Collagen-Functionalized hydroxyapatite promotes biointegration and vascularization of xenogeneic bone grafts by modulating macrophage polarization

Background: In periodontal and bone-defect reconstruction, bovine-derived hydroxyapatite (HA) is widely utilized as a xenogeneic bone graft material. However, its inherent propensity to elicit a foreign body reaction (FBR) often results in a dense fibrous encapsulation at the host–material interface, thereby impeding early vascular ingrowth and integration associated with new bone formation and limiting its efficacy in complex bone defects. Objective: This study aimed to construct a biomimetic type I collagen (Col) coating on HA (HA + Col) and determine whether it reshapes the host-material immune microenvironment. Methods: Using a rat subcutaneous implantation model, we comparatively evaluated immunomodulatory performance and histological outcomes at an acute inflammatory time point (day 2) and a tissue remodeling time point (day 28). Results: Collagen modification markedly altered the nanoscale surface morphology and effectively suppressed excessive inflammatory cell infiltration at early stages. Immunohistochemical and histological analyses showed that HA + Col was associated with shift of macrophages from a pro-inflammatory M1-like profile (iNOS + ) toward a pro-resolving/pro-reparative M2-like profile (CD163 + ). At day 28, compared with unmodified HA, HA + Col significantly reduced fibrous capsule thickness and increased the neovascular area in subcutaneous tissue. Goldner trichrome staining further confirmed improved soft-tissue integration and collagen deposition quality in the HA + Col group. Collectively, collagen functionalization confers immunomodulatory activity to HA, mitigating FBR and establishing an osteoimmune microenvironment favorable for vascularization and soft-tissue integration in subcutaneous tissue. Conclusion: These findings provide a mechanistic rationale for future evaluation of functionalized bone graft substitutes in bone-defect models.