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

Lead Research Organisation: Royal Veterinary College
Department Name: Clinical Sciences and Services

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Chairman of Trials Steering Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact I am Chairman of a Trials Steering Committee for a trial on the effectiveness of PRP (platelet-rich plasma) in the treatment of Achilles tendinopathy in humans. It is a multi-centre trial run from Oxford.
 
Description EU Horizon 2020 Innovative Training Network
Amount € 3,876,961 (EUR)
Funding ID 676338 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 02/2016 
End 01/2020
 
Description Health Innovation Challenge Fund (HICF)
Amount £1,394,604 (GBP)
Funding ID HICF-R10-557 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2016 
End 09/2020
 
Description PhD studentship Scheme
Amount £78,000 (GBP)
Organisation Royal Veterinary College (RVC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2014
 
Description RVC-CDP funding
Amount £24,000 (GBP)
Funding ID 2000 RES 2877 (RVC grant reference number) 
Organisation Royal Veterinary College (RVC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 12/2014
 
Title MION-MRI 
Description A method for tracking stem cells by MRI in vivo, using iron nanoparticles. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This has allowed us to track and to establish the location of stem cells injected into the forelimb tendon synovial sheath by MRI of the forelimbs. The method verified in a small test group that the MSCs could be precisely implanted into the tendon sheath and that the cells were distributed throughout the synovial cavity one week after implantation. Limitations identified where the difficulty in detecting hypointense MION labelled cells against hypointense tendon and large numbers of cells to be detectable using a 1.5Tesla MRI machine. However, this was an essential first objective prior to commencing the main study with a large number of sheep. 
 
Title Optimised tendon histology scoring system 
Description We have developed and validated a modified scoring system of greater relevance for mammalian models of tendon injury 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact This technique is now being used for the assessment of our current experimental work on equine tendon injury 
 
Title Sheep BM and SM MSCs 
Description Mesenchymal stem cell lines derived from sheep bone marrow and tendon sheath synovial membrane (approximately 72 of each). 
Type Of Material Cell line 
Provided To Others? No  
Impact This is an on-going study and we expect notable impacts to arise from the comparison of the stem cell characteristics from the two tissues, in terms of cell surface markers, differentiation ability and efficacy of repair of surgically induced lesions in the sheel forelimb deep digital flexor tendon. 
 
Title Sheep MSC CD markers 
Description Cross species antibodies to characterise CD markers of stem cells are a limiting factor in establishing relevant disease models tin different species to the human. The assays established herein have identified a number of commercially available antibodies (to other species) that have good antigenecity to sheep antigens. This are key to this project to characterise the cells used and will be a useful resource to other investigators for studies of stem cell therapies using the sheep to model diseases. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This has advanced out work in characterising sheep MSCs but is as yet in early stages of the project to have a notable impact to other investigators. 
 
Title Sheep intrasynovial tendon injury model 
Description The establishment (method and procedure) of a novel reproducible large animal model (using arthroscopic surgery in the digital sheath of the ovine distal limb) of tendon injuries that occur in a synovial environment. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Injuries occurring to compressed tendons located within a synovial environment occur commonly in humans (e.g. rotator cuff) and in athletic horses but fail to heal well. Our sheep model provides a suitable and appropriate large animal model to study treatment options and is more appropriate than small animal (rodent) models. The model is highly reproducible, well tolerated by the sheep and its establishment has been crucial to test intra-synovial stem cell therapies for this work. 
 
Title Sheep model of intra-thecal tendon injury 
Description We have developed a new model for the creation of intra-thecal tendon defects using arthroscopic surgery in the digital sheath of the ovine distal limb. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact This model allows the evaluation of treatments (eg cellular therapies) of relevance to human intra-thecal tendon injuries (eg rotator cuff tears). 
 
