Background: Intra-articular corticosteroid injections (IACI) are a commonly used treatment for painful knee osteoarthritis (OA). Response to treatment varies the reason for which is unclear. Further there are no data concerning the impact of accuracy of injection and psychological factors including illness perceptions, pain catastrophizing and depression on outcome following IACI.Objectives: i) to undertake a systematic review looking at predictors of response to IACI in patients with symptomatic knee OA and, ii) to determine the role of psychological factors and accuracy of injection in predicting response to IACI.Methods: A systematic review was conducted using electronic databases for randomised trials and observational studies looking at predictors of response to IACI in knee and hip OA. An observational study of 141 consenting patients (105 primary OA and 36 secondary OA in the context of well controlled rheumatoid arthritis) receiving routine IACI as part of clinical care for knee OA was conducted including baseline assessment and outcome assessments at 3 and 9 weeks. Response was defined as at least 40% reduction of pain from baseline, using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Assessment included ultrasound (US) for features of synovial inflammation), radiographs, and assessment of psychological factors including the revised illness perception questionnaire (IPQR). Accuracy of injection was assessed using US. Characteristics of responders and non-responders to IACI at 3 and 9 weeks were determined using univariate statistics and significant factors entered into logistic regression models. Results: The systematic review found no consistent evidence for any disease or non-disease related predictor of response and no systematic exploration of the effects of psychological factors or accuracy of injection on treatment response. In the observational study, 83 (53%) of 141 subjects were responders to IACI at 3 weeks and 56 (44%) at 9 weeks. In univariate analysis, responders to treatment had higher scores for the IPQR domain treatment control and lower scores for IPQR consequences, depression and pain catastrophizing at both 3 and 9 weeks. Physical and patient related factors, including accuracy of injection and US features, were not associated with outcome, with the exceptions of higher baseline pain and previous experience of injection being associated with non-response at 9 weeks. In multiple regression, treatment control was the only independent predictor of response at 3 weeks. At 9 weeks, treatment control, consequences and depression were independent predictors of treatment outcome. Conclusion: In this observational study illness perceptions and depression predicted the outcome of IACI at 3 and 9 weeks. By contrast, physical factors including accuracy of injection did not influence outcome. Further work is needed to replicate these findings and elucidate mechanisms for these effects.

Articular cartilage injuries occur frequently in the knee joint. Several methods have been implemented clinically, to treat osteochondral defects but none have been able to produce a long term, durable solution. Photopolymerizable cartilage tissue engineering approaches appear promising; however, fundamentally, forming a stable interface between the tissue engineered cartilage and native tissue, mainly subchondral bone and native cartilage, remains a major challenge. The overall objective of this research is to find a solution for the current problem of dislodgment of tissue engineered cartilage at the defect site for the treatment of degraded cartilage that has been caused due to knee injuries or because of mild to moderate level of osteoarthritis. For this, an in-vitro model was created to analyze the integration of tissue engineered cartilage with the bone, healthy and diseased cartilage over time. We investigated the utility of hydroxyapatite (HA) nanoparticles to promote controlled bone-growth across the bone-cartilage interface in an in vitro engineered tissue model system using bone marrow derived stem cells. We also investigated the application of HA nanoparticles to promote enhance integration between tissue engineered cartilage and native cartilage both in healthy and diseased states. Samples incorporated with HA demonstrated significantly higher interfacial shear strength (at the junction between engineered cartilage and engineered bone and also with diseased cartilage) compared to the constructs without HA (p < 0.05), after 28 days of culture. These findings indicate that the incorporation of HA nanoparticles permits more stable anchorage of the injectable hydrogel-based engineered cartilage construct via augmented integration between bone and cartilage.

