Gade, Piyusha
(2019)
Coupled Theoretical and Experimental Methods to Understand Growth and Remodeling of In Situ Engineered Vascular Grafts in Young and Aged Hosts.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In 1975, Rodbard introduced the concept of mechanical homeostasis; that arteries have an inherent capacity to maintain homeostatic stress states by altering their morphology through a negative feedback mechanism in response to mechanical loads. More recently, this capacity has been leveraged to develop acellular, in situ tissue-engineered vascular grafts (iTEVGs) which promote host growth and remodeling (G&R) to develop new arteries (neoarteries) in the tissue's functional site (in situ). These grafts offer a much-needed option to address the lack of viable autologous conduits, difficulties in scaling traditional tissue engineered grafts, and the rising demand for bypass grafting in an aging population. One such acellular, poly (glycerol sebacate) (PGS) iTEVG developed by Wang et al. has demonstrated in situ mature elastin and collagen formation in young hosts. However, the trial and error nature of graft design, coupled with the lack of knowledge of fundamental mechanisms guiding neoarterial G&R impedes efforts to translate these successes across age and species.
In this work, we take a coupled theoretical and experimental approach to understanding salient mechanisms guiding neoartery formation in young and aged hosts. We developed a mathematical model of graft degradation based on in vitro assessment of enzymatic degradation. Next, we translated successful neoartery development from a rat aorta to the substantially smaller, rat carotid artery. We determined that after three-months of remodeling, the neoartery has similar mechanical properties to those of the clinical gold standard, vein graft. We then successfully translated the iTEVG to an aged murine carotid model and assessed differences in mechanical, microstructural, and biological stages of neoarterial G&R in young versus aged hosts over the course of six months. Subsequently, a constrained mixture model-based G&R tool was developed, informed with these experimental data, and used to predict long-term neoarterial G&R response in both age groups. Finally, we identified a common mode of adverse remodeling in neoarteries - rupture and calcification. Motivated by these results, we developed new techniques to analyze calcification in a parallel, model system exhibiting similar modes of adverse remodeling - cerebral aneurysms. These results provide insights for future work developing strategies necessary to optimally design iTEVGs.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
10 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
8 July 2019 |
| Approval Date: |
10 September 2019 |
| Submission Date: |
10 July 2019 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
265 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
vascular grafts, continuum mechanics, modeling |
| Date Deposited: |
10 Sep 2019 16:13 |
| Last Modified: |
10 Sep 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37078 |
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