Description Arthrostem 
Organisation Reference Hospital The Equine
Country Spain 
Sector Hospitals 
PI Contribution This project investigated the use of scaffolds to retain mesenchymal stem cells in a synovial environment (joint). We provided expertise in experiment design and analysis of the data
Collaborator Contribution Our collaborators provided horses with naturally-occurring osteoarthritis for this experimental study.
Impact Analysis of the intra-synovial cell retention with the scaffolds we have investigated for soft tissue implantation did not appear to retain cells any better than simple injection.
Start Year 2015
 
Description DDFT Clinical Trial 
Organisation Animal Health Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Our experience with our novel tendon disease model developed in the MRC-funded project (sheep intra-synovial tendon injury) has led us to initiate a clinical trail jointly with four other referral hospitals in Newmarket - the Animal Health Trust (AHT), Newmarket Hospital (NEH), Rossdales Equine Hospital and Bell Equine Veterinary Hospital - to treat similar naturally-occurring injuries to the deep digital flexor tendon in the horse using mesenchymal stem cells. This is a proof-of-principle trial. Our contribution includes experience in establishing clinical trials in the horse, preparation and clinical delivery of bone marrow-derived mesenchymal stem cells, management and administration of multi-institutional project and providing indirect funding (dedicated personnel to work on the project and institutional facilities) and direct funding (laboratory costs supported by a grant from the Concept Development Fund at the Royal Veterinary College).
Collaborator Contribution The AHT has contributed by recruiting appropriate clinical cases to the study, indirect funding (costs associated with surgeon and hospital charges as well as the training in advanced stem cell characterisation for a postdoc dedicated to this project), and direct funding (for the postdoc). The NEH and Rossdales have contributed by recruiting appropriate clinical cases to the study and indirect funding (costs associated with surgeon and hospital charges).
Impact The trial has been completed and the results were consistent with the sheep model in that there was no tangible additional benefit of the implanted mesenchymal stem cells.
Start Year 2012
 
Description DDFT Clinical Trial 
Organisation Bell Equine Veterinary Clinic
Country United Kingdom 
Sector Hospitals 
PI Contribution Our experience with our novel tendon disease model developed in the MRC-funded project (sheep intra-synovial tendon injury) has led us to initiate a clinical trail jointly with four other referral hospitals in Newmarket - the Animal Health Trust (AHT), Newmarket Hospital (NEH), Rossdales Equine Hospital and Bell Equine Veterinary Hospital - to treat similar naturally-occurring injuries to the deep digital flexor tendon in the horse using mesenchymal stem cells. This is a proof-of-principle trial. Our contribution includes experience in establishing clinical trials in the horse, preparation and clinical delivery of bone marrow-derived mesenchymal stem cells, management and administration of multi-institutional project and providing indirect funding (dedicated personnel to work on the project and institutional facilities) and direct funding (laboratory costs supported by a grant from the Concept Development Fund at the Royal Veterinary College).
Collaborator Contribution The AHT has contributed by recruiting appropriate clinical cases to the study, indirect funding (costs associated with surgeon and hospital charges as well as the training in advanced stem cell characterisation for a postdoc dedicated to this project), and direct funding (for the postdoc). The NEH and Rossdales have contributed by recruiting appropriate clinical cases to the study and indirect funding (costs associated with surgeon and hospital charges).
Impact The trial has been completed and the results were consistent with the sheep model in that there was no tangible additional benefit of the implanted mesenchymal stem cells.
Start Year 2012
 
Description DDFT Clinical Trial 
Organisation Newmarket Equine Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Our experience with our novel tendon disease model developed in the MRC-funded project (sheep intra-synovial tendon injury) has led us to initiate a clinical trail jointly with four other referral hospitals in Newmarket - the Animal Health Trust (AHT), Newmarket Hospital (NEH), Rossdales Equine Hospital and Bell Equine Veterinary Hospital - to treat similar naturally-occurring injuries to the deep digital flexor tendon in the horse using mesenchymal stem cells. This is a proof-of-principle trial. Our contribution includes experience in establishing clinical trials in the horse, preparation and clinical delivery of bone marrow-derived mesenchymal stem cells, management and administration of multi-institutional project and providing indirect funding (dedicated personnel to work on the project and institutional facilities) and direct funding (laboratory costs supported by a grant from the Concept Development Fund at the Royal Veterinary College).
Collaborator Contribution The AHT has contributed by recruiting appropriate clinical cases to the study, indirect funding (costs associated with surgeon and hospital charges as well as the training in advanced stem cell characterisation for a postdoc dedicated to this project), and direct funding (for the postdoc). The NEH and Rossdales have contributed by recruiting appropriate clinical cases to the study and indirect funding (costs associated with surgeon and hospital charges).
Impact The trial has been completed and the results were consistent with the sheep model in that there was no tangible additional benefit of the implanted mesenchymal stem cells.
Start Year 2012
 
