Towards The Development of a Biologically Functional Tissue Engineered Vascular Graft

Coronary artery disease (CAD) is the leading cause of death worldwide [1], and it is predicted that 23 million deaths will be attributed to CAD by 2030. Treatment of CAD has required over 400,000 coronary artery bypass graft (CABG) surgeries every year [2], representing a cost to the country of nearly $439 billion in direct and indirect expenses annually [3]. As autologous veins are often unavailable for in CABG surgeries [4, 5], and commercially available synthetic grafts have shown limited efficacy when used in small diameter vessels [5-7], a readily available tissue engineered vascular graft (TEVG) for use in CABG surgeries would provide drastic improvements in patient care. Despite significant recent progress [7, 8], the development of a biologically functional TEVG that is biocompatible, biofunctional, and anti-thrombogenic has remained elusive [9, 10]. The primary goal of this dissertation is to fabricate a TEVG that supports and modulates the growth and collagen production of vascular smooth muscle cells (VSMCs) and promotes the formation of a functional endothelium. For this purpose, an initial assessment of biocompatibility was performed by culturing SMCs in gelatin/fibrinogen electrospun scaffolds, using exogenous TGFβ2 to modulate cell response. It was demonstrated that that TGFβ2 had a differential effect on cell proliferation, migration, and collagen deposition of SMCs growing in our biopolymer materials. In order to provide additional biofunctionality to the TEVG, a tubular scaffold able to release TGFβ2 was fabricated. The combination of gelatin and PCL at different ratios allowed elution tunability. The released TGFβ2 was bioactive and was able to modulate SMCs growth in vitro and in 3D culture. To evaluate anti-thrombogenicity and perform an additional assessment of biocompatibility, human derived endothelial cells (hCB-ECs) were cultured in surface modified gelatin/fibrinogen/PCL electrospun scaffolds. hCB-ECs growing in the scaffolds showed similar or superior behavior to human umbilical vein ECs (HUVEC) in terms of platelet deposition and activation, producing eNOS, and responding to a proinflammatory stimulus. Our data suggests that a biofunctional biopolymer based TEVG can be fabricated that can control SMC response and promote the formation of a functional endotheliu