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Monitoring Intracranial Cerebral Hemorrhage Using Multicontrast Real-Time Magnetic Particle Imaging

  • Patryk Szwargulski*
    Patryk Szwargulski
    Section for Biomedical Imaging, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
    *Email: [email protected]
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  • , 
  • Maximilian Wilmes
    Maximilian Wilmes
    Department of Neurology, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
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  • , 
  • Ehsan Javidi
    Ehsan Javidi
    Department of Neurology, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
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  • , 
  • Florian Thieben
    Florian Thieben
    Section for Biomedical Imaging, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
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  • , 
  • Matthias Graeser
    Matthias Graeser
    Section for Biomedical Imaging, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
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  • , 
  • Martin Koch
    Martin Koch
    Institute of Medical Engineering, Universität zu Lübeck, Lübeck, DE 23562, Germany
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  • , 
  • Cordula Gruettner
    Cordula Gruettner
    Micromod Partikeltechnologie GmbH, Rostock, DE 18119, Germany
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  • Gerhard Adam
    Gerhard Adam
    Department of Diagnostic and Interventional Radiology and Nuclear Medicine at the, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
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  • , 
  • Christian Gerloff
    Christian Gerloff
    Department of Neurology, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
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  • , 
  • Tim Magnus
    Tim Magnus
    Department of Neurology, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
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  • Tobias Knopp
    Tobias Knopp
    Section for Biomedical Imaging, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
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  • , and 
  • Peter Ludewig*
    Peter Ludewig
    Department of Neurology, and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0001-9025-6402
Cite this: ACS Nano 2020, 14, 10, 13913–13923
Publication Date (Web):September 17, 2020
https://doi.org/10.1021/acsnano.0c06326

Copyright © 2022 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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Magnetic particle imaging (MPI) is an innovative radiation-free tomographic imaging method providing excellent temporal resolution, contrast, sensitivity, and safety. Mobile human MPI prototypes suitable for continuous bedside monitoring of whole-brain perfusion have been developed. However, for the clinical translation of MPI, a crucial gap in knowledge still remains: while MPI can visualize the reduction in blood flow and tissue perfusion in cerebral ischemia, it is unclear whether MPI works in intracranial hemorrhage. Our objective was to investigate the capability of MPI to detect intracranial hemorrhage in a murine model. Intracranial hemorrhage was induced through the injection of collagenase into the striatum of C57BL/6 mice. After the intravenous infusion of a long-circulating MPI-tailored tracer consisting of superparamagnetic iron oxides, we detected the intracranial hemorrhage in less than 3 min and could monitor hematoma expansion in real time. Multicontrast MPI can distinguish tracers based on their physical characteristics, core size, temperature, and viscosity. By employing in vivo multicontrast MPI, we were able to differentiate areas of liquid and coagulated blood within the hematoma, which could provide valuable information in surgical decision making. Multicontrast MPI also enabled simultaneous imaging of hemorrhage and cerebral perfusion, which is essential in the care of critically ill patients with increased intracranial pressure. We conclude that MPI can be used for real-time diagnosis of intracranial hemorrhage. This work is an essential step toward achieving the clinical translation of MPI for point-of-care monitoring of different stroke subtypes.

KEYWORDS:
With 4.1 million cases and 2.8 million deaths per year, intracranial hemorrhage (ICH) is a devastating disease with high rates of mortality and disability. (1) High case fatality rates of 60% at one year and less than 20% of patients regaining functional independence result in an annual loss of 64.5 million years of healthy lives. (1) No specific therapy, either drug or surgical, has shown to significantly improve the outcome. (2) Rebleeding and hematoma expansion, in particular, are associated with poor long-term prognosis, and treatment remains challenging. Early neurological deterioration due to hematoma expansion occurs in more than two-thirds of patients within 48 h. (3) Frequent neurological examinations are necessary to detect clinical deterioration and signs of increased intracranial pressure at an early stage. Reliable and practical techniques that allow for the continuous and noninvasive bedside monitoring of intracranial hemorrhage and cerebral perfusion in these patients do not exist. Drawbacks of transcranial Doppler, (4) near-infrared spectroscopy, (5) and thermal diffusion probes (6) include the monitored volumes being highly regional or invasive implantations being necessary. Although computed tomography (CT) is very precise in detecting intracranial hemorrhage, it exposes the patients to a relatively high radiation dose, and renal disease is a contraindication for the use of CT contrast agents. A device that allows for continuous, radiation-free surveillance of the whole brain at the bedside would be of utmost interest for several pathologic conditions.
Magnetic particle imaging (MPI) is a young imaging technology that could close this healthcare gap. It is a radiation-free, no-tissue-background tomographic imaging method that directly detects superparamagnetic iron oxide particles (SPIOs) three-dimensionally with a superior temporal resolution of 21.54 ms for volumetric imaging. (7) In MPI, two magnetic fields are necessary for image generation. First, a homogeneous sinusoidal magnetic drive field instantaneously flips the SPIOs to induce a signal in the receive coils. For the spatial encoding of this signal, another strong magnetic field creates a field-free region (FFR). Only the particles in the vicinity of the FFR flip and induce a signal. After a raster scan of the FFR, the detected signal is assigned to the current location of the FFR and reconstructed into an image. Its combination of excellent contrast, sensitivity, spatial and temporal resolution, safety, and biocompatible tracers makes MPI a promising tool for vascular applications. (8) A prototype of a mobile human MPI head scanner, which can be operated at a patient’s bedside with a conventional power outlet, was recently developed. (8) It is highly sensitive and allows for the measurement of brain perfusion parameter maps over several days, considering clinically approved tracer dosages. This scanner could minimize time-consuming patient transports and improve treatment times. However, before deploying such a scanner on patients for day-to-day routine imaging in hospitals, it must be clarified whether MPI can detect all stroke subtypes.
While we have demonstrated that ischemic stroke imaging is possible with MPI, (9) it is unclear whether MPI can detect intracranial hemorrhage. Compared to imaging of ischemia, the detection of hemorrhage with MPI is more challenging as the tracer needs to accumulate at the bleeding site to be visible in MPI images. Previous work detecting traumatic brain injury with MPI did not simulate clinical circumstances; for example, the tracer was injected before the actual traumatic injury. (10) Furthermore, the earliest bleeding detection reported thus far was 60 min after injection of the tracer in an intestine bleeding model, (11) which would be too long in the case of a medical emergency. It remains to be answered whether the delay in bleeding detection is a fundamental issue of MPI or whether it can be improved. Should MPI fail to detect bleeding earlier, it is questionable whether this technique is applicable for everyday clinical use. Promisingly, the quality of the scanners, sequences, and image reconstruction algorithms has continuously been optimized. Today, even small amounts of iron in the lower nanogram iron range can be detected. (12) Besides high sensitivity and excellent temporal resolution, the spatial resolution has improved into the μm range. (13) In addition to these improvements, MPI can offer further technological innovations. Recent developments in MPI have enabled the possibility to distinguish tracers by their viscosity and visualize blood coagulation. (14,15) This multicontrast MPI technology has not been exploited for hemorrhage or other disease models thus far. It has the potential to determine whether bleeding has already clotted or whether any areas are still actively bleeding in combination with simultaneous cerebral perfusion imaging.
In this study, we investigated MPI’s capabilities to detect intracranial cerebral hemorrhage in a mouse model. We induced ICH through the intraparenchymal injection of collagenase, which causes active bleeding due to the disruption of the blood–brain barrier. Comparable to the human pathophysiology, this bleeding evolves over hours, mimicking secondary hematoma expansion in patients. After the injection of a long-circulating MPI-tailored SPIO tracer, we performed dynamic 3D-MPI scans with a high spatial and temporal resolution and monitored the animals over the course of 4 weeks. We demonstrate that multicontrast MPI can combine imaging of intracranial bleeding and cerebral perfusion and that MPI is sensitive and fast enough to be suitable as a future clinical imaging method.

Results and Discussion

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Detection of Intracranial Hemorrhage with MPI in C57Bl/6 Mice

The first challenge to overcome was the choice of the optimal tracer and application regimes for the rapid detection of the intracranial hemorrhage (experimental workflow: see Supplemental Figure S1; scanning parameters: Tables S1/S2). Various options were available, including short- and long-circulating tracers, which could be infused continuously or in a pulsed fashion. We started with three different setups: the tracer Perimag (Micromod GmbH, Germany) with a blood half-life of 30 min was either injected as a large bolus of 200 μL (cumulative 1000 μg iron, c[Fe] = 5 mg/mL); as smaller 50 μL boli (cumulative 243 μg iron in 300 μL, c[Fe] = 0.81 mg/mL) every 10 min for 1 h; or continuously injected for 1 h (cumulative 243 μg of iron in 300 μL, flow rate of 0.3 mL/h, c[Fe] = 0.81 mg/mL). Image reconstruction was performed online during the data acquisition using our self-developed MPI reconstruction toolbox. (16) The reconstruction took 8 s per frame, and the images were immediately visible to the investigators.
In all scenarios, we clearly detected the hemorrhage after 90 min (Supplemental Figure S2b/c). However, the earliest time point of the detection differed drastically between the groups: after the injection of a large bolus of Perimag, it took 10 min to visually detect the bleeding, 19 min in the group with repetitive boli, and 23 min in the group with continuous injection. Neither of these injection schemes achieved steady-state concentration of the tracer, despite the adjustment of the injection rate (Supplemental Figure S2a). Digital subtraction of the data to delineate the intracranial hemorrhage did not improve the results (Supplemental Figure S2c). Especially in the groups with repetitive and continuous injection, we saw a steady tracer accumulation in the blood pool, which made it impossible to apply the standard digital subtraction method by subtracting the first baseline images from the follow-up images. Instead, each pixel needed normalization by the data set’s image means to smoothen the concentration–time curves and simulate a steady-state tracer. Nevertheless, without a priori knowledge of the hemorrhage localization, it was difficult to detect the hemorrhage before 60 min in these animals.
Since the time to bleeding detection of the short-circulating tracer was insufficient for clinical workflow, we then investigated the use of long-circulating tracers with a more predictable steady-state signal. Our cooperation partner Micromod developed a PEGylated tracer with a blood half-life of 60 min (Synomag-D, 70 nm, surface: PEG 25000-OMe). Synomag-D provided excellent MPI properties, with a mean signal increase by a factor of 2 compared to Perimag and by a factor of 4 compared to the clinically approved ferucarbotran (Resovist; see Supplemental Figure S3). The long-circulating tracer drastically improved the results. After the injection of a similar amount of tracer (243 μg of iron in 200 μL, c[Fe] = 1.22 mg/mL), it only took 1.80 ± 0.3 min (n = 3) to detect a signal increase in the concentration–time curves (Figure 1b) and 2.63 ± 0.23 min to visualize the intracranial hemorrhage (Figure 1a).

Figure 1

Figure 1. Rapid detection of intracranial hemorrhage with MPI. After the intravenous injection of 200 μL of Synomag-D (243 μg iron, c[Fe] = 1.22 mg/mL), MPI scans were acquired dynamically with a temporal resolution of 21.54 s, resulting in 3D-(+t) MPI data sets. Digital subtraction with a positive-only filter was applied to the 3D-(+t) MPI data sets to delineate the hemorrhage. (a) Early detection and expansion of the intracranial hemorrhage after the tracer injection at several time points on fused MPI/MRI slices (a; upper row: coronal sections; middle row: transversal sections; lower row: sagittal sections; the white asterisk indicates the hemorrhage in MRI and MPI; data without digital subtraction are shown in Supplemental Figure S4; signals were normalized for better visibility). The signal information from these data sets was converted into a concentration–time curve on a voxel by pixel basis (b). Only 1.80 ± 0.3 min passed between the tracer bolus arrival in the brain and the hemorrhage detection. Bleeding continued up to 100 min (a, b). The extravasation of the tracer and expansion of the hemorrhage could be monitored in real time (see Supplemental Video V1). Color coding the tracer arrival time allowed for the differentiation of bleeding areas of different age (c; the needle tip of the syringe marks the collagenase injection site for hemorrhage induction).

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To date, it is the fastest time ever recorded in bleeding detection with MPI and is on par with conventional imaging methods. We employed a tomographic imaging protocol with Lissajous-type sampling and system matrix-based reconstruction in our studies, which differs fundamentally from the projection imaging system, sampling, and reconstruction scheme used in other MPI bleeding studies. (10,11) Our approach was fully 3D and enabled precise and quantitative detection of coagulated blood and organ perfusion with a possible temporal resolution on the millisecond scale. Due to the good temporal resolution of our MPI scanner, the hemorrhage’s expansion could be monitored in real time (see Supplemental Video V1). In the first 20 min, the hemorrhage spread vigorously with a maximum bleeding rate of 0.061 ± 0.023 μL/s at around 4 min. Following this acute bleeding, we observed a phase of slower bleeding rates of 0.003 ± 0.002 μL/s and hematoma expansion up to 100 min after the collagenase injection. The expansion of the bleeding was color-coded by the tracer arrival times and allowed for visualizing and differentiating older and newer bleeding areas within the hemorrhage (Figure 1c). Between the last MPI image and the sacrificing of the animals for ex vivo magnetic resonance imaging (MRI), up to 1 h elapsed. In the collagenase model, hematoma growth can be observed up to 24 h, (17,18) which explains the small differences between the last MPI and MRI images.
To prove that the extravasated tracer generated the in vivo MPI signal within the intracranial hemorrhage, the brain and the hematoma were dissected and presented matching signals (Figure 2a). For the treatment of intracranial bleeding, it is necessary to determine the volume. Until now, the spatial resolution of the MPI was too poor to provide reliable volumetric measurements. By improving the hardware with organ-specific MPI coils, (13) the spatial resolution increased to 1 mm × 1 mm × 0.5 mm compared to initial experiments with a body coil, (12) which yielded about half the resolution. The new hardware allowed us to perform reliable volumetric measurements. A volume rendering of the bleeding in MRI and MPI and a comparison of MPI and histological sections showed comparable dimensions and shapes of the bleeding (Figure 2b/c; Supplemental Video V2). Volumetric measurements of the MPI signal and histological sections showed similar sizes (Figure 2c/d; MPI: 24.54 ± 2.06 mm3vs histology: 23.89 ± 2.42 mm3). The injection of the tracer itself did not increase bleeding volumes. Animals injected with 200 μL of Synomag-D (c[Fe] = 1.22 mg/mL) had similar lesion volumes when compared to control animals without tracer injection (Figure 2d; with tracer: 23.89 ± 2.42 mm3vs without tracer: 24.25 ± 1.23 mm3).

Figure 2

Figure 2. Volumetric measurements of intracranial hemorrhages with MPI. Analyzing the brain and the dissected intracranial hemorrhage ex vivo revealed that the in vivo MPI signal was generated by the intracranial hemorrhage (a: the upper panel shows a photograph of the ex vivo brain and the dissected hemorrhage, while the lower panel shows the corresponding MPI signal). The improved spatial resolution of MPI scanners allowed for calculating the hemorrhage volume. A 3D rendering of the MPI hemorrhage revealed a shape and size comparable to the MRI (b; left images: view from lateral; right images: view from below). The volume of bleeding calculated from the MPI data sets showed sizes comparable to histological sections of the same animals 24 h after the induction of the hemorrhage (c/d). The injection of the tracer did not lead to an increase in bleeding size (d; n.s.: not significant).

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Multicontrast MPI to Distinguish the Physical States of the Tracer

An innovative feature of MPI is the possibility to distinguish tracers based on their physical characteristics, core size, temperature, and viscosity. The feasibility of this technique, called multicontrast MPI, has been demonstrated in simplified in vitro and in vivo experiments. (14,19,20) However, it has not yet been demonstrated whether multicontrast MPI has any benefit for diagnosis or treatment in disease models. Clinically, it would be desirable if multicontrast MPI could provide the possibility to distinguish coagulated from uncoagulated blood and to combine the monitoring of hemorrhage and whole-brain perfusion in vivo.
In the first step, we tested whether a fluid tracer in uncoagulated blood could be distinguished from a tracer that had extravasated and immobilized within the coagulated blood of the intracranial hemorrhage. To encode the physical behavior of these two specific tracer states, we performed calibration measurements to acquire two different MPI system matrices, (21,22) which were necessary for image reconstruction (see Supplemental Methods). To differentiate the immobilized tracer, we obtained a system matrix with concentrated particles immobilized with dental cement. We also acquired an alternative system matrix with dissected tissue of the intracranial hemorrhage after tracer injection. Both system matrices were highly similar, confirming that the coagulation of a blood–tracer mixture within the hemorrhage led to immobilization of the particles (see Supplemental Figure S5). It also showed that it would not be necessary to use biopsy tissue for calibration measurements in future studies. To differentiate the fluid tracer, we calibrated the system matrix with a liquid tracer sample. Both system matrices robustly separated liquid and immobilized tracer in in vitro measurements (Figure 3a/b). The liquid tracer’s system matrix showed minimal signal in the coagulated areas, which could also be caused by small amounts of liquid tracer, e.g., inside the blood vessels.

Figure 3

Figure 3. Multicontrast MPI for the differentiation of fluid and immobilized tracer. Fluid tracer and dissected hemorrhage tissue with immobilized tracer were used for calibration measurement to obtain MPI system matrices for image reconstruction. In an in vitro setting, multicontrast MPI distinguished liquid and immobilized tracer with the dedicated system matrices (a: design of phantom with the different samples of fluid and immobilized tracer and a negative control; b: the corresponding MPI signal of the phantom; the upper image shows an overlay of the reconstruction with the immobilized-dedicated (red) and the liquid-dedicated system matrix (gray), the lower panel shows the separated channels). Applying multicontrast MPI in vivo, we could detect areas with immobilized tracer reflecting areas of coagulated blood inside the hemorrhage (c; upper row: coronal sections of images reconstructed with the system matrix for immobilized tracer; middle row: images reconstructed with the system matrix for fluid tracer; lower row: digital subtraction images of the fluid tracer; bottom row: overlay of all three MPI reconstructions on the top of the corresponding MRI slice).

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After establishing the technique in vitro, we applied multicontrast image reconstruction with the fluid and immobilized system matrices to our in vivo experiments (Figure 3; Supplemental Video V3). We clearly detected areas of immobilized tracer within the hemorrhage, which most likely represent areas of coagulated blood. These regions also matched the parts of the intracranial hemorrhage that occurred soon after the induction of the hemorrhage and should have clotted first (Figure 1c). Whereas the signal from the immobilized tracer was exclusive, the evaluation with the liquid tracer’s system matrix showed areas overlapping with the coagulated areas. This overlapping was reasonable since the in vivo measurements were performed in living animals with persisting blood circulation where both fluid and immobilized tracer coexist.

Simultaneous Multicontrast MPI of Brain Perfusion and Intracranial Hemorrhage

In the second step, we successfully further challenged multicontrast MPI by combining the two different tracers, Perimag and Synomag-D, to perform simultaneous monitoring of the hemorrhage and cerebral perfusion in vivo. After induction of bleeding and imaging with Synomag-D, a second short bolus with Perimag was injected. A few frames before the Perimag bolus were averaged and digitally subtracted from the following frames to remove the signal from residual liquid Synomag-D in the blood and delineate the Perimag bolus. The data were reconstructed with system matrices calibrated with immobilized Synomag-D and liquid Perimag. We could clearly distinguish the hemorrhage (immobilized Synomag-D) while the fluid Perimag bolus passed through the brain (Figure 4a; Supplemental Video V4). Multicontrast MPI allowed us to continuously observe the bleeding and, at the same time, calculate the perfusion parameter maps from the Perimag bolus (Figure 4b/c). The parameter maps for relative cerebral blood volume and flow (rCBV, rCBF) also showed reduced perfusion within the bleeding area, as expected (Figure 4c, red asterisk).

