Multifunctional ROS-responsive bioprosthetic heart valves armored with a puerarin-loaded artificial-plasma hydrogel coating for concurrent thromboresistance and immunomodulation

The advent of minimally invasive transcatheter heart valve replacement has provided a low-risk therapeutic option for valvular heart disease, while driving the escalated clinical demand for bioprosthetic heart valves (BHVs). However, BHVs are susceptible to thrombosis, immunoinflammatory responses, and calcification owing to exposure of the prothrombotic and xenogeneic collagenous matrix and its interactions with the host immune system; these factors collectively accelerate degeneration and severely limit their clinical durability. Herein, a reactive oxygen species (ROS)-responsive artificial-plasma hydroxyethyl starch (HES) layer armored BHV (PUE@HES-GAPP) was constructed. A hydrophilic artificial-plasma coating based on HES was anchored on glutaraldehyde (GA)-crosslinked porcine pericardium substrate via photo-initiated radical polymerization. This artificial-plasma coating serves as a biocompatible physical barrier to shield the thrombogenic collagenous matrix and effectively inhibit platelet aggregation and nonspecific protein adhesion, significantly enhancing the BHVs' hemocompatibility and antithrombotic capacity. Meanwhile, it also served as a scaffold for endothelial cell adhesion and proliferation, improving the endothelialization potential of BHVs. Anti-inflammatory molecule puerarin (PUE) was further loaded onto the artificial-plasma layer surface via dynamic borate ester bonds, thereby achieving the on-demand release of PUE in the inflammatory microenvironment. PUE inhibits the NOD-like receptor, JAK-STAT, and NF-κ B signaling pathways, allowing for precise regulation of the immunoinflammatory responses on BHVs. Subcutaneous implantation experiments in rats confirmed that PUE@HES-GAPP exhibited superior anti-calcification performance at 12 weeks post-implantation. Collectively, the proposed ROS-responsive artificial-plasma modification strategy synergistically enhances the antithrombotic, immunoinflammatory modulation, anti-calcification, and pro-endothelialization properties of BHVs, which provides an innovative material design solution to address the structural degeneration risk of BHVs, holding significant potential for prolonging the lifespan of BHVs. STATEMENT OF SIGNIFICANCE: The clinical durability of BHVs is critically compromised by thrombosis, immunoinflammatory reactions, and pathological calcification, mainly attributed to the interactions between the exposed xenogeneic collagen matrix and the blood. A ROSresponsive artificial-plasma coating was covalently anchored onto the xenogeneic collagen matrix of BHVs to address these challenges. This artificial plasma-based coating serves as a blood-compatible barrier that significantly suppressed calcification, inhibited platelet adhesion and thrombosis, and supported endothelial cell adhesion and proliferation. Puerarin was loaded via ROS-responsive phenylboronic acid ester to achieve microenvironment-responsive on-demand release specifically under inflammatory conditions, thereby locally modulating the immune response and mitigating inflammation. This surface engineering strategy directly targets the key failure mechanisms of BHVs, offering a promising pathway to extend clinical service life of BHVs and pervasive challenges of xenogeneic collagenous vascular biomaterials.