INSIGNEO NEWS | ISSUE 2 | SPRING 2016 1 CLINICAL TRANSLATION PROJECT NEWS EVENTS ROUNDUP

Spring 2016

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CONTENTS AND WELCOME

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The Pam Liversidge Building Sir Frederick Mappin Building

Mappin Street Sheffield

S1 3JD

+44 (0) 114 222 0162 /5 /7 info@insigneo.org www.insigneo.org

@insigneo

Cover: Simulation of walking using a

subject specific musculoskeletal model.

Experimental markers used in motion capture

are represented as red spheres. Muscles are

coloured blue or red depending on their level

of activation (blue: inactive, red: active)

Luca Modenese, Research Associate and

Daniele Ascani, Phd Student, Insigneo Institute

Welcome

Contents Inside this issue

Let’s make a difference

The Insigneo vision statement reads: “INSIGNEO will realise the scientific ambition behind the Virtual Physiological Human, producing a transformational impact on healthcare”. Four years after the birth of Insigneo, I think we can safely say that the first part of this statement is well on its way to being realised. Insigneo members are working in dozens of research projects where the VPH vision is being turned into reality. So I guess it is time that we focus our attention on the second part: producing a transformational impact on healthcare. How do we do this?

The present of Insigneo is with our users: clinical researchers, hospitals and the biomedical industry. The future of Insigneo is with our students, those who will take our place in a few years, and the changes the world is undergoing, which will characterise the type of environment they will have to work in.

To address the present, in the next 12 months, Insigneo will increase its engagement with clinical researchers interested in developing clinically driven research projects that target precise unmet clinical needs; this is something that we already do, but from now on we will do so more systematically, framing our commitment into an offer for collaboration that we hope many clinical researchers will

find hard to resist. We are also expanding our industrial partnerships, and we hope the birth of the Avicenna Alliance, around the theme of in silico clinical trials, will provide a significant opportunity for industrial collaboration with our Institute.

To address the future, we have started to develop the Insigneo Graduate Programme. A masters degree in engineering with biomechanics will be starting this September and in the near future we plan to add a masters in computational medicine, and a masters in bioengineering with a special focus on mechanobiology.

The final element is dear to my heart: one regret I have always had is that VPH technologies are too frequently reserved for meeting the needs of rich countries. The recent announcement of the UK’s £1.5 billion Global Challenges Fund will create an opportunity for all of us to rethink this issue, and look at how technology can improve the health of less developed countries. It is a brave new world, and we are ready for it.

Professor Marco Viceconti Executive Director Insigneo Institute for in silico Medicine May 2016

04 Exchanges and Events

06 Find out more about our Researchers

08 Partnerships and Awards

10 Projects

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EXCHANGES AND EVENTS

University of Kyoto and Insigneo collaborate together

Newton Research Collaboration Programme

The Newton Research Collaboration Programme is a part of the UK Newton Fund allocated by the Royal Academy of Engineering. This fund aims to develop science and innovation partnerships to promote the economic and social welfare of developing countries. A popular way to start these partnerships is through international

exchanges; in practice this means either running a collaborative research project and/or taking residence as a visiting researcher at the partner organisation for a period of three months to a year.

Three researchers* from Insigneo have been funded by the Newton Programme to work on a collaborative project that is investigating the role of haemodynamics in complications that occur after endovascular treatment of intracranial aneurysms. The team consists of a Neuroradiologist from France, and lecturers from Brazil and Argentina. This group of academic staff is working in collaboration with BALT EXTRUSION, a leading manufacturer of flow diverting stents, commonly used to treat intracranial aneurysms.

Dr Marzo (PI) summing up the scientific purpose of the project explained “Patients suffering from cerebral aneurysms (abnormal bulging of a blood vessel) are treated with a

procedure (stenting) that sometimes leads to the dangerous occlusion of the surrounding arteries. We think this might be related to the way blood flows in vessels of a certain anatomy or geometry. We can use our computer models to mimic blood flow in arteries and through stents, and investigate our hypothesis.”

The team has spent two months in Brazil at the Federal University of ABC in Sao Paulo and hopes this will be the basis of further multi-disciplinary collaboration, supporting knowledge transfer and continuous development of computational tools. Researchers from Brazil have visited Sheffield as well as a part of this collaboration.

