John Fenner

A vision and strategy for the virtual physiological human in 2010 and beyond

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.

The EuroPhysiome, STEP and a roadmap for the virtual physiological human.

Biomedical science and its allied disciplines are entering a new era in which computational methods and technologies are poised to play a prevalent role in supporting collaborative investigation of the human body. Within Europe, this has its focus in the virtual physiological human (VPH), which is an evolving entity that has emerged from the EuroPhysiome initiative and the strategy for the EuroPhysiome (STEP) consortium. The VPH is intended to be a solution to common infrastructure needs for physiome projects across the globe, providing a unifying architecture that facilitates integration and prediction, ultimately creating a framework capable of describing Homo sapiens in silico. The routine reliance of the biomedical industry, biomedical research and clinical practice on information technology (IT) highlights the importance of a tailor-made and robust IT infrastructure, but numerous challenges need to be addressed if the VPH is to become a mature technological reality. Appropriate investment will reap considerable rewards, since it is anticipated that the VPH will influence all sectors of society, with implications predominantly for improved healthcare, improved competitiveness in industry and greater understanding of (patho)physiological processes. This paper considers issues pertinent to the development of the VPH, highlighted by the work of the STEP consortium.

A vision and strategy for the virtual physiological human: 2012 update.

European funding under Framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for 5 years. The VPH Network of Excellence (NoE) has been set up to help develop common standards, open source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also working to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by the FP6 STEP project in 2006. In 2010, we wrote an assessment of the accomplishments of the first two years of the VPH in which we considered the biomedical science, healthcare and information and communications technology challenges facing the project (Hunter et al. 2010 Phil. Trans. R. Soc. A 368, 2595–2614 (doi:10.1098/rsta.2010.0048)). We proposed that a not-for-profit professional umbrella organization, the VPH Institute, should be established as a means of sustaining the VPH vision beyond the time-frame of the NoE. Here, we update and extend this assessment and in particular address the following issues raised in response to Hunter et al.: (i) a vision for the VPH updated in the light of progress made so far, (ii) biomedical science and healthcare challenges that the VPH initiative can address while also providing innovation opportunities for the European industry, and (iii) external changes needed in regulatory policy and business models to realize the full potential that the VPH has to offer to industry, clinics and society generally.

Shear Strength of Tissue Bonds as a Function of Bonding Temperature: a Proposed Mechanism for Laser-assisted Tissue Welding

The mechanism of laser bonding is not yet understood, but it is considered to be a thermal rather than a photochemical effect. The conditions required for successful anastomosis remain a controversial topic.In an alternative approach, in vitro tissue bonds were created over the temperature range 20–90°C without the use of a laser by approximating the tissue in a temperature controlled clamp. Bond integrity was assessed by measurement of breaking strength, and the effect of temperature and hydration on bond strength was examined.Bonds created under conditions of dehydration were significantly stronger than their hydrated counterparts. Temperature dependence was also observed, and bond strength significantly increased when temperatures exceeded the tissue denaturation temperature.As a result of these findings, a possible bonding mechanism is proposed.

The Virtual Physiological Human TOOLKIT

The Virtual Physiological Human (VPH) is a major European e-Science initiative intended to support the development of patient-specific computer models and their application in personalized and predictive healthcare. The VPH Network of Excellence (VPH-NoE) project is tasked with facilitating interaction between the various VPH projects and addressing issues of common concern. A key deliverable is the ‘VPH ToolKit’—a collection of tools, methodologies and services to support and enable VPH research, integrating and extending existing work across Europe towards greater interoperability and sustainability. Owing to the diverse nature of the field, a single monolithic ‘toolkit’ is incapable of addressing the needs of the VPH. Rather, the VPH ToolKit should be considered more as a ‘toolbox’ of relevant technologies, interacting around a common set of standards. The latter apply to the information used by tools, including any data and the VPH models themselves, and also to the naming and categorizing of entities and concepts involved. Furthermore, the technologies and methodologies available need to be widely disseminated, and relevant tools and services easily found by researchers. The VPH-NoE has thus created an online resource for the VPH community to meet this need. It consists of a database of tools, methods and services for VPH research, with a Web front-end. This has facilities for searching the database, for adding or updating entries, and for providing user feedback on entries. Anyone is welcome to contribute.

Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases.

Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging. The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P less than 0.05). The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.

