Health at University of Twente

HEALTH AT UNIVERSITY OF TWENTE: HIGH TECH, HUMAN TOUCH 0155

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health at University of twente: HigH TecH, Human ToucH

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High Tech, Human Touch

[ introduction ]

High Tech, Human Touch T

he University of Twente (UT) is celebrating its tenth lustrum under the title ‘50 Years High Tech, Human Touch’. This slogan doesn’t just describe what the UT stands for in the present day, but it also characterises the UT throughout its history.

From day one, our institution identified that significant societal problems can only be solved through a multidisciplinary approach, and the use of technology combined with social sciences from beta and gamma.

Because of this, the UT has a unique profile among the universities in the Netherlands. Not only does it possess unique strengths that push the boundaries of beta and gamma research, but trains engineers in the social sciences and develops social scientists.

We are also an entrepreneurial university. Not only are we extremely strong scientifically in the core technologies of our cutting-edge institutes: MESA+ (nano technology), MIRA (bio technology), CTIT (information technology) and IGS (governance), but we know how to translate this into added value for society and the economy. Over the course of time this has produced more than 700 new companies and around 7,000 high-value jobs, clearly demonstrating that the UT combines fundamental research, applications and an entrepreneurial spirit like no other.

celebrations which brought a new approach to education by inviting visitors onto the campus to experience and ponder various scientific events in fourteen different domes. The tradition of innovation has continued with the introduction of study minors to the recent plans for a technical university and new, broader, bachelor programmes.

Health is one of the most important societal trends in which the UT is focussing its energy. All of our research institutes are contributing to this area, which fits like a glove within the cadre ‘High Tech, Human Touch’.

The interaction between technical, medical and social sciences makes health one of the most dynamic areas of research of today. And in this field, the UT is also demonstrating its strength to innovate, with its unique course in Technical Medicine, which educates medical professionals in the field of medical technology and what is or isn’t possible.

I wish you a great deal of reading pleasure in this book, which illustrates how the UT, with its sometimes stubborn and entrepreneurial attitude, achieves internationally acclaimed breakthroughs in an exciting and relevant area of research: Health. Good health!

Ed Brinksma Rector Magnificus

That entrepreneurial spirit embraces our unstoppable will to innovate and overcome boundaries. This is demonstrated by our“Experiment in the Forest”

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[ table of contents ]

01 chapter 01 introduction

02 Chapter 02 medical imaging & diagnostics

03 Chapter 03 treatment & tissue regeneration

04 Chapter 04 medical robotics & the human body

1.1 page 006

2.1 page 016

3.1 page 034

4.1 page 058

institutes working

richer images for better

helping the body repair

getting on the move again

closely together

treatment

itself

1.2 page 008

2.2 page 018

3.2 page 036

High Tech, Human Touch

Diagnosis of breast can-

How to help patients with

1.3 page 012

cer with sound and light

mira, institute for bio-

research

medical technology and

2.3 page 020

technical medicine

‘our lab is the world

Diabetes type I?

4.2 page 060 Rehabilitation robot gets paralysed patient walking again

3.3 page 038

4.3 page 064

‘You mustn’t lose heart

Operation robot needs

when a great idea just

just a single incision

1.4 page 013

leader’ Five questions for

refuses to work’,

4.4 page 066

centre for telematics and

Michelle Heijblom

Four questions for

A Navigation system for

information technology,

2.4 page 021

Aart van Apeldoorn and

(ctit)

In pursuit of circulating

Mijke Buitinga 3.4 page 040

tumour cells

1.5 page 014 institute for innovation and governance studies

Healing plasters

Converting clever ideas

3.5 page 042

4.6 page 070

Targeted delivery of

From space robotics to

1.6 page 015

Five questions for Leon

mesa+ institute for

Terstappen

nanotechnology

Robotic system for

2.5 page 023 into clinical applications

(igs)

surgeons 4.5 page 069

medicines 3.6 page 044

2.6 page 024

It’s the intensity that

The importance of tiny

prostate cancer diagnosis

prostate interventions

Four questions for Sarthak Misra

makes it so much fun’

4.7 page 072

extracts from the

‘deep insights require long

2.7 page 026

schedules of two

contemplation’ extract

‘I love it when I see a

entrepreneurial professors

bubbles

from the schedule of Michel van Putten

spark in their eyes’

3.7 page 052

from the schedule of

Wearable kidney

4.8 page 076

Vinod Subramaniam

3.8 page 053

‘Suddenly you find you can

2.8 page 032

Playing with molecules

A cosmopolitan career

3.9 page 056 Bernke Papenburg and Materiomics

save lives’ Four questions

for Jarich Spliethoff 4.9 page 077 ‘No-one is in this to get rich’ Five questions for

Marjolein van der Krogt

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High Tech, Human Touch | chapter 01

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Introduction

05 Chapter 05 Lab-on-a-Chip

06 Chapter 06 eHealth & logistics

07

08

Chapter 07 entrepreneurship & special projects

Chapter 08 education at the university of twente

5.1 page 078

6.1 page 100

7.1 page 124

8.1 page 142

A revolutionary form of

support can improve

assisting researchers

training tomorrow’s

nanotechnology

health care processes

in developing actual

5.2 page 080

6.2 page 102

‘Let others see how won-

A cross-border knowledge

7.2 page 126

hub to combat infections

Measuring the success

derful our work is’ Extract from the diary of…

Albert van de Berg 5.3 page 088

6.3 Page 106 Collaboration: the key to success

products

of technology 7.3 page 130

6.4 page 108

5.4 page 091

the smart hospital

7.4 page 132

The link between mice and

6.5 page 112

‘MIRA IS GROWING FAST!’

humans

Remote care via your underwear

from the schedule of 7.5 page 138

5.6 page 095

I DON’T WANT TO WORK IN A

High-tech Health Farm

VACUUM’ Five questions for

7.6 page 140

Miriam Vollenbroek –Hutten

treatments in the fields

Testing male fertility too?

6.7 page 115

5.8 page 098

Mathematics is the key

Drug screening on a chip

‘We have the nerve to take risks’ extract from

the schedule of Heleen Miedema 8.4 page 151 ‘My research is all about

Martijn Kuit

6.6 page 114

5.7 page 096

university of twente 8.3 page 148

and Xsens

The speed of lithium Antibody factory

8.2 page 144 education at the

Per Slycke, Peter Veltink

doctor-in-a-pill

5.5 page 092

health professionals

two worlds meeting’

Five questions for Ana Barradas

to health reform 6.8 page 118 technology to lean on

6.9 page 120 intelligent sensor networks as virtual coach

005

[ chapter 01 ]

Introduction

institutes working closely together 006

High Tech, Human Touch | chapter 01

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Introduction

01 [ intro ] ‘Health’ is a key research theme at the University of Twente (UT). Several hundred researchers are active in the field, operating in a wide range of disciplines, including medical technology, psychology and logistics. The specific strengths of all health researchers at the UT are brought together through national and international networks and partnerships.

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1.2

[ high-tech, human touch ]

explained by Prof. Dr. Clemens van Blitterswijk

Targeted cooperation offers big opportunities 008

High Tech, Human Touch | chapter 01 0x

XXXXXXXXXX | Introduction

[ intro ] The University of Twente (UT) is an

enterprising university, a leader in new technologies and a catalyst for change and renewal in society, also when it comes to health.

Over the past few years, health has developed into one of the key areas of expertise for the UT. Prof.

Dr. Clemens van Blitterswijk, Director of MIRA, the Institute for Biomedical Technology and Technical Medicine, attributes the extraordinarily strong rise of developments in health to the university.

Continued on next page

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continued from page 009

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rom his office in the Zuiderhorst building, in which MIRA is located, Van Blitterswijk explains why, in a relatively short period of time, health has gained so much importance: ‘It is clear that the “greying” of the population brings with it a number of associated problems, such as long-term care funding and the wellbeing of the elderly, which pose important challenges for science and society.

Requirements in terms of health are increasing, and it was therefore a logical step for the board of our university to respond. But, to an extent, this may also have been thanks to the critical mass that we have already built up,’ Van Blitterswijk says, referring to the numerous research institutes at the UT that are involved with health.

These include the MIRA, Biomedical Technology and Technical Medicine, the MESA+ Institute for Nanotechnology, the Institute for Innovation and Governance Studies, as well as the Centre for Telematics and Information Technology. Van Blitterswijk: ‘These are institutes which are well respected in the Netherlands and in some instances far beyond its borders.’

Robot teaches a patient to walk

The technologies developed made in Twente that later find their way into medical applications are numerous, and frequently they’re nothing short of remarkable. Van Blitterswijk highlights just a couple of examples: ‘Take the Lab-on-a-Chip. A whole laboratory in a tiny pill, thanks to nanotechnology. Researchers from BIOS, the Lab-on-a-chip department

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from the research institute MESA+, developed this revolutionary form of nanotechnology. An important step for science, and one which won Professor Albert van den Berg the Spinoza Prize in 2009.

They’re now working hard on a number of applications for the Labon-a-Chip and this has already lead to the development of a fertility test for men and a chip which allows manic-depressive people to control their own medicine intake. Another technology is the LOPES, a robot which helps crippled patients learn to walk again. It was developed

‘ The no-nonsense mentality in Twente is some­ thing special’ by the Biomedical Mechanical Engineering department at the UT. With the LOPES (LOwer-extremity Powered ExoSkeleton), the patient moves with the aid of a robot, which speeds up the rehabilitation process.

The LOPES will go into production at the end of 2012.

Cloaked The UT’s slogan is ‘hightech, human touch’. A well thoughtout motto, which is particularly applicable to health research. Van Blitterswijk explains: ‘Our basis is technology, but around this is wrapped a cloak of social, human and behavioural sciences. In addition to technical scientists, we also employ behavioural scientists, philosophers, psychologists, and communication specialists. We have IT experts, governance specialists

High Tech, Human Touch | chapter 01

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Introduction

and more. For us, it is a welcome challenge to bring both technical and non-technical disciplines together.

A great deal of health-related research is carried out by traditional universities, but they are missing the medical technology component. The majority of technical universities lack the human and behavioural science component. We combine both.’

This combination provides significant advantages, explains Van Blitterswijk: ‘It is very easy to fall into the trap where technicians in a lab find a complete solution to a problem. Even though these solutions might work in practice, they may for example, have no appeal whatsoever to the patient.

By adding a psychological or behavioural science component, the result is a patient-friendly solution.’

He provides a concrete example: ‘At MIRA we’re busy with the issues of tissue regeneration: how do you make damaged tissue whole again? Through contact with one of our philosophers of science it was suggested that we should perhaps also consider the subject of human advancement: making a human better than they actually are. For a philosopher this is a fascinating subject, but for us a subject that’s not at the forefront of our minds.

As a result of this inter-disciplinary interaction, for a short time now we’ve been considering if the area of human advancement is something we should be concerning ourselves with.’

Technological cross-fertilisation can lead to interesting breakthroughs. Van Bitterswijk: ‘At MIRA, we’re working on the regeneration of tissues through the growth of cells. The

Building structures

cells have to grow the right way.

This is now possible with the help of physical parameters. To make this possible we have to be able to build structures on the surface of the cells.

For this, we’re using knowledge from the nanotechnologists at the MESA+ institute, which is one of the leading nano-institutes in the world.’

Another example is eHealth telemonitoring, which involves the remote guidance of diabetes patients via, for example, an app on their smartphone. Van Blitterswijk: ‘It’s extremely helpful for general practitioner and patients. For example, a patient can measure their own blood sugar levels and upload them directly to a website via a telephone. Following this, the GP can look at the results at a convenient time. In this example, three areas of research come together: the IT specialists who develop the app; MIRA which delivers the hardware; and psychologists who research how a patient interacts with this new technology.

According to Van Blitterswijk, collaboration is a process that costs time: ‘Diverse disciplines have to be able to see each others’ added value.

Researchers have to get used to one another and look past their one area of professionalism. I’m not a fan of forced cooperation that people may only pay lip service to. But with a realistic goal in sight, I’m convinced that collaboration offers us great opportunities.’

Spin-off companies In addition to its capacity to collaborate, Van Blitterswijk also refers to another unique characteristic that differentiates the university in Enschede from others: ‘The

no-nonsense mentality in Twente is something special. Lines of communication are short and the dynamism is great, but whatever you do, it has to be useful or have an application in society.

‘Entrepreneurial flare is in the genes of the people here. All institutions combine scientific excellence with a keen eye for knowledge valorisation – the translation of acquired

knowledge into a commercially viable idea – and social application.

They are successful with the generation of spin-off companies.

But however adaptable our discoveries are for societal or commercial gain, we always strive for a balance between relevance in society and the highest scientific standards.’

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X.X 1.3

MIRA

brings top technology to patients [ intro ] MIRA is the Institute for Biomedical Technology

and Technical Medicine at the University of Twente (UT).

It is a leading and fast-growing research institute that develops top technology for first-rate medical solutions.

MIRA is also training a new generation of health care professionals and providing them with a unique focus.

M

IRA’s research will lead to new techniques to repair damaged tissue such as bone and cartilage. It enables doctors to make more effective diagnoses with the aid of improved imaging techniques.

It helps to create drugs that are targeted in their effects, and it offers patient-focused solutions in rehabilitation technology.

MIRA combines fundamental and applied research with clinical practice. It has full professors in all these three realms. It encourages entrepreneurship and industrial collaboration which means its new technologies reach patients sooner and at an affordable price. Through close cooperation with hospitals, industry, and government agencies, MIRA aims to safeguard a leading position in Europe.

The scientific work is gathered into three research tracks, which cover the spectrum of biomedical technology and technical medicine: Tissue Regeneration Imaging and Diagnostics Neural and Motor Systems

Research

Each realm has its own full professorships to safeguard the value of the research. Two clinical professors are also attached to each track. They work for one or two days per week at MIRA and spend the rest of the week working as medical specialists in a hospital. This puts them in an ideal position to formulate clinical research questions and to point out medical practice needs.

Spin-off activities Mira’s research results have given birth to the founding of new companies

0012 012 High High Tech, Human Touch | chapter 01 0x | Introduction XXXXXXXXXX

and dozens of licence deals. These spin-offs deliver technologies to patients at a favourable price. It is the ambition of this institute to spin-off at least four companies per year and to have three companies that employ at least 15 people by 2014. An excellent example of a MIRA spin-off com­pany is XSens (see page 130).

1.4

CTIT

contributes to health care innovation through IT solutions

[ intro ] Medical progress depends heavily on IT. In a time when more people

live longer and demand a higher level of care, the Centre for Telematics and Information Technology (CTIT) contributes to a new medical future through ICT research. It’s a future where cure and care are more personalised and taken out of the hospital into the comfort of your own home.

C

TIT’s researchers are working on smart solutions, for instance sensor networks and remote monitoring. These can be of use to people suffering from chronic diseases, like Chronic Obstructive Pulmonary Disease (COPD), Parkinson and Alzheimer’s disease, or in supporting people to recover after medical treatment or trauma from sports injuries.

Patients can be monitored in their own environment, data will be analysed and appropriate measures can be taken. Nurses can monitor several patients at the same time, ensuring quality care at minimal costs.

Many medical innovations involve robots. Our research on robotics does not only cover the ‘High Tech’ of such embedded

systems in, for example rehabilitation robots, but also addresses questions on the ‘Human Touch’ of the deployment of such robotic support systems.

How do we like being dressed by robots at home, or even, do we trust them enough to let them support us?

In a future where health care will be expensive, highly specialised and complicated, CTIT is working hard on IT solutions to help personalise care, reduce costs, and add to overall wellbeing.

For a more in-depth view of our research, see pages 115-117 and 120-123.

Where care cannot be provided at home, CTIT is also working on improving the logistics and internal processes of hospitals by making them more tailor made to the patient’s needs. CTIT’s spin‑off Smart Signs specialises in personalised wayfinding in hospitals and our centre of expertise, Center for Healthcare Operations Improvement and Research (CHOIR), draws from mathematical theory to shorten waiting time in between appointments.

0013 013

X.X 1.5

IGS

stimulates innovation in health care

[ intro ] With over 300 researchers, mostly in the

social and behavioural sciences, the Institute for Innovation and Governance Studies (IGS) focuses on issues of social and technological innovation in the context of people, organisations and society. With this unique profile, its large size and its proven excellence in research, IGS embodies the ‘human touch’ of the University of Twente.

I

GS research addresses issues of coordination, steering and the operation of (networks of) actors and institutions in health care, from a multi-level, multiactor systems perspective. In this, IGS combines scientific excellence with relevance for public and private stakeholders in the sector, as well as for patients and society.

Main subject areas of research are Health (system) Assessment, Health Promotion and Care, Health Technology Assessment and Economics, Design and Implementation of (e)Health Technologies. In many cases IGS

research is connected or related to health research in other UT institutes.

At the core of the institute, DataLab provides researchers and partners with reliable data and safe and secure facilities for conducting qualitative and quantitative research. It guarantees patient privacy as well as the trustworthiness of research outcome. IGS DataLab stimulates innovations in health care research itself, making sure that IGS stays on the cutting edge of research in this field.

0014 014 High High Tech, Human Touch | chapter 01 0x | Introduction XXXXXXXXXX

IGS is also the provider of knowledge to the spin-off activities of the UT and supports these activities by providing a VentureLab for entrepreneurs.

Thus, IGS is involved in the creation of a large number of UT spin-offs in health care services and technology.

1.6

MESA+

Institute for Nanotechnology Nanotech for better diagnostics and care

[ intro ] A ‘nanopill’ that can detect colorectal cancer at a very early

stage. Hypodermic needles that are so small that you hardly feel them.

New techniques to measure the effect of medication in a single cell.

Nanotechnology, the technology which works at the level of individual molecules, is creating unprecedented new opportunities for the medical community. The MESA+ Institute for Nanotechnology is one of the largest research institutes in the world in this field, with 500 scientists and a state-of-the-art NanoLab. Medical innovation is one of the institute’s major research fields.

T

hanks to the use of micro and nanofluidics, which enable extreme miniaturi­ sation, it is possible to perform medical analyses in a ‘laboratory’ no bigger than a credit card.

This enables rapid point-of-care diagnosis: the lab can come to the patient rather than the other way round. This technology has already led to a device that can be used to measure the level of medicinal products in the blood rapidly, for example. It has also brought about new ways of studying the effect of medicinal products on individual cells. The next step will be to fit the

entire ‘lab’ inside a pill which can carry out its analyses inside the human body.

investigate biological processes at the level of single molecules, so that we can understand the causes of diseases better.

Innovative medicine

Bio-nanotechnology will give a new impetus to medical innovation through new treatment methods and medications. For example, nano-sized particles which attach themselves to specific tumour cells, so that they can be detected more easily. Or the targeted delivery of medicinal products using nanocarriers such as tiny nanobubbles. MESA+ is working on optical techniques to

MESA+ has created an exceptional environment for high-tech startups, with a business development programme and extensive research and production facilities. This has already led to the creation of 45 new businesses. Several startups are also up and running in the health field, such as Micronit, Medimate, Medspray, Lionix, U-Needle, Ostendum, MyLife Technologies and Nanomi.

0015 015

[ chapter 02 ]

meDical imaging & Diagnostics

richer images for better treatment

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HigH TecH, Human ToucH

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chapter 02

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Medical Imaging & Diagnostics

02 [ intro ] the medical imaging and diagnostics programme at the ut aims to visualise and understand the processes in cells and organisms. also, imaging the Body without operating or injecting a contrast fluid significantly reduces the Burden for the patient. our ultimate aim is to create techniQues that enaBle physicians to offer their patients a treatment that is more focused, causes less discomfort and provides a faster cure.

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2.2

Diagnosis of breast cancer with sound and light research [ intro ] Breast cancer screening needs to be improved. So say MIRA

researchers who are working hard to develop an entirely new method of screening. Not based on X-rays, but using a combination of light and sound.

This method is more accurate and also more pleasant and safer for the patient.

B

reast cancer is the most common form of cancer in women; one in nine women develops it at some time in her life.

Every year some 13,000 women in The Netherlands are diagnosed with the disease and around 3,000 die from it. To detect breast cancer at an early stage, women between the ages of 50 and 75 are invited to attend breast screening every two years.

This is traditionally done using X-rays. The breast is clamped firmly between two plates: an unpleasant and even painful experience. The method is far from foolproof: doctors sometimes fail to spot tumours and sometimes they refer women who don’t have cancer, causing them needless worry. And X-rays aren’t without risk. Some groups of women, for example women who have already had breast cancer or have a hereditary variant in the family, are screened every year, sometimes from

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as early an age 30. In such cases, total lifetime radiation exposure can really mount up.

Light and sound MIRA researchers are working on an alternative method of breast cancer screening: a brand-new technology. It uses not X-rays but laser light. Laser light is absorbed well by haemoglobin, the protein in the blood that transports

oxygen. Where the blood flow is greater, more light is absorbed.

And it just so happens that a characteristic of malignant tissue is an increased blood supply. Indeed, various new blood vessels grow in and around the tumour to supply the fast-growing tissue with oxygen and nutrients. This increased vascular growth can be detected using laser light. When the blood absorbs the

[ fig. a ]

High Tech, Human Touch | chapter 02

laser

scattering medium ultrasound detector

|

Medical Imaging & Diagnostics

[ fig. b ] USING LIGHT AND SOUND TO DETECT BREAST CANCER Laser light can be used for the detection of cancer tissue as an alternative to painful mammography.

Blood vessels grow around malignant tissue to provide it with oxygen and nutrients.

The new technique makes use of these blood vessels to detect cancer tissue.

THE SCAN

[ 01 ]

Patient lies on stomach on the examination table.

window for laser light

[ 03 ]

[ 02 ]

laser

ultrasound detector

[ 04 ]

Laser sends light through the breast.

Breast protrudes through the opening.

The detector is connected to a computer.

[ 05 ]

The computer converts the information into a 3D image.

HOW DOES IT WORK?

blood vessels

tumour tissue

[ 01 ]

Haemoglobin in the blood absorbs laser light, which causes the tissue to heat up and expand slightly.

tumour tissue

window

light, it becomes a tiny bit warmer.

As a result, it expands a little locally.

This causes a miniscule pressure wave in the tissue: like a sound wave.

It can be measured using special equipment, giving you a threedimensional image of the tumour.

The MIRA researchers are currently working on a second, improved version of their invention. The technology is not yet on the market; experts believe that will take a few more years.

coLLaBoraTion

sound wave

They are working closely with medical specialists and with the breast clinic at Medisch Spectrum Twente to find out exactly what demands are placed on screening technology in practice. In 2006, a study was launched to test the first version of the apparatus, making MIRA one of the front runners in the world.

In theory, this method can be used to detect tumours only a few millimetres

[ 02 ]

The expansion produces a miniscule sound wave that is picked up by the ultrasound detector.

ultrasound detector

in size. This makes it considerably more accurate than traditional X-ray screening, in which small tumours are often overshadowed by other tissue. And the smaller the tumour when it is detected, the better. In future, the light and sound method may also be suitable for detecting other forms of cancer.

eXTreme precision

next page: FiVe QueStionS FoR MiCHeLLe HeiJBLoM

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2.3

michelle Heijblom

‘Our lab is the world leader’ Michelle Heijblom was an outstanding student and could take her pick of career options. she opted for PhD research in Twente.

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How did you end up in technical medicine? ‘I’ve always found medicine interesting, but I also had a passion for maths and physics as well. Technical medicine seemed an ideal combination to me. I never really saw myself as a doctor in a hospital, but would rather be involved in the development of new equipment. So I came to do the technical medicine course here in Twente. Due to a combination of luck and specific interest, I was then able to start a PhD project in the department.’

2

So it wasn’t because you don’t like dealing with patients? ‘Of course not!’ (laughs) ‘In this research we also work a lot with patients. It’s that variety that I enjoy so much. You’re dealing with people, but also with the technology.’

3

Has this decision brought you what you wanted? ‘I found it hard to picture in advance exactly what the discipline entails. I was part of the first batch of students on the technical medical course, and didn’t really have a career profile in mind. But if you just do what you’re interested in, it’ll always turn out right in the end. And yes, if given the chance I would make the same decision again.’

4

Are there also some things you dread when you come to work in the morning? ‘Just the general things that every PhD student faces: Will I get my project done in time? What if my results are disappointing? When will we finally get such and such a piece of equipment going again?’

5

You were one of the very best students in your year; why didn’t you go to work at a top foreign university, such as Harvard or MIT? ‘I’d come from the other side of the country, and it had taken me long enough to get used to living in Twente.’ (laughs) ‘What’s still most important to me is to do what I enjoy. This job is just what I was looking for, and I feel at home here. Our lab is the world leader. Why would I go anywhere else? Perhaps it’s better for your career to have foreign experience as well, but I’m not really concerned about that.’

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High Tech, Human Touch | chapter 02

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Medical Imaging & Diagnostics

2.4

In pursuit of

circulating tumour cells [ intro ] Leon Terstappen has developed a technology for detecting tumour

cells in the bloodstream. This surprisingly simple invention identifies the type of tumour cells involved and reveals if a treatment is working. An aid like this is much needed in the medical world.