Figure 4

Figure 4. Multicontrast MPI for simultaneous monitoring of intracranial hemorrhage and cerebral perfusion. After the induction of the intracranial hemorrhage, the tracer Synomag-D (c[Fe] = 1.22 mg/mL) was injected for bleeding detection. Two hours later, we injected a 5 μL bolus of the tracer Perimag (c[Fe] = 57 mg/mL) for perfusion imaging with a temporal resolution of 21.54 ms. Images were reconstructed with the system matrix for immobilized Synomag-D and liquid Perimag (a; upper row: overlay of MPI and MRI data; middle row: immobilized tracer/Synomag-D/hemorrhage in red; lower row: fluid tracer/Perimag/cerebral perfusion in blue; the time labels correspond to the concentration–time curve in Figure 4b; the arrow in b marks the time point of the tracer injection). We could clearly detect the hemorrhage while the Perimag bolus passed through the brain in the images (a) and concentration–time curves (b; red line: hemorrhage/Synomag-D signal; blue line: Perimag bolus in the contralateral hemisphere; black dotted line: Perimag signal in a vein). Perfusion parameters maps (c; rCBV, rCBF) were derived from the concentration–time curves and showed decreased perfusion within the hemorrhage (c, red asterisk). A high concentration of the second tracer can shadow the first tracer. The phenomenon is present in the concentration–time curves, which illustrate a drop in the bleeding signal during the injection of Perimag (b).

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Attention must be paid when administering the second tracer for perfusion imaging. Too much tracer for the perfusion bolus can overexpose the signal of the first tracer inside the hemorrhage, which is reflected by a drop in the hemorrhage’s signal during the Perimag injection (Figure 4b; see also Supplemental Figure S6). This can be explained by the fact that MPI is limited in the dynamic range it can resolve. Concentration differences of more than a factor of 50 can usually not be imaged simultaneously, since the higher concentration shadows the lower concentration even if they are spatially separated. In our experiments, we observed that multicontrast MPI was even more prone to the dynamic range limitations and that the separation of two different contrasts worked best if the two tracers had similar concentration.

Long-Term Imaging of Intracranial Hemorrhage with MPI

Superparamagnetic iron oxide particles do not cross the healthy blood–brain barrier, which breaks down multiple times during intracranial hemorrhage. Excessive extravasation of the tracer into the brain parenchyma is not desirable due to the potential side effects of the tracer deposition in the central nervous system. (23) To estimate how much tracer extravasated into the brain parenchyma, we stained the particles with Prussian blue 4 h after the injection. This method stains iron mostly in the ferric but not in the ferrous state. In the first hours after ICH, the iron from the red blood cells is bound to hemoglobin and in the ferrous state. It is therefore not recognized by Prussian blue staining, whereas Perimag or Synomag-D with iron in the ferric state (magnetite) was detected by this method (Figure 5a). (24) We did not see excessive amounts of particles, which were distributed evenly over the area of the intracranial hemorrhage. The Fe3+ amount measured with MPI was 827.3 ± 297.4 ng (n = 4) at day 1. We performed long-term imaging of the ICH with these animals. The MPI signal and the amount of iron quickly decreased. After 3 weeks, the amount of Fe3+ fell to 51.7 ± 41.5 ng (Figure 5b/c), which shows that the biocompatible tracer degraded and did not accumulate in the brain parenchyma (see Supplemental Figure S7).

Figure 5

Figure 5. Long-term MPI of the intracranial hemorrhage shows the degradation of the tracer. Animals were sacrificed 4 h after the induction of the hemorrhage and tracer injection. The amount of tracer inside the hemorrhage was evaluated through Prussian blue staining. This revealed homogeneous extravasation, whereas the staining was negative in animals without tracer injection or the contralateral side (a; upper image: tracer particles are stained in blue; middle image: ICH without injected tracer; lower image: contralateral hemisphere with injected tracer; scale bar: 100 μm). Imaging of the animal after the injection of the tracer (Synomag-D) was performed up to 28 days (b, c; n = 4 until day 23; one animal was imaged until day 28). Magnetic particle imaging signal intensities (b) and the amount of tracer (c) significantly decreased over 3–4 weeks.

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Conclusions

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In this work, we have demonstrated that magnetic particle imaging reliably and quickly detected intracranial hemorrhage in a mouse model. Uncertainties about MPI’s ability to detect bleeding have arisen because MPI is a background-free imaging method, meaning that a tracer needs to be administered to generate an image. MPI can only detect intracranial hemorrhage if there is active bleeding and the tracer is leaking into the tissue. Preliminary work in the field of traumatic brain injury circumvented this problem by injecting the tracer before the injury. (10) We chose an approach that corresponds more to a clinical scenario, where the tracer is injected after the onset of symptoms and bleeding. In our model, we administered the tracer 30 min after the onset of the hemorrhage and quickly detected the ICH within minutes, as well as detected active bleeding up to 100 min. This is very much in line with human observations, where we find hematoma expansion in 73% of the patients within 48 h. (25) The secondary hematoma expansion leads to clinical deterioration and death. It is crucial to detect secondary bleeding early to treat these patients accordingly, such as through surgery. (26) To date, a reliable and fast method to allow for the continuous bedside monitoring of whole-brain perfusion does not exist. Patient surveillance has typically been noninvasive through clinical examination, but this cannot be carried out continuously. MPI can close this healthcare gap and enable noninvasive, permanent monitoring of patients and faster interventions in the case of deterioration. For this purpose, it is another advantage of MPI technology that the scanners can be built very small and can be designed as prehospital and bedside-operated devices. We recently published phantom measurements with a prototype of a mobile human head scanner that can be operated at the bedside with a conventional power outlet. (27)
To deploy MPI as a monitoring device, the rapid detection of rebleeding is a prerequisite. How fast MPI is in this scenario has not yet been conclusively clarified. Recent studies either did not address this issue in-depth (10) or detected initial signs of bleeding after more than 1 h. (11) With the right choice of tracer and tracer application, we detected intracranial hemorrhage within 2.5 min. With this rapid detection, MPI can now clearly compete with conventional imaging techniques, with average stroke examination times of 11–13 min for CT and MRI. (27) In addition, CT and MRI require transportation of the patients, while MPI could be carried out directly at the bedside. MPI might be an ideal technique to monitor hematoma expansion.
Another advantage of MPI is the multicontrast separation, which allows for differentiating tracers based on their viscosity and core size. In our experiments, multicontrast MPI distinguished areas of liquid and coagulated blood within the hematoma, which is not possible with other imaging techniques. Identifying stable areas of coagulated blood and areas of active bleeding is of great interest for surgical interventions, because operating during an active hemorrhage can worsen the outcome. An ultra-early surgical study was halted because there was a high rate of early rebleeding and mortality due to persistently bleeding vessels. (28) MPI could help define a specific time window when surgery is optimally performed depending upon the leaking vessel’s status. Minimally invasive catheter evacuation is a newer surgical approach. (29) A catheter is placed inside the hematoma, followed by intrahemorrhage thrombolysis and drainage of the blood clot over days. Multicontrast MPI could improve the placement of the catheter, monitor thrombolysis, and clot removal to achieve optimal hematoma evacuation.
Additionally, we have demonstrated that, by employing multicontrast MPI, it is possible to perform perfusion imaging while monitoring the intracranial hemorrhage. One of the critical complications of ICH is increased intracranial pressure due to the space restrictions imposed by the skull and hematoma expansion. Increased intracranial pressure leads to insufficient cerebral perfusion and increased secondary injury. With MPI, we could detect a drop in cerebral perfusion and adjust the therapy to control cerebral pressure. Another disease for which MPI could potentially be helpful is subarachnoid hemorrhage (SAH). SAH is usually caused by a rupture of an aneurysmatic cerebral vessel with bleeding into the subarachnoid space. This type of bleeding is also detectable by MPI (see Supplemental Figure S8). The complications that follow such bleeding are typically vasospasms of the cerebral arteries. These vasospasms can cause ischemic strokes due to decreased perfusion. With MPI, early detection and faster treatment of vasospasms with intra-arterial vasodilators would be possible.
In the case of intracranial hemorrhages, volumetric measurements are necessary, since surgical interventions may improve the outcome if the stroke volume exceeds 60 mL in combination with a significant midline shift. (30) Until now, volumetric evaluations of MPI were imprecise due to the limited spatial resolution on the order of >2 mm when imaging at feasible tracer concentrations in vivo. By incorporating new advantages of organ-specific receive coils, (12) we performed volumetric calculations from MPI data, which were within the same range as those obtained from high-resolution MRI and histological evaluations. This was possible due to the high signal–noise ratio (SNR) of the organ-specific receiving coil. This allowed us to use more frequency components in the reconstruction and to reduce the amount of regularization, both of which lead to an improved spatial resolution.
While we have demonstrated that bedside monitoring with MPI could be feasible in the near future, the prehospital application of such a scanner has limitations. Magnetic particle imaging could miss old bleedings because no tracer would leak into the hemorrhagic tissue. In this scenario, MPI could still detect a perfusion deficit, but it would not be able to differentiate between hemorrhagic and ischemic stroke. Therefore, the necessary distinction for a lysis therapy would not be possible.
Toxicity of the tracer materials is another topic that needs addressing. Tracers such as ferucarbotran have been used in patients with minor side effects similar to other tracer materials. (31) Concerns have emerged since cerebral gadolinium deposits have been detected in patients after repetitive applications. (32) Compared to gadolinium, MPI tracers have the advantage of being biodegradable. Accordingly, we found a steady decrease in the tracer signal in the brain parenchyma in our experiments, which can be the result of either local degradation or removal of the particles from the brain parenchyma. For MPI, the tracers require a superparamagnetic state. Degradation of the particles into smaller sized results in the full loss of the MPI signal. (33) Our data suggest that SPIOs get phagocytosed and digested by macrophages or microglia (see Supplemental Figure S7), followed by incorporation of the degraded iron into hemoglobin as observed by others. (34,35) Nevertheless, we cannot exclude that the particles degrade locally and remnants remain in the brain parenchyma. It is necessary to investigate further whether SPIOs get entirely removed from the brain parenchyma or increase neurotoxicity when the blood–brain barrier collapses. In our trials, both in stroke (23) and in bleeding, we did not observe any mortality after tracer injections, and the tracer did not increase bleeding sizes. Another advantage is that we found only small amounts (in the nanogram range) of tracer in the tissue. Due to the high sensitivity of our MPI scanner, including the organ-specific receive coil, even smaller amounts of tracer can be applied in the future.
A further optimization could be in the route of administration of the tracers. The tracers we used in our study can easily be encapsulated into red blood cells, as previously demonstrated. (36) Since red blood cells (RBCs) have a considerably long half-life, only a small amount of tracer needs to be applied. As long-circulating tracers, RBCs are probably also excellently suited for the detection of bleeding. Besides imaging, MPI could improve thrombolysis efficacy through drug targeting and localized hyperthermia, potentially decreasing thrombolysis times drastically. (37−39)
In summary, this work is an important step toward clinical MPI stroke and hemorrhage imaging. Combining our previous studies, (9,27) we have demonstrated that MPI can quickly detect both stroke subtypes, intracranial hemorrhage, and ischemic stroke, which are essential basic requirements for the use of MPI in clinical routine. By enabling the continuous monitoring of patients using mobile MPI scanners, this technology can substantially improve the care of stroke patients in the future.

Methods and Experimental

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1. Induction of Intracranial Hemorrhage

All animal experiments were approved by local animal care committees (Behörde für Lebensmittelsicherheit and Veterinärwesen Hamburg, No. 18/21). We conducted the experiments following the “Guide for the Care and Use of Laboratory Animals” published by the US National Institutes of Health (NIH Publication No. 83-123, revised 1996) and performed all procedures in accordance with the ARRIVE guidelines (http://www.nc3rs.org/ARRIVE). C57BL/6 mice (n = 27, see Supplemental Table S1) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). The mice were kept on a standard 12 h light/dark cycle, at a constant temperature (22 ± 2 °C), and with food and water adlibitum.
Intracranial hemorrhage was induced through the collagenase injection model. Mice were anesthetized with isoflurane (4% for induction; 2.5% for maintenance) in 100% oxygen. The mice were placed in a stereotaxic frame (Stoelting, 51500U), and a 1 cm long incision of the scalp was made over the midline. A cranial burr hole (0.9 mm) was drilled 2.3 mm lateral to the midline and 0.2 mm anterior to the bregma. Bacterial collagenase VII-S (Sigma, Germany, C0773-3KU) dissolved in saline was drawn into a 10 μL Hamilton syringe (Hamilton, 1701RN) connected to a 26-gauge needle (Hamilton, 26G, point style 4, 12°) and inserted into a motorized stereotaxic injector (Stoelting, integrated stereotaxic injector). The 26-gauge needle was slowly introduced 3.7 mm deep into the left striatum, and 0.5 μL of bacterial collagenase (0.075 units) was infused at a rate of 0.5 μL/min. The needle was left in place for 10 min and then slowly withdrawn. For the MPI measurements, the mouse was transferred to the MPI scanner, and anesthesia was maintained with 1.5% isoflurane in 100% O2. The vital parameters were monitored using an animal support unit (Minerve, Esternay, France). Body temperature was maintained throughout the procedure at 37 °C using a feedback-controlled heating device. For the tracer injection, a catheter (inner tube diameter 0.28 mm; Portex, Smiths Medical International Ltd., USA) was placed into the tail vein of the mouse.

2. MPI and MRI Measurements

We performed the main experiments using a preclinical tomographic MPI scanner (Bruker, Germany) that uses a field-free point (FFP) for spatial encoding. Magnetic particle imaging, presented by Gleich and Weizenecker in 2005, is a tracer-based imaging modality. Using external magnetic fields, the FFP was moved along a 3D imaging trajectory and captured the concentration in the vicinity of the FFP. The 3D Lissajous trajectories, which were used in this work, allowed for rapid sampling of 3D imaging volumes with a temporal resolution of 21.54 ms per imaging volume. To increase the detection limit of the commercial device, which was about 160 ng, we used a custom head coil that was mounted directly around the mouse head and improved the SNR by a factor of 200. The design of the coil allowed for easy positioning in the scanner bore without the necessity of additional fiducials. As tracer materials, we used Perimag and Synomag-D (Micromod GmbH, Germany). The injected tracer volume and concentration differed in the performed experiments and are summarized in Supplemental Table S1. In all cases, the tracer was injected with a programmable syringe pump (Aladdin; World Precisions Instruments, USA). The specific magnetic and nonmagnetic characteristics of Perimag and Synomag-D are listed in Supplemental Figure S3. We prepared the immobilized samples that were used for system matrix acquisition of the coagulated tracer channel by mixing Synomag-D with dental cement, which fixated the compound after a short contact time. For image reconstruction in MPI, additionally measured system matrices were needed. Since the bore size of the mouse head coil was too small for a dedicated calibration with a delta sample shifted to different positions in the field of view, we instead used a larger 3D mouse body coil (40 mm inner diameter) for calibration. Since both coils had a different transfer function, all measurements were corrected for the respective transfer function. This correction converted the signal into the magnetic moment of the particles, which is a receive coil independent measure. All measurements and system matrices were scanned with a selection field gradient of 2 T/m and an excitation amplitude of 12 mT in all three excitation directions. The covered field of view was 24 × 24 × 12 mm3. The system matrices were scanned with a 2 × 2 × 1 mm3 delta sample of each tracer material on a grid of 25 × 25 × 13 samples, covering a region of interest of 25 × 25 × 13 mm3.
As a morphological reference for the MPI measurements, we additionally performed post-mortem MRI measurements of the head using a 1 T MRI system (ICON, Bruker BioSpin MRI, Ettlingen, Germany). The heads were measured with two different sequences: first, a T1-weighted Flash sequence with TE = 15 ms, FA = 45°, TR = 444.34 ms, averages = 8, slice orientation: axial, readout direction: ventral-dorsal, 15 slices with a slice thickness of 1 mm, image size of 160 × 160 covering 26 × 26 mm2, and a scan time of 9 min 28 s. The second was a T1 Flash 3D high-resolution sequence with TE = 12 ms, FA = 30°, TR = 45 ms, averages = 4, slice orientation: coronal, readout direction: rostral-caudal, image size of 83 × 83 × 65 covering 24.9 × 24.9 × 19.5 mm3, and a scan time of 17 min 40 s. The MPI/MRI-related measurement and reconstruction parameters are summarized in Supplemental Tables S2/S3/S4.

3. MPI Image Reconstruction and Postprocessing

During the experiments, an online reconstruction tool was used to give direct feedback on the measurements, which was especially important for the multibolus experiments. A high-resolution parameter-tuned reconstruction, including background correction and receive channel and frequency filtering, was performed offline in a postprocessing step. To this end, the open-source MPI image reconstruction package MPIReco was used, (16) which provided both methods for single-contrast and multicontrast reconstruction. Prior to reconstruction, the system matrix was interpolated to a finer grid to achieve a spatial resolution of 1 × 1 × 0.5 mm3. For reconstruction, we used the iterative regularized Kaczmarz algorithm (see Supplemental Methods). For the calculation of perfusion parameter maps, we used the tool previously described. (9) Volume rendering, image registration, and bleeding size determination were performed using the open source software package Slicer 4.10.2. We determined the bleeding size in the MPI images by applying an intensity threshold of 8% of the maximum image intensity to neglect the image noise and calculate a binary mask matching the bleeding. The mask, in combination with the voxel size result, was then used to derive the bleeding size.
For the digital subtraction, a temporal maximum intensity projection (MIP) of the tracer bolus’ initial frames was rendered to generate a baseline image with a signal maximum in arteries and veins. The baseline MIP was subtracted from all subsequent frames. This approach suppressed the surrounding vessels in the images and allowed quick visualization of the hemorrhage signal increase. Since the tracer concentration in the vessels decreases over time, negative values were obtained in the digital subtraction image. These values were set to zero to segment the images of the bleeding region effectively. In the continuous injection scheme and the repetitive bolus case, an additional normalization of the signal intensity was necessary. To this end, each frame, including the reference frames, was normalized prior to subtraction.

4. Histological Analysis

Histological analyses were performed as described. (40) Briefly, mice were deeply anesthetized with isoflurane followed by perfusion through the left ventricle using 10 mL of phosphate-buffered saline and 50 mL of cold 4% paraformaldehyde (PFA). The brains were postfixed in 4% PFA overnight at 4 °C, followed by embedding in paraffin. Brains were cut into 10 μm coronal sections using a Leica microtome. Sections were stained with an iron stain kit according to the manufacturer’s instructions (iron stain kit, HT20-1KT, Sigma-Aldrich, MO, USA) and examined under a Leica DM5000B microscope.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c06326.

  • Supplemental figures illustrating the experimental workflow, the advantages of long-circulation tracer, comparison of the MPI tracers Perimag and Synomag-D, the digital subtraction imaging, analysis of system matrices for multicontrast MPI, challenges of multicontrast MPI, phagocytosis of SPIOs by macrophages and microglia, MPI of subarachnoid hemorrhage; additional tables with the MPI and MRI parameters; additional equations used for multicontrast MPI image reconstruction, image postprocessing, and analysis. (PDF)

  • Supplemental Video V1: Real-time detection of intracranial hemorrhage with magnetic particle imaging (MPG)

  • Supplemental Video V2: Volumetric measurements of intracranial hemorrhage with magnetic particle imaging (MPG)

  • Supplemental Video V3: Differentiation of immobilized vs fluid tracer with multicontrast magnetic particle imaging (MPG)

  • Supplemental Video V4: Simultaneous imaging of hemorrhage and cerebral perfusion with multicontrast magnetic particle imaging (MPG)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Authors
    • Patryk Szwargulski - Section for Biomedical Imaging, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany;  Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany;  Email: [email protected]
    • Peter Ludewig - Department of Neurology, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany;  Orcidhttp://orcid.org/0000-0001-9025-6402;  Email: [email protected]
  • Authors
    • Maximilian Wilmes - Department of Neurology, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    • Ehsan Javidi - Department of Neurology, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    • Florian Thieben - Section for Biomedical Imaging, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany;  Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
    • Matthias Graeser - Section for Biomedical Imaging, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany;  Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
    • Martin Koch - Institute of Medical Engineering, Universität zu Lübeck, Lübeck, DE 23562, Germany
    • Cordula Gruettner - Micromod Partikeltechnologie GmbH, Rostock, DE 18119, Germany
    • Gerhard Adam - Department of Diagnostic and Interventional Radiology and Nuclear Medicine at the, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    • Christian Gerloff - Department of Neurology, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    • Tim Magnus - Department of Neurology, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany
    • Tobias Knopp - Section for Biomedical Imaging, , and University Medical Center Hamburg−Eppendorf, Hamburg, DE 20246, Germany;  Institute for Biomedical Imaging, Hamburg University of Technology, Hamburg, DE 21073, Germany
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by the “Forschungszentrums Medizintechnik Hamburg” (FMTHH) by the Hertie-Stiftung (Hertie Academy of Clinical Neuroscience), the German Research Foundation (DFG; grant numbers: GR 5287/2-1, KN 1108/7-1, DFG FOR 2879 [project LU 1924/1-1 and MA 4375/6-1], SFB 1328 [project A13]), and the “Hermann und Lily Schilling Stiftung”. This work was also supported by the BMBF under the frame of EuroNanoMed III (grant number: 13XP5060B, “Magnetise”).

