ABSTRACT Thrombosis and inflammation, the primary causes of blood‐contacting medical device failure, are initiated by interfacial biofouling. Although zwitterionic hydrogel coatings represent a promising solution, their clinical translation is hampered by the formidable challenge of simultaneously integrating mechanical robustness, high‐strength substrate adhesion, and exceptional antifouling properties. Herein, we report a bioinspired zwitterionic hydrogel coating that overcomes this hurdle through a design combining microstructural alignment with multi‐site chemical anchoring. The coating leverages cellulose nanocrystals (CNC) to induce an aligned microstructure that enhances antifouling through modulated interfacial hydrodynamics, while providing structural reinforcement for superior mechanical stability. An in situ multi‐site chemical anchoring strategy is developed, enabling the coating to achieve an interfacial adhesion energy exceeding 800 J/m 2 on PVC substrates. Inspired by the vascular endothelium, the microstructure‐aligned zwitterionic hydrogel coating significantly inhibits protein adsorption, platelet adhesion, and bacterial colonization. It retains outstanding stability even after 42 days of PBS shearing, 200 cycles of sandpaper abrasion, and 30 min of high‐speed water flushing. Crucially, the coated PVC prevents biofilm formation and mitigates the foreign body response, while also inhibiting thrombus formation in an anticoagulant‐free ex vivo rabbit circulatory model. This work lays the foundation for designing next‐generation hemocompatible coatings for medical devices.
ZHAO et al. (2026) studied this question.