Evaluation of Therapeutics Strategies for Osteoarthritis Using Contrast Based CT Imaging

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Abstract

Osteoarthritis (OA) is the leading cause of disability in the US and is characterized by cartilage degradation, subchondral bone changes and synovial inflammation. OA presents a unique challenge as there are no approved disease modifying OA drugs (DMOADs) and the current mode of treatment is palliative therapy and eventual total joint replacement. Thus, there is a pressing, unmet clinical need to test and develop novel DMOADs to improve outcomes. This includes development and characterization of suitable animal models to provide a test-bed for screening therapeutics.

Cartilage is an avascular tissue containing water which makes imaging cartilage difficult. In order to study pre-clinical models of OA and test therapeutics, an efficient technique with quantitative outcome measures is required. Accordingly, the goal of this thesis was to investigate contrast based CT imaging (EPIC-µCT – Equilibrium partitioning of an ionic contrast agent)as a tool to test therapeutic strategies in a preclinical rat OA model. First, we characterized two different models of joint degeneration, one induced by injection of monosodium iodoacetate (MIA) and a second, created surgically via medial meniscal transection (MMT). Our results indicated that the MIA model leads to global cartilage and bone degeneration whereas the MMT model produces focal defects, similar to human OA. Second, we tested the sensitivity of EPIC-µCT to detect effects of a broad spectrum matrix metalloproteinase inhibitor (MMPi) in the rat MMT model. Our results demonstrated that quantitative measures established by EPICµCT were able to detect damage in cartilage and subchondral bone in response to MMPi treatment with greater sensitivity than the gold standard of histopathology. Finally, we investigated the effects of micronized dehydrated human amnion/chorion membrane (µdHACM) in the rat MMT model. Our results indicated a protective effect of a single intra-articular injection of µ-dHACM at 3 weeks. Treatment of an arthritic joint with a delayed injection also demonstrated a chondro-protective effect of µ-dHACM at a longer time point of 6 weeks. Denaturation of µ-dHACM led to loss of chondroprotective effect at 3 weeks.

Taken together, this thesis presents pioneering work on the use of EPIC-µCT as a quantitative technique to assess cartilage and also presents µ-dHACM as a novel DMOAD to be tested further. This work has provided new insights on the development of OA in the rat MMT model. It is also the first instance of using µ-dHACMas a therapeutic for OA which shows potential to be translated to large animal models and human clinical use. Going forward, EPIC-µCT can be used to screen other therapeutics efficiently and can be adapted to other diseasessuch as juvenile OA, rheumatoid arthritis and osteochondritis dissecans. Ultimately, this technique may enhance the drug testing phase for OA by enabling quicker screening, making the bench to clinic translation a faster process.

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