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     Almajidy, R. K.; Mottaghi, S.; Ajwad, A. A.; Boudria, Y.; Mankodiya, K.; Besio, W.; Hofmann, U. G. A Case for Hybrid BCIs: Combining Optical and Electrical Modalities Improves Accuracy. Front. Human Neurosci. 2023, 17, 1162712,  DOI: 10.3389/fnhum.2023.1162712

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     Graimann, B.; Allison, B. Z.; Pfurtscheller, G. Brain-Computer Interfaces: Revolutionizing Human-Computer Interaction; Springer Science & Business Media, 2010.

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     Pfurtscheller, G.; Aranibar, A. Evaluation of Event-Related Desynchronization (ERD) Preceding and Following Voluntary Self-Paced Movement. Electroencephalography Clin. Neurophysiol. 1979, 46, 138– 146,  DOI: 10.1016/0013-4694(79)90063-4

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     Schalk, G.; Wolpaw, J. R.; McFarland, D. J.; Pfurtscheller, G. EEG-Based Communication: Presence of an Error Potential. Clin. Neurophysiol. 2000, 111, 2138– 2144,  DOI: 10.1016/S1388-2457(00)00457-0

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     EEG-based communication: presence of an error potential

     Schalk G; Wolpaw J R; McFarland D J; Pfurtscheller G

     Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology (2000), 111 (12), 2138-44 ISSN:1388-2457.

     BACKGROUND: EEG-based communication could be a valuable new augmentative communication technology for those with severe motor disabilities. Like all communication methods, it faces the problem of errors in transmission. In the Wadsworth EEG-based brain-computer interface (BCI) system, subjects learn to use mu or beta rhythm amplitude to move a cursor to targets on a computer screen. While cursor movement is highly accurate in trained subjects, it is not perfect. METHODS: In an effort to develop a method for detecting errors, this study compared the EEG immediately after correct target selection to that after incorrect selection. RESULTS: The data showed that a mistake is followed by a positive potential centered at the vertex that peaks about 180 ms after the incorrect selection. CONCLUSION: The results suggest that this error potential might provide a method for detecting and voiding errors that requires no additional time and could thereby improve the speed and accuracy of EEG-based communication.
835. 835

     Bin, G.; Gao, X.; Yan, Z.; Hong, B.; Gao, S. An Online Multi-Channel SSVEP-Based Brain-Computer Interface Using a Canonical Correlation Analysis Method. J. Neural Eng. 2009, 6, 046002,  DOI: 10.1088/1741-2560/6/4/046002

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     Fernandez-Vargas, J.; Pfaff, H. U.; Rodriguez, F. B.; Varona, P. An Online Multi-Channel SSVEP-Based Brain-Computer Interface Using a Canonical Correlation Analysis Method. Front. Neural Circuits 2013, 7, 27,  DOI: 10.3389/fncir.2013.00027

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     Kelly, S. P.; Lalor, E. C.; Reilly, R. B.; Foxe, J. J. Visual Spatial Attention Tracking Using High-Density SSVEP Data for Independent Brain-Computer Communication. IEEE Trans. Neural Syst. Rehabil. Eng. 2005, 13, 172– 178,  DOI: 10.1109/TNSRE.2005.847369

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     Kwak, N.-S.; Müller, K.-R.; Lee, S.-W. A Lower Limb Exoskeleton Control System Based on Steady State Visual Evoked Potentials. J. Neural Eng. 2015, 12, 056009,  DOI: 10.1088/1741-2560/12/5/056009

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     Yin, E.; Zhou, Z.; Jiang, J.; Chen, F.; Liu, Y.; Hu, D. A Novel Hybrid BCI Speller Based on the Incorporation of SSVEP into the P300 Paradigm. J. Neural Eng. 2013, 10, 026012,  DOI: 10.1088/1741-2560/10/2/026012

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     Plonsey, R.; Barr, R. C. Bioelectricity: A Quantitative Approach; Springer Science & Business Media, 2007.

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     Weiskopf, N.; Mathiak, K.; Bock, S. W.; Scharnowski, F.; Veit, R.; Grodd, W.; Goebel, R.; Birbaumer, N. Principles of a Brain-Computer Interface (BCI) Based on Real-Time Functional Magnetic Resonance Imaging (fMRI). IEEE Trans. Biomedical Eng. 2004, 51, 966– 970,  DOI: 10.1109/TBME.2004.827063

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     Goebel, R.; Linden, D. Neurofeedback with Real-Time Functional MRI. In MRI in Psychiatry; Springer, 2014; pp 35– 46.

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     Schröer, S.; Killmann, I.; Frank, B.; Völker, M.; Fiederer, L.; Ball, T.; Burgard, W. An Autonomous Robotic Assistant for Drinking. In 2015 IEEE International Conference on Robotics and Automation (ICRA); IEEE, 2015; pp 6482– 6487.

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     Ball, T.; Nawrot, M.; Pistohl, T.; Aertsen, A.; Schulze-Bonhage, A.; Mehring, C. Towards an Implantable Brain-Machine Interface Based on Epicortical Field Potentials. Biomed. Technol. 2004, 49, 756– 759

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     Nicolelis, M. A.; Lebedev, M. A. Principles of Neural Ensemble Physiology Underlying the Operation of Brain-Machine Interfaces. Nat. Rev. Neurosci. 2009, 10, 530– 540,  DOI: 10.1038/nrn2653

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     Principles of neural ensemble physiology underlying the operation of brain-machine interfaces

     Nicolelis, Miguel A. L.; Lebedev, Mikhail A.

     Nature Reviews Neuroscience (2009), 10 (7), 530-540CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

     Research on brain-machine interfaces has been ongoing for at least a decade. During this period, simultaneous recordings of the extracellular elec. activity of hundreds of individual neurons have been used for direct, real-time control of various artificial devices. Brain-machine interfaces have also added greatly to our knowledge of the fundamental physiol. principles governing the operation of large neural ensembles. Further understanding of these principles is likely to have a key role in the future development of neuroprosthetics for restoring mobility in severely paralysed patients.
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     Thakor, N. V. Translating the Brain-Machine Interface. Sci. Trans. Med. 2013, 5, 210ps17,  DOI: 10.1126/scitranslmed.3007303

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     Soekadar, S. R.; Birbaumer, N.; Slutzky, M. W.; Cohen, L. G. Brain-Machine Interfaces in Neurorehabilitation of Stroke. Neurobiol. Dis. 2015, 83, 172– 179,  DOI: 10.1016/j.nbd.2014.11.025

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     Nicolelis, M. A. L. Methods for Neural Ensemble Recordings; CRC Press: Boca Raton, FL, USA, 1999.

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     Krüger, J.; Caruana, F.; Rizzolatti, G. Seven Years of Recording from Monkey Cortex with a Chronically Implanted Multiple Microelectrode. Front. Neuroeng. 2010, 3, 6,  DOI: 10.3389/fneng.2010.00006

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     Ferro, M. D.; Melosh, N. A. Electronic and Ionic Materials for Neurointerfaces. Adv. Funct. Mater. 2018, 28, 1704335,  DOI: 10.1002/adfm.201704335

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     Simeral, J.; Kim, S.-P.; Black, M.; Donoghue, J.; Hochberg, L. Neural Control of Cursor Trajectory and Click by a Human with Tetraplegia 1000 Days after Implant of an Intracortical Microelectrode Array. J. Neural Eng. 2011, 8, 025027,  DOI: 10.1088/1741-2560/8/2/025027

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     Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array

     Simeral J D; Kim S-P; Black M J; Donoghue J P; Hochberg L R

     Journal of neural engineering (2011), 8 (2), 025027 ISSN:.

     The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point-and-click control of a computer interface to an individual with tetraplegia 1000 days after implantation of this sensor.
854. 854

     Salas, M. A.; Bashford, L.; Kellis, S.; Jafari, M.; Jo, H.; Kramer, D.; Shanfield, K.; Pejsa, K.; Lee, B.; Liu, C. Y. Proprioceptive and Cutaneous Sensations in Humans Elicited by Intracortical Microstimulation. eLife 2018, 7, e32904,  DOI: 10.7554/eLife.32904

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     Mazurek, K. A.; Schieber, M. H. Injecting Information into the Mammalian Cortex: Progress, Challenges, and Promise. Neuroscientist 2021, 27, 129– 142,  DOI: 10.1177/1073858420936253

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     Rincón Montes, V.; Gehlen, J.; Lück, S.; Mokwa, W.; Müller, F.; Walter, P.; Offenhäusser, A. Toward a Bidirectional Communication between Retinal Cells and a Prosthetic Device-A Proof of Concept. Front. Neurosci. 2019, 13, 367,  DOI: 10.3389/fnins.2019.00367

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     Menzel-Severing, J.; Laube, T.; Brockmann, C.; Bornfeld, N.; Mokwa, W.; Mazinani, B.; Walter, P.; Roessler, G. Implantation and Explantation of an Active Epiretinal Visual Prosthesis: 2-Year Follow-Up Data from the EPIRET3 Prospective Clinical Trial. Eye 2012, 26, 501– 509,  DOI: 10.1038/eye.2012.35

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     Zrenner, E. Will Retinal Implants Restore Vision?. Science 2002, 295, 1022– 1025,  DOI: 10.1126/science.1067996

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     Bodybuilding: The bionic human: Will retinal implants restore vision?

     Zrenner, Eberhart

     Science (Washington, DC, United States) (2002), 295 (5557), 1022-1025CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     A no. of research groups are developing elec. implants that can be attached directly to the retina in an attempt to restore vision to patients suffering from retinal degeneration. However, despite promising results in animal expts., there are still several major obstacles to overcome before retinal prostheses can be used clin.
859. 859

     Chen, X.; Wang, F.; Fernandez, E.; Roelfsema, P. R. Shape Perception via a High-Channel-Count Neuroprosthesis in Monkey Visual Cortex. Science 2020, 370, 1191– 1196,  DOI: 10.1126/science.abd7435

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     House, W. F.; Urban, J. Long Term Results of Electrode Implantation and Electronic Stimulation of the Cochlea in Man. Ann. Otology Rhinology Laryngology 1973, 82, 504– 517,  DOI: 10.1177/000348947308200408

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     Zeng, F.-G.; Rebscher, S.; Harrison, W.; Sun, X.; Feng, H. Cochlear Implants: System Design, Integration, and Evaluation. IEEE Rev. Biomed. Eng. 2008, 1, 115– 142,  DOI: 10.1109/RBME.2008.2008250

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     Cochlear implants: system design, integration, and evaluation

     Zeng Fan-Gang; Rebscher Stephen; Harrison William; Sun Xiaoan; Feng Haihong

     IEEE reviews in biomedical engineering (2008), 1 (), 115-42 ISSN:.

     As the most successful neural prosthesis, cochlear implants have provided partial hearing to more than 120000 persons worldwide; half of which being pediatric users who are able to develop nearly normal language. Biomedical engineers have played a central role in the design, integration and evaluation of the cochlear implant system, but the overall success is a result of collaborative work with physiologists, psychologists, physicians, educators, and entrepreneurs. This review presents broad yet in-depth academic and industrial perspectives on the underlying research and ongoing development of cochlear implants. The introduction accounts for major events and advances in cochlear implants, including dynamic interplays among engineers, scientists, physicians, and policy makers. The review takes a system approach to address critical issues in cochlear implant research and development. First, the cochlear implant system design and specifications are laid out. Second, the design goals, principles, and methods of the subsystem components are identified from the external speech processor and radio frequency transmission link to the internal receiver, stimulator and electrode arrays. Third, system integration and functional evaluation are presented with respect to safety, reliability, and challenges facing the present and future cochlear implant designers and users. Finally, issues beyond cochlear implants are discussed to address treatment options for the entire spectrum of hearing impairment as well as to use the cochlear implant as a model to design and evaluate other similar neural prostheses such as vestibular and retinal implants.
862. 862

     Wong, K.; Kozin, E. D.; Kanumuri, V. V.; Vachicouras, N.; Miller, J.; Lacour, S.; Brown, M. C.; Lee, D. J. Auditory Brainstem Implants: Recent Progress and Future Perspectives. Front. Neurosci. 2019, 13, 10,  DOI: 10.3389/fnins.2019.00010

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863. 863

     Ajiboye, A. B.; Willett, F. R.; Young, D. R.; Memberg, W. D.; Murphy, B. A.; Miller, J. P.; Walter, B. L.; Sweet, J. A.; Hoyen, H. A.; Keith, M. W. Restoration of Reaching and Grasping Movements Through Brain-Controlled Muscle Stimulation in a Person with Tetraplegia: A Proof-of-Concept Demonstration. Lancet 2017, 389, 1821– 1830,  DOI: 10.1016/S0140-6736(17)30601-3

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     Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration

     Ajiboye A Bolu; Willett Francis R; Young Daniel R; Memberg William D; Murphy Brian A; Peckham P Hunter; Miller Jonathan P; Sweet Jennifer A; Walter Benjamin L; Hoyen Harry A; Keith Michael W; Simeral John D; Donoghue John P; Hochberg Leigh R; Kirsch Robert F

     Lancet (London, England) (2017), 389 (10081), 1821-1830 ISSN:.

     BACKGROUND: People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain-computer interface (iBCI). METHODS: We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. FINDINGS: The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). INTERPRETATION: To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. FUNDING: National Institutes of Health, Department of Veterans Affairs.
864. 864

     Pfurtscheller, G.; Müller, G. R.; Pfurtscheller, J.; Gerner, H. J.; Rupp, R. ‘Thought’- Control of Functional Electrical Stimulation to Restore Hand Grasp in a Patient with Tetraplegia. Neurosci. Lett. 2003, 351, 33– 36,  DOI: 10.1016/S0304-3940(03)00947-9

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     Cogan, S. F.; Ludwig, K. A.; Welle, C. G.; Takmakov, P. Tissue Damage Thresholds During Therapeutic Electrical Stimulation. J. Neural Eng. 2016, 13, 021001,  DOI: 10.1088/1741-2560/13/2/021001

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     Tissue damage thresholds during therapeutic electrical stimulation

     Cogan Stuart F; Ludwig Kip A; Welle Cristin G; Takmakov Pavel

     Journal of neural engineering (2016), 13 (2), 021001 ISSN:.

     OBJECTIVE: Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. APPROACH: In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. MAIN RESULTS: For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. SIGNIFICANCE: It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device safety.
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     Shannon, R. V. A Model of Safe Levels for Electrical Stimulation. IEEE Trans. Biomed. Eng. 1992, 39, 424– 426,  DOI: 10.1109/10.126616

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     A model of safe levels for electrical stimulation

     Shannon R V

     IEEE transactions on bio-medical engineering (1992), 39 (4), 424-6 ISSN:0018-9294.

     A model is presented that represents a large body of data on safety and damage levels of electrical stimulation. The predictions of the model are consistent with known principles of current flow and known mechanisms of damage around stimulating electrodes. It is proposed that limits on levels of electrical stimulation take into account the location of the electrode relative to the stimulated tissue and these limits can be computed algorithmically from the model.
867. 867

     Pancrazio, J. J.; Cogan, S. F. Editorial for the Special Issue on Neural Electrodes: Design and Applications. Micromachines (Basel) 2019, 10, 466,  DOI: 10.3390/mi10070466

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     Rousche, P. J.; Normann, R. A. A Method for Pneumatically Inserting an Array of Penetrating Electrodes into Cortical Tissue. Ann. Biomed. Eng. 1992, 20, 413– 422,  DOI: 10.1007/BF02368133

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     Jensen, W.; Yoshida, K.; Hofmann, U. G. In-Vivo Implant Mechanics of Flexible, Silicon-Based ACREO Microelectrode Arrays in Rat Cerebral Cortex. IEEE Trans. Biomed. Eng. 2006, 53, 934– 940,  DOI: 10.1109/TBME.2006.872824

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     Pflüger, P.; Pinnell, R. C.; Martini, N.; Hofmann, U. G. Chronically Implanted Microelectrodes Cause c-fos Expression along Their Trajectory. Front. Neurosci. 2020, 13, 1367,  DOI: 10.3389/fnins.2019.01367

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     Richter, A.; Xie, Y.; Schumacher, A.; Löffler, S.; Kirch, R.; Al-Hasani, J.; Rapoport, D. H.; Kruse, C.; Moser, A.; Tronnier, V. A Simple Implantation Method for Flexible, Multisite Microelectrodes into Rat Brains. Front. Neuroeng. 2013, 6, 6,  DOI: 10.3389/fneng.2013.00006

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     Kozai, T. D. Y.; Kipke, D. R. Insertion Shuttle with Carboxyl Terminated Self-Assembled Monolayer Coatings for Implanting Flexible Polymer Neural Probes in the Brain. J. Neurosci. Methods 2009, 184, 199– 205,  DOI: 10.1016/j.jneumeth.2009.08.002

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     Insertion shuttle with carboxyl terminated self-assembled monolayer coatings for implanting flexible polymer neural probes in the brain

     Kozai, Takashi D. Yoshida; Kipke, Daryl R.

     Journal of Neuroscience Methods (2009), 184 (2), 199-205CODEN: JNMEDT; ISSN:0165-0270. (Elsevier B.V.)

     Penetrating microscale microelectrodes made from flexible polymers tend to bend or deflect and may fail to reach their target location. The development of flexible neural probes requires methods for reliable and controlled insertion into the brain. Previous approaches for implanting flexible probes into the cortex required modifications that negate the flexibility, limit the functionality, or restrict the design of the probe. This study investigated the use of an electroneg. self-assembled monolayer (SAM) as a coating on a stiff insertion shuttle to carry a polymer probe into the cerebral cortex, and then the detachment of the shuttle from the probe by altering the shuttle's hydrophobicity. Polydimethylsiloxane (PDMS) and polyimide probes were inserted into an agarose in vitro brain model using silicon insertion shuttles. The silicon shuttles were coated with a carboxyl terminal SAM. The precision of insertion using the shuttle was measured by the percentage displacement of the probe upon shuttle removal after the probe was fully inserted. The av. relative displacement of polyimide probes inserted with SAM-coated shuttles was (1.0 ± 0.66)% of the total insertion depth compared to (26.5 ± 3.7)% for uncoated silicon shuttles. The av. relative displacement of PDMS probes was (2.1 ± 1.1)% of the insertion depth compared to 100% (complete removal) for uncoated silicon shuttles. SAM-coated shuttles were further validated through their use to reliably insert PDMS probes in the cerebral cortex of rodents. This study found that SAM-coated silicon shuttles are a viable method for accurately and precisely inserting flexible neural probes in the brain.
873. 873

     Robinson, J. T.; Pohlmeyer, E.; Gather, M. C.; Kemere, C.; Kitching, J. E.; Malliaras, G. G.; Marblestone, A.; Shepard, K. L.; Stieglitz, T.; Xie, C. Developing Next-Generation Brain Sensing Technologies─A Review. IEEE Sens. J. 2019, 19, 10163– 10175,  DOI: 10.1109/JSEN.2019.2931159

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     Ma, Y.; Luo, Z.; Steiger, C.; Traverso, G.; Adib, F. Enabling Deep-Tissue Networking for Miniature Medical Devices. In Proceedings of the 2018 Conference of the ACM Special Interest Group on Data Communication ; 2018; pp 417– 431.

