From Ultrastructure to Micromechanics: a New Perspective on Cartilage Function, Mechanotransduction and Ageing

The UK is projected to become a hyper-aged society in 2030 with 36% of its population over 55. The early diagnosis and treatment for tissue degeneration are one of the most pressing challenges in healthcare. Osteoarthritis is a form of cartilage degeneration and the most common musculoskeletal disorder. It is affecting nearly one third of adults over 45 years old and causing more than £850 million direct cost in NHS, plus £3.2 billion indirect cost for downtime and community care. By targeting the cartilage, this project will establish a fundamental link between highly sensitive structural biomarkers in tissue degeneration and biomechanical functionality, therefore providing the possibility of identifying new targets for early diagnosis and novel therapies. This will be achieved by combining 1) advanced imaging technique for the subtle structural changes in the cartilage, 2) micromechanical loading to visualise the structural responses under different cartilage conditions, and 3) numerical simulation for analysing the integrity of tissues and the mechanobiological communication of cells at different ages. The outcomes of this project will provide experimental and simulational evidence to inform the clinical translation of the imaging technique for early diagnosis of osteoarthritis, allow quantitative evaluation of the treatment effectiveness of anti-osteoarthritis drugs, and facilitate the development of novel cellular and regenerative therapies. The approach established in this project will lead to a new toolkit of studying biomechanics-centred dysfunctions in a wide range of tissues.

The UK is fast approaching a hyper-aged social structure, and tissue degeneration is inevitable in the ageing population. Early diagnosis and precision treatment for degeneration are two of the most pressing challenges in healthcare (Industrial Strategy Challenge Fund Wave 3), and it is critical to understand the initiation and progression of this process. This project will establish a fundamental link between highly sensitive structural biomarkers in cartilage degeneration and its biomechanical functionality. Such a link allows the identification of the compromised biomechanical functionality in cartilage induced by early and subtle changes in its ultrastructure, thereby facilitating the clinical diagnosis and development of novel therapies. This project targets articular cartilage in ageing, for its relatively simple structure and severe social and economic impact. As the most common form of cartilage degeneration, osteoarthritis (OA) affects more than 8.75 million people in the UK, and it has the largest patient cohort in all musculoskeletal disorders (Arthritis Research UK, Osteoarthritis in General Practice 2014). Total knee arthroplasty is currently the only solution for its end stage, costing the NHS more than £850 million in 2010, plus £3.2 billion indirect costs (National Institute for Health and Care Excellence, Osteoarthritis 2014).

The project outcomes will have significant impacts on three industries, not only providing the scientific insights but also demonstrating the benefits from the advanced imaging technique, micromechanical characterisation and computational simulation framework. It will impact clinical practice by contributing to the quantitative definition and diagnosis of early OA and predictive prognosis of disease progression. It will impact biomedical device companies (e.g. Siemens) by integrating the fundamental knowledge into the development of the diagnostic hardware and the longitudinal monitoring system for diseases and treatments. It will impact the pharmaceutical companies by revealing new targets for anti-OA drug development and providing biomimetic templates for 3D-printed constructs in cellular therapies. The impacts are expected to continue with our current collaborative partners, including Stryker, and new parties to perform proof-of-principle demonstration and trials in future.

Thus, the pathways to impact can be summarised as:
- Publications in high-impact journals of international readership, and presentation of results in prestigious international conferences;
- Visiting the collaborating hospitals and biomedical companies to ensure timely dissemination of the project outcomes and advancements and fostering knowledge transfer partnerships;
- Presenting results in industry conferences, and directly interacting with industrial researchers sharing an interest in developing diagnosis and treatment for OA to maximise their awareness of such advanced framework and knowledge;
- Organising an international symposium under the ImagingBioPro Network to bring together specialists from academia, clinics and industries, to directly deliver impact for these beneficiaries;
- Maximising the impact of this project for wider communities via a dedicated project webpage hosted by the University of Exeter and through multiple social media, to raise the public awareness of the project and its contribution to healthcare;
- Visiting local secondary schools to host an Engineering and Science Day for students and teachers, inspiring and motivating them into the Healthcare discipline by showcasing the research and impact;
- Training a postdoctoral research associate and two PhD students in the emerging field of biomedical engineering, and introducing research-oriented education in both undergraduate and postgraduate courses to promote career interests in this field.