Metabolic small molecules materialized hydrogel promotes diabetic bone regeneration through osteoimmunological remodeling

The clinical repair of diabetic jawbone defects is still yet challenging because of chronic inflammation and dysregulation in metabolism. Metabolic small molecule alpha-ketoglutarate (αKG) and D-mannose displayed promising bone homeostasis rebalance and inflammatory suppression properties respectively. However, traditional oral administrated greatly limits their bioavailability. To rescue the bone regeneration suppression from diabetic conditions, a bioactive hydrogel (GelhMSS) was developed with αKG loaded in degradable spiky mesoporous silica nanoparticles and D-mannose conjugated in the hydrogel network. Owning to the special spiky architecture of this nano-vehicle, the high-efficiently internalized and subsequently released αKG metabolically regulated multiple cellular processes and remarkably rescued the osteogenic differentiation of BMSCs under diabetic conditions. Simultaneously, the conjugated mannose specifically binds with its receptors on the membrane of macrophages and thereafter induces the polarization of macrophages and reprograms the diabetic immune-microenvironment. Moreover, the resulting GelhMSS hydrogel could also synchronously orchestrate the crosstalk between BMSCs and macrophages, resulting in the upregulation of IGF-1 and FAM20C in macrophages and the reactivation of suppressed TGF-β1-pSmad pathway in BMSCs. The diabetic defect bone repairing regulated by GelhMSS hydrogel was further evaluated in vivo experiment. All the results suggest the conspicuous effects of αKG and mannose functionalized hydrogel on bone homeostasis remodeling and immune microenvironment reprograming.