Development of Tissue Engineered Scaffolds for Cardiovascular Repair and Replacement in Pediatric Patients

Congenital Heart Diseases (CHD) are abnormalities present in the heart and great vessels at birth. It is one of the most frequently diagnosed congenital disorders, affecting approximately 40,000 live birth each year in the United States. The incidence of new CHD patients and the relative distribution of defects have not changed over time and remain a birth rate function. Out of the new patients found to have CHD each year, an estimated 2,500 patients have a defect that requires a substitute, non-native valve, or conduit artery to replace structures that are congenitally absent or hypoplastic. Materials in current use for conduit and valve replacement involve varying degrees of stiffness and flexibility, durability, calcification, susceptibility to infection, thrombosis, and a lack of growth potential for the replacement. Biomaterials developed using tissue engineering principles could overcome the limitations encountered with current strategies. This research aims to develop potentially superior valves and conduits using acellular xenograft tissues that are physically cross- linked to protect the Extracellular Matrix (ECM) from rapid degradation. The hypothesis is that such a replacement graft would allow cellular ingrowth of host cells and potentially enable regenerative growth and remodeling of the graft. A decellularization protocol was developed, and the most effective crosslinker protecting the extracellular matrix structure was identified. The decellularized scaffolds crosslinked with Penta galloyl glucose (PGG) were analyzed in-vitro for stability and mechanical properties, in subcutaneous rat and in valve replacement in sheep-models to determine the biocompatibility and functionality of the developed scaffolds. Tissue-engineered scaffolds prepared from decellularized PGG treated tissues were found to have mechanical properties comparable to that of native tissues, while being more resistant to enzymatic degradation. Subcutaneous implantation of scaffolds demonstrated their biocompatibility and superior resistance to calcification compared to currently available glutaraldehyde fixed tissues. The tissue-engineered conduits and valves implanted in large animal models also demonstrated adequate implant functionality, cellular infiltration, implant remodeling, and growth of the implants. PGG treated decellularized xenografts could be an effective replacement option for pediatric patients, reducing the need for reoperations required with current devices