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     Schamel, D.; Mark, A. G.; Gibbs, J. G.; Miksch, C.; Morozov, K. I.; Leshansky, A. M.; Fischer, P. Nanopropellers and Their Actuation in Complex Viscoelastic Media. ACS Nano 2014, 8, 8794– 8801,  DOI: 10.1021/nn502360t

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     Nanopropellers and Their Actuation in Complex Viscoelastic Media

     Schamel, Debora; Mark, Andrew G.; Gibbs, John G.; Miksch, Cornelia; Morozov, Konstantin I.; Leshansky, Alexander M.; Fischer, Peer

     ACS Nano (2014), 8 (9), 8794-8801CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Tissue and biol. fluids are complex viscoelastic media with a nanoporous macromol. structure. Here, we demonstrate that helical nanopropellers can be controllably steered through such a biol. gel. The screw-propellers have a filament diam. of about 70 nm and are smaller than previously reported nanopropellers as well as any swimming microorganism. We show that the nanoscrews will move through high-viscosity solns. with comparable velocities to that of larger micropropellers, even though they are so small that Brownian forces suppress their actuation in pure water. When actuated in viscoelastic hyaluronan gels, the nanopropellers appear to have a significant advantage, as they are of the same size range as the gel's mesh size. Whereas larger helixes will show very low or negligible propulsion in hyaluronan solns., the nanoscrews actually display significantly enhanced propulsion velocities that exceed the highest measured speeds in Newtonian fluids. The nanopropellers are not only promising for applications in the extracellular environment but small enough to be taken up by cells.
876. 876

     Ren, L.; Nama, N.; McNeill, J. M.; Soto, F.; Yan, Z.; Liu, W.; Wang, W.; Wang, J.; Mallouk, T. E. 3D Steerable, Acoustically Powered Microswimmers for Single-Particle Manipulation. Sci. Adv. 2019, 5, eaax3084,  DOI: 10.1126/sciadv.aax3084

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     Martins, N. R.; Angelica, A.; Chakravarthy, K.; Svidinenko, Y.; Boehm, F. J.; Opris, I.; Lebedev, M. A.; Swan, M.; Garan, S. A.; Rosenfeld, J. V. Human Brain/Cloud Interface. Front. Neurosci. 2019, 13, 112,  DOI: 10.3389/fnins.2019.00112

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     Alcântara, C. C.; Landers, F. C.; Kim, S.; De Marco, C.; Ahmed, D.; Nelson, B. J.; Pané, S. Mechanically Interlocked 3D Multi-Material Micromachines. Nat. Commun. 2020, 11, 5957,  DOI: 10.1038/s41467-020-19725-6

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     Mechanically interlocked 3D multi-material micromachines

     Alcantara, C. C. J.; Landers, F. C.; Kim, S.; De Marco, C.; Ahmed, D.; Nelson, B. J.; Pane, S.

     Nature Communications (2020), 11 (1), 5957CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)

     Metals and polymers are dissimilar materials in terms of their physicochem. properties, but complementary in terms of functionality. As a result, metal-org. structures can introduce a wealth of novel applications in small-scale robotics. However, current fabrication techniques are unable to process three-dimensional metallic and polymeric components. Here, we show that hybrid microstructures can be interlocked by combining 3D lithog., mold casting, and electrodeposition. Our method can be used to achieve complex multi-material microdevices with unprecedented resoln. and topol. complexity. We show that metallic components can be combined with structures made of different classes of polymers. Properties of both metals and polymers can be exploited in parallel, resulting in structures with high magnetic responsiveness, elevated drug loading capacity, on-demand shape transformation, and elastic behavior. We showcase the advantages of our approach by demonstrating new microrobotic locomotion modes and controlled agglomeration of swarms.
879. 879

     Agarwal, K.; Jegadeesan, R.; Guo, Y.-X.; Thakor, N. V. Wireless Power Transfer Strategies for Implantable Bioelectronics. IEEE Rev. Biomed. Eng. 2017, 10, 136– 161,  DOI: 10.1109/RBME.2017.2683520

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     Wireless Power Transfer Strategies for Implantable Bioelectronics

     Agarwal Kush; Jegadeesan Rangarajan; Guo Yong-Xin; Thakor Nitish V

     IEEE reviews in biomedical engineering (2017), 10 (), 136-161 ISSN:.

     Neural implants have emerged over the last decade as highly effective solutions for the treatment of dysfunctions and disorders of the nervous system. These implants establish a direct, often bidirectional, interface to the nervous system, both sensing neural signals and providing therapeutic treatments. As a result of the technological progress and successful clinical demonstrations, completely implantable solutions have become a reality and are now commercially available for the treatment of various functional disorders. Central to this development is the wireless power transfer (WPT) that has enabled implantable medical devices (IMDs) to function for extended durations in mobile subjects. In this review, we present the theory, link design, and challenges, along with their probable solutions for the traditional near-field resonant inductively coupled WPT, capacitively coupled short-ranged WPT, and more recently developed ultrasonic, mid-field, and far-field coupled WPT technologies for implantable applications. A comparison of various power transfer methods based on their power budgets and WPT range follows. Power requirements of specific implants like cochlear, retinal, cortical, and peripheral are also considered and currently available IMD solutions are discussed. Patient's safety concerns with respect to electrical, biological, physical, electromagnetic interference, and cyber security from an implanted neurotech device are also explored in this review. Finally, we discuss and anticipate future developments that will enhance the capabilities of current-day wirelessly powered implants and make them more efficient and integrable with other electronic components in IMDs.
880. 880

     Seo, D.; Neely, R. M.; Shen, K.; Singhal, U.; Alon, E.; Rabaey, J. M.; Carmena, J. M.; Maharbiz, M. M. Wireless Recording in the Peripheral Nervous System with Ultrasonic Neural Dust. Neuron 2016, 91, 529– 539,  DOI: 10.1016/j.neuron.2016.06.034

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     Wireless Recording in the Peripheral Nervous System with Ultrasonic Neural Dust

     Seo, Dongjin; Neely, Ryan M.; Shen, Konlin; Singhal, Utkarsh; Alon, Elad; Rabaey, Jan M.; Carmena, Jose M.; Maharbiz, Michel M.

     Neuron (2016), 91 (3), 529-539CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     The emerging field of bioelectronic medicine seeks methods for deciphering and modulating electrophysiol. activity in the body to attain therapeutic effects at target organs. Current approaches to interfacing with peripheral nerves and muscles rely heavily on wires, creating problems for chronic use, while emerging wireless approaches lack the size scalability necessary to interrogate small-diam. nerves. Furthermore, conventional electrode-based technologies lack the capability to record from nerves with high spatial resoln. or to record independently from many discrete sites within a nerve bundle. Here, we demonstrate neural dust, a wireless and scalable ultrasonic backscatter system for powering and communicating with implanted bioelectronics. We show that ultrasound is effective at delivering power to mm-scale devices in tissue; likewise, passive, battery-less communication using backscatter enables high-fidelity transmission of electromyogram (EMG) and electroneurogram (ENG) signals from anesthetized rats. These results highlight the potential for an ultrasound-based neural interface system for advancing future bioelectronics-based therapies.
881. 881

     Seo, D.; Carmena, J. M.; Rabaey, J. M.; Alon, E.; Maharbiz, M. M. Neural Dust: An Ultrasonic, Low Power Solution for Chronic Brain-Machine Interfaces. arXiv , July 8, 2013, 1307.2196, ver. 1 DOI: 10.48550/arXiv.1307.2196 .

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     Gómez-Martínez, R.; Vázquez, P.; Duch, M.; Muriano, A.; Pinacho, D.; Sanvicens, N.; Sánchez-Baeza, F.; Boya, P.; de la Rosa, E. J.; Esteve, J.; Suárez, T.; Plaza, J. A. Intracellular Silicon Chips in Living Cells. Small 2010, 6, 499– 502,  DOI: 10.1002/smll.200901041

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     Intracellular Silicon Chips in Living Cells

     Gomez-Martinez, Rodrigo; Vazquez, Patricia; Duch, Marta; Muriano, Alejandro; Pinacho, Daniel; Sanvicens, Nuria; Sanchez-Baeza, Francisco; Boya, Patricia; de la Rosa, Enrique J.; Esteve, Jaume; Suarez, Teresa; Plaza, Jose A.

     Small (2010), 6 (4), 499-502CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Silicon-based intracellular chips (ICCs) with dimensions smaller than 3 μm were fabricated and collected, internalized inside living cells, and used as intracellular sensors. Results show that silicon-based top-down fabricated ICCs can be internalized by living eukaryotic cells without interfering with cell viability, and functionalized ICCs could be used as intracellular sensors since they can interact with the cell cytoplasm. ICCs have similar dimensions to many synthesized micro- and nanoparticles but they have the advantages of silicon-chip technol.
883. 883

     Marblestone, A. H.; Zamft, B. M.; Maguire, Y. G.; Shapiro, M. G.; Cybulski, T. R.; Glaser, J. I.; Amodei, D.; Stranges, P. B.; Kalhor, R.; Dalrymple, D. A. Physical Principles for Scalable Neural Recording. Front. Comput. Neurosci. 2013, 7, 137,  DOI: 10.3389/fncom.2013.00137

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     Physical principles for scalable neural recording

     Marblestone Adam H; Zamft Bradley M; Maguire Yael G; Shapiro Mikhail G; Cybulski Thaddeus R; Glaser Joshua I; Amodei Dario; Stranges P Benjamin; Kalhor Reza; Dalrymple David A; Seo Dongjin; Alon Elad; Maharbiz Michel M; Carmena Jose M; Rabaey Jan M; Boyden Edward S; Church George M; Kording Konrad P

     Frontiers in computational neuroscience (2013), 7 (), 137 ISSN:1662-5188.

     Simultaneously measuring the activities of all neurons in a mammalian brain at millisecond resolution is a challenge beyond the limits of existing techniques in neuroscience. Entirely new approaches may be required, motivating an analysis of the fundamental physical constraints on the problem. We outline the physical principles governing brain activity mapping using optical, electrical, magnetic resonance, and molecular modalities of neural recording. Focusing on the mouse brain, we analyze the scalability of each method, concentrating on the limitations imposed by spatiotemporal resolution, energy dissipation, and volume displacement. Based on this analysis, all existing approaches require orders of magnitude improvement in key parameters. Electrical recording is limited by the low multiplexing capacity of electrodes and their lack of intrinsic spatial resolution, optical methods are constrained by the scattering of visible light in brain tissue, magnetic resonance is hindered by the diffusion and relaxation timescales of water protons, and the implementation of molecular recording is complicated by the stochastic kinetics of enzymes. Understanding the physical limits of brain activity mapping may provide insight into opportunities for novel solutions. For example, unconventional methods for delivering electrodes may enable unprecedented numbers of recording sites, embedded optical devices could allow optical detectors to be placed within a few scattering lengths of the measured neurons, and new classes of molecularly engineered sensors might obviate cumbersome hardware architectures. We also study the physics of powering and communicating with microscale devices embedded in brain tissue and find that, while radio-frequency electromagnetic data transmission suffers from a severe power-bandwidth tradeoff, communication via infrared light or ultrasound may allow high data rates due to the possibility of spatial multiplexing. The use of embedded local recording and wireless data transmission would only be viable, however, given major improvements to the power efficiency of microelectronic devices.
884. 884

     Ham, D.; Park, H.; Hwang, S.; Kim, K. Neuromorphic Electronics Based on Copying and Pasting the Brain. Nat. Electron. 2021, 4, 635– 644,  DOI: 10.1038/s41928-021-00646-1

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     Gray, C.; Maldonado, P.; Wilson, M.; McNaughton, B. Tetrodes Markedly Improve the Reliability and Yield of Multiple Single-Unit Isolation from Multi-Unit Recordings in Cat Striate Cortex. J. Neurosci. Meth. 1995, 63, 43– 54,  DOI: 10.1016/0165-0270(95)00085-2

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     Tetrodes markedly improve the reliability and yield of multiple single-unit isolation from multi-unit recordings in cat striate cortex

     Gray C M; Maldonado P E; Wilson M; McNaughton B

     Journal of neuroscience methods (1995), 63 (1-2), 43-54 ISSN:0165-0270.

     The majority of techniques for separating multiple single-unit spike trains from a multi-unit recording rely on the assumption that different cells exhibit action potentials having unique amplitudes and waveforms. When this assumption fails, due to the similarity of spike shape among different cells or to the presence of complex spikes with declining intra-burst amplitude, these methods lead to errors in classification. In an effort to avoid these errors, the stereotrode (McNaughton et al., 1983) and later the tetrode (O'Keefe and Reece, 1993; Wilson and McNaughton, 1993) recording techniques were developed. Because the latter technique has been applied primarily to the hippocampus, we sought to evaluate its performance in the neocortex. Multi-unit recordings, using single tetrodes, were made at 28 sites in area 17 of 3 anesthetized cats. Neurons were activated with moving bars and square wave gratings. Single units were separated by identification of clusters in 2-D projections of either peak-to-peak amplitude, spike width, spike area, or the 1st versus 2nd principal components of the waveforms recorded on each channel. Using tetrodes, we recorded a total of 154 single cells (mean = 5.4, max = 9). By cross-checking the performance of the tetrode with the stereotrode and electrode, we found that the best of the 6 possible stereotrode pairs and the best of 4 possible electrodes from each tetrode yielded 102 (mean = 3.6, max = 7) and 95 (mean = 3.4, max = 6) cells, respectively. Moreover, we found that the number of cells isolated at each site by the tetrode was greater than the stereotrode or electrode in 16/28 and 28/28 cases, respectively. Thus, both stereotrodes, and particularly electrodes, often lumped 2 or more cells in a single cluster that could be easily separated by the tetrode. We conclude that tetrode recording currently provides the best and most reliable method for the isolation of multiple single units in the neocortex using a single probe.
886. 886

     Buzsáki, G.; Anastassiou, C. A.; Koch, C. The Origin of Extracellular Fields and Currents─EEG, ECoG, LFP and Spikes. Nat. Rev. Neurosci. 2012, 13, 407– 420,  DOI: 10.1038/nrn3241

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     The origin of extracellular fields and currents - EEG, ECoG, LFP and spikes

     Buzsaki, Gyoergy; Anastassiou, Costas A.; Koch, Christof

     Nature Reviews Neuroscience (2012), 13 (6), 407-420CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

     A review. Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular signal is the synaptic transmembrane current, other sources - including Na+ and Ca2+ spikes, ionic fluxes through voltage- and ligand-gated channels, and intrinsic membrane oscillations - can substantially shape the extracellular field. High-d. recordings of field activity in animals and subdural grid recordings in humans, combined with recently developed data processing tools and computational modeling, can provide insight into the cooperative behavior of neurons, their av. synaptic input and their spiking output, and can increase our understanding of how these processes contribute to the extracellular signal.
887. 887

     Thio, B. J.; Grill, W. M. Relative Contributions of Different Neural Sources to the EEG. NeuroImage 2023, 275, 120179,  DOI: 10.1016/j.neuroimage.2023.120179

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     Næss, S.; Halnes, G.; Hagen, E.; Hagler, D. J., Jr; Dale, A. M.; Einevoll, G. T.; Ness, T. V. Biophysically Detailed Forward Modeling of the Neural Origin of EEG and MEG Signals. NeuroImage 2021, 225, 117467,  DOI: 10.1016/j.neuroimage.2020.117467

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     Hämäläinen, M.; Hari, R.; Ilmoniemi, R. J.; Knuutila, J.; Lounasmaa, O. V. Magnetoencephalography─ Theory, Instrumentation, and Applications to Noninvasive Studies of the Working Human Brain. Rev. Mod. Phys. 1993, 65, 413,  DOI: 10.1103/RevModPhys.65.413

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     Pfurtscheller, G.; Da Silva, F. L. Event-Related EEG/MEG Synchronization and Desynchronization: Basic Principles. Clin. Neurophysiol. 1999, 110, 1842– 1857,  DOI: 10.1016/S1388-2457(99)00141-8

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     Hill, R. M.; Boto, E.; Rea, M.; Holmes, N.; Leggett, J.; Coles, L. A.; Papastavrou, M.; Everton, S. K.; Hunt, B. A.; Sims, D. Multi-Channel Whole-Head OPM-MEG: Helmet Design and a Comparison with a Conventional System. NeuroImage 2020, 219, 116995,  DOI: 10.1016/j.neuroimage.2020.116995

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     Rynes, M. L.; Surinach, D. A.; Linn, S.; Laroque, M.; Rajendran, V.; Dominguez, J.; Hadjistamoulou, O.; Navabi, Z. S.; Ghanbari, L.; Johnson, G. W. Miniaturized Head-Mounted Microscope for Whole-Cortex Mesoscale Imaging in Freely Behaving Mice. Nat. Methods 2021, 18, 417– 425,  DOI: 10.1038/s41592-021-01104-8

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     Zong, W.; Obenhaus, H. A.; Skytøen, E. R.; Eneqvist, H.; de Jong, N. L.; Vale, R.; Jorge, M. R.; Moser, M.-B.; Moser, E. I. Large-Scale Two-Photon Calcium Imaging in Freely Moving Mice. Cell 2022, 185, 1240– 1256,  DOI: 10.1016/j.cell.2022.02.017

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     Large-scale two-photon calcium imaging in freely moving mice

     Zong, Weijian; Obenhaus, Horst A.; Skytoeen, Emilie R.; Eneqvist, Hanna; de Jong, Nienke L.; Vale, Ruben; Jorge, Marina R.; Moser, May-Britt; Moser, Edvard I.

     Cell (Cambridge, MA, United States) (2022), 185 (7), 1240-1256.e30CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

     We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resoln., multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope wt. below 3 g and a highly flexible connection cable, MINI2P allowed stable imaging with no impediment of behavior in a variety of assays compared to untethered, unimplanted animals. The improved cell yield was achieved through a optical system design featuring an enlarged field of view (FOV) and a microtunable lens with increased z-scanning range and speed that allows fast and stable imaging of multiple interleaved planes, as well as 3D functional imaging. Successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas.
894. 894

     Tsien, R. Y. New Calcium Indicators and Buffers with High Selectivity against Magnesium and Protons: Design, Synthesis and Properties of Prototype Structures. Biochemistry 1980, 19, 2396– 2404,  DOI: 10.1021/bi00552a018

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     New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures

     Tsien, Roger Y.

