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Heart-on-a-Chip Model with Integrated Extra- and Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology under Acute Hypoxia

  • Haitao Liu
    Haitao Liu
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    School of Materials Science and Technology, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, China University of Geosciences, Beijing 100083, PR China
    More by Haitao Liu
    Orcidhttp://orcid.org/0000-0003-1824-0304
  • , 
  • Olurotimi A. Bolonduro
    Olurotimi A. Bolonduro
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
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  • , 
  • Ning Hu
    Ning Hu
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    State Key Laboratory of Optoelectronic Materials and Technologies, School of Electronics and Information Technology, Guangdong Province Key Laboratory of Display Material and Technology, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou 510275, PR China
    More by Ning Hu
    Orcidhttp://orcid.org/0000-0001-7178-3952
  • , 
  • Jie Ju
    Jie Ju
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    More by Jie Ju
  • , 
  • Akshita A. Rao
    Akshita A. Rao
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
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  • , 
  • Breanna M. Duffy
    Breanna M. Duffy
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
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  • , 
  • Zhaohui Huang
    Zhaohui Huang
    School of Materials Science and Technology, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, China University of Geosciences, Beijing 100083, PR China
    More by Zhaohui Huang
    Orcidhttp://orcid.org/0000-0001-7188-0875
  • , 
  • Lauren D. Black
    Lauren D. Black
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    Department of Cell, Molecular & Developmental Biology, School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United States
    More by Lauren D. Black
    Orcidhttp://orcid.org/0000-0002-7486-5811
  • , and 
  • Brian P. Timko*
    Brian P. Timko
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    *E-mail: [email protected]
    More by Brian P. Timko
    Orcidhttp://orcid.org/0000-0002-7958-8980
Cite this: Nano Lett. 2020, 20, 4, 2585–2593
Publication Date (Web):February 24, 2020
https://doi.org/10.1021/acs.nanolett.0c00076

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Abstract

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We demonstrated a bioelectronic heart-on-a-chip model for studying the effects of acute hypoxia on cardiac function. A microfluidic channel enabled rapid modulation of medium oxygenation, which mimicked the regimes induced by a temporary coronary occlusion and reversibly activated hypoxia-related transduction pathways in HL-1 cardiac model cells. Extracellular bioelectronics provided continuous readouts demonstrating that hypoxic cells experienced an initial period of tachycardia followed by a reduction in beat rate and eventually arrhythmia. Intracellular bioelectronics consisting of Pt nanopillars temporarily entered the cytosol following electroporation, yielding action potential (AP)-like readouts. We found that APs narrowed during hypoxia, consistent with proposed mechanisms by which oxygen deficits activate ATP-dependent K+ channels that promote membrane repolarization. Significantly, both extra- and intracellular devices could be multiplexed, enabling mapping capabilities unachievable by other electrophysiological tools. Our platform represents a significant advance toward understanding electrophysiological responses to hypoxia and could be applicable to disease modeling and drug development.

KEYWORDS:

Cardiovascular disease (CVD) is the leading cause of death worldwide, with CVD due to ischemic disease accounting for a large proportion of the patient population. (1,2) Cardiac ischemia occurs when an artery supplying blood to the heart muscle is partially or fully blocked. This blockage reduces blood flow to downstream muscle, creating a region of hypoxia. If severe or for an extended time, the ischemia can cause myocardial infarction (MI), leading to tissue death, abnormal cardiac electrophysiology, and functional decline. Despite decades of research, deaths due to ischemic heart disease have increased between 1990 and 2013 by 41.7%. (1) Therefore, there is a clear need for improved preclinical models to develop novel therapeutics.

Bioelectrical activity is a critical component of healthy myocardial function, as it is this organized electrical propagation that induces synchronized pumping. It is known that changes in oxygen level in the microcellular environment induce a number of functional responses among cardiomyocytes (CMs), including changes in resting membrane potential, release of neurotransmitters, shifts in gene expression, altered metabolic functions, and activated ion channels. (3−7) Electrical measurement, such as the shape and duration of action potentials (AP), provides key information on the metabolic state, type, and density of various ion channels within a given cell. (8,9) Many of these changes occur rapidly upon induction of hypoxia, requiring continuous and multiplexed measurement strategies that can record cellular electrophysiology in real time. (7) Furthermore, study of AP changes prior to, during, and after a hypoxic event require stable intracellular probing methods. Current preclinical models for cardiovascular disease, including in vitro cell assays and in vivo animal models, allow for limited to no potential to monitor acute intracellular electrical responses to hypoxic stress. Recent heart-on-a-chip models have effectively recapitulated the structure and function of native myocardium (10) including under hypoxia. (11) However, current models for hypoxia do not provide readouts of electrophysiological activity, which changes rapidly during both hypoxia and recovery. Further studies could better inform future therapeutic development through disease modeling and drug screening applications.

The ideal electrophysiological platform should provide stable, multiplexed bioelectronic readouts while exerting minimal disturbances to cellular function. (12) Patch clamp electrophysiology is considered a gold standard for short-term measurements, but patch pipettes are generally difficult to multiplex and moreover present mechanical mismatches with cell membranes that preclude long-term study. Optical imaging using exogenous or genetically encoded dyes offers spatial mapping of AP propagation, but these techniques require instrumentation that precludes continuous, long-term monitoring, and they may be limited in temporal resolution. Bioelectronic devices such as multielectrode arrays (MEAs) (13−15) or field-effect transistors (FETs) (16−18) offer a compelling alternative, providing electrophysiological readouts with high temporal resolution and at multiple length scales, ranging from subcellular to tissue level. In extracellular configurations, these devices record spikes that only approximate the AP. Nevertheless, they are powerful, because they can be readily multiplexed up to a level of thousands of devices (19) and moreover support long-term cultures. For these reasons, extracellular bioelectronics have enabled fundamental insights into cardiac signaling, disease modeling, and pharmacology. More recently, 3D bioprobes including freestanding nanowire-FETs, (20−22) nanopillars, (23,24) nanomushrooms, (25) and nanovolcanoes (26) have been achieved. These structures could stably enter the cytosol following mechanical, electrical, or chemical perturbations, allowing bioelectronic readouts that were similar or identical to the AP.

In this report, we demonstrate a heart-on-a-chip model consisting of a microfluidic channel and cell culture area with integrated extra- or intracellular bioelectronic devices (Figure 1a). The microfluidic channel enabled temporal modulation of medium oxygenation that we could switch between normoxic (21% O2), hypoxic (1–4% O2), and recovery/reperfusion (21% O2) conditions that mimicked coronary occlusion followed by unblocking. (27) As a cell model, we chose immortalized mouse atrial HL-1 cells, which have been used to study cardiac signaling, electrical coupling, and transcriptional regulation. (28) Moreover, HL-1 cells demonstrated similar responses to ischemia and reperfusion as primary cardiomyocytes. (29) The central innovation of our work relates to the bioelectronic interfaces, which provided continuous readouts of cardiac signaling. The multiplexed signals from extracellular devices enabled us to monitor beat rates, rhythmicity, and wavefront propagation velocities, which changed rapidly during hypoxia and recovery. Our intracellular probes consisted of Pt nanopillar arrays that entered the cytosol following localized membrane poration. (23) These devices provided accurate readouts of the cardiac AP, which contained details about ion channel functions that were not available from extracellular measurements but were crucial to understanding adaptive responses to hypoxia. Significantly, these intracellular probes provided both single-cell resolution and multiplexing capabilities, thereby enabling us to observe spatial heterogeneities in cellular function that are innate in biological systems but could not have been readily recorded using other electrophysiological techniques.

Figure 1

Figure 1. Overview of the heart-on-a-chip platform. (a) (top) Optical image and (bottom) scheme representing fully assembled chip with integrated recording elements, reference electrode, and PDMS channel for media delivery. (b) Representative optical image of an extracellular recording element coated with Pt black (red arrow). (c) Representative optical image of an intracellular recording element comprised of an underlying Au pad with five vertical Pt nanopillars (blue arrow). (d) (top) SEM detail of five vertical nanopillars corresponding to the location marked by the blue arrow in panel c. (inset) Schematic representation of a single nanopillar cross section. (bottom) Cross section of a single nanopillar after etching with FIB. Note that the Pt nanopillar fully penetrated the SiO2 layer to form a junction with the underlying Au layer. (e) Immunostaining of the HL-1 cell monolayer cultured in a PDMS channel at 4 DIV showing α-actinin cytoskeleton (green), Cx-43 gap junction proteins (red), and nuclei (blue, DAPI). (f) Stitched immunofluorescence image showing continuous HL-1 monolayer across the lateral direction of the microfluidic channel. Yellow dotted lines denote edges of the PDMS boundary.

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We fabricated extra- or intracellular bioelectronic devices using top-down photolithography and nanofabrication techniques. All devices were fabricated as 2 × 8 element arrays, with 600 or 1000 μm spacing between devices (Figure S1). For extracellular measurements, we fabricated planar electrodes consisting of 30 μm diameter Au pads and interconnects passivated by a 2 μm thick layer of SU-8. We subsequently coated these electrodes with Pt black, which increased the surface area (30) to yield devices with an impedance of ∼20 kΩ (1 kHz) and filtered baseline noise of <20 μVpp (Figure 1b). For intracellular measurements, we fabricated Pt nanopillar arrays, where each nanopillar was 150–200 nm in diameter and 1.5–2.0 μm in height. These nanopillars were fabricated in groups of 5, e.g., 5 nanopillars on each of 16 underlying Au pads, enabling 16 independently addressable intracellular probes. Each underlying Au pad was passivated with a 200 nm insulating SiO2 layer; we then used focused ion beam (FIB) to mill holes through the passivation followed by Pt deposition. (23) We chose that strategy to ensure that only the nanopillar portion of the device—that is, the portion that could access the intercellular space—would form a bioelectronic interface. A cross section view achieved by FIB/SEM confirmed that the nanopillars fully penetrated the SiO2 layer to make electrical contact with the underlying Au layer (Figure 1d). We also performed electrical impedance measurements to verify the electrical integrity of our SiO2 layer; our nanopillar arrays had impedances of ∼300 kΩ (1 kHz), which was much larger than we recorded for planar devices and consistent with our expectation of a much smaller unpassivated surface area: 4–6 μm2 compared to ∼700 μm2 for planar devices (Figure S2).

We next fabricated fluidic device assemblies by permanently bonding a poly(dimethylsiloxane) (PDMS) channel layer onto the surface of our bioelectronic device chips (Figure 1a). These channels were coated with fibronectin and then seeded with HL-1 cells. After seeding, we flowed medium at a rate of 40 μL/h, which provided sufficient nutrient and oxygen delivery to support a healthy cell culture. (30,31) HL-1 cells demonstrate pacemaker activity; (32) we found that by 3–4 days in vitro (DIV), our cells formed confluent monolayers that beat spontaneously (Movie S1). Immunohistochemistry demonstrated well-defined actinin filaments and significant connexin-43 protein expression, which are associated with cytoskeletal mechanics and electrical coupling, respectively (Figure 1e,f). Generally, connexin-43 proteins were distributed uniformly across cell membranes, which is consistent with other works involving HL-1 cells (33) and attributed to the relatively early stage in culture; we however did note several locations where these proteins were localized at cell–cell junctions as is typical of primary CMs (Figure S3). Our platform maintained healthy cultures for at least 7 DIV.

Cells undergo an adaptive response when exposed to acute hypoxic stress where hypoxia-inducible factor-1-alpha (HIF-1α), a transcriptional regulator, activates in order to increase oxygen delivery and facilitate metabolic adaptation to hypoxia. (34) At the onset of mild hypoxia, HIF-1α translocates into the nucleus, where it binds the HIF-1β subunit and upregulates the relevant genes. (35,36) To assess the ability of our platform activate these signaling pathways, we exposed HL-1 cells at 4 DIV to hypoxic medium (1% O2) for up to 5 h. Immunostaining revealed that by 2.5 h, HIF-1α was strongly expressed and had localized in the nucleus (Figure S4a). This expression was constant throughout the remainder of the hypoxic episode. However, upon applying a normoxic recovery medium for 90 min, HIF-1α returned to basal levels (Figure S4b); HIF-1α degrades with a <5 min half-life posthypoxia. (37) These results demonstrate the ability of our platform to model normoxia, hypoxia, and early stages of recovery.

To validate the ability of our platform to achieve bioelectronic readouts, we first monitored electrophysiology using extracellular electrodes, which yielded ≥85% functional bioelectronic interfaces and enabled continuous recording over the course of the experiment. Prior to inducing hypoxic stress, HL-1 cells beat with a frequency of 3.0 ± 0.5 Hz across N = 8 distinct cultures, consistent with previously reported results for HL-1 cultures in static conditions. (32) To induce a period of acute hypoxia, we switched normoxic media with hypoxic (1% O2) media for 5 h, according to the protocol depicted schematically in Figure 2a. These conditions induced an initial period of tachycardia, with beating frequency increasing from 3.2 to 4.2 Hz, followed by a gradual reduction in frequency until arrhythmia with much longer firing intervals, 4.9 ± 1.5 s. In a separate culture (Figure S5), we induced ischemia gradually by first perfusing 4% O2 medium for 20 min before further reducing O2 to 1%. In that case, we also observed tachycardia, albeit at a slower rate of increase before cresting and then returning to basal. Similar electrophysiological patterns—that is, hypoxia-induced tachycardia followed by a decrease in beat rate to below basal—were also observed in primary murine CMs that were exposed to hypoxic media in static conditions. (38) Arrhythmia is also a symptom of ischemia. (39) We maintained hypoxia for either 5.5 h (Figure 2a) or 20 h (Figure S5); in both cases, rhythmic beating recovered within 30 min after reintroducing normoxic media. The tachycardia present at that time is consistent with reperfusion injury, which is common following ischemia. (40)

Figure 2

Figure 2. Extracellular bioelectronic readouts before, during, and after hypoxia. (a) (top) Scheme of media delivery protocol with distinct regions of normoxia, hypoxia, and recovery and (bottom) HL-1 firing rate. The red dotted box highlights the transition from rhythmic beating to arrhythmia. (b) Representative signals from a single device recorded during (I) normoxia, (II) hypoxia, upon onset of arrhythmia, and (III) recovery. These traces correspond to the points noted in panel a. (inset) Single peak expansions of (black) overlaid individual traces and (red) average of individual traces. (c) Scheme of electrode layout (black dots) and representative multiplexed readouts from a chip with 14 out of 16 functional bioelectronic interfaces. (d,e) Isochronal maps representing signal propagation at two time points each during (d) normoxia and (e) hypoxia for ∼1 h. Black arrow overlays represent the gradient of the isochrones. The area of each map is 1000 μm wide × 4200 μm tall.

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The high yield of multiplexed readouts enabled us to further assess cell–cell communication. Figure 2c shows typical signals from a chip with 14 out of 16 functioning bioelectronic interfaces. Cross-correlation analysis enabled us to construct isochronal maps that provided information about wavefront propagation velocities. We found that under normoxia, wavefronts propagated uniformly with an average speed of 18.9 ± 5.0 mm/s, which is typical for HL-1 cells. (41) These characteristics were stable: another data set collected 10 min later showed a nearly identical propagation pattern and speed, 19.3 ± 5.0 mm/s (Figure 2d). In contrast, 1% O2 hypoxia for 1 h resulted in turbid propagation patterns that changed significantly between successive analyses performed 10 min apart (Figure 2e). We also found that the average propagation speeds were reduced to 11.9 ± 11.0 and 13.3 ± 8.5 mm/s at the two time points shown. While these data represent snapshots at just four time points, we emphasize that they are representative of 6 time points analyzed during normoxia and 14 during a 5 h hypoxic episode. We found that propagation speeds became progressively slower over the course of hypoxia, and normoxic and hypoxic data sets were significantly different (p < 0.001, Welch’s t test) (Figure S6). Collectively, these characteristics—tachycardia, arrhythmia, and reduced propagation velocities—are consistent with cardiac responses to hypoxia, whereby excitation thresholds are decreased and Cx-43 gap junction expression is diminished, leading to reentrant arrhythmias and an increase in tissue impedance. (39) Our results demonstrate the ability of our platform to achieve ischemia-like conditions and moreover establish a time frame for hypoxic responses.

We next sought to achieve intracellular readouts from our microfluidic platform using Pt nanopillar electrodes as shown in Figures 1c,d and S1b. Prior to electroporation, nanopillars recorded extracellular signals with an average magnitude of ∼60 μV and baseline noise of 20 μVpp (Figure 3a). Immediately following electroporation (3 Vpp, 200 μs biphasic square pulses for 2–3 s), we found that nanopillar electrodes recorded intracellular signals with an initial magnitude of 2.3 mV (Figure 3b). The signal shape resembled that of a slow AP, with well-defined rising (phase 0) and falling (phase 3) edges consistent with inward Ca2+ and outward K+ currents, respectively, followed by a refractory period and resting phase (phase 4). These characteristics are consistent with previous reports (8,23) and moreover expected given that HL-1 cells are derived from atrial cardiomyocytes. (42,43) We observed intracellular signals for at least 10 min following electroporation, and we found that their amplitude decreased to ∼7% of the initial value during that time, consistent with sealing of the transient pores. (23) However, both the AP duration at 50% repolarization (APD50) as well as signal shape remained constant during that period (Figure 3c–e).

Figure 3

Figure 3. Electrophysiology using nanopillar electrodes in normoxic media. (a) Representative extracellular signal recorded prior to electroporation. Inset shows expansion of single representative peak. (b) Intracellular signals recorded immediately after electroporation. (c) (blue square) Normalized action potential amplitude and (red circle) APD50 as a function of time after electroporation. Within 2 min, the amplitude of the action potentials decreased to around 24% of the maximum, while APD50 was unchanged. (d) Expansions of peaks shown in panel b at locations noted by red, blue, and yellow arrows, plotted on (left) absolute and (right) normalized scales. Note that the baseline of these peaks is offset for clarity.

