T lymphocytes as critical mediators in tissue regeneration, fibrosis, and the foreign body response.

Research on the foreign body response (FBR) to biomaterial implants has been focused on the roles that the innate immune system has on mediating tolerance or rejection of implants. However, the immune system also involves the adaptive immune response and it must be included in order to form a complete picture of the response to biomaterials and medical implants. In this review, we explore recent understanding about the roles of adaptive immune cells, specifically T cells, in modulating the immune response to biomaterial implants. The immune response to implants elicits a delicate balance between tissue repair and fibrosis that is mainly regulated by three types of T helper cell responses -T helper type 1, T helper type 2, and T helper type 17- and their crosstalk with innate immune cells. Interestingly, many T cell response mechanisms to implants overlap with the process of fibrosis or repair in different tissues. This review explores the fibrotic and regenerative T cell biology and draws parallels to T cell responses to biomaterials. Additionally, we also explore the biomedical engineering advancements in biomaterial applications in designing particle and scaffold systems to modulate T cell activity for therapeutics and devices. Not only do the deliberate engineering design of physical and chemical material properties and the direct genetic modulation of T cells not only offer insights to T cell biology, but they also present different platforms to develop immunomodulatory biomaterials. Thus, an in-depth understanding of T cells' roles can help to navigate the biomaterial-immune interactions and reconsider the long-lasting adaptive immune response to implants, which, in the end, contribute to the design of immunomodulatory medical implants that can advance the next generation of regenerative therapy. STATEMENT OF SIGNIFICANCE: This review article integrates knowledge of adaptive immune responses in tissue damage, wound healing, and medical device implantation. These three fields, often not discussed in conjunction, are important to consider when evaluating and designing biomaterials. Through incorporation of basic biological research alongside engineering research, we provide an important lens through which to evaluate adaptive immune contributions to regenerative medicine and medical device development.