A “ready to move in” osteoporosis bone regeneration material

The repair of osteoporotic bone defects remains challenging because of the hostile pathological microenvironment—resembling “barren soil”—characterized by excessive oxidative stress and persistent inflammation, which impair cell survival and tissue regeneration. To address this problem, we developed a “fertile soil” implant system as a ready-to-use platform for osteoporotic bone regeneration. It consists of: (1) a three-dimensional (3D) -printed β-tricalcium phosphate/gelatin methacryloyl (β-TCP/GelMA) composite scaffold as a structural “soil matrix,” and (2) a Kaempferol-loaded ZIF-8 metal organic framework as an “intelligent nutrient bank” that responsively releases zinc ions and Kaempferol in acidic osteoporotic conditions.In vitro, the implant promoted a shift in macrophage polarisation from a pro-inflammatory M1 phenotype towards a pro-regenerative M2 phenotype. Mechanistic studies showed that this immunomodulatory effect was associated with improved mitochondrial function and reduced mitochondrial DNA (mtDNA) accumulation, accompanied by suppression of the cGAS–STING–TBK1–NF-κB signaling pathway. The implant reversed inflammation-induced metabolic reprogramming in macrophages by reducing glycolytic activity and restoring oxidative phosphorylation, thereby favouring the re-establishment of immune homeostasis. In parallel, the implant directly enhanced the osteogenic differentiation of mesenchymal stem cells and inhibited osteoclastogenesis, helping to restore the balance of bone remodelling. Conditioned-medium experiments further demonstrated that scaffold-mediated macrophage reprogramming established a pro-regenerative microenvironment that indirectly promoted osteogenesis and restrained osteoclast formation. In osteoporotic bone defect models, implantation enhanced new bone formation, improved trabecular microarchitecture, tissue integration, and vascularisation, and reduced local inflammation.In summary, this “ready-to-move in” osteoporotic bone repair system remodels the hostile microenvironment through immunomodulation and direct cell regulation, providing a “fertile soil” that may enhance bone defect repair under osteoporotic conditions.