DOI

10.17077/etd.l3sdfkmq

Document Type

Thesis

Date of Degree

Spring 2018

Degree Name

MS (Master of Science)

Degree In

Biomedical Engineering

First Advisor

Sarah C. Vigmostad

First Committee Member

Michael D. Henry

Second Committee Member

Jia Lu

Third Committee Member

James A. Ankrum

Fourth Committee Member

Seth I. Dillard

Abstract

Cancer metastasis, or the formation of a secondary tumor at a site distant from the primary tumor, is known to be an inefficient process. Historically, it was believed that the shear stresses and forces experienced by cancer cells traveling through the circulatory system are major limiting factors to their metastatic potential and viability. High levels of fluid shear stress are known to be capable of destroying tumor cells. However, more recent research has shown that cancer cells survive migration through the circulatory system and extravasation into distant tissues with a high degree of efficiency, indicating that hemodynamic forces are not primarily responsible for metastatic cancer cell death. A current subject of investigation is the biomechanical effect of fluid shear stress on cancer cells – how do cancer cells react to the fluidic forces and stresses they experience in circulation? This study focused on quantifying the elastic modulus and rupture behavior of prostate cancer and prostate epithelial cells, with and without exposure to fluid shear stress. Micropipette aspiration was the means of inducing deformation and rupture of the cell membrane. Images obtained through micropipette aspiration were analyzed to calculate elastic modulus and to quantify local stresses along the aspirated cell membrane. An axisymmetric stress model of the aspirated cell membrane was solved using MATLAB; the trends for direction and relative magnitude of stresses were confirmed by an Abaqus finite element model.

Results of the micropipette aspiration included statistically significant differences in elastic modulus and rupture pressure between experimental groups. The elastic modulus of epithelial cells exposed to shear stress was significantly higher than that of the cancer cell groups, both exposed and unexposed to shear stress. There was no difference in elastic modulus between cancer cells exposed to shear stress and unexposed to shear stress. This is contrary to the findings of a previous study; prostate cancer cells have been observed to stiffen after exposure to shear stress. It has also been well documented that epithelial cells exhibit higher elastic moduli than cancer cells; however, no difference was observed in this study in the comparison of elastic moduli of cancer and epithelial cells that were unexposed to shear stress. The rupture pressure of the cancer cells unexposed to shear stress was significantly lower than any other group. This suggests a strengthening reaction of the cancer cell membrane in response to shear stress exposure. This effect was observed to be transient; the increase in rupture pressure disappeared by an hour after the shear stress exposure. The epithelial cells did not exhibit any change in rupture pressure after exposure to shear stress. There was no correlation between elastic modulus and rupture pressure; the stiffness of the cells did not indicate how likely they were to rupture.

The MATLAB and Abaqus models agreed well for trends of principal stresses and von Mises stress. The MATLAB model was quite sensitive to the curvature of the spline fitted to the membrane edge, resulting in irregular patterns and some extreme values of stress and making the results difficult to interpret. The maximum stress did tend to increase with increased aspiration pressure. The location of the maximum stress along the membrane did not reliably correspond to the location of rupture during micropipette aspiration. This model may be improved by automating the process of fitting a spline to the edge of the membrane to reduce user error in plotting individual points.

Further studies to characterize the effects of fluid shear stress on cancer cell mechanics will be useful to confirm differences in elastic modulus and rupture pressure and to investigate the effect of time, temperature, cancer cell line, culture medium, and other variables on cancer cell properties.

Pages

xi, 55 pages

Bibliography

Includes bibliographical references (pages 48-52).

Copyright

Copyright © 2018 Leah M. VanDenBosch

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