Frontier Engineering: Progression Grant in Modelling complex and partially identified engineering problems. Application to the musculoskeletal system.

Lead Research Organisation: University of Sheffield
Department Name: Mechanical Engineering

Abstract

Traditional engineering ignores complex interactions across several space-time scales, which does not fit the context of modelling of biological systems where scales overlap and the inherent complexity of multi-scale interaction cannot be avoided. For this reason, in the previously funded MultiSim project, we established a computational platform for the investigation of musculoskeletal disorders, which we successfully applied to the prediction of the risk of fracture in osteoporotic and osteopenic women, and to the pre-clinical investigation of bone remodelling in animal models to assess the effect of new treatments. Full exploitation of this platform, however, is limited by the fact that most of the MultiSim activities evolved around skeletal health only. MultiSim2 will allow us to expand the focus of our Centre to include an equivalently robust and detailed modelling of the skeletal muscles to predict the effects of pathologies such as sarcopenia or neurodegenerative diseases. To do so, we will develop new approaches for better imaging, characterisation and modelling of the muscles and of their interaction with the skeletal system. In our murine work, we will focus on developing noninvasive longitudinal imaging techniques and computational models to support the reduction and partial replacement of the use of mice in musculoskeletal research. We will measure longitudinal changes in muscle properties by using a micro-magnetic resonance imaging (microMRI) system and advanced image processing to predict tissue changes over time. These measurements will be integrated to a framework of available tools to obtain bone properties at high resolution with in vivo micro-Computed Tomography (microCT) and to co-register all the acquired data in space and time. We will use our human models to predict physiological and pathological changes of muscle volumes and masses, variations in muscle fibres, tendon geometric and elastic properties and changes associated with degeneration in the neuromotor control. The comprehensive assessment of changes in different musculoskeletal tissues (bone, muscles, tendons) over time in both patients and animals will allow us to create a combined experimental and computational framework to better understand and model the effect of diseases and to optimise future treatments.

Planned Impact

Computational modelling is widely employed across most engineering domains, and Computational Medicine is increasingly predicting personalised healthcare outcomes. MultiSim has been a significant and successful engineering initiative that has tackled a major issue affecting computational medicine, namely the complexity of building models of physiology that span multiple length-scales, requiring the interconnection of disparate systems. This outcome is already proliferating across academia, and being actively considered for commercial and regulatory use. In MultiSim2 we intend to accelerate the uptake of the technology, by adding to the existing bone biomechanics system a similar mechanism for the complete representation of muscle, allowing us to build an impressive keynote demonstrator that describes sarcopenia (loss of skeletal muscle with age) and can also be applied to many neurodegenerative conditions.
MultiSim is an enabling technology with significant impact across academic, industrial, clinical and socio-economic domains. MultiSim2 will enable the framework to be applied immediately to various categories of problem, employing industrial and clinical pathways to bring socio-economic benefit, which include:
- Sarcopenia, for which we will support developments of new understanding and biomarkers;
- Neurodegenerative diseases, like Motor Neurone Disease, where our integrated muscle models will allow investigation of innovative therapeutic possibilities.
- Revision of long-term care strategies, where our enhanced multiscale prediction will allow to explore changes in population distribution between early and late stage disease
- Longitudinal Studies, where we will explore how our measurement and modelling platform can be used to reduce, even replace, animal studies.
- Comorbidities, where by facilitating the combination of separate disease models, we will offer safe and simple investigative possibilities, where clinical trials bring risk and poor recruitment.

Academic Impact Pathways will entail: publications in peer-reviewed journals and talks at scientific conferences; encouragement of Direct Uptake of our existing web services; organisation of "Modelathons" to promote multi-scale modelling among young researchers; organisation of Creativity@Home events to pursue collective creative discovery on multiscale modelling problems; collaborative dissemination to promote outreach to other EPSRC Frontier Centres and Engineering Networks; securing future funding to enable implementation of an extended series of modelling improvements to fulfil the goals of Healthy Ageing and a Healthy Nation.

Industrial Impact Pathways will leverage on ongoing activities from the Insigneo Institute for in silico Medicine, targeting drug developers, medical device designers, regulatory agencies and technology transfer.

Clinical Impact Pathways will seek increased engagement with clinical experts in musculoskeletal care, to improve understanding, extend dialogue, and identify clinical targets of importance to patients. This will leverage on the links that our group has with the UK's clinical networks, with support groups and charitably-supported communities.

Socioeconomic Impact Pathways will entail the continuous assessment of the market potential for each of the proposed developments, and the likely economic justification for their introduction, with dedicated socioeconomic and industrial assessment of change management within healthcare.

Additional Impact Pathway Activities will target Domain Migration (through internal dissemination activities) and optimisation of Knowledge, Standards, IP, Open Access processes to optimise the use of data and digital tools to further research and patient care.

Publications

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