The role of macrophages in fracture healing: a narrative review of the recent updates and therapeutic perspectives.

Objective: This review addresses the latest advances in research on the role of macrophages in fracture healing, exploring their relationship with failures in bone consolidation and the perspectives for the development of advanced and innovative therapies to promote bone regeneration.

Background: The bone can fully restore its form and function after a fracture. However, the regenerative process of fracture healing is complex and is influenced by several factors, including macrophage activity. These cells have been found in the fracture site at all stages of bone regeneration, and their general depletion or the knockdown of receptors that mediate their differentiation, polarization, and/or function result in impaired fracture healing.

Methods: The literature search was carried out in the PubMed database, using combinations of the keywords "macrophage", "fracture healing, "bone regeneration", and "bone repair". Articles published within the last years (2017-2022) reporting evidence from in vivo long bone fracture healing experiments were included.

Conclusions: Studies published in the last five years on the role of macrophages in fracture healing strengthened the idea that what appears to be essential when it comes to a successful consolidation is the right balance between the M1/M2 populations, which have different but complementary roles in the process. These findings opened promising new avenues for the development of several macrophage-targeted therapies, including the administration of molecules and/or biomaterials intended to regulate macrophage differentiation and polarization, the local transplantation of macrophage precursors, and the use of exosomes to deliver signaling molecules that influence macrophage activities. However, more research is still warranted to better understand the diversity of macrophage phenotypes and their specific roles in each step of fracture healing and to decipher the key molecular mechanisms involved in the in vivo crosstalk between macrophages and other microenvironmental cell types, such as endothelial and skeletal stem/progenitor cells.