*Dr Cecile Perrault, Dr Alberto Marzo and Dr Paul Watton

There are plenty of opportunities to participate in social and fund raising events throughout the year. Pictured on this page is our very own version of ‘Bake Off’ (1), and Insigneo winning 3rd place at a corporate active challenge (2).

3. Our researchers actively participate in a number of national research networks. This year we hosted the 2nd Multiscale Biology Network meeting. The Network is a platform to discuss multiscale phenomena in biological systems.

4. Many of our events are held at the prestigious Mappin Hall, University of Sheffield. Pictured here is the N8 Research Networking Group event attended by guest speakers from Imperial College London, NUI Galway and the University of Manchester. The N8 group is a partnership of the eight most research-intensive universities in the north of England.

5. Researchers and post-docs brainstorm at the 2015 MultiSim Modelathon competition. The Modelathon involves working in groups to solve a multiscale modelling challenge and then presenting results in front of a panel of academic and industry experts. To register and find out more about the next Modelathon visit: multisim-insigneo.org/modelathon/

We are participating in a three month student exchange with the Institute for Frontier Medical Sciences at Kyoto University. Under reciprocal arrangements, Kyoto University will send a PhD student to Insigneo over the summer of 2016.

The exchange in Kyoto will be based in a biomechanics lab led by Professor Taiji Adachi. The cutting-edge laboratory specialises in mechanotransduction using a

multiscale approach and owns advanced atomic force microscopy (AFM) equipment.

As a part of this exchange Stefania Marcotti, a PhD student, will be working under the supervision of Professor Adachi and will utilise the excellent AFM facilities during her stay. This collaboration aims to offer an opportunity to share expertise in the understanding of mechanotransduction at different dimensional scales.

EventsOut and about with Insigneo

Global ExchangesFind out more about our collaborative research projects in Brazil and Japan

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FIND OUT MORE ABOUT OUR RESEARCHERS

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I have a keen interest in software engineering, modelling and simulation of biological systems. I feel my PhD at Insigneo gave an ideal opportunity to study these areas in depth.

I found Insigneo’s multidisciplinary approach to learning fitted in well with the field of in silico modelling. The education and training facilities to support PhD students, particularly the doctoral training program, scientific seminars and technical workshops provided a perfect platform for me to improve my knowledge and expand my skills.

Interestingly, my current role is very closely related to my area of research. As a Research Scientist my role is to develop safety pharmacology algorithms and approaches for our company’s Simcyp’s Cardiac Safety Simulator (Simcyp-CSS), this product is used in early assessment of a drug’s cardiac side effects.

The system is a biology-driven, modelling and simulation based platform for the assessment of the pro-arrhythmic potency of drugs, new chemical entities, and other xenobiotics within the targeted clinical population. The CSS platform can inform decision making at every stage of drug development. In pre-clinical development, it brings together quantitative structure activity relationship (QSAR) and in vitro physiological measurements, generating early information on cardiac safety without incurring additional cost. During clinical development, in vivo data can be combined with CSS to enable a more robust assessment of cardiac risk with focus on the impact of population variability.

The Simcyp simulator is used by all of the top 10 global pharmaceutical companies, together with the US Food and Drug Administration (FDA) and other key regulatory agencies

for assisting in dose selection and informing product labelling.

I found my experience at the Insigneo Institute to be of a world class standard that challenged me to my full potential. My PhD has been crucial in providing me with skills and a strong theoretical knowledge to carry out my current role with confidence.

Working collaboratively on a frequent basis is a key element in my role. At Insigneo researchers are divided into groups that work collaboratively together to find a solution to a real life problem. I found this engagement with people outside my immediate area of research particularly interesting. Besides providing practical team working skills it allowed me to broaden my horizons and look at the bigger picture of in silico medical research as a whole. I have found the modelling techniques I learnt during my PhD have really helped in my current role.

Three 6 month bursaries have been awarded in the 4th call for the Insigneo bursary for Clinical Translation. Each bursary is headed by one clinical and one non-clinical Insigneo member. The funding for the bursaries is provided

by the Sheffield Hospitals Charity and the ultimate scope of the bursaries is to improve our ability to translate the results of our technological research into clinical practice.

