Publications blog

2022 

Personalised 3D Assessment of Trochanteric Soft Tissues Improves Hip Fracture Classification AccuracyNew accordion title

The soft fatty tissues around the hip can reduce the force of impact following a fall to the side. Therefore, it is important to account for the influence of these tissues when determining a patient's hip fracture risk. It is possible to measure the three-dimensional geometry of these tissues in a personalised manner by processing clinical computed tomography (CT) images. As such, this would be a step change from the state-of-the-art, whereby body mass index (BMI) is measured and tissue geometry is estimated based on a representative dependence between BMI and geometry. Moreover, such estimates are currently available only for tissue geometry at a single hip impact orientation, even though actual falls to the side can vary substantially in terms of impact orientation.

So where is the catch? CT images are not routinely used in clinical pathways due to factors such as expensive equipment, higher radiation dose, and expensive post-processing costs. Hence, before introducing into a clinical pathway, it is important to estimate how much fracture risk prediction would improve if soft tissue geometry was characterised in a subject-specific and/or orientation-specific manner. This is what the current study set about to investigate, specifically by quantifying how accurately a predictor could distinguish which subjects in a cohort of British post-menopausal women had suffered a hip fracture or not (also called classification accuracy).

We found that soft tissue geometry estimated using BMI was a significant underestimate of personalized and orientation-specific measures of tissue geometry. When the latter were used, fracture classification accuracy improved compared to the state-of-the-art. The improvement was smaller when orientation-specificity was suppressed and there was no improvement whatsoever when personalisation was suppressed instead. The results of this study suggest that clinical pipelines should focus on measuring soft tissue geometry in a person specific manner, and technologies that improve three-dimensional characterisation need not be prioritised.

Aldieri, A., Terzini, M., Audenino, A. L., Bignardi, C., Paggiosi, M., Eastell, R., Viceconti, M., Bhattacharya, P. (2022), "Personalised 3D Assessment of Trochanteric Soft Tissues Improves Hip Fracture Classification Accuracy", Annals of Biomedical Engineering. 

Variations of lower-limb joint kinematics associated with the use of different ankle joint models

In this study we showed for the first time that different definitions of ankle joint axes affect not only the ankle kinematics but, more interestingly, also the kinematics of the proximal joints. These variations can be substantial at individual level, hence potentially affecting the comparisons across studies or leading to erroneous clinical conclusions.

Montefiori, E., Hayford, C. F., Mazzà, C. (2022), "Variations of lower-limb joint kinematics associated to the use of different ankle joint models", Journal of Biomechanics, 136, 111072.

2021

Delivering computationally-intensive Digital Patient applications to the clinic: an exemplar solution to predict femoral bone strength from CT data

Fragility hip fractures are common amongst elderly people and often lead to serious consequences such as permanent disability or death. They are caused by osteoporosis, a disease which weakens the bones making them more prone to fracture. The incidence of such fractures could be reduced by identifying the individuals who are more likely to suffer a fragility fracture. This is possible using methods such as dual-energy X-ray absorptiometry imaging (DXA), which measures the bone mineral density, or with other techniques such as FRAX, developed in Sheffield. These techniques can reach an accuracy of 75%. 

In recent years, researchers have developed procedures to estimate bone strength using personalised finite element (FE) models built from computed tomography (CT) images. This approach has proven more accurate than traditional methods currently used in clinical settings, but has not been widely adopted in hospitals because it requires sophisticated software, highly trained personnel and high performance computing (HPC) resources. To increase the clinical uptake of FE predictive models the University of Sheffield, in collaboration with Sheffield Teaching Hospitals, has developed a service called "Computed Tomography To Strength" (CT2S). Doctors in the hospital request the analysis of a patient by accessing the website of the service. Using a combination of open source software, the website initiates a secure transfer of the medical CT images from the hospital's database to the INSIGNEO's one. An operator then downloads and processes the images to build a personalised FE model of the patient. To estimate the strength, 28 loading simulations are performed on the local HPC cluster at The University of Sheffield. After the analysis, the results are sent to the clinician in a PDF document. The entire workflow can be executed in 3.5 hours.

CT2S is built on open source software, meaning that can be easily deployed in other institutions, thus further increasing the uptake of FE based methods for bone strength prediction.

Benemerito, I., Griffiths, W., Allsopp, J., Furnass, W., Bhattacharya, P., Marzo, A., Wood., S., Viceconti, M., Narracott, A. (2021), "Delivering computationally-intensive Digital Patient applications to the clinic: an exemplar solution to predict femoral bone strength from CT data", Computer Methods and Programs in Biomedicine. 

A systematic approach to the scale separation problem in the development of multiscale models

A microscopic pore in a clay brick collapses in response to an earthquake occurring in a region where there stands a building comprising a masonry wall containing the said clay brick. The causal dependence between the earthquake and masonry fracture is obvious. However, it is equally obvious that if we choose an instrument to measure how much the pore in the brick collapses, then that instrument cannot measure the magnitude of the seismic wave (and vice-versa).

This limitation is called the curse of resolution. It is inherent in problems where characteristics of a physical system have a cause–effect relationship but these characteristics are observable at vastly different space and/or time scales. Such problems are known as multiscale problems, and these occur across a great diversity of engineering domains.

One such domain is biomechanics, which is our research interest. The various shots a professional tennis player makes over a tournament season cause a specific bone cell (located somewhere in one of the bones of the player's arm) to deposit a specific amount of bone mineral during this period. If we choose an instrument to measure how far the player's arm travels during a single shot, then that instrument cannot measure the depth of the bone mineral layer deposited by the cell during this time (and vice-versa). So here too, we meet a multiscale problem.

Computational models are being increasingly employed to solve multiscale problems. Computational models are digital twins of a physical system (that may or may not possess multiscale characteristics). A computational model has the advantage that it can be analysed non-invasively to understand the physical system it represents. In an earlier review paper, we considered some multiscale computational models that were applied to various biomechanics problems. In that paper, we categorised these models according to their motivation for credibility.

That review paper did not explore an important operational issue in multiscale modelling. The particular issue is that a vast majority of these multiscale models described the constituent "scales" of the problem with ambiguous references to the instrumentations used. In our view, this leaves open the possibility of misinterpreting scales, leading to poor model reproducibility, model use in inappropriate contexts, etc.

To correct this problem, the present study describes a novel approach to multiscale modelling. This approach systematically applies an instrumentation capability based definition of scale to all aspects of multiscale model development and model credibility assessment. The application of this approach is illustrated by considering problems of significant interest to clinicians and drug developers in the area of bone health. The versatility of the approach is demonstrated by considering various combinations of available instruments for characterising the system at hand.

As the approach does not specify any mathematical form the equations must take, it could be applicable to a great variety of multiscale problems across engineering domains. The paper also discusses the complementarity of the present approach with some existing multiscale modelling approaches.

Bhattacharya, P., Li, Q., Lacroix, D., Kadirkamanathan, V., Viceconti, M. (2021), "A systematic approach to the scale separation problem in the development of multiscale models", PLoS One, 16(5): e0251297.

Non-invasive prediction of the mouse tibia mechanical properties from microCT images

Osteoporosis is one of the most common chronic diseases of the musculoskeletal system. New bone treatments require in vivo testing before clinical translation, and the mouse tibia is one of the most commonly used animal models.

In order to evaluate the effect of treatments on bone and to facilitate clinical translation of the results, it is important to accurately estimate the tibia strength in preclinical studies. In this study, we have used computational (finite element) models to estimate the strength of twenty tibiae and evaluated the predictive accuracy of each method against experimental data. The geometry of each tibia was acquired using high-resolution computed tomography images, which were subsequently used to generate the computational models. Afterwards, each tibia was tested in compression to measure their mechanical properties.

