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CiPA and the New Cardiotoxicity Paradigm Part 2: Platforms – Microelectrode Array and Voltage-Sensing Optics

A key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative is the ability to collect electrophysiological data in a high-throughput screening (HTS) configuration at 37°C. Two platforms have been selected for evaluation under CiPA; Multi-Electrode (also known as Micro-Electrode) Arrays (MEA) and Voltage-Sensing Optical (VSO) systems.

MEAs offer a variety of throughput levels, up to 96-well plates. At the center of each well is a network of electrodes, each connecting to a signal amplifier outside the well. Human stem cell derived cardiomyocytes are cultured directly on the electrodes, which measure the electrical impulses and variations generated by the cell and can report many physiologically relevant endpoints. Because MEA-based assays read electrophysiological data and do not rely on dyes, long-term exposure studies are possible. VSO systems, on the other hand, require voltage-sensitive dyes, which can be cytotoxic, causing cell damage and signal loss over prolonged exposure periods. However, both platforms tested in the preliminary study conducted by the Myocyte Working Group under CiPA sought to measure different endpoints indicative of cardiotoxic response. The MEA subgroup evaluated the ability of MEA platforms to assess “time to peak field potential repolarization, beat frequency, amplitude of depolarization spike, and incidence of arrhythmias.” Meanwhile, the VSO subgroup collected data on “spike amplitude, waveform triangulation, APD90, beat frequency and incidence of arrhythmia.”

Volunteer organisations from industries across the pharmaceutical and biotechnology landscape participated in this initial study. The US FDA also completed a concurrent study comparing MEA and VSO platforms. While commenting on specific results would be speculation at this point, data that have been presented showed concordance with results from the volunteer organisations. The Japanese iPS Cardiac Safety Assessment (JiCSA) has also conducted experiments using human stem cell-derived cardiomyocytes on MEA platforms to evaluate both applicability to cardiotoxicity assessment (field potential duration and incidence of EADs) and inter-lab variability of data collected. These results will be included in the dataset that is used to establish the standardized protocols under the CiPA paradigm.

Part 1: Overview
Part 3: In Silico Prediction
Part 4: Clinical Translation