This year’s winners are: Dr John Fenner and Dr Helen Griffiths; Dr Alberto Marzo and Dr Timothy Ellam; Dr Claudia Mazzà and Dr Krishnan PS Nair.

As the first in silico medicine technologies enter clinical practice, top class health providers all over the world are starting to recruit engineers with in silico technology skills. There is also a growing demand for engineers in the biomedical industry, start-ups and in companies that use in silico technology for the design and assessment of their products such as sportswear, law-enforcement vests, workplace ergonomics, and vehicle safety.

To give a taste of what it would be like to work in this niche area we have selected some of Sheffield’s best 2nd and 3rd year undergraduates on mechanical and bioengineering programmes and paired them up with post-doctoral researchers and PhD students at our Institute.

Students will be trained on specific software tools used in data processing and multiscale modelling. Once trained, they will process data for some

of our research projects during a ten week summer placement. We hope that the practical skills gained on this placement provide a strong starting point for anyone interested in a career in this speciality.

Where are they now?Mitra Abbasi graduated with a PhD in 2015 and now works in a research-based company that provides modelling and simulation software to the pharmaceutical industry

Sheffield Hospital Charities sponsors bursaries for Clinical Translation

Insigneo Student Placement Programme

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PARTNERSHIPS AND AWARDS

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Professor Wendy Tindale, Scientific Director of Medical Imaging & Medical Physics at Sheffield Teaching Hospitals NHS Foundation Trust and founding member of Insigneo’s Board, has contributed to the development of many clinical science innovations that have improved frontline care during her career. Professor Tindale, who has an OBE for Services to Healthcare, is also the Clinical Director of the National Institute of Health Research Devices for Dignity Healthcare Technology Co-operative, which focuses on harnessing technology to improve patient dignity.

She received the accolade at the 2016 Chief Scientific Officer’s Awards in London. It recognises her as an exceptional individual, who has used her skills and scientific ability for maximum patient and service benefit, engaged and collaborated with wider professional groups and demonstrated the broad contribution that scientists make to the NHS.

She said: “I am delighted and humbled to receive this award, which is really for the great teams of healthcare scientists and other professionals that I have had the fortune to work with over many years.

Operating at the forefront of science and innovation, their skills and expertise make such an important contribution to high quality patient care.”

Through her work with Devices for Dignity, she has been at the forefront of developing technology to help people with long term illnesses or disabilities manage their conditions with dignity and independence.

Most recently, Devices for Dignity has collaborated with other teams to successfully develop a novel, supportive neck collar for people with Motor Neurone Disease and a digital bladder diary to help people with urinary incontinence manage their condition.

As a Board member of Insigneo and one of the first group of Insigneo Fellows to be announced, Professor Tindale sees her role in the Institute as bridging the gap between the needs of the NHS and the solutions that computational modelling can offer. Making the right connections, highlighting opportunities for new applications of engineering in medicine and providing constructive challenge are all part of what she brings to the role, from the perspective of a practising healthcare scientist.

During her career she has also worked on projects including the design of artificial heart valves, where she gained her Doctorate degree, and the development of new scanning techniques for medical imaging. She led a successful bid, announced in January, for the Sheffield City Region to be recognised as a national ‘Test Bed’ for trialling new technologies to help patients to self-care. She has extensive experience in frontline patient care as well as healthcare innovation, and has successfully translated research findings into patient benefits. She has contributed to numerous national and international committees and published widely in scientific literature.

After several years of effective technical collaborations, Dassault Systèmes SIMULIA (“SIMULIA”) and the Insigneo Institute for in silico Medicine have established a pioneering partnership for biomedical engineering with a mission of transforming healthcare through the use of realistic simulation and advanced visualisation.

The partnership was formalised by the signing of a memorandum of understanding and is the natural result of the increasingly significant collaboration between Insigneo and SIMULIA to boost joint academic research and provide students with practical experience of the commercial translation of their academic work. SIMULIA has been a valuable partner of Insigneo since its inception in 2012, providing a high level of technical input, supporting key educational events, and furthering complex research and development.

