Modulating immune microenvironment during bone repair using biomaterials: Focusing on the role of macrophages

Bone is a self-regenerative tissue that can repair small defects and fractures. In large defects, bone tissue is unable to provide nutrients and oxygen for repair, and autologous grafting is used as the gold standard. As an alternative method, the bone tissue regeneration approach uses osteoconductive biomaterials to overcome bone graft disadvantages. However, biomaterials are considered as foreign components that can stimulate host immune responses. Although traditional principles have been aimed to minimize immune reactions, the design of biomaterials has steadily shifted toward creating an immunomodulatory microenvironment to harness immune cells and responses to repair damaged tissue. Among immune cells, macrophages secrete various immunomodulatory mediators and crosstalk with bone-forming cells and play key roles in bone tissue engineering. Macrophage polarization toward M1 and M2 subtypes mediate pro-inflammatory and anti-inflammatory responses, respectively, which are crucial for bone repairing at different stages. This review provides an overview of the crosstalk between various immune cells and biomaterials, macrophage polarization, and the effect of physicochemical properties of biomaterials on the immune responses, especially macrophages, in bone tissue engineering.