An injectable GelMA-CMCS double-network cryogel for enhanced bone regeneration

초록

Minimally invasive bone repair requires injectable scaffolds, yet conventional single-network hydrogels are too soft to provide adequate mechanical support or promote osteogenesis. Achieving both injectability and osteogenic stiffness therefore remains a major challenge. Here, we developed a gelatin methacryloyl (GelMA)–carboxymethyl chitosan (CMCS) double-network (DN) cryogel using a sequential crosslinking strategy: EDC/NHS-mediated amide coupling first established the CMCS network, followed by LAP-initiated UV photo-crosslinking of the GelMA network. The resulting DN cryogels showed increasing Young's modulus with higher CMCS incorporation while maintaining an interconnected macroporous architecture. Despite the increased stiffness, the cryogels remained injectable, rapidly recovered their original shape after needle passage, and protected encapsulated cells during injection. CMCS incorporation further imparted antibacterial and antioxidant activities. The optimized GC2D cryogel exhibited the highest Young's modulus and the lowest degradation rate. Importantly, the DN cryogels were cytocompatible and enhanced osteogenic differentiation of hBMSCs in vitro, with osteogenic gene expression increasing at higher CMCS content. Consistently, the cryogels promoted new bone formation in an in vivo mouse cranial defect model, with GC2D achieving the most substantial regeneration. The GelMA–CMCS DN cryogel thus provides an injectable system for minimally invasive bone tissue engineering. © 2026 Elsevier B.V.

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