| Summary: | <p> Cardiovascular disease continues to be the leading cause of morbidity and mortality in the US and worldwide. Traditional treatments include vascular surgeries, such as angioplasty, stent placement, and vascular graft or vascular reconstruction. Of importance for this dissertation are the outcomes following vascular graft surgeries. More than 50% of vascular grafts fail within the first few years due to maladaptive responses, such as inflammation. There is a critical need to develop improved treatments to the traditional grafting procedures. One proposal to enhance outcomes is the use of cellularized, low modulus, synthetic poly(ethylene) glycol (PEG)-based biomaterials. PEG-based hydrogels have been shown to support the 3D growth and differentiation of vascular cells and may provide structural support for the vessel. A principal concern is that a growing percentage of individuals contain anti-PEG antibodies, including IgG antibodies. T cells are mediators of antibody production and play a major role in angiogenesis and in the development of arthrosclerosis. Therefore, studies to elucidate the T cell-PEG matrix interactions are needed to control and predict maladaptive responses. Here, an established murine D10-IL2, Th2 cell line, was used as a model of T lymphocyte activity to: 1) better understand the influence of PEG on T cell metabolism; 2) determine the consequence of an acute Th2 inflammatory microenvironment on the expression of pro-inflammatory responses in fibroblasts within the 3D matrix; and 3) investigate antigen presenting cell (APC)-independent T cell activation. This research demonstrated that Th2 cells experience a reversible suppression of mitochondrial membrane potential (ΔΨm) upon initial exposure to PEG. Data also suggested that T cells were susceptible to APC-independent activation during contact with the PEG matrix, as measured by an increase in IL4 and IL10 expression and the production of inflammatory cytokines (IGFBP-3, CTACK, MIP2, LIX). Additionally, this research led to the development of a bio-degradable PEG-based hydrogel system. This allowed for the investigation of aortic fibroblast cell responses to an acute inflammatory 3D microenvironment and demonstrated that the hydrogel system provided a limited protective barrier during inflammation. This research has public health benefits and has provided an improved understanding of the immunogenic nature of PEG.</p>
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