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Biomaterials are considered prominent tools in regenerative medicine that support the restoration of tissue defects and retain physiologic functionality. Although commonly used in the medical field, these constructs are inherently foreign toward the host and induce an immune response at the material\u2013tissue interface, defined as the foreign body response (FBR). A strong connection between the foreign body response and tissue regeneration is suggested, in which an appropriate amount of immune response and macrophage polarization is necessary to trigger autologous tissue formation. Recent developments in this field have led to the characterization of immunomodulatory traits that optimizes bioactivity, the integration of biomaterials and determines the fate of tissue regeneration. This review addresses a variety of aspects that are involved in steering the inflammatory response, including immune cell interactions, physical characteristics, biochemical cues, and metabolomics. 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