A multi-in-one strategy with glucose-triggered long-term antithrombogenicity and sequentially enhanced endothelialization for biological valve leaflets

Abstract

Bioprosthetic heart valves are commonly applied in heart valve replacement, while the effectiveness is limited by inflammation, calcification and especially thrombosis. Surface modification is expected to endow the biological valves with versatility. Herein, a multi-in-one strategy was established to modify biological valves with long-term antithrombogenicity and sequentially enhanced endothelialization triggered by glucose, in which the direct thrombin inhibitor rivaroxaban (RIVA)-loaded nanogels were embedded and the detachable polyethylene glycol (PEG) was grafted. These two anticoagulant strategies were connected by glucose oxidase (GOx), which catalyzed the oxidation of glucose to produce hydrogen peroxide (H2O2) and local acidic environment. The generated H2O2 stimulated H2O2-responsive nanogels release RIVA to obtain continuous antithrombogenicity. Meanwhile, PEG was attached to the surface via pH-sensitive bonds, which prevented thrombus formation by resisting the serum proteins and platelets adhesion at the initial stage of material/blood contact. Sequentially, PEG gradually peeled off under the local weak acidic environment, which ultimately resulted in the endothelialization enhancement. Within such multi-in-one strategy, the biological valve leaflets induced long-term anticoagulant performance, gradually enhanced endothelialization and improved tissue affinity, including anti-calcification and anti-inflammation, indicating the potential of the response sequence matching between materials and tissues after implantation, which might improve performance of biological heart valves.