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Item Does bone-to-cartilage fluid transport exist and is it relevant to joint health?(Montana State University - Bozeman, College of Engineering, 2024) Hislop, Brady David; Chairperson, Graduate Committee: Ronald K. June II; This is a manuscript style paper that includes co-authored chapters.Osteoarthritis (OA) afflicts millions of people each year. The onset of OA has been associated with many factors including increased bone-cartilage fluid transport, yet a cure remains elusive. To implicate bone-cartilage fluid transport in the progression of OA, further studies are needed on fluid transport in health. Recent studies have challenged the assumption that no fluid transport occurs between bone and cartilage in healthy joints. However, many gaps remain in our understanding of bone-to-cartilage fluid transport, including 1) do fluid pressure gradients develop at the bone-cartilage interface, 2) do traumatic injuries impact subchondral bone stiffness, and synovial fluid metabolism 3) do larger molecules move from bone-to-cartilage and does cyclic loading enhance such movement, 4) what material properties influence bone-to-cartilage fluid transport 5) do distinct metabolism changes occur with osteoarthritis, evaluated using a novel clustering method. Our results showed the development of fluid pressure gradients at the osteochondral interface, and that cyclic compression enhances bone-cartilage fluid transport. Furthermore, our results showed that proteoglycan loss, and decreased subchondral bone stiffness increased bone-cartilage fluid transport. Finally, we showed that in the first week after traumatic joint injuries (e.g., ACL tears) subchondral bone volume decreases, and subchondral bone stiffness increases, while the synovial fluid metabolism shifts. In conclusion, we showed that osteochondral fluid transport is enhanced by cyclic compression for larger molecules than previously studied (3kDa dextran), and that material parameters changes associated with the progression of OA alter bone-cartilage fluid transport. These studies provide novel understanding of bone-to-cartilage fluid transport, leading us one step closer to understanding OA as a whole joint disease.Item Investigating high-risk biomechanics in agricultural work(Montana State University - Bozeman, College of Engineering, 2022) Doud, Devon Michael; Chairperson, Graduate Committee: Scott Monfort; This is a manuscript style paper that includes co-authored chapters.Statement of Purpose: Osteoarthritis, a debilitating disease resulting in cartilage degradation and loss of mobility, is often instigated by injury or excessive loading of unconditioned articular cartilage. Although agricultural laborers are especially at risk of developing osteoarthritis, quantitative characterizations of occupation-specific activities have not previously been established. Deep flexion movements common to these groups (e.g., squatting or kneeling) may cause excessive contact forces on unconditioned cartilage, potentially initiating osteoarthritis development. Additionally, although cognitive loads can significantly alter gait mechanics, the effects of dual-task conditions (e.g., visual Stroop tests while walking) on contact forces have not previously been established. The purpose of this thesis is to better understand potential factors of osteoarthritis development in agricultural laborers by investigating occupational-specific movement patterns and joint loading during common occupational tasks. Methods: The first study evaluated seasonal differences in activity levels for farmers and ranchers by measuring movement intensity via wearable triaxial accelerometers. We hypothesized that ranchers would exhibit consistently high activity levels and that both groups would show an increase in movement intensity in their respective high seasons. The second study sought to establish the effects of cognitive challenges on tibiofemoral contact forces during normal gait and kneel-to-stand transitions in healthy adults. We hypothesized that dual-task conditions would correspond with increased peak tibiofemoral contact forces and that these forces would be positioned farther from the joint center along the mediolateral axis during dual-task conditions. Results: The first study findings largely supported the hypothesis: increased movement intensity during high seasons were recorded for both groups, with farmers exhibiting a larger seasonal fluctuation for moderate intensity activities. The second study did not support the hypothesis: cognitive loading did not significantly affect the magnitude of peak contact forces, and peak contact forces occurred closer to the joint center during dual-task conditions than during single-task conditions. However, post hoc analysis suggested that other portions of the contact force time series during stance phase were affected by cognitive challenges. Conclusions: This thesis provides foundational steps in understanding potential contributing factors of osteoarthritis development in agricultural laborers, directing future investigations towards transitional contact forces in movements simulating livestock handling.Item WOMAC score and arthritis diagnosis predict decreased agricultural productivity(Springer Science and Business Media LLC, 2021-02) Webber, Eliza J.; Tran, Tan; June, Ronald; Healy, Emily; Andrews, Tara M.; Younkin, Roubie; MacDonald, Justin; Adams, Erik S.Background. Arthritis and joint pain are highly prevalent in agricultural (ag) workers. Many ag operations are sustained by a small number of workers, and the disability of even one worker thus contributes