Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches.

A coordinated interaction between osteogenesis and osteoimmune microenvironment is essential for successful bone healing. In particular, macrophages play a central regulatory role in all stages of bone repair. Depending on the signals they sense, these highly plastic cells can mediate the host immune response against the exterior signals of molecular stimuli and implanted scaffolds, to exert regenerative potency to a varying extent. In this article, we first encapsulate the immunomodulatory functions of macrophages during bone regeneration into three aspects, as sweeper, mediator and instructor. We introduce the phagocytic role of macrophages in different bone healing periods ('sweeper') and overview a variety of paracrine cytokines released by macrophages either mediating cell mobilisation, vascularisation and matrix remodelling ('mediator'), or directly driving the osteogenic differentiation of bone progenitors and bone repair ('instructor'). Then, we systematically classify and discuss the emerging engineering strategies to recruit, activate and modulate the phenotype transition of macrophages, to exploit the power of endogenous macrophages to enhance the performance of engineered bone tissue.