Multi-electrode Array System Research Articles

Obtaining Multi-electrode Array Recordings from Human Induced Pluripotent Stem Cell-Derived Neurons.

Neuronal electrical properties are often aberrant in neurological disorders. Human induced pluripotent stem cells (hiPSCs)-derived neurons represent a useful platform for neurological disease modeling, drug discovery and toxicity screening in vitro. Multi-electrode array (MEA) systems offer a non-invasive and label-free platform to record neuronal evoked-responses concurrently from multiple electrodes. To better detect the neural network changes, we used the Axion Maestro MEA platform to assess neuronal activity and bursting behaviors in hiPSC-derived neuronal cultures. Here we describe the detailed protocol for neuronal culture preparation, MEA recording, and data analysis, which we hope will benefit other researchers in the field.

A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes

IntroductionHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established. MethodsExtracellular field potentials (FPs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system. The effects on FPs were evaluated with 60 drugs, including 57 with various clinical torsadogenic risks. Actual drug concentrations in medium were measured using the equilibrium dialysis method with a Rapid Equilibrium Dialysis device. Relative torsade de pointes (TdP) scores were determined for each drug according to the degree of FP duration prolongation and early afterdepolarization occurrence. The margins were calculated from the free concentration in medium and free effective therapeutic plasma concentration. Each drug's results were plotted on a two-dimensional map of relative TdP risk scores versus margins. ResultsEach drug was categorised as high, intermediate, or low risk based on its location within predefined areas of the two-dimensional map. We categorised 19 drugs as high risk; 18 as intermediate risk; and 17 as low risk. We examined the concordance between our categorisation of high and low risk drugs against the torsadogenic risk categorisation in CredibleMeds®. Our system demonstrated high concordance, as reflected in a sensitivity of 81%, specificity of 87%, and accuracy of 83%. DiscussionThese results indicate that our torsadogenic risk assessment is reliable and has a potential to replace the hERG assay for torsadogenic risk prediction, however, this system needs to be improved for the accurate of prediction of clinical TdP risk. Here, we propose a novel drug induced torsadogenic risk categorising system using hiPSC-CMs and the MEA system.

The unbound concentration of multimodal drugs in the assay medium used in the multi-electrode array system for cardiac risk assessment with iPS cell-derived cardiomyocytes

The unbound concentration of multimodal drugs in the assay medium used in the multi-electrode array system for cardiac risk assessment with iPS cell-derived cardiomyocytes

ヒトiPS細胞由来心筋細胞Cor.4Uを用いた多電極アレイシステムによる催不整脈作用評価系の検証－CSAHi - JiCSAの協働

ヒトiPS細胞由来心筋細胞Cor.4Uを用いた多電極アレイシステムによる催不整脈作用評価系の検証－CSAHi - JiCSAの協働

Points to consider for a validation study of iPS cell-derived cardiomyocytes using a multi-electrode array system

Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) provide a novel assay system to assess cardiac safety in drug development to overcome a problem of species difference in non-clinical testing during drug development. Using the multi-electrode array (MEA) platform, electrophysiological activities of iPS-CMs can be recorded easily to assess QT prolongation and proarrhythmic potential of drug candidates. Here we have established a standardized protocol to evaluate the possibility of iPS-CMs, and shared the protocol with an international consortium. To obtain reproducible and reliable experimental data from these cells, we determined the optimal experimental conditions, such as cell density, MEA coating, culture conditions, high-pass filter frequency, definition of early afterdepolarization or triggered activity, and calibration compounds. Based on the protocol, our validation study using 60 compounds is in progress. Thus, MEA-based experiments using iPS-CMs would be a standard testing method to evaluate QT prolongation and proarrhythmic potentials.