     Biochemistry (1980), 19 (11), 2396-404CODEN: BICHAW; ISSN:0006-2960.

     A new family of high-affinity buffers and optical indicators for Ca2+ was synthesized. The parent compd. was K 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate (KI) [73630-08-7] a relative of the well-known chelator EGTA in which methylene links between oxygen and nitrogen were replaced by benzene rings. I and its derivs. shared the high selectivity for Ca2+ over Mg2+ of EGTA, but were much less affected by pH changes and were faster at taking up and releasing Ca2+. The affinity of the parent compd. for Ca2+ (dissocn. const. 1.1 × 10-7 M in 0.1 M KCl) may be strengthened or weakened by electron-withdrawing or -releasing substituents on the arom. rings. The Ca2+ and Mg2+ affinities may further be altered by replacing the ether oxygens by heterocyclic nitrogen atoms. The compds. described were fluorescent Ca2+ indicators absorbing in the UV region; the very large spectral shifts obsd. on binding Ca2+ fit the prediction that complexation should hinder the conjugation of the nitrogen lone-pair electrons with the arom. rings. Derivs. with quinoline nuclei were notable for their high sensitivity of fluorescent quantum yield to the binding of Ca2+ but not of Mg2+. Preliminary biol. tests revealed little or no binding to membranes or toxic effects following intracellular microinjection.
895. 895

     Stosiek, C.; Garaschuk, O.; Holthoff, K.; Konnerth, A. In Vivo Two-Photon Calcium Imaging of Neuronal Networks. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 7319– 7324,  DOI: 10.1073/pnas.1232232100

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     In vivo two-photon calcium imaging of neuronal networks

     Stosiek, Christoph; Garaschuk, Olga; Holthoff, Knut; Konnerth, Arthur

     Proceedings of the National Academy of Sciences of the United States of America (2003), 100 (12), 7319-7324CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Two-photon calcium imaging is a powerful means for monitoring the activity of distinct neurons in brain tissue in vivo. In the mammalian brain, such imaging studies have been restricted largely to calcium recordings from neurons that were individually dye-loaded through microelectrodes. Previous attempts to use membrane-permeant forms of fluorometric calcium indicators to load populations of neurons have yielded satisfactory results only in cell cultures or in slices of immature brain tissue. Here we introduce a versatile approach for loading membrane-permeant fluorescent indicator dyes in large populations of cells. We established a pressure ejection-based local dye delivery protocol that can be used for a large spectrum of membrane-permeant indicator dyes, including calcium green-1 acetoxymethyl (AM) ester, Fura-2 AM, Fluo-4 AM, and Indo-1 AM. We applied this dye-loading protocol successfully in mouse brain tissue at any developmental stage from newborn to adult in vivo and in vitro. In vivo two-photon Ca2+ recordings, obtained by imaging through the intact skull, indicated that whisker deflection-evoked Ca2+ transients occur in a subset of layer 2/3 neurons of the barrel cortex. Thus, our results demonstrate the suitability of this technique for real-time analyses of intact neuronal circuits with the resoln. of individual cells.
896. 896

     Trevathan, J. K.; Asp, A. J.; Nicolai, E. N.; Trevathan, J.; Kremer, N. A.; Kozai, T. D. Y.; Cheng, D.; Schachter, M.; Nassi, J. J.; Otte, S. L. Calcium Imaging in Freely-Moving Mice During Electrical Stimulation of Deep Brain Structures. J. Neural Eng. 2021, 18, 026008,  DOI: 10.1088/1741-2552/abb7a4

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897. 897

     Harvey, C. D.; Collman, F.; Dombeck, D. A.; Tank, D. W. Intracellular Dynamics of Hippocampal Place Cells During Virtual Navigation. Nature 2009, 461, 941– 946,  DOI: 10.1038/nature08499

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898. 898

     Dombeck, D. A.; Khabbaz, A. N.; Collman, F.; Adelman, T. L.; Tank, D. W. Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice. Neuron 2007, 56, 43– 57,  DOI: 10.1016/j.neuron.2007.08.003

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899. 899

     Thurley, K.; Henke, J.; Hermann, J.; Ludwig, B.; Tatarau, C.; Wätzig, A.; Herz, A. V.; Grothe, B.; Leibold, C. Mongolian Gerbils Learn to Navigate in Complex Virtual Spaces. Behav. Brain Res. 2014, 266, 161– 168,  DOI: 10.1016/j.bbr.2014.03.007

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900. 900

     Hill, B. C.; Schubert, E. D.; Nokes, M. A.; Michelson, R. P. Laser Interferometer Measurement of Changes in Crayfish Axon Diameter Concurrent with Action Potential. Science 1977, 196, 426– 428,  DOI: 10.1126/science.850785

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     900

     Laser interferometer measurement of changes in crayfish axon diameter concurrent with action potential

     Hill B C; Schubert E D; Nokes M A; Michelson R P

     Science (New York, N.Y.) (1977), 196 (4288), 426-8 ISSN:0036-8075.

     Small rapid changes in the diameter of an axon takes place when an action potential progresses along the axon. In the giant axon of the crayfish these occur within a period of about 1 millisecond and are typically about 18 angstroms in total amplitude.
901. 901

     Kim, G.; Kosterin, P.; Obaid, A.; Salzberg, B. A Mechanical Spike Accompanies the Action Potential in Mammalian Nerve Terminals. Biophys. J. 2007, 92, 3122– 3129,  DOI: 10.1529/biophysj.106.103754

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902. 902

     Akkin, T.; Landowne, D.; Sivaprakasam, A. Detection of Neural Action Potentials Using Optical Coherence Tomography: Intensity and Phase Measurements with and without Dyes. Front. Neuroenerg. 2010, 2, 22,  DOI: 10.3389/fnene.2010.00022

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903. 903

     Ling, T.; Boyle, K. C.; Goetz, G.; Zhou, P.; Quan, Y.; Alfonso, F. S.; Huang, T. W.; Palanker, D. Full-Field Interferometric Imaging of Propagating Action Potentials. Light Sci. Appl. 2018, 7, 107,  DOI: 10.1038/s41377-018-0107-9

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     903

     Full-field interferometric imaging of propagating action potentials

     Ling, Tong; Boyle, Kevin C.; Goetz, Georges; Zhou, Peng; Quan, Yi; Alfonso, Felix S.; Huang, Tiffany W.; Palanker, Daniel

     Light: Science & Applications (2018), 7 (1), 107CODEN: LSAIAZ; ISSN:2047-7538. (Nature Research)

     Currently, cellular action potentials are detected using either elec. recordings or exogenous fluorescent probes that sense the calcium concn. or transmembrane voltage. Ca imaging has a low temporal resoln., while voltage indicators are vulnerable to phototoxicity, photobleaching, and heating. Here, we report full-field interferometric imaging of individual action potentials by detecting movement across the entire cell membrane. Using spike-triggered averaging of movies synchronized with elec. recordings, we demonstrate deformations up to 3 nm (0.9 mrad) during the action potential in spiking HEK-293 cells, with a rise time of 4 ms. The time course of the optically recorded spikes matches the elec. waveforms. Since the shot noise limit of the camera (∼2 mrad/pix) precludes detection of the action potential in a single frame, for all-optical spike detection, images are acquired at 50 kHz, and 50 frames are binned into 1 ms steps to achieve a sensitivity of 0.3 mrad in a single pixel. Using a self-reinforcing sensitivity enhancement algorithm based on iteratively expanding the region of interest for spatial averaging, individual spikes can be detected by matching the previously extd. template of the action potential with the optical recording. This allows all-optical full-field imaging of the propagating action potentials without exogeneous labels or electrodes.
904. 904

     Yang, Y.; Liu, X.-W.; Wang, H.; Yu, H.; Guan, Y.; Wang, S.; Tao, N. I Maging Action Potential in Single Mammalian Neurons by Tracking the Accompanying Sub-Nanometer Mechanical Motion. ACS Nano 2018, 12, 4186– 4193,  DOI: 10.1021/acsnano.8b00867

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905. 905

     Fitzgerald, P. B.; Fountain, S.; Daskalakis, Z. J. A Comprehensive Review of the Effects of rTMS on Motor Cortical Excitability and Inhibition. Clin. Neurophysiol. 2006, 117, 2584– 2596,  DOI: 10.1016/j.clinph.2006.06.712

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906. 906

     Krieg, T. D.; Salinas, F. S.; Narayana, S.; Fox, P. T.; Mogul, D. J. PET-Based Confirmation of Orientation Sensitivity of TMS-Induced Cortical Activation in Humans. Brain Stimulation 2013, 6, 898– 904,  DOI: 10.1016/j.brs.2013.05.007

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907. 907

     Adair, D.; Truong, D.; Esmaeilpour, Z.; Gebodh, N.; Borges, H.; Ho, L.; Bremner, J. D.; Badran, B. W.; Napadow, V.; Clark, V. P. Electrical Stimulation of Cranial Nerves in Cognition and Disease. Brain Stimulation 2020, 13, 717– 750,  DOI: 10.1016/j.brs.2020.02.019

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908. 908

     Tufail, Y.; Matyushov, A.; Baldwin, N.; Tauchmann, M. L.; Georges, J.; Yoshihiro, A.; Tillery, S. I. H.; Tyler, W. J. Transcranial Pulsed Ultrasound Stimulates Intact Brain Circuits. Neuron 2010, 66, 681– 694,  DOI: 10.1016/j.neuron.2010.05.008

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     908

     Transcranial pulsed ultrasound stimulates intact brain circuits

     Tufail, Yusuf; Matyushov, Alexei; Baldwin, Nathan; Tauchmann, Monica L.; Georges, Joseph; Yoshihiro, Anna; Tillery, Stephen I. Helms; Tyler, William J.

     Neuron (2010), 66 (5), 681-694CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     Electromagnetic-based methods of stimulating brain activity require invasive procedures or have other limitations. Deep-brain stimulation requires surgically implanted electrodes. Transcranial magnetic stimulation does not require surgery, but suffers from low spatial resoln. Optogenetic-based approaches have unrivaled spatial precision, but require genetic manipulation. In search of a potential soln. to these limitations, we began investigating the influence of transcranial pulsed ultrasound on neuronal activity in the intact mouse brain. In motor cortex, ultrasound-stimulated neuronal activity was sufficient to evoke motor behaviors. Deeper in subcortical circuits, we used targeted transcranial ultrasound to stimulate neuronal activity and synchronous oscillations in the intact hippocampus. We found that ultrasound triggers TTX-sensitive neuronal activity in the absence of a rise in brain temp. (<0.01°C). Here, we also report that transcranial pulsed ultrasound for intact brain circuit stimulation has a lateral spatial resoln. of approx. 2 mm and does not require exogenous factors or surgical invasion.
909. 909

     Wattiez, N.; Constans, C.; Deffieux, T.; Daye, P. M.; Tanter, M.; Aubry, J.-F.; Pouget, P. Transcranial Ultrasonic Stimulation Modulates Single-Neuron Discharge in Macaques Performing an Antisaccade Task. Brain Stimulation 2017, 10, 1024– 1031,  DOI: 10.1016/j.brs.2017.07.007

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     There is no corresponding record for this reference.
910. 910

     Kubanek, J.; Shukla, P.; Das, A.; Baccus, S. A.; Goodman, M. B. Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System. J. Neurosci. 2018, 38, 3081– 3091,  DOI: 10.1523/JNEUROSCI.1458-17.2018

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     910

     Ultrasound elicits behavioral responses through mechanical effects on neurons and ion channels in a simple nervous system

     Kubanek, Jan; Shukla, Poojan; Das, Alakananda; Baccus, Stephen A.; Goodman, Miriam B.

     Journal of Neuroscience (2018), 38 (12), 3081-3091CODEN: JNRSDS; ISSN:1529-2401. (Society for Neuroscience)

     Focused ultrasound has been shown to stimulate excitable cells, but the biophys. mechanisms behind this phenomenon remain poorly understood. To provide addnl. insight, we devised a behavioral-genetic assay applied to the well-characterized nervous system of Caenorhabditis elegans nematodes. We found that pulsed ultrasound elicits robust reversal behavior in wild-type animals in a pressure-, duration-, and pulse protocol-dependent manner. Responses were preserved in mutants unable to sense thermal fluctuations and absent in mutants lacking neurons required for mechanosensation. Addnl., we found that the worm's response to ultrasound pulses rests on the expression of MEC-4, a DEG/ENaC/ASIC ion channel required for touch sensation. Consistent with prior studies of MEC-4-dependent currents in vivo, the worm's response was optimal for pulses repeated 300-1000 times per s. Based on these findings, we conclude that mech., rather than thermal, stimulation accounts for behavioral responses. Further, we propose that acoustic radiation force governs the response to ultrasound in a manner that depends on the touch receptor neurons and MEC-4-dependent ion channels. Our findings illuminate a complete pathway of ultrasound action, from the forces generated by propagating ultrasound to an activation of a specific ion channel. The findings further highlight the importance of optimizing ultrasound pulsing protocols when stimulating neurons via ion channels with mechanosensitive properties.
911. 911

     Lee, J.; Ko, K.; Shin, H.; Oh, S.-J.; Lee, C. J.; Chou, N.; Choi, N.; Oh, M. T.; Lee, B. C.; Jun, S. C. A MEMS Ultrasound Stimulation System for Modulation of Neural Circuits with High Spatial Resolution in Vitro. Microsyst. Nanoeng. 2019, 5, 28,  DOI: 10.1038/s41378-019-0070-5

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     There is no corresponding record for this reference.
912. 912

     Wells, J.; Kao, C.; Mariappan, K.; Albea, J.; Jansen, E. D.; Konrad, P.; Mahadevan-Jansen, A. Optical Stimulation of Neural Tissue in Vivo. Opt. Lett. 2005, 30, 504– 506,  DOI: 10.1364/OL.30.000504

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     912

     Optical stimulation of neural tissue in vivo

     Wells Jonathon; Kao Chris; Mariappan Karthik; Albea Jeffrey; Jansen E Duco; Konrad Peter; Mahadevan-Jansen Anita

     Optics letters (2005), 30 (5), 504-6 ISSN:0146-9592.

     For more than a century, the traditional method of stimulating neural activity has been based on electrical methods, and it remains the gold standard to date. We report a technological breakthrough in neural activation in which low-level, pulsed infrared laser light is used to elicit compound nerve and muscle potentials in mammalian peripheral nerve in vivo. Optically induced neural action potentials are spatially precise, artifact free, and damage free and are generated by use of energies well below tissue ablation threshold. Thus optical stimulation presents a simple yet novel approach to contact-free in vivo neural activation that has major implications for clinical neurosurgery, basic neurophysiology, and neuroscience.
913. 913

     Wells, J.; Konrad, P.; Kao, C.; Jansen, E. D.; Mahadevan-Jansen, A. Pulsed Laser versus Electrical Energy for Peripheral Nerve Stimulation. J. Neurosci. Methods 2007, 163, 326– 337,  DOI: 10.1016/j.jneumeth.2007.03.016

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914. 914

     Richter, C. P.; Matic, A. I.; Wells, J. D.; Jansen, E. D.; Walsh, J. T. Neural Stimulation with Optical Radiation. Laser Photonics Rev. 2011, 5, 68– 80,  DOI: 10.1002/lpor.200900044

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     914

     Neural stimulation with optical radiation

     Richter, Claus-Peter; Matic, Agnella Izzo; Wells, Jonathon D.; Jansen, E. Duco; Walsh, Joseph T., Jr.

     Laser & Photonics Reviews (2011), 5 (1), 68-80CODEN: LPRAB8; ISSN:1863-8880. (Wiley-VCH Verlag GmbH & Co. KGaA)

     A review. This paper reviews the existing research on IR neural stimulation, a means of artificially stimulating neurons that has been proposed as an alternative to elec. stimulation. IR neural stimulation (INS) is defined as the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. The foremost advantage of using optical radiation for neural stimulation is its spatial resoln. Exogenously applied or trans-genetically synthesized fluorophores are not used to achieve stimulation. Here, current work on INS is presented for motor nerves, sensory nerves, central nervous system, and in vitro prepns. A discussion follows addressing the mechanism of INS and its potential use in neuroprostheses. A brief review of neural depolarization involving other optical methods is also presented. Topics covered include optical stimulation concurrent with elec. stimulation, optical stimulation using exogenous fluorophores, and optical stimulation by transgenic induction of light-gated ion channels.
915. 915

     Schlett, P.; Wegner, C.; Krueger, T. B.; Hofmann, U. G. Towards Safe Infrared Nerve Stimulation: A Systematic Experimental Approach. In 2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC); IEEE, 2019; pp 5909– 5912.

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     There is no corresponding record for this reference.
916. 916

     Shapiro, M. G.; Homma, K.; Villarreal, S.; Richter, C.-P.; Bezanilla, F. Infrared Light Excites Cells by Changing Their Electrical Capacitance. Nat. Commun. 2012, 3, 736,  DOI: 10.1038/ncomms1742

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     916

     Infrared light excites cells by changing their electrical capacitance

     Shapiro Mikhail G; Homma Kazuaki; Villarreal Sebastian; Richter Claus-Peter; Bezanilla Francisco

     Nature communications (2012), 3 (), 736 ISSN:.

