Megan Cooke

Doctoral Researcher
Physical Sciences for Health CDT 

Thesis project - "The development and biophysical characterization of novel biomimetic models for the repair of joint tissue in early osteoarthritis"

Supervisors:
Professor Liam Grover, School of Chemical Engineering
Dr Simon Wyn Jones, Institute of Inflammation and Ageing
Dr Iain Styles, School of Computer Science
Dr Richard Williams, School of Chemical Engineering

Osteoarthritis (OA) is a degenerative joint disease characterised by the loss of cartilage in joints, which usually acts as a shock absorber between the bones. It is a painful and disabling condition seen in the knees, hips, toes, fingers and spine. It is highly prevalent, currently affecting the knees of 4.71 million people in the UK, a number which is expected to reach 8.3 million by 2035 due to an ageing and increasingly obese population (Arthritis Research UK, 2013). At present, treatment options are limited to pain relief, microfracture surgery or implanting cells from a different region of the body which is associated with further issues. More commonly, when the disease reaches ‘end-stage’ patients undergo joint replacement surgeries. Joint replacements have a lifespan of 10-15 years after which time they fail and must be replaced again, meaning more invasive surgery and an increasing loss of bone mass (Smith et al., 2012). As the population ages and more people outlive their replacement joints, the need for these revision surgeries is increasing. Therefore there is an increasing need to treat OA before a joint replacement is required. Research efforts in this area currently investigate two options: to develop disease-modifying drugs which would slow or prevent cartilage damage; to develop a method for the regeneration of cartilage which can then be integrated into the joint without tissue rejection.

This project aims to gain a better understanding of the diseased joint and then develop a 3D biological model that mimics a diseased joint. This information can then be translated into potential targets for new drug compounds. The first stage of this project will include a physical and structural analysis of healthy and diseased tissue and then a comparison of this to biochemical analysis of the same tissue. This will attempt to find correlations between changes in structure and biochemical activity in an osteoarthritic joint.

The second stage will use the evidence from the first to develop a model with gel-like materials (hydrogels), derived from natural sources. It will be similar to the structure of the bone-cartilage interface, and will have a gradient of cartilage cells (chondrocytes) and bone-forming cells (osteoblasts). Chondrocytes will release factors such as collagen type II which produce a cartilage extracellular matrix (ECM) to replace the gel material as it slowly degrades, while the osteoblasts will produce mineral deposits, the first stage in bone formation. The response of the cells will be measured and analysed by measuring their gene expression to determine which proteins they will produce and hence the ECM components that they secrete. Production of structural components by osteoblasts and chondrocytes will be measured by Raman mapping (which shows specific deposition of materials such as collagen), micro-computed tomography and micro-x-ray fluorometry. The data will then be computationally fused to draw comparisons between regions of compositional, structural and elemental interest. When the model best replicates a diseased joint, it will be used to test the effect of new drugs on the cells. This will be the first step in understanding the likely response of the joint tissue when these drugs are administered to human patients.

This project uses physical sciences to develop a technique to better understand osteoarthritis with the ultimate aim to develop a research tool for new drug targets. The integration of computational sciences will allow for better analysis of the accumulated data for optimisation of the model.

(1)     ArthritisResearchUK (2013) Osteoarthritis in general practice
(2)     Smith AJ, et al. (2012) Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet 379(9822):1199-1204