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GLOBAL WATCH MISSION REPORT

Microfluidics for thedevelopment, production and delivery of high-volumeproducts – a mission to theNetherlands and Germany

APRIL 2006

Global Watch Missions

DTI Global Watch Missions enable small groups ofUK experts to visit leading overseas technologyorganisations to learn vital lessons about innovationand its implementation, of benefit to entire industriesand individual organisations.

By stimulating debate and informing industrialthinking and action, missions offer uniqueopportunities for fast-tracking technology transfer,sharing deployment know-how, explaining newindustry infrastructures and policies, and developingrelationships and collaborations. Around 30 missionstake place annually, with the coordinatingorganisation receiving guidance and financial supportfrom the DTI Global Watch Missions team.

Disclaimer

This report represents the findings of a missionorganised by Faraday Packaging Partnership (FPP)with the support of DTI. Views expressed reflect aconsensus reached by the members of the missionteam and do not necessarily reflect those of theorganisations to which the mission members belong,FPP or DTI.

Comments attributed to organisations visited duringthis mission were those expressed by personnelinterviewed and should not be taken as those of theorganisation as a whole.

Whilst every effort has been made to ensure thatthe information provided in this report is accurateand up to date, DTI accepts no responsibilitywhatsoever in relation to this information. DTI shallnot be liable for any loss of profits or contracts orany direct, indirect, special or consequential loss ordamages whether in contract, tort or otherwise,arising out of or in connection with your use of thisinformation. This disclaimer shall apply to themaximum extent permissible by law.

Microfluidics for the development,

production and delivery ofhigh-volume products

– a mission to the Netherlands and Germany

REPORT OF A DTI GLOBAL WATCH MISSION APRIL 2006

FARADAY

PACKAGINGPARTNERSHIP

ACKNOWLEDGMENTS 4

1 EXECUTIVE SUMMARY 5AND RECOMMENDATIONS

1.1 Executive summary 51.2 Recommendations 6

2 INTRODUCTION 7

2.1 Background to the mission 72.2 Mission coordinating body 82.3 Microfluidics in the UK 82.4 Broad objectives of the mission 92.5 The Netherlands and Germany 92.6 Mission team 92.7 Background research 9

3 INTRODUCTION TO 10MICROFLUIDICS

3.1 Substrate materials 103.2 Functions that can be 10

implemented3.3 Market sectors 11

4 OVERVIEW OF THE 12MICROFLUIDICS SUPPLY CHAIN

4.1 The microfluidics supply chain 13in the Netherlands4.1.1 Technology R&D 144.1.2 Foundries 144.1.3 Product and system design 14

4.2 The microfluidics supply chain 15in Germany4.2.1 Technology R&D 154.2.2 Foundries 154.2.3 Product and system design 15

4.3 Summary of key microfluidics 16activities elsewhere in Germany4.3.1 Baden-Wuerttemberg 164.3.2 North Rhine-Westphalia (NRW) 174.3.3 Berlin-Brandenburg 174.3.4 Thueringia (Erfurt-Jena- 17

Ilmenau triangle)4.3.5 Bavaria 184.3.6 Saxony 18

5 MICROFLUIDICS IN THE 19CHEMICAL SECTOR

5.1 ‘Microreaction’ 205.2 Microreactor component 20

construction5.3 Approaches to microreaction 21

engineering5.4 Scale-up (numbering up/ 22

scaling out)5.5 Process chemistry expertise 225.6 Advantages of microreaction 23

5.6.1 Quality of chemical reaction 235.6.2 Exothermic reactions 235.6.3 High-pressure reactions 235.6.4 Novel chemistry 235.6.5 Scaling 235.6.6 Safety 24

5.7 Summary 255.8 Future prospects 25

6 MICROFLUIDICS IN THE 27PHARMACEUTICAL SECTOR

6.1 Discovery 276.2 Scale-up 286.3 Quality control 296.4 Delivery and clinical testing 296.5 Summary and conclusions 30

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MICROFLUIDICS FOR THE DEVELOPMENT, PRODUCTION AND DELIVERY OF HIGH-VOLUME PRODUCTS – A MISSION TO THE NETHERLANDS AND GERMANY

CONTENTS

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7 MICROFLUIDICS IN THE 32HOUSEHOLD, PERSONAL CAREAND FOOD SECTORS

7.1 Increased availability of compact, 32low-cost and low power consumptionmicrofluidic components

7.2 Self-diagnosing and self- 33monitoring devices

7.3 Highly integrated microanalytical 33systems for kinetic studies, processcontrol and product development

7.4 Advance of module-based 33microfluidic systems

7.5 Novel membrane-based material 34processing techniques

7.6 Summary 34

8 MECHANISMS FOR 35STIMULATING THE UPTAKE OF MICROFLUIDICS BY INDUSTRY IN THE NETHERLANDS ANDGERMANY

8.1 Introduction 358.2 Overview of the Netherlands 35

8.2.1 Networking 368.2.2 Reconfiguration 368.2.3 Support 368.2.4 Company-university 37

relations8.3 Overview of Germany 38

8.3.1 Support for IMM 388.3.2 IMM reconfiguration 388.3.3 A wider view of 39

microfluidics in Germany8.3.4 uVT network and 41

standardisation8.3.5 Training and education 418.3.6 Important intermediary 41

organisations8.4 Conclusions and 42

recommendations

9 EMERGING AREAS OF 43MICROFLUIDIC TECHNOLOGY

9.1 Introduction 439.2 Examples of new technologies 43

and applications9.2.1 Micro boiling heat transfer 439.2.2 Liquid-wall interactions 449.2.3 Fluorescence 44

enhancement technology9.2.4 Micro inhaler for drug 44

delivery9.2.5 Micro electrolyte analysers 45

for point of care9.2.6 Micro fuel cell technology 459.2.7 Nanowires 469.2.8 Lab-on-a-chip 469.2.9 Microporous structures 469.2.10 Polymer-based 46

microfluidics

APPENDICES

A VISIT REPORTS 47

A.1 British Embassy, Den Haag 48A.1.1 Lyn Parker – 48

British AmbassadorA.1.2 M Leo Zonnefeld – 48

Science AttachéA.2 Ralph Lindken – Laboratory for 49

Aero- and Hydrodynamics, DelftUniversity of Technology

A.3 Delft University of Technology 50 A.4 TNO 50 A.5 MESA+ Institute at Twente 51

UniversityA.5.1 Twente University 51A.5.2 MESA+ Institute for 51

NanotechnologyA.5.3 Microfluidics Network 52A.5.4 Technical highlights 53

A.5.4.1 Fluid physics 53A.5.4.2 Lab-on-a-chip 53A.5.4.3 Membrane 53

technologiesA.5.4.4 Future industrial 54

developmentsA.5.4.5 Han Gardeniers – 54

BioChipA.6 Concept to Volume (C2V) 54A.7 Micronit Microfluidics BV 55A.8 LioniX BV 56A.9 CSEM SA 57 A.10 Protron Microtech 58 A.11 Bartels Mikrotechnik GmbH 58 A.12 microTEC 58A.13 IMM – Institut für Mikrotechnik 59

Mainz GmbHA.14 CPC – Cellular Process 61

Chemistry Systems GmbH andSynthacon GmbH

A.15 ThinXXS Microtechnology AG 63

B MISSION TEAM AND ITP 64CONTACT DETAILS

B.1 David Anthony Barrow 65B.2 Martin James Day 66B.3 Yulong Ding 67B.4 Yiton Fu 68B.5 Simon Robert Gibbon 69B.6 Timothy George Ryan 70B.7 Alberto Simoncelli 71B.8 Nicola Smoker (ITP) 72B.9 Julian Darryn White 73B.10 Kevin John Yallup 74

C LIST OF EXHIBITS 75

D GLOSSARY 76

• The mission team wish to extend theirdeepest thanks to the host organisationsfor their hospitality, openness and supportthat helped to make this mission such asuccess.

• We would also like to thank the staff at theBritish Embassy in Den Haag for theirhospitality, advice, organisation andassistance with the visits. In particular thedelegates would like to extend their thanksto Leo Zonneveld and Kanwal Ishfaq.

• The team would also like to thanknumerous people in DTI who made thismission possible and the Global WatchService for funding this mission. Particularmention goes to Nicki Smoker who helpedto organise the German leg of the visit,Farida Isroliwala and Robert Dugon for theirsupport in organising the mission, andCharlotte Leiper for her help in organisingthe post-mission dissemination activities.

ACKNOWLEDGMENTS

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1 EXECUTIVE SUMMARY AND RECOMMENDATIONS

1.1 Executive summary1.2 Recommendations

1.1 Executive summary

The DTI Global Watch Mission on thedevelopment, production and delivery of high-volume products in the Netherlands andGermany was organised to increase theawareness of commercial benefits of theapplication of microfluidics technologies in UKindustry. During the course of the mission inApril 2006 the UK team held five days ofmeetings with over 22 academic andindustrial groups in the Netherlands andGermany involved with the commercialisationof microfluidics technology.

The mission concentrated on chemical,pharmaceutical, household goods andpersonal care sectors where it was felt thatthe UK may be slow to take advantage of thisnew technology in comparison to thecountries visited. Sectors where microfluidicsis already established or close tocommercialisation, such as ink-jet printing andmedical devices, were not included. Duringthe course of the mission the teamencountered significant evidence ofcommercial activity in the medical devicesector in both Germany and the Netherlands.

Both the Netherlands and Germany haveworld-leading activities in thecommercialisation of microfluidics. TheNetherlands has advanced activities inbiotechnology-related areas, food processingand instrumentation. Germany has a strongposition across a number of areas; particularlynotable are chemicals, pharmaceuticals and biotechnology.

The technology supply chain in both countriesis fully populated with organisations includingacademic groups, research institutes, devicefoundries and numerous product and systemdevelopment companies. As befits a largereconomy, there is a higher level of activity inGermany which has led to a community ofdynamic product and system developmentcompanies. In addition the mission teamobserved significant end-user engagement inthe German chemical industry.

The chemical sector is one area whereGermany has a strong lead in applyingmicrofluidics. Two companies (CPC/Synthaconand Ehrfeld) offering integrated reactorsystems and process development serviceswere visited. Benefits of using amicroreaction approach have been identifiedfor hazardous reactions, the production ofhigh-value chemicals and where it is difficultto obtain high yields in conventionalequipment. The next five years will be criticalfor microfluidics in this sector in determininghow widely the technology will be adopted bychemical companies.

There is activity in microfluidics in thepharmaceutical sector in both theNetherlands and Germany. There are anumber of areas where application is gainingacceptance. In drug discovery and testing,microfluidics is being developed for a numberof key processes such as proteincrystallisation and cell-based testing of drugcandidates. Another area of application isdrug delivery and patient monitoring where aDutch group is developing chips that canmonitor lithium levels in patients.Microfluidics could also benefit the scale-upto manufacturing of drugs; however, limitedevidence for this was seen on the mission.

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Microfluidics in the household, personal careand food sectors is still in the early stages.One or two specific examples of microfluidicapplications were noted. The Germancompany Bartels Mikrotechnik GmbH hasproduced a micropump that is suitable fordelivering small volumes of fluids. Onepotential application for this device is indomestic steam irons. High-end packaginghas been developed using microfluidicnozzles to deliver very fine droplets forcosmetic applications. Membrane systemsare under development for applications suchas filtration and emulsification. Aquamarijn, aDutch company, is working with a large Dutchbeer-brewing company to field-test filtrationmembranes in a pilot filtration plant installedin a high-volume production plant.

Both the Netherlands and Germany have putsignificant investment into microtechnologiesand some of it has been very successful. TheNetherlands has a well integrated nationalinfrastructure for innovation. There is a strongfocus on the generation of an entrepreneurialenvironment starting with universities.Notable in this area is the University ofTwente and the MESA+ Institute which isuniquely focused on commercial activity andhas been successful in creating spin-outswith a high survival rate.

The mission visited IMM in Germany whichhas been successful in creating numerousspin-outs over the last 15 years. These havereceived considerable help from IMM duringthe early stages of their development andmany are now successfully establishingthemselves as commercial companies.

Microfluidics technology is still developingand many new technologies are emerging. Much of the innovation is being driven by theneeds of new products. As the application ofmicrofluidics in many areas is still immature,it is likely that there will continue to be astream of new technologies and productinnovations for many years to come before

specific approaches become widely acceptedas the standard for a given application.

1.2 Recommendations

While microfluidics is still an emergingtechnology, there are many indications fromthe Netherlands and Germany that it couldproduce some degree of disruption in thesectors studied in this report. UK companiesin chemical, pharmaceutical, household,personal care and the food industries need tostart the process of engaging with thistechnology, if they are not already.

A new focus on systems integration is nowenabling the acceleration of microfluidicscommercialisation which has hitherto beenhindered in the Netherlands and Germany.The UK should recognise that many end-usercorporations, particularly in bulk materialsmanufacture, require complete turnkeysolutions (not curiosity chips) if the potentialof microfluidics is to be realised. Means tostimulate the development of completesystems should be sought.

The evidence from the microfluidicscompanies clustered around or associatedwith Twente University and IMM suggest thataffordable, direct, hands-on access tomicrofabrication tools is a key requirement forencouraging a dynamic industrial microfluidicscluster, where start-ups and spin-outs are theprincipal commercial entities.

Microfluidics is an area where the UK hasalready had some success through theCambridge ink-jet cluster and some medicaldevice companies. The UK should continue tocapitalise on its skills in engineering andproduct development to expand the range ofapplications for microfluidics to other areas.

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2 INTRODUCTION

2.1 Background to the mission2.2 Mission coordinating body2.3 Microfluidics in the UK2.4 Broad objectives of the mission2.5 The Netherlands and Germany2.6 Mission team2.7 Background research

2.1 Background to the mission

Microfluidics is the manipulation, processingand measurement of fluids on a micro scale.A sense of the scale involved can be obtainedby considering that the channels and otheractive features of microfluidic devices aretypical less than 100 µm across. Suchdimensions are similar to or smaller than thedimensions of a human hair. By processingfluids on such microscopic scales it ispossible to obtain novel processing regimes.

Important features of these processingregimes include:

• The potential for processing very smallvolumes of fluids – important in manybiochemical applications where often verylittle of the sample is available

• Processing takes place in a laminar flowregime which means that mixing is byextremely well controlled and predictablediffusion processes

• Temperature control for exo- andendothermic reactions can be significantlybetter than in bulk processing technologies

• Many different process stages can beintegrated onto a single chip

Such features can lead to many benefits –small sample size, very precise control ofprocessing and reaction conditions, whichenables yields and process times to be greatlyimproved, greatly increased safety forpotentially explosive reactions and the ability toproduce a complete ‘lab-on-a-chip’ disposabledevice that can perform an integrated functionsuch as sample preparation, reaction andmeasurement. Such devices can be smallenough to be the basis for hand-helddiagnostic and monitoring tools that open upthe prospect of future applications inhealthcare, environmental monitoring,industrial monitoring, security and defence.

As a result of its exciting potential,microfluidics represents one of the fastestgrowing sectors of micro- andnanotechnology (MNT) exploitation withpresent-day applications andcommercialisation in life sciences, drugtesting and discovery, industrial monitoringand the chemical industry. Future applicationareas are as diverse as consumer products,food, agriculture, environmental monitoring,fuel cells and for cooling high-performancecomputer chips. In fact there are potentiallymany new applications waiting to bediscovered for this exciting new technology.

Microfluidics has already achieved one verynotable success as the cornerstone for ink-jetprinting technology. The print heads in thistechnology are built around arrays of nozzlesthat are capable of ejecting very small – tensof picolitre (pl) – quantities of liquid in anaccurately controlled pattern onto thesubstrate that is to be printed on.

Longer term, microfluidics could impact avery diverse range of markets spanning food,

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household products, personal care products,healthcare products and pharmaceuticals,offering the opportunity to develop smart andintelligent products at low cost. Applicationscould include automated product delivery,bespoke drug delivery systems and smartpackaging. Many of these applications will beeffected through integration into productpackaging, with the dividing line betweenpack and product being very blurred.

2.2 Mission coordinating body

Faraday Packaging Partnership (FPP), jointlyfunded by UK government and industry, is thelargest innovation support and developmentnetwork within the packaging arena, helpingto deliver a new dimension in packagingdesign and innovation. FPP works with someof the world’s ‘elite’ in the creation and supplyof fast-moving packaged consumer goods(FMCG) and is also a specialist applicationsnode of the recently launched MaterialsKnowledge Transfer Network. Technology forIndustry (TFI) Ltd organised and led themission on behalf of FPP (further informationon TFI is given in Appendix B.10).

2.3 Microfluidics in the UK

As noted above, ink-jet printing is a globalmarket for microfluidics, and the UK has beenone of the leaders in the development of thistechnology. A significant cluster of companieshas formed in the Cambridge region basedaround ink-jet printing including companiesthat develop high-perfomance ink-jet printheads and novel applications for such toolsincluding printable displays and electronics.Companies involved in this cluster includeXaar, Domino, Inca, Xennia, Linx, CambridgeDisplay Technology and Plastic Logic.

The UK has strengths in a number ofapplication areas that can use microfluidics,for example speciality chemicals,pharmaceuticals, medical devices, personalcare and household products. Given the wide

range of potential new application areas theUK should be able to develop other world-class clusters of companies based around theapplication of microfluidics to one or more ofthese sectors.

At the other end of the technology pipeline anumber of UK universities are engaged inresearch into the fundamental aspects ofmicrofluidics and the development of noveldevices suitable for a range of applications.Some of the universities involved in thedevelopment of microfluidics are Leeds,Cardiff, Bristol, Edinburgh, Imperial,Southampton, Cambridge, Cranfield and Hull.Two of these universities, Leeds and Cardiff,were represented on the mission team. Inaddition to the universities involved in thedevelopment of microfluidics technology anumber of research organisations are involvedin the development of microfluidicstechnology and devices. Some examplesinclude the Centre for Microfluidics andMicrosystems Modelling at Daresbury,Council for the Central Laboratory of theResearch Councils (CCLRC) and QinetiQ.

There are a number of organisations capableof fabricating microfluidic devices includingtwo that are participating in the DTI-fundedprogramme to establish centres of excellencein MNT. The two centres are Fluence, whichis hosted by Epigem, focusing on polymermicrofluidic devices, and Dolomite focusingon glass microfluidic devices. A number ofother organisations have the capability toprototype and/or manufacture microfluidicdevices including Innos (silicon) and Centrefor Integrated Photonics (glass). There arealso companies that are developingmicrofluidic devices and integrated systemsthat use microfluidics as a component. Manyof the companies in the Cambridge ink-jetcluster fall into this category. Outside of theink-jet cluster there are a number of small ormedium sized biotechnology companies suchas Genapta, Q-Chip, Randox and Syrris.

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The area where the UK is relatively weakcompared to the target countries, andGermany in particular, is in pull for microfluidictechnology from existing industries. It is theobjective of this mission to stimulate interestfrom a number of industrial sectors where it isbelieved that prospective competitors arealready engaging with this technology and arelikely to reap the benefits in terms of morecompetitive products in the near future. ManyUK companies engaged in biotechnology havealready started to take microfluidics seriouslyand a few, such as GlaxoSmithKline, aremaking significant progress in leveraging thistechnology. However, there are many moresectors where the level of interest isconsiderably lower, for example fine chemicals,personal care and household goods.

2.4 Broad objectives of the mission

• To increase awareness in UKmanufacturing industries such as FMCG,chemical and pharmaceutical aboutcommercial benefits of the application ofmicrofluidic technologies

• To promote exploration of application of microfluidics to consumer products and their packaging, in particular in relation to food, household, personal careand pharmaceuticals

2.5 The Netherlands and Germany

The mission visited the Netherlands andGermany due to their world-leading positionin these technologies at both academic andindustrial level, with a surge of commercialactivity and several high-profile start-upcompanies being formed or companyacquisitions taking place, as evidenced viarecent conferences and workshops coveringthese technologies.

Many of the world’s leading microfluidiccomponent suppliers are based in Germany(D) and the Netherlands (NL). These include

Burkert (D), Boehringer Microparts (D), BartelsMikrotechnik (D), Erhfeld Technologies (D),ThinXXS (D), LTF (D), LioniX (NL), C2V (NL),Micronit (NL), Mikroglas (D) and many more.

Dutch and German research institutes areworld class in microfluidic technologies, egthe Universities of Delft, Eindhoven andTwente (which hosts the MESA+ Institute)and TNO (NL); IMM, HSG-IMIT, theUniversities of Freiburg and Munich, and FZK(D). HSG-IMIT and the University of Freiburghave implemented a technology transfernetwork over the last few years aimed atcommercialisation of microfluidictechnologies, funded by the European Union’s(EU) Europractice programme.

German and Dutch end-user industries andsystems integrators are actively working withmicrofluidic technologies, eg Shell, Akzo-Nobel and DSM (NL); Degussa, Bayer, BASF,Clariant, Merck and Siemens Axiva (D).

2.6 Mission team

The team represents all areas of interest inmicrofluidics in the UK including academics,component manufacturers, systemintegrators, large end users and technologystrategy. Profiles for the team members areincluded in Appendix B.

2.7 Background research

A number of pieces of backgroundinformation and research have been used indesigning this mission. One of the mainpieces of research has been carried out by TFIin conjunction with the global MNTcommercialisation organisation MANCEF. Inthis work, TFI has been developing roadmapsfor the development of microfluidics in anumber of application sectors. Otherbackground research has been carried out atMANCEF’s global commercialisationconference COMS2005.

