The impact of biomaterial characteristics on macrophage phenotypes in tissue engineering: a review

Macrophages are highly plastic cells central to pathogen removal, tissue regeneration, and inflammation, making them key targets in biomaterial design for improved clinical outcomes. Foreign body responses (FBRs) to implanted biomaterials often involve excessive macrophage-mediated inflammation, leading to fibrotic encapsulation, infection, and implant failure. Advances in tissue engineering demonstrate that macrophage polarization - the transition from pro-inflammatory M1 to anti-inflammatory M2 phenotypes - can be influenced by biomaterial properties to mitigate these responses and enhance regeneration. This review synthesizes the relationship between biomaterial properties, such as surface chemistry, structure, and stiffness, and their ability to modulate macrophage behavior. Key innovations, including tailored scaffold architectures, bioactive coatings, and cytokine delivery systems, have shown promise in guiding macrophage polarization for improved bone, soft tissue, and head and neck reconstruction outcomes. Strategies like hydrogels and nanostructured materials enable spatially and temporally controlled macrophage modulation, mimicking native extracellular matrix dynamics, mitigating chronic inflammation, and accelerating vascularization, extracellular matrix remodeling, and tissue integration. By integrating recent findings, this review provides a framework for designing biomaterials that actively modulate macrophage activity to overcome FBR and enhance healing. It identifies critical gaps, such as understanding macrophage-stromal interactions, developing personalized biomaterial designs to address patient variability, and leveraging advanced technologies like artificial intelligence in scaffold optimization. These insights advance the development of biomaterials that restore tissue function and address unmet clinical needs in regenerative medicine.