Signing the agreement on behalf of SIMULIA, Steve Levine, Senior Director of Virtual Human Modeling (VHM) commented “This was a natural next step for us, as evidenced by the tremendous success of our collaboration on the MySpine project on patient-specific simulations of the lumbar spine, there are obvious

synergies between our organisations. We have shown through the Living Heart Project and related virtual human modeling initiatives, our commitment to driving innovation, accelerating the pace of translational science, and enabling entrepreneurs through the 3DEXPERIENCE Lab, we are very much aligned with Insigneo’s strategic objectives. Together we have the expertise and necessary ingredients to lead a transformation in the healthcare industry.”

Stressing the vital importance of industrial collaboration, Insigneo’s Director of Research, Professor Damien Lacroix, warmly welcomed the strengthening of this partnership, heralding a new phase in the translation of in silico medicine into mainstream clinical practice. Professor Lacroix said, “As researchers we strive to develop the best possible engineering tools for diagnosis, treatment and prognostic improvement in clinical disease. With SIMULIA we are ensuring that professional software can be effectively and safely deployed in clinic, helping to demonstrate how in silico technologies can bring benefit to clinicians and patients alike.”

Our strategic partnership with simulation world leader

Insigneo Board member named Healthcare Scientist of the YearProfessor Wendy Tindale, a Sheffield scientist who joined the NHS as an 18-year-old junior technologist has been named as the national Healthcare Scientist of the Year

Professor Wendy Tindale (centre) with Professor Sue Hill (NHS Chief Scientific Officer for England) and Dave West (of sponsors Health Service Journal)

“The partnership was formalised by the signing of a memorandum of understanding and is the natural result of the increasingly significant collaboration between Insigneo and SIMULIA to boost joint academic research and provide students with practical experience of the commercial translation of their academic work.”

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PROJECTS

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Avicenna (980-1037), was a Persian physician and philosopher who first gave a formal structure to the process of evaluating the effect of a treatment on a disease. He introduced systematic experimentation and quantification of the study of physiology and the introduction of experimental medicine, clinical trials, randomised controlled trials and efficacy tests. The fundamental nature of clinical trials has changed surprisingly little since then and the need for long and complex experiments in vitro, on animals, and then on people and patients during clinical trials pushes development costs to unsustainable levels. The beginning of the 21st century, however, saw the birth of in silico medicine, a new way to investigate living organisms and the diagnosis, treatment, or prevention of disease through modelling, simulation and visualisation of biological and medical processes using computer simulations. In silico Clinical Trials (ISCTs) are “the use of individualised computer simulation in the development or regulatory evaluation of a medicinal product, medical device or medical intervention”. Supplementing clinical trials with ISCTs could result in

faster, cheaper and better trials, both in animals and humans.

The Avicenna Project

The European Commission (EC) funded the Avicenna Support Action to develop a ‘roadmap’ describing the route by which ISCTs will be introduced into clinical trials. This Roadmap - “In silico Clinical Trials: How Computer Simulation will transform the Biomedical Industry” was published in January 2016.

What does the Roadmap say?

The roadmap provides an in-depth analysis of the research and technological development challenges that need to be overcome in order to have wider and more effective adoption of in silico technologies in the development of biomedical products. It proposes that industrial and academic stakeholders explore the formation of a pre-competitive alliance to coordinate and implement public and privately funded research on this topic. It also proposes that regulatory bodies across the world embrace innovation and, in collaboration with academic

and industrial experts, develop the framework of standards, protocols and shared resources required to evaluate the safety and the efficacy of biomedical products using ISCT.

The Roadmap can be downloaded at: avicenna-isct.org/roadmap/

The future – The Avicenna Alliance

Turning these ideas into a reality becomes the task of the newly created “Avicenna Alliance – Association for Predictive Medicine” - industry and research organisations who have a commercial or research interest in in silico medicine and seek to put the Avicenna roadmap into policy and ensure the development of a regulated in silico market. The Alliance bridges the gap between the scientific community, industry and policy makers by advocating for policy changes that take into account scientific and market developments. Its

association with the Virtual Physiological Human Institute, which has recently been appointed to the eHealth Stakeholder Group of the EC, provides the Alliance access to a key influential group in Brussels.

