Post-traumatic osteoarthritis in mice following mechanical injury to the synovial joint

We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention

Doctor of Philosophy

dissertationWhile the healthy hip provides decades of pain free articulation, the cartilage and labrum may degenerate during the process of osteoarthritis (OA). Most hip OA is caused by subtle pathomorphologies, including acetabular dysplasia and acetabular retroversion. The link between pathomorphology and OA is thought to be mechanical, but the mechanics have not been quantified. The aim of this dissertation was to provide insight into the pathogenesis of hip OA via finite element (FE) modeling. The objectives were two-fold: to validate a subject-specific modeling protocol for a series of specimens and assess the effects of assumptions on model predictions, and to use the modeling protocol to evaluate soft tissue mechanics in pathomorphologic hips in comparison to normal hips. For the first objective, FE predictions of contact stress and contact area were directly validated for five cadaveric specimens, and the specimen- and region-specific hyperelastic material behavior of cartilage was determined. FE predictions of contact stress and contact area were in good agreement with experimental results, and were relatively insensitive to the assumed cartilage constitutive model. There were distinct regional differences in the hyperelastic material behavior of human hip cartilage, with stiffer lateral than medial cartilage and stiffer acetabular than femoral cartilage. In order to investigate the mechanical link between pathomorphology and hip OA, FE models of ten hips with normal morphology, ten hips with acetabular dysplasia and ten hips with acetabular retroversion were generated. FE models of dysplastic acetabula demonstrated the importance of the acetabular labrum in load support in the dysplastic hip. FE models of retroverted acetabula demonstrated distinct superomedial contact patterns in comparison to distributed contact patterns in the normal hip. Finally, the effects of cartilage constitutive model on predictions of transchondral maximum shear stress and first principal strain were evaluated. In contrast to contact stress and contact area, maximum shear stress and first principal strain were sensitive to the cartilage constitutive model. Overall, this dissertation provides novel insights into the contact mechanics of pathomorphologic hips that may be important in the pathogenesis of OA, as well as the technical foundation for studies evaluating additional mechanical variables in the human hip

A systems view of risk factors for knee osteoarthritis reveals insights into the pathogenesis of the disease.

Early detection of osteoarthritis (OA) remains a critical yet unsolved multifaceted problem. To address the multifaceted nature of OA a systems model was developed to consolidate a number of observations on the biological, mechanical and structural components of OA and identify features common to the primary risk factors for OA (aging, obesity and joint trauma) that are present prior to the development of clinical OA. This analysis supports a unified view of the pathogenesis of OA such that the risk for developing OA emerges when one of the components of the disease (e.g., mechanical) becomes abnormal, and it is the interaction with the other components (e.g., biological and/or structural) that influences the ultimate convergence to cartilage breakdown and progression to clinical OA. The model, applied in a stimulus-response format, demonstrated that a mechanical stimulus at baseline can enhance the sensitivity of a biomarker to predict cartilage thinning in a 5 year follow-up in patients with knee OA. The systems approach provides new insight into the pathogenesis of the disease and offers the basis for developing multidisciplinary studies to address early detection and treatment at a stage in the disease where disease modification has the greatest potential for a successful outcome

Subchondral Bone Cysts - Filling the Void

Subchondral bone cysts (SBCs) are voids that can occur in the bones of young horses, especially horses intended for performance. Believed to be caused by trauma or osteochondrosis, these defects most often occur in the medial femoral condyle (MFC). Current treatments for equine SBCs have poor outcomes and have not improved over the last several decades. The gold standard for surgical treatment consists of cyst debridement and grafting. However, radiographic healing is not often reported, and when it is, only 20% of horses exhibit full radiographic healing. A novel treatment strategy has been recently introduced that places a lag screw across the SBC and has demonstrated high rates of radiographic healing. However, the mechanics of how a transcondylar lag screw could enhance SBC healing are unknown. The goals of this study were to determine a plausible mechanism of SBC initiation and growth, as well as understand the mechanics of the transcondylar lag screw. A finite element modeling approach has been taken to examine the mechanics associated with SBCs. Using CT scans from young Thoroughbred horses, several finite element models have been developed for this study. The results of this study show that high-impact loading from gallop can cause stresses high enough to initiate bone damage in a healthy equine stifle joint. Additionally, once a small defect has manifested, stresses rise even higher and further damage is likely. Medial meniscus stress also increases with a MFC SBC, which suggests that secondary injury to the medial meniscus may be due to a disrupted load path through the MFC. Furthermore, it was determined that the transcondylar screw is able to heal SBCs by providing enough mechanical stimulus to the adjacent bone to promote bone formation. Not only is the stimulus for growth present, but the screw also aligns third principal stresses transverse to trabecular orientation across the cyst. This encourages bone to form across the void, as opposed to trabecular thickening, which results in the sclerosis typically seen in MFC SBCs. Lastly, it was determined that larger cysts respond best to the transcondylar screw. Full penetration of the screw into the cystic cavity provides the highest bone-forming stimulus, and also best aligns stresses across the void. This work demonstrates that trauma can initiate SBCs and that the transcondylar screw provides a unique mechanism to enhance healing. Since humans are susceptible to a wide range of bone defects that exhibit similar characteristic of an equine SBC, it is believed that there is huge potential for translational applications

