Abstract Body: Introduction: To improve drug development outcomes and advance personalized medicine, the FDA’s Modernization Act 3.0 advocates nonclinical testing methods such as organ-on-chip (OOC) models. However, current commercial or lab-made OOC devices must improve fluid-flow stability, cell maturity, and immune system incorporation to match the reliability of animal models.
Hypothesis: We hypothesize that combining continuous mechanical and fluidic stimulation with co-culture of hiPSC-derived immune cells improves cardiac function and physiological relevance in heart-on-chip models.
Goals: This study aims to enhance iPSC-derived cardiomyocyte and endothelial cell maturity, incorporate immune cells, and assess cardiac function following drug-induced cardiotoxicity using a commercially available OOC platform.
Methods: Human iPSC-derived cardiomyocytes were cultured on the upper channel of an Emulate® organ-on-chip, separated by a porous membrane from the bottom channel containing human iPSC-derived endothelial cells. Continuous medium flow and mechanical stimulation were maintained. Structural and functional responses of the cardiac tissues to sorafenib-induced cardiotoxicity were assessed. Additionally, fluorescent reporter hiPSC-derived macrophages (iMACs) were introduced into endothelial and cardiomyocyte channels to evaluate immune cell recruitment and functional impact on cardiac cells.
Results: Continuous flow and mechanical stimulation significantly improved cellular maturity of both cardiomyocytes and endothelial cells compared to static conditions. Sorafenib exposure demonstrated measurable cardiotoxicity, characterized structurally and functionally. Notably, co-culture with iMACs enhanced cardiomyocyte function, indicated by increased contractility within 24 hours. Furthermore, active recruitment of iMACs from endothelial to cardiomyocyte channels was observed, suggesting potential protective roles of immune cells in preserving cardiac tissue function under stress.
Conclusions: Integrating iPSC-derived immune cells into heart-on-chip models enhances physiological relevance and cardiac tissue stability, advancing personalized medicine capabilities. This refined approach demonstrates substantial potential for personalized, reliable preclinical drug screening and improved healthcare outcomes.