A Needlelike Nano-hydroxyapatite-Based Hydrogel Accelerates Critical Bone Defect Regeneration via Osteo-/Angiogenesis and Osteoimmune Regulation

The management of critical-sized bone defects has attracted heightened interest due to its challenging nature. To date, numerous engineered tissues incorporating nano-hydroxyapatite (nHap) have been proposed; however, nHap continues to encounter limitations, particularly regarding its inadequate immunomodulatory effects on bone. Therefore, needlelike nHap (NnHap)-based scaffolds were fabricated using a polylactic acid derivative and carboxymethyl chitosan. We hypothesize that NnHap@CP can not only promote bone immunomodulatory effects and angiogenesis in human umbilical vein endothelial cells through M2 subtype polarization but also directly promote osteogenesis in rat bone-marrow-derived mesenchymal stem cells (rBMSCs). Furthermore, mass spectrometry was employed to determine that osteoprotegerin/RANK/RANKL may represent a potential signaling pathway through which NnHap@CP enhances the osteogenesis of rBMSCs. In our study, NnHap@CP demonstrated a satisfactory effect on M2 subtype polarization in macrophages and enhanced osteogenesis in rBMSCs, as observed in an in vitro study. We employed NnHap@CP for the in vivo examination of a rat model with cranial critical-sized bone defects. We discovered that NnHap@CP significantly enhances new bone regeneration and neovascularization, potentially serving as an innovative treatment strategy for critical bone defects.