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To analyze the intracellular electrophysiology of HL-1 cells under hypoxia, we investigated the APD50, AP duration at 90% repolarization (APD90), and depolarization time (Figure 4a). We chose to study these parameters under normoxia (0 h) and at three time points under 1% O2 hypoxia (2, 4, and 6 h) given the time course of responses observed with extracellular readouts. By the 6 h time point, our intracellular probes recorded arrhythmia with long firing intervals (Figure 4b) similar to those shown in Figure 2b,II. We observed a substantial reduction in mean APD50 (−46%), APD90 (−34%), and depolarization time (−44%) by the 2 h time point, which persisted through 4 and 6 h (Figure 4d–g). These changes are expected given that we also observed HIF-1α activation by 2 h as shown in Figure S4. AP shortening is also expected given that hypoxia lowers intracellular ATP and activates ATP-dependent potassium channels, which promote membrane repolarization. (44)

Figure 4

Figure 4. Intracellular electrophysiology of HL-1 cells during 1% O2 hypoxic stress. (a) Schematic representation of typical HL-1 AP highlighting key parameters. (b) Intracellular recording showing arrhythmic beating after 6 h of hypoxic stress. (c) Representative examples of AP recordings following 0, 2, 4, or 6 h of hypoxic stress. Note that the 0 h time point represents normoxia. (d–f) Summary statistics representing (d) APD50, (e) APD90, and (f) depolarization time corresponding to each time point represented in panel c. (g) Percentage change for APD50, APD90, and depolarization time throughout hypoxia. Statistics are from N = 14 different cells in 4 different cultures. *P < 0.05, **P < 0.01, ***P < 0.0005, ****P < 0.0001 in Welch’s t test. All error bars denote s.d.

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A distinct advantage of our nanopillar approach is that it not only enables accurate AP measurements but also does so at the single-cell level. This functionality opens avenues to spatially map intracellular features within the same sample, thereby providing insights into heterogeneities that would not be revealed by lower-resolution or ensemble techniques. To explore this possibility, we recorded intracellular signals from five devices simultaneously, under normoxia or after 2 h of exposure to hypoxia (1% O2), as shown in Figure 5a. Propagation maps of signals along these linear device arrays showed qualitative characteristics similar to those presented in Figure 2, with uniform propagation in the normoxic sample compared to nonuniform propagation in the hypoxic sample. The corresponding propagation speeds are 22.7 ± 0.6 and 27.3 ± 5.2 mm/s, respectively (Figure 5b). (45) Heat maps representing the electrophysiological properties of each trace demonstrate that APD50, APD90, and depolarization time generally decrease with hypoxia (Figure 5c), consistent with the statistical analysis presented in Figure 4. Interestingly, however, each group includes one clear outlier: an abnormally short AP in the normoxia group and an abnormally long AP in the hypoxia group. These outliers represent the innate variabilities in biological systems: for example, HL-1 cells exhibit substantial phenotypic/electrophysiological variability, (46,47) while nuclear HIF-1α is activated nonuniformly, particularly at early stages of hypoxia. (48) Similar variability gradients have been observed among and within clusters of human embryonic stem-cell-derived cardiac cell clusters, using optical dyes. (49)

Figure 5

Figure 5. Multiplexed intracellular recordings. (a) Representative APs simultaneously recorded under (left) normoxia and (right) hypoxia after 2 h. The color-coded legend represents the corresponding device arrangement; spacing between devices is 600 μm. (b) Propagation maps correlating to each trace and spatial location shown in panels a and b. Each map is 3600 μm tall and represents propagation along the direction of the linear device array. (c) Heat maps representing APD50, APD90, and depolarization time corresponding to each trace and spatial location shown in panels a and b.

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We have demonstrated an ischemia-on-a-chip model with integrated extra- or intracellular bioelectronic devices. These devices provided electrophysiological readouts with complementary attributes: extracellular devices recorded stable signals with high device yield, which enabled us to continuously monitor beat frequency and wavefront propagation, while intracellular devices provided accurate recordings of the AP. While this work focused solely on the effects of hypoxia, other factors that are relevant to ischemia including acidosis, hyperkalemia, nutrient deprivation, and waste accumulation (27) could be incorporated into the model by modulating the composition or flow of the medium. Our proof-of-concept multiplexing capabilities—limited to 16 devices here—could also be extended to much larger or denser arrays. For example, >1000-element nanoelectrode arrays capable of parallel, network-level intracellular recording from CMs (50) and connected neurons (51) have been demonstrated. Improvements upon our nanofabrication techniques to achieve probes with nanoscale concavities, (25) smaller diameters, (20−22) and/or biochemical (26,52) surface ligands could promote membrane integration and yield more stable and long-term intracellular recordings. We could also adapt our platform to include 3D cardiac tissue constructs with embedded bioelectronic devices, (14,18,53) which would more adequately recapitulate endogenous tissues. The distinct advantages of our platform could be applicable to a wide variety of conditions relevant to hypoxia or ischemia. For example, multiplexed outputs are relevant to assessing responses to oxygen concentration gradients and borderzone infarcts, while continuous, real-time readouts are relevant to understanding the rapid changes that occur during reperfusion injuries. Further studies could yield fundamental insights into cardiac signaling pathways or provide a high-throughput platform for assessing therapeutics.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.nanolett.0c00076.

  • Movie S1. Spontaneous beating of cells that formed confluent monolayers (MP4)

  • Materials and Methods; Scheme S1. Illustration of microfluidic chip with integrated nanopillar microelectrode arrays; Scheme S2. Strategy to generate hypoxic medium flow; Figure S1. Design of MEA devices; Figure S2. Representative electrical impedance spectra of planar and nanopillar bioelectronic devices; Figure S3. Gap junction localization; Figure S4. HIF-1α validation of heart-on-a-chip; Figure S5. Extracellular bioelectronic readouts before, during, and after hypoxia; Figure S6. Summary of wavefront propagation speeds derived from isochronal map (PDF)

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  • Corresponding Author
  • Authors
    • Haitao Liu - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States;  School of Materials Science and Technology, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, China University of Geosciences, Beijing 100083, PR China;  Orcidhttp://orcid.org/0000-0003-1824-0304
    • Olurotimi A. Bolonduro - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    • Ning Hu - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States;  State Key Laboratory of Optoelectronic Materials and Technologies, School of Electronics and Information Technology, Guangdong Province Key Laboratory of Display Material and Technology, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou 510275, PR China;  Orcidhttp://orcid.org/0000-0001-7178-3952
    • Jie Ju - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    • Akshita A. Rao - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    • Breanna M. Duffy - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    • Zhaohui Huang - School of Materials Science and Technology, Beijing Key Laboratory of Materials Utilization of Nonmetallic Minerals and Solid Wastes, National Laboratory of Mineral Materials, China University of Geosciences, Beijing 100083, PR China;  Orcidhttp://orcid.org/0000-0001-7188-0875
    • Lauren D. Black - Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States;  Department of Cell, Molecular & Developmental Biology, School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United States;  Orcidhttp://orcid.org/0000-0002-7486-5811
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by a Tufts Collaborates grant (to B.P.T.), a Tufts Research Advancement Fund award (to B.P.T.), a Department of Defense Grant W81XWH-16-1-0304 (to L.D.B.), an American Heart Association Grant-in-Aid Award 16GRNT27760100 (to L.D.B.), a Student National Scholarship (to H.L.), and a China National Scholarship (to N.H). This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award no. 1541959. CNS is part of Harvard University.

