Activating the SDF-1/CXCR4 axis: Notoginsenoside R1-Functionalized zinc scaffolds accelerate fracture healing and angiogenesis in diabetic osteoporosis.

Effective treatment of diabetic osteoporotic fractures (DOF) requires biomaterials capable of promoting vascularized bone regeneration. A biodegradable porous zinc (Zn) scaffold incorporating sustained-release Notoginsenoside R1 (NGR1), referred to as Zn-NGR1, was developed using powder metallurgy and impregnation techniques. Comprehensive characterization by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and high-performance liquid chromatography (HPLC) confirmed the scaffold's morphology, composition, and controlled NGR1 release. In a streptozotocin (STZ)-induced diabetic and ovariectomized (OVX) rat model with femoral fractures, Zn-NGR1 implantation markedly accelerated fracture healing, enhanced angiogenesis as demonstrated by hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and immunohistochemistry/immunofluorescence (IHC/IF) analysis for cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF), and improved mechanical strength in three-point bending tests. Bone volume fraction (BV/TV) increased by 20 % compared with controls. Transcriptomic profiling (RNA sequencing, RNA-seq) combined with network pharmacology and machine learning analysis identified the stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis as the principal pathway activated by NGR1. In vitro, Zn-NGR1 significantly enhanced bone marrow mesenchymal stem cell (BMSC) and human umbilical vein endothelial cell (HUVEC) proliferation and migration, promoted osteogenic differentiation, and stimulated angiogenesis through SDF-1/CXCR4 upregulation, confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. In vivo validation demonstrated that Zn-NGR1 facilitates diabetic fracture healing by activating the SDF-1/CXCR4 axis, thereby promoting osteogenesis and angiogenesis. These findings indicate that Zn-NGR1 scaffolds represent a promising biomaterial strategy for improving DOF repair through targeted modulation of the SDF-1/CXCR4 axis.