By comparing the computational and experimental results, we defined a procedure that can be applied to study the effect of interventions on the bone mechanical properties.

Oliviero, S., Roberts, M., Owen, R., Reilly, G. C., Bellantuono, I., Dall’Ara, E. (2021), “Non-invasive prediction of the mouse tibia mechanical properties from microCT images: comparison between different Finite Element models”, Biomechanics and Modelling in Mechanobiology.

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).

The Role of the Loading Condition in Predictions of Bone Adaptation in a Mouse Tibial Loading Model

The in vivo tibial loading model in mice is increasingly used to study bone adaptation but the interaction between external loading and physiological loading in engendering bone changes have not been determined. Hence the aim of this work was to determine the effect of different applied loads on finite element predictions of bone adaptation.

Longitudinal micro-computed tomography (micro-CT) imaging and in vivo loading were performed once every 2 weeks from weeks 18 to 22 of age, to quantify the shape change, remodelling, and changes in densitometric properties. Predictions of bone adaptation were performed under physiological loads, nominal 12N axial load and combined nominal 12N axial load superimposed to the physiological load, and compared to the experimental results.

Predictions of densitometric properties were most similar to the experimental data for combined loading, followed closely by physiological loading conditions. All predicted densitometric properties were significantly different for the 12N and the combined loading conditions. Spatial prediction of locations of bone remodelling were not significantly different from all three loading conditions. The results suggest the adaptive response of bone are in response to both passive mechanical loading and daily physiological load.

Cheong, V. S., Kadirkamanathan, V., Dall'Ara, E. (2021), "The role of the loading condition in predictions of bone adaptation in a mouse tibial loading model", Frontiers in Bioengineering and Biotechnology, 9, pp 461. 

A novel approach to evaluate the effects of artificial bone focal lesion on the three-dimensional strain distributions within the vertebral body

Evaluation of strength of the bone affected by the presence of metastases is fundamental to assess the fracture risk. This work proposes a  method to evaluate the variations of strain distributions due to metastatic lesions within the vertebra.  

Five porcine vertebrae were tested in compression inside a micro computed tomography scanner.   Principal strains were computed within the bone by means of digital volume correlation (BoneDVC). 

All intact specimens showed a consistent strain distribution. The artificial lesion generally doubled the strain in the middle portion of the specimen, probably due to stress concentrations close to the defect.  

In conclusion, a robust method  was developed and will be used to improve  clinical assessment of fracture risk in metastatic spines.

Palanca M., De Donno G., Dall’Ara E., (2021), "A novel approach to evaluate the effects of artificial bone focal lesion on the three-dimensional strain distributions within the vertebral body", PlosOne, 16(6): e0251873.

Type, size, and position of metastatic lesions explain the deformation of the vertebrae under complex loading conditions

Bone metastases may lead to spine instability and increase the risk of fracture. 

A novel biomechanical approach was used to evaluate the effect of lesion type, size, and location on the mechanical competence of the metastatic vertebra. 

Vertebrae with metastases were collected from a donation programme. The size and position of the metastases were evaluated. The vertebrae were tested in different loading conditions and the strain distribution was measured with Digital Image Correlation.  

The metastatic type characterizes the vertebral behaviour. Once the position of the lytic lesion with respect to the loading direction was taken into account, the size of the lesion was significantly correlated with the perturbation to the strain distribution. 

These results highlight the relevance of the size and location of the lytic lesion in driving the spinal biomechanical instability.

Palanca M., Barbanti-Bròdano G., Marras D., Marciante M., Serra M., Gasbarrini A., Dall’Ara E., Cristofolini L. (2021), "Type, size, and position of metastatic lesions explain the deformation of the vertebrae under complex loading conditions", Bone, 151 (116028). 

MicroFE models of porcine vertebrae with induced bone focal lesions: validation of predicted displacements with Digital Volume Correlation

Micro Finite Element models have the potential of predicting the mechanical behavior of vertebrae with metastatic lesions at tissue level through laboratory studies, but their predictions must be validated against experimental measurements.

In this study, porcine vertebrae (with and without artificial lesions) were mechanically tested within a microCT scanner, and the displacement field was measured though a global Digital Volume Correlation approach.  

Simplified linear microFE models of the vertebrae, based on microCT images, were developed.  

Boundary conditions were imposed from DVC data, and the displacement field was predicted.

The comparison between the predicted displacements and the measured displacements showed an excellent agreement in the middle portion of the vertebral body, both with and without lesions.  By contrast, poor correlation was found in the closeness of the growth plates. 

In conclusion, these simplified models can predict how close to failure a bone is. More complex models instead are required to predict regions with high deformation. 

Palanca, M., Oliviero, S., Dall'Ara, E. (2021), "MicroFE models of porcine vertebrae with induced bone focal lesions: Validation of predicted displacements with digital volume correlation", Journal of the Mechanical Behavior of Biomedical Materials.

Patient-Specific Finite Element Models of Posterior Pedicle Screw Fixation: Effect of Screw’s Size and Geometry

Pedicle screw fixation is extensively performed to treat spine injuries. Post-operative complications may arise from this surgery leading to back pain or revisions. Finite element (FE) models could be used to predict the outcomes of surgeries and test the effect of different screw’s sizes.

The aim of this study was to generate patient-specific Computed Tomography (CT)-based FE models of human vertebrae with two pedicle screws, verify the models, and use them to evaluate the effect of the screws’ size and geometry on the mechanical properties of the screws-vertebra structure.

We found that changes in screw’s length resulted in significantly lower differences in peak stress in the screws, mean strain in the bone around the screw and maximum deflection of the structure with respect to changes in screw’s diameter. In addition, the maximum deflection predicted with realistic or simplified screws correlated very well, while the peak stress in screws with realistic or simplified design correlated well but simplified models underestimated the peak stress.

In conclusion, the results showed that the diameter of the screw has a major role on the mechanics of the screw-vertebral structure for each patient. Simplified screws can be used to estimate the mechanical properties of the implanted vertebrae, but the systematic underestimation of the peak stress should be considered when interpreting the results from the FE analyses.

Sensale, M., Vendeuvre, T., Schilling, C., Grupp, T., Rochette, M., & Dall’Ara, E. (2021). "Patient-specific finite element models of posterior pedicle screw fixation: effect of screw’s size and geometry". Frontiers in Bioengineering and Biotechnology, 9, 175.

2020

Femoral neck strain prediction during level walking using a combined musculoskeletal and finite element model approach

 Coupled musculoskeletal-finite element modelling approaches have emerged in recent years as a novel way to investigate femoral neck loading during various daily activities.

Combining personalised gait data with finite element models will not only allow us to study changes in motion/movement but also their effects on critical internal structures, such as the femur. This study, for the first time, proposed a pipeline for a fully personalised multiscale (body-organ level) model to investigate the strain levels at the femoral neck during a normal gait walking cycle.

Muscle forces derived from the body level musculoskeletal models were used as boundary constraints on the finite element femur models. The results suggested that personal variation among individuals is substantial in terms of the amount of load induced in the femoral neck during normal walking. However, the highest femoral neck loads occur at the toe-off and/or heel strike phases of the gait cycle. The model can be extended to be used for various applications, such as orthopaedics, where this modelling approach could help planning treatment for hip and knee replacement.

Altai, Z., Montefiori, E., van Veen, B., Paggiosi, M. A., McCloskey, E. V., Viceconti, M., Mazzà, C., Li, X. (2021), “Femoral neck strain prediction during level walking using a combined musculoskeletal and finite element model approach”, PLoS ONE, 16(2): e0245121.