References

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    The fast and accurate assessment of cerebral perfusion is fundamental for the diagnosis and successful treatment of stroke patients. Magnetic particle imaging (MPI) is a new radiation-free tomog. imaging method with a superior temporal resoln., compared to other conventional imaging methods. In addn., MPI scanners can be built as prehospital mobile devices, which require less complex infrastructure than computed tomog. (CT) and magnetic resonance imaging (MRI). With these advantages, MPI could accelerate the stroke diagnosis and treatment, thereby improving outcomes. Our objective was to investigate the capabilities of MPI to detect perfusion deficits in a murine model of ischemic stroke. Cerebral ischemia was induced by inserting of a microfilament in the internal carotid artery in C57BL/6 mice, thereby blocking the blood flow into the medial cerebral artery. After the injection of a contrast agent (superparamagnetic iron oxide nanoparticles) specifically tailored for MPI, cerebral perfusion and vascular anatomy were assessed by the MPI scanner within seconds. To validate and compare our MPI data, we performed perfusion imaging with a small animal MRI scanner. MPI detected the perfusion deficits in the ischemic brain, which were comparable to those with MRI but in real-time. For the first time, we showed that MPI could be used as a diagnostic tool for relevant diseases in vivo, such as an ischemic stroke. Due to its shorter image acquisition times and increased temporal resoln. compared to that of MRI or CT, we expect that MPI offers the potential to improve stroke imaging and treatment.
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  10. 10
    Orendorff, R.; Peck, A. J.; Zheng, B.; Shirazi, S. N.; Matthew Ferguson, R.; Khandhar, A. P.; Kemp, S. J.; Goodwill, P.; Krishnan, K. M.; Brooks, G. A.; Kaufer, D.; Conolly, S. First in Vivo Traumatic Brain Injury Imaging via Magnetic Particle Imaging. Phys. Med. Biol. 2017, 62, 3501– 3509,  DOI: 10.1088/1361-6560/aa52ad
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    10
    First in vivo traumatic brain injury imaging via magnetic particle imaging
    Orendorff, Ryan; Peck, Austin J.; Zheng, Bo; Shirazi, Shawn N.; Ferguson, R. Matthew; Khandhar, Amit P.; Kemp, Scott J.; Goodwill, Patrick; Krishnan, Kannan M.; Brooks, George A.; Kaufer, Daniela; Conolly, Steven
    Physics in Medicine & Biology (2017), 62 (9), 3501-3509CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
    Emergency room visits due to traumatic brain injury (TBI) is common, but classifying the severity of the injury remains an open challenge. Some subjective methods such as the Glasgow Coma Scale attempt to classify traumatic brain injuries, as well as some imaging based modalities such as computed tomog. and magnetic resonance imaging. However, to date it is still difficult to detect and monitor mild to moderate injuries. In this report, we demonstrate that the magnetic particle imaging (MPI) modality can be applied to imaging TBI events with excellent contrast. MPI can monitor injected iron nanoparticles over long time scales without signal loss, allowing researchers and clinicians to monitor the change in blood pools as the wound heals.
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  11. 11
    Yu, E. Y.; Chandrasekharan, P.; Berzon, R.; Tay, Z. W.; Zhou, X. Y.; Khandhar, A. P.; Ferguson, R. M.; Kemp, S. J.; Zheng, B.; Goodwill, P. W.; Wendland, M. F.; Krishnan, K. M.; Behr, S.; Carter, J.; Conolly, S. M. Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model. ACS Nano 2017, 11, 12067– 12076,  DOI: 10.1021/acsnano.7b04844
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    11
    Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model
    Yu, Elaine Y.; Chandrasekharan, Prashant; Berzon, Ran; Tay, Zhi Wei; Zhou, Xinyi Y.; Khandhar, Amit P.; Ferguson, R. Matthew; Kemp, Scott J.; Zheng, Bo; Goodwill, Patrick W.; Wendland, Michael F.; Krishnan, Kannan M.; Behr, Spencer; Carter, Jonathan; Conolly, Steven M.
    ACS Nano (2017), 11 (12), 12067-12076CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Gastrointestinal (GI) bleeding causes more than 300,000 hospitalizations per yr in the United States. Imaging plays a crucial role in accurately locating the source of the bleed for timely intervention. Magnetic particle imaging (MPI) is an emerging clin. translatable imaging modality that images superparamagnetic iron-oxide (SPIO) tracers with extraordinary contrast and sensitivity. This linearly quant. modality has zero background tissue signal and zero signal depth attenuation. MPI is also safe: there is zero ionizing radiation exposure to the patient and clin. approved tracers can be used with MPI. In this study, we demonstrate the use of MPI along with long-circulating, PEG-stabilized SPIOs for rapid in vivo detection and quantification of GI bleed. A mouse model genetically predisposed to GI polyp development (ApcMin/+) was used for this study, and heparin was used as an anticoagulant to induce acute GI bleeding. We then injected MPI-tailored, long-circulating SPIOs through the tail vein, and tracked the tracer biodistribution over time using our custom-built high resoln. field-free line (FFL) MPI scanner. Dynamic MPI projection images captured tracer accumulation in the lower GI tract with excellent contrast. Quant. anal. of the MPI images show that the mice experienced GI bleed rates between 1 and 5 μL/min. Although there are currently no human scale MPI systems, and MPI-tailored SPIOs need to undergo further development and evaluation, clin. translation of the technique is achievable. The robust contrast, sensitivity, safety, ability to image anywhere in the body, along with long-circulating SPIOs lends MPI outstanding promise as a clin. diagnostic tool for GI bleeding.
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  12. 12
    Graeser, M.; Knopp, T.; Szwargulski, P.; Friedrich, T.; von Gladiss, A.; Kaul, M.; Krishnan, K. M.; Ittrich, H.; Adam, G.; Buzug, T. M. Towards Picogram Detection of Superparamagnetic Iron-Oxide Particles Using a Gradiometric Receive Coil. Sci. Rep. 2017, 7, 6872,  DOI: 10.1038/s41598-017-06992-5
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    12
    Towards Picogram Detection of Superparamagnetic Iron-Oxide Particles Using a Gradiometric Receive Coil
    Graeser Matthias; Friedrich Thomas; von Gladiss Anselm; Buzug Thorsten M; Knopp Tobias; Szwargulski Patryk; Knopp Tobias; Szwargulski Patryk; Kaul Michael; Ittrich Harald; Adam Gerhard; Krishnan Kannan M
    Scientific reports (2017), 7 (1), 6872 ISSN:.
    Superparamagnetic iron-oxide nanoparticles can be used in medical applications like vascular or targeted imaging. Magnetic particle imaging (MPI) is a promising tomographic imaging technique that allows visualizing the 3D nanoparticle distribution concentration in a non-invasive manner. The two main strengths of MPI are high temporal resolution and high sensitivity. While the first has been proven in the assessment of dynamic processes like cardiac imaging, it is unknown how far the detection limit of MPI can be lowered. Within this work, we will present a highly sensitive gradiometric receive-coil unit combined with a noise-matching network tailored for the imaging of mice. The setup is capable of detecting 5 ng of iron in-vitro with an acquisition time of 2.14 sec. In terms of iron concentration we are able to detect 156 μg/L marking the lowest value that has been reported for an MPI scanner so far. In-vivo MPI mouse images of a 512 ng bolus and a 21.5 ms acquisition time allow for capturing the flow of an intravenously injected tracer through the heart of a mouse. Since it has been rather difficult to compare detection limits across MPI publications we propose guidelines to improve the comparability of future MPI studies.
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  13. 13
    Graeser, M.; Ludewig, P.; Szwargulski, P.; Foerger, F.; Liebing, T.; Forkert, N. D.; Thieben, F.; Magnus, T.; Knopp, T. Organ Specific Head Coil for High Resolution Mouse Brain Perfusion Imaging Using Magnetic Particle Imaging arXiv e-prints [Online], 2020; p. arXiv:2004.11728. https://ui.adsabs.harvard.edu/abs/2020arXiv200411728G (accessed April 01, 2020).
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  14. 14
    Möddel, M.; Meins, C.; Dieckhoff, J.; Knopp, T. Viscosity Quantification Using Multi-Contrast Magnetic Particle Imaging. New J. Phys. 2018, 20, 083001,  DOI: 10.1088/1367-2630/aad44b
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    Murase, K.; Song, R.; Hiratsuka, S. Magnetic Particle Imaging of Blood Coagulation. Appl. Phys. Lett. 2014, 104, 252409,  DOI: 10.1063/1.4885146
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    15
    Magnetic particle imaging of blood coagulation
    Murase, Kenya; Song, Ruixiao; Hiratsuka, Samu
    Applied Physics Letters (2014), 104 (25), 252409/1-252409/4CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
    We investigated the feasibility of visualizing blood coagulation using a system for magnetic particle imaging (MPI). A magnetic field-free line is generated using two opposing neodymium magnets and transverse images are reconstructed from the third-harmonic signals received by a gradiometer coil, using the max. likelihood-expectation maximization algorithm. Our MPI system was used to image the blood coagulation induced by adding CaCl2 to whole sheep blood mixed with magnetic nanoparticles (MNPs). The "MPI value" was defined as the pixel value of the transverse image reconstructed from the third-harmonic signals. MPI values were significantly smaller for coagulated blood samples than those without coagulation. We confirmed the rationale of these results by calcg. the third-harmonic signals for the measured viscosities of samples, with an assumption that the magnetization and particle size distribution of MNPs obey the Langevin equation and log-normal distribution, resp. We concluded that MPI can be useful for visualizing blood coagulation. (c) 2014 American Institute of Physics.
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  16. 16
    Knopp, T.; Hofmann, M. Online Reconstruction of 3D Magnetic Particle Imaging Data. Phys. Med. Biol. 2016, 61, N257– 67,  DOI: 10.1088/0031-9155/61/11/N257
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    16
    Online reconstruction of 3D magnetic particle imaging data
    Knopp, T.; Hofmann, M.
    Physics in Medicine & Biology (2016), 61 (11), N257-N267CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
    Magnetic particle imaging is a quant. functional imaging technique that allows imaging of the spatial distribution of super-paramagnetic iron oxide particles at high temporal resoln. The raw data acquisition can be performed at frame rates of more than 40 vols. s-1. However, to date image reconstruction is performed in an offline step and thus no direct feedback is available during the expt. Considering potential interventional applications such direct feedback would be mandatory. In this work, an online reconstruction framework is implemented that allows direct visualization of the particle distribution on the screen of the acquisition computer with a latency of about 2 s. The reconstruction process is adaptive and performs block-averaging in order to optimize the signal quality for a given amt. of reconstruction time.
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  17. 17
    Rosenberg, G. A.; Mun-Bryce, S.; Wesley, M.; Kornfeld, M. Collagenase-Induced Intracerebral Hemorrhage in Rats. Stroke 1990, 21, 801– 7,  DOI: 10.1161/01.STR.21.5.801
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    17
    Collagenase-induced intracerebral hemorrhage in rats
    Rosenberg, Gary A.; Mun-Bryce, Sheila; Wesley, Mary; Kornfeld, Mario
    Stroke (1990), 21 (5), 801-7CODEN: SJCCA7; ISSN:0039-2499.
    Intracranial bleeding is an important cause of brain masses and edema. To study the pathophysiol. of intracerebral hemorrhage, exptl. hemorrhages were produced in 53 rats and the lesions were characterized by histol., brain water content, and behavior. Adult rats had 2 μL saline contg. 0.5 unit bacterial collagenase infused into the left caudate nucleus. Histol., erythrocytes were seen around blood vessels at the needle puncture site within the first hour. By 4 h there were hematomas, the size of which depended on the amt. of collagenase injected. Necrotic masses contg. fluid, blood cells, and fibrin were seen at 24 h. Lipid-filled macrophages were obsd. at 7 days and cysts at 3 wk. Water content was significant increased 4, 24, and 48 h after infusion at the needle puncture site and for 24 h in posterior brain sections. Behavioral abnormalities were present for 48 h, with recovery of function occurring during the first week. Brain tissue contains Type IV collagen in the basal lamina. Collagenase, which occurs in an inactive form in cells, is released and activated during injury, leading to disruption of the extracellular matrix. Collagenase-induced intracerebral hemorrhage is a reproducible animal model for the study of the effects of the hematoma and brain edema.
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  18. 18
    Manaenko, A.; Chen, H.; Zhang, J. H.; Tang, J. Comparison of Different Preclinical Models of Intracerebral Hemorrhage. Acta Neurochir Suppl 2011, 111, 9– 14,  DOI: 10.1007/978-3-7091-0693-8_2
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    18
    Comparison of different preclinical models of intracerebral hemorrhage
    Manaenko Anatol; Chen Hank; Zhang John H; Tang Jiping
    Acta neurochirurgica. Supplement (2011), 111 (), 9-14 ISSN:0065-1419.
    Intracerebral hemorrhage (ICH) is the most devastating type of stroke. It is characterized by spontaneous bleeding in brain parenchyma and is associated with a high rate of morbidity and mortality. Presently, there is neither an effective therapy to increase survival after intracerebral hemorrhage nor a treatment to improve the quality of life for survivors. A reproducible animal model of spontaneous ICH mimicking the development of acute and delayed brain injury after ICH is an invaluable tool for improving our understanding of the underlying mechanisms of ICH-induced brain injury and evaluating potential therapeutic interventions. A number of models have been developed. While different species have been studied, rodents have become the most popular and widely utilized animals used in ICH research. The most often used methods for experimental induction of ICH are injection of bacterial collagenase and direct injection of blood into the brain parenchyma. The "balloon" method has also been used to mimic ICH for study. In this summary, we intend to provide a comparative overview of the technical methods, aspects, and pathologic findings of these types of ICH models. We will also focus on the similarities and differences among these rodent models, achievements in technical aspects of the ICH model, and discuss important aspects in selecting relevant models for study.
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  19. 19
    Rahmer, J.; Halkola, A.; Gleich, B.; Schmale, I.; Borgert, J. First Experimental Evidence of the Feasibility of Multi-Color Magnetic Particle Imaging. Phys. Med. Biol. 2015, 60, 1775– 91,  DOI: 10.1088/0031-9155/60/5/1775
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    19
    First experimental evidence of the feasibility of multi-color magnetic particle imaging
    Rahmer J; Halkola A; Gleich B; Schmale I; Borgert J
    Physics in medicine and biology (2015), 60 (5), 1775-91 ISSN:.
    Magnetic particle imaging is a new approach to visualizing magnetic nanoparticles. It is capable of 3D real-time in vivo imaging of particles injected into the blood stream and is a candidate for medical imaging applications. To date, only one particle type has been imaged at a time, however, the ability to separate signals acquired simultaneously from different particle types or from particles in different environments would substantially increase the scope of the method. Different colors could be assigned to different signal sources to allow for visualization in a single image. Successful signal separation has been reported in spectroscopic experiments, but it was unclear how well separation would work in conjunction with spatial encoding in an imaging experiment. This work presents experimental evidence of the separability of signals from different particle types and aggregation states (fluid versus powder) using a 'multi-color' reconstruction approach. Several mechanisms are discussed that may form the basis for successful signal separation.
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  20. 20
    Shasha, C.; Teeman, E.; Krishnan, K. M.; Szwargulski, P.; Knopp, T.; Möddel, M. Discriminating Nanoparticle Core Size Using Multi-Contrast MPI. Phys. Med. Biol. 2019, 64, 074001,  DOI: 10.1088/1361-6560/ab0fc9
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    20
    Discriminating nanoparticle core size using multi-contrast MPI
    Shasha, Carolyn; Teeman, Eric; Krishnan, Kannan M.; Szwargulski, Patryk; Knopp, Tobias; Moeddel, Martin
    Physics in Medicine & Biology (2019), 64 (7), 74001CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
    Magnetic particle imaging (MPI) is an imaging modality that detects the response of a distribution of magnetic nanoparticle tracers to alternating magnetic fields. There has recently been exploration into multi-contrast MPI, in which the signal from different tracer materials or environments is sep. reconstructed, resulting in multi-channel images that could enable temp. or viscosity quantification. In this work, we apply a multi-contrast reconstruction technique to discriminate between nanoparticle tracers of different core sizes. Three nanoparticle types with core diams. of 21.9 nm, 25.3 nm and 27.7 nm were each imaged at 21 different locations within the scanner field of view. Multi-channel images were reconstructed for each sample and location, with each channel corresponding to one of the three core sizes. For each image, signal wt. vectors were calcd., which were then used to classify each image by core size. With a block averaging length of 10 000, the median signal-to-noise ratio was 40 or higher for all three sample types, and a correct prediction rate of 96.7% was achieved, indicating that core size can effectively be predicted using signal wt. vector classification with close to 100% accuracy while retaining high MPI image quality. The discrimination of the core size was reliable even when multiple samples of different core sizes were placed in the measuring field.
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  21. 21
    Weber, A.; Werner, F.; Weizenecker, J.; Buzug, T. M.; Knopp, T. Artifact Free Reconstruction with the System Matrix Approach by Overscanning the Field-Free-Point Trajectory in Magnetic Particle Imaging. Phys. Med. Biol. 2016, 61, 475– 87,  DOI: 10.1088/0031-9155/61/2/475
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    21
    Artifact free reconstruction with the system matrix approach by overscanning the field-free-point trajectory in magnetic particle imaging
    Weber, A.; Werner, F.; Weizenecker, J.; Buzug, T. M.; Knopp, T.
    Physics in Medicine & Biology (2016), 61 (2), 475-487CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
    Magnetic particle imaging is a tracer-based imaging method that utilizes the non-linear magnetization response of iron-oxide for detg. their spatial distribution. The method is based on a sampling scheme where a sensitive spot is moved along a trajectory that captured a predefined field-of-view (FOV). However, particles outside the FOV also contribute to the measurement signal due to their rotation and the non-sharpness of the sensitive spot. In the present work we investigate artifacts that are induced by particles not covered by the FOV and show that the artifacts can be mitigated by using a system matrix that covers not only the region of interest but also a certain area around the FOV. The findings are esp. relevant when using a multi-patch acquisition scheme where the boundaries of neighboring patches have to be handled.
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  22. 22
    Knopp, T.; Weber, A. Sparse Reconstruction of the Magnetic Particle Imaging System Matrix. IEEE Trans Med. Imaging 2013, 32, 1473– 80,  DOI: 10.1109/TMI.2013.2258029
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    22
    Sparse reconstruction of the magnetic particle imaging system matrix
    Knopp Tobias; Weber Alexander
    IEEE transactions on medical imaging (2013), 32 (8), 1473-80 ISSN:.
    Magnetic particle imaging allows to determine the spatial distribution of magnetic nanoparticles in vivo. The system matrix in magnetic particle imaging is commonly acquired in a tedious calibration scan and requires to measure the system response at numerous positions in the field-of-view. In this paper, we propose a method that significantly reduces the number of required calibration scans. It exploits the special structure of the system matrix and applies sparse reconstruction techniques. Experiments show that the number of calibration scans can be reduced by a factor of ten with only marginal loss of image quality.
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  23. 23
    Guo, B. J.; Yang, Z. L.; Zhang, L. J. Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Front. Mol. Neurosci. 2018, 11, 335,  DOI: 10.3389/fnmol.2018.00335
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    23
    Gadolinium deposition in brain: current scientific evidence and future perspectives
    Guo, Bang J.; Yang, Zhen L.; Zhang, Long J.
    Frontiers in Molecular Neuroscience (2018), 11 (), 335/1-335/12CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)
    In the past 4 years, many publications described a concn.-dependent deposition of gadolinium in the brain both in adults and children, seen as high signal intensities in the globus pallidus and dentate nucleus on unenhanced T1-weighted images. Postmortem human or animal studies have validated gadolinium deposition in these T1-hyperintensity areas, raising new concerns on the safety of gadolinium-based contrast agents (GBCAs). Residual gadolinium is deposited not only in brain, but also in extracranial tissues such as liver, skin, and bone. This review summarizes the current evidence on gadolinium deposition in the human and animal bodies, evaluates the effects of different types of GBCAs on the gadolinium deposition, introduces the possible entrance or clearance mechanism of the gadolinium and potential side effects that may be related to the gadolinium deposition on human or animals, and puts forward some suggestions for further research.
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  24. 24
    Castellani, R. J.; Mojica, G.; Perry, G. The Role of the Iron Stain in Assessing Intracranial Hemorrhage. Open Neurol. J. 2016, 10, 136– 142,  DOI: 10.2174/1874205X01610010136
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    24
    The role of the iron stain in assessing intracranial hemorrhage
    Castellani, Rudy J.; Mojica, Gruschenka; Perry, George
    Open Neurology Journal (2016), 10 (), 136-142CODEN: ONJPCX; ISSN:1874-205X. (Bentham Open)
    The timing of the breakdown of red blood cells and organization of hemorrhage has significance in the catabolism of heme and the processing of iron, but also has a practical application in terms of assigning, or attempting to assign, a time course with respect to traumatic events (e.g. contusions and hemorrhages). Attempts to date contusions, however, have generally been unsuccessful by macroscopic observation, whereas the microscopic observations provide broad data but are also anatomically imprecise as a function of time. Intracranial lesions are of particular significance with respect to the timing of organizing hemorrhage given the acute, and often life-threatening nature of the hemorrhages, and the medicolegal investigation into potential crimes. Of concern is that the Prussian Blue reaction for iron, a relatively straightforward histochem. reaction that has been in use for over 150 years, is sometimes suggested as a diagnostic test for chronicity. Therefore, this study examd. the utility of the Prussian Blue iron stain in living patients with intracranial hemorrhages and well-defined symptom onset, to test whether the presence of Prussian Blue reactivity could be correlated with chronicity. It was found that out of 12 cases with intracranial hemorrhage, eight cases showed at least focal iron reactivity. The duration from symptom onset to surgery in those eight cases ranged from < 24 h to more than 3 days. Of those cases with no iron reactivity, the duration from symptom onset to surgery ranged from < 24 h to six days. In conclusion, the Prussian Blue reaction was unreliable as an indicator of timing in intracranial hemorrhage. The use of the Prussian blue reaction as an independent indicator of chronicity is therefore not valid and can be misleading. Caution is indicated when employing iron staining for timing purposes, as its only use is to highlight, as opposed to identify, pre-existing lesions. With respect to brain lesions, the Prussian blue reaction should not be used in place of the clin. timing of the neurol. decline, or clin. data that is otherwise more accurate and less susceptible to false pos. results.
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  25. 25
    Davis, S. M.; Broderick, J.; Hennerici, M.; Brun, N. C.; Diringer, M. N.; Mayer, S. A.; Begtrup, K.; Steiner, T. Hematoma Growth is a Determinant of Mortality and Poor Outcome after Intracerebral Hemorrhage. Neurology 2006, 66, 1175– 81,  DOI: 10.1212/01.wnl.0000208408.98482.99
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    25
    Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage
    Davis S M; Broderick J; Hennerici M; Brun N C; Diringer M N; Mayer S A; Begtrup K; Steiner T
    Neurology (2006), 66 (8), 1175-81 ISSN:.
    BACKGROUND: Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. METHODS: To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. RESULTS: Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. CONCLUSIONS: Hematoma growth is an independent determinant of both mortality and functional outcome after intracerebral hemorrhage. Attenuation of growth is an important therapeutic strategy.
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  26. 26
    de Oliveira Manoel, A. L. Surgery for Spontaneous Intracerebral Hemorrhage. Crit Care 2020, 24, 45,  DOI: 10.1186/s13054-020-2749-2
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    26
    Surgery for spontaneous intracerebral hemorrhage
    de Oliveira Manoel Airton Leonardo; de Oliveira Manoel Airton Leonardo
    Critical care (London, England) (2020), 24 (1), 45 ISSN:.
    Spontaneous intracerebral hemorrhage is a devastating disease, accounting for 10 to 15% of all types of stroke; however, it is associated with disproportionally higher rates of mortality and disability. Despite significant progress in the acute management of these patients, the ideal surgical management is still to be determined. Surgical hematoma drainage has many theoretical benefits, such as the prevention of mass effect and cerebral herniation, reduction in intracranial pressure, and the decrease of excitotoxicity and neurotoxicity of blood products.Several surgical techniques have been considered, such as open craniotomy, decompressive craniectomy, neuroendoscopy, and minimally invasive catheter evacuation followed by thrombolysis. Open craniotomy is the most studied approach in this clinical scenario, the first randomized controlled trial dating from the early 1960s. Since then, a large number of studies have been published, which included two large, well-designed, well-powered, multicenter, multinational, randomized clinical trials. These studies, The International Surgical Trial in Intracerebral Hemorrhage (STICH), and the STICH II have shown no clinical benefit for early surgical evacuation of intraparenchymal hematoma in patients with spontaneous supratentorial hemorrhage when compared with best medical management plus delayed surgery if necessary. However, the results of STICH trials may not be generalizable, because of the high rates of patients' crossover from medical management to the surgical group. Without these high crossover percentages, the rates of unfavorable outcome and death with conservative management would have been higher. Additionally, comatose patients and patients at risk of cerebral herniation were not included. In these cases, surgery may be lifesaving, which prevented those patients of being enrolled in such trials. This article reviews the clinical evidence of surgical hematoma evacuation, and its role to decrease mortality and improve long-term functional outcome after spontaneous intracerebral hemorrhage.
