Development of cardiotoxicity evaluation method using HD-CMOS-MEA

Abstract

Cardiotoxicity is a common reason for drug discontinuation in new drug development. In vitro microelectrode array (MEA) method using hiPSC-CMs is expected to be an alternative method to animal experiments, but there is a problem that the hiPSC-CMs cannot mature sufficiently in the case of two-dimensional culture. In addition, the evaluation method of MEA is mainly based on the field potential duration (FPD) as an index, and the mechanism of action based on conduction velocity and propagation pattern has not been predicted. The purpose of this research is to construct an evaluation method focusing on conduction velocity and propagation pattern as an evaluation index of MEA. In order to enable detailed conduction velocity and conduction pattern analysis, hiPSC-CMs were measured using a 240,000-electrode HD-CMOS-MEA with high-density microelectrodes instead of conventional MEA. HD-CMOS-MEA has a resolution that can record 1 cell with several tens of electrodes, and was able to accurately detect the origin of pulsation and conduction direction. We detected 6 drug responses, and by using new parameters that can be evaluated by CMOS-MEA measurement, it has become possible to detect the toxicity of mexiletine, which was difficult to detect with the conventional evaluation method. The cardiotoxicity assessment using HD-CMOS-MEA has the potential to detect cardiotoxicity risks that could not be detected by conventional MEA analysis based on new parameters. It is expected to become a new evaluation method with the development of a method for maturation of hiPSC-CMs.