Hopkins, Timothy ORCID: https://orcid.org/0000-0002-0300-8230 (2021) Investigating the impact of subchondral bone health and activity levels on cartilage repair in the knee. Doctoral thesis, Keele University.

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Abstract

Damage to the articular cartilage (AC) in the human knee, caused by physical trauma or degenerative disease, represents a common and complex clinical problem. AC has a very limited capacity for self-repair and, once damaged, rarely heals spontaneously. Several surgical interventions have been developed to restore the articular surface and prevent further AC damage and loss. Among these, cell therapies such as Autologous Chondrocyte Implantation (ACI) have demonstrated good mid- to long-term results in the treatment of chondral lesions. However, questions remain regarding the factors that influence a successful repair.
In this thesis, a Delphi consensus study among a panel of experts was used to identify research priorities in the cartilage repair field. The Delphi study highlighted factors that the panel agreed upon as being important in influencing the success of cartilage repair, some of which were used to develop or refine research questions for this thesis. The panel agreed that the subchondral bone (SB) was an important factor in cartilage repair and should be taken into account when planning therapeutic interventions, and that demographic and rehabilitative factors were also important factors.
An in vitro co-culture model was established and used to model the interaction between exogenous cells implanted as part of a cell-based, tissue engineering strategy for AC lesions, and the native endogenous cells of the SB. The co-culture model tested the effect of bone marrow-derived mesenchymal stromal cells (BM-MSCs), isolated from regions of the joint with varying degrees of SB degeneration, on the behaviour of allogeneic chondrocytes obtained from a donor with no history of OA. Chondrocytes cocultured with BM-MSCs obtained from the more degenerated regions of the joint demonstrated a decrease in anabolic activity, with a downregulation of genes that encode the major extracellular cartilage matrix proteins (collagen type 2 and aggrecan) and a corresponding decrease in the production of glycosaminoglycans (GAGs). Transforming growth factor-β1 (TGF-β1) was identified as a protein that was differentially secreted by the BM-MSCs obtained from more and less degenerate SB regions and could be implicated in the differences in chondrocyte behaviour. A preliminary study was carried out to investigate the histological and cellular characteristics of a clinically accessible measure of SB health, the presence of bone marrow oedema-like signals (BMELs) on magnetic resonance images (MRIs). Tissue from these areas, although similar in appearance on MRI, demonstrated a large amount of histological heterogeneity, although no cellular characteristics were identified that could explain these differences.
Finally, data collected as part of an on-going trial of cell therapies for the treatment of AC lesions, Autologous Chondrocytes, Stem Cells or the Two? (ASCOT), was analysed to investigate the relation between activity levels and knee function in the post-operative period. The influence of various demographic, anthropometric and psychological factors on this relation was also investigated. There was variation between patients in the relationship between activity levels and knee function, which correlated with the patients’ negative affect (NA), a psychosocial construct that determines how an individual experiences negative emotions. NA was also found to be the best predictor of the primary outcome measure of the ASCOT trial, even when accounting for demographic, anthropometric and clinical factors. The results presented in this thesis add to current knowledge on the contribution of SB health, activity levels and psychosocial factors to the outcomes of cartilage repair therapy.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Contributors: Kuiper, JH (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 24 Mar 2021 12:36
Last Modified: 24 Mar 2021 12:36
URI: https://eprints.keele.ac.uk/id/eprint/9304

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