Biomedical Engineering Department Theses and Dissertations

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    Targeting Bone Quality in Murine Models of Osteogenesis Imperfecta, Diabetes, and Chronic Kidney Disease
    (2024-05) Kohler, Rachel; Wallace, Joseph; Allen, Matthew; Bidwell, Joseph; Surowiec, Rachel
    Skeletal fragility can be caused by a wide array of diseases and disorders, but the most difficult etiologies to clinically circumvent are those in which the body loses not just bone mass but the ability to create healthy bone tissue. While in conditions such as osteoporosis (the most prevalent cause of age-related skeletal fragility in which elevated resorption without compensatory elevated formation leads to bone loss), interventions can target bone remodeling pathways to protect and increase bone mass, many other diseases are characterized by genetic and metabolic crippling of the remodeling process, rendering those same mass-based interventions less effective at reducing fracture risk. Osteogenesis imperfecta (OI) is a class of genetic disorders in which gene mutations affect the formation of collagen, a crucial building block of bone tissue that makes up 90% of its organic matrix, leading to lost bone mass and quality. As the main genetic causes of OI cannot currently be directly treated, therapeutic OI treatments are needed that improve tissue-level material properties. Similarly, metabolic conditions such as diabetes, a disorder in which the body cannot properly regulate blood sugar due to loss of insulin production and/or efficacy, can have multi-organ impacts including increased risk of developing chronic kidney disease and skeletal fragility. Type 2 diabetes is especially notorious for increasing fracture risk despite maintained or even increased apparent bone mass, which is strong evidence that intrinsic bone material properties are impaired by the disease state. A possible solution to the bone quality problem may be treatments that increase bone water content, as amplifying the water content of bone can improve multi-scale material properties such as collagen fibril elasticity and whole-bone toughness. Therefore, increasing bone hydration could be a way of improving tissue-level material properties, despite being unable to eradicate the genetic or metabolic disorders that alter how collagen is produced and incorporated into the bone matrix. To that end, this dissertation presents several studies that characterize models of osteogenesis imperfecta and diabetic kidney disease in mice and investigate methods of rescuing skeletal fragility in these animals through treatments that target both bone mass and bone quality with ties to tissue hydration.
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    Characterization of Biomimetic Spinal Cord Stimulations for Restoration of Sensory Feedback
    (2024-05) Zeiser, Sidnee L.; Yadav, Amol; Yoshida, Ken; Berbari, Edward; Sangha, Susan; Surowiec, Rachel
    Sensory feedback is a critical component for controlling neuroprosthetic devices and brain-machine interfaces (BMIs). A lack of sensory pathways can result in slow, coarse movements when using either of these technologies and, in addition, the user is unable to fully interact with the environment around them. Spinal cord stimulation (SCS) has shown potential for restoring these pathways, but traditional stimulation patterns with constant parameters fail to reproduce the complex neural firing necessary for conveying sensory information. Recent studies have proposed various biomimetic stimulation patterns as a more effective means of evoking naturalistic neural activity and, in turn, communicating meaningful sensory information to the brain. Unlike conventional patterns, biomimetic waveforms vary in frequency, amplitude, or pulse-width over the duration of the stimulation. To better understand the role of these parameters in sensory perception, this thesis worked to investigate the effects of SCS patterns utilizing stochastic frequency modulation, linear frequency modulation, and linear amplitude modulation. By calculating sensory detection thresholds and just-noticeable differences, the null hypothesis for stochastically-varied frequency and linear amplitude modulation techniques was rejected.
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    Impact of Diet on the KK-Ay Mouse Model of Type 2 Diabetes
    (2024-05) Reul, Olivia; Wallace, Joseph M.; Allen, Matthew R.; Surowiec, Rachel K.