Abbreviations

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AP

action potential

APD50

action potential duration, 50% repolarization

APD90

action potential duration, 90% repolarization

CM

cardiomyocyte

DIV

days in vitro

FIB

focused ion beam

HIF-1α

hypoxia-inducible factor-1α

MEA

mutielectrode array

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    Journal of Biological Chemistry (1998), 273 (19), 11619-11624CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Cardiomyocytes suppress contraction and O2 consumption during hypoxia. Cytochrome oxidase undergoes a decrease in Vmax during hypoxia, which could alter mitochondrial redox and increase generation of reactive oxygen species (ROS). We therefore tested whether ROS generated by mitochondria act as second messengers in the signaling pathway linking the detection of O2 with the functional response. Contracting cardiomyocytes were superfused under controlled O2 conditions while fluorescence imaging of 2,7-dichlorofluorescein (DCF) was used to assess ROS generation. Compared with normoxia (PO2∼107 torr, 15% O2), graded increases in DCF fluorescence were seen during hypoxia, with responses at PO2 = 7 torr > 20 torr > 35 torr. The antioxidants 2-mercaptopropionyl glycine and 1,10-phenanthroline attenuated these increases and abolished the inhibition of contraction. Superfusion of normoxic cells with H2O2 (25 μM) for >60 min mimicked the effects of hypoxia by eliciting decreases in contraction that were reversible after washout of H2O2. To test the role of cytochrome oxidase, sodium azide (0.75-2 μM) was added during normoxia to reduce the Vmax of the enzyme. Azide produced graded increases in ROS signaling, accompanied by graded decreases in contraction that were reversible. These results demonstrate that mitochondria respond to graded hypoxia by increasing the generation of ROS and suggest that cytochrome oxidase may contribute to this O2 sensing.
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  4. 4
    Dutta, S.; Minchole, A.; Quinn, T. A.; Rodriguez, B. Electrophysiological properties of computational human ventricular cell action potential models under acute ischemic conditions. Prog. Biophys. Mol. Biol. 2017, 129, 40– 52,  DOI: 10.1016/j.pbiomolbio.2017.02.007
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    4
    Electrophysiological properties of computational human ventricular cell action potential models under acute ischemic conditions
    Dutta Sara; Minchole Ana; Rodriguez Blanca; Quinn T Alexander
    Progress in biophysics and molecular biology (2017), 129 (), 40-52 ISSN:.
    Acute myocardial ischemia is one of the main causes of sudden cardiac death. The mechanisms have been investigated primarily in experimental and computational studies using different animal species, but human studies remain scarce. In this study, we assess the ability of four human ventricular action potential models (ten Tusscher and Panfilov, 2006; Grandi et al., 2010; Carro et al., 2011; O'Hara et al., 2011) to simulate key electrophysiological consequences of acute myocardial ischemia in single cell and tissue simulations. We specifically focus on evaluating the effect of extracellular potassium concentration and activation of the ATP-sensitive inward-rectifying potassium current on action potential duration, post-repolarization refractoriness, and conduction velocity, as the most critical factors in determining reentry vulnerability during ischemia. Our results show that the Grandi and O'Hara models required modifications to reproduce expected ischemic changes, specifically modifying the intracellular potassium concentration in the Grandi model and the sodium current in the O'Hara model. With these modifications, the four human ventricular cell AP models analyzed in this study reproduce the electrophysiological alterations in repolarization, refractoriness, and conduction velocity caused by acute myocardial ischemia. However, quantitative differences are observed between the models and overall, the ten Tusscher and modified O'Hara models show closest agreement to experimental data.
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  5. 5
    Nakada, Y.; Canseco, D. C.; Thet, S.; Abdisalaam, S.; Asaithamby, A.; Santos, C. X.; Shah, A. M.; Zhang, H.; Faber, J. E.; Kinter, M. T.; Szweda, L. I.; Xing, C.; Hu, Z.; Deberardinis, R. J.; Schiattarella, G.; Hill, J. A.; Oz, O.; Lu, Z.; Zhang, C. C.; Kimura, W.; Sadek, H. A. Hypoxia induces heart regeneration in adult mice. Nature 2017, 541 (7636), 222– 227,  DOI: 10.1038/nature20173
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    5
    Hypoxia induces heart regeneration in adult mice
    Nakada, Yuji; Canseco, Diana C.; Thet, SuWannee; Abdisalaam, Salim; Asaithamby, Aroumougame; Santos, Celio X.; Shah, Ajay M.; Zhang, Hua; Faber, James E.; Kinter, Michael T.; Szweda, Luke I.; Xing, Chao; Hu, Zeping; Deberardinis, Ralph J.; Schiattarella, Gabriele; Hill, Joseph A.; Oz, Orhan; Lu, Zhigang; Zhang, Cheng Cheng; Kimura, Wataru; Sadek, Hesham A.
    Nature (London, United Kingdom) (2017), 541 (7636), 222-227CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 wk, results in inhibition of oxidative metab., decreased reactive oxygen species prodn. and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxemia 1 wk after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping anal. confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.
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  6. 6
    Kubasiak, L. A.; Hernandez, O. M.; Bishopric, N. H.; Webster, K. A. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (20), 12825– 12830,  DOI: 10.1073/pnas.202474099
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    6
    Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3
    Kubasiak, Lori A.; Hernandez, Olga M.; Bishopric, Nanette H.; Webster, Keith A.
    Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (20), 12825-12830CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Coronary artery disease leads to injury and loss of myocardial tissue by deprivation of blood flow (ischemia) and is a major underlying cause of heart failure. Prolonged ischemia causes necrosis and apoptosis of cardiac myocytes and vascular cells; however, the mechanisms of ischemia-mediated cell death are poorly understood. Ischemia is assocd. with both hypoxia and acidosis due to increased glycolysis and lactic acid prodn. We recently reported that hypoxia does not induce cardiac myocyte apoptosis in the absence of acidosis. We now report that hypoxia-acidosis-assocd. cell death is mediated by BNIP3, a member of the Bcl-2 family of apoptosis-regulating proteins. Chronic hypoxia induced the expression and accumulation of BNIP3 mRNA and protein in cardiac myocytes, but acidosis was required to activate the death pathway. Acidosis stabilized BNIP3 protein and increased the assocn. with mitochondria. Cell death by hypoxia-acidosis was blocked by pretreatment with antisense BNIP3 oligonucleotides. The pathway included extensive DNA fragmentation and opening of the mitochondrial permeability transition pore, but no apparent caspase activation. Overexpression of wild-type BNIP3, but not a translocation-defective mutant, activated cardiac myocyte death only when the myocytes were acidic. This pathway may figure significantly in muscle loss during myocardial ischemia.
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  7. 7
    Martewicz, S.; Michielin, F.; Serena, E.; Zambon, A.; Mongillo, M.; Elvassore, N. Reversible alteration of calcium dynamics in cardiomyocytes during acute hypoxia transient in a microfluidic platform. Integrative Biology 2012, 4 (2), 153– 164,  DOI: 10.1039/C1IB00087J
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    7
    Reversible alteration of calcium dynamics in cardiomyocytes during acute hypoxia transient in a microfluidic platform
    Martewicz, S.; Michielin, F.; Serena, E.; Zambon, A.; Mongillo, M.; Elvassore, N.
    Integrative Biology (2012), 4 (2), 153-164CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)
    Heart disease is the leading cause of mortality in western countries. Apart from congenital and anatomical alterations, ischemia is the most common agent causing myocardial damage. During ischemia, a sudden decrease in oxygen concn. alters cardiomyocyte function and compromises cell survival. The calcium handling machinery, which regulates the main functional features of a cardiomyocyte, is heavily compromised during acute hypoxic events. Alterations in calcium dynamics have been linked to both short- and long-term consequences of ischemia, ranging from arrhythmias to heart failure. In this perspective, we aimed at investigating the calcium dynamics in functional cardiomyocytes during the early phase of a hypoxic event. For this purpose, we developed a microfluidic system specifically designed for controlling fast oxygen concn. dynamics through a gas micro-exchanger allowing in line anal. of intracellular calcium concn. by confocal microscopy. Exptl. results show that exposure of Fluo-4 loaded neonatal rat cardiomyocytes to hypoxic conditions induced changes in intracellular Ca2+ transients. Such behavior was reversible and was detected for hypoxic levels below 5% of oxygen partial pressure. The obsd. changes in Ca2+ dynamics were mimicked using specific L-type Ca2+ channel antagonists, suggesting that alterations in calcium channel function occur at low oxygen levels. Reversible alteration in ion channel function, that takes place in response to changes in cellular oxygen, might represent an adaptive mechanism of cardiopreservation during ischemia.
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  8. 8
    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.
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  9. 9
    Zhu, Z.; Burnett, C. M.; Maksymov, G.; Stepniak, E.; Sierra, A.; Subbotina, E.; Anderson, M. E.; Coetzee, W. A.; Hodgson-Zingman, D. M.; Zingman, L. V. Reduction in number of sarcolemmal KATP channels slows cardiac action potential duration shortening under hypoxia. Biochem. Biophys. Res. Commun. 2011, 415 (4), 637– 641,  DOI: 10.1016/j.bbrc.2011.10.125
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    9
    Reduction in number of sarcolemmal KATP channels slows cardiac action potential duration shortening under hypoxia
    Zhu, Zhiyong; Burnett, Colin M.-L.; Maksymov, Gennadiy; Stepniak, Elizabeth; Sierra, Ana; Subbotina, Ekaterina; Anderson, Mark E.; Coetzee, William A.; Hodgson-Zingman, Denice M.; Zingman, Leonid V.
    Biochemical and Biophysical Research Communications (2011), 415 (4), 637-641CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (KATP) channels. KATP channel expression has a significant physiol. impact on action potential duration shortening and myocardial energy consumption in response to physiol. heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant neg. KATP channel subunit were compared with littermate controls. Evaluation of KATP channel whole cell current and channel no./patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80-85% redn. in cardiac KATP channel c.d. results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the no. of functional cardiac sarcolemmal KATP channels is a crit. determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.
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  10. 10
    Ribas, J.; Sadeghi, H.; Manbachi, A.; Leijten, J.; Brinegar, K.; Zhang, Y. S.; Ferreira, L.; Khademhosseini, A. Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development. Appl. In Vitro Toxicol 2016, 2 (2), 82– 96,  DOI: 10.1089/aivt.2016.0002
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    10
    Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development
    Ribas Joao; Sadeghi Hossein; Manbachi Amir; Leijten Jeroen; Brinegar Katelyn; Zhang Yu Shrike; Khademhosseini Ali; Ribas Joao; Sadeghi Hossein; Manbachi Amir; Leijten Jeroen; Brinegar Katelyn; Zhang Yu Shrike; Khademhosseini Ali; Ribas Joao; Sadeghi Hossein; Leijten Jeroen; Ferreira Lino; Ferreira Lino; Khademhosseini Ali; Khademhosseini Ali; Khademhosseini Ali
    Applied in vitro toxicology (2016), 2 (2), 82-96 ISSN:2332-1512.
    Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human in vivo dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system-in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development.
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  11. 11
    Kang, Y. B. A.; Eo, J.; Bulutoglu, B.; Yarmush, M. L.; Usta, O. B. Progressive hypoxia-on-a-chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease. Biotechnol. Bioeng. 2020, 117, 763,  DOI: 10.1002/bit.27225
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    11
    Progressive hypoxia-on-a-chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease
    Kang, Young Bok; Eo, Jinsu; Bulutoglu, Beyza; Yarmush, Martin L.; Usta, O. Berk
    Biotechnology and Bioengineering (2020), 117 (3), 763-775CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)
    Oxygen is vital to the function of all tissues including the liver and lack of oxygen, i.e., hypoxia can result in both acute and chronic injuries to the liver in vivo and ex vivo. Furthermore, a permanent oxygen gradient is naturally present along the liver sinusoid, which plays a role in the metabolic zonation and the pathophysiol. of liver diseases. Accordingly, here, we introduce an in vitro microfluidic platform capable of actively creating a series of oxygen concns. on a single continuous microtissue, ranging from normoxia to severe hypoxia. This range approx. captures both the physiol. relevant oxygen gradient generated from the portal vein to the central vein in the liver, and the severe hypoxia occurring in ischemia and liver diseases. Primary rat hepatocytes cultured in this microfluidic platform were exposed to an oxygen gradient of 0.3-6.9%. The establishment of an ascending hypoxia gradient in hepatocytes was confirmed in response to the decreasing oxygen supply. The hepatocyte viability in this platform decreased to approx. 80% along the hypoxia gradient. Simultaneously, a progressive increase in accumulation of reactive oxygen species and expression of hypoxia-inducible factor 1a was obsd. with increasing hypoxia. These results demonstrate the induction of distinct metabolic and genetic responses in hepatocytes upon exposure to an oxygen (/hypoxia) gradient. This progressive hypoxia-on-a-chip platform can be used to study the role of oxygen and hypoxia-assocd. mols. in modeling healthy and injured liver tissues. Its use can be further expanded to the study of other hypoxic tissues such as tumors as well as the investigation of drug toxicity and efficacy under oxygen-limited conditions.
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  12. 12
    Bolonduro, O. A.; Duffy, B. M.; Rao, A. A.; Black, L. D.; Timko, B. P. From Biomimicry to Bioelectronics: Smart Materials for Cardiac Tissue Engineering. Nano Res. 2020  DOI: 10.1007/s12274-020-2682-3 .
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    Spira, M. E.; Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 2013, 8 (2), 83– 94,  DOI: 10.1038/nnano.2012.265
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    13
    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.
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  14. 14
    Feiner, R.; Engel, L.; Fleischer, S.; Malki, M.; Gal, I.; Shapira, A.; Shacham-Diamand, Y.; Dvir, T. Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function. Nat. Mater. 2016, 15 (6), 679– 85,  DOI: 10.1038/nmat4590
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    14
    Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function
    Feiner, Ron; Engel, Leeya; Fleischer, Sharon; Malki, Maayan; Gal, Idan; Shapira, Assaf; Shacham-Diamand, Yosi; Dvir, Tal
    Nature Materials (2016), 15 (6), 679-685CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, freestanding electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular elec. activities and the on-demand provision of elec. stimulation for synchronizing cell contraction. We also show that electroactive polymers contg. biol. factors can be deposited on designated electrodes to release drugs in the patch microenvironment on demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function.
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  15. 15
    Xu, L.; Gutbrod, S. R.; Bonifas, A. P.; Su, Y.; Sulkin, M. S.; Lu, N.; Chung, H. J.; Jang, K. I.; Liu, Z.; Ying, M.; Lu, C.; Webb, R. C.; Kim, J. S.; Laughner, J. I.; Cheng, H.; Liu, Y.; Ameen, A.; Jeong, J. W.; Kim, G. T.; Huang, Y.; Efimov, I. R.; Rogers, J. A. 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat. Commun. 2014, 5, 3329,  DOI: 10.1038/ncomms4329
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    15
    3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium
    Xu Lizhi; Gutbrod Sarah R; Bonifas Andrew P; Jang Kyung-In; Ying Ming; Lu Chi; Webb R Chad; Liu Yuhao; Ameen Abid; Jeong Jae-Woong; Kim Gwang-Tae; Rogers John A; Su Yewang; Sulkin Matthew S; Laughner Jacob I; Efimov Igor R; Lu Nanshu; Chung Hyun-Joong; Liu Zhuangjian; Kim Jong-Seon; Cheng Huanyu; Huang Yonggang
    Nature communications (2014), 5 (), 3329 ISSN:.
    Means for high-density multiparametric physiological mapping and stimulation are critically important in both basic and clinical cardiology. Current conformal electronic systems are essentially 2D sheets, which cannot cover the full epicardial surface or maintain reliable contact for chronic use without sutures or adhesives. Here we create 3D elastic membranes shaped precisely to match the epicardium of the heart via the use of 3D printing, as a platform for deformable arrays of multifunctional sensors, electronic and optoelectronic components. Such integumentary devices completely envelop the heart, in a form-fitting manner, and possess inherent elasticity, providing a mechanically stable biotic/abiotic interface during normal cardiac cycles. Component examples range from actuators for electrical, thermal and optical stimulation, to sensors for pH, temperature and mechanical strain. The semiconductor materials include silicon, gallium arsenide and gallium nitride, co-integrated with metals, metal oxides and polymers, to provide these and other operational capabilities. Ex vivo physiological experiments demonstrate various functions and methodological possibilities for cardiac research and therapy.
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  16. 16
    Timko, B. P.; Cohen-Karni, T.; Yu, G.; Qing, Q.; Tian, B.; Lieber, C. M. Electrical recording from hearts with flexible nanowire device arrays. Nano Lett. 2009, 9 (2), 914– 8,  DOI: 10.1021/nl900096z
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    16
    Electrical Recording from Hearts with Flexible Nanowire Device Arrays
    Timko, Brian P.; Cohen-Karni, Tzahi; Yu, Guihua; Qing, Quan; Tian, Bozhi; Lieber, Charles M.
    Nano Letters (2009), 9 (2), 914-918CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    The authors show that nanowire field-effect transistor (NWFET) arrays fabricated on both planar and flexible polymeric substrates can be reproducibly interfaced with spontaneously beating embryonic chicken hearts in both planar and bent conformations. Simultaneous recordings from glass microelectrode and NWFET devices show that NWFET conductance variations are synchronized with the beating heart. The conductance change assocd. with beating can be tuned substantially by device sensitivity, although the voltage-calibrated signals, 4-6 mV, are relatively const. and typically larger than signals recorded by microelectrode arrays. Multiplexed recording from NWFET arrays yielded signal propagation times across the myocardium with high spatial resoln. The transparent and flexible NWFET chips also enable simultaneous elec. recording and optical registration of devices to heart surfaces in three-dimensional conformations not possible with planar microdevices. The capability of simultaneous optical imaging and elec. recording also could be used to register devices to a specific region of the myocardium at the cellular level, and more generally, NWFET arrays fabricated on increasingly flexible plastic and/or biopolymer substrates have the potential to become unique tools for elec. recording from other tissue/organ samples or as powerful implants.
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  17. 17
    Cohen-Karni, T.; Timko, B. P.; Weiss, L. E.; Lieber, C. M. Flexible electrical recording from cells using nanowire transistor arrays. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (18), 7309– 13,  DOI: 10.1073/pnas.0902752106
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    17
    Flexible electrical recording from cells using nanowire transistor arrays
    Cohen-Karni, Tzahi; Timko, Brian P.; Weiss, Lucien E.; Lieber, Charles M.
    Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (18), 7309-7313CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Semiconductor nanowires (NWs) have unique electronic properties and sizes comparable with biol. structures involved in cellular communication, thus making them promising nanostructures for establishing active interfaces with biol. systems. We report a flexible approach to interface NW field-effect transistors (NWFETs) with cells and demonstrate this for silicon NWFET arrays coupled to embryonic chicken cardiomyocytes. Cardiomyocyte cells were cultured on thin, optically transparent polydimethylsiloxane (PDMS) sheets and then brought into contact with Si-NWFET arrays fabricated on std. substrates. NWFET conductance signals recorded from cardiomyocytes exhibited excellent signal-to-noise ratios with values routinely > 5 and signal amplitudes that were tuned by varying device sensitivity through changes in water gate-voltage potential, Vg. Signals recorded from cardiomyocytes for Vg from -0.5 to +0.1 V exhibited amplitude variations from 31 to 7 nS whereas the calibrated voltage remained const., indicating a robust NWFET/cell interface. In addn., signals recorded as a function of increasing/decreasing displacement of the PDMS/cell support to the device chip showed a reversible >2× increase in signal amplitude (calibrated voltage) from 31 nS (1.0 mV) to 72 nS (2.3 mV). Studies with the displacement close to but below the point of cell disruption yielded calibrated signal amplitudes as large as 10.5 ± 0.2 mV. Last, multiplexed recording of signals from NWFET arrays interfaced to cardiomyocyte monolayers enabled temporal shifts and signal propagation to be detd. with good spatial and temporal resoln. Our modular approach simplifies the process of interfacing cardiomyocytes and other cells to high-performance Si-NWFETs, thus increasing the exptl. versatility of NWFET arrays and enabling device registration at the subcellular level.
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  18. 18
    Dai, X.; Zhou, W.; Gao, T.; Liu, J.; Lieber, C. M. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues. Nat. Nanotechnol. 2016, 11 (9), 776– 82,  DOI: 10.1038/nnano.2016.96
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    18
    Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues
    Dai, Xiaochuan; Zhou, Wei; Gao, Teng; Liu, Jia; Lieber, Charles M.
    Nature Nanotechnology (2016), 11 (9), 776-782CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    Real-time mapping and manipulation of electrophysiol. in three-dimensional (3D) tissues could have important impacts on fundamental scientific and clin. studies, yet realization is hampered by a lack of effective methods. Here the authors introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and a submillisecond temporal resoln. Real-time extracellular action potential (AP) recordings reveal quant. maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topol. of 3D conducting pathways in developing cardiac tissues and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. The authors further demonstrate simultaneous multisite stimulation and mapping to actively manipulate the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacol. and electronic therapeutics.
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    Tsai, D.; Sawyer, D.; Bradd, A.; Yuste, R.; Shepard, K. L. A very large-scale microelectrode array for cellular-resolution electrophysiology. Nat. Commun. 2017, 8, 1802,  DOI: 10.1038/s41467-017-02009-x
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    19
    A very large-scale microelectrode array for cellular-resolution electrophysiology
    Tsai David; Sawyer Daniel; Bradd Adrian; Yuste Rafael; Shepard Kenneth L
    Nature communications (2017), 8 (1), 1802 ISSN:.
    In traditional electrophysiology, spatially inefficient electronics and the need for tissue-to-electrode proximity defy non-invasive interfaces at scales of more than a thousand low noise, simultaneously recording channels. Using compressed sensing concepts and silicon complementary metal-oxide-semiconductors (CMOS), we demonstrate a platform with 65,536 simultaneously recording and stimulating electrodes in which the per-electrode electronics consume an area of 25.5 μm by 25.5 μm. Application of this platform to mouse retinal studies is achieved with a high-performance processing pipeline with a 1 GB/s data rate. The platform records from 65,536 electrodes concurrently with a ~10 μV r.m.s. noise; senses spikes from more than 34,000 electrodes when recording across the entire retina; automatically sorts and classifies greater than 1700 neurons following visual stimulation; and stimulates individual neurons using any number of the 65,536 electrodes while observing spikes over the entire retina. The approaches developed here are applicable to other electrophysiological systems and electrode configurations.
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  20. 20
    Tian, B.; Lieber, C. M. Nanowired Bioelectric Interfaces. Chem. Rev. 2019, 119 (15), 9136– 9152,  DOI: 10.1021/acs.chemrev.8b00795
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    Nanowired Bioelectric Interfaces
    Tian, Bozhi; Lieber, Charles M.
    Chemical Reviews (Washington, DC, United States) (2019), 119 (15), 9136-9152CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Biol. systems have evolved biochem., elec., mech., and genetic networks to perform essential functions across various length and time scales. High-aspect-ratio biol. nanowires, such as bacterial pili and neurites, mediate many of the interactions and homeostasis in and between these networks. Synthetic materials designed to mimic the structure of biol. nanowires could also incorporate similar functional properties, and exploiting this structure-function relationship has already proved fruitful in designing biointerfaces. Semiconductor nanowires are a particularly promising class of synthetic nanowires for biointerfaces, given (1) their unique optical and electronic properties and (2) their high degree of synthetic control and versatility. These characteristics enable fabrication of a variety of electronic and photonic nanowire devices, allowing for the formation of well-defined, functional bioelec. interfaces at the biomol. level to the whole-organ level. In this Focus Review, we first discuss the history of bioelec. interfaces with semiconductor nanowires. We next highlight several important, endogenous biol. nanowires and use these as a framework to categorize semiconductor nanowire-based biointerfaces. Within this framework we then review the fundamentals of bioelec. interfaces with semiconductor nanowires and comment on both material choice and device design to form biointerfaces spanning multiple length scales. We conclude with a discussion of areas with the potential for greatest impact using semiconductor nanowire-enabled biointerfaces in the future.
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    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 (8), 783– 790,  DOI: 10.1038/s41565-019-0478-y
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    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.
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    Eschermann, J. F.; Stockmann, R.; Hueske, M.; Vu, X. T.; Ingebrandt, S.; Offenhäusser, A. Action potentials of HL-1 cells recorded with silicon nanowire transistors. Appl. Phys. Lett. 2009, 95 (8), 083703  DOI: 10.1063/1.3194138
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    Action potentials of HL-1 cells recorded with silicon nanowire transistors
    Eschermann, Jan Felix; Stockmann, Regina; Hueske, Martin; Vu, Xuan Thang; Ingebrandt, Sven; Offenhaeusser, Andreas
    Applied Physics Letters (2009), 95 (8), 083703/1-083703/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
    Silicon nanowire (NW) transistors were fabricated in a top-down process. These devices were used to record the extracellular potential of the spontaneous activity of cardiac muscle HL-1 cells. their signals were measured by direct dc sampling of the drain current. An improved signal-to-noise ratio compared to planar field-effect devices was obsd. Furthermore the signal shape was evaluated and could be assocd. to different membrane currents. With these expts., a qual. description of the properties of the cell-NW contact was obtained and the suitability of these sensors for electrophysiol. measurements in vitro was demonstrated. (c) 2009 American Institute of Physics.
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    Xie, C.; Lin, Z.; Hanson, L.; Cui, Y.; Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotechnol. 2012, 7 (3), 185– 90,  DOI: 10.1038/nnano.2012.8
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    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.
