Poly(lactic-co-glycolic) acid porous microspheres for the sequential delivery of apoptotic vesicles and strontium in maxillofacial bone regeneration

• ApoVs and Sr were incorporated into PLGA porous microspheres for biological and chemical agents delivery sequentially. • ApoVs recruit endogenous stem cells via the HIF-1α/SDF-1 axis, followed by Sr-mediated long-term osteogenesis for bone regeneration . • The sequential release platform provides a novel strategy for the clinical treatment of maxillofacial bone defects . Maxillofacial bone defects , whether caused by disease or trauma, are a common clinical condition, but their effective treatment continues to pose significant challenges. Although tissue engineering offers a promising strategy for addressing bone defects, difficulties remain in achieving the tailored release of bioactive factors and mitigating potential risks associated with stem cells. In this study, strontium (Sr) and human bone marrow mesenchymal stem cell (hBMMSC)-derived apoptotic vesicles (apoVs) incorporated into poly(lactic-co-glycolic) acid (PLGA) porous microspheres (PMs) via biomineralisation and electrostatic interactions were applied to repair maxillofacial bone defects. The initial rapid release of apoVs was followed by the sustained release of Sr over 90 days. The PLGA hybrid PMs @ ApoVs were assessed in vitro for their cytotoxicity, migration, and osteogenic effects, and their superior bone regeneration effect was validated in rat cranial defects in vivo . The enhanced bone regeneration was attributed to the initial induction of the HIF-1α/SDF-1 axis by apoVs, which facilitated the recruitment of endogenous stem cells, along with the subsequent long-term sustained release of strontium ions (Sr 2+ ). In summary, osteogenic PLGA hybrid PMs @ ApoVs with simultaneous chemical (Sr) and biological (extracellular vesicles) decoration and sequential delivery represent an innovative strategy for the clinical treatment of maxillofacial bone defects.