Sustainable Collagen-Based Hydrogel Integrated with Bioactive Glass for Minimally Invasive, Growth Factor-Free Immunomodulatory Maxillofacial Bone Regeneration.

Regenerating complex oral and maxillofacial bone defects is challenging due to irregular anatomy and limitations of conventional grafts, including donor morbidity, infection risks, and invasiveness. Natural hydrogels often lack mechanical strength and osteoinductivity, while growth factor-based approaches suffer from instability, high costs, and complexity. Herein, a novel injectable thermosensitive nanocomposite hydrogel is developed by integrating tilapia-derived type I collagen, chitosan, and zinc-doped mesoporous bioactive glass nanoparticles (Zn-MBGNs), crosslinked via genipin. This sustainable composite exhibits favorable thermoresponsiveness, shear-thinning injectability, porous structure, enhanced mechanical properties, controlled degradation, and superior biocompatibility. It demonstrates dual biofunctionality: immunomodulation by repolarizing LPS-stimulated M1 macrophages toward an anti-inflammatory M2 phenotype and promoted osteogenesis in bone marrow mesenchymal stem cells. In vivo, the hydrogel significantly accelerates repair of critical-sized calvarial bone defects in rats, as evidenced by micro-CT, histological, and immunofluorescence analyses showing enhanced vascularization and osteogenic markers. This multifunctional platform introduces a dual-pathway mechanism, direct Zn2 +-mediated osteogenesis combined with indirect macrophage polarization, for efficient bone regeneration, offering a minimally invasive, growth factor-free strategy with high translational potential for maxillofacial reconstruction.