Role of the inter-fascicular matrix in age related deterioration of tendon mechanical function

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We have preliminary evidence that the interfascicular matrix (IFM) is a key determinant of tendon failure properties and fatigue resistance. We hypothesise that injury prone energy storing tendons have an extensible IFM with minimal hysteresis, leading to a structure with improved fatigue resistance. Poor optimisation of the IFM or structural changes with age may predispose individuals to tendinopathy.

This project aims to investigate the role of the IFM in modulating fatigue resistance. Using an equine model, we will compare IFM composition and mechanics between a high strain energy storing and a low strain positional tendon, correlating these data with the mechanical characteristics of the tendons. Looking specifically at the energy storing tendon, we will then establish how the IFM changes with ageing and how this influences fatigue resistance. Finally, we will use knockout models and enzymatic techniques to manipulate IFM composition, and establish how this influences our findings.

The equine model proves an ideal energy storing tendon, with similar properties to the human Achilles. It is also large enough to be used for a series of experiments, enabling paired statistical analyses of the influence of IFM organisation and age on tendon function. IFM composition will be assessed using histology, immunohistochemistry, mass spectroscopy and qPCR. IFM, fascicle and tendon mechanical properties will be determined using quasi-static and cyclic fatigue tests to failure.

Data will provide greater understanding of how injury and ageing influence tendon mechanics via the IFM and may provide insights into methods of limiting injury risk. This will inform treatment practices, and facilitate the design of targeted drugs or treatments for the IFM. It may also be possible to develop training protocols to encourage appropriate IFM development, with the long term goals of decreasing the incidence of tendon injury and improving recovery rate post-injury.

Tendon disorders are highly debilitating and painful, and musculoskeletal injuries lead to more days off work than any other illness, costing the economy over £7 billion a year (1). Tendon injury is also common in horses (2) and with a total economic impact of over £3 billion a year from horse racing (3), preventing tendon injuries is high priority (4). A key outcome from our grant is improved understanding of tendon fatigue resistance which is fundamental to preventing damage. We anticipate considerable long term societal benefits to patients with tendon injuries, both preventing new cases and improving healing. This will improve quality of life, reduce strain on the NHS, and lower costs associated with time off work. Such findings are also directly relevant to horses. Around 16,000 race horses are in training each year (3), and tendon injury rate is as high as 43% with very few horses returning to racing post injury; preventing these injuries is essential for the economic health of the industry and to improve equine welfare (5). To realise these potential impact opportunities, we will target our research towards clinical colleagues and medical or healthcare companies.

This project will benefit academics and clinicians with an interest in tendon (dys)function. In the short term, our understanding of how tendons respond to load may clarify optimal methods for treating tendon injury. There is no current consensus on tendon treatment, and no clear physiotherapy regime to promote healing. The PI works closely with a clinical physiotherapist specialising in tendon disorders, and the pair have developed techniques for investigating in vivo tendon biomechanics. We anticipate using these systems to translate our in vitro findings to an in vivo setting and determine optimal physiotherapy training mechanisms for tendon repair. We also have a veterinary surgeon and academic within the current investigative team, enabling us to translate our research across veterinary boundaries. Discussions with these healthcare partners will not only provide valuable feedback on the clinical relevance of our data, but also allow us to consider the optimal methods of disseminating our findings in a manner accessible to healthcare professionals.

Towards the end of the grant we will focus on R&D investment. In characterising the key matrix components that protect tendon from damage, this work will be of interest to companies keen to develop products to prevent or treat tendon injury. There is also strong potential for collaboration with biomaterials and tissue engineering companies. The composite structure of tendon appears key to its optimal function and fatigue resistance. Characterising this will enable us to identify the specific material requirements that must be recapitulated in artificial tendons, significantly improving our potential for developing functional repairs. With skills in biomaterials amongst the applicants, we would remain closely involved in the development of repair solutions. The team has experience of working with medical device companies focused on tissue implant products (e.g. Tissue Science Laboratories; now Coviden), enabling us to advance research towards biomaterial tendon repairs. We also predict tissue engineering benefits, specifically relating to the biological and mechanical environment surrounding cells in the non-collagenous tendon matrix. We anticipate that our data will highlight how cell environment differs in healthy and damaged tendon, providing insights into the optimal in vitro environment for promoting tendon repair. As an additional area of expertise within the research team, we would aim to develop links with tissue engineering companies to take this forward.
1 Bevan 2007 Pub The Work Foundation
2 Clegg 2012 Equine Vet J 44:371
3 Deloitte LLP 2009 Pub British Horseracing Authority
4 HBLB 2012 Scope of veterinary research interests & current specific priorities
5 Dowling 2000 Equine Vet J 32:369