Investigation of the Structural Quality of Bone and Cartilage Repair Following Cell Therapy

Using the body's own cells, known as "cell therapy", is an attractive way to repair worn or damaged body parts. For many years, our Centre has help patients who have knee cartilage damage by using cartilage cells to help repair areas of damaged cartilage. A handful of small studies in humans have shown that stem cells could also be used, not only to help repair cartilage, but also to help repair the underlying bone. The two cells types in combination might help even better. To find out, the charity Arthritis Research UK is funding a clinical trial in our Centre to compare cartilage cells versus stem cells versus the two cell types together.

This trial forms a unique opportunity to find out not only which type of cell is better, but also how the cells help repair and which patients are best suited for this treatment. This grant application asks for funding to help us finding out how these different cell types, both alone and in combination, behave inside the joint. We especially like to know how they go on to produce cartilage and bone, arranged in the right way, with the right properties to improve knee function. It will also help us to find out beforehand which cell types are best for which patient, or perhaps identify patients beforehand for whom cell therapy is not a good option. If so, it would save them pinning their hopes on this treatment.

Our clinical experience has shown us that the full benefit of cell therapy is seen around one year after cell implantation. At this time point we plan to use a range of techniques to identify and quantify the different types of repair tissue produced. These techniques include Magnetic Resonance Imaging (MRI), visual inspection of the joint itself during knee joint surgery, and examining biopsies of repair tissue down the microscope. MRI can show us how much new cartilage and bone have formed, if the new tissue fills the whole damaged area, how smooth the surface of the cartilage is and how well attached it is to the adjacent normal cartilage. Histology using the microscope and other specialised techniques can show the actual molecules which are present, how they are arranged and how the cells are behaving. We will be able to compare cartilage cells and stem cells and see if one type is better than the other at forming good quality cartilage and/or bone.

To identify patients for whom cell therapy is not a good option, we will measure which of the thousands of genes are switched on in the cells that we implant. By comparing between the genes and the measurements we do on the patients at one year, we hope to find gene patterns that identify such patients.

We aim to study the structural quality of bone and cartilage repair tissue in degenerate or injured knee joints following cell therapy with either chondrocytes and/or mesenchymal stromal cells. We have already been granted funding by Arthritis Research UK to carry out a randomised controlled trial in 114 subjects to compare the clinical benefit of the three cell therapy strategies (Autologous Stem cells, Chondrocytes Or the Two, ASCOT). The work described in this proposal would require the subjects recruited into the ASCOT trial to undergo 3 additional sets of investigations: imaging, arthroscopy and histological assessments at approximately 1 year after the cell implantation. The main objectives of this 'add-on' study would be (1) To determine the structural quality of repair tissue which forms in these patients, using MRI/CT, visual assessment and histology (including immunohistochemistry). This will allow us to look at a whole range of outcomes including: repair cartilage thickness, volume, signal intensity, surface integrity, morphology and biochemical content and subchondral bone structure including the presence of inflammation, oedema and cysts, determination of cortical integrity, bone densitometry, macroscopic appearance of the repair site and the adjacent tissues. (2) To relate structural quality of repair to the clinical outcome of the patients, the characteristics of the cells being implanted and the environment they will be implanted into (cell characterisation and biomarker analysis funded elsewhere). (3) To investigate whether MRI or CT can be used in aiding the selection of patients who will benefit from ACI. (4) To trial an FT-IRIS probe to investigate the integrity, composition and organisation of the repair tissue in a less invasive way than by biopsy. (5) To help to elucidate which cell types are most appropriate for treating joints with osteochondral defects or osteoarthritis.

Workers in academia will benefit directly. These benefits have been described in the above section "Academic beneficiaries".
The most direct beneficiaries from the research will be patients with cartilage and bone defects and/or early osteoarthritis. The data from the research, combined with the primary outcome of the trial, will demonstrate to the patients and their doctor or surgeon which type of cell therapy gives most benefit in the short term and leads to cartilage-like tissue that is most likely to provide long-term benefits.
Practicing surgeons and doctors will also benefit from the proposed research. The data on histology and imaging from the proposed work will substantiate findings from the proposed trial, and increase trust in the trial results.
The public bodies NICE (National Institute for Health and Care Excellence) and the NHS will be beneficiaries of this work. Biopsy data plays an important role in the long-term models that NICE uses to determine cost-benefit of cell therapy. Without such data, long-term forecasting is more difficult. Autologous Chondrocyte Implantation (ACI) is currently available on the NHS as part of a clinical trial, pending further advice from NICE. A trial with biopsy will help NICE to analyze the cost-benefit of the three arms in the trial. The NICE advice will then help the NHS in their decision of providing cell therapy to cartilage patients.
Business and industry can benefit, especially if bone marrow stromal cells prove beneficial to cartilage patients. Although the trial uses autologous cells, allogeneic cells may provide similar benefits. Several companies are investigating the use of allogeneic mesenchymal stem cells. Companies involved in autologous cell culturing will also benefit by the extended evidence from the data on the efficacy of cell therapy to repair cartilage damage.
Another sector to benefit, in particular, will be charities involved with patients with joint disorders. Arthritis Research UK, one of those charities, funds the clinical trial to which this the current research proposal is attached. Arthritis Research UK is very interested in cartilage repair strategies, as demonstrated by their willingness to fund the clinical trial. The proposed research will enhance the conclusions from the trial, thus helping the charity in advising the public. Arthritis Care, another charity supporting people with arthritis, will also be interested in the research. Many of its members discuss the merits of cell therapy on their forums.