In the US alone, approximately 1.4 million patients require small-caliber (<6 mm ID) coronary artery or peripheral vessel grafts each year. Over 10% of these patients have no suitable autologous vessels for grafting. However, current synthetic prostheses, such as expanded polytetrafluoroethylene (ePTFE) grafts, display high failure rates in small-diameter applications. Tissue engineered vascular grafts (TEVGs) are therefore being actively developed for small-caliber applications. Although significant progress has been made, TEVG clinical viability has been hampered by: 1) thrombogenicity resulting from inadequate endothelialization, 2) the frequent need for pre-implantation cell and/or construct culture, 3) short- and long-term compliance mismatch between graft and host tissue, and 4) inadequate long-term mechanical strength resulting from insufficient neomatrix deposition by associated cells. We propose to address these limitations by developing a multilayered vascular graft (MLVG) which: 1) allows immediate formation of a stable, luminal cell lining for short- and long-term thromboresistance, 2) incorporates medial and luminal hydrogel layers specifically designed to direct human adipose-derived mesenchymal stem cells (ASCs) toward vascular smooth muscle cell (VSMC) or endothelial cell (EC) fates, respectively, 3) combines these hydrogels with a central electrospun mesh designed for short-term compliance-matching, and 4) includes an electrospun sleeve providing for burst strength, adventitial cell recruitment, and vaso vasorum ingrowth. The proposed studies will focus on developing the proposed medial and luminal hydrogel layers. Towards this end, we will execute the following Specific Aims:
AIM 1 : Identify growth-factor laden, PEG hydrogel formulations inductive of ASC differentiation into VSMC-like phenotypes and medial layer-appropriate extracellular matrix synthesis.
AIM 2 : Identify growth factor-laden, PEG "cement" formulations that promote ASC differentiation into EC-like phenotypes.
Cardiovascular diseases, including coronary artery disease and peripheral arterial disease, affect approximately 1 in 3 Americans and remain the leading cause of mortality in the United States. Tissue engineered vascular grafts (TEVGs) have the potential to replace damaged arteries without the complications associated with autologous or current synthetic grafts. However, the clinical viability of TEVGs has been hampered by: 1) limited endothelialization, 2) the need for cell and/or construct pre-culture, 3) short- and long- term compliance mismatch, and 4) inadequate long-term burst strength. The proposed multilayer graft seeks to address each of these limitations to TEVG success. The present studies focus on initial development of the luminal and medial layers of this multilayer graft.