? Blood vessel replacement is a common treatment for vascular diseases. Tissue engineering is a promising approach to the fabrication of non-thrombogenic and mechanically durable vascular grafts. Our goal is to engineer bone marrow stem cells and electrospun nanofibrous scaffolds to construct tissue-engineered vascular graft (TEVG) that closely matches the composition, structure and mechanical property of native blood vessel. Bone marrow contains vascular endothelial precursor cells (EPCs) and mesenchymal stem cell (MSC). MSC can differentiate into a variety of cell types, including vascular smooth muscle cell (SMC). We hypothesize that: (1) bone marrow stem cells can be used to derive endothelial cells (ECs) and SMCs to construct TEVGs, (2) bioactive nanofibrous scaffolds with aligned nanofibers can promote MSC differentiation, matrix remodeling and the formation of microstructure as in native vessel, and (3) mechanical loading can promote MSC differentiation, matrix remodeling and EC monolayer retention. To test our hypothesis, four Specific Aims are proposed: (1) To engineer bioactive nanofibrous scaffolds and characterize MSC-scaffold interactions; (2) To determine MSC differentiation and matrix remodeling in TEVG in response to mechanical loading; (3) To construct EC monolayer in TEVG using EPCs and determine the effect of flow on EC remodeling; (4) To determine the remodeling and patency of small-diameter TEVGs in vivo. The nanofibers in the tubular scaffolds will be aligned in the circumferential direction to mimic the matrix alignment in native blood vessels and guide the MSC alignment. RGD peptide and TGF-p will be conjugated to the nanofibers to promote matrix remodeling and MSC differentiation into SMC. Mechanical loading will be applied to the tubular scaffolds to further enhance matrix remodeling and MSC differentiation. Bone marrow derived ECs will be cultured as monolayer on the luminal surface of TEVG, and will be pre-conditioned by fluid shear stress. The mechanical property and structure of the TEVGs will be determined. Bypass surgery will be performed in animal model to determine the continued remodeling and patency of small TEVGs. Manufacturing-related issues such as Good Manufacturing Practices, biomarker monitoring, storage and caling-up will be addressed. The accomplishment of this project will lead to the development of innovative technologies to engineer stem cells and nanofibrous scaffolds for the construction of small TEVGs. ? ? ?
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