Fetal Cardiac Extracellular Matrix Incorporated Into Silk Scaffolds Leads to Beneficial Cardiovascular Patch Remodeling in a Large Animal Model of <scp>RVOT</scp> Surgical Repair

Approximately 50% of patients that undergo surgical reconstruction to repair the congenital heart defect tetralogy of Fallot (ToF) experience adverse effects by the age of 50. These effects can be linked to the poor healing response elicited by the synthetic materials in the commonly used cardiovascular patches. Extracellular matrix (ECM) biomaterial-based therapies, on the other hand, have been shown to elicit positive healing responses in various tissues and pathologies, including those in the heart. Few studies, however, have been directed towards the development of an ECM-based cardiovascular patch that can realistically fill the voids in tissue present in ToF patients. Furthermore, cardiac ECM is typically derived from adult sources, despite knowledge that only fetal and neonatal rodents can fully regenerate functional cardiac tissue. Here, we demonstrate the widening of the RVOT in young porcine with a novel cardiovascular patch fabricated from fetal cardiac ECM and silk fibroin (cECM-silk). Histological analyses show our fetal cECM-silk patches improve patch-tissue integration and patch degradation compared to a clinical-standard GORE ACUSEAL cardiovascular patch, as a representative of expanded polytetrafluoroethylene (ePTFE)-based material. Our fetal cardiac ECM-silk patches also improve vascularization in and around the patch and reduce the detrimental fibrotic response typically seen with the GORE ACUSEAL patches. Finally, the culture of activated cardiac fibroblasts in vitro showed analogous reduction in fibroblast activation when treated with solubilized fetal cECM. Our results suggest that fetal cECM is a potential alternative cardiovascular patch material that enables improved healing responses over synthetic materials post-surgical repair of ToF and other CHDs.