Dataset associated with this paper 

Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise

Osteoporosis is a bone disease that leads to bone fragility and an increased risk of their fracture. By 2025, osteoporosis will cost the NHS over £2.2 billion per year, with limited treatments available to tackle it. Our work aims to help uncover new treatments by finding conditions that improve bones’ health.

Healthy bones are maintained by a well-balanced process of building and demolishing at the microscopic scale, and when this is disturbed, osteoporosis develops. So understanding the factors affecting this process and their interactions will help us realise how osteoporosis develops, and so how to treat it better. Such factors are combined with mechanical stimulation and cellular biochemical activity.

Our paper uses a pioneering computational model and a novel analytical technique to examine combined mechanical and biochemical stimulation. It demonstrated that mRNA production of bone formation markers, though chaotic at first glance, contains within it information about how cells interpret combined mechanical and biochemical stimuli and translate it into the production of bone formation markers. The paper proposes new intracellular targets and regimes to treat osteoporosis.

Ascolani, G., Skerry, T. M., Lacroix, D., Dal’Ara, E., Shuaib, A. (2020), “Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise”, Interface Focus, 11(1): 20190136.

An extended discrete element method for the estimation of contact pressure at the ankle joint during stance phase

Abnormalities in the ankle contact pressure are related to the onset of osteoarthritis. In vivo measurements are not possible with currently available techniques, so computational methods are often used instead.

The discrete element method (DEM) is a computational technique that models the articular cartilage as a bed of independent springs, assuming a linearly elastic behaviour and absence of relative motion between the bones. In this study, we present the extended DEM (EDEM) which is able to track the motion of talus over time.

The method was used, with input data from a subject-specific musculoskeletal model, to predict the contact pressure in the ankle joint during gait. Results show that the motion of the talus had more effect on the extension and shape of the pressure distribution than it had on the magnitude of the pressure: EDEM predicted wider contact areas than DEM and less uniform pressure distribution.

We also evaluated the role played by the material properties of ankle ligaments and the geometry of the ankle cartilage, revealing that the thickness of the cartilage layers greatly influences the computed contact patterns.

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

White Rose Research Online version 

Acknowledgements: UK EPSRC (MultiSim project, EP/K03877X/1), European Commission (MD-PAEDIGREE project, FP7-ICT Programme, Project ID: 600932)

Bone remodelling in the mouse tibia is spatiotemporally modulated by oestrogen deficiency and external mechanical loading: A combined in vivo/in silico study

 Understanding how bone formation and resorption are affected by several repeated periods of mechanical stimuli is important for developing personalised treatment plans for osteoporosis.

In this study, the load-induced bone changes after the first and second week of mechanical loading was quantified for the first time in an animal model of osteoporosis. Computational modelling (finite element analysis) was used to evaluate the extent bone adaptation is driven by mechanical factors.

This combined experimental-computational approach improves our understanding of the drivers for bone adaptation, which can be applied to design better interventions and biomaterials to treat osteoporosis.

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.

Effect of size and location of simulated lytic lesions on the structural properties of human vertebral bodies, a micro-finite element study

 The study of the risk of fractures in cancer patients with spine metastases is important to improve the quality of life of patients. Currently, the risk of fracture in these patients is evaluated using clinical scoring systems that account for information about the location of the cancer, the pain, and other qualitative factors.

While this approach is the best that can be done in clinics right now, it does not always provide a clear guideline for the treatment of some patients. The aim of this study was to develop an engineering tool that could help in the long term to improve these scoring systems, by including parameters about the size and position of the metastases.

For doing this, an approach that converts high-resolution images of the human vertebrae into a biomechanical model has been developed and the criticality of single or multiple lesions of different size and in different positions on the bone resistance to fracture has been developed. The results of these computational models showed that the size of the lesions had a dominant effect on the bone mechanical properties compared to the location of the lesions within the spine.

This study highlights the potential of computational models to study the effect of lesions on the mechanical properties of the human vertebral body and how this information can be used in future to improve clinical tools.

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.

MRI-based anatomical characterisation of lower-limb muscles in older women

 The ability of muscles to produce force depends, among others, on their anatomical features and it is altered by ageing-associated weakening. This MRI-based study quantified for the first time anatomical asymmetry of lower-limb muscles in older women by characterising muscle volume, length, and physiological cross-sectional area (PCSA) and their variability, between body sides and between individuals.

Results suggest that symmetry should not be assumed in older women and heavily question the validity of a generic-scaled approach when modelling the musculoskeletal system in older populations. The unique dataset of muscle segmentation made available with this paper could support the development of alternative population-based scaling approaches, together with that of automatic tools for muscle segmentation.

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

Dataset associated with this 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

 This study quantified the individual and combined longitudinal effects of PTH(1–34) and loading on the bone morphometric and densitometric properties in ovariectomised mice.

Ovariectomised C57BL/6 mice were treated either with injections of PTH(1–34); compressive loading of the right tibia; both interventions concurrently; or both interventions on alternating weeks. Right tibiae were longitudinally imaged six times over 10 weeks using high-resolution microCT and the properties of the bone were quantified in 40 different regions along the limb length.

The study showed that combined treatment had increased, albeit highly region-dependent, benefits to cortical bone that were largest in midshaft regions subjected to higher strains under compressive loads. Whereas combined treatment may limit benefits of loading on the trabecular bone.

Roberts, B.C., Arredondo Carrera, H.M., Zanjani-pour, S., Boudiffa, 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, 8889.

A new approach to comprehensively evaluate the morphological properties of the human femoral head: example of application to osteoarthritic joint

 Osteoarthritis affects the properties of the joints, changing their shape and mechanical response, and inducing pain in the patient. However, little is known about how these properties are related to the function of the joint, which is fundamental to optimise prosthesis and other interventions for treating this disease. This is due to the fact that it is not easy to measure the properties of the involved bone due to limitation in imaging and analyses.

The goal of this study was to develop a method to elucidate whether changes due to the disease are localised to discrete regions of the femoral head in patients with hip osteoarthritis. Whole femoral heads extracted from osteoarthritic and healthy controls underwent high resolution images and the properties of the bone have been measured with some semi-automatic algorithms in 37 different regions of the femoral head.

The study showed how the developed approach can be used to study the detailed regional effects of different diseases affecting the human femoral head, such as osteoarthritis, osteoporosis, or dysplasia.

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.

Heterogeneous strain distribution in the subchondral bone of osteoarthritic femoral heads measured with digital volume correlation

Osteoarthritis affects the properties of the joints, changing their shape and mechanical response, and inducing pain in the patient.

We still do not know how the complex structure of osteoarthritic bone deforms under load, due to the challenging experimental approaches required to evaluate the internal deformation in bone specimens. The goal of this study was to develop a method based on Digital Volume Correlation to elucidate whether the local deformation in osteoarthritic femoral heads is related to the degeneration of the subchondral bone due to the disease.

Whole femoral heads extracted from osteoarthritic patients during standard total joint replacement surgeries were mechanically tested within a high-resolution micro-computed tomography scanner. The images of the undeformed and deformed specimens were processed with the BoneDVC algorithm to evaluate the bone deformation, which identified regions of highly localised deformation in function of the bone microstructure.

This approach will be expanded in the future to identify the weakest regions of osteoarthritic femoral heads in a large database of specimens collected from different disease levels. 

Volumes of interest (VOIs) were extracted from one of the OA specimens to evaluate uncertainties within a representative total volume (blue), central region in the trabecular bone (green) and regions containing cysts (red) and sclerotic bone (yellow). (b) DVC strain fields for the four VOI’s under zero-strain (repeated images) and 1% virtual compressive apparent strain (1% VD). (c–e) Little difference in the measures of standard deviation of the error (SDER) measures was observed across each of the four VOI’s, and with nodal spacings equivalent to 1.01, 1.95, 2.73 and 3.90 mm under each of the 0% compression and 1% and 5% virtual compressive apparent strain cases.

