Browsing by Author "Wallace, Joseph"
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Item 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, AdamUnderstanding 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.Item Creating Virtual Spaces to Build Community Among Students Entering an Undergraduate Biomedical Engineering Program(Springer Nature, 2020-08-20) Higbee, Steven; Miller, Sharon; Waterfill, Abigail; Maxey, Kayla; Stella, Julie; Wallace, Joseph; Biomedical Engineering, School of Engineering and TechnologyAfter the transition to online instruction in response to the COVID-19 pandemic, students in our program lamented the loss of connection to their peers, more so than diminished access to faculty, teaching assistants, or other resources. Fortunately, given that the semester was well underway when the transition occurred and few students in our courses were new to our BME program, we feel that students missed out on relatively few formative community-building experiences. This would not be the case for a fall semester of online instruction, however, so we must take action for the sake of our incoming class of undergraduate students. Our experience from spring 2020 and our review of the relevant literature suggest that we can be successful at building community among our new cohort of BME students, regardless of the mode of instruction.Item Disabling the Transcription Factor Nmp4 from Osteogenic Precursors Enhances the Skeleton's Response to the Osteoporosis Drug Parathyroid Hormone(2022-08) Atkinson, Emily Grace; Bidwell, Joseph P.; Robling, Alexander G.; Plotkin, Lilian I.; Wallace, Joseph; Organ, Jason M.; Evans-Molina, CarmellaActivation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis. Yet, FDA-approved osteoanabolics, e.g., parathyroid hormone (PTH) have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice, exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues, therefore, to determine whether the suppression of PTHinduced bone formation is cell autonomous, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+ to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+ targeting mature osteoblasts and (iii) Dmp1Cre+ to disable Nmp4 in transitional osteocytes. Virgin female Cre+ and Cre- mice (10wks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1–34 at 30μg/kg, or vehicle for 4wks or 7wks. The skeletal response was assessed using dual-energy X-ray absorptiometry, microcomputed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl;Prx1Cre+ mice recapitulated the global Nmp4-/- skeletal phenotype in the femur, i.e., an enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared to their Nmp4fl/fl;Prx1Cre- controls. This was not observed in the spine, where Prx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl;BglapCre+) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl;Dmp1Cre+) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4-/- MSPCs drive the enhanced response to PTH therapy, and Nmp4 has stage-specific effects on osteoanabolism.Item DYRK1A-Related Trabecular Defects in Male Ts65Dn Mice Emerge During a Critical Developmental Window(2021-08) LaCombe, Jonathan M.; Roper, Randall; Goodlett, Charles; Li, Jiliang; Wallace, Joseph; Meyer, JasonDown syndrome (DS) is a complex genetic disorder caused by the triplication of human chromosome 21 (Hsa21). The presence of an extra copy of an entire chromosome greatly disrupts the copy number and expression of over 350 protein coding genes. This gene dosage imbalance has far-reaching effects on normal development and aging, leading to cognitive and skeletal defects that emerge earlier in life than the general population. The present study begins by characterizing skeletal development in young male Ts65Dn mice to test the hypothesis that skeletal defects in male Ts65Dn mice are developmental in nature.Femurs from young mice ranging from postnatal day 12- to 42-days of age (P12-42) were measured and analyzed by microcomputed tomography (μCT). Cortical defects were present generally throughout development, but trabecular defects emerged at P30 and persisted until P42. The gene Dual-specificity tyrosine-regulated kinase 1a (Dyrk1a) is triplicated in both DS and in Ts65Dn mice and has been implicated as a putative cause of both cognitive and skeletal defects. To test the hypothesis that trisomic Dyrk1a is related to the emergence of trabecular defects at P30, expression of Dyrk1a in the femurs of male Ts65Dn mice was quantified by qPCR. Expression was shown to fluctuate throughout development and overexpression generally aligned with the emergence of trabecular defects at P30. The growth rate in trabecular measures between male Ts65Dn and euploid littermates was similar between P30 and P42, suggesting a closer look into cellular mechanisms at P42. Assessment of proliferation of BMSCs, differentiation and activity of osteoblasts showed no significant differences between Ts65Dn and euploid cellular activity, suggesting that the cellular microenvironment has a greater influence on cellular activity than genetic background. These data led to the hypothesis that reduction of Dyrk1a gene expression and pharmacological inhibition of DYRK1A could be executed during a critical period to prevent the emergence of trabecular defects at P30. To tests this hypothesis, doxycycline-induced cre-lox recombination to reduce Dyrk1a gene copy number or the DYRK1A inhibitor CX-4945 began at P21. The results of both genetic and pharmacological interventions suggest that trisomic Dyrk1a does not influence the emergence of trabecular defects up to P30. Instead, data suggest that the critical window for the rescue of trabecular defects lies between P30 and P42.Item Empathy and ethical becoming in biomedical engineering education: A mixed methods study of an animal tissue harvesting laboratory(Taylor & Francis, 2021) Hess, Justin