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Models and Mechanisms to Evaluate Tissue Engineered Vascular Graft Stenosis

Clark, Elizabeth
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492735573118956

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Congenital heart disease represents the most common form of birth defect and is present in up to 1% of all live births. Of particular interest to our group is the treatment of single ventricle disease, specifically hypoplastic left heart syndrome (HLHS) in which left-sided heart structures including the left ventricle, aorta, and mitral valve are malformed. We utilize tissue engineering principles to provide palliative treatment with Tissue-Engineered Vascular Grafts (TEVG) that allow for growth of the child’s own tissues. The TEVG overcomes limitations present in other composite grafts including thrombogenicity and lack of growth capacity. One limitation of our TEVG is that a small percentage of children develop critical stenosis requiring the utilization of interventional cardiovascular techniques. Developing both large and small animal models of TEVG stenosis will allow us to better understand clinical data sets as well as provide models to better characterize the development of neotissue formation and stenosis. The long-term goal of this project is to develop a second-generation composite vascular graft for use in children. The objective of this study is to elucidate the mechanism of TEVG neotissue formation in immunocompetent mice (Mus musculus) and characterize neotissue formation in a sheep (Ovis aries) model. Echocardiography, angiography, and magnetic resonance imaging are routinely used to evaluate children that have received the TEVG to treat HLHS. While angiography remains the clinical gold standard for evaluation of the lumen it only indirectly evaluates the vessel wall. Therefore, we sought to evaluate intravascular ultrasound (IVUS) to characterize neotissue formation in an in vivo ovine surgical model. IVUS demonstrated close correlation to angiographic and histologic changes. Additionally, IVUS measurement of graft lumen morphometry correlates with angiography measurements. This provides further data to support the use of IVUS in a clinical setting. Future preclinical experiments will utilize this modality as an additive approach to characterize the development of TEVG stenosis and neotissue remodeling over time, with specific regard to response to treatment with both interventional and therapeutic approaches. Previous research by our lab C57BL/6 mice has suggested that the transforming growth factor-ß (TGF-ß)/Smad2-3 pathway is involved in the development of TEVG stenosis. While the specific role of the TGF-ß pathway in the development of stenosis remains unknown, this pathway is upregulated in stenotic TEVG. To this end, this work seeks to evaluate the TGF-ß pathway in Cdh5-lineage cells in vivo in mice implanted with TEVG. A conditional genetic murine model was developed with endothelial-derived (Cdh5) loss of the TGF-ß receptors, TßRI and TßRII. Although TEVG have a low incidence of stenosis in both treated and control animals, Cdh5 TGF-ß pathway modulation results in altered neotissue formation including collagen production and polymeric degradation at early timepoints. We rationalize that by elucidating the cell(s) of origin for the neotissue and the role of TGF-ß receptor pathway will enable the development of targeted therapies in combination with TEVGs to improve clinical outcomes for children.
Christopher Breuer, MD (Advisor)
Keith Gooch, PhD (Committee Member)
Krista La Perle, DVM, PhD (Committee Member)
Joy Lincoln, PhD (Committee Member)
165 p.
Biology; Biomedical Engineering; Biomedical Research; Medical Imaging; Medicine; Pathology
CHD; HLHS; TEVG; tissue engineering; IVUS; TGF-beta; stenosis

Recommended Citations

Citations

  • Clark, E. (2017). Models and Mechanisms to Evaluate Tissue Engineered Vascular Graft Stenosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492735573118956

    APA Style (7th edition)

  • Clark, Elizabeth. Models and Mechanisms to Evaluate Tissue Engineered Vascular Graft Stenosis. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492735573118956.

    MLA Style (8th edition)

  • Clark, Elizabeth. "Models and Mechanisms to Evaluate Tissue Engineered Vascular Graft Stenosis." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492735573118956

    Chicago Manual of Style (17th edition)

osu1492735573118956
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This open access ETD is published by The Ohio State University and OhioLINK.