DECELLULARIZED PERICARDIUM/POLY(PROPYLENE FUMARATE) BIOHYBRID SCAFFOLDS FOR SMALL DIAMETER VASCULAR GRAFTS

Abstract

Coronary artery bypass grafting (CABG) surgeries are a routine treatment for blockages in the coronary arteries. Autologous vessels from the patient are the gold standard of care, but they risk morbidity at the donor site, are restricted by availability, and yield high failure rates. Although commercially available synthetic grafts present an alternative conduit, they are characterized by high failure rates in small diameter vascular grafts, originating from inappropriate mechanical and biological properties. Tissue engineering endeavors have explored a plethora of materials for small diameter vascular grafts (< 6 mm) and have made significant contributions to the field; yet none have been able to provide a clinically feasible approach due to the complexity of native vessels. The work presented here is aimed at the development of a biohybrid vascular graft with spatially controllable, long-term heparin delivery. In the first part of this project, we establish a protocol for the decellularization of membranous tissues. We show that the abbreviated methodology effectively removes cellular content and preserves the extracellular matrix (ECM) in bovine pericardium (BP), with similar results in porcine urinary bladder matrix (UBM), as well. Next, we utilize decellularized bovine pericardium (dECM) and poly(propylene fumarate) (PPF) to construct a biohybrid (dECM+PPF) vascular graft. We demonstrate that the addition of PPF has beneficial impacts on the degradation of dECM. Further, we show that the dECM+PPF vascular graft has similar mechanical behavior to native vessels and supports growth and remodeling in vivo. Finally, we design and implement a heparin-loaded gelatin methacrylate (gelMA) interlayer as a technique for spatial and temporal control of drug delivery. The physical properties of gelMA can be altered with shadow masks during UV crosslinking to elicit unique release profiles. The masks lead to sustained release in dECM+PPF and induce distinct endothelial cell responses. The findings described in this dissertation detail the successful development of a biohybrid vascular graft that contains a spatially and temporally controllable heparin-delivery layer. This work provides an alternative approach for small diameter vascular grafts, as well as a drug delivery method that can be used to improve clinical outcomes in vascular grafts.