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3.1 Substrate materials3.2 Functions that can be

implemented3.3 Market sectors

Microfluidics is a platform technology that canbe manufactured using a wide range ofsubstrate materials which can be structured tocreate a number of different types of functions(channels, mixers, valves etc) on a single chip.The technology has potential to realisedisruptive changes in many application areas.

3.1 Substrate materials

Polymer is likely to be the most widely usedsubstrate material in the long term because ofits low cost which makes it very suitable forapplications where a microfluidic device iseither used once and disposed of or wherecost is very critical. The disadvantages ofpolymer are that it is not a robust material andit will not withstand high temperatures or harshchemical environments, and there is alikelihood of materials leaching from thesubstrate and contaminating sensitive chemicalprocesses being carried out on the chip.

Glass is a more robust material with betterchemical and temperature resistance;however, the evidence to date indicates thatglass microfluidic devices will have a highercost per function when manufactured involume than their polymer equivalents. Glassis often favoured where sensitive chemicalreactions are involved as its properties andeffect on reactions are well characterised.

Silicon has been used widely in the pastbecause of the recent developments in high-precision processing of this material and isstill used to provide low-volume prototypes

and products and where direct integration ofelectronics adds value. However, the cost ofsilicon is likely to be uncompetitive in thelong run and a more likely approach that isalready finding favour in some products isthat silicon sensors will be hybridised, egwith polymer microfluidic devices, to createadvanced sensors.

Metals are also finding favour in somemicrofluidic devices, particularly in the volumeprocessing of chemicals where the excellenttemperature, pressure and chemical resistanceand thermal conductivity are essential. Metalmicrofluidic devices are likely to be moreexpensive than polymer devices and aretherefore likely to be used in applicationswhere a permanent device is used to carry outmanufacturing of high volumes of materials.

3.2 Functions that can be

implemented

Microfluidic devices can be manufactured in anumber of different ways including bonding ofsilicon and glass wafers, plastic injectionmoulding or lamination and metal machiningand bonding. This diverse range of techniquescan be used to make devices that have just onefunction (eg a mixer) or chips where severalfunctions are integrated into one substrate.

The range of functions that can beimplemented includes:

• Channels which can be used for movingfluids around ‘on chip’

• Functionalised channels where there hasbeen either surface modification to interactwith the fluids flowing past or separatingmedia to assist separation processes

• Mixers – basically long channels where

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3 INTRODUCTION TO MICROFLUIDICS

diffusive mixing of different fluids cantake place

• Heating and cooling• Valves to control flow down channels• Pumps to move fluids around on chip –

several methods are available includingcapillary mechanisms, mechanical pumpsand electrical pumping

• Sensors such as electrodes or opticalsensors which can be either printed in thechannel or introduced by combining sensors

• Optical windows and other components• Nozzles for delivering fluid droplets• Microfilters

With this wide range of capabilities it ispossible to build single fluidic chips that cancarry out a diverse range of functions such as chemical synthesis, chemical analysis,DNA amplification, nanoparticle production,nanodispersion production and many more possibilities.

One of the challenges in designing completesystems on a chip is controlling the cost andtime of design to achieve a given function.Design and simulation tools are available formicrofluidics; however, they are still relativelynew and it may require a number of physical

iterations to converge on a working design fora device.

3.3 Market sectors

Microfluidics has the potential to penetrate alarge number of market sectors. There are anumber of technology drivers such as smallsample volumes, improved process controland the ability to make disposable devicesthat make it an attractive solution to a numberof challenges.

Microfluidics has already been successful ininformation and communication technology(ICT) where ink-jet printers are widely used fordomestic and commercial applications. Thetotal market for ink-jet print heads is estimatedat $2.5 billion (~£1.4 billion) for 2009. Exhibit 3.1 is a roadmap for the application ofmicroreaction technology into a number ofthe sectors that are covered in this report. Itindicates that microfluidics should be used inthe short term in lab-based tests such asanalysis of DNA or proteins. In the mediumterm it will move into pharmaceuticals, finechemicals and personal/home care. Longerterm applications include the food sector andbulk chemicals.

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Food andbeverages Polymers

Basicchemicals

€350/t

€200,000/t

Main usetodayLab

systemsInnovation

friendly

Energy

Personal/home care

Pharmacy

Fine chemicals

Long term

At present

Short Long

Knowledge about microreaction technology

Mark

et

en

try

Exhibit 3.1 Applications of microreaction (source: PAMIR study, IMM, 2002)

4 OVERVIEW OF THE MICROFLUIDICS SUPPLY CHAIN

4.1 The microfluidics supply chain in the Netherlands4.1.1 Technology R&D4.1.2 Foundries4.1.3 Product and system design

4.2 The microfluidics supply chain in Germany4.2.1 Technology R&D4.2.2 Foundries4.2.3 Product and system design

4.3 Summary of key microfluidics activities elsewhere in Germany4.3.1 Baden-Wuerttemberg4.3.2 North Rhine-Westphalia (NRW)4.3.3 Berlin-Brandenburg4.3.4 Thueringia (Erfurt-Jena-

Ilmenau triangle)4.3.5 Bavaria4.3.6 Saxony

Exhibit 4.1 is a schematic supply chain formicrofluidics technology. It can be seen thatmany different types of organisations need tobe involved in bringing a new microfluidicdevice or technology to the market. In order tohave a vibrant microfluidics industry within acountry, it is important that a complete supplychain should exist in that country. It is possiblefor gaps in the supply chain to be filled byexternal sources; however, in emergingtechnologies such as microfluidics, closeproximity of suppliers and users can acceleratethe commercialisation of new technology.

At present, a lot of new microfluidic devicesand technology concepts are being developedin universities and other research laboratories,either as part of ‘blue skies’ projects orincreasingly in more application-focusedprojects. Device foundries manufacturemicrofluidic devices and can be either an

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Exhibit 4.1 Schematic supply chain for microfluidics technology

Manufacturingequipment

Functionalcoatings

Devicefoundry

Sensors/detectors

R&D

Materials

Productdevelopment

Systemdevelopment End user

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internal captive facility or one of theincreasing number of independent foundriesthat are becoming available around the world.It is often necessary for the devicemanufacturers to add additional componentsinto the microfluidic system, for examplesensors or some form of functionalisation tooptimise selected regions of the device forspecific processes.

Product development for microfluidics is still anarea where there are a number of challenges:

• Modelling and simulation tools are still quiteimmature, and product development canhave a significant trial and error component

• The cost of design iterations can be quite high

• Many of the technologies employed to manufacture microfluidic devices are not very cost effective for low-volumeproduction

• Microfluidic product design is still relativelynew and there are few experienceddesigners in this area

The issue of product development can befurther complicated by the fact that amicrofluidic device is often just onecomponent of a larger system that is neededto deliver the desired function to the enduser. The larger system may involve additionalhardware (eg pumps, flow controllers),software, and measurement systems (eg optical probes).

Many product and system developmentgroups are part of an end user ofmicrofluidics. However, many end users donot wish to engage with the technology atthis level; rather they require a turnkeysolution that delivers the desired result withno need on their part to understand theunderlying technologies. One encouragingfeature of the last few years has been theemergence of product and systemdevelopment houses to serve potential user communities.

Of the two countries studied in this visit,Germany has the most developed supplychain for microfluidics, with manyorganisations at all points in the chain fromfundamental research and development(R&D) through to end users engaging withthe technology and product groups withinGermany. To some extent this is to beexpected as the German economy is muchlarger than the Dutch economy (for examplethe GDP is estimated to be five times larger).Due to a combination of this scale and thecommitment of German regional and national governments to industry andmanufacturing using advanced technologies,the overall microfluidics industry appears tobe very strong in Germany and in the processof generating a number of commercialsuccess stories.

In comparison, microfluidics in the UK (with aGDP around 80% that of Germany and a littleless than four times that of the Netherlands)is underperforming relative to either of thecountries studied. As is often the case inmany areas of technology, the UK is wellendowed with R&D groups that are activelyresearching the technology; however, the restof the supply chain is relatively poorlypopulated, and end-user communities arelagging behind those encountered, especiallyin Germany. In general, the UK usercommunities appear to have a lower level ofawareness of microfluidics and its potentialimpact on their sector; where there is someawareness, they appear to be more reluctantto engage with this disruptive new technology.

4.1 The microfluidics supply chain in

the Netherlands

The supply chain in the Netherlands issomewhat better developed than that in theUK. There are organisations throughout thechain that can engage with end customersand, based on activity levels observedamongst the product designers, there aresome end customers starting to engage with

the technology. Although there are end usersin the Netherlands, many of the supplycompanies nonetheless adopt an internationaloutlook, some even supplying into the UKmarket already.

4.1.1 Technology R&D

Three technology R&D centres were visitedin the Netherlands:

• TU Delft• University of Twente• TNO

There are a number of other active R&Dcentres including the Universities ofGroeningen and Wageningen and PhilipsMiPlaza. Exhibit 4.2 shows a map of theacademic groups involved in the NetherlandsMinacNed – a nationwide network of groupsactive in MNT, including microfluidics.

Exhibit 4.2 Map of microfluidics R&D centres in theNetherlands (courtesy Richard Schaafoort, MinacNed)

Of the centres visited, Delft was biasedtowards more fundamental research whileTwente had a very comprehensive

programme integrated into the MESA+Institute which covered everything fromfundamental physics through to applieddevice research. MESA+ has also spawned anumber of spin-outs which arecommercialising microfluidics. Interactionwith the MESA+ Institute is possible at anumber of different levels.

4.1.2 Foundries

The main foundries available in theNetherlands are all based around Twente, onebeing Micronit, a spin-out from MESA+ thatfocuses on the production of glassmicrofluidic devices for a wide range ofapplications and is competing withcompanies worldwide such as Micralyne inCanada. The other foundry is the MESA+Institute itself which offers some potential forthe fabrication of microfluidic devices via anopen access university environment.

4.1.3 Product and system design

The mission saw a few organisationsengaged in product and system design in theNetherlands. The majority were small ormedium sized enterprises (SMEs) althoughTNO, the Netherlands Organisation forApplied Scientific Research, was also involvedwith some industrial product developments.

Many of the SMEs were spin-outs from theMESA+ Institute and had been through theMESA+ incubation process. Examplesinclude LioniX (general MNT design andproduct development), ChemtriX(microfluidics for chemical applications) andC2V (developing microfluidics based gaschromatographs). Other companies had alsotaken advantage of the MESA+ incubatorsuch as Aquamarijn, which itself was abusiness accelerator for a number of focusedproduct companies (eg Nanomi BV,Medspray BV) developing micro- andnanofiltration for a range of applications.Overall, the impression was of a number of

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small companies actively developingproducts and succeeding in engaging withlarger end users.

4.2 The microfluidics supply chain in

Germany

The supply chain in Germany is more maturethan in the Netherlands with organisationsthroughout the supply chain and supplycompanies successfully engaging with end-user companies. There has been somemerger and acquisition (M&A) activity inGermany wherein SME companies withpromising products have been acquired bylarge corporate players that want to use thetechnology in core product ranges. As in theNetherlands, companies in Germany areaddressing international markets.

However, in contrast to the Netherlands,complete supply chains exist within Germany,sometimes clustered within one region. Forexample the mission uncovered a very strongsupply chain for microfluidic devices in thechemical industry based in the state ofHessen where technology suppliers, productdevelopers and end users all work together todevelop microfluidic-based manufacturingplants for commercial use. The mission visitedthe Frankfurt region and was able to samplesome of the overall activity in Germany.

4.2.1 Technology R&D

There are a number of microfluidicstechnology R&D centres in Germany. The mission visited the Institute forMicrotechnology Mainz (Institut fürMikrotechnik Mainz GmbH – IMM), one ofthe leading institutes for applied research intomicrofluidics technology, which has produceda number of spin-out companies (see below).Other institutes that are working onmicrofluidics include FZK (ForschungszentrumKahrlsruhe) and HSG-IMIT (Institut für Mikro-und Informationstechnik der Hahn-Schickard-Gesellschaft eV).

4.2.2 Foundries

Although no foundries were visited on theofficial agenda, a number were contacted atthe Hannover Messe and at other previousevents. These include private companies suchas Microtec (polymer microfluidics),Chemnitz, Microfluidics Chip Shop (polymermicrofluidics) and Micreon (lasermicromachining). With the exception ofMicrofluidics Chip Shop, the foundries werenot specialised in microfluidics but offered theability to build microfluidic devices.Discussions with Microtec during theHannover Messe indicated that it expected tosee significant growth in its microfluidicsbusiness, mainly from Germany but also fromoutside the country.

In addition to the private companies, thereare a number of university-based open-accesscentres such as the Microsystems CentrumBremen (MCB), MST Factory Dortmund,Bayerisches Laserzentrum and Institut fürMikrosystemtechnik (IMTEK, Freiburg) whichoffer access to facilities and technologies andsupport a number of spin-outs. All of theseinstitutes are working in several differentareas of microsystems but they have somelevel of activity in microfluidics.

4.2.3 Product and system design

There are a number of product and systemdesign companies in Germany. Overall activitylevels appeared to be significantly higher thanin the Netherlands and the companies arebetter linked in to local end users.

There are a number of organisations such asIMM, HSG-IMIT (Villingen-Schwenningen) andFZK which are federal and/or state backed butengage with industry on commercial projects.These organisations typically work with alocal university-based foundry to developprototypes for industry. They are also involvedin technology transfer of manufacturabledevices to industry.

In addition there are a number of privatecompanies that are developing microfluidicdevices. Many of these are spin-outs frominstitutes such as IMM. For example,ThinXXS, Ehrfeld (recently acquired by Bayerand being integrated into its chemicalbusiness), Cellular Process ChemistrySystems GmbH (CPC), Mikroglas andAzurchem have all spun out of IMM and areengaged in microfluidics.

Many companies are associated with auniversity-based technology centre which actsas its prototyping and low-volumemanufacturing foundry – ProtronMikrotechnik/MCB and ThinXXS/IMM areexamples of this. One result of the relationshipwith a local foundry is that the company tendsto specialise in a starting material such assilicon, polymer, glass or metal.

A wide range of different markets are beingaddressed by German companies, including thechemical industry, medical devices, proteomicsand genomics, security and defence.

4.3 Summary of key microfluidics

activities elsewhere in Germany

4.3.1 Baden-Wuerttemberg

FZK is arguably the most important researchinstitution in Germany in the field ofmicrosystems technology, with a strong focuson microfluidics. Other importantorganisations in Baden-Wuerttemberg includethe Fraunhofer Institute for ChemicalTechnology (ICT) in Karlsruhe, IMTEK at theUniversity of Freiburg (medical/life sciences),Fraunhofer IPM, IAF and ISE (also inFreiburg), Fraunhofer IPA and IGB (Stuttgart),and HSG-IMIT in Villingen-Schwenningen.

HSG-IMIT coordinated the European networkof excellence on microfluidics, the LiquidHandling Competence Centre (LICOM) from2000 to 2005 whose focus was to supportthe industrial take-up of microfluidics.

The focus was initially across all sectors butlater narrowed to life sciences due to limitedsuccess in other sectors where developmentcosts often proved prohibitive. Key barriers tothe utilisation of microfluidic technologieswere identified as:

• Lack of suppliers of components andsystems, and limited commercialinfrastructure

• Lack of standards• High component costs

Typical applications included implantable drugdelivery systems, capillary chips, flowsensors, and biosensor systems for chemicalbiological agent detection (defence). Theimportance of mixed technology prototypingand manufacturing, including polymer, silicon,glass and metal technologies as well as add-on process such as surface functionalisationwere highlighted, and therefore the need forstrongly interdisciplinary consortia.

HSG-IMIT has now refocused on thedevelopment of self-generating energysystems, smart textiles and micro-medicaltechnologies (dosing instruments, intelligentplasters, smart pills).

Fraunhofer ICT heads the Fraunhofer Alliancefor Modular Microreaction Systems (FAMOS)which comprises six Fraunhofer Institutescovering chemical, ceramic, laser, production,microintegration and environmentaltechnologies. FAMOS has developed amodular microreaction system (Exhibit 4.3).

Exhibit 4.3 FAMOS microreaction platform

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The Baden-Wuerttemberg region is alsohome to a number of important companiessuch as Bosch and BASF, Siemens Axiva, anda range of SMEs with biochip and laboratoryautomation technologies.

4.3.2 North Rhine-Westphalia (NRW)

In 1999 the city of Dortmund decided toinvest in microsystems technology (MST) aspart of its regeneration strategy, and attracteda number of start-up companies to locate in anew MST incubator with the first open-access facility in Germany (mst.factory).Dortmund now has 28 MST-relatedcompanies employing 8% of all Europeanemployees in MST/MEMS (micro-electro-mechanical systems). It has the only businesscompetition for microtechnology in Germany(www.start2grow.de).

IVAM, Germany’s trade association for MST,is based in Dortmund and manages a nationalMST technology transfer network funded bythe Federal Ministry of Economics andTechnology (BMWi).

Other important organisations in NRW are theForschungszentrum Jülich, one of Germany’slarge-scale research facilities having a stronglife science focus, the Fraunhofer Institute forMicroelectronic Switching and Systems (IMS,Duisburg), and a number of companies aroundDüsseldorf.

4.3.3 Berlin-Brandenburg

Berlin’s activities in MST focus on medicaland biotechnologies, automotive andtransport technologies and ICT. Noteworthy organisations:

• The technology transfer networkMicrosystems Technology (www.mst-berlin.de)

• Centre for Microsystems Technology(ZEMI) – ZEMI has started a collaboration(named EMiL) with the Leibniz Institute for

Agricultural Engineering Potsdam-Bornim(ATB) aiming to develop MST for innovativefood production; projects will include amobile system for the measurement ofmeat freshness and other sensor systemsfor the monitoring of the supply chain frommanufacturer to point of sale

• Fraunhofer Institute for Reliability andMicrointegration (IZM)

• Technical University Berlin, Institute for Engineering Design, Micro and Medical Technology

• Fraunhofer Institute for ProductionSystems and Design Technology (IPK)

• BESSY (Berlin Synchrotron RadiationFacility) Application Centre forMicroengineering (AZM) – AZM hasdeveloped a microfluidic system for theamperometric analysis of cosmetics andfoods; a micromixer has been developedthat can overcome mixing problems withviscous fluids; made of polymethyl-methacrylate (PMMA), it is cheap andtransparent, reusable and chemicallyresistant

4.3.4 Thueringia (Erfurt-Jena-Ilmenautriangle)

This region has substantial activity inmicrofluidics with a strong emphasis on lifescience applications, built on its historicalstrengths in optics and laser technologies,with organisations such as the Friedrich-Schiller University, Technical University ofIlmenau and the ApplikationszentrumMikrotechnik Jena (AMT), competencenetworks BioInstruments and Optonet, andcompanies such as Carl Zeiss Jena, Jenoptikand Jenapharm, with a large number ofSMEs including Analytik Jena AG, Clondiag,Cybio and Mildendo.

TU Ilmenau established a Centre for Micro-and Nanotechnologies (ZMN) adjacent to itsexisting MNT Institute in 2002. This 2000 m2

facility has 680 m2 of clean rooms (classes10,000, 1,000 and 100) and is set up to work

with various materials – silicon, polymer,ceramic and hybrid. The focus is onchemosensors and fluidic platforms for singlecell and single molecule manipulation, withapplications in diagnostics, in particular inpharmaceutical and environmentalapplications. The €32 million (~£22 million)investment cost was financed by the FreistaatThüringen and the Federal Ministry ofEducation and Research (BMBF), and up to€10 million (~£6.9 million) is available over 10years to attract leading researchers to Ilmenau.

4.3.5 Bavaria

The Munich region (Martinsried) is Germany’sleading biotechnology location, with a focuson therapeutics, and there are a number ofcompanies such as Advalytix utilisingmicrofluidics in such applications, as well asthe Technical University, Ludwig-MaximiliansUniversity, and the Fraunhofer IMS.

Siemens is developing a multi-analytecontinuous online water sensor to detectchemical contamination – a cost-effective,online fluorescence immunoassay biosensor system utilising microfluidicsampling and flowcell, and 32 signaldetection array monitoring.

4.3.6 Saxony

There is a strong focus in this region (centredaround Dresden/Chemnitz) on automotiveapplications, with significant microfluidicsactivities in the universities and technologyparks in both cities.

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5.1 ‘Microreaction’5.2 Microreactor component

construction5.3 Approaches to microreaction

engineering5.4 Scale-up (numbering up/

scaling out)5.5 Process chemistry expertise5.6 Advantages of microreaction

5.6.1 Quality of chemical reaction5.6.2 Exothermic reactions5.6.3 High-pressure reactions5.6.4 Novel chemistry5.6.5 Scaling5.6.6 Safety

5.7 Summary5.8 Future prospects

Chemistry in microfluidic systems has beenwidely performed across Europe, the USA andAsia at the laboratory scale for both screeningcompounds and developing reactionmechanisms either as part of high-throughputautomated systems or as part of manualreaction pathway development programmes.The laboratory use of microfluidics to carry outchemistry has been most widely adopted bythe biochemical sciences for diagnostic andscreening applications. Due to its relativematurity and widespread global commercialadoption, this area was not covered by thismission, which focused on emergingtechnologies and applications.

The popular chemistry and chemicalengineering magazines have carried a numberof articles over the last few years which haveannounced the arrival of microchemicalmanufacturing.1 All of these articles havehighlighted the strength of microchemistry in Germany.