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  27. 27
    Graeser, M.; Thieben, F.; Szwargulski, P.; Werner, F.; Gdaniec, N.; Boberg, M.; Griese, F.; Moddel, M.; Ludewig, P.; van de Ven, D.; Weber, O. M.; Woywode, O.; Gleich, B.; Knopp, T. Human-Sized Magnetic Particle Imaging for Brain Applications. Nat. Commun. 2019, 10, 1936,  DOI: 10.1038/s41467-019-09704-x
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    Human-sized magnetic particle imaging for brain applications
    Graeser M; Thieben F; Szwargulski P; Werner F; Gdaniec N; Boberg M; Griese F; Moddel M; Knopp T; Graeser M; Thieben F; Szwargulski P; Werner F; Gdaniec N; Boberg M; Griese F; Moddel M; Knopp T; Ludewig P; van de Ven D; Weber O M; Woywode O; Gleich B
    Nature communications (2019), 10 (1), 1936 ISSN:.
    Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmolFe ml(-1), which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.
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  28. 28
    Morgenstern, L. B.; Demchuk, A. M.; Kim, D. H.; Frankowski, R. F.; Grotta, J. C. Rebleeding Leads to Poor Outcome in Ultra-Early Craniotomy for Intracerebral Hemorrhage. Neurology 2001, 56, 1294– 9,  DOI: 10.1212/WNL.56.10.1294
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    28
    Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage
    Morgenstern L B; Demchuk A M; Kim D H; Frankowski R F; Grotta J C
    Neurology (2001), 56 (10), 1294-9 ISSN:0028-3878.
    BACKGROUND: A modest benefit was previously demonstrated for hematoma evacuation within 12 hours of intracerebral hemorrhage onset. Perhaps surgery within 4 hours would further improve outcome. METHODS: Adult patients with spontaneous supratentorial intracerebral hemorrhage were prospectively enrolled. Craniotomy and clot evacuation were commenced within 4 hours of symptom onset in all cases. Mortality and functional outcome were assessed at 6 months. This group of patients was compared with patients treated within 12 hours of symptom onset using the same surgical and medical protocols. RESULTS: The study was stopped after a planned interim analysis of 11 patients in the 4-hour surgery arm. Median time to surgery was 180 minutes; median hematoma volume was 40 mL; median baseline NIH Stroke Scale score was 19 and Glasgow Coma Scale score was 12. Six-month mortality was 36% and median Barthel score was 75 in survivors. Postoperative rebleeding occurred in four patients, three of whom died. A relationship between postoperative rebleeding and mortality was apparent (p = 0.03). Rebleeding occurred in 40% of the patients treated within 4 hours, compared with 12% of the patients treated within 12 hours (p = 0.11). There was a clear correlation between improved outcome and smaller postsurgical hematoma volume (p = 0.04). CONCLUSIONS: Surgical hematoma evacuation within 4 hours of symptom onset is complicated by rebleeding, indicating difficulty with hemostasis. Maximum removal of blood remains a predictor of good outcome.
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  29. 29
    Hanley, D. F.; Thompson, R. E.; Muschelli, J.; Rosenblum, M.; McBee, N.; Lane, K.; Bistran-Hall, A. J.; Mayo, S. W.; Keyl, P.; Gandhi, D.; Morgan, T. C.; Ullman, N.; Mould, W. A.; Carhuapoma, J. R.; Kase, C.; Ziai, W.; Thompson, C. B.; Yenokyan, G.; Huang, E.; Broaddus, W. C. Safety and Efficacy of Minimally Invasive Surgery plus Alteplase in Intracerebral Haemorrhage Evacuation (MISTIE): A Randomised, Controlled, Open-Label, Phase 2 Trial. Lancet Neurol. 2016, 15, 1228– 1237,  DOI: 10.1016/S1474-4422(16)30234-4
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    29
    Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral hemorrhage evacuation (MISTIE): a randomized, controlled, open-label, phase 2 trial
    Hanley, Daniel F.; Thompson, Richard E.; Muschelli, John; Rosenblum, Michael; McBee, Nichol; Lane, Karen; Bistran-Hall, Amanda J.; Mayo, Steven W.; Keyl, Penelope; Gandhi, Dheeraj; Morgan, Tim C.; Ullman, Natalie; Mould, W. Andrew; Carhuapoma, J. Ricardo; Kase, Carlos; Ziai, Wendy; Thompson, Carol B.; Yenokyan, Gayane; Huang, Emily; Broaddus, William C.; Graham, R. Scott; Aldrich, E. Francois; Dodd, Robert; Wijman, Cristanne; Caron, Jean-Louis; Huang, Judy; Camarata, Paul; Mendelow, A. David; Gregson, Barbara; Janis, Scott; Vespa, Paul; Martin, Neil; Awad, Issam; Zuccarello, Mario
    Lancet Neurology (2016), 15 (12), 1228-1237CODEN: LNAEAM; ISSN:1474-4422. (Elsevier Ltd.)
    Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral hemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral hemorrhage. MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomize patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral hemorrhage of 20 mL or higher to std. medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, no. NCT00224770. Between Feb 2, 2006, and Apr. 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the std. medical care group. The primary outcomes did not differ between the std. medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic hemorrhages were more common in the MIS plus alteplase group than in the std. medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051). MIS plus alteplase seems to be safe in patients with intracerebral hemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addn. of surgical management as a therapeutic strategy for intracerebral hemorrhage. National Institute of Neurol. Disorders and Stroke, Genentech, and Codman.
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  30. 30
    Fung, C.; Murek, M.; Z’Graggen, W. J.; Krahenbuhl, A. K.; Gautschi, O. P.; Schucht, P.; Gralla, J.; Schaller, K.; Arnold, M.; Fischer, U.; Mattle, H. P.; Raabe, A.; Beck, J. Decompressive Hemicraniectomy in Patients with Supratentorial Intracerebral Hemorrhage. Stroke 2012, 43, 3207– 11,  DOI: 10.1161/STROKEAHA.112.666537
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    30
    Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage
    Fung Christian; Murek Michael; Z'Graggen Werner J; Krahenbuhl Anna K; Gautschi Oliver P; Schucht Philippe; Gralla Jan; Schaller Karl; Arnold Marcel; Fischer Urs; Mattle Heinrich P; Raabe Andreas; Beck Jurgen
    Stroke (2012), 43 (12), 3207-11 ISSN:.
    BACKGROUND AND PURPOSE: Decompressive craniectomy (DC) lowers intracranial pressure and improves outcome in patients with malignant middle cerebral artery stroke. Its usefulness in intracerebral hemorrhage (ICH) is unclear. The aim of this study was to analyze feasibility and safety of DC without clot evacuation in ICH. METHODS: We compared consecutive patients (November 2010-January 2012) with supratentorial ICH treated with DC without hematoma evacuation and matched controls treated by best medical treatment. DC measured at least 150 mm and included opening of the dura. We analyzed clinical (age, sex, pathogenesis, Glasgow Coma Scale, National Institutes of Health Stroke Scale), radiological (signs of herniation, side and size of hematoma, midline shift, hematoma expansion, distance to surface), and surgical (time to and indication for surgery) characteristics. Outcome at 6 months was dichotomized into good (modified Rankin Scale 0-4) and poor (modified Rankin Scale 5-6). RESULTS: Twelve patients (median age 48 years; interquartile range 35-58) with ICH were treated by DC. Median hematoma volume was 61.3 mL (interquartile range 37-83.5 mL) and median preoperative Glasgow Coma Scale was 8 (interquartile range 4.3-10). Four patients showed signs of herniation. Nine patients had good and 3 had poor outcomes. Three patients (25%) of the treatment group died versus 8 of 15 (53%) of the control group. There were 3 manageable complications related to DC. CONCLUSIONS: DC is feasible in patients with ICH. Based on this small cohort, DC may reduce mortality. Larger prospective cohorts are warranted to assess safety and efficacy.
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  31. 31
    Onishi, H.; Murakami, T.; Kim, T.; Hori, M.; Hirohashi, S.; Matsuki, M.; Narumi, Y.; Imai, Y.; Sakurai, K.; Nakamura, H. Safety of Ferucarbotran in MR Imaging of the Liver: A Pre- and Postexamination Questionnaire-Based Multicenter Investigation. J. Magn Reson Imaging 2009, 29, 106– 11,  DOI: 10.1002/jmri.21608
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    31
    Safety of ferucarbotran in MR imaging of the liver: a pre- and postexamination questionnaire-based multicenter investigation
    Onishi Hiromitsu; Murakami Takamichi; Kim Tonsok; Hori Masatoshi; Hirohashi Shinji; Matsuki Mitsuru; Narumi Yoshifumi; Imai Yasuharu; Sakurai Kousuke; Nakamura Hironobu
    Journal of magnetic resonance imaging : JMRI (2009), 29 (1), 106-11 ISSN:1053-1807.
    PURPOSE: To prospectively investigate, by means of a pre-and postexamination questionnaire, the types and frequency of adverse reactions to ferucarbotran (Resovist), a superparamagnetic iron oxide (SPIO) contrast agent. MATERIALS AND METHODS: This study was approved by the ethics committee of each of the institutions involved, and all patients gave written informed consent. One questionnaire asking about baseline symptoms before the injection of ferucarbotran, and one about adverse events over a period of seven days after injection were given to 315 patients who underwent ferucarbotran-enhanced magnetic resonance imaging (MRI) of the liver at several institutions. The data for baseline symptoms were used for reference to exclude false-positive adverse reactions and were also compared with the adverse event data to determine with McNemar's chi-squared test the incidence of each symptom. RESULTS: Before MR examination, 249 clinical symptoms were reported by 102 of 315 patients (32.4%). After the injection of ferucarbotran, 169 adverse events were observed in 78 patients (24.8%). Eventually, 70 adverse events occurring in 45 patients (14.3%) were judged to be adverse reactions to ferucarbotran, defined as possibly or definitely ferucarbotran-related events. All reactions were of mild intensity. CONCLUSION: Ferucarbotran can be considered safe for clinical use in liver MRI.
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    Kanda, T.; Ishii, K.; Kawaguchi, H.; Kitajima, K.; Takenaka, D. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-Based Contrast Material. Radiology 2014, 270, 834– 41,  DOI: 10.1148/radiol.13131669
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    32
    High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material
    Kanda Tomonori; Ishii Kazunari; Kawaguchi Hiroki; Kitajima Kazuhiro; Takenaka Daisuke
    Radiology (2014), 270 (3), 834-41 ISSN:.
    PURPOSE: To explore any correlation between the number of previous gadolinium-based contrast material administrations and high signal intensity (SI) in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: The institutional review board approved this study, waiving the requirement to obtain written informed consent. A group of 381 consecutive patients who had undergone brain MR imaging was identified for cross-sectional analysis. For longitudinal analysis, 19 patients who had undergone at least six contrast-enhanced examinations were compared with 16 patients who had undergone at least six unenhanced examinations. The mean SIs of the dentate nucleus, pons, globus pallidus, and thalamus were measured on unenhanced T1-weighted images. The dentate nucleus-to-pons SI ratio was calculated by dividing the SI in the dentate nucleus by that in the pons, and the globus pallidus-to-thalamus SI ratio was calculated by dividing the SI in the globus pallidus by that in the thalamus. Stepwise regression analysis was undertaken in the consecutive patient group to detect any relationship between the dentate nucleus-to-pons or globus pallidus-to-thalamus SI ratio and previous gadolinium-based contrast material administration or other factors. A random coefficient model was used to evaluate for longitudinal analysis. RESULTS: The dentate nucleus-to-pons SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus-to-thalamus SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288), radiation therapy (P = .009; regression coefficient, -0.014; 95% CI: -0.025, -0.004; standardized regression coefficient, -0.151), and liver function (P = .031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107). The dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios in patients who had undergone contrast-enhanced examinations were significantly greater than those of patients who had undergone unenhanced examinations (P < .001 for both). CONCLUSION: High SI in the dentate nucleus and globus pallidus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast material administrations.
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    Tay, Z. W.; Hensley, D. W.; Chandrasekharan, P.; Zheng, B.; Conolly, S. M. Optimization of Drive Parameters for Resolution, Sensitivity and Safety in Magnetic Particle Imaging. IEEE Trans Med. Imaging 2020, 39, 1724– 1734,  DOI: 10.1109/TMI.2019.2957041
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    Optimization of Drive Parameters for Resolution, Sensitivity and Safety in Magnetic Particle Imaging
    Tay Zhi Wei; Hensley Daniel W; Chandrasekharan Prashant; Zheng Bo; Conolly Steven M
    IEEE transactions on medical imaging (2020), 39 (5), 1724-1734 ISSN:.
    Magnetic Particle Imaging is an emerging tracer imaging modality with zero background signal and zero ionizing radiation, high contrast and high sensitivity with quantitative images. While there is recent work showing that the low amplitude or low frequency drive parameters can improve MPI's spatial resolution by mitigating relaxation losses, the concomitant decrease of the MPI's tracer sensitivity due to the lower drive slew rates was not fully addressed. There has yet to be a wide parameter space, multi-objective optimization of MPI drive parameters for high resolution, high sensitivity and safety. In a large-scale study, we experimentally test 5 different nanoparticles ranging from multi to single-core across 18.5 nm to 32.1 nm core sizes and across an expansive drive parameter range of 0.4 - 416 kHz and 0.5 - 40 mT/ μ0 to assess spatial resolution, SNR, and safety. In addition, we analyze how drive-parameter-dependent shifts in harmonic signal energy away and towards the discarded first harmonic affect effective SNR in this optimization study. The results show that when optimizing for all four factors of resolution, SNR, discarded-harmonic-energy and safety, the overall trends are no longer monotonic and clear optimal points emerge. We present drive parameters different from conventional preclinical MPI showing ~ 2-fold improvement in spatial resolution while remaining within safety limits and addressing sensitivity by minimizing the typical SNR loss involved. Finally, validation of the optimization results with 2D images of phantoms was performed.
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    Wang, Y. X. Superparamagnetic Iron Oxide Based MRI Contrast Agents: Current Status of Clinical Application. Quant Imaging Med. Surg 2011, 1, 35– 40
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    Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application
    Wang Yi-Xiang J
    Quantitative imaging in medicine and surgery (2011), 1 (1), 35-40 ISSN:2223-4292.
    Superparamagnetic iron oxide (SPIO) MR contrast agents are composed of nano-sized iron oxide crystals coated with dextran or carboxydextran. Two SPIO agents are clinically approved, namely: ferumoxides (Feridex in the USA, Endorem in Europe) with a particle size of 120 to 180 nm, and ferucarbotran (Resovist) with a particle size of about 60 nm. The principal effect of the SPIO particles is on T2* relaxation and thus MR imaging is usually performed using T2/T2*-weighted sequences in which the tissue signal loss is due to the susceptibility effects of the iron oxide core. Enhancement on T1-weighted images can also be seen with the smaller Resovist. Both Feridex and Resovist are approved specifically for MRI of the liver. The difference being that Resovist can be administered as a rapid bolus (and thus can be used with both dynamic and delayed imaging), whereas Feridex needs to be administered as a slow infusion and is used solely in delayed phase imaging. In the liver, these particles are sequestered by phagocytic Kupffer cells in normal reticuloendothelial system (RES), but are not retained in lesions lacking Kupffer cells. Consequently, there are significant differences in T2/T2* relaxation between normal tissue and lesions, resulting in increased lesion conspicuity and detectability. SPIO substantially increase the detectability of hepatic metastases. For focal hepatocellular lesions, SPIO-enhanced MR imaging exhibits slightly better diagnostic performance than dynamic CT. A combination of dynamic and static MR imaging technique using T1- and T2 imaging criteria appears to provide clinically more useful patterns of enhancement. Feridex and Resovist are also used for evaluating macrophage activities in some inflammatory lesions, but their clinical values remain to be further confirmed. The clinical development of Ferumoxtran (Combidex in the USA, Sinerem in Europe), designed for lymph node metastasis evaluation, is currently stopped.
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    Gu, J.; Xu, H.; Han, Y.; Dai, W.; Hao, W.; Wang, C.; Gu, N.; Xu, H.; Cao, J. The Internalization Pathway, Metabolic Fate and Biological Effect of Superparamagnetic Iron Oxide Nanoparticles in the Macrophage-Like RAW264.7 Cell. Sci. China: Life Sci. 2011, 54, 793– 805,  DOI: 10.1007/s11427-011-4215-5
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    The internalization pathway, metabolic fate and biological effect of superparamagnetic iron oxide nanoparticles in the macrophage-like RAW264.7 cell
    Gu, Jing Li; Xu, Hai Fei; Han, Ye Hua; Dai, Wei; Hao, Wei; Wang, Chun Yu; Gu, Ning; Xu, Hai Yan; Cao, Ji Min
    Science China: Life Sciences (2011), 54 (9), 793-805CODEN: SCLSCJ; ISSN:1674-7305. (Science China Press)
    The potential applications of superparamagnetic iron oxide nanoparticles (SPIONs) in several nanomedical fields have attracted intense interest based on the cell-nano interaction. However, the mechanisms underlying cell uptake, the intracellular trail, final fate and the biol. effects of SPIONs have not yet been clearly elucidated. Here, we showed that multiple endocytic pathways were involved in the internalization process of SPIONs in the RAW264.7 macrophage. The internalized SPIONs were biocompatible and used three different metabolic pathways: The SPIONs were distributed to daughter cells during mitosis; they were degraded in the lysosome and free iron was released into the intracellular iron metabolic pool; and, the intact SPIONs were potentially exocytosed out of the cells. The internalized SPIONs did not induce cell damage but affected iron metab., inducing the upregulation of ferritin light chain at both the mRNA and protein levels and ferroportin 1 at the mRNA level. These results may contribute to the development of nanobiol. and to the safe use of SPIONs in medicine when administered as a contrast medium or a drug delivery tool.
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    Antonelli, A.; Szwargulski, P.; Scarpa, E. S.; Thieben, F.; Cordula, G.; Ambrosi, G.; Guidi, L.; Ludewig, P.; Knopp, T.; Magnani, M. Development of Long Circulating Magnetic Particle Imaging Tracers: Use of Novel Magnetic Nanoparticles and Entrapment into Human Erythrocytes. Nanomedicine (London, U. K.) 2020, 15, 739– 753,  DOI: 10.2217/nnm-2019-0449
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    Development of long circulating magnetic particle imaging tracers: use of novel magnetic nanoparticles and entrapment into human erythrocytes
    Antonelli, Antonella; Szwargulski, Patryk; Scarpa, Emanuele-Salvatore; Thieben, Florian; Cordula, Gruettner; Ambrosi, Gianluca; Guidi, Loretta; Ludewig, Peter; Knopp, Tobias; Magnani, Mauro
    Nanomedicine (London, United Kingdom) (2020), 15 (8), 739-753CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)
    Aim: Magnetic particle imaging (MPI) is highly promising for biomedical applications, but optimal tracers for MPI, namely superparamagnetic iron oxide-based contrast agents, are still lacking. Materials & methods: The encapsulation of com. available nanoparticles, specifically synomag-D and perimag, into human red blood cells (RBCs) was performed by a hypotonic dialysis and isotonic resealing procedure. The amts. of superparamagnetic iron oxide incorporated into RBCs were detd. by Fe quantification using NMR and magnetic particle spectroscopy. Results: Perimag-COOH nanoparticles were identified as the best nanomaterial for encapsulation in RBCs. Perimag-COOH-loaded RBCs proved to be viable cells showing a good magnetic particle spectroscopy performance, while the magnetic signal of synomag-D-COOH-loaded RBCs dropped sharply. Conclusion: Perimag-COOH-loaded RBCs could be a potential tool for MPI diagnostic applications.
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    Voros, E.; Cho, M.; Ramirez, M.; Palange, A. L.; De Rosa, E.; Key, J.; Garami, Z.; Lumsden, A. B.; Decuzzi, P. TPA Immobilization on Iron Oxide Nanocubes and Localized Magnetic Hyperthermia Accelerate Blood Clot Lysis. Adv. Funct. Mater. 2015, 25, 1709– 1718,  DOI: 10.1002/adfm.201404354
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    TPA (tissue plasminogen activator) immobilization on iron oxide nanocubes and localized magnetic hyperthermia accelerate blood clot lysis
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    Advanced Functional Materials (2015), 25 (11), 1709-1718CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The low specificity and high risk of intracranial hemorrhage assocd. with currently approved thrombolytic therapies limit their efficacy in recanalizing occluded vessels. Here, a nanoscale thrombolytic agent is demonstrated by immobilizing tissue plasminogen activator mols. (tPA) over 20 nm clustered iron oxide nanocubes (NCs). The resulting nanoconstructs (tPA-NCs) are capable of dissolving clots via both direct interaction of tPA with the fibrin network (chem. lysis) and localized hyperthermia upon stimulation of superparamagnetic NCs with alternating magnetic fields (AMFs) (mech. lysis). In vitro, as compared to free tPA, the proposed nanoconstructs demonstrate a ≈100-fold increase in dissoln. rate, possibly because of a more intimate interaction of tPA with the fibrin network. The clot dissoln. rate is further enhanced (≈10-fold) by mild, localized heating resulting from the exposure of tPA-NCs to AMF. Intravital microscopy expts. demonstrate blood vessel reperfusion within a few minutes post tail vein injection of tPA-NCs. The proposed nanoconstructs also exhibit high transverse relaxivity (>400 × 10-3 M-1 s-1) for magnetic resonance imaging. The multifunctional properties and the 3 orders of magnitude enhancement in clot dissoln. make tPA-NCs a promising nano-theranosis agent in thrombotic disease.
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    Tay, Z. W.; Chandrasekharan, P.; Chiu-Lam, A.; Hensley, D. W.; Dhavalikar, R.; Zhou, X. Y.; Yu, E. Y.; Goodwill, P. W.; Zheng, B.; Rinaldi, C.; Conolly, S. M. Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy. ACS Nano 2018, 12, 3699– 3713,  DOI: 10.1021/acsnano.8b00893
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    Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy
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    ACS Nano (2018), 12 (4), 3699-3713CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Image-guided treatment of cancer enables physicians to localize and treat tumors with great precision. Here, the authors present in vivo results showing that an emerging imaging modality, magnetic particle imaging (MPI), can be combined with magnetic hyperthermia into an image-guided theranostic platform. MPI is a noninvasive 3D tomog. imaging method with high sensitivity and contrast, zero ionizing radiation, and is linearly quant. at any depth with no view limitations. The same superparamagnetic iron oxide nanoparticle (SPIONs) tracers imaged in MPI can also be excited to generate heat for magnetic hyperthermia. The authors demonstrate a theranostic platform, with quant. MPI image guidance for treatment planning and use of the MPI gradients for spatial localization of magnetic hyperthermia to arbitrarily selected regions. This addresses a key challenge of conventional magnetic hyperthermia-SPIONs delivered systemically accumulate in off-target organs (e.g., liver and spleen), and difficulty in localizing hyperthermia results in collateral heat damage to these organs. Using a MPI magnetic hyperthermia workflow, the authors demonstrate image-guided spatial localization of hyperthermia to the tumor while minimizing collateral damage to the nearby liver (1-2 cm distance). Localization of thermal damage and therapy was validated with luciferase activity and histol. assessment. Apart from localizing thermal therapy, the technique presented here can also be extended to localize actuation of drug release and other biomech.-based therapies. With high contrast and high sensitivity imaging combined with precise control and localization of the actuated therapy, MPI is a powerful platform for magnetic-based theranostics.
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    Simultaneous Magnetic Particle Imaging and Navigation of large superparamagnetic nanoparticles in bifurcation flow experiments
    Griese, Florian; Knopp, Tobias; Gruettner, Cordula; Thieben, Florian; Mueller, Knut; Loges, Sonja; Ludewig, Peter; Gdaniec, Nadine
    Journal of Magnetism and Magnetic Materials (2020), 498 (), 166206CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)
    Magnetic Particle Imaging (MPI) has been successfully used to visualize the distribution of superparamagnetic nanoparticles within 3D vols. with high sensitivity in real time. Since the magnetic field topol. of MPI scanners is well suited for applying magnetic forces on particles and micron-sized ferromagnetic devices, MPI has been recently used to navigate micron-sized particles and micron-sized swimmers. In this work, we analyze the magnetophoretic mobility and the imaging performance of two different particle types for Magnetic Particle Imaging/Navigation (MPIN). MPIN constantly switches between imaging and magnetic modes, enabling quasi-simultaneous navigation and imaging of particles. We det. the limiting flow velocity to be 8.18 mL s-1 using a flow bifurcation expt., that allows all particles to flow only through one branch of the bifurcation. Furthermore, we have succeeded in navigating the particles through the branch of a bifurcation phantom narrowed by either 60% or 100% stenosis, while imaging their accumulation on the stenosis. The particles in combination with therapeutic substances have a high potential for targeted drug delivery and could help to reduce the dose and improve the efficacy of the drug, e.g. for specific tumor therapy and ischemic stroke therapy.
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    Ludewig, P.; Sedlacik, J.; Gelderblom, M.; Bernreuther, C.; Korkusuz, Y.; Wagener, C.; Gerloff, C.; Fiehler, J.; Magnus, T.; Horst, A. K. Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits MMP-9-Mediated Blood-Brain-Barrier Breakdown in a Mouse Model for Ischemic Stroke. Circ. Res. 2013, 113, 1013– 22,  DOI: 10.1161/CIRCRESAHA.113.301207
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    40
    Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits MMP-9-Mediated Blood-Brain-Barrier Breakdown in a Mouse Model for Ischemic Stroke
    Ludewig, Peter; Sedlacik, Jan; Gelderblom, Mathias; Bernreuther, Christian; Korkusuz, Yuecel; Wagener, Christoph; Gerloff, Christian; Fiehler, Jens; Magnus, Tim; Horst, Andrea Kristina
    Circulation Research (2013), 113 (8), 1013-1022CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)
    Rationale: Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion mol. 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated. Objective: We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1 and wild-type mice. Methods and results: Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we obsd. increased stroke vols., BBB breakdown and edema formation, redn. of cerebral perfusion, and brain atrophy in Ceacam1 mice. This translated into poor performance in neurol. scoring and high poststroke-assocd. mortality. Elevated neutrophil influx, hyperprodn., and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1 mice were confirmed by immune fluorescence, flow cytometry, zymog., and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1 mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochem. of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1 matrix metalloproteinase-9 neutrophils in the ischemic hemispheres. Conclusions: CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
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  • Abstract