INITIAL OBSERVATIONS USING A NOVEL “CINE” MAGNETIC RESONANCE IMAGING TECHNIQUE TO DETECT CHANGES IN ABDOMINAL MOTION CAUSED BY ENCAPSULATING PERITONEAL SCLEROSIS

Encapsulating peritoneal sclerosis (EPS) is an uncommon complication of peritoneal dialysis (PD), with high mortality and morbidity. The peritoneum thickens, dysfunctions, and forms a cocoon that progressively “strangulates” the small intestine, causing malnutrition, ischemia, and infarction. There is as yet no reliable noninvasive means of diagnosis, but recent developments in image analysis of cine magnetic resonance imaging for the recognition of adhesions offers a way forward. We used this protocol before surgery in 3 patients with suspected EPS. Image analysis revealed patterns of abdominal movement that were markedly different from the patterns in healthy volunteers. The volunteers showed marked movement throughout the abdomen; in contrast, movement in EPS patients was restricted to just below the diaphragm. This clear difference provides early “proof of principle” of the approach that we have developed.

Strength of tissue bonds as a function of surface apposition

Laser assisted vascular anastomoses have potential advantages over sutured anastomoses, but the mechanism of bonding is not understood. Current theories propose that the bonding process is primarily thermal, but recent work has implicated dehydration as an important factor. Bonds created by dehydration have shown similarities to argon laser bonds, but the wide range of scatter in bond strength warranted further investigation.This was addressed through creation of in vitro tissue bonds at 55°C. Following rehydration, bond integrity was evaluated by measurement of breaking strength. A progressive series of modifications was applied to bonding technique to investigate the effect of particular parameters on breaking strength. These included use of a microtome to cut smoother tissue faces, removal of inter-surface air gaps and varying the pressure applied to the bonding surfaces. Mean bond strength remained constant except when bonding under high pressure. Scatter in bond strength about the mean was markedly reduced by improving surface intimacy through removal of inter-surface air gaps.

Digital human modelling: a global vision and a european perspective

The Physiome is an umbrella term that refers to human modelling with mathematics and computational methods, accommodating cross-disciplinary science (chemistry, biology, physics) and a breadth of dimensional and temporal scale (sub-cellular to organs, sub-microsecond to tens-of-years). The Virtual Physiological Human is a European initiative that is intended to provide a unifying architecture for the integration and cooperation of multi-scale physiome models, thereby creating a predictive platform for the description of human beings in silico. Unlike the Genome, the challenge of the Physiome may be almost unbounded, as the desire for increased detail imposes a continuing pressure for ever-finer data granularity, and the necessary Information Technology (IT) infrastructure spawns innovations that surpass conventional solutions. It is foreseen that maturing physiome activities will increasingly influence medicine, biomedical research and commercial developments, and the central role of IT highlights the need for a specific and robust IT infrastructure. The European Commission has experience of supporting challenging technical endeavours through its Framework Programmes of research, and in the forthcoming 7th Framework Programme, it will invite researchers from within and outside Europe to unite in seeking solutions to key issues of the Physiome. The Virtual Physiological Human (VPH) investment programme will establish the necessary infrastructure and address the grand technical challenges identified by experts. This paper examines the background to the strategy and the ways in which the programmes structure has been determined.

Uncertainty assessment of imaging techniques for the 3D reconstruction of stent geometry

This paper presents a quantitative assessment of uncertainty for the 3D reconstruction of stents. This study investigates a CP stent (Numed, USA) used in congenital heart disease applications with a focus on the variance in measurements of stent geometry. The stent was mounted on a model of patient implantation site geometry, reconstructed from magnetic resonance images, and imaged using micro-computed tomography (CT), conventional CT, biplane fluoroscopy and optical stereo-photogrammetry. Image data were post-processed to retrieve the 3D stent geometry. Stent strut length, separation angle and cell asymmetry were derived and repeatability was assessed for each technique along with variation in relation to μCT data, assumed to represent the gold standard. The results demonstrate the performance of biplanar reconstruction methods is comparable with volumetric CT scans in evaluating 3D stent geometry. Uncertainty on the evaluation of strut length, separation angle and cell asymmetry using biplanar fluoroscopy is of the order ±0.2mm, 3° and 0.03, respectively. These results support the use of biplanar fluoroscopy for in vivo measurement of 3D stent geometry and provide quantitative assessment of uncertainty in the measurement of geometric parameters.