1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy

Status epilepticus (SE) initiates epileptogenesis to transform normal brain to epileptic state which is characterized by spontaneous recurrent seizures (SRS). Prior to SRS, progressive changes occur in the brain soon after SE, for example, loss of blood–brain barrier (BBB) integrity, neuronal hyper-excitability (epileptiform spiking), neuroinflammation [reactive gliosis, high levels of reactive oxygen/nitrogen species (ROS/RNS)], neurodegeneration and synaptic re-organization. Our hypothesis was that modification of early epileptogenic events will alter the course of disease development and its progression. We tested the hypothesis in the rat kainate model of chronic epilepsy using a novel disease modifying drug, 1400W, a highly selective inhibitor of inducible nitric oxide synthase (iNOS/NOS-II). In an in vitro mouse brain slice model, using a multi-electrode array system, co-application of 1400W with kainate significantly suppressed kainate-induced epileptiform spiking. In the rats, in vivo, 4h after the induction of SE with kainate, 1400W (20mg/kg, i.p.) was administered twice daily for three days to target early events of epileptogenesis. The rats were subjected to continuous (24/7) video-EEG monitoring, remotely, for six months from epidurally implanted cortical electrodes. The 1400W treatment significantly reduced the epileptiform spike rate during the first 12–74h post-SE, which resulted in >90% reduction in SRS in long-term during the six month period when compared to the vehicle-treated control group (257±113 versus 19±10 episodes). Immunohistochemistry (IHC) of brain sections at seven days and six months revealed a significant reduction in; reactive astrogliosis and microgliosis (M1 type), extravascular serum albumin (a marker for BBB leakage) and neurodegeneration in the hippocampus, amygdala and entorhinal cortex in the 1400W-treated rats when compared to the vehicle control. In the seven day group, hippocampal Western blots revealed downregulation of inwardly-rectifying potassium (Kir 4.1) channels and glutamate transporter-1 (GLT-1) levels in the vehicle group, and 1400W treatment partially reversed Kir 4.1 levels, however, GLT-1 levels were unaffected. In the six month group, a significant reduction in mossy fiber staining intensity in the inner molecular layer of the dentate gyrus was observed in the 1400W-treated group. Overall these findings demonstrate that 1400W, by reducing the epileptiform spike rate during the first three days of post-insult, potentially modifies epileptogenesis and the severity of chronic epilepsy in the rat kainate model of TLE.

Resting electrical network activity in traps of the aquatic carnivorous plants of the genera Aldrovanda and Utricularia.

In this study the MEA (multielectrode array) system was used to record electrical responses of intact and halved traps, and other trap-free tissues of two aquatic carnivorous plants, Aldrovanda vesiculosa and Utricularia reflexa. They exhibit rapid trap movements and their traps contain numerous glands. Spontaneous generation of spikes with quite uniform shape, propagating across the recording area, has been observed for all types of sample. In the analysis of the electrical network, higher richer synchronous activity was observed relative to other plant species and organs previously described in the literature: indeed, the time intervals between the synchronized clusters (the inter-spike intervals) create organized patterns and the propagation times vary non-linearly with the distance due to this synchronization. Interestingly, more complex electrical activity was found in traps than in trap-free organs, supporting the hypothesis that the nature of the electrical activity may reflect the anatomical and functional complexity of different organs. Finally, the electrical activity of functionally different traps of Aldrovanda (snapping traps) and Utricularia (suction traps) was compared and some differences in the features of signal propagation were found. According to these results, a possible use of the MEA system for the study of different trap closure mechanisms is proposed.

CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability-

In vitro screening of hERG channels are recommended under ICH S7B guidelines to predict drug-induced QT prolongation and Torsade de Pointes (TdP), whereas proarrhythmia is known to be evoked by blockage of other ion channels involved in cardiac contraction and compensation mechanisms. A consortium for drug safety assessment using human iPS cells-derived cardiomyocytes (hiPS-CMs), CSAHi, has been organized to establish a novel in vitro test system that would enable better prediction of drug-induced proarrhythmia and QT prolongation. Here we report the inter-facility and cells lot-to-lot variability evaluated with FPDc (corrected field potential duration), FPDc10 (10% FPDc change concentration), beat rate and incidence of arrhythmia-like waveform or arrest on hiPS-CMs in a multi-electrode array system.Arrhythmia-like waveforms were evident for all test compounds, other than chromanol 293B, that evoked FPDc prolongation in this system and are reported to induce TdP in clinical practice. There was no apparent cells lot-to-lot variability, while inter-facility variabilities were limited within ranges from 3.9- to 20-folds for FPDc10 and about 10-folds for the minimum concentration inducing arrhythmia-like waveform or arrests.In conclusion, the new assay model reported here would enable accurate prediction of a drug potential for proarrhythmia.