    Diabetes is an international health crisis with 1 in 10 (537 million) adults worldwide living with diabetes, and type 2 diabetes (T2D) composing 90% of these cases [1]. T2D is a disease characterized by insulin resistance that leads to pancreatic β cell dysfunction and hyperglycemia. It is known to have deleterious effects on various organ systems, including the skeletal system, leading to an increased fracture risk, despite normal or elevated bone mineral density (BMD). Due to this unique facet of T2D, the cause of this elevated fracture risk has recently become an area of focus both in the clinic and in research. One of the primary concerns when researching this disease state is the use of a model capable of mimicking the complex multisystem effects of diabetes, including the skeletal outcomes. The Yellow Kuo Kondo (KK-Ay) mouse model has shown promise as a non-diet dependent obese model of T2D. In this model, mice heterozygous for a mutation in the agouti gene (Ay) are treated as an obese model of T2D (KK-Ay) while those that are homozygous (no mutation) are a non-diabetic obese control [2]. Although previous studies have revealed this model can display the multisystem effects of diabetes [3,4], data suggest that the efficacy of the model may in fact be reliant on diet. To explore this, mice were placed on separate diets, half on a standard chow (LabDiet 5001) diet and the other half on a diet recommended by Jackson Laboratory for this strain (LabDiet 5LG4). Animals were aged to 16 weeks (wks) with blood glucose (BG) and body weight (BW) monitored every other week and glucose tolerance tests (GTT) and insulin tolerance tests (ITT) performed at 15 wks. At 16 wks, animals were sacrificed via cardiac exsanguination to collect whole blood and blood serum followed by cervical dislocation. The pancreas, bilateral tibiae, and bilateral femora were collected from each animal immediately following sacrifice. Diet did in fact have a significant impact on both the skeletal and metabolic phenotype associated with T2D. Results suggest that future studies should employ the 5LG4 diet in heterozygous animals and the 5001 diet in homozygous animals to better explore the impacts of T2D against a non-diabetic control.
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    Exploration of Sinusoidal Low Frequency Alternating Current Stimulation to Block Peripheral Nerve Activity
    (2024-05) Horn, Michael Ryne; Yoshida, Ken; Ward, Mathew P.; Berbari, Edward J.; Schild, John H.
    Sinusoidal low frequency alternating current (LFAC) stimulation is a novel mode of electrical modulation observed in the Bioelectroics Lab in 2017. LFAC is capable of blocking the single fiber action potentials (APs) of the earthworm with only a few 100’s of µA. The goal of this dissertation was to further explore and characterize the LFAC waveform to determine it’s feasibility as a method for block in the mammalian peripheral nervous system (PNS). To better understand the mechanisms of LFAC block (LFACb), a blend of in-silico modeling work was explored and the predictions were validated with ex-vivo and in-vivo experiments. This dissertation is divided into five chapters. The first chapter will explore the history of bioelectricity, the current state of in-silico modeling and methods of nerve block used in the PNS. The second chapter explores a major modeling assumption, the conductivity and permittivity of the nerve laminae of a mammalian nerve bundle. Four point electrochemical impedance spectroscopy (EIS) was performed on excised canine vagus nerve to evaluate the electrical properties of the perineurium and epineurium. This study’s result, found that the corner frequency of the perineurium (2.6kHz) and epineurium (370Hz) were much lower than previously assumed. This explain a major difference between LFACb and the more established kilohertz frequency alternating current (kHFAC) block. The third chapter revisits the initial earthworm experiments during the discovery of LFACb. The effect of conduction slowing was observed in these earthworm experiments and were also seen in a mammalian canine vagus nerve and in the Horn-Yoshida-Schild (HYS) autonomic unmyelinated axon mode. These experiments showed that LFACb occurs as a cathodic block in which the sodium channels are held inactive. Chapter 4 explored the window between LFACb and LFAC activation (LFACa). The window between the two states was describes by LFAC amplitude and LFAC frequency in an in-vivo rat sciatic nerve and an in-silico model of a myelinated motor neuron, the McIntyre-Richardson-Grill (MRG) axon model. Geometrical effects were also observed by varying the bipolar pair of contacts used to deliver the LFACb waveform from an asymmetrical tripolar cuff electrode. Plantar flexor force measurements and electromyography (EMG) of the lateral gastrocnemius (LG) and soleus (Sol) were used to quantify the effects of the LFAC waveform. Convergence between in-silico modeling and in-vivo results showed promise that modeling efforts could be used with confidence to explore the LFAC block-activation more completly. LFACa was found to be highly dependent on frequency with increasing frequency lowering the threshold of activation. LFACb was shown to be mostly invariant to frequency. The final chapter takes the information found in this dissertation and summarizes it. Future work on LFAC is also proposed and the hypothesized results presented with the findings from this dissertation and available literature.