     Optical stimulation has enabled important advances in the study of brain function and other biological processes, and holds promise for medical applications ranging from hearing restoration to cardiac pace making. In particular, pulsed laser stimulation using infrared wavelengths >1.5 μm has therapeutic potential based on its ability to directly stimulate nerves and muscles without any genetic or chemical pre-treatment. However, the mechanism of infrared stimulation has been a mystery, hindering its path to the clinic. Here we show that infrared light excites cells through a novel, highly general electrostatic mechanism. Infrared pulses are absorbed by water, producing a rapid local increase in temperature. This heating reversibly alters the electrical capacitance of the plasma membrane, depolarizing the target cell. This mechanism is fully reversible and requires only the most basic properties of cell membranes. Our findings underscore the generality of pulsed infrared stimulation and its medical potential.
917. 917

     Fribance, S.; Wang, J.; Roppolo, J. R.; de Groat, W. C.; Tai, C. Axonal Model for Temperature Stimulation. J. Comput. Neurosci. 2016, 41, 185– 192,  DOI: 10.1007/s10827-016-0612-x

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     There is no corresponding record for this reference.
918. 918

     Fiebig, R. Revival of the Magnetoelectric Effect. J. Phys. D 2005, 38, R123– R152,  DOI: 10.1088/0022-3727/38/8/R01

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     918

     Revival of the magnetoelectric effect

     Fiebig, Manfred

     Journal of Physics D: Applied Physics (2005), 38 (8), R123-R152CODEN: JPAPBE; ISSN:0022-3727. (Institute of Physics Publishing)

     A review. Recent research activities on the linear magnetoelec. (ME) effect-induction of magnetization by an elec. field or of polarization by a magnetic field-are reviewed. Beginning with a brief summary of the history of the ME effect since its prediction in 1894, the paper focuses on the present revival of the effect. Two major sources for 'large' ME effects are identified. (i) In composite materials the ME effect is generated as a product property of a magnetostrictive and a piezoelec. compd. A linear ME polarization is induced by a weak ac magnetic field oscillating in the presence of a strong dc bias field. The ME effect is large if the ME coeff. coupling the magnetic and elec. fields is large. Expts. on sintered granular composites and on laminated layers of the constituents as well as theories on the interaction between the constituents are described. In the vicinity of electromech. resonances a ME voltage coeff. of up to 90 V cm-1 Oe-1 is achieved, which exceeds the ME response of single-phase compds. by 3-5 orders of magnitude. Microwave devices, sensors, transducers and heterogeneous read/write devices are among the suggested tech. implementations of the composite ME effect. (ii) In multiferroics the internal magnetic and/or elec. fields are enhanced by the presence of multiple long-range ordering. The ME effect is strong enough to trigger magnetic or elec. phase transitions. ME effects in multiferroics are thus 'large' if the corresponding contribution to the free energy is large. Clamped ME switching of elec. and magnetic domains, ferroelec. reorientation induced by applied magnetic fields and induction of ferromagnetic ordering in applied elec. fields were obsd. Mechanisms favoring multiferroicity are summarized, and multiferroics in reduced dimensions are discussed. In addn. to composites and multiferroics, novel and exotic manifestations of ME behavior are investigated. This includes (i) optical second harmonic generation as a tool to study magnetic, elec. and ME properties in one setup and with access to domain structures; (ii) ME effects in colossal magnetoresistive manganites, superconductors and phosphates of the LiMPO4 type; (iii) the concept of the toroidal moment as manifestation of a ME dipole moment; (iv) pronounced ME effects in photonic crystals with a possibility of electromagnetic unidirectionality. The review concludes with a summary and an outlook to the future development of magnetoelecs. research.
919. 919

     Eerenstein, W.; Mathur, N.; Scott, J. F. Multiferroic and Magnetoelectric Materials. Nature 2006, 442, 759– 765,  DOI: 10.1038/nature05023

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     919

     Multiferroic and magnetoelectric materials

     Eerenstein, W.; Mathur, N. D.; Scott, J. F.

     Nature (London, United Kingdom) (2006), 442 (7104), 759-765CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     A review. A ferroelec. crystal exhibits a stable and switchable elec. polarization that is manifested in the form of cooperative at. displacements. A ferromagnetic crystal exhibits a stable and switchable magnetization that arises through the quantum mech. phenomenon of exchange. There are very few multiferroic' materials that exhibit both of these properties, but the magnetoelec. coupling of magnetic and elec. properties is a more general and widespread phenomenon. Although work in this area can be traced back to pioneering research in the 1950s and 1960s, there has been a recent resurgence of interest driven by long-term technol. aspirations.
920. 920

     Yu, Z.; Chen, J. C.; He, Y.; Alrashdan, F. T.; Avants, B. W.; Singer, A.; Robinson, J. T.; Yang, K. Multisite Bio-Stimulating Implants Magnetoelectrically Powered and Individually Programmed by a Single Transmitter. In 2021 IEEE Custom Integrated Circuits Conference (CICC); IEEE: 2021; pp 1– 2.

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     There is no corresponding record for this reference.
921. 921

     Chen, J. C.; Kan, P.; Yu, Z.; Alrashdan, F.; Garcia, R.; Singer, A.; Lai, C. E.; Avants, B.; Crosby, S.; Li, Z. A Wireless Millimetric Magnetoelectric Implant for the Endovascular Stimulation of Peripheral Nerves. Nat. Biomed. Eng. 2022, 6, 706– 716,  DOI: 10.1038/s41551-022-00873-7

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     921

     A wireless millimetric magnetoelectric implant for the endovascular stimulation of peripheral nerves

     Chen Joshua C; Lai C S Edwin; Hartgerink Jeffrey D; Robinson Jacob T; Kan Peter; Garcia Roberto; Robledo Ariadna; Yu Zhanghao; Alrashdan Fatima; Singer Amanda; Avants Ben; Yang Kaiyuan; Robinson Jacob T; Singer Amanda; Robinson Jacob T; Crosby Scott; Li Zhongxi; Peterchev Angel V; Goetz Stefan M; Wang Boshuo; Peterchev Angel V; Goetz Stefan M; Felicella Michelle M; Peterchev Angel V; Goetz Stefan M; Peterchev Angel V; Goetz Stefan M; Hartgerink Jeffrey D; Sheth Sunil A; Robinson Jacob T

     Nature biomedical engineering (2022), 6 (6), 706-716 ISSN:.

     Implantable bioelectronic devices for the simulation of peripheral nerves could be used to treat disorders that are resistant to traditional pharmacological therapies. However, for many nerve targets, this requires invasive surgeries and the implantation of bulky devices (about a few centimetres in at least one dimension). Here we report the design and in vivo proof-of-concept testing of an endovascular wireless and battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via traditional surgeries. The device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable 1 mm × 0.8 mm system-on-a-chip. Implantation of the device directly on top of the sciatic nerve in rats and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter) allowed for wireless stimulation of the animals' sciatic and femoral nerves. Minimally invasive magnetoelectric implants may allow for the stimulation of nerves without the need for open surgery or the implantation of battery-powered pulse generators.
922. 922

     Singer, A.; Dutta, S.; Lewis, E.; Chen, Z.; Chen, J. C.; Verma, N.; Avants, B.; Feldman, A. K.; O’Malley, J.; Beierlein, M. Magnetoelectric Materials for Miniature, Wireless Neural Stimulation at Therapeutic Frequencies. Neuron 2020, 107, 631– 643, e5  DOI: 10.1016/j.neuron.2020.05.019

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     922

     Magnetoelectric Materials for Miniature, Wireless Neural Stimulation at Therapeutic Frequencies

     Singer, Amanda; Dutta, Shayok; Lewis, Eric; Chen, Ziying; Chen, Joshua C.; Verma, Nishant; Avants, Benjamin; Feldman, Ariel K.; O'Malley, John; Beierlein, Michael; Kemere, Caleb; Robinson, Jacob T.

     Neuron (2020), 107 (4), 631-643.e5CODEN: NERNET; ISSN:0896-6273. (Cell Press)

     A major challenge for miniature bioelectronics is wireless power delivery deep inside the body. Electromagnetic or ultrasound waves suffer from absorption and impedance mismatches at biol. interfaces. On the other hand, magnetic fields do not suffer these losses, which has led to magnetically powered bioelectronic implants based on induction or magnetothermal effects. However, these approaches have yet to produce a miniature stimulator that operates at clin. relevant high frequencies. Here, we show that an alternative wireless power method based on magnetoelec. (ME) materials enables miniature magnetically powered neural stimulators that operate up to clin. relevant frequencies in excess of 100 Hz. We demonstrate that wireless ME stimulators provide therapeutic deep brain stimulation in a freely moving rodent model for Parkinson's disease and that these devices can be miniaturized to millimeter-scale and fully implanted. These results suggest that ME materials are an excellent candidate to enable miniature bioelectronics for clin. and research applications.
923. 923

     Yue, K.; Guduru, R.; Hong, J.; Liang, P.; Nair, M.; Khizroev, S. Magneto-Electric Nano-Particles for Non-Invasive Brain Stimulation. PLoS One 2012, 7, e44040,  DOI: 10.1371/journal.pone.0044040

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     There is no corresponding record for this reference.
924. 924

     Kaushik, A.; Jayant, R. D.; Sagar, V.; Nair, M. The Potential of Magneto-Electric Nanocarriers for Drug Delivery. Expert Opin. Drug Delivery 2014, 11, 1635– 1646,  DOI: 10.1517/17425247.2014.933803

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     924

     The potential of magneto-electric nanocarriers for drug delivery

     Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan

     Expert Opinion on Drug Delivery (2014), 11 (10), 1635-1646CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)

     Introduction: The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concn. at the target site, novel nanocarriers (NCs) were designed, for example, magneto-elec. (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery. Areas covered: This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood-brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted. Expert opinion: Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of elec.-magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.
925. 925

     Guduru, R.; Liang, P.; Hong, J.; Rodzinski, A.; Hadjikhani, A.; Horstmyer, J.; Levister, E.; Khizroev, S. Magnetoelectric ’Spin’on Stimulating the Brain. Nanomedicine 2015, 10, 2051– 2061,  DOI: 10.2217/nnm.15.52

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     There is no corresponding record for this reference.
926. 926

     Wang, Y.; Guo, L. Nanomaterial-Enabled Neural Stimulation. Front. Neurosci. 2016, 10, 69,  DOI: 10.3389/fnins.2016.00069

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     926

     Nanomaterial-Enabled Neural Stimulation

     Wang Yongchen; Guo Liang

     Frontiers in neuroscience (2016), 10 (), 69 ISSN:1662-4548.

     Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed.
927. 927

     Guduru, R.; Liang, P.; Yousef, M.; Horstmyer, J.; Khizroev, S. Mapping the Brain’s electric fields with Magnetoelectric Nanoparticles. Bioelectron. Med. 2018, 4, 10,  DOI: 10.1186/s42234-018-0012-9

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928. 928

     Gleich, B.; Weizenecker, J. Tomographic Imaging Using the Nonlinear Response of Magnetic Particles. Nature 2005, 435, 1214– 1217,  DOI: 10.1038/nature03808

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     928

     Tomographic imaging using the nonlinear response of magnetic particles

     Gleich, Bernhard; Weizenecker, Juergen

     Nature (London, United Kingdom) (2005), 435 (7046), 1214-1217CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     The use of contrast agents and tracers in medical imaging has a long history. They provide important information for diagnosis and therapy, but for some desired applications, a higher resoln. is required than can be obtained using the currently available medical imaging techniques. Consider, for example, the use of magnetic tracers in magnetic resonance imaging: detection thresholds for in vitro and in vivo imaging are such that the background signal from the host tissue is a crucial limiting factor. A sensitive method for detecting the magnetic particles directly is to measure their magnetic fields using relaxometry; but this approach has the drawback that the inverse problem (assocd. with transforming the data into a spatial image) is ill posed and therefore yields low spatial resoln. Here we present a method for obtaining a high-resoln. image of such tracers that takes advantage of the nonlinear magnetization curve of small magnetic particles. Initial 'phantom' expts. are reported that demonstrate the feasibility of the imaging method. The resoln. that we achieve is already well below 1 mm. We evaluate the prospects for further improvement, and show that the method has the potential to be developed into an imaging method characterized by both high spatial resoln. as well as high sensitivity.
929. 929

     Weizenecker, J.; Gleich, B.; Rahmer, J.; Dahnke, H.; Borgert, J. Three-Dimensional Real-Time in Vivo Magnetic Particle Imaging. Phys. Med. Biol. 2009, 54, L1,  DOI: 10.1088/0031-9155/54/5/L01

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     929

     Three-dimensional real-time in vivo magnetic particle imaging

     Weizenecker J; Gleich B; Rahmer J; Dahnke H; Borgert J

     Physics in medicine and biology (2009), 54 (5), L1-L10 ISSN:0031-9155.

     Magnetic particle imaging (MPI) is a new tomographic imaging method potentially capable of rapid 3D dynamic imaging of magnetic tracer materials. Until now, only dynamic 2D phantom experiments with high tracer concentrations have been demonstrated. In this letter, first in vivo 3D real-time MPI scans are presented revealing details of a beating mouse heart using a clinically approved concentration of a commercially available MRI contrast agent. A temporal resolution of 21.5 ms is achieved at a 3D field of view of 20.4 x 12 x 16.8 mm(3) with a spatial resolution sufficient to resolve all heart chambers. With these abilities, MPI has taken a huge step toward medical application.
930. 930

     Stehning, C.; Gleich, B.; Rahmer, J. Simultaneous Magnetic Particle Imaging (MPI) and Temperature Mapping Using Multi-Color MPI. Int. J. Magn. Part. Imaging 2016, 2, 1612001,  DOI: 10.18416/ijmpi.2016.1612001

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     There is no corresponding record for this reference.
931. 931

     Wells, J.; Paysen, H.; Kosch, O.; Trahms, L.; Wiekhorst, F. Temperature Dependence in Magnetic Particle Imaging. AIP Adv. 2018, 8, 056703,  DOI: 10.1063/1.5004506

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     931

     Temperature dependence in magnetic particle imaging

     Wells, James; Paysen, Hendrik; Kosch, Olaf; Trahms, Lutz; Wiekhorst, Frank

     AIP Advances (2018), 8 (5), 056703/1-056703/7CODEN: AAIDBI; ISSN:2158-3226. (American Institute of Physics)

     Exptl. results are presented demonstrating how temp. can influence the dynamics of magnetic nanoparticles (MNPs) in liq. suspension, when exposed to alternating magnetic fields in the kilohertz frequency range. The measurements used to probe the nanoparticle systems are directly linked to both the emerging biomedical technique of magnetic particle imaging (MPI), and to the recently proposed concept of remote nanoscale thermometry using MNPs under AC field excitation. Here, we report measurements on three common types of MNPs, two of which are currently leading candidates for use as tracers in MPI. Using highly-sensitive magnetic particle spectroscopy (MPS), we demonstrate significant and divergent thermal dependences in several key measures used in the evaluation of MNP dynamics for use in MPI and other applications. The temp. range studied was between 296 and 318 K, making our findings of particular importance for MPI and other biomedical technologies. Furthermore, we report the detection of the same temp. dependences in measurements conducted using the detection coils within an operational preclin. MPI scanner. This clearly shows the importance of considering temp. during MPI development, and the potential for temp.-resolved MPI using this system. We propose possible phys. explanations for the differences in the behaviors obsd. between the different particle types, and discuss our results in terms of the opportunities and concerns they raise for MPI and other MNP based technologies. (c) 2018 American Institute of Physics.
932. 932

     Christiansen, M. G.; Senko, A. W.; Anikeeva, P. Magnetic Strategies for Nervous System Control. Annu. Rev. Neurosci. 2019, 42, 271– 293,  DOI: 10.1146/annurev-neuro-070918-050241

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     932

     Magnetic Strategies for Nervous System Control

     Christiansen, Michael G.; Senko, Alexander W.; Anikeeva, Polina

     Annual Review of Neuroscience (2019), 42 (), 271-293CODEN: ARNSD5; ISSN:0147-006X. (Annual Reviews)

     Magnetic fields pass through tissue undiminished and without producing harmful effects, motivating their use as a wireless, minimally invasive means to control neural activity. Here, we review mechanisms and techniques coupling magnetic fields to changes in electrochem. potentials across neuronal membranes. Biol. magnetoreception, although incompletely understood, is discussed as a potential source of inspiration. The emergence of magnetic properties in materials is reviewed to clarify the distinction between biomols. contg. transition metals and ferrite nanoparticles that exhibit significant net moments. We describe recent developments in the use of magnetic nanomaterials as transducers converting magnetic stimuli to forms readily perceived by neurons and discuss opportunities for multiplexed and bidirectional control as well as the challenges posed by delivery to the brain. The variety of magnetic field conditions and mechanisms by which they can be coupled to neuronal signaling cascades highlights the desirability of continued interchange between magnetism physics and neurobiol.
933. 933

     Anikeeva, P. O.; Chen, R.; Christiansen, M. G. Independent Magnetically-Multiplexed Heating of Portions of a Target. US 9,681,979, 2017.

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     There is no corresponding record for this reference.
934. 934

     Hensley, D.; Tay, Z. W.; Dhavalikar, R.; Zheng, B.; Goodwill, P.; Rinaldi, C.; Conolly, S. Combining Magnetic Particle Imaging and Magnetic Fluid Hyperthermia in a Theranostic Platform. Phys. Med. Biol. 2017, 62, 3483,  DOI: 10.1088/1361-6560/aa5601

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     934

     Combining magnetic particle imaging and magnetic fluid hyperthermia in a theranostic platform

     Hensley Daniel; Tay Zhi Wei; Dhavalikar Rohan; Zheng Bo; Goodwill Patrick; Rinaldi Carlos; Conolly Steven

     Physics in medicine and biology (2017), 62 (9), 3483-3500 ISSN:.

     Magnetic particle imaging (MPI) is a rapidly developing molecular and cellular imaging modality. Magnetic fluid hyperthermia (MFH) is a promising therapeutic approach where magnetic nanoparticles are used as a conduit for targeted energy deposition, such as in hyperthermia induction and drug delivery. The physics germane to and exploited by MPI and MFH are similar, and the same particles can be used effectively for both. Consequently, the method of signal localization through the use of gradient fields in MPI can also be used to spatially localize MFH, allowing for spatially selective heating deep in the body and generally providing greater control and flexibility in MFH. Furthermore, MPI and MFH may be integrated together in a single device for simultaneous MPI-MFH and seamless switching between imaging and therapeutic modes. Here we show simulation and experimental work quantifying the extent of spatial localization of MFH using MPI systems: we report the first combined MPI-MFH system and demonstrate on-demand selective heating of nanoparticle samples separated by only 3 mm (up to 0.4 °C s(-1) heating rates and 150 W g(-1) SAR deposition). We also show experimental data for MPI performed at a typical MFH frequency and show preliminary simultaneous MPI-MFH experimental data.
935. 935

     Shoffstall, A. J.; Paiz, J. E.; Miller, D. M.; Rial, G. M.; Willis, M. T.; Menendez, D. M.; Hostler, S. R.; Capadona, J. R. Potential for Thermal Damage to the Blood-Brain Barrier During Craniotomy: Implications for Intracortical Recording Microelectrodes. J. Neural Eng. 2018, 15, 034001,  DOI: 10.1088/1741-2552/aa9f32

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     There is no corresponding record for this reference.
936. 936

     Schlett, P.; Mottaghi, S.; Buchholz, O.; Hofmann, U. G. First Steps towards Localized Opening of the Blood-Brain-Barrier by IR Laser Illumination through the Rodent Skull. Curr. Dir. Biomed. Eng. 2019, 5, 211– 214,  DOI: 10.1515/cdbme-2019-0054

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     There is no corresponding record for this reference.
937. 937

     Desai, S. A.; Rolston, J. D.; Guo, L.; Potter, S. M. Improving Impedance of Implantable Microwire Multi-Electrode Arrays by Ultrasonic Electroplating of Durable Platinum Black. Front. Neuroeng. 2010, 3, 5,  DOI: 10.3389/fneng.2010.00005

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     937

     Improving impedance of implantable microwire multi-electrode arrays by ultrasonic electroplating of durable platinum black

     Desai, Sharanya Arcot; Rolston, John D.; Guo, Liang; Potter, Steve M.

