3D vascularized cardiac organoid on-chip for modeling of dytropic and mitogenic cardiomyopathy.

In this project, we aim at generating 3D vascularized human cardiac organoids on-chip as unprecedented in vitro disease model to unravel novel molecular mechanistic insights on the pathogenesis of Duchenne Muscular Dystrophy (DMD)- and Alström Syndrome (ALMS)-associated cardiomyopathy. The 3D organoids will be generated via an autonomous cell aggregation process using a medium-throughput multi-microwells platform, and the disease phenotypes will be characterized to confirm their validity as 3D disease models. The novelty and innovation lie on the creation of a microfluidic-based vascular bed, which allows angiogenic sprouting and vascular invasion into the 3D organoids by human induced pluripotent stem cells-derived endothelial cells (hiPSC-ECs). This results in perfusable vasculatures directly connecting the 3D organoids to endothelialized microchannels. Importantly, this vascular bed consists of a novel polyethylene glycol (PEG)-based hydrogel system functionalized with combinatorial cardiovascular-specific peptides that optimally support the growth of hiPSC-ECs and diseased cardiomyocytes derived from DMD and ALMS patients. The resulted perfusable vasculature line will be used to simulate intravenous injection of drug candidates for the assessment of their efficacy on ameliorating dystrophic and mitogenic cardiomyopathy, hence providing proof-of-principle of these on-chip platforms as valid disease models on-chip to unravel DMD and ALMS pathogenesis and for drug discovery.