Engineering thick human cardiac tissue constructs with patterned, perfusable microvessels for treatment of myocardial infarction

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PROJECT SUMMARY Causing the death of more than 17 million people every year, cardiovascular disease is the leading cause of death worldwide. Progressive heart failure caused by myocardial infarction, or death of cardiac tissue due to a blockage in the coronary vasculature, is a major contributor to this burden. During a heart attack, up to 25% of the left ventricle’s contractile cells may be lost, leading to a remodeling response that leaves the heart wall thin and scarred and greatly reduces cardiac function. Besides whole heart transplantation, available treatment options can only slow the progression of disease and provide palliative care. As such, there is a great clinical need for therapies that prevent or treat the ruinous aftermath of myocardial infarction by restoring both the muscle tissue and the complex vasculature that is needed to support the muscle tissue. Implantable cellularized cardiac patches have emerged as a potential approach to treat myocardial infarction because complex tissues can be created by tuning architecture and allowing the tissues to mature. Although advances in tissue engineering and pluripotent stem cell technology have resulted in cardiac tissues that show promise for improving heart function, current implantable cellularized cardiac patches remain insufficiently thin due to inadequate nutrient supply. Previous approaches of vascularizing cardiac tissues have heavily relied on self-assembly of endothelial networks, leaving them minimally perfusable, or utilize scaffold materials that inadequately balance the stiffness required for vascular integrity with the remodeling capacity needed support cardiomyocyte coupling and rapid host vascular infiltration needed for efficient perfusion in vivo. To address this need, we propose to engineer thick, densely cellularized cardiac patches by incorporating a patterned, perfusable vasculature into a collagen scaffold for implantation onto infarcted hearts. Our group has previously developed a technique incorporating injection molding and soft lithography to generate perfusable vasculatures embedded within collagen matrices and demonstrated that endothelial cells will readily remodel the matrix while the perfusable vasculature remains intact. In this proposal, we will utilize this technique to generate cardiac tissues containing stem cell-derived cardiomyocytes and perfusable networks of stem cell-derived endothelial cells. We hypothesize that incorporating patterned, perfusable endothelial networks into cardiac tissues will enhance cardiomyocyte survival and function in vitro as well as promote rapid host vascular integration and tissue survival after implantation. To test this hypothesis, we will utilize a multilayer stacking technique to generate 3-mm thick cardiac tissues with a three-dimensional vascular network to enable greater tissue perfusion. We will assess tissue survival, maturation, and function in these tissues and similar tissues without perfusable vascular networks. We will then implant thick cardiac tissues onto infarcted rat hearts and investigate whether pre-perfused endothelial networks improve long-term survival of thick tissues. If successful, this platform will enable long-term survival of thicker cardiac tissues than has previously been achieved.