The transfer of microfluidics from chemistryto chemical engineering occurred first inGermany, largely driven by IMM andDECHEMA, the German Association ofChemical Engineers, and building onGermany’s strong chemical and chemicalengineering industries, particularly along theRhine and Main rivers. To a lesser extent thistransfer is also taking place in other countries,either directly or indirectly under the auspicesof programmes such as processintensification. In Germany, the focus haschanged from purely providing evidence thata reaction can be carried out to focusing onthe technology needed to underpin theengineering and design philosophy neededfor the production of larger quantities ofchemicals using micro process engineeringby ‘microreactors’. The progress has beenwell documented in a series of internationalconferences.2 A number of textbooks havebeen produced which document how to usemicrofluidics for chemical processing.3

5 MICROFLUIDICS IN THE CHEMICAL SECTOR

1 www.rsc.org/chemistryworld/Issues/2004/January/bountiful.asp – C O’Driscoll, Small is bountiful, Chemistry World, January 2004;

http://pubs.acs.org/cen/coverstory/83/8322finechemicals.html – A M Theyer, Harnessing microreactions, Chemical & Engineering News, 30 May 2005, 83(22): 43-52

2 IMRET 1-8 – International Conference on Microreaction Technology – odd proceedings published by Springer, even proceedings published by AIChE,

eg IMRET 8 in Proceedings of AIChE Spring Meeting 2005

3 V Hessel, S Hardt, H Lowe, Chemical Micro Process Engineering – Fundamentals, Modelling and Reactions, Wiley-VCH, 2004; V Hessel, H Lowe, A Muller, G

Kolb, Chemical Micro Process Engineering – Processing and Plants, Wiley-VCH, 2005; N Kockmann, Micro Process Engineering – Fundamentals, Devices,

Fabrication and Applications, Wiley-VCH 2006

5.1 ‘Microreaction’

Microreaction is the carrying out of chemicalprocessing operations in microfluidic systemsor, more generally, in systems withmicrostructured components. It is possible tocarry out many of the classical unit operationsof chemical engineering in microfluidicsystems – mixing, heat exchange, chemicalreaction etc. However, microreaction researchhas generally concentrated on the reactionpart of chemical processing and less on thepre- and post-reaction steps of purifyingreagents and products, removing wasteproducts and introducing catalysts.

Microreaction is most likely to be suitable forreactions where:

• Reaction times are short• Reactions are highly exothermic or highly

endothermic• Reactants, intermediates or products are

explosive or unsafe in large quantities• Scale-up issues are to be avoided• Optimisation of selectivity and/or yield

is required

Microreaction is not suitable for all chemicalreactions, particularly those involving highlyviscous reactants or products and truly longreaction times. In addition, the presence ofsolids or gases will complicate the design ofan appropriate microchannel system, wherelarge particles or large gas bubbles have thepotential to stop the system from functioning.However, one of the most often quotedexamples of microreaction production is thatof azo pigments by Clariant (80 t/y), where asystem has been built which usesmicrostructured components to produce aparticulate product.4

One of the most significant differencesbetween microreaction and standardlaboratory chemical development (and manychemical production processes) is thatmicroreactions are inherently continuousprocesses. Whilst continuous processes arewell understood by chemical engineers andprocess chemists, they are not thedevelopment methods traditionally taught toorganic chemists, and hence a degree ofretraining will be necessary to have suchsystems adopted at the discovery stagewithin chemical companies. Equally, whilecontinuous processes are common withincommodity chemical manufacture, much ofpharmaceutical, fine and specialitymanufacture occurs in batch reactors. Thevalue of the chemicals manufactured and therate of change of these batch chemicalswould normally mean that these companieswould be the early adopters of a noveladvantageous technology; however, theinexperience of the development chemist andthe current reliance on batch technology formanufacture have certainly been factorswhich have prevented wide-scale uptake.Needless to say, the examples that do existare in the fine chemicals area – such asClariant’s pigment processing, Merck’s twotonne production with 10 different two-stagereactions5 and Sigma-Aldrich advertising itsuse of microreaction for the manufacture ofsmall quantities of materials using traditionallydifficult chemistries.6

5.2 Microreactor component

construction

Microreactors have been constructed from allthe standard materials used to makemicrofluidic components but, depending onthe approach to microreactions, somematerials may be favoured over others.

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4 www.clariant.com/C12568C5004FDBD7/vwWebDownloadsWT/development_clariant_factbook_1_E.pdf – description by Clariant of its use of a microreactor to

make an azo pigment

5 www.abctechnologies.ch/2004/download/Grund-Web.pdf – presentation at abc Technologies 2004 (Accelerated Bio and Chem Technologies), Basel,

Switzerland, 22-23 January 2004

6 www.sigmaaldrich.com/aldrich/bulletin/al_chemfile_v5_n7.pdf – Sigma Aldrich ChemFiles, Vol 5(7), July 2005

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A number of academic groups andcompanies have concentrated onconstruction materials and methods –embossing/moulding of polymers (Epigem7,ThinXXS8), etching of silicon (ProtronMikrotechnik9), etching of glass (LioniX10,Mikroglas11, Micronit12), metal systems basedon build-up of machined foil layers to givecomplex internal fluid paths (CPC13),microengineered metal systems bearing acloser relationship to precision engineering(Ehrfeld Mikrotechnik BTS14), and IMM15 hasused all these fabrication methods.

5.3 Approaches to microreaction

engineering

There have been two different approachesdeveloped to microreactor design:

• Design an individual microreactor foreach reaction. This has typically involvedthe use of glass to make reactors withoptimised reaction volumes and/or reactiontimes and the incorporation of necessaryelements such as mixing or heat exchange.This approach has also been put intoproduction using metal systems. Theultimate version of this approach has beensuggested for complete reaction processingincluding the incorporation on the glassmicroreactor of pre- and post- reactionprocess operations such as filtration(Delft/Twente, LioniX/ChemTrix, IMM).

• Develop a set of classical chemicalengineering unit operations (modules)at the microscale which can be bolted

together in the correct form for a particularreaction and then reassembled in adifferent form when a different reaction isrequired (IMM, Ehrfeld, Mikroglas).

The first approach includes many of theessential advantages espoused formicroreaction – optimum reaction times, heatexchange conditions, optimum mixing – butrequires the development of a complete newmicroreactor system for each reaction (or atleast each class or type of reaction) to beperformed. The second approach is morepragmatic, allowing a toolkit to be producedwhich can be reused, albeit at the cost ofpotentially imperfect reaction conditions.

The German Chemical Engineering Society’s(DECHEMA) Reaction Engineering Divisionhas set up an industrial panel on MicroProcess Engineering which ran a strategicresearch project Modular Micro ChemicalEngineering (MicroChemTec/µChemTec) from2001 to 2005.16 This project produced thedesign of a construction kit from whichmodular microsystems can be built formicroprocess engineering. This was effectivelya standard which manufacturers ofmicrosystem components could use to offercomponents to an end user who could thencombine them with those from othermanufacturers to construct a complete reactorsystem. Hence the project defined standardelectrical, fluidic, optical and mechanicalinterfaces as well as geometric, thermal andtechnological housing interfaces. While it ispossible to buy a number of componentswhich do adhere to this standard, it would not

7 www.epigem.co.uk/products-fluidics.htm – polymer microfluidic kit

8 www.thinxxs.com/development/index_development.html – modular polymer microfluidic kit

9 www.protron-mikrotechnik.de – microfluidic systems from silicon, using MEMs techniques of construction

10 www.lionixbv.nl/microfluidics/mf.html – glass microfluidic and microreactor systems

11 www.mikroglas.com/index_e.html – glass microfluidic systems made using Foturan as photosensitive glass

12 www.micronit.nl/en/about_microfluidics.php – glass microfluidic systems, focused on lab-on-chip applications

13 www.cpc-net.com – metal microreaction systems

14 www.ehrfeld-shop.biz/shop/catalog/index.php – metal microengineering reaction systems

15 www.imm-mainz.de/seiten/en/u_050527115229_2085.php – range of IMM’s manufacturing technologies

16 www.microchemtec.de/content.php?pageId=2435&lang=en – description of MicroChemTec approach, list of members and components catalogue

appear to have been widely adopted as anumber of companies prefer to offer their ownproprietary modular architectures (Ehrfeld/Mikroglas/FAMOS17). One reason for this maybe that the requirements for standardisationled to a system with a relatively high deadvolume which can be detrimental to overallsystem performance.

A hybrid approach also exists where systemsare constructed which are optimised for aclass of reactions rather than a single reaction(IMM, CPC).

IMM’s presence in all areas really underlinesthe key role it has played in the developmentof microreaction technology.

5.4 Scale-up (numbering up/

scaling out)

Normal chemical process developmentinvolves scale-up where chemistry developedin round bottom flasks in a laboratory is takenvia pilot plant operation to full productionprocessing. This scale-up is complex due tothe big difference in scale resulting in fluidflow and heat transfer process changes whichcan not be fully predicted. Hence scale-up isan expensive and time-consuming process,with the potential risk of failure due tounforeseen problems.

Pure microreaction offers a new paradigmcalled either ‘numbering up’ or ‘scaling out’,where multiple copies of the laboratorymicroreactor are taken to the production plant,and simply by running multiple systems inparallel the necessary quantities are produced(ChemTrix). It has been argued that thisintroduces new complexity due to the numberof individual reactors that potentially needindependent control and monitoring systems.

A more pragmatic approach has been takenby a number of companies where productiondevices are produced which are larger in sizewith a higher throughput, but the internalmicrostructure is essentially identical to thatof the original laboratory microreactor (CPC,Ehrfeld, IMM). It has been argued thatdespite the change in microreactor thismethod of scale-up avoids the normal lengthyscale-up process. Currently these largerdevices have all been made in metal, eitherstainless steel or Hastelloy.

5.5 Process chemistry expertise

A number of companies have developedmicrochemical systems for laboratory-scaleuse that produce small quantities ofchemicals for development. Syrris, a UK-based company, is a leader in this area.

The initial work in microprocess chemicalengineering was driven by the ability of thegroups involved to construct microchannelsystems using the technology with which theywere familiar. These groups then interactedwith other groups who were able to specifythe key features needed to run a particularchemistry in a microreactor. A number ofcompanies were established that were able tomake the necessary components but did notoffer the application expertise. Thesecompanies fell into two categories: companiesthat were effectively microfluidic foundrieswho had found another market for theirproducts (LioniX, Mikroglas, Micronit) andcompanies specifically set up to producemicroreaction systems (CPC, Ehrfeld).

This has now changed, with the major playersin the microprocess engineering marketoffering to develop a complete reactionpathway, design a microchemical plant,optimise the process, deliver the completechemical plant and operations manual for auser-defined chemical requirement.

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17 www.microreaction-technology.info – Fraunhofer Alliance’s (FAMOS) modular microfluidics system

23


Ehrfeld has become part of Bayer TechnicalServices18, CPC has spun out a newcompany, Synthacon19, and LioniX hasinvested in a joint venture (JV), ChemTrix,with the University of Hull. All thesecompanies now offer a complete ‘turnkey’service, but at this time it is not known howextensive the work carried out by thesecompanies has been due to the proprietarynature of their work.

Mikroglas has produced a number oflaboratory systems which are self containedwith microfluidics, pumps and controls allintegrated.

5.6 Advantages of microreaction

5.6.1 Quality of chemical reaction

Processes within microfluidic systems can bedesigned in such a way that transportprocesses can be made highly reproducible,resulting in better selectivity, higher yields ofthe correct products with the correctstereochemistry and better control of reactions.

These benefits are gained by the scale of themicrofluidic channels resulting in both shorterand more reproducible times for transportprocesses. Heat can be introduced andextracted from within a few micrometres ofwhere the reaction is happening. Mixing canbe effected by a number of mechanisms togive very precise conditions and hence highlyhomogeneous conditions over time.

5.6.2 Exothermic reactions

The small scale of the reacting volume meansthat even if a reaction is highly exothermic,resulting in ‘runaway’ in normal chemicalproduction systems, at the microreactionscale no such problems exist. The heat canbe removed from the system rapidly due to

the inherently large surface-to-volume ratioand short distances.

5.6.3 High-pressure reactions

The small scale of operation also facilitatesreactions being easily carried out at highpressures with minimal extra engineering dueto the low stored energy within the system.

5.6.4 Novel chemistry

The combination of the improved quality ofreactions, ability to carry out exothermicreactions and operate routinely at highpressures offers the facility to change thechemistry toolkit being used.

The potential to carry out novel chemistrywithin microreactors has yet to be fullyexploited; however, there are strongindications of the potential. The work of PaulWatts at the University of Hull has pointedtowards some of the potential, and HanGardeniers in the BioChip group at Twentehas produced ‘open bench’ high-pressurelaboratory microreactor systems that wouldnormally have required special facilities tooperate under these reaction conditions.

5.6.5 Scaling

In the development of any new chemicalmanufacturing process using classical chemicalengineering technology, scale-up is a timeconsuming and often difficult process, wherethe laboratory flask chemistry is transferred tosteel reactors or continuous large-scaleprocessing. This is due to major differences inmixing, residence times and heat transferbrought about by the difference in physicalscale of operation. One of the key benefits ofusing microreactors is that scale-up issues canbe avoided, as scale-up is not necessary.

18 www.research.bayer.com/medien/pages/3985/microreaction.pdf – chemical plant in a briefcase

19 www.synthacon.biz/index.php?menuSel=1 – ‘from milligram to ton quantities within the same production environment’

Ideally, the microreaction is developed andoptimised in a specific microreactor in thelaboratory, experimental quantities ofchemicals are produced, tested and qualified,and then pilot plant scale production is carriedout by scaling out or numbering up thesystem. Scaling out or numbering up involvesthe operation of multiple microreactors inparallel with no difference in the microreactorgeometry, flow conditions, residence times orheat transfer conditions from the laboratorymicroreactor, as a large number of identicalmicroreactors are being used to get theincreased output instead of one large one.Production operation is then similar, but witheven more microreactors run in parallel.

Exhibit 5.1 Ehrfeld modular microreaction toolbox andpilot/production plant system

Scaling has also been achieved byconstruction of new microreactors of a largerscale but with the same internal microchanneldimensions – nominally once againovercoming scale-up issues but with farhigher throughput than achieved with theoriginal laboratory-scale devices.

CPC offers a range of different systemconfigurations to deal with scale-up (Exhibit 5.2).

5.6.6 Safety

Microfluidic processes are inherently saferthan macrofluidic processes, purely due to thesmaller quantities of materials present withinthe system at any one time. In addition, assmall quantities of explosive materials do less

damage than larger quantities, toxic materialsare less hazardous in smaller quantities andthe energy stored in pressurised systemsscales with the size of the pressure vesselmeaning failure of a small system results in aminuscule energy release when that vessel isonly micrometres in cross section.

IMM has developed a parallel microreactorplant for the manufacture of nitroglycerine forpharmaceutical application, which is operatingin China.20 Each tablet only requires a smallamount of nitroglycerine, so the continuoussmall-scale operation of a microreactor wasideal for this application and entirely removedthe need to handle large quantities ofexplosive nitroglycerine.

However, it should be borne in mind that thisdoes not overcome issues with storage ofpotentially large quantities of reactants orproducts due to economies of scale in supplyor shipping.

The nitroglycerine production story was alsoreported as a dangerous trend in theproliferation of high technology that could beused by terrorists.21

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CYTOS M System

CYTOS Lab System

CYTOS Pilot System

20 mg 2 g 2 kg 2,000 kg

per experiment/run

Exhibit 5.2 CPC’s CYTOS M (micro), L (lab) and P (pilot) systems

20 www.imm-mainz.de/upload/dateien/PR%202005-11-09e.pdf – nitroglycerine production in China

21 http://news.nationalgeographic.com/news/2005/08/0811_050811_terrorism.html – Pocket-size reactors may raise chemical terrorism risk, National Geographic

News, 11 August 2005

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5.7 Summary

Microstructured or near microstructured flowshave long been key to chemical processengineering and will continue to be so, inheterogeneous catalysis, filtration, heatexchangers etc. A number of companiesaround the world, but particularly in theNetherlands and Germany, are now offering adifferent vision where a large range ofprocesses can be most effectively carried outin micro flows.

The companies offering microprocessengineering have now reached a size wherethey are able to offer integrated services tothe chemical industry. There is now acompetitive supplier situation, with supplierorganisation and some attempts atstandardisation. However, it is not obviousthat the customers are as well developed asthe suppliers.

The next five years will be a critical provingtime for microchemical manufacture. Eithermicroprocess engineering will have becomealmost invisible as a standard tool within the chemical engineer’s toolkit, brought intouse for certain processes at certain scales, or microreaction will have been reconfined to the laboratory with the current production examples having been seen as unique opportunities.

5.8 Future prospects

Currently, microreaction technology is still intechnology push mode, whilst collaborativeprojects such as those detailed below aim toproduce more market pull. All these projectscombine technology producers with chemicalproducers and as such aim to bridge thetechnology gap between them.

NEDO in Japan carried out a three-yearstrategic project during 2002-2005 aimed atproducing practical application ofmicrochemical process technologies in2005.22 The project built and demonstrated amicroreactor system to carry outorganometallic chemistries.

The IMPULSE (Integrated Multiscale ProcessUnits with Locally Structured Elements)project is a four-year, 20 company, EUcollaborative project which started in 2005.23

IMM is one of the partners. The backgroundto the IMPULSE project is that the adoptionof microstructured components in chemicalapplications has been almost entirely at thelaboratory scale; however, the benefits for theEU are far greater if the technologies areadopted widely in production. IMPULSE isaimed at addressing the factors which arestopping technology push being turned intomarket pull and hence mass uptake.IMPULSE states that these factors are that‘no reliable design methodologies, techno-economic evaluation tools or decision criteriafor this purpose exist today’. The goals of theIMPULSE project are the following:

• Proof of principle for IMPULSE approachesin several supply-chain sectors

• Validated business cases for selectedapplications

• ‘Teachable’ generic design methodologyand optimisation techniques

• Evaluation of the benefits of multiscaledesign to eco-efficiency, safety andsustainability in chemicals production and use

To do this the IMPULSE consortium has a setof process-technology objectives which willdetermine the choice of the chemicalprocesses for investigation:

22 www.nedo.go.jp/english/activities/1_sangyo/3/p02016e.html – Production, Analysis and Measurement System for Microchemical Technology Project of the

New Energy and Industrial Technology Development Organisation (NEDO), Japan

23 www.impulse-project.net – Integrated Multiscale Process Units with Locally Structured Elements.

• Replacement of batch processes bysteady-state continuous flow systems

• Modular processes for variable throughputand mass customisation

• Integration/connection of innovativeequipment for retrofit into existing plant

• Miniaturisation of process systems fordistributed/delocalised production

A more focused EU project aimed at provingthe benefits of microreaction technology,specifically nitration reactions, is NEPUMUC(New Eco-efficient Industrial Process UsingMicrostructured Unit Components).24 This isan eight-partner pan-European project whichwill integrate sensors, actuators and reactorsto produce a complete nitration system.

The educational gap has also been noted,where microsystems courses teach how toconstruct systems that could be used asmicroreactors, but traditional chemistry/chemical engineering courses do not teach theuse of such systems. Both the Netherlandsand Germany are funding increases in the useof microsystems throughout technicaleducation, some of which is directed at theuse of microreaction technologies.

26


24 www.nepumuc.info/index.htm – New Eco-efficient Industrial Process Using Microstructured Unit Components – ‘Safe and environmental friendly production of

sensitive compounds ensured by process intensification’ – EU funded project, started 2005

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6.1 Discovery6.2 Scale-up6.3 Quality control6.4 Delivery and clinical testing6.5 Summary and conclusions

To put the opportunities available intoperspective it is perhaps best to look at thevarious stages in the life cycle of acommercial drug. For this discussion they can be divided as follows:

• Discovery – compound generation andscreening

• Scale-up – increasing amounts of materialavailable

• Quality control – during manufacture• Delivery and clinical testing – for

introducing the drug to the body and formeasuring the sensitivity and effectivenessof a particular compound

In all stages of the life cycle of a commercialdrug, microfluidic technology could have asignificant impact on the time to market,quality of outcomes and cost. Each stage isnow considered in turn.

6.1 Discovery

Using the inherent properties of microfluidicsystems, it is possible to synthesisecompounds dynamically using flow chemistrysystems. In particular, small organicmolecules can be generated using anautomatic multistep reaction system. Thepotential is that the method will begin toobviate the need for compound libararies,which are by nature complicated andexpensive. In order for this to happen, largepharmaceutical companies will need tosubstantially change their approach to valuing

their discovery systems from counting thenumber of compounds in libraries tounderstanding the flexibility of theirautomated chemistry systems and howinventive their medicinal chemists are.

The systems of Ehrfeld and CPC/Synthaconwent some way to satisfying therequirements of being able to synthesise verysimple compounds ‘on the fly’ but lacked asophisticated mechanism for performingmultistage synthesis, needed for small-molecule generation. In most cases acontinuous microreactor based system needsto be flexible and perform dozens ofsequential steps. From the evidencepresented, this surpasses the capability ofthe current product offerings.

Another issue that needs to be addressed isthat of quality assurance (QA). In particular, ifthe chemistry is done in stainless steelchannels then characterising the reaction isdifficult. In contrast, Mikroglas and Micronitmake transparent and electrically insulatingglass chips allowing electrical and opticalprobing of the reactions taking place. This ability would provide an extra level ofassurance to the chemist that the reactionsare proceeding as expected. In the UK, Syrris Ltd has developed systems dedicatedto compound formulation based on glasschips, which from the above appears to bethe best strategy.

A central issue which is intrinsic tomicrofluidic-based systems is the limitedproduction capacity of a single channel.Presently this is probably too small for all butthe most frugal of plate-based assay systems.To some extent, until this deadlock is brokenit could well be the limiting factor in the

6 MICROFLUIDICS IN THE PHARMACEUTICAL SECTOR

rollout of such technology as a replacementfor conventional sample-in-a-bottle compound libraries.