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

Development of subject-specific finite element models of the mouse knee joint for preclinical applications

 Osteoarthritis affects the properties of the joints, changing their shape and mechanical response, and inducing pain in the patient.

Mouse models are commonly used to identify the effect of mechanical instability of the joint on its structure and to optimise treatments for reducing joint degeneration. Computational models can be used to better understand the effect of the degeneration on the joint properties and to reduce and partially replace the usage of mice in research.

However, creating realistic models of the mouse knee joint is not trivial due to the complexity of the structure. The goal of this study was to develop finite element models of the mouse knee joint with increasing complexity in order to evaluate the effect of model simplification on the prediction of the joint properties.

We have shown that it is important to model realistically the cartilage layers and the meniscus in the models in order to obtain realistic results. The model will be applied in the future to evaluate the effect of post-traumatic osteoarthritis on the mouse knee joint and to optimise treatments for this disease. 

Masks of the features for the different models with decreasing complexity in frontal section (left) and the generated finite element models after meshing (right) for: model including individual cartilage layers with meniscus (A,B); model including individual cartilage layers without meniscus (C,D); model including homogeneous cartilage layers with different thickness values for the lateral and medial condyles (E,F); model including homogeneous cartilage layer with the same value of thickness for both condyles (G,H).

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 Bioengineering and Biotechnology; 8:558815

2019

Finite Element Modelling of the Developing Infant Femur Using Paired CT and MRI Scans

 Through the MultiSim project in Sheffield, we have pioneered modelling technologies to investigate very young children’s bone using personalised computer models based on CT and MRI scans. This work is the first of its kind to combine information obtained from paired CT/MRI data in order to create detailed models of the developing long bones including both mineralised and non-mineralised components. The project is in collaboration with the Great Ormond Street Hospital in London and Sheffield Children’s Hospital.

Two computer models of the developing femurs were created for a 4-month and a 7-month old, where the mechanical responses of the bone were studied using computational simulations.

This study helped to further our understanding of young and immature bones in humans, in the application to a wide range of childhood musculoskeletal diseases as well as in the diagnosis of suspected child abuse.

Castro, A. P. G, Altai, Z., Offiah, A. C., Shelmerdine, S. C., Arthurs, O.J., Li, X., Lacroix, D. (2019), “Finite Element Modelling of the Developing Infant Femur Using Paired CT and MRI Scans”, Plos One, 14(6): e0218268

Biomechanical assessment of vertebrae with lytic metastases with subject-specific finite element models

The assessment of risk of vertebral fracture in patients with lytic metastases is challenging, due to the complexity in understanding their impact on vertebral strength. Currently, surgeons have to decide whether to fix the spine with implants or not, just based on their experience and on qualitative scoring systems such as the Spinal Instability Neoplastic Score (SINS).

However, there are cases in which clear guidelines are not available. In our lab, we have developed computational models to predict how critical is the lesion in the vertebra and to help the surgeon in assessing the strength of the bone from a computed tomography image of the patient.

In this study, we have demonstrated the potential of this new approach and in the future, we will use it to better classify patients that need treatment.

Costa, M. C., Eltes, P., Lazary, A., Varga, P. P., Viceconti, M., Dall’Ara, E. (2019), “Biomechanical assessment of vertebrae with lytic metastases with subject-specific finite element models”, Journal of the Mechanical Behavior of Biomedical Materials, 98, pp 268-290.

Prenatal growth map of the mouse knee joint by means of deformable registration technique

 Joint morphogenesis is the process of development of the joint that starts before birth.

It is important to study joint morphogenesis in order to understand how it is related to musculoskeletal diseases and to optimise related interventions. In several cases, the interventions are tested on animal models and the mouse pre-natal model is typically used to test the effect of diseases and treatments on the joints.

In this study, we developed a procedure that combines Optical Projection Tomography imaging (OPT) and a deformable registration algorithm to obtain realistic 3D realistic high-resolution developmental map of the prenatal mouse knee joint. We have found that the developed procedure has acceptable uncertainties of the displacement measurements and that it is well reproducible.

This approach will be used to study how growth and adaptation are directed by biological and mechanobiological factors.

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.

Effect of cell sample size in atomic force microscopy nanoindentation

 Cells in the human body can be classified in many different ways. One of these is looking at their mechanical properties, and therefore at how stiff or soft they are. This characteristic has been shown to correlate to different functions in health and disease, with cells changing their mechanics when undergoing specific processes.

A method to characterise cell mechanics is atomic force microscopy: a probe is pressed on the sample and an indentation at the nano-scale is performed.

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Cell populations, however, present a certain degree of variability in their characteristics and therefore a suitable number of cells have to be tested to obtain reliable information on their mechanics. The aim of this work is to propose a tool to get this estimate.

To achieve this, a large dataset of indentation measurements was obtained on bone cells and analysed to study population variability. The developed tool is available as an open-source repository and guidelines are provided for its use for atomic force microscopy experimental design.

Marcotti, S., Reilly, G. C., Lacroix, D. (2019), “Effect of cell sample size in atomic force microscopy nanoindentation”, Journal of the Mechanical Behavior of Biomedical Materials, 94, pp 259-266.

White Rose Research Online

Linking Joint Impairment and Gait Biomechanics in Patients with Juvenile Idiopathic Arthritis

 This study, carried out as part of the MD-PAEDIGREE project, combines medical resonance images (MRI) and motion capture analysis to produce personalised musculoskeletal models employed in the investigation of joint impairment in children Juvenile Idiopathic Arthritis (JIA).

Currently, the assessment of JIA mostly relies on the quantification of the local inflammation and damage in the joint region using static images. Linking these observations to more dynamic information about the joint functional biomechanics might better predict the disease progression and support the treatment planning.

In this study, joint kinetic parameters, such as joint powers and contact forces, were investigated and correlated to joint impairment, assessed with MRI-based evaluation. A moderate to strong correlation was observed between the impairment of one limb and the loading on the opposite limb, suggesting risky compensatory strategies being adopted, especially at the knee level.

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.

The longitudinal effects of ovariectomy on the morphometric, densitometric and mechanical properties in the murine tibia: A comparison between two mouse strains

 A thorough assessment of any prospective animal model of human disease is necessary before the substantial investment of resources into a preclinical study of potential therapies. Oestrogen-deficiency and related bone loss following ovariectomy is a common animal model of osteoporosis.

In this study we quantified the effects of ovariectomy on the tibia bone morphometric, densitometric and mechanical properties in two common mouse strains, C57BL/6 and BALB/c, using in vivo microCT and micro-finite element analysis to 10 weeks following surgery.

Results show persistent trabecular bone loss and inhibition of cortical bone thickening in C57BL/6 mice that was not apparent or otherwise transient in BALB/c. This difference in the bony response to ovariectomy between the mouse strains suggests that BALB/c may be most useful in short term, and C57BL/6 most useful in long term, investigations of anti-osteoporotic therapies.

This research helped to inform the selection of C57BL/6 in a MULTISIM study on the combined effects of anabolic treatments, PTH(1-34) and mechanical loading, for low bone mass that is currently ongoing within our laboratory.

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.

Heterogeneity in the mechanical properties of integrins determines mechanotransduction dynamics in bone osteoblasts

 We know that the effect on the skeleton of brief periods of exercise persists for over 24 hours – effectively, bone remembers what loads it has experienced and uses that information to adapt its structure. This tunes the skeleton to become strong enough to support habitual loads and provide a safety factor so that it should not break in normal use.

