A pleiotropic SIS-based hydrogel with immunomodulation via NLRP3 inflammasome inhibition for diabetic bone regeneration

Abstract

As a progressive inflammatory disease, diabetes mellitus significantly changes the immuno-microenvironment, causing an elevation in M1 macrophages and inflammatory mediators. This inflammation condition possesses a negative impact on the cellular function of osteoblasts and vascular endothelial cells, resulting in impaired bone defect repair involving both angiogenesis and osteogenesis. In our study, a good biocompatible hydrogel, GB@SIS, was successfully fabricated for bone repair under diabetic conditions. This hydrogel consists of a porcine small intestinal submucosal (SIS) extracellular matrix with thermosensitivity, bionic structure, and pro-angiogenic properties, and BMP-4 loaded on graphene oxide (GO) can be sustainably released from the hydrogel. In vitro studies have shown that the composite hydrogel possesses a good ability to promote angiogenesis and enhance osteogenesis. Additionally, the hydrogel was also able to promote macrophage conversion from M1 to M2 macrophages, which subsequently results in the release of osteogenesis-related factors, specifically BMP-2. In a diabetic rat model with critical-size cranial defects, the GB@SIS hydrogel modulates the inflammatory microenvironment and significantly accelerates the process of bone repair. Subsequent investigations have revealed that the GB@SIS hydrogel exerts immunomodulatory effects via the suppression of the NLRP3 signaling pathway and the elevation of adhesion-related protein expression. In conclusion, the GB@SIS hydrogel demonstrates promising osteogenic characteristics as a biomaterial, exhibiting bone immunomodulatory properties that hold potential for its application in bone regeneration therapy specifically for diabetic patients.