6.2 Scale-up

Once an interesting compound is discovered,increasing amounts are needed during thevarious phases of clinical trials, maturing to acapability to produce the quantity of productrequired by the market. It will continue to bethe case that most compounds fail tobecome drugs released onto the market. Ifthis happens, any investment in plant to makea failed compound further heightens theultimate cost. Unfortunately, with currentbatch processing techniques a perfectsynchronisation of investment in new plantand successful passage through clinical trialsis difficult. With the flexibility and inherentlymodular nature of microfluidic-based systemsit is possible to grow the production systemfrom a single continuous line to multiple linesas the demand for compounds increases.Using the fine-grained nature of microfluidicproduction systems it is possible to matchthe output capacity to the compoundrequirements in almost real time.

As scale-up can be achieved by formingparallel arrays of smaller pretested productionunits then there is hope that the US Food andDrug Administration (FDA) approval processcan ultimately be simplified. However, it isopen to question whether using an array ofsmall production units does not raise otherquestions in terms of monitoring and controlof the process. In particular, each channelcontributing to the end product would have tobe monitored. If a significant number ofchannels were to be used, ie many hundreds,then this could result in an unacceptablemeasurement and control overhead beingintroduced. Inevitably this would reduce theoverall advantage of such an approach.

From the companies and organisationsprofiled, there were a number of examples ofhow this type of scale-up can occur given thecaveats expressed above. One of the mostpertinent examples was from IMM that isdeveloping a pharmaceutical nitroglycerineproduction plant, now operating in China.25

Here the parallel microreactor concept hasbeen developed into a monolithic unit wheremany parallel reaction channels are fabricatedinto the volume of a plate device (Exhibit 6.1).

Exhibit 6.1 Nitroglycerine production plant (>100 l/hsolution) using microstructured reactors set inoperation in Xi´an, China (courtesy IMM, Germany)

The advantages of microfluidics in thisexample are safety and yield. Because themicroreactor has a high surface-to-volume

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25 www.imm-mainz.de/upload/dateien/PR%202005-11-09e.pdf

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ratio, heat can be pumped into an endothermicreaction or, conversely, easily taken out if it isexothermic. This allows the reactiontemperature to be optimally controlled withinstrict predetermined limits. Such control hasother added benefits in this case as theproduct is highly explosive. The ability to exactfine control of the temperature means that amicrofluidic-based plant is always kept withinstrict operational limits, increasing safety.

When this ability is coupled with the fastdiffusion-mediated mixing and the almostintrinsic ability to pressurise the channel tomany bars, many reactions could be speededup significantly. If all these factors are takentogether, the time to reach the reactionequilibrium can be shortened, sometimessignificantly, which has the effect ofincreasing the purity of the end productcompared to standard flask-type reactors.Overall this leads to a significant saving intime, materials and energy. This should belooked at in the context of the performanceof the current production methods. Inparticular, there have been studies whichshow that presently, in the averagepharmaceutical production process, for everykilo of finished product, up to fifty kilos ofwaste are formed, which are often hazardousand as a result expensive to dispose of.26, 27

There are other, more specialised areas of thepharmaceutical industry that could benefitdisproportionately from this technology.Orphan drugs are loosely defined as thosethat fight rare diseases and as a consequenceare only needed in small quantities. An orphandrug might only require 100 kg/y, in whichcase the microfluidic system used to developthe compound could also, if run continuously,produce enough finished chemical for the endmarket. This has the possibility ofrevolutionising the field, where at presentcompounds with a significant potential benefit

often languish in the laboratory as the cost ofthe scale-up is not compensated for by thesize of the end market.

Overall the use of microfluidic-basedproduction systems offers the virtuouscombination of cost reduction, increased yieldand improved safety.

6.3 Quality control

Despite the high capital cost and the highgross margin on drugs, batch production isstill dominant in the pharmaceutical industry.This leads to a relatively slow and expensiveramp-up process and high cost of failure ifthere is a quality control (QC) problem with aparticular batch as very often the whole batchis proved worthless.

Microfluidics could contribute significantly toalleviating these shortcomings. In particular,microfluidic-based measurement systemscould monitor batch quality throughout themanufacturing process. To obtain a validreading only minute samples are needed, andbeing able to perform a wide range ofchemical reactions quickly will help to stemany problems that might end up spoiling thewhole batch, particularly in the morecomplex, multistage reactions. In the longerterm, if continuous production microfluidicreactors replace batch systems, diagnosticelements could be included in situ as part ofthe reactor.

6.4 Delivery and clinical testing

When a drug compound enters the body itcan undergo a number of chemical reactions,either in the process of its therapeutic action,or ones which cause unwanted side effects.

The clinical effectiveness of a compound andany potential side effects need to be

26 http://nano.cancer.gov/news_center/monthly_feature_2005_jun.pdf

27 www.rsc.org/chemistryworld/Issues/2004/January/bountiful.asp

thoroughly characterised in the clinical trialsbefore release. After a drug is launched intothe market, testing certain characteristics ofthe recipient can augment its effectiveness.This could also help to detect whether a drugis likely to cause side effects in a particularcandidate. Furthermore, although at first sightit seems elementary, dose monitoring of bloodserum levels usually ensures that the courseof treatment works at optimal effectiveness.

In all these aspects, microfluidics could, andprobably will, make significant contributions.Even before clinical trials begin, techniquessuch as single-cell patch clamping will help inascertaining a detailed understanding of themechanism of action and any associatedtoxicity of a compound. In this respect theability of ThinXXS to produce small featuredsilicon microfluidic structures is being utilisedby Sophion Bioscience A/S in Denmark tomake a state-of-the-art single-cell patchclamping device (Exhibit 6.2).

Exhibit 6.2 An integrated microfluidic device for theion channel screening of living cells co-developed andmanufactured by ThinXXS Microtechnology for SophionBioscience A/S (courtesy Sophion Bioscience A/S)

In first-stage clinical trials, the ability to rapidlytest potential adverse side effects before thepatient has been injected will alleviate anumber of risk factors that could result inpatient harm. These could be simple chemicaltests or more sophisticated genomic-basedtests that look for genetic markers in thepatient indicating positive or adverse activity

of the compound. As the compoundprogresses to commercial release the sametests could be used in frontline care tooptimise who gets the drug and who doesn’t.

Another issue faced in frontline care is that ofpatients not taking the drugs in theprescribed manner, normally termed asnoncompliance. In this case either the bloodserum levels of the compound do not remainhigh enough or they vary widely as patientstry to ‘catch up’ if they have missed a dose. Ithas recently been shown that 25% ofpatients do not take a sufficient amount ofthe drugs they have been prescribed to gainany medical benefit. The benefit of usingmicrofluidics in solving this is exemplified bythe work of the Bios Lab-on-a-Chip Group atthe University of Twente. Here the group hasdeveloped a rapid test for measuring bloodlevels of lithium in patients diagnosed withbipolar disorder. Lithium helps to stabilise thecondition, but if the levels drop too lowthrough noncompliance or other issues, arelapse of the condition can occur.

6.5 Summary and conclusions

Due to the nature of its product, thepharmaceutical industry must be extremelysafety conscious and conservative in itsapproach to all phases of development andmanufacture. At the moment the industry and its investors strongly perceive there is alack of new drugs being discovered. Accordingly, despite microfluidics offeringsignificant benefits at all stages of theprocess, it will be adopted initially in theprimary stages of development, in the so-called discovery phase. Initially it willconcentrate on areas such as real timegeneration of compounds for screeningsystems and as a diagnostic tool in earlystage drug trials to screen out various geneticfactors that may influence the outcome ofhuman trials.

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Looking at the evidence, it appears thatmicrofluidics is not being used for themanufacture of mainstream medicines at themoment, although it is being used for certainspecialised compounds (nitroglycerine) andprecursors. The mission encountered anumber of groups who had or weredeveloping technology with the goal ofcreating mainstream manufacturing systems,but the hurdles to be overcome are many andvaried and will demand an interdisciplinaryapproach. Crucially it needs the buy-in of thepharmaceutical companies themselves andalthough the mission saw evidence that thisis beginning to happen in Germany, withBayer’s acquisition of Ehrfeld, it did not see awholesale embrace of the technology by thesector as a technology for manufacturing.Despite this, the potential contribution ofmicrofluidics to the manufacturing process issignificant and as the pharmaceutical industryis often fairly coy about its means ofproduction, many aspects will probably beshrouded in confidentiality at this time.

In the USA the FDA has begun a long-termprogramme for increasing the effectiveness ofmedicines whilst reducing their often very highcosts.28 FDA has identified that microfluidicscould play a key role in this programme.

Due to the dominance of the pharmaceuticalindustry in the UK, creating such acoordinated approach could reap richdividends for the UK high-tech economy as awhole. In part this could be done byleveraging off the products and servicesavailable worldwide.

28 www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

7 MICROFLUIDICS IN THE HOUSEHOLD, PERSONAL CARE AND FOOD SECTORS

7.1 Increased availability of compact,low-cost and low power consumptionmicrofluidic components

7.2 Self-diagnosing and self-monitoring devices

7.3 Highly integrated microanalytical systems for kinetic studies, process control and product development

7.4 Advance of module-based microfluidic systems

7.5 Novel membrane-based material processing techniques

7.6 Summary

Various advances in microfluidics technologywere observed during this mission. Theadvances that could benefit the food andhome and personal care (HPC) businessesare summarised as the following.

7.1 Increased availability of compact,

low-cost and low power

consumption microfluidic

components

One example is the micropump developed byBartels Mikrotechnik GmbH, overall size 14 x14 x 3.5 mm and weight 0.8 g, which can beoperated for up to 72 hours on an AA batteryand can deliver 500 mbar pressure. Accordingto Bartels, the cost of this pump could bereduced to <€1/unit (<£0.70/unit) for large-volume production. This pump has beendeveloped in collaboration with a consumergoods company for pumping fluids in acommercial perfume delivery device.

Such components are applicable for the novelpackaging of foods and HPC products. In fact,packaging of this kind can already be foundon the market. For example, in the SK-II air

touch foundation, launched by Procter &Gamble (P&G), a nozzle-based ionisationtechnique has been integrated into thepackaging. According to P&G, a perfect veil ofluxurious monolayer coverage of foundationdroplet can be delivered through such apackaging, and SK-II is sold as a premiumproduct in Japan. Such embeddedmicrofluidic devices, even invisible to theconsumers, can greatly improve usageexperiences of the products.

Innovative packaging of this kind could befurther stimulated by the availability of aneven wider range of functional and reliablemicrofluidic components.

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Exhibit 7.1 Micropump manufactured by BartelsMikrotechnik GmbH

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7.2 Self-diagnosing and self-

monitoring devices

According to the companies visited in thismission, such as ThinXXS, the range ofmicrofluidic-based self-diagnosing and self-monitoring devices is expanding. Currently,most of these devices are developed forpeople with health problems, particularlychronic problems such as stress anddiabetes, which demand long-term self-management.

However, as the concept of preventive healthbecomes more widespread, such devicescould be accepted by the majority of thepopulation as the tools to help them remainhealthy, include consuming healthier foodsand HPC products. As the cost of thesedevices decreases, thanks to innovation and economies of scale, the barrier ofintroducing such applications is becomingprogressively smaller.

7.3 Highly integrated microanalytical

systems for kinetic studies, process

control and product development

Such systems have been widely used by thepharmaceutical and chemical industries, as

well as life science research, for over adecade. Still, novel systems are beingdeveloped by research institutes and SMEswhich aim to provide further improvedfunctionalities and serve a wider range ofapplications. Examples include integratedsystems containing multiple microfluidic andoptic components developed by LioniX, andthe micro NMR being developed in theMESA+ Institute.

These systems, along with themethodologies developed upon them, arehighly applicable to the food and HPCindustries, for developing, screening, andmodifying novel ingredients, such asingredients used for functional foods andappealing cosmetics.

7.4 Advance of module-based

microfluidic systems

Module-based microfluidic systems arecomprised of various blocks; each oneperforms a basic process operation, such asmixing, dispersing or heat transferring. Thesemodules can be freely combined by means ofclamping devices on top of a base plate toform completed systems, therefore can betailored towards particular applications by theend users. Such systems have beendeveloped in Germany since 2000 and thetechnical advance in this area is highly evident.

A few SMEs that are pushing this field havebeen visited during this trip; they are EhrfeldMikrotechnik, CPC, Synthacon and Mikroglas.According to these SMEs, the number ofpharmaceutical and chemical companies inGermany that are testing and adopting suchsystems has increased rapidly in the lastcouple of years.

These are encouraging developments.However, the applicability of such systems tofoods and HPC products is still limited for atleast three reasons:

Exhibit 7.2 P&G’s SK-II air touch foundation

• The main application of such systems iscontinuous chemical synthesis. There areconsiderable differences between chemicalsynthesis processes and materialstructuring processes such asencapsulation and emulsification, whichare the more commonly used processesfor food and HPC products. Furthermore,the fluidic materials involved in food andHPC products are often of high viscosity.This presents further challenges to themicrofluidic systems, in the sense ofcontrolling pressure and flow distribution,as well as managing clogging and surfacecontamination-related fouling.

• The economic return of such systems isa debatable issue. For example, CPCrecommends that its system is mostsuitable for making products with a marketvalue >€5,000/kg (>£3,400/kg) due to theconsiderable installation and maintenancecost. However, Ehrfeld claims that itssystem could be economical for makingproducts with a value as low as a few€/kg. Such a difference is not obviouslyexplainable; therefore further investigationand verification would be valuable.

• The experience of running such systemsfor extended time periods is still verylimited; therefore information on longerterm reliability and maintenance costs issparse. This will be perceived as a high riskfactor by the relatively low cost-based foodand HPC industries.

Nonetheless, there is great value in thecapability of manipulating system designs tomeet the reaction requirements, and theknowledge on manifold design and flowdistribution management which can belearned from modular microfluidic systems.

7.5 Novel membrane-based material

processing techniques

Using membrane-based techniques formaterial processing is not new. However, acouple of SMEs, such as Aquamarijn andNanomi, and the Membrane TechnologyGroup in the MESA+ Institute, consider thattheir membranes have more to offer than theconventional ones. The common features ofthese membranes are massively parallelpores with reduced pore size and improvedpore distribution, all enabled bymicrofabrication techniques. Applications thatare relevant to foods and HPC products are:

• Aerosol generation, as proved by itsadaptation into drug inhalers

• Filtration, as demonstrated by its usage forlarge-volume filtration of beers

• Emulsification, which is still mainly in theR&D stage

7.6 Summary

The potential applications of microfluidicdevices for foods and HPC products could bebroad. This field is currently lagging behindfine chemicals and pharmaceuticals. Therealisation of such potential depends on thebalance of cost, reliability, life span and thethroughput of microfluidic devices.

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8 MECHANISMS FOR STIMULATING THE UPTAKE OF MICROFLUIDICS BY

INDUSTRY IN THE NETHERLANDS AND GERMANY

8.1 Introduction8.2 Overview of the Netherlands

8.2.1 Networking8.2.2 Reconfiguration8.2.3 Support8.2.4 Company-university

relations8.3 Overview of Germany

8.3.1 Support for IMM8.3.2 IMM reconfiguration8.3.3 A wider view of

microfluidics in Germany8.3.4 uVT network and

standardisation8.3.5 Training and education8.3.6 Important intermediary

organisations8.4 Conclusions and recommendations

8.1 Introduction

The objective of stimulating investment innew industries, company formation, products,and the restructuring of large companies tomeet the challenges and opportunities ofglobalisation, is an issue on all national andregional agendas. Microfluidics is an enablingtechnology that has for a while created newindustry (eg ink-jet printing), is now enablingthe creation of new mainstream products (eg point-of-use diagnostics) and is expectedto create many more (eg precision synthesisof chemicals). Processes aimed at theeffective utilisation of the science andeducational base, in creating newtechnologies, their understanding and uptakewere presented to the mission team. Thisalso extended to the range of processes, andcurrent initiatives to extend and improvethem, that have been implemented over thelast 10-15 years, particularly in the

Netherlands. The team were exposed to themeasures being taking within the educationalsystem in the Netherlands and the associatedroles of the universities and technologyinstitutes (TNO in the Netherlands and, untilrecently privatised, IMM in Germany),together with case histories of severalbeneficiary companies.

8.2 Overview of the Netherlands

In the last 10-15 years the Netherlands hasmaintained a steady investment inmicroelectronics, ICT, microsystems,speciality chemicals and polymers. Resourceshave been focused in areas where thecountry has competitive advantage andstrategic need. Investment in the integrationand expansion of these technologies is beingprogressed, in part, under the promotion ofnanotechnology. The technical universities(TUs) have held a distinguished role in theinnovation process which is ‘managed’ and isbeing reinforced by government and industryled actions. In the university sector, fivecentres of excellence, with 30 newprofessorial positions, are to be created innanotechnology, ICT, sustainable energy, fluidand soil mechanics with €50 million (~£34 million) of government investment.Applications where microfluidic R&D isrelevant to the Dutch economy includeconsumer electronics, healthcare products,process intensification in food manufacture,and sensors for quality control in greenhouse agriculture.

The Netherlands has a well integratednational infrastructure for innovation withengagement of the universities, technologytransfer and industry support institutions (eg TNO, MESA+) and industry (eg Philips,

Unilever). Government support andstimulation measures in the field of MNTwere apparent at all levels with emphasis onensuring the science and technology (S&T)base was at the high level required to sustainboth (1) the global competitiveness of keylarge companies, such as Philips and Unilever,and (2) the generation and support of anentrepreneurial environment in which start-upand spin-out companies are created fromboth universities and large companies.Managed networking, reconfiguration andsupport initiatives are well-funded, matureand operational at all levels as evidenced bythe examples below.

8.2.1 Networking

The University of Delft is a partner in a globalbionanotechnology R&D programme withleading academic groups in the USA (Harvard,MIT) and Japan (Tokyo) and wheremicrofluidics is employed as an enabling tool.

In 2007 the three TUs (Twente, Delft,Eindhoven) are to be formed as a federation.This will (a) build, and further focus activity,on business through new company andproduct creation, and (b) further support theexisting good success rate in spin-outcompany creation and incubation throughfacilities access and research programmes.Within these universities are (1) the MESA+Institute for Nanotechnology at Twente; (2)the Kavli Institute of Nanoscience at DelftUniversity (coordinating the MicroNedprogramme – see below); and (3) specialistmicro- and nanoengineering groups atEindhoven University.

Additional to the government subsidisedprogrammes already referred to there is anestablished National Microfluidics Network ledby Richard Schasfoort at Twente University. Thisis an inclusive supply chain network which actsto enable a coherent visibility of technologyproviders to end users. Some companiesinterviewed found this network useful whilst

other more established microfluidics suppliercompanies were less enthusiastic.

8.2.2 Reconfiguration

The Holst Centre represents an innovativeand international collaboration on ‘foil’ or‘panel’ based microsystems between theNetherlands (TNO) and Belgium (IMEC)bringing together technology platforms(including microfluidics) in both silicon andpolymer electronics.

The restructuring of Philips has (1) createdspin-out companies with expertise in bothelectrowetting (surface microfluidics) andpolymer ‘microfluidic displays’, (2) providedopen-access MNT facilities at the EindhovenHigh Technology Campus, and (3) invested innew R&D towards applications in healthcare.Unilever may also restructure to stimulatemore innovation.

8.2.3 Support

Regional initiatives continue to be takenincluding the use of European RegionalDevelopment Funds (ERDF) – East Netherlands.

A jointly funded €30 million (~£21 million)micronanostructuring and characterisationfacility is under construction at TU Delft as acollaboration with TNO. This will provide astate-of-the-art facility in which microfluidic(and other) devices, components andsystems may be developed by both academeand industry.

TNO has a presence on the managementboards at the technical universities of Delftand Eindhoven to guide, facilitate and supportthe wider industrial use of the science base.TNO has facilities and objectives of its ownincluding inward investment.

Young and old entrepreneurs are motivatedand provided with the training and facilities

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needed to start up new companies, and theirachievements are recognised and openlycelebrated by government ministers (egMicronit Microfluidics BV).

The University of Twente which hosts theMESA+ Institute has a uniquely supportiveenvironment for the creation of newenterprises from academic research. Anentrepreneurial attitude is instilled in bothacademic staff and PhD graduates alike bytwo distinctive factors:

• PhD graduates receive a salary (not astipend as is usual in the UK), undertakemore teaching and supervisoryresponsibilities, and also must consider thecommercial implications of their researchand opportunities for a spin-out or start-upwithin their four-year work-study period

• Academic staff hold devolved responsibilityto raise the main part of their own researchfunds which includes all infrastructure andfacilities provision; despite this, businessangel and venture capital (VC) investmentappears to be in short supply and some ofthe Dutch microfluidics companies visitedwere backed by British financiers

Long-term commitment and continuity ofregional support spanning over 20 years inthe field of lab-on-chip technology is evident,particularly at Twente University which hostedthe first international conference on microTotal Analysis Systems (µTAS) in 1994.

