Osteon-Inspired Dual-Ring Hydrogel Scaffold with Spatially Programmed Cell Encapsulation for Enhanced Angiogenesis and Osteogenesis in Bone Repair

Repairing large bone defects remains a significant clinical challenge, as they exceed the bone's innate regenerative capacity. The current gold standard, autologous bone grafting, is constrained by donor site morbidity, limited tissue availability, and additional surgical risks. Bone tissue engineering offers a compelling alternative; yet achieving fully functional, vascularized bone regeneration remains challenging. Inspired by the hierarchical architecture of native osteons, a dual-ring hydrogel scaffold was developed by incorporating the zwitterionic monomer 2-(methacryloyloxy)ethyl choline phosphate (MCP) into a gelatin methacryloyl (GelMA) matrix. This design facilitated spatially programmed encapsulation of human umbilical vein endothelial cells (HUVECs) and bone marrow-derived mesenchymal stem cells (BMSCs), replicating the cellular spatial organization of native osteons. MCP integration imparted the GelMA hydrogel with enhanced hydrophilicity, tunable porosity, and optimized mechanical and degradable properties. Optimized GelMA-MCP formulations supported the cell-specific viability and functional activity of HUEVCs and BMSCs, while the spatial configuration promoted synergistic angiogenesis and osteogenesis. Both in vitro and in vivo evaluations demonstrated that the osteon-like scaffold significantly enhanced angiogenesis and bone regeneration compared to mixed or single-cell controls. This study describes a modular and biomimetic strategy for engineering vascularized bone tissue through the integration of functional monomers and spatially guided cell patterning.