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Engineering in vitro microenvironments for translation of cell-based therapies for tendon repair

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A promising approach to tissue engineering for transplants flexes its muscles

Tissue transplants could revolutionise outcomes but have faced numerous difficulties and limited success. EU-funded researchers have found ways to successfully culture 3D tissues with exciting results and tremendous potential for many tissue types.

Fundamental Research

Skeletal muscles move our body parts – even our eyeballs – with the help of tendons (dense fibrous connective tissues) that connect them to their targets. Intense, repetitive mechanical forces over the course of our lifetimes can leave tendons prone to degeneration, injury and tearing with aging or overuse. Tendon injuries not only affect quality of life but also cost millions of dollars, either spent on treatment or lost due to inability to work. The Marie Skłodowska-Curie programme supported the establishment of a European training network (ETN) to address this. Via the Tendon Therapy Train project, the ETN demonstrated the successful formation of 3D tendon-like tissues from cultures of tendon cells (tenocytes) as well as through the differentiation of bone marrow- and adipose-derived stem cells. This bottom-up approach to tissue engineering is also proving effective with other tissues. It could lead to fast, affordable and clinically relevant transplants with better outcomes for a variety of conditions.

Mimicking nature

Tissue grafts are currently the gold standard for tendon repairs but they face many challenges. These include limited tissue available from a patient’s own body and risks of infection and rejection with grafts from other people or species. Project coordinator Dimitrios Zeugolis of the National University of Ireland Galway and the project team set out to develop 3D tendon tissue in culture using self-assembly principles to address the problem. Universities, companies and hospitals worked with 15 doctoral students to develop ex vivo culture environments like that of native tendon tissue. The young researchers used varied approaches to overcome challenges, surpassing expectations and shining light on future potential. Zeugolis states: “Introducing inert macromolecules in the culture media to ‘crowd’ the cells’ culture space was very effective. It fostered increased deposition of extracellular matrix, enabling us to culture a tissue of implantable size much more quickly than previously possible.” A three-layer collagen scaffold designed for enthesis tissue (where the tendon inserts in the bone, a site of significant stress concentration) induced bone marrow stem cell differentiation to the three different lineages found in the enthesis. Zeugolis continues: “This was very challenging technically and we are very excited about the results and potential impact.” Furthest along is a skin graft prototype that has shown preclinical proof of concept (in animal models and early safety testing). Thermo-responsive polymers as substrates were an unplanned route that has also shown promising growth induction.

Stretching the scope of tendons

“Our main advantage is much more extracellular matrix than usual. This matrix provides structure as well as substance for the cells and results in much healthier tissue that can maintain its phenotype for clinical efficacy,” Zeugolis summarises. The regenerative medicine market was valued at USD 5.4 billion in 2016 and is estimated to reach USD 39.3 billion by 2023 with CAGR of 32.2 %. The project’s 3D tissue engineering outcomes are on their way to penetrating it, starting with wound healing and tendon repair. Applications to bone, cartilage and ocular tissues could come next. Thanks to the Tendon Therapy Train project, affordable and effective tissue transplants are out of the starting block and sprinting toward availability.

Keywords

Tendon Therapy Train, tissue, tendon, culture, transplant, extracellular matrix, enthesis, graft, tissue engineering, stem cell, regenerative medicine, scaffold, wound healing

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