Endothelial function-biomimetic hydrogel-surface engineered non-glutaraldehyde bioprosthetic valve with antithrombotic, immunomodulatory and pro-endothelialization performance

The progress of transcatheter valve replacement has significantly reduced the risk of valve replacement, increasing the demand for bioprosthetic heart valves (BHVs). Currently, the defects of BHVs, including thrombosis, poor endothelialization, calcification, and immune responses that are associated with glutaraldehyde crosslinking and their xenogeneic collagenous matrix, have accelerated the degeneration of BHVs. Herein, we constructed an endothelial function biomimetic hydrogel surface engineered non-glutaraldehyde BHV based on bioinspired catechol-crosslinking system and metal-chelation. An endothelial glycocalyx-like layer was anchored on BHV through the bioinspired oxidative coupling of catecholic porcine pericardium and alginate to mimic the endothelial glycocalyx on the inner wall of blood vessels, by which we also simultaneously achieved the crosslinking of BHV and the enrichment of bioactive catechols on BHV. Furthermore, the copper ions were introduced through chelation with alginate and catechol to impart glutathione peroxidase (GPx)-like functionality to BHVs, which mimicked the nitroxide (NO) generation performance of endothelium. The engineered BHV not only resisted the thrombosis, alleviated oxidative stress and modulated the immune responses but also facilitated the endothelialization. Moreover, the calcification of the BHVs was also significantly reduced in rat subcutaneous model. Altogether, this work presents significant potential to prolong the service life of BHVs.

Statement of Significance

Bioprosthetic heart valves (BHVs) are prone to degeneration due to thrombosis, poor endothelialization, calcification, and immune responses which are closely associated with the defects of glutaraldehyde crosslinking and their xenogeneic collagenous matrix. Based on catechol cross-linking and metal-phenol chemistry, we engineered a non-glutaraldehyde BHV with an endothelial function biomimetic hydrogel surface to prevent thrombosis, reduce calcification, and enhance endothelialization and immunomodulation. The endothelial function biomimetic hydrogel surface resists blood fouling and thrombosis, forming a catechol-rich entity to alleviate oxidative stress and modulate immune responses. The incorporation of copper ions confers GPx-like functionality, mimicking endothelial nitric oxide generation and facilitating the endothelialization. This work holds potential to extend the lifespan of BHVs and presents a promising candidate for the next generation of multi-functional BHVs.