A summary of recent stimulation measuresby the Netherlands Government waspresented to the mission team by LeoZonneveld, Science Attaché at the BritishEmbassy in Den Haag. In The Netherlands aconvergence approach to nanotechnology istaken, integrating the molecular andnanoscale within microelectronics,microsystems and macro-scale systems toenable new business opportunities.Microfluidics (and indeed millimetre-scale

fluidics) is therefore treated as an integral partof the nanotechnology programme and thusan accurate figure on support for microfluidicscannot be easily determined.Nanotechnology, genomics and ICT are thethree national priorities which togetherreceived €800 million (~£550 million) in grantaid under ICES/KIS following a 1999 review ofcompetitiveness in key technologies. €147 million (~£101 million) grant aidspecifically for nanotechnology (€130 million(~£90 million) in 2004 and €17 million (~£12 million) in 2006) comprises threedelivery platforms:

• NanoNed – €95 million (~£66 million) –nanotechnology R&D and infrastructurelargely at MESA+ and Kavli

• BioMaDe – €7 million (~£5 million) –biomaterials and biosensor R&D at TUEnschede

• MicroNed – €23 million (~£16 million) –microsystems awareness and R&Dactivities directed from TU Delft

NanoNed, the largest platform, is executedby a consortium of seven universities withTNO and Philips with an industriallyenhanced value totalling €235 million (~£162 million) during 2005-9. NanoNedcomprises 11 large independent programmesof which ‘nanofluidics’ (incorporatingmicrofluidics) is one. In addition, theprogramme also incorporates an €85 million(~£59 million) laboratory infrastructureenhancement programme.

8.2.4 Company-university relations

The British Embassy assisted meetingsbetween the mission team and leaders of theinitiatives referred to above as reported insections elsewhere in this report.Testimonials from the management of threestart-up microfluidics companies clusteredaround the Twente University MESA+Institute in Enschede were taken. Theseexample companies included C2V, LioniX and

Micronit, all of which have made good use of the measures made available bygovernment to assist the creation and growth of their companies.

Significantly, the survival rate of this companycluster is ~75% (unusually high for start-ups)and is attributed, in part, to the close workingrelationship with the MESA+ micronano-fabrication clean-room facility which thecompanies have direct, hands on, openaccess to. This key enabling action allowsengineers from the companies to use theclean-room facility on a swipe card, accountcharging basis. Extremely close proximity ofthe companies’ offices adjacent to, andcontiguous with, the offices of MESA+academic staff enables intimate cooperationand intermixing between staff.

The MESA+ Institute has enabled 33 spin-outenterprises (several in microfluidics) duringthe last 15 years. This success rate isattributed also in part to the devolved duty toscout and convert to a business two of themost promising opportunities per year, twoyears earlier than would otherwise occur.Significantly, a centralised technology transferoffice for the university was long recognisedas essentially ineffectual.

8.3 Overview of Germany

The mission visited IMM and some of itsassociated spin-out and start-up companies.IMM is one the oldest experiments intechnology transfer in the development ofEuropean MNT and the use of governmentstimulation measures to create newtechnology and markets. Over a 15-yearperiod IMM has evolved its mission fromleading edge, fast-track research to appliedresearch and dissemination through spin-outs.IMM and its associated spin-out companiesarguably represent the leading cluster ofmicrofluidics companies in Germany to dateand were the focus for the mission activitiesin Germany.

8.3.1 Support for IMM

IMM was founded as a non-profit makingresearch institute (company) using publicmoney from the region and other publicsources. This involved the transfer of itsfounder, Professor Wolfgang Ehrfeld, andassociated technology from FZK to lead theInstitute in Mainz. At around this timeMicroparts, a polymer componentmicromoulding company, was alsoestablished as a spin-out company from FZK.Microparts was later acquired by one of itscustomers, Boehringer Ingelheim, to producedrug delivery nebulisers. Over a 15-yearperiod IMM has evolved from being a whollypublic funded non-profit making company tobeing a limited company or GmbH and hasprogressively reduced its dependence onpublic funds to ~60% in 2006.

With significant foresight the original purposeof IMM was to encourage the adoption ofMST in the chemicals, polymers,manufacturing and processing industrieswhilst simultaneously minimising risk. Theimplementation of this plan involvedmachinery suppliers of strategic importance tothe German economy in order to maintain theindustrial competitiveness. IMM evolved froma period of R&D leadership to technologytransfer and exploitation by industry. Ofparticular note is the role of the Ehrfeld familyin leading the first two phases. Innovation(success in the marketplace) is being achievedby application development by IMM and itsspin-out companies and market exploitation bycompanies adopting the technology.

8.3.2 IMM reconfiguration

The positioning of IMM continues to changeas a result of personnel and equipmenttransfer to spin-out companies. Themigrations of most significance were thecreation of the companies CPC, Ehrfeld andThinXXS which were all visited by themission. Whilst IMM is a company it still

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receives a certain level of state subsidythrough research and training grants. IMMcontinues to operate in similar markets as itsspin-out companies with activities in metalmicroreactor development and polymermicromoulding. This is considered by some todistort the marketplace against the favour ofits spin-outs. In the case of metalmicroreactors, CPC and Ehrfeld relocated.Polymer micromoulding capital assets weretransferred to a new IMM-enabled technicalfacility at Zweibrücken. The principalmotivation for creating this new facility wasto regenerate the economy of theZweibrücken region after military operationshad diminished there. ThinXXS is essentially apolymer microfluidics spin-out that currentlyrents office and microfabrication facility spacebut also has direct open access to the newZweibrücken microfabrication facilities.

Mikroglas, also a spin-out of IMM, visited themission team in London. This helpedformulate a more substantive picture of theprocess by which a microfluidics industry hasbeen created in Germany. Each companyoccupies its distinctive niche space in themarket whilst there is some inevitablebusiness overlap. Nevertheless, this hascreated a supply chain to larger companies inboth the medical products and chemicalsindustries and where inter-company tradingand acquisitions were evident. Although eachIMM spin-out has a distinct business modelthere is an internal competitive marketbetween the parent and offspring, particularlynow the former has become a GmbH.

8.3.3 A wider view of microfluidics inGermany

The Federal Ministry of Education andResearch (BMBF) is the main funding vehiclefor microsystems technology in Germany and has allocated over €600 million (~£410 million) to microsystems engineeringsince 1990.

According to the Association of GermanEngineers (VDI) study Schlüsseltechnologien2010, the annual turnover (2003) of Germanindustry in selling MEMS components was€4.2 billion (~£2.9 billion), whilst systemssales accounted for €277 billion (~£191billion). An estimated 680,000 jobs dependon MEMS, with 49,000 directly in theproduction of MEMS components. The valuecreation landscape is dominated by SMEsbut Germany’s large companies, particularlyin the chemical, pharmaceutical, electronicsand automotive sectors, provide a route tomarket – Merck, Aventis, Siemens, Bosch,Degussa, BASF, Bayer, Boehringer Ingelheimto name just a few.

The current Microsystems FrameworkProgramme ‘Mikrosystemtechnik 2004-2009’,with a budget of some €260 million (~£180million), is the fourth consecutive five-yearfunding programme. The first threeprogrammes involved 349 collaborativeprojects with total funding (including industrialcontribution) of over €1 million (£690,000),and involving 800 organisations of which 80%were SMEs. It is not known what proportionof this funding has gone into microfluidicsand microreaction technologies; however, it issubstantial – for example, BMBF contributed€15 million (~£10 million) over three years to2004 for the development of a microreactiontechnology supply chain. Exhibit 8.1 is a shorthistory of microfluidics technology indicatingsome of the progress that has been made in Germany.

The current funding programme is set withinthe framework of four themes:

• Life science – healthcare and diagnosis,personalised therapy, microsurgery,intelligent implants, food/nutrition

• Mobility – self-generating energysystems, eg via radio frequencyidentification (RFID); miniaturised energysystems, eg via micro fuel cells

• Industrial processes – ‘new chemistry’,automation, robotics

• Systems integration – intelligent systems involving macro-, micro- and nano-scale integration

The programme covers collaborative R&D,infrastructure, information/communicationactivities, with a strong focus onmicroprocess engineering, particularly safesynthesis in turnkey microchemical andbiochemical processes, microfluidic analysisand the integration of sensing inmicroprocess technologies. The emphasis isclose to market, ie on the development ofindustrial manufacturing processes, andspecifically on the removal of identifiedbarriers such as:

• Shortage of peripheral components,particularly for process control

• Standardisation and modularisation ofcomplex systems

• Improving knowledge on stability andreliability

• Establishing complete processes that can allow economic impacts to be properly assessed

• Training and educational needs

An introduction to the aims of the currentprogramme can be found atwww.bmbf.de/pub/microsystems.pdf

Funding has included some major activitiessuch as Projekt Mikrosystemtechnik at FZK,with a current annual budget of €34 million

40


Exhibit 8.1 Microfluidics development

Ink-jetprinting

Heattransfer Lab-on-a-chip Microreaction Micro

fuel cells1970

1980

1990

2000

2010

1977: Piezoelectricink-jet printer(Siemens)

1981: Bubble-jetprinter (Canon)

1981: Microchannelheat exchanger(Tuckerman & Pease)

1979: Microchannelgas chromatograph(Terry)

1988/1989:Micropumps

1989: First gas-phase system (FZK)

1990: μTAS (Manz)

1998/1999:Commercialisation(Agilent/Caliper)

1999:Commercialisation(CPC)

2004/2005:Portable powerapplications andcommercialisation(MTI and others)

41


(~£23 million), focused on industrialapplications of microprocess engineering,microsensor systems, microfluidics andmicro-optics, with healthcare applicationsbeing dominant. Longer-term work onmicrostructuring techniques, new materialsdevelopment and characterisation (polymers,metals and ceramics) and packagingmethodologies is also undertaken, incooperation with 50 other research facilities.

Funding for microfluidics technologies is alsocontained within other BMBF fundingprogrammes such as Framework ConceptNanotechnology (€50-200 million/y ≈ £34-140 million/y), New Materials, Research forTomorrow’s Production, Intelligent Systems,production-integrated environmentaltechnology, healthcare and biotechnologyprogrammes. Further funding may come fromresearch foundations such as the GermanEnvironment Foundation (DBU), as well as fromthe German Research Foundation (DFG) whichfunds university and technical college researchprogrammes. The current six-year DFG fundingprogramme which started in 2004 includes 14 priority themes which collectively have €38 million (~£26 million) funding forcollaborative projects. These include:

• Nano- and microfluidics: from molecularmotion to continuous flow – coordinatedby the University of Saarland

• New strategies for measurement andtesting in the production of microsystemsand nanostructures – coordinated by theUniversity of Erlangen

8.3.4 uVT network and standarisation

An innovative industry-driven consortiumproject on modular microprocessengineering (uVT) was funded by the BMBF.uVT sought to develop standard interfacesfor functional microfluidics modules that,when integrated, would constitute aminiaturised chemical processing plant, orretrofit to existing plant. The interfacing of

modules each performing different discretefunctions has long been considered ahindrance to the commercialisation ofmicrofluidics technology (particularlymicroreactors for long-duration usage).

The project output a very impressive solution tothis requirement with several companiesinitially adopting the standard for its modularproducts. This potentially allows users andsystems integrators to construct multifunctionalsystems based on devices sourced fromseveral different manufacturers. However,despite this seemingly excellent development,the standardisation approach is beingincreasingly abandoned by the consortiumpartners, each preferring to promote their ownspecific standard in order to corner the market.

8.3.5 Training and education

There are many initiatives to assist thedevelopment of MST skills. ‘MicrosystemsEngineer’ has been a formal profession since1998 and some hundreds of apprenticeshipshave been completed since then. There arealso MST retraining courses offered by anumber of public institutions that are offeredon a local basis. Teaching is generally done bycompany experts. ‘Pro-mst’ is a dedicatedtraining foundry in Zweibrücken – acomprehensive clean-room facility andinfrastructure for MST training and education,based in the Fachhochschule Kaiserslautern.The ‘model project’ Corporate-Learning-Network MST in Dortmund is a network ofeducating institutions in the MST/MEMSsector. Other regions have similar initiatives.

8.3.6 Important intermediaryorganisations

• IVAM – Association of Companies andInstitutes in Microsystem Technology:www.ivam.de

• DECHEMA – Society for ChemicalEngineering and Biotechnology:www.dechema.de

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• AMA – Association for Sensor technology:www.ama-sensorik.de

• VDMA – German Engineering Federation:www.vdma.org/microtechnology

• ZVEI – Electrical and ElectronicManufacturers’ Association: www.zvei.org

8.4 Conclusions and recommendations

A new focus on systems integration is nowenabling the acceleration of microfluidicscommercialisation which has hitherto beenhindered in the Netherlands and Germany.The UK would do well to recognise that manyend-user corporations, particularly in bulkmaterials manufacture, require completeturnkey solutions (not curiosity chips) if thepotential of microfluidics is to be realised.

The example of Twente Universitydemonstrates that risk-averse centralisedtechnology transfer offices in UK universities,which once may have served a usefulpurpose, are now possibly a hindrance to theaccelerated establishment of spin-outs, and ascheme to decentralise target-basedresponsibility to departments and researchgroups could be piloted, benchmarking theTwente example. Twente University also helda sensible attitude regarding the value of itsintellectual property (IP).

The evidence from the microfluidics companiesclustered around or associated with TwenteUniversity and IMM suggest that affordable,direct, hands-on access to microfabricationtools is a key (if not the key) requirement forencouraging a dynamic industrial microfluidicscluster where start-ups and spin-outs are theprincipal commercial entities.

9.1 Introduction9.2 Examples of new technologies

and applications9.2.1 Micro boiling heat transfer9.2.2 Liquid-wall interactions9.2.3 Fluorescence enhancement

technology9.2.4 Micro inhaler for drug delivery9.2.5 Micro electrolyte analysers for

point of care9.2.6 Micro fuel cell technology9.2.7 Nanowires9.2.8 Lab-on-a-chip9.2.9 Microporous structures9.2.10 Polymer-based microfluidics

9.1 Introduction

Microfluidics represents one of the mostimportant and exciting technological areas inmicrotechnology over the past two decades. Itwas driven principally by the needs of microflowsensors, micropumps and microvalves in theearly stages of development. This hasundergone substantial changes over the yearsand microfluidics developments have beendominated by life science and chemistry relatedapplications. Today’s emerging application areasinclude DNA separation and analysis, drugscreening, microfiltration/emulsification,detection of Legionella and of a range ofbiological and chemical contaminants in potableand waste water.

Germany and the Netherlands are seen astwo major players in microfluidics R&D inEurope. The mission enabled the team to see,to meet and to discuss with both academicand industrial representatives of the twocountries. Although the overall impression is

that there are numerous microfluidic productsthat await industrial take-up, there are newR&D programmes aiming at new technologiesrelated to microfluidics. Examples are given inSection 9.2 below.

Much of the innovation in the microfluidicsarea is being driven by the needs of newproducts. The use of microfluidics inmanufacturing is clearly an immature yetemerging area. As reported elsewhere, thereare applications of microfluidics to be found inthe process industries – production ofnanoparticles, refining, filtration etc – and incommercial use, many in the medical field.

Product innovation companies demandcomplete systems rather than individualcomponents to meet the functionalityrequired to fulfil a specific application.Because microfluidics is still at an immaturestage of commercialisation in manyapplications, there is still considerableinnovation in the application of the technologyand the design of devices for each newapplication. This is leading to a highly diverseset of underlying materials and microfluidictechnologies and this situation will persist formany years into the future.

9.2 Examples of new technologies

and applications

9.2.1 Micro boiling heat transfer

Thermal management of small-scale devices,particularly electronics, is regarded as thebottleneck of further device miniaturisation.Researchers at Delft University looked atsmall-scale boiling heat transfer with a 4.5 mm boiling container.29 They found that

43


9 EMERGING AREAS OF MICROFLUIDIC TECHNOLOGY

29 www.ahd.tudelft.nl

the wall-water heat flux could be 10 timeshigher than large pool experiments at asuperheat of ~10 K. This is significant and maybring in innovations to thermal management.

9.2.2 Liquid-wall interactions

The behaviour of liquid flow and heat transferin microchannels depends on the propertiesof both the liquid and wall materials and theirinteractions. The presence of a secondcomponent, particularly gas, greatly affectsthe flow and heat transfer. This is not newand microfluidics device/productmanufacturers and operators know this verywell. For example, degassing the liquid isabsolutely necessary in many cases toensure a successful operation. However, howthe gas component distributes over the crosssection of the microchannels and how theywould affect the flow and heat transferbehaviour are unknown.

This has recently been addressed byscientists of the University of Twente usingthe molecular dynamics simulationapproach.30 They found that liquid-gasmixtures in contact with walls exhibit gasenrichment at the wall, and the enrichmentincreases with increasing wall hydrophobicity.For hydrophobic walls, the gas concentrationat the wall can be over two orders ofmagnitudes higher than that in the bulk liquid.The presence of the gas enrichment at thewall can modify the liquid structureconsiderably and enhances the wall slip. Theenrichment of gas at the wall region was alsoshown to reduce the surface tension.

The findings above bear significance in thedesign and operation of microfluidic devicesand could lead to innovations.

9.2.3 Fluorescence enhancementtechnology

Assay sensitivity can be an important issuefaced by scientists and engineers working inthe pharmaceutical and biotechnology areas.Attophotonics Biosciences GmbH31 hasdeveloped a fluorescence boostingtechnology termed Attophotonics REF chips.The technology is able to give 10-100 timesenhancement of the fluorescent signals thusallowing increased sensitivity, improved dataoutput and optimised utilisation of thevaluable sample materials.

The Attophotonics technology utilises thin-filmphysics and Maxwell equations as thetheoretical basis. The technology is realisedby a stable setup together with wellestablished surface chemistries forbiomolecule immobilisation. The incident fieldof an electromagnetic wave excites thefluorophores on top of the setup. Additionalexcitation derives from the reflected wave,and the enhancement in fluorescence signalis gained by a focusing effect. More photonsper fluorophore are directed towards theobjective of the analyser. The technology canbe used with the established protocols andbuffer solutions. Array scanners, fluorescencemicroscopes and standard lab equipment canbe used.

9.2.4 Micro inhaler for drug delivery

Inhalation is regarded as one of the mostpromising technologies for drug delivery. Thereare lots of R&D activities in this area withinboth academic and industrial communities.Under the brand of Respimat Soft Mist,Boehringer Ingelheim Microparts32 hasdeveloped a propellant-free inhalation devicefor the therapy of respiratory diseases. Thedevice makes use of microfabricated high-precision nozzle structures which enable

44


30 See, for example, Dammer S M and Lohse D (2006): Gas-enrichment at the liquid-wall interfaces, submitted to Condensed Matter, 0510687

31 www.attophotonics.com

32 www.boehringer-ingelheim.de/microparts

uniform nebulisation of a small dose ofmedicine in the respirable droplet size.

9.2.5 Micro electrolyte analysers forpoint of care

Monitoring of the lithium level in the blood ona regular basis is important for people onmedication for manic depressive illness.Medimate33 has been developing lab-on-a-chip technology based on the microchipcapillary electrophoresis for lithium levelmonitoring. The technology uses an electricfield across a microchannel, which enablesthe charged species to be separated anddetected in only a few seconds.

The technology only needs one droplet ofblood for the analysis and patients can use itat home so providing point-of-carediagnostics. Medimate is expected to launchthe prototype by the end of 2007.

9.2.6 Micro fuel cell technology

Micro fuel cells are small-sized power sourcesthat convert chemical energy into electricalenergy. Fuel cells operate by oxidisingcombustible fuel, such as hydrogen or alcohol.These energy sources, on a large scale, havebeen deployed in motor vehicles. Most ofthese devices use hydrogen. Recently, scaled-down fuel cells have been developed for usewith devices such as digital cameras, portableradios and notebook computers. Thesedevices use fuels other than hydrogen, mostnotably methanol. Microfluidics plays a majorrole in such technology.

Despite not playing the leading role in thedevelopment of micro fuel cells, there aresome activities in European countries,particularly in Germany, where a BMBF-fundedprogramme ‘Micro Fuel Cell’ has operatedsince 2004 with technical goals clearly defined:

• Electrical capacity <100 W • Gravimetric power density >200 W/kg• Volumetric power density >150 W/l• Energy density >1,000 Wh/l• Cost <€4/W (£3/W)• Operating lifetime >2,000 h

A number of German institutes and a fewcompanies such as Smart Fuel Cell GmbH(Munich) and 3P Energy GmbH (Schwerin) aredeveloping microfluidic fuel cell componentsand systems. Examples include:

• Fraunhofer IZM in Berlin has adapted wafer-level and foil processes, used in theproduction of high-density interconnectelectronic modules, for the fabrication oflow-cost polymer electrolyte membrane(PEM) micro fuel cells; a demonstrator of 4 cm3 volume (complete system) is claimedto yield 2.1 Wh at a current of 10 mA

• A research partnership between theUniversity of Freiburg and Micronas AG isdeveloping a 4 mm2 PEM fuel cell on alow-power chip for use in poweringautonomous sensors

• Fraunhofer ISE in Freiburg has developed aminiature electrolyser that enables metalhydride hydrogen storage units to be filledwith hydrogen quickly and at point of use;in just 12 minutes it generates enoughhydrogen from water to power acamcorder for 2 hours

• FZK’s Institute for MicroprocessEngineering and IMM are both working onmicrostructured reformers and gascleaning for a range of fuels

• Biofuel cells are being developed at IMTEK(University of Freiburg) within an EUFramework VI project ‘Healthy Aims’; thework is evaluating a direct glucose fuel cell

45


33 www.medimate.nl

(DGFC) and a mammalian bio fuel cell forlow-power medical implants (~100 µW)and integration into medical devices

• Other prototype products34

The worldwide market for micro fuel cells isexpected to increase in the coming years astechnologies improve and costs reduce.