D

octors today can detect and treat cancer much more effectively than they could, say, ten years ago. But it’s still hard to check if a given treatment is working.

Wait-and-see is the motto. It takes months, and many sessions of chemotherapy, before doctors dare to conclude that the treatment isn’t working. Such a conclusion is drawn when scans show that tumours are still present. But then it’s sometimes too late to change strategy. In any case, much unnecessary suffering

has already taken place. Sometimes it’s just easier on the patient to discontinue the chemotherapy if it isn’t helping.

Leon Terstappen, a medical biophysicist at the University of Twente, and his colleagues have found a way to establish far earlier if a treatment is working. He has developed a technology that doctors can use to detect individual tumour cells in the blood. These ‘circulating’ tumour

circulating cells

cells are a sign that the cancer is spreading or ‘metastasising’. If cells are still found after one round of chemotherapy, that’s not a good sign.

Then you may as well discontinue the treatment.

The technology, named CellSearch, uses the fact that tumour cells are an entirely different cell type than blood cells. Every cell type has specific projections on the

Lock and key

Continued on next page

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[ fig. a ] TRACKING DOWN MIGRATING TUMOUR CELLS Migrating tumour cells in the blood are a sign that cancer is spreading. The number of such cells indicates the aggressiveness and type of cancer. Doctors can use this information to select a treatment.

blood cell

blood circulation

tumour cell

Tumour cells are entirely different from blood cells.

They have characteristic projections on the cell wall.

The CellSearch technique makes use of specially designed particles (antibodies) that specifically bind to the projections of cancer cells.

magnetised antibodies

HOW DOES IT WORK?

[ 01 ]

Antibodies are fitted in conjugated magnetic particles.

[ 02 ]

They are then added to a blood sample.

[ 03 ]

magnet

magnet

tumour cells

blood

Tumour cells present in the blood will adhere to the antibodies.

Continued FRoM page 021

outside of the cell which are typical of that cell type. CellSearch uses specially developed particles that specifically adhere to the projections of tumour cells. These particles are antibodies: proteins which adhere only to certain other particles via the lock-and-key principle. The CellSearch antibodies are fitted with small magnetic particles so they can be ‘fished out’ from the blood again using a magnet. If tumour cells were present in the blood, some of them will have stuck to the antibodies. After a special staining, they can then be detected and counted under the microscope.

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microscope

HigH TecH, Human ToucH

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The number of tumour cells in the blood is a measure of the cancer’s aggressiveness. The tumour cells also reveal what type of cancer it is.

Based on this information, doctors can infer which treatment has the best chance of success. reTicenT CellSearch is already on the market but, especially in Europe, is used mainly in a research context. The medical world is still hesitant: first, it wants to see more research results showing how the technology can best be applied, and that it is indeed worthwhile. In addition, doctors are very reticent when it comes to discontinuing

chapter 02

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Medical Imaging & Diagnostics

[ 04 ]

The particles can be removed from the blood with a magnet.

[ 05 ]

Once special stains have been added, the tumour cells can be detected and counted under the microscope. This information is used to select a treatment.

treatment. They don’t want to run the risk of missing a chance of a cure, even a very small one. avoiding suFFering and cosTs

For the time being, the American Food and Drug Administration has only approved CellSearch for the monitoring of patients with metastasised breast, prostate and colorectal cancer. But in the near future other forms of cancer will also be added, and the technology will probably find its way into European practice as well.

The health insurers will probably be the ones to tip the balance: CellSearch can avoid not only a lot of suffering, but also a lot of costs.

2.5

leon terstappen

Converting clever ideas into clinical applications cellsearch, a technology that doctors can use to detect tumour cells in the Blood, won an american prize last year: the priX gallien, a prestigious prize for the Best scientific invention to have made it as a successful technology. cellsearch was developed under the direction of leon terstappen.

1

Are you pleased with the prize? ‘Outside applied medicine, few people will have heard of it.’ (laughs) ‘But within our discipline it’s a very valuable award. So yes, I’m very pleased with it. No, there’s no financial reward attached. It’s purely the honour.

Perhaps I should mention it on my CV.’

2

Does this prize open new doors for you, and for CellSearch?

‘I think so. This is something very specific that I can show to investors. In 2008, Johnson&Johnson took over the company that I’d set up to launch CellSearch. But I’m still involved as a consultant. And until the technology is fully developed, new investment will be needed.’

3

But why did you go back to academia after setting up your own company? ‘Science is important, and I’m passionate about it. And where can you do science better than at a university?

Moreover, I’ve now gone through the whole journey from idea to execution once. So I’ve been there, done that. Now I’m much more interested in tackling new projects and guiding young people.’

4

As a professor, do you still draw on your experience in industry? ‘I try to teach my students about everything that’s involved in bringing a new technology onto the market. What challenges do you meet? How do you apply for a patent? How much money do you need? Many students haven’t the faintest idea that it can easily take hundreds of millions of euro, especially in the clinical test phase.’

5

So purely fundamental research is not for you?

‘No, or I wouldn’t be here. At MIRA we convert smart ideas into clinical applications. In that respect, I’ve found my niche.’

023

2.6

The importance of tiny bubbles Bubbles are more useful than you think. They have numerous applications in the medical world. For example, you can use them to clean root canals in dentistry or to increase the contrast of imaging technologies. You can also use them to deliver drugs to exactly the right place in the body. This is what researchers in MIRA’s Physics of Fluids department are working on.

I

magine a typical foetal ultra­ sound scan in the hospital. You can see all sorts of tissue, bone and cartilage, but it’s hard to see the blood flowing in the organs.

This is because blood doesn’t reflect ultrasound that well. In medical diagnosis, however, the blood flow is often the subject of interest. In the case of a heart attack, for example, you want to know where the blood flow is disrupted. And when looking for a tumour, you want to know where there’s increased blood supply, as that is a sign of malignancy.

Tiny bubbles can help to make that blood flow visible. That’s because the ultrasound waves cause the bubbles to vibrate. The bubble vibrations produce a characteristic echo which can be measured with the handheld probe. A single microbubble reflects ultrasound a billion times better than a red blood cell. But if you sim­ply inject these bubbles into the bloodstream, they’d dissolve immediately because they’re so small. So researchers coat the micro­bubbles with a monolayer of phospholipids. That’s the same substance as our cell mem­branes are made of. The precise ap­ plication determines the choice of material for the coating. For ima­ ging applications you want a thin

024

and flexible skin; for drug delivery applications it needs to be thick and firm.

Yes, another application for tiny bubbles is as carriers for drugs. Using ultrasound at the right frequency, you can burst them open at precisely the right location, near a tumour site where you want to deliver the drug.

Or you can design them to adhere specifically to cancer cells. The bubbles have a receptor on their coating that precisely matches an abnormal protein molecule on the outside of a cancer cell. They can then deliver their cargo with utmost precision. That’s far more beneficial than the typical chemotherapy administered today, which works throughout the whole body, killing both tumour and healthy cells alike.

Delivering medicines

MIRA’s Physics of Fluids team has one of the most advanced pieces of research apparatus ever built: a camera which can take 25 million images per second to closely examine how tiny bubbles vibrate or burst. This camera was developed at the University of Twente and is the only one of its kind. Everything that researchers see with the camera is new to science.

Many of these tiny bubble

Supercamera

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Tiny bubbles sent into the blood stream can help to make blood flow visible because of their ability to reflect ultrasound much better than blood itself.

technologies are already applied in clinical practice. New technologies are tested extensively to investigate whether the principle works and if it is safe. However, clinical tests are not the prime focus of the Physics of Fluids researchers. Their main aim is to understand the underlying physical mechanisms. What exactly happens to these tiny bubbles?

How do they behave under different conditions? How can you boost the contrast, or direct the local injection of drugs? Only when more is known about these physical processes will researchers be able to refine even more of these exciting new medical applications.

025

2.7

[ extract from the schedule of... ]

Vinod Subramaniam

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‘ I love it when I see a spark in their eyes’ [ intro ] Vinod Subramaniam is fascinated by the ‘puzzling

Parkinson protein’ (alpha-synuclein ) and enjoys working with young people.

027

08:00 Dropping off my daughter at daycare

‘I have a two-and-a-half year-old daughter called Mira. In fact, our MIRA institute was named after her – although I had little or nothing to do with that. The anecdote is that at the time, Clemens van Blitterswijk, the scientific director, was mulling over the name of the institute. He saw a picture of my newly born daughter, and liked the look of wonder in her eyes. Mira is short for “mirabilis”, which means “wonderful” in Latin.’ He felt that

028

described the spirit of the institute.

As they say, the rest is history.’

9:00

Meeting with the research group ‘On Monday mornings, we usually get together with the entire research group to discuss science and listen to infor­mal presentations. When people explain their line of reasoning to their colleagues, they’re challenged to think about why they do certain things in a certain way. That’s really enriching. You become far more critical towards your own approach.

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And others may come up with solutions to your problems from unexpected angles.’

11:00 Walking around and

drinking coffee with colleagues ‘What happens in the corridors is incredibly important. This is a small university where you always meet people who are working on

‘ Mira is short for “mirabilis”, which means “wonderful” in Latin.’

[ who is... ] Hoofdstuk 3 P. 45 De foto van de patiënt met elektroden op het hoofd past hier inhoudelijk helemaal niet. Er is in de tekst geen enkele verwijzing naar. Wat mij betreft kan hij dus weg, of ergens anders.

who is vinod suBramaniam?

Vinod Subramaniam (1967) is a biophysicist who was born in india, but who has spent his entire adult life in other parts of the world. after obtaining a Masters and phd degree in the uS, he worked in germany and england for some time before coming to twente in 2004. at MiRa, he leads the imaging & diagnostics group. His own research focuses on the biophysics of protein aggregation in parkinson’s disease. Subramaniam lives in enschede together with his wife Sowmya and their daughter Mira.

interesting projects. There’s a highly collaborative atmosphere. You start talking about your research and the other person says: “Hey, perhaps you want to try this or that experiment.”

You start out with a particular idea and end up with something completely different. That’s how the best scientific ideas are born.’

11:30

Brief meeting with our new communications officer ‘I spend a lot of time meeting with people, and these meetings are not always about science. I find it rewarding to contribute my knowledge and expertise to the university. But I have to keep the balance in mind. Sometimes I need to step back and return to the core business of doing actual science.’

13:00 Meeting with a PhD

student

‘I like teaching. I’m a professor, and teaching is what I do a lot

of the time. I’m in this business because I like working with young people. I love it when I see a spark in their eyes: “Hey, I’ve got it now!”

Unfortunately I barely have any time now to do experiments myself, but I often visit my students in the lab.

When I see what they are doing, I say: “Wow, can you really do that?

Try doing this or that for a change.

Or perhaps run this experiment, or turn that knob.” It is fantastic to see that they can use your advice to improve their research.’

14:00 Attending an

undergraduate diploma ceremony ‘In itself these ceremonies are perhaps not the most exciting events.

However, I find it important to show up in my penguin suit together with my fellow professors and make a true show out of it. You want to contribute to these kids’ memories of the experience. It’s such a dramatic event, also for their parents. The toga is not the handiest garment, but I quite like it, because it lends a sort of formality and style to the academic world. I can see the value of it.’

16:00 Meeting with a Masters student

‘These meetings are much more basic than meetings with PhD students. In this meeting we discuss, for instance, how to formulate a decent hypothesis, how to set up Continued on next page

029

[ fig. a ] ABNORMAL CLUSTERS OF PROTEIN IN THE BRAIN Neurological diseases like Parkinson's and Alzheimer's are characterised by ‘abnormal’ protein clusters in the brain. The main question in this research project is: “What causes these clusters?”

Research questions

[ 01 ]

[ 02 ]

ARE PLAQUES THE CAUSE OR

WHAT CAUSES THE FIRST

SYMPTOMS OF DISEASE?

AGGREGATION STEPS?

Cause: Plaques cause the cellular recycling machinery for misfolded proteins to fail.

Symptoms: Plaques are reflections of underlying disturbances of the recycling machinery or other cellular processes.

A mutation in the protein?

Interactions with other Metal proteins? ions?

THE ABNORMAL BUILDING OF CLUSTERS

[ 01 ]

[ 02 ]

[ 03 ]

[ 04 ]

[ 05 ]

[ 06 ]

protein molecule

misfolded protein molecule

two molecules stick together

more molecules stick together

formation of ‘fibrillar’ structures

formation of clumps called ‘amyloid plaques’

Continued FRoM page 029

colleagues who are working on a certain research question, and who are interested in experiments

a smart experiment, and how to present the results.’

17:00

Meeting with a postdoc who is working on a grant proposal ‘This meeting is again entirely different. The postdoc and I communicate on a much more equal level. I try helping him with the experience that I have when it comes to applying for funding. We discuss different ways of formulating the proposal, and weigh the various options.’

18:00 Telephone conference with a colleague in the US ‘Sometimes I get a call from

030

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‘I have a Twents dictionary on my night table’

18:30 Cooking dinner

‘I love cooking. Dutch, Indian, Chinese, anything. My wife and I like to invite people over for dinner parties. Nowadays we don’t do that as much as we used to, unfortunately. But I still enjoy making our daily dinners.’

20:00 Tying up some loose ends

that we do. They wonder if they can apply our experiments to their work. I always try to help them as much as I can. We’re all working on the same fundamental problems. We all just want to find out what is really going on with these proteins.’

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‘In the evenings I usually have a couple of hours of work left to do.

Different things: answering emails, grading papers, reviewing articles.

I work 50 or 60 hours a week, if not more. Is that absolutely necessary? No, perhaps not. But I like it.’

22:30 Reading a book

‘I read voraciously. All kinds of things: novels, autobiographies, other non-fiction like Freefall by Joseph Stiglitz, about the collapse of the financial markets. But I also like Harry Potter. And I have a Twents dictionary on my night table.

This whole notion of dialects is fascinating.’

Clusters of proteins in the brain neurological diseases like parkinson’s

these aggregates a symptom

and alzheimer’s result from ‘abnormal’

or a cause of the disease? in fact

proteins that build up in the brain. ‘ab-

we still don’t know.’

normal’, in this case means that the proteins are folded incorrectly. and since

FirsT sTeps

their function is intimately connected

Subramaniam is trying to answer is

with their structure, this misfolding can

what triggers the very first aggrega-

have major consequences.

tion steps: two protein molecules that

another question that

stick together, and then stick to other aggregaTing proTeins

‘normally,

molecules. ‘the focus in this kind of

the body has a mechanism at its

research has always been on the end

disposal that recognises such misfolded

stage’, explains Subramaniam, ‘in other

proteins, and then gets rid of them’,

words, on the large protein aggregates.

says Vinod Subramaniam. ‘in parkinson

But what if the real toxicity lies in the

and alzheimer patients, however, this

initial stages? What if the molecule

mechanism does not work properly. We

pairs or small aggregates are toxic, and

still don’t quite know why that is.’

the formation of larger aggregates is

Yet it must have evolved for a reason.

in patients with neurological diseases,

actually a defence mechanism, pushing

the parkinson research is pretty fasci-

these misfolded proteins start to

the proteins towards the more harm-

nating. and great fun. although i am

aggregate. they form stiff, thread-like

less stages? if that is true, all efforts

under no illusion that we will solve the

structures of about ten nanometres in

to break down the larger aggregates

problem any time soon. the thing is that

diameter. these will then further clump

through medication are counterproduc-

there’s still a vast amount of informa-

together to form larger structures called

tive. this kind of basic information is

tion to be gathered and knowledge to

plaques. ‘the fundamental question

therefore absolutely vital.’

be learned for the next 20 years. Yes, of

that puzzles me as a biophysicist’, says

course that’s frustrating. We still have

Subramaniam, ‘is: what are the forces

cHameLeon

that cause these proteins to aggregate?

have been written about apha-synuclein’,

chameleon: it constantly changes shape

is it happening because this correcting

Subramaniam concludes, ‘but nobody

and structure. But that’s what makes it

mechanism is failing? or is it the other

actually knows what it does. We all

so fascinating. every day i wake up and

way around: is the mechanism failing

have it in our brains in the “normal”

i say: “ha, that’s a puzzle that i still need

because these proteins aggregate? are

form, but we don’t know its function.

to solve”.’

‘More than 4,000 papers

no idea about this protein. it’s like a

031

2.8

the cosmopolitan career of VinoD subramaniam Vinod Subramaniam

1967

1985

1967-1985:

1985-1989:

1989-1996:

Childhood in India

Cornell University, Ithaca, New York, US: College of Engineering

University of Michigan, Ann Arbor: PhD research

Subramaniam obtained a scholarship to

Yet the more he submerged himself in

go to Cornell university.

the advanced spectroscopy of semicon-

Vinod Subramaniam was born in Madras.

He grew up and went to school in new delhi.

ductors, the less Subramaniam seemed

‘My childhood was happy, absolutely.

to like it.

New Delhi is a huge city, teeming with

‘I went there to study computer science.

life and humanity. Chaotic at times, but

It was the eighties, and everybody

the sights, sounds, and smells are like

wanted to be a computer scientist. But

‘I soon realised that semiconductor

nothing else I’ve ever experienced.’

as soon as I did my first programming

physics didn’t really interest me. But my

class, I said: “No way! This ain’t for me.”

supervisor was a really great guy: a fan-

Instead I studied electrical engineering

tastic physicist and a remarkable human

with a focus on lasers and optics. I was

being. I wanted to keep working for him.

fascinated by all those upcoming laser

Luckily, he also had another lab, where

technologies.’

he used laser technology to study protein folding. So I asked him if I could work there, and he said yes. I loved the stuff.’

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1989

1996

2002

2004

1996-2002:

2002-2004:

2004-present:

Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Pharmaceutical company Astra-Zeneca, Loughborough, United Kingdom

Professor at the University of Twente

after gaining his phd, Subramaniam had

By that time, Subramaniam had met

twente: they were recruiting a professor

plenty of options in the uS. However, he

his wife and got married. His wife also

of biophysical engineering.

chose to move to germany instead.

comes from india but had lived in the uS.

While working in england, Subramaniam was approached by the university of

‘They do top-level research over there,

She liked the idea of living in europe but

‘But I liked my job in England, and I’d only

preferred an english-speaking country.

just got started. So I said no. But a few months later they came back and said:

fantastic. I thought I’d stay there for a year or two and then return to the US.

‘It was good for me to see the other

we really want to speak with you. Several

But I stayed for six years. It was one of

side of the coin. Ninety percent of the

months passed and they persisted, and

the best periods of my life.’

students I teach end up in industry. See-

in the end I said yes. Twente has a world

ing things from an industrial perspective

class package of knowledge and infra-

has helped me as a scientist. And my

structure. Top-notch people.’

students can only benefit from knowing what industry wants.’

033

[ chapter 03 ]

treatMent & tissue regeneration

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Treatment & Tissue Regeneration

03 helping the body to repair itself

[ intro ] Researchers at the UT are developing a wide range of new therapies and treatment options.

Some involve no more than altering a single molecule, while others entail the rehabilitation of the entire body. From repairing a bone fracture by simply applying a gel, to cancer therapy based on minuscule droplets of medicine, or a portable kidney machine which will replace daily dialysis.

Tissue regeneration research at MIRA develops technologies that restore the function of diseased and damaged organs. Biologists, chemists, nanotechnologists and engineers work closely together to apply the scientific breakthroughs that can speed up patient recovery.

035

3.2

How to help patients with Diabetes type I? [ intro ] Growing a new organ and implanting it into a patient is still in the

realms of the impossible. But the Tissue Regeneration group is working hard on an important intermediate step. The researchers are making scaffolds on which insulin-producing cells are grown. These scaffolds can be implanted into people with type I diabetes.

D

iabetes is a serious metabolic disorder. In people with type I diabetes, the pancreas produces too little insulin. The insulin producing beta-cells residing in the so-called islets of Langerhans in this organ are damaged or destroyed by the patient’s own immune system by this disease. The body needs insulin to be able to store sugar from the blood after meals.

The special groups of cells are not only responsible for the production of insulin but also detect how much sugar is in the blood, and whether more or less insulin is needed to maintain proper sugar levels.

There are two ways of treating patients with type I diabetes. First, they can inject themselves with insulin several times a day or they can use an automatic insulin pump. However, the side effects of this diabetes can be quite harmful on the long term. Chronic diabetes leads to blindness, kidney failure and impaired blood supply to limbs, potentially leading to

amputation. For patients who have severe difficulties in maintaining their sugar levels, an alternative is a transplant of islets of Langerhans from deceased donors. The first form of treatment is fairly stressful, while the second is still very inefficient: around 80% of donor cells are lost during or shortly after transplantation. Consequently, cells from three donors are needed to help one diabetes patient. But there is still a major shortage of donors. So until a way is found to culture new islets of Langerhans, scientists are seeking a more efficient method to introduce donor cells into the patient’s body.

Inefficient

036

Microwells all in a row MIRA researchers are working on a very advanced method. They have designed scaffolds made of a special polymer which contain tiny wells. These wells or shallow compartments are arranged in neat rows, in which cells can be grown.

The wells are just a few hundred microns wide. They are used to

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Donor cells are grown in tiny protective wells, so they can be safely transplanted.

protect the islets of Langerhans, whilst still allowing them to live in an optimum environment. The cells are ultimately transplanted into the patient’s body, scaffold and all. This doesn’t necessarily have to be near the pancreas; for example, it can be under the skin, in a muscle or in the abdominal wall. In any case, the cells need to end up in a location with a good blood supply. Then they can release their insulin into the blood, and obtain oxygen and nutrients themselves.

[ fig. a ] CULTURING ISLETS OF LANGERHANS In the case of diabetes the pancreas produces too little insulin, which is needed for the storage of sugar from food.

The patient then needs to inject insulin several times per day. However, an alternative is being worked on.

Islets of Langerhans in the pancreas are responsible for regulating the blood sugar level and the production of insulin.

In type 1 diabetes patients, the islets are damaged.

CULTURING

‘Scaffolds’ are being worked on: a protective bedding in which the islets can grow. scaffold

dimensions: several hundred micrometres

The researchers are currently refining the scaffolds by researching the effectiveness of different materials and designs. Both these factors affect the survival of cells in the wells, and hence their functioning. And because this principle is still so new, the researchers have to discover what works best through trial and error. The first step is to test various ways of making a scaffold out of the polymer material.

For example, by compressing mats of thin polymer fibres in pre­formed

porous maTs

Islets of Langerhans

Transplantation of donor islets of Langerhans is an alternative.

However, that is not yet efficient: about 80% of the cells are lost during transplantation.

pancreas

hydrogel with growth factors cultured islet

The entire scaffold is transplanted into the body, not necessarily in the pancreas but always near a blood vessel.

moulds. This produces a porous film containing the microwells. Because the material is porous, oxygen and glucose can reach the cells easily.

The degree of porosity determines not only how well these substances can pass through the material, but also how sturdy it is. The MIRA researchers plan to study the effect of all these variables in greater depth. conDucTing Trials The next step is to determine the right living environment for the cells. For

scaffold

blood vessel

islets secrete insulin into the blood

islets absorb oxygen and nutrients from the blood

example, should growth factors be added to the support material to ensure that the blood flow in the islets gets going as quickly as possible? And where is the ideal spot in the body to implant the scaffold? To answer that second question, the researchers are first of all conducting trials in animals.

Human trials are still some way off. But the principle works; the researchers are already convinced of that.

NExT PAgE: fOUR QUESTIONS fOR AART VAN APELDOORN AND MIJKE BUITINgA

037

3.3

Aart van Apeldoorn and Mijke Buitinga

‘ You mustn’t lose heart when a great idea just refuses to work’

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Aart van Apeldoorn is working on a range of projects to design an alternative strategy for the transplantation of Islets of Langerhans. One of them is Mijke Buitinga’s PhD project.

1

Why is this research important?

Buitinga: ‘Diabetes is a common illness, and a serious one. There’s no satisfactory treatment yet. Patients have to inject insulin throughout their lives, which is stressful and doesn’t work well for everyone.

And transplants are still not very efficient.’

Van Apeldoorn: ‘Our research is focused directly on helping patients.

The aim is quite clear. We’re dealing with a condition where an organ is no longer functioning properly, and we need a solution. The research is extremely application-oriented.’

subject itself is fairly new, but we can apply a variety of existing knowledge about cell growth and support materials to the making of artificial organs. That’s really challenging.’

Buitinga: ‘Plus the fact that you’re combining several different scientific disciplines. You’re working on a technical solution to a clinical problem. One minute you’re sitting at the computer thinking about the design of a scaffold, and the next minute you’re in the lab testing whether it’ll actually work in a living animal. I would never want to do just one thing or the other.’

2

3

Have you found your niche in this department, and in this research?

Van Apeldoorn: ‘Absolutely. I can put all of my creativity into it. The

What do you enjoy most about this research?