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    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 (6), 3932– 3939,  DOI: 10.1021/acs.nanolett.7b01523
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    24
    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.
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    Fendyur, A.; Spira, M. E. Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes. Front. Neuroeng. 2012, 5, 21,  DOI: 10.3389/fneng.2012.00021
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    Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes
    Fendyur, Anna; Spira, Micha E.
    Frontiers in Neuroengineering (2012), 5 (Aug.), 21CODEN: FNREIF; ISSN:1662-6443. (Frontiers Media S.A.)
    Cardiol. research greatly rely on the use of cultured primary cardiomyocytes (CMs). The prime methodol. to assess CM network electrophysiol. is based on the use of extracellular recordings by substrate-integrated planar Micro-Electrode Arrays (MEAs). Whereas this methodol. permits simultaneous, long-term monitoring of the CM elec. activity, it limits the information to extracellular field potentials (FPs). The alternative method of intracellular action potentials (APs) recordings by sharp- or patch-microelectrodes is limited to a single cell at a time. Here, we began to merge the advantages of planar MEA and intracellular microelectrodes. To that end we cultured rat CM on micrometer size protruding gold mushroom-shaped microelectrode (gMμEs) arrays. Cultured CMs engulf the gMμE permitting FPs recordings from individual cells. Local electroporation of a CM converts the extracellular recording configuration to attenuated intracellular APs with shape and duration similar to those recorded intracellularly. The procedure enables to simultaneously record APs from an unlimited no. of CMs. The electroporated membrane spontaneously recovers. This allows for repeated recordings from the same CM a no. of times (>8) for over 10 days. The further development of CM-gMμE configuration opens up new venues for basic and applied biomedical research.
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    Desbiolles, B. X. E.; de Coulon, E.; Bertsch, A.; Rohr, S.; Renaud, P. Intracellular Recording of Cardiomyocyte Action Potentials with Nanopatterned Volcano-Shaped Microelectrode Arrays. Nano Lett. 2019, 19 (9), 6173– 6181,  DOI: 10.1021/acs.nanolett.9b02209
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    Intracellular Recording of Cardiomyocyte Action Potentials with Nanopatterned Volcano-Shaped Microelectrode Arrays
    Desbiolles, B. X. E.; de Coulon, E.; Bertsch, A.; Rohr, S.; Renaud, P.
    Nano Letters (2019), 19 (9), 6173-6181CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Micronanotechnol.-based multielectrode arrays have led to remarkable progress in the field of transmembrane voltage recording of excitable cells. However, providing long-term optoporation- or electroporation-free intracellular access remains a considerable challenge. In this study, a novel type of nanopatterned volcano-shaped microelectrode (nanovolcano) is described that spontaneously fuses with the cell membrane and permits stable intracellular access. The complex nanostructure was manufd. following a simple and scalable fabrication process based on ion beam etching redeposition. The resulting ring-shaped structure provided passive intracellular access to neonatal rat cardiomyocytes. Intracellular action potentials were successfully recorded in vitro from different devices, and continuous recording for more than 1 h was achieved. By reporting transmembrane action potentials at potentially high spatial resoln. without the need to apply phys. triggers, the nanovolcanoes show distinct advantages over multielectrode arrays for the assessment of electrophysiol. characteristics of cardiomyocyte networks at the transmembrane voltage level over time.
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    Chen, T.; Vunjak-Novakovic, G. In vitro Models of Ischemia-Reperfusion Injury. Regen Eng. Transl Med. 2018, 4 (3), 142– 153,  DOI: 10.1007/s40883-018-0056-0
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    In vitro Models of Ischemia-Reperfusion Injury
    Chen Timothy; Vunjak-Novakovic Gordana; Vunjak-Novakovic Gordana
    Regenerative engineering and translational medicine (2018), 4 (3), 142-153 ISSN:2364-4133.
    Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hIPS-CMs are relatively fetal in phenotype, and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic.
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    White, S. M.; Constantin, P. E.; Claycomb, W. C. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am. J. Physiol-Heart C 2004, 286 (3), H823– H829,  DOI: 10.1152/ajpheart.00986.2003
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    Teixeira, G.; Abrial, M.; Portier, K.; Chiari, P.; Couture-Lepetit, E.; Tourneur, Y.; Ovize, M.; Gharib, A. Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes. J. Mol. Cell. Cardiol. 2013, 56, 55– 62,  DOI: 10.1016/j.yjmcc.2012.11.023
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    Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes
    Teixeira, Geoffrey; Abrial, Maryline; Portier, Karine; Chiari, Pascal; Couture-Lepetit, Elisabeth; Tourneur, Yves; Ovize, Michel; Gharib, Abdallah
    Journal of Molecular and Cellular Cardiology (2013), 56 (), 55-62CODEN: JMCDAY; ISSN:0022-2828. (Elsevier B.V.)
    Reperfusion of the heart after an ischemic event leads to the opening of a nonspecific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening is an effective strategy to prevent cardiomyocyte death. The matrix protein cyclophilin-D (CypD) is the best-known regulator of mPTP opening. In this study we confirmed that preconditioning and postconditioning with CypD inhibitor cyclosporin-A (CsA) reduced cell death after hypoxia-reoxygenation (H/R) in wild-type (WT) cardiomyocytes and HL-1 mouse cardiac cell line as measured by nuclear staining with propidium iodide. The complex I inhibitor rotenone (Rot), alone, had no effect on HL-1 and WT cardiomyocyte death after H/R, but enhanced the native protection of CypD-knocked-out (CypD KO) cardiomyocytes. Redn. of cell death was assocd. with a delay of mPTP opening challenged by H/R and obsd. by the calcein loading CoCl2-quenching technique. Simultaneous inhibition of complex I and CypD increased in a synergistic manner the calcium retention capacity in permeabilized cardiomyocytes and cardiac mitochondria. These results demonstrated that protection by complex I inhibition was CypD dependent.
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    Maoz, B. M.; Herland, A.; Henry, O. Y. F.; Leineweber, W. D.; Yadid, M.; Doyle, J.; Mannix, R.; Kujala, V. J.; FitzGerald, E. A.; Parker, K. K.; Ingber, D. E. Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab Chip 2017, 17 (13), 2294– 2302,  DOI: 10.1039/C7LC00412E
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    Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities
    Maoz, Ben M.; Herland, Anna; Henry, Olivier Y. F.; Leineweber, William D.; Yadid, Moran; Doyle, John; Mannix, Robert; Kujala, Ville J.; FitzGerald, Edward A.; Parker, Kevin Kit; Ingber, Donald E.
    Lab on a Chip (2017), 17 (13), 2294-2302CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
    Here we demonstrate that microfluidic cell culture devices, known as Organs-on-a-Chips can be fabricated with multifunctional, real-time, sensing capabilities by integrating both multi-electrode arrays (MEAs) and electrodes for transepithelial elec. resistance (TEER) measurements into the chips during their fabrication. To prove proof-of-concept, simultaneous measurements of cellular elec. activity and tissue barrier function were carried out in a dual channel, endothelialized, heart-on-a-chip device contg. human cardiomyocytes and a channel-sepg. porous membrane covered with a primary human endothelial cell monolayer. These studies confirmed that the TEER-MEA chip can be used to simultaneously detect dynamic alterations of vascular permeability and cardiac function in the same chip when challenged with the inflammatory stimulus tumor necrosis factor alpha (TNF-a) or the cardiac targeting drug isoproterenol. Thus, this Organ Chip with integrated sensing capability may prove useful for real-time assessment of biol. functions, as well as response to therapeutics.
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    Yang, M.; Lim, C. C.; Liao, R.; Zhang, X. A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy. Biosens. Bioelectron. 2007, 22 (8), 1688– 93,  DOI: 10.1016/j.bios.2006.07.032
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    A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy
    Yang, Mo; Lim, Chee Chew; Liao, Ronglih; Zhang, Xin
    Biosensors & Bioelectronics (2007), 22 (8), 1688-1693CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    Cardiac hypertrophy is an established and independent risk factor for the development of heart failure and sudden cardiac death. At the level of individual cardiac myocytes (heart muscle cells), the cell morphol. alters (increase in cell size and myofibrillar re-organization) and protein synthesis is activated. In this paper, a novel cardiomyocyte-based impedance sensing system with the assistance of dielectrophoresis cell concn. is reported to monitor the dynamic process of endothelin-1-induced cardiomyocyte hypertrophy. A dielectrophoresis (DEP) microfluidic device is fabricated capable of concg. cells from a dil. sample to form a confluent cell monolayer on the surface of microelectrodes. This device can increase the sensitivity of the impedance system and also has the potential to reduce the time for detection by a significant factor. To examine the feasibility of this impedance sensing system, cardiomyocytes are treated with endothelin-1, a known hypertrophic agent. ET-1 induces a continuous rise in cardiomyocyte impedance, which the authors interpret as strengthening of cellular attachments to the surface substrate. An equivalent circuit model is introduced to fit the impedance spectrum to fully understand the impedance sensing system.
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    Yang, Z.; Murray, K. T. Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells. J. Cardiovasc. Pharmacol. 2011, 57 (1), 28– 36,  DOI: 10.1097/FJC.0b013e3181fda7c4
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    Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells
    Yang, Zhenjiang; Murray, Katherine T.
    Journal of Cardiovascular Pharmacology (2011), 57 (1), 28-36CODEN: JCPCDT; ISSN:0160-2446. (Lippincott Williams & Wilkins)
    Although normally absent, spontaneous pacemaker activity can develop in human atrium to promote tachyarrhythmias. HL-1 cells are immortalized atrial cardiomyocytes that contract spontaneously in culture, providing a model system of atrial cell automaticity. Using electrophysiol. recordings and selective pharmacol. blockers, we investigated the ionic basis of automaticity in atrial HL-1 cells. Both the sarcoplasmic reticulum Ca release channel inhibitor ryanodine and the sarcoplasmic reticulum Ca ATPase inhibitor thapsigargin slowed automaticity, supporting a role for intracellular Ca release in pacemaker activity. Addnl. expts. were performed to examine the effects of ionic currents activating in the voltage range of diastolic depolarization. Inhibition of the hyperpolarization-activated pacemaker current, If, by ivabradine significantly suppressed diastolic depolarization, with modest slowing of automaticity. Block of inward Na currents also reduced automaticity, whereas inhibition of T- and L-type Ca currents caused milder effects to slow beat rate. The major outward current in HL-1 cells is the rapidly activating delayed rectifier, IKr. Inhibition of IKr using dofetilide caused marked prolongation of action potential duration and thus spontaneous cycle length. These results demonstrate a mutual role for both intracellular Ca release and sarcolemmal ionic currents in controlling automaticity in atrial HL-1 cells. Given that similar internal and membrane-based mechanisms also play a role in sinoatrial nodal cell pacemaker activity, our findings provide evidence for generalized conservation of pacemaker mechanisms among different types of cardiomyocytes.
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    Martins-Marques, T.; Anjo, S. I.; Pereira, P.; Manadas, B.; Girao, H. Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart. Mol. Cell. Proteomics 2015, 14 (11), 3040– 55,  DOI: 10.1074/mcp.M115.052894
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    Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart
    Martins-Marques, Tania; Anjo, Sandra Isabel; Pereira, Paulo; Manadas, Bruno; Girao, Henrique
    Molecular & Cellular Proteomics (2015), 14 (11), 3040-3055CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
    The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-contg. channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been assocd. with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the mol. mechanisms underlying pathol. malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biol. functions of Cx43. In the present report, we applied a quant. SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemia-reperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biol. processes such as metab., signaling and trafficking. The interaction of Cx43 with proteins involved in gene transcription strengthens the emerging concept that Cx43 has a role in gene expression regulation. Importantly, our data shows that the interactome of Cx43 (Connexome) is differentially modulated in diseased hearts. Overall, the characterization of Cx43-interacting network may contribute to the establishment of new therapeutic targets to modulate cardiac function in physiol. and pathol. conditions. Data are available via ProteomeXchange with identifier PXD002331.
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    Semenza, G. L. Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 2014, 76, 39– 56,  DOI: 10.1146/annurev-physiol-021113-170322
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    Hypoxia-inducible factor 1 and cardiovascular disease
    Semenza, Gregg L.
    Annual Review of Physiology (2014), 76 (), 39-56CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews)
    A review. Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metab. and redox homeostasis. Anal. of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a crit. protective role in the pathophysiol. of ischemic heart disease and pressure-overload heart failure.
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  35. 35
    Chu, W.; Wan, L.; Zhao, D.; Qu, X.; Cai, F.; Huo, R.; Wang, N.; Zhu, J.; Zhang, C.; Zheng, F.; Cai, R.; Dong, D.; Lu, Y.; Yang, B. Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1alpha-mediated TRPC signalling. J. Cell Mol. Med. 2012, 16 (9), 2022– 34,  DOI: 10.1111/j.1582-4934.2011.01497.x
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    Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signalling
    Chu, Wenfeng; Wan, Lin; Zhao, Dan; Qu, Xuefeng; Cai, Fulai; Huo, Rong; Wang, Ning; Zhu, Jiuxin; Zhang, Chun; Zheng, Fangfang; Cai, Ruijun; Dong, Deli; Lu, Yanjie; Yang, Baofeng
    Journal of Cellular and Molecular Medicine (2012), 16 (9), 2022-2034CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
    Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study was designed to investigate the role of HIF-1α in mild hypoxia-induced cardiomyocytes hypertrophy and its underlying mechanism. Mild hypoxia (MH, 10% O2) caused hypertrophy in cultured neonatal rat cardiac myocytes, which was accompanied with increase of HIF-1α mRNA and accumulation of HIF-1α protein in nuclei. Transient receptor potential canonical (TRPC) channels including TRPC3 and TRPC6, except for TRPC1, were increased, and Ca2+-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca2+-calcineurin signals were inhibited by an HIF-1α specific blocker, SC205346 (30 μM), whereas promoted by HIF-1α overexpression. Electrophysiol. voltage-clamp demonstrated that DAG analog, OAG (30 μM), induced TRPC current by as much as 170% in neonatal rat cardiomyocytes overexpressing HIF-1α compared to neg. control. These results implicate that HIF-1α plays a key role in development of cardiac hypertrophy in responses to hypoxic stress. Its mechanism is assocd. with up-regulating TRPC3, TRPC6 expression, activating TRPC current and subsequently leading to enhanced Ca2+-calcineurin signals.
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    Lee, J. W.; Ko, J.; Ju, C.; Eltzschig, H. K. Hypoxia signaling in human diseases and therapeutic targets. Exp. Mol. Med. 2019, 51 (6), 68,  DOI: 10.1038/s12276-019-0235-1
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    Semenza, G.; Hydroxylation, L. of HIF-1: Oxygen Sensing at the Molecular Level. Physiology 2004, 19 (4), 176– 182,  DOI: 10.1152/physiol.00001.2004
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    Hydroxylation of HIF-1: Oxygen sensing at the molecular level
    Semenza, Gregg L.
    Physiology (2004), 19 (Aug.), 176-182CODEN: PHYSCI; ISSN:1548-9213. (International Union of Physiological Sciences)
    A review. The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in Po2 are transduced to effect changes in gene expression.
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    Yeung, C. K.; Sommerhage, F.; Wrobel, G.; Law, J. K.; Offenhausser, A.; Rudd, J. A.; Ingebrandt, S.; Chan, M. To establish a pharmacological experimental platform for the study of cardiac hypoxia using the microelectrode array. J. Pharmacol. Toxicol. Methods 2009, 59 (3), 146– 52,  DOI: 10.1016/j.vascn.2009.02.005
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    To establish a pharmacological experimental platform for the study of cardiac hypoxia using the microelectrode array
    Yeung, Chi-Kong; Sommerhage, Frank; Wrobel, Guenter; Law, Jessica Ka-Yan; Offenhaeusser, Andreas; Rudd, John Anthony; Ingebrandt, Sven; Chan, Mansun
    Journal of Pharmacological and Toxicological Methods (2009), 59 (3), 146-152CODEN: JPTMEZ; ISSN:1056-8719. (Elsevier)
    Simultaneous recording of elec. potentials from multiple cells may be useful for physiol. and pharmacol. research. The present study aimed to establish an in vitro cardiac hypoxia exptl. platform on the microelectrode array (MEA). Embryonic rat cardiac myocytes were cultured on the MEAs. Following ≥ 90 min of hypoxia, changes in lactate prodn. (mM), pH, beat frequency (beats per min, bpm), extracellular action potential (exAP) amplitude, and propagation velocity between the normoxic and hypoxic cells were compared. Under hypoxia, the beat frequency of cells increased and peaked at around 42.5 min (08.1 ± 3.2 bpm). The exAP amplitude reduced as soon as the cells were exposed to the hypoxic medium, and this redn. increased significantly after approx. 20 min of hypoxia. The propagation velocity of the hypoxic cells was significantly lower than that of the control throughout the entire 90+ min of hypoxia. The rate of depolarization and Na+ signal gradually reduced over time, and these changes had a direct effect on the exAP duration. The extracellular electrophysiol. measurements allow a partial reconstruction of the signal shape and time course of the underlying hypoxia-assocd. physiol. changes. The present study showed that the cardiac myocyte-integrated MEA may be used as an exptl. platform for the pharmacol. studies of cardiovascular diseases in the future.
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    Cascio, W. E.; Yang, H.; Muller-Borer, B. J.; Johnson, T. A. Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation. J. Electrocardiol 2005, 38 (4 Suppl), 55– 59,  DOI: 10.1016/j.jelectrocard.2005.06.019
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    Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation
    Cascio Wayne E; Yang Hua; Muller-Borer Barbara J; Johnson Timothy A
    Journal of electrocardiology (2005), 38 (4 Suppl), 55-9 ISSN:0022-0736.
    Sudden cardiac death accounts for more than half of all cardiovascular deaths in the US, and a large proportion of these deaths are attributed to ischemia-induced ventricular fibrillation. As such, the mechanisms underlying the initiation and maintenance of these lethal rhythms are of significant clinical and scientific interest. In large animal hearts, regional ischemia induces two phases of ventricular arrhythmia. The first phase (1A) occurs between 5 and 7 min after arrest of perfusion. This phase is associated with membrane depolarization, a mild intracellular and extracellular acidification and a small membrane depolarization. A second phase (1B) of ventricular arrhythmia occurs between 20 and 30 minutes after arrest of perfusion. This phase occurs at a time when ischemia-induced K+ and pH changes are relatively stable. The arrhythmia is presumed to relate to the process of cell-to-cell electrical uncoupling because a rapid increase of tissue impedance precedes the onset of the arrhythmia. Of note is that tissue resistance is primarily determined by the conductance properties of the gap junctions accounting for cell-to-cell coupling. Impulse propagation in heart is determined by active and passive membrane properties. An important passive cable property that is modulated by ischemia is intercellular resistance and is determined primarily by gap junctional conductance. As such changes in Impulse propagation during myocardial ischemia are determined by contemporaneous changes in active and passive membrane properties. Cellular K loss, intracellular and extracellular acidosis and membrane depolarization are important factors decreasing excitatory currents, while the collapse of the extracellular compartment and cell-to-cell electrical uncoupling increase the resistance to current flow. The time-course of cellular coupling is closely linked to a number of physiological processes including depletion of ATP, and accumulation of intracellular Ca2+. Hence, interventions such as ischemic preconditioning attenuate the effect of subsequent ischemia, delay the onset of cell-to-cell electrical uncoupling and likewise delay the onset of ischemia-induced arrhythmia.
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    Lujan, H. L.; DiCarlo, S. E. Reperfusion-induced sustained ventricular tachycardia, leading to ventricular fibrillation, in chronically instrumented, intact, conscious mice. Physiol. Rep. 2014, 2 (6), e12057,  DOI: 10.14814/phy2.12057
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    Dang, K. M.; Rinklin, P.; Afanasenkau, D.; Westmeyer, G.; Schurholz, T.; Wiegand, S.; Wolfrum, B. Chip-Based Heat Stimulation for Modulating Signal Propagation in HL-1 Cell Networks. Adv. Biosyst 2018, 2 (12), 1800138,  DOI: 10.1002/adbi.201800138
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    Claycomb, W. C.; Lanson, N. A.; Stallworth, B. S.; Egeland, D. B.; Delcarpio, J. B.; Bahinski, A.; Izzo, N. J. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (6), 2979– 2984,  DOI: 10.1073/pnas.95.6.2979
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    HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte
    Claycomb, William C.; Lanson, Nicholas A., Jr.; Stallworth, Beverly S.; Egeland, Daniel B.; Delcarpio, Joseph B.; Bahinski, Anthony; Izzo, Nicholas J., Jr.
    Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (6), 2979-2984CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The authors derived a cardiac muscle cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 cells can be serially passaged, yet they maintain the ability to contract and retain differentiated cardiac morphol., biochem., and electrophysiol. properties. Ultrastructural characteristics typical of embryonic atrial myocytes, were found consistently in the cultured HL-1 cells. RT-PCR-based anal. confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of α-cardiac myosin heavy chain, α-cardiac actin, and connexin 43. They also expressed the gene for atrial natriuretic factor. Immunohistochem. staining of the HL-1 cells indicated that the distribution of the cardiac-specific markers, desmin, sarcomeric myosin, and atrial natriuretic factor, was similar to that of cultured atrial cardiomyocytes. A delayed rectifier K+ current (IKr) was the most prominent outward current in HL-1 cells. The activating currents desplayed inward rectification and deactivating current tails, were voltage-dependent, satd. at »+20 mV, and were highly sensitive to dofetilide (IC50 = 46.9 nM). Specific binding of [3H]dofetilide was saturable and fit a 1-site binding isotherm with a Kd of 140 ±60 nM and a Bmax of 118 fmol per 105 cells. HL-1 cells represent a cardiac myocyte cell line that can be repeatedly passaged and yet maintain a cardiac-specific phenotype.
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    Lin, Z. C.; McGuire, A. F.; Burridge, P. W.; Matsa, E.; Lou, H.-Y.; Wu, J. C.; Cui, B. Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease. Microsystems & Nanoengineering 2017, 3, 16080,  DOI: 10.1038/micronano.2016.80
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    Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease
    Lin, Ziliang Carter; McGuire, Allister F.; Burridge, Paul W.; Matsa, Elena; Lou, Hsin-Ya; Wu, Joseph C.; Cui, Bianxiao
    Microsystems & Nanoengineering (2017), 3 (), 16080CODEN: MNIACT; ISSN:2055-7434. (Nature Publishing Group)
    The measurement of the electrophysiol. of human pluripotent stem cell-derived cardiomyocytes is crit. for their biomedical applications, from disease modeling to drug screening. Yet, a method that enables the high-throughput intracellular electrophysiol. measurement of single cardiomyocytes in adherent culture is not available. To address this area, we have fabricated vertical nanopillar electrodes that can record intracellular action potentials from up to 60 single beating cardiomyocytes. Intracellular access is achieved by highly localized electroporation, which allows for low impedance elec. access to the intracellular voltage. Herein, we demonstrate that this method provides the accurate measurement of the shape and duration of intracellular action potentials, validated by patch clamp, and can facilitate cellular drug screening and disease modeling using human pluripotent stem cells. This study validates the use of nanopillar electrodes for myriad further applications of human pluripotent stem cell-derived cardiomyocytes such as cardiomyocyte maturation monitoring and electrophysiol.-contractile force correlation.
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    Shaw, R. M.; Rudy, Y. Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration. Cardiovasc. Res. 1997, 35 (2), 256– 72,  DOI: 10.1016/S0008-6363(97)00093-X
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    Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration
    Shaw R M; Rudy Y
    Cardiovascular research (1997), 35 (2), 256-72 ISSN:0008-6363.
    OBJECTIVE: To study the ionic mechanisms of electrophysiologic changes in cell excitability and action potential duration during the acute phase of myocardial ischemia. METHODS: Using an ionic-based theoretical model of the cardiac ventricular cell, the dynamic LRd model, we have simulated the three major component conditions of acute ischemia (elevated [K]o, acidosis and anoxia) at the level of individual ionic currents and ionic concentrations. The conditions were applied individually and in combination to identify ionic mechanisms responsible for reduced excitability at rest potentials, delayed recovery of excitability, and shortened action potential duration. RESULTS: Increased extracellular potassium ([K]o) had the major effect on cell excitability by depolarizing resting membrane potential (Vrest), causing reduction in sodium channel availability. Acidosis caused a [K]o-independent reduction in maximum upstroke velocity, (dVm/dt)max. A transition from sodium-current dominated to calcium-current dominated upstroke occurred, and calcium current alone was able to sustain the upstroke, but only after sodium channels were almost completely (97%) inactivated. Acidic conditions prevented the transition to calcium dominated upstroke by acidic reduction of both sodium and calcium currents. Anoxia, simulated by lowering [ATP]i and activating the APT-dependent potassium current, IK(ATP), was the only process that could decrease action potential duration by more than 50% and reproduce AP shape changes that are observed experimentally. Acidic or anoxic depression of the L-type calcium current could not reproduce the observed action potential shape changes and APD shortening. Delayed recovery of excitability, known as 'post-repolarization refractoriness', was determined by the voltage-dependent kinetics of sodium channel recovery; Vrest depolarization caused by elevated [K]o increased the time constant of (dVm/dt)max recovery from tau = 10.3 ms at [K]o = 4.5 mM to tau = 81.4 ms at [K]o = 12 mM, reflecting major slowing of sodium-channel recovery. Anoxia and acidosis had little affect on tau. CONCLUSIONS: The major conditions of acute ischemia, namely elevated [K]o, acidosis and anoxia, applied at the ionic channel level are sufficient to simulate the major electrical changes associated with ischemia. Depression of membrane excitability and delayed recovery of excitability in the single, unloaded cell are caused by elevated [K]o with additional excitability depression by acidosis. Major changes in action potential duration and shape can only be accounted for by anoxia-dependent opening of IK(ATP).
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  45. 45

