A nitric oxide-releasing zwitterionic glycocalyx-mimetic hydrogel armored bioprosthetic valve with integrated antithrombotic, endothelialization-promoting, and immunomodulatory capacities.

Abstract

The global prevalence of heart valve disease (HVD) is currently increasing with the population ages, and heart valve replacement surgery is considered as the definitive treatment for HVD. Bioprosthetic heart valves (BHVs) are widely implanted with the development of transcatheter heart valve replacement. Nonetheless, BHVs are prone to degeneration within 10-15 years due to the inherent drawbacks including thrombosis, poor endothelialization, inflammation, and calcification. Herein, a nitric oxide-releasing zwitterionic glycocalyx-mimetic hydrogel armored bioprosthetic valve (AHS-P) was engineered. Zwitterionic glycocalyx-mimetic hydrogel surface was uniformly welded on the BHV by photo-induced polymerization, which markedly enhanced the hydrophilicity and biocompatibility of BHV, effectively resisting the adhesion of plasma proteins and platelets, and inhibiting thrombosis. With the introduction of l-arginine on glycocalyx-mimetic hydrogel, nitric oxide (NO) was intracellularly generated from the dynamically released l-Arg by the NOS to regulate the immune responses, and the growth and adhesion of endothelial cells (HUVECs) was also facilitated by activating the RhoA-ROCK and PI3K/AKT/mTOR signaling pathways. The immune-inflammatory reactions on AHS-P were also modulated, with downregulated TNF-α and M1 macrophages and upregulated IL-10 and M2 macrophages, creating an immune-balancing microenvironment for enhanced biocompatibility. Furthermore, rat subcutaneous implantation showed that the calcification degree of AHS-P was markedly reduced. Collectively, the engineered BHV (AHS-P) demonstrated enhanced antithrombosis, anticalcification, endothelialization and immunoregulation performances, offering a new way to extend the service life of BHVs. STATEMENT OF SIGNIFICANCE: This work developed a nitric oxide-releasing zwitterionic glycocalyx-mimetic hydrogel-coated BHV to overcome key limitations such as thrombosis, poor endothelialization, inflammation, and calcification-issues associated with the cytotoxic xenogeneic collagenous matrix of BHVs. Zwitterionic glycocalyx-mimetic hydrogel was welded on BHVs to shield the matrix, resist the thrombosis and calcification, and serve as the scaffold for endothelialization. l-Arg was then incorporated to enable NO release, promoting endothelial cell adhesion and growth via RhoA-ROCK and PI3K/AKT/mTOR pathway activation. The immune-inflammatory reactions on BHVs were also downregulated. This work synergistically improved the antithrombosis, anticalcification, endothelialization and immunoregulation performances of BHVs, offering a promising strategy to extend BHV longevity.