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

10 25 50

publication icon
Angelini L (2021) A Multifactorial Model of Multiple Sclerosis Gait and its Changes Across Different Disability Levels. in IEEE transactions on bio-medical engineering

publication icon
Cheong V (2021) The Role of the Loading Condition in Predictions of Bone Adaptation in a Mouse Tibial Loading Model in Frontiers in Bioengineering and Biotechnology

 
Title Angels of the North 
Description MultiSim's Director, Claudia Mazzà has been collaborating with dancer and choreographer Freddie Garland, Tenfoot Dance Company, in her continuing project 'Women's Movement 100: Angels of the North' to create a filmed performance about women's suffrage, emancipation and health for the University of Sheffield's Festival of the Mind. Watch the resulting podcast (https://festivalofthemind.sheffield.ac.uk/2020/spiegeltent/womens-movement-100-podcast/) and film (https://festivalofthemind.sheffield.ac.uk/2020/spiegeltent/womens-movement-100-film/). Data captured at Insigneo's Motion Capture and Virtual Reality Laboratory from some of the dancers involved in the Women's Movement 100 can be seen as delicate, abstracted moving dots and tracing lines superimposed over portions of the film, reflecting the movements used by the dancers in the film. Women's Movement 100: Angels of the North One-hundred women from local communities and further afield took part in this project, which gives artistic form to the patterns and waves of the women's movement over the last century, as explored in Department of History Professor, Julie Gottlieb's research. Women's Movement 100 refers to both political and physical movement. The biomechanics of the female physical movement is an important component of MultiSim's research. Freddie and some of her dancers started to explore their choreography in the motion capture laboratory with MultiSim and Mobilise-D researchers: Erica Montefiori, Kirsty Scott and Tecla Bonci. Early results of this collaboration were presented at the University of Sheffield's 2020 Festival of the Mind in September. 
Type Of Art Film/Video/Animation 
Year Produced 2020 
Impact Collaboration with dancer and choreographer Freddie Garland and Julie Gottlieb, Professor of Modern History at the University of Sheffield. Wide exposure of project to broad non-technical audience. 
URL https://www.sheffield.ac.uk/multisim-insigneo/news/angels-north
 
Title Data for MicroCT-based MicroFE of human vertebrae 
Description This file contains the results collected in the study: "Effect of size and location of simulated lytic lesions on the structural properties of human vertebral bodies, a micro-finite element study" by "M.C. Costa, L.B. Bresani Campello, M. Ryan, J. Rochester, M. Viceconti, E. Dall'Ara" published in Bone Reports:https://doi.org/10.1016/j.bonr.2020.100257.In order to access the original raw files the reader can contact the the corresponding author (Dr Enrico Dall'Ara, e.dallara@sheffield.ac.uk). The files are stored in the University of Sheffield file-store at the link:https://web-unidrive.sheffield.ac.uk/shared/bone_biomechanics1/Projects/15_METVERT/DD_SimulatedMetastases/ 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with the research community. 
URL https://figshare.shef.ac.uk/articles/Data_for_MicroCT-based_MicroFE_of_human_vertebrae/11958954
 
Title Data for paper "Is a wearable sensor based characterisation of gait robust enough to overcome differences between measurement protocols? A multi-centric pragmatic study in patients with Multiple Sclerosis" 
Description This repository has been created to support the paper "Is a wearable sensor based characterisation of gait robust enough to overcome differences between measurement protocols? A multi-centric pragmatic study in patients with Multiple Sclerosis". The excel file includes both demographic and clinical information of each participant (1st worksheet) and the gait outcomes extracted from the wearable sensors for each participant (mean and SD values, 2nd worksheet). For details email l.angelini@sheffield.ac.uk 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_paper_Is_a_wearable_sensor_based_characterisat...
 
Title Data for paper "MRI-based anatomical characterisation of lower-limb muscles in older women" 
Description This Figshare contains:1. additional material.docx, including supplementary information associated with the paper "MRI-based anatomical characterisation of lower-limb muscles in older women";2. Segmentations for the eleven subjects in the study labelled as MC17, MC18, MC19, MC20, MC22, MC24, MC25, MC26, MC27, MC28, MC29 (corresponding to Subject 1 to 11, respectively, see additional material for details):a. bone and soft tissue (skin) segmentations as stl files;b. muscle segmentations as stl files;3. Muscle centrelines as vtk files. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_paper_MRI-based_anatomical_characterisation_of...
 
