Sequentially regulated immuno-osteogenic bioceramics enhance the regeneration of osteoporotic bone defects

Sequentially regulating immune-osteogenesis to orderly transition from the inflammatory phase to bone reconstruction, and enhancing bone regeneration while inhibiting osteoclastic resorption, are crucial for the treatment of osteoporotic bone defect. Herein, the sequential loading and controlled release of interleukin-4 (IL-4) and alendronate (AL) based on the 3D-printed β-tricalcium phosphate (β-TCP) scaffolds were achieved via the Michael addition reaction combined with physical adsorption. IL-4 was rapidly released within two days, promoting M2 polarization of macrophage and secretion of anti-inflammatory and osteogenesis-associated factors. Meanwhile<i>,</i> AL was sequentially released over a two-week period, promoting the osteogenic differentiation of mouse bone mesenchymal stem cells (mBMSCs) while inhibiting the formation of osteoclasts. Bone regeneration efficacy in <i>vivo</i> was assessed using an osteoporotic rat femoral defect model. Microcomputed tomography (micro-CT) and histological analyses revealed that the functionalized scaffolds (TCP-PDA/AL-IL-4) exhibited superior osteogenic properties. Significantly, the bone mineral apposition rate (MAR) and the amount of newly formed bone increased in the TCP-PDA/AL-IL-4 groups, while the osteoclast population reduced. This study proposes a highly effective strategy for developing bone regeneration and repair materials specifically tailored for the osteoporotic bone defect.