The mechanism behind bone load memory is difficult to explore because many very complex experiments would be needed to test each idea. Here we have developed a computer model to explore the way that different signals could provide long-lasting influences on bone cells to fit with the timing of their ability to respond and influence bone structure.

Cells in bone are attached to the hard mineralised material by molecules called integrins, and we have modelled the effect of different sensitivity of those integrins to deformation of bone due to loading. Our model follows the change from a mechanical event in bone to biochemical signals within the cell that can control other cells which make or remove bone.

This research is important because age reduces the sensitivity of bone to exercise stimuli, so understanding this mechanism may lead toward ways to maintain or increase bone strength in older people, where fracture is a growing problem.

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

Pre-operative Prediction of Soft Tissue Balancing in Knee Arthoplasty

 A 2011 survey made over 18 developed high-income countries reported that over 1.3 million total knee replacements are performed every year worldwide. Since then, this number has increased because of the ageing of the population. While only a few per cent of the patients experience problems so severe as to face a new operation, between 20% and 40% (depending on the studies) report some functional limitation in their daily life due to the implant, so severe that they are unhappy of the surgical outcome.

This paper summarises the first part of the work done by the group of named authors over three years, aimed at the development of a personalised planning of the total knee replacement surgery that ensures the best possible functional outcome.

In this first part we conduct a study that could be impossible in physical patients because it would need us to repeat the same operation on them many times, which is impossible. But a virtual patient can be re-operated as many times as we need; using a fully validated computer model, we were able to show how even small differences in the way the surgery is formed can modify the balance of the tissues wrapping the knee, producing major or minor functional limitations.

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. White Rose Research Online version

2018

Comparison of HR-pQCT- and microCT-based finite element models

 The bedrock of developing robust Virtual Physiological Human is a robust and accurate digital transformation of existing medical procedures. The development of high-resolution imaging systems such as HR-pQCT (High-Resolution Peripheral Quantitative Computed Tomography) has provided clinicians with a powerful tool for a 3D visualisation of patients’ internal bone structures (e.g. trabecular regions) which are prone to ageing-related diseases such as osteoporosis.

Building on HR-pQCT imaging advancement, the engineering FE (Finite Element) technique has also been incorporated to predict the mechanical characteristics of the monitored trabecular bone structures under certain loading scenarios.

Nevertheless, the reliability of the FE results is strongly coupled with the accuracy of the assessment of the trabecular bone structure from the clinical images. In this study, we investigate the accuracy of HR-pQCT-based FE predictions with respect to those generated from high-resolution scans of the same specimens acquired with micro-Computed Tomography (MicroCT).

This study focused on human cadaveric calcaneum, where the mechanical and microstructural properties of the trabecular tissue play a dominant role. A range of morphological and mechanical properties was evaluated for each sample (see figure).

In summary, we have found that the morphology, and as a result, the mechanical properties, of HR-pQCT-based models are considerably different from their corresponding microCT models. Our investigation has shown that this disparity is strongly attributed to the procedure to analyse the low-resolution images and to convert them to computational models.

Further analyses are required to address whether more sophisticated image processing techniques may improve the accuracy of clinical models of the trabecular bone of the calcaneus.

Alsayednoor, J., Metcalf, L., Rochester, J., Dall’Ara, E., McCloskey, E., Lacroix, D. (2018) "Comparison of HR-pQCT- and microCT-based finite element models for the estimation of the mechanical properties of the calcaneus trabecular bone", Biomechanics and Modelling in Mechanobiology (2018), pp 1-16.

MultiSim’s research on the strength of children’s bones could help in the design of safer car seats

New research from MultiSim’s academics based at Insigneo and Sheffield Children’s hospitals looks into the strength of children’s bones which could help in the design of safer car seats.

The first study of its kind into infant bone strength in relation to age and weight using computer simulations The research from the University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust and The Children’s Hospital Charity could help companies manufacturing children’s safety products, such as car seats, use the modelling of bone strength in designing and testing their products before bringing them to market Bone fractures are common in childhood and account for 25 per cent of all paediatric injuries The findings can be used to aid clinical diagnosis in determining whether broken bone injuries are accidental or inflicted

The research team is continuing their work in this area and will be building on the current research to assess other long bones, such as the tibia, expand their database to ensure a good representation of children in each age range, and look at more complex injury scenarios.

Researchers at the University of Sheffield have successfully used computer-simulated models and medical imaging to test the strength of young children’s bones, producing results that could help car seat manufacturers design safer car seats for young children.

The study, the first on infant bone strength in relation to age/weight using models developed from modern medical images, is published today in the Journal of Biomechanics and Modelling in Mechanobiology.

The research used CT scans – x-rays to take detailed pictures of the bones from different angles – and subsequent computer models to set up scenarios looking at how a different amount of force affects the bones, bending and twisting the bones to detect the breaking point.

These non-invasive techniques created 3D models of the femur (thigh bone) in the study of children’s bones in the newborn to three-year-old age range.

This is the age range that has had the least research conducted previously but also the ages where children can’t talk or communicate effectively about how their injury occurred. There is also a period of rapid growth between these ages and the researchers were able to determine how bones developed during this time and how bone strength changed.

Protection has improved significantly since the introduction of car seats but car accidents are still a leading cause of life-threatening injury in children. Computer-aided engineering is an essential part of vehicle development and safety assessments are increasingly relying on simulations. Therefore, it is vital that the correct simulations, using accurate models, are used to ensure optimum safety.

Current testing for car seats in simulated crash tests often use scaled-down models of adults to simulate a child in a given situation. However, anatomically, a toddler has a very different bone structure to an adult – the bones are not fully formed and still growing.

Dr Xinshan Li, from the Insigneo Institute for in silico Medicine and the Department of Mechanical Engineering at the University of Sheffield, said: “There is currently very little research looking into the bone strength of young children. Our data can be applied to help car seat manufacturers, pram manufacturers, toy manufacturers and any other companies designing children’s products, to design and make safer products and use our modelling of bone strength in testing their products before bringing them to market.

“We will be continuing our research in this area and hope to work in partnership with these industries to demonstrate the impact our work could have in helping to prevent and minimise the impact of potential accidents. This will give parents peace of mind that their child is as safe as possible and that the products they are using have been tested using the very latest and accurate techniques.”

Dr Amaka Offiah, Reader in Paediatric Musculoskeletal Imaging in the Department of Oncology and Metabolism at the University of Sheffield, and Honorary Consultant Paediatric Radiologist at Sheffield Children’s Hospital said: “Bone fractures are common in childhood and have been estimated to account for 25 per cent of all paediatric injuries. They can broadly be categorised into accidental or inflicted injuries.

“Currently, distinguishing between these can often be extremely difficult. Due to the difficulties in obtaining paediatric bone samples, there has been a lack of research to provide evidence-based information on bone strength in young children.

“In addition to the child safety industry-based applications, the findings from our study can be used in future to aid clinical diagnosis. If we can provide a table that shows bone strength by age range for different bones in the body, we can then calculate the force required to break that particular bone. This would help clinicians to use evidence-based information to decide whether an injury is accidental or inflicted, particularly for younger children who aren’t able to articulate how the injury occurred. We are grateful to The Children’s Hospital Charity, who funded the initial work in this area.”

The Insigneo Institute for in silico Medicine is a collaborative initiative between the University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children’s NHS Foundation Trust (in silico medicine is also known as computational medicine). It is a multidisciplinary collaboration between over 140 academics and clinicians to develop computer simulations of the human body and its disease processes that can be used directly in clinical practice to improve diagnosis and treatment. MultiSim is an Engineering and Physical Sciences Research Council (EPSRC) funded programme which is based in Insigneo.

