Master of Sciences, Case Western Reserve University, 2023, Applied Anatomy

The sympathetic nervous system, a subdivision of the autonomic nervous system, innervates glands, smooth and cardiac muscle of the body and drives the “fight or flight” response. The objective of this study is to use anatomical and radiological methods to definitively identify and investigate the sympathetic chain, specifically ganglia from stellate through T5. The overarching goal of this research is to help guide clinical treatments, including nerve block and ligation procedures, for various disorders of the sympathetic nervous system, including cardiac arrhythmias, hyperhidrosis and pain syndromes. This study uses anatomical methods, including cadaveric dissection, optical tracking, anatomic relationships and landmarks, to investigate the characteristics of the sympathetic chain. This study also uses radiologic methods, including conventional radiography and 3 Tesla (T) magnetic resonance imaging (MRI) with a high-resolution 3D constructive interference in steady state (CISS) sequence, to provide a clinically applicable comparison to gross anatomic observations and measurements.

Committee: Andrew Crofton (Committee Co-Chair); Ari Blitz (Committee Co-Chair); Darin Croft (Committee Member) Subjects: Anatomy and Physiology; Biology; Health; Health Sciences; Medical Imaging; Medicine; Neurobiology; Neurology; Neurosciences; Radiology

Doctor of Philosophy, The Ohio State University, 2018, Materials Science and Engineering

Third generation Al-Cu-Li alloys have improved localized corrosion resistance compared to previous generations and are attractive to the aerospace industry because of the mix of low density and good mechanical properties. Al-Cu-Li alloy AA2099 (Al 2.7Cu 1.8Li 0.6Zn 0.3Mg 0.3Mn 0.08Zr) is a newer precipitation-strengthened alloy with a cleaner microstructure that contributes to increased corrosion resistance. However, there is still a susceptibility for intergranular and inter-subgranular (IGC/IsGC). Because localized corrosion associated with coarse constituent particles is diminished due to alloy cleanliness, intergranular forms of attack are a larger factor in the corrosion profile of this alloy. The susceptibility to localized corrosion in AA2099 was characterized based on the attack morphology after exposure to various NaCl aqueous solutions. Alloy samples were subjected to a series of artificial heat treatments conducted at temperatures ranging from 120°C to 180°C for times ranging from 12 to 168 hours, corresponding to time and temperature ranges that are commensurate with commercial practice. The resulting microstructures were analyzed using scanning transmission electron microscopy (TEM), electron back-scattering, and diffraction methods, which characterized the precipitates formed during artificial aging. The formation of the strengthening phase T1 (Al2CuLi) was of particular interest due to its reported anodic behavior relative to the alloy matrix. This particle is prone to corrosion attack and plays a significant role in the evolution of localized corrosion mode and morphology depending on its location within the alloy. The results from the exposure experiments provided a map for the various heat treatments to identify when IsGC susceptibility will occur. Results showed that AA2099 went through several attack categories as samples were aged to under-aged (UA), peak-aged (PA), and over-aged (OA) conditions. The morphology in the cross section progre (open full item for complete abstract)

Committee: Rudolph Buchheit (Advisor) Subjects: Materials Science

Doctor of Philosophy, Case Western Reserve University, 2017, Biomedical Engineering

Quantification of tissue properties has long been a research goal in Magnetic Resonance Imaging (MRI). However, the long acquisition time of the conventional quantitative method prohibited its adoption in the clinic. The recently proposed Magnetic Resonance Fingerprinting (MRF) is a novel framework that simultaneously quantifies multiple tissue properties using pseudorandom acquisition parameters. It breaks the convention of MRI which acquires a steady- state signal with fixed acquisition parameters, and thus MRF can exploit all degrees of freedom in the pulse sequence design. With nearly unlimited choices of sequence parameters, the thesis explored and presented MRF methods based on the QUick Echo Split NMR technique (QUEST) to reduce the Specific Absorption Rate (SAR), the Fast Imaging with Steady-state Precession (FISP) to improve the performance with off-resonance, the Double Echo Steady-state (DESS) to quantify diffusion, and a Simultaneous MultiSlice (SMS) MRF to further reduce the acquisition time. The development of these novel methods improves the robustness of MRF and have the potential to extend MRF to wide ranges of applications.

