Acta Biomater. 2026 Sep 12:S1742-7061(26)00619-7. doi: 10.1016/j.actbio.2026.09.020. Online ahead of print.
ABSTRACT
The growing burden of valvular heart disease has led to increased use of bioprosthetic heart valves (BHVs), yet limited durability remains a major challenge. Although calcification, chronic inflammation and mechanical injury are recognized contributors to BHVs degeneration, their relative contributions and interactions within implanted BHVs remain insufficiently resolved, partly because direct pathological evidence from long-term clinical explants is limited. Here, comparative pathological analysis of long-term failed BHVs and procedurally retrieved non-degenerated valves confirmed pronounced inflammation and reactive oxygen species (ROS) accumulation in the failed leaflets, providing clinically relevant cues for material design. Guided by these findings, we designed a ROS-responsive diclofenac-containing zwitterionic nanogel composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and diclofenac-thioketal acrylate (DTA), and immobilized it onto glutaraldehyde-fixed pericardium (Glut) to construct a multifunctional modified pericardium, termed Glut-MPC-DTA. The nanogel exhibited good colloidal stability in aqueous solution and favorable biocompatibility. Under oxidative conditions, it enabled accelerated ROS-responsive drug release, supporting on-demand anti-inflammatory activity. Compared with Glut, Glut-MPC-DTA improved cytocompatibility and hemocompatibility, reduced platelet, blood-cell and inflammatory-cell adhesion, and markedly inhibited calcification in vivo. It also attenuated inflammatory-cell adhesion and proinflammatory responses in vitro, while suppressing cellular infiltration and proinflammatory responses in vivo. Transcriptomic analysis further revealed a shift toward an immunoregulatory and inflammation-resolving profile, suggesting that effective control of inflammation may alleviate the pro-degenerative interfacial microenvironment and thereby help interrupt the inflammation-driven degenerative cascade, ultimately improving the durability of BHVs. STATEMENT OF SIGNIFICANCE: Bioprosthetic heart valve (BHV) failure remains a major limitation of valve replacement, but many anti-degeneration coatings are designed empirically rather than from the pathology of failed clinical valves. This work is significant because it converts two clinically observed degenerative cues, inflammation and reactive oxygen species (ROS) accumulation, into a disease-responsive biomaterial interface. By integrating a zwitterionic anti-biofouling network with ROS-triggered diclofenac release, the coating is designed to regulate blood/material and cell/material interactions while suppressing the inflammatory microenvironment that promotes calcific degeneration. Beyond improving one valve coating, this study illustrates a pathology-guided design principle for blood-contacting cardiovascular biomaterials: material interfaces can be engineered to sense and counteract local degenerative cues.
PMID:42731800 | DOI:10.1016/j.actbio.2026.09.020