Professor Damien Lacroix, Director of MultiSim, said: “The MultiSim project provided resources for this research, as the research team were able to use the same modelling techniques and software we created to look into musculoskeletal diseases and apply this to modelling for children’s bones to test their strength.
“The potential applications of this research are far-reaching and demonstrate how computer simulations can potentially save time and provide a more reliable diagnosis for clinicians.”

Altair, Z., Viceconti, M., Offiah, A. C., Li, X., (2018), "Investigating the mechanical response of paediatric bone under bending and torsion using finite element analysis", Biomechanics and Modeling in Mechanobiology, pp1-9.

This study was supported by the Higher Committee for Education Development in Iraq (HCED). The project also received funding from the MultiSim Project and the European Commission H2020 programme through the CompBioMed Centre of Excellence.

Poroelastic Modelling of Highly Hydrated Collagen Hydrogels: Experimental Results vs. Numerical Simulation with Custom and Commercial Finite Element Solvers

 With non-stop advances in computational methods and tools, researchers have a wide range of possibilities when it comes to choosing the most appropriate software for their work.

In the field of biomechanics and biomaterials, one of the most used tools to predict and understand the behaviour of materials and devices is the finite element method, which allows for the computational evaluation of loads and deformations of a given structure.

The present work deals with the comparison of two different finite element programs on the modelling of one of the most important biomaterials: collagen. On the one hand, V-Biomech® is a custom solver, developed by a group of researchers to mimic the behaviour of biomaterials such as this very same collagen. On the other hand, Abaqus® is a widely spread software, which covers the modelling of most materials and possible designs, even if not specifically collagen or other biomaterials.

The interesting outcome of this work is that both programs have shown to be able to mimic the behaviour of collagen, as previously experimentally registered by other researchers in the field. Thus, the researcher working on the behaviour of highly hydrated biomaterials has the option of choosing a large spectrum commercial tool or a dedicated one, depending on the needs of the work.

Castro, A. P. G., Yao, J., Battisti, T., Lacroix, D. (2018), “Poroelastic Modeling of Highly Hydrated Collagen Hydrogels: Experimental Results vs. Numerical Simulation With Custom and Commercial Finite Element Solvers”, Frontiers in Bioengineering and Biotechnology, 6, Article 142

White Rose Research Online version

Variability in strain distribution in the mice tibia loading model: A preliminary study using digital volume correlation

 The study of bone remodelling, how bone tissue changes over time due to the activity of bone cells, is fundamental for a better understanding of musculoskeletal diseases and to design new treatments.

Bone adapts to external loading and exercise can be used to stimulate the formation of new tissue in order to strengthen the bones.  Animal studies on small rodents, in particular mice and rats, provide a good environment to study bone remodelling related to controlled mechanical stimuli.

In these experiments, the mouse is placed under anaesthesia for a few minutes and its leg is positioned between two loading plates and small, high rate loads are imposed to the limb between the knee and the ankle. This procedure, with minimal discomfort for the animals, aims to apply an axial load to the tibia that would stimulate cell activity and increasing the bone mass. Nevertheless, considering the complexity of the mechanical test, it is impossible to control the transverse loading, which could affect dramatically the deformation of the bone, which drives the bone formation.

Therefore, the aim of this study was to combine state of the art experimental and image processing approaches to evaluate the realistic deformation imposed to the mouse tibia during these experiments. We designed a small loading device that replicates the loading conditions imposed during one of the animal experiments. We mechanically tested three hindlimbs dissected from cadaver mice used in previous studies with that jig, which can be placed inside a high-resolution scanning machine. We acquired high-resolution three-dimensional images of the mouse tibia before and after the load was imposed, by using a micro-computed tomography. Finally, we processed the collected images with a digital volume correlation (DVC) approach developed in the MULTISIM project.  This approach allows computing the deformation of the bone under the specific loading condition.

With this workflow, we showed for the first time the realistic deformation of the bone in typical loading experiments.  Moreover, we have shown that the loading protocol can induce pretty different deformations according to the positioning of the bone in the testing machine.

These results are fundamental for the development of computational models for predicting bone remodelling over time, one of the main objectives of the MULTISIM consortium.

Giorgi, M., Dall’Ara, E. (2018), “Variability in strain distribution in mice tibia loading model: A preliminary study using digital volume correlation”, Medical Engineering & Physics.

Validation of calcaneus trabecular microstructure measurements by HR-pQCT

 In the clinical management of osteoporosis, the most common bone disease that is associated with reduced bone strength and increased risk of broken bones (fractures), it is useful to be able to assess bone strength in individual patients. Bone strength depends on the amount of bone (bone mass) as well as its structure.

The heel bone is a very accessible site for assessing bone strength but, to date, the assessments have largely been undertaken with ultrasound-based devices that measure bone mass but only indirectly tell us something about bone structure. Recently, high-resolution x-ray imaging, using a device called the XtremeCT, has been developed to allow visualisation of the bone structure down to a resolution of approximately 0.1 millimetres, enabling us to see if the bone structure is thin and porous (weak) or thick and dense (strong). The aim of our work was to develop a procedure to image the heel bone using the XtremeCT and test its accuracy in assessing heel bone structure.

Ten human cadaveric feet were used to develop the method. Measurements of heel bone microstructure from the XtremeCT images were compared to ‘gold standard’ images, obtained in the laboratory by a scanner that is of such high resolution (0.02 millimetres) that it cannot be used in living human samples.  We experimented with short and long scan durations, to see if the scan intensity (longer duration) could improve the accuracy of the structure assessment.

We found that the measurement of heel bone mass by the XtremeCT accurately reflected that measured by the ‘gold standard’ method, regardless of the scan duration. In contrast, the number and spacing of the structures within the heel bone was more strongly correlated with the ‘gold standard’ when the longer scan durations were used. Importantly, the accuracy of these measurements in the latter scans was similar to those reported at the wrist and ankle in previous research studies using the XtremeCT. The accuracy of the structural measurements was most accurate when the region measured lay closer to the upper surface of the bone (see the figure), because of the higher bone mass in this region and the lower quantity of surrounding bones and soft tissues (e.g. fat, muscle, tendons and ligaments).

In summary, our method produced accurate measurements of heel bone microstructure using the XtremeCT device, particularly in the upper regions of the heel bone. Using longer scan durations might be warranted for measurements in clinical studies in an attempt to improve measurement accuracy, but this may not be possible as even minor movements of the heel might detract from the accuracy.

Metcalf, L. M., Dall’Ara, E., Paggiosi, M. A., Rochester, J. A., Vilayphiou, N., Kemp, G. J., McCloskey, E. V. (2018) “Validation of calcaneus trabecular microstructure measurements by HR-pQCT”, Bone, 106, pp 69-77.

Image-based Kinematic Ankle Models for Children affected by Juvenile Idiopathic Arthritis

 This study, carried on as part of the MD-PAEDIGREE project, presents an innovative application for kinematic ankle models, used here to understand possible disease-specific gait patterns in children affected by Juvenile Idiopathic Arthritis.

The proposed methodology is based on the identification of the tibiotalar and subtalar axes from medical images through morphological fitting of the articular surfaces of the talus. Axes measurements proved to be repeatable and in line with ex-vivo data. Kinematic results confirmed the absence of a disease-specific gait pattern in the ankle, as suggested by the heterogeneity of the children’s clinical profile, including various diseases sub-types and manifestations.

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

 White Rose Research Online version

2017

Multiscale modelling methods in biomechanics

 Dr Pinaki Bhattacharya talks about his research on the categorisation for multiscale modelling in biomechanics.