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    Figure 1

    Figure 1. Rapid detection of intracranial hemorrhage with MPI. After the intravenous injection of 200 μL of Synomag-D (243 μg iron, c[Fe] = 1.22 mg/mL), MPI scans were acquired dynamically with a temporal resolution of 21.54 s, resulting in 3D-(+t) MPI data sets. Digital subtraction with a positive-only filter was applied to the 3D-(+t) MPI data sets to delineate the hemorrhage. (a) Early detection and expansion of the intracranial hemorrhage after the tracer injection at several time points on fused MPI/MRI slices (a; upper row: coronal sections; middle row: transversal sections; lower row: sagittal sections; the white asterisk indicates the hemorrhage in MRI and MPI; data without digital subtraction are shown in Supplemental Figure S4; signals were normalized for better visibility). The signal information from these data sets was converted into a concentration–time curve on a voxel by pixel basis (b). Only 1.80 ± 0.3 min passed between the tracer bolus arrival in the brain and the hemorrhage detection. Bleeding continued up to 100 min (a, b). The extravasation of the tracer and expansion of the hemorrhage could be monitored in real time (see Supplemental Video V1). Color coding the tracer arrival time allowed for the differentiation of bleeding areas of different age (c; the needle tip of the syringe marks the collagenase injection site for hemorrhage induction).

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    Figure 2

    Figure 2. Volumetric measurements of intracranial hemorrhages with MPI. Analyzing the brain and the dissected intracranial hemorrhage ex vivo revealed that the in vivo MPI signal was generated by the intracranial hemorrhage (a: the upper panel shows a photograph of the ex vivo brain and the dissected hemorrhage, while the lower panel shows the corresponding MPI signal). The improved spatial resolution of MPI scanners allowed for calculating the hemorrhage volume. A 3D rendering of the MPI hemorrhage revealed a shape and size comparable to the MRI (b; left images: view from lateral; right images: view from below). The volume of bleeding calculated from the MPI data sets showed sizes comparable to histological sections of the same animals 24 h after the induction of the hemorrhage (c/d). The injection of the tracer did not lead to an increase in bleeding size (d; n.s.: not significant).

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    Figure 3

    Figure 3. Multicontrast MPI for the differentiation of fluid and immobilized tracer. Fluid tracer and dissected hemorrhage tissue with immobilized tracer were used for calibration measurement to obtain MPI system matrices for image reconstruction. In an in vitro setting, multicontrast MPI distinguished liquid and immobilized tracer with the dedicated system matrices (a: design of phantom with the different samples of fluid and immobilized tracer and a negative control; b: the corresponding MPI signal of the phantom; the upper image shows an overlay of the reconstruction with the immobilized-dedicated (red) and the liquid-dedicated system matrix (gray), the lower panel shows the separated channels). Applying multicontrast MPI in vivo, we could detect areas with immobilized tracer reflecting areas of coagulated blood inside the hemorrhage (c; upper row: coronal sections of images reconstructed with the system matrix for immobilized tracer; middle row: images reconstructed with the system matrix for fluid tracer; lower row: digital subtraction images of the fluid tracer; bottom row: overlay of all three MPI reconstructions on the top of the corresponding MRI slice).

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    Figure 4

    Figure 4. Multicontrast MPI for simultaneous monitoring of intracranial hemorrhage and cerebral perfusion. After the induction of the intracranial hemorrhage, the tracer Synomag-D (c[Fe] = 1.22 mg/mL) was injected for bleeding detection. Two hours later, we injected a 5 μL bolus of the tracer Perimag (c[Fe] = 57 mg/mL) for perfusion imaging with a temporal resolution of 21.54 ms. Images were reconstructed with the system matrix for immobilized Synomag-D and liquid Perimag (a; upper row: overlay of MPI and MRI data; middle row: immobilized tracer/Synomag-D/hemorrhage in red; lower row: fluid tracer/Perimag/cerebral perfusion in blue; the time labels correspond to the concentration–time curve in Figure 4b; the arrow in b marks the time point of the tracer injection). We could clearly detect the hemorrhage while the Perimag bolus passed through the brain in the images (a) and concentration–time curves (b; red line: hemorrhage/Synomag-D signal; blue line: Perimag bolus in the contralateral hemisphere; black dotted line: Perimag signal in a vein). Perfusion parameters maps (c; rCBV, rCBF) were derived from the concentration–time curves and showed decreased perfusion within the hemorrhage (c, red asterisk). A high concentration of the second tracer can shadow the first tracer. The phenomenon is present in the concentration–time curves, which illustrate a drop in the bleeding signal during the injection of Perimag (b).

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    Figure 5

    Figure 5. Long-term MPI of the intracranial hemorrhage shows the degradation of the tracer. Animals were sacrificed 4 h after the induction of the hemorrhage and tracer injection. The amount of tracer inside the hemorrhage was evaluated through Prussian blue staining. This revealed homogeneous extravasation, whereas the staining was negative in animals without tracer injection or the contralateral side (a; upper image: tracer particles are stained in blue; middle image: ICH without injected tracer; lower image: contralateral hemisphere with injected tracer; scale bar: 100 μm). Imaging of the animal after the injection of the tracer (Synomag-D) was performed up to 28 days (b, c; n = 4 until day 23; one animal was imaged until day 28). Magnetic particle imaging signal intensities (b) and the amount of tracer (c) significantly decreased over 3–4 weeks.

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    This article references 40 other publications.

