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Macrophages play an important role in tissue repair, regeneration, and the ability of biomaterials to mediate these processes. Macrophages are highly plastic cells that exhibit altered behavior in response to changes in the microenvironment. With the growing knowledge of the roles that different macrophage phenotypes play in specific pathologies and/or injuries, researchers are now focusing on designing biomaterials to actively control macrophage behavior and promote healing outcomes. In this review, we highlight a variety of biomaterial strategies for controlling macrophage phenotype in chronic wounds, tissue defects, and inflammatory conditions, although these strategies can be applied to many other applications. In particular, we highlight the different situations in which biomaterials should inhibit or promote M1 or M2 activation, or both, for therapeutic outcomes.

Macrophages, the primary cells of the inflammatory response, are major regulators of healing, and mediate both bone fracture healing and the inflammatory response to implanted biomaterials. However, their phenotypic contributions to biomaterial-mediated bone repair are incompletely understood. Therefore, we used gene expression and protein secretion analysis to investigate the interactions in vitrobetween primary human monocyte-derived macrophages and ceramic scaffolds that have been shown to have varying degrees of success in promoting bone regeneration in vivo. Specifically, baghdadite (Ca3ZrSi2O9) and strontium–hardystonite–gahnite (Sr–Ca2ZnSi2O7–ZnAl2O4) scaffolds were chosen as two materials that enhanced bone regeneration in vivoin large defects under load compared with clinically used tricalcium phosphate–hydroxyapatite (TCP–HA). Principal component analysis revealed that the scaffolds differentially regulated macrophage phenotype. Temporal changes in gene expression included shifts in markers of pro-inflammatory M1, anti-inflammatory M2a and pro-remodelling M2c macrophage phenotypes. Of note, TCP–HA scaffolds promoted upregulation of many M1-related genes and downregulation of many M2a- and M2c-related genes. Effects of the scaffolds on macrophages were attributed primarily to direct cell–scaffold interactions because of only minor changes observed in transwell culture. Ultimately, elucidating macrophage–biomaterial interactions will facilitate the design of immunomodulatory biomaterials for bone repair.