NEXT GENERATION BIOENGINEERED HUMAN MYOCARDIUM

Abstract

Cardiac patches consisting of induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) show beneficial effects when placed on the infarcted heart and the first human clinical trials have been approved. However, current patches do not replicate myocardial tissue, lacking 3D organization, mechanical properties, cellular maturity, and relevant thickness, and thereby fail to provide real contractile support to the failing heart. Previously, we have shown that melt electrowritten (MEW) hexagonal fiber scaffolds can be used to generate contractile cardiac patches that mimic native mechanical properties, thereby inducing iPSC‐CM maturation and tissue organization.[1] Although a huge step forward, these constructs do not yet fully replicate myocardial cellular and ECM composition and organization, and myocardial 3D fiber alignment. To tackle these hurdles, we have investigated the incorporation of additional cardiac cell types like iPSC‐derived cardiac fibroblasts (cFBs) and endothelial cells (ECs), the use of various myocardial and EC‐optimized bioinks for extrusion‐based bioprinting to allow for strategic cell‐type arrangement, and introducing 3D myocardial fiber‐angle orientation by stacking hexagonal MEW scaffolds. We found that the addition of cFBs, the optimization of hydrogel/ECM composition and stiffness (Collagen‐GelMA), and increasing thickness (1cm) and fiber organization by strategically stacking hexagonal meshes, led to the formation of a thick synchronously contracting myocardial tissue‐like construct. Our constructs showed a multi‐layered 3D fiber organization, with cells aligning with the hexagonal microarchitectures and an increase in maturation. Taken together, we have developed a next‐generation bioengineered myocardium with a more native‐like muscle structure and the potential to provide real functional support to the injured heart.