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      BACKGROUND: Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). METHODS: In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0-3 vs 4-6. Secondary outcomes included other mRS cutpoints and mRS "shift analysis." Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. RESULTS: Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5-6 or 6 was defined as "poor outcome." CONCLUSION: HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.
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      British journal of anaesthesia (2006), 97 (1), 26-38 ISSN:0007-0912.
      Raised intracranial pressure (ICP) and low cerebral blood flow (CBF) are associated with ischaemia and poor outcome after brain injury. Therefore, many management protocols target these parameters. This overview summarizes the technical aspects of ICP and CBF monitoring, and their role in the clinical management of brain-injured patients. Furthermore, some applications of these methods in current research are highlighted. ICP is typically measured using probes that are inserted into one of the lateral ventricles or the brain parenchyma. Therapeutic measures used to control ICP have relevant side-effects and continuous monitoring is essential to guide such therapies. ICP is also required to calculate cerebral perfusion pressure which is one of the most important therapeutic targets in brain-injured patients. Several bedside CBF monitoring devices are available. However, most do not measure CBF but rather a parameter that is thought to be proportional to CBF. Frequently used methods include transcranial Doppler which measures blood flow velocity and may be helpful for the diagnosis and monitoring of cerebral vasospasm after subarachnoid haemorrhage or jugular bulb oximetry which gives information on adequacy of CBF in relation to the metabolic demand of the brain. However, there is no clear evidence that incorporating data from CBF monitors into our management strategies improves outcome in brain-injured patients.
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      NeuroImage (2014), 85 Pt 1 (), 6-27 ISSN:.
      This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.
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      Rosenthal, G.; Sanchez-Mejia, R. O.; Phan, N.; Hemphill, J. C., 3rd; Martin, C.; Manley, G. T. Incorporating a Parenchymal Thermal Diffusion Cerebral Blood Flow Probe in Bedside Assessment of Cerebral Autoregulation and Vasoreactivity in Patients with Severe Traumatic Brain Injury. J. Neurosurg. 2011, 114, 62– 70,  DOI: 10.3171/2010.6.JNS091360
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      Rosenthal Guy; Sanchez-Mejia Rene O; Phan Nicolas; Hemphill J Claude 3rd; Martin Christine; Manley Geoffrey T
      Journal of neurosurgery (2011), 114 (1), 62-70 ISSN:.
      OBJECT: Cerebral autoregulation may be altered after traumatic brain injury (TBI). Recent evidence suggests that patients' autoregulatory status following severe TBI may influence cerebral perfusion pressure management. The authors evaluated the utility of incorporating a recently upgraded parenchymal thermal diffusion probe for the measurement of cerebral blood flow (CBF) in the neurointensive care unit for assessing cerebral autoregulation and vasoreactivity at bedside. METHODS: The authors evaluated 20 patients with severe TBI admitted to San Francisco General Hospital who underwent advanced neuromonitoring. Patients had a parenchymal thermal diffusion probe placed for continuous bedside monitoring of local CBF ((loc)CBF) in addition to the standard intracranial pressure and brain tissue oxygen tension (P(bt)O(2)) monitoring. The CBF probes were placed in the white matter using a separate cranial bolt. A pressure challenge, whereby mean arterial pressure (MAP) was increased by about 10 mm Hg, was performed in all patients to assess autoregulation. Cerebral CO(2) vasoreactivity was assessed with a hyperventilation challenge. Local cerebral vascular resistance ((loc)CVR) was calculated by dividing cerebral perfusion pressure by (loc)CBF. Local cerebral vascular resistance normalized to baseline ((loc)CVR(normalized)) was also calculated for the MAP and hyperventilation challenges. RESULTS: In all cases, bedside measurement of (loc)CBF using a cranial bolt in patients with severe TBI resulted in correct placement in the white matter with a low rate of complications. Mean (loc)CBF decreased substantially with hyperventilation challenge (-7 ± 8 ml/100 g/min, p = 0.0002) and increased slightly with MAP challenge (1 ± 7 ml/100 g/min, p = 0.17). Measurements of (loc)CBF following MAP and hyperventilation challenges can be used to calculate (loc)CVR. In 83% of cases, (loc)CVR increased during a hyperventilation challenge (mean change +3.5 ± 3.8 mm Hg/ml/100 g/min, p = 0.0002), indicating preserved cerebral CO(2) vasoreactivity. In contrast, we observed a more variable response of (loc)CVR to MAP challenge, with increased (loc)CVR in only 53% of cases during a MAP challenge (mean change -0.17 ± 3.9 mm Hg/ml/100 g/min, p = 0.64) indicating that in many cases autoregulation was impaired following severe TBI. CONCLUSIONS: Use of the Hemedex thermal diffusion probe appears to be a safe and feasible method that enables continuous monitoring of CBF at the bedside. Cerebral autoregulation and CO(2) vasoreactivity can be assessed in patients with severe TBI using the CBF probe by calculating (loc)CVR in response to MAP and hyperventilation challenges. Determining whether CVR increases or decreases with a MAP challenge ((loc)CVR(normalized)) may be a simple provocative test to determine patients' autoregulatory status following severe TBI and helping to optimize CPP management.
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      Tomographic imaging using the nonlinear response of magnetic particles
      Gleich, Bernhard; Weizenecker, Juergen
      Nature (London, United Kingdom) (2005), 435 (7046), 1214-1217CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The use of contrast agents and tracers in medical imaging has a long history. They provide important information for diagnosis and therapy, but for some desired applications, a higher resoln. is required than can be obtained using the currently available medical imaging techniques. Consider, for example, the use of magnetic tracers in magnetic resonance imaging: detection thresholds for in vitro and in vivo imaging are such that the background signal from the host tissue is a crucial limiting factor. A sensitive method for detecting the magnetic particles directly is to measure their magnetic fields using relaxometry; but this approach has the drawback that the inverse problem (assocd. with transforming the data into a spatial image) is ill posed and therefore yields low spatial resoln. Here we present a method for obtaining a high-resoln. image of such tracers that takes advantage of the nonlinear magnetization curve of small magnetic particles. Initial 'phantom' expts. are reported that demonstrate the feasibility of the imaging method. The resoln. that we achieve is already well below 1 mm. We evaluate the prospects for further improvement, and show that the method has the potential to be developed into an imaging method characterized by both high spatial resoln. as well as high sensitivity.
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      Bakenecker, A. C.; Ahlborg, M.; Debbeler, C.; Kaethner, C.; Buzug, T. M.; Ludtke-Buzug, K. Magnetic Particle Imaging in Vascular Medicine. Innov Surg Sci. 2018, 3, 179– 192,  DOI: 10.1515/iss-2018-2026
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      Magnetic particle imaging in vascular medicine
      Bakenecker Anna C; Ahlborg Mandy; Debbeler Christina; Kaethner Christian; Buzug Thorsten M; Ludtke-Buzug Kerstin
      Innovative surgical sciences (2018), 3 (3), 179-192 ISSN:.
      Magnetic particle imaging (MPI) is a new medical imaging technique that enables three-dimensional real-time imaging of a magnetic tracer material. Although it is not yet in clinical use, it is highly promising, especially for vascular and interventional imaging. The advantages of MPI are that no ionizing radiation is necessary, its high sensitivity enables the detection of very small amounts of the tracer material, and its high temporal resolution enables real-time imaging, which makes MPI suitable as an interventional imaging technique. As MPI is a tracer-based imaging technique, functional imaging is possible by attaching specific molecules to the tracer material. In the first part of this article, the basic principle of MPI will be explained and a short overview of the principles of the generation and spatial encoding of the tracer signal will be given. After this, the used tracer materials as well as their behavior in MPI will be introduced. A subsequent presentation of selected scanner topologies will show the current state of research and the limitations researchers are facing on the way from preclinical toward human-sized scanners. Furthermore, it will be briefly shown how to reconstruct an image from the tracer materials' signal. In the last part, a variety of possible future clinical applications will be presented with an emphasis on vascular imaging, such as the use of MPI during cardiovascular interventions by visualizing the instruments. Investigations will be discussed, which show the feasibility to quantify the degree of stenosis and diagnose strokes and traumatic brain injuries as well as cerebral or gastrointestinal bleeding with MPI. As MPI is not only suitable for vascular medicine but also offers a broad range of other possible applications, a selection of those will be briefly presented at the end of the article.
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      Ludewig, P.; Gdaniec, N.; Sedlacik, J.; Forkert, N. D.; Szwargulski, P.; Graeser, M.; Adam, G.; Kaul, M. G.; Krishnan, K. M.; Ferguson, R. M.; Khandhar, A. P.; Walczak, P.; Fiehler, J.; Thomalla, G.; Gerloff, C.; Knopp, T.; Magnus, T. Magnetic Particle Imaging for Real-Time Perfusion Imaging in Acute Stroke. ACS Nano 2017, 11, 10480 DOI: 10.1021/acsnano.7b05784 .
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      Magnetic Particle Imaging for Real-Time Perfusion Imaging in Acute Stroke
      Ludewig, Peter; Gdaniec, Nadine; Sedlacik, Jan; Forkert, Nils D.; Szwargulski, Patryk; Graeser, Matthias; Adam, Gerhard; Kaul, Michael G.; Krishnan, Kannan M.; Ferguson, R. Matthew; Khandhar, Amit P.; Walczak, Piotr; Fiehler, Jens; Thomalla, Goetz; Gerloff, Christian; Knopp, Tobias; Magnus, Tim
      ACS Nano (2017), 11 (10), 10480-10488CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      The fast and accurate assessment of cerebral perfusion is fundamental for the diagnosis and successful treatment of stroke patients. Magnetic particle imaging (MPI) is a new radiation-free tomog. imaging method with a superior temporal resoln., compared to other conventional imaging methods. In addn., MPI scanners can be built as prehospital mobile devices, which require less complex infrastructure than computed tomog. (CT) and magnetic resonance imaging (MRI). With these advantages, MPI could accelerate the stroke diagnosis and treatment, thereby improving outcomes. Our objective was to investigate the capabilities of MPI to detect perfusion deficits in a murine model of ischemic stroke. Cerebral ischemia was induced by inserting of a microfilament in the internal carotid artery in C57BL/6 mice, thereby blocking the blood flow into the medial cerebral artery. After the injection of a contrast agent (superparamagnetic iron oxide nanoparticles) specifically tailored for MPI, cerebral perfusion and vascular anatomy were assessed by the MPI scanner within seconds. To validate and compare our MPI data, we performed perfusion imaging with a small animal MRI scanner. MPI detected the perfusion deficits in the ischemic brain, which were comparable to those with MRI but in real-time. For the first time, we showed that MPI could be used as a diagnostic tool for relevant diseases in vivo, such as an ischemic stroke. Due to its shorter image acquisition times and increased temporal resoln. compared to that of MRI or CT, we expect that MPI offers the potential to improve stroke imaging and treatment.
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      Orendorff, R.; Peck, A. J.; Zheng, B.; Shirazi, S. N.; Matthew Ferguson, R.; Khandhar, A. P.; Kemp, S. J.; Goodwill, P.; Krishnan, K. M.; Brooks, G. A.; Kaufer, D.; Conolly, S. First in Vivo Traumatic Brain Injury Imaging via Magnetic Particle Imaging. Phys. Med. Biol. 2017, 62, 3501– 3509,  DOI: 10.1088/1361-6560/aa52ad
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      First in vivo traumatic brain injury imaging via magnetic particle imaging
      Orendorff, Ryan; Peck, Austin J.; Zheng, Bo; Shirazi, Shawn N.; Ferguson, R. Matthew; Khandhar, Amit P.; Kemp, Scott J.; Goodwill, Patrick; Krishnan, Kannan M.; Brooks, George A.; Kaufer, Daniela; Conolly, Steven
      Physics in Medicine & Biology (2017), 62 (9), 3501-3509CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
      Emergency room visits due to traumatic brain injury (TBI) is common, but classifying the severity of the injury remains an open challenge. Some subjective methods such as the Glasgow Coma Scale attempt to classify traumatic brain injuries, as well as some imaging based modalities such as computed tomog. and magnetic resonance imaging. However, to date it is still difficult to detect and monitor mild to moderate injuries. In this report, we demonstrate that the magnetic particle imaging (MPI) modality can be applied to imaging TBI events with excellent contrast. MPI can monitor injected iron nanoparticles over long time scales without signal loss, allowing researchers and clinicians to monitor the change in blood pools as the wound heals.
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      Yu, E. Y.; Chandrasekharan, P.; Berzon, R.; Tay, Z. W.; Zhou, X. Y.; Khandhar, A. P.; Ferguson, R. M.; Kemp, S. J.; Zheng, B.; Goodwill, P. W.; Wendland, M. F.; Krishnan, K. M.; Behr, S.; Carter, J.; Conolly, S. M. Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model. ACS Nano 2017, 11, 12067– 12076,  DOI: 10.1021/acsnano.7b04844
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      11
      Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model
      Yu, Elaine Y.; Chandrasekharan, Prashant; Berzon, Ran; Tay, Zhi Wei; Zhou, Xinyi Y.; Khandhar, Amit P.; Ferguson, R. Matthew; Kemp, Scott J.; Zheng, Bo; Goodwill, Patrick W.; Wendland, Michael F.; Krishnan, Kannan M.; Behr, Spencer; Carter, Jonathan; Conolly, Steven M.
      ACS Nano (2017), 11 (12), 12067-12076CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Gastrointestinal (GI) bleeding causes more than 300,000 hospitalizations per yr in the United States. Imaging plays a crucial role in accurately locating the source of the bleed for timely intervention. Magnetic particle imaging (MPI) is an emerging clin. translatable imaging modality that images superparamagnetic iron-oxide (SPIO) tracers with extraordinary contrast and sensitivity. This linearly quant. modality has zero background tissue signal and zero signal depth attenuation. MPI is also safe: there is zero ionizing radiation exposure to the patient and clin. approved tracers can be used with MPI. In this study, we demonstrate the use of MPI along with long-circulating, PEG-stabilized SPIOs for rapid in vivo detection and quantification of GI bleed. A mouse model genetically predisposed to GI polyp development (ApcMin/+) was used for this study, and heparin was used as an anticoagulant to induce acute GI bleeding. We then injected MPI-tailored, long-circulating SPIOs through the tail vein, and tracked the tracer biodistribution over time using our custom-built high resoln. field-free line (FFL) MPI scanner. Dynamic MPI projection images captured tracer accumulation in the lower GI tract with excellent contrast. Quant. anal. of the MPI images show that the mice experienced GI bleed rates between 1 and 5 μL/min. Although there are currently no human scale MPI systems, and MPI-tailored SPIOs need to undergo further development and evaluation, clin. translation of the technique is achievable. The robust contrast, sensitivity, safety, ability to image anywhere in the body, along with long-circulating SPIOs lends MPI outstanding promise as a clin. diagnostic tool for GI bleeding.
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    12. 12
      Graeser, M.; Knopp, T.; Szwargulski, P.; Friedrich, T.; von Gladiss, A.; Kaul, M.; Krishnan, K. M.; Ittrich, H.; Adam, G.; Buzug, T. M. Towards Picogram Detection of Superparamagnetic Iron-Oxide Particles Using a Gradiometric Receive Coil. Sci. Rep. 2017, 7, 6872,  DOI: 10.1038/s41598-017-06992-5
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      12
      Towards Picogram Detection of Superparamagnetic Iron-Oxide Particles Using a Gradiometric Receive Coil
      Graeser Matthias; Friedrich Thomas; von Gladiss Anselm; Buzug Thorsten M; Knopp Tobias; Szwargulski Patryk; Knopp Tobias; Szwargulski Patryk; Kaul Michael; Ittrich Harald; Adam Gerhard; Krishnan Kannan M
      Scientific reports (2017), 7 (1), 6872 ISSN:.
      Superparamagnetic iron-oxide nanoparticles can be used in medical applications like vascular or targeted imaging. Magnetic particle imaging (MPI) is a promising tomographic imaging technique that allows visualizing the 3D nanoparticle distribution concentration in a non-invasive manner. The two main strengths of MPI are high temporal resolution and high sensitivity. While the first has been proven in the assessment of dynamic processes like cardiac imaging, it is unknown how far the detection limit of MPI can be lowered. Within this work, we will present a highly sensitive gradiometric receive-coil unit combined with a noise-matching network tailored for the imaging of mice. The setup is capable of detecting 5 ng of iron in-vitro with an acquisition time of 2.14 sec. In terms of iron concentration we are able to detect 156 μg/L marking the lowest value that has been reported for an MPI scanner so far. In-vivo MPI mouse images of a 512 ng bolus and a 21.5 ms acquisition time allow for capturing the flow of an intravenously injected tracer through the heart of a mouse. Since it has been rather difficult to compare detection limits across MPI publications we propose guidelines to improve the comparability of future MPI studies.
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      Graeser, M.; Ludewig, P.; Szwargulski, P.; Foerger, F.; Liebing, T.; Forkert, N. D.; Thieben, F.; Magnus, T.; Knopp, T. Organ Specific Head Coil for High Resolution Mouse Brain Perfusion Imaging Using Magnetic Particle Imaging arXiv e-prints [Online], 2020; p. arXiv:2004.11728. https://ui.adsabs.harvard.edu/abs/2020arXiv200411728G (accessed April 01, 2020).
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      Möddel, M.; Meins, C.; Dieckhoff, J.; Knopp, T. Viscosity Quantification Using Multi-Contrast Magnetic Particle Imaging. New J. Phys. 2018, 20, 083001,  DOI: 10.1088/1367-2630/aad44b
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      Murase, K.; Song, R.; Hiratsuka, S. Magnetic Particle Imaging of Blood Coagulation. Appl. Phys. Lett. 2014, 104, 252409,  DOI: 10.1063/1.4885146
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      Magnetic particle imaging of blood coagulation
      Murase, Kenya; Song, Ruixiao; Hiratsuka, Samu
      Applied Physics Letters (2014), 104 (25), 252409/1-252409/4CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)
      We investigated the feasibility of visualizing blood coagulation using a system for magnetic particle imaging (MPI). A magnetic field-free line is generated using two opposing neodymium magnets and transverse images are reconstructed from the third-harmonic signals received by a gradiometer coil, using the max. likelihood-expectation maximization algorithm. Our MPI system was used to image the blood coagulation induced by adding CaCl2 to whole sheep blood mixed with magnetic nanoparticles (MNPs). The "MPI value" was defined as the pixel value of the transverse image reconstructed from the third-harmonic signals. MPI values were significantly smaller for coagulated blood samples than those without coagulation. We confirmed the rationale of these results by calcg. the third-harmonic signals for the measured viscosities of samples, with an assumption that the magnetization and particle size distribution of MNPs obey the Langevin equation and log-normal distribution, resp. We concluded that MPI can be useful for visualizing blood coagulation. (c) 2014 American Institute of Physics.
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      Knopp, T.; Hofmann, M. Online Reconstruction of 3D Magnetic Particle Imaging Data. Phys. Med. Biol. 2016, 61, N257– 67,  DOI: 10.1088/0031-9155/61/11/N257
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      Online reconstruction of 3D magnetic particle imaging data
      Knopp, T.; Hofmann, M.
      Physics in Medicine & Biology (2016), 61 (11), N257-N267CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
      Magnetic particle imaging is a quant. functional imaging technique that allows imaging of the spatial distribution of super-paramagnetic iron oxide particles at high temporal resoln. The raw data acquisition can be performed at frame rates of more than 40 vols. s-1. However, to date image reconstruction is performed in an offline step and thus no direct feedback is available during the expt. Considering potential interventional applications such direct feedback would be mandatory. In this work, an online reconstruction framework is implemented that allows direct visualization of the particle distribution on the screen of the acquisition computer with a latency of about 2 s. The reconstruction process is adaptive and performs block-averaging in order to optimize the signal quality for a given amt. of reconstruction time.
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    17. 17
      Rosenberg, G. A.; Mun-Bryce, S.; Wesley, M.; Kornfeld, M. Collagenase-Induced Intracerebral Hemorrhage in Rats. Stroke 1990, 21, 801– 7,  DOI: 10.1161/01.STR.21.5.801
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      17
      Collagenase-induced intracerebral hemorrhage in rats
      Rosenberg, Gary A.; Mun-Bryce, Sheila; Wesley, Mary; Kornfeld, Mario
      Stroke (1990), 21 (5), 801-7CODEN: SJCCA7; ISSN:0039-2499.
      Intracranial bleeding is an important cause of brain masses and edema. To study the pathophysiol. of intracerebral hemorrhage, exptl. hemorrhages were produced in 53 rats and the lesions were characterized by histol., brain water content, and behavior. Adult rats had 2 μL saline contg. 0.5 unit bacterial collagenase infused into the left caudate nucleus. Histol., erythrocytes were seen around blood vessels at the needle puncture site within the first hour. By 4 h there were hematomas, the size of which depended on the amt. of collagenase injected. Necrotic masses contg. fluid, blood cells, and fibrin were seen at 24 h. Lipid-filled macrophages were obsd. at 7 days and cysts at 3 wk. Water content was significant increased 4, 24, and 48 h after infusion at the needle puncture site and for 24 h in posterior brain sections. Behavioral abnormalities were present for 48 h, with recovery of function occurring during the first week. Brain tissue contains Type IV collagen in the basal lamina. Collagenase, which occurs in an inactive form in cells, is released and activated during injury, leading to disruption of the extracellular matrix. Collagenase-induced intracerebral hemorrhage is a reproducible animal model for the study of the effects of the hematoma and brain edema.