    These speeds are on the same order as those derived from extracellular electrodes. We note however that they do not represent the true wavefront velocity but rather a projection along the direction of the linear electrode array.

    There is no corresponding record for this reference.
  46. 46
    Sartiani, L.; Bochet, P.; Cerbai, E.; Mugelli, A.; Fischmeister, R. Functional expression of the hyperpolarization-activated, non-selective cation current I(f) in immortalized HL-1 cardiomyocytes. J. Physiol. 2002, 545 (1), 81– 92,  DOI: 10.1113/jphysiol.2002.021535
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    Functional expression of the hyperpolarization-activated, non-selective cation current If in immortalized HL-1 cardiomyocytes
    Sartiani, Laura; Bochet, Pascal; Cerbai, Elisabetta; Mugelli, Alessandro; Fischmeister, Rodolphe
    Journal of Physiology (Cambridge, United Kingdom) (2002), 545 (1), 81-92CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)
    HL-1 cells are adult mouse atrial myocytes induced to proliferate indefinitely by SV40 large T antigen. These cells beat spontaneously when confluent and express several adult cardiac cell markers including the outward delayed rectifier K+ channel. Here, we examd. the presence of a hyperpolarization-activated If current in HL-1 cells using the whole-cell patch-clamp technique on isolated cells enzymically dissocd. from the culture at confluence. Cell membrane capacitance (Cm) ranged from 5 to 53 pF. If was detected in about 30% of the cells, and its occurrence was independent of the stage of the culture. If maximal slope conductance was 89.7 ± 0.4 pS pF-1 (n = 10). If current in HL-1 cells showed typical characteristics of native cardiac If current: activation threshold between -50 and -60 mV, half-maximal activation potential of -83.1 ± 0.7 mV (n = 50), reversal potential at -20.8 ± 1.5 mV (n = 10), time-dependent activation by hyperpolarization and blockade by 4 mM Cs+. In half of the cells tested, activation of adenylyl cyclase by the forskolin analog L858051 (20 μM) induced both a ∼6 mV pos. shift of the half-activation potential and a ∼37% increase in the fully activated If current. RT-PCR anal. of the hyperpolarization-activated, cyclic nucleotide-gated channels (HCN) expressed in HL-1 cells demonstrated major contributions of HCN1 and HCN2 channel isoforms to If current. Cytosolic Ca2+ oscillations in spontaneously beating HL-1 cells were measured in Fluo-3 AM-loaded cells using a fast-scanning confocal microscope. The oscillation frequency ranged from 1.3 to 5 Hz, and the spontaneous activity was stopped in the presence of 4 mM Cs+. Action potentials from HL-1 cells had a triangular shape, with an overshoot at +15 mV and a maximal diastolic potential of -69 mV, i.e. more neg. than the threshold potential for If activation. In conclusion, HL-1 cells display a hyperpolarization-activated If current, which might contribute to the spontaneous contractile activity of these cells.
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    Dias, P.; Desplantez, T.; El-Harasis, M. A.; Chowdhury, R. A.; Ullrich, N. D.; Cabestrero de Diego, A.; Peters, N. S.; Severs, N. J.; MacLeod, K. T.; Dupont, E. Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line. PLoS One 2014, 9 (2), e90266  DOI: 10.1371/journal.pone.0090266
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    Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line
    Dias, Priyanthi; Desplantez, Thomas; El-Harasis, Majd A.; Chowdhury, Rasheda A.; Ullrich, Nina D.; de Diego, Alberto Cabestrero; Peters, Nicholas S.; Severs, Nicholas J.; MacLeod, Kenneth T.; Dupont, Emmanuel
    PLoS One (2014), 9 (2), e90266/1-e90266/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The HL-1 atrial line contains cells blocked at various developmental stages. To obtain homogeneous sub-clones and correlate changes in gene expression with functional alterations, individual clones were obtained and characterized for parameters involved in conduction and excitation-contraction coupling. Northern blots for mRNAs coding for connexins 40, 43 and 45 and calcium handling proteins (sodium/calcium exchanger, L- and T-type calcium channels, ryanodine receptor 2 and sarco-endoplasmic reticulum calcium ATPase 2) were performed. Connexin expression was further characterized by western blots and immunofluorescence. Inward currents were characterized by voltage clamp and conduction velocities measured using microelectrode arrays. The HL-1 clones had similar sodium and calcium inward currents with the exception of clone 2 which had a significantly smaller calcium c.d. All the clones displayed homogeneous propagation of elec. activity across the monolayer correlating with the levels of connexin expression. Conduction velocities were also more sensitive to inhibition of junctional coupling by carbenoxolone (∼80%) compared to inhibition of the sodium current by lidocaine (∼20%). Elec. coupling by gap junctions was the major determinant of conduction velocities in HL-1 cell lines. In summary we have isolated homogeneous and stable HL-1 clones that display characteristics distinct from the heterogeneous properties of the original cell line.
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    Hafez, P.; Chowdhury, S. R.; Jose, S.; Law, J. X.; Ruszymah, B. H. I.; Ramzisham, A. R. M.; Ng, M. H. Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes. Cardiovasc Eng. Techn 2018, 9 (3), 529– 538,  DOI: 10.1007/s13239-018-0368-8
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    Zhu, R. J.; Millrod, M. A.; Zambidis, E. T.; Tung, L. Variability of Action Potentials Within and Among Cardiac Cell Clusters Derived from Human Embryonic Stem Cells. Sci. Rep. 2016, 6, 18544,  DOI: 10.1038/srep18544
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    Variability of Action Potentials Within and Among Cardiac Cell Clusters Derived from Human Embryonic Stem Cells
    Zhu, Renjun; Millrod, Michal A.; Zambidis, Elias T.; Tung, Leslie
    Scientific Reports (2016), 6 (), 18544CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    Electrophysiol. variability in cardiomyocytes derived from pluripotent stem cells continues to be an impediment for their scientific and translational applications. We studied the variability of action potentials (APs) recorded from clusters of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using high-resoln. optical mapping. Over 23,000 APs were analyzed through four parameters: APD30, APD80, triangulation and fractional repolarization. Although measures were taken to reduce variability due to cell culture conditions and rate-dependency of APs, we still obsd. significant variability in APs among and within the clusters. However, similar APs were found in spatial locations with close proximity, and in some clusters formed distinct regions having different AP characteristics that were reflected as sep. peaks in the AP parameter distributions, suggesting multiple electrophysiol. phenotypes. Using a recently developed automated method to group cells based on their entire AP shape, we identified distinct regions of different phenotypes within single clusters and common phenotypes across different clusters when sepg. APs into 2 or 3 subpopulations. The systematic anal. of the heterogeneity and potential phenotypes of large populations of hESC-CMs can be used to evaluate strategies to improve the quality of pluripotent stem cell-derived cardiomyocytes for use in diagnostic and therapeutic applications and in drug screening.
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    Abbott, J.; Ye, T.; Qin, L.; Jorgolli, M.; Gertner, R. S.; Ham, D.; Park, H. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nat. Nanotechnol. 2017, 12 (5), 460– 466,  DOI: 10.1038/nnano.2017.3
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    CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging
    Abbott, Jeffrey; Ye, Tianyang; Qin, Ling; Jorgolli, Marsela; Gertner, Rona S.; Ham, Donhee; Park, Hongkun
    Nature Nanotechnology (2017), 12 (5), 460-466CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    Developing a new tool capable of high-precision electrophysiol. recording of a large network of electrogenic cells has long been an outstanding challenge in neurobiol. and cardiol. Here, the authors combine nanoscale intracellular electrodes with complementary metal-oxide-semiconductor (CMOS) integrated circuits to realize a high-fidelity all-elec. electrophysiol. imager for parallel intracellular recording at the network level. The CMOS nanoelectrode array has 1024 recording/stimulation 'pixels' equipped with vertical nanoelectrodes, and can simultaneously record intracellular membrane potentials from hundreds of connected in vitro neonatal rat ventricular cardiomyocytes. The authors demonstrate that this network-level intracellular recording capability can be used to examine the effect of pharmaceuticals on the delicate dynamics of a cardiomyocyte network, thus opening up new opportunities in tissue-based pharmacol. screening for cardiac and neuronal diseases as well as fundamental studies of electrogenic cells and their networks.
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    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.
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  • Abstract

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    Figure 1

    Figure 1. Overview of the heart-on-a-chip platform. (a) (top) Optical image and (bottom) scheme representing fully assembled chip with integrated recording elements, reference electrode, and PDMS channel for media delivery. (b) Representative optical image of an extracellular recording element coated with Pt black (red arrow). (c) Representative optical image of an intracellular recording element comprised of an underlying Au pad with five vertical Pt nanopillars (blue arrow). (d) (top) SEM detail of five vertical nanopillars corresponding to the location marked by the blue arrow in panel c. (inset) Schematic representation of a single nanopillar cross section. (bottom) Cross section of a single nanopillar after etching with FIB. Note that the Pt nanopillar fully penetrated the SiO2 layer to form a junction with the underlying Au layer. (e) Immunostaining of the HL-1 cell monolayer cultured in a PDMS channel at 4 DIV showing α-actinin cytoskeleton (green), Cx-43 gap junction proteins (red), and nuclei (blue, DAPI). (f) Stitched immunofluorescence image showing continuous HL-1 monolayer across the lateral direction of the microfluidic channel. Yellow dotted lines denote edges of the PDMS boundary.

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    Figure 2

    Figure 2. Extracellular bioelectronic readouts before, during, and after hypoxia. (a) (top) Scheme of media delivery protocol with distinct regions of normoxia, hypoxia, and recovery and (bottom) HL-1 firing rate. The red dotted box highlights the transition from rhythmic beating to arrhythmia. (b) Representative signals from a single device recorded during (I) normoxia, (II) hypoxia, upon onset of arrhythmia, and (III) recovery. These traces correspond to the points noted in panel a. (inset) Single peak expansions of (black) overlaid individual traces and (red) average of individual traces. (c) Scheme of electrode layout (black dots) and representative multiplexed readouts from a chip with 14 out of 16 functional bioelectronic interfaces. (d,e) Isochronal maps representing signal propagation at two time points each during (d) normoxia and (e) hypoxia for ∼1 h. Black arrow overlays represent the gradient of the isochrones. The area of each map is 1000 μm wide × 4200 μm tall.

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    Figure 3

    Figure 3. Electrophysiology using nanopillar electrodes in normoxic media. (a) Representative extracellular signal recorded prior to electroporation. Inset shows expansion of single representative peak. (b) Intracellular signals recorded immediately after electroporation. (c) (blue square) Normalized action potential amplitude and (red circle) APD50 as a function of time after electroporation. Within 2 min, the amplitude of the action potentials decreased to around 24% of the maximum, while APD50 was unchanged. (d) Expansions of peaks shown in panel b at locations noted by red, blue, and yellow arrows, plotted on (left) absolute and (right) normalized scales. Note that the baseline of these peaks is offset for clarity.

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    Figure 4

    Figure 4. Intracellular electrophysiology of HL-1 cells during 1% O2 hypoxic stress. (a) Schematic representation of typical HL-1 AP highlighting key parameters. (b) Intracellular recording showing arrhythmic beating after 6 h of hypoxic stress. (c) Representative examples of AP recordings following 0, 2, 4, or 6 h of hypoxic stress. Note that the 0 h time point represents normoxia. (d–f) Summary statistics representing (d) APD50, (e) APD90, and (f) depolarization time corresponding to each time point represented in panel c. (g) Percentage change for APD50, APD90, and depolarization time throughout hypoxia. Statistics are from N = 14 different cells in 4 different cultures. *P < 0.05, **P < 0.01, ***P < 0.0005, ****P < 0.0001 in Welch’s t test. All error bars denote s.d.