Van Apeldoorn: ‘Its interdisciplinary nature. I sometimes joke that we try to steal as much as possible

from other groups. An awful lot of research within MIRA is relevant to what we’re doing. So we’re always asking ourselves: is anyone working on interesting techniques? Can we incorporate them into our research line? It’s this talking to other experts, and trying to solve problems together, that makes this work so much fun.’

4

Do things sometimes go wrong?

Buitinga laughs: ‘Of course, a lot of things go wrong. Especially on the practical side. Progress is very slow in this sort of research. It’s sometimes really depressing when you’ve thought of a good idea that refuses to work. You’ve got to be able to cope with that. But as long as you keep focused on your goal, you’ll stay motivated.’

039

3.4

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Healing plasters Worn cartilage in a joint causes patients a lot of pain. Weight-bearing or bending is difficult and sometimes almost impossible.

Unfortunately, at the moment there is no curative treatment. The only option is pain control. Marcel Karperien’s department is working on a solution to this common complaint: a gel that is injected into the joint. There it hardens to form a protective layer over the damaged cartilage. The gel binds to the cartilage and is biodegradable.

The intention is that it will be replaced in time by the body’s own cartilage. Initial trials are due to start shortly. Not in humans as yet, but in horses, which also commonly suffer from wear and tear of the joints.

This image, made with an electron microscope, shows how the healing plaster cavities capture cartilage cells, which are stimulated to form a matrix. This cartilage matrix is shown by the blue colour in the less enhanced image.

041

3.5

Targeted delivery of medicines Delivering medicines to exactly the right place in the body: that’s the challenge which MIRA researchers have set themselves. They’re designing a broad range of smart technologies to realise that goal, ranging from ingenious ‘clothes lines’ to little bubbles that stick to a specific site.

W

hen you take an aspirin for a headache, the active ingredient enters the bloodstream via the stomach and the intestines. It goes not only to the head, but to the entire body. And the same is true of all medicines, whether adminis­tered in pill form or as an injection. This is far from ideal. It’s wasteful and can also be unhealthy: the medicine can cause damage if it ends up at the wrong place.

‘It would be ideal’, says Professor Johan Engbersen, ‘if you could get the medicine delivered exclusively to exactly the right place like some sort of parcel. That sounds simple, but is in fact so difficult that we’ll probably never succeed entirely.’ But Engbersen and his colleagues, not only at MIRA but also elsewhere in the world, have already made good progress.

Engbersen: ‘We use a whole arsenal of chemistry and physics to devise a specific solution for every challenge.’

Passive or active One approach to deliver a medicine to the right spot, Engbersen explains, is by using a passive mechanism. For example, solid tumours are well-supplied with blood vessels. And just like the tumour, these blood vessels grow very quickly. As a result, they’re not entirely perfect: they leak. ‘By

042

ma­king particles loaded with medicine (nanomedicines) so small that they can only leave the bloodstream via such leaks’, says Engbersen, ‘means they end up just near the tumour cells.’ However, Engbersen and his collea­gues are working mainly on active mechanisms: systems in which par­ticles are designed to adhere selecti­vely to the right cells. For example, the particle has a specially designed chemical group at its surface that binds specifically to a receptor on a cancer cell. ‘We really do work like a postal service’, says the professor. ‘First we carefully parcel up the vulnerable cargo, then we stick the right address on it, and finally we make sure that the parcel can also be opened again once it has arrived at its destination.’

In some cases these parcels contain a medicine, but in others they contain genetic material. For example, a section of DNA can take over the role of a defective section in the target cell. This is a form of gene therapy, a technology which is hardly used yet because it is fraught with snags.

‘Gene therapy as it has developed so far uses a virus to introduce the DNA into the target cell’, explains Engbersen. However, this has a number of disadvantages, such as adverse immune reactions, which

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strongly hamper further clinical development. ‘We’re investigating whether you can design a synthetic carrier instead. With the polymers we are using you can vary the structure, and hence the effectiveness, more easily. And you can make sure that the material is fully biodegradable and therefore has no toxic effects.’

Parcels like these can be composed of polymer chains that are fold up to a sort of ball in which the genetic material is packaged, but not necessarily: they can also take the form of a tangled ball. ‘We are also designing a sort of clothes line on which you can hang all sorts of stuff ’, says Engbersen, ‘and which folds itself up to various extents. The kind of chemical groups that you hang on that line determines, for example, whether the parcel is watersoluble or oily. The choice depends on the application.’ Moreover, the links chosen for the clothes line determine how and when the line breaks up and releases its cargo, and how easily the pieces of clothes line can be cleared up in the body again.

The choice of clothes-pegs can also help to determine the effect of the medicine. ‘Imagine a substance that kills cells, which you want to use against a tumour’, says Engbersen.

Clothes line

[ fig. a ] TARGETED MEDICINES Medicines or genetic material delivered to exactly the right spot in the body, like addressed postal packages.

polymer that works like a ‘clothes line’

link particle

The researchers design a sort of ‘clothes line’ that you can hang particles on. The design of the clothes line ensures that the links release the particles in a phased manner.

That way the particles can do their job only when they reach the right spot.

The packages are smaller than a ten-thousandth of a millimetre and contain polymer strands in which, or on which, medicines are attached.

particle

particle HOW DOES IT WORK? cancer cell cell

cell nucleus

The design of the particles is such that they preferentially bind to the right cell. For example, they can have a chemical group that preferably attaches to a cancer cell.

[ 01 ]

‘You want the substance to do its work only in the tumour, and not elsewhere in the body. Therefore we design the chemotherapeutic delivery system in such a way that the substance is not active while it’s still attached to the clothes line. By attaching it to the clothes line with a connection that can only be cut by an enzyme that is common in cancer cells, but not healthy cells, it is then possible to activate the medicine only in the tumour cells.’

The delivered particle finds its way to the cell that absorbs it.

[ 02 ]

The particle releases its contents. For example, a piece of DNA that activates the cell to to produce a therapeutic protein, or in the case of cancer cells a cytotoxic compound that kills the cell.

enDless possiBiliTies Engbersen enthuses about a number of other tricks that the parcels can be equipped with, such as miniscule gold rods that can be heated up from outside the body using a targeted beam of infrared light. This heating causes the package to break down, or to attach itself somewhere. Or you can put magnetic particles in the parcels, and then assemble them at a specific place in the body with the aid of a magnet.

The possibilities are endless. Virtu-

ally every wish-list can be translated into material properties. But the difficulty lies in actually applying the discoveries into clinical practice. The journey from idea to application is a long one. ‘First you have to describe your discovery in miniscule detail, because you’re often dealing with very complex particles. And then you have to go through the whole process of cell experiments in the laboratory, animal experiments and clinical trials. It’s a lengthy business.’

043

3.6

[ extracts from the schedules of... ]

clemens van blitterswijk and joost de bruijn

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‘it’s the intensity that makes it so much fun’ [ intro ] Two entrepreneurial professors explain

why they each have one foot in industry and the other in academia.

045

Clemens van Blitterswijk

7:00 Leave the house

‘I live in Friesland, not awfully convenient when you work in Twente, and have to be in Bilthoven a lot as well. But it’s just such a nice place to live… I stay over in Twente and I work at home one day a week, which cuts down the travelling. But I often put my time in the car to good use. This morning, for example, I had a telephone conversation with a colleague about MIRA’s new Materiomics research line.’

9:00

At MIRA: recordings for television science programme Labyrinth ‘The programme is doing a series on the theme of “making”. This episode was about making medical devices.

I’m happy to contribute. Not just for

046

the reputation of our institute but also because I think we owe that to the public. Our work is largely funded by tax revenues, so you really should take the trouble to explain what you do and why.’

11:00 Consultation on

Pre-Seed Grant

‘Life Sciences Pre-Seed Grant, which I chair, awards grants of up to a quarter of a million euro to new businesses to start up their research line. It’s a Netherlands Genomics Initiative and the Netherlands Organisation for Scientific Research project.

I think this sort of work is enormously important. It’s how innovation really gets off the ground.’

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‘It’s always inspiring to think about how you can best guide young people.’

13:00

Discussion with a promising prospective professor ‘We’re looking for a new clinical professor, and this is a very serious candidate. In this meeting we’re discussing how he would fill in the details of the post.’

14:00 Discussion with a Canadian colleague

‘This colleague will be spending a year here as a visiting professor.

He is on a sabbatical from his own university. Exchanges like these

From chance discovery to million-dollar deal Progentix has its origins in the larger company IsoTis. In the late 1990s, IsoTis was working on growing bone with the aid of stem cells and special support materials. Clemens van Blitterswijk and Joost de Bruijn, who knew each other from their work on biomaterials at Leiden University, were both working at IsoTis. In 2002, however, Van Blitterswijk elected to take up a professorship at the University of Twente, partly financed

by IsoTis. ‘I had to choose: carry on in business or go back to academia’, he says. ‘As a CEO I would have to give up research, whereas in Twente I can now do both. I research and teach, but I’m also involved in numerous start-ups and new businesses, such as Progentix,

[ who are... ] are vitally important for MIRA’s international character. Very fruitful for both parties.’

15:30 Consultation with the dean of the faculty

‘We hold these discussions on a regular basis, to look at how we can strengthen the teaching. That’s one of the things I’d miss if I only worked in industry: being involved in teaching. It’s always inspiring to think about how you can best guide young people.’

Who are Clemens van Blitterswijk (left) and Joost de Bruijn (Right)?

Clemens van Blitterswijk (1957) is MIRA’s scientific director and the leader of the Tissue Regeneration track.

He is also involved in numerous start-ups. Joost de Bruijn (1966) is the founder and director of Progentix, a

17:00 Telephone conver­­sa­tion

Bilthoven-based company associated

‘It’s a substantive discussion invol­ving an exchange of ideas. But we’re also looking at whether he might be able to come over and reinforce MIRA’s ranks.’

London. Both lead international lives and

with a colleague in New York

with the University of Twente. He is also a professor at Queen Mary, University of work in both industry and academia: Van Blitterswijk at the University of Twente, and De Bruijn at Queen Mary, University of London.

where I’m on the Management Board.’

Continued on next page

Progentix was set up in 2004 by De Bruijn, after leaving IsoTis. ‘I was fascinated by the possibility of growing bone without stem cells or growth factors’, he says. ‘Just a support material that stimulates bone growth: it was a chance discovery that seemed too good to be true. But it really worked.’

The large American company, NuVasive, showed an interest almost immediately.

NuVasive is a listed company specialised in innovative techniques for surgery on the vertebrae. ‘You need a partnership like that’, says De Bruijn. ‘We could never invest enough ourselves to embark on the long journey to clinical practice.’ In 2009, after six months of negotiations, the two companies entered into a partnership. Under that partnership NuVasive invested 80 million dollars and in so doing acquired a share in Progentix.

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continued from page 047

18:00 In the car back to Friesland

‘On the way I have another telephone conversation with one of my PhD students about his research. He’s now at the stage of writing his thesis.’

20:00 Go for a run

‘On days like these I don’t get home until 8 pm. I then like to go for a run in the evenings, although I’ve not got round to it much recently. I really should start to make time for it again. My ambition was to run the marathon in under three hours, but I haven’t managed that so far.’

21:00 A quick check on the horses

‘My wife and daughter have a number of Icelandic horses. In fact, we have a sort of small stud farm at home. I get involved with that a bit from time to time. It’s great to focus on something completely different from work for a while.’

Entrepreneur and professor Is it possible to combine being both a professor and an entrepreneur?

Is such a partnership between a company and a university department common?

Van Blitterswijk: ‘It’s mainly a lot of hard work. You work around the clock. In the evening you’re often still meeting with US investors, for example, and in the morning you’re all set again for a discussion in the lab.’

Van Blitterswijk (laughs): ‘Our depart­ ment in Twente has one spin-off a year on average. You mustn’t forget: a lab can think up great ideas, but that’s still a far cry from a useful product on the market. For that you need investments and long test periods. You can only do that with the help of a company. But large, existing companies are often very rigid and suffer from “not invented here” syndrome: they’re only inte­ rested in their own discoveries.

In that case spin-offs are the ideal solution: the link between a scientific discovery and a patented invention that actually makes it onto the market.’

De Bruijn: ‘But

the skills are not so different. In both jobs you have to achieve good results, sell them, be financially responsible and attract and motivate good people.’

‘That does mean that you can’t be a professor who’s just at the university. You have a quite different schedule: everything goes on at the same time.’

Van Blitterswijk:

‘It’s that intensity that makes it so much fun. The early days of Progentix were incredibly busy, for example.

But then it’s even better when it works. After that we really had to kick the habit.’

De Bruijn:

Van Blitterswijk: ‘The two jobs often complement each other.

And that’s only to your benefit when it comes to things like applying for government funding, for example. You’re not in your department so much, but your double role does produce more in terms of collaboration and financing.’

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‘Spin-offs are much more dynamic. It’s not easy for a large company to develop a new technology. It always has to make a profit, keep shareholders happy, so it doesn’t want to take on too much risk. And a large company is less stable. As soon as a new director arrives, its course can change completely. Small ones often concentrate on one technology that they believe in heart and soul. And they have a very tight-knit team.’

De Bruijn:

Van Blitterswijk: ‘A spin-off is very much like a university department in fact. With 40 people, you still have a very strong sense of belonging to a group: this is what we stand for and this is what we want to achieve.’

Joost de Bruijn

9:00

Discuss schedule with secretary ‘And then half an hour answering business emails and signing a pile of documents.’

9:30

the renowned American journal PNAS (Proceedings of the National Academy of Sciences). We’ve received a lot of responses, from colleagues, but also from journalists.’

we have entered into partnership with. They’re shareholders in our business, so we are accountable to them. But these meetings always yield useful insights as well.’

10:30

14:00 Prepare for a

Interview with a journalist about Progentix

Meeting with the Progentix Supervisory Board

‘Our technology has been in the news a lot lately. A number of articles have already appeared in the national newspapers. Recently, some highly promising results of our technology were published in

‘These are very important meetings for us. We discuss the progress made, both technological and commercial. The meeting is also attended by representatives of NuVasive, the American company

lecture on ‘industry and future perspectives’ ‘Once every two weeks I fly over to London for the day to give a lecture to students. This time I’m Continued on next page

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continued from page 049

Ceramic powder slowly changes into bone New bone has grown (red) on Progentix granules (grey) implanted in an animal bone with a defect.

preparing a lecture about stem cells, tissue engineering and regenerative medicine. It’s a lot of fun to do; the lecture is always attended by some highly enthusiastic students who ask lots of questions. On these days I also have meetings with PhD students and colleagues. Yes, I really do feel part of that department, even though I’m only there a couple of times a month. It used to be more often, but it’s getting increasingly difficult to combine with Progentix.

But at the moment I don’t want to give it up altogether; I find teaching much too enjoyable and inspiring for that. Even though these are long days: I leave the house at 5am and get back at 11pm.’

16:00 Dealing with

A simple fracture usually heals by itself.

certain proteins. In time the synthetic

But sometimes the bone is too badly

material dissolves by itself, leaving just

damaged, or too much is missing. After

the body’s own bone.

a serious accident, for example, or after a tumour has been removed from the

Exactly how it works is not clear yet.

bone. In such cases, doctors need to give

But the fact is, it does work. Progentix

the bone a helping hand. For example,

has now further refined the material

they take a piece of bone from some-

through trial and error: composition,

where else in the body, often the pelvis.

grain size and porosity have now been

This has its drawbacks: it creates a hole

optimised to promote maximum bone

and the surgery is often accompanied

growth. The researchers have success-

by a lot of pain. An alternative is to use

fully tested their discovery on animals,

a piece of bone from a donor, or a pros-

and initial trials on humans are highly

thesis made of metal. But these “dead”

promising. The bone heals neatly and

materials will never really become part

grows only where intended. The results

of the bone, and there’s always a risk of

are as good as those of autologous

infection or rejection.

bone transplants, but without the unpleasant side effects.

the commercial aspects of Progentix

Progentix, a company associated with the University of Twente, is bringing

The material is easy and cheap to pro-

‘I’m still closely involved in the company’s financial and staffing matters, but also in the technology.

I think that’s important. Talking with people, listening to what’s going on.

There are 22 of us now, and we’re still expanding.’

a new alternative onto the market: a

duce. It is expected to make its market

powder containing synthetic calcium

debut shortly and accelerate the devel-

phosphate. By chance, Progentix direc-

opment of bone surgery worldwide. A

tor Joost de Bruijn and his colleagues

more user-friendly variant is already in

discovered that this material promotes

the pipeline, in the form of a paste that

bone growth by attracting stem cells and

is easier for the surgeon to insert.

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17:00

21:30

Checking and signing potential business partner’s term sheet

Telephone conference with NuVasive colleagues in the US

‘Apart from Progentix, we’re also working on other start-ups. For one of them, we’re in talks with a major commercial party that’s interested in an exclusive licence on our technology. The term sheet containing the terms and conditions of our agreement has been negotiated and we’re flying abroad next week to discuss the draft contract.’

‘Often I can’t avoid having to do some work at home, answering emails, reviewing scientific articles, etc. In view of the time difference with the West coast of the US, there are often conference calls with our NuVasive colleagues as well.

Sometimes you really do have to talk live. Luckily it’s not too much trouble in my case. I don’t have any children and my partner is also closely involved in Progentix as a consultant, so she knows what it’s like. In fact, sometimes she takes part in these conversations herself.’

18:00 Back home; go for a run

‘I always try to set aside time for running. I’m training for the New York marathon, although I’ve just put myself out of the running due to a calf injury. It’s great to clear my head of everything during a run. Especially when it’s busy at work. I find it easy to leave work behind. Some people need a week to wind down on holiday. Not me.’

‘It’s great to clear my head of everything during a run’

A blend of cultures MIRA’s employees work a lot across borders, both literally and through their contacts in Twente.

Van Blitterswijk: ‘MIRA aims for a cosmopolitan character. Why is that important? For a commercial rea­son, first of all. It’s essential to have a large international network. Invigorating ideas and chances for collaboration often come from other countries. In­ sti­tutes with staff from other coun­tries get that for free. Those contacts will benefit you throughout your career.’

‘And it also creates a special atmosphere. You develop bonds quicker. Foreign staff don’t know anyone else, so they’re keen to socialise with their colleagues.’

De Bruijn:

‘It’s wonderful to see how quickly foreigners feel at home here. Within a year you see Chinese and Indian staff eating Dutch-style sandwiches for lunch. The labs are very friendly. And that benefits the quality of the work.’

Van Blitterswijk:

De Bruijn: ‘And there’s also a practical reason why there are so many foreigners here. Good PhD students are very hard to find.’

Van Blitterswijk: ‘There are 17 million people in the Netherlands, and seven billion in the rest of the world. So it’s logical that there’s more talent abroad than here. And all that debate in society about foreigners and integration… none of that comes into play in the lab.’

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3.7

Wearable kidney

Membrane scientists at MIRA are designing artificial kidneys that will greatly improve the lives of kidney patients. These artificial filtering units are more effective in cleansing blood and smaller and easier to use than the current technology.

MIRA’s goal is to use these novel artificial kidneys in portable and/or wearable devices.

W

e don’t usually think about it, but our kidneys play a vital role in our bodies. They filter dangerous toxins from our blood and produce various important hormones. If your kidneys don’t function properly, this has a major impact on your life. Once a kidney has deteriorated beyond a certain point then there are only two options: receive a donor kidney, or regularly have the blood cleaned outside the body in a treatment called dialysis. Dialysis patients have to visit a clinic or hospital three to four times a week and spend several hours hooked up to a large dialysis machine that cleans the blood.

Quality of life In the Netherlands, around 40,000 people suffer from kidney damage. Some 13,000 patients have end-stage kidney disease (kidney failure) 6,000 of those are on dialysis treatment and 7,000 have received a donor transplant. Despite the high costs of dialysis treatment, which amount to over 75,000 euro per patient per year, it only has limited success. The mortality of these patients remains excessively high, whereas their quality of life is generally low.

052

At home Due to a shortage of donor organs, the waiting time for a donor kidney is currently about four years.

Scientists are therefore exploring alternatives for improving patients’ lives. One option is to improve the current dialysis treatment. Dialysis equipment is being made smaller, portable and more patient-friendly.

This allows people to perform the treatment at home, for instance while they are sleeping.

Scientists at MIRA are participating in the consortium funded by the Dutch Kidney Foundation, which aims to develop a wearable kidney: a small dialysis device that can be easily carried by the patient. The challenge is to make this device small enough to be wearable, yet effective in cleansing the blood, safe, and easy to use.

body fader On behalf of the Dutch Kidney Foundation, MIRA scientists are helping to develop a small device which is light and small enough to carry around comfortably, yet purifies the blood effectively.

Mixed Matrix Membranes

Dimitris Stamatialis and his colleagues in the Membrane Technology group are working on a crucial element of the wearable kidney: the membrane, a so-called mixed matrix membrane (MMM).

This is a filter that selectively removes toxins from blood. This novel filter is prepared by putting small porous particles into a polymer

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sponge. When this filter is placed in contact with blood, the blood cells cannot enter the sponge due to their size, whereas the smaller toxins pass through and are selectively captured by the porous particles.

3.8

To engineer bone, a scaffold prepared from a rigid biodegradable polymer is used. The very small size and the exact features of the structure – prepared by stereolithography – are evident from the comparison with a match.

Playing with molecules [ intro ] Repairing a fracture with a screw that later disappears by itself.

Delivering medicines to precisely the right place in the body with the aid of tiny, biodegradable capsules. Or making a blood vessel from a material which is replaced in time by the body’s own cells. All of this is possible with biodegradable polymers.

Continued on next page

053

P

olymer chemistry is like playing with Lego. You use molecules as building bricks and put them together to make long chains. By choosing the molecules carefully, you can give the polymeric material the exact properties you require. For example, you can vary its strength, its stiffness, the extent to which it attracts water, its biodegradability and the ease with which it can be moulded into the right shape.

This is what Dirk Grijpma and his colleagues from the Biomaterials Science and Technology group are working on. ‘We make a range of plastics which the body can break down itself in the long run’, says Grijpma. ‘Our materials are compatible with the body’s own cells, and are designed in such a way that they get cells to do exactly what we want. For example, growing and forming tissue in a certain shape. For this process we need to design both the material and its shape.’

Grijpma cites the example of implants that promote bone growth. These provide a solution when a bone is missing following a serious trauma or the removal of a tumour. Surgeons sometimes transplant a piece of the patient’s own bone from a different part of the body, but this has various drawbacks. It creates a wound somewhere else, and the piece of bone is often not the right shape.

And with a non-biodegradable material, such as metal, there’s always a risk of infection. ‘Those drawbacks don’t apply to our alternative: a prosthesis made of a

Implants

054

biodegradable polymer mixed with a material that promotes bone growth’, says Grijpma. ‘You make a scaffold on which autologous cells grow and form tissue. The scaffold is gradually resorbed by the body, ultimately leaving just the patient’s own bone.’

Bone tissue is not the only thing you can grow on a scaffold: blood vessels are another possibility. ‘It would be great if after a heart attack, you could replace the blocked blood vessel with a vessel made from the body’s own cells’, says Grijpma. ‘We’re working hard on that at present. We make small porous tubes of a bio degradable polymer and “seed” it with cells.

Under the right growth conditions in a bioreactor, these cells start to spread, proliferate and perform the desired function.’ Application in humans is not on the immediate horizon, but trials in animals to date have proved very promising. The researchers have already managed to replace a section of the aorta in mice.

According to Grijpma: ‘The material appeared to be strong enough to be sutured, and there were no leaks.

We’re now working hard to make experiments on humans possible.’

Seeding cells

Another development that Grijpma is proud of is a new technique for building three-dimensional polymer structures with considerable accuracy: stereolithography. This technique uses a resin which hardens under the influence of light. In such a resin, a beam of light can build up – layer by layer – a solid structure that precisely matches the structure designed by the researchers on the computer. ‘The technique has been

New resin technique

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around for a while’, says Grijpma, ‘but so far only using resins that are not biodegradable. Ours are.

What’s more, we can now build these structures in the presence of living cells using hydrogel materials.’

These cells are mixed with the liquid resin. When this hardens, they end up in and on the threedimensional structure, where they can still perform their function.

The technique makes it possible to design an ideal structure for cells.

For example, a porous structure which allows the efficient supply of nutrients and removal of waste substances. And you can make sure that a material has the best mechanical properties combined with high porosity.

A tubular scaffold prepared from a flexible polymer (left) next to a pig blood vessel (right).

As the implanted scaffold grows its own cells, the polymer base dissolves.

Bringing an antiadhesion agent on to the market ‘By chance, we made an interesting discovery’, says Dirk Grijpma. ‘When sterilising a certain polymer with gamma radiation we found that the radiation makes the material not only more flexible but also elastic. It becomes a sort of biodegradable rubber. This appealed to us immediately: nothing like it existed as yet.’ The depart­ ment applied for a patent and sought funding to do something with the idea.