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      Manaenko, A.; Chen, H.; Zhang, J. H.; Tang, J. Comparison of Different Preclinical Models of Intracerebral Hemorrhage. Acta Neurochir Suppl 2011, 111, 9– 14,  DOI: 10.1007/978-3-7091-0693-8_2
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      Comparison of different preclinical models of intracerebral hemorrhage
      Manaenko Anatol; Chen Hank; Zhang John H; Tang Jiping
      Acta neurochirurgica. Supplement (2011), 111 (), 9-14 ISSN:0065-1419.
      Intracerebral hemorrhage (ICH) is the most devastating type of stroke. It is characterized by spontaneous bleeding in brain parenchyma and is associated with a high rate of morbidity and mortality. Presently, there is neither an effective therapy to increase survival after intracerebral hemorrhage nor a treatment to improve the quality of life for survivors. A reproducible animal model of spontaneous ICH mimicking the development of acute and delayed brain injury after ICH is an invaluable tool for improving our understanding of the underlying mechanisms of ICH-induced brain injury and evaluating potential therapeutic interventions. A number of models have been developed. While different species have been studied, rodents have become the most popular and widely utilized animals used in ICH research. The most often used methods for experimental induction of ICH are injection of bacterial collagenase and direct injection of blood into the brain parenchyma. The "balloon" method has also been used to mimic ICH for study. In this summary, we intend to provide a comparative overview of the technical methods, aspects, and pathologic findings of these types of ICH models. We will also focus on the similarities and differences among these rodent models, achievements in technical aspects of the ICH model, and discuss important aspects in selecting relevant models for study.
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      Rahmer, J.; Halkola, A.; Gleich, B.; Schmale, I.; Borgert, J. First Experimental Evidence of the Feasibility of Multi-Color Magnetic Particle Imaging. Phys. Med. Biol. 2015, 60, 1775– 91,  DOI: 10.1088/0031-9155/60/5/1775
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      19
      First experimental evidence of the feasibility of multi-color magnetic particle imaging
      Rahmer J; Halkola A; Gleich B; Schmale I; Borgert J
      Physics in medicine and biology (2015), 60 (5), 1775-91 ISSN:.
      Magnetic particle imaging is a new approach to visualizing magnetic nanoparticles. It is capable of 3D real-time in vivo imaging of particles injected into the blood stream and is a candidate for medical imaging applications. To date, only one particle type has been imaged at a time, however, the ability to separate signals acquired simultaneously from different particle types or from particles in different environments would substantially increase the scope of the method. Different colors could be assigned to different signal sources to allow for visualization in a single image. Successful signal separation has been reported in spectroscopic experiments, but it was unclear how well separation would work in conjunction with spatial encoding in an imaging experiment. This work presents experimental evidence of the separability of signals from different particle types and aggregation states (fluid versus powder) using a 'multi-color' reconstruction approach. Several mechanisms are discussed that may form the basis for successful signal separation.
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    20. 20
      Shasha, C.; Teeman, E.; Krishnan, K. M.; Szwargulski, P.; Knopp, T.; Möddel, M. Discriminating Nanoparticle Core Size Using Multi-Contrast MPI. Phys. Med. Biol. 2019, 64, 074001,  DOI: 10.1088/1361-6560/ab0fc9
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      Discriminating nanoparticle core size using multi-contrast MPI
      Shasha, Carolyn; Teeman, Eric; Krishnan, Kannan M.; Szwargulski, Patryk; Knopp, Tobias; Moeddel, Martin
      Physics in Medicine & Biology (2019), 64 (7), 74001CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
      Magnetic particle imaging (MPI) is an imaging modality that detects the response of a distribution of magnetic nanoparticle tracers to alternating magnetic fields. There has recently been exploration into multi-contrast MPI, in which the signal from different tracer materials or environments is sep. reconstructed, resulting in multi-channel images that could enable temp. or viscosity quantification. In this work, we apply a multi-contrast reconstruction technique to discriminate between nanoparticle tracers of different core sizes. Three nanoparticle types with core diams. of 21.9 nm, 25.3 nm and 27.7 nm were each imaged at 21 different locations within the scanner field of view. Multi-channel images were reconstructed for each sample and location, with each channel corresponding to one of the three core sizes. For each image, signal wt. vectors were calcd., which were then used to classify each image by core size. With a block averaging length of 10 000, the median signal-to-noise ratio was 40 or higher for all three sample types, and a correct prediction rate of 96.7% was achieved, indicating that core size can effectively be predicted using signal wt. vector classification with close to 100% accuracy while retaining high MPI image quality. The discrimination of the core size was reliable even when multiple samples of different core sizes were placed in the measuring field.
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    21. 21
      Weber, A.; Werner, F.; Weizenecker, J.; Buzug, T. M.; Knopp, T. Artifact Free Reconstruction with the System Matrix Approach by Overscanning the Field-Free-Point Trajectory in Magnetic Particle Imaging. Phys. Med. Biol. 2016, 61, 475– 87,  DOI: 10.1088/0031-9155/61/2/475
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      Artifact free reconstruction with the system matrix approach by overscanning the field-free-point trajectory in magnetic particle imaging
      Weber, A.; Werner, F.; Weizenecker, J.; Buzug, T. M.; Knopp, T.
      Physics in Medicine & Biology (2016), 61 (2), 475-487CODEN: PHMBA7; ISSN:0031-9155. (IOP Publishing Ltd.)
      Magnetic particle imaging is a tracer-based imaging method that utilizes the non-linear magnetization response of iron-oxide for detg. their spatial distribution. The method is based on a sampling scheme where a sensitive spot is moved along a trajectory that captured a predefined field-of-view (FOV). However, particles outside the FOV also contribute to the measurement signal due to their rotation and the non-sharpness of the sensitive spot. In the present work we investigate artifacts that are induced by particles not covered by the FOV and show that the artifacts can be mitigated by using a system matrix that covers not only the region of interest but also a certain area around the FOV. The findings are esp. relevant when using a multi-patch acquisition scheme where the boundaries of neighboring patches have to be handled.
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      Knopp, T.; Weber, A. Sparse Reconstruction of the Magnetic Particle Imaging System Matrix. IEEE Trans Med. Imaging 2013, 32, 1473– 80,  DOI: 10.1109/TMI.2013.2258029
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      22
      Sparse reconstruction of the magnetic particle imaging system matrix
      Knopp Tobias; Weber Alexander
      IEEE transactions on medical imaging (2013), 32 (8), 1473-80 ISSN:.
      Magnetic particle imaging allows to determine the spatial distribution of magnetic nanoparticles in vivo. The system matrix in magnetic particle imaging is commonly acquired in a tedious calibration scan and requires to measure the system response at numerous positions in the field-of-view. In this paper, we propose a method that significantly reduces the number of required calibration scans. It exploits the special structure of the system matrix and applies sparse reconstruction techniques. Experiments show that the number of calibration scans can be reduced by a factor of ten with only marginal loss of image quality.
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      Guo, B. J.; Yang, Z. L.; Zhang, L. J. Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Front. Mol. Neurosci. 2018, 11, 335,  DOI: 10.3389/fnmol.2018.00335
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      Gadolinium deposition in brain: current scientific evidence and future perspectives
      Guo, Bang J.; Yang, Zhen L.; Zhang, Long J.
      Frontiers in Molecular Neuroscience (2018), 11 (), 335/1-335/12CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)
      In the past 4 years, many publications described a concn.-dependent deposition of gadolinium in the brain both in adults and children, seen as high signal intensities in the globus pallidus and dentate nucleus on unenhanced T1-weighted images. Postmortem human or animal studies have validated gadolinium deposition in these T1-hyperintensity areas, raising new concerns on the safety of gadolinium-based contrast agents (GBCAs). Residual gadolinium is deposited not only in brain, but also in extracranial tissues such as liver, skin, and bone. This review summarizes the current evidence on gadolinium deposition in the human and animal bodies, evaluates the effects of different types of GBCAs on the gadolinium deposition, introduces the possible entrance or clearance mechanism of the gadolinium and potential side effects that may be related to the gadolinium deposition on human or animals, and puts forward some suggestions for further research.
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      Castellani, R. J.; Mojica, G.; Perry, G. The Role of the Iron Stain in Assessing Intracranial Hemorrhage. Open Neurol. J. 2016, 10, 136– 142,  DOI: 10.2174/1874205X01610010136
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      The role of the iron stain in assessing intracranial hemorrhage
      Castellani, Rudy J.; Mojica, Gruschenka; Perry, George
      Open Neurology Journal (2016), 10 (), 136-142CODEN: ONJPCX; ISSN:1874-205X. (Bentham Open)
      The timing of the breakdown of red blood cells and organization of hemorrhage has significance in the catabolism of heme and the processing of iron, but also has a practical application in terms of assigning, or attempting to assign, a time course with respect to traumatic events (e.g. contusions and hemorrhages). Attempts to date contusions, however, have generally been unsuccessful by macroscopic observation, whereas the microscopic observations provide broad data but are also anatomically imprecise as a function of time. Intracranial lesions are of particular significance with respect to the timing of organizing hemorrhage given the acute, and often life-threatening nature of the hemorrhages, and the medicolegal investigation into potential crimes. Of concern is that the Prussian Blue reaction for iron, a relatively straightforward histochem. reaction that has been in use for over 150 years, is sometimes suggested as a diagnostic test for chronicity. Therefore, this study examd. the utility of the Prussian Blue iron stain in living patients with intracranial hemorrhages and well-defined symptom onset, to test whether the presence of Prussian Blue reactivity could be correlated with chronicity. It was found that out of 12 cases with intracranial hemorrhage, eight cases showed at least focal iron reactivity. The duration from symptom onset to surgery in those eight cases ranged from < 24 h to more than 3 days. Of those cases with no iron reactivity, the duration from symptom onset to surgery ranged from < 24 h to six days. In conclusion, the Prussian Blue reaction was unreliable as an indicator of timing in intracranial hemorrhage. The use of the Prussian blue reaction as an independent indicator of chronicity is therefore not valid and can be misleading. Caution is indicated when employing iron staining for timing purposes, as its only use is to highlight, as opposed to identify, pre-existing lesions. With respect to brain lesions, the Prussian blue reaction should not be used in place of the clin. timing of the neurol. decline, or clin. data that is otherwise more accurate and less susceptible to false pos. results.
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      Davis, S. M.; Broderick, J.; Hennerici, M.; Brun, N. C.; Diringer, M. N.; Mayer, S. A.; Begtrup, K.; Steiner, T. Hematoma Growth is a Determinant of Mortality and Poor Outcome after Intracerebral Hemorrhage. Neurology 2006, 66, 1175– 81,  DOI: 10.1212/01.wnl.0000208408.98482.99
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      25
      Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage
      Davis S M; Broderick J; Hennerici M; Brun N C; Diringer M N; Mayer S A; Begtrup K; Steiner T
      Neurology (2006), 66 (8), 1175-81 ISSN:.
      BACKGROUND: Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. METHODS: To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. RESULTS: Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. CONCLUSIONS: Hematoma growth is an independent determinant of both mortality and functional outcome after intracerebral hemorrhage. Attenuation of growth is an important therapeutic strategy.
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    26. 26
      de Oliveira Manoel, A. L. Surgery for Spontaneous Intracerebral Hemorrhage. Crit Care 2020, 24, 45,  DOI: 10.1186/s13054-020-2749-2
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      26
      Surgery for spontaneous intracerebral hemorrhage
      de Oliveira Manoel Airton Leonardo; de Oliveira Manoel Airton Leonardo
      Critical care (London, England) (2020), 24 (1), 45 ISSN:.
      Spontaneous intracerebral hemorrhage is a devastating disease, accounting for 10 to 15% of all types of stroke; however, it is associated with disproportionally higher rates of mortality and disability. Despite significant progress in the acute management of these patients, the ideal surgical management is still to be determined. Surgical hematoma drainage has many theoretical benefits, such as the prevention of mass effect and cerebral herniation, reduction in intracranial pressure, and the decrease of excitotoxicity and neurotoxicity of blood products.Several surgical techniques have been considered, such as open craniotomy, decompressive craniectomy, neuroendoscopy, and minimally invasive catheter evacuation followed by thrombolysis. Open craniotomy is the most studied approach in this clinical scenario, the first randomized controlled trial dating from the early 1960s. Since then, a large number of studies have been published, which included two large, well-designed, well-powered, multicenter, multinational, randomized clinical trials. These studies, The International Surgical Trial in Intracerebral Hemorrhage (STICH), and the STICH II have shown no clinical benefit for early surgical evacuation of intraparenchymal hematoma in patients with spontaneous supratentorial hemorrhage when compared with best medical management plus delayed surgery if necessary. However, the results of STICH trials may not be generalizable, because of the high rates of patients' crossover from medical management to the surgical group. Without these high crossover percentages, the rates of unfavorable outcome and death with conservative management would have been higher. Additionally, comatose patients and patients at risk of cerebral herniation were not included. In these cases, surgery may be lifesaving, which prevented those patients of being enrolled in such trials. This article reviews the clinical evidence of surgical hematoma evacuation, and its role to decrease mortality and improve long-term functional outcome after spontaneous intracerebral hemorrhage.
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    27. 27
      Graeser, M.; Thieben, F.; Szwargulski, P.; Werner, F.; Gdaniec, N.; Boberg, M.; Griese, F.; Moddel, M.; Ludewig, P.; van de Ven, D.; Weber, O. M.; Woywode, O.; Gleich, B.; Knopp, T. Human-Sized Magnetic Particle Imaging for Brain Applications. Nat. Commun. 2019, 10, 1936,  DOI: 10.1038/s41467-019-09704-x
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      27
      Human-sized magnetic particle imaging for brain applications
      Graeser M; Thieben F; Szwargulski P; Werner F; Gdaniec N; Boberg M; Griese F; Moddel M; Knopp T; Graeser M; Thieben F; Szwargulski P; Werner F; Gdaniec N; Boberg M; Griese F; Moddel M; Knopp T; Ludewig P; van de Ven D; Weber O M; Woywode O; Gleich B
      Nature communications (2019), 10 (1), 1936 ISSN:.
      Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmolFe ml(-1), which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.
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    28. 28
      Morgenstern, L. B.; Demchuk, A. M.; Kim, D. H.; Frankowski, R. F.; Grotta, J. C. Rebleeding Leads to Poor Outcome in Ultra-Early Craniotomy for Intracerebral Hemorrhage. Neurology 2001, 56, 1294– 9,  DOI: 10.1212/WNL.56.10.1294
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      28
      Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage
      Morgenstern L B; Demchuk A M; Kim D H; Frankowski R F; Grotta J C
      Neurology (2001), 56 (10), 1294-9 ISSN:0028-3878.
      BACKGROUND: A modest benefit was previously demonstrated for hematoma evacuation within 12 hours of intracerebral hemorrhage onset. Perhaps surgery within 4 hours would further improve outcome. METHODS: Adult patients with spontaneous supratentorial intracerebral hemorrhage were prospectively enrolled. Craniotomy and clot evacuation were commenced within 4 hours of symptom onset in all cases. Mortality and functional outcome were assessed at 6 months. This group of patients was compared with patients treated within 12 hours of symptom onset using the same surgical and medical protocols. RESULTS: The study was stopped after a planned interim analysis of 11 patients in the 4-hour surgery arm. Median time to surgery was 180 minutes; median hematoma volume was 40 mL; median baseline NIH Stroke Scale score was 19 and Glasgow Coma Scale score was 12. Six-month mortality was 36% and median Barthel score was 75 in survivors. Postoperative rebleeding occurred in four patients, three of whom died. A relationship between postoperative rebleeding and mortality was apparent (p = 0.03). Rebleeding occurred in 40% of the patients treated within 4 hours, compared with 12% of the patients treated within 12 hours (p = 0.11). There was a clear correlation between improved outcome and smaller postsurgical hematoma volume (p = 0.04). CONCLUSIONS: Surgical hematoma evacuation within 4 hours of symptom onset is complicated by rebleeding, indicating difficulty with hemostasis. Maximum removal of blood remains a predictor of good outcome.
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    29. 29
      Hanley, D. F.; Thompson, R. E.; Muschelli, J.; Rosenblum, M.; McBee, N.; Lane, K.; Bistran-Hall, A. J.; Mayo, S. W.; Keyl, P.; Gandhi, D.; Morgan, T. C.; Ullman, N.; Mould, W. A.; Carhuapoma, J. R.; Kase, C.; Ziai, W.; Thompson, C. B.; Yenokyan, G.; Huang, E.; Broaddus, W. C. Safety and Efficacy of Minimally Invasive Surgery plus Alteplase in Intracerebral Haemorrhage Evacuation (MISTIE): A Randomised, Controlled, Open-Label, Phase 2 Trial. Lancet Neurol. 2016, 15, 1228– 1237,  DOI: 10.1016/S1474-4422(16)30234-4
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      29
      Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral hemorrhage evacuation (MISTIE): a randomized, controlled, open-label, phase 2 trial
      Hanley, Daniel F.; Thompson, Richard E.; Muschelli, John; Rosenblum, Michael; McBee, Nichol; Lane, Karen; Bistran-Hall, Amanda J.; Mayo, Steven W.; Keyl, Penelope; Gandhi, Dheeraj; Morgan, Tim C.; Ullman, Natalie; Mould, W. Andrew; Carhuapoma, J. Ricardo; Kase, Carlos; Ziai, Wendy; Thompson, Carol B.; Yenokyan, Gayane; Huang, Emily; Broaddus, William C.; Graham, R. Scott; Aldrich, E. Francois; Dodd, Robert; Wijman, Cristanne; Caron, Jean-Louis; Huang, Judy; Camarata, Paul; Mendelow, A. David; Gregson, Barbara; Janis, Scott; Vespa, Paul; Martin, Neil; Awad, Issam; Zuccarello, Mario
      Lancet Neurology (2016), 15 (12), 1228-1237CODEN: LNAEAM; ISSN:1474-4422. (Elsevier Ltd.)
      Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral hemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral hemorrhage. MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomize patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral hemorrhage of 20 mL or higher to std. medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, no. NCT00224770. Between Feb 2, 2006, and Apr. 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the std. medical care group. The primary outcomes did not differ between the std. medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic hemorrhages were more common in the MIS plus alteplase group than in the std. medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051). MIS plus alteplase seems to be safe in patients with intracerebral hemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addn. of surgical management as a therapeutic strategy for intracerebral hemorrhage. National Institute of Neurol. Disorders and Stroke, Genentech, and Codman.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSnsbnO&md5=6853e320d7c81fe52e8d3ff2f1fcf2ea
    30. 30
      Fung, C.; Murek, M.; Z’Graggen, W. J.; Krahenbuhl, A. K.; Gautschi, O. P.; Schucht, P.; Gralla, J.; Schaller, K.; Arnold, M.; Fischer, U.; Mattle, H. P.; Raabe, A.; Beck, J. Decompressive Hemicraniectomy in Patients with Supratentorial Intracerebral Hemorrhage. Stroke 2012, 43, 3207– 11,  DOI: 10.1161/STROKEAHA.112.666537
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      30
      Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage
      Fung Christian; Murek Michael; Z'Graggen Werner J; Krahenbuhl Anna K; Gautschi Oliver P; Schucht Philippe; Gralla Jan; Schaller Karl; Arnold Marcel; Fischer Urs; Mattle Heinrich P; Raabe Andreas; Beck Jurgen
      Stroke (2012), 43 (12), 3207-11 ISSN:.
      BACKGROUND AND PURPOSE: Decompressive craniectomy (DC) lowers intracranial pressure and improves outcome in patients with malignant middle cerebral artery stroke. Its usefulness in intracerebral hemorrhage (ICH) is unclear. The aim of this study was to analyze feasibility and safety of DC without clot evacuation in ICH. METHODS: We compared consecutive patients (November 2010-January 2012) with supratentorial ICH treated with DC without hematoma evacuation and matched controls treated by best medical treatment. DC measured at least 150 mm and included opening of the dura. We analyzed clinical (age, sex, pathogenesis, Glasgow Coma Scale, National Institutes of Health Stroke Scale), radiological (signs of herniation, side and size of hematoma, midline shift, hematoma expansion, distance to surface), and surgical (time to and indication for surgery) characteristics. Outcome at 6 months was dichotomized into good (modified Rankin Scale 0-4) and poor (modified Rankin Scale 5-6). RESULTS: Twelve patients (median age 48 years; interquartile range 35-58) with ICH were treated by DC. Median hematoma volume was 61.3 mL (interquartile range 37-83.5 mL) and median preoperative Glasgow Coma Scale was 8 (interquartile range 4.3-10). Four patients showed signs of herniation. Nine patients had good and 3 had poor outcomes. Three patients (25%) of the treatment group died versus 8 of 15 (53%) of the control group. There were 3 manageable complications related to DC. CONCLUSIONS: DC is feasible in patients with ICH. Based on this small cohort, DC may reduce mortality. Larger prospective cohorts are warranted to assess safety and efficacy.
