Multifunctional Silk Fibroin Hydrogel Incorporated with MgFe-Layered Double Hydroxide-Based MOF Composite for Orchestrating Bone Regeneration

Bone regeneration is a multifaceted process that requires the coordinated interactions among osteoblasts, endothelial cells, and even osteoclasts. Current biomaterials, however, rarely combine the capacity for multicellular modulation with ease of fabrication and high biocompatibility. Herein, a simple strategy of introducing tannic acid (TA) and MgFe layered double hydroxide (MgFe-LDH), as metal-organic frameworks (MOFs), into silk fibroin (SF) hydrogel is developed to construct a highly biocompatible, multi-functional hydrogel (SF/TA/MgFeLDH) system. The MOFs structure not only enhances the mechanical properties but also avoids rapid degradation of conventional SF/TA hydrogel, providing a good match to bone regeneration. More importantly, the SF/TA/MgFeLDH hydrogel system exhibits good promotion of osteogenic differentiation and angiogenesis while simultaneously suppressing the osteoclastic differentiation in vitro, due to the sustained release of bioactive Mg2+ and Fe3+ ions. Mechanistically, bulk RNA sequencing (RNA-seq) revealed that the hydrogel promotes osteogenesis by upregulating endogenous bone morphogenetic protein-2 (BMP2), which subsequently activates the downstream BMP2/SMAD/RUNX2 signaling pathway. Finally, in multiple bone defect animal models, the system exhibits superior vascularized bone regeneration ability compared to SF/TA controls. This study provides a promising biomaterial with potential clinical application for targeting bone regeneration.