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Schickel Dissertation Final 22Jul14.pdf (5.82 MB)

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Biomechanics of Idiopathic Pulmonary Fibrosis and Inferior Vena Cava Filter Perforation

Schickel, Maureen Erin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1406048985

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the accumulation of scar tissue within the lung interstitium caused by excessive extracellular matrix (ECM) production and remodeling by myofibroblasts. There are no approved treatments available and the standard of care focuses on supportive therapies and lung transplant. Previous studies have shown that ECM substrates affect cellular proliferation, differentiation, motility, and invasion which are all important components of scar tissue production in IPF, highlighting the importance of physiological in vitro models of IPF. It is known that cells can communicate over long distances on biological ECMs compared to linear elastic substrates; however, researchers continue to debate whether the fibers or strain-hardening property of the biological materials cause the increased cellular sensing. Thus, we have developed computational models to test the effects of fibers and strain-hardening materials independently which cannot be performed in an in vitro setting. The ets (E twenty-six) family of transcription factors regulates cellular proliferation, differentiation, migration, and ECM production. Previously, phosphorylated ets-2 has been found in human IPF lung biopsies and an ets-2 mutant mouse (where ets-2 phosphorylation was blocked) was protected from bleomycin induced pulmonary fibrosis; however, it is unclear how the ets-2 mutation prevents fibrosis. Thus, we utilized an ex vivo microenvironment assay to measure expression of pro-fibrotic genes in addition to performing multiple cellular biomechanical assays. Major findings: 1. ECM fibers were responsible for stress transmission between cells, a property facilitated by cellular remodeling of the ECM fibers into bundles 2.Strain-hardening materials did not increase stress transmission between cells compared to the fibrous or linear elastic ECMs Thus, ECM fibers which are remodeled into bundles are responsible for transmitting stresses over long distances 1.The ets-2 mutant cells expressed significantly less pro-fibrotic genes compared to wildtype cells when cultured on a fibrotic microenvironment compared to a non-fibrotic microenvironment 2.Decreased ECM remodeling in the ets-2 mutant fibroblasts compared to wildtype fibroblasts correlated with a decrease in contractility and adhesion 3.Scratch wound and ibidi based time-lapse imaging assays showed that the ets-2 mutant fibroblasts migrated slower and less directionally compared to wildtype cells Thus, cell contractility, adhesion, and migration may be novel targets for IPF treatment Pulmonary embolism (PE) is the third largest cause of death in hospitalized patients and is caused when a blood clot traveling through the vasculature and is trapped in the lung, causing tissue dysfunction and/or tissue death. Clinically, PEs are usually prevented with anticoagulants, but in certain cases, an inferior vena cava filter (IVCF) is used to trap the clot before it reaches the lung. Recently the FDA released a warning on the long-term use of retrievable IVCF due to the possibility of device-related complications including IVCF strut perforation, but there is currently no recommendation to monitor retrievable IVCFs while in use. Thus, we performed a retrospective study of patient CT scans to identify at-risk groups for IVCF strut perforation. In addition, we developed computational models to predict IVCF strut perforations. Major findings: 1. IVCF strut perforations increase logarithmically over time 2. Women and patients with a history of malignancy are at a higher risk for IVCF strut perforation Thus, retrievable IVCFs should be removed as soon as possible and follow-up imaging should be tailored based on the likelihood of perforation while an IVCF is in use 3. Forces from the IVCF struts applied to the IVC wall correlate with strut deformation 4. IVCF strut perforation could be predicted for struts with large forces in computational models based on patient CT images Thus, computational models could be used as a tool to predict future IVCF strut perforations
Samir Ghadiali, Ph.D. (Advisor)
Keith Gooch, Ph.D. (Committee Member)
Richard Hart, Ph.D. (Committee Member)
Heather Powell, Ph.D. (Committee Member)
163 p.
Biomechanics; Biomedical Engineering; Biomedical Research
Idiopathic Pulmonary Fibrosis; Cellular Biomechanics; Inferior Vena Cava Filter Perforation

Recommended Citations

Citations

  • Schickel, M. E. (2014). Biomechanics of Idiopathic Pulmonary Fibrosis and Inferior Vena Cava Filter Perforation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406048985

    APA Style (7th edition)

  • Schickel, Maureen. Biomechanics of Idiopathic Pulmonary Fibrosis and Inferior Vena Cava Filter Perforation. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1406048985.

    MLA Style (8th edition)

  • Schickel, Maureen. "Biomechanics of Idiopathic Pulmonary Fibrosis and Inferior Vena Cava Filter Perforation." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406048985

    Chicago Manual of Style (17th edition)

osu1406048985
603
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