Delivery of Interleukin 4 from a Titanium Substrate Coated with Graphene Oxide for Enhanced Osseointegration by Regulating Macrophage Polarization

Macrophage-related inflammation has been identified as a possible predictor of the success or failure of implants based on their polarization of the pro-inflammatory/anti-inflammatory (M1/M2) phenotype. The purpose of this study was to deliver interleukin 4 (IL-4, a cytokine that triggers M2 polarization of macrophages) from a titanium substrate by a graphene oxide (GO) coating to regulate the macrophage-related inflammatory response and improve the implant performance. The GO/IL-4 coating showed good biocompatibility and promoted macrophages polarization to the M2 phenotype in vitro. Conditioned media from macrophages cultured on a GO/IL-4 surface promoted the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). As the inflammatory response at the interface of GO/IL-4 weakened, the percentage of M2-polarized macrophages increased and the best stability, bone-implant contact, and osteogenesis were observed in vivo. These results demonstrate that the macrophage-related inflammatory response plays a crucial role in osteogenesis around implants and that this GO/IL-4 coating provides an effective strategy for promoting implant osseointegration by regulating immune function.