Multiscale modelling in biomechanics is a relatively new research domain. It has potential applications in preventing and developing treatments for a wide variety of diseases, however, because of this wide-ranging applicability, multiscale models that exist are also very different from each other. The broad range of application of multiscale modelling in biomechanics, on one- hand signifies its importance but at the same time presents unique challenges in categorising research carried out within. This review will benefit researchers in critiquing future research directions in this domain. It is timely because the domain is relatively new and much work remains to be done.”

This creates difficulties in assessing how the field of research is progressing and in determining what questions remain unanswered. These questions are important for researchers and science policy makers associated with this research domain.

In this paper, we proposed a categorisation for multiscale models in biomechanics. The categorisation is based on what motivates a given model. One possible motivation is to simply confirm that the ’cause’ assumed by a multiscale model agrees with observations. A more ambitious motivation is to show that the model can ‘predict’ accurately. The most ambitious motivation is to demonstrate that the multiscale model determines an ‘effect’ that is not possible by the best available single-scale model. In this review paper, we provided tests to determine the category of motivation for a given model. The tests are obviously stricter when going from a causal confirmation type model to one that is motivated by determination of effect. We showed how these tests could be put to practice by applying them to a large body of original research articles.

From this exercise, a unified picture emerged for the first time regarding the progress made in multiscale modelling in biomechanics. It was found that the overwhelming number of models (73/85) were motivated by causal confirmation, whereas only one model (out of 85) was motivated by determination of effect. From a medical perspective, musculoskeletal biomechanics and cardiovascular biomechanics are especially important sub-domains of biomechanics. Therefore in this review, we highlighted open questions in these sub-domains which, if answered, would advance the state-of-the-art along more ambitiously motivated models.

Bhattacharya, P., Viceconti, M. (2017), "Multiscale Modeling Methods in Biomechanics",  WIREs Systems Biology and Medicine , e1375.

Micro Finite Element models of the vertebral body: Validation of local displacement predictions

 Computational models can be used to estimate the mechanical properties of bones under certain loading conditions. However, even if they are based on high-resolution micro-computed tomography (microCT) scans which provide information about the bone density and micro architecture, they need to be validated against accurate and well controlled experiments in the laboratory.

In this study we used a combination of high-resolution imaging, state of the art experimental testing and complex image processing techniques to understand how computational models predict the local displacements and strains of porcine vertebral bodies tested in compression.

This study shows for the first time that the models can predict quantitatively the local displacements and qualitatively the strain distribution within the vertebral body, independently from the considered bone types. Work still needs to be done to predict the stiffness and strength of the bone without tuning the input parameters.

Costa, C., Tozzi, G., Cristofolini, L., Danesi, V., Viceconti, M., Dall’Ara, E. (2017), "Micro Finite Element models of the vertebral body: Validation of local displacement predictions", PloS One , 12 (7): e0180151.

Precision of Digital Volume Correlation Approaches

University of Sheffield researchers are improving the assessment of deformation in bone tissue using the “Digital Volume Correlation” (DVC) approach that is considered a state-of-the-art image-processing technique.

This research aims to improve our knowledge about bone fracture mechanism.

Particularly focusing on the bone fracture mechanism due to bone and joint diseases such as osteoporosis or osteoarthritis and novel treatments.

DVC allows measuring of the full field of deformation of a particular bone specimen. The bone specimen is subjected to a certain loading condition, and then the resulting deformation is observed by combining high-resolution three-dimensional imaging and complex image processing.  However, in order to fully understand the potential of this novel technique in different applications, we need to evaluate its measurement accuracy.

Dr Enrico Dall’Ara of the MultiSim project, based at the University of Sheffield’s Insigneo Institute, in collaboration with colleagues at the University of Portsmouth and the University of Bologna, have assessed the precision of this method over the past years in different applications. This manuscript summarises the obtained results.

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.

A new proxy measurement algorithm with applications to vertical ground reaction forces with wearable sensors

 A proxy measurement is commonly used when direct measures of the outcome are unobservable and/or unavailable. This paper is a typical and successful application of proxy measurement strategy.

In this particular application, wearable IMU (Inertia Measurement Unit) sensors were used to measure the accelerations at different body levels. The acceleration signals were used as the proxy variable of vertical ground reaction force (vGRF) during daily activities such as walking, and the dynamical relationship between vGRF and the accelerations was explored. The developed algorithm was then used to estimate vGRF from these acceleration recordings.

The research carried out in this paper has important implications for many applications such as healthcare. Actually, the analysis of ground reaction force is central in many scientific and engineering fields, including biomechanics, medical science, sports science, and robotics.

In human biomechanics and humanoid robotics, for example, postural control is critical for understanding balance and locomotion, where the control strategies for bipedal systems heavily rely on the knowledge of the GRF and its point of application, i.e., the centre of pressure (COP).

In healthcare, estimating the GRF and joint moments of patients in daily life activities could have a substantial clinical impact by providing assessments of pathological gait, fall detection in the elderly, and biofeedback data for home interventions.

This piece of research provides a promising low-cost method for monitoring GRF in real-life settings and introduces a novel generic approach for replacing the direct determination of difficult to measure variables in many applications.

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.

Fine tuning scan time for improving preclinical assessment of bone tissue

MultiSim’s researchers are trying to find ways to reduce and refine animal testing in pre-clinical trials by using computer models and medical imaging.  One application of these approaches is to study the effect of skeletal diseases such as osteoporosis and its treatments.

At the University of Sheffield, high-resolution scans can be performed on mice to measure the properties of the same bone in the same animal over time using a technique called in vivo micro-Computed Tomography scanning.

It is important to optimise scanning procedures in order to find the best compromise between the measured outcomes and the length of the scan, in order to reduce the discomfort of the animal and to minimise the required radiation dose on them, which may affect significantly the outcome of the study.

The study was conducted by Dr Enrico Dall’Ara and Professor Marco Viceconti of the MultiSim project, based at the University of Sheffield’s Insigneo Institute in collaboration with the NC3Rs, a UK-based scientific organisation dedicated to replacing, refining and reducing the use of animals in research and testing (the 3Rs).

Oliviero, S., 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.

Journal of Biomechanics: Accuracy of synchrotron-based digital volume correlation for bone tissue

MultiSim’s Dr Enrico Dall’Ara talks about his paper on the accuracy of synchrotron-based digital volume correlation for bone tissue. His research was featured on the homepage of the Journal of Biomechanics edition published in July 2017.

Understanding bone mechanics at different hierarchical levels is fundamental to improve preclinical and clinical assessments of bone strength. Digital Volume Correlation (DVC) is the only experimental measurement technique used for measuring local displacements and calculating local strains within bones. To date, it is mainly based on images acquired with standard micro-computed tomography that can be installed in every laboratory.

While the uncertainties of this method based on such images are good in measuring local displacements, its precision in measuring deformations is still low, limiting its application. An alternative to improve the precision of this method could be improving the resolution of the input images, for example by acquiring them with synchrotron radiation micro-computed tomography.

In this study, we evaluated the precision of DVC if based on images of bones acquired at the Diamond Light Source, only Synchrotron facility available in the UK. Different types of bones (cortical and trabecular bovine bone and murine tibiae) were each scanned repeatedly with excellent resolution (1.6 micrometres in voxel size). The uncertainties of a global DVC algorithm (ShIRT-FE) developed in Sheffield were evaluated for both displacement and strain measurements. The results showed a great improvement of the precision of the method when compared to previous DVC measurements, for all bone types.

This study shows for the first time that the uncertainties of DVC based on Synchrotron light high-resolution scans are low enough to measure accurately the local deformation at the tissue level and to use this information to validate computational models that aim to predict bone deformation at that dimensional level.

