Biomimetic hydrogel strategy inspired by sea cucumbers: Integrating antibacterial, osteoimmune, and osteogenic functions for infected bone repair.

Abstract

Infected bone defects remain a major clinical challenge due to persistent bacterial colonization and chronic inflammation that impair bone regeneration. Chitosan modified with gallic acid (CG) had attracted considerable attention for antibacterial, reactive oxygen species (ROS) scavenging, adhesive and drug-loading capacity. However, its ability to simultaneously balance antibacterial activity, potent immunomodulation, and osteogenesis remains limited. Therefore, inspired by the hierarchical "coelomic matrix-glycoprotein layer-spicule network" of sea cucumbers achieving primary defense, immune regulation, and structural repair, we developed a self-assembling injectable hydrogel (CG/BG/Sa) composed of gallic acid-modified chitosan (CG), sialic acid (Sa), and bioactive glass (BG). The CG matrix mimicked the coelomic matrix, providing a robust antibacterial barrier (>95%), efficient ROS scavenging (91.44%), and sustained Sa release, while exhibiting strong NIR-responsive photothermal conversion that further enhanced bacterial eradication. Released Sa functioned as a glycoprotein-like layer, inducing M2 macrophage polarization (1.62-fold) to remodel the osteoimmune microenvironment and protect stem cells. Meanwhile, BG acted as dispersed spicules, enhancing mechanical stability and releasing Ca²⁺/PO₄^3- ions to promote osteogenic and angiogenic differentiation. In vivo, the photothermal-enhanced antibacterial effect further reduced inflammation and promoted osteogenesis and neovascularization. Mechanistically, CG/BG/Sa upregulated the PPAR signaling pathway while suppressing Toll-like receptor signaling, thereby accelerating bone defect repair (1.80-fold). Collectively, this biomimetic hydrogel integrated antibacterial, immunoregulatory, and osteoinductive activities, offering a promising therapeutic platform for the precise treatment of infectious bone defects.