Author ORCID Identifier

https://orcid.org/0000-0002-7833-4495

Document Type

Dissertation

Date of Award

2022

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Zhongkui Hong

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis, one of the primary CVDs, is characterized as a chronic inflammatory disease. In the initial stages of atherosclerosis, there is a buildup of cholesterol and lipoproteins that triggers monocytes to enter the arterial wall and begin accumulating lipids. Vascular smooth muscle cells (VSMCs) begin to detach and migrate from the media toward the intima in a process known as phenotypic switching. Phenotypic switching transitions VSMCs from a contractile to synthetic phenotype and they gain the capacity for migration, proliferation, and secretion of extracellular matrix (ECM) proteins. Synthetic VSMCs experience a variety of microenvironments of differing stiffness and composition within the atherosclerotic plaque which elicit different biomechanical responses. The growth of atherosclerotic plaques can cause stenosis and reduced blood flow. One treatment for this is revascularization surgery using vascular grafts to bypass blockages. In this dissertation, we examine how VSMC biomechanics change in response to substrate stiffness and composition. Then we developed an electrospun polycaprolactone (PCL)-silk fibroin (SF) electrospun scaffold for use in vascular tissue engineering. In specific aim 1, the effect of substrate stiffness and collagen or fibronectin coatings on VSMC migration and cytoskeletal organization was analyzed. Protein coatings and substrate stiffness were found to synergistically regulate migration and cortical actin organization in the opposite manner. In specific aim 2, the differences in biomechanics of atherosclerotic ApoE-/- and wild type (WT) VSMCs was analyzed. ApoE-/- VSMCs were found to have lower adhesion forces but increased migration capacity, cytoskeletal alignment, and stiffness, with the latter two being enhanced by increasing substrate stiffness. In specific aim 3, an exploration into the use of electrospun PCL-SF scaffolds as vascular grafts was conducted. The addition of SF improved the mechanical properties of the graft, making them more similar to those of native arteries, as well as increasing the diameter of the nanofibers. Furthermore, the PCL-SF scaffolds supported the differentiation of mesenchymal stem cells into VSMC-like cells. Therefore, this dissertation provides further insights in the alteration of VSMC biomechanics during atherosclerosis and a promising material for the development a tissue engineered vascular graft.

Subject Categories

Biomedical Engineering and Bioengineering

Keywords

Cardiovascular disease

Number of Pages

221

Publisher

University of South Dakota

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