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Item Aging aggravates intervertebral disc degeneration by regulating transcription factors toward chondrogenesis(Wiley, 2020-02) Silva, Matthew J.; Holguin, Nilsson; Anatomy and Cell Biology, School of MedicineOsterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of Wnt signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates the differentiation of prehypertrophic chondrocyte-like cells and inactivates Wnt signaling, but its interactive role with osterix is unclear. First, compared to young-adult (5 mo), mechanical compression of old (18 mo) IVD induced greater IVD degeneration. Aging (5 vs 12 mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated the transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12 mo IVD. Next, using an Ai9/td reporter and immunohistochemical staining, annulus fibrosus and nucleus pulposus cells of young-adult IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells inactivated Wnt signaling in the nucleus pulposus by 95%, degenerated the IVD to levels similar to aging and compression, reduced the biomechanical properties by 45-70%, and reduced the transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of Wnt signaling in osterix-expressing cells may limit regeneration by depleting the progenitors and attenuating the expansion of chondrocyte-like cells.Item Association between Preseason/Regular Season Head Impact Exposure and Concussion Incidence in NCAA Football(ACSM, 2022-06) Stemper, Brian D.; Harezlak, Jaroslaw; Shah, Alok S.; Rowson, Steven; Mihalik, Jason P.; Riggen, Larry; Duma, Stefan; Pasquina, Paul; Broglio, Steven P.; Mcallister, Thomas W.; Mccrea, Michael A.; CARE Consortium Investigators; Psychiatry, School of MedicinePurpose Contact sport athletes are exposed to a unique environment where they sustain repeated head impacts throughout the season and can sustain hundreds of head impacts over a few months. Accordingly, recent studies outlined the role that head impact exposure (HIE) has in concussion biomechanics and in the development of cognitive and brain-based changes. Those studies focused on time-bound effects by quantifying exposure leading up to the concussion, or cognitive changes after a season in which athletes had high HIE. However, HIE may have a more prolonged effect. This study identified associations between HIE and concussion incidence during different periods of the college football fall season. Methods This study included 1120 athlete seasons from six National Collegiate Athletic Association Division I football programs across 5 yr. Athletes were instrumented with the Head Impact Telemetry System to record daily HIE. The analysis quantified associations of preseason/regular season/total season concussion incidence with HIE during those periods. Results Strong associations were identified between HIE and concussion incidence during different periods of the season. Preseason HIE was associated with preseason and total season concussion incidence, and total season HIE was associated with total season concussion incidence. Conclusions These findings demonstrate a prolonged effect of HIE on concussion risk, wherein elevated preseason HIE was associated with higher concussion risk both during the preseason and throughout the entire fall season. This investigation is the first to provide evidence supporting the hypothesis of a relationship between elevated HIE during the college football preseason and a sustained decreased tolerance for concussion throughout that season.Item Big Data Edge on Consumer Devices for Precision Medicine(IEEE, 2022) Stauffer, Jake; Zhang, Qingxue; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and EngineeringConsumer electronics like smartphones and wearable computers are furthering precision medicine significantly, through capturing/leveraging big data on the edge towards real-time, interactive healthcare applications. Here we propose a big data edge platform that can, not only capture/manage different biomedical dynamics, but also enable real-time visualization of big data. The big data can also be uploaded to cloud for long-term management. The system has been evaluated on the real-world biomechanical data-based application, and demonstrated its effectiveness on big data management and interactive visualization. This study is expected to greatly advance big data-driven precision medicine applications.Item Biomechanics of Smooth Muscle Cell Differentiation: Experimental Study using an Innovative in vitro Mechanical System(Office of the Vice Chancellor for Research, 2013-04-05) Akella, ArunIdentifying mechanisms that regulate different smooth muscle cell (SMC) gene expressions is critical for understanding the SMC phenotype and genotype in both physiological and pathological conditions, as SMCs’ primary role is to control the slow, involuntary movement of hollow organs such as blood vessels, airways, gastrointestinal, urinary and reproductive tracks. Previous in vitro studies indicated that specific genes were lost and there was a slight change in the physical structure of the SMCs. This was due to the overwhelming complexity of the in vivo environment which could not be accurately simulated in vitro. It is hypothesized that if SMCs are cultured in vitro by subjecting them to controlled mechanical stresses (cyclic strains at various frequencies and time durations), they will retain the same level of gene expression as in vivo. The objective is to evaluate subsequent changes in the SMC lineage based on gene expression changes. To accomplish this, a novel