9.2.7 Nanowires

The use of nanowires was demonstrated atTU Delft. Silicon nanowires (20-50 nm) havethe same thickness as DNA, certainenzymes, viruses etc. This could lead todetection of single viruses, antigens, proteins,toxins and be of use in the design of smartdrugs, biocides/herbicides etc. Earlierdiagnosis and online monitoring of health areshort-term applications. The ultimate goalcould be ‘proteomics on a chip’ to aid thestudy of diseases and development ofappropriate vaccines, diagnostics, drugs andtreatment regimens.

9.2.8 Lab-on-a-chip

TNO in Delft described the development of a‘lab-on-a-chip’ which could reduce the timetaken to detect agents such as anthrax from12 days via agar plates to a few hours andbelow. This is one of the major currentinterests in microfluidics, enabling DNA andprotein analysis, chemical reactions, high-throughput screening, ion/particlecharacterisation and all manner ofmixing/heating/control/separation of liquids.

9.2.9 Microporous structures

Outside the space of channel-based devices,the mission team observed that there are anumber of related applications for pores andvery small surface features. The use ofmicroporosity was discussed by a number ofthe host organisations. Potential uses include

microsieves for filtration and separation,scaffolds for tissue engineering, and self-cleaning surfaces.

A related area is in fuel cells wheremicrostructured polymer surfaces can be usedto improve the efficiency of these devices.

9.2.10 Polymer-based microfluidics

One of the key trends in microfluidics is theincreasing use of polymer-based devices.Polymers are expected to offer the lowestprice per unit for individual devices, and usingcurrently available high-volume productiontechnologies such as microinjection mouldingor hot embossing are able to manufacturedevices at costs that are suitable fordisposable applications.

According to ThinXXS in Zweibrücken, futureapplications for polymer-based microfluidicsdevices based on lab-on-a-chip technologyinclude point-of-care diagnostics, drugdiscovery and development, andenvironmental analysis (water/food/agrochemical). The main volume drivercurrently is human diagnostics, eg the blood-glucose testing market.

Exhibit 9.1 Value of the blood-glucose monitoringmarket as a function of where the test is administered

46


34 www.fuelcells.org/microTechnical.pdf

Where test is administered Value of market

Laboratory $36 million (~£20 million)

Physician’s office $500 million (~£275 million)

Self administered, home based

$1,700 million (~£935 million)

Appendix AVISIT REPORTS

A.1 British Embassy, Den HaagA.1.1 Lyn Parker – British

AmbassadorA.1.2 M Leo Zonnefeld –

Science AttachéA.1.2.1 Government

policyA.1.2.2 UniversitiesA.1.2.3 Commercial

organisationsA.2 Ralph Lindken – Laboratory for

Aero- and Hydrodynamics, DelftUniversity of Technology

A.3 Delft University of Technology A.4 TNO A.5 MESA+ Institute at Twente University

A.5.1 Twente UniversityA.5.2 MESA+ Institute for

NanotechnologyA.5.3 Microfluidics NetworkA.5.4 Technical highlights

A.5.4.1 Fluid physicsA.5.4.2 Lab-on-a-chipA.5.4.3 Membrane

technologiesA.5.4.4 Future industrial

developmentsA.5.4.5 Han Gardeniers –

BioChipA.6 Concept to Volume (C2V)A.7 Micronit Microfluidics BVA.8 LioniX BVA.9 CSEM SA A.10 Protron Microtech A.11 Bartels Mikrotechnik GmbH A.12 microTECA.13 IMM – Institut für Mikrotechnik

Mainz GmbHA.14 CPC – Cellular Process

Chemistry Systems GmbH and Synthacon GmbH

A.15 ThinXXS Microtechnology AG

47


A.1 British Embassy, Den Haag

A.1.1 Lyn Parker – British Ambassador

The Ambassador gave a brief introduction andan overview of the mission.

A.1.2 Leo Zonnefeld – Science Attaché

A.1.2.1 Government policy

Nanotechnology is one of three Netherlandsgovernment technology platforms, alongsidegenomics and ICT. The three platforms received€800 million (~£550 million) in grant aid underICES/KIS in 1999. Nanotechnology wasawarded a further €130 million (~£90 million)(2004 extended programme) and €17 million(~£12 million) in 2006. Under this nationalplatform there are three specific programmes:

• NanoNed – activities at MESA+ and Kavli)– €95 million (~£66 million)

• BioMaDe – largely in biosensors,Enschede – €7 million (~£5 million)

• MicroNed – activities directed from DelftUniversity – €23 million (~£16 million)

The mission would meet most of the keypeople involved in these programmes.

The Ministry of Education and Sciencesbelieves current regulatory structures aresufficient for nanotechnology development;however, it has been stated thatsupplementary regulations will be introducedfor nanoparticles once new toxicity modelshave been developed. Overall thegovernment believes there is no real groundfor unrest or unease. Obviously anyNetherlands action has to be seen in thecontext of the EU Action Plan for 2005-2009demanding a coherent European strategy andimplementation which takes society with it.

A cross-departmental Netherlands group hasbeen set up to create conditions for favourableand safe development of nanotechnology; this

will present a paper to parliament in July 2006and from this a Government Vision fornanotechnology will emerge. It is planned tostart a programme of public engagementwhen the Government Vision is in place.Michael Rose of UK Defra visited two weeksearlier to compare notes with his Dutchcounterparts. It would appear that the Dutchpublic is about 12 months behind the UKpublic in its awareness of nanotechnology.

A.1.2.2 Universities

The Government has announced it will beinvesting €50 million (~£34 million) in thecreation of centres of excellence, with 30 extra professorial posts being created. Thefirst step of the process is the creation of fivecentres of excellence in nanotechnology, ICT,sustainable energy, fluid and soil mechanics.The second step will be the federation of thethree TUs (3TU – Twente, Delft andEindhoven) to take effect next year.

The leading universities for nanotechnologywithin the Netherlands are:

• Twente with the MESA+ Institute forNanotechnology

• Delft with the Kavli Institute and input in MicroNed

• Eindhoven with specialist engineeringexperience

A.1.2.3 Commercial organisations

The largest companies in the Netherlands –Shell, Akzo, Unilever and Philips – are allinvolved in nanotechnology activities. Philipswith organic electronics and self-assembly ofdisplays being key new technology platformswhich have been publicly announced. Theactivities of the other companies are onlyseen through a number of universitycollaborations and funding.

A number of small companies are active in thearea – the mission would meet CV2 (Vincent

48


Spiering in Twente) involved in manufacture ofmicrosystems, optics design software andrecently OEM products for analyticalinstruments based on microtechnology; andLioniX (Rene Heideman in Twente) involved inintegrated optics and microfluidics. Theyrecently developed a capillary electrophoresischip. They work with Pirelli, Siemens, Unileverand ESTEC Noordwijk. Micronit (Ronnie van’tOever in Twente) is well known for lab-on-a-chip developments and a kit for fluidinterconnections – it has been awarded thevan Kroonenburg prize.

A.2 Ralph Lindken – Laboratory for

Aero- and Hydrodynamics, Delft

University of Technology

The Delft work on microfluidics grew out ofmacrofluidics work. The department starteddoing microfluidics work fairly recently andhas been looking at a range of differentapplications. Another activity of thedepartment is to study better process controlwhere use of scaling effects is key.

In the transfer of computational expertisefrom macrofluidics to microfluidics, thescaling effects mean that in microfluidicsdifferent forces, surface tension and viscosity,dominate compared to macroscopic systemswhere gravitational effects are key; this hasmeant that novel computational codes havebeen developed to include these forces.

The group has deep expertise in particleimage velocimetry (PIV) and has developed aµPIV technique that is able to carry out single-pixel correlation which gives very high spatialresolution. The group also make extensiveuse of stereo µPIV to give a full picture ofthree-dimensional (3D) particle flow.Epifluorescent imaging combined with µPIV isused to reduce reflections which enable goodimages to be obtained from microfluidicsystems. Image preprocessing is used toeliminate noise and get particle centres;these are then correlated to get a full 2D

velocity map – then enhance this further bylooking for movement over single pixel area.

A number of studies have been undertakenwith the enhanced µPIV technique:

• An extensive work programme is beingcarried out to characterise flow profiles atthe walls of microfluidic channels. This willallow the characterisation of the exactmagnitude of wall slip which is a keyfactor in the behaviour of fluid inmicrofluidic channels.

• The study of avian embryo hearts has beenmade possible by the use of µPIVcombined with ultrasound Dopplermeasurements to get the heartbeat. Thevelocity measurement can then be fitted tothe heartbeat rhythm. Stealth liposomesare used as tracer particles. The analysisproduces a 3D distribution of shear stresswithin the heart. The objective of the workis then to link the behaviour of the heart tothe expression of different genes, whichare manipulated to understand the linkbetween genetics and heart performance.

• Studies have been carried out onthermophoresis and thermodiffusion –basically particles move more when hot sosome of the particles move into the coldarea, where they don’t move as much, soparticles that move to the cold region don’tget out. This effect is the basis of thermalfield fractionation.

The group is setting up collaboration withTNO to investigate microevaporation which itsees as a highly promising method ofproducing high-efficiency cooling systems.

The group has been working with Philips onon-site analysis.

Work has been carried out on precipitation in amicroreactor, with a tortuous mixing/nucleationregion followed by a long growth region and

49


then a quench region where a cold channel isused to kill the reaction. An antisolvent isintroduced to bring the salt fully out of solutionand allow separation. This is achieved on asingle glass chip.

A.3 Delft University of Technology

The team first visited the Delft Centre forMechatronics and Microsystems located atDelft University of Technology. Professor vanKeulen gave a brief introduction to theUniversity, the Centre and his own research,followed by a presentation by Professor VanRijin and discussion.

The University was founded in 1842. It nowemploys 4,700 staff members and has~14,000 students. The university has facultiesand takes ~180 PhD students a year. TheDelft Centre for Mechatronics andMicrosystems involves ~100 full-timeequivalents (FTEs). It has four cluster areas,including precision motion (nano-scaleprecision), precision bio-nano, andmicrofabrication. Facilities are shared acrossthe centre. It is a virtual centre with PhDs andpostdoctoral research associates (PDRAs)shared by different groups. Equipment canonly be purchased if several groups expresscommon interest.

Professor Keulen also briefly describedMicroNed, a network comprising ~30 researchcentres and industrial partners, with funding of€56 million (~£39 million) for 2010 with 50%met by industrial companies. MicroNed hasfour clusters: SMACT (wet microsystem),MUFAC (micofactory), FUNNMOD (modelling)and MISAT (microsatellite).

Professor Keulen briefly described his ownresearch on modelling and optimisation usingmultilevel optimsation.

Professor Cees Van Rijn presented hisactivities, particularly the spin-offs he helpedto set up, eg Microfiltration BV, Medspray

Drug Delivery BV, Nanosens BV, LotusPolymer Moulding BV. He highlighted ultrafastfiltration using nano and micron membrane(Microsieve), and demonstrated theapplication areas of the filter, eg milk andbeer. The use of microsieve could process aliquid flux of ~8,000 l/m2 h and reduce thecost of filtration from ~€0.75 (£0.52) to~€0.25 (£0.17) per hectolitre (hl) of beer.

Professor Cees Van Rijn also briefly introducedtechnologies of emulsion, porous capillarybreakup, nanowire biosensors and biochips.

A.4 TNO

The team then visited the Industrial Modellingand Control department of TNO Science andIndustry located in Delft, where threepresentations were given by TNO personnel:

Dr Heri WerijManagerIndustrial Modelling and Control

TNO is a national research organisation. It is acompany but receives funding from theGovernment. It has five core areas:

• Quality of Life• Defence, Security and Safety• Science and Industry• Built Environment and Geosciences• ICT

The area of Science and Industry consists ofnine departments:

• Materials Technology• Design and Manufacturing• Micro Devices Technology• Opto-mechanical Instrumentation• Industrial Modelling and Control• Imaging Systems• Automotive• Testing and Consultancy• Holst Centre

50


TNO employs about 5,000 people and has an annual turnover of ~€550 million (£380 million) of which one third is from Government funding and two thirdsfrom sales.

TNO Science and Industry employs ~1,000people (excluding hired staff) and has anannual turnover of €112 million (~£77 million).

TNO Science and Industry has been workingin areas such as:

• High-end equipment for ultrapreciseproduction and measurements – TNO isthe preferred R&D supplier of ASML(microchips), supplying equipment andtechnologies for micro and nanolithography, optics, precision mechanics etc

• Optimising production for the processindustry – flow and structural dynamics,process modelling and control, separationtechnology and acoustics

• Innovations in materials – materialperformance, multilayer devices, surfacesand coatings

• Smart manufacturing• Mobility and transport safety

TNO and Delft are investing €17 million (~£12 million) in building a joint centre forMNT. New facilities are shared by the twoorganisations and are for open access.

Cor RopsProcess Systems and Processes DivisionIndustrial Modelling and Control

Mr Rops – who is a TNO employee but is doinga PhD at Delft – gave several examples ofprojects that TNO is or has been working on:

• Micro heat spreader – aiming atdeveloping a technology that has a coolingcapacity exceeding 1 MW/m2, low mass,high reliability and can be space-proven;getting space-proven is difficult

• Micro evaporator – a project withQinetiQ aiming to increase the heattransfer capacity and to enhanceoperational stability

• SAMPRED – sample preparationtechniques for detecting warfare agentsand bioagents

Christophe HoegaertsProject managerIndustrial Modelling and Control

TNO is not a technology push but rather anindustrial pull.

There is a JV between TNO and iMac.

A.5 MESA+ Institute at Twente

University

A.5.1 Twente University

Professor Henk Zijm, Rector Magnificus ofTwente University, explained how the rapidloss of 125,000 textile worker jobs aroundEnschede in two decades was a primaryimpetus to establish the university. Heoutlined how the board was industriallydominated and extolled the entrepreneurialethos that pervades the university wherebudgets for research groups (staff andinfrastructure) are output based, respondingrapidly to changing scientific and technicalopportunities and priorities.

A.5.2 MESA+ Institute of Nanotechnology

Professor Kees Eijkel is Technical CommercialDirector of the MESA+ Institute ofNanotechnology which is now aninternationally recognised centre. MESA+was originally founded on sensor-actuatortechnologies and a very strong focus onmicrofluidics. This stems in part from thepioneering research of Professor PietBergveld who invented the ion-sensitive field-effect transistor (ISFET) whilst at the Institute.MESA+ accommodates 450 people (60%

51


temporary), has 20 chairs and is one of theleading European players in the field ofmicrofluidics. It is funded by an annual budgetof ~€31 million (£21 million), 50% of which isderived from industry.

Developing the theme of Twente as theentrepreneurial university, Professor Eijkelexplained how MESA+ has taken a leadingposition in the development of MNT in theNetherlands, for example as founder ofMINAC35 which is the Dutch microsystemsand nanotechnology supply chain cluster thatundertakes coordination and promotion ofresearch and education.

Additionally, Professor Eijkel outlined the themeof how MESA+ had developed a strategy forrapid business formation through its acceleratorMESA+ International Ventures Ltd (see Chapter8). Significantly, he highlighted the lack of acentrally orchestrated technology transfer officefor the university as a key success factorcontributing to the 33 businesses that havespun out of MESA+ over the last 15 years.Thirteen of these companies are active alongthe microfluidics value chain, including (directly)IBIS, Aquamrign, C2V, LioniX, Micronit,Medspray, Immunicon, Nanomi, CapiliX,Medimate and (indirectly) Sentron, Nanosense,EMI, Optisense.

Extensive facility sharing (the local MNTecosystem) between research groups andwith industry was shown to be a veryimportant success parameter. The current1,250 m2 comprehensive clean-roommicronanofabrication facility, which is sharedby academics and industry on a swipe-cardfee-paying basis, is now being supplementedby a completely new clean-room facility thatwill be built adjacent to the existing one.

The success story of MESA+ has been duein part to the long-duration commitment ofsupport received from the regionaldevelopment agency. Albert Hoogeveen,senior project manager for foreigninvestments, explained how there was anintimate day-to-day liaison between MESA+operations and his regional office inEnschede, ensuring that the Institute isefficiently and effectively promoted andsupported. Additionally, he detailed how pre-seed financial support could rapidly be madeavailable to develop fledgling business ideasinto viable business propositions.

With a wider overview, Mr Hoogeveenshowed how the Netherlands had identifiedfood, health and technology as its ‘triangle’ ofindustrial priorities, with Twente Universityacting as a focus for its ‘Techno Valley’(highlighting biomedical engineering,nanotechnology, ICT, tissue engineering,rehabilitation and minimally invasivediagnostics). He identified interdisciplinary‘collaboration’ and effective industrial-academic relations as the cornerstone tofuture success.

A.5.3 Microfluidics Network

Dr Richard Schasfoort provided an overview ofthe Dutch Microfluidics Network led byTwente University. This is a priority networkingplatform within the umbrella projectMinacNed36 which has a wider role in MNT.

The Microfluidics Network is an inclusivesupply chain network of ~50 organisationswhich acts to enable a coherent visibility of technology providers to end users.Approximately 60% of the partners areindustrial, ranging from micro enterprisessuch as Aquamarijn BV and LioniX BV to large corporates such as Philips and Texas Instruments.

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35 www.minac.nl

36 www.minacned.nl

The principal activities are to provide a portalto Dutch activities in microfluidics, promotefacility sharing, entrepreneurial ventures andfacilitate new R&D and technology transfer.

A.5.4 Technical highlights

Several key presentations provide a snapshotof the extensive research activitiesundertaken at the MESA+ Institute:

A.5.4.1 Fluid physics

The fluid physics research group led byProfessor Detlef Lohse undertakes theoretical,modelling and experimental research on fluidmotion, surface interactions, particle movementand, in particular, bubble phenomena.

A custom, high-speed framing cameraemploying a helium-driven turbine rotating atspeeds of up to 20,000 Hz provides a uniquetool for experimental investigations. Theinstrument is equipped with 128 charge-coupled devices (CCDs) allowing image captureat rates up to 25 million frames per second.

The group specialises in sonic-inducedphenomena, especially the role of bubblebehaviour at boundaries such as cellmembranes and fluidic duct walls. Researchteams range from interest in macroscopic(Navier Stokes) to mesoscopic (LatticeBoltzmann) and microscopic (moleculardynamics) effects. The research investigatessome of the fundamental questions (egliquid-surface interactions at the nano-scale)which will underpin future more applieddevelopments of microfluidics.

A.5.4.2 Lab-on-a-chip

The Lab-on-a-Chip Group (BIOS) is led byProfessor Albert van den Berg, who holds adistinguished international reputation in thefield. His colleague Dr Han Gardeniers (see also Section A.5.4.5) provided some‘snapshot samples’ of research themes with

a highly selective overview of microfluidicsfor chemical processing. Thesedevelopments included:

• Integrated microsensors (pH, CO2,biomass) for process control of bioreactors

• Chip-based microcoil NMR detector for on-line analysis of chemicals synthesis

• PDMS (polydimethyl siloxane) split-and-mixmicrofluidic reactor arrays

• Micromachined chip-based monolithic(packed) HPLC (high-performance liquidchromatography) columns

• High-pressure chips for use withsupercritical fluid-based chemistry

A.5.4.3 Membrane technologies

The Membrane Technology Group takes aninterdisciplinary approach to molecularseparations (filtration and emulsification) bycombining the disciplines of colloid interfacescience, materials science and processing,mass transport modelling, systems anddevice integration. The Chair in Membraneand Interface Science is held by ProfessorMathias Wessling, who outlined the severalresearch themes orientated on applications topharmaceuticals, gas, water, chemicals,petrochemicals and food.

In particular, the technique of phase separationmicromoulding was considered in some detail.This is a new versatile replication method toproduce thin polymeric microfluidic deviceswith tunable porosity. The method is based onphase separation of a polymer solution on amicrostructured mould. Compared to existingmicrofabrication techniques, such as etchingand hot embossing, the technique offers four advantages:

• A simple and cheap process that can beperformed at room temperature outsideclean-room facilities

• Very broad range of applicable materials(including materials that could not beprocessed before)

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• Ability to make thin flexible chips• Ability to introduce and tune porosity in

the chip

By introducing porosity, the channel walls canbe used for selective transport of gases,liquids and solutes. This leads to the on-chipintegration of multiple unit operations, such asreaction, separation, gas-liquid contacting andmembrane emulsification. Using a hollow-fibrevariant, the production of monodisperseemulsions with droplets ~1.4 times capillarydiameter were shown. This appeared to holdconsiderable near-term application potential inmany fast-moving consumer products.

A.5.4.4 Future industrial developments

Discussions resulting from the presentationsfocused on how microenterprises developingmicrofluidics could identify the mostappropriate application and target end-usercompanies for their technologies. Whilstapplications in point-of-use diagnostics hadbeen prominent in the past it was consideredthat future mass-market applications may beless immediately obvious. The examples ofelectrowetting lenses for mobile phonecameras and microfluidic large-area‘diagnostics displays’ using flat-paneltechnology were cited.

A.5.4.5 Han Gardeniers – BioChip

The BioChip group at Twente has beendeveloping a range of microfluidics forchemical processing, based on glassmicroreactor technology. In order tomanufacture the microfluidic devices they usethe MESA+ facilities.

A novel high-pressure microreactor has beendeveloped which needs no containment as apressure reactor, allowing a full high-pressurelaboratory to be run on an open laboratorybench. The microfluidic system is able toachieve 700 bar and is able to carry outreactions in supercritical CO2.

Dr Han Gardeniers is a member of BIOS –the Lab-on-a-Chip Group directed byProfessor Albert van den Berg, one of the keydevelopers of the original lab-on-a-chipconcept 20 years ago.