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    31. 31
      Onishi, H.; Murakami, T.; Kim, T.; Hori, M.; Hirohashi, S.; Matsuki, M.; Narumi, Y.; Imai, Y.; Sakurai, K.; Nakamura, H. Safety of Ferucarbotran in MR Imaging of the Liver: A Pre- and Postexamination Questionnaire-Based Multicenter Investigation. J. Magn Reson Imaging 2009, 29, 106– 11,  DOI: 10.1002/jmri.21608
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      31
      Safety of ferucarbotran in MR imaging of the liver: a pre- and postexamination questionnaire-based multicenter investigation
      Onishi Hiromitsu; Murakami Takamichi; Kim Tonsok; Hori Masatoshi; Hirohashi Shinji; Matsuki Mitsuru; Narumi Yoshifumi; Imai Yasuharu; Sakurai Kousuke; Nakamura Hironobu
      Journal of magnetic resonance imaging : JMRI (2009), 29 (1), 106-11 ISSN:1053-1807.
      PURPOSE: To prospectively investigate, by means of a pre-and postexamination questionnaire, the types and frequency of adverse reactions to ferucarbotran (Resovist), a superparamagnetic iron oxide (SPIO) contrast agent. MATERIALS AND METHODS: This study was approved by the ethics committee of each of the institutions involved, and all patients gave written informed consent. One questionnaire asking about baseline symptoms before the injection of ferucarbotran, and one about adverse events over a period of seven days after injection were given to 315 patients who underwent ferucarbotran-enhanced magnetic resonance imaging (MRI) of the liver at several institutions. The data for baseline symptoms were used for reference to exclude false-positive adverse reactions and were also compared with the adverse event data to determine with McNemar's chi-squared test the incidence of each symptom. RESULTS: Before MR examination, 249 clinical symptoms were reported by 102 of 315 patients (32.4%). After the injection of ferucarbotran, 169 adverse events were observed in 78 patients (24.8%). Eventually, 70 adverse events occurring in 45 patients (14.3%) were judged to be adverse reactions to ferucarbotran, defined as possibly or definitely ferucarbotran-related events. All reactions were of mild intensity. CONCLUSION: Ferucarbotran can be considered safe for clinical use in liver MRI.
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    32. 32
      Kanda, T.; Ishii, K.; Kawaguchi, H.; Kitajima, K.; Takenaka, D. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-Based Contrast Material. Radiology 2014, 270, 834– 41,  DOI: 10.1148/radiol.13131669
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      32
      High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material
      Kanda Tomonori; Ishii Kazunari; Kawaguchi Hiroki; Kitajima Kazuhiro; Takenaka Daisuke
      Radiology (2014), 270 (3), 834-41 ISSN:.
      PURPOSE: To explore any correlation between the number of previous gadolinium-based contrast material administrations and high signal intensity (SI) in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: The institutional review board approved this study, waiving the requirement to obtain written informed consent. A group of 381 consecutive patients who had undergone brain MR imaging was identified for cross-sectional analysis. For longitudinal analysis, 19 patients who had undergone at least six contrast-enhanced examinations were compared with 16 patients who had undergone at least six unenhanced examinations. The mean SIs of the dentate nucleus, pons, globus pallidus, and thalamus were measured on unenhanced T1-weighted images. The dentate nucleus-to-pons SI ratio was calculated by dividing the SI in the dentate nucleus by that in the pons, and the globus pallidus-to-thalamus SI ratio was calculated by dividing the SI in the globus pallidus by that in the thalamus. Stepwise regression analysis was undertaken in the consecutive patient group to detect any relationship between the dentate nucleus-to-pons or globus pallidus-to-thalamus SI ratio and previous gadolinium-based contrast material administration or other factors. A random coefficient model was used to evaluate for longitudinal analysis. RESULTS: The dentate nucleus-to-pons SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus-to-thalamus SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288), radiation therapy (P = .009; regression coefficient, -0.014; 95% CI: -0.025, -0.004; standardized regression coefficient, -0.151), and liver function (P = .031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107). The dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios in patients who had undergone contrast-enhanced examinations were significantly greater than those of patients who had undergone unenhanced examinations (P < .001 for both). CONCLUSION: High SI in the dentate nucleus and globus pallidus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast material administrations.
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    33. 33
      Tay, Z. W.; Hensley, D. W.; Chandrasekharan, P.; Zheng, B.; Conolly, S. M. Optimization of Drive Parameters for Resolution, Sensitivity and Safety in Magnetic Particle Imaging. IEEE Trans Med. Imaging 2020, 39, 1724– 1734,  DOI: 10.1109/TMI.2019.2957041
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      33
      Optimization of Drive Parameters for Resolution, Sensitivity and Safety in Magnetic Particle Imaging
      Tay Zhi Wei; Hensley Daniel W; Chandrasekharan Prashant; Zheng Bo; Conolly Steven M
      IEEE transactions on medical imaging (2020), 39 (5), 1724-1734 ISSN:.
      Magnetic Particle Imaging is an emerging tracer imaging modality with zero background signal and zero ionizing radiation, high contrast and high sensitivity with quantitative images. While there is recent work showing that the low amplitude or low frequency drive parameters can improve MPI's spatial resolution by mitigating relaxation losses, the concomitant decrease of the MPI's tracer sensitivity due to the lower drive slew rates was not fully addressed. There has yet to be a wide parameter space, multi-objective optimization of MPI drive parameters for high resolution, high sensitivity and safety. In a large-scale study, we experimentally test 5 different nanoparticles ranging from multi to single-core across 18.5 nm to 32.1 nm core sizes and across an expansive drive parameter range of 0.4 - 416 kHz and 0.5 - 40 mT/ μ0 to assess spatial resolution, SNR, and safety. In addition, we analyze how drive-parameter-dependent shifts in harmonic signal energy away and towards the discarded first harmonic affect effective SNR in this optimization study. The results show that when optimizing for all four factors of resolution, SNR, discarded-harmonic-energy and safety, the overall trends are no longer monotonic and clear optimal points emerge. We present drive parameters different from conventional preclinical MPI showing ~ 2-fold improvement in spatial resolution while remaining within safety limits and addressing sensitivity by minimizing the typical SNR loss involved. Finally, validation of the optimization results with 2D images of phantoms was performed.
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      Wang, Y. X. Superparamagnetic Iron Oxide Based MRI Contrast Agents: Current Status of Clinical Application. Quant Imaging Med. Surg 2011, 1, 35– 40
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      34
      Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application
      Wang Yi-Xiang J
      Quantitative imaging in medicine and surgery (2011), 1 (1), 35-40 ISSN:2223-4292.
      Superparamagnetic iron oxide (SPIO) MR contrast agents are composed of nano-sized iron oxide crystals coated with dextran or carboxydextran. Two SPIO agents are clinically approved, namely: ferumoxides (Feridex in the USA, Endorem in Europe) with a particle size of 120 to 180 nm, and ferucarbotran (Resovist) with a particle size of about 60 nm. The principal effect of the SPIO particles is on T2* relaxation and thus MR imaging is usually performed using T2/T2*-weighted sequences in which the tissue signal loss is due to the susceptibility effects of the iron oxide core. Enhancement on T1-weighted images can also be seen with the smaller Resovist. Both Feridex and Resovist are approved specifically for MRI of the liver. The difference being that Resovist can be administered as a rapid bolus (and thus can be used with both dynamic and delayed imaging), whereas Feridex needs to be administered as a slow infusion and is used solely in delayed phase imaging. In the liver, these particles are sequestered by phagocytic Kupffer cells in normal reticuloendothelial system (RES), but are not retained in lesions lacking Kupffer cells. Consequently, there are significant differences in T2/T2* relaxation between normal tissue and lesions, resulting in increased lesion conspicuity and detectability. SPIO substantially increase the detectability of hepatic metastases. For focal hepatocellular lesions, SPIO-enhanced MR imaging exhibits slightly better diagnostic performance than dynamic CT. A combination of dynamic and static MR imaging technique using T1- and T2 imaging criteria appears to provide clinically more useful patterns of enhancement. Feridex and Resovist are also used for evaluating macrophage activities in some inflammatory lesions, but their clinical values remain to be further confirmed. The clinical development of Ferumoxtran (Combidex in the USA, Sinerem in Europe), designed for lymph node metastasis evaluation, is currently stopped.
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    35. 35
      Gu, J.; Xu, H.; Han, Y.; Dai, W.; Hao, W.; Wang, C.; Gu, N.; Xu, H.; Cao, J. The Internalization Pathway, Metabolic Fate and Biological Effect of Superparamagnetic Iron Oxide Nanoparticles in the Macrophage-Like RAW264.7 Cell. Sci. China: Life Sci. 2011, 54, 793– 805,  DOI: 10.1007/s11427-011-4215-5
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      35
      The internalization pathway, metabolic fate and biological effect of superparamagnetic iron oxide nanoparticles in the macrophage-like RAW264.7 cell
      Gu, Jing Li; Xu, Hai Fei; Han, Ye Hua; Dai, Wei; Hao, Wei; Wang, Chun Yu; Gu, Ning; Xu, Hai Yan; Cao, Ji Min
      Science China: Life Sciences (2011), 54 (9), 793-805CODEN: SCLSCJ; ISSN:1674-7305. (Science China Press)
      The potential applications of superparamagnetic iron oxide nanoparticles (SPIONs) in several nanomedical fields have attracted intense interest based on the cell-nano interaction. However, the mechanisms underlying cell uptake, the intracellular trail, final fate and the biol. effects of SPIONs have not yet been clearly elucidated. Here, we showed that multiple endocytic pathways were involved in the internalization process of SPIONs in the RAW264.7 macrophage. The internalized SPIONs were biocompatible and used three different metabolic pathways: The SPIONs were distributed to daughter cells during mitosis; they were degraded in the lysosome and free iron was released into the intracellular iron metabolic pool; and, the intact SPIONs were potentially exocytosed out of the cells. The internalized SPIONs did not induce cell damage but affected iron metab., inducing the upregulation of ferritin light chain at both the mRNA and protein levels and ferroportin 1 at the mRNA level. These results may contribute to the development of nanobiol. and to the safe use of SPIONs in medicine when administered as a contrast medium or a drug delivery tool.
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    36. 36
      Antonelli, A.; Szwargulski, P.; Scarpa, E. S.; Thieben, F.; Cordula, G.; Ambrosi, G.; Guidi, L.; Ludewig, P.; Knopp, T.; Magnani, M. Development of Long Circulating Magnetic Particle Imaging Tracers: Use of Novel Magnetic Nanoparticles and Entrapment into Human Erythrocytes. Nanomedicine (London, U. K.) 2020, 15, 739– 753,  DOI: 10.2217/nnm-2019-0449
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      36
      Development of long circulating magnetic particle imaging tracers: use of novel magnetic nanoparticles and entrapment into human erythrocytes
      Antonelli, Antonella; Szwargulski, Patryk; Scarpa, Emanuele-Salvatore; Thieben, Florian; Cordula, Gruettner; Ambrosi, Gianluca; Guidi, Loretta; Ludewig, Peter; Knopp, Tobias; Magnani, Mauro
      Nanomedicine (London, United Kingdom) (2020), 15 (8), 739-753CODEN: NLUKAC; ISSN:1748-6963. (Future Medicine Ltd.)
      Aim: Magnetic particle imaging (MPI) is highly promising for biomedical applications, but optimal tracers for MPI, namely superparamagnetic iron oxide-based contrast agents, are still lacking. Materials & methods: The encapsulation of com. available nanoparticles, specifically synomag-D and perimag, into human red blood cells (RBCs) was performed by a hypotonic dialysis and isotonic resealing procedure. The amts. of superparamagnetic iron oxide incorporated into RBCs were detd. by Fe quantification using NMR and magnetic particle spectroscopy. Results: Perimag-COOH nanoparticles were identified as the best nanomaterial for encapsulation in RBCs. Perimag-COOH-loaded RBCs proved to be viable cells showing a good magnetic particle spectroscopy performance, while the magnetic signal of synomag-D-COOH-loaded RBCs dropped sharply. Conclusion: Perimag-COOH-loaded RBCs could be a potential tool for MPI diagnostic applications.
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    37. 37
      Voros, E.; Cho, M.; Ramirez, M.; Palange, A. L.; De Rosa, E.; Key, J.; Garami, Z.; Lumsden, A. B.; Decuzzi, P. TPA Immobilization on Iron Oxide Nanocubes and Localized Magnetic Hyperthermia Accelerate Blood Clot Lysis. Adv. Funct. Mater. 2015, 25, 1709– 1718,  DOI: 10.1002/adfm.201404354
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      37
      TPA (tissue plasminogen activator) immobilization on iron oxide nanocubes and localized magnetic hyperthermia accelerate blood clot lysis
      Voros, Eszter; Cho, Minjung; Ramirez, Maricela; Palange, Anna Lisa; De Rosa, Enrica; Key, Jaehong; Garami, Zsolt; Lumsden, Alan B.; Decuzzi, Paolo
      Advanced Functional Materials (2015), 25 (11), 1709-1718CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The low specificity and high risk of intracranial hemorrhage assocd. with currently approved thrombolytic therapies limit their efficacy in recanalizing occluded vessels. Here, a nanoscale thrombolytic agent is demonstrated by immobilizing tissue plasminogen activator mols. (tPA) over 20 nm clustered iron oxide nanocubes (NCs). The resulting nanoconstructs (tPA-NCs) are capable of dissolving clots via both direct interaction of tPA with the fibrin network (chem. lysis) and localized hyperthermia upon stimulation of superparamagnetic NCs with alternating magnetic fields (AMFs) (mech. lysis). In vitro, as compared to free tPA, the proposed nanoconstructs demonstrate a ≈100-fold increase in dissoln. rate, possibly because of a more intimate interaction of tPA with the fibrin network. The clot dissoln. rate is further enhanced (≈10-fold) by mild, localized heating resulting from the exposure of tPA-NCs to AMF. Intravital microscopy expts. demonstrate blood vessel reperfusion within a few minutes post tail vein injection of tPA-NCs. The proposed nanoconstructs also exhibit high transverse relaxivity (>400 × 10-3 M-1 s-1) for magnetic resonance imaging. The multifunctional properties and the 3 orders of magnitude enhancement in clot dissoln. make tPA-NCs a promising nano-theranosis agent in thrombotic disease.
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    38. 38
      Tay, Z. W.; Chandrasekharan, P.; Chiu-Lam, A.; Hensley, D. W.; Dhavalikar, R.; Zhou, X. Y.; Yu, E. Y.; Goodwill, P. W.; Zheng, B.; Rinaldi, C.; Conolly, S. M. Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy. ACS Nano 2018, 12, 3699– 3713,  DOI: 10.1021/acsnano.8b00893
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      38
      Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy
      Tay, Zhi Wei; Chandrasekharan, Prashant; Chiu-Lam, Andreina; Hensley, Daniel W.; Dhavalikar, Rohan; Zhou, Xinyi Y.; Yu, Elaine Y.; Goodwill, Patrick W.; Zheng, Bo; Rinaldi, Carlos; Conolly, Steven M.
      ACS Nano (2018), 12 (4), 3699-3713CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Image-guided treatment of cancer enables physicians to localize and treat tumors with great precision. Here, the authors present in vivo results showing that an emerging imaging modality, magnetic particle imaging (MPI), can be combined with magnetic hyperthermia into an image-guided theranostic platform. MPI is a noninvasive 3D tomog. imaging method with high sensitivity and contrast, zero ionizing radiation, and is linearly quant. at any depth with no view limitations. The same superparamagnetic iron oxide nanoparticle (SPIONs) tracers imaged in MPI can also be excited to generate heat for magnetic hyperthermia. The authors demonstrate a theranostic platform, with quant. MPI image guidance for treatment planning and use of the MPI gradients for spatial localization of magnetic hyperthermia to arbitrarily selected regions. This addresses a key challenge of conventional magnetic hyperthermia-SPIONs delivered systemically accumulate in off-target organs (e.g., liver and spleen), and difficulty in localizing hyperthermia results in collateral heat damage to these organs. Using a MPI magnetic hyperthermia workflow, the authors demonstrate image-guided spatial localization of hyperthermia to the tumor while minimizing collateral damage to the nearby liver (1-2 cm distance). Localization of thermal damage and therapy was validated with luciferase activity and histol. assessment. Apart from localizing thermal therapy, the technique presented here can also be extended to localize actuation of drug release and other biomech.-based therapies. With high contrast and high sensitivity imaging combined with precise control and localization of the actuated therapy, MPI is a powerful platform for magnetic-based theranostics.
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    39. 39
      Griese, F.; Knopp, T.; Gruettner, C.; Thieben, F.; Müller, K.; Loges, S.; Ludewig, P.; Gdaniec, N. Simultaneous Magnetic Particle Imaging and Navigation of Large Superparamagnetic Nanoparticles in Bifurcation Flow Experiments. J. Magn. Magn. Mater. 2020, 498, 166206,  DOI: 10.1016/j.jmmm.2019.166206
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      39
      Simultaneous Magnetic Particle Imaging and Navigation of large superparamagnetic nanoparticles in bifurcation flow experiments
      Griese, Florian; Knopp, Tobias; Gruettner, Cordula; Thieben, Florian; Mueller, Knut; Loges, Sonja; Ludewig, Peter; Gdaniec, Nadine
      Journal of Magnetism and Magnetic Materials (2020), 498 (), 166206CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)
      Magnetic Particle Imaging (MPI) has been successfully used to visualize the distribution of superparamagnetic nanoparticles within 3D vols. with high sensitivity in real time. Since the magnetic field topol. of MPI scanners is well suited for applying magnetic forces on particles and micron-sized ferromagnetic devices, MPI has been recently used to navigate micron-sized particles and micron-sized swimmers. In this work, we analyze the magnetophoretic mobility and the imaging performance of two different particle types for Magnetic Particle Imaging/Navigation (MPIN). MPIN constantly switches between imaging and magnetic modes, enabling quasi-simultaneous navigation and imaging of particles. We det. the limiting flow velocity to be 8.18 mL s-1 using a flow bifurcation expt., that allows all particles to flow only through one branch of the bifurcation. Furthermore, we have succeeded in navigating the particles through the branch of a bifurcation phantom narrowed by either 60% or 100% stenosis, while imaging their accumulation on the stenosis. The particles in combination with therapeutic substances have a high potential for targeted drug delivery and could help to reduce the dose and improve the efficacy of the drug, e.g. for specific tumor therapy and ischemic stroke therapy.
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    40. 40
      Ludewig, P.; Sedlacik, J.; Gelderblom, M.; Bernreuther, C.; Korkusuz, Y.; Wagener, C.; Gerloff, C.; Fiehler, J.; Magnus, T.; Horst, A. K. Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits MMP-9-Mediated Blood-Brain-Barrier Breakdown in a Mouse Model for Ischemic Stroke. Circ. Res. 2013, 113, 1013– 22,  DOI: 10.1161/CIRCRESAHA.113.301207
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      40
      Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits MMP-9-Mediated Blood-Brain-Barrier Breakdown in a Mouse Model for Ischemic Stroke
      Ludewig, Peter; Sedlacik, Jan; Gelderblom, Mathias; Bernreuther, Christian; Korkusuz, Yuecel; Wagener, Christoph; Gerloff, Christian; Fiehler, Jens; Magnus, Tim; Horst, Andrea Kristina
      Circulation Research (2013), 113 (8), 1013-1022CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)
      Rationale: Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion mol. 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated. Objective: We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1 and wild-type mice. Methods and results: Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we obsd. increased stroke vols., BBB breakdown and edema formation, redn. of cerebral perfusion, and brain atrophy in Ceacam1 mice. This translated into poor performance in neurol. scoring and high poststroke-assocd. mortality. Elevated neutrophil influx, hyperprodn., and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1 mice were confirmed by immune fluorescence, flow cytometry, zymog., and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1 mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochem. of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1 matrix metalloproteinase-9 neutrophils in the ischemic hemispheres. Conclusions: CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c06326.

    • Supplemental figures illustrating the experimental workflow, the advantages of long-circulation tracer, comparison of the MPI tracers Perimag and Synomag-D, the digital subtraction imaging, analysis of system matrices for multicontrast MPI, challenges of multicontrast MPI, phagocytosis of SPIOs by macrophages and microglia, MPI of subarachnoid hemorrhage; additional tables with the MPI and MRI parameters; additional equations used for multicontrast MPI image reconstruction, image postprocessing, and analysis. (PDF)

    • Supplemental Video V1: Real-time detection of intracranial hemorrhage with magnetic particle imaging (MPG)

    • Supplemental Video V2: Volumetric measurements of intracranial hemorrhage with magnetic particle imaging (MPG)

    • Supplemental Video V3: Differentiation of immobilized vs fluid tracer with multicontrast magnetic particle imaging (MPG)

    • Supplemental Video V4: Simultaneous imaging of hemorrhage and cerebral perfusion with multicontrast magnetic particle imaging (MPG)


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