Intrasynovial soft tissue healing - a novel translational goal for mesenchymal stem cell therapy

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Shoulder pain in very common in humans, of which the most common cause is a tear to a complex arrangement of tendons in the shoulder known as the 'rotator cuff'. Signs include shoulder pain and an inability to raise the arm above the head. These injuries occur as part of an age-related degenerative process and current treatments, frequently involving the injection of corticosteroids into the area, have been shown to be largely ineffective in the long term, even though they can produce short-term pain relief. Surgical repairs of persistent and severe rotator cuff tears are expensive and also frequently fail. There is therefore a need to improve methods of treating this very common condition. One of the leading candidates to provide this extra impetus to achieve functional repair is the use of stem cell therapy. We have recently shown that the use of adult stem cells (known as mesenchymal stem cells) brings apparent clinical benefit in the treatment of equine overstrain tendon injuries and so we propose to deliver live stem cells from the same individual who has the injury, prepared from two different but clinically practical sources - from the bone marrow or from the synovial cells within, or lining, the cavity in which the tendon lies. These cells could be easily delivered either by injection or at the time of surgery. This project tests the hypothesis that the administration of stem cells will improve the healing of tendons inside a synovial environment. It will use a large animal experimental model with similarities to the natural disease in humans to support a subsequent (if the project is successful) application to undertake a 'first-in-man' clinical trial after the conclusion of the project.The project is composed of two complimentary, but not inter-dependent, project phases. The first will investigate, in the laboratory, the effects of stem cells on tendon sections in a culture dish. This will allow us to determine optimal dosages, compare the performance of the different cell types, and evaluate two possible mechanisms of action - the ability of the cells to 'seal' the surface of a damaged tendon and to actively heal it - which has enabled us to limit the number of animals needed in the second phase of the study. Here we will use a novel, recently validated, but more highly relevant, cost-effective model in the sheep. This model consists of a reproducible surgical defect in a tendon created by key-hole surgery which does not result in significant discomfort post-operatively but does produce a similar lack of healing to that seen in rotator cuff disease. The use of a 'large animal' model also enables us to use cells prepared from the same animal in a manner identical to that proposed for use in humans thereby making it most relevant to inform the early translation of the technology subsequently for human medical use.