Degeneration mechanisms and advancements in optimization for preparation and crosslinking strategy of pericardium-based bioprosthetic heart valves.

Valvular heart disease (VHD), clinically manifested as the malfunction of heart valves, greatly threatens public health worldwide. The morbidity and mortality of VHD increase significantly with age, and the high prevalence of VHD in aging society has prompted the urgency for effective treatment. Prosthetic heart valve replacement is currently recognized as the gold standard for VHD treatment. Bioprosthetic heart valves (BHVs), generally manufactured from glutaraldehyde crosslinked xenogeneic tissue, exhibited better hemodynamics and lower thrombogenicity than mechanical heart valves (MHVs) and could be implanted by transcatheter valve replacement systems, which markedly improved the efficiency of VHD therapy, especially for the elderly patients. However, BHVs degenerate within 10-15 years after implantation, which is greatly associated with their defects including cytotoxicity, calcification, immune response, matrix degradation, mechanical damage, and thrombosis. To prolong the service life of BHVs, recent studies have developed a series of innovative modification strategies to improve the biocompatibility, mechanical performance, matrix components stability, anticalcification, and antithrombotic properties of conventional glutaraldehyde crosslinked BHVs. Moreover, a series of new crosslinking and modification strategies have been proposed and developed to fabricate non-glutaraldehyde crosslinked BHVs with good stability, biocompatibility, hemocompatibility, anticalcification property, durability, and hydrodynamics. In this review, we first summarized the defects of BHVs and the related reasons from the perspective of biomaterials, and then comprehensively detailed the functional modification strategies for BHVs based on glutaraldehyde crosslinking. We provided detailed insights into novel non-glutaraldehyde crosslinking and modification strategies for BHVs. Finally, the current challenges and prospects of BHVs were also discussed. STATEMENT OF SIGNIFICANCE: Bioprosthetic heart valves (BHVs) currently face challenges such as cytotoxicity, thrombosis, calcification, and immunoinflammatory responses, which contribute to structural valve degeneration and reduce the longevity of BHVs. This review provides a comprehensive introduction to the detailed defects associated with glutaraldehyde crosslinked BHVs from the perspective of biomaterials. It then thoroughly elaborates on the modification strategies based on glutaraldehyde crosslinking, as well as detailed insights into novel non-glutaraldehyde crosslinking strategies for BHVs. Finally, the challenges and prospects facing BHVs are discussed.