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    Framework for In-Silico Neuromodulatory Peripheral Nerve Electrode Experiments to Inform Design and Visualize Mechanisms
    (2023-08) Lazorchak, Nathaniel; Yoshida, Ken; Alfrey, Karen; Berbari, Edward
    The nervous system exists as our interface to the world, both integrating and interpreting sensory information and coordinating voluntary and involuntary movements. Given its importance, it has become a target for neuromodulatory therapies. The research to develop these therapies cannot be done purely on living tissues - animals, manpower, and equipment make that cost prohibitive and, given the cost of life required, it would be unethical to not search for alternatives. Computation modeling, the use of mathematics and modern computational power to simulate phenomena, has sought to provide such an alternative since the work of Hodgkin and Huxley in 1952. These models, though they cannot yet replace in-vivo and in-vitro experiments, can ease the burden on living tissues and provide details difficult or impossible to ascertain from them. This thesis iterates on previous frameworks for performing in-silico experiments for the purposes of mechanistic exploration and threshold prediction. To do so, an existing volume conductor model and validated nerve-fiber model were joined and a series of programs were developed around them to perform a set of in-silico experiments. The experiments are designed to predict changes in thresholds of behaviors elicited by bioelectric neuromodulation to parametric changes in experimental setup and to explore the mechanisms behind bioelectric neuromodulation, particularly surrounding the recently discovered Low Frequency Alternating Current (LFAC) waveform. This framework improved upon its predecessors through efficiency-oriented design and modularity, allowing for rapid simulation on consumer-grade computers. Results show a high degree of convergence with in-vivo experimental results, such as mechanistic alignment with LFAC and being within an order of magnitude of in-vivo pulse-stimulation threshold results for equivalent in-vivo and in-silico experimental designs.
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    A Finite Element Model for Investigation of Nuclear Stresses in Arterial Endothelial Cells
    (2022-12) Rumberger, Charles B.; Ji, Julie; Tovar, Andres; Yokota, Hiroki
    Cellular structural mechanics play a key role in homeostasis by transducing mechanical signals to regulate gene expression and by providing adaptive structural stability for the cell. The alteration of nuclear mechanics in various laminopathies and in natural aging can damage these key functions. Arterial endothelial cells appear to be especially vulnerable due to the importance of shear force mechanotransduction to structure and gene regulation as is made evident by the prominent role of atherosclerosis in Hutchinson-Gilford progeria syndrome (HGPS) and in natural aging. Computational models of cellular mechanics may provide a useful tool for exploring the structural hypothesis of laminopathy at the intracellular level. This thesis explores this topic by introducing the biological background of cellular mechanics and lamin proteins in arterial endothelial cells, investigating disease states related to aberrant lamin proteins, and exploring computational models of the cell structure. It then presents a finite element model designed specifically for investigation of nuclear shear forces in arterial endothelial cells. Model results demonstrate that changes in nuclear material properties consistent with those observed in progerin-expressing cells may result in substantial increases in stress concentrations on the nuclear membrane. This supports the hypothesis that progerin disrupts homeostatic regulation of gene expression in response to hemodynamic shear by altering the mechanical properties of the nucleus.
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    The Skeletal Phenotype Of The Kk/Ay Murine Model Of Type 2 Diabetes
    (2022-08) Chowdhury, Nusaiba Nahola; Wallace, Joseph; Allen, Matthew; Bone, Robert; Na, Sungsoo
    Type-2-diabetes (T2D) is a progressive metabolic disease characterized by insulin resistance and β-cell dysfunction leading to persistent hyperglycemia. It is a multisystem disease that causes deterioration of multiple organ systems and obesity. Of interest, T2D affects the urinary system and is the leading cause of kidney disease. Both T2D and chronic kidney negatively impacts the skeletal system and increases fracture incidence in patients. Therefore, it is important to establish an animal model that captures the complex multiorgan effects that is common in T2D. In this study, we characterized the metabolic phenotype of the KK/Ay mouse model, a polygenic mutation model of T2D. We concluded that KK/Ay mice closely mimic T2D and are hyperglycemic, hyperinsulinemic and insulin resistant. KK/Ay mice have also had worsened kidney function as supported by elevated levels of blood urea nitrogen, phosphorous, creatinine, and calcium in plasma exhibiting the kidney’s inefficiency in clearing waste from the body. Even though we were able to confirm a metabolic phenotype for T2D and diabetic nephropathy, the skeletal effects of the disease were minimal and major differences in bone physiology were driven by sex differences. This study offered valuable insight into preliminary endpoints for the KK/Ay mouse mode that will decide the direction for future use of this model. We plan to use older mice in future studies to allow a longer time for skeletal effects to more prominently manifest.
