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European funding under framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for nearly 2 years. The VPH network of excellence (NoE) is helping in the development of common standards, open-source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also helping to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by framework 6 strategy for a European physiome (STEP) project in 2006. It is now time to assess the accomplishments of the last 2 years and update the STEP vision for the VPH. We consider the biomedical science, healthcare and information and communications technology challenges facing the project and we propose the VPH Institute as a means of sustaining the vision of VPH beyond the time frame of the NoE.

Bone biomechanics have been extensively investigated in the past both with in vitro experiments and numerical models. In most cases either approach is chosen, without exploiting synergies. Both experiments and numerical models suffer from limitations relative to their accuracy and their respective fields of application. In vitro experiments can improve numerical models by: (i) preliminarily identifying the most relevant failure scenarios; (ii) improving the model identification with experimentally measured material properties; (iii) improving the model identification with accurately measured actual boundary conditions; and (iv) providing quantitative validation based on mechanical properties (strain, displacements) directly measured from physical specimens being tested in parallel with the modelling activity. Likewise, numerical models can improve in vitro experiments by: (i) identifying the most relevant loading configurations among a number of motor tasks that cannot be replicated in vitro; (ii) identifying acceptable simplifications for the in vitro simulation; (iii) optimizing the use of transducers to minimize errors and provide measurements at the most relevant locations; and (iv) exploring a variety of different conditions (material properties, interface, etc.) that would require enormous experimental effort. By reporting an example of successful investigation of the femur, we show how a combination of numerical modelling and controlled experiments within the same research team can be designed to create a virtuous circle where models are used to improve experiments, experiments are used to improve models and their combination synergistically provides more detailed and more reliable results than can be achieved with either approach singularly.

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.

The mechanical strength of human bones has often been investigated in the past. Bone failure is related to musculoskeletal loading, tissue properties, bone metabolism, etc. This is intrinsically a multiscale problem. However, organ-level performance in most cases is investigated as a separate problem, incorporating only part (if any) of the information available at a higher scale (body level) or at a lower one (tissue level, cell level). A multiscale approach is proposed, where models available at different levels are integrated. A middle-out strategy is taken: the main model to be investigated is at the organ level. The organ-level model incorporates as an input the outputs from the body-level (musculoskeletal loads), tissue-level (constitutive equations) and cell-level models (bone remodelling). In this paper, this approach is exemplified by a clinically relevant application: fractures of the proximal femur. We report how a finite-element model of the femur (organ level) becomes part of a multiscale model. A significant effort is related to model validation: a number of experiments were designed to quantify the model's sensitivity and accuracy. When possible, the clinical accuracy and the clinical impact of a model should be assessed. Whereas a large amount of information is available at all scales, only organ-level models are really mature in this perspective. More work is needed in the future to integrate all levels fully, while following a sound scientific method to assess the relevance and validity of such an integrated model.

Hardness of trabecular human bone, evaluated by microindentation testing, has generally been measured on embedded tissues. It was known that this was not ideal but it had been preferred to other conditions (e.g. wet or dehydrated) as the trabeculae could withstand the applied load and the measurements were reliable. The aim of this study was to investigate if the tissue condition of the specimen and the applied load would alter the hardness values measured by Vickers microindentation. Vickers hardness values of human trabecular bone from the femoral head, prepared in three different ways (wet, dry and embedded) and tested with two different loads (50 and 25 gf), were measured. No significant difference was found between the two different loads. However, in several cases the 50 gf indentations had to be redone because they were too large or the trabecula broke locally. Even if the outlines of the indentations on wet bone were slightly less marked than the ones done on dehydrated or embedded bone, it was possible to measure the hardness. Significant differences of Vickers hardness values were found between the three preparations: the hardness increased passing from wet to dried (10%) and from wet to embedded (35%). Whereas the variation coefficient of the three tissue conditions were comparable. In conclusion, it is recommended to test human trabecular bone in a wet condition as it better represents the in vivo condition. Furthermore the use of a 25 gf load is suggested, allowing hardness measurements on almost all trabeculae without breaking them.

Background: The number of in vivo clinical biomedical experiments based on computed tomography is increasing. International radiation-protection bodies are promoting the use of low-dose computed tomography to reduce radiation absorption by the subject undergoing imaging. On the other hand no data exist in the literature to quantify whether or not low-dose computed tomography would lead to a decrease of result quality when used for three-dimensional bone modeling and related measurements., Methods: This paper aimed at finding a consensus between minimal X-ray radiation of the subject, and satisfactory image data quality, especially for accurate three-dimensional bone modeling. Several standard computed tomography and low-dose computed tomography sequences were analyzed in three tests and statistically compared., Findings: Absence of significant difference between standard and low-dose computed sequences indicated that the low-dose setting would not produce less accurate three-dimensional models, while it decreased the effective X-ray dose up to 90% compared to standard settings., Interpretation: Low-dose computed tomography seems suitable for accurate three-dimensional bone modeling, while the related effective X-ray radiation is low. Such setting is therefore advised for any in vivo medical imaging aiming to collect bone data.

The aim of this study was to assess the accuracy of a six-degrees-of-freedom application for pre-operative planning of total hip replacement in a virtual reality (VR) environment. A test was performed estimating the system inherent accuracy. The users can move objects in the VR environment with an intrinsic accuracy almost four orders of magnitude greater than the object dimension. A second unambiguous and relevant task was defined to assess the accuracy achievable with the interface in a specific planning task. The results were compared with those obtained with 2D interfaces for both the stem and the cup component. The RMSE was assumed as an indicator of the achievable accuracy. The accuracy of the immersive interface was comparable with that achievable with a standard mouse - monitor interface. The users were consistent using the VR interface, confirming the high usability of the new interface and the steep learning curve of users unfamiliar with the new environment. This study has demonstrated that the application of VR environment for pre-operative planning of total hip replacement may help to shorten the duration of the positioning and to yield consistent results even with first-time users.