Variability of intervertebral joint stiffness between specimens and spine levels.

Introduction: Musculoskeletal multibody models of the spine can be used to investigate the biomechanical behaviour of the spine. In this context, a correct characterisation of the passive mechanical properties of the intervertebral joint is crucial. The intervertebral joint stiffness, in particular, is typically derived from the literature, and the differences between individuals and spine levels are often disregarded. Methods: This study tested if an optimisation method of personalising the intervertebral joint stiffnesses was able to capture expected stiffness variation between specimens and between spine levels and if the variation between spine levels could be accurately captured using a generic scaling ratio. Multibody models of six T12 to sacrum spine specimens were created from computed tomography data. For each specimen, two models were created: one with uniform stiffnesses across spine levels, and one accounting for level dependency. Three loading conditions were simulated. The initial stiffness values were optimised to minimize the kinematic error. Results: There was a range of optimised stiffnesses across the specimens and the models with level dependent stiffnesses were less accurate than the models without. Using an optimised stiffness substantially reduced prediction errors. Discussion: The optimisation captured the expected variation between specimens, and the prediction errors demonstrated the importance of accounting for level dependency. The inaccuracy of the predicted kinematics for the level-dependent models indicated that a generic scaling ratio is not a suitable method to account for the level dependency. The variation in the optimised stiffnesses for the different loading conditions indicates personalised stiffnesses should also be considered load-specific.

Development and validation of a semi-automated and unsupervised method for femur segmentation from CT.

Quantitative computed tomography (QCT)-based in silico models have demonstrated improved accuracy in predicting hip fractures with respect to the current gold standard, the areal bone mineral density. These models require that the femur bone is segmented as a first step. This task can be challenging, and in fact, it is often almost fully manual, which is time-consuming, operator-dependent, and hard to reproduce. This work proposes a semi-automated procedure for femur bone segmentation from CT images. The proposed procedure is based on the bone and joint enhancement filter and graph-cut algorithms. The semi-automated procedure performances were assessed on 10 subjects through comparison with the standard manual segmentation. Metrics based on the femur geometries and the risk of fracture assessed in silico resulting from the two segmentation procedures were considered. The average Hausdorff distance (0.03 ± 0.01 mm) and the difference union ratio (0.06 ± 0.02) metrics computed between the manual and semi-automated segmentations were significantly higher than those computed within the manual segmentations (0.01 ± 0.01 mm and 0.03 ± 0.02). Besides, a blind qualitative evaluation revealed that the semi-automated procedure was significantly superior (p < 0.001) to the manual one in terms of fidelity to the CT. As for the hip fracture risk assessed in silico starting from both segmentations, no significant difference emerged between the two (R2 = 0.99). The proposed semi-automated segmentation procedure overcomes the manual one, shortening the segmentation time and providing a better segmentation. The method could be employed within CT-based in silico methodologies and to segment large volumes of images to train and test fully automated and supervised segmentation methods.

Chronological Changes in Sagittal Femoral Bowing after Primary Cementless Total Hip Arthroplasty: A Comparative 3D CT Study.

Little is known about dynamic changes of femoral anatomy after total hip arthroplasty (THA), in particular about sagittal femoral bowing (SFB). A 3D CT study was designed to evaluate the chronological changes of SFB after cementless femoral stem implantation for primary THA. Ten patients who underwent unilateral primary THA with a cementless femoral stem, with 2 consecutive CT scans (extending from the fourth lumbar vertebra to the tibial plateaus), performed before THA and at least 3 years after THA, were enrolled. The 3D models of femurs were created using image segmentation software. Using the two CT scans, SFB values of the proximal and middle thirds were calculated on the replaced and untreated sides by two different observers. Eight anatomical stems and two conical stems were involved. The post-operative CT was performed at an average follow-up of 6.5 years after THA (range: 3-12.5). The measurements performed by the two observers did not differ in the proximal and middle regions. A significant difference between the pre-operative and post-operative SFB compared to the untreated side was found in the proximal femur segment (p = 0.004). Use of a cementless stem in THA induced chronological changes in SFB of the proximal femur, after a minimum timespan of 3 years.

Position paper 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. Healthcare professionals and patients can also use the VHT infrastructure 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.

Cost-Effectiveness Analysis of CT-Based Finite Element Modeling for Osteoporosis Screening in Secondary Fracture Prevention: An Early Health Technology Assessment in the Netherlands.

Objective. To conduct cost-utility analyses for Computed Tomography To Strength (CT2S), a novel osteoporosis screening service, compared with dual-energy X-ray absorptiometry (DXA), treat all without screening, and no screening methods for Dutch postmenopausal women referred to fracture liaison service (FLS). CT2S uses CT scans to generate femur models and simulate sideways fall scenarios for bone strength assessment. Methods. Early health technology assessment (HTA) was adopted to evaluate CT2S as a novel osteoporosis screening tool for secondary fracture prevention. We constructed a 2-dimensional simulation model considering 4 strategies (no screening, treat all without screening, DXA, CT2S) together with screening intervals (5 y, 2 y), treatments (oral alendronate, zoledronic acid), and discount rate scenarios among Dutch women in 3 age groups (60s, 70s, and 80s). Strategy comparisons were based on incremental cost-effectiveness ratios (ICERs), considering an ICER below €20,000 per QALY gained as cost-effective in the Netherlands. Results. Under the base-case scenario, CT2S versus DXA had estimated ICERs of €41,200 and €14,083 per QALY gained for the 60s and 70s age groups, respectively. For the 80s age group, CT2S was more effective and less costly than DXA. Changing treatment from weekly oral alendronate to annual zoledronic acid substantially decreased CT2S versus DXA ICERs across all age groups. Setting the screening interval to 2 y increased CT2S versus DXA ICERs to €100,333, €55,571, and €15,750 per QALY gained for the 60s, 70s, and 80s age groups, respectively. In all simulated populations and scenarios, CT2S was cost-effective (in some cases dominant) compared with the treat all strategy and cost-saving (more effective and less costly) compared with no screening. Conclusion. CT2S was estimated to be potentially cost-effective in the 70s and 80s age groups considering the willingness-to-pay threshold of the Netherlands. This early HTA suggests CT2S as a potential novel osteoporosis screening tool for secondary fracture prevention. Highlights: For postmenopausal Dutch women who have been referred to the FLS, direct access to CT2S may be cost-effective compared with DXA for age groups 70s and 80s, when considering the ICER threshold of the Netherlands. This study positions CT2S as a potential novel osteoporosis-screening tool for secondary fracture prevention in the clinical setting.A shorter screening interval of 2 y increases the effectiveness of both screening strategies, but the ICER of CT2S compared with DXA also increased substantially, which made CT2S no longer cost-effective for the 70s age group; however, it remains cost-effective for individuals in their 80s.Annual zoledronic acid treatment with better adherence may contribute to a lower cost-effectiveness ratio when comparing CT2S to DXA screening and the treat all strategies for all age groups.

Comparative validation of two patient-specific modelling pipelines for predicting knee joint forces during level walking.

Over the past few years, the use of computer models and simulations tailored to the patient's physiology to assist clinical decision-making has increased enormously.While several pipelines to develop personalized models exist, their adoption on a large scale is still limited due to the required niche computational skillset and the lengthy operations required. Novel toolboxes, such as STAPLE, promise to streamline and expedite the development of image-based skeletal lower limb models. STAPLE-generated models can be rapidly generated, with minimal user input, and present similar joint kinematics and kinetics compared to models developed employing the established INSIGNEO pipeline. Yet, it is unclear how much the observed discrepancies scale up and affect joint contact force predictions. In this study, we compared image-based musculoskeletal models developed (i) with the INSIGNEO pipeline and (ii) with a semi-automated pipeline that combines STAPLE and nmsBuilder, and assessed their accuracy against experimental implant data.Our results showed that both pipelines predicted similar total knee joint contact forces between one another in terms of profiles and average values, characterized by a moderately high level of agreement with the experimental data. Nonetheless, the Student t-test revealed statistically significant differences between both pipelines. Of note, the STAPLE-based pipeline required considerably less time than the INSIGNEO pipeline to generate a musculoskeletal model (i.e., 60 vs 160 min). This is likely to open up opportunities for the use of personalized musculoskeletal models in clinical practice, where time is of the essence.

Modeling Human Suboptimal Control: A Review.

This review paper provides an overview of the approaches to model neuromuscular control, focusing on methods to identify nonoptimal control strategies typical of populations with neuromuscular disorders or children. Where possible, the authors tightened the description of the methods to the mechanisms behind the underlying biomechanical and physiological rationale. They start by describing the first and most simplified approach, the reductionist approach, which splits the role of the nervous and musculoskeletal systems. Static optimization and dynamic optimization methods and electromyography-based approaches are summarized to highlight their limitations and understand (the need for) their developments over time. Then, the authors look at the more recent stochastic approach, introduced to explore the space of plausible neural solutions, thus implementing the uncontrolled manifold theory, according to which the central nervous system only controls specific motions and tasks to limit energy consumption while allowing for some degree of adaptability to perturbations. Finally, they explore the literature covering the explicit modeling of the coupling between the nervous system (acting as controller) and the musculoskeletal system (the actuator), which may be employed to overcome the split characterizing the reductionist approach.

Credibility assessment of computational models according to ASME V&V40: Application to the Bologna Biomechanical Computed Tomography solution.

BACKGROUND AND OBJECTIVE: When a computational model aims to be adopted beyond research purposes, e.g. to inform a clinical or regulatory decision, trust must be placed in its predictive accuracy. This practically translates into the need to demonstrate its credibility. In fact, prior to its adoption for regulatory purposes, an in silico methodology should be proven credible enough for the scope. This has become especially relevant as, although evidence of the safety and efficacy of new medical products or interventions has been traditionally provided to the regulator experimentally, i.e., in vivo or ex vivo, recently the idea to inform a regulatory decision in silico has made its way in the regulatory scenario. While a harmonised technical standard is currently missing in the EU regulatory system, in 2018 the ASME issued V&V40-2018, where a risk-based framework to assess the credibility of a computational model through the performance of predefined credibility activities is provided. The credibility framework is here applied to Bologna Biomechanical Computed Tomography (BBCT) solution, which predicts the absolute risk of fracture at the femur for a subject. BBCT has recently been the object of a qualification advice request to the European Medicine Agency. METHODS: The full implementation of ASME V&V40-2018 framework on BBCT is shown. Starting from BBCT proposed context of use the whole credibility plan is presented and the credibility activities (Verification, Validation, Applicability) described together with the achieved credibility levels. RESULTS: BBCT risk is judged medium, and the credibility levels achieved considered acceptable. The uncertainties intrinsically present in the material properties assignment affected BBCT predictions to the highest extent. CONCLUSIONS: This work provides the practical application of the ASME V&V40-2018 risk-based credibility assessment framework, which could be applied to demonstrate model credibility in any field and support future regulatory submissions and foster the adoption of In Silico Trials.

Impact of previous lumbar spine surgery on total hip arthroplasty and vice versa: How long should we be concerned about mechanical failure?

INTRODUCTION: This registry study aims to assess the prevalence and demographic characteristics of patients with lumbar spine (LS) surgical procedures who undergo total hip arthroplasty (THA), to compare the long-term survival and causes of failure of THA in patients who previously underwent LS fusion and non-fusion surgical procedures, and to evaluate the risk of undergoing a revision LS surgery after THA. MATERIALS AND METHODS: Patients who underwent LS surgery followed by THA were identified by cross-referencing data from the Orthopedic Prosthetic Implants Registry and the Regional Hospital Discharge Database. Three groups of THA patients were identified: patients who underwent previous lumbar surgery with fusion (LS fusion-THA), without fusion (LS non-fusion-THA), and a control group with only THA (No LS surgery-THA). Demographic data, THA survival, number and causes of failure, and data on revision procedures on THA and LS were collected. RESULTS: Of the total of 79,984 THA, 2.2% of patients had a history of LS procedures. THA only patients showed better results, while patients in the LS fusion-THA group had worse implant survival at 5-year follow-up. In the LS fusion-THA and LS non-fusion-THA, mechanical THA failures were more frequent in the first two years after implantation. There were no differences between groups regarding the risk of undergoing LS revision surgery. CONCLUSIONS: LS surgery negatively affects THA survivorship. In patients who previously underwent LS fusion and non-fusion surgical procedures, most THA failure occurs in the first two years after implant. The study contributes to the understanding of the relationship between the hip and the LS and provides useful guidance for clinical practice.

Magnetic resonance-based hip muscles retrospective analysis shows deconditioning and recovery after total hip arthroplasty surgery.

PURPOSE: The purpose of this study is to estimate the effect of unilateral hip osteoarthritis (OA) on hip muscle volume and fatty infiltration and to evaluate changes of muscles after total hip arthroplasty (THA) surgery. METHODS: A retrospective analysis was conducted on patients with unilateral hip OA subjected to THA with perioperative pelvic girdle 1.5 T magnetic resonance imaging (MRI). Thirty-five patients were included. Ten of these have also postoperative MRIs. Medius gluteus (MG) and iliopsoas (IP) muscles were manually segmented on the MRI scans, the corresponding 3D muscle geometries were reconstructed, and the volumes extracted. Muscle quality was assessed using the Goutallier classification on coronal MRI images. Volume and muscle quality differences were calculated between healthy and affected side. RESULTS: Pre-operatively, MG and IP on the affected side presented a mean muscle volume 17.5 ± 18% (p < 0.001) and 14.4 ± 15.8% (p < 0.001) smaller than the healthy counterpart, respectively. Muscles on the affected side showed a significant higher grade of fatty infiltration compared to the healthy side (p < 0.05 for MG; p < 0.001 for IP). At an average follow-up of 13 ± 5.3 months after THA, MG, and IP muscles of the affected hip showed an average 22.8% (p < 0.001) and 28.2% (p < 0.001) volume increase after THA. Also, the healthy side showed a significant increase of muscle volume for IP (17.1% p < 0.001). No significant change for MG muscle was observed. CONCLUSIONS: The study demonstrated preoperative reduced muscle volume and higher fatty infiltration at the muscles of the OA hip compared to the contralateral healthy one. A significant positive effect of THA on hip muscle volume was observed. These findings give an interesting insight on muscle deconditioning and recovery in patients undergoing THA.

Intra-operator Repeatability of Manual Segmentations of the Hip Muscles on Clinical Magnetic Resonance Images.

The manual segmentation of muscles on magnetic resonance images is the gold standard procedure to reconstruct muscle volumes from medical imaging data and extract critical information for clinical and research purposes. (Semi)automatic methods have been proposed to expedite the otherwise lengthy process. These, however, rely on manual segmentations. Nonetheless, the repeatability of manual muscle volume segmentations performed on clinical MRI data has not been thoroughly assessed. When conducted, volumetric assessments often disregard the hip muscles. Therefore, one trained operator performed repeated manual segmentations (n = 3) of the iliopsoas (n = 34) and gluteus medius (n = 40) muscles on coronal T1-weighted MRI scans, acquired on 1.5 T scanners on a clinical population of patients elected for hip replacement surgery. Reconstructed muscle volumes were divided in sub-volumes and compared in terms of volume variance (normalized variance of volumes - nVV), shape (Jaccard Index-JI) and surface similarity (maximal Hausdorff distance-HD), to quantify intra-operator repeatability. One-way repeated measures ANOVA (or equivalent) tests with Bonferroni corrections for multiple comparisons were conducted to assess statistical significance. For both muscles, repeated manual segmentations were highly similar to one another (nVV: 2-6%, JI > 0.78, HD < 15 mm). However, shape and surface similarity were significantly lower when muscle extremities were included in the segmentations (e.g., iliopsoas: HD -12.06 to 14.42 mm, P < 0.05). Our findings show that the manual segmentation of hip muscle volumes on clinical MRI scans provides repeatable results over time. Nonetheless, extreme care should be taken in the segmentation of muscle extremities.

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.

Lateral unicompartmental knee arthroplasty (UKA) showed a lower risk of failure compared to medial unicompartmental knee arthroplasty in the Register of Prosthetic Orthopedic Implants (RIPO).

INTRODUCTION: The present study aimed to investigate differences in survivorship between medial and lateral unicompartmental knee arthroplasty (UKA) by analyzing the data of an Italian regional registry. The hypothesis was that, according to recent literature, lateral implants have comparable survivorship with regard to the medial implants. MATERIALS AND METHODS: The Register of Orthopaedic Prosthetic Implants (RIPO) of Emilia-Romagna (Italy) database was searched for all UKAs between July 1, 2000, and December 31, 2019. For both cohorts, subject demographics and reasons for revision were presented as a percentage of the total cohort. Kaplan-Meier survivorship analysis was performed using revision of any component as the endpoint and survival times of unrevised UKAs taken as the last observation date (December 31, 2019, or date of death). RESULTS: Patients living outside the region and symmetrical implants (which do not allow the compartment operated to be traced) were excluded. 5571 UKAs implanted on 5172 patients (5215 medial UKAs and 356 lateral UKAs) were included in the study. The survivorship analysis revealed 13 failures out of 356 lateral UKAs (3.7%) at a mean follow-up of 6.3 years and 495 failures out of 5215 medial UKAs (9.5%) at a mean follow-up of 6.7 years. The medial UKAs had a significantly higher risk of failure, with a Hazard Ratio of 2.6 (CI 95% 1.6-4.8; p < 0.001), adjusted for age, gender, weight, and mobility of the insert. Both the groups revealed a good survival rate, with 95.2% of lateral implants and 87.5% of medial implants still in situ at 10 years of follow-up. CONCLUSIONS: Lateral UKA is a safe procedure showing longer survivorship than medial UKAs (95.2% and 87.5% at 10 years, respectively) in the present study. LEVEL OF EVIDENCE: Level 3, therapeutic study.

A Credibility Assessment Plan for an In Silico Model that Predicts the Dose-Response Relationship of New Tuberculosis Treatments.

Tuberculosis is one of the leading causes of death in several developing countries and a public health emergency of international concern. In Silico Trials can be used to support innovation in the context of drug development reducing the duration and the cost of the clinical experimentations, a particularly desirable goal for diseases such as tuberculosis. The agent-based Universal Immune System Simulator was used to develop an In Silico Trials environment that can predict the dose-response of new therapeutic vaccines against pulmonary tuberculosis, supporting the optimal design of clinical trials. But before such in silico methodology can be used in the evaluation of new treatments, it is mandatory to assess the credibility of this predictive model. This study presents a risk-informed credibility assessment plan inspired by the ASME V&V 40-2018 technical standard. Based on the selected context of use and regulatory impact of the technology, a detailed risk analysis is described together with the definition of all the verification and validation activities and related acceptability criteria. The work provides an example of the first steps required for the regulatory evaluation of an agent-based model used in the context of drug development.

On the use of wearable sensors as mobility biomarkers in the marketing authorization of new drugs: A regulatory perspective.

The loss of mobility is a common trait in multiple health conditions (e.g., Parkinson's disease) and is associated with reduced quality of life. In this context, being able to monitor mobility in the real world, is important. Until recently, the technology was not mature enough for this; but today, miniaturized sensors and novel algorithms promise to monitor mobility accurately and continuously in the real world, also in pathological populations. However, before any such methodology can be employed to support the development and testing of new drugs in clinical trials, they need to be qualified by the competent regulatory agencies (e.g., European Medicines Agency). Nonetheless, to date, only very narrow scoped requests for regulatory qualification were successful. In this work, the Mobilise-D Consortium shares its positive experience with the European regulator, summarizing the two requests for Qualification Advice for the Mobilise-D methodologies submitted in October 2019 and June 2020, as well as the feedback received, which resulted in two Letters of Support publicly available for consultation on the website of the European Medicines Agency. Leveraging on this experience, we hereby propose a refined qualification strategy for the use of digital mobility outcome (DMO) measures as monitoring biomarkers for mobility in drug trials.

Effect of particularisation size on the accuracy and efficiency of a multiscale tumours' growth model.

In silico, medicine models are frequently used to represent a phenomenon across multiples space-time scales. Most of these multiscale models require impracticable execution times to be solved, even using high performance computing systems, because typically each representative volume element in the upper scale model is coupled to an instance of the lower scale model; this causes a combinatory explosion of the computational cost, which increases exponentially as the number of scales to be modelled increases. To attenuate this problem, it is a common practice to interpose between the two models a particularisation operator, which maps the upper-scale model results into a smaller number of lower-scale models, and an operator, which maps the fewer results of the lower-scale models on the whole space-time homogenisation domain of upper-scale model. The aim of this study is to explore what is the simplest particularisation / homogenisation scheme that can couple a model aimed to predict the growth of a whole solid tumour (neuroblastoma) to a tissue-scale model of the cell-tissue biology with an acceptable approximation error and a viable computational cost. Using an idealised initial dataset with spatial gradients representative of those of real neuroblastomas, but small enough to be solved without any particularisation, we determined the approximation error and the computational cost of a very simple particularisation strategy based on binning. We found that even such simple algorithm can significantly reduce the computational cost with negligible approximation errors.

Experimental validation of a subject-specific finite element model of lumbar spine segment using digital image correlation.

Pathologies such as cancer metastasis and osteoporosis strongly affect the mechanical properties of the vertebral bone and increase the risk of fragility fractures. The prediction of the fracture risk with a patient-specific model, directly generated from the diagnostic images of the patient, could help the clinician in the choice of the correct therapy to follow. But before such models can be used to support any clinical decision, their credibility must be demonstrated through verification, validation, and uncertainty quantification. In this study we describe a procedure for the generation of such patient-specific finite element models and present a first validation of the kinematics of the spine segment. Quantitative computed tomography images of a cadaveric lumbar spine segment presenting vertebral metastatic lesions were used to generate the model. The applied boundary conditions replicated a specific experimental test where the spine segment was loaded in compression-flexion. Model predictions in terms of vertebral surface displacements were compared against the full-field experimental displacements measured with Digital Image Correlation. A good agreement was obtained from the local comparison between experimental data and simulation results (R2 > 0.9 and RMSE% <8%). In conclusion, this work demonstrates the possibility to apply the developed modelling pipeline to predict the displacement field of human spine segment under physiological loading conditions, which is a first fundamental step in the credibility assessment of these clinical decision-support technology.

Toward A Regulatory Pathway for the Use of in Silico Trials in the CE Marking of Medical Devices.

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing.

A theoretical analysis of the scale separation in a model to predict solid tumour growth.

Solid tumour growth depends on a host of factors which affect the cell life cycle and extracellular matrix vascularization that leads to a favourable environment. The whole solid tumour can either grow or wither in response to the action of the immune system and therapeutics. A personalised mathematical model of such behaviour must consider both the intra- and inter-cellular dynamics and the mechanics of the solid tumour and its microenvironment. However, such wide range of spatial and temporal scales can hardly be modelled in a single model, and require the so-called multiscale models, defined as orchestrations of single-scale component models, connected by relation models that transform the data for one scale to another. While multiscale models are becoming common, there is a well-established engineering approach to the definition of the scale separation, e.g., how the spatiotemporal continuum is split in the various component models. In most studies scale separation is defined as natural, linked to anatomical concepts such as organ, tissue, or cell; but these do not provide reliable definition of scales: for examples skeletal organs can be as large as 500 mm (femur), or as small as 3 mm (stapes). Here we apply a recently proposed scale-separation approach based on the actual experimental and computational limitations to a patient-specific model of the growth of neuroblastoma. The resulting multiscale model can be properly informed with the available experimental data and solved in a reasonable timeframe with the available computational resources.

Personalised 3D Assessment of Trochanteric Soft Tissues Improves HIP Fracture Classification Accuracy.

Passive soft tissues surrounding the trochanteric region attenuate fall impact forces and thereby control hip fracture risk. The degree of attenuation is related to Soft Tissue Thickness (STT). STT at the neutral hip impact orientation, estimated using a regression relation in body mass index (BMI), was previously shown to influence the current absolute risk of hip fracture (ARF0) and its fracture classification accuracy. The present study investigates whether fracture classification using ARF0 improves when STT is determined from the subject's Computed-Tomography (CT) scans (i.e. personalised) in an orientation-specific (i.e. 3D) manner. STT is calculated as the shortest distance along any impact orientation between a semi-automatically segmented femur surface and an automatically segmented soft tissue/air boundary. For any subject, STT along any of the 33 impact orientations analysed always exceeds the value estimated using BMI. Accuracy of fracture classification using ARF0 improves when using personalised 3D STT estimates (AUC = 0.87) instead of the BMI-based STT estimate (AUC = 0.85). The improvement is smaller (AUC = 0.86) when orientation-specificity of CT-based STT is suppressed and is nil when personalisation is suppressed instead. Thus, fracture classification using ARF0 improves when CT is used to personalise STT estimates and improves further when, in addition, the estimates are orientation specific.