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.

Graphene oxide-modified silk fibroin/nanohydroxyapatite scaffold loaded with urine-derived stem cells for immunomodulation and bone regeneration

“…The scaffolds without GO were labeled “control,” the GO-free scaffolds loaded with 1.5 × 10 5 USCs were labeled “U,” the scaffolds containing 0.1% GO were labeled “GO,” and the scaffolds containing 0.1% GO loaded with 1.5 × 10 5 USCs were labeled “GO+U.” Rat peritoneal macrophages were used in this study because of the low immunogenicity of USCs. The macrophages were identified and provided by Dr. Min Zou [ 43 ]. Macrophages numbering 2 × 10 5 were seeded in the lower chamber of a 24-well Transwell plate (0.4 μm, Corning, USA) in macrophage culture medium.…”

Supramolecular Peptide Nanofiber Hydrogels for Bone Tissue Engineering: From Multihierarchical Fabrications to Comprehensive Applications

“…For example, IL‐4 is a well‐characterized cytokine that could activate M2 phenotypes, and it was first loaded on graphene oxide (GO) coupled with BMP‐2 for controlled release. [ 214 ] Then, both factors were embedded in carboxymethyl chitosan/PEG diacrylate hybrid hydrogels, and the results demonstrated that the hydrogel encapsulated with IL‐4 and BMP‐2 could induce M2 macrophage polarization and the osteogenic differentiation of MSCs in vitro, and reduce inflammation with enhanced bone neoformation in vivo. [ 214 ] Besides, rosiglitazone is also an immunoregulator with the ability to promote M2 phenotypes, which has been used for bone regeneration.…”

“…IPN involves constructing multinetwork hydrogels which are characterized by fully or partially interfaced networks. [ 214 ] PEG is one of the most commonly used biomaterials that could provide precise mechanical control with good resistance to proteolysis. Goktas et al.…”

Novel insights into nanomaterials for immunomodulatory bone regeneration

“…NMs can play as a modulator to control immune response directly through their components, structures or indirectly as integrated carriers of bioactive molecules. In particular, recent studies have indicated that engineered NMs possess great ability to control the polarization direction of macrophages and promote the osteogenic of MSCs, which may be a promising candidate for immunomodulatory bone regeneration [109].…”