Regulation of the diabetic immune microenvironment by metformin-loaded strontium-doped mesoporous bioactive glass facilitates bone regeneration

Abstract

Chronic inflammation and oxidative stress in the diabetic microenvironment often hinder the healing of bone defects. Metformin (MET), the first-line diabetes medication, was shown to alter macrophage polarization toward an anti-inflammatory M2 phenotype, while simultaneously suppressing excessive reactive oxygen species (ROS) generation. Strontium-doped mesoporous bioactive glasses (SrMBG) also showed promising benefits in promoting bone regeneration. Aiming to improve the diabetic immune microenvironment within bone defects, in this study we loaded SrMBG mesopores with increasing amounts of MET. MET-loaded SrMBG (MET/SrMBG) extracts promoted macrophage differentiation toward the M2 phenotype and reduced ROS production in vitro. The possibility of facilitating osteogenic differentiation of bone marrow stromal cells (BMSCs) in vivo led us to develop 3D-printed MET/SrMBG scaffolds. Experiments utilizing a critical-size calvarium defect model in diabetic rats confirmed that implanting the MET/SrMBG scaffold enhanced bone repair owing to the effects of MET regulating M2 type macrophage polarization and mitigating oxidative stress to improve the inflammatory microenvironment.