A novel multifunctional nanocomposite hydrogel orchestrates the macrophage reprogramming-osteogenesis crosstalk to boost bone defect repair

Repairing bone defects is a complex cascade reaction process, as immune system regulation, vascular growth, and osteogenic differentiation are essential. Thus, developing a tissue-engineered biomaterial that caters to the complex healing process of bone regeneration remains a major clinical challenge. In the study, Ca 2+ -TA-rGO (CTAG)/GelMA hydrogels were synthesized by binding Ca 2+ using metal chelation to graphene oxide (GO) nanosheets reduced by tannic acid (TA-rGO) and doping them into gelatin methacrylate (GelMA) hydrogels. TA and rGO exhibited biocompatibility and immunomodulatory properties in this composite, while Ca 2+ promoted bone formation and angiogenesis. This novel nanocomposite hydrogel demonstrated good mechanical properties, degradability, and conductivity, and it could achieve slow Ca 2+ release during bone regeneration. Both in vitro and in vivo experiments revealed that CTAG/GelMA hydrogel modulated macrophage reprogramming and induced a shift from macrophages to healing-promoting M2 macrophages during the inflammatory phase, promoted vascular neovascularization, and facilitated osteoblast differentiation during bone formation. Moreover, CTAG/GelMA hydrogel could downregulate the NF-κB signaling pathway, offering new insights into regulating macrophage reprogramming-osteogenic crosstalk. Conclusively, this novel multifunctional nanocomposite hydrogel provides a multistage treatment for bone and orchestrates macrophage reprogramming-osteogenic crosstalk to boost bone repair. Graphical Abstract