DOI
https://doi.org/10.25772/8XW8-W838
Author ORCID Identifier
https://orcid.org/0009-0002-3708-1935
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Rene Olivares-Navarrete
Abstract
Unresolved healing and localized chronic inflammation are common occurrences after biomaterial implantation, resulting in unfavorable clinical outcomes such as implant failure or fibrous encapsulation. T cells are adaptive immune cells found in lymph nodes, thymus, spleen, bone marrow, and around biomaterials, significantly impacting the degree of inflammation and wound healing. T cells are vital for inflammatory cytokine production and modulation of innate immune cells, including neutrophils and macrophages. T cells can be differentiated into two primary subsets, CD4+ and CD8+ T cells, playing distinctive roles in various pathologies and disease states. While T cells have been characterized well in response to pathogenic infection, autoimmune disease, and cancer, the contribution of T cells in the inflammatory response to biomaterial implantation remains understudied.
We investigated the hypothesis that T cells are fundamental for amplification and resolution of the inflammatory response and the generation of new bone post-implantation. In the work completed in my Ph.D., we have 1) established how the deficiency of T cells impacts macrophage polarization, mesenchymal stem cell recruitment, mesenchymal stem cell proliferation, as well as how T cells polarize in response to physicochemical cues on biomaterials, 2) distinguished CD4+ and CD8+ T cells in their respective contribution to modulation of the inflammatory response and new bone formation, 3) determined the efficacy of regulatory T cells in accelerating resolution of inflammation and healing post-implantation using adoptive transfer, and 4) understood how T cells are involved in prolonged or chronic inflammation associated with obesity and poorly integrating biomaterials. We utilized in vivo models using transgenic knockouts, as well as in vitro coculture systems, to determine the significance of T cells and T cell phenotypes in the inflammatory response at the peri-implant interface.
αβ T cells are vital for attenuating neutrophils and pro-inflammatory macrophages, while promoting anti-inflammatory macrophage polarization. Additionally, αβ T cells, specifically CD4+ T cells, are essential for mesenchymal stem cell recruitment and proliferation resulting in enhanced bone formation. We found that regulatory T cells are a critical T cell phenotype in the immune response, facilitating suppression of inflammation and new tissue formation after injury. By elucidating the function of various T cell subsets in the peri-implant microenvironment, these findings have enhanced the understanding of T cell physiology in the context of tissue repair. Furthermore, we have identified specific T cell phenotypes that can be isolated as a potential therapeutic to accelerate inflammatory resolution and enhance bone healing in clinically relevant conditions.
Rights
© Derek Avery
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
10-11-2024