Description DDFT Clinical Trial 
Organisation Rossdales Equine Hospital, Newmarket
Country United Kingdom 
Sector Hospitals 
PI Contribution Our experience with our novel tendon disease model developed in the MRC-funded project (sheep intra-synovial tendon injury) has led us to initiate a clinical trail jointly with four other referral hospitals in Newmarket - the Animal Health Trust (AHT), Newmarket Hospital (NEH), Rossdales Equine Hospital and Bell Equine Veterinary Hospital - to treat similar naturally-occurring injuries to the deep digital flexor tendon in the horse using mesenchymal stem cells. This is a proof-of-principle trial. Our contribution includes experience in establishing clinical trials in the horse, preparation and clinical delivery of bone marrow-derived mesenchymal stem cells, management and administration of multi-institutional project and providing indirect funding (dedicated personnel to work on the project and institutional facilities) and direct funding (laboratory costs supported by a grant from the Concept Development Fund at the Royal Veterinary College).
Collaborator Contribution The AHT has contributed by recruiting appropriate clinical cases to the study, indirect funding (costs associated with surgeon and hospital charges as well as the training in advanced stem cell characterisation for a postdoc dedicated to this project), and direct funding (for the postdoc). The NEH and Rossdales have contributed by recruiting appropriate clinical cases to the study and indirect funding (costs associated with surgeon and hospital charges).
Impact The trial has been completed and the results were consistent with the sheep model in that there was no tangible additional benefit of the implanted mesenchymal stem cells.
Start Year 2012
 
Description ESTEM 
Organisation Reference Hospital The Equine
Country Spain 
Sector Hospitals 
PI Contribution The work with this group has developed non-invasive labelling technologies for monitoring mesenchymal stem cell districution and retention after implantation in horses (see Becerra et al., Journal of Orthopaedic Research, 2013 for initial output). This project uses this technology to test different methods for improving retention of stem cells within tendon lesions in horses with natural disease. We are contributing by providing the technology for cell retention. In addition we will be training our partner in the application of this technology.
Collaborator Contribution Our partner has secured the funding for this work and will recruit the horses, provide the surgery and hospital facilities.
Impact Becerra P1, Valdés Vázquez MA, Dudhia J, Fiske-Jackson AR, Neves F, Hartman NG, Smith RK. Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy. J Orthop Res. 2013 Jul;31(7):1096-102. doi: 10.1002/jor.22338. Epub 2013 Mar 18.
Start Year 2012
 
Description HICF Project 
Organisation University of Oxford
Department Botnar Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group undertook the pre-clinical work for a nano fibre scaffold being developed for rotator cuff repair in humans, using the same model in the sheep developed during the MRC project.
Collaborator Contribution Our collaborators developed the scaffold and provided it for use in the sheep model
Impact The pre-clinical results in the sheep model were highly positive which achieved the relevant milestone to continue with its development for human use. Two papers have been prepared and submitted for publication and are currently under review.
Start Year 2016
 
Description ITN Tendon Therapy Train 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution We are part of a consortium providing training for Early Stage Researchers (ESRs) in the field of regenerative medicine for tendons. We have two ESRs who are working on the use of mesenchymal stem cells for tendon repair
Collaborator Contribution The partners are developing a bioengineered cell composite for testing by us in a large animal model
Impact None at present - in vivo work to begin in May 2018
Start Year 2016
 