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    Figure 5

    Figure 5. Multiplexed intracellular recordings. (a) Representative APs simultaneously recorded under (left) normoxia and (right) hypoxia after 2 h. The color-coded legend represents the corresponding device arrangement; spacing between devices is 600 μm. (b) Propagation maps correlating to each trace and spatial location shown in panels a and b. Each map is 3600 μm tall and represents propagation along the direction of the linear device array. (c) Heat maps representing APD50, APD90, and depolarization time corresponding to each trace and spatial location shown in panels a and b.

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      The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (KATP) channels. KATP channel expression has a significant physiol. impact on action potential duration shortening and myocardial energy consumption in response to physiol. heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant neg. KATP channel subunit were compared with littermate controls. Evaluation of KATP channel whole cell current and channel no./patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80-85% redn. in cardiac KATP channel c.d. results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the no. of functional cardiac sarcolemmal KATP channels is a crit. determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.
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    10. 10
      Ribas, J.; Sadeghi, H.; Manbachi, A.; Leijten, J.; Brinegar, K.; Zhang, Y. S.; Ferreira, L.; Khademhosseini, A. Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development. Appl. In Vitro Toxicol 2016, 2 (2), 82– 96,  DOI: 10.1089/aivt.2016.0002
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      10
      Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development
      Ribas Joao; Sadeghi Hossein; Manbachi Amir; Leijten Jeroen; Brinegar Katelyn; Zhang Yu Shrike; Khademhosseini Ali; Ribas Joao; Sadeghi Hossein; Manbachi Amir; Leijten Jeroen; Brinegar Katelyn; Zhang Yu Shrike; Khademhosseini Ali; Ribas Joao; Sadeghi Hossein; Leijten Jeroen; Ferreira Lino; Ferreira Lino; Khademhosseini Ali; Khademhosseini Ali; Khademhosseini Ali
      Applied in vitro toxicology (2016), 2 (2), 82-96 ISSN:2332-1512.
      Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human in vivo dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system-in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development.
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    11. 11
      Kang, Y. B. A.; Eo, J.; Bulutoglu, B.; Yarmush, M. L.; Usta, O. B. Progressive hypoxia-on-a-chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease. Biotechnol. Bioeng. 2020, 117, 763,  DOI: 10.1002/bit.27225
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      11
      Progressive hypoxia-on-a-chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease
      Kang, Young Bok; Eo, Jinsu; Bulutoglu, Beyza; Yarmush, Martin L.; Usta, O. Berk
      Biotechnology and Bioengineering (2020), 117 (3), 763-775CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)
      Oxygen is vital to the function of all tissues including the liver and lack of oxygen, i.e., hypoxia can result in both acute and chronic injuries to the liver in vivo and ex vivo. Furthermore, a permanent oxygen gradient is naturally present along the liver sinusoid, which plays a role in the metabolic zonation and the pathophysiol. of liver diseases. Accordingly, here, we introduce an in vitro microfluidic platform capable of actively creating a series of oxygen concns. on a single continuous microtissue, ranging from normoxia to severe hypoxia. This range approx. captures both the physiol. relevant oxygen gradient generated from the portal vein to the central vein in the liver, and the severe hypoxia occurring in ischemia and liver diseases. Primary rat hepatocytes cultured in this microfluidic platform were exposed to an oxygen gradient of 0.3-6.9%. The establishment of an ascending hypoxia gradient in hepatocytes was confirmed in response to the decreasing oxygen supply. The hepatocyte viability in this platform decreased to approx. 80% along the hypoxia gradient. Simultaneously, a progressive increase in accumulation of reactive oxygen species and expression of hypoxia-inducible factor 1a was obsd. with increasing hypoxia. These results demonstrate the induction of distinct metabolic and genetic responses in hepatocytes upon exposure to an oxygen (/hypoxia) gradient. This progressive hypoxia-on-a-chip platform can be used to study the role of oxygen and hypoxia-assocd. mols. in modeling healthy and injured liver tissues. Its use can be further expanded to the study of other hypoxic tissues such as tumors as well as the investigation of drug toxicity and efficacy under oxygen-limited conditions.
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    12. 12
      Bolonduro, O. A.; Duffy, B. M.; Rao, A. A.; Black, L. D.; Timko, B. P. From Biomimicry to Bioelectronics: Smart Materials for Cardiac Tissue Engineering. Nano Res. 2020  DOI: 10.1007/s12274-020-2682-3 .
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    13. 13
      Spira, M. E.; Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 2013, 8 (2), 83– 94,  DOI: 10.1038/nnano.2012.265
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      13
      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.
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    14. 14
      Feiner, R.; Engel, L.; Fleischer, S.; Malki, M.; Gal, I.; Shapira, A.; Shacham-Diamand, Y.; Dvir, T. Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function. Nat. Mater. 2016, 15 (6), 679– 85,  DOI: 10.1038/nmat4590
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      14
      Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function
      Feiner, Ron; Engel, Leeya; Fleischer, Sharon; Malki, Maayan; Gal, Idan; Shapira, Assaf; Shacham-Diamand, Yosi; Dvir, Tal
      Nature Materials (2016), 15 (6), 679-685CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, freestanding electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular elec. activities and the on-demand provision of elec. stimulation for synchronizing cell contraction. We also show that electroactive polymers contg. biol. factors can be deposited on designated electrodes to release drugs in the patch microenvironment on demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function.
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    15. 15
      Xu, L.; Gutbrod, S. R.; Bonifas, A. P.; Su, Y.; Sulkin, M. S.; Lu, N.; Chung, H. J.; Jang, K. I.; Liu, Z.; Ying, M.; Lu, C.; Webb, R. C.; Kim, J. S.; Laughner, J. I.; Cheng, H.; Liu, Y.; Ameen, A.; Jeong, J. W.; Kim, G. T.; Huang, Y.; Efimov, I. R.; Rogers, J. A. 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat. Commun. 2014, 5, 3329,  DOI: 10.1038/ncomms4329
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      15
      3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium
      Xu Lizhi; Gutbrod Sarah R; Bonifas Andrew P; Jang Kyung-In; Ying Ming; Lu Chi; Webb R Chad; Liu Yuhao; Ameen Abid; Jeong Jae-Woong; Kim Gwang-Tae; Rogers John A; Su Yewang; Sulkin Matthew S; Laughner Jacob I; Efimov Igor R; Lu Nanshu; Chung Hyun-Joong; Liu Zhuangjian; Kim Jong-Seon; Cheng Huanyu; Huang Yonggang
      Nature communications (2014), 5 (), 3329 ISSN:.
      Means for high-density multiparametric physiological mapping and stimulation are critically important in both basic and clinical cardiology. Current conformal electronic systems are essentially 2D sheets, which cannot cover the full epicardial surface or maintain reliable contact for chronic use without sutures or adhesives. Here we create 3D elastic membranes shaped precisely to match the epicardium of the heart via the use of 3D printing, as a platform for deformable arrays of multifunctional sensors, electronic and optoelectronic components. Such integumentary devices completely envelop the heart, in a form-fitting manner, and possess inherent elasticity, providing a mechanically stable biotic/abiotic interface during normal cardiac cycles. Component examples range from actuators for electrical, thermal and optical stimulation, to sensors for pH, temperature and mechanical strain. The semiconductor materials include silicon, gallium arsenide and gallium nitride, co-integrated with metals, metal oxides and polymers, to provide these and other operational capabilities. Ex vivo physiological experiments demonstrate various functions and methodological possibilities for cardiac research and therapy.
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    16. 16
      Timko, B. P.; Cohen-Karni, T.; Yu, G.; Qing, Q.; Tian, B.; Lieber, C. M. Electrical recording from hearts with flexible nanowire device arrays. Nano Lett. 2009, 9 (2), 914– 8,  DOI: 10.1021/nl900096z
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      16
      Electrical Recording from Hearts with Flexible Nanowire Device Arrays
      Timko, Brian P.; Cohen-Karni, Tzahi; Yu, Guihua; Qing, Quan; Tian, Bozhi; Lieber, Charles M.
      Nano Letters (2009), 9 (2), 914-918CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      The authors show that nanowire field-effect transistor (NWFET) arrays fabricated on both planar and flexible polymeric substrates can be reproducibly interfaced with spontaneously beating embryonic chicken hearts in both planar and bent conformations. Simultaneous recordings from glass microelectrode and NWFET devices show that NWFET conductance variations are synchronized with the beating heart. The conductance change assocd. with beating can be tuned substantially by device sensitivity, although the voltage-calibrated signals, 4-6 mV, are relatively const. and typically larger than signals recorded by microelectrode arrays. Multiplexed recording from NWFET arrays yielded signal propagation times across the myocardium with high spatial resoln. The transparent and flexible NWFET chips also enable simultaneous elec. recording and optical registration of devices to heart surfaces in three-dimensional conformations not possible with planar microdevices. The capability of simultaneous optical imaging and elec. recording also could be used to register devices to a specific region of the myocardium at the cellular level, and more generally, NWFET arrays fabricated on increasingly flexible plastic and/or biopolymer substrates have the potential to become unique tools for elec. recording from other tissue/organ samples or as powerful implants.
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    17. 17
      Cohen-Karni, T.; Timko, B. P.; Weiss, L. E.; Lieber, C. M. Flexible electrical recording from cells using nanowire transistor arrays. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (18), 7309– 13,  DOI: 10.1073/pnas.0902752106
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      17
      Flexible electrical recording from cells using nanowire transistor arrays
      Cohen-Karni, Tzahi; Timko, Brian P.; Weiss, Lucien E.; Lieber, Charles M.
      Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (18), 7309-7313CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Semiconductor nanowires (NWs) have unique electronic properties and sizes comparable with biol. structures involved in cellular communication, thus making them promising nanostructures for establishing active interfaces with biol. systems. We report a flexible approach to interface NW field-effect transistors (NWFETs) with cells and demonstrate this for silicon NWFET arrays coupled to embryonic chicken cardiomyocytes. Cardiomyocyte cells were cultured on thin, optically transparent polydimethylsiloxane (PDMS) sheets and then brought into contact with Si-NWFET arrays fabricated on std. substrates. NWFET conductance signals recorded from cardiomyocytes exhibited excellent signal-to-noise ratios with values routinely > 5 and signal amplitudes that were tuned by varying device sensitivity through changes in water gate-voltage potential, Vg. Signals recorded from cardiomyocytes for Vg from -0.5 to +0.1 V exhibited amplitude variations from 31 to 7 nS whereas the calibrated voltage remained const., indicating a robust NWFET/cell interface. In addn., signals recorded as a function of increasing/decreasing displacement of the PDMS/cell support to the device chip showed a reversible >2× increase in signal amplitude (calibrated voltage) from 31 nS (1.0 mV) to 72 nS (2.3 mV). Studies with the displacement close to but below the point of cell disruption yielded calibrated signal amplitudes as large as 10.5 ± 0.2 mV. Last, multiplexed recording of signals from NWFET arrays interfaced to cardiomyocyte monolayers enabled temporal shifts and signal propagation to be detd. with good spatial and temporal resoln. Our modular approach simplifies the process of interfacing cardiomyocytes and other cells to high-performance Si-NWFETs, thus increasing the exptl. versatility of NWFET arrays and enabling device registration at the subcellular level.
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    18. 18
      Dai, X.; Zhou, W.; Gao, T.; Liu, J.; Lieber, C. M. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues. Nat. Nanotechnol. 2016, 11 (9), 776– 82,  DOI: 10.1038/nnano.2016.96
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      18
      Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues
      Dai, Xiaochuan; Zhou, Wei; Gao, Teng; Liu, Jia; Lieber, Charles M.
      Nature Nanotechnology (2016), 11 (9), 776-782CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      Real-time mapping and manipulation of electrophysiol. in three-dimensional (3D) tissues could have important impacts on fundamental scientific and clin. studies, yet realization is hampered by a lack of effective methods. Here the authors introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and a submillisecond temporal resoln. Real-time extracellular action potential (AP) recordings reveal quant. maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topol. of 3D conducting pathways in developing cardiac tissues and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. The authors further demonstrate simultaneous multisite stimulation and mapping to actively manipulate the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacol. and electronic therapeutics.
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    19. 19
      Tsai, D.; Sawyer, D.; Bradd, A.; Yuste, R.; Shepard, K. L. A very large-scale microelectrode array for cellular-resolution electrophysiology. Nat. Commun. 2017, 8, 1802,  DOI: 10.1038/s41467-017-02009-x
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      19
      A very large-scale microelectrode array for cellular-resolution electrophysiology
      Tsai David; Sawyer Daniel; Bradd Adrian; Yuste Rafael; Shepard Kenneth L
      Nature communications (2017), 8 (1), 1802 ISSN:.
      In traditional electrophysiology, spatially inefficient electronics and the need for tissue-to-electrode proximity defy non-invasive interfaces at scales of more than a thousand low noise, simultaneously recording channels. Using compressed sensing concepts and silicon complementary metal-oxide-semiconductors (CMOS), we demonstrate a platform with 65,536 simultaneously recording and stimulating electrodes in which the per-electrode electronics consume an area of 25.5 μm by 25.5 μm. Application of this platform to mouse retinal studies is achieved with a high-performance processing pipeline with a 1 GB/s data rate. The platform records from 65,536 electrodes concurrently with a ~10 μV r.m.s. noise; senses spikes from more than 34,000 electrodes when recording across the entire retina; automatically sorts and classifies greater than 1700 neurons following visual stimulation; and stimulates individual neurons using any number of the 65,536 electrodes while observing spikes over the entire retina. The approaches developed here are applicable to other electrophysiological systems and electrode configurations.
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    20. 20
      Tian, B.; Lieber, C. M. Nanowired Bioelectric Interfaces. Chem. Rev. 2019, 119 (15), 9136– 9152,  DOI: 10.1021/acs.chemrev.8b00795
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      20
      Nanowired Bioelectric Interfaces
      Tian, Bozhi; Lieber, Charles M.
      Chemical Reviews (Washington, DC, United States) (2019), 119 (15), 9136-9152CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Biol. systems have evolved biochem., elec., mech., and genetic networks to perform essential functions across various length and time scales. High-aspect-ratio biol. nanowires, such as bacterial pili and neurites, mediate many of the interactions and homeostasis in and between these networks. Synthetic materials designed to mimic the structure of biol. nanowires could also incorporate similar functional properties, and exploiting this structure-function relationship has already proved fruitful in designing biointerfaces. Semiconductor nanowires are a particularly promising class of synthetic nanowires for biointerfaces, given (1) their unique optical and electronic properties and (2) their high degree of synthetic control and versatility. These characteristics enable fabrication of a variety of electronic and photonic nanowire devices, allowing for the formation of well-defined, functional bioelec. interfaces at the biomol. level to the whole-organ level. In this Focus Review, we first discuss the history of bioelec. interfaces with semiconductor nanowires. We next highlight several important, endogenous biol. nanowires and use these as a framework to categorize semiconductor nanowire-based biointerfaces. Within this framework we then review the fundamentals of bioelec. interfaces with semiconductor nanowires and comment on both material choice and device design to form biointerfaces spanning multiple length scales. We conclude with a discussion of areas with the potential for greatest impact using semiconductor nanowire-enabled biointerfaces in the future.
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      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 (8), 783– 790,  DOI: 10.1038/s41565-019-0478-y
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      21
      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.
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    22. 22
      Eschermann, J. F.; Stockmann, R.; Hueske, M.; Vu, X. T.; Ingebrandt, S.; Offenhäusser, A. Action potentials of HL-1 cells recorded with silicon nanowire transistors. Appl. Phys. Lett. 2009, 95 (8), 083703  DOI: 10.1063/1.3194138
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      Action potentials of HL-1 cells recorded with silicon nanowire transistors
      Eschermann, Jan Felix; Stockmann, Regina; Hueske, Martin; Vu, Xuan Thang; Ingebrandt, Sven; Offenhaeusser, Andreas
      Applied Physics Letters (2009), 95 (8), 083703/1-083703/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
      Silicon nanowire (NW) transistors were fabricated in a top-down process. These devices were used to record the extracellular potential of the spontaneous activity of cardiac muscle HL-1 cells. their signals were measured by direct dc sampling of the drain current. An improved signal-to-noise ratio compared to planar field-effect devices was obsd. Furthermore the signal shape was evaluated and could be assocd. to different membrane currents. With these expts., a qual. description of the properties of the cell-NW contact was obtained and the suitability of these sensors for electrophysiol. measurements in vitro was demonstrated. (c) 2009 American Institute of Physics.
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      Xie, C.; Lin, Z.; Hanson, L.; Cui, Y.; Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotechnol. 2012, 7 (3), 185– 90,  DOI: 10.1038/nnano.2012.8
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      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.
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    24. 24
      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 (6), 3932– 3939,  DOI: 10.1021/acs.nanolett.7b01523
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      24
      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.
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      Fendyur, A.; Spira, M. E. Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes. Front. Neuroeng. 2012, 5, 21,  DOI: 10.3389/fneng.2012.00021
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      Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes
      Fendyur, Anna; Spira, Micha E.
      Frontiers in Neuroengineering (2012), 5 (Aug.), 21CODEN: FNREIF; ISSN:1662-6443. (Frontiers Media S.A.)
      Cardiol. research greatly rely on the use of cultured primary cardiomyocytes (CMs). The prime methodol. to assess CM network electrophysiol. is based on the use of extracellular recordings by substrate-integrated planar Micro-Electrode Arrays (MEAs). Whereas this methodol. permits simultaneous, long-term monitoring of the CM elec. activity, it limits the information to extracellular field potentials (FPs). The alternative method of intracellular action potentials (APs) recordings by sharp- or patch-microelectrodes is limited to a single cell at a time. Here, we began to merge the advantages of planar MEA and intracellular microelectrodes. To that end we cultured rat CM on micrometer size protruding gold mushroom-shaped microelectrode (gMμEs) arrays. Cultured CMs engulf the gMμE permitting FPs recordings from individual cells. Local electroporation of a CM converts the extracellular recording configuration to attenuated intracellular APs with shape and duration similar to those recorded intracellularly. The procedure enables to simultaneously record APs from an unlimited no. of CMs. The electroporated membrane spontaneously recovers. This allows for repeated recordings from the same CM a no. of times (>8) for over 10 days. The further development of CM-gMμE configuration opens up new venues for basic and applied biomedical research.
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    26. 26
      Desbiolles, B. X. E.; de Coulon, E.; Bertsch, A.; Rohr, S.; Renaud, P. Intracellular Recording of Cardiomyocyte Action Potentials with Nanopatterned Volcano-Shaped Microelectrode Arrays. Nano Lett. 2019, 19 (9), 6173– 6181,  DOI: 10.1021/acs.nanolett.9b02209
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      26
      Intracellular Recording of Cardiomyocyte Action Potentials with Nanopatterned Volcano-Shaped Microelectrode Arrays
      Desbiolles, B. X. E.; de Coulon, E.; Bertsch, A.; Rohr, S.; Renaud, P.
      Nano Letters (2019), 19 (9), 6173-6181CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Micronanotechnol.-based multielectrode arrays have led to remarkable progress in the field of transmembrane voltage recording of excitable cells. However, providing long-term optoporation- or electroporation-free intracellular access remains a considerable challenge. In this study, a novel type of nanopatterned volcano-shaped microelectrode (nanovolcano) is described that spontaneously fuses with the cell membrane and permits stable intracellular access. The complex nanostructure was manufd. following a simple and scalable fabrication process based on ion beam etching redeposition. The resulting ring-shaped structure provided passive intracellular access to neonatal rat cardiomyocytes. Intracellular action potentials were successfully recorded in vitro from different devices, and continuous recording for more than 1 h was achieved. By reporting transmembrane action potentials at potentially high spatial resoln. without the need to apply phys. triggers, the nanovolcanoes show distinct advantages over multielectrode arrays for the assessment of electrophysiol. characteristics of cardiomyocyte networks at the transmembrane voltage level over time.
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    27. 27
      Chen, T.; Vunjak-Novakovic, G. In vitro Models of Ischemia-Reperfusion Injury. Regen Eng. Transl Med. 2018, 4 (3), 142– 153,  DOI: 10.1007/s40883-018-0056-0
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      In vitro Models of Ischemia-Reperfusion Injury
      Chen Timothy; Vunjak-Novakovic Gordana; Vunjak-Novakovic Gordana
      Regenerative engineering and translational medicine (2018), 4 (3), 142-153 ISSN:2364-4133.
      Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human induced pluripotent stem cells (hIPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hIPS-CMs are relatively fetal in phenotype, and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic.
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    28. 28
      White, S. M.; Constantin, P. E.; Claycomb, W. C. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. Am. J. Physiol-Heart C 2004, 286 (3), H823– H829,  DOI: 10.1152/ajpheart.00986.2003
