The aim to produce a truly stable artificial blood vessel containing no synthetic material requires invasion and in growth of endothelial cell and smooth muscle cells as well as fibroblasts into the scaffold. This can be achieved either in vivo from the adjacent tissue or circulating cells after implantation, or in vitro by means of cultivated cells. Such graft should not induce substantial inflammatory reactions that could either damage its wall, setting the scene for long term aneurysm formation or trigger acute thrombosis. Based on such tissue engineering principles and our preliminary data, we propose a central hypothesis that a novel small diameter vascular graft can be tissue-engineered from the porcine carotid artery by decellularization, heparin covalent linkage, and heparin binding growth factors, and endothelial progenitor cell (EPC) seeding; and this graft may maintain its mechanical property and natural compliance; reduce host immune response; provide anticoagulation surface; and accelerate vascular cell growth and remodeling, thereby maintaining a long term potency in vivo.
Three specific aims are proposed below to test our central hypothesis:
Aim 1 : To determine the mechanical property, natural compliance, host immune response, and anticoagulation property of decellularized-heparinized porcine carotid artery grafts (D-H grafts). We will test the hypothesis that D-H grafts may maintain their mechanical property and natural compliance, provide anticoagulation surface, and reduce host immune response. Both in vitro and animal models are included. Carotid artery bypass surgery using D-H grafts will be performed in dogs (xenogenic setting) and in pigs (allogenic setting).
Aim 2 : To determine the effect of bFGF binding to D-H grafts on vascular cell growth and repopulation of the grafts. We will test the hypothesis that bFGF binding to D-H grafts may promote vascular cell growth and repopulation of the grafts, thereby accelerating vascular healing and remodeling. Characteristics of bFGF binding and release and effect on cell proliferation and anticoagulation will be investigated in vitro. In vivo performance of bFGF bound D-H grafts will be studied.
Aim 3 : To characterize cell proliferation and differentiation of EPC and its application with bFGF bound D-H grafts. We will test the hypothesis that bFGF bound D-H grafts may enhance EPC proliferation and differentiation, and EPC seeded bFGF bound D-H grafts may have better healing and remodeling characteristics as compared to un-seeded grafts. EPC will be isolated and characterized from dog or pig peripheral blood. The effect of bFGF and hemodynamics on EPC differentiation and proliferation will be investigated. In vivo performance of EPC seeded bFGF bound D-H grafts will be studied. This study represents a multidisciplinary approach including tissue engineering, cellular and molecular biology, and animal models. Success of this proposal will directly indicate the clinical applications of tissue engineered small diameter vascular grafts.
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