Multifunctional Biomimetic Hematoma Microspheres for Sustained Local Hydrogen Sulfide (H 2 S) Delivery to Enhance Vascularized Bone Regeneration

ABSTRACT While conventional large bone defect healing is a complicated process with multiple physiological limitations, our approach leverages hematoma's innate regenerative capabilities‐particularly its structure and biological functions, inculding multi‐functional regulation response, activating cell autophagy, resisting persistent inflammation and enhancing angiogenesis/osteogenesis eventually, which supports a new strategy to bone repair solutions. This biomimetic strategy is more compatible with the process of bone regeneration, thereby shifting the implant paradigm from passive structural support to active biological regulation. Inspired by the balloon structure, we developed microfluidic biomimetic hematoma microspheres featuring: pH‐responsive GelMA outer layer and NaHS‐loaded liposomal core. This dual‐component system spatiotemporally releases H 2 S in acidic bone defects, simultaneously decreasing chronic inflammation, promoting angiogenesis, activating autophagy and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC). ‌This biomimetic strategy recapitulates key hematoma‐mediated osteogenic processes, where controlled H 2 S release orchestrates the interplay of angiogenesis, inflammation resolution, cell autophagy and osteogenesis.