Title Data for the paper: "Bone remodelling in the mouse tibia is spatio-temporally modulated by oestrogen deficiency and external mechanical loading: a combined in vivo/ in silico study" 
Description Data used in the paper : "Bone remodelling in the mouse tibia is spatio-temporally modulated by oestrogen deficiency and external mechanical loading: a combined in vivo/ in silico study"byVee San Cheong, Bryant Roberts, Visakan Kadirkamanathan, Enrico Dall'Arapublished in Acta BiomaterialiaWe share here an example of in vivo microCT images collected for a mouse that underwent ovariectomy at week 14 of age and mechanical loading at week 19 and 21 of age. In vivo 3D microCT images of the mouse tibia have been acquired at week 14, 18, 20, and 22 of age. The registered and cropped images are reported here.In case the reader is interested in the whole database they should contact Dr Enrico Dall'Ara (e.dallara@sheffield.ac.uk). 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_the_paper_Bone_remodelling_in_the_mouse_tibia_...
 
Title Data for the paper: "Development of subject-specific finite element models of the mouse knee joint for preclinical applications" 
Description Data for the paper: "Development of subject-specific finite element models of the mouse knee joint for preclinical applications"by:Sahnd Zanjani-Pour, Mario Giorgi, Enrico Dall'Arapublished in:Frontiers in Bioengineering and Biotechnology (Biomechanics) https://www.frontiersin.org/articles/10.3389/fbioe.2020.558815/abstractMicroCT images of the native bones and PTA stained bones have been reported after registrations. These images were used to create the finite element models of the mouse knee joint including bone, cartilage, and idealised meniscus as described in the paper. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_the_paper_Development_of_subject-specific_fini...
 
Title Data for the paper: "Non-invasive prediction of the mouse tibia mechanical properties from microCT images: comparison between different finite element models" 
Description Data used in the paper: "Non-invasive prediction of the mouse tibia mechanical properties from microCT images: comparison between different finite element models"Oliviero, Owen, Reilly, Bellantuono, Dall'Arapublished in BMMBWe share here an example of ex vivo microCT image used for the assessment, and the results obtained from the different analyses.Short description of the files included:-microFE_results.xlsx includes:Stiffness estimated for each specimen with microFE models, and correlations with experimental data.Failure load estimated with microFE models, and correlations with experimental data, for each model type:Hexahedral Homogeneous modelsHexahedral models with subject-specific modulusTedrahedral Homogenous modelsTetrahedral models with subject-specific modulusHexahedral Heterogeneous modelsTetrahedral Homogeneous models -microCT data:Example of a segmented microCT image used as input for the microFE model (Specimen1, C57BL/6J, wild type, 16 weeks of age, right tibia).In case the reader is interested in the whole database they should contact Dr Enrico Dall'Ara (e.dallara@sheffield.ac.uk). 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_the_paper_Non-invasive_prediction_of_the_mouse...
 
Title Data for the paper: "Optimization of the failure criterion in micro-Finite Element models of the mouse tibia for the non-invasive prediction of its failure load in preclinical applications" 
Description Data used in the paper: "Optimization of the failure criterion in micro-Finite Element models of the mouse tibia for the non-invasive prediction of its failure load in preclinical applications"Oliviero, Owen, Reilly, Bellantuono, Dall'Arapublished in JMBBMWe share here an example of ex vivo microCT image used for the assessment, and the results obtained from the different analyses.Short description of the files included:Densitometric_and_morphometric_parameters.xlsx includes:-Densitometric parameters, and correlations with experimental mechanical data, calculated for each specimen and each region of interestTotal = total volume of interest (80% of tibia length)10 Longitudinal sections: section 1 corresponds to proximal tibia, section 10 corresponds to distal tibiaSectors: anterior (A), posterior (P), medial (M) and lateral (L)-Morphometric parameters calculated for each specimen, and correlations with experimental mechanical data. -microFE_results.xlsx includes:Stiffness estimated for each specimen with microFE models, and correlations with experimental data.Failure load estimated with microFE models, and correlations with experimental data, for each failure criterion:Pistoia methodCompression: tibia fails when a portion of the nodes (failure volume) reaches a critical compressive (third principal) strain levelTension: tibia fails when a portion of the nodes reaches a critical tensile (first principal) strain levelCompression&Tension: tibia fails when a portion of the nodes reaches a critical strain, either in tension or in compressionSections: tibia fails when the median first principal strain or third principal strain in one section (tibia divided into ten portions) or in one sector (tibia divided into ten sections and each section divided into anterior and posterior partitions; 20 portions in total) reaches a critical strain level -microCT data:Example of a segmented microCT image used as input for the microFE model (Specimen1, C57BL/6J, wild type, 16 weeks of age, right tibia).In case the reader is interested in the whole database they should contact Dr Enrico Dall'Ara (e.dallara@sheffield.ac.uk). 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_the_paper_Optimization_of_the_failure_criterio...
 