Committee: Mark Griswold PhD (Advisor); Nicole Seiberlich PhD (Committee Chair); Xin Yu PhD (Committee Member); Erkki Somersalo PhD (Committee Member); Jeffrey Sunshine MD,PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, University of Akron, 2015, Chemistry

Multiple systems were studied to advance the understanding of the chemical composition of the materials. These materials contained various structures or structures within different physical phases. Solid-state NMR techniques were used to probe effects of different chemical processes and environmental conditions on the chemical structures and phase composition of these materials. Much of the high thermal and chemical resistance of poly(vinylidene-co-hexafluoropropylene) is gained from cross-linking. The insolubility of the cross-linked fluoroelastomer has prevented the characterization of the structure at the cross-link site by NMR. Samples from each of the four stages of the cross-linking of poly(vinylidene-co-hexafluoropropylene) were analyzed with solid-state NMR to determine the chemical structure at the cross-linking site and the effects of cross-linking on the mobility of the elastomer chains. Spectral overlap from chemical shift dispersion hindered the use of simple 1D techniques to assign structural components to peaks in the NMR spectra. Relaxation studies that measured T1, T2, and T1ρ relaxation times were used to assign new peaks in the NMR spectra to the fluoride salts that are produced during cross-linking. The NMR relaxation data also indicated no reduction in the mobility of the fluoroelastomer from cross-linking. The chemical structure of the cross-link site was partially characterized by 2D-NMR. However, the amorphous nature of the polymer inhibited a full characterization of this location with 2D-NMR techniques. The structures that were identified at the cross-link site supported proposed structures. Solutions of NaCl and dextrose used in the preservation of premixed drugs were analyzed to distinguish the solid and liquid phases over a temperature range of -60 to 20 °C. The large chemical shift dispersion in the NMR spectra made analysis of the frequency domain data difficult. The time domain data of the single pulse NMR experiments were analyzed (open full item for complete abstract)

Committee: Peter Rinaldi Dr. (Advisor); Chrys Wesdemiotis Dr. (Committee Member); David Modarelli Dr. (Committee Member); Leah Shriver Dr. (Committee Member); Elizabeth McCord Dr. (Committee Member); Toshikazu Miyoshi Dr. (Committee Member) Subjects: Analytical Chemistry; Chemistry

Doctor of Philosophy, Case Western Reserve University, 2015, Biomedical Engineering

Magnetic Resonance (MR) is an exceptionally powerful and versatile measurement technique. The basic structure of an MR experiment has remained nearly constant for almost 50 years. Here we introduce a novel paradigm, Magnetic Resonance Fingerprinting (MRF) that permits the non-invasive quantification of multiple important properties of a material or tissue simultaneously through a new approach to data acquisition and post-processing. MRF provides a new mechanism to quantitatively detect and analyze complex changes that can represent physical alterations of a substance or early indicators of disease. MRF can also be used to specifically identify the presence of a target material or tissue, which will increase the sensitivity, specificity, and speed of an MR study, and potentially lead to new diagnostic testing methodologies. Because of its basis in pattern recognition, MRF inherently suppresses measurement errors and thus can improve accuracy and efficiency compared to previous approaches. By taking the advantage of the extra degrees of freedom of the MRF concept, the MRF-Music sequence is presented as a special form of the MRF to improve the patients' comfort level during the MR scans while still maintaining a high image quality and scan efficiency.

Committee: Mark Griswold (Advisor); Nicole Seiberlich (Committee Chair); Vikas Gulani (Committee Member); David Wilson (Committee Member); Jeffrey Duerk (Committee Member); Daniela Calvetti (Committee Member) Subjects: Biomedical Engineering

Master of Science (MS), Ohio University, 2009, Environmental Studies (Arts and Sciences)

Toluene is a major component of gasoline and is a widely used industrial solvent. It contaminates surface and groundwater and poses a menacing threat to human health. Toluene is not a carcinogen; however, in mixtures it enhances the effect of carcinogens. This research uses a molecular approach to study toluene biodegradation by the facultative, denitrifier Thauera aromatic strain T1 (T.aromatica strain T1). This strain is able to degrade toluene into non aromatic compounds under anaerobic conditions and use it as a sole carbon and energy source. Previous work identified the tutE tutFDGH gene cluster as essential for the first step of anaerobic toluene biodegradation. The aim of this research is to determine the role of selected amino acids in the function of the TutH protein in toluene biodegradation by T.aromatica strain T1. This work determined if changes can be made to certain amino acids in the TutH protein without disrupting protein function. We identified amino acids of interest by computer analysis and used site-directed mutagenesis to generate the desired changes. Based on computer analysis, I formed a hypothesis that changing the amino acid leucine at position 266 into valine , changing serine at position 5 into theronine, or changing tyrosine at position 283 into phenyalanine will not disrupt the TutH protein function. We performed site-directed mutagenesis on TutH and determined that two of these altered proteins (L266V and S5T) failed to complement a strain unable to produce TutH while altered protein containing Y283F succeeded in complementing a strain unable to produce TutH. It is important to identify tolerated amino acids because researchers can use them to change the range of substrates. This research will further the understanding of the toluene metabolism in the environment and may help in the remediation of contaminated sites. Also, this research will contribute to the development of a more efficient toluene bio-degradation pathway. Ideal (open full item for complete abstract)