to economic hardship. This study investigated associations between joint health in Montana ag workers and economic well-being and work capacity. Methods. This observational mixed-methods study utilized quantitative survey data and qualitative focus group data. 299 ranchers and farmers in 9 Montana counties completed either an online or paper survey that included participant demographics, joint symptoms, history of arthritis and arthritis type, financial status, work capacity, and the need to rely on others to complete one’s work. The Western Ontario and McMaster Universities arthritis index (WOMAC) survey was completed by those with hip or knee pain. Data were entered into REDCap v8.9.2 for analysis with SAS 9.4, using logistic and linear regression models to detect associations between covariables and to calculate odds ratios and confidence intervals. Focus groups were held with ranchers in two Montana counties, discussing similar topics, and the themes expressed were identified. Results. 87.6% of survey respondents reported joint pain, 47.8% a diagnosis of arthritis, and 22.4% osteoarthritis (OA). A 10-point increase in WOMAC was significantly associated with lower work capacity (OR 2.00; 95% CI [1.58, 2.55], p < 0.01), worse financial condition (OR 1.23; 95% CI [1.01,1.48], p = 0.04), and increased reliance on others (OR 1.82; 95% CI [1.32, 2.55], p < 0.01). An arthritis diagnosis was associated with worsening work capacity (OR 4.66; 95% CI [2.71, 8.01], p < 0.01) and increased odds of relying on others (OR 3.23; 95% CI [1.56, 6.66], p < 0.01). A diagnosis of OA was significantly associated with decreased work capacity (OR 3.47; 95% CI [1.97, 6.11], p < 0.01). Unadjusted for age and BMI, we found a significant association between years spent working in agriculture and joint health, which became non-significant after adjusting for age and BMI. Focus group themes included decreased productivity with increased joint symptoms and a tendency for ranchers to avoid interaction with the health care system. Conclusion. Poor joint health is associated with economic risk on Montana ranches and farms.Item In vitro and in vivo systems mechanobiology of osteoarthritic chondrocytes(Montana State University - Bozeman, College of Engineering, 2015) Zignego, Donald Lee; Chairperson, Graduate Committee: Ronald K. June II; Aaron A. Jutila, Martin K. Gelbke and Daniel M. Gannon were co-authors, and Ronald K. June was a corresponding author of the article, 'The mechanical microenviroment of high concentration agarose for applying deformation to primary chondrocytes' in the journal 'Journal of biomechanics' which is contained within this thesis.; Aaron A. Jutila was a main author, Bradley K. Hwang, Jonathan K. Hilmer, Timothy Hamerly, Cody A. Minor and Seth T. Walk were co-authors, and Ronald K. June was a corresponding author of the article, 'Candidate mediators of chondrocyte mechanotransduction via targeted and untargeted metabolomic measurements' in the journal 'Archives of biochemistry and biophysics' which is contained within this thesis.; Carley N. McCutchen, Jonathan K. Hilmer were co-authors, and Ronald K. June was a corresponding author of the article, 'Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids' submitted to the journal 'Arthritis and rheumatology' which is contained within this thesis.; Jonathan K. Hilmer was a co-author, and Ronald K. June was a corresponding author of the article, 'Shotgun phosphoproteomics identifies activation of vimentin, ankyrin, vam6/vpS39-like protein in primary human osteoarthritic chondrocytes after mechanical stimulation' submitted to the journal 'eLife' which is contained within this thesis.; Sarah E. Mailhiot, Timothy Hamerly, Edward E. Schmidt were co-authors, and Ronald K. June was a corresponding author of the article, 'Alterations in joint metabolomics following surgical destabilization and exercise in a novel cartilage reporter mouse model' submitted to the journal 'Annals of biomedical engineering' which is contained within this thesis.All cells are subjected to and respond to mechanical forces, but the underlying processes linking the mechanical stimuli to biological responses are poorly understood. In the joints of the body (e.g. the knee, hip, etc...) articular cartilage serves as a low friction, load bearing material and is subjected to near-constant mechanical loading. Through excessive loading of the joint, usually caused by obesity or injury, the protective articular cartilage begins to diminish, leading to the progression of osteoarthritis (OA). Osteoarthritis is the most common joint disorder in the world and is characterized by the deterioration of articular cartilage. Determining the link between cartilage deterioration and mechanical loading is one motivation that drove this research. Articular cartilage is composed of a dense extracellular matrix (ECM), a less-stiff pericelluar matrix (PCM), and highly specialized cells called chondrocytes. As the sole cell type in cartilage, chondrocytes are responsible for the healthy turnover of the ECM by creating, maintaining, and repairing the matrix. Multiple lines of evidence suggest chondrocytes can transduce mechanical stimuli into biological signals. The hypothesis for this research is that physiologically pertinent loading of chondrocytes results in a specific set of bio-signals resulting in matrix synthesis. To test this hypothesis, two unbiased, large-scale metabolomic and phosphoproteomic datasets were generated by modeling physiological compressive loading on 3D-embedded chondrocytes. To assess loading-induced changes in metabolites (e.g. small molecules representing the