A Tri-Culture Heart-on-a-Chip Platform With iPSC-Derived Cardiac Cells for Predictive Cardiotoxicity Testing.

Abstract

Drug development is hindered by high attrition rates, with clinical trial failures accounting for 90% of unsuccessful candidates and 60% of R&D costs, often due to unanticipated cardiotoxicity. Existing models lack physiological relevance, particularly the vascular component critical for drug distribution and cardioprotection. To address this, we developed a heart-on-a-chip (HoC) platform integrating human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells from a single cell line, ensuring genetic uniformity and native-like cell-cell interactions. The tri-culture system maintained >90% cell viability under perfusion for 7 days and exhibited functional maturity, as demonstrated by expected chronotropic responses to the β-agonist isoproterenol. Crucially, the inclusion of endothelial cells mitigated doxorubicin-induced cardiotoxicity, a protective effect absent in conventional models, highlighting the endothelial layer's role in replicating in vivo drug responses. By combining physiological mimicry with scalability, this HoC platform offers a transformative tool for improving preclinical cardiotoxicity assessment and reducing reliance on animal models.