Integrating heart-on-chip technology and 3D porcine living myocardial slices for cardiotoxicity screening

Cardiotoxic events are a major challenge in drug development and a leading cause for market withdrawal. Cardiotoxicity frequently originates from electrophysiological alterations within cardiomyocytes, therefore increasing risk of life-threatening arrhythmias. Current preclinical 2D cell culture models lack the structural and functional complexity of mature myocardium. To address this limitation, we validated a microphysiological system (MPS) with porcine ex vivo living myocardial slices (LMS) incorporating a dualpacing strategy (S1S2) that was developed for direct assessment of effective refractory period (ERP) duration of action potential. Ex vivo cultivated porcine LMS responded to dual pacing and displayed action potential durations comparable to healthy human hearts. Specific human ether-ago-go-related gene (hERG) potassium channel blockade with Dofetilide prolonged ERP in a dose-dependent manner. Of great interest, our model was validated by mimicking the clinically cardiotoxic side effect of Cisapride. Titration of Cisapride triggered an elongated ERP, thus confirming cardiotoxicity screening power. Our newly developed MPSlms Tox platform enhances translatability by incorporating mature cardiac tissue and potently allows multidose drug testing from a single donor heart thereby elegantly reducing animal studies.