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Title: Improving models for translational research in osteoarthritis
Author: McLure, Stewart William Douglas
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Recent advances in medical technology have revealed osteoarthritis to be truly multifactorial, affecting all the major tissues in synovial joints. Despite these advances and the fact that osteoarthritis is the most prevalent joint disease worldwide, our grasp of its etiology and underlying pathological process is still remarkably poor. Subchondral bone pathology in osteoarthritis is one area in particular that has been neglected. Thus, investigators must focus on defining the processes that control the causation and repair mechanisms in osteoarthritis before a viable therapeutic target is identified. In vitro investigations have relied on animal models in osteoarthritis research; however the degree to which they reflect human properties differs and their validity remains in question. The overall aim of this thesis was to develop a greater understanding of the osteoarthritis disease process and characterise the tibiofemoral osteochondral properties of three quadrupeds, to improve in vitro osteoarthritis research. A novel fully quantitative methodology was utilised to characterise the natural history of bone marrow lesions, a form of trabecular bone disruption, in subjects with knee osteoarthritis. Using a combination of manual image segmentation and automated statistical bone shape modelling the spatial distribution and volumetric change over a 24 month period was investigated. Furthermore, cartilage segmentations were incorporated to determine whether bone marrow lesions correlated with osteochondral progression in osteoarthritis. Results revealed the lesions to be inherently unstable and prevalent in subjects with knee osteoarthritis. The spatial distribution and significant association to deleterious joint loading environment suggested a mechanical role in bone marrow lesion genesis. Worsening cartilage pathology was significantly associated with increased bone marrow lesion volume and a striking co-location between trabecular disruption and cartilage denudation was identified. These findings identified a clear need for further investigations focussed on the role of trabecular bone changes in osteoarthritis. In vitro analysis was targeted as a potential forum for these studies . - vi- Animals slaughtered for human consumption are routinely used in vitro for musculoskeletal studies. Unfortunately little data has been published validating model selection. A series of imaging and mechanical testing techniques were used to characterise variation in the osteochondral properties of porcine, bovine and ovine stifle joints. Significant interspecies variation in animal maturity and osteochondral morphological and mechanical properties were identified. Results indicated none of the quadrupeds provided an ideal whole joint model for the human knee; but careful selection based on empirical evidence and study goals could be justified. In conclusion, more must be done to investigate how trabecular disruption affects the osteoarthritis pathological pathway, particularly in articular cartilage. In vitro analysis offers a controlled environment to perform these investigations; however access to human cadaveric tissue is notoriously challenging. In vitro quadruped animal models offer an alternative tissue source; however species selection must be validated based on tissue properties, and the inherent limitations of the model must be recognised.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available