Microfluidic GelMA/Bone-Derived Extracellular Matrix Microgels for Enhanced Stem Cell-Based Bone Regeneration

Critical-sized bone defects caused by trauma or surgery exceed the innate regenerative capacity of bone, posing significant clinical challenges. Tissue engineering strategies based on injectable hydrogels and mesenchymal stem cells (MSCs) offer promise due to their adaptability to irregular defects. However, most current systems lack modular regenerative architecture and hierarchical biochemical cues needed to mimic native bone microenvironments, thereby limiting regenerative efficacy. In this study, we engineered modular, cell-laden microgels composed of bone-derived decellularized extracellular matrix (BdECM) precisely integrated into gelatin methacrylate/polyethylene glycol diacrylate (GelMA/PEGDA) hydrogel networks (P-GE) to facilitate regeneration of critical-sized bone defects. Leveraging microfluidic encapsulation combined with ultraviolet-induced cross-linking, these P-GE microgels exhibited consistent structural integrity, tunable and excellent injectability, which showed robust proliferation and osteogenic differentiation of encapsulated rat bone marrow mesenchymal stem cells (BMSCs) in vitro. In vivo implantation of cell laden P-GE microgels achieved near-complete calvarial repair accompanied by significant collagen and osteopontin deposition. Moreover, microgels established a favorable microenvironment and sufficient space for sustained cell infiltration, proliferation, and osteogenic differentiation, thereby facilitating efficient bone regeneration. As an advanced biomimetic strategy, BdECM-based cell-laden microgels offer a structurally and biologically optimized platform for bone tissue engineering.