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    A Comparative Analysis of Local and Global Peripheral Nerve Mechanical Properties During Cyclical Tensile Testing
    (2022-05) Doering, Onna Marie; Yoshida, Ken; Wallace, Joseph; Goodwill, Adam
    Understanding the mechanical properties of peripheral nerves is essential for chronically implanted device design. The work in this thesis aimed to understand the relationship between local deformation responses to global strain changes in peripheral nerves. A custom-built mechanical testing rig and sample holder enabled an improved cyclical uniaxial tensile testing environment on rabbit sciatic nerves (N=5). A speckle was placed on the surface of the nerve and recorded with a microscope camera to track local deformations. The development of a semi-automated digital image processing algorithm systematically measured local speckle dimension and nerve diameter changes. Combined with the measured force response, local and global strain values constructed a stress-strain relationship and corresponding elastic modulus. Preliminary exploration of models such as Fung and 2-Term Mooney-Rivlin confirmed the hyperelastic nature of the nerve. The results of strain analysis show that, on average, local strain levels were approximately five times smaller than globally measured strains; however, the relationship was dependent on global strain magnitude. Elastic modulus values corresponding to ~9% global strains were 2.070 ± 1.020 MPa globally and 10.15 ± 4 MPa locally. Elastic modulus values corresponding to ~6% global strains were 0.173 ± 0.091 MPa globally and 1.030 ± 0.532 MPa locally.
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    Building a Tensegrity-Based Computational Model to Understand Endothelial Alignment Under Flow
    (2021-12) Al-Muhtaseb, Tamara; Ji, Julie; Na, Sungsoo; Tovar, Andres
    Endothelial cells form the lining of the walls of blood vessels and are continuously subjected to mechanical stimuli from the blood flow. Microtubule-organizing center (MTOC), also known as centrosome is a structure found in eukaryotic cells close to the nucleus. MTOC relocates relative to the nucleus when endothelial cells are exposed to shear stress which determines their polarization, thus it plays a critical role in cell migration and wound healing. The nuclear lamina, a mesh-like network that lies underneath the nuclear membrane, is composed of lamins, type V intermediate filament proteins. Mutations in LMNA gene that encodes A-type lamins cause the production of a mutant form of lamin A called progerin and leads to a rare premature aging disease known as Hutchinson-Gilford Progeria Syndrome (HGPS). The goal of this study is to investigate how fluid flow affects the cytoskeleton of endothelial cells. This thesis consists of two main sections; computational mechanical modeling and laboratory experimental work. The mechanical model was implemented using Ansys Workbench software as a tensegrity-based cellular model in order to simulate the state of an endothelial cell under the effects of induced shear stress from the blood fluid flow. This tensegrity-based cellular model - composed of a plasma membrane, cytoplasm, nucleus, microtubules, and actin filaments - aims to understand the effects of the fluid flow on the mechanics of the cytoskeleton. In addition, the laboratory experiments conducted in this study examined the MTOC-nuclear orientation of endothelial cells under shear stress with the presence of wound healing. Wild-type lamin A and progerin-expressing BAECs were studied under static and sheared conditions. Moreover, a custom MATLAB code was utilized to measure the MTOC-nuclear orientation angle and classification. Results demonstrate that shear stress leads to different responses of the MTOC orientation between the wild-type and progerin-expressing cells around the vertical wound edge. Future directions for this study involve additional experimental work together with the improved simulation results to confirm the MTOC orientation relative to the nucleus under shear stress.
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    Sex-Specific Bone Phenotype in the Streptozotocin-Induced Murine Model of Diabetes
    (2021-08) Hatch, Jennifer; Wallace, Joseph M.; Allen, Matthew R.; Bone, Robert N.; Li, Jilliang; Na, Sungsoo
    Bone disease and degradation is a ubiquitous problem, the complexity and treatment of which humanity has only begun to understand. Diabetes Mellitus is a disease which, in all forms, profoundly effects the organs of the body, bone included. As is often the case in biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Although there are several reported mouse models for diabetes, until now there has been no characterization of bone disease in any model where diabetes occurs with equal frequency in males and females in greater than 90% of animals. In this study, a protocol for reliable induction of diabetes in both sexes using intraperitoneal injections of Streptozotocin was developed. The resulting bone phenotype in male and female mice was characterized and compared to weight and age matched control groups. In this model female diabetic mice exhibited a robust deficit in bone quality, while both sexes experienced loss of beta-cell mass and increased glycation of hemoglobin rendering the diabetic mice unable to produce insulin endogenously. Further, these mice were unable to metabolize exogenous insulin injected during insulin tolerance testing. This model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.