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      Teixeira, G.; Abrial, M.; Portier, K.; Chiari, P.; Couture-Lepetit, E.; Tourneur, Y.; Ovize, M.; Gharib, A. Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes. J. Mol. Cell. Cardiol. 2013, 56, 55– 62,  DOI: 10.1016/j.yjmcc.2012.11.023
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      29
      Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes
      Teixeira, Geoffrey; Abrial, Maryline; Portier, Karine; Chiari, Pascal; Couture-Lepetit, Elisabeth; Tourneur, Yves; Ovize, Michel; Gharib, Abdallah
      Journal of Molecular and Cellular Cardiology (2013), 56 (), 55-62CODEN: JMCDAY; ISSN:0022-2828. (Elsevier B.V.)
      Reperfusion of the heart after an ischemic event leads to the opening of a nonspecific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening is an effective strategy to prevent cardiomyocyte death. The matrix protein cyclophilin-D (CypD) is the best-known regulator of mPTP opening. In this study we confirmed that preconditioning and postconditioning with CypD inhibitor cyclosporin-A (CsA) reduced cell death after hypoxia-reoxygenation (H/R) in wild-type (WT) cardiomyocytes and HL-1 mouse cardiac cell line as measured by nuclear staining with propidium iodide. The complex I inhibitor rotenone (Rot), alone, had no effect on HL-1 and WT cardiomyocyte death after H/R, but enhanced the native protection of CypD-knocked-out (CypD KO) cardiomyocytes. Redn. of cell death was assocd. with a delay of mPTP opening challenged by H/R and obsd. by the calcein loading CoCl2-quenching technique. Simultaneous inhibition of complex I and CypD increased in a synergistic manner the calcium retention capacity in permeabilized cardiomyocytes and cardiac mitochondria. These results demonstrated that protection by complex I inhibition was CypD dependent.
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    30. 30
      Maoz, B. M.; Herland, A.; Henry, O. Y. F.; Leineweber, W. D.; Yadid, M.; Doyle, J.; Mannix, R.; Kujala, V. J.; FitzGerald, E. A.; Parker, K. K.; Ingber, D. E. Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab Chip 2017, 17 (13), 2294– 2302,  DOI: 10.1039/C7LC00412E
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      Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities
      Maoz, Ben M.; Herland, Anna; Henry, Olivier Y. F.; Leineweber, William D.; Yadid, Moran; Doyle, John; Mannix, Robert; Kujala, Ville J.; FitzGerald, Edward A.; Parker, Kevin Kit; Ingber, Donald E.
      Lab on a Chip (2017), 17 (13), 2294-2302CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
      Here we demonstrate that microfluidic cell culture devices, known as Organs-on-a-Chips can be fabricated with multifunctional, real-time, sensing capabilities by integrating both multi-electrode arrays (MEAs) and electrodes for transepithelial elec. resistance (TEER) measurements into the chips during their fabrication. To prove proof-of-concept, simultaneous measurements of cellular elec. activity and tissue barrier function were carried out in a dual channel, endothelialized, heart-on-a-chip device contg. human cardiomyocytes and a channel-sepg. porous membrane covered with a primary human endothelial cell monolayer. These studies confirmed that the TEER-MEA chip can be used to simultaneously detect dynamic alterations of vascular permeability and cardiac function in the same chip when challenged with the inflammatory stimulus tumor necrosis factor alpha (TNF-a) or the cardiac targeting drug isoproterenol. Thus, this Organ Chip with integrated sensing capability may prove useful for real-time assessment of biol. functions, as well as response to therapeutics.
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    31. 31
      Yang, M.; Lim, C. C.; Liao, R.; Zhang, X. A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy. Biosens. Bioelectron. 2007, 22 (8), 1688– 93,  DOI: 10.1016/j.bios.2006.07.032
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      A novel microfluidic impedance assay for monitoring endothelin-induced cardiomyocyte hypertrophy
      Yang, Mo; Lim, Chee Chew; Liao, Ronglih; Zhang, Xin
      Biosensors & Bioelectronics (2007), 22 (8), 1688-1693CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      Cardiac hypertrophy is an established and independent risk factor for the development of heart failure and sudden cardiac death. At the level of individual cardiac myocytes (heart muscle cells), the cell morphol. alters (increase in cell size and myofibrillar re-organization) and protein synthesis is activated. In this paper, a novel cardiomyocyte-based impedance sensing system with the assistance of dielectrophoresis cell concn. is reported to monitor the dynamic process of endothelin-1-induced cardiomyocyte hypertrophy. A dielectrophoresis (DEP) microfluidic device is fabricated capable of concg. cells from a dil. sample to form a confluent cell monolayer on the surface of microelectrodes. This device can increase the sensitivity of the impedance system and also has the potential to reduce the time for detection by a significant factor. To examine the feasibility of this impedance sensing system, cardiomyocytes are treated with endothelin-1, a known hypertrophic agent. ET-1 induces a continuous rise in cardiomyocyte impedance, which the authors interpret as strengthening of cellular attachments to the surface substrate. An equivalent circuit model is introduced to fit the impedance spectrum to fully understand the impedance sensing system.
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      Yang, Z.; Murray, K. T. Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells. J. Cardiovasc. Pharmacol. 2011, 57 (1), 28– 36,  DOI: 10.1097/FJC.0b013e3181fda7c4
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      Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells
      Yang, Zhenjiang; Murray, Katherine T.
      Journal of Cardiovascular Pharmacology (2011), 57 (1), 28-36CODEN: JCPCDT; ISSN:0160-2446. (Lippincott Williams & Wilkins)
      Although normally absent, spontaneous pacemaker activity can develop in human atrium to promote tachyarrhythmias. HL-1 cells are immortalized atrial cardiomyocytes that contract spontaneously in culture, providing a model system of atrial cell automaticity. Using electrophysiol. recordings and selective pharmacol. blockers, we investigated the ionic basis of automaticity in atrial HL-1 cells. Both the sarcoplasmic reticulum Ca release channel inhibitor ryanodine and the sarcoplasmic reticulum Ca ATPase inhibitor thapsigargin slowed automaticity, supporting a role for intracellular Ca release in pacemaker activity. Addnl. expts. were performed to examine the effects of ionic currents activating in the voltage range of diastolic depolarization. Inhibition of the hyperpolarization-activated pacemaker current, If, by ivabradine significantly suppressed diastolic depolarization, with modest slowing of automaticity. Block of inward Na currents also reduced automaticity, whereas inhibition of T- and L-type Ca currents caused milder effects to slow beat rate. The major outward current in HL-1 cells is the rapidly activating delayed rectifier, IKr. Inhibition of IKr using dofetilide caused marked prolongation of action potential duration and thus spontaneous cycle length. These results demonstrate a mutual role for both intracellular Ca release and sarcolemmal ionic currents in controlling automaticity in atrial HL-1 cells. Given that similar internal and membrane-based mechanisms also play a role in sinoatrial nodal cell pacemaker activity, our findings provide evidence for generalized conservation of pacemaker mechanisms among different types of cardiomyocytes.
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    33. 33
      Martins-Marques, T.; Anjo, S. I.; Pereira, P.; Manadas, B.; Girao, H. Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart. Mol. Cell. Proteomics 2015, 14 (11), 3040– 55,  DOI: 10.1074/mcp.M115.052894
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      Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart
      Martins-Marques, Tania; Anjo, Sandra Isabel; Pereira, Paulo; Manadas, Bruno; Girao, Henrique
      Molecular & Cellular Proteomics (2015), 14 (11), 3040-3055CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
      The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-contg. channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been assocd. with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the mol. mechanisms underlying pathol. malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biol. functions of Cx43. In the present report, we applied a quant. SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemia-reperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biol. processes such as metab., signaling and trafficking. The interaction of Cx43 with proteins involved in gene transcription strengthens the emerging concept that Cx43 has a role in gene expression regulation. Importantly, our data shows that the interactome of Cx43 (Connexome) is differentially modulated in diseased hearts. Overall, the characterization of Cx43-interacting network may contribute to the establishment of new therapeutic targets to modulate cardiac function in physiol. and pathol. conditions. Data are available via ProteomeXchange with identifier PXD002331.
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      Semenza, G. L. Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 2014, 76, 39– 56,  DOI: 10.1146/annurev-physiol-021113-170322
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      Hypoxia-inducible factor 1 and cardiovascular disease
      Semenza, Gregg L.
      Annual Review of Physiology (2014), 76 (), 39-56CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews)
      A review. Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metab. and redox homeostasis. Anal. of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a crit. protective role in the pathophysiol. of ischemic heart disease and pressure-overload heart failure.
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    35. 35
      Chu, W.; Wan, L.; Zhao, D.; Qu, X.; Cai, F.; Huo, R.; Wang, N.; Zhu, J.; Zhang, C.; Zheng, F.; Cai, R.; Dong, D.; Lu, Y.; Yang, B. Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1alpha-mediated TRPC signalling. J. Cell Mol. Med. 2012, 16 (9), 2022– 34,  DOI: 10.1111/j.1582-4934.2011.01497.x
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      Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signalling
      Chu, Wenfeng; Wan, Lin; Zhao, Dan; Qu, Xuefeng; Cai, Fulai; Huo, Rong; Wang, Ning; Zhu, Jiuxin; Zhang, Chun; Zheng, Fangfang; Cai, Ruijun; Dong, Deli; Lu, Yanjie; Yang, Baofeng
      Journal of Cellular and Molecular Medicine (2012), 16 (9), 2022-2034CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
      Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study was designed to investigate the role of HIF-1α in mild hypoxia-induced cardiomyocytes hypertrophy and its underlying mechanism. Mild hypoxia (MH, 10% O2) caused hypertrophy in cultured neonatal rat cardiac myocytes, which was accompanied with increase of HIF-1α mRNA and accumulation of HIF-1α protein in nuclei. Transient receptor potential canonical (TRPC) channels including TRPC3 and TRPC6, except for TRPC1, were increased, and Ca2+-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca2+-calcineurin signals were inhibited by an HIF-1α specific blocker, SC205346 (30 μM), whereas promoted by HIF-1α overexpression. Electrophysiol. voltage-clamp demonstrated that DAG analog, OAG (30 μM), induced TRPC current by as much as 170% in neonatal rat cardiomyocytes overexpressing HIF-1α compared to neg. control. These results implicate that HIF-1α plays a key role in development of cardiac hypertrophy in responses to hypoxic stress. Its mechanism is assocd. with up-regulating TRPC3, TRPC6 expression, activating TRPC current and subsequently leading to enhanced Ca2+-calcineurin signals.
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      Lee, J. W.; Ko, J.; Ju, C.; Eltzschig, H. K. Hypoxia signaling in human diseases and therapeutic targets. Exp. Mol. Med. 2019, 51 (6), 68,  DOI: 10.1038/s12276-019-0235-1
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      Semenza, G.; Hydroxylation, L. of HIF-1: Oxygen Sensing at the Molecular Level. Physiology 2004, 19 (4), 176– 182,  DOI: 10.1152/physiol.00001.2004
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      Hydroxylation of HIF-1: Oxygen sensing at the molecular level
      Semenza, Gregg L.
      Physiology (2004), 19 (Aug.), 176-182CODEN: PHYSCI; ISSN:1548-9213. (International Union of Physiological Sciences)
      A review. The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in Po2 are transduced to effect changes in gene expression.
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      Yeung, C. K.; Sommerhage, F.; Wrobel, G.; Law, J. K.; Offenhausser, A.; Rudd, J. A.; Ingebrandt, S.; Chan, M. To establish a pharmacological experimental platform for the study of cardiac hypoxia using the microelectrode array. J. Pharmacol. Toxicol. Methods 2009, 59 (3), 146– 52,  DOI: 10.1016/j.vascn.2009.02.005
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      To establish a pharmacological experimental platform for the study of cardiac hypoxia using the microelectrode array
      Yeung, Chi-Kong; Sommerhage, Frank; Wrobel, Guenter; Law, Jessica Ka-Yan; Offenhaeusser, Andreas; Rudd, John Anthony; Ingebrandt, Sven; Chan, Mansun
      Journal of Pharmacological and Toxicological Methods (2009), 59 (3), 146-152CODEN: JPTMEZ; ISSN:1056-8719. (Elsevier)
      Simultaneous recording of elec. potentials from multiple cells may be useful for physiol. and pharmacol. research. The present study aimed to establish an in vitro cardiac hypoxia exptl. platform on the microelectrode array (MEA). Embryonic rat cardiac myocytes were cultured on the MEAs. Following ≥ 90 min of hypoxia, changes in lactate prodn. (mM), pH, beat frequency (beats per min, bpm), extracellular action potential (exAP) amplitude, and propagation velocity between the normoxic and hypoxic cells were compared. Under hypoxia, the beat frequency of cells increased and peaked at around 42.5 min (08.1 ± 3.2 bpm). The exAP amplitude reduced as soon as the cells were exposed to the hypoxic medium, and this redn. increased significantly after approx. 20 min of hypoxia. The propagation velocity of the hypoxic cells was significantly lower than that of the control throughout the entire 90+ min of hypoxia. The rate of depolarization and Na+ signal gradually reduced over time, and these changes had a direct effect on the exAP duration. The extracellular electrophysiol. measurements allow a partial reconstruction of the signal shape and time course of the underlying hypoxia-assocd. physiol. changes. The present study showed that the cardiac myocyte-integrated MEA may be used as an exptl. platform for the pharmacol. studies of cardiovascular diseases in the future.
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      Cascio, W. E.; Yang, H.; Muller-Borer, B. J.; Johnson, T. A. Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation. J. Electrocardiol 2005, 38 (4 Suppl), 55– 59,  DOI: 10.1016/j.jelectrocard.2005.06.019
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      Ischemia-induced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation
      Cascio Wayne E; Yang Hua; Muller-Borer Barbara J; Johnson Timothy A
      Journal of electrocardiology (2005), 38 (4 Suppl), 55-9 ISSN:0022-0736.
      Sudden cardiac death accounts for more than half of all cardiovascular deaths in the US, and a large proportion of these deaths are attributed to ischemia-induced ventricular fibrillation. As such, the mechanisms underlying the initiation and maintenance of these lethal rhythms are of significant clinical and scientific interest. In large animal hearts, regional ischemia induces two phases of ventricular arrhythmia. The first phase (1A) occurs between 5 and 7 min after arrest of perfusion. This phase is associated with membrane depolarization, a mild intracellular and extracellular acidification and a small membrane depolarization. A second phase (1B) of ventricular arrhythmia occurs between 20 and 30 minutes after arrest of perfusion. This phase occurs at a time when ischemia-induced K+ and pH changes are relatively stable. The arrhythmia is presumed to relate to the process of cell-to-cell electrical uncoupling because a rapid increase of tissue impedance precedes the onset of the arrhythmia. Of note is that tissue resistance is primarily determined by the conductance properties of the gap junctions accounting for cell-to-cell coupling. Impulse propagation in heart is determined by active and passive membrane properties. An important passive cable property that is modulated by ischemia is intercellular resistance and is determined primarily by gap junctional conductance. As such changes in Impulse propagation during myocardial ischemia are determined by contemporaneous changes in active and passive membrane properties. Cellular K loss, intracellular and extracellular acidosis and membrane depolarization are important factors decreasing excitatory currents, while the collapse of the extracellular compartment and cell-to-cell electrical uncoupling increase the resistance to current flow. The time-course of cellular coupling is closely linked to a number of physiological processes including depletion of ATP, and accumulation of intracellular Ca2+. Hence, interventions such as ischemic preconditioning attenuate the effect of subsequent ischemia, delay the onset of cell-to-cell electrical uncoupling and likewise delay the onset of ischemia-induced arrhythmia.
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      Lujan, H. L.; DiCarlo, S. E. Reperfusion-induced sustained ventricular tachycardia, leading to ventricular fibrillation, in chronically instrumented, intact, conscious mice. Physiol. Rep. 2014, 2 (6), e12057,  DOI: 10.14814/phy2.12057
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      Dang, K. M.; Rinklin, P.; Afanasenkau, D.; Westmeyer, G.; Schurholz, T.; Wiegand, S.; Wolfrum, B. Chip-Based Heat Stimulation for Modulating Signal Propagation in HL-1 Cell Networks. Adv. Biosyst 2018, 2 (12), 1800138,  DOI: 10.1002/adbi.201800138
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      Claycomb, W. C.; Lanson, N. A.; Stallworth, B. S.; Egeland, D. B.; Delcarpio, J. B.; Bahinski, A.; Izzo, N. J. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (6), 2979– 2984,  DOI: 10.1073/pnas.95.6.2979
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      HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte
      Claycomb, William C.; Lanson, Nicholas A., Jr.; Stallworth, Beverly S.; Egeland, Daniel B.; Delcarpio, Joseph B.; Bahinski, Anthony; Izzo, Nicholas J., Jr.
      Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (6), 2979-2984CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The authors derived a cardiac muscle cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 cells can be serially passaged, yet they maintain the ability to contract and retain differentiated cardiac morphol., biochem., and electrophysiol. properties. Ultrastructural characteristics typical of embryonic atrial myocytes, were found consistently in the cultured HL-1 cells. RT-PCR-based anal. confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of α-cardiac myosin heavy chain, α-cardiac actin, and connexin 43. They also expressed the gene for atrial natriuretic factor. Immunohistochem. staining of the HL-1 cells indicated that the distribution of the cardiac-specific markers, desmin, sarcomeric myosin, and atrial natriuretic factor, was similar to that of cultured atrial cardiomyocytes. A delayed rectifier K+ current (IKr) was the most prominent outward current in HL-1 cells. The activating currents desplayed inward rectification and deactivating current tails, were voltage-dependent, satd. at »+20 mV, and were highly sensitive to dofetilide (IC50 = 46.9 nM). Specific binding of [3H]dofetilide was saturable and fit a 1-site binding isotherm with a Kd of 140 ±60 nM and a Bmax of 118 fmol per 105 cells. HL-1 cells represent a cardiac myocyte cell line that can be repeatedly passaged and yet maintain a cardiac-specific phenotype.
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    43. 43
      Lin, Z. C.; McGuire, A. F.; Burridge, P. W.; Matsa, E.; Lou, H.-Y.; Wu, J. C.; Cui, B. Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease. Microsystems & Nanoengineering 2017, 3, 16080,  DOI: 10.1038/micronano.2016.80
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      43
      Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease
      Lin, Ziliang Carter; McGuire, Allister F.; Burridge, Paul W.; Matsa, Elena; Lou, Hsin-Ya; Wu, Joseph C.; Cui, Bianxiao
      Microsystems & Nanoengineering (2017), 3 (), 16080CODEN: MNIACT; ISSN:2055-7434. (Nature Publishing Group)
      The measurement of the electrophysiol. of human pluripotent stem cell-derived cardiomyocytes is crit. for their biomedical applications, from disease modeling to drug screening. Yet, a method that enables the high-throughput intracellular electrophysiol. measurement of single cardiomyocytes in adherent culture is not available. To address this area, we have fabricated vertical nanopillar electrodes that can record intracellular action potentials from up to 60 single beating cardiomyocytes. Intracellular access is achieved by highly localized electroporation, which allows for low impedance elec. access to the intracellular voltage. Herein, we demonstrate that this method provides the accurate measurement of the shape and duration of intracellular action potentials, validated by patch clamp, and can facilitate cellular drug screening and disease modeling using human pluripotent stem cells. This study validates the use of nanopillar electrodes for myriad further applications of human pluripotent stem cell-derived cardiomyocytes such as cardiomyocyte maturation monitoring and electrophysiol.-contractile force correlation.
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    44. 44
      Shaw, R. M.; Rudy, Y. Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration. Cardiovasc. Res. 1997, 35 (2), 256– 72,  DOI: 10.1016/S0008-6363(97)00093-X
      Google Scholar
      44
      Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration
      Shaw R M; Rudy Y
      Cardiovascular research (1997), 35 (2), 256-72 ISSN:0008-6363.
      OBJECTIVE: To study the ionic mechanisms of electrophysiologic changes in cell excitability and action potential duration during the acute phase of myocardial ischemia. METHODS: Using an ionic-based theoretical model of the cardiac ventricular cell, the dynamic LRd model, we have simulated the three major component conditions of acute ischemia (elevated [K]o, acidosis and anoxia) at the level of individual ionic currents and ionic concentrations. The conditions were applied individually and in combination to identify ionic mechanisms responsible for reduced excitability at rest potentials, delayed recovery of excitability, and shortened action potential duration. RESULTS: Increased extracellular potassium ([K]o) had the major effect on cell excitability by depolarizing resting membrane potential (Vrest), causing reduction in sodium channel availability. Acidosis caused a [K]o-independent reduction in maximum upstroke velocity, (dVm/dt)max. A transition from sodium-current dominated to calcium-current dominated upstroke occurred, and calcium current alone was able to sustain the upstroke, but only after sodium channels were almost completely (97%) inactivated. Acidic conditions prevented the transition to calcium dominated upstroke by acidic reduction of both sodium and calcium currents. Anoxia, simulated by lowering [ATP]i and activating the APT-dependent potassium current, IK(ATP), was the only process that could decrease action potential duration by more than 50% and reproduce AP shape changes that are observed experimentally. Acidic or anoxic depression of the L-type calcium current could not reproduce the observed action potential shape changes and APD shortening. Delayed recovery of excitability, known as 'post-repolarization refractoriness', was determined by the voltage-dependent kinetics of sodium channel recovery; Vrest depolarization caused by elevated [K]o increased the time constant of (dVm/dt)max recovery from tau = 10.3 ms at [K]o = 4.5 mM to tau = 81.4 ms at [K]o = 12 mM, reflecting major slowing of sodium-channel recovery. Anoxia and acidosis had little affect on tau. CONCLUSIONS: The major conditions of acute ischemia, namely elevated [K]o, acidosis and anoxia, applied at the ionic channel level are sufficient to simulate the major electrical changes associated with ischemia. Depression of membrane excitability and delayed recovery of excitability in the single, unloaded cell are caused by elevated [K]o with additional excitability depression by acidosis. Major changes in action potential duration and shape can only be accounted for by anoxia-dependent opening of IK(ATP).
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    45. 45