Description Professor Allen Goodship 
Organisation University College London
Department Institute of Orthopaedics and Musculoskeletal Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Running experiments
Collaborator Contribution Provision of facilities and surgical equipment Assistance with animal models Project data discussion
Impact Successful MRC grant application Numerous previous successful grant applications and publications
Start Year 2012
 
Description Professor Andy Carr 
Organisation University of Oxford
Department Botnar Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Running experiments
Collaborator Contribution Discussion of project design and relevance to human clinical practice
Impact Successful MRC grant application Successful TSB grant application
Start Year 2009
 
Description Professor Dennis McGonnagle and Dr. Elena Jones 
Organisation University of Leeds
Department Leeds Institute of Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Running FACs experiments
Collaborator Contribution FACS analysis of stem cells
Impact Successful MRC application
Start Year 2012
 
Title ASCAT 
Description Safety trial in man of a stem cell therapy for Achilles tendinopathy (in collaboration with the Royal National Orthopaedic Hospital, Stanmore) - funded by the UK Stem Cell Foundation and due to commence in November 2014. This project has commenced recruitment of patients and is ongoing. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact This trial will support the translation of cell therapies into medical practice. 
URL http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=17031
 
Title Bioyarn 
Description The development of the ovine model during our MRC-funded project resulted in its slight modification and use for the testing of a novel nanofibre suture material and scaffold for tendon repair being developing as part of a Health Innovation Challenge Fund (The Wellcome Trust) project, led by one of the co-applicants (Professor Andy Carr). 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact The development of this medical device offers a real prospect of improving the healing of intra-synovial tendon defects - the subject of our MRC-funded work which failed to show a benefit of mesenchymal stem cells administered intra-synovially. It also offers a future possibility of combining with mesenchymal stem cells in the device to potentially improve its capabilities further. 
 
Title RVC-AHT-NEH-Rossdales DDFT trial 
Description Intra-synovial injected autologous bone marrow derived mesenchymal stem cell therapy for the treatment of naturally-occurring deep digital flexor tendon injuries that occur within a synovial environment (digital sheath) of the horse's distal limb. Analogous to the sheep experimental model developed in this project and to naturally-occurring rotator cuff tears in humans. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact Early stage currently. Main impact has been to form collaborations with key clinical referral institutions to conduct this clinical trial. 
 
Title Digital sheath tenoscopy in the sheep 
Description We have adapted the techniques of digital sheath tenoscopy used routinely in the horse (an unusual surgical technique in humans) for use in the sheep for the purpose of this project. This required the use of a small 2.4mm arthroscope and expertise to accurately enter the digital sheath distal to the level of the metacarpophalangeal joint. The advantages of this new technique is that it is minimally invasive, allows excellent visualisation of the structures in the digital sheath at adequate magnification to undertake surgical procedures, and involves continuous flushing with isotonic saline thereby minimising the risks of infection. As a result this minimally invasive technique of creating a linear defect in the deep digital flexor tendon is associated with negligible pain (no lameness is observed in the sheep afterwards) and creates a lesion that does not heal spontaneously over 6 months, making if ideal to test therapeutic strategies for failed tendon healing in a synovial environment. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2012 
Impact This technique was developed for the MRC project (work began on this in 2011 but the technique was mainly used during the project (2012-2015)). After its successful use, it has been adopted for a subsequent study on implants for intra-synovial tendon repair. 
 
Description AAEP 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk entitled 'How to select cases and utilise stem cells for tendon injury' to a large group of veterinary health professionals. This talk generated questions and discussion afterwards.