Predicting Meniscus Mechanical Properties using Quantitative Magnetization Transfer Magnetic Resonance Imaging

Osteoarthritis (OA) is a degenerative joint disease that affects the entire knee joint, afflicting approximately 13% of the Canadian population. The meniscus plays a key role in load bearing and stability of the knee joint, and its functionality is compromised throughout OA progression. Currently there does not exist a way to study the relationship between meniscal tissue degeneration and mechanical properties in vivo, but Quantitative Magnetization Transfer Magnetic Resonance Imaging (qMT MRI) is a quantitative MRI technique which may be a good candidate for this application. This is because qMT models soft tissues in a comparable way to how tissues are modeled mechanically, and qMT is dependent on water/macromolecule interactions similar to meniscal tissue functionality. The aim of this project is to assess whether qMT metrics – bound-pool fraction (f), magnetization exchange rate (k), and relaxation times of the free and bound pools (T1f, T2f, and T2b) – accurately predict experimentally-derived mechanical properties – aggregate modulus (Ha) and permeability (kp) – of excised meniscal samples. Six human cadaver knee specimens were imaged using qMT MRI techniques in order to obtain imaging metrics of the menisci. Subsequent to imaging, 59 core meniscal samples were tested using a stress relaxation approach in a confined compression testing configuration in order to obtain Ha and kp of the samples as measures of mechanical properties. A Spearman’s rho correlation was then performed on the mechanical properties and the imaging metrics of the core samples of the menisci to determine how well the imaging metrics predict the mechanical properties. One correlation, albeit weak, was found between mechanical properties and qMT metrics (Ha and T2b); however, this may be due to homogeneity in meniscal health of the specimens limiting the ability for correlations to be detected. Moderate to strong negative correlations between T1 relaxation time and f, and k were found. These relationships should be further explored as T1 is an often neglected imaging metric, and qMT in the meniscus is quite unexplored. T1 was found to have a moderate correlation with T2. These results reinforce that qMT is viable to use in the meniscus, but that further work needs to be done in order to determine if it can be used as a non-invasive method of assessing meniscal tissue mechanical properties

The Effect of Mechanical Loading on Articular Cartilage

The effect of mechanical loading on articular cartilage is the topic chosen for the second editorial of this newly launched journal. The aim of this interesting editorial is to illustrate the cell signaling correlated to the mechanical loading, some aspects of the mechanobiology and the positive and negative effects of the mechanical loading on articular cartilage. The benefits of the mechanical loading on articular cartilage have been shown to have a short- and long-term effectiveness. In this article, the role of mechanical signaling in the maintenance of articular cartilage and how the alterations in normal signaling can lead to joint pathology have been discussed

Impact of Footwear on Mechanisms of Knee Osteoarthritis Progression

Knee osteoarthritis (OA) is a debilitating disease affecting the entire knee joint by inducing pathological changes to the cartilage and menisci. Currently, the etiology of OA is not completely understood. However, altered gait mechanics, specifically increased joint loading, of OA patients have a clear association with both symptomatic and structural OA progression. Non-surgical intervention tools, such as variable stiffness shoes (VSS), have been developed as a way to decrease loading within the knee joint. However, with external moments being surrogate measures for knee loading, it is unclear if changes in knee moments with the footwear are sufficient to result in a clinical benefit. Therefore, this project’s purpose was to investigate whether a VSS intervention can alter knee joint loading and menisci function in a knee OA population. We used gait analysis, musculoskeletal modeling, and finite element (FE) analysis to determine the effect of VSS on gait mechanics, knee joint contact force, and menisci stress and strain, compared to a control shoe. We found knee moments did not decrease with the VSS intervention. Furthermore, participants who did experience a decrease in knee adduction moment did not always experience a decrease in medial compartment contact force. However, results from our FE modeling of the tibiofemoral joint indicate significant changes in knee joint contact force can influence stress placed on the menisci. Results from this study suggest knee contact forces and tissue stress, not only external moments, should be considered when investigating if VSS can positively impact an OA population