‘But bringing a product onto the market ourselves is not our priority of course’,

The group has now developed a whole series of biodegradable resins with a range of properties: from glassy and hard to rubbery and elastic, and from soft materials with hydrogel-like properties to ceramiccontaining materials that promote bone growth. ‘The possibilities are endless’, says Grijpma, ‘especially in combination with the computercontrolled structure design. For example, where a tumour has been removed from a jawbone, you can take a CT scan of the site and then design a prosthesis that fits exactly.’

The next challenge is to grow different types of cell together on a scaffold. This will ultimately make it possible to produce complicated tissues, such as liver tissue or bone containing blood vessels. And then there are also the systems for delivering substances, such as medicines, to exactly the right place in the body.

This can be done, for example, by packaging the medicine in tiny capsules made of a biodegradable

New challenges

Microscopic image shows how bone cells

says Grijpma. ‘So we set up a company

grow on the scaffold.

called Medisse, which makes materials that prevent adhesions after surgery.'

Almost all operations, around 80 to 90%, result in an adhesion somewhere in

polymer. Such particles are small enough to be injected into the bloodstream. ‘Antibiotics can also be packaged in this way’, says Grijpma, ‘as equally growth factors which ensure that cells develop into a specific cell type. The latter is useful if you want to culture a certain tissue from stem cells.’

Antibiotics and growth factors can also be incorporated in a biodegradable bone screw. ‘You can kill two birds with one stone’, says Grijpma. ‘You can fix a fracture with a strong material that in time disappears, while at the same time you release antibiotics and growth factors aimed at specific targets.’

Does the group have any other plans? ‘Yes of course, there are many more possibilities’, says the researcher. ‘There’s an enormous demand in the medical world for new materials: better, stronger, more flexible, better geared to the

the area affected: scar formation binds together tissues that should remain separate. This sometimes necessitates further surgery. ‘So there is an enormous market for a product that prevents adhesions’, says Grijpma. ‘Medisse makes a thin film of biodegradable material that is placed between the organs during surgery. After two weeks the risk of adhesions has passed and the material is reabsorbed.’

The first investors have now come forward and the product is currently being tested by an external party. Once it has been approved as ‘safe’, Grijpma believes that clinical experiments will soon follow.

‘I have every confidence in it.’

function. The challenge is to devise materials that are demonstrably bet­ter. And then to convince the regulatory authorities and doctors of that.’

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3.9

Bernke Papenburg and Materiomics Bernke Papenburg is the project leader of the Materiomics start-up. Materiomics researchers work on how the properties of materials – such as structure and surface – influence biological processes. For example, they screen materials for use as supports for cell growth. Or they work on surfaces which can reduce the vulnerability of medical implants to infection. Materiomics is currently still part of the university, but during 2011 it will become an independent private company.

A high-magnification picture of a chip where each of the nearly 4,400 small compartments contains structures with different shapes, dimensions and/ or spacing.

1999

1999-2004:

2004-2009:

Degree in chemical technology at the University of Twente

Graduation research project and then PhD research at the Membrane Tech­no­logy Group, in colla­bo­ration with the Tissue Regeneration Department

What do you do if medicine is too ‘medical’ for you, but physics and chemistry by themselves are too technical? Then you go for a combination.

In any case, that was the strategy adopted by Bernke Papenburg. Courses

Papenburg studied scaffolds as supports

on the cells growing on it. I was keen

in biomedical technology or technical

on which cells can be grown. The whole

to develop it further as a PhD student.

medicine didn’t exist at the time, so she

scaffold can subsequently be introduced

And fortunately, I could. This was a

went for chemical technology.

into the body, where the cells then

fascinating time as well. Especially

start to perform their natural function.

thanks to the collaboration with other

‘Above all, I didn’t want to go into

To replace a vein, for example. She

disciplines and the freedom I had to fill

research. I was afraid that it would

developed this principle further during

in the details of my own research.’

be too theoretical. It was only when I

her own PhD research.

was about to graduate that I became fascinated by research. You devise a

‘It was tremendously exciting research.

specific theory, think about how you can

We had found a broadly applicable

test it, and then go and do it. It’s much

method that can change the surface of

more applied than I thought.’

a scaffold, exerting a strong influence

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2005

2009

2009-2010:

2010-present:

Postdoc position at Tufts University in Medford, greater Boston area, MA, US

Project leader Materiomics, MIRA

2010

Together with her colleagues,

‘Using our chips you can study a huge

Papenburg designs chips with nearly

number of different variables quickly and

Papenburg had the opportunity to do

4,400 compartments, each of which

efficiently. With that information, our

postdoctoral research in Boston, where

is just a few hundred microns wide.

ultimate goal is not just to control cell

she worked on biomedical implants

The compartments vary in shape and

growth but also, for example, to reduce

made of natural silk. But after a year

structure. Stem cells are seeded into

the risk of clotting and infection with

she returned to The Netherlands, mainly

them. Using the chip, the researchers

various medical implants.’

because her boyfriend lives here.

can investigate how the nature of each compartment influences the growth of

‘The University of Twente had

the stem cells and their development

contacted me. Did I want to help set

into specialised cells, such as fat cells or

up the Materiomics start-up? It was

bone cells.

a unique opportunity for me. But I’m glad I had that year in Boston first.

It was very inspiring to do research outside Europe for a change. You see how people from other cultures tackle things. For example, Americans work far more on short-term goals. They just go for it, with no ifs and buts.’

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[ chapter 04 ]

Medical Robotics & the Human Body

getting on the move again 058

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04 [ intro ] The UT carries out research in the realm of Medical Robotics and the Human Body.

Most of this research is done by the Neural and Motor Systems research track at the MIRA institute. This track examines the interplay between brain, nerves, muscles and the skeleton. The work has a firm scientific basis and is driven by specific healthcare questions. The pioneering research focuses on restoring function to the neural and motor systems. Current topics include helping patients to rehabilitate with the aid of robots, selective electrostimulation and innovative prosthetic devices.

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4.2

Rehabilitation robot

gets paralysed patient walking again [ intro ] In the future, people recovering from

partial paralysis after a stroke will get help with walking from a robot. The computer-controlled LOPES machine developed by MIRA literally gives them a bit of a leg-up. It’s unique in the world.

L

aced into the LOPES (Lower extremity Powered ExoSkeleton), the patient looks like a sort of Robocop from the well-known film

by Paul Verhoeven. A frame wraps around the pelvis, the legs are laced into two huge bundles of mechanics.

Taking heavy mechanical steps, the

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patient walks on a treadmill, while suspended in a safety harness and controlled by brake cables connected to the robot motors. ‘The patient feels stabilised, but the machine doesn’t take over completely. The rehabilitation robot is intended as a support, not a replacement’, explains researcher Edwin van Asseldonk in the laboratory which is home to the LOPES machine. ‘If your tennis coach holds your racket constantly when you’re hitting the ball, you won’t learn to play tennis. The same applies to a person who has to learn to walk again.’ From his place at the computer, movement scientist Van Asseldonk can make the patient do what he wants. Take big steps, bend or swing the legs out better? A piece of cake, a couple of mouse clicks and the patient’s movements have been adjusted. But Van Asseldonk only does that if it is really necessary.

Red and blue line The computer screen displays two lines: one blue, one red. The blue line is the patient’s current gait, while the red represents the way an able-bodied person walks. The aim of practising with the rehabilitation robot is to bring the two lines closer and closer together.

The machine has sensors at the pelvis, hip and knee joints which monitor the patient’s movements closely. The sensors send their information to the computer. Based on this data, the researchers can compute each movement separately.

For each individual patient, they can also determine how movements should normally be performed and how they are restricted. For example, if a patient has trouble

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The rehabilitation robot stabilises the patient while

walking because his knee doesn’t bend enough as he swings his leg forward, this is unerringly recorded by the sensors. After analysing the data, the computer issues a tailormade recommendation as to how the movement can best be adjusted.

The protective ‘exoskeleton’ prevents injuries from to the over-stretching of joints and muscles.

Robot replaces physiotherapist

The intention is that the constant corrections will lead to changes in the brain. Because, in fact, it’s mainly the brain that the LOPES robot is training. In people who’ve had a stroke or a brain haemorrhage, the problem lies not in the muscles but in the control of the muscles. As a result of getting patients to walk on a treadmill and adjusting their movements at the same time via sensory information, the brain adapts.

The outcome is that patients gain more control over the way they walk.

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stimulating her to make the right moves.

The LOPES robot is doing the same thing that physiotherapists do at present. A patient who’s unable to walk as the result of a stroke, partial spinal cord lesion or serious orthopaedic surgery usually receives training from two physiotherapists.

One provides support and gives instructions while the other helps the patient to take steps on the treadmill.

But this is hard physical work for the physiotherapists and takes up a lot of their time. As a result, it’s becoming increasingly difficult to continue these types of therapy under the continued pressure on healthcare.

In The Netherlands alone, there are forty thousand cases of stroke or cerebral haemorrhage every year.

In a large proportion of these cases, patients are left with partial paralysis of the legs. The idea behind LOPES

Medical Robotics & the Human Body

is to get the robot to do the heavy physiotherapy work, thus relieving the care providers of a substantial burden.

Sensation of freedom Rehabilita­ tion robots are already on the market, one producer being the Swiss company Lokomat. ‘But those machines’ range of movement is much smaller than that of LOPES’, says Van Asseldonk. ‘In our machine people don’t need to move along set lines, thanks to special mechanical additions and advanced control of the robot. The sensation of freedom that the patient gets in the LOPES makes our technology unique.’ To achieve this, mechanical engineers build complicated frame structures which are designed using a virtual centre of rotation at the point where the patient’s pelvis is located. These ensure that patients barely notice that they are being supported from behind, but nevertheless don’t fall over.

New prototype Before LOPES makes its debut in rehabilitation clinics, however, there’s still a lot of research and development to be done on the gait robot. In collaboration with Het Roessingh

rehabilitation centre in Enschede, the Sint Maartenskliniek in Nijmegen and technology firms MOOG and Demcon, MIRA researchers are currently pulling out all the stops to improve the control systems.

The machine also needs to be more compact, more user-friendly and lighter. One option in this respect is to alter how the forces are transferred from the motors to the legs. The aim is to have a second, completely new LOPES prototype within 18 months.

The research at MIRA also focuses on the precise learning mechanisms of people receiving gait training in the machine. We know that patients who are unable to walk, or walk normally, as the result of a stroke immediately try to counterbalance this by adopting different gait patterns. The question for the researchers is whether they should encourage this effort or curb it. Does every patient find his own alternative gait strategy, or is it better to encourage gait patterns found to be ideal for the average walker?

MIRA has been given a grant to investigate whether rehabilitation in the LOPES robot is quicker when combined with

Mindwalker

a technique that increases the excitability of areas of the brain. Van Asseldonk: ‘We attach electrodes to the patient’s head, near the command centre in the brain. Our aim is to stimulate that centre while the patient is training in LOPES.’ Short magnetic pulses are sent out from a coil of copper wire on top of the patient’s head, generating tiny currents in the brain. These pulses stimulate the areas of the brain responsible for walking movements.

Science fiction Couldn’t the patient’s brain ultimately control the robot legs? Van Asseldonk: ‘That would be great, and that’s why we’re investigating that possibility now. If this so-called Mindwalker works, then in the future patients will be able to send commands to the robot legs using a specially developed helmet. And, in a manner of speaking, take their exoskeleton to the supermarket.’ It sounds like science fiction. Van Asseldonk: ‘Yes it does, and that’s what makes our discipline so exciting. Combining fundamental research with robot technology to help patients with serious motor problems. What more could you want?’

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4.3 Below surgeon Ivo Broeders working in a present day operating room. To the right a future surgeon at work with the help of a robot.

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Operation robot needs just a single incision

‘K

eyhole operations’ are a welcome outcome for patients because they are

not left with a large scar but three or four small incisions. Single incision operations are even less demanding as only a single small entry point to the body is made. Robots play a valuable role in supporting the surgeon during such challenging operations.

For example, they can work very precisely, never suffer from shaking hands and never experience backache when operating from an inconvenient angle. MIRA is working on the ‘TeleFlex’ robot in close collaboration with surgeon and clinical professor Ivo Broeders.

Using this robot the doctor can operate a flexible tube from his cockpit chair with the aid of a computer and joysticks. This tube is equipped with a camera and various work channels. These allow the surgeon to observe the body and perform small interventions.

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4.4

TLEM­safe The basis of TLEM­safe (Twente Lower Extremity Model) is a dataset compiled by dissecting the

A navigation system for surgeons leg – the ‘lower extremity’ – of one person.

[ intro ] During complex leg operations, surgeons often decide where to

reconnect muscles based purely on intuition and experience. With varying degrees of success. MIRA researchers are developing a detailed computer model of the musculoskeletal system of AN INDIVIDUAL PATIENT. This model can guide the surgeon unerringly and increases the chances of a successful operation.

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A

computer animation shows the contours of a leg with a pattern of brightlycoloured lines. The animation shows precisely how the forces are distributed between the muscles.

With split-second accuracy, you can determine how the forces must have changed during a movement.

And with considerable accuracy you can calculate how much power a muscle must deliver for the patient to move as efficiently as possible.

This is important because it shows which muscles the surgeon can cut in and which he must spare at all costs to ensure the patient will walk again after the operation. Crucial knowledge, especially during radical surgery in which the surgeon has to remove a large part of a muscle or bone due , for example, to a tumour.

Muscles sometimes have to be rerouted. The model can also be useful in treating a common congenital deformation of the hip joint. The head of the femur sometimes has to be relocated to enable a person to walk normally. The computer model can tell the surgeon exactly where it should be located in the pelvis.

The basis of TLEM­safe (Twente Lower Extremity Model) is a dataset compiled by dissecting the leg – the ‘lower extremity’ – of one person. All the muscles, tendons, insertions and bones were picked apart, measured in the smallest detail, and digitised. However, the resulting wealth of information cannot be applied to every patient on a one-for-one basis. Therefore a method has been devised for adapting the model to the individual

[ fig. a ] SURGEON’S NAVIGATION SYSTEM A dataset for surgeons that provides a detailed picture of the musculoskeletal system of the leg. The TLEM system helps the surgeon to prepare for the operation.

The surgeon enters the information obtained from the X-ray or MRI scan into the computer. Then the system issues a patient-specific advice about how the operation can best be performed.

HOW DOES IT WORK?

[ 01 ]

[ 02 ]

[ 03 ]

The TLEM basic model on which the muscle line of action and attachment points can be seen.

X-ray image of the damage in the patient.

This information is entered into the TLEM system.

The TLEM patientspecific model.

The surgeon practises by performing a test operation on the computer.

TLEM navigation system

Drudgery

screen with X-ray and TLEM model as reference

[ 04 ] During the operation, the surgeon works with the navigation system that registers the position of bones with the aid of cameras.

Then the surgeon can see on the screen if the operation is being performed accurately.

Source image TLEM model: AnyBody Technology

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patient. This is done by mapping differences in muscle geometry and size using an MRI scan.

Researchers translate these data into a three-dimensional computer model. Surgeons can use the model to prepare for their operations more effectively. And even practise virtually beforehand. This way it will be easier to predict whether a person will indeed be able to walk again after radical surgery.

Less Risk of a wHeeLcHaiR Researchers compare the computer navigation system that they are developing for surgeons to a TomTom: it tells the surgeon exactly where certain muscles should be moved to, just like a car being guided to its destination along a predetermined route. For example, if a surgeon wants to turn a muscle or section of bone through ten degrees during an operation, he can do so with extraordinary accuracy using the navigation system, assisted by cameras and markers which are attached to the bone.

Over the next four years, MIRA will work to refine the system further by means of laboratory tests. After that the model should be ready for the trial phase. The researchers from Twente are working closely with colleagues from Radboud University Nijmegen Medical Centre, Warsaw University of Technology and a number of specialist companies. It is expected that several hundred people a year in The Netherlands who need to undergo a serious leg operation will benefit from TLEMsafe in that their chances of ending up in a wheelchair will be reduced.

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4.5

Robotic system for prostate cancer diagnosis [ intro ] Every day countless men have tissue samples removed from their

prostate for biopsy tests. An intervention that is painful for the patient and challenging for the doctor. A robotic system that can work under the guidance of an MRI scanner can provide a solution.

C

urrently it’s quite a hassle for a doctor to remove a small piece of tissue (‘biopsy’) from the prostate, if a tumour is suspected. An MRI scan is used to determine where exactly the tissue sample must be taken from. The doctor then has to insert a needle through tissue and muscles in search of suspected cells. Difficult, because when a sample is being taken the prostate can suddenly move, causing the needle to miss its target. Therefore, in practice the doctor pricks three or four times to make sure the job’s done. Painful for the patient, but also far from ideal for the doctor who has to keep on walking in and out of the MRI room.

And if the sampling goes wrong, the analyst will receive healthy-looking

prostate cells even though cancer cells might have been right next to them. Therefore, a doctor can never be absolutely certain if a reassuring diagnosis is right.

Performing the intervention inside the MRI scanner would be far easier. Then the doctor could see in real time if he has reached the target. That’s not possible, however, as the doctor cannot work in the MRI scanner’s strong magnetic field. And using a robot system to obtain a piece of tissue from the prostate is also easier said than done: the strong magnets in the MRI room would still form an obstacle. That might all change in the future though.

Because in the five-year project

Google Maps

Minimally Invasive Robotics In An MRI Environment (MIRIAM), MIRA is working on a solution to the problem. A multidisciplinary team, which includes Radboud University Nijmegen Medical Centre and commercial partners, is building an advanced robotic system from non-magnetic materials. The system receives continuous feedback from the MRI scanner about where the needle is. If the needle deviates from the predetermined route, the robot can bring it back on course.

The MIRIAM project team is also developing models to predict the movements in the organ tissue. The researchers describe it as ‘a sort of Google Maps for the body’. This give continued on next page

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4.6

sarthak misra

From space robotics to prostate interventions

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Sarthak Misra started his career in space research. The Canadian made the switch from the Johns Hopkins University in Baltimore to the Control Engineering Group of MIRA, where he leads the MIRIAM project.

1

What exactly did you do in space research? ‘In the International Space Station Program, Canada is leading the construction and operation of the Space Station robotics. For example, Canada built the robot arm for the space shuttle. As a dynamics and control analyst I looked at what sort of movements a robot must make to transfer a payload safely from the space shuttle to the space station. The payloads are sometimes the size of a bus. I also developed emergency scenarios in the event something goes wrong. This work involved working closely with mission planners at NASA in Houston.’

2

Isn’t the switch from space to the prostate a ‘giant leap’? ‘No. Of course modelling tissues is different from working in aerospace engineering. And the ultimate objective – improved patient care – is also different. But the fundamental engineering principles for robotics are the same. In both cases you develop techniques to move robots in safety critical environments. My background in aerospace engineering is a big advantage in the work I'm doing now.’

3

What attracted you to Enschede, after gaining your PhD at the world-famous Johns Hopkins University in Baltimore? ‘MIRA was simply the best choice for me. I valued how I could set up my own line of research here and the funding I could receive for this. On top of that, I already had various contacts with researchers at Twente and also other Dutch universities, such as Delft, Nijmegen and Utrecht. And on a more personal note, my wife is Dutch. She didn’t object to returning to The Netherlands. We live in Zwolle, which is a very different environment for me – compared to living in Montreal or Baltimore, but that’s simply a matter of adjustment.’

4

Is research your mission or merely a stepping stone to a spin-off company? ‘I enjoy the freedom that an academic environment offers and I’ve got no plans to leave it. Of course it would be great if my research led to a spin-off. But my work with students, fellow researchers and colleagues isn’t something I’d give up lightly. I’m now an assistant professor and that position gives me plenty of opportunities to develop myself.’

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the doctor step-by-step information about the route the needle must take to reach its target. The computer model also helps to accurately predetermine where the needle can best be inserted.

With MIRIAM, the researchers want to develop a surgical technique that minimises the inconvenience of a prostate intervention. No less than onein-six men in the Western world experience prostate cancer at some point in their lives. In Europe alone this translates to more than 300,000 new cases a year. For the time being, the researchers are concentrating on prostate cancer. However, in the future this technique could be used to investigate liver ablations or breast biopsies as well.

Tests on cadavers

The greatest challenge is getting the different systems to faultlessly communicate with each other. Yet the project team is confident that in five years time they’ll have a prototype ready to undergo tests on cadavers.

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4.7

[ extract from the schedule of... ]

Michel van Putten

‘ deep insights require long contemplation’ [ intro ] Michel van Putten is a researcher,

professor, doctor and physicist. He regards MIRA’s high ambitions as an intellectual challenge.

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11.00 Meeting with Tom Schwarz, venture capitalist (Twente Technology Fund)

7.00 Getting up

‘Always hard. I have a coffee with my girlfriend and try to get going.

I like to go on until very late in the evening. I wish I could get by on four hours’ sleep, like Napoleon, because there’s such a lot of fun stuff to do.

But I need my seven hours.’

8.00 Meeting with Edwin van Asseldonk

‘Edwin is keen to start using a technique that sends a small direct current through the brain from a band placed around the patient’s head. Administering those few milliamperes in certain areas of the brain might help in rehabilitating patients after a stroke. Effects have already been measured, on muscle control for example, but the results in patients are still modest. For measurements in patients, the medical ethics committee must give its consent of course. That’s what we’re talking about.’

9.30 Patient consultations

‘Consultations are still important to me. My core business is clinical neurophysiology – measuring and interpreting signals and (increasingly) ‘adjusting’ functions

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‘In the holidays I may spend three hours a day at the grand piano, in my music room.’ using signals. But we’re developing that technology for people made of flesh and blood. Which is why it’s good to keep seeing patients as well.

On the other hand, it’s not easy to do eminent science with a pager in your pocket. Because you can be torn away from your contemplations at any time. Deep insights require a lot of time and energy, long brooding.

Einstein said: “I’m not cleverer than other people, I just think about things for longer.” There’s a grain of truth in that.

Today I have to tell a patient that he’s probably suffering from one of the most serious neurological conditions there are: ALS. It’s an incurable disease in which the patient becomes progressively paralysed. Usually, you die of it within a few years. Of course, I don’t enjoy having to tell someone this, but it’s part of the job. Still, an odd contrast if the next patient is suffering from a sore leg due to a hernia.’

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‘Tom is someone who looks at whether new developments can potentially lead to a spin-off. And whether it’s attractive to put venture capital into them. I want to set up a Centre for Clinical Neurosciences, in addition to the Centre for Medical Imaging. I’m interested mainly in the brain, especially epilepsy, how you can diagnose the disease and how it comes about. Epilepsy is common and there’s still much to discover about the networks within the brain that result in the disease. In the Centre for Clinical Neurosciences, we hope to be able to work with new techniques and make progress as a result. By combining the expertise and technical facilities jointly built up

by MIRA and the University of Twente, we can make real breakthroughs. I’m convinced of that. Shoot for the stars and you’ll reach the moon.’

13.00

With Chin (PhD student) to the hospital’s stroke unit ‘Chin is investigating if activity occurs in the brain when a person merely

Medical Robotics & the Human Body

Automatic brain monitoring At MIRA, Michel van Putten is developing a system that automatically analyses the graphic reproduction of measured brain waves (EEGs). This makes it much easier to diagnose brain conditions. This means that in critical situations in the operating theatre or intensive care, a neurologist no longer needs to be continuously present to monitor brain activity. A machine can (to some extent) take over that task.

looks at a movement. Studies in monkeys point to this. The main thing we want to know is whether it can help someone who’s been left paralysed by a stroke. We’re therefore looking at EEGs from stroke patients. Apart from the stroke unit, I also visit the intensive care unit a lot, to see patients with brain injury due to an accident or severe epilepsy, or because they’ve been resuscitated. As neurologists, we play an important role in deciding whether or not to continue treatment as we try to predict the extent to which the brain will recover.’

14.30 Guest lecture on

19.00 Playing the piano

‘I’ve been playing since I was 11 and having lessons since I was 16.

I play a couple of times a week. I’m no great talent, but I like practising and I practise hard. At the moment I’m doing Grieg’s Lyrische Stücke and Gerschwin’s Preludes. In the holidays I can spend three hours a day at the grand piano, in my music room. But when it’s as busy as now, it sometimes gets forgotten. It’s a

[ who is... ] Who is Michel van Putten?

Michel van Putten (1963) has been professor of Clinical Neurophysiology at the University of Twente since December 2009. He is also head of the Clinical Neurophysiology Department at Medisch Spectrum Twente.

Van Putten studied technical physics in Delft and did his PhD in measurements using advanced flow meters. He had

Brain signals should be measured more often

previously completed a degree in medicine as well, specialising in neurology and clinical neurophysiology. Measuring and analysing measurements are in Van Putten’s blood: his father has a laboratory

epilepsy

One way of studying the condition of

at home where he develops new

‘I really enjoy doing this, especially the challenge of having contact with the audience. The nicest compliment I ever had was from the father of a student: “My daughter says: it’s like cabaret, what Van Putten does.” It’s true, of course, that your lecture needs an element of theatre if you want to keep an audience captivated.’

a person’s brain is to attach electrodes

techniques for gas measurements, among

to his head and measure brain signals.

other things.