Background: Knee osteoarthritis (OA) is the most common type of OA and is a major cause of pain and thus results in disability for daily activities among persons living in the community. OA currently has no cure. In addition to the conflicting recommendations from clinical guidelines, evidence about the extent to which long-term use of intra-articular injections improves patient outcomes is also lacking. Methods: Using data from the Osteoarthritis Initiative (OAI), marginal structural models (MSMs) applying inverse probability treatment weights (IPTW) were used to examine the effectiveness of intra-articular injections and changes in symptoms over time. The specific aims of this dissertation were to: 1) evaluate longitudinal use of intra-articular injections after treatment initiation among persons with radiographic knee OA; 2) quantify the extent to which intra-articular injection relieves symptoms among persons with radiographic knee OA; and 3) evaluate the performance of missing data techniques under the setting of MSMs. Results: Of those initiating injections, ~19% switched, ~21% continued injection type, and ~60% did not report any additional injections. For participants initiating corticosteroid (CO) injections, greater symptoms post-initial injection rather than changes in symptoms over time were associated with continued use compared to one-time use. Among participants with radiographic evidence of knee OA, initiating treatments with either CO or hyaluronic acid (HA) injections was not associated with reduced symptoms compared to non-users over two years. Compared to inverse probability weighting (IPW), missing data techniques such as multiple imputation (MI) produced less biased marginal causal effects (IPW: -2.33% to 15.74%; -1.88% to 4.24%). For most scenarios, estimates using MI had smaller mean square error (range: 0.013 to 0.024) than IPW (range: 0.027 to 0.22). Conclusions: Among participants with radiographic evidence of knee OA living in the community, the proportion of those switching injection use and one-time users was substantial after treatment initiation. In addition, initiating injection use was not associated with reduced symptoms over time. With respect to issues of missing data, using MI may confer an advantage over IPW in MSMs applications. The results of this work highlight the importance of using comparative effectiveness research with non-experimental data to study these commonly used injections and may help to understand the usefulness of these treatments for patients with knee OA.

Antecedentes: la evidencia disponible sobre la pseudopatela baja (PPB) es limitada. El propósito de este estudio era investigar prospectivamente la aparición de PPB después de la artroplastia total de rodilla (ATR) primaria y sus consecuencias clínicas en una serie de pacientes con un seguimiento mínimo de 2 años. La PPB se definió como una rótula distalmente desplazada en relación con la tróclea femoral con ausencia de acortamiento del tendón rotuliano debido a la elevación de la línea articular. Métodos: serie prospectiva de 354 pacientes con una edad media de 71,7 (rango, 52-87) años. La evaluación clínica fue realizada por la Knee Society Scores (KSS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short-Form 12-item (SF12) y rango de movimiento (ROM). La altura de la rótula se evaluó mediante los índices de Insall-Salvati (ISR) y Blackburne-Peel (BPR). Resultados: el seguimiento medio fue de 3,6 (rango, 2,0-6,6) años. En el posoperatorio, 286 (80,7%) pacientes tenían una altura patelar normal, 17 (4,8%) una verdadera patela baja (VPB) y 51 (14,4%) una PPB. No hubo diferencias significativas entre los 3 grupos en la escala KSS-función media (p= 0,107), ROM (p= 0,408), WOMAC-dolor (p= 0,095), WOMAC-rigidez (p= 0,279) o SF12-mental (p= 0,363). Entre los grupos normales y PPB, no hubo diferencias significativas en la media de KSS-rodilla (p= 0,903), WOMAC-función (p= 0,294) o SF12-físico (p= 0,940). Sin embargo, el grupo TPB tuvo una media de KSS-rodilla (p= 0,031), WOMAC-función (p= 0,018) y SF12-física (p= 0,005) significativamente peores en comparación con los otros 2 grupos. Conclusión: la PPB fue un hallazgo relativamente común, pero no se encontraron diferencias significativas en términos de resultados clínicos en comparación con los pacientes con altura rotuliana posoperatoria normal La VPB fue poco frecuente, pero estos pacientes tuvieron resultados clínicos significativamente peores que aquellos con PPB o altura patelar normal.

The main goal of this diploma thesis is to determine the role of hyaluron acid and phospholipids on friction and lubrication of articular cartilage in regard to optimization of viscosupplements. This is carried out by measuring the coefficient of friction of the articular cartilage with several lubricants. Cartilage is lubricated particularly by a conventional viscosuplement, optimized viscosuplementation with phospholipids and model synovial fluid. In order to observe the function of those viscosuplements in the human body, both are mixed with the model synovial fluid, ubiquitous in human joints, in given ratio. Experiments revealed high friction when it comes to convectional viscosupplementation as opposed to low friction of the optimized viscosuplement with phospholipids. The same situation occurs when cartilage is lubricated with those viscosuplements mixed with model synovial fluid which might lead to development of a new, better, viscosupplementation based on hyaluron acid and phospholipids.

