Human Tendon-CHIP: Novel In Vitro Predictive Models To Explore Tendinopathy

Tendinopathy is a highly painful and debilitating condition, markedly reducing quality of life for millions of people. It is common among athletes and accounts for many sporting injuries, but is also regularly seen in the non-sporting public and impacts ability to work and general mobility. Unfortunately, current treatments often do not restore tendon function because we do not yet understand the complex biological processes driving tendinopathy. This is partly because the research models we use to investigate tendinopathy are not sufficiently alike human tendon. Animals generally do not develop tendinopathy in the same manner and models using human cells have not captured the recently identified diversity of human tendon cells, making it difficult to accurately study the disease. This project aims to address these gaps by developing advanced in vitro (lab-based) models of human tendinopathy, capturing the diverse cell populations and tissue environments of human tendon, to provide the crucial platforms we need to understand and treat tendinopathy. Termed organ-on-a-chip technology, this new approach brings together cutting-edge engineering and biology to build controlled, miniaturised organ environments containing human cells, to accurately reflect human biology and allow researchers to study disease and treatments in ways previously not possible. Our “tendon-chips” will simulate the complex micro-environment of human tendon, including the different cell types in tendon, tendon-specific vascular cells (that form blood vessels), and immune cells. We will build one chip on a commercially available chip-system, to offer the research community a widely accessible platform. It will include a tendon compartment and a vasculature compartment, linked by a semi-permeable membrane, enabling us to investigate the inflammatory processes and immune cell recruitment occurring in tendinopathy. We will also develop a custom-built chip with three compartments, namely the vasculature and two compartments for the two different tendon cell populations. This is important, as research suggests it is interaction between tendon-specific cell populations which drives disease, so separating the cells allows us specific insights into those interactions. We must ensure robust, repeatable human-relevance in our models, so we will identify optimal conditions for maintaining cells in the chips, to ensure they thrive and behave as they would in the body. This includes finding the materials to house the cells and adjusting factors like nutrient availability, stiffness of the surfaces, and mechanical forces that mimic how tendons are stressed during movement. Once built, we will investigate how to drive tendinopathy in our model. By testing how tendon cells respond to mechanical stress, inflammation, and other disease-causing signals, we will uncover the specific cellular and molecular drivers of the disease. In summary, we aim to build new, human-relevant tendon models and drive them to tendinopathy, to provide new understanding of the processes leading to tendinopathy and inform the development of more effective therapies. The benefits of this work are far-reaching. Establishing a new standard in disease modelling, this research aligns with the MRC’s focus on advancing molecular and cellular medicine. Our models have the potential to reduce reliance on animal models, speed up the discovery of new treatments, and improve outcomes for patients suffering from tendinopathy, by guiding researchers, clinicians, and pharmaceutical companies in developing new drugs and regenerative therapies for tendinopathy. Ultimately, this project aims to reduce the burden of this condition on individuals and healthcare systems, offering hope for more effective management of tendon disease.