Browsing by Author "Wagner, Diane"
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Item A Reproducible Cartilage Impact Model to Generate Post-Traumatic Osteoarthritis in the Rabbit(MyJove Corporation, 2023-11-21) Dilley, Julian; Noori-Dokht, Hessam; Seetharam, Abhijit; Bello, Margaret; Nanavaty, Aaron; Natoli, Roman M.; McKinley, Todd; Bault, Zachary; Wagner, Diane; Sankar, Uma; Anatomy, Cell Biology and Physiology, School of MedicinePost-traumatic osteoarthritis (PTOA) is responsible for 12% of all osteoarthritis cases in the United States. PTOA can be initiated by a single traumatic event, such as a high-impact load acting on articular cartilage, or by joint instability, as occurs with anterior cruciate ligament rupture. There are no effective therapeutics to prevent PTOA currently. Developing a reliable animal model of PTOA is necessary to better understand the mechanisms by which cartilage damage proceeds and to investigate novel treatment strategies to alleviate or prevent the progression of PTOA. This protocol describes an open, drop tower-based rabbit femoral condyle impact model to induce cartilage damage. This model delivered peak loads of 579.1 ± 71.1 N, and peak stresses of 81.9 ± 10.1 MPa with a time-to-peak load of 2.4 ± 0.5 ms. Articular cartilage from impacted medial femoral condyles (MFCs) had higher rates of apoptotic cells (p = 0.0058) and possessed higher Osteoarthritis Research Society International (OARSI) scores of 3.38 ± 1.43 compared to the non-impacted contralateral MFCs (0.56 ± 0.42), and other cartilage surfaces of the impacted knee (p < 0.0001). No differences in OARSI scores were detected among the non-impacted articular surfaces (p > 0.05).Item Effects of modeling methods on the finite element analysis results of orthodontic applications(2017) Liu, Yanzhi; Chen, Jie; Wagner, Diane; El-Mounayri, HazimItem Factors influencing cartilage wear in an accelerated in vitro test: collagen fiber orientation, anatomic location, cartilage composition, and photo-chemical crosslinking(2018) Hossain, M. Jayed; Wagner, Diane; Jones, Alan; Holguin, NilssonArticular cartilage (AC) is a strong but flexible connective tissue that covers and protects the end of the long bones. Although cartilage has excellent friction and wear properties that allow smooth joint function during daily activities, these properties are not fully understood. Many material properties of cartilage are anisotropic and vary with anatomic location and the composition of the tissue, but whether this is also true for cartilage friction and wear has not been previously determined. Furthermore, cartilage disease and injury are major health concerns that affect millions of people, but there are few available treatments to prevent the progression of cartilage degeneration. Collagen crosslinking may be a potential treatment to reduce cartilage wear and slow or prevent the progression of cartilage disease. The objectives of this thesis were to investigate the relationships between the friction/wear characteristics of cartilage and the orientation of the preferred fiber direction, the anatomic location of the tissue, the composition of the tissue, and exogenous photochemical crosslinking. In the superficial zone, AC has preferential fiber direction which leads to anisotropic material behavior. Therefore, we hypothesized that AC will show anisotropic behavior between longitudinal and transverse direction in an accelerated, in vitro wear test on bovine cartilage in terms of friction and wear. This hypothesis was proven by the quantification of glycosaminoglycans released from the tissue during the wear test, which showed that more glycosaminoglycans were released when the wear direction was transverse to the direction of the fibers. However, the hydroxyproline released from the tissue during the wear test was not significantly different between the two directions, nor was the coefficient of friction. The material properties of AC can also vary with anatomic location, perhaps due to differences in how the tissue is loaded in vivo. We hypothesized that cartilage from a higher load bearing site will give better wear resistance than cartilage from lower load bearing regions. However, no differences in friction or wear were observed between the different anatomic locations on the bovine femoral condyles. The concentration of collagen, glycosaminoglycans, cells and water in the tissue was also quantified, but no significant differences in tissue composition were found among the locations that were tested. Although wear did not vary with anatomic location, variation in the wear measurements were relatively high. One potential source of variation is the composition of the cartilage. To determine whether cartilage composition influences friction and wear, a correlation analysis was conducted. An accelerated, in vitro wear test was conducted on cartilage from bovine femoral condyles, and the tissue adjacent to the wear test specimens