Biomechanics-based in silico medicine: The manifesto of a new science

In this perspective article we discuss the role of contemporary biomechanics in the light of recent applications such as the development of the so-called Virtual Physiological Human technologies for physiology-based in silico medicine. In order to build Virtual Physiological Human (VPH) models, computer models that capture and integrate the complex systemic dynamics of living organisms across radically different space–time scales, we need to re-formulate a vast body of existing biology and physiology knowledge so that it is formulated as a quantitative hypothesis, which can be expressed in mathematical terms. Once the predictive accuracy of these models is confirmed against controlled experiments and against clinical observations, we will have VPH model that can reliably predict certain quantitative changes in health status of a given patient, but also, more important, we will have a theory, in the true meaning this word has in the scientific method. In this scenario, biomechanics plays a very important role, biomechanics is one of the few areas of life sciences where we attempt to build full mechanistic explanations based on quantitative observations, in other words, we investigate living organisms like physical systems. This is in our opinion a Copernican revolution, around which the scope of biomechanics should be re-defined. Thus, we propose a new definition for our research domain “Biomechanics is the study of living organisms as mechanistic systems”

The Virtual Physiological Human: Ten Years After

Biomedical research and clinical practice are struggling to cope with the growing complexity that the progress of health care involves. The most challenging diseases, those with the largest socioeconomic impact (cardiovascular conditions; musculoskeletal conditions; cancer; metabolic, immunity, and neurodegenerative conditions), are all characterized by a complex genotype–phenotype interaction and by a “systemic” nature that poses a challenge to the traditional reductionist approach. In 2005 a small group of researchers discussed how the vision of computational physiology promoted by the Physiome Project could be translated into clinical practice and formally proposed the term Virtual Physiological Human. Our knowledge about these diseases is fragmentary, as it is associated with molecular and cellular processes on the one hand and with tissue and organ phenotype changes (related to clinical symptoms of disease conditions) on the other. The problem could be solved if we could capture all these fragments of knowledge into predictive models and then compose them into hypermodels that help us tame the complexity that such systemic behavior involves. In 2005 this was simply not possible—the necessary methods and technologies were not available. Now, 10 years later, it seems the right time to reflect on the original vision, the results achieved so far, and what remains to be done

Validation of homogenized finite element models of human metastatic vertebrae using digital volume correlation

The incidence of vertebral fragility fracture is increased by the presence of preexisting pathologies such as metastatic disease. Computational tools could support the fracture prediction and consequently the decision of the best medical treatment. Anyway, validation is required to use these tools in clinical practice. To address this necessity, in this study subject-specific homogenized finite element models of single vertebrae were generated from micro CT images for both healthy and metastatic vertebrae and validated against experimental data. More in detail, spine segments were tested under compression and imaged with micro CT. The displacements field could be extracted for each vertebra singularly using the digital volume correlation full-field technique. Homogenized finite element models of each vertebra could hence be built from the micro CT images, applying boundary conditions consistent with the experimental displacements at the endplates. Numerical and experimental displacements and strains fields were eventually compared. In addition, the outcomes of a micro CT based homogenized model were compared to the ones of a clinical-CT based model. Good agreement between experimental and computational displacement fields, both for healthy and metastatic vertebrae, was found. Comparison between micro CT based and clinical-CT based outcomes showed strong correlations. Furthermore, models were able to qualitatively identify the regions which experimentally showed the highest strain concentration. In conclusion, the combination of experimental full-field technique and the in-silico modelling allowed the development of a promising pipeline for validation of fracture risk predictors, although further improvements in both fields are needed to better analyse quantitatively the post-yield behaviour of the vertebra

Multi-vertebral CT-based FE models implementing linear isotropic population-based material properties for the intervertebral discs cannot accurately predict strains

Vertebral fractures prediction in clinics lacks of accuracy. The most used scores have limitations in distinguishing between subjects at risk or not. Finite element (FE) models generated from computed tomography (CT) of these patients may improve the predictive capability. Many models have already been proposed but the most of them considered the single vertebral body, excluding from the analysis the role of the inter-vertebral discs in the distribution of the load through the spine. Multi-vertebral models instead allow to examine more complex boundary condition. However, CT scans do not provide subject-specif information about the material properties of the disc. Consequently, the goal of the study was to validate a multi-vertebral FE model with subject specific modelling of the vertebral bone and population-based properties assigned to the disc, idealizing them with a linear isotropic material. Boundary condition were assigned in order to reproduce an experimental test performed on the same specimen and recorded using digital image correlation technique (DIC). FE and DIC strains on the vertebral surfaces are compared point-wise. Young's modulus values in the range 25-30 MPa allowed to achieve a comparable order of magnitude between experimental and computational data. However, the two distribution remained strongly different. To conclude, subject-specific material properties need to be assigned also to the discs as well as to the vertebrae to achieve acceptable accuracy in the assessment of the fracture risk.Comment: 18 pages, 6 figures submitted to Biomechanics and Modeling in Mechanobiolog

Identification of a lumped-parameter model of the intervertebral joint from experimental data

Through predictive simulations, multibody models can aid the treatment of spinal pathologies by identifying optimal surgical procedures. Critical to achieving accurate predictions is the definition of the intervertebral joint. The joint pose is often defined by virtual palpation. Intervertebral joint stiffnesses are either derived from literature, or specimen-specific stiffnesses are calculated with optimisation methods. This study tested the feasibility of an optimisation method for determining the specimen-specific stiffnesses and investigated the influence of the assigned joint pose on the subject-specific estimated stiffness. Furthermore, the influence of the joint pose and the stiffness on the accuracy of the predicted motion was investigated. A computed tomography based model of a lumbar spine segment was created. Joints were defined from virtually palpated landmarks sampled with a Latin Hypercube technique from a possible Cartesian space. An optimisation method was used to determine specimen-specific stiffnesses for 500 models. A two-factor analysis was performed by running forward dynamic simulations for ten different stiffnesses for each successfully optimised model. The optimisations calculated a large range of stiffnesses, indicating the optimised specimen-specific stiffnesses were highly sensitive to the assigned joint pose and related uncertainties. A limited number of combinations of optimised joint stiffnesses and joint poses could accurately predict the kinematics. The two-factor analysis indicated that, for the ranges explored, the joint pose definition was more important than the stiffness. To obtain kinematic prediction errors below 1 mm and 1° and suitable specimen- specific stiffnesses the precision of virtually palpated landmarks for joint definition should be better than 2.9 mm

From the digital twins in healthcare to the Virtual Human Twin: a moon-shot project for digital health research

The idea of a systematic digital representation of the entire known human pathophysiology, which we could call the Virtual Human Twin, has been around for decades. To date, most research groups focused instead on developing highly specialised, highly focused patient-specific models able to predict specific quantities of clinical relevance. While it has facilitated harvesting the low-hanging fruits, this narrow focus is, in the long run, leaving some significant challenges that slow the adoption of digital twins in healthcare. This position paper lays the conceptual foundations for developing the Virtual Human Twin (VHT). The VHT is intended as a distributed and collaborative infrastructure, a collection of technologies and resources (data, models) that enable it, and a collection of Standard Operating Procedures (SOP) that regulate its use. The VHT infrastructure aims to facilitate academic researchers, public organisations, and the biomedical industry in developing and validating new digital twins in healthcare solutions with the possibility of integrating multiple resources if required by the specific context of use. The VHT infrastructure can also be used by healthcare professionals and patients for clinical decision support or personalised health forecasting. As the European Commission launched the EDITH coordination and support action to develop a roadmap for the development of the Virtual Human Twin, this position paper is intended as a starting point for the consensus process and a call to arms for all stakeholders

Computational modelling of the scoliotic spine: A literature review

open4siScoliosis is a deformity of the spine that in severe cases requires surgical treatment. There is still disagreement among clinicians as to what the aim of such treatment is as well as the optimal surgical technique. Numerical models can aid clinical decision-making by estimating the outcome of a given surgical intervention. This paper provided some background information on the modelling of the healthy spine and a review of the literature on scoliotic spine models, their validation, and their application. An overview of the methods and techniques used to construct scoliotic finite element and multibody models was given as well as the boundary conditions used in the simulations. The current limitations of the models were discussed as well as how such limitations are addressed in non-scoliotic spine models. Finally, future directions for the numerical modelling of scoliosis were addressed.Marco Viceconti and Giorgio Davico were supported by the EU funded project Mobilise-D. The charity Reuse-WithLove is gratefully acknowledged for the financial support to this research.openGould, Samuele L; Cristofolini, Luca; Davico, Giorgio; Viceconti, MarcoGould, Samuele L; Cristofolini, Luca; Davico, Giorgio; Viceconti, Marc

Computational modelling of the scoliotic spine: A literature review

Scoliosis is a deformity of the spine that in severe cases requires surgical treatment. There is still disagreement among clinicians as to what the aim of such treatment is as well as the optimal surgical technique. Numerical models can aid clinical decision-making by estimating the outcome of a given surgical intervention. This paper provided some background information on the modelling of the healthy spine and a review of the literature on scoliotic spine models, their validation, and their application. An overview of the methods and techniques used to construct scoliotic finite element and multibody models was given as well as the boundary conditions used in the simulations. The current limitations of the models were discussed as well as how such limitations are addressed in non-scoliotic spine models. Finally, future directions for the numerical modelling of scoliosis were addressed

Statistical Properties of a Virtual Cohort for In Silico Trials Generated with a Statistical Anatomy Atlas

Osteoporosis-related hip fragility fractures are a catastrophic event for patient lives but are not frequently observed in prospective studies, and therefore phase III clinical trials using fractures as primary clinical endpoint require thousands of patients enrolled for several years to reach statistical significance. A novel answer to the large number of subjects needed to reach the desired evidence level is offered by In Silico Trials, that is, the simulation of a clinical trial on a large cohort of virtual patients, monitoring the biomarkers of interest. In this work we investigated if statistical aliasing from a custom anatomy atlas could be used to expand the patient cohort while retaining the original biomechanical characteristics. We used a pair-matched cohort of 94 post-menopausal women (at the time of the CT scan, 47 fractured and 47 not fractured) to create a statistical anatomy atlas through principal component analysis, and up-sampled the atlas in order to obtain over 1000 synthetic patient models. We applied the biomechanical computed tomography pipeline to the resulting virtual cohort and compared its fracture risk distribution with that of the original physical cohort. While the distribution of femoral strength values in the non-fractured sub-group was nearly identical to that of the original physical cohort, that of the fractured sub-group was lower than in the physical cohort. Nonetheless, by using the classification threshold used for the original population, the synthetic population was still divided into two parts of approximatively equal number