It will offer a central resource of experts to work with regulators, commissioners and politicians to establish computer modelling and simulation as core technology in 21st century medical and surgical practice. The Alliance can be accessed at avicenna-alliance.com/

A new collaboration: Avicenna Alliance, the Association for Predictive MedicineEnhanced knowledge, improved decisions, better outcomes

Insigneo: Quo Vadis?An introduction to principles, projects, progress and plans

One day, the map could be the territory

In silico - computational - medicine is the use of computer simulation in the prevention, diagnosis, prognostic assessment and treatment of disease. Although arguably this concept embraces the overall analysis of the NHS, the work done in the Insigneo Institute focuses on the modelling of physiology, and seeks ultimately to build a series of interconnecting simulations that represent the entirety of bodily processes, in sickness and health. The target species is human, but the modelling of animal physiology has a part to play.

Start Me Up

Modelling can refer to any conceptual representation of reality, and therefore has been the essence of medical practice for all history. Though the term in silico, indicating the use of computers, was introduced only in 1989, the practical use of computer modelling in medicine probably began in the 1960s, and certainly includes the pioneering work in cardiac electrophysiology conducted by perhaps the founding father of the in silico movement, Professor Denis Noble, who today still remains active in his Oxford laboratory.

Early 3D

By the 1970s, engineers in the aerospace, nuclear and automotive industries, already familiar with sophisticated 3D computer modelling techniques - finite element analysis and computational fluid dynamics - were considering whether those approaches could usefully be applied to medicine, and isolated pockets of research grew up across the world, with collaborative groups of engineers and clinicians exploring the possibilities. Inevitably, results were primitive, as the meagre computational resources struggled with the size of the problems.

Funding

The largest obstacle to early progress was the difficulty in identifying funding sources. Crossover activities between engineering and medicine are notoriously complex because of traditional divisions in funding targets, and the largest contribution to progress came from the European Commission. As a result of a long but sympathetic process of discussions

the 7th Framework Programme for Research included around €220M€ for in silico medicine, under the heading Virtual Physiological Human. This giant, big-picture approach to what has become an entire new discipline, is firmly established in silico activities as of mainstream importance. In the next section we look at the developmental story behind Insigneo’s key research foci, in the musculoskeletal and cardiovascular domains.

Building on isolated pioneering work in the 1990s, in the early 2000s the musculoskeletal community, with an emphasis on the Istituto Ortopedico Rizzoli in Bologna, started to work seriously on the problem of multiscale modelling and computation which had come to dominate the research area.

Initial work

In a series of projects from 2002 onwards, work began recognising the multiscale nature of the problem, and the need to cope with data from multiple sources. The engineering team in Bologna established that an approach focused on the development of comprehensive reusable computational tools would be key to future success, and so began a dedicated effort that has driven the success of several large, important projects described below. Key members of the Bologna team relocated to Insigneo in 2012.

VPH-OP

There are nearly four million osteoporotic bone fractures per year that cost the European health system more than 30 billion Euro annually, and this figure could double by 2050. After the first fracture, the chances of having another one increase by 86%, so prevention is necessary.

The first step in reducing recurrent fractures is identifying an accurate predictor for patient-specific risk that considers both the skeletal determinants and the neuromuscular condition. For this VPH-OP developed a multiscale modelling technology based on conventional diagnostic imaging methods that makes it possible, in a clinical setting, to predict for each patient the strength of their

bones, how this strength is likely to change over time, and the probability that they could overload their bones during daily life. With these three predictions, the evaluation of the absolute risk of bone fracture is much more accurate than any prediction based on external and indirect determinants, as it is in current clinical practice.

MySpine

Treatment and prognosis of spinal disc degeneration are still based on trial and error clinical decisions from the surgeon leading to numerous post treatment complications and eventual morbidity. MySpine developed a rational engineering approach based on advanced ICT and patient-specific predictive systems. In silico virtual assessment of the evolution of treatments for patient-specific lumbar spine geometries, tissue properties, and loading histories is the cornerstone of such predictive system.

The predictive system consists of a set of specialised computing platforms, including a geometrical and mechanical patient-specific model and, based on the analysis of each integrated biomechanical and mechanobiological model, results are

evaluated probabilistically, helping clinicians to assess safely the risks and benefits of each simulated treatment. The project has had a significant impact on eHealth by bringing a new engineering rationale into the clinical decision process.

MultiSim

The vision of the MultiSim programme is to develop a modelling framework focused on the human musculoskeletal system but designed as a generic platform to address other engineering challenges that involve multiscale modelling, unobservable states and variables, and uncertainty. The work is creating a new generation of predictive models capable of handling complex multiscale and multiphysics problems, characterised by uncertain and incomplete information, and these radically new approaches will be applied to modelling the musculoskeletal system by integrating all interactions across space-time from the cellular scale up to the whole organism scale, individualised to each patient.

The need for MultiSim’s platform for the management of musculoskeletal disorders is essential considering that total healthcare expenditure in the UK has doubled between 2000-2010 to a staggering 10% of GDP. During this period about half of the annual cost increase has been attributed to the use of new technologies or the intensified use of old ones, such as CT scans. To control the spiralling cost, models are required to pre-assess patient specific diagnosis and treatment procedures, to predict the benefits, quality of life improvement and costs; in brief, to aid decision making for the individual patient.

Multi-Scale, Multi-Science Modelling

Most physiological processes are inherently multiscale. Increasingly we represent not only physics processes but also chemistry and biology. The concept of hypermodelling - the combination of many sub-models - is now being adopted in the musculoskeletal sector. Fundamental work is needed to formalise the description of interactions, scale-dependent coupling and uncertainty propagation.

Many clinical decision processes require information in timescales incompatible with the operation of sophisticated models, which sometimes run for weeks. There is a great need for advances in reduced-order modelling techniques to support clinical applications. Where these depend on pre-computed solutions, we need more effective strategies for solution-space sampling and model execution.

Parameters and personalisation

All models, whether single or multiscale, include parameters (coefficients in constitutive equations, the impedance of a distal vasculature, etc.) and central to the effective utilisation of models in diagnosis and the personalisation of interventions is the tuning of the parameters to represent the individual. Progress is required in the interpretation of the wider heterogeneous data available from the clinical record, and from electively-worn devices.

The physiological envelope

An important, and currently under-appreciated and under-utilised, element of analysis is the need to represent the physiological envelope, so the model is able to describe the individual not only under conditions that might be measured in clinic, but also as they live their lives. This ‘service envelope’ has not yet been adequately explored in the context of patient-specific modelling.

For further information on any of the information above, please contact info@insigneo.org

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With mostly EC support and a systematic approach, the group that is now Insigneo’s core cardiovascular team developed an accelerating series of computational innovations.

1999 Bloodsim introduced fluid/solid interactions

2000 SimBio developed libraries of re-usable tools

2001 COPHIT extended models to include the pulmonary system and airways

2002 SupMes tackled the issue of vessel movement, now being elaborated for Adhesions detection (2006)

2002 GEMSS demonstrated migration of tools to the supercomputing GRID environment

2004 Epitheliome demonstrated agent-based modelling for cell interaction description

2005 C-Cares applied bond-graph methods permitting organ level models to be represented at system-level

2006 @neurIST developed a potentially multi million euro-saving approach to cerebral aneurysm assessment

2006 COAST began the process of multiscale representation in cardiovascular applications

2008 EPSRC ‘Grand challenge’: A comprehensive state-of-the-art approach to cardiac synchronisation

2008 ARCH, a dramatically translational project to improve patient’s practical treatment experience

2008 euHeart, State-of-the-art cardiac/ cardiovascular modelling with balanced development/translation

2010 VPH-Share, the provision of a community- level data computation/model system in the Cloud

2013 Angiogram IAYN, a 100-patient trial of a close-to-clinic coronary artery intervention assessment tool

2016 EurValve, ultimate integration of modelling, machine learning, data interpretation for decision support

Musculoskeletal Developments – Bologna, Barcelona and Beyond

Cardiovascular Developments – Sheffield

Where Next? Insigneo is now tackling these major issues…

20 patients has already taken place and we are two thirds of the way through the next study involving 100 patients. This will proceed to a large scale trial of 1000 patients within the next two years.

It is important that the development of such models is undertaken in an iterative process that involves comparing the virtual model to the traditional way of assessing patients, ensuring that the method is accurate, quicker and robust, and easily usable in a clinical setting.

There are numerous other applications of in silico techniques for example, the development of diseases can be modelled virtually over time. This is particularly useful (albeit challenging!) for patients with multiple comorbidities as it may be possible to predict how one disease might affect another and how treatments will come together. This is a really complex area.

