Osteoarthritis (OA) is a degenerative disease of the joint that leads to joint instability, degradation of the articular cartilage surface and eventually joint failure. Articular cartilage surfaces exhibit unique mechanical behaviors, bearing and distributing loads across joint surfaces, but have poor regenerative capacities. Human Mesenchymal Stem Cells (hMSCs) present a promising treatment to target OA, relying on their regenerative capacity and structural contributions to tissue repair, along with their immunomodulatory and anti-inflammatory properties. The multipotency of hMSCs allow these cells to differentiate towards osteogenic, chondrogenic and adipogenic lineages and directly incorporate into native tissue. hMSCs also possess the capacity to induce numerous paracrine-mediated processes including the recruitment of stem and progenitor cells, prevention of apoptosis, facilitation of beneficial remodeling and modulation of the immune response. Through encapsulating hMSCs, the effects of their paracrine action were studied directly, as the capsule presents a mechanical barrier for direct physical interaction and integration of these cells within the native tissue. The objective of this study was to utilize encapsulation of hMSCs to determine the paracrine effects of hMSCs on the progression of OA. OA was surgically induced in rats via the medial meniscus transection (MMT) surgery, which presents the phenotypical cartilage degradation associated with OA at 3 weeks. The efficacy of hMSC intervention was assessed using Lewis Rats with MMT (n=5 per group). Intra-articular injections of encapsulated hMSCs were given one day post-op and 3 weeks post-op for the 3-week and 6-week MMT studies, respectively. Animals were euthanized on the final day for both the immediate and delayed treatment studies. Micro-structural changes of the articular cartilage, osteophytes and subchondral bone of the medial tibial plateau were assessed using contrast enhanced microCT. We hypothesized that the intra-articular delivery of encapsulated hMSCs will have a positive effect, via paracrine-mediated action, on the onset and development of OA. The capsules also have the potential to improve retention and cell viability in the knee joint space. Each of these factors could contribute to enhanced therapeutic potential of the hMSC treatment. Utilizing NIR labeled sodium alginate capsules, a retention profile for the capsules yielded a tau value of 11.48 days, whereas previous studies have shown scaffold free hMSCs show complete clearance in 7 days. The 3-week MMT, run to analyze the effects of immediate treatment of encapsulated hMSCs on the onset of OA, showed a trend towards decreased cartilage thickness and a decreased surface roughness for the hMSC group in comparison to the Saline group, specifically. Additionally, the hMSC group showed a trend towards increased mineralized osteophyte volume for the hMSC group in comparison to the Saline group. Analysis of the subchondral bone yielded no differences between the hMSC and Saline groups for bone morphology. The 6 week MMT study was run to analyze the effects of a delayed treatment of encapsulated hMSCs on OA after the disease had developed. This study showed a similar result with the immediate treatment study for surface roughness, with the hMSC group showing a decrease in comparison to the Saline group. However, no differences were noted for cartilage thickness between the two respective groups. To further analyze the cartilage in the later stages of OA, exposed bone was quantified yielding a trend towards decreased exposed bone in the hMSC group in comparison to the Saline group. The mineralized osteophyte volume for the hMSC group, of the delayed treatment study, yielded a significantly higher value than all other groups. Additionally, the subchondral bone of the hMSC group trended towards a decreased porosity in comparison to the Saline group. This is one of the first studies to use sodium alginate encapsulation of hMSCs as an innovative scaffold means for intra-articular injections into the knee space. Encapsulated hMSCs permitted not only enhanced cellular retention in the knee space but showed a potential chondroprotective role of the paracrine signaling properties of hMSCs in the early stages of OA. These advantages of encapsulated hMSCs were countered by enhancements of secondary OA phenotypic changes, mainly increased mineralized osteophyte volume and a trend towards increased subchondral bone sclerosis in the later stages of OA. hMSCs have shown great potential as disease modifying drugs and through this study we have further explored the efficacy of these drugs for future treatments of OA. This study has high clinical relevance and with clinical practice running well ahead of current scientific evidence, it is imperative that these findings be considered not only in pre-clinical work but in current and future clinical trials. / 2018-07-11T00:00:00Z

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.