Although most tissue types are capable of some form of self-repair and regeneration, injuries that are larger than a critical threshold or those occurring in the setting of certain diseases can lead to impaired healing and ultimately loss of structure and function. The immune system plays an important role in tissue repair and must be considered in the design of therapies in regenerative medicine. In particular, macrophage cell therapy has emerged as a promising strategy that leverages the reparative roles of these cells. Macrophages are critical for successful tissue repair and accomplish diverse functions throughout all phases of the process by dramatically shifting in phenotypes in response to microenvironmental cues. Depending on their response to various stimuli, they may release growth factors, support angiogenesis, and facilitate extracellular matrix remodeling. However, this ability to rapidly shift phenotype is also problematic for macrophage cell therapy strategies, because adoptively transferred macrophages fail to maintain therapeutic phenotypes following their administration to sites of injury or inflammation. Biomaterials are a potential way to control macrophage phenotype in situ while also enhancing their retention at sites of injury. Cell delivery systems incorporated with appropriately designed immunomodulatory signals have potential to achieve tissue regeneration in intractable injuries where traditional therapies have failed. Here we explorecurrent challenges in macrophage cell therapy, especially retention and phenotype control, how biomaterials may overcome them, and opportunities for next generation strategies. Biomaterials will be an essential tool to advance macrophage cell therapy for widespread clinical applications.
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