Elucidation of Topographical Design Principles for Electrospun Matrices
Abstract/Contents
- Abstract
- Synthetic vascular grafts are characterized by poor long-term patency as low as 50% for small-diameter applications. Thrombosis is a major cause of failure and is attributed to the inability of the neighboring, quiescent endothelium to migrate and proliferate across the graft luminal surface. Hence, there is a large clinical need for implantable biomaterials that promote endothelial migration and proliferation. Recent strategies for engineering implantable biomaterials in the vasculature have leveraged well-defined mechanical and biochemical design principles to achieve such cellular phenotypes. However, despite the clear influence of native extracellular matrix topography on endothelial cell physiology and morphology in vivo, well-defined design principles regarding fibrous matrix topography are lacking. Here, we engineer and characterize an electrospun elastin-like protein platform with mean fiber diameter varied from 0.8 to 2.0 μm, independently of biochemical and mechanical properties. We then demonstrate that an increase in topographical size scale from the submicron to micron level drives an increase in endothelial cell migration and proliferation, specifically through the disruption of VE-cadherin cell junctions. The resulting loss of contact inhibition via VE-cadherin and upsurge in cytoskeletal contractility-induced mechanotransduction signaling is associated with a monolayer-wide shift in intracellular signaling (ERK1/2 phosphorylation, YAP localization), transcriptional activity (nuclear actin accumulation, interleukin 8 expression) and even epigenetic regulation (heterochromatin fraction) in response to more undulant fibrous topography. Finally, we propose and assess a mechanism linking undulant fibrous topography to endothelial cell junction disruption, wherein increased membrane curvature around larger diameter fibers imparts local tensile forces via the cytoskeleton to physically disrupt junction integrity. Results here have implications not only for the design of next generation vascular grafts that maintain long term patency by supporting migratory and proliferative endothelial phenotypes, but also for current understanding of how topographical features of the native vascular extracellular matrix drive cellular organization and organogenesis.
Description
| Type of resource | text |
|---|---|
| Date created | April 2015 |
Creators/Contributors
| Author | Mascharak, Shamik |
|---|---|
| Advisor | Heilshorn, Sarah |
| Contributing author | Benitez, Patrick |
| Contributing author | Proctor, Amy |
| Editor | Huang, Kerwyn Casey |
| Editor | Dunn, Alexander |
| Degree granting institution | Stanford University. Department of Bioengineering. |
Subjects
| Subject | Bioengineering |
|---|---|
| Subject | Materials Science and Engineering |
| Subject | electrospinning |
| Subject | vascular grafts |
| Subject | topography |
| Subject | VE-cadherin |
| Subject | mechanotransduction |
| Subject | YAP |
| Subject | endothelial cell |
| Subject | endothelium |
| Subject | matrix |
| Subject | fabric |
| Subject | cytoskeleton |
| Subject | nuclear actin |
| Subject | epigenetic regulation |
| Subject | Firestone Medal for Excellence in Undergraduate Research |
| Genre | Thesis |
Bibliographic information
Access conditions
- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Preferred citation
- Preferred Citation
- Mascharak S. Elucidation of topographical design principles for electrospun matrices. Honors Thesis, Department of Bioengineering. Stanford University, 2015. http://purl.stanford.edu/xb449qg4071
Collection
Undergraduate Theses, School of Engineering
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- Contact
- shamikm@alumni.stanford.edu
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