     Frontiers in Neuroengineering (2010), 3 (May), 5CODEN: FNREIF; ISSN:1662-6443. (Frontiers Research Foundation)

     Implantable microelectrode arrays (MEAs) have been a boon for neural stimulation and recording expts. Com. available MEAs have high impedances, due to their low surface area and small tip diams., which are suitable for recording single unit activity. Lowering the electrode impedance, but preserving the small diam., would provide a no. of advantages, including reduced stimulation voltages, reduced stimulation artifacts and improved signal-to-noise ratio. Impedance redns. can be achieved by electroplating the MEAs with platinum (Pt) black, which increases the surface area but has little effect on the phys. extent of the electrodes. However, because of the low durability of Pt black plating, this method has not been popular for chronic use. Sonicoplating (i.e. electroplating under ultrasonic agitation) has been shown to improve the durability of Pt black on the base metals of macro-electrodes used for cyclic voltammetry. This method has not previously been characterized for MEAs used in chronic neural implants. We show here that sonicoplating can lower the impedances of microwire multi-electrode arrays (MMEA) by an order of magnitude or more (depending on the time and voltage of electroplating), with better durability compared to pulsed plating or traditional DC methods. We also show the improved stimulation and recording performance that can be achieved in an in vivo implantation study with the sonicoplated low-impedance MMEAs, compared to high-impedance unplated electrodes.
938. 938

     Kozai, T. D.; Alba, N. A.; Zhang, H.; Kotov, N. A.; Gaunt, R. A.; Cui, X. T. Nanostructured Coatings for Improved Charge Delivery to Neurons. In Nanotechnology and Neuroscience: Nano-Electronic, Photonic and Mechanical Neuronal Interfacing; Springer, 2014; pp 71– 134.

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     There is no corresponding record for this reference.
939. 939

     Janders, M.; Egert, U.; Stelzle, M.; Nisch, W. In Novel Thin Film Titanium Nitride Micro-Electrodes with Excellent Charge Transfer Capability for Cell Stimulation and Sensing Applications; Proceedings of the 18th Annual Conference of the IEEE Engineering in Medicine and Biology Society; Amsterdam; , Boom, H.; Robinson, C.; Rutten, W.; Neuman, M.; Wijkstra, H., Ed.; IEEE: Amsterdam, 1996.

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     There is no corresponding record for this reference.
940. 940

     Łapkowski, M.; Proń, A. Electrochemical Oxidation of Poly(3, 4-ethylenedioxythiophene)─“In Situ” Conductivity and Spectroscopic Investigations. Synth. Met. 2000, 110, 79– 83,  DOI: 10.1016/S0379-6779(99)00271-4

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     940

     Electrochemical oxidation of poly(3,4-ethylenedioxythiophene) - "in situ" conductivity and spectroscopic investigations

     Lapkowski, M.; Pron, A.

     Synthetic Metals (2000), 110 (1), 79-83CODEN: SYMEDZ; ISSN:0379-6779. (Elsevier Science S.A.)

     Electrochem. oxidn. of poly(3,4-ethylenedioxythiophene) (PEDOT) was studied by cyclic voltammetry combined with in-situ cond. measurements, UV-vis-NIR, and Raman spectroelectrochem. studies. The oxidn. doping process can be adequately described by a heterogeneous two-phase model in which the doped conducting phase grows at the expense of the undoped, neutral phase. The extension of the scanning potential to 1400 mV vs. Ag/AgCl revealed a finite potential window of PEDOT cond. The existence of this potential window can be rationalized within the framework of the two-phase model of electrochem. doping, assuming the coexistence of percolating conductive and insulating networks. Doping-induced changes in the Raman spectra of PEDOT indicate that, unlike in other polythiophenes, the ground state of the neutral polymer is quinoid in nature and upon doping it is transformed into the benzenoid moiety.
941. 941

     Ludwig, K. A.; Uram, J. D.; Yang, J. Y.; Martin, D. C.; Kipke, D. R. Chronic Neural Recordings Using Silicon Microelectrode Arrays Electrochemically Deposited with a Poly(3,4-ethylenedioxythiophene) (PEDOT) film. J. Neural Eng. 2006, 3, 59– 70,  DOI: 10.1088/1741-2560/3/1/007

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     941

     Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film

     Ludwig Kip A; Uram Jeffrey D; Yang Junyan; Martin David C; Kipke Daryl R

     Journal of neural engineering (2006), 3 (1), 59-70 ISSN:1741-2560.

     Conductive polymer coatings can be used to modify traditional electrode recording sites with the intent of improving the long-term performance of cortical microelectrodes. Conductive polymers can drastically decrease recording site impedance, which in turn is hypothesized to reduce thermal noise and signal loss through shunt pathways. Moreover, conductive polymers can be seeded with agents aimed at promoting neural growth toward the recording sites or minimizing the inherent immune response. The end goal of these efforts is to generate an ideal long-term interface between the recording electrode and surrounding tissue. The goal of this study was to refine a method to electrochemically deposit surfactant-templated ordered poly(3,4-ethylenedioxythiophene) (PEDOT) films on the recording sites of standard 'Michigan' probes and to evaluate the efficacy of these modified sites in recording chronic neural activity. PEDOT-coated site performance was compared to control sites over a six-week evaluation period in terms of impedance spectroscopy, signal-to-noise ratio, number of viable unit potentials recorded and local field potential recordings. PEDOT sites were found to outperform control sites with respect to signal-to-noise ratio and number of viable unit potentials. The benefit of reduced initial impedance, however, was mitigated by the impedance contribution of typical silicon electrode encapsulation. Coating sites with PEDOT also reduced the amount of low-frequency drift evident in local field potential recordings. These findings indicate that electrode sites electrochemically deposited with PEDOT films are suitable for recording neural activity in vivo for extended periods. This study also provided a unique opportunity to monitor how neural recording characteristics develop over the six weeks following implantation.
942. 942

     Green, R.; Matteucci, P.; Hassarati, R.; Giraud, B.; Dodds, C.; Chen, S.; Byrnes-Preston, P.; Suaning, G.; Poole-Warren, L.; Lovell, N. Performance of Conducting Polymer Electrodes for Stimulating Neuroprosthetics. J. Neural Eng. 2013, 10, 016009,  DOI: 10.1088/1741-2560/10/1/016009

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     942

     Performance of conducting polymer electrodes for stimulating neuroprosthetics

     Green R A; Matteucci P B; Hassarati R T; Giraud B; Dodds C W D; Chen S; Byrnes-Preston P J; Suaning G J; Poole-Warren L A; Lovell N H

     Journal of neural engineering (2013), 10 (1), 016009 ISSN:.

     OBJECTIVE: Recent interest in the use of conducting polymers (CPs) for neural stimulation electrodes has been growing; however, concerns remain regarding the stability of coatings under stimulation conditions. These studies examine the factors of the CP and implant environment that affect coating stability. The CP poly(ethylene dioxythiophene) (PEDOT) is examined in comparison to platinum (Pt), to demonstrate the potential performance of these coatings in neuroprosthetic applications. APPROACH: PEDOT is coated on Pt microelectrode arrays and assessed in vitro for charge injection limit and long-term stability under stimulation in biologically relevant electrolytes. Physical and electrical stability of coatings following ethylene oxide (ETO) sterilization is established and efficacy of PEDOT as a visual prosthesis bioelectrode is assessed in the feline model. MAIN RESULTS: It was demonstrated that PEDOT reduced the potential excursion at a Pt electrode interface by 72% in biologically relevant solutions. The charge injection limit of PEDOT for material stability was found to be on average 30× larger than Pt when tested in physiological saline and 20× larger than Pt when tested in protein supplemented media. Additionally stability of the coating was confirmed electrically and morphologically following ETO processing. It was demonstrated that PEDOT-coated electrodes had lower potential excursions in vivo and electrically evoked potentials (EEPs) could be detected within the visual cortex. SIGNIFICANCE: These studies demonstrate that PEDOT can be produced as a stable electrode coating which can be sterilized and perform effectively and safely in neuroprosthetic applications. Furthermore these findings address the necessity for characterizing in vitro properties of electrodes in biologically relevant milieu which mimic the in vivo environment more closely.
943. 943

     Castagnola, E.; Carli, S.; Vomero, M.; Scarpellini, A.; Prato, M.; Goshi, N.; Fadiga, L.; Kassegne, S.; Ricci, D. Multilayer Poly(3, 4-ethylenedioxythiophene)-dexamethasone and Poly(3, 4-ethylenedioxythiophene)-Polystyrene Sulfonate-Carbon Nanotubes Coatings on Glassy Carbon Microelectrode Arrays for Controlled Drug Release. Biointerphases 2017, 12, 031002,  DOI: 10.1116/1.4993140

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     There is no corresponding record for this reference.
944. 944

     Ferlauto, L.; D’Angelo, A. N.; Vagni, P.; Airaghi Leccardi, M. J. I.; Mor, F. M.; Cuttaz, E. A.; Heuschkel, M. O.; Stoppini, L.; Ghezzi, D. Development and Characterization of PEDOT: PSS/Alginate Soft Microelectrodes for Application in Neuroprosthetics. Front. Neurosci. 2018, 12, 648,  DOI: 10.3389/fnins.2018.00648

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     944

     Development and Characterization of PEDOT:PSS/Alginate Soft Microelectrodes for Application in Neuroprosthetics

     Ferlauto Laura; D'Angelo Antonio Nunzio; Vagni Paola; Airaghi Leccardi Marta Jole Ildelfonsa; Cuttaz Estelle Annick; Ghezzi Diego; Mor Flavio Maurizio; Heuschkel Marc Olivier; Stoppini Luc

     Frontiers in neuroscience (2018), 12 (), 648 ISSN:1662-4548.

     Reducing the mechanical mismatch between the stiffness of a neural implant and the softness of the neural tissue is still an open challenge in neuroprosthetics. The emergence of conductive hydrogels in the last few years has considerably widened the spectrum of possibilities to tackle this issue. Nevertheless, despite the advancements in this field, further improvements in the fabrication of conductive hydrogel-based electrodes are still required. In this work, we report the fabrication of a conductive hydrogel-based microelectrode array for neural recording using a hybrid material composed of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate), and alginate. The mechanical properties of the conductive hydrogel have been investigated using imaging techniques, while the electrode arrays have been electrochemically characterized at each fabrication step, and successfully validated both in vitro and in vivo. The presence of the conductive hydrogel, selectively electrodeposited onto the platinum microelectrodes, allowed achieving superior electrochemical characteristics, leading to a lower electrical noise during recordings. These findings represent an advancement in the design of soft conductive electrodes for neuroprosthetic applications.
945. 945

     Stocking, K. C.; Vazquez, A. L.; Kozai, T. Intracortical Neural Stimulation with Untethered, Ultrasmall Carbon Fiber Electrodes Mediated by the Photoelectric Effect. IEEE Trans. Biomed. Eng. 2019, 66, 2402– 2412,  DOI: 10.1109/TBME.2018.2889832

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     There is no corresponding record for this reference.
946. 946

     Choi, S.; Han, S. I.; Kim, D.; Hyeon, T.; Kim, D. H. High-Performance Stretchable Conductive Nanocomposites: Materials, Processes, and Device Applications. Chem. Soc. Rev. 2019, 48, 1566– 1595,  DOI: 10.1039/C8CS00706C

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     946

     High-performance stretchable conductive nanocomposites: materials, processes, and device applications

     Choi, Suji; Han, Sang Ihn; Kim, Dokyoon; Hyeon, Taeghwan; Kim, Dae-Hyeong

     Chemical Society Reviews (2019), 48 (6), 1566-1595CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     Highly conductive and intrinsically stretchable electrodes are vital components of soft electronics such as stretchable transistors and circuits, sensors and actuators, light-emitting diode arrays, and energy harvesting devices. Many kinds of conducting nanomaterials with outstanding elec. and mech. properties have been integrated with elastomers to produce stretchable conductive nanocomposites. Understanding the characteristics of these nanocomposites and assessing the feasibility of their fabrication are therefore crit. for the development of high-performance stretchable conductors and electronic devices. We herein summarise the recent advances in stretchable conductors based on the percolation networks of nanoscale conductive fillers in elastomeric media. After discussing the material-, dimension-, and size-dependent properties of conductive fillers and their implications, we highlight various techniques that are used to reduce the contact resistance between the conductive filler materials. Furthermore, we categorize elastomer matrixes with different stretchabilities and mech. properties based on their polymeric chain structures. Then, we discuss the fabrication techniques of stretchable conductive nanocomposites toward their use in soft electronics. Finally, we provide representative examples of stretchable device applications and conclude the review with a brief outlook for future research.
947. 947

     Cho, K. W.; Sunwoo, S. H.; Hong, Y. J.; Koo, J. H.; Kim, J. H.; Baik, S.; Hyeon, T.; Kim, D. H. Soft Bioelectronics Based on Nanomaterials. Chem. Rev. 2022, 122, 5068– 5143,  DOI: 10.1021/acs.chemrev.1c00531

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     947

     Soft Bioelectronics Based on Nanomaterials

     Cho, Kyoung Won; Sunwoo, Sung-Hyuk; Hong, Yongseok Joseph; Koo, Ja Hoon; Kim, Jeong Hyun; Baik, Seungmin; Hyeon, Taeghwan; Kim, Dae-Hyeong

     Chemical Reviews (Washington, DC, United States) (2022), 122 (5), 5068-5143CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

     A review. Recent advances in nanostructured materials and unconventional device designs have transformed the bioelectronics from a rigid and bulky form into a soft and ultrathin form and brought enormous advantages to the bioelectronics. For example, mech. deformability of the soft bioelectronics and thus its conformal contact onto soft curved organs such as brain, heart, and skin have allowed researchers to measure high-quality biosignals, deliver real-time feedback treatments, and lower long-term side-effects in vivo. Here, we review various materials, fabrication methods, and device strategies for flexible and stretchable electronics, esp. focusing on soft biointegrated electronics using nanomaterials and their composites. First, we summarize top-down material processing and bottom-up synthesis methods of various nanomaterials. Next, we discuss state-of-the-art technologies for intrinsically stretchable nanocomposites composed of nanostructured materials incorporated in elastomers or hydrogels. We also briefly discuss unconventional device design strategies for soft bioelectronics. Then individual device components for soft bioelectronics, such as biosensing, data storage, display, therapeutic stimulation, and power supply devices, are introduced. Afterward, representative application examples of the soft bioelectronics are described. A brief summary with a discussion on remaining challenges concludes the review.
948. 948

     Choi, S.; Han, S. I.; Jung, D.; Hwang, H. J.; Lim, C.; Bae, S.; Park, O. K.; Tschabrunn, C. M.; Lee, M.; Bae, S. Y.; Yu, J. W.; Ryu, J. H.; Lee, S. W.; Park, K.; Kang, P. M.; Lee, W. B.; Nezafat, R.; Hyeon, T.; Kim, D. H. Highly Conductive, Stretchable and Biocompatible Ag-Au Core-Sheath Nanowire Composite for Wearable and Implantable Bioelectronics. Nat. Nanotechnol. 2018, 13, 1048– 1056,  DOI: 10.1038/s41565-018-0226-8

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     948

     Highly conductive, stretchable and biocompatible Ag-Au core-sheath nanowire composite for wearable and implantable bioelectronics

     Choi, Suji; Han, Sang Ihn; Jung, Dongjun; Hwang, Hye Jin; Lim, Chaehong; Bae, Soochan; Park, Ok Kyu; Tschabrunn, Cory M.; Lee, Mincheol; Bae, Sun Youn; Yu, Ji Woong; Ryu, Ji Ho; Lee, Sang-Woo; Park, Kyungpyo; Kang, Peter M.; Lee, Won Bo; Nezafat, Reza; Hyeon, Taeghwan; Kim, Dae-Hyeong

     Nature Nanotechnology (2018), 13 (11), 1048-1056CODEN: NNAABX; ISSN:1748-3387. (Nature Research)

     Wearable and implantable devices require conductive, stretchable and biocompatible materials. However, obtaining composites that simultaneously fulfil these requirements is challenging due to a trade-off between cond. and stretchability. Here, we report on Ag-Au nanocomposites composed of ultralong gold-coated silver nanowires in an elastomeric block-copolymer matrix. Owing to the high aspect ratio and percolation network of the Ag-Au nanowires, the nanocomposites exhibit an optimized cond. of 41,850 S cm-1 (max. of 72,600 S cm-1). Phase sepn. in the Ag-Au nanocomposite during the solvent-drying process generates a microstructure that yields an optimized stretchability of 266% (max. of 840%). The thick gold sheath deposited on the silver nanowire surface prevents oxidn. and silver ion leaching, making the composite biocompatible and highly conductive. Using the nanocomposite, we successfully fabricate wearable and implantable soft bioelectronic devices that can be conformally integrated with human skin and swine heart for continuous electrophysiol. recording, and elec. and thermal stimulation.
949. 949

     Leber, A.; Dong, C.; Laperrousaz, S.; Banerjee, H.; Abdelaziz, M. E. M. K.; Bartolomei, N.; Schyrr, B.; Temelkuran, B.; Sorin, F. Highly Integrated Multi-Material Fibers for Soft Robotics. Adv. Sci. 2023, 10, 2204016,  DOI: 10.1002/advs.202204016

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     949

     Highly Integrated Multi-Material Fibers for Soft Robotics

     Leber, Andreas; Dong, Chaoqun; Laperrousaz, Stella; Banerjee, Hritwick; Abdelaziz, Mohamed E. M. K.; Bartolomei, Nicola; Schyrr, Bastien; Temelkuran, Burak; Sorin, Fabien

     Advanced Science (Weinheim, Germany) (2023), 10 (2), 2204016CODEN: ASDCCF; ISSN:2198-3844. (Wiley-VCH Verlag GmbH & Co. KGaA)

     Soft robots are envisioned as the next generation of safe biomedical devices in minimally invasive procedures. Yet, the difficulty of processing soft materials currently limits the size, aspect-ratio, manufg. throughput, as well as, the design complexity and hence capabilities of soft robots. Multi-material thermal drawing is introduced as a material and processing platform to create soft robotic fibers imparted with multiple actuations and sensing modalities. Several thermoplastic and elastomeric material options for the fibers are presented, which all exhibit the rheol. processing attributes for thermal drawing but varying mech. properties, resulting in adaptable actuation performance. Moreover, numerous different fiber designs with intricate internal architectures, outer diams. of 700μm, aspect ratios of 103, and a fabrication at a scale of 10s of meters of length are demonstrated. A modular tendon-driven mechanism enables 3-dimensional (3D) motion, and embedded optical guides, elec. wires, and microfluidic channels give rise to multifunctionality. The fibers can perceive and autonomously adapt to their environments, as well as, probe elec. properties, and deliver fluids and mech. tools to spatially distributed targets.
950. 950