cell stretching device is being developed that will stimulate cultured SMCs by allowing both culturing and stretching of cells on the same unit. This also effectively reduces the working time needed by researchers to complete each run. The expected outcome will be the effects of different mechanical stresses on cell survival over time. Specifically, SMC lineage assessment and western blot analysis will be done. The results will hopefully prove that in vivo conditions of SMCs can be successfully simulated in vitro. The research will help in comparing the oxidative stresses, hyperglycemia, lipotoxicity and calcification responses on specific SMC types in vitro, and offer new insights into the genetic and environmental bases of SMC diseases. This is critical for research in areas such as drug screening and tissue engineering. For future research, co-culture systems may be studied as the device is capable of culturing two cell-types in the same environment.Item A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD(Wiley, 2014-04) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone II, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.; Department of Medicine, IU School of MedicinePatients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about oversuppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for 10 weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by micro-computed tomography (µCT) and both equally suppressed the mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.Item A critical evaluation of the T-Scan digital occlusion analysis system(2023-07-12) Bawa, Devaansh; Katona, Thomas R.Background: Universally used clinical armamentaria such as articulating paper, film, and silk, introduce an inter-dental material, thus leading to artefactual occlusal contact force measurements. Although the state-of-the-art high-tech T-Scan Novus similarly engages the dentition, the company promotes claims asserting T-Scan’s ability to provide reliable measurements of contact forces and their timing. Aims: A purpose of this study was to evaluate T-Scan’s capability to measure occlusal contact forces and their timing. Another purpose was to examine T-Scan’s data processing algorithm. Methods: The forces experienced by contacting crown-crown (control) and crown-sensor-crown (T-Scan) configurations with denture teeth were measured by a load cell. For statistical purposes, 21 occlusal relationships, in 0.05 mm incremental shifts of the lower member, were tested. The load cell-measured in-occlusal plane components (Fx and Fy) of the occlusal contact forces, for control and T-Scan, were isolated from the 5th chomp (of 7) during occlusion and disclusion when the bite force (Fz) was 15 N and 25 N. These Fx and Fy were used to calculate Flateral, the magnitude of the in-occlusal plane component of the occlusal contact force, Flateral. The effects on Flateral of bite force, occlusion/disclusion, and group (test/control) were analyzed using three-way repeated measures ANOVA. Results: The crown-crown Flateral forces are significantly (p<.001) larger than those of crown-sensor-crown. The presence of the sensor also alters the direction of Flateral. Additionally, the duration of a T-Scan chomp was about ½ seconds longer than control. Examination of the numerical algorithm reveals violations of basic engineering mechanics principles. Conclusion: The T-Scan system relies on engineering mechanics (statics) calculations that use artefactual occlusal contact force magnitude measurements, approximated artefactual contact point location measurements, and assumed occlusal contact force directions. As magnitude, location and direction comprise the essential defining parameters of a force vector, just one of the 3 deficiencies, by itself, is sufficient evidence to declare the impossibility of meaningful T-Scan analyses.Item The effects of antagonist size and shape on occlusal contact forces(2022-08-26) Falasz, Adam G.; Katona, Thomas R.Background: Occlusion is a biomechanical phenomenon wherein teeth experience loads (forces and moments) in three dimensions. These load profiles are complex and are often simplified in laboratory experiments and numerical models with the use of, for example, a spherical antagonist. Objective: The purpose of this study was to examine the effects of antagonist shape (denture tooth vs. steel spherical balls) and sphere size (2.9 vs. 5.9 mm diameter) on occlusal contact forces in paired 1st molar/1st molar and 1st molar/sphere systems. Methods: The occlusal forces experienced by in-vitro occluding two-element (tooth/tooth and tooth/spherical indenter) systems were measured. The occlusal relationship was altered by 0.05 mm incremental shifts of the lower member into 21 positions. Results: The data indicate that the peak magnitudes and/or directions of the in-occlusal plane force components acting on the tooth were significantly different (p values from <0.001 to 0.03) with the 3 loading protocols. Conclusion: Spherical indenters cannot replicate the mechanical environment produced by natural molar crowns. Thus, spheres should not be used in studies related to the loading of the tooth support structures (periodontal ligament, root and bone), and implant bodies and attachments.Item Effects of modeling methods on the finite element analysis results of orthodontic applications(2017) Liu, Yanzhi; Chen, Jie; Wagner, Diane; El-Mounayri, HazimItem 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.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.
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