was analyzed for collagen, glycosaminoglycan, cell, and water content. Because wear occurs on the cartilage surface, the superficial zone of the cartilage might play an important role in wear test. Therefore, composition of the adjacent cartilage was determined in both the superficial zone and the full thickness of the tissue. A significant negative correlation was found between wear and collagen content in the full thickness of the tissue, and between the initial coefficient of friction and the collagen content in the superficial zone. This correlation suggests that variation in the collagen content in the full thickness of the cartilage partially explains differences in amount of wear between specimens. The wear resistance of cartilage can be improved with exogenous crosslinking agents, but the use of photochemical crosslinking to improve wear resistance is not well understood. Two photochemical crosslinking protocols were analyzed to improve the wear resistance of the cartilage by using chloro-aluminum phthalocyanine tetrasulfonic acid (CASPc) and 670nm laser light. The cartilage treated with the two crosslinking protocols had lower wear than the non-treated group without changing the friction properties of the cartilage.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 Image Based Computational Hemodynamics for Non-Invasive and Patient-Specific Assessment of Arterial Stenosis(2019-08) Khan, Md Monsurul Islam; Yu, Huidan; Wagner, Diane; Zhu, LikunWhile computed tomographic angiography (CTA) has emerged as a powerful noninvasive option that allows for direct visualization of arterial stenosis(AS), it cant assess the hemodynamic abnormality caused by an AS. Alternatively, trans-stenotic pressure gradient (TSPG) and fractional flow reserve (FFR) are well-validated hemodynamic indices to assess the ischemic severity of an AS. However, they have significant restriction in practice due to invasiveness and high cost. To fill the gap, a new computational modality, called InVascular has been developed for non-invasive quantification TSPG and/or FFR based on patient's CTA, aiming to quantify the hemodynamic abnormality of the stenosis and help to assess the therapeutic/surgical benefits of treatment for the patient. Such a new capability gives rise to a potential of computation aided diagnostics and therapeutics in a patient-specific environment for ASs, which is expected to contribute to precision planning for cardiovascular disease treatment. InVascular integrates a computational modeling of diseases arteries based on CTA and Doppler ultrasonography data, with cutting-edge Graphic Processing Unit (GPU) parallel-computing technology. Revolutionary fast computing speed enables noninvasive quantification of TSPG and/or FFR for an AS within a clinic permissible time frame. In this work, we focus on the implementation of inlet and outlet boundary condition (BC) based on physiological image date and and 3-element Windkessel model as well as lumped parameter network in volumetric lattice Boltzmann method. The application study in real human coronary and renal arterial system demonstrates the reliability of the in vivo pressure quantification through the comparisons of pressure waves between noninvasive computational and invasive measurement. In addition, parametrization of worsening renal arterial stenosis (RAS) and coronary arterial stenosis (CAS) characterized by volumetric lumen reduction (S) enables establishing the correlation between TSPG/FFR and S, from which the ischemic severity of the AS (mild, moderate, or severe) can be identified. In this study, we quantify TSPG and/or FFR for five patient cases with visualized stenosis in coronary and renal arteries and compare the non-invasive computational results with invasive measurement through catheterization. The ischemic severity of each AS is predicted. The results of this study demonstrate the reliability and clinical applicability of InVascular.Item Image Segmentation, Parametric Study, and Supervised Surrogate Modeling of Image-based Computational Fluid Dynamics(2022-05) Islam, Md Mahfuzul; Yu, Huidan (Whitney); Du, Xiaoping; Wagner, DianeWith the recent advancement of computation and imaging technology, Image-based computational fluid dynamics (ICFD) has emerged as a great non-invasive capability to study biomedical flows. These modern technologies increase the potential of computation-aided diagnostics and therapeutics in a patient-specific environment. I studied three components of this image-based computational fluid dynamics process in this work. To ensure accurate medical assessment, realistic computational analysis is needed, for which patient-specific image segmentation of the diseased vessel is of paramount importance. In this work, image segmentation of several human arteries, veins, capillaries, and organs was conducted to use them for further hemodynamic simulations. To accomplish these, several open-source and commercial software