Development of human iPSC-derived cardiomyocytes-based heart-on-a-chip with customized multi-electrode array for drug-induced cardiotoxicity evaluations

Abstract

The heart is an essential organ at the beginning and end of life. Cardiotoxicity directly related to life is emphasized as an absolute safety factor in drug development, so it is indispensable to evaluate it accurately. That is why establishing a novel platform that can precisely recapitulate human cardiophysiological properties is necessary. Here, we report a human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes-based heart-on-a-chip integrated with a customized multi-electrode array (cMEA), capable of actualizing a cardiac muscle fascicle and surrounding capillaries tridimensionally. The differences in experimental reproducibility, scale of field potential wave, and gene expression patterns according to the two-dimensional cell-level and three-dimensional tissue-level culture are confirmed. Excellent accuracy of drug efficacy/toxicity of the chip is also verified relative to other conventional cell culture platforms by looking at heart rate changes depending on drug type and concentration/time. Additionally, we checked that kinetic/electrophysiological/molecular biological analysis can be performed with our chip by applying motion tracking, cMEA, and RNA sequencing. Thus, our platform is expected to be used as a tool for more exact cardiotoxicity tests with high reproducibility and multi-angle analysis in line with new pharmacological safety assessments such as comprehensive cardiac arrhythmias assessment (CiPA).