Title Data for the paper: "PTH(1-34) treatment and/or mechanical loading have different osteogenic effects on the trabecular and cortical bone in the ovariectomized C57BL/6 mouse" 
Description Link to the data used in:Roberts, Arredondo Carrera, Zanjani-pour, Boudiff, Wang, Gartland and Dall'AraPTH(1-34) treatment and/or mechanical loading have different osteogenic effects on the trabecular and cortical bone in the ovariectomized C57BL/6 mouseScientific Reports 10, 8889 (2020).All the procedures were performed under a British Home Office licence (PF61050A3) and in compliance with the Animal (Scientific Procedures) Act 1986.The images and data are too large to be uploaded in ORDA. The whole dataset can be assessed at: https://web-unidrive.sheffield.ac.uk/shared/multisim2/WP7/PTH_Loading/. Please contact the senior author at: e.dallara@sheffield.ac.uk or the Project Management Office at: pmo@insigneo.org if you are interested in working on the files.In this repository we have uploaded only the result file obtained from assessment of the microCT images. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Dataset shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Data_for_the_paper_PTH_1-34_treatment_and_or_mechanical...
 
Title Femoral neck strain prediction during level walking using a combined musculoskeletal and finite element model approach 
Description The full of set of data contains; peak first and third principal strains at the femoral neck as predicted by the FE model, hip and knee joint contact forces personolised by the body weight, and Gluteus Medius muscle forces as calculated by the musculoskeletal model. Those are reported for the five cases and along the 100% of one gait cycle.The study was approved by the Health Research Authority of East of England (Cambridgeshire and Hertfordshire Research Ethics Committee, reference 16/EE/0049). 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Data shared with research community. 
URL https://figshare.shef.ac.uk/articles/dataset/Femoral_neck_strain_prediction_during_level_walking_usi...
 
Description CLEAR IDEAS Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact MultiSim2 goes 'Beyond Academia' with a CLEAR IDEAS Workshop
On Wednesday, 23rd October, our MultiSim2 project hosted a Clear Ideas workshop: Beyond Academia. The workshop was attended by the MultiSim2 team and Insigneo Associate Members from the IMSB (Integrated Musculo-Skeletal Biomechanics) group explored how to take their research Beyond Academia to the clinic, industry and the public. This workshop was funded through EPSRC's Creativity@Home initiative, to bring creative thinking workshops and skills to the Engineering and Physical Science research community.

Dr Kamal Birdi facilitated this creative thinking CLEAR IDEAS workshop to address these topics and, in the process, demonstrate the creative thinking skills and techniques behind this framework. Three groups, each focusing one of the three Beyond Academia aspects, worked through the steps of Illuminate, Diagnose, Erupt, Assess and Select, to better understand the challenges of taking research beyond academia and develop creative solutions to address them. During the process they were exposed to creative thinking techniques, such as using the analogy of your favourite restaurant, movie or holiday to create solutions or how a world of smart, little people would solve their problems for them, and translating these ideas back to the real world.

At the end of the workshop the teams shared their ideas for demonstrating the benefits of computer modelling to clinicians, improving the quality of software through bug fixing competitions, and using student projects to develop the public facing websites.
Year(s) Of Engagement Activity 2020
URL https://www.sheffield.ac.uk/multisim-insigneo/news/multisim2-goes-beyond-academia-clear-ideas-worksh...
 
Description Modelathon 2020 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Aim of Modelathon: To engage researchers in the field of musculoskeletal and cardiovascular research with the principles and practice of multiscale modelling through addressing an authentic research challenge using both industrial and open source research tools and frameworks. To raise the profile of the project amongst the academic community and industry.

The MultiSim Modelathon brings together PhD and PostDoc researchers in the field of Multi-Scale Modelling and Biomechanical Engineering, from around the world, to compete in teams against one another to solve a complex multi-scale modelling problem. This three-day event is based on the concept of a hackathon event where different teams work on a challenging problem to 'hack' a computer code. Here there is no 'hacking' but 'modelling'. The teams competed to solve a challenging multi-scale biomechanical problem within the musculoskeletal system using state-of-the-art techniques and software.

Industry members and multi-scale experts supported the event, including software providers and Ansys, Simpleware, Materialise and Simulia. They supported the Modelathon by providing licences for the academic developers preparing and testing the challenges before the event, and the Modelathon participants during the event. They provided expertise and technical support during the event to encourage participants to make the most of the software available and sponsored the events to subsidise the costs to the participants.

In 2017, a scene-setting one-day symposium was added to the Modelathon.

The 2018 and 2020 offerings of the Modelathon were co-sponsored and supported by OATech+, and focused on the clinical problem of osteoarthritis in the hip and knee joints respectively.

Each year the Modelathon attracts approximately 25 researchers.
Year(s) Of Engagement Activity 2020
URL http://multisim-insigneo.org/modelathon/