Functional Oxidized Hyaluronic Acid Cross‐Linked Decellularized Heart Valves for Improved Immunomodulation, Anti‐Calcification, and Recellularization

Abstract Tissue engineering heart valves (TEHVs) are expected to address the limitations of mechanical and bioprosthetic valves used in clinical practice. Decellularized heart valve (DHV) is an important scaffold of TEHVs due to its natural three‐dimensional structure and bioactive extracellular matrix, but its mechanical properties and hemocompatibility are impaired. In this study, DHV is cross‐linked with three different molecular weights of oxidized hyaluronic acid (OHA) by a Schiff base reaction and presented enhanced stability and hemocompatibility, which could be mediated by the molecular weight of OHA. Notably, DHV cross‐linked with middle‐ and high‐molecular‐weight OHA could drive the macrophage polarization toward the M2 phenotype in vitro. Moreover, DHV cross‐linked with middle‐molecular‐weight OHA scaffolds are further modified with RGD‐PHSRN peptide (RPF‐OHA/DHV) to block the residual aldehyde groups of the unreacted OHA. The results show that RPF‐OHA/DHV not only exhibits anti‐calcification properties, but also facilitates endothelial cell adhesion and proliferation in vitro. Furthermore, RPF‐OHA/DHV shows excellent performance under an in vivo hemodynamic environment with favorable recellularization and immune regulation without calcification. The optimistic results demonstrate that OHA with different molecular weights has different cross‐linking effects on DHV and that RPF‐OHA/DHV scaffold with enhanced immune regulation, anti‐calcification, and recellularization properties for clinical transformation.