17.30

missing out on information about the

‘The topic is a study of patients following resuscitation in our intensive care unit. We’re also going to discuss the algorithms she’s developed, which give us a real-time understanding of the functioning of the brain, and the scientific article she’s written about these. Writing things up is not only important because it enables you to show colleagues elsewhere what you’re working on.

It also helps to bring structure to what you’ve done. The best thing, of course, is when it leads to other people picking it up elsewhere.’

nals are reproduced as symbols that are

Meeting with Marleen Cloostermans (PhD student)

Using a computer, you can display the frequency of brain waves, whether they match on left and right, and whether they show regular patterns. Van Putten believes that such measurements are still under-used in intensive care units in The Netherlands. Consequently, we’re condition of the brain. Using computer algorithms, Van Putten attempts to convert the patterns in which brain sigeasier to ‘read’. This allows you to develop a system that can be handled, in principle, by any healthcare provider instead of just a handful of brain specialists.

real shame, because you soon notice it in your playing; playing the piano requires motor skills that you have to practise almost continuously.’

20.00 Giving a

presentation to neurologists from the region

‘Once a month there’s a scientific

presentation for current and future neurologists in the region. Usually we have a speaker from somewhere else, but the speaker dropped out this time. So I’m giving a presentation myself about EEG monitoring in the intensive care unit.’

23.00

Home to my computers ‘A quick pop upstairs to look at my algorithms. I’m a reasonably good programmer. I normally have two desktops rattling away day and night. I get them to “look” at brain signals. They’re currently comparing EEG patterns in patients under anaesthetic with measurements from the same patients in a waking state.

It’s exciting. You’re trying to identify the characteristic differences in the interactions of neural networks in the brain between a person who’s awake and a person who isn’t.’

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4.8

jaRich spliethoFF

Suddenly you find you can save lives Jarich splieThoff is seT To gradUaTe in Technical medicine. afTer five years of sTUdy, loTs of Jobs on The side and foUr placemenTs, he’s almosT ready To make The big leap.

1

How do you look back on your degree programme, now it’s almost finished? ‘Technical medicine is seen as a hard degree programme within the University of Twente: six years, with a timetable of up to eight hours a day. But I’ve always really enjoyed it, so I didn’t mind working hard. The typical technical medicine student is energetic and enterprising; it’s no coincidence that I often meet fellow students on committees of student associations.’

2

During your placement, was it a shock to suddenly find yourself in a hospital, with real patients, some of whom seriously ill? ‘Yes, but mainly in a positive sense. During my degree, I’d mainly been concerned with solving theoretical problems and doing sums. Suddenly, you realise you can use that to save people’s lives! That was a real eye-opener.’

3

Soon you’ll have graduated. What then? ‘I can see myself starting up my own business some day, once I’ve had a good idea. But first I want to get to know the medical world a bit better.’

4

How has that medical world welcomed you so far? ‘There’s a small group of doctors who still have to get used to our role. They sometimes make disparaging comments like: “So you’ve come to twiddle the knobs then?” But most doctors are surprised about what we can contribute and say that there’s an enormous demand for our know-how.’ more on page 142

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4.9

MaRjolein van deR kRogt

‘No-one is in this to get rich’ hUman movemenT scienTisT marJolein van der krogT has been working on mira’s Tlemsafe proJecT since march 2010. The posT-doc from amsTerdam is a specialisT in gaiT analysis and modelling and The effecTs of cerebral palsy.

1

What attracted you to the human movement sciences? ‘I’ve always played a lot of sports and was very interested in how people can achieve top performance. That’s one of the questions that human movement science seeks to answer.’

2

Have you reached a top level in sport yourself, perhaps as a result of that? ‘No such luck, I’m an enthusiastic amateur racing cyclist and speed skater.’

3

Can you get rich from your work? ‘If that’s what you want, you’d be better off doing something else.

For me, that’s not what it’s about. But the idea is, of course, that you develop things there’s a demand for. And if that means I get a nice patent to my name one day then I might become rich after all.’ (laughs heartily)

4

But why would a city girl come to the provinces? ‘Well I don’t live here.

Enschede is definitely a nice place, and quick to get to, but for the time being I’m staying in Amsterdam. I also work at the VU University there three days a week. And my husband works in the Amsterdam area. The atmosphere in Enschede is quite different from Amsterdam. I’d miss life in the big city if I lived in Twente. But I’m really glad to be part of a very enthusiastic and active workgroup here.’

5

What goals do you have in your work?

‘Who knows, perhaps becoming a professor. But mainly, continuing to enjoy my work.’

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[ chapter 05 ]

Lab-on-a-Chip

a revolutionary form of nano足 technology

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Lab-on-a-Chip

05 [ intro ] A complete laboratory, no bigger than a pill. ‘Lab-ona-Chip’ nanotechnology makes this possible. In future, a patient will simply swallow the mini-lab which will monitor the levels of various substances in the body and transmit the results directly to the doctor. At the UT, researchers from BIOS, the Labon-a-Chip department within the MESA+ Research Institute, are developing this revolutionary form of nanotechnology. It represents a huge scientific advance, for which Professor Albert van den Berg was awarded the Spinoza Prize, the Netherlands’ most prestigious scientific award, in 2009. Twente researchers are now working on various applications for the Lab-on-a-Chip. To date, they have produced a fertility test for men and a chip which helps patients with manic depression manage their own medication. Another ongoing project focuses on a ‘nanopill’ which can detect bowel cancer.

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5.2

[ extract interview from ] the schedule of... ]

Albert van de Berg

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Lab-on-a-Chip

‘ Let others see how wonderful our work is.’ [ intro ] Albert van den Berg is a professor at

the University of Twente and head of the BIOS Lab-on-a-Chip group at the MESA+ Institute.

Continued on next page

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[ who is... ] Who is Albert van den Berg?

Prof. Dr. Ir. Albert van den Berg is a professor at the University of Twente (UT) and head of the BIOS Lab-on-aChip group at the MESA+ Institute.

He received his doctoral on chemically modified transistors (ISFET) in 1988.

Between 1988 and 1993 he worked in Neuchatel, Switzerland, where he spent his free time in the mountains. Climbing, biking and skiing remain key pastimes of his, despite the flat Dutch landscape.

He returned to the UT as a research coordinator with MESA+ and in 1998

NaNOcancer

became a professor. In 2002 he was awarded the title of Albert de Simon

With, among others, Prof. Dr. Bob

blood in the faeces. We want to develop

Stevin Meester from STW and in 2009

Pinedo, Emeritus Professor of Oncology

a pill which measures the presence of

he won the prestigious Spinoza Prize for

and Prof. Dr. Dave Blank, Director of

cancer-specific DNA in the intestines. If

his work with Lab-on-a Chip. His current

MESA+, Albert van den Berg is part of

detected, this allows you carry out further

research focuses on micro analysis

the NaNOcancer Foundation.

specific tests and treat patients at a

and nano sensors, nano fluidics and on

Intestinal cancer is the second most

very early stage. Prof. Dr. Bob Pinedo is

research into biological cells on chips,

common form of cancer among men

actively seeking funds for this research.

with application in health care and the

and women. A polyp in the intestines

‘The NaNOcancer foundation is

environment.

can become malignant and release cell

predominantly a regional initiative, with

material, generating cancer-specific

contributions from notable individuals

DNA in the intestine. ‘We want to

from Twente. This summer the open-air

be able to detect this with a nano

concert from the ‘Oosten’ orchestra

sensor. What happens right now is

generated a sizeable fund to allow the

that people only visit the doctor when

project to commence. This week the

the symptoms start to show, such as

priorities will be defined.’

8:25 Avoiding the traffic jams

‘My home in Nijverdal is located in beautiful countryside – relatively hilly by Dutch standards. I love to mountain bike around and about. In the morning, however, when I am driving to work, there are frequent traffic jams between where I live and the university. If I leave at 7.45

then I only arrive at 8.45 at work. If I leave at 8.15 then I arrive just after nine o’clock.’

9:00 Check emails

‘On average I’m travelling for one week per month, and even though I still keep up-to-date with emails while I’m away, there’s always more to answer after a week out

of the office. Last week I was in Johannesburg for a workshop about the use of our chips in the third world. We also have a student exchange programme there. This morning I was contacted for more details on potential exchange candidates at the UT.’

9:40 Preparation for a

review

‘The UT is one of the donors for the Technical Sciences Foundation (STW) and tomorrow I have to attend a review in Utrecht. We’ll be discussing the future of the Continued on next page

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Foundation and I’ll be providing feedback about their manner of working.’

10:00 Chair management meeting

‘Once a month the entire management meet together. All 40 researchers discuss the future of our work and look for opportunities for improving quality. It lasts nearly an hour. I’m generally not a fan of meetings, with the exception of efficient meetings.

11:15 Telephone call about

intestinal juices

‘Our nanopill measures defective DNA in the intestines. This can be an early indication of colonic cancer.

Last year I met a gastroenterologist

‘Lunch is always a great opportunity to catch up with colleagues’ during a workshop in Leiden. He was calling to say that he could supply intestinal juices for tests with our nanopill.’

11:25 Transplant techniques ‘STW has a users committee for the project ‘Fertility-chip’. I’m discussing the commercialisation of our Fertility-chip with Professor Dr. Didi Braat. The chip automatically measures the quantity and motility (motion capability) of sperm in one

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drop of sperm. Smaller hospitals currently inspect this visually. If the test can be automated, people would be able to carry this out at home.

We are also in talks with a business developer who wants to apply for a Valorisation Grant to bring this product to market.’

12:00 Lunch in the Faculty Club

‘The UT offers excellent lunch facilities which I take advantage of a couple of times a week. I’m careful about what I choose because next year I’ll be taking part in a long bike tour, and the fewer kilos I have to carry the better. But lunch is always a great opportunity to catch up with colleagues.’

13:00 Edit an article

Chips for Africa In Johannesburg, during the workshop, Microfluidics for African Health (MicroMed-A) researchers, care providers and governments spoke about the possibilities for Lab-on-a-Chip to help the heavily HIV, TBC and malaria affected communities.

In the townships there’s also a need for

‘I have to edit a complex article for Physical Review Letters (PRL) about how DNA moves in a nano channel.

It’s based on pretty fundamental research by a group made up of Detlef Lohse, Spinoza and Stevin laureates, and the article contains several complex scientific formulas.

We want to develop a chip which will sequence single DNA molecules and determine the order of the different bases. To achieve this we make use of fundamental physical-chemical processes in the nano channel.’

equipment which can provide quick test

14:00 Consultation

was a useful and informative week, with

‘Together with Wouter Olthuis and the Chief Technology Officer of SenzAir BV, we discuss the progress we’ve made with the development of his product: a chip which measures ammonia in breath. Five years ago, one of our researchers completed his doctorate on this subject and SenzAir are now bringing it to market. One

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results. A visit to a couple of clinics where more than 80 per cent of the patients were HIV positive was particularly hard-hitting.

There are interesting possibilities for these kinds of scenarios. Van den Berg: ‘Currently people have to wait three days to get their results back from the lab. Often sick people have had to walk for hours to reach the clinic, and with such a long waiting time we lose patients unnecessarily.’ One of the outcomes from the workshop is a programme for exchanging expertise between the universities of Twente and Pretoria. ‘It a great deal of discussion about content, but also about needs and opportunities.

The HIV epidemic in Africa has captured my personal interest, but in order to achieve something, advanced (nano) technology alone is not sufficient. There’s also an urgent need for improved infrastructure, such as clean water, reliable electricity supplies and improved roads.’

‘I’m generally not a fan of meetings, with the exception of efficient meetings’

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of our postdoctorate researchers is also involved with the company. The sensitivity of the chip is excellent.

Breath analysis is “blowable” and therefore much more comfortable for the patient compared with having a tube inserted in their throat.’

15:00 The fiftieth question ‘With the aim of inspiring and enthusing researchers, The Royal Netherlands Academy of Arts and Science (KNAW) has put together a science agenda with 49 urgent questions. I’m on the board of

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the Academy and we decided to, “make a nice round number out of them.” As a result the Academy offered an award of €5,000 to a young academic for the best fiftieth question. I have to broadcast it via Twitter. The fiftieth question is: “How do we deal with the risks of technological innovation?”’

15:15 Consultation with two

PhD students

‘The daily guidance of PhD students is carried out by their coach, but at least once every two months I

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also arrange a progress update with them. Today in the meeting I asked if they would prefer to incorporate a larger group. This would reduce my time in meetings, but they were afraid that they would no longer receive my undivided attention. So we’ll keep it as it is.’

16:15 Lithium chip update

‘The CTO of Medimate arrives to discuss the UT-developed lithium chip that they would like to bring to market. The chip measures the level of lithium in blood. With

Thousands of compartments Lorentz Workshops bring a number of disciplines together to decide what, together, they should research. The technology of Lab-on-a-Chip is an interesting fit with cell biology. Van den Berg: ‘the workshops, which we play a role in organising, result in new directions for our research, for example tissues and organs on chips.’

This approach to research leads to a clear reduction in the use of animals for testing. ‘Medical tests on rats and mice have two disadvantages. We don’t want to have to use animals for testing, and mice and rats provide only limited information about the impact on humans, as there is currently no model to link mice and humans. What would happen if we could put human cells on a chip? With microfluidics – the extremely precise manipulation of fluids on a micro and nano scale – medicines can be applied to multiple cells to determine what their effects are. Chips would be divided into hundreds or thousands of compartments equipped with electrical nano wires that measure resistance.

‘This would reduce the need for testing on animals and provide more information. It’s a possibility that we could even join cells, to enable us to see what would happen when medicine is sent to, or from, the kidneys.’

the measuring equipment from Medimate, this means that people no longer have to visit the hospital for testing. Partner company Blue4Green uses a tweaked version of the chip to measure calcium levels in cows. Sometimes cows require extra calcium, for example, after calving. However, if they receive too much extra calcium it can cause them heart damage.’

17:00

Reading, reading and yet more reading ‘On quieter days I can often be found behind my desk reading articles at concept stage, proposals, and specialist journals. I also like to do this at the end of the day..’

18:15 Homeward bound

‘Dinner is almost ready, so it’s time to head home. At this time of the day there are rarely traffic jams, so I’m on time for dinner with my wife and two children who still live at

home. The eldest has just moved to Amsterdam to study.’

20:30 A speech

‘During the year, I give around 40 speeches to a range of audiences, from school children to medical professionals. It’s part of my wider remit to allow others to see how wonderful the work we do is. The NanoLab is a fantastic facility.

Sixty million euro was spent on equipment, and if I’m honest, it’s better-equipped than both Harvard and MIT. We are extremely proud of it and aren’t shy of saying so.

Speeches are a form of publicity, but they can also deliver the unexpected.

At the end of one evening a lady asked me not only if she could make a donation to our Foundation, which finances nano research for the fight against cancer, but also if she could offer herself for trials.’

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Doctorin-a-pill [ intro ] Screening for intestinal cancer normally takes place using

endoscopy or colonoscopy – painful and uncomfortable procedures which are logistically challenging, and often don’t find anything. The nanopill contains a Lab-on-a-Chip equipped with nano wires that can detect small cancer specific DNA fragments at an early stage of development, long before a cancerous tumour develops.

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pill that can detect cancer sounds almost too futuristic to be true. However, a concrete foundation for the nanopill has already been laid and could well become reality within the next 15 years. The pill, which has a large but acceptable format, is made up of a tiny pump that takes in fluid from the intestines. The fluid then flows through a chip which ‘captures’ deviant DNA. A salt solution then flushes the DNA from the chip along a surface capable of taking measurements. All other substances are washed away and the pill leaves the body naturally.

Such a pill would provide an early indication of the presence of a specific deviant DNA, an indication of intestinal cancer. Currently,

through symptoms such as blood in their stools, people discover the cancer too late, often after it has had time to develop. Deviant DNA is a clear indicator of intestinal cancer in the early stages.

The size of the pill is AOOO, around 1cm diameter and 2.5 cm long. According to official guidelines this is the largest format that people are able to swallow. All of the equipment in the pill has to fit within these dimensions.

The nanopill provides an indication of where it is in the body and only takes in fluid once it reaches the intestines. The pill doesn’t use GPS to indicate its location as this can only determine the location from

Determining the location

above. ‘Philips Medical have already developed a pill which determines its location based on temperature, the time that it has been moving and the acidity of its environment,’ explains researcher Wouter Sparreboom.

‘This is proven to work, so we’re also going to use this method.’

Miniscule Sparreboom’s specialism lies in the tiny pump, measuring just a few millimetres, which takes in the fluid. Sparreboom: ‘Pumps described in literature, or available for sale, simply weren’t suitable. We needed a pump that operated under low voltage, was energy efficient and that could withstand the fluids that is had to take in. We eventually decided to Continued on next page

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‘The detection element of the nanopill is the most important innovation in this product’

The wires work in an extremely small space. Sparreboom: ‘Twente has already been working on the miniaturisation of electronic measuring methods for 30 years.

The expertise developed with larger sensors has been transferred to smaller ones, less than one micrometre in diameter. The technology existed already, but through this project we’ve developed it further and made it simpler to reproduce.’

For intestinal cancer, the ‘at risk’ members of the population have not yet been determined. So far, research has focussed on the technology and not the patient.

Sparreboom suggests: ‘people of a certain age, with a family history of intestinal cancer. The exact parameters of the group is still unclear, therefore a broader population survey might be helpful, similar to what’s currently taking place for breast cancer.’ After breast and prostate cancer, intestinal cancer is the most common form of cancer among men and women.

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produce one ourselves.’ Over the course of a year, Sparreboom has had a sample made from glass and silicon rubber, which is almost robust enough to withstand the acidic environment in the intestine and which operates on a low voltage battery. It could be smaller, and for this we’re currently looking for a partner who can produce the part in low volumes. The smallest size of the pump so far is 30 micrometres – half the diameter of a hair. It shouldn’t be too small, as it then risks becoming blocked by particles floating in the intestinal fluids.

Most important discovery

The big­gest innovation used in the nanopill, and the focus of researcher Sonyue Chen, are the nano wires complete with receptor molecules, and attached to the sensors. A chemical reaction enables them to ‘catch’ the DNA molecules. All other

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substances are ignored by these biomarkers. A saline solution then flushes the DNA along the nano wires. The measuring apparatus records a change in value caused by variations in resistance, and the presence of deviant DNA is registered. This is transmitted wirelessly to the outside world.

In contrast to the fertility chip, which measures impedance through the liquid, the nanopill measures impedance through a nano wire. Chen: ‘The detection of DNA was mostly done using optical methods with a large sample and, for example, a laser. These measurements are too large for a pill. Electronically speaking it was possible for us to make everything smaller, simply by following the same trends used by other electronic equipment. The detection element of the nanopill, the nano wires from the UT, are the most important innovation in this product.’

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Despite the increasingly shorter time taken for ideas to reach the market, the implementation of medical developments is still measurable in years. In the coming decade we still won’t see the nanopill on the market, but the knowledge and expertise gained through this project can be put to good use on other projects.

Sparreboom: ‘Even if there is just one receptor molecule that can capture interesting biomarkers, we will discover it.’

5.4

The link between mice and humans [ intro ] Traditionally, growing cells for testing medicine on tissues and

organs has been done using a Petri dish. The UT does this at a micrometre level – a chip. The challenge is to cultivate tissues that have exactly the same characteristics as the human body, as this results in quicker and more realistic tests.

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ostdoctoral researcher, Andries van der Meer is working on a realistic model for growing tissues and organs in a lab – the link between mice and humans.

‘Researchers isolate cells from the tissues and organs of test animals, healthy volunteers and patients, and then cultivate them. By doing this on a chip, fewer cells are required and it results in a more realistic model, as we take into account factors such as blood flow and combining growth together with other tissues. This simulates the situation in the human body very closely.

This new method adds most value in the early stages of medicine tests. ‘Our technology can quickly determine if a substance has a chance.

For clinical trials, this allows us to rule out thousands of substances relatively quickly and cheaply.’

The healthy cells are nurtured with proteins, sugars, and growth factors.

‘After this they’re grown on our chips in cultivation chambers measuring 1cm x 0.5mm x 100µm. We place two types of cells next to each other, one from the blood vessel wall and one

from the brain tissue. It is important that the blood-brain barrier between them remains intact, so that the cells behave as they would in the human body.’ The tissues grown in the lab displays the desired characteristics.

‘Firstly we’re testing with substances which we know the behaviour of,’ says Van der Meer.‘After this we’ll use experimental substances. We’re also using as many chips as possible, connected in parallel, as this allows us to simultaneously test as many substances as possible.

Van der Meer is working on the blood-brain barrier, the blood vessel tissue in the brain that determines which substances may, or may not, enter the brain. ‘These substances are difficult to predict, as there are no rules, and therefore we have to test everything. This is because the transport through the barrier is active: the cell walls actively take in everything that they need, and pump everything that enters passively, back out again.’

Cultivation chambers

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5.5

The speed of lithium [ intro ] Manic depressives who take lithium currently need to have their

blood tested several times a year at the hospital. Next year, a lithium chip with a measuring device will be available on the market. This will allow people to check if the level of lithium they are taking is correct or needs to be adjusted in their own homes.

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ithium is an effective treatment for manic depression and is taken by around 30,000 people in The Netherlands each year. It is an affordable medicine that levels out manic-depressive cycles. The downside of lithium is that several times a year, users have to have their blood tested. Too little lithium is ineffective in suppressing the manic or depressive cycles. Too much lithium results in poisoning, with devastating consequences such as kidney failure or brain damage.

Twice a year, patients provide a blood sample at the hospital and this is subsequently tested in a large machine. Two days later, they receive the results from the laboratory and the amount of lithium they take will be adjusted accordingly. If the amount of lithium in their blood turns out to be too high, then two days’ waiting is, in fact, two days too long.

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Measuring with a chip Pieternel Kölling, Psychitrist at Medisch Spectrum Twente, works with many manic-depressive patients. In 2002, he and Prof. Dr. Albert van den Berg, head of BIOS Lab-on-a-Chip, came up with the idea of a handy

‘With the lithium chip, people get more control over their treatment’ apparatus which would enable patients to measure their own blood lithium levels at home. Around ten years later the apparatus has reached the stage where it is almost ready to go to market. Prof. Dr. Jan Eijkel from the BIOS Group and Scientific Advisor at Medimate: ‘With the lithium chip, people get more control over their treatment. They can

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measure their lithium levels and following a consultation with the psychiatrist, decide if they need to increase or decrease their dosage.

This will also save the hospital time and expense.’

In 2001 PhD Student Elwin Vrouwe started his research into the possibilities of a lithium chip.

Four years later he was able to present a principle. It appeared to be possible to accurately measure concentrations of lithium in blood using a chip. Eijkel: ‘The end result of his thesis was a glass plate measuring 3cm x 1.5cm, containing micro channel and electrodes. This set-up proved his theory, but was far from a final product. ‘You still had to fill the micro channel yourself, with a large risk of air bubbles and it involved a complicated juggling of liquids to apply the blood sample.

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Furthermore the interpretation of the results was too complex,’ says Vrouwe. In 2006 Vrouwe’s research results led to the startup of the company Medimate, which would ultimately develop an apparatus that everyone was able to use.

Air bubbles Medimate developed a disposable chip in a small plastic box. The patient pricks their finger, opens the box and places a drop of blood on the chip. After closing the lid, the box is inserted into the measuring apparatus, which, after a few minutes, provides the lithium concentration in milliMol per litre.

Before reaching this stage a number of challenges had to be overcome.

Eijkel: ‘It’s unbelievable how much doesn’t go according to plan during the development process, particularly when the product concerned is going to be used by people. For example, the results from the chip cannot deviate from the golden standard: the results provided by previously approved tests.’ The chip isn’t permitted to give an error reading in 90 per cent of cases, and the hardware must also be reliable. ‘To simplify things, we now work with a chip that’s been prefilled with liquid,’ says Eijkel.

‘In a warm environment the liquid in the chip leaked out of the micro channel along the seal. Medimate resolved this in an ingenious way by inserting a small air bubble in the chip which prevents the pressure from becoming too high.’ The chip also has to be robust enough and remain intact if someone tries to force it into the measuring apparatus

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incorrectly. It needs to withstand even the clumsiest of users.

Speed The measuring apparatus generates an electric field of 1,000 volts to attract the target field ions and charged atoms. Positive ions are attracted to the negative electrode.

Smaller ions have less resistance

Lithium is an effective treat­ment for manic depression and move quicker than larger ions.

Put simply, the large lithium ions don’t move as fast and therefore get left behind the smaller sodium ions which are found in blood. The two groups of ions pass the electrodes at different times and the number of ions is measured through the changes in conductivity. Eijkel:

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‘The best part of this technology, capillary electrophoresis, is that it can be used to measure other ions such as sodium and calcium.