Synchronization of Large Clusters of Cardiomyocytes Connected by Fibroblasts

To analyze the synchronization process of clusters of chicken embryo-derived cardiomyocytes, we used the on-chip multi electrode arrays (MEA) system with agarose microchambers. In previous studies of the mouse-derived cardiomyocytes, it is known that fibroblasts propagate action potential if the distance is within 300μm. In addition, in the synchronization process of a single cardiomyocyte, it is also known that a cell with stable beating becomes pacemaker. Two sets of cardiomyocyte clusters were connected with fibroblasts by additional agarose micro fabrication during cell culture, and fibroblasts distance changed 600 μm, 300 μm, 150 μm. For evaluating synchronization, we used three indication that Inter Spike Interval ( ISI ), Coefficient of Variation ( CV ), Delay time. ISI represents beating rate of cardiomyocytes clusters, and it measured each 1 minutes every 10 minutes until beating stopped. CV represents fluctuation of the beating. In the two sets of clusters, we were elected each channel which is suitable for the analysis. For the analysis of the data, we used “ MATLAB ”.As a result, clusters of chicken embryo-derived cardiomyocytes were synchronized within the fibroblast distance of 300 μm, and pace making is not depended on the fast beating rate or the stability of fluctuation. It was suggested that anather mechanism of synchronization between large size clusters of cardiomyocyte exists different from tissues or single cardiomyocytes.

Electrophysiological maturation and drug responses of human induced pluripotent stem cell-derived cortical neuronal networks over 1 years culture

Event Abstract Back to Event Electrophysiological maturation and drug responses of human induced pluripotent stem cell-derived cortical neuronal networks over 1 years culture Ikuro Suzuki1*, Aoi Odawara1, Hiroki Katoh1 and Naoki Matsuda1 1 Tohoku Institute of Technology, Department of Electronics, Japan Motivation Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for drug discovery and toxicity testing. However, the immaturity of cultured human iPSC-derived neurons and the lack of established functional evaluation methods are problematic. The purpose of this study was to evaluate the physiological maturation and drug responses depending on culture days using multi-electrode array (MEA) system, and to detect the epilepsy pehnomena and the effects of ani epilepsy drugs as an application example. Material and Methods Human induced PSC-derived cerebral cortical neurons (hyCCNs; ax0026F, Axol Bioscience Inc., UK) [1] were cultured at 1.0 ~ 106 cells/cm2 on 64-channel MEA chips (MED-P515A; Alpha Med Scientific) coated with Axol Sure Bond Coating Solution (Axol Sure Bond Coating solusion; ax0041, Axol Bioscience Inc.) at 37‹C in a 5% CO2/95% air atmosphere. Spontaneous and evoked extracellular field potentials were acquired at 37‹C under a 5% CO2 atmosphere using a 64-channel MEA system (MED64-Basic; Alpha Med Scientific) at a sampling rate of 20 kHz/channel. Signals were low-pass filtered at 100 Hz and stored on a personal computer. Spontaneous firing was recorded every week for over 600 days. To investigate pharmacological effects depending culture days, we administered 10 ƒÊM bicuculline, 5 ƒÊM kainic acid, 50 ƒÊM CNQX, and 50 ƒÊM AP-5 at 10-15 and 33-36 weeks culture respectively. To detect the epilepsy pehnomena and the effects of ani-epilepsy drugs (AEDs), we administerd pentylentetrazole (PTZ) and typical AEDs (phenytoin and sodium valproate (VPA). Results We have succeeded in detection of spontaneous firings over 600 days and the future of time course. Syncronized burst firings (SBFs), in which generated by chemical synapse transmission, were observed over 10-13 weeks. As the culture days has passed, the number of occurrences of SBFs were increased up to approximately 30 weeks. Both spontaneous firings and evoked responses, we detected the effects of typical synaptic-related drugs at 33-36 weeks compaird to 10-15 weeks culture, indicative of greater functional maturation. Moreover, we also detected the induction of epileptic seizure by PTZ, in which high frequency SBFs were generated by 0.1-1mM PTZ administration, and the effects of AEDs [2]. Discussion Synchronized spike bursts are critical for information transfer within the cortex and are indicators of functional maturation. Such SBFs were first observed at 10?13 weeks and increased in frequency up to approximately 30 weeks. In rat cortical neurons at 1/4 cell density, synchronized firing attributable to chemical synaptic transmission occurred after only 1 week in culture, suggesting that hiPSC-derived cortical neurons require much longer to achieve functional maturation in vitro. Nonetheless, this extra time is reasonable considering the advantages for translational research presented by human neurons. These spontaneous and evoked responses also showed progressive changes in pharmacological response. In particular, the detection of fully functional NMDA responses is important because the NMDA receptor mediates several forms of neuroplasticity related to learning. Moreover, NMDA overactivity is a key pathogenic event in numerous acute and chronic neurodegenerative diseases. We also suggest that the human iPSC-derived neuron culture is a useful model system to investigate the effects of common AEDs and an alternative to animal experiments for drug screening. In addition, our assay can be adapted to iPSC-derived neurons from epilepsy patients. Conclusion We found that functional maturation in hiPSC-derived coritical neurons need the long-term culture over 20-30 weeks. Evaluation of drug responses is suitable to the culture sample over 20- 30 weeks. We have proved the MEA coupled hiPSC-derived neuronal neurons is useful to neuropharmacological/neurotoxicological assays for drug screening by detecting the drug effects both spontaneous firings and evoked responses. Our results also provide an important indication for the international standardization of evaluation procedures using in vitro human central neurons [2]. Acknowledgements We thank Axol Bioscience and Alpha Med Scientific Company for supporting this research. This study was supported by JSPS KAKENHI Grant Number 26560247, 14J11194.

