Heart-on-a-chip using human iPSC-derived cardiomyocytes with integrated vascular endothelial layer based on culture patch as a potential platform for drug evaluation

Many strategies have been adopted to construct in vitro myocardium models, which are of great value to both drug cardiotoxicity evaluation and cardiovascular drug development. Especially the recent rapid development of human induced pluripotent stem cell (hiPSC) technology and the rise of organ-on-a-chip technique provide great potential to achieve more physiologically relevant in vitro models. However, the recapitulation of the key role of the vasculature endothelial layer for the drug action on myocardium in the models is still challenging. In this work, we developed an openable heart-on-a-chip system using highly purified functional hiPSC derived cardiomyocytes (hiPSC-CMs) with integrated a vascular endothelial layer based on our previous proposed culture patch method. The purity and functionality of the differentiated hiPSC-CMs were characterized, which were applied into the lower chamber of the sandwich-structured device to form the CM layer. The integrity and cell morphology of the endothelial layer on culture patch as well as the influence of fluid shear force were studied, which was integrated in between the upper and lower chambers. The constructed heart-on-a-chip was finally applied for drug testing. The effect of two cardiac targeting drugs (isoproterenol and E-4031) directly on the hiPSC-CMs or after penetrating through the endothelial layer under static or dynamic conditions was evaluated. The results demonstrated the significance of vascular layer in the in vitro myocardium models for drug testing, as well as the advantage and potential of the proposed platform for cardiovascular drug evaluation with more human physiological relevance.