Everything with a charge can be separated in this manner. It is important that the difference in the speed of the ions is sufficient; otherwise they won’t pass each other in the electric field. Happily, almost nothing moves at the same speed as lithium.’

Large-scale testing Based on research so far, in 2010 Medimate decided to redesign both the chip and the measuring apparatus from scratch. The new chips resolved all existing issues and are due to be tested together with the measuring apparatus before the end of 2011. Eijkel: ‘We expect to start producing both the chips and the measuring apparatus in large quantities at the end of 2011, ready for large-scale testing with lithium users in the first quarter of 2012.’

5.6

Antibody factory Antibodies are important for detecting and attacking proteins that cause disease, but it is still not possible to produce them synthetically. The way they are currently cultivated, is cumbersome and inefficient.

Hybridomas, created using technology are inexhaustible antibody factories.

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arge numbers of white blood cells are required for the development of new medicines. Every white blood cell produces a specific antibody that attaches itself to a particular protein. With this knowledge, antibodies can be used to block or activate specific proteins and as a result stop or slow down a disease.

It is impossible to synthetically manufacture antibodies or the white blood cells which they produce. Real blood cells are required to produce them. Postdoctoral researcher Floor Wolbers: ‘After just one week, the blood cell dies and your “antibody factory” disappears.’ This is the reason that laboratories work with hybridomas.

Immortal cultivation A hybridoma is a fusion between a white blood cell and a cancer cell. So long as it is supplied with sugars and proteins, this limitless dividing cell is an immortal antibody factory. Wolbers: ‘Fusion is more than simply a case of mixing. A strong electric shock is used to start the fusion between the cell membranes from both cells. Resulting hybridomas then have to be fished out of the cultivation. People in Twente were in no doubt that ‘there must be a more efficient way of doing this.’

Wolbers and her colleagues developed a chip with two micro channels – one for oil and one for water. These fluids don’t mix, but result in water droplets suspended in a stream of oil. ‘We can produce droplets in a very controlled manner. We do this alternately: first a white cell in water, followed by a cancer cell. In the next part of the chip the cells flow together in a water droplet and a pulse of electricity is used to fuse the two cells. This works a lot faster and we don’t need as many cells.’

The ‘droplet-based platform’ works, so the next stage is to further develop the part of the chip where the miraculous fusion takes place. The research is now focussing on the development of minute cultivation chambers for the hybridomas. ‘By drawing these off, we can produce a steady stream of antibodies.’ The development of this fully integrated platform is expected to take two years to complete. According to Wolbers: ‘There are no fundamental road blocks, it’s simply a question of integrating the technologies.’

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5.7

Fertility on a chip

Testing male fertility too? [ intro ] A new Fertility-chip is now able to accurately perform a sperm count.

The Fertility-chip is an important step in the journey towards a compact apparatus which can carry out a reliable pre-scan for male fertility.

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hen Loes Segerink began her research, the inability of couples to conceive was far from her mind. ‘I was 23, and nobody in my friendship group had even thought about having children. Fertility research on a chip had simply never been done at the BIOS Lab-on-a-Chip group.

It was my thesis, but I wasn’t alone in supporting it.’ Four years later and she couldn’t be more aware of the emotional side of the problem.

‘For my research, I worked together with a gynaecologist in a hospital in Twente. A couple of times per week I completed his rounds with him and sat in on consultations. When people find it difficult to conceive, it has a huge impact on their lives.’

To measure the fertility of a man, an analysis is made of the motility (movement) and concentration of the sperm in his semen. In many smaller hospitals this is often done by analysing a sperm sample under a microscope. Larger hospitals take an image of the sperm and the count is performed automatically. ‘But this type of machine requires someone to operate it,’ explains Segerink. ‘And the machine only indicates if the fertility is above or below a specific reference value. If this turns out to be the case, then further research in a lab is required.’

With the Fertility-chip, a man would be able to carry out an accurate self-analysis in the privacy of his own home. This would save hospitals time and money, but would also alleviate some of the embarrassment and awkwardness commonly associated with collecting a semen sample. However, as with many

Accurate analysis

‘We are the first to use this technique to measure spermatozoa in a liquid’ newly developed technologies, it will take a number of years before hometesting can be implemented.

Thinner than a hair The Fertilitychip measures the resistance of one drop of sperm via a micro channel fitted with two electrodes. The principal is not as straightforward as it might sound. On a glass plate measuring 1.5 x 1 cm Segerink makes a channel measuring just 40 micrometres. This is thinner than the diameter of a hair. On one side of the channel she attaches two electrodes to measure the impedance. This is the resistance caused by a fluid when an alternating current passes through it. The difference in cell size (sperm compared to white

blood cells) causes a peak which can be detected by the measuring equipment. Segerink: ‘We are the first to use this technique to measure spermatozoa in a liquid.’ Based on the peaks, the number of sperm in the semen can be measured automatically and thus the level of fertility determined.

Applications Based on a business plan which outlined the veterinary and human applications of the chip, Segerink received a Valorisation Grant from STW. ‘We’re planning to make a company out of this project.

Counting the cells in liquid can be used for a number of applications.

It’s interesting for cattle breeding as applications for animals have less severe rules to comply with and are therefore easier to bring to market.

For applications related to humans we have to involve far more parties, such as health insurance companies and doctors. For animals there is no discussion about ethics as the animal is not subjected to any form of pain for this research.’

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5.8

Drug screening on a chip [ intro ] Pharmaceutical companies invest remarkable amounts of time and

money in the development of medicines. Thousands of substances are tested for potential side effects on both animals and humans. Drug screening on a chip can replace a large proportion of these tests and, as a result, deliver numerous benefits.

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efore a medicine is approved for human use, hundreds of thousands of substances have to be tested for possible side effects. In the liver, enzymes convert medicines into by-products. In some cases this can result in strange side effects for a patient. Indeed, not everybody reacts in the same way to medicine since individuals have different enzymes.

replicaTion For four years, researcher Mathieu Odijk worked on a chip that could mimic what happened in the human body when medicine was taken. Odijk: ‘To a certain degree, this complex reaction can be replicated in a lab, delivering quicker results. In addition, the advantage of a chip without cells is that there is no adhesion to the cell membrane, therefore the signal that we’re measuring is also cleaner.’

In the liver, the enzyme Cytochrome P450 metabolises around 75 per cent of all currently available medicines.

This enzyme oxidises substances so that they become easily soluble in water, which allows them to pass out of the body. With drug screening on a chip, the medicine that needs to be tested is dissolved in water and passed through a chip, which oxidises the substance in the same way as an enzyme would. The resulting substances are measured using a mass spectrometer. Odijk: ‘With a number of medicines, we already know exactly what happens in the human body. We have tested these on the chip and they work in exactly the same way. A number of pharmaceutical companies are now running a limited number of tests using the chip. Unilever is one of the companies using this method.

In some instances, substances that a person rubs into their skin can also end up in their blood stream and ultimately in their liver. Our method of testing is therefore also of particular interest for these types of companies.’

University lecturer Severine le Gac is working on a technology platform that will enable the pharmaceutical industry to focus on protein molecules in the cell membrane. This double layer around a cell, the lipid bilayer, holds ions, proteins and molecules in place. When it comes into contact with water, the cell membranes arrange themselves in exactly the same way, and as a result, form a barrier to some substances, while allowing others through.

This principal is the basis for the lipid bilayer model. Le Gac:

eFFecTive screening

‘Pharmaceutical companies are particularly interested in these protein molecules as they can cause, for example cystic fibrosis, when they don’t function properly.

These membrane proteins are also responsible for the communication between the cell, its environment and other cells. A disturbance can lead to changes in biological processes such as abnormal cell division or cancer. Finally, these proteins can be easily reached through medicine.’ To effectively screen medicines using a chip, protein molecules must be embedded in an environment which resembles that of the cell membrane.

‘The fact that we can reproduce this leads to cheaper and quicker tests.

This method has already attracted the attention of a pharmaceutical company that develops medicines for hereditary cystic fibrosis.’

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[ chapter 06 ]

eHealth & Logistics

support can improve health care processes

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06 [ intro ] The right form of support can greatly improve health care processes, and make life much easier for the patient. Good health care relies on more than effective drugs and expert doctors. A new approach to the organisation and appliance of technology make health care services better, faster and more convenient. The UT is working on ‘smart’ systems which will promote online contact with doctors and cut waiting times. Research focuses on a wide range of topics: from better building and organising of care in hospitals to new sensor techniques which help patients remain independent for as long as possible.

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A cross-border knowledge hub to combat infections [ intro ] Up to 150,000 infections occur in the EU each year, resulting in

annual costs of up to 380 million euro. The University of Twente has joined forces with European partners to help prevent and combat infections, thus reducing costs and saving lives.

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Dr. Lisette van Gemert-Pijnen is one of the driving forces behind this successful project

he University of Twente (UT) has already acquired a wealth of experience in cross-border co-operation thanks to its participation in the MRSA-net project. This interregional project in the Euregio Twente/Munsterland focused on combating MRSA, or methicillinresistant Staphylococcus aureus.

MRSA is the term used for a number of strains of the Staphylococcus aureus bacteria which is extremely dangerous, especially for patients who are already ill.

Dr. Lisette van Gemert-Pijnen, head of Twente University’s Centre for eHealth Research & Disease Management, was one of the driving forces behind this successful project.

The new project, EurSafety Healthnet, builds on the infrastructure and contacts developed during MRSA-net, but has a broader scope. ‘EurSafety Health-net focuses on the problem of drug-resistance in general, not just in relation to MRSA. Our aim is to improve the safety of care providers and patients in the northern border region by creating an infrastructure that encourages collaboration between health professionals and patients.

This platform can be used to exchange knowledge about and coordinate action against infections.’ Besides the University of Twente, participants in the EU-initiative include: Interreg DeutschlandNederland, the North Rhine-Westphalia Ministry of Economic Affairs, Enterprise and Energy, the Ministry of Economic Affairs, Labour and Transport of Lower Saxony and the Dutch provinces of Overijssel, Gelderland and Limburg.

between the Netherlands and Germany among others

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Creating a dashboard Infections and drug-resistance are a major problem, especially in the border region. Van Gemert-Pijnen explains: ‘Here, people who live in the Netherlands may work in Germany or visit a German hospital – and vice versa. At present, policies, protocols and treatments can vary from country to country. This makes it easier for infections to spread.

Working together to address these problems makes far more sense.’

To facilitate cooperation, the University of Twente is working on an international infection management platform. The platform acts as a knowledge hub and combines a wide range of applications. ‘Our objective is to ensure that the platform contains all the information that health care professionals and patients may need. This can range from an overview of protocols and policy documents to an epidemiologic map and interactive features such as online consultancy and e-coaching.’

Van Gemert-Pijnen continues: ‘All the information is presented on a dashboard that is accessible via a single link. Easy access is paramount: information must be available on a variety of devices such as PC, tablet and smartphone.’

The plat­form is currently taking shape, with applications and information regularly being added and updated both by the research group and by health care professionals. ‘We have already included information from the MRSA-net project and we’ve started working on an Antibiotic

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ranging from test results to local trends in drug-resistant bacteria.

And online forums are being set up: professionals can post a question and get input from colleagues and experts almost immediately.’

Wherever possible, the centre for eHealth develops technology in collaboration with stakeholders and end-users. Van Gemert-Pijnen: ‘For EurSafety Health-net to be a success, the information presented on its dashboard has to be relevant for individual users and easy for them to use. Only listening to health care professionals and patients from different regions and learning more about their needs can help us to achieve this. It’s a continuous process.’

Stewardship programme. Research estimates that half of the antibiotic use in the EU is irresponsible.

Excessive or wrong use of antibiotics can lead to more resistant bacteria and make it easier for bacteria to spread. We can only achieve the objectives we have set out to accomplish within EurSafety Healthnet if we address these issues too.’

Fortunately, this doesn’t mean that health care professionals will have to plough through even more protocols.

Van Gemert-Pijnen and her team believe in a more interactive approach. ‘In addition to making the protocols themselves more user-friendly, we are developing eLearning modules that will make it easy for users to refresh and expand their knowledge of antibiotics.

Digital Decision Aids will also help health care professionals to make better-informed choices. We’re developing algorithms to include different types of information,

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Autonomous platform The research project is scheduled to run until 2014, but Van Gemert-Pijnen hopes that its benefits will be lasting. ‘If EurSafety Health-net is a success, we expect it to develop into an autonomous platform. Health care professionals, experts, health care institutes, the European Centre for Disease Prevention and Control (ECDC) and patients will then continue to embrace the initiative and use it to exchange knowledge about infections and to expand their own expertise. Developing new antibiotics is a time-consuming and costly process: pharmaceutical companies have no commercial interest in doing this. We will have to make do with the drugs that we have and use them as efficiently and effectively as possible.

I believe that EurSafety Health-net has an important role to play in achieving this.’

Improving the safety of care providers and patients The EurSafety Health-net project is one

management platform to optimise com-

and practical web-based decision support

of the initiatives of the European Union

munication and improve the exchange

instructions (e.g. MRSA-net) and an Anti-

and regional governments to design

of knowledge regarding infectious

biotics Stewardship Programme (ASP), a

an infrastructure for a cross-border

diseases. The content of this Dashboard

new programme for the responsible use

approach to the problem of drug-resis-

and its various web-based applications

of antibiotics. It consists of a package of

tance. Its aim is to improve the safety

is developed and enhanced in close col-

measures, guidelines and aids to help

of care providers and patients in the

laboration with the care providers and

care providers in their daily work. Using

border regions, where the problem is

patients who will ultimately use it.

antibiotics responsibly can help to reduce

most noticeable.

Key elements in the EurSafety Health-

hospital infections.

As part of this, the University of Twente

net project are the translation of infec-

is setting up an international infection

tion prevention guidelines into workable

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6.3

Collaboration: the key to success Dutch Rheumatoid Arthritis Monitoring B.V. – or DREAM for short – is a joint project of the University of Twente and the Radboud University Nijmegen Medical Centre. The two universities work closely with 12 hospitals in the northeast of the Netherlands. The project has two main goals: to stimulate rheumatologic research and to raise the quality of care offered to patients suffering from rheumatoid arthritis.

DREAM is a showcase for the successful combination of ‘high tech’ and ‘human touch’. A computer-based toolbox facilitates the collaboration between health care providers, patients and researchers. The toolbox includes an user-friendly item response system that helps DREAM to gather more detailed and more relevant patient information.

This information and other research data are stored in a web-based portal.

Participating hospitals can access and update data, and review the progress made. Patients can also log in to check their own personal file.

This computer-assisted approach is a success: the portal already contains data from some 3,000 patients. Prof. Dr. Mart van de Laar, who heads the DREAM project together with Prof. Dr. Piet van Riel from Radboud UMC, expects this figure to rise to 10,000 in coming years.

Data gathered sheds light on a wide range of aspects, such as how rheumatoid arthritis develops, the effectiveness of biologicals and the success rate of different care strategies.

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6.4

The smart hospital [ intro ] Plans on paper are brought to life using visualisation and simulation

technology. This technology has started to be used in hospital design too.

The latest models developed by the University of Twente enable you to take a stroll through the wards, rearrange the layout of the operating theatres and keep track of costs - all at the same time!

C

onstruction is often long and always costly. Getting things right first time is important: it saves time, budget and the effort of making post-construction alterations. In the health care sector especially, all three of these resources are increasingly limited. So when it comes to building new, or renovating existing, health care centres such as hospitals and clinics, it is essential to ensure that the new design meets the – often very different – demands of stakeholders. The University of Twente believes that visualisation and simulation technology can be useful in accelerating these complex decision-making processes. Dr. Timo Hartmann, assistant professor at the university’s Construction Management & Engineering department and founder of VISICO, the department’s Center for Visua­li­zation and Simulation in Construction, has developed models that combine data from stakeholders and use it to generate a

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number of design scenarios, based on varying parameters.

The modelling process Many different parties have a stake in the design or renovation of health care facilities. Medical and supporting staff, of course, but also medical equipment suppliers, the catering company, local politicians, the council, insurance companies, et cetera. Each stakeholder has his own set of requirement. Surgeons and nurses, for instance, generally have distinct preferences for the location and layout of medical facilities. These can range from surgeons wanting hospital rooms in the vicinity of operating theatres, to nurses needing sufficient working space around patient beds. Even simple requirements such as these can, however, conflict with other requirements. The layout criteria of medical equipment suppliers, for instance, which may require extra space adjacent to operating

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theatres for emergency generators or gas connections, or the hospital accountant’s aim to convert every square metre available into extra patient beds.

Getting all stakeholders requirements on the table is an extremely important step in the design and construction process.

When this has been done, the next step is to develop models that convey stakeholder requirements in a clear and concise way. For a nurse or a doctor, this can mean displaying the new hospital design in 3D or 4D and enabling them to ‘walk through’ the building for a virtual work experience. The controller, on the other hand, may be more comfortable reviewing a mathematical model of costs and benefits. Developers at VISICO advise on how design models can be used and combined in a single platform to create different design Continued on next page

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continued from page 108

scenarios and allow for better decision-making processes. A clash detection algorithm is used to determine whether there are conflicting requirements and if so, in which areas choices need to be made.

how different choices influence the results in different ways. Ultimately, the purpose is to reach a joint decision: which scenario meets all the different requirements best?

With the modelling complete, stakeholders meet to discuss design scenarios. Parameters can vary from scenario to scenario: the number of beds can fluctuate, the space available for operating theatres, parking facilities for staff and visitors – even the number of tables in the canteen can be a variable! ‘This can save a tremendous amount of time,’ Hartmann says. ‘Research at Stanford University indicates that up to 80 per cent of a meeting can be spent on exchanging information.

Generating scenarios based on a joint model can speed up this process. Reviewing the different design scenarios helps stakeholders to immediately get to grips with the impact of everyone’s requirements, have more meaningful discussions with each other based on facts and as a result, make more-informed choices.’ VISICO’s most recent models can even be tweaked during the meeting, to show stakeholders

Besides saving costs, visualisation and simulation models can even save lives. Hospitals and health care centres cannot completely shut down during a renovation

Virtual models, tangible benefits

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process. However, construction activities – and the dust they create in particular– can present a serious threat to immune-compromised patients. Airborne pathogens attach themselves to the dust particles and can easily spread through the premises. Patients in the risk group can become ill or even die as a result of this. Says Hartmann: ‘By doing a thorough risk assessment beforehand and including this risk assessment data in the visualisation and simulation model, we can significantly reduce the risk run by patients in general and immunecompromised patients in particular.’

In one case, for instance, the model showed that placing dust walls – one of the usual measures taken to prevent dust from spreading – actually created more dust, thus creating another risk for patients.

Hartmann concludes: ‘Complex situations like these show how important it is that our hospitals are designed the smart way!’

Cost benefits of 3D/4D modelling mechanical, plumbing, electrical and fire protection systems generally account for approximately 40-60% of total construction costs. during the construction of the Camino medical office Building in California, 3d/4d visualisation and simulation models were used during the design and construction of these systems. Which cost benefits did this generate?

20-30% increase in field productivity thanks to pre-fabrication of systems designed using the new models zero field conflicts between systems modelled and coordinated. on a project of a comparable size and complexity, 100-200 field conflicts would be normal 40% of contingency money used instead of an average of 80% increased planning reliability: 83% versus 60% on other, well-managed projects.

SourCe: Cife WorKing paper #102, Center for integrated faCiLitY engineering, Stanford uniVerSitY, deCemBer 2006

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6.5

Remote care via your underwear

[ intro ] The population is ageing and so the number of cases of chronic disease is increasing.

To stop the health care system becoming overburdened in the long term, researchers at MIRA are devising techniques for supporting patients at home.

U

sing modern sensor and computer technology to monitor patients recovering from an illness or accident seems straightforward enough. You give them a device they can use to report their own blood pressure and heart rate and that keeps an eye on what they’re getting up to each day.

The device sends all of the data to a computer. If the computer notes any abnormalities or discovers that the patient is failing to comply with the treatment prescribed, it sends a warning to both patient and doctor.

The doctor can then intervene quickly or the patient can get a fullyautomated rap on the knuckles.

Turning the process on its head

Yet it’s not quite that simple in practice. As many as three-quarters of ‘telemedicine’ applications fail and never reach a large group of patients.

This might be because most of these programmes are developed too much from the perspective of technology.

Researchers at MIRA are therefore attempting to turn the development process on its head: first go and see what the user needs. And then devise technology to fit. Patients and their care providers can therefore indicate

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Home monitoring of patients is done by means of a Body Area Network.

how a programme should function.

And they can test the prototype first.

Only then do you end up with an application that patients will actually use.

The experts in information, communications and biomedical technology who are collaborating in the MIRA research focus mainly on rehabilitation patients. The majority of these are older patients who have difficulty in moving, and patients with cancer, respiratory conditions or chronic pain. But patients who are obese or suffering from psychiatric

Invisible technology

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problems are also eligible. The home monitoring of such patients is often done by means of a Body Area Network (BAN). This consists of a sensor system and a Personal Digital Assistant (PDA), a device around the size of a mobile phone. From the world of sport, people are familiar with special sensor bands placed around the chest, which measure heart rate and respiration or even record ECGs. The researchers in Twente have also developed tops and underwear which incorporate activity sensors. As a result, the technology is almost invisible but nevertheless ensures that a

supervising health care provider can tell at a distance whether a rehabilitating patient is keeping to his prescribed programme of activities. And with very little effort from the patient.

Avoiding revolving door patients

Isn’t it hard to teach older people how to work with such complicated computer-controlled programmes?

‘Nonsense’, says researcher Miriam Vollenbroek-Hutten. ‘You just have to make it easy: big letters, not too many buttons. I always say: if it’s no more complicated than using a cash point or the remote control, then anyone can handle it.’ The devices record everything. Are patients spreading their prescribed exercises properly throughout the day? Or are they crumpling in a heap after over-exerting themselves in the morning – a common phenomenon?

By keeping a close eye on this sort of thing, individualised support and efficient follow-up care is possible.

This stops you getting ‘revolving door’ patients.

On balance, it saves on costs.

Which is important, because health care is at risk of becoming unaffordable. This is partly due to the increasing number of older people and chronically ill. The ageing population, moreover, means that there are fewer and fewer staff to do all the work in health care facilities.

If the current trends continue, around 25 per cent of the working population will have to work in health care by 2025. Which is of course impossible. Thinking up clever applications which reduce the pressure on hospitals and staff is therefore a research field with huge (market) potential for MIRA.

The Body Area Network consists of a sensor system and a personal electronic device.

Less pain due to muscle relaxation

MIRA was recently involved in a highly successful trial with chronic pain patients. The patients were given a device that measured, among other things, how much strain they put on their muscles. The Twente researchers monitored the patients continuously and consulted them extensively about how satisfied they were with the device. With the measurement results obtained, the health care providers then went back to the patients. They could show them precisely whether they had relaxed their muscles enough. The result? Within a few weeks, the pain patients were not only much more aware of what they were doing with their muscles, but they also had significantly less pain. The success of the trial can’t just be put down to effective technical gadgets. An important aim of the Twente telemonitoring project is of course to develop high-quality measuring equipment. Contact points and sensors shouldn’t break down if a patient starts to sweat, and technical aids should be easy to operate.

But good coaching for rehabilitating patients is at least as important. The researchers discovered that people need help with integrating their exercises into their daily lives. And

although it’s an enormous advance for doctors to be able to monitor people 24 hours a day instead of just during a consultation, it drives patients crazy if they’re given feedback too often. So the results should be discussed regularly, but not excessively.

The human touch is still important

What is the ultimate aim? A care robot that analyses the incoming data in a fully automated manner and then, independently, sends instructions, advice, reprimands or indeed compliments to the patient, who is sitting at home by himself? Intelligent decision support is very important but fully controlled by technology is not what Miriam Vollenbroek-Hutten believes in. ‘The human role will always be important. Research shows that patients need trusted relationships with others in order to persevere.’ For that very reason the MIRA researchers plan to launch virtual group training courses in the near future, teaching patients to use the technology to contact and support each other. This seems to be the ideal way to outsource care and also make it more fun for the patient. next page: Five questions for Miriam Vollenbroek-Hutten

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6.6

miriam vollenbroek-Hutten

‘I don’t want to work in a vacuum’ parT-Time professor miriam vollenbroek-huTTen works for mira in developing Telemedicine applicaTions. as a specialisT in The biomedical healTh sciences, she also works on rehabiliTaTion Technology for roessingh research and developmenT in enschede.

1

Isn’t it difficult being at the University of Twente amongst all those techies? ‘Interacting with ‘techies’ is of course vital for developing innovations. My role is to bridge the gap between care and technology.

I’ve learned to speak the techie language well and I’m learning more every day. Every so often, though, I have to admit that I’m not a techie myself. But luckily the culture here is so open that you can just say if things are getting a bit too complicated.’