Blanking circuits: Culprit or Savior?

Blanking circuits: Culprit or Savior?

Establishment of a Human Neuronal Network Assessment System by Using a Human Neuron/Astrocyte Co-Culture Derived from Fetal Neural Stem/Progenitor Cells

Using human cell models mimicking the central nervous system (CNS) provides a better understanding of the human CNS, and it is a key strategy to improve success rates in CNS drug development. In the CNS, neurons function as networks in which astrocytes play important roles. Thus, an assessment system of neuronal network functions in a co-culture of human neurons and astrocytes has potential to accelerate CNS drug development. We previously demonstrated that human hippocampus-derived neural stem/progenitor cells (HIP-009 cells) were a novel tool to obtain human neurons and astrocytes in the same culture. In this study, we applied HIP-009 cells to a multielectrode array (MEA) system to detect neuronal signals as neuronal network functions. We observed spontaneous firings of HIP-009 neurons, and validated functional formation of neuronal networks pharmacologically. By using this assay system, we investigated effects of several reference compounds, including agonists and antagonists of glutamate and γ-aminobutyric acid receptors, and sodium, potassium, and calcium channels, on neuronal network functions using firing and burst numbers, and synchrony as readouts. These results indicate that the HIP-009/MEA assay system is applicable to the pharmacological assessment of drug candidates affecting synaptic functions for CNS drug development.

Induction of long-term potentiation and depression phenomena in human induced pluripotent stem cell-derived cortical neurons

Plasticity such as long-term potentiation (LTP) and long-term potentiation depression (LTD) in neuronal networks has been analyzed using in vitro and in vivo techniques in simple animals to understand learning, memory, and development in brain function. Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for understanding the plasticity mechanism in human neuronal networks, thereby elucidating disease mechanisms and drug discoveries. In this study, we attempted the induction of LTP and LTD phenomena in a cultured hiPSC-derived cerebral cortical neuronal network using multi-electrode array (MEA) systems. High-frequency stimulation (HFS) produced a potentiated and depressed transmission in a neuronal circuit for 1 h in the evoked responses by test stimulus. The cross-correlation of responses revealed that spike patterns with specific timing were generated during LTP induction and disappeared during LTD induction and that the hiPSC-derived cortical neuronal network has the potential to repeatedly express the spike pattern with a precise timing change within 0.5 ms. We also detected the phenomenon for late-phase LTP (L-LTP) like plasticity and the effects for synchronized burst firing (SBF) in spontaneous firings by HFS.In conclusion, we detected the LTP and LTD phenomena in a hiPSC-derived neuronal network as the change of spike pattern. The studies of plasticity using hiPSC-derived neurons and a MEA system may be beneficial for clarifying the functions of human neuronal circuits and for applying to drug screening.

CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia — Effects of 7 reference compounds at 10 facilities

IntroductionDrug-induced QT prolongation is a major safety issue during drug development because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT prolongation and arrhythmia. MethodsTen facilities evaluated the effects of 7 reference drugs (E-4031, moxifloxacin, flecainide, terfenadine, chromanol 293B, verapamil, and aspirin) using a MED64 MEA system with commercially available hiPS-CMs. Field potential duration (FPD), beat rate, FPD corrected by Fridericia's formula (FPDc), concentration inducing FPDc prolongation by 10% (FPDc10), and incidence of arrhythmia-like waveform were evaluated. ResultsThe inter-facility variability of absolute values before drug application was similar to the intra-facility variability for FPD, beat rate, and FPDc. The inter-facility variability of FPDc10 for 5 reference drugs ranged from 1.8- to 5.8-fold. At all 10 facilities, E-4031, moxifloxacin, and flecainide prolonged FPDc and induced arrhythmia-like waveforms at concentrations 1.8- to 6.1-fold higher than their FPDc10. Terfenadine prolonged FPDc and induced beating arrest at 8.0 times the FPDc10. The average FPDc10 values for E-4031, moxifloxacin, and terfenadine were comparable to reported plasma concentrations that caused QT prolongation or Torsade de Pointes in humans. Chromanol 293B, a IKs blocker, also prolonged FPDc but did not induce arrhythmia-like waveforms, even at 7.4 times the FPDc10. In contrast, verapamil shortened FPDc and aspirin did not affect FPDc or FP waveforms. DiscussionMEA with hiPS-CMs can be a generalizable method for accurately predicting both QT prolongation and arrhythmogenic liability in humans.

Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes

IntroductionMulti-electrode array (MEA) systems and human induced pluripotent stem (iPS) cell-derived cardiomyocytes are frequently used to characterize the electrophysiological effects of drug candidates for the prediction of QT prolongation and proarrhythmic potential. However, the optimal experimental conditions for obtaining reliable experimental data, such as high-pass filter (HPF) frequency and cell plating density, remain to be determined. MethodsExtracellular field potentials (FPs) were recorded from iPS cell-derived cardiomyocyte sheets by using the MED64 and MEA2100 multi-electrode array systems. Effects of HPF frequency (0.1 or 1Hz) on FP duration (FPD) were assessed in the presence and absence of moxifloxacin, terfenadine, and aspirin. The influence of cell density on FP characteristics recorded through a 0.1-Hz HPF was examined. The relationship between FP and action potential (AP) was elucidated by simultaneous recording of FP and AP using a membrane potential dye. ResultsMany of the FP waveforms recorded through a 1-Hz HPF were markedly deformed and appeared differentiated compared with those recorded through a 0.1-Hz HPF. The concentration–response curves for FPD in the presence of terfenadine reached a steady state at concentrations of 0.1 and 0.3μM when a 0.1-Hz HPF was used. In contrast, FPD decreased at a concentration of 0.3μM with a characteristic bell-shaped concentration–response curve when a 1-Hz HPF was used. The amplitude of the first and second peaks in the FP waveform increased with increasing cell plating density. The second peak of the FP waveform roughly coincided with AP signal at 50% repolarization, and the negative deflection at the second peak of the FP waveform in the presence of E-4031 corresponded to early afterdepolarization and triggered activity. DiscussionFP can be used to assess the QT prolongation and proarrhythmic potential of drug candidates; however, experimental conditions such as HPF frequency are important for obtaining reliable data.