Committee: Peter Coschigano (Advisor); Michele Morrone (Committee Chair); Erin Murphy (Committee Member) Subjects: Microbiology

Doctor of Philosophy (PhD), Ohio University, 2007, Biological Sciences (Arts and Sciences)

Toluene is an aromatic hydrocarbon that is widely used in our everyday life. It is a major water-soluble constituent of petroleum and can pollute surface as well as ground waters. The toxic nature of toluene is responsible for causing severe health hazards. The study of toluene degrading bacteria has attracted attention because of their potential to clean up spills. Thauera aromaticastrain T1 is one such bacterium capable of degrading toluene under anaerobic conditions. The tutE tutFDGHgene cluster is essential for the first step of anaerobic toluene degradation in T. aromaticastrain T1. The tutF, tutDand tutGgenes are proposed to code for the three subunits of the enzyme benzylsuccinate synthase, which is involved in the initial step of anaerobic toluene degradation pathway. The tutEgene is proposed to code for the enzyme benzylsuccinate synthase activase. The precise role of the tutHgene in toluene degradation is currently unknown, but it is proposed to have an ATP/GTP binding domain and is assumed to be involved in benzylsuccinate synthase complex formation. This is consistent with its proposed role as a chaperone of “ATPases Associated with a Variety of Cellular Activities” (AAA) class. Work presented here demonstrates that the gene tutHis essential for toluene metabolism. A plasmid carrying an in-frame tutHdeletion was unable to produce wild-type TutH protein in a tutGchromosomal deletion background (chromosomal deletion in tutGdoes not result in production of TutH due to a polar effect on downstream genes). The resultant construct was unable to complement a polar tutGchromosomal mutation, indicating the importance of tutHin toluene degradation. Further, site-directed mutagenesis was used to identify amino acids in TutH that are essential for toluene metabolism. The TutH putative ATP/GTP binding domain was disrupted by changing glycine, lysine and serine at positions 52, 53 and 54 to alanine, arginine and alanine respectively. Additionally, other amino acids wh (open full item for complete abstract)

Committee: Peter Coschigano (Advisor) Subjects:

Doctor of Engineering, Cleveland State University, 2009, Fenn College of Engineering

Novel tyramine-based hyaluronan (HA) and collagen hydrogels have been developed in which cross-linking is accomplished via peroxidase-mediated dityramine linkages allowing direct cross-linking in vivo. These TB hydrogels possess advantageous physical properties, which include excellent biocompatibility and the ability to mimic the biological, structural and mechanical properties of normal, healthy tissues, including cartilage, and thus provide for synthetic, implantable biomaterials suitable for a wide range of tissue types. The efficacy of these TB-hydrogels has been previously tested in a number of clinically relevant animal models, which have evaluated their applicability for the repair/replacement of various tissues, including cartilage. Nevertheless, there exists a fundamental need for non-destructive methods to identify, distinguish, quantify and trace these biomaterials in vivo. Magnetic Resonance Imaging (MRI) is a broadly used non-invasive clinical imaging methodology that allows direct visualization of soft tissues. Our results indicated that T1 and T2 mapping can differentiate and measure changes in HA and collagen concentration both alone and in combination with composite materials, composed of HA and collagen at the concentrations found in cartilage resulting in T1 values representative of cartilage. Furthermore, the dGEMRIC technique was able to quantify the HA concentration in phantoms of known HA concentration. These MRI techniques could detect and differentiate the tyramine-based hydrogels in implanted joints, and accurately quantify their volumes.

Committee: Anthony Calabro PhD (Committee Chair); Nolan Holland PhD (Committee Co-Chair); Lars Gilbertson PhD (Committee Member); Mark Kayanja MD, PhD (Committee Member); Miron Kaufman PhD (Committee Member) Subjects: Biomedical Research; Materials Science; Polymers

Doctor of Philosophy, Case Western Reserve University, 2011, Biomedical Engineering