L.; Miller, Sharon; Higbee, Steven; Fore, Grant A.; Wallace, Joseph; Biomedical Engineering, School of Engineering and TechnologyBiomedical engineering presents a unique context for ethics education due to the human-centric nature of biomedical engineering coupled with the pervasiveness of animal-based practices. This study summarises the design of a pedagogical practice intended to enhance students’ abilities to recognise ethical issues in biomedical engineering practice and inquire into normative aspects of the discipline. The context of the study is an introductory biomechanics course wherein students harvested animal tissue, critically reflected on this experience, and discussed the experience in class. We brought two theoretical frameworks to this investigation pertaining to empathy and ethical becoming. We employed a four-phase mixed methods research design that included quantitative comparisons of changes in empathy and related phenomena, thematic analysis of written reflections, an observation and focus group, and triangulation of these results. Quantitative data remained stable before and after the course. Thematic analysis of reflections revealed five themes: research design, treatment of animals, beneficence, worth of life, and emotional engagement. The observational and focus group results emphasise affective considerations of engineering practice. This study provides a guide for future biomedical engineering education efforts that deal with ethically sensitive, emotionally powerful, and visceral experiences, as well as for research pertaining to empathy and ethical becoming.Item Experimental and Computational Analysis of Dynamic Loading for Bone Formation(2013-11-12) Dodge, Todd Randall; Wallace, Joseph; Na, Sungsoo; Yokota, Hiroki, 1955-; Schild, John H.Bone is a dynamic tissue that is constantly remodeling to repair damage and strengthen regions exposed to loads during everyday activities. However, certain conditions, including long-term unloading of the skeleton, hormonal imbalances, and aging can disrupt the normal bone remodeling cycle and lead to low bone mass and osteoporosis, increasing risk of fracture. While numerous treatments for low bone mass have been devised, dynamic mechanical loading modalities, such as axial loading of long bones and lateral loading of joints, have recently been examined as potential methods of stimulating bone formation. The effectiveness of mechanical loading in strengthening bone is dependent both on the structural and geometric characteristics of the bone and the properties of the applied load. For instance, curvature in the structure of a bone causes bending and increased strain in response to an axial load, which may contribute to increased bone formation. In addition, frequency of the applied load has been determined to impact the degree of new bone formation; however, the mechanism behind this relationship remains unknown. In this thesis, the application of mechanical loading to treat osteoporotic conditions is examined and two questions are addressed: What role does the structural geometry of bone play in the mechanical damping of forces applied during loading? Does mechanical resonance enhance geometric effects, leading to localized areas of elevated bone formation dependent on loading frequency? Curvature in the structure of bone was hypothesized to enhance its damping ability and lead to increased bone formation through bending. In addition, loading at frequencies near the resonant frequencies of bone was predicted to cause increased bone formation, specifically in areas that experienced high principal strains due to localized displacements during resonant vibration. To test the hypothesis, mechanical loading experiments and simulations using finite element (FE) analysis were conducted to characterize the dynamic properties of bone. Results demonstrate that while surrounding joints contribute to the greatest portion of the damping capacity of the lower limb, bone absorbs a significant amount of energy through curvature-driven bending. In addition, results show that enhanced mechanical responses at loading frequencies near the resonant frequencies of bone may lead to increased bone formation in areas that experience the greatest principal strain during vibration. These findings demonstrate the potential therapeutic effects of mechanical loading in preventing costly osteoporotic fractures, and explore characteristics of bone that may lead to optimization of mechanical loading techniques. Further investigation of biomechanical properties of bone may lead to the prescribing of personalized mechanical loading treatments to treat osteoporotic diseases.Item Global Deletion of Sost Increases Intervertebral Disc Hydration But May Trigger Chondrogenesis(2020-05) Kroon, Tori; Holguin, Nilsson; Wallace, Joseph; Wagner, DianeIntervertebral discs (IVD) degenerate earlier than many other musculoskeletal tissues and will continue to degenerate with aging. IVD degeneration affects up to 80 percent of the adult population and is a major contributing factor to low back pain. Anti-sclerostin antibody is an FDA-approved treatment for osteoporosis in postmenopausal women at high-risk for fracture and, as a systemic stimulant of the Wnt/LRP5/β-Catenin signaling pathway, may impact the IVD. Stabilization of β-Catenin in the IVD increases Wnt signaling and is anabolic to the extracellular matrix (ECM), while deletion of β-catenin or LRP5 decreases Wnt signaling and is catabolic to the ECM. Here, we hypothesized that a reduction of Sost would stimulate ECM anabolism. Lumbar and caudal (tail) IVD and vertebrae of Sost KO and WT (wildtype) mice (n=8 each) were harvested at 16 weeks of age and tested by MRI, histology, immunohistochemistry, Western Blot, qPCR, and microCT. Compared to WT, Sost KO reduced sclerostin protein and Sost gene expression. Next, Sost