Immunomodulatory 3D-printed hydroxyapatite/tricalcium phosphate/polycaprolactone scaffolds promote bone regeneration via macrophage polarization

Excessive inflammation remains a significant impediment to the regeneration of critical-sized bone defects, where the local immune microenvironment plays a crucial role in osteogenesis. However, most bone scaffolds primarily emphasize mechanical support and osteoconductivity, while their immunomodulatory potential remains largely unexplored. In this study, we designed and fabricated three-dimensional–printed hydroxyapatite/β-tricalcium phosphate/polycaprolactone (HTP) composite scaffolds to regulate macrophage polarization and promote bone regeneration. The HTP scaffolds demonstrated exceptional structural integrity and mechanical strength, facilitating the adhesion, proliferation, and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Notably, the HTP scaffolds effectively modulated the immune microenvironment by inhibiting the polarization of pro-inflammatory M1 macrophages and promoting their transition toward the regenerative M2 phenotype. This immunomodulatory effect further enhanced osteogenic factor secretion, establishing a correlation between immunoregulation and osteogenesis. In a rat calvarial defect model, the HTP scaffolds significantly increased M2 macrophage infiltration, promoted angiogenesis, and accelerated new bone formation compared to other groups. This study demonstrates that three-dimensional–printed HTP composite scaffolds promote bone regeneration and angiogenesis by establishing a regenerative immune microenvironment, highlighting their potential as an advanced immunomodulatory platform for bone tissue engineering.