Optimizing type H vessels formation <i>via</i> short fibers 3D scaffolds with maintaining redox homeostasis for osteoporotic bone remodeling.

Abstract

Precise regulation of intraosseous angiogenesis is essential for effectively repairing osteoporotic bone defects. However, the dual imbalance of redox homeostasis and the osteogenesis-angiogenesis coupling within the osteoporotic microenvironment poses significant challenges for bone regeneration. Here, we developed a polydopamine (PDA)-modified injectable short-fiber 3D scaffold (PSF@P-SLP) <i>via</i> short fibers homogenization to remodel the osteoporotic microenvironment and enhance bone healing. The scaffold surface was modified with PDA, which induced the <i>in situ</i> aggregation of short fibers into a porous 3D network, promoting directional cell migration and nutrient exchange. Moreover, parathyroid hormone [PTH (1-34)] loaded ROS-responsive thioether-phospholipid liposomes (P-SLP) were conjugated to the PDA coating through catechol groups, enabling sustained PTH release and efficient ROS scavenging <i>via</i> thioether oxidation. <i>In vitro</i>, PSF@P-SLP significantly reduced ROS levels, promoted osteogenic differentiation of mesenchymal stem cells, and enhanced the proliferation and migration of endothelial cells. <i>In vivo</i>, the scaffold facilitated both type H vessels formation and osteogenesis, accelerating the repair of osteoporotic bone defects. Collectively, this study presents a novel therapeutic strategy utilizing PTH (1-34)-loaded injectable short-fiber 3D scaffolds that modulate oxidative stress and restore osteogenesis-angiogenesis coupling within the osteoporotic niche, demonstrating strong translational potential for bone tissue engineering.