KO increased the hydration of the IVD and the proteoglycan stain in the nucleus pulposus and decreased the expression of genes associated with IVD degeneration, e.g., heat shock proteins. However, deletion of Sost was compensated by less unphosphorylated (active) β-Catenin protein in the cell nucleus, upregulation of Wnt signaling inhibitors Dkk1 and sFRP4, and catabolic ECM gene expression. Consequently, notochordal and early chondrocyte-like cells (CLCs) were replaced by mature CLCs. Overall, Sost deletion increased hydration and proteoglycan protein content, but activated a compensatory suppression of Wnt signaling that may trigger chondrogenesis and may potentially be iatrogenic to the IVD in the long-term.Item In vitro evaluation of polymerization energy for bulk fill composites(2016-05) AlRasheed, Rawan S.; Platt, Jeffery A.; Wallace, Joseph; Matis, Bruce A.; Cook, Norman Blaine; Chu, Tien-Min GabrielRecently, the concept of “bulk-fill” resin-based composites (RBCs) has been re-emphasized, with claimed improvements in depth of cure (DOC) with similar mechanical properties and comparable adaptation to walls and margins relative to conventional composite. More research is needed to carefully examine the properties of these new materials. The objective of this study was to measure the light energy, microhardness (VHN), and elastic modulus across the depth of one conventional and three bulk-fill RBCs. Materials and Methods: Three commercially available bulk-fill RBCs (Tetric EvoCeram Bulk Fill [TE], SonicFill [SF], X-tra fill[XF]) and one conventional RBC (Premise [PR]) were evaluated (n = 10). DOC (using Vickers’s microhardness), elastic modulus (using atomic force microscopy), and the mean irradiance and total light energy transmitted through different thicknesses of RBC were measured by a spectrometer. The effects of group, location, and curing depth on VHN were analyzed using mixed-model ANOVA. Elastic modulus and light energy comparisons were made using two-way ANOVA, with a significance level of 5 percent. Results: There was a significant difference in the depths for the mean irradiance and total energy between different depths in all materials. All materials achieved the manufacturers’ claimed DOC. XF had the highest DOC with 7 mm and a light energy of 0.56± 0.02 J/cm2 at 7 mm. PR had the lowest DOC with 3 mm and a light energy of 0.84 ±0.12 J/cm2 at 3 mm. The elastic modulus showed significant variation in depth profiles that were different than the DOC. Significance: The manufacturers’ claims for bulk-fill DOC were achieved using a microhardness method. However, this method failed to detect the quality of the polymerization. Assessment of the elastic modulus using AFM is a promising method for greater understanding of the polymerization.Item Influence of Mechanical Stimulation on the Quantity and Quality of Bone During Modeling(2016) Berman, Alycia G.; Wallace, Joseph; Na, Sungsoo; Li, Jiliang; Yoshida, KenSkeletal fractures due to bone disease impact an estimated 1.5 million Americans per year, creating a large economic burden on our society. Treatment of bone diseases prior to fracture often involves bisphosphonates (current gold-standard in osteoporosis care and prevention). Although bisphosphonates decrease fracture incidence, they often improve bone mass without regard for bone quality. Thus, although bisphosphonates increase the amount of bone present, the inherent bone material strength often decreases, creating a trade-off that increases the risk of atypical fractures after long-term use. This trade-off demonstrates the need for a treatment that targets both bone quality AND quantity. Although bone quality is important, the components of bone that contribute to bone quality are incompletely understood, making it difficult to create new pharmacological agents. With this in mind, my particular area of interest is in understanding how mechanical stimuli protects the formation of bone, leading to improved bone quality. Initially, this area was explored through use of tibial loading in a disease mouse model (osteolathyrism, induced by injection of beta-aminoproprionitrile) as a means of assessing how the body is able to compensate for decreased bone quality. The results of the BAPN and tibial loading studies indicated that injecting mice with BAPN may not be the ideal method to induce osteolathyrism. However, other intriguing results from the BAPN studies then led us into an exploration of how tibial loading itself contributes to bone quality.Item Mechano-sensitivity of nuclear lamin proteins in endothelial cells(2016-07-22) Jiang, Yizhi; Ji, Julie Ying Hui; Na, Sungsoo; Wallace, JosephAtherosclerosis is a chronic disease that happens mostly in aged people, and recently studies have showed many similarities between Hutchinson Gilford Progeria Syndrome (HGPS) cells and aging cells, implicating dysfunctions of lamin A/C in aging process and atherosclerosis, as HGPS is caused by a mutated form of lamin A/C. Blood flow in arteries is generating shear stress that is mostly applied on endothelial cells that align along inner blood vessel wall. At the same time, endothelial cells are also under stretch by periodic arterial pulses. Considering the fact that atherosclerosis is prone to developing at arterial branches with disturbed shear and increased stretch, it is highly possible that laminar flow and proper stretch force are regulating endothelium to function appropriately. In this thesis, the investigation of what effects laminar flow or cyclic stretch can bring to endothelial cells was conducted, and examination of lamin A/C expression under mechanical forces were elaborated and incorporated with cell senescence. Results showed that laminar shear stress and stretch force can regulate lamin A/C expression in different patterns, which were impaired in senescent cells.