functional state of the cell) and proteome-wide patterns of post-translational modifications (i.e. phosphorylation), chondrocytes were encapsulated in physiologically stiff agarose, compressively loaded in tissue culture, and analyzed via liquid chromatography -- mass spectrometry (LC-MS). The results helped identify global and local biological patterns in the chondrocytes which are a direct result from mechanical loading. In addition, a novel mouse model that expresses cartilage specific bioluminescence was used to assess loading induced changes in vivo. The results from the mouse model allowed for in vivo validation and integration of the in vitro results from the metabolomic and phosphoproteomic results. To my knowledge, such research has never been done, and considerably expands the scientific knowledge of chondrocyte mechanotransduction.Item Development and validation of a system for studying chondrocyte mechanotransduction with preliminary metabolomic results(Montana State University - Bozeman, College of Engineering, 2013) Jutila, Aaron Arthur; Chairperson, Graduate Committee: Ronald K. June IIOsteoarthritis (OA) is a degenerative disease currently affecting over 46 million Americans. OA is most commonly characterized by breakdown of articular cartilage within the joint resulting in abnormal loading, loss of motion, and pain. Articular cartilage is the tough, flexible, load-bearing material that allows for joints to articulate smoothly i.e. running with relative ease. Currently there is no cure for this disease and the exact causes remain relatively unknown. Chondrocytes are the only cell type found in cartilage and are responsible for all biological maintenance and repair. Previous studies have shown that chondrocytes respond to mechanical load by cellular mechanotransduction, the process by which cells convert mechanical stimuli into biochemical activity. The aim of this thesis is to study the effects that mechanical loads have on human chondrocyte metabolism to better understand OA. To study chondrocyte mechanotransduction it was vital to develop a machine that could simulate in vivo loading of chondrocytes within the human knee joint. A bioreactor was designed, built, and validated that can simulate physiological loading in a tissue culture environment. This bioreactor was then used to characterize the mechanical properties of a viscoelastic material (agarose) capable of maintaining viable 3-Dimensional cell cultures. Inside the body chondrocytes are surrounded by a pericellular matrix (PCM), which provides a unique stiffness much less than the stiffness of cartilage. The mechanical property tests performed on agarose allowed for an accurate representation of this cellular microenvironment. Agarose gel concentrations were found that can model both healthy PCM and OA PCM stiffness. Methods were then developed to encapsulate living chondrocytes within these physiologically stiff gels. Utilizing these newly developed gel constructs and custom built bioreactor, 3-Dimensional chondrocyte suspensions were subjected to dynamic compression simulating normal physiological loading i.e. walking. It was hypothesized that moderate dynamic loading would promote changing in the central metabolism pathways, such as glycolysis. To study this hypothesis, mass-spectrometry techniques were utilized to identify metabolites present in each sample, and if the amount of each metabolite changed due to dynamic compression. These results provide a robust foundation for understanding cellular mechanotransduction.Item Mouse/rat knee static loading test apparatus(Montana State University - Bozeman, College of Engineering, 2013) Rose, Thomas Joseph; Chairperson, Graduate Committee: Ronald K. June IIOsteoarthritis (OA) involves mechanically-related cartilage deterioration and affects millions worldwide. To date no effective treatments for OA exist and to expedite the solution process rodent models that mimic human disease are used before attempting to apply to human models. Rodent models of osteoarthritis involve mechanical destabilization of the knee joint which likely changes the contact pressure distribution. However, no methods currently exist for measuring the contact pressure distribution in mouse or rat knees. Therefore, the objective was to develop a method to measure the contact pressure distribution within a mouse knee. This research designed and tested an apparatus to apply loads to mouse knees based on measurements of young mouse knees and mature rat knees. Applied loads were used to explore measureable pressure zone shifts within the knee for varying flexion angles. Measurements of the tibia plateau were used to estimate contact area for an expected pressure range. Based on this preliminary information, a machine was designed to incorporate 6 degrees of freedom that allows the application of compressive loading while allowing the knee as natural of movement as possible. To apply the load a mechanical system was devised to both measure and apply joint loading. Several iterations of both of these systems were considered and the final product was created for testing. Several hurdles were overcome during testing, which included creating a method to interface the biological knee to the mechanical system, developing a technique to measure the pressure distribution of extremely small areas, and the requirement for accurate calibration of both the load application and measurement. It is assumed that the results will be the first pressure distribution measurements in the murine knee. Extension of these results may yield valuable insight into the mechanical environment of rodent osteoarthritis models.