Corrosion of Pipeline Steel X-60 Under Field-Collected Sludge Deposit in a Simulated Sour Environment

The inhibition of under deposit corrosion (UDC) of steel X-60 (UNS K03006) was studied under field-collected sludge deposits in a simulated sour environment by means of linear polarization resistance (LPR), coupled multi-electrode array system (CMAS), and weight-loss coupons. X-ray diffraction (XRD) and energy-dispersive x-ray spectroscopy (EDS) techniques were employed to identify the deposit composition. The adsorption of two corrosion inhibitors, fatty acid imidazoline and benzyl alkyl pyridinyl quaternary ammonium chloride (benzyl chloride quaternary), designed for steel corrosion protection in sour environments, and their inhibition activities under sludge deposits were investigated. The significance of determining the adsorption affinity of the inhibitors to field-sludge deposit in the selection of corrosion inhibitors was also demonstrated. The XRD analysis indicated that the field-sludge deposit consisted mainly of calcite phase. Fatty acid imidazoline inhibitor was found to exhibit higher affinit...

A novel high throughput approach to screen for cardiac arrhythmic events following stem cell treatment

Although stem cell therapy is promising for repairing damaged cardiac tissue and improving heart function, there are safety concerns, especially regarding the risk of arrhythmias, which can be life threatening. To address this issue, we propose to develop a novel screening system to evaluate arrhythmic risk associated with stem cell therapy using a high-throughput multielectrode array system that can measure conduction velocity and action potential duration in cardiomyocytes co-cultured with different types of stem cells, such as mesenchymal stem cells, skeletal myoblasts, and resident cardiac stem cells. We will assess the arrhythmic potential of each of these types of stem cells under normoxic and hypoxic conditions, with/without application of oxidative stress or catecholamines. We hypothesize that these methods will prove to be an effective way to screen for arrhythmic risk of cardiac stem cell therapy. Ultimately, our approach can potentially be personalized to develop a robust screening protocol in order to identify which stem cell type carries the least amount of risk for arrhythmia. This system will have great clinical benefit to improve the risk/benefit ratio of human stem cell therapy for heart disease.

Electrical spiking in bacterial biofilms.

In nature, biofilms are the most common form of bacterial growth. In biofilms, bacteria display coordinated behaviour to perform specific functions. Here, we investigated electrical signalling as a possible driver in biofilm sociobiology. Using a multi-electrode array system that enables high spatio-temporal resolution, we studied the electrical activity in two biofilm-forming strains and one non-biofilm-forming strain. The action potential rates monitored during biofilm-forming bacterial growth exhibited a one-peak maximum with a long tail, corresponding to the highest biofilm development. This peak was not observed for the non-biofilm-forming strain, demonstrating that the intensity of the electrical activity was not linearly related to the bacterial density, but was instead correlated with biofilm formation. Results obtained indicate that the analysis of the spatio-temporal electrical activity of bacteria during biofilm formation can open a new frontier in the study of the emergence of collective microbial behaviour.

MAPPING REGIONAL REPOLARISATION GRADIENTS IN THE FAILING HUMAN VENTRICLE USING CARDIAC SLICES

Regional differences in repolarisation have been shown to contribute to ventricular arrhythmias in animal models of heart failure, however little is known about their presence and role in the human heart. In this study we investigated regional electrophysiological properties in the failing human ventricle using cardiac slices prepared from the left ventricular free wall (LV) and from the left side of the ventricular septum (LVS). Cardiac slices (300 µm thick) were prepared from ventricular biopsies obtained from heart failure patients undergoing heart transplant. Slices were point-stimulated at cycle lengths (CL) ranging from 500 ms to 4000 ms, and analysed using a multi-electrode array system. Field potential duration (FPD), an index of action potential duration, was measured. FPD was significantly longer in slices from the LVS versus slices from the LV at all pacing cycle lengths (CL 500 ms: 368±13 ms in LVS vs 330±7 ms in LV, n=7 slices/2 hearts, p

Toward quasi-in vivo from in vitro assay (I): Development of spatial conductance fluctuation measurement assay using a human cardiomyocyte line-network cell chip with multielectrode array system for in vitro predictive proarrhythmic cardiotoxicity

Toward quasi-in vivo from in vitro assay (I): Development of spatial conductance fluctuation measurement assay using a human cardiomyocyte line-network cell chip with multielectrode array system for in vitro predictive proarrhythmic cardiotoxicity