Microsphere Strategy to Generate Conformal Bone Organoid Units with Osteoimmunomodulation and Sustainable Oxygen Supply for Bone Regeneration

Repairing large bone defects remains a major challenge, as current strategies-including autografts, allografts, and tissue-engineered scaffolds-are limited by donor shortage, suboptimal biocompatibility, and insufficient control of the regenerative microenvironment. Bone organoids offer a promising strategy by simulating bone tissue functions and microenvironments in vitro, showing great potential for bone repair. However, current bone organoids still face issues such as insufficient oxygen supply, and limited immune modulation, reducing their effectiveness for complex bone defect repair, especially when precise shape conformity is required. To address these challenges, bone organoid unit based on silk hydrogel microspheres is developed, introducing oxygen-releasing components and immune cells to better mimic the bone repair environment and enable conformal filling of irregular defects. In vitro, the system formed bone organoid units through 28 days culture that sustained cell viability, promoted M2 macrophage polarization, and enhanced osteogenesis and angiogenesis. In a critical-sized mouse cranial defect model, this strategy outperformed traditional approaches, showing superior bone regeneration and tissue integration. These findings indicate that the strategy effectively addresses key obstacles in bone repair, such as oxygen supply, immune modulation, and shape conformity, providing a promising solution for personalized bone regeneration.