2

Do you enjoy the work? ‘Yes, my work is my hobby as well. It’s very invigorating on the one hand, and is a new challenge every time. On the other hand, I’m working to develop very practical applications. I’m doing something for society. That’s very important to me. I don’t want to work in a vacuum, I want to stay in contact with the people who are actually involved in health care.’

3

And if it doesn’t work as you want then where do you channel your frustration? ‘Then I look for a different way of doing it. There’s always more than one road that leads to Rome. I’m an optimist by nature.

For me, the glass is half full rather than half empty.’

4

Do you like it in Twente? ‘I’m a born and bred ‘Tukker’, so I feel right at home here. I wouldn’t want to be without the peace and space you find here.’

5

What do you hope to achieve at MIRA? ‘I want us to achieve an international top position in telemedicine.

The combination of information technology and biomedical technology that we have in house is fairly unique in the world. We can use that to create a profile for ourselves. We certainly don’t need to confine our ambitions to the Netherlands.’

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6.7

cHoir knowledge centre makes tHe invisible visible

matHematics is tHe key to HealtH reForm [ intro ] The demand for healTh care is on The rise, buT The resources To

provide iT simply cannoT keep up. as a resulT, work pressure increases and The desirabiliTy of jobs in The secTor plummeTs. using maThemaTical modelling, researchers maarTje Zonderland and nikky korTbeek from The cenTer for healTh care operaTions improvemenT and research (choir), demonsTraTe The poTenTial for improvemenTs in complex healTh care processes.

b

y splitting responsibilities more effectively, one of the Leiden University Medical Center (LUMC) clinics now treats 15 per cent more patients, without increased waiting times. The Academic Medical Center (AMC) is also benefiting from a ten per cent improvement in productivity due to improved staff planning based on forecasts of the inflow of patients from A&E and operating theatres. At the same hospital, a day care centre for children with muscle diseases has reduced the number of hospital visits per patient, from an average of seven per year, to just two.

You both joined CHOIR as PhD students. In addition you also work as advisors for the LUMC and the AMC. Where do you get your motivation from? nikky: ‘The way we currently organise health care processes is not sustainable for the future. They need to be streamlined in a way which protects or even increases quality. Hospital processes are extremely complex, therefore medical personnel are extremely cautious when it comes to changing ways of working or management.

Using mathematical modelling and techniques that we have designed,

we can test new management concepts and improvements which, without our models, may otherwise have remained undetected. The outcome has helped us to optimise their processes.’

Do you have an example? maarTje: ‘In the neurosurgery

department of the LUMC we managed to reduce the number of scheduled operations which were cancelled and limit the time that the operating theatres remained empty. Forty per cent of operations Continued on next page

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X.X

Nikky Kortbeek. continued from page 115

are semi-urgent, meaning they have to take place within two weeks.

These operations take place during normal hours and operating theatre time is reserved for this. However, if this isn’t sufficient, then scheduled operations have to be cancelled. This is less than optimal, particularly with regards to complex neurosurgery procedures, which people need to prepare themselves for. On the other hand, theatre time is scarce and expensive. The prospect of operating theatres standing empty because fewer than expected semi-urgent operations have taken place, is an unwelcome one.

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With the new method, based on a waiting list model, you achieve a balance between the time that the operating theatre remains unused, and the number of scheduled operations which have to be cancelled. By attaching costs to each of these factors, you influence the optimal operating theatre time that needs to be reserved for semi-urgent patients. The LUMC is enthusiastic about the results and we’re investigating if the method is also suitable for other departments within the hospital.

Nikky: ‘Another example is the Children’s Muscular Diseases Centre at the AMC. Children with muscle diseases are often treated by a number of specialists. This results in a lot of organising for the parents and, for some children, a tiring trip to hospital, five to ten times per year.

The AMC wanted to set up a day care centre which would act as one

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‘The way we currently organise health care processes is not sustainable for the future’ central location to assist with quicker diagnoses and more appropriate health care. We implemented the wishes and requirements from doctors and patients into a mathematical model which produces a daily planning. It is a complex puzzle that is almost impossible to solve manually. Which treatments or tests does a patient need? In which order? Are there consultations that need to be attended by a number of different doctors? How many breaks does a child need? And how do you put the medical personnel’s time to best use? With the modelling we have developed, this can all be optimised in a just few minutes, and the number of hospital visits required is reduced from an average of seven to just two per year.’

How unique is CHOIR? Nikky: ‘It’s unique in combining fundamental research with specific research results to produce new methods. For example, I have developed a method to calculate the behaviour of Petri nets. In Petri nets you have places, and tokens that move from place to place. For example, a patient who is moved from the operating theatre to the recovery department, and so on. You can use this method to make predictions about waiting times, the number of operating theatres required, the number of beds and potential

bottlenecks. We’ve demonstrated this at the surgical division of the AMC, which, as a result, has treated the same number of patients using ten per cent less beds. CHOIR is unique in that we have a firm foundation, but at the same time, a non-case-specific solution, which can be used elsewhere. On the basis of our modelling, software tools are being developed which hospitals can start to work with.’

Where does your added value lie?

Maartje: ‘During the optimisation

of processes, politics and emotion

will play a role, and sometimes this makes it difficult to find a solution.

The advantage of transferring these processes to mathematics is that you have to specify things accurately – information that wasn’t previously known has to be uncovered. I find an enormous added value in that we’re able to objectively and safely show the consequences of different choices, without the trial and error which would normally have to take place. Health care providers are often astounded by the opportunities for improvement. There is almost always a solution available that is both good for the patient and good for the health care institute. Another area of added value is that we have a “helicopter view” of the whole health care chain rather than just one specific area, which is often the case with medical specialists.’

CHOIR CHOIR is in the world’s top three health care research institutes. Currently, 25 employees work on an average of 30 projects per year in structural partnerships with various hospitals. CHOIR assists health care institutes with new technologies that help them to deliver high-quality care at minimal cost and to constantly innovate.

This involves the use of mathematical modelling techniques and simulation for the development of information technology applications, and management principles, such as total quality management, safety management, lean production and the optimisation of logistics. CHOIR also trains health care managers in the Operations Management discipline.

Maartje Zonderland.

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6.8 X.X

Technology to lean on [ intro ] Dementia can make daily life hard to cope with. Smart

alarm systems and clever living aids can provide patients and their carers with welcome support.

D

ementia and technology is a relatively new area of expertise but one that is sure to grow more important in the coming years. In the Netherlands, for instance, some 100,000 people have been diagnosed with dementia and it is estimated that a further 120,000 are undiagnosed. By 2050, these numbers are likely to increase by 45.9 per cent. How can we take care of this rapidly growing group, now and in the future?

Technology could play an important role in keeping care manageable, in terms of both staff and costs.

At the University of Twente’s Center for eHealth Research, PhD candidate Nienke Nijhoff has been investigating dementia-oriented technology.

At home In the home situation, dementia-oriented technology is aimed at enabling patients to remain

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at home for as long as possible. A second objective is to support carers – often family and neighbours – and make their lives a little easier.

Nijhoff did trials with sensorbased systems that help carers monitor daily activities from a distance. Preventative systems use sensors to follow patients during their daily routines and detect any irregularities that could indicate the need for extra care. Alarm systems keep track of patients’ movements throughout the day and night; an alarm signal indicates unusual activity.

Carers and patients were generally enthusiastic about these systems.

The relatively high costs of technology are, however, an issue.

At present, there are few subsidies for dementia-oriented domotics even though postponing the move to a nursing home can lead to lower costs for care.

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In nursing homes Technology used in nursing homes is aimed at supporting nurses and nursing assistants in their work. Equally important is raising patients’ quality of life, for instance by maintaining (a degree of) autonomy.

Sensor-based systems help staff to monitor daily activity. Nijhoff tested a listening system that uses acoustic sensors to detect movement and alert nursing staff in case of problems. She also introduced an IST Vivago watch to help monitor patients’ sleep-wake patterns. The watch enables nursing staff to detect sleeping problems and resolve them.

Nursing staff was sceptical at first but once they saw how useful the technology was, they quickly adopted it. Problems arose if staff hadn’t been properly instructed or if protocols hadn’t been adapted. ‘My advice is to focus more on the implementation,’

Technology used in nursing homes is aimed at supporting nurses and nursing assistants in their work Nijhoff says. ‘This should be addressed early in the development phase to avoid problems during introduction. And in an ideal situation, the technology itself would be developed in collaboration with nurses and patients.’

Here too, costs are an issue even though the technology can also generate cost-savings, for instance by enabling staff to work more efficiently. Exploring costs and benefits in a business case is worthwhile. Nijhoff: ‘I hope that in the future, technology will be widely used and there will be more ways of financing it.’

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6.9

Intelligent sensor networks as virtual coach

[ intro ] A wireless sensor system that measures

movements, checks blood oxygen levels and provides real-time feedback to the user. For patients with chronic obstructive pulmonary disease (COPD), this could be a vital development.

Exercise is extremely important for these patients, but due to breathing difficulties they can’t exercise or dare to engage in light physical activity only. The intelligent sensor network can help them take the first step.

F

irst came the mainframe computer, then the personal computer and now the time has arrived for intelligent environments that can support people in their daily lives. Pervasive Systems Professor, Paul Havinga, needs no convincing. ‘Tens of minicomputers equipped with sensors predict the wishes of the user and react accordingly. It is noteworthy than not everything runs via a central computer. Through

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wireless-network technology, the devices or nodes can communicate directly.’ Together, the sensor nodes form a network. If one malfunctions, the system doesn’t fail, the surrounding nodes simply take over its work. According to Havinga, you could build one fire detector that measures a range of variables, but there’s also an alternative – one which detects humidity, another temperature or light and a different one again for gasses. By bringing the data together – sensor fusion – and analysing this using a form of artificial intelligence, you get a more reliable picture of what’s happening, in a shorter space of time.

Following the wisdom of ‘many minds are better than one’, the sensors make up a collective intelligence system that observes, understands and acts. Areas of research from Pervasive Systems play a part in this vision: large-scale monitoring, distributed reasoning and wireless control.

The potential areas of application for such a network are far-reaching, from accurate measurements of the water quality at the Great Barrier Reef, to mini-helicopters that independently recognise fire on, for example, an industrial zone or in the city. Where necessary, sensors can be deployed to judge the situation on the ground more accurately. In chaotic and complex situations, the system is ideal for helping to achieve a good overview.

These are applications that Havinga and his team have already thought

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‘An ageing population means that more and more people will require assistance’ about, along with applications in the field of health and wellbeing, which are both exceptionally well suited to the use of sensor networks.

‘An ageing population means that more and more people will require

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assistance, while at the same time there are fewer and fewer people to offer it. For example, it could assist people with early stages of dementia, who aren’t ready for medical help, but want to maintain their independence and their quality of life.

‘And what about prevention?

Exercise is good for you, but how do we measure its effects? For top athletes, it is possible to take various measurements using a stationary bike on a treadmill, but that’s not representative of the environment the athletes operate in. Bicycle racing could take place over, say, Belgium’s cobbled streets.

This is where an intelligent sensor network, capable of feeding back measurements in every situation, comes into its own. For example, to prevent injuries while biking, it can alert you if you’re making a particular movement which could be bad for you. Or, for people recovering from a hip replacement at home, it could alert them if they are moving in the wrong way. By doing this, not only do you remove pressure on the health system, but also care workers and other people affected.’

The technology used for coaching COPD patients is currently undergoing further development by the spin-off company Inertia Technology. A small sensor node attached to the belt of the patient measures their speed, rotation and direction of movement.

That information is shared via smartphone, tablet or personal computer, six times per minute by running an application which measures the effort of the patient plotted on a graph, alongside a graph of the desired exercise pattern. In addition to this, the patient also receives short instructions on a screen, such as, ‘Keep going!’ or ‘Time to get some fresh air’, or ‘Take a break’.

Developing pervasive sensing technology In 2004, Raluca Marin-Perianu and her husband Mihai came to the Netherlands as PhD students at the faculty of Computer Science in the Pervasive Systems department.

They are now working for the department on diverse regional, national and international projects and have set up the spin-off company Inertia Technology.

On which projects have you worked? What was the goal?

Mihai: ‘We are involved with a number of projects: IS-ACTIVE, SENIOR and CareBOX. Every project focuses on a particular problem or sickness, such as COPD, rehabilitation after a knee or hip operation and Alzheimer’s disease. With pervasive sensing technology, we believe we can achieve a number of breakthroughs.

The technology can help to improve the quality of life for these people, results in fewer hospitalisations and reduces pressure on carers.’

How does it work?

Raluca: ‘Through the projects, we are developing compact, portable, intelligent and wireless pervasive sensing technology. We use sensors to measure, for example, the physical condition of the user, and provide them with up-to-the-minute feedback. These intelligent sensor networks can contribute to helping millions of people deal with chronic illnesses and, as a result, maintain their independence.’

Are there tangible results?

‘Our work has delivered proven devices, such as the wireless sensor platform ProMove, which records three-dimensional movements for subsequent analysis. In addition Mihai:

to this, we develop the intelligent software and algorithms for the real-time analysis of sensor data, and the intuitive interfaces for providing feedback to the user. These can vary from smartphones to simple LED lamps. The user tests, which validate the technology and identify benefits for the end user, are equally as vital.’

Where did the idea to start your own company come from?

Raluca: ‘We wanted to be able to transfer the potential of pervasive sensing technology from the lab into practice. The health-care industry and Ambient Assisted Living* are perfectly suited for the application of this technology. Together with medical centres and hospitals, we can design, develop and validate solutions to some of the biggest problems created by the ageing population in Europe.’

Mihai: ‘I

hope that this technology will have a huge impact on the quality of life for many people and at the same time, reduce the building pressure on health care.’

*A large European research programme that is looking into opportunities for IT to improve the quality of life for the elderly and strengthen the European economy through innovation.

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[ chapter 07 ]

Entrepreneurship & Special Projects

assisting researchers in developing actual products 124

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07 [ intro ] the ut is ‘the enterprising university’. after all, scientific knowleDge is only of value if it has an impact on society. the university is actively working to improve all aspects of health care By assisting researchers in Developing actual proDucts. scientists are stimulateD anD supporteD to Bring their technology to the market via their own spinoff company or By license agreements at eXisting companies. the university can assess its potential successes at a very early stage of technological Development. furthermore, the ut is collaBorating with government, other universities anD companies on large-scale new proJects: for instance, the state-of-the-art centre for meDical imaging, is collaBorating with the university meDical center groningen anD the german electronics giant, siemens.

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7.2

Measuring the success of technology [ intro ] Developing a smart technology is one thing. But getting it onto the market is a completely different ball game. Many inventions, however brilliant, never get further than the test phase. MIRA’s Health Technology and Services Research department led by professor Maarten IJzerman, is trying to do something about this. It was for instance consulted by Philips concerning its technology for malaria diagnosis.

T

ake a newly developed technique for breast cancer examination: photoacoustics (see page 018). A sort of echo based on light; the technique dispenses with the need for harmful X-rays.

The Health Technology and Services Research (HTSR) department is attempting to answer two questions regarding this new technique. First, is it really as good as the current

technique? Is it more expensive and, if so, is it so much better that we’re prepared to pay extra for it? And second, how do you make sure that it can be used in practice?

Getting a new technique used in practice is far from simple. It’s not just a matter of replacing the existing apparatus; the doctors and analysts also need to be trained in using the Continued on next page

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Effective and cost efficient New preventative methods are not always as successful as was hoped for.

A prime example of this is the reaction of young women to tests for the HPV virus, a key cause of cervical cancer.

Researcher Marjon Witting: ‘This method is proven to be effective, but not if only 30 per cent of the target group does not take the test.’

Witting carried out research into a screening procedure that can identify hip defects more quickly in three-month-old babies. When the hip joints of young children don’t grow sufficiently this can cause serious problems for them as young adults. Hip dysplasia leads to an early form of hip wear, which will eventually require surgery.

Screening currently takes place during a physical examination carried out by the pediatrician, however Witting investigated screening using ultrasound, similar to pregnancy ultrasounds, as an alternative.

An apparatus which detects any defect is placed on the hip. Witting: ‘we know that this type of screening is effective and cost -effective. Research shows this to be the case, but how does this work in practice? How many cases would be prevented and what are the costs?

‘We ran tests in the Salland and Utrecht regions to see if people would make use of this type of screening. People were trained to use the screening equipment, GPs referred parents and the logistics were set up. Among other things the test looked at the way in which parents should be invited for the screening and the tone of the message. Witting: ‘Do we put people at ease or make them concerned? Through a like-for-like test we uncovered vital information which policy makers can use to make more informed decisions over the national implementation of screening programmes.’

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continued from page 127

new equipment. And who’s going to pay for this transition? So besides the technical aspects this research also has medical and socio-scientific elements. What are the consequences of introducing a new technology?

Does it improve health care? Or just make it more expensive? And is that worth paying for?

The HTSR group certainly doesn’t work on the basis of scientific curiosity alone. ‘It’s important that our work is useful to society’, says IJzerman. ‘We use our knowledge to give advice, for example advising the government on whether a population study into intestinal cancer is a good idea. And we advise businesses on the right way to introduce a technology. Sometimes we do that as a department, but we’ve also set up a separate consultancy business especially for this purpose.’

IJzerman cites another example.

Malaria is a huge problem in many developing countries. People often live far away from a hospital.

So when they fall ill it’s not easy for them to find out if they have malaria. Therefore they often fail to get the right medicines, or they don’t get them on time. Philips is currently developing technology which allows malaria diagnoses to be made without complicated hospital apparatus. People can do it themselves, or have it done in a local health centre. An invention like this makes health care more accessible. If people no longer need to go to hospital for a diagnosis, they can obtain medicines sooner.

This could prevent many deaths.

Philips has approached HTSR for advice. According to IJzerman, Consultancy

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Philips’ invention of a new technology for the diagnosis of malaria made the Dutch national news. Philips asked MIRA to evaluate the technology and its usability.

‘We’re currently trying to answer a number of questions. Which of the various possible technologies is the most promising? How big is the risk of people making mistakes when using it? What are the costs? What are the consequences of earlier diagnosis: how many deaths can you prevent?

How much does it save you in costs?

And of course: is it a smart approach to the problem, or would you do better to invest in more health centres?’

Support in the design phase This type of research isn’t new. It’s also being done in other places in The

Netherlands and elsewhere in the world. ‘What is new’, says IJzerman, ‘is that at HTSR, we’re also looking at techniques that are not yet fully developed. We can support businesses in making decisions as early as in the design phase.’

And are businesses interested?

‘Of course. It’s becoming ever clearer that success is not just about scientific excellence. The real challenges are often in an entirely different area. You can’t let every technology loose on society just like that.’

MammaPrint Research carried out by Valesca Retèl,

ising technologies in the area of health

who works for the Dutch Cancer

care. The results of the study showed

Institute at the Antoni van Leeuwen-

that MammaPrint is efficient and easy to

hoek Hospital (NKI-AVL), focuses on

implement into daily hospital practices. In-

the efficiency and effectiveness of the

formation regarding the social implications

MammaPrint, or 70 gene profile. This

of such an implementation is normally

is a diagnostic test, developed by the

only gathered after the conclusion of clini-

NKI-AVL, that can, with great accuracy,

cal studies. Retèl looked at how she could

determine the chance that a breast

already make MammaPrint accessible for

tumour will metastisize to other parts

women with breast cancer while these

of the body, and thus determine the

studies were ongoing. The CTA method

need for additional treatments such as

can be a deciding factor in, for example,

chemotherapy.

reimbursement from health insurance

Retèl makes use of the Constructive

companies and, at an early stage, can

Technology Assessment (CTA) method,

provide support for promising technolo-

which developed from a broad societal

gies to be made available to patients more

evaluation of earlier, complex, but prom-

quickly.

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Increased urgency Epidemiologist, Carine Doggen, re-

on a beach in Harderwijk. Should he or

searches how accident and emergency

she go to the local hospital or be flown in

(A&E) facilities should be organised to

the trauma helicopter to Zwolle? And how

optimally serve the patient, hospital and

would the treatment look after this?

medical specialists. The registration of

The processes for each hospital vary

patient flows indicated that the types

enormously and therefore the reseach

of care delivered by A&E is extremely

team looked at triage protocols, the

broad. Patients arrive with acute com-

process of determining the priority of

plaints via their General Pracitioner (GP),

patients’ treatments based on the severity

the trauma team or their own initia-

of their condition. ‘Harmonisation results

tive. The exact demands on care were

in improved efficiency and prevents over

researched over a number of weeks in

triage. When uncertain, people tend to call

the Zwolle region and the Euregio, an

on the full trauma team. If, as a result, a

area which covers the eastern part of

surgeon has to leave the operating room,

Flevoland up to and including parts of

this isn’t a win-win for anyone.’

the German border regions. The area

Another question is the extent to which

covered has an estimated population of

technology can improve decision-making

around 2.5 million.

during acute care. For example, by taking

The research provided an insight into the

diagnostic capabilities to the patient.

periods of peak demand for hospitals

Together with the Dutch National Institute

and patient survival rates. The aim was

of Public Health and the Environment

to find ways to help care providers make

(RIVM). and the Jeroen Bosch Hospital,

improved decisions about the treat-

research is being carried out into the

ments provided to emergency patients

effects of diganosis by the GP or with the

and where these should take place. Dog-

use of bio markers to quickly diagnose a

gen: ‘Take for example the scenario that

heart attack, for example.

someone has a suspected heart attack

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7.3

Per Slycke, Peter Veltink and Xsens Hollywood films like ‘Alice in Wonderland’ and ‘Iron Man 2’ used the special sensor suits from Xsens to make perfect animations. The movement measurement systems of the Twente company are also used worldwide by the gaming and robot industry and by movement scientists. Xsens was founded in 2000 by two former students from the University of Twente: Per Slycke and Casper Peeters. Right from the start their source of inspiration was professor Peter Veltink, who works at MIRA. Per Slycke

1998

2000

Peter Veltink

2002

1998-1999

2002

First experiments with sensor shoes

Xsens falters

Veltink and Slycke worked on a method

the intended client, a heart-rate meter

to improve estimation of orientation and

manu­facturer, pulled out. That was hardly

change of position during a movement.

surprising as it was the middle of the

The advanced measuring equipment

‘dot-com crisis’ when the Internet bubble

they developed for this can record body movements in 3D.

Just before the sale of the invention,

2000

burst. After all the investments made, Xsens was left with empty hands.

a speedometer for runners. We needed

Founding Xsens Technologies

be flexible as a company and find other

help to develop the sensors we wanted

Market interest became more serious.

opportunities. In that same year we sold

to use for this. We were lucky. One of the

The company was set up with support

the first 3D movement technology to

leading groups in this area, that of Peter

from the University of Twente’s TOP

completely different markets, such as

Veltink, was at the University of Twente.’

funds.

stabilisation and navigation for unmanned

Veltink: ‘They came to me as young

Slycke: ‘The real start’

recently graduated physicists who were

Veltink: ‘The concept worked, with a

Veltink: ‘A disappointment, but not a

determined to set up a company. Their

gyroscope and acceleration sensors that

failure.’

‘RunnersWatch’ was interesting, as it

formed the basis of the speedometer.

was more than just a step counter.’

They tested it here on the athletics track

Slycke: ‘ We had the idea of developing

Slycke: ‘At such a moment you need to

underwater robots. The basis for a new

with this sensor on the shoe.’

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product line had been laid.’

Scene from the 3d animation film alice in Wonderland with actors Crispin glover and Helena Bonham Carter. (photos disney Home entertainment)

2005

2010

2010 2005

Tenth anniversary of Xsens

Key patent filed for new Xsens products

pany, which has opened a second office

Some 70 people now work for the comin Los angeles and has agents

Slycke: ‘a milestone, although you still

all over the world. Veltink has been

have to wait five years before a patent

honoured with the ‘partnership award’:

is actually granted. Meanwhile we also

a bronze gyroscope.

concluded three important license agree-

Los angeles, united States, italy, france,

ments with the university of twente

Slycke: ‘peter Veltink has always been

ireland, enschede, Sweden, germany, Bulgaria,

that formed the basis for the forceShoe.

a source of inspiration, due to his clear

Hungary, east turkey, Japan, China, Korea

that’s a shoe which measures the ground

vision. He provides a broad framework

and india.

reaction forces and foot movements in

that we develop further in our products

order to create 3d images of the walking

for measurements on people.’

patterns and study balance of gait. it will

VelTink: ‘i’m proud of course. Six of my

be marketed in 2011.’

phds are working at xsens. We benefit

VelTink: ‘a working sensor system for

enormously from the relationship. their

measuring relative distances on the

elaboration of ideas continually yields

body did not yet exist. it’s therefore very

new research questions.’

important.the concept of a forceShoe and, related, powersensing/powerglove has, in my view, high potential.’

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7.4

[ extract interview from ] the schedule of... ]

Martijn Kuit

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‘ MIRA is growing fast!’ [ intro ] As managing director of MIRA, Martijn Kuit

is scientific director Clemens van Blitterswijk’s right hand man. he works hard on realising ambitious plans for MIRA’s growth and successfully combines this with his family life.

