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

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.

Rotator cuff tears in humans are common but are still associated with poor outcomes because of their location under compression and within a synovial environment which limits repair. This project tests the hypothesis that the intra-synovial administration of cultured autologous bone marrow or synovial fluid derived mesenchymal stem cells (MSCs) will improve intra-synovial healing of tendons. The project is composed of two complimentary, but not inter-dependent, work packages. The first will establish the relative ability of both two types of MSCs (leading candidates for clinical use derived from bone marrow and synovial fluid/membrane) to augment repair in vitro via two possible mechanisms -engraftment and sealing of the tendon defect to prevent loss of extracellular matrix components which drive synovial inflammation, and their capacity to modulate new matrix synthesis and repair of the defect. The second work package utilises a recently validated, novel, and more highly relevant, cost-effective injury model in a cost-effective large animal (sheep). This model consists of a reproducible surgical defect created tenoscopically in an intra-synovial portion of a tendon that is under compressive load, more analgous to rotator cuff disease than current laboratory animal models of shoulder tendon transection in a quadruped (which are extrasynovial). The use of a large animal enables us to perform autologous injection of MSCs in a manner identical to that proposed for use in humans. This controlled study will compare the effects of treatment with the two types of MSC with saline injection. The data provided in this study will provide in vitro mechanistic data and experimental in vivo verification in a large animal experimental model with similarities to the natural disease in humans to support an application for a Clinical Trials Authorisation for a 'first-in-man' clinical trial planned to dovetail with the end of this project.

Rotator cuff degeneration and tears pose a significant socioeconomic and treatment challenge. It is the second most common problem in professional sport but also affects the wider population, being the third most common musculoskeletal complaint in general practice with up to 30% of all adults being affected, and 40-50% of patients in the UK consulting their general practitioners for shoulder pain.
The absence of curative treatments usually results in 40-50% of patients having persistent or recurrent symptoms after a year. Even surgical approaches, which are expensive, have a high failure rate and are often unsuccessful in the long term.

This study has been designed both to validate a novel research model for studying this area of major and unsatisfied clinical need, and to answer outstanding questions relating to a cell therapeutic approach within a synovial cavity, so as to justify the subsequent application for a Clinical Trials Authorisation.

Beyond the beneficiaries within the academic communities concerned with this research, several distinct groups have the potential to benefit from its outputs: primarily patients (ageing population and injured athletes) - the large number of people with shoulder pain, as well as potentially other intra-synovial tendon or ligament injuries (together with veterinary patients - from a UK population of circa 800,000 'equine athletes') - who may regain considerable quality of life, a return to professional activity or greater independence and freedom from pain through effective novel stem-cell based therapies.

The ability to offer effective treatment for these conditions will impact significantly on health services. It is anticipated that stem-cell based therapy would be relatively low-cost in comparison with surgery and associated management, and over time there should be significant cost savings through the reduced care needs of ageing/injured patients helped towards greater independence. Consequently the families of patients and other carers, along with charities active in healthcare, fitness and wellbeing will also gain benefit. Outside the NHS, private human and veterinary medicine may benefit through a novel clinical business opportunity, and may be supported by companies offering expansion of harvested stem cells (as is currently undertaken by VetCell for treatment of equine digital flexor tendon overstrain injury).

The concept of a biological, cell-based therapy has already attracted much interest from the potential 'users' of the technology such as orthopaedic surgeons and sports physicians, and so if the technology proves successful in this animal model, we believe that such users will very quickly 'buy into' the use of this technology within the clinical setting. There are several leading UK surgeons, including one of the co-applicants (Professor Carr), who are keen to pursue this technology in a well-constructed human clinical trial, should the evidence provided by this study indicate that this approach is likely to be successful and safe. Discussions with clinicians have prompted comments such as: "At present the management of human tendinopathy is more an art than a science but this approach could potentially reverse that situation"; and "If you assume that degeneration of the shoulder with tendonitis is universal, the numbers of patients who might benefit from your injection is immense .... In summary I think the treatment would be useful to both me and my colleagues."

If both this study and the subsequent human clinical trial are successful, we anticipate that the adoption of the technology would be rapid, providing impact with substantial reach and significance.