Cardiovascular diseases affect 70 million Americans, resulting in an economic burden of $300 billion and accounting for nearly 40% of all deaths in the US. Conventional treatments of myocardial injury do not achieve myocardial regeneration. Therefore, stem cell and tissue engineering based approaches for cardiac tissue regeneration have been actively pursued. Existing scaffold based 3D tissue engineering approaches accomplish tissue regeneration in non-biomimetic environments and with limited control over 3D architecture. Mimicking the 3D cellular organization and replicating mechanical loading patterns seen in vivo will address shortcomings associated with conventional techniques and significantly enhance functionality of tissues generated in vitro. In this proposal, we will enable a platform technology for magnetic cellular assembly of multiple cell types encapsulated in magnetic hydrogels (M-Gels) that mimic the tissue-level cell densities to form 3D cardiac tissue structures. Microscale perfusion networks will be integrated into the 3D constructs to ensure delivery of nutrients and meet the high metabolic needs of cardiac cells. Patterned constructs will be cultured within a microfluidic Cardiac Cell Culture Model (CCCM) that accurately replicates pressure and stretch loading seen in the left ventricle. Our prior work clearly demonstrates our ability to pattern complex architectures in both 2D and 3D and accomplish cell culture within the CCCM under realistic mechanical stresses that promote cyclic stretch, cell alignment and spontaneous synchronous contractions. Specifically we will: (A) accomplish assembly of cardiac cells encapsulated in magnetic hydrogels (M-gels) around a sacrificial porogen network to attain in vivo like tissue-level cell densities and architecture, (B) utilize th CCCM to culture magnetically assembled cardiac tissue constructs in a cell culture environment that mimics the pressure-volume changes seen in the left ventricle and enable extraction of intact tissue following culture and (C) accomplish characterization of morphological and functional properties of magnetically assembled and microfluidically conditioned tissue constructs in vitro and determine the role of 3D patterning, integration of microscale perfusion networks and culture under loading regimens of pressure and stretch on in vitro cardiogenesis and the ability to generate functional myocardial tissue that can potentially be used to repair myocardial infarctions. Though chick embryonic cardiac cell populations will be used to demonstrate the feasibility of proposed activities, the developed techniques will be compatible with cardiac stem and progenitor cell populations for generation of functional cardiac patches.
The goal of this proposal is to design a strategy to generate functional cardiac tissue in vitro which can be surgically placed to repair myocardial infarctions in the heart. Using new and unique technologies to accomplish 3D magnetic assembly of cardiac cells, integrate microscale vasculature and culture cells under pressure-volume changes in the heart we will attempt to mimic the structural and functional details of the in vivo environment.
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