Emerging Strategies for Biomaterials-Mediated Reprogramming of Macrophages in Tissue Repair and Regeneration

Adult tissue repair is often limited, resulting in fibrotic scar formation rather than functional regeneration. Macrophages are central regulators of this process, driving inflammation, tissue formation, and remodeling. Increasing evidence demonstrates that macrophages exhibit substantial heterogeneity and plasticity, transitioning along a continuum of phenotypes in response to evolving microenvironmental cues rather than existing as discrete M1/M2 subsets. This functional diversity reflects their critical role across all stages of tissue repair, from early inflammatory responses to later regenerative and remodeling phases. Recent advances in bioengineering have enabled the development of biomaterial-based strategies to reprogram macrophages and enhance tissue repair. These include the controlled delivery of immunomodulatory biochemical signals, such as cytokines, proteins, and metabolites; the engineering of matrix biophysical properties, including stiffness, viscoelasticity, and topography; and the enhancement of efferocytosis to promote inflammation resolution and tissue homeostasis. These approaches demonstrate that macrophage behavior can be modulated through both biochemical and physical cues to improve regenerative outcomes across diverse tissue contexts. This review summarises current understanding of macrophage heterogeneity and plasticity during tissue repair and highlights emerging biomaterials-driven strategies for macrophage reprogramming, providing a framework for leveraging macrophage function to support effective tissue regeneration.