Effects of Surgical Repair or Reconstruction on Radiocarpal Mechanics from Wrists with Scapholunate Ligament Injury

Osteoarthritis as a result of injury/trauma is a significant problem, and there is still a need to develop tools for evaluating joint injuries and the effectiveness of surgical treatments. For the wrist in particular, injury to the scapholunate ligament from impact loading, can lead to scapholunate joint instability. Without treatment, this can lead to progressive development of wrist osteoarthritis. Joint contact pressures are important mechanical factors in the etiology of osteoarthritis, and these can be determined non-invasively through computer modeling. Hence, the goal of this work was to investigate the effects of scapholunate ligament injury and surgical repair on radioscapholunate contact mechanics, through surface contact modeling (SCM) and finite element modeling (FEM). The modeling process required geometries, boundary conditions and a contact relationship. Magnetic resonance imaging (MRI) was used to acquire images of the normal, injured and post-operative wrists, while relaxed and during active grasp loading. Surface and volumetric models were generated from the relaxed images, while kinematic boundary conditions were determined from image registration between the relaxed and loaded images. To improve the automatic image registration process, the effects of initial manual registration on the outcome of final registration accuracy, were investigated. Results showed that kinematic accuracy and subsequent contact mechanics were improved by performing a manual registration to align the image volumes as close as possible, before auto-registration. Looking at the effects of scapholunate ligament injury, results showed that contact forces, contact areas, peak and mean contact pressures significantly increased in the radioscaphoid joint. The locations of contact also shifted with injury. This novel data showed that contact mechanics was altered for the worse after injury. Novel contact mechanics data on the effects of surgical repair were also obtained. Results showed that radiolunate peak and mean contact pressures decreased significantly compared to injured, which indicated the possibility of restoring normal mechanics post surgery. SCM results were compared to FEM results to demonstrate the feasibility of the surface contact modeling approach for clinical applications. Contact parameters compared well between the two techniques. This work demonstrated the potential of MRI-based SCM as a tool to evaluate joint injuries and subsequent treatments, for clinical applications

Load Bearing Characteristics Of Implants For Osteochondral Defect Repair

Objective: To measure changes in joint contact mechanics, during simulated gait, in the presence of a medial femoral osteochondral defect and after filling the defect using two different polyvinyl alcohol implant configurations. Methods: Seven human cadaveric knees were tested under simulated gait, while the contact stresses on the tibial plateau were recorded using an electronic sensor. Each knee was tested using the following conditions: intact, defect, and after the defect has been filled with either 10% PVA, 20% PVA, 10% PVA + a porous titanium base, or 20% PVA + porous titanium base. Changes in contact area, total force, weight center of contact, and stress pattern differences were measured for each knee. Results: At 14% of the gait cycle, there were no changes in contact area observed between conditions. At 45% of the gait cycle, differences were seen in the meniscal-cartilage contact area with increases in contact area between the intact and 10% PVA as well as 20% PVA scaffolds. At 14% of gait, there was a significant increase in total force between intact and defect conditions and between defect and 20% PVA + pTi in the menical-cartilage region with forces of 179 ± 113 N, 278 ± 113 N, and 193 ± 96 N for the intact, defect, and 20% PVA + pTi respectively. At 45% of gait, there was a significant difference in total force between intact condition and the defect condition in the meniscal-cartilage contact area with average total force of 90 ± 73 N and 148 ± 75 N respectively. Differences were found in the cartilage-cartilage total force at 45% of gait between intact and all other conditions and between defect and 20% PVA + pTi. The total forces were 486 ± 134 N for the intact, 360 ± 158 N for the defect, and 431 ± 177 for the 20% PVA + pTi, and the remaining implants tested having total force values below 412 N. Conclusions: The presence of an osteochondral defect causes an increase in loading on the meniscus. Implants in the range of tissue engineered constructs can partially restore joint loading but cause alterations in contact stress patterns