Melatonin and calcium phosphate crystal-loaded poly(<sc>l</sc>-lactic acid) porous microspheres reprogram macrophages to improve bone repair

The bone immune microenvironment can influence the occurrence and progression of bone defects. To date, research on promoting macrophage M2 polarization to improve bone injury repair has been insufficient. In this study, we designed an injectable poly(l-lactic acid) (PLLA) porous microsphere that forms calcium phosphate crystals on its surface by binding to melatonin, followed by bionanomimetic mineralization in vitro. The microsphere is injectable and degradable, and its release of melatonin (MT) and calcium phosphate (CaP) crystals promotes macrophage M2 polarization, reprogramming of macrophages, and enhanced osteogenesis. After LPS stimulation, the proportion of M2-polarized macrophages in the MS@CaP@MT group was 39.2 +/- 2.7%, significantly higher than that in other groups (P < 0.05). Further, in the MS@CaP@MT group, rats exhibited bone mineral densities of 129.4 +/- 12.8 mg cc(-1) at 2 weeks and 171.6 +/- 13.6 mg cc(-1) at 4 weeks in the defect area, which were significantly higher than those in other groups (P < 0.05). Using an animal model of femoral condylar defects, we demonstrated that MT PLLA porous microspheres loaded with calcium phosphate crystals can improve the immune microenvironment and form a microsphere-centered osteogenesis model. This significantly accelerates bone defect repair and provides a potential strategy for bone defect treatment.<br />