     Jung, D.; Lim, C.; Shim, H. J.; Kim, Y.; Park, C.; Jung, J.; Han, S. I.; Sunwoo, S.-H.; Cho, K. W.; Cha, G. D.; Kim, D. C.; Koo, J. H.; Kim, J. H.; Hyeon, T.; Kim, D.-H. Highly Conductive and Elastic Nanomembrane for Skin Electronics. Science 2021, 373, 1022– 1026,  DOI: 10.1126/science.abh4357

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     950

     Highly conductive and elastic nanomembrane for skin electronics

     Jung, Dongjun; Lim, Chaehong; Shim, Hyung Joon; Kim, Yeongjun; Park, Chansul; Jung, Jaebong; Han, Sang Ihn; Sunwoo, Sung-Hyuk; Cho, Kyoung Won; Cha, Gi Doo; Kim, Dong Chan; Koo, Ja Hoon; Kim, Ji Hoon; Hyeon, Taeghwan; Kim, Dae-Hyeong

     Science (Washington, DC, United States) (2021), 373 (6558), 1022-1026CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)

     Skin electronics require stretchable conductors that satisfy metallike cond., high stretchability, ultrathin thickness, and facile patternability, but achieving these characteristics simultaneously is challenging. We present a float assembly method to fabricate a nanomembrane that meets all these requirements. The method enables a compact assembly of nanomaterials at the wateroil interface and their partial embedment in an ultrathin elastomer membrane, which can distribute the applied strain in the elastomer membrane and thus lead to a high elasticity even with the high loading of the nanomaterials. Furthermore, the structure allows cold welding and bilayer stacking, resulting in high cond. These properties are preserved even after high-resoln. patterning by using photolithog. A multifunctional epidermal sensor array can be fabricated with the patterned nanomembranes.
951. 951

     Zhu, B.; Wang, H.; Liu, Y.; Qi, D.; Liu, Z.; Wang, H.; Yu, J.; Sherburne, M.; Wang, Z.; Chen, X. Skin-Inspired Haptic Memory Arrays with an Electrically Reconfigurable Architecture. Adv. Mater. 2016, 28, 1559– 1566,  DOI: 10.1002/adma.201504754

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     951

     Skin-Inspired Haptic Memory Arrays with an Electrically Reconfigurable Architecture

     Zhu, Bowen; Wang, Hong; Liu, Yaqing; Qi, Dianpeng; Liu, Zhiyuan; Wang, Hua; Yu, Jiancan; Sherburne, Matthew; Wang, Zhaohui; Chen, Xiaodong

     Advanced Materials (Weinheim, Germany) (2016), 28 (8), 1559-1566CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     The prepn. is successfully achieved of haptic memory devices for the mimicry of human haptic memory through the integration of resistive switching memory devices with resistive pressure sensors, where the resistance states in a memory cell can be elec. reconfigured by applied pressure on a pressure sensor. Moreover, the applied pressure distribution could be recorded by introducing memory cell arrays, where each integrated device could be attributed to combination of a pressure sensor and memory device that connect in series. The integration of memory device and pressure sensor is realized by replacing the bottom electrode of a pressure sensor with the electrode of a resistive switching memory device. In this way, the resistance changes in a pressure sensor induced by external pressures will result in the voltage changes on the electrode of a resistive switching memory cell, leading to its resistance state change, and the pressure information will be retained by the memory device. The resistive pressure sensor takes microstructured poly(dimethylsiloxane) film embedded with silver nanowires as sensitive layer.
952. 952

     Liu, Y.; Liu, Z.; Zhu, B.; Yu, J.; He, K.; Leow, W. R.; Wang, M.; Chandran, B. K.; Qi, D.; Wang, H.; Chen, G.; Xu, C.; Chen, X. Stretchable Motion Memory Devices Based on Mechanical Hybrid Materials. Adv. Mater. 2017, 29, 1701780,  DOI: 10.1002/adma.201701780

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     There is no corresponding record for this reference.
953. 953

     Wan, C.; Chen, G.; Fu, Y.; Wang, M.; Matsuhisa, N.; Pan, S.; Pan, L.; Yang, H.; Wan, Q.; Zhu, L.; Chen, X. An Artificial Sensory Neuron with Tactile Perceptual Learning. Adv. Mater. 2018, 30, e1801291,  DOI: 10.1002/adma.201801291

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     There is no corresponding record for this reference.
954. 954

     He, K.; Liu, Y.; Wang, M.; Chen, G.; Jiang, Y.; Yu, J.; Wan, C.; Qi, D.; Xiao, M.; Leow, W. R.; Yang, H.; Antonietti, M.; Chen, X. An Artificial Somatic Reflex Arc. Adv. Mater. 2020, 32, e1905399,  DOI: 10.1002/adma.201905399

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     954

     An Artificial Somatic Reflex Arc

     He, Ke; Liu, Yaqing; Wang, Ming; Chen, Geng; Jiang, Ying; Yu, Jiancan; Wan, Changjin; Qi, Dianpeng; Xiao, Meng; Leow, Wan Ru; Yang, Hui; Antonietti, Markus; Chen, Xiaodong

     Advanced Materials (Weinheim, Germany) (2020), 32 (4), 1905399CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)

     The emulation of human sensation, perception, and action processes has become a major challenge for bioinspired intelligent robotics, interactive human-machine interfacing, and advanced prosthetics. Reflex actions, enabled through reflex arcs, are important for human and higher animals to respond to stimuli from environment without the brain processing and survive the risks of nature. An artificial reflex arc system that emulates the functions of the reflex arc simplifies the complex circuit design needed for "central-control-only" processes and becomes a basic electronic component in an intelligent soft robotics system. An artificial somatic reflex arc that enables the actuation of electrochem. actuators in response to the stimulation of tactile pressures is reported. Only if the detected pressure by the pressure sensor is above the stimulus threshold, the metal-org.-framework-based threshold controlling unit (TCU) can be activated and triggers the electrochem. actuators to complete the motion. Such responding mechanism mimics the all-or-none law in the human nervous system. As a proof of concept, the artificial somatic reflex arc is successfully integrated into a robot to mimic the infant grasp reflex. This work provides a unique and simplifying strategy for developing intelligent soft robotics, next-generation human-machine interfaces, and neuroprosthetics.
955. 955

     He, K.; Liu, Y.; Yu, J.; Guo, X.; Wang, M.; Zhang, L.; Wan, C.; Wang, T.; Zhou, C.; Chen, X. Artificial Neural Pathway Based on a Memristor Synapse for Optically Mediated Motion Learning. ACS Nano 2022, 16, 9691– 9700,  DOI: 10.1021/acsnano.2c03100

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     955

     Artificial Neural Pathway Based on a Memristor Synapse for Optically Mediated Motion Learning

     He, Ke; Liu, Yaqing; Yu, Jiancan; Guo, Xintong; Wang, Ming; Zhang, Liandong; Wan, Changjin; Wang, Ting; Zhou, Changjiu; Chen, Xiaodong

     ACS Nano (2022), 16 (6), 9691-9700CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

     Animals execute intelligent and efficient interactions with their surroundings through neural pathways, exhibiting learning, memory, and cognition. Artificial autonomous devices that generate self-optimizing feedback mimicking biol. systems are essential in pursuing future intelligent robots. Here, we report an artificial neural pathway (ANP) based on a memristor synapse to emulate neuromorphic learning behaviors. In our ANP, optical stimulations are detected and converted into elec. signals through a flexible perovskite photoreceptor. The acquired elec. signals are further processed in a zeolitic imidazolate frameworks-8 (ZIF-8)-based memristor device. By controlling the growth of the ZIF-8 nanoparticles, the conductance of the memristor can be finely modulated with elec. stimulations to mimic the modulation of synaptic plasticity. The device is employed in the ANP to implement synaptic functions of learning and memory. Subsequently, the synaptic feedbacks are used to direct a robotic arm to perform responding motions. Upon repeatedly "reviewing" the optical stimulation, the ANP is able to learn, memorize, and complete the specific motions. This work provides a promising strategy toward the design of intelligent autonomous devices and bioinspired robots through memristor-based systems.
956. 956

     Tee, B. C.-K.; Chortos, A.; Berndt, A.; Nguyen, A. K.; Tom, A.; McGuire, A.; Lin, Z. C.; Tien, K.; Bae, W.-G.; Wang, H.; Mei, P.; Chou, H.-H.; Cui, B.; Deisseroth, K.; Ng, T. N.; Bao, Z. A Skin-Inspired Organic Digital Mechanoreceptor. Science 2015, 350, 313– 316,  DOI: 10.1126/science.aaa9306

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     956

     A skin-inspired organic digital mechanoreceptor

     Tee, Benjamin C.-K.; Chortos, Alex; Berndt, Andre; Nguyen, Amanda Kim; Tom, Ariane; McGuire, Allister; Lin, Ziliang Carter; Tien, Kevin; Bae, Won-Gyu; Wang, Huiliang; Mei, Ping; Chou, Ho-Hsiu; Cui, Bianxiao; Deisseroth, Karl; Ng, Tse Nga; Bao, Zhenan

     Science (Washington, DC, United States) (2015), 350 (6258), 313-316CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     Human skin relies on cutaneous receptors that output digital signals for tactile sensing in which the intensity of stimulation is converted to a series of voltage pulses. We present a power-efficient skin-inspired mechanoreceptor with a flexible org. transistor circuit that transduces pressure into digital frequency signals directly. The output frequency ranges between 0 and 200 Hz, with a sublinear response to increasing force stimuli that mimics slow-adapting skin mechanoreceptors. The output of the sensors was further used to stimulate optogenetically engineered mouse somatosensory neurons of mouse cortex in vitro, achieving stimulated pulses in accordance with pressure levels. This work represents a step toward the design and use of large-area org. electronic skins with neural-integrated touch feedback for replacement limbs.
957. 957

     Kim, Y.; Chortos, A.; Xu, W.; Liu, Y.; Oh, J. Y.; Son, D.; Kang, J.; Foudeh, A. M.; Zhu, C.; Lee, Y.; Niu, S.; Liu, J.; Pfattner, R.; Bao, Z.; Lee, T.-W. A Bioinspired Flexible Organic Artificial Afferent Nerve. Science 2018, 360, 998– 1003,  DOI: 10.1126/science.aao0098

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     957

     A bioinspired flexible organic artificial afferent nerve

     Kim, Yeongin; Chortos, Alex; Xu, Wentao; Liu, Yuxin; Oh, Jin Young; Son, Donghee; Kang, Jiheong; Foudeh, Amir M.; Zhu, Chenxin; Lee, Yeongjun; Niu, Simiao; Liu, Jia; Pfattner, Raphael; Bao, Zhenan; Lee, Tae-Woo

     Science (Washington, DC, United States) (2018), 360 (6392), 998-1003CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

     The distributed network of receptors, neurons, and synapses in the somatosensory system efficiently processes complex tactile information. The authors used flexible org. electronics to mimic the functions of a sensory nerve. The artificial afferent nerve collects pressure information (1 to 80 kilopascals) from clusters of pressure sensors, converts the pressure information into action potentials (0 to 100 Hz) by using ring oscillators, and integrates the action potentials from multiple ring oscillators with a synaptic transistor. Biomimetic hierarchical structures can detect movement of an object, combine simultaneous pressure inputs, and distinguish braille characters. Furthermore, the authors connected the artificial afferent nerve to motor nerves to construct a hybrid bioelectronic reflex arc to actuate muscles. The system has potential applications in neurorobotics and neuroprosthetics.
958. 958

     Zhang, M.; Tang, Z.; Liu, X.; Van der Spiegel, J. Electronic Neural Interfaces. Nat. Electron. 2020, 3, 191– 200,  DOI: 10.1038/s41928-020-0390-3

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     There is no corresponding record for this reference.
959. 959

     Sabandal, J. M.; Berry, J. A.; Davis, R. L. Dopamine-Based Mechanism for Transient Forgetting. Nature 2021, 591, 426– 430,  DOI: 10.1038/s41586-020-03154-y

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     There is no corresponding record for this reference.
960. 960

     Keene, S. T.; Lubrano, C.; Kazemzadeh, S.; Melianas, A.; Tuchman, Y.; Polino, G.; Scognamiglio, P.; Cina, L.; Salleo, A.; van de Burgt, Y.; Santoro, F. A Biohybrid Synapse with Neurotransmitter-Mediated Plasticity. Nat. Mater. 2020, 19, 969– 973,  DOI: 10.1038/s41563-020-0703-y

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     960

     A biohybrid synapse with neurotransmitter-mediated plasticity

     Keene, Scott T.; Lubrano, Claudia; Kazemzadeh, Setareh; Melianas, Armantas; Tuchman, Yaakov; Polino, Giuseppina; Scognamiglio, Paola; Cina, Lucio; Salleo, Alberto; van de Burgt, Yoeri; Santoro, Francesca

     Nature Materials (2020), 19 (9), 969-973CODEN: NMAACR; ISSN:1476-1122. (Nature Research)

     Brain-inspired computing paradigms led to substantial advances in the automation of visual and linguistic tasks by emulating the distributed information processing of biol. systems1. The similarity between artificial neural networks (ANNs) and biol. systems has inspired ANN implementation in biomedical interfaces including prosthetics2 and brain-machine interfaces3. While promising, these implementations rely on software to run ANN algorithms. Ultimately, it is desirable to build hardware ANNs4,5 that can both directly interface with living tissue and adapt based on biofeedback6,7. The first essential step towards biol. integrated neuromorphic systems is to achieve synaptic conditioning based on biochem. signaling activity. Here, the authors directly couple an org. neuromorphic device with dopaminergic cells to constitute a biohybrid synapse with neurotransmitter-mediated synaptic plasticity. By mimicking the dopamine recycling machinery of the synaptic cleft, the authors demonstrate both long-term conditioning and recovery of the synaptic wt., paving the way towards combining artificial neuromorphic systems with biol. neural networks.
961. 961

     Li, J.; Liu, Y.; Yuan, L.; Zhang, B.; Bishop, E. S.; Wang, K.; Tang, J.; Zheng, Y. Q.; Xu, W.; Niu, S.; Beker, L.; Li, T. L.; Chen, G.; Diyaolu, M.; Thomas, A. L.; Mottini, V.; Tok, J. B.; Dunn, J. C. Y.; Cui, B.; Pasca, S. P.; Cui, Y.; Habtezion, A.; Chen, X.; Bao, Z. A Tissue-Like Neurotransmitter Sensor for the Brain and Gut. Nature 2022, 606, 94– 101,  DOI: 10.1038/s41586-022-04615-2

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     961

     A tissue-like neurotransmitter sensor for the brain and gut

     Li, Jinxing; Liu, Yuxin; Yuan, Lei; Zhang, Baibing; Bishop, Estelle Spear; Wang, Kecheng; Tang, Jing; Zheng, Yu-Qing; Xu, Wenhui; Niu, Simiao; Beker, Levent; Li, Thomas L.; Chen, Gan; Diyaolu, Modupeola; Thomas, Anne-Laure; Mottini, Vittorio; Tok, Jeffrey B.-H.; Dunn, James C. Y.; Cui, Bianxiao; Pasca, Sergiu P.; Cui, Yi; Habtezion, Aida; Chen, Xiaoke; Bao, Zhenan

     Nature (London, United Kingdom) (2022), 606 (7912), 94-101CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)

     Neurotransmitters play essential roles in regulating neural circuit dynamics both in the central nervous system as well as at the peripheral, including the gastrointestinal tract1-3. Their real-time monitoring will offer crit. information for understanding neural function and diagnosing disease1-3. However, bioelectronic tools to monitor the dynamics of neurotransmitters in vivo, esp. in the enteric nervous systems, are underdeveloped. This is mainly owing to the limited availability of biosensing tools that are capable of examg. soft, complex and actively moving organs. Here we introduce a tissue-mimicking, stretchable, neurochem. biol. interface termed NeuroString, which is prepd. by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer. NeuroString sensors allow chronic in vivo real-time, multichannel and multiplexed monoamine sensing in the brain of behaving mouse, as well as measuring serotonin dynamics in the gut without undesired stimulations and perturbing peristaltic movements. The described elastic and conformable biosensing interface has broad potential for studying the impact of neurotransmitters on gut microbes, brain-gut communication and may ultimately be extended to biomol. sensing in other soft organs across the body.
962. 962

     Wang, T.; Wang, M.; Wang, J.; Yang, L.; Ren, X.; Song, G.; Chen, S.; Yuan, Y.; Liu, R.; Pan, L.; Li, Z.; Leow, W. R.; Luo, Y.; Ji, S.; Cui, Z.; He, K.; Zhang, F.; Lv, F.; Tian, Y.; Cai, K.; Yang, B.; Niu, J.; Zou, H.; Liu, S.; Xu, G.; Fan, X.; Hu, B.; Loh, X. J.; Wang, L.; Chen, X. A Chemically Mediated Artificial Neuron. Nat. Electron. 2022, 5, 586– 595,  DOI: 10.1038/s41928-022-00803-0

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     962

     A chemically mediated artificial neuron

     Wang, Ting; Wang, Ming; Wang, Jianwu; Yang, Le; Ren, Xueyang; Song, Gang; Chen, Shisheng; Yuan, Yuehui; Liu, Ruiqing; Pan, Liang; Li, Zheng; Leow, Wan Ru; Luo, Yifei; Ji, Shaobo; Cui, Zequn; He, Ke; Zhang, Feilong; Lv, Fengting; Tian, Yuanyuan; Cai, Kaiyu; Yang, Bowen; Niu, Jingyi; Zou, Haochen; Liu, Songrui; Xu, Guoliang; Fan, Xing; Hu, Benhui; Loh, Xian Jun; Wang, Lianhui; Chen, Xiaodong

     Nature Electronics (2022), 5 (9), 586-595CODEN: NEALB3; ISSN:2520-1131. (Nature Portfolio)

     Brain-machine interfaces typically rely on electrophysiol. signals to interpret and transmit neurol. information. In biol. systems, however, neurotransmitters are chem.-based interneuron messengers. This mismatch can potentially lead to incorrect interpretation of the transmitted neuron information. Here we report a chem. mediated artificial neuron that can receive and release the neurotransmitter dopamine. The artificial neuron detects dopamine using a carbon-based electrochem. sensor and then processes the sensory signals using a memristor with synaptic plasticity, before stimulating dopamine release through a heat-responsive hydrogel. The system responds to dopamine exocytosis from rat pheochromocytoma cells and also releases dopamine to activate pheochromocytoma cells, forming a chem. communication loop similar to interneurons. To illustrate the potential of this approach, we show that the artificial neuron can trigger the controllable movement of a mouse leg and robotic hand.
963. 963

     Park, Y.; Franz, C. K.; Ryu, H.; Luan, H.; Cotton, K. Y.; Kim, J. U.; Chung, T. S.; Zhao, S.; Vazquez-Guardado, A.; Yang, D. S.; Li, K.; Avila, R.; Phillips, J. K.; Quezada, M. J.; Jang, H.; Kwak, S. S.; Won, S. M.; Kwon, K.; Jeong, H.; Bandodkar, A. J.; Han, M.; Zhao, H.; Osher, G. R.; Wang, H.; Lee, K.; Zhang, Y.; Huang, Y.; Finan, J. D.; Rogers, J. A. Three-Dimensional, Multifunctional Neural Interfaces for Cortical Spheroids and Engineered Assembloids. Sci. Adv. 2021, 7, eabf9153,  DOI: 10.1126/sciadv.abf9153

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     There is no corresponding record for this reference.
964. 964

     Norton, J. J. S.; Lee, D. S.; Lee, J. W.; Lee, W.; Kwon, O.; Won, P.; Jung, S.-Y.; Cheng, H.; Jeong, J.-W.; Akce, A.; Umunna, S.; Na, I.; Kwon, Y. H.; Wang, X.-Q.; Liu, Z.; Paik, U.; Huang, Y.; Bretl, T.; Yeo, W.-H.; Rogers, J. A. Soft, Curved Electrode Systems Capable of Integration on the Auricle as a Persistent Brain-Computer Interface. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 3920– 3925,  DOI: 10.1073/pnas.1424875112

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     964

     Soft, curved electrode systems capable of integration on the auricle as a persistent brain-computer interface

     Norton, James J. S.; Lee, Dong Sup; Lee, Jung Woo; Lee, Woosik; Kwon, Ohjin; Won, Phillip; Jung, Sung-Young; Cheng, Huanyu; Jeong, Jae-Woong; Akce, Abdullah; Umunna, Stephen; Na, Ilyoun; Kwon, Yong Ho; Wang, Xiao-Qi; Liu, Zhuang Jian; Paik, Ungyu; Huang, Yonggang; Bretl, Timothy; Yeo, Woon-Hong; Rogers, John A.

     Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (13), 3920-3925CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

     Recent advances in electrodes for noninvasive recording of electroencephalograms expand opportunities collecting such data for diagnosis of neurol. disorders and brain-computer interfaces. Existing technologies, however, cannot be used effectively in continuous, uninterrupted modes for more than a few days due to irritation and irreversible degrdn. in the elec. and mech. properties of the skin interface. Here we introduce a soft, foldable collection of electrodes in open, fractal mesh geometries that can mount directly and chronically on the complex surface topol. of the auricle and the mastoid, to provide high-fidelity and long-term capture of electroencephalograms in ways that avoid any significant thermal, elec., or mech. loading of the skin. Exptl. and computational studies establish the fundamental aspects of the bending and stretching mechanics that enable this type of intimate integration on the highly irregular and textured surfaces of the auricle. Cell level tests and thermal imaging studies establish the biocompatibility and wearability of such systems, with examples of high-quality measurements over periods of 2 wk with devices that remain mounted throughout daily activities including vigorous exercise, swimming, sleeping, and bathing. Demonstrations include a text speller with a steady-state visually evoked potential-based brain-computer interface and elicitation of an event-related potential (P300 wave).
965. 965

     Yu, K. J.; Kuzum, D.; Hwang, S.-W.; Kim, B. H.; Juul, H.; Kim, N. H.; Won, S. M.; Chiang, K.; Trumpis, M.; Richardson, A. G.; Cheng, H.; Fang, H.; Thompson, M.; Bink, H.; Talos, D.; Seo, K. J.; Lee, H. N.; Kang, S.-K.; Kim, J.-H.; Lee, J. Y.; Huang, Y.; Jensen, F. E.; Dichter, M. A.; Lucas, T. H.; Viventi, J.; Litt, B.; Rogers, J. A. Bioresorbable Silicon Electronics for Transient Spatiotemporal Mapping of Electrical Activity from the Cerebral Cortex. Nat. Mater. 2016, 15, 782– 791,  DOI: 10.1038/nmat4624

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     965

     Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex

     Yu, Ki Jun; Kuzum, Duygu; Hwang, Suk-Won; Kim, Bong Hoon; Juul, Halvor; Kim, Nam Heon; Won, Sang Min; Chiang, Ken; Trumpis, Michael; Richardson, Andrew G.; Cheng, Huanyu; Fang, Hui; Thompson, Marissa; Bink, Hank; Talos, Delia; Seo, Kyung Jin; Lee, Hee Nam; Kang, Seung-Kyun; Kim, Jae-Hwan; Lee, Jung Yup; Huang, Younggang; Jensen, Frances E.; Dichter, Marc A.; Lucas, Timothy H.; Viventi, Jonathan; Litt, Brian; Rogers, John A.

     Nature Materials (2016), 15 (7), 782-791CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)

     Bioresorbable silicon electronics technol. offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort assocd. with surgical extn. Applications include postoperative monitoring and transient physiol. recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiol. signals from the cortical surface and the subgaleal space. The devices detect normal physiol. and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to std. clin. systems and reduced tissue reactivity relative to conventional clin. electrocorticog. (ECoG) electrodes. This technol. offers general applicability in neural interfaces, with addnl. potential utility in treatment of disorders where transient monitoring and modulation of physiol. function, implant integrity and tissue recovery or regeneration are required.
966. 966

     Viventi, J.; Kim, D.-H.; Vigeland, L.; Frechette, E. S.; Blanco, J. A.; Kim, Y.-S.; Avrin, A. E.; Tiruvadi, V. R.; Hwang, S.-W.; Vanleer, A. C.; Wulsin, Drausin F.; Davis, K.; Gelber, C. E.; Palmer, L.; Spiegel, J. V. d.; Wu, J.; Xiao, J.; Huang, Y.; Contreras, D.; Rogers, J. A.; Litt, B. Flexible, Foldable, Actively Multiplexed, High-Density Electrode Array for Mapping Brain Activity in Vivo. Nat. Neurosci. 2011, 14, 1599– 1605,  DOI: 10.1038/nn.2973

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     966

     Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo

     Viventi, Jonathan; Kim, Dae-Hyeong; Vigeland, Leif; Frechette, Eric S.; Blanco, Justin A.; Kim, Yun-Soung; Avrin, Andrew E.; Tiruvadi, Vineet R.; Hwang, Suk-Won; Vanleer, Ann C.; Wulsin, Drausin F.; Davis, Kathryn; Gelber, Casey E.; Palmer, Larry; Van der Spiegel, Jan; Wu, Jian; Xiao, Jianliang; Huang, Yonggang; Contreras, Diego; Rogers, John A.; Litt, Brian

     Nature Neuroscience (2011), 14 (12), 1599-1605CODEN: NANEFN; ISSN:1097-6256. (Nature Publishing Group)

     Arrays of electrodes for recording and stimulating the brain are used throughout clin. medicine and basic neuroscience research, yet are unable to sample large areas of the brain while maintaining high spatial resoln. because of the need to individually wire each passive sensor at the electrode-tissue interface. To overcome this constraint, the authors developed new devices that integrate ultrathin and flexible silicon nanomembrane transistors into the electrode array, enabling new dense arrays of thousands of amplified and multiplexed sensors that are connected using fewer wires. This system was used to record spatial properties of cat brain activity in vivo, including sleep spindles, single-trial visual evoked responses and electrog. seizures. It was found that seizures may manifest as recurrent spiral waves that propagate in the neocortex. The developments reported here herald a new generation of diagnostic and therapeutic brain-machine interface devices.
967. 967

     Park, D.-W.; Schendel, A. A.; Mikael, S.; Brodnick, S. K.; Richner, T. J.; Ness, J. P.; Hayat, M. R.; Atry, F.; Frye, S. T.; Pashaie, R. Graphene-Based Carbon-Layered Electrode Array Technology for Neural Imaging and Optogenetic Applications. Nat. Commun. 2014, 5, 5258,  DOI: 10.1038/ncomms6258

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     967

     Graphene-based carbon-layered electrode array technology for neural imaging and optogenetic applications

     Park, Dong-Wook; Schendel, Amelia A.; Mikael, Solomon; Brodnick, Sarah K.; Richner, Thomas J.; Ness, Jared P.; Hayat, Mohammed R.; Atry, Farid; Frye, Seth T.; Pashaie, Ramin; Thongpang, Sanitta; Ma, Zhenqiang; Williams, Justin C.

     Nature Communications (2014), 5 (), 5258CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

     Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from UV to IR could allow for simultaneous electrophysiol. and optical imaging, as well as optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mech. flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high-resoln. neurophysiol. recording. We characterize optical transparency of the device at >90% transmission over the UV to IR spectrum and demonstrate its utility through optical interface expts. that use this broad spectrum transparency. These include optogenetic activation of focal cortical areas directly beneath electrodes, in vivo imaging of the cortical vasculature via fluorescence microscopy and 3D optical coherence tomog. This study demonstrates an array of interfacing abilities of the CLEAR device and its utility for neural applications.
968. 968

     Hamill, O. P.; Marty, A.; Neher, E.; Sakmann, B.; Sigworth, F. J. Improved Patch-Clamp Techniques for High-Resolution Current Recording from Cells and Cell-Free Membrane Patches. European Journal of Physiology, Plügers Archiv. 1981, 391, 85– 100,  DOI: 10.1007/BF00656997

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     968

     Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches

     Hamill O P; Marty A; Neher E; Sakmann B; Sigworth F J

     Pflugers Archiv : European journal of physiology (1981), 391 (2), 85-100 ISSN:0031-6768.

     1. The extracellular patch clamp method, which first allowed the detection of single channel currents in biological membranes, has been further refined to enable higher current resolution, direct membrane patch potential control, and physical isolation of membrane patches. 2. A description of a convenient method for the fabrication of patch recording pipettes is given together with procedures followed to achieve giga-seals i.e. pipette-membrane seals with resistances of 10(9) - 10(11) omega. 3. The basic patch clamp recording circuit, and designs for improved frequency response are described along with the present limitations in recording the currents from single channels. 4. Procedures for preparation and recording from three representative cell types are given. Some properties of single acetylcholine-activated channels in muscle membrane are described to illustrate the improved current and time resolution achieved with giga-seals. 5. A description is given of the various ways that patches of membrane can be physically isolated from cells. This isolation enables the recording of single channel currents with well-defined solutions on both sides of the membrane. Two types of isolated cell-free patch configurations can be formed: an inside-out patch with its cytoplasmic membrane face exposed to the bath solution, and an outside-out patch with its extracellular membrane face exposed to the bath solution. 6. The application of the method for the recording of ionic currents and internal dialysis of small cells is considered. Single channel resolution can be achieved when recording from whole cells, if the cell diameter is small (less than 20 micrometer). 7. The wide range of cell types amenable to giga-seal formation is discussed.
969. 969

     Behrends, J. C.; Fertig, N. Planar Patch Clamping. In Patch-Clamp Analysis: Advanced Techniques, Walz, W., Ed. Humana Press: Totowa, NJ, 2007; pp 411– 433.

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     There is no corresponding record for this reference.
970. 970

     Fertig, N.; Blick, R. H.; Behrends, J. C. Whole Cell Patch Clamp Recording Performed on a Planar Glass Chip. Biophys. J. 2002, 82, 3056– 3062,  DOI: 10.1016/S0006-3495(02)75646-4

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     There is no corresponding record for this reference.
971. 971

     Fertig, N.; Klau, M.; George, M.; Blick, R. H.; Behrends, J. C. Activity of Single Ion Channel Proteins Detected with a Planar Microstructure. Appl. Phys. Lett. 2002, 81, 4865– 4867,  DOI: 10.1063/1.1531228

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     971

     Activity of single ion channel proteins detected with a planar microstructure

     Fertig, Niels; Klau, Michele; George, Michael; Blick, Robert H.; Behrends, Jan C.

     Applied Physics Letters (2002), 81 (25), 4865-4867CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)

     We present recordings of currents mediated by single ion channel proteins obtained using planar, microstructured glass chips. In these chips, pores with diams. of 1-2 μm are produced by ion track etching and are used for patch clamping instead of using the classical micropipette. Our results represent success in using such devices to record from single channels in cell membranes. The planar chip greatly enhances the accessibility of the ion channel contg. membrane and can serve as a workbench for expts. on single ion channels using combinations of patch clamp current recording with other single mol. techniques.
972. 972

     Pamir, E.; George, M.; Fertig, N.; Benoit, M. Planar Patch-Clamp Force Microscopy on Living Cells. Ultramicroscopy 2008, 108, 552– 557,  DOI: 10.1016/j.ultramic.2007.08.013

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     972

     Planar patch-clamp force microscopy on living cells

     Pamir, Evren; George, Michael; Fertig, Niels; Benoit, Martin

     Ultramicroscopy (2008), 108 (6), 552-557CODEN: ULTRD6; ISSN:0304-3991. (Elsevier B.V.)

     Here we report a new combination of the patch-clamp technique with the at. force microscope (AFM). A planar patch-clamp chip microstructured from borosilicate glass was used as a support for mech. probing of living cells. The setup not only allows for immobilizing even a non-adherent cell for measurements of its mech. properties, but also for simultaneously measuring the electrophysiol. properties of a single cell. As a proof of principle expt. we measured the voltage-induced membrane movement of HEK293 and Jurkat cells in the whole-cell voltage clamp configuration. The results of these measurements are in good agreement with previous studies. By using the planar patch-clamp chip for immobilization, the AFM not only can image non-adhering cells, but also gets easily access to an electrophysiol. controlled cellular probe at low vibrational noise.
973. 973

     Obergrussberger, A.; Stolzle-Feix, S.; Becker, N.; Bruggemann, A.; Fertig, N.; Möller, C. Novel Screening Techniques for Ion Channel Targeting Drugs. Channels 2015, 9, 367– 375,  DOI: 10.1080/19336950.2015.1079675

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     973

     Novel screening techniques for ion channel targeting drugs

     Obergrussberger Alison; Stolzle-Feix Sonja; Becker Nadine; Bruggemann Andrea; Fertig Niels; Moller Clemens

     Channels (Austin, Tex.) (2015), 9 (6), 367-75 ISSN:.

     Ion channels are integral membrane proteins that regulate the flux of ions across the cell membrane. They are involved in nearly all physiological processes, and malfunction of ion channels has been linked to many diseases. Until recently, high-throughput screening of ion channels was limited to indirect, e.g. fluorescence-based, readout technologies. In the past years, direct label-free biophysical readout technologies by means of electrophysiology have been developed. Planar patch-clamp electrophysiology provides a direct functional label-free readout of ion channel function in medium to high throughput. Further electrophysiology features, including temperature control and higher-throughput instruments, are continually being developed. Electrophysiological screening in a 384-well format has recently become possible. Advances in chip and microfluidic design, as well as in cell preparation and handling, have allowed challenging cell types to be studied by automated patch clamp. Assays measuring action potentials in stem cell-derived cardiomyocytes, relevant for cardiac safety screening, and neuronal cells, as well as a large number of different ion channels, including fast ligand-gated ion channels, have successfully been established by automated patch clamp. Impedance and multi-electrode array measurements are particularly suitable for studying cardiomyocytes and neuronal cells within their physiological network, and to address more complex physiological questions. This article discusses recent advances in electrophysiological technologies available for screening ion channel function and regulation.
974. 974

     Obergrussberger, A.; Bruggemann, A.; Goetze, T. A.; Rapedius, M.; Haarmann, C.; Rinke, I.; Becker, N.; Oka, T.; Ohtsuki, A.; Stengel, T.; Vogel, M.; Steindl, J.; Mueller, M.; Stiehler, J.; George, M.; Fertig, N. Automated Patch Clamp Meets High-Throughput Screening: 384 Cells Recorded in Parallel on a Planar Patch Clamp Module. J. Lab. Autom. 2016, 21, 779– 793,  DOI: 10.1177/2211068215623209

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     974

     Automated Patch Clamp Meets High-Throughput Screening: 384 Cells Recorded in Parallel on a Planar Patch Clamp Module

     Obergrussberger Alison; Bruggemann Andrea; Goetze Tom A; Rapedius Markus; Haarmann Claudia; Rinke Ilka; Becker Nadine; Stengel Timo; Vogel Marius; Steindl Juergen; Mueller Max; Stiehler Johannes; George Michael; Fertig Niels; Oka Takayuki; Ohtsuki Atsushi

     Journal of laboratory automation (2016), 21 (6), 779-793 ISSN:.

     We have developed an automated patch clamp module for high-throughput ion channel screening, recording from 384 cells simultaneously. The module is incorporated into a laboratory pipetting robot and uses a 384-channel pipettor head for application of cells and compounds. The module contains 384 amplifier channels for fully parallel recordings using a digital amplifier. Success rates for completed experiments (1- to 4-point concentration-response curves for cells satisfying defined quality control parameters) of greater than 85% have been routinely achieved with, for example, HEK, CHO, and RBL cell lines expressing hNaV1.7, hERG, Kir2.1, GABA, or glutamate receptors. Pharmacology experiments are recorded and analyzed using specialized software, and the pharmacology of hNaV1.7 and hERG is described. Fast external solution exchange rates of <50 ms are demonstrated using Kir2.1. Short exposure times are achieved by stacking the external solutions inside the pipette of the robot to minimize exposure of the ligand on the receptor. This ensures that ligand-gated ion channels, for example, GABA and glutamate described in this report, can be reproducibly recorded. Stem cell-derived cardiomyocytes have also been used with success rates of 52% for cells that have a seal resistance of >200 MΩ, and recordings of voltage-gated Na(+) and Ca(2+) are shown.
975. 975

     Cohen, M. S.; Bookheimer, S. Y. Localization of Brain Function Using Magnetic Resonance Imaging. Trends Neurosci. 1994, 17, 268– 277,  DOI: 10.1016/0166-2236(94)90055-8

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     Ogawa, S.; Lee, T.-M. Magnetic Resonance Imaging of Blood Vessels at High Fields: In Vivo and in Vitro Measurements and Image Simulation. Magn. Res. Med. 1990, 16, 9– 18,  DOI: 10.1002/mrm.1910160103

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     Buxton, R. B. Introduction to Functional Magnetic Resonance Imaging: Principles and Techniques; Cambridge University Press, 2009.