packages were implemented. This study incorporates a new computational platform, called InVascular, to quantify the 4D velocity field in image-based pulsatile flows using the Volumetric Lattice Boltzmann Method (VLBM). We also conducted several parametric studies on an idealized case of a 3-D pipe with the dimensions of a human renal artery. We investigated the relationship between stenosis severity and Resistive index (RI). We also explored how pulsatile parameters like heart rate or pulsatile pressure gradient affect RI. As the process of ICFD analysis is based on imaging and other hemodynamic data, it is often time-consuming due to the extensive data processing time. For clinicians to make fast medical decisions regarding their patients, we need rapid and accurate ICFD results. To achieve that, we also developed surrogate models to show the potential of supervised machine learning methods in constructing efficient and precise surrogate models for Hagen-Poiseuille and Womersley flows.Item Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates(The Company of Biologists, 2018-09-25) Klymenko, Yuliya; Wates, Rebecca B.; Weiss-Bilka, Holly; Lombard, Rachel; Liu, Yueying; Campbell, Leigh; Kim, Oleg; Wagner, Diane; Ravosa, Matthew J.; Stack, M. Sharon; Mechanical and Energy Engineering, School of Engineering and TechnologyEpithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. EOC dissemination is predominantly via direct extension of cells and multicellular aggregates (MCAs) into the peritoneal cavity, which adhere to and induce retraction of peritoneal mesothelium and proliferate in the submesothelial matrix to generate metastatic lesions. Metastasis is facilitated by the accumulation of malignant ascites (500 ml to >2 l), resulting in physical discomfort and abdominal distension, and leading to poor prognosis. Although intraperitoneal fluid pressure is normally subatmospheric, an average intraperitoneal pressure of 30 cmH2O (22.1 mmHg) has been reported in women with EOC. In this study, to enable experimental evaluation of the impact of high intraperitoneal pressure on EOC progression, two new in vitro model systems were developed. Initial experiments evaluated EOC MCAs in pressure vessels connected to an Instron to apply short-term compressive force. A Flexcell Compression Plus system was then used to enable longer-term compression of MCAs in custom-designed hydrogel carriers. Results show changes in the expression of genes related to epithelial-mesenchymal transition as well as altered dispersal of compressed MCAs on collagen gels. These new model systems have utility for future analyses of compression-induced mechanotransduction and the resulting impact on cellular responses related to intraperitoneal metastatic dissemination.This article has an associated First Person interview with the first authors of the paper.Item The Quantification of Force Distribution of a Vibrational Device for Accelerating Tooth Movement(2019-08) Akbari, Amin; Chen, Jie; Wagner, Diane; Holguin, NilssonOne of the most common concern among patients who need orthodontic treatment is treatment duration. The ability to accelerate orthodontic tooth movements would be bene cial to reduce the undesired side-effects of prolonged treatment. Methods have been used in conjugate with common orthodontic appliances to shorten the treatment. One of them is to use vibrational force (VF), which is non-invasive. The VF stimulates bone modeling and remodeling, which is essential to tooth movement. However, commercial devices used in the clinic failed to deliver consistent outcomes. The effects of the VF highly depend on its intensity the tooth receives. There must be a range of stimulation that optimizes the ffeects. The stimulation outside the range either have no effects or creates damages, which adversely affects the orthodontic treatment. Since these devices have generic mouthpiece and teeth are in di erent heights, hence some teeth cannot get force stimulation and others may be overloaded. The current designs also do not have ability to adjust the level of VF intensity that individual tooth needs, as in some cases orthodontists are required to move a tooth faster than others or even slower, which needs the device to be personalized. There- fore, the primary cause of inconsistent clinical outcomes is the inadequate design of the mouthpiece of the current device. The goal of this study is to design a better vibratory device that not only guarantees VF delivery but also enables orthodontists to control the level of VF on the individual tooth, which meets the patient's treat- ment needs. This is a preliminary study to understand the effects of different design parameters affecting the VF distribution on teeth. A nite element model, which consists of human upper and lower jaws in their occlusal positions and a mouthpiece, was created. The VF was from a vibratory source with a peak load of 0.3N and speci ed frequencies (30 and 120 