Development of Hybrid Biomaterials For Reconstruction of Cardiovascular Tissue

Abstract

Congenital heart defects in the pediatric population require severe surgery to reconstruct vessels and structures in malformed heart tissue. Reconstructive surgery at an early age leaves many patients with synthetic, non-living and possibly failing grafts that require subsequent surgeries. A biodegradable scaffold can support regeneration of the vascular wall by the patient’s own tissues, and eventually degrade away, leaving a functional and patient maintained tissue in its place. Extracellular matrix (ECM) based scaffolds are uniquely equipped to enhance host cell recruitment and modulate the immune response. Natural healing responses are initiated by native biochemical and physical cues provided by the ECM to endothelial cells and key immune system responders. However, ECM-based scaffolds may degrade rapidly or not possess the elastic strength required for vascular grafts. The work presented here is aimed at the development of a biohybrid scaffold, consisting of the ECM-based material pericardium and synthetic polymers. This combination results in a single material that retains mechanical integrity from the polymer and provides bioactivity from the pericardium matrix. The first aim of this research develops a compliant patch material as a replacement for chemically crosslinked pericardium currently used in surgical applications. Reinforcing pericardium with the polymer PPF creates a mechanically resilient scaffold, with reduced inflammatory markers compared to chemically crosslinked or untreated controls. In addition to cues provided by the matrix molecules of pericardium, the polymer layer can serve as a platform to further facilitate or direct the remodeling by releasing bioactive cargo from the polymer layer to the pericardium matrix. The benefits of the hybrid material are not limited to a layered scaffold, as demonstrated in the second aim. Here, the applicability of the pericardium polymer hybrid is expanded to control shape and mechanical properties in a hydrogel scaffold. In this dissertation, we have successfully developed two distinct hybrid materials that maintain the bioactivity of an ECM-based material to support native cell remodeling, and incorporate control over degradation and magnitude of host response from the polymer. Used as vascular scaffolds, these materials have potential to reduce subsequent surgical intervention by creating a lasting and living vascular patch.