Palanca, M., Bodey, A. J., Giorgi, M., Viceconti, M., Lacroix, D., Cristofolini, L., Dall'Ara, E. (2017) "Local displacement and strain uncertainties in different bone types by digital volume correlation of synchrotron microtomograms", Journal of Biomechanics, 58, pp 27-36

A new approach to measuring strain in bones

Evaluating the deformation field in bones under loading is very important to better understand the effect of pathologies or treatments with biomaterials. Unfortunately due to a bone heterogeneous and complex structure, the experimental measurement of bone specimens in the laboratory is not trivial, and current methods are limited to analyses on the surface of the bone.

The Digital Volume Correlation (DVC) approach applied to repeated high-resolution scans of the specimens can measure the strain distribution inside bone structures but researchers need to learn more about its precision in the case of natural and treated bones.

In this study the authors including Enrico Dall’Ara of the MultiSim project evaluated the precision of two independent DVC approaches when applied five natural porcine vertebrae. The authors also tested the methods for measurements of strain in porcine vertebrae where a clinical biomaterial used to treat the vertebrae was injected.

Their study clearly showed that, when sufficient care is dedicated to preliminary methodological work, different DVC computation approaches allow measuring the strain in natural and treated bones with an acceptable error.

Palanca, M., Bodey, A. J., Giorgi, M., Viceconti, M., Lacroix, D., Cristofolini, L., Dall'Ara, E. (2017), "Local displacement and strain uncertainties in different bone types by digital volume correlation of synchrotron microtomograms", Journal of Biomechanics , 58, pp 27-36. 

Moving from laboratory to real-life conditions: influence on the assessment of variability and stability of gait

 Researchers from MultiSim have been involved in a collaborative study about measuring gait analysis outside laboratory conditions. This collaboration was a result of the European Society of Biomechanics 2016 mobility award for young researchers awarded to Paola Tamburini.

Gait analysis (i.e. measuring how someone walks) can be a handy tool to assess how well someone walks and if walking is impaired eg as a result of diseases that impact movement quality. Previously, conducting gait analysis required expensive equipment and trained specialists, and to bring the person being observed to a clinic or a laboratory.

However, walking in a clinic/laboratory probably isn’t the best replication of walking in a free-living environment without observation. Thanks to technological advancements we now have devices that can measure movement (inertial measurement units) and have both adequate battery life and are physically small enough to unobtrusively measure people’s movements from different locations of the body. They also do not require a clinic/laboratory. These small devices continuously measure movement many times per second, and as a result, new ways of measuring movement quality have been created.

The two types of new measures that exist are the variability of gait and stability of gait. At present, it is not known whether variables are useful when measured in a clinic/laboratory change when measured in a free-living environment or vice versa. This experiment tested whether healthy and young individuals’ gait changed when tested in different environments. It was predicted that their gait variability would change but their stability would not.

To test this theory, 19 participants were measured walking in four different environments. One to replicate gait analysis in a laboratory/clinic and another to do the same but outdoors and over a longer distance. In the two other conditions tested, the participant was free to walk wherever they liked in: an urban environment (city centre) and corridors of a large university building. For the last two environments, the participant would have to avoid obstacles such as pedestrians, whereas, for the first two environments, the examiners ensured their walking would not be disturbed.

Results showed that the prediction was correct whereby the gait stability did not change between environments but gait variability did. As a result, if using these gait variability measures to assess how well someone is walking, the environment in which the walking was tested should be considered when interpreting the results. Whereas for gait stability measures, which are proposed to be better indicative of motor control, when making comparisons for healthy participants, the environment does not need to be considered. Future work is required to see if these results are reflected in groups where gait is expected to be impaired.

This study provides evidence that it may be possible to measure gait stability in all environments and consequently this method of gait analysis may be used to measure gait without the need for a visit to a clinic or laboratory. This makes this new approach have cost and logistical advantages over our current approach.

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. 

Research on Digital volume correlation (DVC)

 Strain uncertainties from two digital volume correlation approaches in prophylactically augmented vertebrae:
A newly developed technique called digital volume correlation (DVC) can be used to access the internal deformation of heterogeneous materials and structures.
DVC has been exploited over the past decade to measure complex deformation fields within biological tissues, such as bone and other biological materials.

Clinical use of DVC:
However, before adopting this promising technique in a clinically-relevant context, the research community should focus on understanding the reliability of such a method in different applications. The aim of this study was to evaluate the precision of this method applied with two different approaches to different microstructures within vertebral bodies treated with a biomaterial, usually used for fixing vertebral fractures.

Results:
The results showed that the precision of both approaches depended mainly on one input parameter and on the different microarchitecture found within the samples.  One of the two methods, ShIRT-FE (combination of the Sheffield image registration toolkit of a finite element software package) was found to be more accurate at the border as less affected by the absence of features outside the specimen.

In conclusion, this study has provided, for the first time, a factual indication of the reliability and limitations for the application of DVC in estimating the micromechanics of different portions of the vertebral body. Furthermore, the current results could provide very useful information for the validation of subject-specific computational models based on high-resolution images of a vertebra with injectable biomaterials.

Tozzi, G., Dall’Ara, E., Palanca, M., Curto, M., Innocente, F., Cristofolini, L. (2017), “Strain uncertainties from two digital volume correlation approaches in prophylactically augmented vertebrae: local analysis on bone and cement-bone microstructures”, Journal of the Mechanical Behavior of Biomedical Materials, 67, pp 117-126

 White Rose Research Online version

2016

Neck muscle weakness due to motor neurone disease

An orthosis is an externally applied device that is designed and fitted to the body to achieve one or more of the following goals:

• control biomechanical alignment
• correct or accommodate deformity
• protect and support an injury.

Cervical orthoses are prescribed for a range of conditions from muscles spasms to more serious conditions such as motor neurone disease. Motor neurone disease is a neurodegenerative disease that leads to muscle weakness and that can also involve neck muscles. Orthoses (collars) are designed to immobilise the neck. The aim is to rest the neck and give support. This helps affected muscles to relax and inflammation to subside.  However, most commercially available orthoses are uncomfortable and strenuous to wear for a long time. The Sheffield Support Snood’s main feature is to offer selective support through the presence of adjustable supports (Fig 1),  according to an individual’s disease development.

“Since we also aimed at proposing a protocol easily translatable in a clinical context for future tests in patients with motor neurone disease, wearable inertial magneto units were used for the assessment. The use of these sensors is really advantageous in clinical applications, since it allows measurements to be performed in a clinical setting, with reduced discomfort to the patient,” said Silvia.

This study involved 12 healthy subjects and aimed at assessing the differences between two existing cervical orthoses, the Headmaster (Symmetric Designs) and the Vista(Aspen Medical Products), and a newly developed cervical orthosis, the Sheffield Support Snood (Device for Dignity Healthcare Technology Cooperative), specifically designed for people affected by neck muscle weakness, such as motor neurone disease patients.

The Sheffield Support Snood, tested using this new protocol, confirmed its ability to offer support only for those movements where this was needed and without limiting concurrent movements in other planes. In addition, in its more supportive configuration, it showed a support comparable to the Vista in all the directions tested.

Driven by the encouraging results obtained with healthy subjects, we tested the new orthosis also with people affected by neck muscle weakness due to motor neurone disease.

Pancani, S., Rowson, J., Tindale, W., Heron, N., Langley, J., McCarthy, A. D., Quinn, A., Reed, H., Stanton A., Shaw, P. J., McDermott, C. J., Mazzà, C. (2015), "Assessment of the Sheffield Support Snood, an innovative cervical orthosis designed for people affected by neck muscle weakness", Clinical Biomechanics, 32, pp 201-206.