A variety of other projects within BIOS areaimed at developing chemical solutions:

• ChipChemStation – on-line kinetic studiesof organic reaction in a chip by massspectrometry

• Fed batch on a chip – the development of anew technological platform to performcontrolled fed-batch fermentations in avery small volume (50-300 µl) arranged onplates (eg 96 or 384 wells)

• PicoASPECT – on-chip cleavage ofpeptides with analysis of the resultingfragments by mass spectrometry

• Versatile micro NMR

The BIOS group also uses a range of differenttechnologies to produce ‘chips’; silicontechnology, via use of the MESA+ facilities,allows the production of chips with integratedsensors as reactor which allow themeasurement of pH, dissolved oxygen,biomass etc to be carried out in situ; PDMS,simple in laboratory fabrication, is used forrapid microfabrication of passive chips; moresophisticated fabrication technologies arebeing used to produce chips with nanopillarswhich allow micromachined HPLC columns tobe fabricated.

A.6 Concept to Volume (C2V)

PO Box 3187500 AH EnschedeNETHERLANDS

T +31 534 889 889F +31 534 889 890www.c2v.nl

Employees: N/AAnnual growth: N/A

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Profile

C2V supplies high-added-value OEM productsfor analytical instruments and detectors, forsecurity, life sciences and process controlapplications, using MEMS technologies andits microDELTA integration platform. Thesecomprise:

• Microanalytical components • Microchromatograph components and

systems – HPLC, micro gaschromatography (GC)

• Microfluidic components and integratedsystems

• Microvalves and microvalve arrays • Micro flow sensors, nanomixers, nanofilters • Micro nozzles, sprayers, actuators/

positioners

Customers

C2V often works on a customer-specifiedbasis. Its customers operate in security, lifesciences, industrial process control, telecom,and space markets and are locatedworldwide. The customer profile variesbetween large multinationals and SMEs. Italso works for research institutes enablinguniversities to perform leading-edge researchby providing customised tools such asinnovative hardware as well as its softwaretools. The projects are divided into milestonesconnected with deliverables, in order tominimise risks and costs.

Business model

C2V is an OEM product supplier of high-added-value custom MEMS and integratedoptics products and services, offering:

• Design to manufacturability • Supply of products in variable volumes • Industrialisation of specific processes

and packaging • Software toolkit supporting design

and manufacturing

Clean room

C2V process engineers and operators work ina 1,030 m2, four inch clean-room facility,where the wafers are handled in a class 100environment. The clean room is fully equippedwith all necessary apparatus and processfacilities. The largest part of the clean room isdedicated to MST to make MEMS devices.

Assembly and test facilities

C2V has a qualified precision engineeringteam with focused experience on micro andminiature packaging and assembly services.These activities fit into a systems integrationapproach or design for manufacturingapproach, where they assist in the wholedevelopment cycle from early concept to(high) volume production.

C2V’s precision engineering capabilities areoffered to achieve solutions which satisfycustomer design problems and productionneeds. The precision engineering capabilitiesenable integration on the system level, oftenleading to higher yields and lowermanufacturing costs. Its precision engineeringservices are part of MEMS developmentprogrammes, or are stand-alone projects.

A.7 Micronit Microfluidics BV

Hengelosestraat 7057521 PA EnschedeNETHERLANDS

T +31 53 483 65 [email protected] www.micronit.com

Employees: 25Annual growth: 50-80%

Profile

Micronit focuses on lab-on-chip development,design and production. It is capable of rapid

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prototyping of microfluidic chips. These chipsare available in various dimensions, createdwith several techniques and different materials.

The company serves customers worldwide,mainly in Europe and North America. Marketsserved are pharmacy, biotech and finechemicals, and are large multinationals, start-up companies, institutes and universities.

With a combination of its standard products,technical capabilities and knowledge,Micronit develops microfluidic devices for avariety of applications.

Facilities

For the majority of production, Micronit has itsown clean-room infrastructure. There is an in-house powderblasting line and a class 1,000clean room capable of producing up to 500,000glass chips per year. Micronit also hires clean-room space at the MESA+ Institute. In thisspace Micronit manages its own pilot line forrapid prototyping and medium-volumeproduction. Equipment includes a mask aligner,an aligned bonder, etching equipment, wetbenches, programmable hot stages, annealingfurnaces etc.

Other capabilities

Silicon processes supported are plasma-enhanced chemical vapour deposition(PECVD) and low-pressure chemical vapourdeposition (LPCVD), deep reactive ion etching(DRIE), potassium hydroxide (KOH) etching ofsilicon, anodic and direct bonding,electroplating, dicing etc.

Micronit entered the Dutch DeloitteTechnology Fast 50 in 2005 in thirteenthposition, as the only MNT company in theranking. The world market leader indeveloping and fabricating glass microchipswas ranked that high thanks to its strongturnover growth. Over the period 2000-2004,turnover grew no less than 1,157%.

A.8 LioniX BV

PO Box 4567500 AH EnschedeNETHERLANDS

T +31 53 489 3827F +31 53 489 [email protected] www.lionixbv.nl

Employees: 22Annual growth: N/A

Profile

LioniX is a leading provider in developmentand small- to high-volume production ofleveraging and innovative products based onMST and MEMS. Its core technologies areintegrated optics and microfluidics.

Customers

Its customers operate in telecom, industrialprocess control, life sciences and spacemarkets and include OEMs, multinationalsand VC start-up companies as well asresearch institutions from around the world.

Strategy

LioniX offers design for manufacturing andhorizontal integration by partnering withMEMS/MST foundries and suppliers ofcomplementary technologies. Cooperationsare based on subcontracting, licensing ofintellectual property rights (IPR), or JVs.

IPR

LioniX has an IPR agreement on technologywith the MESA+ Institute and is rapidly buildingup a firm IPR position in its core competencesintegrated optics and microfluidics.

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Facilities

LioniX uses state-of-the-art facilities of theMESA+ Institute. In addition it has its privateclean-room facilities with equipment for itsproprietary technologies.

Additional notes

ChemtriX, a JV between LioniX and theUniversity of Hull, was set up in December2005 to manufacture glass chemicalmicroreactor systems. Paul Watts, who iscurrently CEO from the University of Hull,provides the chemistry expertise and LioniXprovides the manufacturing experience toproduce the glass microreactor components.The company’s initial aim is to produceproducts derived from the product line ofanother LioniX JV, Capilix, which manufacturescapillary electrophoresis microfluidics.

The initial product will be based on a Capilix‘chip’ holder which contains both fluid andelectrical connections into which the desiredmicroreactor chip is connected. This allowsmicroreactor chips to be produced usingstandard microsystem techniques and then allthe external connections are handled bydocking with the chip handler. Scale-out willbe achieved in the first instance by using acomplete glass wafer which contains tenchips without dicing to produce a tenfoldscale-out. Further scale-out will be achieved bystacking completed wafers into a matrix whichcould contain 100 microreactors in parallel.

The technology inheritance from LioniX toChemtriX means that ChemtriX is able toincorporate electrodes and optic-fibreconnections with ease. It is working onincorporating Peltier elements, so that thechip can be both locally heated and cooled.

A.9 CSEM SA

CSEM SA, the Swiss Centre for Electronicsand Microtechnology, is a privately held,knowledge-based company, active in the fieldof MNT, microelectronics, systems engineeringand ICT. It currently employs around 250people and has research centres in Neuchâtel(headquarters), Zurich and Alpnach.

The company is subsidised by the SwissGovernment, which provides about 25% ofits finance. Other financial incomes are fromEU and regional projects, as well as industrialprojects. CSEM is not a profit-drivenorganisation – it reinvests heavily in order tostay ahead of the technologies. It releasesthe technology know-how to the market bygenerating spin-off companies – 22 spin-offsin the past five years.

CSEM has a microfluidics team with about 10people, mainly working on separating andhandling of cells, and smart chips forbiochemistry analysis and environmentalmonitoring. According to Dr Krieger, CSEM’sMarketing Manager, its technical strength is insystem integration, ie putting optics, electronicsand microfluidics devices into a single systemto achieve specified functionalities.

Dr Krieger also emphasised that the companyis interested in applying its knowledge in themass production market, and intends toachieve that through collaborations –competing is not the way to survive in thisstill small market; small companies shouldfind a way to work together instead ofcompeting with each other.

Q: Is the Swiss microfluidic network useful inthe sense of finding customers for SMEs?

A: Without the network, everyone actsindividually, no-one knows what other peopleare doing and there are a lot of confusions. Inthis sense the network is useful. However,the cost of transferring functional prototypes

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to mass production has been tremendouslyunderestimated by most people. This hindersthe progress of SMEs, and the network is notthat helpful in this aspect.

A.10 Protron Microtech

Starting from 1999 the company hasexpertise in microfluidics, micro-optics andRF-MEMS. Its current focus is on silicon-based devices, mainly for two reasons:

• Polymer-based microfludic devices areunsuitable for chemical reactionapplications due to material instability

• Silicon can be processed into ultrafinestructures which are unachievable in anyother material

Its customers are from the USA and Europe,mainly Germany. Most customers useProtron’s microfluidic devices for researchpurposes and for making DNA chips.

Q: How do you compete for the market andthe killer application?

A: It is a growing market. Biotech companieswere going downhill two years ago; however,they are now getting stabilised and themarket is coming back. Protronhas achieved more than 15% annual growthin the past couple of years. So far, theInternet has been the best marketing channelfor the company.

A.11 Bartels Mikrotechnik GmbH

The company started about 10 years ago byusing an excimer laser to structure plasticmaterials. Recently it has developed thepiezoelectric-based micropump, which isentirely fabricated out of plastics except the piezo-diaphragm. It currently employs25 people.

The specifications of the micropump are:

• Size: 14 x 14 x 3.5 mm• Weight: 0.8 g• Lifetime: >9,000 h• Power consumption: 0.08 W, with battery

life of 72 h for continuous operation• Pumping pressure: 0.5 bar• Flow viscosity: 120 mPa s• Particle tolerance: < 50 mm• Flow rate: 50 nl/min to 5 ml/min for liquid,

50 µl/min to 15 ml/min for gas

The cost of the micropump could potentiallygo down to €1 (~£0.69) for volumeproduction (2 million units).

Other products from this company aremicrovalves, capillary electrophoresis (CE)chips and nanowell plates.

A.12 microTEC

Gesellshaft für Mikrotechnologie mbHBismarckstrasse 142bD-47057 DuisburgGERMANY

T +49 203 306 2054F +49 203 306 [email protected] www.microtec-d.com

The microTEC stand at Hannover Fair wasvisited on 26 April 2006 at the invitation ofthe CEO/CFO Andrea Reinhardt, anddiscussions were held with joint CEO/CTOand founder Dipl-Ing Reiner Götzen and withDr Helge Bohlmann.

The business of microTEC is in the use of itsproprietary microsystems rapid-prototypingtechnology (RMPD) based on direct-writemethods. In addition to its establishedservices in micromechanics and microsystempackaging, microTEC is building a distinctoffering in lab-on-a-chip device fabricationfrom computer-aided design (CAD) to series

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production. As with most of the companiesvisited employing polymer technology,microTEC is looking to benefit from thegrowth opportunities in diagnostics. It seeksto provide expertise in function integrationand to deliver the product volumes requiredcost effectively.

The mission team is grateful to AndreaReinhardt for her input to the study of start-upstimulation measures and her experience infunding microTEC through a combination offounder’s contributions and, in the case ofmicroTEC, the use of bank funds and equity.This again highlighted the relatively low use ofVC funds in both the Netherlands andGermany. The importance of obtaining a mixof skills and genders to create an effectivemanagement team was noted. Also, studieson entrepreneurship highlighted that spin-outsresulting from large companies, including as aresult of restructuring, had an important roleto play as well as university start-ups.

A.13 IMM – Institut für Mikrotechnik

Mainz GmbH

Personnel

Dr Klaus Stefan DreseHead of Fluidics and Simulation Department

Company background

IMM is an application-oriented R&Denterprise whose aim is to bridge the gapbetween academic research and industry inthe fields of:

• Chemical process engineering• Bio-microfluidics• 3D microstructuring techniques• Fuel processing

An emerging fifth area of research is inpolymer-hybrid technologies (especiallyconducting polymers).

IMM was established in 1991 by the localgovernment under the leadership of Prof IngWolfgang Ehrfeld (coming from FZK).

Website

www.imm-mainz.de – this contains a lot ofinformation, including the IMM catalogue ofmicroreactors.

Vital statistics

• Turnover: ~€11 million (£7.6 million)• Employees: 119• Ownership: public (German federal state of

Rhineland-Palatinate) • Funding: 1/3 State, 1/3 industrial projects,

1/3 public projects• Profit: non-profit organisation• Spin-offs: ~11, creating more than 200 jobs

in Rhineland-Palatinate• Education: >1,000 people have done

internship and research at IMM• Projects: >800 high-tech projects

completed • Partnerships: extensive list of academic

and industrial collaborations

The company is strongly market oriented and,apart from PhD students, the majority of theactivities are industry driven, including publiclyfunded projects.

Given the legal structure the company cannotmake more than 7% of turnover from directsales.

Notable spin-offs are Microglas, CPC andEhrfeld Mikrotechnik.

Up to 80% of personnel time is dedicateddirectly to projects (the rest being meetings,writing research papers, maintenance, andother non-project activities).

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Chemical process engineering

IMM’s major competence areas are:

• Chemical process development• Component and process simulation • Mixing technology • Organic, fine and functional chemicals

synthesis• Catalyst preparation and testing• Energy generation and heat management• Fuel processing• Customised and off-the-shelf components • Customer-specific plant design and

construction• Unitised fluidic-bus for microstructured

devices

IMM publishes a quite extensive catalogue ofmicrocomponents that it sells on the openmarket (available on the website). The aim ofthese sales is not profit but a service to theindustry. To avoid competition with its spin-offMikroglas, IMM does not offer glass.

Among the many products are the slitinterdigital micro mixer (SIMM) which usesmultilamination and geometric focusing andhas been used by a large number ofcustomers and is manufactured by advancedsilicon etching (ASE); the high-pressureSIMM, resisting up to 600 bar; and theCaterpillar Split-Recombine Micro Mixer. A mixer more oriented to production is theStar Laminator, which is offered in flowsranging from 300 l/h to 30 m3/h; also themicro falling film reactor and micro bubblecolumn reactor; and microchannel heatexchangers are produced by diffusion bondingin collaboration with Heatric.

Some examples of applications are: creammanufacturing pilot plant to perform 8-15component mixing with microstructuredmixers; table-top plants for fine and specialitychemicals; lab-scale plant for catalyst testingfor propane steam reforming; and pilot-scaleplant for iso-octane reforming (5 kW).

Success stories from IMM include theSeptember 2005 start-up of a plant in Chinafor the production of nitroglycerine formedical applications (15 kg/h) for Hi-anChemical Industrial Group (HAC).

Fuel processing


• Design, fabrication and testing of reformersfor methanol, propane, octane

• Catalyst screening reactors• Selective oxidation reactors• Water-gas-shift reactors• Heat exchangers• Evaporators• Preparation of catalyst coatings on

microstructured devices• Catalyst/reactor testing

Power range of the device is between 100 Wand 10 kW.

Microstructuring technologies


• Deep lithography• Photolithography• Etching • Micromoulding• Diffusion • Deposition• Plasma treatment• Micrometrology• Laser micromachining• Mechanical micromachining

IMM’s facility includes several fabricationlaboratories.

IMM is also active in the field of sensors,including optical sensors. An exemplar wasgiven in the area of developing cost-effectivesensor systems for ultraviolet-visible (UV-VIS)and near infrared (NIR) radiation.

One microfluidic development has beenpresented in detail, namely the chip-based-lab, whose code name is ‘1 week 2 chip’,meaning that the development process is sooptimised that with only an idea on Monday,the first tests on the actual chip can beperformed on Friday, vs a typical developmenttime of half a year.

The goal is to speed up to the maximum thedevelopment time for the microfluidicinfrastructure in order to focus more on thebiology and the actual fluidics.

The goal has been achieved by usingstandardised assembly process andstandardised components.

General discussion

A very important and time-consuming aspectof microfluidic development is IP mapping.

Future for materials: for disposable this isplastic (as a cost of less than €1/pc (£0.69/pc)is needed); for microreaction technology it isstainless steel (can go up to 900oC, andplastics at the same characteristic cost€1,000/kg (~£690/kg)).

Successful start-ups in the field of microfluidicsare often bought by bigger companies (exampleof Microparts, acquired by Boehringer).

VC in Germany is tight, while it is relativelyeasy to find partners, technology andinfrastructure. Usually the VC comes from theUK or Switzerland.

The focus in the industry is moving fromtechnology push to application pull.

The microreaction field is less developed thanthe microfluidic/bio field and is usually drivenby chemical companies that want betterquality and simpler processes. The mostinterested companies are into fine chemicalsrather than bulk production.

Fuel processes are becoming more and moreinteresting because of the needs in theautomotive industry.

A.14 CPC – Cellular Process Chemistry

Systems GmbH and Synthacon

GmbH

www.cpc-net.com www.synthacon.biz

Personnel

Heinz J Benninghoff Sales, CPC

Ansgar Kursawe R&D, CPC

Martin J H Leitgeb CEO Synthacon

Company background

CPC was established in 1999 as a spin-offfrom IMM. Synthacon was established in2004, acquiring pilot capability from CPC. Thetwo companies work together, and CPCowns 20% of Synthacon.

CPC owns the patents (17 families ofpatents filed) and manufactures the reactors,while Synthacon provides custom synthesisand custom manufacturing based on CPC technology.

Vision and mission

The vision for the foundation of CPC was:‘seamless small molecule synthesis fromdiscovery through to manufacturing’, and itsstated mission is: ‘accelerate drug developmentand eliminate synthesis transfer risk’.

Vital statistics

• Turnover: ~€2 million (£1.4 million) for CPC,~€1 million (£0.7 million) for Synthacon

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• Employees: 10 CPC, 20 Synthacon• Ownership: private• Funding: undisclosed• Profit: undisclosed• Projects: ~40 research units sold to

chemical companies and universitiesglobally; at least one customisedmanufacturing system sold to Clariant (forproduction of pigments of improved quality)

Technology

CPC is specialised in microreactiontechnology. The heart of CPC is the patentedCYTOS microreaction technology. CYTOS is astandard and highly optimised integratedpreheater, mixer, cooler, residence-timemodule, assembled by metal diffusionbonding. It comes in three sizes, each onetargeted at a specific stage of the moleculedevelopment process (Exhibit A.1).

Exhibit A.1 CPC’s CYTOS modules

The technology uses massive parallel scale-up, ie there are more channels in the biggerversions but the fundamental transformationsare the same, so the behaviour is identical.Within the ranges the scale-up concept isseveral times proven by CPC.

The M System is particularly indicated inthose conditions where there is an extremelylimited or expensive supply of reagents.

The reactor is integrated in a fully controllablemodule that can automate up to 50 differentreaction conditions, with flows from 20 µl/minto 2 ml/min, temperature between -60 and300oC, including sequential synthesis.

The Lab System is more flexible and the flowrate is higher. Residence time modules up to135 min can be added.

The Pilot System actually comprises 11 parallelLab modules, each independently controlled.

Technically, the advantage of performing areaction in a microreactor is stemming from:

• Mixing: very fast and uniform mixing bydiffusion; typical reaction channel is 200 µm diameter, and one of theingredients is added in a series ofopenings of ~60 µm at the beginning ofthe channel; this creates a series ofstriations with a dimension of 30 µm,where diffusion mixing is facilitated

• Heat transfer: greatly improved thanks tothe high surface-to-volume ratio; the heattransfer coefficient is ~2,800 W/m2 K (or 30,000 kW/m3 K; for comparison aMettler-Toledo reaction calorimeter RC1has 7 kW/m3/K)

• Small volume: flame-arresting effect ofmicrochannels coupled with very smallhold-up of reagents; the Pilot System israted at up to 6 bar

The consequences on the production arebetter yields and selectivities, potentiallyresulting in lower costs, fast time to marketand improved safety (including ability tohandle unstable intermediates).

The CYTOS modules are not recommendedin case of:

• Slow reactions• Reactions starting or finishing with

suspensions• Reactions using or generating gases

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Module Experiment size Application

CYTOS M System

200 mg – 20 g Route scouting,library synthesis,processdevelopment

CYTOS Lab System

2 g – 20 kg Processdevelopment, kgsynthesis, buildingblocks

CYTOS Pilot System

20 kg – 20 t Fast 100 kgproduction

CYTOSProduction

2,000 t/y

• Incompatibility with stainless steel orhastelloy

• Highly viscous liquids (microtechnologyallows operation at higher temperature,which lowers the viscosity)

A.15 ThinXXS Microtechnology AG

Amerikastrasse 21 66482 ZweibrückenGERMANY

T +49 6332 8002 10F +49 6332 8002 [email protected]

On Friday 28 April 2006 the mission washosted by the co-founders of the company,Dr Hans-Joachim Hartmann who presentedthe company and Dr Lutz Weber who led thetour of the facilities.

The Zweibrücken site was occupied by IMMat the request of the local region and linkedto the local university, colleges and schools toassist with inward investment and jobcreation after the withdrawal of militarypersonnel at the end of the Cold War. Thismodel of locating microfluidics activity in oldbarracks has been followed elsewhere inGermany in the area of Freiburg, where HSG-IMIT is linked to the University of Freiburg.

IMM relocated its polymer micromouldingcapability including precision mould toolfabrication and injection moulding machines.The founders and employees (12) of ThinXXSwere previously employed by IMM; in thecase of Dr Hartmann for 10 years where hewas previously head of microfluidics.