      These speeds are on the same order as those derived from extracellular electrodes. We note however that they do not represent the true wavefront velocity but rather a projection along the direction of the linear electrode array.

      There is no corresponding record for this reference.
    46. 46
      Sartiani, L.; Bochet, P.; Cerbai, E.; Mugelli, A.; Fischmeister, R. Functional expression of the hyperpolarization-activated, non-selective cation current I(f) in immortalized HL-1 cardiomyocytes. J. Physiol. 2002, 545 (1), 81– 92,  DOI: 10.1113/jphysiol.2002.021535
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      46
      Functional expression of the hyperpolarization-activated, non-selective cation current If in immortalized HL-1 cardiomyocytes
      Sartiani, Laura; Bochet, Pascal; Cerbai, Elisabetta; Mugelli, Alessandro; Fischmeister, Rodolphe
      Journal of Physiology (Cambridge, United Kingdom) (2002), 545 (1), 81-92CODEN: JPHYA7; ISSN:0022-3751. (Cambridge University Press)
      HL-1 cells are adult mouse atrial myocytes induced to proliferate indefinitely by SV40 large T antigen. These cells beat spontaneously when confluent and express several adult cardiac cell markers including the outward delayed rectifier K+ channel. Here, we examd. the presence of a hyperpolarization-activated If current in HL-1 cells using the whole-cell patch-clamp technique on isolated cells enzymically dissocd. from the culture at confluence. Cell membrane capacitance (Cm) ranged from 5 to 53 pF. If was detected in about 30% of the cells, and its occurrence was independent of the stage of the culture. If maximal slope conductance was 89.7 ± 0.4 pS pF-1 (n = 10). If current in HL-1 cells showed typical characteristics of native cardiac If current: activation threshold between -50 and -60 mV, half-maximal activation potential of -83.1 ± 0.7 mV (n = 50), reversal potential at -20.8 ± 1.5 mV (n = 10), time-dependent activation by hyperpolarization and blockade by 4 mM Cs+. In half of the cells tested, activation of adenylyl cyclase by the forskolin analog L858051 (20 μM) induced both a ∼6 mV pos. shift of the half-activation potential and a ∼37% increase in the fully activated If current. RT-PCR anal. of the hyperpolarization-activated, cyclic nucleotide-gated channels (HCN) expressed in HL-1 cells demonstrated major contributions of HCN1 and HCN2 channel isoforms to If current. Cytosolic Ca2+ oscillations in spontaneously beating HL-1 cells were measured in Fluo-3 AM-loaded cells using a fast-scanning confocal microscope. The oscillation frequency ranged from 1.3 to 5 Hz, and the spontaneous activity was stopped in the presence of 4 mM Cs+. Action potentials from HL-1 cells had a triangular shape, with an overshoot at +15 mV and a maximal diastolic potential of -69 mV, i.e. more neg. than the threshold potential for If activation. In conclusion, HL-1 cells display a hyperpolarization-activated If current, which might contribute to the spontaneous contractile activity of these cells.
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    47. 47
      Dias, P.; Desplantez, T.; El-Harasis, M. A.; Chowdhury, R. A.; Ullrich, N. D.; Cabestrero de Diego, A.; Peters, N. S.; Severs, N. J.; MacLeod, K. T.; Dupont, E. Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line. PLoS One 2014, 9 (2), e90266  DOI: 10.1371/journal.pone.0090266
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      47
      Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line
      Dias, Priyanthi; Desplantez, Thomas; El-Harasis, Majd A.; Chowdhury, Rasheda A.; Ullrich, Nina D.; de Diego, Alberto Cabestrero; Peters, Nicholas S.; Severs, Nicholas J.; MacLeod, Kenneth T.; Dupont, Emmanuel
      PLoS One (2014), 9 (2), e90266/1-e90266/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The HL-1 atrial line contains cells blocked at various developmental stages. To obtain homogeneous sub-clones and correlate changes in gene expression with functional alterations, individual clones were obtained and characterized for parameters involved in conduction and excitation-contraction coupling. Northern blots for mRNAs coding for connexins 40, 43 and 45 and calcium handling proteins (sodium/calcium exchanger, L- and T-type calcium channels, ryanodine receptor 2 and sarco-endoplasmic reticulum calcium ATPase 2) were performed. Connexin expression was further characterized by western blots and immunofluorescence. Inward currents were characterized by voltage clamp and conduction velocities measured using microelectrode arrays. The HL-1 clones had similar sodium and calcium inward currents with the exception of clone 2 which had a significantly smaller calcium c.d. All the clones displayed homogeneous propagation of elec. activity across the monolayer correlating with the levels of connexin expression. Conduction velocities were also more sensitive to inhibition of junctional coupling by carbenoxolone (∼80%) compared to inhibition of the sodium current by lidocaine (∼20%). Elec. coupling by gap junctions was the major determinant of conduction velocities in HL-1 cell lines. In summary we have isolated homogeneous and stable HL-1 clones that display characteristics distinct from the heterogeneous properties of the original cell line.
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    48. 48
      Hafez, P.; Chowdhury, S. R.; Jose, S.; Law, J. X.; Ruszymah, B. H. I.; Ramzisham, A. R. M.; Ng, M. H. Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes. Cardiovasc Eng. Techn 2018, 9 (3), 529– 538,  DOI: 10.1007/s13239-018-0368-8
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      There is no corresponding record for this reference.
    49. 49
      Zhu, R. J.; Millrod, M. A.; Zambidis, E. T.; Tung, L. Variability of Action Potentials Within and Among Cardiac Cell Clusters Derived from Human Embryonic Stem Cells. Sci. Rep. 2016, 6, 18544,  DOI: 10.1038/srep18544
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      49
      Variability of Action Potentials Within and Among Cardiac Cell Clusters Derived from Human Embryonic Stem Cells
      Zhu, Renjun; Millrod, Michal A.; Zambidis, Elias T.; Tung, Leslie
      Scientific Reports (2016), 6 (), 18544CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Electrophysiol. variability in cardiomyocytes derived from pluripotent stem cells continues to be an impediment for their scientific and translational applications. We studied the variability of action potentials (APs) recorded from clusters of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using high-resoln. optical mapping. Over 23,000 APs were analyzed through four parameters: APD30, APD80, triangulation and fractional repolarization. Although measures were taken to reduce variability due to cell culture conditions and rate-dependency of APs, we still obsd. significant variability in APs among and within the clusters. However, similar APs were found in spatial locations with close proximity, and in some clusters formed distinct regions having different AP characteristics that were reflected as sep. peaks in the AP parameter distributions, suggesting multiple electrophysiol. phenotypes. Using a recently developed automated method to group cells based on their entire AP shape, we identified distinct regions of different phenotypes within single clusters and common phenotypes across different clusters when sepg. APs into 2 or 3 subpopulations. The systematic anal. of the heterogeneity and potential phenotypes of large populations of hESC-CMs can be used to evaluate strategies to improve the quality of pluripotent stem cell-derived cardiomyocytes for use in diagnostic and therapeutic applications and in drug screening.
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    50. 50
      Abbott, J.; Ye, T.; Qin, L.; Jorgolli, M.; Gertner, R. S.; Ham, D.; Park, H. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nat. Nanotechnol. 2017, 12 (5), 460– 466,  DOI: 10.1038/nnano.2017.3
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      50
      CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging
      Abbott, Jeffrey; Ye, Tianyang; Qin, Ling; Jorgolli, Marsela; Gertner, Rona S.; Ham, Donhee; Park, Hongkun
      Nature Nanotechnology (2017), 12 (5), 460-466CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      Developing a new tool capable of high-precision electrophysiol. recording of a large network of electrogenic cells has long been an outstanding challenge in neurobiol. and cardiol. Here, the authors combine nanoscale intracellular electrodes with complementary metal-oxide-semiconductor (CMOS) integrated circuits to realize a high-fidelity all-elec. electrophysiol. imager for parallel intracellular recording at the network level. The CMOS nanoelectrode array has 1024 recording/stimulation 'pixels' equipped with vertical nanoelectrodes, and can simultaneously record intracellular membrane potentials from hundreds of connected in vitro neonatal rat ventricular cardiomyocytes. The authors demonstrate that this network-level intracellular recording capability can be used to examine the effect of pharmaceuticals on the delicate dynamics of a cardiomyocyte network, thus opening up new opportunities in tissue-based pharmacol. screening for cardiac and neuronal diseases as well as fundamental studies of electrogenic cells and their networks.
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    51. 51
      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,  DOI: 10.1038/s41551-019-0455-7
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      51
      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.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVarsLfP&md5=ae50c8f680c0548a2130b8a9d0892762
    52. 52
      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 (2), 1509– 13,  DOI: 10.1021/acs.nanolett.6b00020
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      52
      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.
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    53. 53
      Liu, H. T.; Haider, B.; Fried, H. R.; Ju, J.; Bolonduro, O.; Raghuram, V.; Timko, B. P. Nanobiotechnology: 1D nanomaterial building blocks for cellular interfaces and hybrid tissues. Nano Res. 2018, 11 (10), 5372– 5399,  DOI: 10.1007/s12274-018-2189-3
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      There is no corresponding record for this reference.

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    • Movie S1. Spontaneous beating of cells that formed confluent monolayers (MP4)

    • Materials and Methods; Scheme S1. Illustration of microfluidic chip with integrated nanopillar microelectrode arrays; Scheme S2. Strategy to generate hypoxic medium flow; Figure S1. Design of MEA devices; Figure S2. Representative electrical impedance spectra of planar and nanopillar bioelectronic devices; Figure S3. Gap junction localization; Figure S4. HIF-1α validation of heart-on-a-chip; Figure S5. Extracellular bioelectronic readouts before, during, and after hypoxia; Figure S6. Summary of wavefront propagation speeds derived from isochronal map (PDF)


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