Advances in oxygen microenvironment-modulating hydrogel systems for bone regeneration

Bone defect repair is often accompanied by inadequate vascularization and persistent hypoxia, which restrict cell survival, hinder angiogenesis, and ultimately impair osteogenesis, thereby posing a major challenge to effective bone regeneration. To overcome these limitations, hydrogel systems designed to modulate the local oxygen microenvironment have attracted increasing attention in bone tissue engineering. Owing to their favorable biocompatibility, injectability, and three-dimensional network architectures, these systems incorporate peroxide-based oxygen generators, perfluorocarbon oxygen carriers, and enzyme- or nanozyme-mediated oxygen-producing modules, enabling controlled, sustained, or microenvironment-responsive oxygen release while partially mitigating oxidative stress. This review summarizes recent advances in oxygen-releasing hydrogels, with an emphasis on hydrogel matrix selection, oxygen sources and loading strategies, and the regulation of oxygen release kinetics. The biological mechanisms underlying their pro-regenerative effects are further discussed, including the alleviation of local hypoxia, promotion of angiogenesis and osteogenic differentiation, and modulation of inflammatory responses and the immune microenvironment. Experimental evidence indicates that these hydrogel systems can substantially improve the quality of newly formed bone and enhance repair efficiency in calvarial and other small-animal bone defect models. Importantly, emerging studies suggest that successful bone regeneration depends not simply on increasing oxygen availability, but on achieving an appropriate balance among oxygen release intensity, duration, and the stage-specific requirements of bone repair. Future work should therefore prioritize quantitative control of oxygen release kinetics, long-term biosafety, and stability in complex pathological microenvironments to advance clinical translation.