Greater adoption of the technology in clinical practice.
Year(s) Of Engagement Activity 2014
URL http://www.aaep.org/info/2014-program
 
Description Advances in the pathophysiology, diagnosis and treatment of tendinitis and osteoarthritis in horses, Dubai, October 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a continuing professional development course for equine veterinarians, mainly from Dubai, the Middle East, Africa and China. I gave a number of talks but the relevant one to our MRC-funded work was entitled 'Treatment of tendon injuries: Regenerative Medicine'.
Year(s) Of Engagement Activity 2016
URL http://www.aliuscpd.com
 
Description American University in the Emirates, panel discussion "Application of stem cell therapy in the veterinary horse clinic" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact A panel discussion on the potential commercial investment in veterinary stem cell applications for the horse, camel and falcons in the United Arab Emirates. Panel included the Principal of the AUE, Ministry of Interior, CEO of an American Biotech company. Discussion based around the potential for the exchange of knowledge and investment it both the academic and commercial levels for clinical use of stem cells in the region. The main outcome was to table further discussions to establish details and formal proposals with the American company in collaboration with the United Arab Emirates University (College of Food and Agricultural faculty).
Year(s) Of Engagement Activity 2019
 
Description BSMB 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Poster entitled 'Engraftment of implanted mesenchymal stem cells at specific intra-synovial locations' (MR Khan, RD Godoy, AE Goodship1, RKW Smith and J Dudhia) generated discussion at the British Society for Matrix Biology meeting.

Exposure of our research to the wider research community.
Year(s) Of Engagement Activity 2014
URL http://www.bsmb.ac.uk/meetings-index/building-the-extracellular-matrix-molecules-cells-and-evolution...
 
Description BioWednesday May 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Gave presentation entitled 'A rapid commercial translation of stem cell treatment for equine tendon injuries - highs and lows' to local SMEs, consisting of a mix of people from scientists to business people, lay people and undergraduates.

Interaction with potential industry partners
Year(s) Of Engagement Activity 2013
URL http://www.lbic.com/news-and-events/biowednesday
 
Description British Equine Veterinary Association Pre-congress workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was a pre-congress work-shop for veterinary practitioners interested in new developments for the treatment of musculoskeletal disease. I was asked to give a presentation on 'The science behind regenerative medicine' and included data generated from our MRC-funded work. The delegates were equine veterinarians who have access to the use of stem cells for the treatment of tendon and ligament and joint diseases in horses so knowledge on the science behind their use is essential for these products to be used correctly.
Year(s) Of Engagement Activity 2016
URL https://www.beva.org.uk/Home/Education/CPD/Event-Details/eventDateId/72
 
Description Continuing Professional Development course for veterinary practitioners (VetPD) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact CPD course for veterinary practitioners where I discussed the advances in regenerative medicine, including our studies on intra-synovial administration of mesenchymal stem cells investigated in this project.
Year(s) Of Engagement Activity 2015,2016
 
Description Funding raising activity for stem cell company, Recellerate (USA) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation on the translation of regenerative medicine into the veterinary field, including the additional options for treating human intra-synovial disease disease, at which our project was aimed.
Year(s) Of Engagement Activity 2015
 
Description Havemeyer - Regenerative Medicine 2016 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Havemeyer workshops bring together expert medical and veterinary practitioners to discuss the current state-of-play in a specific area with respect to identifying further directions for research. Professor Roger Smith was the co-organiser of this focus group entitled 'Second Workshop on Regenerative Medicine'.
Year(s) Of Engagement Activity 2016
URL http://www.havemeyerfoundation.org/workshops-group6.htm
 
Description Havemeyer - Tendons 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Havemeyer workshops bring together expert medical and veterinary practitioners to discuss the current state-of-play in a specific area with respect to identifying further directions for research. This focus group was on 'Tendinopathies - Workshop III' and was co-organised by Professor Roger Smith. Dr. Dudhia also participated.
Year(s) Of Engagement Activity 2017
URL http://www.havemeyerfoundation.org/workshops-group6.htm
 
Description Havemeyer 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A focussed workshop attended by 30 professionals in the field of tendinopathies, the purpose of which was to generate current progress in the field and identify new direction of research and clinical applications.
Year(s) Of Engagement Activity 2017
URL http://havemeyerfoundation.org/workshops-group6.htm
 