A polyconvex continuum-level proteoglycan Cauchy stress function was developed based on the continuum electromechanical Poisson-Boltzmann unit cell model for proteoglycan interactions. The resulting proteoglycan model was combined with a novel collagen fibril model and a ground substance matrix material to create a polyconvex constitutive finite element model of articular cartilage. The true collagen fibril modulus , and the ground substance matrix shear modulus , were varied to obtain the best fit to experimental tension, confined compression, and unconfined compression data for native explants and explants cultured in insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1). Results indicate that culture in IGF-1 results in a weakening of the COL fibers compared to native explants, and culture in TGF-β1 results in a strengthening of the COL fibers compared to native explants. These results elucidate the biomechanical changes in collagen fibril modulus, and ground matrix shear modulus following in vitro culture with IGF-1 and TGF-β1. Understanding the constitutive effects of growth factor stimulated culture may have applications in AC repair and tissue engineering.

A poroelastic finite element model of a heterogeneous articular cartilage disc was created to examine the tissue response to low amplitude (± 2% strain), low frequency (0.1 Hz) dynamic unconfined compression (UCC). A strong correlation has been made between the relative fluid velocity and stimulation of glycosaminoglycan synthesis. A contour plot of the model shows the relative fluid velocity during compression exceeds a trigger value of 0.25 μm/s at the radial periphery. Dynamic UCC biochemical results have also reported a higher glycosaminoglycan content in this region versus that of day 0 specimens. Fluid velocity was also found not to be the dominant physical mechanism that stimulates collagen synthesis; the heterogeneity of the fluid velocity contour plot conflicts with the homogeneous collagen content from the biochemical results. It was also found that a Tresca (shear) stress trigger of 0.07 MPa could provide minor stimulation of glycosaminoglycan synthesis. A feasibility study on modeling a heterogeneous disc was conducted and found convergence issues with the jump in properties from the superficial to middle layers of the disc. It is believed that the superficial layer contains material properties that allow the tissue to absorb much of the compressive strain, which in turn increases pressure and causes convergence issues in ABAQUS. The findings in this thesis may help guide the development of a growth and remodeling routine for articular cartilage.

Osteoarthritis (OA) affects an estimated 250 million people worldwide, representing an enormous economic and social burden across demographic groups. While classically attributed to ‘wear and tear’ of the articular cartilage, there is a growing appreciation that OA is a whole-joint disease with a complex etiology involving the synovium and surrounding tissues. The synovium is a specialized connective tissue membrane that envelops the diarthrodial joint and maintains the synovial fluid environment through molecular secretion as well as bi-directional filtration of these constituents, nutrients, and cellular waste products. Moreover, synovium-derived cells have been directly implicated in both the native repair response as well as degradation of articular cartilage. Much of the existing research of synovium has been conducted in the context of rheumatoid arthritis (RA). And while synovitis is a key feature of both RA and OA, clinical reports have described OA synovium as distinct in its cellular and structural composition, molecular secretion, and chronic onset. However, literature studies have not adequately addressed the mechanisms by which alterations in synovium structure-function affect joint and cartilage health, particularly the contribution of different cell types within the synovium to solute transport and lubrication. The work described in this dissertation addresses these knowledge gaps in the context of existing and emerging OA therapies, namely glucocorticoids and electrical stimulation. We anticipate that a more comprehensive characterization of changes to the synovium composition, secretion of key metabolic mediators, lubrication properties, as well as its ability to regulate solute transport in and out of the joint space will not only contribute to our basic science understanding of the synovium but also the development and modification of therapeutic strategies aimed at restoring and maintaining joint health. This characterization will be facilitated by our laboratory’s expertise in tissue engineering and explant culture, IL-1 and DEX stimulation, and electrical stimulation of joint tissues. The approach of using an engineered synovium model is attractive in that quantitative high throughput in vitro mechanistic studies can be performed on tissues that are fabricated from cells derived from normal and OA synovium of patients and corresponding immune cells at defined density and cell type ratios. It also facilitates isolating effects of certain cell types or starting composition that are found in explant specimens. Intra-articular glucocorticoid injections are commonly administered to patients in an effort to control inflammation and pain. And while these high dose injections are known to have significant detrimental local and systemic effects, comparatively low doses of dexamethasone (DEX), a synthetic glucocorticoid, are known to have pro-anabolic and anti-catabolic effects on cartilage cultures. Our laboratory has published extensively on the benefits of DEX stimulation in growth and maintenance of engineered and explanted cartilage as well as chondroprotection from pro-inflammatory cytokines (e.g interleukin-1; IL-1), both in juvenile bovine basic science and adult canine preclinical systems. However, the concomitant effects of DEX on synovium structure-function have not been elucidated. In Part I, we describe a functional tissue engineered synovium model that was validated against explant behavior. We were able to recapitulate many of the unique structural and functional characteristics of synovium, including protein expression, intimal lining formation, solute transport, and friction coefficient. Additionally, changes in engineered synovium structure-function mirrored that of explants when treated with IL-1 or DEX. The engineered synovium model was then expanded to include resident macrophage-like synoviocytes (MLS), demonstrating the key role that these cells play in structural reorganization of synovium. The model was also translated to human cells, showing the potential of the system for personalized medicine. Finally, motivated by insights into solute transport in the synovium as well as its strong anti-inflammatory response to DEX, we developed a sustained low-dose DEX delivery platform for mitigating synovial inflammation while simultaneously stimulating cartilage growth. Utilizing a preclinical adult canine model, we showed that extended intra-articular delivery of DEX improved functional outcomes and cartilage tissue quality. In Part II, we evaluated synovium behavior and cartilage repair in response to modes of electrical stimulation. Electrical stimulation of cells and tissues has been a topic of interest for decades, owed in part to the knowledge that endogenous electric field (EF) gradients guide cell behavior during embryogenesis and wound healing. Pulsed electromagnetic fields (PEMFs) have been used in a clinical setting to stimulate bone repair and alleviate pain, however their use for OA and cartilage repair is controversial. Culture studied of PEMFs have shown anti-catabolic and pro-anabolic effects on isolated FLS and cartilage, respectively. And previous work in our laboratory demonstrated directed 2D migration of synoviocytes and chondrocytes in response to direct current (DC) EF stimulation. These modes of electrical stimulation have not been explored in synovium explants, so it is unclear to what extent the observed phenomena translate to the 3D tissue environment. For the first time, we characterized the biological response of both healthy bovine and OA human synovium explants, showing distinct anti-inflammatory behavior in bovine tissues and a highly variable response in arthritic human tissues, likely due to different inflammatory cell content. Motivated by the potent anti-inflammatory effect seen in normal tissue and previous work showing a pro-anabolic effect on cartilage, the PEMF system was then adapted for use with a preclinical adult canine model of engineered cartilage repair. In this model, PEMFs significantly enhanced functional outcomes and cartilage tissue quality. Finally, we investigated the potential for direct synovial cell-mediated cartilage repair via induced migration with DC EFs. By developing and validating a novel tissue-scale bioreactor capable of applying DC EFs in sterile culture conditions to three-dimensional constructs, we showed increased recruitment of synovial repair cells to the site of a cartilage wound. Taken together, the sum of the work builds on existing therapeutic strategies by developing models to understand the contribution of the synovium to joint maintenance and repair. By modeling dexamethasone- and electrical- induced changes to composition and function of synovium and cartilage, via complementary explant and engineered approaches, valuable mechanistic insights into osteoarthritis pathogenesis and cartilage repair were gathered. These findings lay the groundwork for more complex and personalized in vitro models of OA and motivate future work to capitalize on knowledge of the functional plasticity of the synovium to develop synovium-targeted strategies for OA treatment and prevention.

