Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine strategies.

Macrophages are a highly heterogeneous and plastic population of cells that are crucial for tissue repair and regeneration. This has made macrophages a particularly attractive target for biomaterial-directed regenerative medicine strategies. However, macrophages also contribute to adverse inflammatory and fibrotic responses to implanted biomaterials, typically related to the foreign body response (FBR). The traditional model in the field asserts that the M2 macrophage phenotype is pro-regenerative and associated with positive wound healing outcomes, whereas the M1 phenotype is pro-inflammatory and associated with pathogenesis. However, recent studies indicate that both M1 and M2 macrophages play different, but equally vital, roles in promoting tissue repair. Furthermore, recent technological developments such as single-cell RNA sequencing have allowed for unprecedented insights into the heterogeneity within the myeloid compartment, related to activation state, niche, and ontogenetic origin. A better understanding of the phenotypic and functional characteristics of macrophages critical to tissue repair and FBR processes will allow for rational design of biomaterials to promote biomaterial-tissue integration and regeneration. In this review, we discuss the role of temporal and ontogenetic macrophage heterogeneity on tissue repair processes and the FBR and the potential implications for biomaterial-directed regenerative medicine applications. STATEMENT OF SIGNIFICANCE: This review outlines the contributions of different macrophage phenotypes to different phases of wound healing and angiogenesis. Pathological outcomes, such as chronic inflammation, fibrosis, and the foreign body response, related to disruption of the macrophage inflammation-resolution process are also discussed. We summarize recent insights into the vast heterogeneity of myeloid cells related to their niche, especially the biomaterial microenvironment, and ontogenetic origin. Additionally, we present a discussion on novel tools that allow for resolution of cellular heterogeneity at the single-cell level and how these can be used to build a better understanding of macrophage heterogeneity in the biomaterial immune microenvironment to better inform immunomodulatory biomaterial design.