Disease on-a-Chip Modeling

Despite significant efforts in the study of cardiovascular diseases (CVDs), they persist as the leading cause of mortality worldwide. Considerable research into human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has highlighted their immense potential in the development of in vitro human cardiac tissues for broad mechanistic, therapeutic, and patient-specific disease modeling studies in the pursuit of CVD research. However, the relatively immature state of hPSC-CMs remains an obstacle to enhance the clinical relevance of engineered cardiac tissue models. We have developed a microfluidic platform for 3D modeling cardiac tissues. Our platform is precisely engineered through the incorporation of staggered microposts to enable long-term culture and maturation of cardiac cells, resulting in the formation of physiologically relevant cardiac tissues with anisotropy that mimics native myocardium.

Myocardial ischemia on-a-chip recapitulates ischemic insult through exposure of mature 3D cardiac tissues to hypoxic environments using our anisotropic heart-on-chip device. We have shown extensive validation and molecular-level analyses of the model in its ability to recapitulate myocardial ischemia in response to hypoxia, demonstrating the 1) induction of tissue fibrosis through upregulation of contractile fibers, 2) dysregulation in tissue contraction through functional assessment, 3) upregulation of hypoxia-response genes and downregulation of contractile-specific genes through targeted qPCR, and 4) transcriptomic pathway regulation of hypoxic tissues. Further, we investigated the complex response of ischemic myocardial tissues to reperfusion, identifying 5) cell toxicity, 6) sustained contractile irregularities, as well as 7) re-establishment of lactate levels and 8) gene expression, in hypoxic tissues in response to ischemia reperfusion injury.