Induction of M2‐Type Macrophage Differentiation for Bone Defect Repair via an Interpenetration Network Hydrogel with a GO‐Based Controlled Release System

Abstract

Recently, biomaterials with immune-regulating properties have emerged as crucial new platforms for bone tissue engineering. Inducing macrophages to differentiate into M2 subtype can reduce immune inflammatory response and accelerate tissue repair after implantation. An interpenetration network hydrogel is developed utilizing graphene oxide (GO)-carboxymethyl chitosan (CMC)/poly(ethylene glycol) diacrylate (PEGDA), in which two bioactive molecules, interleukin-4 (IL-4) and bone morphogenetic protein-2 (BMP-2), are loaded and released in a controlled manner to induce macrophages to differentiate into M2 type and enhance bone formation. These two factors are initially loaded with GO and then embedded into the CMC/PEGDA hydrogel for sustained release. Results indicate that the hydrogel shows enhanced mechanical stiffness, strength, and stability. The hydrogel loaded with IL-4 and BMP-2 significantly promotes both macrophage M2-type differentiation and bone marrow mesenchymal stem cell osteogenesis differentiation in vitro. Furthermore, in vivo studies show that the implantation of this hydrogel markedly reduces local inflammation while enhancing bone regeneration at 8 weeks post-implantation. In all, the findings suggest that hydrogel loaded with IL-4 and BMP-2 has synergistic effects on bone regeneration. Such an induction and immunomodulation system offers a promising strategy for the development of future bone immune regulation and tissue engineering applications.