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     Heeger, D. J.; Ress, D. What Does fMRI Tell Us about Neuronal Activity?. Nat. Rev. Neurosci. 2002, 3, 142– 151,  DOI: 10.1038/nrn730

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     What does fMRI tell us about neuronal activity?

     Heeger, David J.; Ress, David

     Nature Reviews Neuroscience (2002), 3 (2), 142-151CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)

     A review. In recent years, cognitive neuroscientists have taken great advantage of functional magnetic resonance imaging (fMRI) as a non-invasive method of measuring neuronal activity in the human brain. But what exactly does fMRI tell us. We know that its signals arise from changes in local hemodynamics that, in turn, result from alterations in neuronal activity, but exactly how neuronal activity, hemodynamics and fMRI signals are related is unclear. It has been assumed that the fMRI signal is proportional to the local av. neuronal activity, but many factors can influence the relationship between the two. A clearer understanding of how neuronal activity influences the fMRI signal is needed if we are correctly to interpret functional imaging data.
979. 979

     Bookheimer, S. Functional MRI of Language: New Approaches to Understanding the Cortical Organization of Semantic Processing. Annu. Rev. Neurosci. 2002, 25, 151– 188,  DOI: 10.1146/annurev.neuro.25.112701.142946

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     Ogawa, S.; Tank, D. W.; Menon, R.; Ellermann, J. M.; Kim, S. G.; Merkle, H.; Ugurbil, K. Intrinsic Signal Changes Accompanying Sensory Stimulation: Functional Brain Mapping with Magnetic Resonance Imaging. Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 5951– 5955,  DOI: 10.1073/pnas.89.13.5951

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     Glover, G. H. Overview of Functional Magnetic Resonance Imaging. Neurosurg. Clinics 2011, 22, 133– 139,  DOI: 10.1016/j.nec.2010.11.001

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     Logothetis, N. K. What We Can Do and What We Cannot Do with fMRI. Nature 2008, 453, 869– 878,  DOI: 10.1038/nature06976

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     What we can do and what we cannot do with fMRI

     Logothetis, Nikos K.

     Nature (London, United Kingdom) (2008), 453 (7197), 869-878CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

     Functional magnetic resonance imaging (fMRI) is currently the mainstay of neuroimaging in cognitive neuroscience. Advances in scanner technol., image acquisition protocols, exptl. design, and anal. methods promise to push forward fMRI from mere cartog. to the true study of brain organization. However, fundamental questions concerning the interpretation of fMRI data abound, as the conclusions drawn often ignore the actual limitations of the methodol. Here I give an overview of the current state of fMRI, and draw on neuroimaging and physiol. data to present the current understanding of the haemodynamic signals and the constraints they impose on neuroimaging data interpretation.
983. 983

     Cohen, M. S.; Weisskoff, R. M. Ultra-Fast Imaging. Magn. Res. Imag. 1991, 9, 1– 37,  DOI: 10.1016/0730-725X(91)90094-3

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     Bollmann, S.; Barth, M. New Acquisition Techniques and Their Prospects for the Achievable Resolution of fMRI. Prog. Neurobiol. 2021, 207, 101936,  DOI: 10.1016/j.pneurobio.2020.101936

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     Gore, J. C. Principles and Practice of Functional MRI of the Human Brain. J. Clin. Invest. 2003, 112, 4– 9,  DOI: 10.1172/JCI200319010

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     Huettel, S. A. Event-Related fMRI in Cognition. Neuroimage 2012, 62, 1152– 1156,  DOI: 10.1016/j.neuroimage.2011.08.113

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     Event-related fMRI in cognition

     Huettel Scott A

     NeuroImage (2012), 62 (2), 1152-6 ISSN:.

     A primary advantage of functional magnetic resonance imaging (fMRI) over other techniques in neuroscience is its flexibility. Researchers have used fMRI to study a remarkable diversity of topics, from basic processes of perception and memory, to the complex mechanisms of economic decision making and moral cognition. The chief contributor to this experimental flexibility-indeed, to the growth of fMRI itself-has been the development of event-related experimental designs and associated analyses. The core idea of an event-related design, as first articulated in the late 1990s, is the separation of cognitive processes into discrete points in time (i.e., "events") allowing differentiation of their associated fMRI signals. By modeling brain function as a series of transient changes, rather than as an ongoing state, event-related fMRI allowed researchers to create much more complex paradigms and more dynamic analysis methods. Yet, this flexibility came with a cost. As the complexity of experimental designs increased, fMRI analyses became increasingly abstracted from the original data, which in turn has had consequences both positive (e.g., greater use of model-based fMRI) and negative (e.g., fewer articles plot the timing of activation). And, as event-related methods have become ubiquitous, they no longer represent a distinct category of fMRI research. In a real sense, event-related fMRI has now become, simply, fMRI.
987. 987

     Buckner, R. L.; Koutstaal, W.; Schacter, D. L.; Rosen, B. R. Functional MRI Evidence for a Role of Frontal and Inferior Temporal Cortex in Amodal Components of Priming. Brain 2000, 123, 620– 640,  DOI: 10.1093/brain/123.3.620

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     D’Esposito, M.; Zarahn, E.; Aguirre, G. K. Event-Related Functional MRI: Implications for Cognitive Psychology. Psychol Bull. 1999, 125, 155,  DOI: 10.1037/0033-2909.125.1.155

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     Moerel, M.; Yacoub, E.; Gulban, O. F.; Lage-Castellanos, A.; De Martino, F. Using High Spatial Resolution fMRI to Understand Representation in the Auditory Network. Prog. Neurobiol. 2021, 207, 101887,  DOI: 10.1016/j.pneurobio.2020.101887

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     Toi, P. T.; Jang, H. J.; Min, K.; Kim, S.-P.; Lee, S.-K.; Lee, J.; Kwag, J.; Park, J.-Y. In Vivo Direct Imaging of Neuronal Activity at High Temporospatial Resolution. Science 2022, 378, 160– 168,  DOI: 10.1126/science.abh4340

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     In vivo direct imaging of neuronal activity at high temporospatial resolution

     Toi, Phan Tan; Jang, Hyun Jae; Min, Kyeongseon; Kim, Sung-Phil; Lee, Seung-Kyun; Lee, Jongho; Kwag, Jeehyun; Park, Jang-Yeon

     Science (Washington, DC, United States) (2022), 378 (6616), 160-168CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)

     There has been a long-standing demand for noninvasive neuroimaging methods that can detect neuronal activity at both high temporal and high spatial resoln. We present a two-dimensional fast line-scan approach that enables direct imaging of neuronal activity with millisecond precision while retaining the high spatial resoln. of magnetic resonance imaging (MRI). This approach was demonstrated through in vivo mouse brain imaging at 9.4 T during elec. whisker-pad stimulation. In vivo spike recording and optogenetics confirmed the high correlation of the obsd. MRI signal with neural activity. It also captured the sequential and laminar-specific propagation of neuronal activity along the thalamocortical pathway. This high-resoln., direct imaging of neuronal activity will open up new avenues in brain science by providing a deeper understanding of the brain's functional organization, including the temporospatial dynamics of neural networks.
991. 991

     Cohen, J. D.; Daw, N.; Engelhardt, B.; Hasson, U.; Li, K.; Niv, Y.; Norman, K. A.; Pillow, J.; Ramadge, P. J.; Turk-Browne, N. B. Computational Approaches to fMRI Analysis. Nat. Neurosci. 2017, 20, 304– 313,  DOI: 10.1038/nn.4499

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     Thomas, A. W.; Heekeren, H. R.; Müller, K.-R.; Samek, W. Analyzing Neuroimaging Data Through Recurrent Deep Learning Models. Front. Neurosci. 2019, 13, 1321,  DOI: 10.3389/fnins.2019.01321

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     Kriegeskorte, N.; Mur, M.; Bandettini, P. A. Representational Similarity Analysis-Connecting the Branches of Systems Neuroscience. Front. Sys. Neurosci. 2008, 2, 4,  DOI: 10.3389/neuro.06.004.2008

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     Maloney, R. T. The Basis of Orientation Decoding in Human Primary Visual Cortex: Fine-or Coarse-Scale Biases?. J. Neurophysiol. 2015, 113, 1– 3,  DOI: 10.1152/jn.00196.2014

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     Schuck, N. W.; Niv, Y. Sequential Replay of Nonspatial Task States in the Human Hippocampus. Science 2019, 364, eaaw5181,  DOI: 10.1126/science.aaw5181

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     Wittkuhn, L.; Schuck, N. W. Dynamics of fMRI Patterns Reflect Sub-Second Activation Sequences and Reveal Replay in Human Visual Cortex. Nat. Commun. 2021, 12, 1795,  DOI: 10.1038/s41467-021-21970-2

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     Tang, J.; LeBel, A.; Jain, S.; Huth, A. G. Semantic Reconstruction of Continuous Language from Non-Invasive Brain Recordings. Nat. Neurosci. 2023, 26, 858,  DOI: 10.1038/s41593-023-01304-9

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     Semantic reconstruction of continuous language from non-invasive brain recordings

     Tang, Jerry; LeBel, Amanda; Jain, Shailee; Huth, Alexander G.

     Nature Neuroscience (2023), 26 (5), 858-866CODEN: NANEFN; ISSN:1097-6256. (Nature Portfolio)

     Abstr.: A brain-computer interface that decodes continuous language from non-invasive recordings would have many scientific and practical applications. Currently, however, non-invasive language decoders can only identify stimuli from among a small set of words or phrases. Here we introduce a non-invasive decoder that reconstructs continuous language from cortical semantic representations recorded using functional magnetic resonance imaging (fMRI). Given novel brain recordings, this decoder generates intelligible word sequences that recover the meaning of perceived speech, imagined speech and even silent videos, demonstrating that a single decoder can be applied to a range of tasks. We tested the decoder across cortex and found that continuous language can be sep. decoded from multiple regions. As brain-computer interfaces should respect mental privacy, we tested whether successful decoding requires subject cooperation and found that subject cooperation is required both to train and to apply the decoder. Our findings demonstrate the viability of non-invasive language brain-computer interfaces.
998. 998

     Biswal, B.; Zerrin Yetkin, F.; Haughton, V. M.; Hyde, J. S. Functional Connectivity in the Motor Cortex of Resting Human Brain Using Echo-Planar MRI. Magn. Res. Med. 1995, 34, 537– 541,  DOI: 10.1002/mrm.1910340409

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     Bernstein-Eliav, M.; Tavor, I. The Prediction of Brain Activity from Connectivity: Advances and Applications. Neuroscientist 2024, 30, 367,  DOI: 10.1177/10738584221130974

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      Liu, Y.; Nour, M. M.; Schuck, N. W.; Behrens, T. E.; Dolan, R. J. Decoding Cognition from Spontaneous Neural Activity. Nat. Rev. Neurosci. 2022, 23, 204– 214,  DOI: 10.1038/s41583-022-00570-z

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      Logothetis, N. K.; Pauls, J.; Augath, M.; Trinath, T.; Oeltermann, A. Neurophysiological Investigation of the Basis of the fMRI Signal. Nature 2001, 412, 150– 157,  DOI: 10.1038/35084005

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      Neurophysiological investigation of the basis of the fMRI signal

      Logothetis, Nikos K.; Pauls, Jon; Augath, Mark; Trinath, Torsten; Oettermann, Axel

      Nature (London, United Kingdom) (2001), 412 (6843), 150-157CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

      Functional magnetic resonance imaging (fMRI) is widely used to study the operational organization of the human brain, but the exact relationship between the measured fMRI signal and the underlying neural activity is unclear. Here we present simultaneous intracortical recordings of neural signals and fMRI responses. We compared local field potentials (LFPs), single- and multi-unit spiking activity with highly spatio-temporally resolved blood-oxygen-level-dependent (BOLD) fMRI responses from the visual cortex of monkeys. The largest magnitude changes were obsd. in LFPs, which at recording sites characterized by transient responses were the only signal that significantly correlated with the haemodynamic response. Linear systems anal. on a trial-by-trial basis showed that the impulse response of the neurovascular system is both animal- and site-specific, and that LFPs yield a better est. of BOLD responses than the multi-unit responses. These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output.
1002. 1002

      Attwell, D.; Buchan, A. M.; Charpak, S.; Lauritzen, M.; MacVicar, B. A.; Newman, E. A. Glial and Neuronal Control of Brain Blood Flow. Nature 2010, 468, 232– 243,  DOI: 10.1038/nature09613

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      Glial and neuronal control of brain blood flow

      Attwell, David; Buchan, Alastair M.; Charpak, Serge; Lauritzen, Martin; MacVicar, Brian A.; Newman, Eric A.

      Nature (London, United Kingdom) (2010), 468 (7321), 232-243CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

      Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurol. disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.
1003. 1003

      Tian, P.; Teng, I. C.; May, L. D.; Kurz, R.; Lu, K.; Scadeng, M.; Hillman, E. M.; De Crespigny, A. J.; D’Arceuil, H. E.; Mandeville, J. B. Cortical Depth-Specific Microvascular Dilation Underlies Laminar Differences in Blood Oxygenation Level-Dependent Functional MRI Signal. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 15246– 15251,  DOI: 10.1073/pnas.1006735107

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      Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional mri signal

      Tian, Peifang; Teng, Ivan C.; May, Larry D.; Kurz, Ronald; Lu, Kun; Scadeng, Miriam; Hillman, Elizabeth M. C.; De Crespigny, Alex J.; D'Arceuil, Helen E.; Mandeville, Joseph B.; Marota, John J. A.; Rosen, Bruce R.; Liu, Thomas T.; Boas, David A.; Buxton, Richard B.; Dale, Anders M.; Devor, Anna

      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (34), 15246-15251, S15246/1-S15246/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

      Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diams. of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The obsd. BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.
1004. 1004

      Kok, P.; Bains, L. J.; van Mourik, T.; Norris, D. G.; de Lange, F. P. Selective Activation of the Deep Layers of the Human Primary Visual Cortex by Top-Down Feedback. Curr. Biol. 2016, 26, 371– 376,  DOI: 10.1016/j.cub.2015.12.038

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      Nunes, D.; Gil, R.; Shemesh, N. A Rapid-Onset Diffusion Functional MRI Signal Reflects Neuromorphological Coupling Dynamics. Neuroimage 2021, 231, 117862,  DOI: 10.1016/j.neuroimage.2021.117862

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      Jung, W. B.; Jiang, H.; Lee, S.; Kim, S.-G. Dissection of Brain-Wide Resting-State and Functional Somatosensory Circuits by fMRI with Optogenetic Silencing. Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2113313119,  DOI: 10.1073/pnas.2113313119

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      Lee, J. H.; Liu, Q.; Dadgar-Kiani, E. SOlving Brain Circuit Function and Dysfunction with Computational Modeling and Optogenetic fMRI. Science 2022, 378, 493– 499,  DOI: 10.1126/science.abq3868

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      Solving brain circuit function and dysfunction with computational modeling and optogenetic fMRI

      Lee, Jin Hyung; Liu, Qin; Dadgar-Kiani, Ehsan

      Science (Washington, DC, United States) (2022), 378 (6619), 493-499CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)

      Can we construct a model of brain function that enables an understanding of whole-brain circuit mechanisms underlying neurol. disease and use it to predict the outcome of therapeutic interventions. How are pathologies in neurol. disease, some of which are obsd. to have spatial spreading mechanisms, assocd. with circuits and brain function. In this review, we discuss approaches that have been used to date and future directions that can be explored to answer these questions. By combining optogenetic functional magnetic resonance imaging (fMRI) with computational modeling, cell type-specific, large-scale brain circuit function and dysfunction are beginning to be quant. parameterized. We envision that these developments will pave the path for future therapeutics developments based on a systems engineering approach aimed at directly restoring brain function.
1008. 1008

      Angelovski, G.; Fouskova, P.; Mamedov, I.; Canals, S.; Toth, E.; Logothetis, N. K. Smart Magnetic Resonance Imaging Agents That Sense Extracellular Calcium Fluctuations. ChemBioChem. 2008, 9, 1729– 1734,  DOI: 10.1002/cbic.200800165

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      Smart magnetic resonance imaging agents that sense extracellular calcium fluctuations

      Angelovski, Goran; Fouskova, Petra; Mamedov, Ilgar; Canals, Santiago; Toth, Eva; Logothetis, Nikos K.

      ChemBioChem (2008), 9 (11), 1729-1734CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)

      The synthesis and characterization of 2 novel Gd3+ complexes that exhibit a marked relaxivity response with high selectivity and full reversibility in their interaction with Ca2+ are reported. Physicochem. characterization of both complexes emphasized the high relaxivity changes upon alteration of Ca2+ concn. Their behavior in a biol. relevant medium, model brain extracellular fluid, is extremely promising.
1009. 1009

      Miller, A. D.; Ozbakir, H. F.; Mukherjee, A. Calcium-Responsive Contrast Agents for Functional Magnetic Resonance Imaging. Chem. Phys. Rev. 2021, 2, 021301,  DOI: 10.1063/5.0041394

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      Sorger, B.; Goebel, R. Real-Time fMRI for Brain-Computer Interfacing. Handbook of Clinical Neurology 2020, 168, 289– 302,  DOI: 10.1016/B978-0-444-63934-9.00021-4

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      Shibata, K.; Watanabe, T.; Sasaki, Y.; Kawato, M. Perceptual learning incepted by decoded fMRI neurofeedback without stimulus presentation. Science 2011, 334, 1413– 1415,  DOI: 10.1126/science.1212003

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      Georgiadis, M.; Schroeter, A.; Gao, Z.; Guizar-Sicairos, M.; Liebi, M.; Leuze, C.; McNab, J. A.; Balolia, A.; Veraart, J.; Ades-Aron, B.; Kim, S.; Shepherd, T.; Lee, C. H.; Walczak, P.; Chodankar, S.; DiGiacomo, P.; David, G.; Augath, M.; Zerbi, V.; Sommer, S.; Rajkovic, I.; Weiss, T.; Bunk, O.; Yang, L.; Zhang, J.; Novikov, D. S.; Zeineh, M.; Fieremans, E.; Rudin, M. Nanostructure-Specific X-ray Tomography Reveals Myelin Levels, Integrity and Axon Orientations in Mouse and Human Nervous Tissue. Nat. Commun. 2021, 12, 2941,  DOI: 10.1038/s41467-021-22719-7

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      Georgiadis, M.; Guizar-Sicairos, M.; Zwahlen, A.; Trüssel, A. J.; Bunk, O.; Müller, R.; Schneider, P. 3D Scanning SAXS: A Novel Method for the Assessment of Bone Ultrastructure Orientation. Bone 2015, 71, 42– 52,  DOI: 10.1016/j.bone.2014.10.002

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      3D scanning SAXS: A novel method for the assessment of bone ultrastructure orientation

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