Engineering of bioprosthetic heart valves with synergistic zwitterionic surface modification and zirconium cross-linking for improved biocompatibility and durability.

Bioprosthetic heart valves (BHVs) are frequently utilized in surgeries for heart valve replacement to address valvular heart disease (VHD). Despite their widespread use, BHVs still face challenges in clinical applications, such as thrombosis, calcification, immune responses, poor re-endothelialization, infection, component degradation, and mechanical failure, which are largely due to the heterogeneous cross-linking effects. To address these issues, we propose a synergistic engineering strategy based on sequential zwitterionic surface modification and zirconium cross-linking to improve the biocompatibility and durability of BHVs. After surface modification via ring-opening reactions of zwitterionic epoxy copolymers (PGSB) on collagen fibers of decellularized porcine pericardium (D-PP), the zwitterionic PGSB significantly promoted the uniform transfer of zirconium ions (Zr⁴⁺) and further coordinated with Zr⁴⁺ to achieve homogeneous cross-linking between collagen fibers. Compared to conventional glutaraldehyde (GA)-cross-linked PP, PGSB/Zr-PP showed enhanced anti-thrombotic performance, attenuated immune rejection, accelerated endothelialization, and over 95 % reduction in calcification after 90 days of subcutaneous implantation, collectively indicating improved biocompatibility. Furthermore, this homogeneously cross-linked PGSB/Zr-PP exhibited undetectable component degradation and simultaneous improvements in both strength and toughness, all of which are essential for improving the durability of BHVs. Intriguingly, the zwitterionic sulfobetaine groups could be converted into bactericidal quaternary ammonium groups upon coordination with Zr⁴⁺, resulting in strong antibacterial and anti-biofilm activities beneficial for preventing life-threatening prosthetic valve endocarditis. More importantly, PGSB/Zr-PP met the ISO 5840-3 standards required for BHV applications in terms of hydrodynamic performance and 200-million-cycle durability. These results demonstrate that PGSB/Zr-PP would be a promising alternative to GA-cross-linked BHVs. STATEMENT OF SIGNIFICANCE: Mainstream glutaraldehyde-cross-linked BHV face persistent clinical challenges, including thrombosis, calcification, immune response, poor re-endothelialization, infection, component degradation, and mechanical failure. Although various non-glutaraldehyde cross-linkers have been investigated, few strategies effectively address these challenges due to the heterogeneous nature of cross-linking. Herein, we present a synergistic engineering strategy based on sequential zwitterionic surface modification and zirconium cross-linking. This strategy produces homogeneously cross-linked BHVs with comprehensive improvements in anti-thrombogenicity, immune compatibility, endothelialization, resistance to calcification and infection, enzymatic stability, and mechanical strength. Notably, the aortic BHV fabricated via this method met the ISO 5840-3 standards for hydrodynamic performance and durability, demonstrating its long-term clinical potential.