Osteoarthritis is a degenerative joint disease which affects the entire joint; however, one of its hallmarks is the progressive degeneration of the articular cartilage layer. Patients suffering from osteoarthritis exhibit chronic pain, stiffness, and a decreased range of motion, greatly affecting their quality of life. No drugs have been approved to stop the progression of osteoarthritis and focus solely on the management of symptoms. This is partly due to the challenges in delivering drugs to afflicted joints, and specifically to cartilage due to its lack of vasculature. While intra-articular injection holds promise for the local administration of drugs, small molecules are rapidly cleared from the synovial fluid. As a result, there is a need to develop effective drug delivery strategies to improve residence times in the joint to elicit a sustained therapeutic effect. Previous studies identified polyphosphate as a pro-anabolic molecule, promoting glycosaminoglycan and collagen accumulation in cartilage constructs. Therefore, polyphosphate may be a therapeutic of interest to address the degeneration of articular cartilage in patients suffering from osteoarthritis. In this study, calcium-polyphosphate and strontium-polyphosphate particles were synthesized and characterized as a potential drug carrier into articular cartilage. Physicochemical characterization revealed that the particles exhibit a spherical morphology, have a negative zeta potential, and are nanoscale in size. Biological characterization in chondrocytes confirmed cellular uptake of the particles and demonstrated a size and concentration-dependent cytotoxicity at high concentrations. Furthermore, treatment of chondrocytes with these particles resulted in a reduction in metabolic activity and cell proliferation, confirming biological effects. Preliminary studies using cartilage explants suggest that the particles can penetrate and be retained in cartilage tissue. Therefore, from the results obtained within this study, the polyphosphate-based particles may be a potential drug delivery strategy for delivery into articular cartilage.

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