Multiscale modelling workflows and applications

MultiSim has integrated the ongoing musculoskeletal research within the University of Sheffield into the grand vision of the grant. This has resulted in the development of models at all scales and integration into a multi-scale platform, with three application workflows:

  1. A workflow for the prediction of femoral fractures in osteoporotic patients. We have been able to show that patient-specific predictions of the risk of fracture in post-menopausal woman were more accurate with computer simulations than current clinical standard.
  2. The development of computational tools for children musculoskeletal diseases such as the diagnosis of unexplained fractures in the child.
  3. The development of a murine platform for the complete study of multiscale modelling and the possibility to validate the tools developed at each scale and their integration from the cell to the organ levels.

A general hypermodelling framework concept was constructed to enable multiscale modelling across space and time by defining inputs and outputs between scales within each application. In addition, a general IT infrastructure is being developed to provide successful applications as an online service to external users by establishing a workflow of software applications using Taverna.

The diagram below shows how the original MultiSim work packages feed into the application workflows developed.

Workflow and work packages relationship revised

Application 1 Prediction of Osteoporotic Fractures and Application 3 Murine Model, have subsequently been developed into mature workflows illustrated in the two videos below.

Application 1 workflow: Prediction of osteoporotic fracture


This video shows how movement data and image data from image data from MRI and CT scans are be combined to develop musculoskeletal kinematic models and finite element models to predict the risk of fracture.

The embedded PDF below provides a summary of the workflow and team that are developing it.


Publications related to Application 1


Altai, Z., Viceconti, M., Li, X., Offiah, A. C. (2020), “Investigating Rolling as Mechanism for Humeral Fractures in Non-Ambulant Infants: A Preliminary Finite Element Study”, Clinical Radiology, 75 (1), 78.e9-78.e16, URL: 

Benemerito, I., Modenese, L., Montefiori, E., Mazzà, C., Viceconti, M., Lacroix, D., Guo, L. (2020), “An extended discrete element method for the estimation of contact pressure at the ankle joint during stance phase”, Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine, URL: 

Montefiori, E., Kalkman, B. M., Henson, W. H., Paggiosi, M. A., McCloskey, E. V., Mazzà, C. (2020), “MRI-based anatomical characterisation of limb muscles in post-menopausal woman”, PLoS ONE, URL:

Ryan, M., Barnett, L., Rochester, J., Wilkinson, J. M., Dall’Ara, E. (2020), “A new approach to comprehensively evaluate the morphological properties of the human femoral head: example of application to osteoarthritic joint”, Scientific Reports, 10, Article number: 5538, URL: 

Ryan, M., Oliviero, S., Costa, M. C., Wilkinson, J. M., Dall’Ara, E. (2020), “Heterogeneous strain distribution in the subchondral bone of osteoarthritic femoral heads measured with digital volume correlation”, Materials, 13(20), 4619, URL:

van Veen, B. C., Mazzà, C., Viceconti, M. (2020), “The uncontrolled manifold theory can explain only part of the inter-trial variability of knee contact force during level walking”, IEEE Transactions on Neural Systems & Rehabilitation Engineering, 28 (8), URL:

Wang, N., Niger, C., Li, N., Richards, G. O., Skerry, T. M. (2020), “Cross-species RNA-Seq study comparing transcriptome signatures of enriched osteocyte populations in the tibia and skull”, Frontiers in Endocrinology, 11, p 693, URL:

Winsor, C., Li, X., Qasim, M., Henak, C. R., Pickhardt, P. J., Ploeg, H., Viceconti, M. (2020), “Evaluation of patient tissue selection methods for deriving equivalent density calibration for femoral bone quantitative CT analyses”, Bone, 115759, URL:


Altai, Z., Qasim, M., Li, X., Viceconti, M. (2019), “The Effect of Boundary and Loading Conditions on Patient Classification Using Finite Element Predicted Risk of Fracture”, Clinical Biomechanics, 68, pp 137-143, URL:

Montefiori, E., Modenese, L., Di Marco, R., Magni-Manzoni, S., Malattia, C., Petrarca, M., Ronchetti, A., de Horatio, L. T., van Dijkhuizen, P., Wang, A., Wesarg, S., Viceconti, M., Mazzà, C.; MD-PAEDIGREE Consortium (2019), “An image-based kinematic model of the tibiotalar and subtalar joints and its application to gait analysis in children with Juvenile Idiopathic Arthritis”, Journal of Biomechanics, 85, pp 27-36, URL:

Montefiori, E., Modenese, L., Di Marco, R., Magi-Manzoni, S., Malattia, C., Petrarca, M., Ronchetti, A., Tanturri de Horatio, L., van Dijkhuizen, P., Wang, A., Wesarg, S., Viceconti, M., Mazzà, C. for the MD-PAEDIGREE Consortium (2019), “Linking joint impairments and gait biomechanics in patients with Juvenile Idiopathic Arthritis”, Annals of Biomedical Engineering, 47 (11), pp 2155-2167, URL:

van Veen, B. C., Montefiori, E., Modenese, L., Mazzà, C., Viceconti, M. (2019), “Muscle Recruitment Strategies Can Reduce Joint Loading During Level Walking”, Journal of Biomechanics, 97, 109368, URL:

Viceconti, M., Ascani, D., Mazzà, C. (2019), “Pre-operative Prediction of Soft Tissue Balancing in Knee Arthoplasty Part 1: Effect of Surgical Parameters During Level Walking”, Journal of Orthopaedic Research, URL:,


Bhattacharya, P., Altai, Z., Qasim, M., Viceconti, M. (2018), “A Multiscale Model to Predict Current Absolute Risk of Femoral Fracture in a Postmenopausal Population”, Biomechanics and Modeling in Mechanobiology, 18 (2), pp 301-318, URL:

Di Marco, R., Scalona, E., Pacilli, A., Cappa, P., Mazzà, C., Rossi, S. (2018), “How to choose and interpret similarity indices to quantify the variability in gait joint kinematics”, International Biomechanics, 5 (1), pp 1‑8, URL:

Modenese, L., Montefiori, E., Wang, A., Wesarg, S., Viceconti, M., Mazzà, C. (2018), “Investigation of the dependence of joint contact forces on musculotendon parameters using a codified workflow for image-based modelling”, Journal of Biomechanics, 16 (3), pp 216-223, URL:

Shahabpoor, E., Pavic, A. (2018), “Estimation of Vertical Walking Ground Reaction Force in Real-life Environment from Single IMU Sensor”, Journal of Biomechanics, URL:

Shahapoor, E., Pavic, A., Brownjohn, J. M. W., Billings, S. A., Guo, L., Bocian, M. (Published), “Real-Life Measurement of Tri-Axial Walking Ground Reaction Forces Using Optimal Network of Wearable Inertial Measurement Units”, IEEE Transactions on Neural Systems and Rehabilitation Engineering, 26 (6), URL:

Tagliapietra, L., Modenese, L., Reggiani, M., Ceseracciu, E., Mazzà, C. (2018), “Validation of a model-based inverse kinematics approach based on wearable inertial sensors”, Computer Methods in Biomechanics and Biomedical Engineering, URL:

Tamburini, P., Storm, F., Buckley, C., Bisi, M. C., Stagni, R., Mazzà, C (2018), “Moving from laboratory to real life conditions: influence on the assessment of variability and stability of gait”, Gait and Posture, 59, pp 248-252, URL:

Viceconti, M., Qasim, M., Bhattacharya, P., Li. X. (2018), “Are CT-Based Finite Element Model Predictions of Femoral Bone Strengthening Clinically Useful?”, Current Osteoporosis Reports, URL:


Dall’Ara, E., Eastell, R., Viceconti, M., Pahr, D., Yang, L. (2016), “Experimental Validation of DXA-based Finite Element models for prediction of femoral strength”, Journal of the Mechanical Behavior of Biomedical Materials, 63, pp 17-25, URL:

Guo, Y., Storm, F., Zhao, Y., Billings, S. A., Pavic, A., Mazzà, C., Guo, L. (2017), “A New Proxy Measurement Algorithm with Applications to Vertical Ground Reaction Forces with Wearable Sensors”, Sensors, 17 (10), pp 2181-2195, URL:

Hannah I., Montefiori E., Modenese L., Prinold, J., Viceconti M., Mazzà C. (2017), “Sensitivity of a juvenile subject-specific musculoskeletal model of the ankle joint to the variability of operator dependent input”, Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine, 231 (5), pp415-422, URL:

Moissenet, F., Modenese, L., Dumas, R. (2017), “Alterations of musculoskeletal models for a more accurate estimation of lower limb joint contact forces during normal gait: A systematic review”, Journal of Biomechanics, 63, pp 8-20, URL: 

Shahabpoor, E., Pavic, A. (2017), “Measurement of Walking Ground Reactions in Real-Life Environments: A Systematic Review of Techniques and Technologies”, Sensors, 17 (9), 2085, URL:


Hannah, I., Sawacha, Z., Guiotto, A., Mazzà, C. (2016), “Relationship between sagittal plane kinematics, foot morphology and vertical forces applied to three regions of the foot”, International Biomechanics, 3 (1), pp 50-56, URL:

Lamberto, G., Martelli, S., Cappozzo, A., Mazzà, C. (2016), “To what extent is joint and muscle mechanics predicted by musculoskeletal models sensitive to soft tissue artefacts?”, Journal of Biomechanics, Available online 24 August 2016, URL:

Qasim, M., Farinella, G., Zhang, J., Li, X., Yang, L., Eastell, R., Viceconti, M. (2016), “Patient-Specific Finite Element Estimated Femur Strength as a Predictor of the Risk of Hip Fracture: The Effect of Methodological Determinants”, Osteoporosis International, 27 (9), pp 2815-2822, URL:

Storm, F., Buckley, C., Mazzà, C. (2016), “Gait event detection in indoor and outdoor settings: accuracy of two inertial sensors based methods”, Gait and Posture, 50, pp 42-46, URL:

Application 3 workflow: Murine model

This video shows how the murine models developed in MultiSim can be used to improve the current preclinical assessment of new interventions through better experiments, better endpoints and validated multiscale models.

The embedded PDF below provides a summary of the workflow and team that are developing it.
Publications related to Application 3


Oliviero, S., Owen, R., Reilly, G. C., Bellantuono, I., Dall’Ara, E. (2021), “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”, Journal of the Mechanical Behavior of Biomedical Materials, 113 (104190), URL:


Ascolani, G., Skerry, T. M., Lacroix, D., Dal’Ara, E., Shuaib, A. (2020), “Revealing hidden information in osteoblast’s mechanotransduction through analysis of time patterns of critical events”, BMC Bioinformatics, 21 (114), URL: 

Cheong, V. S., Roberts, B. C., Kadirkamanathan, V., Dall’Ara, E. (2020), “Bone remodelling in the mouse tibia is spatio-temporally modulated by oestrogen deficiency and external mechanical loading: a combined in vivo/in silico study”, Acta Biomaterialia, URL:

Costa, M. C., Bresani Campello, L. B., Ryan, M., Rochester, J., Viceconti, M., Dall’Ara, D. (2020), “Effect of size and location of simulated lytic lesions on the structural properties of human vertebral bodies, a micro-finite element study”, Bone Reports, 12, 100257, URL: 

Kusins, J., Knowles, N., Columbus, M., Oliviero, S., Dall’Ara, E., Athwal, G. S., Ferreira, L. M. (2020), “The Application of Digital Volume Correlation (DVC) to Evaluate Strain Predictions Generated by Finite Element Models of the Osteoarthritic Humeral Head”, Annals of Biomedical Engineering, URL:

Rakowski, A. G., Veličković P., Dall’Ara E., Liò P. (2020), “ChronoMID – Cross-modal neural networks for 3-D temporal medical imaging data”, PLoS ONE, 15 (2), e0228962, URL: 

