Tendon organoid for drug screening – TENORS

Chronic tendon injury or tendinopathy is a major health issue. Causes of tendinopathies are multiple and include, excess load, intense training, metabolic disorders, ageing and drugs. Drug-induced tendon disorders are often underestimated and pointed out only when the molecule has been authorized for therapeutic use. Tendinopathy symptoms go from pain to rupture, that request a specific surgery and long term rehabilitation. Therefore, being able to evaluate such deleterious side effects with the help of powerful preclinical models should contribute to preventive medicine.

In TENORS, we propose to exploit tissue engineering strategies to develop bioinspired tendon organoids. Institut Mondor de Recherche Biomédicale (IMRB - Créteil) will provide human adipose derived stroma cells. They will be cultured under dynamic conditions on electrospun matrices, following protocols established with the other partners, i.e. the laboratory of Biomechanics and Bioengineering of UTC (BMBI- UMR CNRS 7338) and the laboratory of Biological Development (LBD - UMR CNRS 7622) of IBPS at Sorbonne Université. The application of cyclic mechanical stretching will orientate these stem cells towards a mature tendon lineage. Different configurations will lead to the biological and mechanical characteristics of healthy tendon (including tendon associated to a muscle patch in a bioinspired approach) or to a disabled state in link with ageing or metabolic disorder.

The newly built tissues will thus be composed of cells, biomaterial scaffold acting as a mechanical support, and neo-synthesized extracellular matrix. To mimic ageing or metabolic disorders such as diabetes, we will alter this extracellular matrix with sugars. The mechanically weakened matrix will become more sensitive to drugs. These models will be validated as tendon toxicity assay, using drugs already known to affect tendons.

Up to now, tendon organoid, in a healthy state or even less in altered one, has not been developed and used for such application. The success will be ensured by the pluri-disciplinary consortium (bioengineering, biomaterials, biomechanics, cell biology, developmental biology, biophysics, pharmacy) gathered to achieve this proof of concept.

At the end, several tendon organoids will be available and well characterized, both on the biomechanical and biological sides. In a transfer of technology process, they can be exploited in the pharma industry or in related contract research organization (CRO) in a preclinical evaluation studies of their novel drug candidates. This work fully fits into the 3R recommendations, as an alternative to animal studies with complex in vitro models using human cells. The attrition rate of drug candidates occurring during clinical studies could thus be reduced, as well as costs and development times for the pharma companies. Our models can also be exploited in fundamental research to better understand the mechanisms of tendon maturation and degeneration.