Harnessing Immunomodulation: How Calcium Phosphate Biomaterials Orchestrate Bone Regeneration

The immune system and biomaterials exhibit a well-documented synergistic interplay, essential for bone defect healing. Calcium phosphate (CaP) biomaterials, notably hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate, are widely employed as bone substitutes due to their inherent osteoconductivity. A key challenge for synthetic CaPs is augmenting their osteoinductive potential. Indeed, the limited translation of biomaterials into clinical practice may largely stem from insufficient immunomodulatory understanding. Current evidence reveals the complex host immune response to CaPs, which is mediated by physical and biochemical properties. Harnessing immunomodulatory strategies could bridge inflammatory modulation and osteogenesis, thereby enhancing bone regeneration. This review systematically analyzes recent advances in the molecular mechanisms of immune cell responses to CaPs during bone defect healing, deepening our understanding of immunomodulatory strategies for bone regeneration. Furthermore, key knowledge gaps are highlighted to inspire the development of spatiotemporally responsive CaPs for bone tissue engineering.