Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Engineering

First Advisor

John F. Eberth

Abstract

Aortopathies constitute a broad class of diseases affecting the aorta – the largest artery responsible for distributing oxygenated blood to the systemic circulation. Specifically, aortic aneurysms (AAs) are described as a focal dilation of the vascular wall exceeding 50% of the normal vessel diameter. Ultimately AAs may stabilize, dissect, or rupture, with the latter virtually ensuring mortality. Currently clinicians consider prophylactic intervention based on size and growth-rate criteria that have been estimated from large-cohort statistical analyses. These criteria, however, fail to address the underlying mechanisms. Furthermore, 13% of small-to-mid sized AAs have been found to rupture prior to meeting these criteria. Clearly there exists a need for improved methods of evaluating aneurysm stability and predicting outcomes that can be utilized for patient-specific care strategies. Although advanced AAs are dangerous in the normal population, those suffering from heritable connective tissue disorders such as Loeys-Dietz Syndrome (LDS) present even greater clinical challenges. In either case, perioperative mortality rates for prophylactic repair are high, burdening clinicians with the decision to weigh the risks between intervention or rupture. Currently, there are no approved therapeutic management strategies for mitigation of AAs.

On the microstructural level, AAs present as complex, spatially heterogeneous tissues not well suited for analysis by conventional biomechanical techniques. In this dissertation we utilize gold nanoparticles to target degraded elastin at the site of murine aneurysmal aortas and employ micro-computed tomography (micro-CT) to assess damage. Elastin is a key structural protein, fundamental to the healthy function of large arteries. Proteolytic degradation is performed using intraluminal elastase infusion to provide insight into the severity of AA disease with biaxial mechanical characteristics assessed in situ. We further utilize three mouse models of transforming growth factor beta (TGFβ) deficient mice (Tgfb1+/-, Tgfb2+/-, Tgfb3+/-) to replicate the impaired passive and active mechanics of the ascending thoracic aorta that are commonly observed in LDS patients. These results are compared to controls and to the extreme case of elastase-induced thoracic AAs in order to capture the full spectrum of elastopathic aortic disease. To measure the complex strain fields from inflated and extended mouse AAs under physiological conditions, we developed and validated a device capable of full-field Stereo Digital Image Correlation (Stereo DIC) of submerged specimens. Bolstering experimental techniques for AA analysis that capture the complex soft tissue mechanical response can improve temporal and longitudinal studies that drive new therapeutic or interventional avenues with the potential for broad-reaching clinical translation. The associated mortality rates and lack of clinical options for AA patients motivate further studies to improve AA research in hopes of clarifying AA disease etiologies.

Rights

© 2019, Brooks Alexander Lane

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