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The foreign body response (FBR) remains a clinical challenge in the field of biomaterials due to its ability to elicit a chronic and sustained immune response. Modulating the immune response to materials is a modern paradigm in tissue engineering to enhance repair while limiting fibrous encapsulation and implant isolation. Though the classical mediators of the FBR are well-characterized, recent studies highlight that our understanding of the cell types that shape the FBR may be incomplete. In this review, we discuss the emerging role of T cells, stromal-immune cell interactions, and senescent cells in the biomaterial response, particularly to synthetic materials. We emphasize future studies that will deepen the field's understanding of these cell types in the FBR, with the goal of identifying therapeutic targets that will improve implant integration. Finally, we briefly review several considerations that may influence our understanding of the FBR in humans, including rodent models, aging, gut microbiota, and sex differences. A better understanding of the heterogeneous host cell response during the FBR can enable the design and development of immunomodulatory materials that favor healing.

Fibrosis is a pathological accumulation of excessive collagen that underlies many of the most common diseases, representing dysfunction of the essential processes of normal tissue healing. Fibrosis research aims to limit this response without ameliorating the essential role of fibrogenesis in organ function. However, the absence of a realistic in vitromodel has hindered investigation into mechanisms and potential interventions because the standard 2D monolayer culture of fibroblasts has limited applicability. We sought to develop and optimize fibrosis spheroids: a scaffold-free three-dimensional human fibroblast-macrophage spheroid system representing an improved benchtop model of human fibrosis. We created, characterized and optimized human fibroblast-only spheroids, demonstrating increased collagen deposition compared to monolayer fibroblasts, while spheroids larger than 300 μm suffered from progressively increasing apoptosis. Next, we improved the spheroid system with the addition of human macrophages to more precisely recapitulate the environment during fibrogenesis, creating a hybrid spheroid system with different ratios of fibroblasts and macrophages ranging from 2 : 1 to 64 : 1. We found that in the hybrid spheroids (particularly the 16 : 1 [F16] ratio) more fibroblasts were activated, with greater macrophage polarization towards a pro-inflammatory M1 phenotype. Hybrid spheroids containing higher ratios of macrophages showed greater macrophage heterogeneity and less fibrogenesis, while low macrophage ratios limited macrophage-induced effects and yielded less collagen deposition. The F16 group also had the highest expression levels of fibrosis-related genes (Col-1a1, Col-3a1and TGF-β) and inflammation-related genes (TNF, IL1βand IL6). IF staining demonstrated that F16 spheroids had the highest levels of αSMA, collagen-1 and collagen-3 deposition among all groups as well as formation of a dense collagen rim surrounding the spheroid. Future studies exploring the greater fibrotic activity of F16 spheroids may provide new mechanistic insights into diseases involving excessive fibrotic activity. Microtissue fibrosis models capable of achieving greater clinical fidelity have the potential to combine the relevance of animal models with the scale, cost and throughput of in vitrotesting.