Roberts, B. C., Arrendondo Carrera, H. M., Zanjani-pour, S., Boudiff, M., Wang, N., Gartland, A., Dall’Ara, E. (2020), “PTH(1-34) treatment and/or mechanical loading have different osteogenic effects on the trabecular and cortical bone in the ovariectomized C57BL/6 mouse”, Scientific Reports, 10, Article number: 8889, URL:

Zanjani-Pour, S., Giorgi, M., Dall’Ara, E. (2020), “Development of subject specific finite element models of the mouse knee joint for preclinical applications”, Frontiers in Bioengineering and Biotechnology, 8: 558815, URL:


Cheong, V. S., Campos Marin, A., Lacroix, D., Dall’Ara, E. (2019), “A novel algorithm to predict bone changes in the mouse tibia properties under physiological conditions”, Biomechanics and Modeling in Mechanobiology, URL: 

Giorgi, M., Sotirou, V., Franchini, N., Conigliaro, S., Biganardi, C., Nowlan, N. C., Dall’Ara, E., (2019), “Prenatal growth map of the mouse knee joint by means of deformable registration technique”, PLoS One, 14 (1): e0197947, URL:

Oliviero, S., Giorgi, M., Laud, P. J., Dall’Ara, E. (2019), “Effect of repeated in vivo microCT imaging on the properties of the mouse tibia”, PLoS One, 14 (11): e0225127, URL: 

Roberts, B. C., Giorgi, M., Oliviero, S., Wang, N., Boudiffa, M., Dall’Ara, E. (2019), “The longitudinal effects of ovariectomy on the morphometric, densitometric and mechanical properties in the murine tibia: a comparison between two mouse strains”, Bone, 127, pp 260-270, URL:

Shuaib, A., Motan, D., Bhattacharya, P., McNabb, A., Skerry, T. M., Lacroix, D. (2019), “Heterogeneity in The Mechanical Properties of Integrins Determines Mechanotransduction Dynamics in Bone Osteoblasts”, Scientific Reports, 9, Article number: 13113, URL:

Zhang, Y., Dall’Ara, E., Viceconti, M., Kadirkamanathan, V. (2019), “A new method to monitor bone geometry changes at different spatial scales in the longitudinal in vivo μCT studies of mice bones”, PLoS One, 14(7): e0219404 , URL:


Oliviero, S., Giorgi, M., Dall’Ara, E. (2018), “Validation of Finite Element models of the Mouse Tibia using Digital Volume Correlation”, Journal of the Mechanical Behavior of Biomedical Materials, 86, pp 172–184, URL:


Dall’Ara, E., Peña-Fernández, M., Palanca, M., Giorgi, M., Cristofolini, L., Tozzi, G. (2017), “Precision of DVC approaches for strain analysis 1 in bone imaged with μCT at different dimensional levels”, Frontiers in Materials: Mechanics of Materials, 4, Article 31, URL: 

Oliviero, S., Y., Lu, Y., Viceconti, M., Dall’Ara, E. (2017), “Effect of integration time on the morphometric, densitometric and mechanical properties of the mouse tibia”, Journal of Biomechanics, 65, pp 203-211, URL:

Lu, Y., Boudiffa, M., Dall’Ara, E., Liu, Y., Bellantuono, I., Viceconti, M. (2017), “Longitudinal effects of Parathyroid Hormone treatment on morphological, densitometric and mechanical properties of mouse tibia”, Journal of the Mechanical Behavior of Biomedical Materials, 75, pp 244-251,


Giorgi, M., Verbruggen, S. W., Lacroix, D. (2016), “In silico bone mechanobiology: Modelling a multi-faceted biological system”, WIREs Systems Biology and Medicine, 8 (6), pp 485-505, URL:

Lu, Y., Boudiffa, M., Dall’Ara, E., Bellantuono, I., Viceconti, M. (2016), “Development of a protocol to quantify local bone adaptation over space and time: Quantification of reproducibility”, Journal of Biomechanics, 49 (10), pp 2095-2099, URL:

Wittkowske, C., Reilly, G. C., Lacroix, D., Perrault, C. M. (2016), “In vitro bone cell models: Impact of fluid shear stress on bone formation”, Frontiers in Bioengineering and Biotechnology, 4 (87), 22 pages, URL: