Towards a comprehensive biomechanical assessment of the elderly combining in vivo data and in silico methods.

The aging process is commonly accompanied by a general or specific loss of muscle mass, force and/or function that inevitably impact on a person's quality of life. To date, various clinical tests and assessments are routinely performed to evaluate the biomechanical status of an individual, to support and inform the clinical management and decision-making process (e.g., to design a tailored rehabilitation program). However, these assessments (e.g., gait analysis or strength measures on a dynamometer) are typically conducted independently from one another or at different time points, providing clinicians with valuable yet fragmented information. We hereby describe a comprehensive protocol that combines both in vivo measurements (maximal voluntary isometric contraction test, superimposed neuromuscular electrical stimulation, electromyography, gait analysis, magnetic resonance imaging, and clinical measures) and in silico methods (musculoskeletal modeling and simulations) to enable the full characterization of an individual from the biomechanical standpoint. The protocol, which requires approximately 4 h and 30 min to be completed in all its parts, was tested on twenty healthy young participants and five elderlies, as a proof of concept. The implemented data processing and elaboration procedures allowing for the extraction of several biomechanical parameters (including muscle volumes and cross-sectional areas, muscle activation and co-contraction levels) are thoroughly described to enable replication. The main parameters extracted are reported as mean and standard deviation across the two populations, to highlight the potential of the proposed approach and show some preliminary findings (which were in agreement with previous literature).

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.

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.

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.

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.

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

Throughout engineering there are problems where it is required to predict a quantity based on the measurement of another, but where the two quantities possess characteristic variations over vastly different ranges of time and space. Among the many challenges posed by such 'multiscale' problems, that of defining a 'scale' remains poorly addressed. This fundamental problem has led to much confusion in the field of biomedical engineering in particular. The present study proposes a definition of scale based on measurement limitations of existing instruments, available computational power, and on the ranges of time and space over which quantities of interest vary characteristically. The definition is used to construct a multiscale modelling methodology from start to finish, beginning with a description of the system (portion of reality of interest) and ending with an algorithmic orchestration of mathematical models at different scales within the system. The methodology is illustrated for a specific but well-researched problem. The concept of scale and the multiscale modelling approach introduced are shown to be easily adaptable to other closely related problems. Although out of the scope of this paper, we believe that the proposed methodology can be applied widely throughout engineering.

Are CT-Based Finite Element Model Predictions of Femoral Bone Strength Clinically Useful?

PURPOSE OF REVIEW: This study reviews the available literature to compare the accuracy of areal bone mineral density derived from dual X-ray absorptiometry (DXA-aBMD) and of subject-specific finite element models derived from quantitative computed tomography (QCT-SSFE) in predicting bone strength measured experimentally on cadaver bones, as well as their clinical accuracy both in terms of discrimination and prediction. Based on this information, some basic cost-effectiveness calculations are performed to explore the use of QCT-SSFE instead of DXA-aBMD in (a) clinical studies with femoral strength as endpoint, (b) predictor of the risk of hip fracture in low bone mass patients. RECENT FINDINGS: Recent improvements involving the use of smooth-boundary meshes, better anatomical referencing for proximal-only scans, multiple side-fall directions, and refined boundary conditions increase the predictive accuracy of QCT-SSFE. If these improvements are adopted, QCT-SSFE is always preferable over DXA-aBMD in clinical studies with femoral strength as the endpoint, while it is not yet cost-effective as a hip fracture risk predictor, although pathways that combine both QCT-SSFE and DXA-aBMD are promising.

In silico assessment of biomedical products: The conundrum of rare but not so rare events in two case studies.

In silico clinical trials, defined as "The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention," have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients' phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern.

Are spontaneous fractures possible? An example of clinical application for personalised, multiscale neuro-musculo-skeletal modelling.

Elderly frequently present variable degrees of osteopenia, sarcopenia, and neuromotor control degradation. Severely osteoporotic patients sometime fracture their femoral neck when falling. Is it possible that such fractures might occur without any fall, but rather spontaneously while the patient is performing normal movements such as level walking? The aim of this study was to verify if such spontaneous fractures are biomechanically possible, and in such case, which conditions of osteoporosis, sarcopenia, and neuromotor degradation could produce them. To the purpose, a probabilistic multiscale body-organ model validated against controlled experiments was used to predict the risk of spontaneous fractures in a population of 80-years old women, with normal weight and musculoskeletal anatomy, and variable degree of osteopenia, sarcopenia, and neuromotor control degradation. A multi-body inverse dynamics sub-model, coupled to a probabilistic neuromuscular sub-model, and to a femur finite element sub-model, formed the multiscale model, which was run within a Monte Carlo stochastic scheme, where the various parameters were varied randomly according to well defined distributions. The model predicted that neither extreme osteoporosis, nor extreme neuromotor degradation alone are sufficient to predict spontaneous fractures. However, when the two factors are combined an incidence of 0.4% of spontaneous fractures is predicted for the simulated population, which is consistent with clinical reports. When the model represented only severely osteoporotic patients, the incidence of spontaneous fractures increased to 29%. Thus, is biomechanically possible that spontaneous femoral neck fractures occur during level walking, due to a combination of severe osteoporosis and severe neuromotor degradation.

Assessing biocomputational modelling in transforming clinical guidelines for osteoporosis management.

Biocomputational modelling as developed by the European Virtual Physiological Human (VPH) Initiative is the area of ICT most likely to revolutionise in the longer term the practice of medicine. Using the example of osteoporosis management, a socio-economic assessment framework is presented that captures how the transformation of clinical guidelines through VPH models can be evaluated. Applied to the Osteoporotic Virtual Physiological Human Project, a consequent benefit-cost analysis delivers promising results, both methodologically and substantially.

Policy needs and options for a common approach towards modelling and simulation of human physiology and diseases with a focus on the virtual physiological human.

Life is the result of an intricate systemic interaction between many processes occurring at radically different spatial and temporal scales. Every day, worldwide biomedical research and clinical practice produce a huge amount of information on such processes. However, this information being highly fragmented, its integration is largely left to the human actors who find this task increasingly and ever more demanding in a context where the information available continues to increase exponentially. Investments in the Virtual Physiological Human (VPH) research are largely motivated by the need for integration in healthcare. As all health information becomes digital, the complexity of health care will continue to evolve, translating into an ever increasing pressure which will result from a growing demand in parallel to limited budgets. Hence, the best way to achieve the dream of personalised, preventive, and participative medicine at sustainable costs will be through the integration of all available data, information and knowledge.

Re-use of explanted osteosynthesis devices: a reliable and inexpensive reprocessing protocol.

INTRODUCTION: Orthopaedic surgical treatments emphasizing immobilization using open reduction and internal fixation with osteosynthesis devices are widely accepted for their efficacy in treating complex fractures and reducing permanent musculoskeletal deformity. However, such treatments are profoundly underutilized in low- and middle-income countries (LMIC), partially due to inadequate availability of the costly osteosynthesis devices. Orthopaedic surgeons in some LMIC regularly re-use osteosynthesis devices in an effort to meet treatment demands, even though such devices typically are regulated for single-use only. The purpose of this study is to report a reprocessing protocol applied to explanted osteosynthesis devices obtained at a leading trauma care hospital. METHODS: Explanted osteosynthesis devices were identified through a Register of Explanted Orthopaedic Prostheses. Guidelines to handle ethical issues were approved by the local Ethical Committee and informed patient consent was obtained at the time of explant surgery. Primary acceptance criteria were established and applied to osteosynthesis devices explanted between 2005 and 2008. A rigorous protocol for conducting decontamination and visual inspection based on specific screening criteria was implemented using simple equipment that is readily available in LMIC. RESULTS: A total of 2050 osteosynthesis devices, including a large variety of plates, screws and staples, were reprocessed using the decontamination and inspection protocols. The acceptance rate was 66%. Estimated labour time and implementation time of the protocol to reprocess a typical osteosynthesis unit (1 plate and 5 screws) was 25 min, with an estimated fixed cost (in Italy) of €10 per unit for implementing the protocol, plus an additional €5 for final sterilization at the end-user hospital site. DISCUSSION: This study was motivated by the treatment demands encountered by orthopaedic surgeons providing medical treatment in several different LMIC and their need for access to basic osteosynthesis devices. The rigorous decontamination protocol and generalized inspection criteria proved useful for efficiently screening a large volume of devices. Given that re-used osteosynthesis devices can yield satisfactory results, this study addresses potential complications of re-used devices and valid concerns that relate to patient safety. Implementing this defined reprocessing protocol into existing re-use practises in LMIC helps to limit the risks of inadequate sterilization and structural failure without adding additional risks to patients receiving re-used devices.

Assessment of femoral neck fracture risk for a novel proximal epiphyseal hip prosthesis.

BACKGROUND: This study addresses the risk of femoral neck fracture associated with resurfacing hip prostheses. A novel cemented Proximal Epiphyseal Replacement (PER) featuring a short curved stem was investigated. METHODS: Seven pairs of femurs were in vitro tested. One femur of each pair was randomly assigned for PER implantation. The contralateral femur was tested intact. All femurs were loaded to failure in a validated, physiological configuration. High-speed videos (10,000-12,000 frames/s) were acquired to identify the location of fracture initiation. For comparison, data were included from Birmingham Hip Resurfacing previously tested in an identical fashion (N=3). FINDINGS: Relative to the contralateral intact femurs, the failure load of the PER and Birmingham implants was 15.4% higher and 10.0% lower, respectively. In six of the seven PER implants, fracture initiation (neck or inter-trochanteric) was similar to the contralateral intact femurs, suggesting comparable stress distribution. Conversely, fracture initiation in the Birmingham implants occurred at the lateral prosthesis rim, which differed substantially from the intact femurs. No correlation existed between bone quality and strengthening/weakening effect of the PER (failure load of implant as a percentage of intact: R^2=0.067). Conversely, Birmingham implantation weakened the femurs with lower density (R^2=0.92). Therefore, unlike most resurfacing prostheses, the PER seems suitable also for osteoporotic subjects. INTERPRETATION: This study seems to confirm that resurfacing with a Birmingham Hip tends to reduce the strength of the proximal femur. The opposite seemed to happen with the PER, which slightly reduced the risk of neck fracture, also in low-quality bones.

Multimodal fusion of biomedical data at different temporal and dimensional scales.

The introduction of integrative approaches to biomedical research (integrative biology, physiome, Virtual Physiological Human, etc.) poses original problems to computer aided medicine: the need to operate with large amounts of data that are strongly heterogeneous in structure, format and even in the knowledge domain that generated them; the need to integrate all of these data into a coherent whole; the further complication imposed by the fact that more and more frequently these data are captured at very different dimensional and/or temporal scales. The present study describes a first attempt at providing an interactive visualisation environment for homogeneous biomedical data defined over radically different spatial or temporal scales. In particular, we describe new strategies for the management of the dimensional information of highly heterogeneous data types; the management of temporal multiscaling; for 3D unstructured spatial multiscale visualisation and the related interaction paradigms and user interface. Preliminary results with a prototype implementation based on the OpenMAF application framework (http://www.openmaf.org) indicate that it is possible to develop effective environments for interactive visualisation of multiscale biomedical data.

Designing a socio-economic assessment method for integrative biomedical research: the Osteoporotic Virtual Physiological Human project.

In integrative biomedical research, methods assessing the clinical or even socio-economic impact of more complex technologies such as Information and Communication Technology (ICT)-based tools for modelling and simulation of human physiology have rarely been applied. The EU funded Osteoporotic Virtual Physiological Human (VPHOP) research project, part of the Virtual Physiological Human (VPH) European initiative, will create a patient-specific hypermodel to predict the absolute risk of bone fracture much more accurately than predictions based on current clinical practice. The project has developed an innovative, multilevel generic methodological framework to assess the clinical and socio-economic impact of biocomputational models. The assessment framework consists of three components: a socio-economic cost benefit analysis, health economic analysis of care pathways, and disease cost simulation models. Through its holistic perspective, the method provides a tool to appraise the overall value of biocomputational models for society.

A new method of in vitro wear assessment of the UHMWPE tibial insert in total knee replacement.

The wear of the ultra-high-molecular-weight polyethylene (UHMWPE) tibial insert was determined using a four-station knee simulator. The bearings were subjected to flexion/extension (between 0 and 58 degrees ), anterior-posterior translation (between 0 and -5.2 mm), internal-external rotation (between -1.9 degrees and +5.7 degrees ), and a maximum axial load of 2.6 KN, as per ISO 14243-1,2,3. The wear tests were run at a frequency of 1.1 Hz for 5 million cycles, and the wear of the inserts (n = 3) was determined using the gravimetric method. The novelty of the study was a special setup developed to simulate, as realistically as possible, in vivo conditions; this involved fixing the femoral component to the distal end of a synthetic femur model by a qualified orthopedic surgeon using an approved method. After 5 million cycles, the mean weight losses were 11.16, 19.74, and 12.61 mg for specimens #1, #2, and #3, respectively. Visual and nondestructive inspections for each of the test specimens showed similar wear tracks and these were very similar to those seen on inserts retrieved after 2 years in vivo. These results show the efficacy of the new in vitro UHMWPE wear assessment method. Furthermore, a comparison between the present in vitro results and those reported in a relevant previous study provide some insight into the influence of the method used to fix the femoral component to the simulator on the wear magnitude and patterns of the tibial insert.

Primary stability of an anatomical cementless hip stem: a statistical analysis.

The primary stability that the surgeon can achieve during surgery is a determinant of the clinical success of cementless implants. Thus, estimating what level of primary stability can be obtained with a new design is an important aspect of pre-clinical evaluation. The primary stability of a cementless hip stem is not only affected by the implant design, but also by other factors such as the mechanical quality of the host bone, the presence of gaps around the bone-implant interface, the body weight of the patient, and the size of the implant. Even the most extensive experimental study can only explore a small sub-set of all possible combinations found in vivo. To overcome this limitation, we propose a combination of experimental and numerical methods. The primary stability of a cementless anatomical stem is assessed in vitro. A finite element model is developed to accurately replicate the same experiment. The model is then parameterised over the various factors that affect the primary stability, and used in a Monte Carlo scheme to assess the primary stability over a simulated population. In this study, the method was used to investigate the mechanical stability of an anatomical cementless stem over more than 1000 simulated cases. Twenty cases were found macroscopically unstable, due to a combination of unfavourable conditions. The rest of the Monte Carlo sample showed on average a peak micromotion under stair climbing loading of 206 +/- 159 microm. The proposed method can be used to evaluate new designs in conditions more representative of the variability in clinical practice.