Hz). The element size was determined through a convergence test and the model was validated experimentally. Results showed that the VF distribution among the teeth relies on the material property of the mouthpiece. The distribution is uneven, meaning some teeth bearing much more load than others. This means, with the current device design, teeth would be a ected with di erent level of force stimulation, which results in di erent clinical outcomes consequently. Dynamic load (VF) changes the force distribution on the teeth comparing to the dis- tribution from a static load. Frequency does not affect the peak load. Finally, the study demonstrated that the level of VF stimulation can be adjusted by introducing clearance or interference between the teeth and mouthpiece. It is feasible to control the level of the VF intensity for individual tooth based on treatment requirement.Item A study on the material characterization and finite element analysis of digital materials and their applications(2017-12) Lopez, Eduardo Salcedo; Ryu, Jong E.; Tovar, Andres; Wagner, DianeMaterial jetting (MJ) additive manufacturing (AM) has experienced an increased adoption in several industry areas and as well as research applications. One of MJ’s distinct benefits is the ability to print tunable composites, digital materials (DM) by carefully adjusting the ratio of droplets of heterogeneous base-polymeric inks. However, the lack of material information usable in computer simulations has hampered its acceptance in some end-use applications. For these materials to be used in Finite Element Analysis (FEA) simulations the mechanical properties of the DMs need to be characterized into usable material models. DMs printable with an MJ printer has a wide variety of materials properties, ranging from flexible silicone rubber to rigid Acrylonitrile Butadiene Styrene (ABS). Therefore, to cohesively express the mechanical behavior of the DMs it is necessary to utilize non-linear material models. The objective this research is to conduct physical testing to characterize the mechanical behavior of DMs printable with an MJ. Subsequently, to validate the effectiveness of the material models for multi-DM prints. Utilizing the newly characterized material models two use cases were investigated, with the goal of improving the performance of printed parts through simulation. In this study, an MJ printer was used to fabricate the test specimens as well as the components used in the use case studies. The study was focused on the family of six DMs printable from the mixture of the base polymers Tango Black+ (TB+) and Vero White+ (VW+). To characterize the mechanical properties of the materials a tensile test was conducted utilizing the KS-M6518 standard as a basis. The mechanical properties of the DMs were then fitted into four non-linear models and the results compared. The fitted models were, the Neo Hookean model, a two-parameter, three-parameter, and a five-parameter Mooney Rivlin model. To confidently use the material models for multi-DM prints FEA simulations need to validate the accuracy to which they can predict the deformation of the samples under load. To compare the results of the computer simulations and the physical test, strain maps for both results were analyzed. Four different test specimens were printed and tested. A baseline single material samples were compared to three multi-material samples with different embedded structures. The results confirmed the validity of the material models even when used for multi-DM prints. The recently characterized models are utilized in two use case studies which showcase the potential of DMs. The first use case was focused on printing multi-DM substrates for the use of stretchable electronics. The second use case investigated the benefits of utilizing multiple materials to create 3D conductive traces utilizing a new method, the “swollen-off” method. Both case studies showed the benefits of utilizing DMs as well as the applicability of the material models in predictive simulations.Item Systemic Inhibition or Global Deletion of CaMKK2 Protects Against Post-Traumatic Osteoarthritis(Elsevier, 2022) Mével, Elsa; Shutter, Jennifer A.; Ding, Xinchun; Mattingly, Brett T.; Williams, Justin N.; Li, Yong; Huls, Anthony; Kambrath, Anuradha Valiya; Trippel, Stephen B.; Wagner, Diane; Allen, Matthew R.; O’Keefe, Regis; Thompson, William R.; Burr, David B.; Sankar, Uma; Anatomy, Cell Biology and Physiology, School of MedicineObjective: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). Methods: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1β (IL)-1β for 24 or 48 h to investigate gene and protein expression. Results: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1β treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1β, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1β-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. Conclusions: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.