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Title: Novel strategies for enhancing tissue integration in cartilage repair
Author: Davies, Lindsay
ISNI:       0000 0004 2749 5998
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2006
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Articular cartilage is found on the surface of opposing long bones within the synovial joint and aids to dissipate loads. Adult cartilage lacks the ability to initiate a repair response when injured due to its aneural and avascular nature. Surgical techniques have been developed to enhance this repair process but none to date rival that of natural cartilage. Repair tissue is often of a fibrocartilaginous nature which does not have the biomechanical stability of articular cartilage. Integration between newly synthesised tissue and the endogenous cartilage is invariably poor as well, leading to degeneration of the repair tissue and surrounding cartilage with time. The aim of this study was to develop strategies for the enhancement of integration between new and pre-existing articular cartilage to form a more biomechanically stable repair tissue. The migratory capacities of chondrocytes isolated from young and mature articular cartilage have been investigated using a Boyden chamber system, as well as the effects of different matrix substrates and chemoattractants on this process. Using this system the substrate dependent chemotactic effects of insulin-like growth factor 1 (IGF-1) and transforming growth factor beta 1 (TGFbeta1) were only seen if the cells were seeded onto a fibronectin substrate. The inhibitory effect of chondroitin sulphate (CS) chains on chondrocyte migration was also demonstrated. Further experiments using an in vitro model of cartilage injury confirmed this, as it was demonstrated that chondrocytes migrated into chondroitinase ABC treated cartilage but not into untreated controls. Biosynthesis studies were used to demonstrate the anabolic effects of IGF-1 and TGFpi on chondrocytes. Radiolabelled sulphate and proline were used as a measure of sulphated glycosaminoglycan and collagen biosynthesis respectively. These experiments demonstrated increased biosynthesis of both matrix molecules by chondrocytes from both age groups in response to these growth factors. In addition, these results suggest that the newly synthesised molecules were assembled into an extracellular matrix by the cells. The results from both the migration and biosynthesis experiments demonstrated the potential of IGF-1 and TGFbeta1 for enhancing cartilage repair, but also illustrated the limitations of their short half lives. Constructs encoding the mature peptides of IGF-1 and TGFbeta1 were therefore developed for transfection into chondrocytes. The ability of these transfected cells to migrate was investigated on a chondroitinase ABC treated aggrecan substrate. Here a constant trend of increased migration with the transfected cells was seen when compared to controls. This study demonstrates the ability of chondrocytes from both young and mature articular cartilage to migrate. This is the first study to report this using skeletally mature articular cartilage. In addition, the inhibitory effects of CS chains in chondrocyte migration have been shown using both the Boyden chamber system and an in vitro model of cartilage injury. The over-expression of IGF-1 and TGFbeta1 in articular chondrocytes demonstrated the possibility of increasing both the migration of cells into articular cartilage as well as up- regulating their capacity for matrix biosynthesis, thereby creating an integrated repair tissue improving on current repair strategies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available