Description Havemeyer Conference on Regenerative Medicine 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I was Co-Chair of this workshop made up of leading scientists (both veterinary and basic scientists) interested in regenerative medicine. I gave a presentation on the current challenges for stem cell therapy (exemplified by some of the results from our MRC-funded work) and Dr. Dudhia (co-applicant) presented the data from the MRC project.
Year(s) Of Engagement Activity 2016
URL http://havemeyerfoundation.org/workshops-group6.htm
 
Description ISTS 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact I was an invited plenary speaker for a talk entitled 'Stem cell therapy for tendinopathy - what is the evidence from large animal models?' at the International Scientific Tendinopathy Symposium. This generated some questions and discussion afterwards.

Greater understanding of the role of large animal models for the testing of novel treatment strategies for tendon disease.
Year(s) Of Engagement Activity 2014
URL http://www.ibme.ox.ac.uk/ists2014/Home.html
 
Description InGeneron course, Jan 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was a course based around the clinical use of cell therapy in equine patients (sponsored by a company, InGeneron and supported by the British Equine Veterinary Association). I was invited to act as a one of the speakers and demonstrators on the course.
Year(s) Of Engagement Activity 2017
URL https://www.beva.org.uk/Home/Education/CPD/Event-Details/eventDateId/136
 
Description International Society of Ligament and Tendon 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Paper presentation on distribution of stem cells using non-invasive monitoring in horses (ISLT - San Francisco, Feb 3rd 2012)

Dissemination of results
Year(s) Of Engagement Activity 2012
 
Description London Matrix Biology 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Regional forum in the matrix biology field, with about 50 participants. A poster presentation entitled "Assessment of the intra-thecal engraftment of synovial membrane derived mesenchymal stromal cells" MR Khan, RKW Smith, R DeGodoy, S Dakin, F David, AE Goodship, J Dudhia. London Matrix Biology forum, October 2013, Rayne Institute, University College London.

This provided experience for networking with peers for an early career postdoc (employed on this award).
Year(s) Of Engagement Activity 2013
 
Description London Matrix Biology 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A poster entitled 'Assessment of the intra-thecal engraftment of synovial membrane derived mesenchymal stromal cells' (MR Khan, RKW Smith, R DeGodoy, S Dakin, F David, AE Goodship, J Dudhia) generated discussion during the poster session.

Greater exposure of our research to the wider research community.
Year(s) Of Engagement Activity 2014
 
Description Lyon Comparative Symposium 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a plenary talk entitled 'Mesenchymal stem cells in the treatment of tendon injuries in racing Thoroughbreds and sports horses' at the 1st European Comparative Symposium on Equine and Human Sports Medicine, Rehabilitation and Traumatology which generated considerable discussion afterwards in the audience of human and veterinary health professionals and industry participants.

Wider dissemination of our research findings and their relevance to the human medical field.
Year(s) Of Engagement Activity 2014
URL http://www.feiworldcupfinals-lyon.com/uploads/sfSympalBossMediaPlugin/document/9b2a1777c3f97f37a5e94...
 
Description ORS 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Poster at the Orthopaedic Research Society Annual Meeting on 'Modulatory effects of mesenchymal stem cells adhered to tendon surfaces in-vitro' (Garvican, Alves, Smith, and Dudhia)


Many discussions around poster
Year(s) Of Engagement Activity 2013
 
Description ORS 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Poster presented entitled 'Comparing the intra-thecal tendon sheath engraftment of synovial membrane and bone marrow derived mesenchymal stromal cells' at the Annual Meeting of the Orthopaedic Research Society which generated discussion around the poster and an abstract publication.

