A 3D-printed GTP@PTH composite scaffold with synergistic immunomodulatory and osteogenic capabilities for osteoporotic bone regeneration

The treatment of osseous deficiencies in osteoporotic patients continues to pose significant clinical difficulties, requiring scaffolds that can simultaneously modulate the regenerative immune microenvironment and restore bone homeostasis. Here, we fabricated porous microspheres capable of the sustained release of the immunomodulator proanthocyanidin (PC) and the bone‑anabolic regulator PTH(1‑34). These microspheres were then integrated into a 3D‑printed organic–inorganic composite scaffold that exhibited high compressive strength and modulus. The scaffold’s interconnected porosity supported tissue in‑growth, while its high modulus and inorganic salt composition promoted osteogenic differentiation of stem cells. In parallel, surface‑grafted alendronate (ALN) regulated osteoblast/osteoclast activity and chelated calcium ions on the bone surface to form stable interfacial structures. Both in vitro and in vivo studies indicate that the GTP@PTH scaffold, leveraging the combined actions of PC and PTH (1–34), modulates the immune microenvironment and skeletal homeostasis to support bone regeneration. This system restrains M1 macrophage polarization, promotes an M2 phenotype, and limits osteoclast over-differentiation, thus enhancing osteogenic activity. Such a multifunctional platform shows considerable promise for repairing bone defects under osteoporotic conditions, offering a viable approach for developing clinically applicable biomaterial solutions