133

6:30 Get up, check emails and bring the kids to school

‘My kids love it here. We used to live in the Randstad; due to a lack of space the playground was on the school’s roof. Now we’re in the middle of the woods. The school is in the woods, the after-school care centre is in the woods and when we step out of our front door we’re in the woods in no time as well. The children play a lot outside and really enjoy that. There’s also plenty to do

134

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in the city of Enschede. When I first came here I thought it might be a bit quiet, as Enschede is in a rural area.

However, the city has recently grown and changed a lot; now there are loads of trendy neighbourhoods.’

9:00

Consultation with venture capitalist about start-up ‘Tom Schwarz helps me with setting up entrepreneurial activities. The fantastic technology developed here

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must reach the patients and not sit collecting dust in the cellars of the University of Twente. But we don’t want to be technology pushers.

That’s why we do everything possible to encourage entrepreneurship or to market our discoveries in other ways. For example, we’re currently holding meetings with researchers who are busy with a start-up. They’ve asked us to transfer the patent to them and they would also like the university to become a shareholder

Entrepreneurship & Special Projects

[ who is... ] in the new limited company. In principle, we’re interested in that option. Finding capital and reaching agreements about who has the rights to what when the product becomes profitable in the future, is of course a complicated process. Tom advises us about the so-called capitalisation table.’

The Centre for Medical Imaging (CMI) will provide new technologies to make even better images of the body than is currently possible by using MRi scans, Ct scans, x-rays or ultrasound. We do that by combining signals such as light and sound and by developing innovative contrast media. in CMi, MiRa is collaborating with the university Medical Centre groningen and with the german electronics giant Siemens. CMi is spread over two physical locations: from 2012 onwards the technological aspects will be worked on out at a refurbished building next to MiRa, while the technologies will be applied to patients at the hospital in groningen.

Martijn Kuit [1975] was appointed as the managing director of the fledging MiRa institute in May 2009. He was previously the director of the Centre for entrepreneurship at delft university of

10:00 Interview with

technology as well as managing director of

‘MIRA is appearing in the news more often, with new discoveries or with “political” successes from the institute.

This interview has been requested because we’re involved in four of the eight centres that the Dutch science funding body NWO recently appointed as centres of research excellence with respect to innovative medical devices. For us this means growth as well as the recognition that we’re on the right track as an institute. The initiatives chosen by the Netherlands Organisation for Scientific Research (NWO), fit in seamlessly with the research we’re doing here.’

until 2002, Martijn was involved in research.

science journalist

Centre for Medical Imaging

who is martiJn kuit?

the research programme next generation infrastructures at the same university. up He gained his doctorate with a thesis about strategic behaviour and regulatory styles in the energy sector. Martijn lives in Boekelo, just outside enschede, with his wife and two sons.

University of Oxford and Imperial College in London. He’s impressed by what we’re doing here and has decided to join us. It’s nice to see that our visibility is increasing and that talent from abroad is now following what we do. That says something about the growing strength of our institute.’

11:00 First meeting with new 13:00 Lunch meeting with colleague Christian Beckmann

Joris Laarman, artist

‘MIRA is growing fast! Over the next few years we’ll appoint some 150 new people. Christian is one of them.

We’ve spent the past few months carefully thinking about the scientific focus we want to give to our new professorships. We’ve looked at how we can interconnect these and make sure they relate well to the consortia in which we’re a partner, such as the Centre for Medical Imaging and LEO. Now we’re looking for candidates. Christian is somebody who we’re very happy to have found.

He has previously worked at both the

‘We eat in our institute’s restaurant, which is usually full of noisy students. Joris is an artist who we’ve already worked with on several occasions [see also page 098]. He’s just back from New York, where he exhibited his Half Life, a lamp of living cells. Biochemistry meets interior design! Such ventures are also possible at MIRA. We’re a young institute with a lot of young people; we work hard and a lot is expected from you. But that doesn’t mean Continued on next page

135

continued from page 135

being serious all the time. Fun is also a part of our DNA. That can take the form of humorous projects with artists, an original competition or quite simply a fantastic party with good food, great music, dancing and a decent drink. The management

‘ There’s a clear professional ethos, but that goes hand in hand with a certain ease’

Centres of Research Excellence The Dutch science funding body Netherlands Organisation for Scientific

team reflects that pleasure; it struck me from the moment I came here. There’s a clear business and professional ethos but that goes hand in hand with a certain ease. Here, you’re allowed to sit with your feet up on the table and I really like that!’

14:30 Meeting with architect

about the new location for the Centre for Medical Imaging

‘In 2012, the Centre for Medical Imaging will move to a building right next door to MIRA. The old chemical technology building will be completely stripped and refurbished for this purpose. Researchers will soon share that building with patients who will benefit from the most advanced equipment. The patients will then of course need to be separated from the people working on the equipment. And we’ll need to keep sensitive equipment well away from lifts and cars as these can cause disruptions. I need to

136

Research (NWO) has made about 200 million euro available for collaborations between universities, industry and medical

discuss these requirements with the architect.’

institutes that wish to develop health care

16:00 Meeting about

In 2010, eight national partnerships were

the inaugural International Federation of Biomedical Institutes conference ‘The work we do at MIRA takes pla­ce in an international context as a matter of course. People from all four corners of the globe work here, English is our medium of communication, and we only publish in international journals. We want to collaborate more closely with other European institutes. So we’re examining the option of setting up a federation of biomedical institutes.

This has many advantages, For example, working together makes it easier for us to benefit from European grants. The University of Twente is an entrepreneurial

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by means of technological innovations. selected, the so-called centres of research excellence. MIRA is involved in no less than half of these happy few: in two cases as the official technical scientific leader and in two others as a partner.

MIRA is the official technical scientific leader for the Centre for Medical Imaging [see page 134] and the Centre for Care Technology Research, a partnership that includes the University of Twente, Maastricht University and TNO, which will develop technology for an improved diagnosis, monitoring and treatment of patients outside the hospital. MIRA is a partner in NeuroControl, a consortium that works on improved rehabilitation techniques, and in SPRINT, which will develop smart prostheses to allow patients to move more easily.

Entrepreneurship & Special Projects

university in every respect. I have considerable freedom, and we’re going to set up a lot of new things.

That’s exciting.’

work for half the night so that you can play with your children in the sandpit in the afternoon, then, in principle, that’s fine with us.’

17:00

19:30 Reading the

‘I really value being with my children in the evening and eating with them. From nine to five I’m at the institute and outside those hours

‘I read the papers for myself, and for MIRA of course. We want to make connections with what’s happening, also locally. The High Tech Health Farm is a superb example of that [see page 050].’

Off home, cook, eat and take the kids to bed

‘We don’t want to be technology pushers’

newspapers

20:30 Jogging

‘I go jogging for 30 to 45 minutes twice a week in the woods close to home, come rain or shine. I always

I’m at home. However, this doesn’t mean that I never work then. Early in the morning, late in the evening or sometimes even in the middle of the night, I’m often behind my computer. The same is true for many parents at MIRA. We’re flexible as an employer: we’re very clear about what we expect from you, how you do things is up to you. If you want to

the High tech Health farm [see page 138].

feel really good afterwards.’

21:30 Reading a book

‘Now I’m reading Zoete Mond [Sweet Mouth] by Thomas Rosenboom.

It’s a novel that’s set in the 1960s and describes the rivalry between a vet and a village prankster. I read literature but also enjoy a popular American thriller once in a while.

But I leave management books untouched these days. I read enough of those during my studies and my PhD research. Now I develop my management skills by simply getting on with the job. That’s how you learn the most.’

LEO, centre for Service Robotics Leo is a broad consortium that works on

and clinical trials, robotic technology

intelligent service robots for a variety of

will mature to enter the operating the-

purposes, including medical applications.

atre and clinic for routine applications.

Besides MiRa, partners include regional

after exploratory missions to Japan

high-tech companies and ontwikkelings-

and to Boston, Baltimore and Chicago,

maatschappij oost-nV.

the initiative is starting to gain a more

Robotics is the emerging technology in

definite shape. from 2012 onwards,

health care fields such as surgery and reha-

Leo will be housed next to the Centre

bilitation. it offers new and improved surgi-

for Medical imaging. our ambition is

cal procedures, better training results and

to turn the east of the netherlands into

enhanced comfort and safety for patients.

a leading player in robotics for health

after many years of fundamental research

care and medicine.

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7.5

hiGh-tEch hEalth FarM WElcoME to thE hEalth carE oF thE FuturE.

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P

atient-specific care, close to home, supported by state-of-the-art techno­

logies. This is the essence of the High-Tech Health Farm being developed by MIRA and Provincie Overijssel, which will form a link between home and hospital. A range of new technologies will have a place there, for both diagnosis and treatment.

For example, a new method for preventing the breakdown of cartilage in the knee [see page 40/41]. Or a quick, safe breast examination by means of light and sound [see page 18]. The farm doesn’t exist yet.

Over the next few years a team composed of MIRA, Medisch Spectrum Twente, Isala Klinieken Zwolle, Zorg Groep Twente, Meander Ziekenhuis Amersfoort and the university medical centres of Utrecht and Nijmegen will work out where and how it can best be built.

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7.6 X.X

Treatments in the field [ intro ] The companies Micronit and Blue4Green are spinoffs from research at

the UT. Micronit develops the world’s smallest and most complex chips, and Blue4Green was the first to produce a portable lab for veterinarians.

A

quarter of all cows have a calcium deficiency after calving. This results in lower resistance in the cow, and can lead to a variety of diseases, with associated financial consequences for the farmer. An overdose of calcium is equally as detrimental for the animal.

The knowledge acquired by the UT during the development of the lithium chip has been applied to a machine which can measure the amount of calcium and magnesium in the blood. Called

Early stages

140

capillary electrophoresis, it identifies different types of ions based on their conductivity. This technology was developed commercially by Blue4Green. Researcher Erik Staijen identified that the chip might be useful for the veterinary market. ‘It’s possible for us to measure anything that contains charged particles, so I called various veterinarians to see if they would be interested in such a chip. They were particularly interested if this would enable them to detect low calcium levels at an early stage, and therefore prevent other illnesses.’ Staijen still

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finds it fascinating that something he conjured up in a moment’s inspiration has become a commercial product. ‘My relationship with the university is still very strong and we’re working closely together to improve the technology. For the UT, valorisation of research results also plays an important role as it can lead indirectly to new research.

The possibilities are endless, and therefore there’s a lot happening.’

Three minutes Identifying interested veterinarians was no problem at all. Staijen: ‘When

Entrepreneurship & Special Projects

veterinarians don’t have their own facilities, they have to send a blood sample to a commercial lab and then wait a couple of days for the result. The Labbook® developed by Blue4Green brings the ‘point of care’ directly to the field. Now, the vet only has to take a sample of blood from the tail, place a drop on the chip and within three minutes he has the result.’

The Labbook® is in the beta phase of development, and is already in use.

Staijen: ‘My role is to validate and calibrate the technology. Together with the Graafschap Dierenartsen veterinary practice we’ve carried out around 2,000 tests on cows from 23 different dairy farms. Based on this data we have developed the Dry2Fresh programme. This is a protocol for veterinarians to follow based on the results of the test.’ The calcium levels in the blood can be influenced by a number of factors, such as the stabling and diet. ‘The Labbook® is a totally new concept and while veterinarians still have to get used to this new way of working, the number of users is growing rapidly.’

Micronit develops the world’s smallest and most complex chips.

Enough markets Ronny van ‘t Oever is co-founder and CTO of Micronit Microfluidics, a company that produces a number of Labon-a-Chip products. His focus lies in identifying new markets.

‘Blue4Green works with the smallest and most complex chip in the world.

By increasing the funcionality or making it as small as possible we’re striving to leave as little as possible unused space on a chip.’ At Micronit there’s also an intensive cooperation between entrepreneurs and professors at the university.

Our platform can measure any kind of ion in water, meaning there are numerous potential markets.

‘It’s impossible to examine all the opportunities right now,’ explains Van ‘t Oever. ‘Marketing the technology via parties like Blue4Green is our chosen route to market.’ Micronit’s products are already used for DNA analysis and sequencing by, among others, technologically advanced companies in Silicon Valley. ‘They’re raising the profile of DNA using our chips.’

There are also numerous opportunities for the private market.

Van ‘t Oever: ‘Our products allow people to monitor themselves more effectively and for longer. We bring the laboratory to the people instead of the other way around. In a country with an ageing population this is extremely useful. It gives people control over their lives and saves time and resources for care organisations. It would be great if we could find a partner who appreciates just how pressing this issue is.’

Blue4Green was the first to produce a portable lab for veterinarians.

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[ chapter 08 ]

Education at the University of Twente

training tomorrow’s health professionals 142

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Education at the University of Twente

08 143

8.2

EDUCATION AT University of Twente [ intro ] The University of Twente (UT) provides a genuine academic community

in which researchers and students inspire one another. Research and teaching are interconnected: researchers also teach and supervise PhD students working on their thesis or students working on their final project. Our students look beyond the boundaries of their own discipline and across national boundaries as well. Teaching has both a multidisciplinary and international focus. At the MIRA institute there are three health education programmes: Technical Medicine, Biomedical Technology and Health Science. The new Experimental Centre for Technical Medicine (ECTM) at the University offers a large state-of-the-art learning environment for students and medical professionals.

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Education at the University of Twente

Health Sciences

Technical medicine

Biomedical technology

Programme: Bachelor’s and Master’s

Programme: Bachelor’s and Master’s

Programme: Bachelor’s and Master’s

Language of the degree programme: English

Language of the degree programme: Dutch

Language of the degree programme: English

Duration: three years for a Bachelor’s and

Duration: three years for a Bachelor’s,

Duration: three years for a Bachelor’s,

one year for a Master’s

three years for a Master’s

two years for a Master’s

Prior education: university preparatory

Prior education: university preparatory

Prior education: university preparatory

education (VWO) with subject cluster na-

education (VWO) with subject cluster

education (VWO) with subject cluster

ture and technology, or nature and health.

nature & technology with biology, or

nature and technology, or nature and

Other clusters preferably with biology and

nature and health with maths B and

health with maths B and physics

mathematics.

physics

Students are trained to become: biomedical

Students are trained to become: Health

Students are trained to become: health

engineers, capable of designing and

scientists, professionals that study and

professionals who improve and

developing new technology for the

manage the quality and efficiency of medi-

modernise patient diagnosis and

health sector

cal technologies and health services.

treatment with the aid of technology

Specialisations: human function technology

Specialisations: Health Services & Man-

Specialisations: medical signalling,

and molecular, cellular and tissue engi­neering

agement (HSM) and Health Technology

reconstructive medicine, robotics and

Graduates work in: academic institutes,

Assessment & Innovation (HTA&I).

imaging

hospitals, companies and engineering firms

Graduates work in: academic institutes,

Graduates work in: academic institutes,

hospitals, industry, consultancies and

hospitals, companies

governmental institutes

Technical medicine is a young and growing science. Technology has brought about impressive improvements in medical diagnostics and treatment options. It’s not only increasing in importance but also in complexity. A new generation of trained professionals is therefore needed: experts who can apply this specific medical technology properly.

The biomedical technology degree program­me trains students to become engineers capable of designing and developing new technology to benefit human health.

They push back the frontiers of technical possibilities in prevention, treatment and care and they come up with solutions to improve people’s quality of life. Areas of application include body-friendly implants, tissue engineering, threedimensional imaging of organs and rehabilitation aids.

Health Scientists are trained to analyse the effects and efficiency of health care operations and health care provision in comparative health systems. Students in the specialisation of Health Services & Management study the quality, efficiency and optimisation of health operations in hospitals and primary care. Students in the specialisation Health Technology Assessment & Innovation evaluate the efficacy and efficiency of health care technologies to support industries and regulatory agencies in deciding on the adoption and coverage of new medical products.

145

ECTM Courses The Experimental Centre for Technical

the Experimental Medical Diagnostic

Medicine (ECTM) is a research, develop-

Laboratory.

ment and education facility. It is used

As well as the Technical Medicine

as a learning environment in which the

programme, the ECTM plays an active

authentic professional environment

role in the field of postgraduate medi-

is simulated and fits the demands for

cal education and training for medical

training Technical Medicine students and

residents and specialists. A range of

other health care professionals. Further-

courses have been developed in recent

more, it is a research facility in which

years,which participants of several

equipment and intervention modalities

medical institutions can subscribe to.

can be developed and evaluated and

Tailor-made courses are developed in

where research with human subjects

close collaboration with hospitals or user

is carried out. The total facility contains

groups, to ensure the highest quality and

1,300 square metres that are specifically

a perfect fit with user demands.

designed for the ECTM. Key points of the ECTM courses Highlights of the ECTM are: the simu-

Focus on safety and innovation

lated Operating Room and Intensive

Expertise through practical experience

Care Unit; several cutting edge medical

Transfer to professional practice

simulators for acute care situations,

Unique educational design

minimally invasive interventions and the

State-of-the-art facilities and equipment

use of medical imaging techniques; and

Integration of medicine and technology

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Education at the University of Twente

147

8.3

[ extract from the schedule of... ]

heleen miedema

‘ we have the nerve to take risks’ [ intro ] Heleen Miedema, programme director for

biomedical technology and technical medicine, wants to modernise education and has a keen eye for developments relevant to this. That’s why her schedule includes so many meetings.

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Education at the University of Twente

7:30 Breakfast

‘I’m not really a morning person. I’m not grouchy, but I like a quiet start to the day. And with a daughter in Leiden and a son in England, I can have that. My husband leaves for work early, so I have plenty of time to myself.’

9:00

Meeting of MIRA management team ‘Research and education are inex­ tricably interlinked. Good scientists can explain the essence of their discipline to students and encourage

‘Good scientists encourage students to develop their own ideas’ them to develop their own ideas. And the converse is also true. A lecturer is inspired by his or her undergraduates

and PhD students. The directors of MIRA believe it is vital to develop a clear line in research and to merge it with education. So, as the director for education I’m also a member of the MIRA management team.

Today’s agenda includes how we can translate the entrepreneurial nature of scientific research to the teaching programme. The entrepreneurial professors have an important role to play in this respect.’

10:00 On to meeting of the biomedical technology curriculum committee

‘The University of Twente is an entrepreneurial university. That means we have the nerve to take risks. We don’t train people through pre-programmed instruction. We aim to develop professionals who take initiatives; so we shouldn’t teach them to imitate their lecturers.

Instead of a dusty book, we present them with a real-life problem and information; they find the solution themselves. With this we challenge

students to get the best out of themselves. We encourage them to come up with their own solutions and keep each other sharp. It’s important to recognise this attitude when designing new educational initia­ tives. The discipline of biomedical technology is constantly developing.

So we regularly take a critical look at the teaching to see if the objectives are still being met. These are very stimulating meetings, where a lot of creative ideas are shared.’

11:00 Meeting with a team of educational researchers

‘Working in science is not just a job, it’s also an attitude. With technical medicine, we’ve devised and set up an entirely new degree programme.

Now we want to check if we’ve made valid decisions. So we’ve made the teaching a subject of research. We’re not just exploring the question of what technical medicine students should think and learn; our interests are broader than that. How do people acquire skills? How do you teach

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15:00 Meeting with the

people to think creatively? How do you teach them to position themselves? We do this with a team of cognitive psychologists and educationalists.’

secretaries of the biomedical technology and technical medicine degree programmes, Rita ter Weele and Danielle Heskamp

12:00 Lunch with

‘Being the programme director of two degree programmes is a challenge.

It’s only possible with good support.

I sometimes joke that they’re my guardians. That’s putting it a bit strongly. But essentially they contribute to and monitor my schedule. As they know what I’m doing and, more importantly, understand what the various meetings are about, they can be proactive and make sure that what we agree upon happens. This afternoon we’re discussing the schedule for the immediate future.’

anniversary committee

‘An entrepreneurial university is characterised by the relationship it has with the society it serves.

Researchers derive their questions from society, and provide it

‘I experience the University as a collegial environment and a warm nest’

17:00

Meeting of vocational service committee, Enschede Rotary

with answers. So for our 50th anniversary, we want to throw a party that includes our neighbours and shows people what we do. I’m keen to contribute to that.’

‘I’m a member of the Rotary Club.

I like the fact that it takes you outside your own little world. I’m on the vocational service committee.

Vocational service lies at the heart of the club. What drives people in their work and what dilemmas can they be confronted with? We invite people to come and talk to us about this.

It could be a lawyer who can get a rapist off on a technicality, although it conflicts with his own sense of justice. When you’re struggling with something in your own organisation, discussing the problem with outsiders can be a breath of fresh air. They can look at it from a different angle. My penchant for broadening horizons fits in well with my job. On a professional level I’m also constantly monitoring what’s going on in society. I’ve noticed that

14:00 Meeting of the

Board of Directors of Medisch Spectrum Twente

‘The Board of Directors of Medisch Spectrum Twente sent me an invitation. They want to modernise the training for anaesthesia assistants. They believe we can play a role in this with the Experimental Centre for Technical Medicine. We already contribute to the Bachelor’s and Master’s teaching. And in the future we’ll play a growing role in postgraduate teaching and in the professional development of various health professionals.’

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[ who is... ]

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chapter 08

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who is heleen miedema?

Heleen Miedema (1956) holds a Master’s in Educational Psychology from Leiden University. She has held various positions in vocational education and since 1998 she has been developing teaching programmes at the University of Twente. According to her, you can only do this if you have a good understanding of the discipline you’re teaching in and the profession you’re training for. This means talking to people, listening carefully and inspiring people at the same time. Heleen lives in Enschede with her husband and has two grown-up children.

University College in Utrecht is very successful. That makes me wonder if it’s possible to create a University College for Engineering here.’

20:00 Housewarming party at Kim’s

‘My colleague Kim moved to an unusual house recently. A converted barn, in fact. We’re going to celebrate that. I experience the University of Twente as a collegial environment and a warm nest. A psychologist once told me that to be known, recognised and acknowledged as a person is important for your well being. This applies to everyone, both students and staff. I’m trying to create an organisation which puts that principle into practice and respects people’s individuality. I tell students and colleagues: “go on, surprise me”.

You can be yourself, and if you work hard you’re also allowed to make mistakes. All you need is the guts to try something. Plodders don’t interest me very much.’

Education at the University of Twente

8.4

ana Barradas

My research is all about two worlds meeting ana barradas came To enschede from porTUgal in 2006 To sTUdy biomedical engineering. afTer gradUaTing she was asked To conTinUe as a phd sTUdenT. she didn’T have To Think Twice!

1

What brought you to MIRA? ‘I wanted to take some classes at master’s level and combine this with experiencing a different lifestyle. I considered Norway and Sweden but the change in climate would have been too dramatic. Then a friend told me of these two interesting research groups in Twente: Polymer chemistry and Biomaterials and Tissue Regeneration.’

2

And how do you like our Dutch lifestyle? ‘Everything here seems to flow far easier than in Portugal. Things are less rigid and bureaucratic. And people are more helpful, both in science and in private life. I fit well into this pragmatic, direct culture. Like most foreigners, it’s only the food and the weather I complain about.’

3

Was the educational programme also different?

‘Very much so. I was used to seven or eight hours a day of lectures: just sitting back and listening. When I came here, it was two hours of that. The rest of the time, we were challenged to explore what we liked, talk to lecturers and develop our own thoughts.’

4

Does that make you a better researcher? ‘Yes it does, provided the lecturers keep you on the right track.

Nowadays, you can see a shift to more active forms of education everywhere. Holland is a trailblazer in this respect.’

5

What do you want to do after this? ‘I’m torn between academic research and business. Science attracts me because it’s challenging and vibrant. Yet I’m also pulled to business because from an almost limitless range of scientific ideas it selects just a few that can change people’s lives.’

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Credits Published by G+J Corporate Media on

behalf of the University of Twente Publisher Petra Schuttel Executive editors Marcel Hammink and

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Mariette Huisjes Design Sjoukje Kloostra Text Edo Beerda, Nienke Beitema, Thiemo

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Veldman. And also the professional and personal archives of the University of Twente Infographics Steffi Padmos, Schwandt

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All rights reserved. No part of this publi足 cation may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the University of Twente.

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0153

HEALTH AT UNIVERSITY OF TWENTE: HIGH TECH, HUMAN TOUCH Health has become a key research theme at the University of Twente (UT).

Hundreds of our scientists are active in the field and their close cooperation is a firm embodiment of the UT-slogan ‘high-tech, human touch’.

In other words, wrapped around our technology is a cloak of social, human and behavioural sciences.

In this book you will find some great examples of the health technologies that are developed at the UT. Learn about a complete laboratory in a pill, robots that help us to rehabilitate and a new generation of scanners to detect breast cancer. Read about three special health education programmes and the state-of-the-art Experimental Center for Technical Medicine. Last but not least, discover how the UT actively promotes scientists to start their own companies to make actual products out of their research. Ultimately, the health technologies developed at the UT will benefit patients all over the world.

WWW.UTWENTE.NL