Three Birds, One Stone: An Osteo‐Microenvironment Stage‐Regulative Scaffold for Bone Defect Repair through Modulating Early Osteo‐Immunomodulation, Middle Neovascularization, and Later Osteogenesis

In order to repair critical‐sized bone defects, various polylactic acid‐glycolic acid (PLGA)‐based hybrid scaffolds are successfully developed as bone substitutes. However, the byproducts of these PLGA‐based scaffolds are known to acidify the implanted site, inducing tiresome acidic inflammation. Moreover, these degradation productions cannot offer an osteo‐friendly microenvironment at the implanted site, matching natural bone healing. Herein, inspired by bone microenvironment atlas of natural bone‐healing process, an osteo‐microenvironment stage‐regulative scaffold (P80/D10/M10) is fabricated by incorporating self‐developed decellularized bone matrix microparticles (DBM‐MPs) and multifunctional magnesium hydroxide nanoparticles (MH‐NPs) into PLGA with an optimized proportion using low‐temperature rapid prototyping (LT‐RP) 3D‐printing technology. The cell experiments show that this P80/D10/M10 exhibits excellent properties in mechanics, biocompatibility, and biodegradability, meanwhile superior stimulations in osteo‐immunomodulation, angiogenesis, and osteogenesis. Additionally, the animal experiments determined that this P80/D10/M10 can offer an osteo‐friendly microenvironment in a stage‐matched pattern for enhanced bone regeneration, namely, optimization of early inflammation, middle neovascularization, and later bone formation. Furthermore, transcriptomic analysis suggested that the in vivo performance of P80/D10/M10 on bone defect repair is mostly attributed to regulating artery development, bone development, and bone remodeling. Overall, this study reveals that the osteo‐microenvironment stage‐regulative scaffold provides a promising treatment for bone defect repair. Inspired by the bone microenvironment atlas of natural bone healing, an osteo‐microenvironment stage‐regulative scaffold is printed by incorporating self‐developed DBM‐MPs and multifunctional MH‐NPs into PLGA with an optimized proportion. This scaffold is suitable as a bone substitute for filling bone defects. More importantly, as degradation, it can sequentially modulate early inflammation, middle vascularization, and later osteogenesis, thus enhancing bone regeneration.