Spontaneous immunomodulation and regulation of angiogenesis and osteogenesis by Sr/Cu-borosilicate glass (BSG) bone cement to repair critical bone defects

Injectable bone biomaterials like bone cement should be designed and fabricated with certain biological criteria,which include:1)recruitment and polarization of the macrophages from M1(pro-inflammatory)to M2(anti-inflammatory)phenotype,2)enhance vascularization,and 3)activate osteogenic differentiation of bone marrow-derived stem cells to promote bone healing.So far,no injectable biomaterials could spontaneously regulate the entire bone healing process that involves inflammation,angiogenesis,and osteogenesis.Therefore,in this study,we designed bone cement comprised of strontium and copper-incorporated borosilicate glass(Sr/Cu-BSG)in the liquid phase of chitosan to modulate bone healing.In vitro studies showed that the controlled release of Sr and Cu ions up-regulated anti-inflammatory genes(IL-1Ra and TGF-β1)while down-regulating pro-inflammatory genes(IL-1βand IL-6)in macrophages at 3 days.Sr and Cu ions also increased the expressions of angiogenic genes(VEGF and bFGF)in HUVECs at 5 days and osteogenic genes(Runx-2,OCN,and OPN)in hBMSCs at 7,14,and 21 days.5Sr3Cu-BSG bone cement exhibited the best anti-inflammatory,angiogenic,and osteogenic properties among the bone cement groups with different Sr and Cu ratios.Short-term and long-term implantation of Sr/Cu-BSGs in femoral condylar bone defects of rats and rabbits confirmed the in vitro results,where the degradation rate of Sr/Cu-BSG matched the bone healing rate.Similar to in vitro,the 5Sr3Cu-BSG group also showed the highest bone formation in vivo.Excellent physical and chemical properties,along with its bone repairing ability,make the Sr/Cu-BSG bone cement a good candidate biomaterial for treating bone defects.