4-Octyl itaconate modified demineralized bone matrix scaffold improves bone repair by regulating early inflammation

Macrophages are involved in the early inflammation during tissue repair and play a distinctive role in maintaining the stability of the tissue microenvironment. However, it is still very difficult to accurately regulate the phenotypic transformation of macrophages during bone repair. The current study innovatively used 4-octyl itaconate (OI), a cell-permeable derivative of an endogenous anti-inflammatory metabolite itaconate (IA), to regulate the polarization of macrophages and enhance the quality of bone repair. Chitosan (CS) was selected as a bridge in coating OI on demineralized bone matrix (DBM) scaffold to generate three-dimensional (3D) bone integration scaffold (OI/CS/DBM scaffold). Whether this metabolite derivative can exert the same anti-inflammatory effect as the metabolite itself was validated both in vitro and in vivo. In vitro cellular results showed that both OI and OI/CS/DBM scaffold could promote the formation of anti-inflammatory phenotype of macrophages, and the osteogenic differentiation of mesenchymal stem cells (MSCs) was indirectly enhanced by macrophage supernatant medium. In vivo studies of a rat skull defect model further proved that the OI/CS/DBM scaffold could improve the bone integration. In this study, the OI/CS/DBM scaffold was successfully fabricated as a vehicle for delivering OI, which was proved to have the ability to promote bone integration by regulating early inflammation. The present results may provide a novel method to improve bone repair with metabolites derivative to regulate the inflammation.