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Tendon Therapy Train Report Summary

Project ID: 676338
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - Tendon Therapy Train (Engineering in vitro microenvironments for translation of cell-based therapies for tendon repair)

Reporting period: 2016-02-01 to 2018-01-31

Summary of the context and overall objectives of the project

The Tendon Therapy Train programme will develop the world’s first three-dimensional cell assembled prototype for tendon repair, the clinical relevance of which will be assessed in suitable preclinical models to demonstrate proof of principle. Coordinated by the National University of Ireland, Galway, the consortium further consists of four academic beneficiaries: University of Minho (Portugal), Maastricht University (Netherlands), Royal Veterinary College (UK) and The Technological Educational Institute of Epirus (Greece); and three industry beneficiaries: Sofradim Production (France), Proxy Biomedical (Ireland) and Stemcell Technologies (UK); combining expertise in cell culture, in vitro and in vivo modelling and medical devices. The consortium includes three human and veterinary hospitals as partners.
Over 20 million tendon procedures take place annually worldwide with associated healthcare expenditure estimated at €145 billion per annum. Current surgical interventions are based on tissue grafts, biomaterials, cell injections and biomaterial-cells combinations. Unfortunately, current surgical repairs preclinical and clinical trials show that tissue grafts are characterised do not restore tendon function, imposing the need for new functional and clinically relevant regeneration strategies.
The hypothesis for Tendon Therapy Train is that an in vitro microenvironment that will imitate the native human / equine tendon tissue milieu will maintain the phenotype of tendon derived cells (TDCs) and differentiate bone marrow stem cells (BMSCs), adipose derived stem cells (ADSCs) and dermal fibroblasts (DFs) towards tenogenic lineage and ultimately facilitate the development of a functional cell assembled tendon equivalent. The Tendon Therapy Train programme is divided into six specific objectives:
• 1: Engineering optimal culture conditions to maintain human / equine TDC phenotype.
• 2: Engineering optimal culture conditions to differentiate human / equine BMSCs, ADSCs and DFs towards tenogenic lineage.
• 3: Development of three-dimensional human / equine tendon substitutes.
• 4: Assessment of prototypes in preclinical models.
• 5: Development of roadmap to commercialisation.
• 6: Development of world-class doctoral programme in ATMPs

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Ethical approvals and licences for human and animal tissues for cell extraction have been granted. Protocols for human and animal tenocyte isolation, characterisation and culture have been established. Work is continuing on the establishment of protocols for tenogenic phenotype maintenance of TDCs and tenogenic differentiation of BMSCs, ADSCs and DFs based on growth factors. In excess of eight growth factors at varying concentrations in simultaneous or serial fashion and with single or multiple time-points have been assessed. D. Berdecka has identified TGF-B3 as the most effective growth factor for ADSC supplementation. A. Dei has identified a serum-free medium able to support expansion and differentiation of BMSCs towards tenogenic lineage. A. Rampin has demonstrated enhanced viability, metabolic activity and collagen deposition when supplementing equine TDCs with equine serum.
Protocols for fabricating natural and synthetic substrates with different stiffness have been established, as have protocols for imprinting different topographies on natural and synthetic substrates of different stiffness. S Vermeulen and A. Dede have engineered and biologically validated two biomechanical model systems, i.e. a tenogenic surface topography and decellularised tendon matrix, that will represent the mechanical niche of the tendon in future differentiation experiments. S. Ribeiro has produced a range of thermal pressed biodegradable polymeric films with varying stiffness that can modulate stem cell differentiation. Biological assessment of polymeric substrates with varying rigidity is being conducted. Collagen-based substrates with variable rigidity which can maintain topographical features in wet state have been developed. E. Pugliese has fabricated and characterised collagen type I sponges that can be functionalized with tenogenic bioactive agents for a controlled and sustained release. S. Guillamin has investigated stem cell differentiation towards tenogenic lineage using a 3D hierarchical micro-porous collagen sponge.

Work in ongoing on protocols for optimal MMC conditions for enhanced ECM deposition from TDCs and BMSCs, ADSCs and DFs differentiated toward tenogenic lineage. A selection of clinically relevant crowders has been identified and is being assessed. S. Galvez has shown that hyaluronic acid works as an MMC, enhancing ECM deposition in ADSC culture. A. Djalali Curvas has investigated the effects of MMC on the enhancement of the bioactivity in vitro.
Work on oxygen tension and mechanical loading applied to culture conditions is ongoing. Optimal oxygen tension conditions for ECM deposition have been identified. These conditions continue to be assessed under synergistic crowding conditions. A de Pieri has fabricated electrospun thermoresponsive nanofibres that sustain the growth and detachment of ECM-rich cell sheets in a macromolecular crowded microenvironment. D. Tsiapalis has shown that the synergistic effect of optimal macromolecular crowding and oxygen tension conditions can accelerate the production of ECM substitutes, which in turn can stimulate tenogenic phenotype maintenance. I. Sallent is using biophysical stimuli on a collagen scaffold to differentiate stem cells towards the tenogenic lineage, enabling the development of a tendon-like tissue in vitro.

G. Sivelli has optimised an in vitro cell culture model for tendon inflammation and a method to isolate and characterise equine TDC and BMSC derived extracellular vesicles.
Preparatory work is underway on preclinical assessment of the tendon substitute. I. Francois has validated clinical, histological and immunohistochemistry techniques and a scoring system to determine tendon healing for use in a preclinical equine model for translation of cell-based therapies

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Tissue grafts are the gold standard in clinical practice. However, in severe injuries and degenerative conditions, the quantity and quality of autografts needed cannot be met. The use of allografts and xenografts is also limited. Cell-based reparative strategies have shown poor results. Advances in engineering, chemistry and cell biology have led to the development of tissue engineered by self-assembly (TESA), advanced therapy medicinal products (ATMPs). Despite the efficacious results that TESA therapies have obtained to-date, few ATMPs have been commercialised due to the still primitive ex vivo culture conditions. ATMP therapies require removal of cells from their optimal tissue niche and propagation in vitro. Bereft of their optimal tissue context, cells perform poorly; lose their functionality and their therapeutic potential.
Tendon Therapy Train will generate impactful Tier 1 conference papers and peer-reviewed Journal Publications. The project will provide a superior solution for patients suffering tendon injury improving their quality of life. It will also aid in reducing pre and post-operative healthcare costs, currently estimated at €145 billion per annum worldwide. Developed platform technologies will be applied to other tissues facilitating a new product family of biologically active tissue substitutes for use in the healthcare sector and in vitro pathophysiology models.

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