Dissemination of our research findings related to the MRC-funded project.
Year(s) Of Engagement Activity 2014
URL http://www.ors.org/2014annualmeeting/
 
Description Orthopaedic Research Society invited webinar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited webinar on Cellular Therapies in Tendon Repair and Regeneration by the Orthopaedic Research Society
Year(s) Of Engagement Activity 2018
URL https://www.ors.org/ors-education-online/
 
Description Panel membership at commercial conference 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Member of a panel (Break out panel: exploring the crossover between human and veterinary applications for stem cells) at the World Advanced Therapies and Regenerative Medicine Congress in London in May 2018
Year(s) Of Engagement Activity 2018
 
Description Regenerative Medicine Focused Meeting RVC 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Gave a presentation entitled 'Stem cell research at the RVC: the horse experience' to stimulate discussion relating to the formation of a veterinary stem cell centre at the Royal Veterinary College. This resulted in considerable discussion surrounding this topic.

There was interest in our proposal from industry partners.
Year(s) Of Engagement Activity 2014
 
Description Regenerative Medicine Workshop Keele 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Gave a plenary talk entitled 'Is the horse a relevant model for stem cell therapy of tendon disease?' which generated questions and discussion afterwards and the talk was uploaded onto the website for wider dissemination.

Greater understanding of the relevance of large animal models for testing regenerative therapies.
Year(s) Of Engagement Activity 2014
URL http://www.epsrc-regen-med.org/wp-content/uploads/2014/01/PreclinModelRegenMedFlyer10.pdf
 
Description SIMCAV Brazil 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Professor Smith was an invited speaker to give a number of presentations on the treatment of tendon injuries in horses and the use of mesenchymal stem cells for tendon repair to a large group of Brazilian veterinary practitioners
Year(s) Of Engagement Activity 2017
URL https://simcavufmg.files.wordpress.com/2016/12/pragramac3a7c3a3o-simcav.pdf
 
Description United Arab Emirates University talk and discussion on the application of Stem Cells in the Veterinary Clinic 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A business event at the UAEU at the College of Food and Agricultural for the exchange of knowledge for the clinical application of stem cells in the veterinary clinic. This event included the College Dean, Head of Department, senior academic staff and the CEO of ReCellerate (American Biotech), and the strategic officer of a local investment company. The main outcome was to establish a proposal that outlines the key aims for investing in regenerative medicine research at the College as well as linking this with commercial translation to the horse, camel and falconry clinics in the region.
Year(s) Of Engagement Activity 2019
 
Description University of MINO 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact A teaching lecture on animal models and ex vivo explant systems to study and clinically translate orthopaedic research (""Upsizing the lab - experiences of large animal translational models for orthopaedics"). The lecture was at University of MINO (Portugal) at the 3B's Research Institution and made a comparison on strengths of using ex vivo tissue models (used in the NIHR project) and large animal models for successful translation into the clinic. Outcome, potential collaborative work with the 3B's Institute in this area.
Year(s) Of Engagement Activity 2018
URL http://www.3bs.uminho.pt
 
Description Veterinary industry presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Presentations to multiple conferences on stem cells - audiences consist of veterinary surgeons, both in the UK and abroad on the use of stem cells in musculoskeletal disease - approximately 10-15 per year (12 in 2012).
2 talks given to the horse-owning public on tendon injuries and the use of stem cells in treatment of these injuries

Excellent feedback on presentations on course feedback forms
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
URL http://www.vetpd.com/
 
Description Visiting lecture at the Cambridge Veterinary School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Invited lecture to veterinary undergraduates at Cambridge University to educate them in the current research in regenerative medicine and where our experimental study was discussed.
Year(s) Of Engagement Activity 2015
 
Description WVOC 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave two invited talks entitled 'Cellular Approaches to ligament and tendon injury' and 'Debates on bone marrow stem cells' at the World Veterinary Orthopaedic Conference which stimulated questions and discussion afterwards.

Greater acceptance of cell therapies for clinical use in the horse.
Year(s) Of Engagement Activity 2014
URL http://vosdvm.org/meetings/
 
Description World Equine Veterinary Association Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The World Equine Veterinary Association is an organisation that aims to educate countries with low levels of equine veterinary education. In 2018 their congress was based in Beijing, Chin a and Professor Roger Smith was asked to give a talk entitled 'Stem cell therapy - efficacy of its therapeutic uses' where I included details of our MRC project.
Year(s) Of Engagement Activity 2018