Myocardial infarction, one of the deadly disease in the world, is caused by the blockage of coronary artery. The resulting ischemia and nutrient starving conditions induce extensive death of cardiomyocytes, which is non-regenerative. The ensuing remodeling process causes the thinning of left ventrical wall and increase in wall stress. This entire process resulted in permentent damage in heart function.
Stem/progenitor cell therapy that employing stem/progenitor cells, extracellular matrix, and regulatory factors has been demonstrated to be effective in restoring heart function. However, two key issues need to be addressed: 1) reestablishing vasculatures in engineered cardiac tissue constructs; 2) stimulating the survival and differentiation of transplanted stem/progenitor cells.
The overall objective of this thesis is to design a series of 3-D tissue constructs to address these two major issues. To better mimic the morphology and mechanical anisotropy of the natural ECM, electrospining was employed to fabricate anisotropic fibrous tissue constructs, thus providing a native-like structural environment and stress transfer pattern for embedded cells. To accelerate vasculaturization in fibrous constructs, a growth factor gradient was introduced into electrospun PCL scaffolds to emulate the in vivo chemotaxis microenvironment for native blood vessel formation. Both in vitro and in vivo studies demonstrated that the bFGF gradients were able to attract cell migration into the scaffolds. After subcutaneous implantation, a high density of mature (CD31+ and α-SMA+) blood vessels was formed in scaffold loaded with bFGF gradient, which demonstrated that mimicking the in vivo chemotaxis microenvironment could accelerate angiogenesis in the constructs. To ameliorate the deleterious effect of hypoxic condition, insulin like growth factor (IGF-1), basic fibroblast growth factor (bFGF), and oxygen releasing complex PVP/H2O2, were encapsulated into PLGA microspheres and delivered into the tissue constructs to stimulate the survival and differentiation of cardiosphere derived cells (CDCs) under hypoxic condition, which mimics that of the ischemia in infarct heart. Other than these biochemical cues, the efficacy of a biomechanical cue, matrix stiffness, on cell differentiation was also evaluated. An optimal modulus was found for fibrous scaffold to direct the differentiation of CDCs towards cardiomyocytes.