Psoralen immunomodulation: In vitro macrophage reprogramming to enhance osseointegration of 3D-printed porous titanium scaffolds in osteoporosis

Psoralen inhibits osteoclast activity and bone resorption while enhancing osteoblast activity and bone formation. However, its role in modulating macrophage polarization to enhance osteoblast function and scaffold osseointegration under osteoporotic conditions remains underexplored. We fabricated Voronoi-structured metal scaffolds by 3D printing and evaluated psoralen in vitro in a macrophage–bone marrow mesenchymal stem cell co-culture system using serum from psoralen-treated rats, and in vivo in an osteoporotic bone-defect model with oral psoralen administration. The results demonstrated that psoralen treatment promoted M2 macrophage polarization, increased the M2/M1 ratio, and upregulated osteogenic gene expression in vitro. Improved bone formation parameters—including bone volume fraction, trabecular thickness, and trabecular number—around the implanted scaffolds were observed in vivo. The findings suggest a synergistic effect between gradient scaffold structures and psoralen in enhancing M2-mediated osteogenesis. Taken together, these findings may provide novel strategies for improving bone repair and prosthesis integration in osteoporosis.