Biomedical Engineering Department Theses and Dissertations

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Browsing Biomedical Engineering Department Theses and Dissertations by Author "Allen, Matthew R."

Now showing 1 - 4 of 4
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    The Effects of Zoledronate and Raloxifene Combination Therapy on Diseased Mouse Bone
    (2019-05) Powell, Katherine M.; Wallace, Joseph M.; Yokota, Hiroki; Allen, Matthew R.
    Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissue’s ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the quality-based effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchical levels.
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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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    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.
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    Thermoneutral Housing Did Not Impact the Combined Effects of External Loading and Raloxifene on Bone Morphology and Mechanical Properties in Growing Female Mice
    (2020-12) Tastad, Carli A.; Wallace, Joseph M.; Allen, Matthew R.; Li, Jiliang
    Raloxifene is an FDA-approved selective estrogen receptor modulator (SERM) that improves tissue quality by binding to collagen and increasing the bound water content in the bone matrix in a cell-independent manner. In this thesis, active tissue formation was induced by non-invasive external tibial loading in female mice and combined with raloxifene treatment to assess their combined effect on bone morphology and mechanical properties. Thermoregulation is an important factor that could have physiological consequences on research outcomes, and was introduced as an additional experimental factor in this study. We hypothesized that by removing the mild cold stress under which normal lab animals are housed, a metabolic boost would allow for further architectural and mechanical improvements as a result of the combination of tibial loading and raloxifene treatment. Ten week old female C57BL/6J mice were treated with raloxifene, underwent tibial loading to a strain level of 2050µε and were housed in thermoneutral conditions (32°C) for 6 weeks. We investigated bone morphology through microcomputed tomography (µCT) and mechanical properties via four-point bending and fracture toughness testing. Results indicated a combined improvement by external loading and raloxifene on geometry, particularly in the cancellous region of the bone, and also in bone mechanics leading to greater improvements than either treatment individually. Temperature did not have a robust impact on either bone architecture or mechanical integrity.