The viewing room, protected from the X rays by lead glass, is currently the province of the Physiologist, who monitors the patient’s blood pressure,

heart rate and heart rhythm. In the future, the Radiographer will be able to run the VirtuHeart™ system and let the Cardiologist know, within minutes of completion of the angiogram, whether and where stents should be inserted.

In the case of VirtuHeartTM, one important factor that will ease the translation of this research tool into practice is that the measure computed to assess the severity of disease in a coronary artery – the Fractional Flow Reserve (FFR) - is already recognised as the gold standard for assessing the physiological significance of coronary artery disease during routine coronary angiography. However, current tests are invasive, time-consuming and complex to perform, requiring the passage of a pressure wire into the vessel and administration of a drug. If this measurement can be obtained from an image-based model, half the battle is won, and in terms of translation there is not such a steep hill to climb as the measurement has already been validated and accepted by the clinical community.

What is the process of ‘translating’ a model into a manufactured product?

Predictive models which are intended for clinical use are classified as medical devices and, as such, in Europe and so in the UK, are regulated under the EU Medical Devices Directives. We need to keep this in mind during the initial development stage and have an understanding of the approval process so that maybe at a later stage industry can produce the device commercially.

Without this integrated approach from the beginning we might end up developing something that is completely useless. We have built up symbiotic relationships with industry, where we share our ideas and look if a piece of technology is of commercial interest.

Once a piece of technology is ready how is it adopted in clinics?

Everything in medicine is formal, clinicians work with guidelines and the guidelines are based on bodies of literature to develop best practice. If we are to be successful in getting our models adopted they have to be able to be integrated within routine clinical workflows with minimal to no disruption. In the future, if necessary, we can perhaps pursue more disruptive approaches and go a bit further, however, at the moment, we need to ensure that our models can be integrated into current workflows.

My vision is for the development of technology that can be used in any hospital irrespective of whether it is a high tech research hospital or the more routine District General. I strongly believe that technology that is easy to use and commercially viable has a much better chance of being widely adopted.

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FEATURE

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Clinical translation of in silico medicine involves creating representative and reliable models of the human body that provide accurate predictions to help clinicians in diagnosis and treatment. We interviewed Pat Lawford who is Professor of Physiological Modelling within the Faculty of Medicine Dentistry and Health, and Director of Clinical Translation, for Insigneo to find out more about this exciting new area of medicine. Professor Lawford’s own work focuses on the use of models both in the development and evaluation of cardiovascular devices and as aids to help clinicians in their choice of treatment for the individual patient.

How does the process of translating research into clinical practice begin?

The clinicians we work with are enthusiastic about the potential of in silico medicine and often will come to us with very complex problems where current approaches require invasive tests or are lacking in some way. We then try and find out if there is anything we can develop to help them.

The first step in finding a solution is to develop a theoretical model. The idea is to bring clinicians, engineers, and computer scientists together so that there is a constant dialogue with clinicians from the very start.

Although modelling usually starts with a gross simplification of the situation, you can keep adding more and more detail to the model until you get closer and closer to an adequate representation of the real situation.

Could you give an example of a current in silico trial taking place?

Over the last few years Julian Gunn, Professor of Interventional Cardiology, has been leading a team of clinicians, physicists, mathematicians, and engineers in the development of an innovative clinical tool (VIRTUheartTM ) which can be used to investigate diseased coronary arteries.

This model could be used to help to decide if a patient needs a stent, for example, and where this should be placed for maximum benefit to the patient. A pilot study involving

The viewing room, protected from the X rays by lead glass, is currently the province of the Physiologist, who monitors the patient’s blood pressure, heart rate and heart rhythm. In the future, the Radiographer will be able to run the VirtuHeart™ system and let the Cardiologist know, within minutes of completion of the angiogram, whether and where stents should be inserted.

One of the cardiac catheter laboratories at the Northern General Hospital, Sheffield. The patient (hidden under the blue sheets) is awake while the Interventional Cardiologist and his nursing assistant pass the cardiac catheter via the radial artery to the left coronary artery. They are guided by the X ray machine in the background, and the images are displayed on the screens in front of them.

The A-Z of Clinical Translation of in silico Medicine An interview with Professor Pat Lawford

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