Our current inability to vascularize and perfuse thick cell masses has hindered efforts to engineer many types of functional tissues including, most critically, cardiac muscle. To serve as a graft for myocardial repair, an engineered cardiac construct must be thick and compact, contain physiologic density of differentiated cells, and contract synchronously in response to electrical stimulation. In addition, the graft must have a capability to integrate with the host vasculature in order to maintain the viability and function of transplanted cells. We propose to engineer functional vascularized myocardium by integrating and advancing our ongoing efforts in the areas of cardiac tissue engineering (MIT) and vascular tissue engineering (Duke). We hypothesize that the cultivation of cardiac myocytes and endothelial cells on specialized scaffolds (highly porous, biodegradable, elastic, with an array of channels) in a bioreactor with medium perfusion and electrical stimulation will promote functional assembly of synchronously contractile engineered muscle. We further hypothesize that vascularization in vitro will enhance the graft capacity for survival, integration and function in vivo. In order to test these hypotheses, which have been derived from two lines of our previous investigations, we propose studies with the following Specific Aims: (1) High density culture of cardiac myocytes on channeled scaffolds with medium perfusion and electrical stimulation, (2) Tissue engineering of a vascularized network, and (3) Tissue engineering and functional characterization of a vascularized cardiac muscle. The effects of perfusion and electrical stimulation on the progression of endothelial cell and myocyte assembly into a synchronously contractile myocardium will be studied in vitro and in vivo (implantation onto a left ventricle in an adult rat model of infarction). Tissue structure and function will be characterized at various hierarchical scales (molecular, structural, functional) and the obtained experimental and modeling data will be used to tailor the conditions and duration of cultivation and engineer implantable grafts. As such, the current proposal is a blueprint for the generation of vascularized cardiac muscle suitable for implantation into injured myocardium.
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