Parathyroid Hormone-Related Protein-Loaded Organic and Inorganic Hybrid Aerogel Bone Scaffolds Regulate Bone Regeneration by Balancing Osteogenesis and Osteoclastogenesis

Critical-sized bone defects present formidable challenges in orthopedic reconstruction due to the inability of existing biomaterial scaffolds to concurrently regulate osteogenic-osteoclastic coupling and vascularization. Conventional hydroxyapatite (HA)-based grafts often fail to stimulate angiogenesis and may impede remodeling by suppressing osteoclastogenesis. Herein, a PTHrp-loaded organic-inorganic hybrid aerogel scaffold (PTHrp-NCHA) is developed, designed to regulate bone regeneration by synergistically promoting osteoblast and osteoclast activity while enhancing vascularization. The scaffold, composed of nanocellulose, collagen, and hydroxyapatite, provides a biomimetic porous structure, which enables PTHrp to penetrate deep into the material, ensuring a sustained release for over 14 days that maintains effective drug concentrations locally, stimulating angiogenesis and osteoblast differentiation. HA and PTHrp synergistically promote bone regeneration. On the one hand, HA promotes bone regeneration through its inherent osteogenic properties. In addition, PTHrp promotes osteoclast differentiation by regulating RANKL, and its strong osteoclast performance is offset by the osteogenic performance of HA. The biomimetic scaffold significantly enhanced the proliferation, osteogenic, and angiogenic potential in vitro, as demonstrated by upregulated osteogenic (OCN, BMP-2) and angiogenic marker (VEGF). In vivo, the rabbit femoral condyle defect model reveals that PTHrp-NCHA facilitates extensive bone ingrowth, as evidenced by micro-CT and H&E staining. These findings provide a robust foundation for the clinical translation of PTHrp-based scaffolds in regenerative medicine.