Ca2+ cycling between the cellular and subcellular compartments plays an important role in regulating cardiac contraction. Disturbance in Ca2+ handling occurs in heart failure and is closely related to abnormal contractile performance. The influx of extracellular Ca2+ through L-type calcium channel is the trigger and a key player in the Ca2+ cycling process. However, there are limited ways to measure it in vivo. Recently, manganese (Mn2+)-enhanced MRI (MEMRI) has been proposed as a promising probe to assess Ca2+ uptake because Mn2+ also enters the cell through the Ca2+ channels. However, quantitative analysis and substantial validation are still lacking, which has limited the application of MEMRI as an in vivo method for quantitative delineation of the Ca2+ influx rate. In the current thesis project, a quantitative MEMRI method was developed and validated using small animal models. The sensitivity to subtle alterations in Ca2+ influx rate was demonstrated in a qualitative MEMRI study using a genetically manipulated mouse model that manifested slightly altered L-type Ca2+ channel activity. To provide quantitative estimation of Mn2+ dynamics, fast T1 mapping techniques were developed based on the direct linear relationship between Mn2+ concentration and proton R1. An ECG-triggered saturation recovery Look-Locker (SRLL) method and a model-based compressed sensing method was developed and validated, respectively. When these two methods were combined, rapid T1 mapping (< 80s) of both myocardium and blood were achieved at high spatial resolution (234x469 μm2). Subsequently, a kinetic model was developed to determine Ca2+ influx rate from the quantitative MEMRI measurements. The robustness and accuracy of estimated Ca2+ influx rate was validated using perfusion MEMRI datasets with L-type Ca2+ channel activity well controlled by buffer ingredients. In conclusion, the accomplishment of this project provides a robust MEMRI method for in vivo quantification of L-type Ca2+ (open full item for complete abstract)

Committee: Xin Yu (Committee Chair); Chris Flask (Committee Member); Mark Griswold (Committee Member); David Rosenbaum (Committee Member); David Wilson (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Medical Imaging; Radiation; Radiology

Doctor of Philosophy, Case Western Reserve University, 2010, Neurosciences

Degeneration of chronically demyelinated axons is the leading causative factor in the progression of symptoms experienced by patients with multiple sclerosis (MS), despite the fact that MS has defied classification as a primary neurodegenerative disease. While there are many potential causes of neuronal damage immediately following demyelination, it is within the context of chronic demyelination that the fundamental and intrinsic mechanisms of axonal function can, themselves, become detrimental to axonal integrity. In the wake of demyelination, extensive submembranous cytoskeletal derangement occurs, allowing the once-nodal voltage-gated sodium channels (NaV) to diffuse along the denuded length of the axon. The immediate impact on the axon is two-fold; first is a spatially unrestricted influx of sodium and an associated increase in axoplasmic sodium ([Na]i), second is abrogation of saltatory conduction, which relies on focal sodium influx. In response to a global increase in [Na]i, typically caused by an action potential, the sodium/potassium adenosine triphosphatase (Na/K ATPase), or the sodium pump, hydrolyzes ATP to power the active transport of three intracellular sodium ions for two extracellular potassium ions and, thereby, repolarization of the cell. The cell is driven into an energy debt, causing stress to mitochondria and, thereby, decreasing ATP production. Without sufficient axonal ATP, the Na/K ATPase cannot transport ions across the axolemma. With the Na/K ATPases unable to transport additional sodium across the axolemma, [Na]i increases and the sodium/calcium exchanger (NCX) is driven to reverse its function and exchange intracellular sodium for extracellular calcium. An unchecked rise in axoplasmic calcium can lead to the induction of many deleterious calcium-dependent degradative pathways and the eventual degeneration of the demyelinated axon. In these studies, the “secondary neurodegeneration” of MS is explored; specifically, how the energetic prope (open full item for complete abstract)

Committee: Bruce Trapp Ph.D. (Advisor); Robert Miller Ph.D. (Committee Chair); Gary Landreth Ph.D. (Committee Member); Evan Deneris Ph.D. (Committee Member); Nancy Oleinick Ph.D. (Committee Member) Subjects: Anatomy and Physiology; Biology; Biomedical Research; Neurology; Pharmaceuticals; Scientific Imaging

Master of Sciences (Engineering), Case Western Reserve University, 2008, Biomedical Engineering

Atherosclerotic vulnerable plaque imaging is an important clinical goal. Cryo-imaging can validate vessel tissue classification. A validation study showed overall sensitivity of 89% using naive raters. However, cryo-imaging cannot be clinically translated. Instead, MRI microcoil imaging shows promise. An important component of MR tissue identification is parameter estimation of T1, T2, and proton density. A new parameter estimation method based on Maximum Likelihood Estimation accounting for Rician noise bias with Markov Random Field spatial regularization was developed. A flat image test case shows decreased noise levels comparable to neighborhood averaging. For the lowest signal-to-noise ratio test case, neighborhood averaging decreased the standard deviation of the error to 34% of the single-pixel techniques, while the new method decreased it 37-43%. Tests using simulated phantom image also show well-preserved edges, which is not possible with neighborhood averaging. Finally, the algorithm was tested on brain data to fit T2*, showing visually positive results.

Committee: David Wilson (Advisor); Mark Pagel (Committee Member); Jeff Duerk (Committee Member) Subjects: Biomedical Research; Engineering; Radiology