Using chondroitin sulfate lithium hydrogel for diabetic bone regeneration via regulation of macrophage polarization

Bone regeneration in a diabetic environment remains a clinical challenge because of the proinflammatory microenvironment and malfunction of osteogenesis. Traditional therapy for bone defects doesn't work out in diabetes. Therefore, we introduced lithium (Li) into chondroitin sulfate (CS) and developed a crosslinked hydrogel composed of gelatin methacryloyl (GelMA) and chondroitin sulfate lithium (CS-Li) which could release Li in a sustained manner. This crosslinked hydrogel has a porous microstructure, excellent biocompatibility, and osteogenesis properties. With the synergetic effects of CS and Li, this crosslinked hydrogel regulates macrophage polarization to anti-inflammatory phenotype in the high glucose microenvironment and alleviates the inhibition of angiogenesis and osteogenesis caused by diabetes both in vitro and in vivo. The relationship between macrophage polarization and the promotion of angiogenesis and osteogenesis in diabetic microenvironments may be attributed to the activation of Glycogen synthase kinase-3β/β-catenin pathways. Overall, significant results in this study present that CS-Li was a potential therapy for bone defects in diabetic patients.