Osteoimmunity-regulating nanosilicate-reinforced hydrogels for enhancing osseointegration.

Following the introduction of osteo-immunomodulation as a new and important strategy to enhance material osseointegration, achieving an appropriate immune response after biomaterial implantation has become a significant challenge for efficient bone repair. In this study, a nanosilicate-reinforced sodium alginate (SA) hydrogel was fabricated by introducing montmorillonite (MMT) nanoparticles. Meanwhile, an immunogenically bioactive agent, harmine (HM), was loaded and released to induce macrophage differentiation into the M2 type. The fabricated SA/MMT/HM (SMH) hydrogel exhibited improved mechanical stiffness and stability, which also efficiently promoted macrophage anti-inflammatory M2 phenotype polarization and enhanced the secretion of pro-tissue healing cytokines for inducing a favorable immunomodulatory microenvironment for the osteogenic differentiation of bone marrow stromal cells (BMSCs). Furthermore, a rat air-pouch model and a critical-size bone defect model were used and the results showed that the SMH hydrogel increased the proportion of M2 macrophages and markedly reduced local inflammation, while enhancing desirable new bone formation. Transcriptomic analysis revealed that the SMH hydrogel accelerated the M1-to-M2 transition of macrophages by inhibiting relevant inflammatory signaling pathways and activating the PI3K-AKT1 signaling pathway. Taken together, this high-intensity immunomodulatory hydrogel may be a promising biomaterial for bone regeneration and provide a valuable base and positive enlightenment for massive bone defect repair.