The company’s initial funding was supplied bythe founders using the Government’sunsecured loans programme to stimulatestart-ups. Funding has also been obtainedfrom ‘Pricap’, which is a group of 20-30individuals. One of these individuals hasbecome personally and proactively involved.

ThinXXS has access to the facilities of IMMon an open-accesss basis and has locatedThinXXS machinery and employees in theIMM facility. ThinXXS was established toprovide a route to manufacture using IPlicensed from IMM.

The history of the company, since beingestablished in 2001, has been to work withOEMs on a development contract basis andto provide a route to component and modulemanufacture to meet the needs of thecustomers it has worked with during theproduct development phase.

The company is focused on supportingemerging microfluidics applications wherethere is forecast to be a requirement for highvolumes of components. These are marketsdriven by the expectation that healthcarediagnostics and environmental monitoring willbecome increasingly decentralised andportable, involving analysis of increasinglysmaller sample quantities at the point of useand care. However, currently as elsewhere,its current customers are developing lab-on-a-chip devices mainly for in-lab use.

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B.1 David Anthony BarrowB.2 Martin James DayB.3 Yulong DingB.4 Yiton FuB.5 Simon Robert GibbonB.6 Timothy George RyanB.7 Alberto SimoncelliB.8 Nicola Smoker (ITP)B.9 Julian Darryn WhiteB.10 Kevin John Yallup

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Appendix BMISSION TEAM AND ITP CONTACT DETAILS

B.1

David Anthony Barrow

Research Professor

metaFABCardiff UniversitySchool of EngineeringCardiffWalesCF24 3AAUK

T +44 (0)29 2087 5921F +44 (0)29 2087 [email protected] www.metaFAB.netwww.engin.cf.ac.uk

Founded in 1883, Cardiff is internationallyrecognised as being among the very top tierof Britain’s research intensive universities andis a member of the prestigious Russell Groupof leading universities. It has over 5,000employees engaged in teaching and research.

DTI has established a network of openaccess facilities in MicroNanoTechnology(MNT). metaFAB is a new MNT networknode and integrates the resources of diverseresearch centres and supply chain partners tooffer innovative, high-level solutions basedMNT convergence.

One strong component of metaFAB is itsmultidisciplinary activities in microfluidics andthe new metaFAB Extreme Laser Facilitywhich features a unique dualfemtosecond/157 nm excimer lasermachining station. This is ideal for rapidmicromachining of fluidic structures in UVtransmissive materials such as fused silicaand fluoropolymers.

Platform technologies

• Multiphase microfluidics, encapsulation• 157 nm laser micromachining

Areas for potential collaboration

• Emulsion formation• Microseparations devices• Laser micromachining of fluidic devices

from fluoropolymers• PEEK• Fused silica• Microreactor scale-out• New company formation

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B.2

Martin James Day

Sales & Marketing Director

Carclo Technical Plastics47 Wates WayMitchamSurreyCR4 4HRUK

T +44 (0)208 685 5116F +44 (0)208 640 [email protected] www.carclo-plc.com

Carclo Technical Plastics specialises ininjection moulding and assembly of high-volume diagnostic, optical, medical andpharma applications. It is a service companythat manufactures for blue chip OEMs inEurope and the USA.

Turnover is £16 million with 250 employees.Facilities are based in Mitcham, SouthLondon and Slough. Group facilities arelocated elsewhere in the UK, USA, CzechRepublic, China and India.

The business also focuses on technologydevelopment and has a large engineeringstaff to support this direction.


• Injection moulding• Assembly• Plastics welding• Plastics printing• Optical design• Mould tooling• High-quality optical polishing• Optical coating• Plasma coating• Ink-jet deposition


• Fine feature tooling• Optical design and readers• Surface coating

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B.3

Yulong Ding

Senior Lecturer

University of LeedsClarendon RoadLeedsWest YorkshireLS2 9JTUK

T +44 (0)113 343 2747F +44 (0)113 343 [email protected] www.leeds.ac.uk/speme/ipse

The University of Leeds is one of the UK’s mostpopular universities, particularly in medicine,history, psychology, law, English, accounting andfinance, management studies, theatre andperformance, dentistry and geography. It is oneof the top 10 universities in the UK in terms ofresearch power, market share of researchfunding and number of applicants.

The university of employs 7,581 staffmembers. It currently has 32,241 studentsand an additional 32,062 on short courses. Itsannual turnover is £345 million.


• Nanoparticles• Nanofluids• Nanofluidics• Scale-up• Transport Phenomena


• Multiphase flow, mixing and heat transferin microfluidic channels

• Control of flow in microfluidic systemsusing noninvasive methods

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B.4

Yiton Fu

Microsystems Specialist

Unilever Corporate ResearchColworthSharnbrookBedfordMK44 1LQUK

T +44 (0)1234 222 406F +44 (0)1234 228 [email protected] www.unilever.com

Unilever is one of the world’s largest fast-moving consumer good companies. Itscorporate purpose is to add vitality to life bymeeting the everyday needs for nutrition,hygiene and personal care with brands thathelp people feel good, look good and getmore out of life. The company employs250,000 people worldwide and the annualturnover for 2005 is ~€40 billion (~£28 billion).


• Microfluidics• Miniaturised devices and systems


• Point of sale/point of usemanufacturing/delivery

• Function added packaging• Microfluidic based portable devices for

analytical and diagnostics applications • R&D facilities for product formulation,

material processibility etc• Novel material processing/manufacturing

techniques

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B.5

Simon Robert Gibbon

Team Leader

ICI Strategic Technology GroupR224 Wilton CentreRedcarTS10 4RFUK

T +44 (0)1642 435 838F +44 (0)1642 435 [email protected] www.ici.com

ICI creates, develops and markets productsthat make the world look brighter, tastefresher, smell sweeter and feel smoother:paint, food ingredients, fragrances, personalcare, electronic adhesives, packagingadhesives, speciality polymers.

The ICI Group is an international business. Itemploys more than 33,000 people worldwide.Its product range is 50,000 strong and in 2004its sales touched £5.6 billion.

The ICI Group comprises the internationalbusinesses of National Starch and ChemicalCompany, Quest International, Uniqema andICI Paints – as well as the Regional & IndustrialGroup, made up of businesses which are moreregional in their scope with principal locationsin India, Pakistan and Argentina.

ICI Strategic Technology Group is ICI’scorporate research centre based in the North-East of England, comprising 60 technologists.


• Speciality chemical manufacture• Formulation science


• Chemical production using microfluidics• Controlled delivery using microfluidics• Formulation investigation using

microfluidics

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B.6

Timothy George Ryan

Managing Director

Epigem LtdMalmo Court Kirkleatham Business ParkRedcar Redcar and ClevelandTS10 5SQUK

T +44 (0)1642 496 300 F +44 (0)1642 496 [email protected] www.epigem.co.uk

Epigem’s business is polymer microengineeringfor the optoelectronics and microsystems(MNT) industries. The company develops andmanufactures components and modules forchemicals, electronics and instrumentationcompanies by integrating, for example, micro-optic, microelectronic and microfluidictechnologies. Film wet coating andembossing/imprinting services are also offered.

Epigem is MNT Quality Mark and ISO9001:2000 certified for all processes, and‘Investors in People’ certified. Epigem was afinalist in the MX-2005 ManufacturingExcellence Awards in the Customer Focusand Best SME categories.

The company employs 12 people with a 2005turnover of £920,000.


Products supplied by Epigem are interconnectcomponents providing micro-optical,microelectronic and microfluidic functionality.Epigem’s facilities include a manufacturingline for microfluidic components and modulesand a film coating/embossing pilot line forpolymer waveguide manufacture that is alsoused for polymer display, auto ID anddisposable sensors development. AllEpigem’s processes are scaleable by eitherbatch or reel-to-reel manufacture.Energy/environment friendly additiveprocesses are used. Technology owned bythe company includes 3D interconnection ofmicrofluidic channels; novel sealing ofglass/silicon parts within a polymer package;integration of micro-optics (diffractive,microlenses, waveguides); fine lineelectrodes for analysis and process controland fluid handling using integral membranediaphragm valves; micro- and nanoparticles;nanoporous film.


• MNT product development services(polymer MNT specialists)

• Manufacture of microfluidic devices• Tools to accelerate microfluidic

product creation• Device functions: microvalves, 3D channels

and vias fluid interconnection, surfaceinteraction options, micro-electrodes,micro-optics, antifouling

• Design of instrument modules andconsumables in biotechnology

• Integration of analysis and process control functions

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B.7

Alberto Simoncelli

Fabric & Home Care Engineering – Technology Leader

P&G Technical Centres LtdLongbentonNewcastle upon TyneTyne & WearNE12 9TSUK

T +44 (0)191 228 1227F +44 (0)178 427 [email protected] www.pg.com

Procter & Gamble (P&G) provides brandedproducts and services of superior quality andvalue that improve the lives of the world’sconsumers. It manufactures a wide range ofconsumer goods for personal care, householdand home, health and wellbeing, baby andfamily and pet nutrition and care. P&Gemploys over 139,000 people worldwide andhas recently acquired Gillette. Group turnoverfor 2005 was $56.7 billion (~£31.2 billion).

P&G has a strong interest in fluidicsprocessing and is interested inevaluating the potential for microfluidics.


• Fluids processing


• Microfluidics for formula development,novel fluid processing techniques andproduct quality improvements

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B.8

Nicola Smoker

International Technology Promoter

DTI Global Watch ServicePera Innovation ParkMelton MowbrayLeicestershireLE13 0PB

T +44 (0)1664 501 551F +44 (0)1664 501 [email protected] www.globalwatchservice.com/itp

The DTI Global Watch Service assists UKindustry in identifying and accessing newtechnologies from overseas and to identifycollaboration partners for the developmentand implementation of new technologies.

This activity has three key elements:

• DTI International Technology Promoters(ITPs), who are technology transferspecialists providing UK (and overseas)companies with hands-on assistance withinternational technology transfer objectivesand technology collaborations

• Technology missions, which allow groupsof specialists to evaluate technologies thatare under development outside the UK

• Information viawww.globalwatchservice.com and amagazine – Global Watch – highlightingemerging technology developments fromacross the world


• Providing assistance to UK companiesseeking technologies and partnerships inmainland Europe, and to Europeancompanies seeking technologypartnerships and licensees in UK

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B.9

Julian Darryn White

CEO

genapta LtdWilliam James HouseCambridgeCB4 0WXUK

T +44 (0)1223 426 666F +44 (0)1223 426 [email protected] www.genapta.com

Genapta is a specialist engineering companywith core expertise in building opticalequipment using narrow core optical fibres.The expertise has evolved into genaptadeveloping full-up microfluidic assay platformsfor GSK and academic groups. The device isused in order to test the activity of potentialcompounds in real time, using less than 0.1%of the material that a conventional test mayconsume, in fields such as drug discovery.

Single molecule DNA sequencing is alsobeing addressed using genapta’s technology.Here the device has the potential to directlyread individual base pairs as unwound strandsof DNA pass by the reading head.

In 2004/05 the company’s turnover was£195,000 with five employees.


• Optical fluorescence• Resonant energy transfer• Fluorescent polarisation• Laser technology• Motion control• Confocal optical measurements• Single molecule detection• Reaction kinetics, time resolved


• Optical microfluidic instrumentation,methods and new applications

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B.10

Kevin John Yallup

Technical Director

Technology for Industry LtdE-space North181 Wisbech RoadLittleportCambridgeshireCB6 1RAUK

T +44 (0)1353 865 400F +44 (0)1353 865 [email protected] www.tfi-ltd.co.uk

Technology for Industry (TFI) is a specialisedconsultancy that focuses on thecommercialisation of micro- andnanotechnology (MNT). Over the last 14 yearsTFI has become the market leader in the MNTconsultancy sector in the UK and hassuccessfully carried out projects in Europe,Canada and the USA. TFI has extensiveknowledge in the field of microfluidics which isone of the more promising MNT technologiesin the short to medium term and has thepotential to cause significant disruption acrossa wide range of market sectors.

TFI works with industry, regional and nationalgovernments and academics to help themaddress the challenges of turning newtechnology into profitable businesses. TFI hasa good understanding of both the end-usermarkets for MNT and the technologies and isable to facilitate the process of finding newtechnologies for companies looking tostrengthen their existing products, findingnew markets for suppliers of technologiesand identifying the best strategy formaximising return on investment for publicand private investors in technology.

TFI has particular skills and experience in:

• Industrial sectors such as medical,pharmaceutical, advanced engineering,chemical

• Universities and research organisations• Technology companies – working in areas

such as microfluidics, biotechnology,microsystems technology, nano particlesand coatings, microelectronics andphotonics

TFI employs eight people and has a turnoverof €530,000 (~£370,000).


• Microfluidics• Biotechnology• Microsystems technology• Nano particles and coatings• Microelectronics and photonics


• Commercialisation of technologies• Benchmarking• Development of roadmaps for

technologies, products and applications• Finding partners

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Appendix CLIST OF EXHIBITS

Exhibit Page Caption

3.1 11 Applications of microreaction (source: PAMIR study, IMM, 2002)

4.1 12 Schematic supply chain for microfluidics technology4.2 14 Map of microfluidics R&D centres in the Netherlands (courtesy Richard

Schaafoort, MinacNed)4.3 16 FAMOS microreaction platform

5.1 24 Ehrfeld modular microreaction toolbox and pilot/production plant system5.2 24 CPC’s CYTOS M (micro), L (lab) and P (pilot) systems

6.1 28 Nitroglycerine production plant (>100 l/h solution) using microstructuredreactors set in operation in Xi´an, China (courtesy IMM, Germany)

6.2 30 An integrated microfluidic device for the ion channel screening of living cellsco-developed and manufactured by ThinXXS Microtechnology for SophionBioscience A/S (courtesy Sophion Bioscience A/S)

7.1 32 Micropump manufactured by Bartels Mikrotechnik GmbH7.2 33 P&G’s SK-II air touch foundation

8.1 40 Microfluidics development

9.1 46 Value of the blood-glucose monitoring market as a function of where thetest is administered

A.1 62 CPC’s CYTOS modules

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~ approximately≈ approximately equal to< less than> greater than% per cent€ euro (€1 ≈ £0.69 ≈ $1.26, Jun 06)£ pound sterling (£1 ≈ €1.45 ≈ $1.82, Jun 06)$ US dollar ($1 ≈ £0.55 ≈ €0.80, Jun 06)µl microlitre = 10-6 l = 10-9 m3

µm micrometre = 10-6 mµPIV microparticle image velocimetryµW microwatt = 10-6 W2D two-dimensional 3D three-dimensional A unit of electric current = 1 C/sAMA AMA Association for Sensor Technology eV (Germany)AMT Applikationszentrum Mikrotechnik Jena – Application Centre for Microtechnology

Jena (Germany)ASE advanced silicon etchingATB Leibniz-Institut für Agrartechnik Potsdam-Bornim eV – Leibniz Institute for

Agricultural Engineering Potsdam-Bornim (Germany)AZM Anwendungszentrum für Mikrotechnik – Application Centre for

Microengineering (BESSY, Germany)bar unit of pressure = 105 PaBESSY Berliner Elektronenspeicherring-Gesellschaft für Synchrotronstrahlung mbH

(Germany)BIOS Lab-on-a-Chip Group (University of Twente, Netherlands)BMBF Bundesministerium für Bildung und Forschung – Federal Ministry of Education

and Research (Germany)BMWi Bundesministerium für Wirtschaft und Technologie – Federal Ministry of

Economics and Technology (Germany)oC degrees CelsiusC coulomb – unit of electric chargeCAD computer-aided designCCD charge-coupled deviceCCLRC Council for the Central Laboratory of the Research Councils (UK)CE capillary electrophoresisCEO Chief Executive OfficerCFO Chief Financial Officercm centimetre = 0.01 mcm3 cubic centimetre = 10-6 m3

CO2 carbon dioxide

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Appendix DGLOSSARY

CPC Cellular Process Chemistry Systems GmbH (Germany)CSEM Centre Suisse d’Electronique et de Microtechnique – Swiss Centre for

Electronics and MicrotechnologyCTO Chief Technology OfficerD GermanyDBU Deutsche Bundesstiftung Umwelt – German Environment Foundation DECHEMA Gesellschaft für Chemische Technik und Biotechnologie eV – Society for

Chemical Engineering and Biotechnology (Germany)DFG Deutsche Forschungsgemeinschaft – German Research Foundation DGFC direct glucose fuel cell DNA deoxyribonucleic acidDRIE deep reactive ion etchingDTI Department of Trade and Industry (UK)EC European CommissionERDF European Regional Development Fund (EC)ESTEC European Space Research and Technology Centre (Netherlands)EU European UnionF faxFAMOS Fraunhofer Alliance for Modular Microreaction Systems (Germany)FDA Food and Drug Administration (USA)FMCG fast-moving consumer goods FPP Faraday Packaging Partnership (UK)FTE full-time equivalentFZK Forschungszentrum Karlsruhe (Germany)g gram = 0.001 kgGC gas chromatographyGSK GlaxoSmithKline plc (UK)h hour = 3,600 shl hectolitre = 100 lHPC home and personal care HPLC high-performance liquid chromatographyHSG-IMIT Institut für Mikro- und Informationstechnik der Hahn-Schickard-Gesellschaft

eV (Germany)Hz hertz – unit of frequency = 1 cycle/sIAF Fraunhofer-Institut für Angewandte Festkörperphysik – Fraunhofer Institute for

Applied Solid-State Physics (Germany)ICES/KIS Interdepartementale Commissie voor Economische Structuurversterking/

Kennisinfrastructuur (working group, Netherlands)ICI Imperial Chemical Industries PLC (UK)ICT (1) information and communication technology (2) Fraunhofer-Institut für

Chemische Technologie – Fraunhofer Institute for Chemical Technology (Germany) ID identificationIGB Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik – Fraunhofer

Institute for Interfacial Engineering and Biotechnology (Germany)IMM Institut für Mikrotechnik Mainz GmbH – Institute for Microtechnology Mainz

(Germany)IMPULSE Integrated Multiscale Process Units with Locally Structured Elements

(project, EC)

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IMS Fraunhofer-Institut für Mikroelektronische Schaltungen und Systeme – FraunhoferInstitute for Microelectronic Switching and Systems (Germany)

IMTEK Institut für Mikrosystemtechnik – Institute of Microsystem Technology (Universityof Freiburg, Germany)

IP intellectual propertyIPA Fraunhofer-Institut für Produktionstechnik und Automatisierung – Fraunhofer

Institute for Manufacturing Engineering and Automation (Germany)IPK Fraunhofer-Institut für Produktionsanlagen und Konstruktionstechnik – Fraunhofer

Institute for Production Systems and Design Technology (Germany)IPM Fraunhofer-Institut für Physikalische Messtechnik – Fraunhofer Institute for

Physical Measurement Techniques (Germany)IPR intellectual property rightsISE Fraunhofer-Institut für Solare Energiesysteme – Fraunhofer Institute for Solar

Energy Systems (Germany)ISFET ion-sensitive field-effect transistor ISO International Organization for StandardizationITP International Technology Promoter (network, DTI)IVAM Interessengemeinschaft von Unternehmen und Instituten aus der

Mikrosystemtechnik – Association of Companies and Institutes in MicrosystemTechnology (Germany)

IZM Fraunhofer-Institut für Zuverlässigkeit und Mikrointegration – Fraunhofer Institutefor Reliability and Microintegration (Germany)

J joule = 1 N m = 1 W sJV joint ventureK kelvin – unit of temperaturekg kilogramKOH potassium hydroxideKTN Knowledge Transfer Network (UK)kW kilowatt = 1,000 Wl litre = 0.001 m3

LICOM Liquid Handling Competence Centre (Germany/international)LPCVD low-pressure chemical vapour depositionm metrem2 square metrem3 cubic metreM&A merger and acquisitionmA milliampere = 0.001 AMANCEF Micro and Nano Commercialization Education Foundation (USA)mbar millibar = 0.001 bar = 100 PaMCB Microsystems Centrum Bremen (Germany)MEMS micro-electro-mechanical systemsmg milligram = 0.001 g = 10-6 kgmin minuteMINAC Microsystem and Nanotechnology Cluster (Netherlands)MIT Massachusetts Institute of Technology (USA)ml millilitre = 0.001 l = 10-6 m3

mm millimetre = 0.001 mmm2 square millimetre = 10-6 m2

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MNT micro- and nanotechnology mPa millipascal – unit of pressure = 0.001 PaMST microsystems technologyMW megawatt = 106 WN newton – unit of force = 1 kg m/s2

N/A not availableNEDO New Energy and Industrial Technology Development Organisation (Japan)NEPUMUC New Eco-efficient Industrial Process Using Microstructured Unit Components

(project, EC)NIR near infrared (radiation)nl nanolitre = 10-9 l = 10-12 m3

NL Netherlandsnm nanometre = 10-9 mNMR nuclear magnetic resonanceNRW North Rhine-Westphalia (state, Germany)OEM original equipment manufacturerP&G Procter & Gamble Pa pascal – unit of pressure = 1 N/m2

PDMS polydimethyl siloxanePDRA postdoctoral research associatePECVD plasma-enhanced chemical vapour depositionPEEK polyetheretherketonePEM polymer electrolyte membrane pH potential of hydrogen (measure of acidity or alkalinity)PhD Doctor of PhilosophyPIV particle image velocimetry pl picolitre = 10-12 l = 10-15 m3

plc/PLC public limited companyPMMA polymethylmethacrylateQA quality assurance QC quality controlR&D research and developmentRF radio requencyRFID radio frequency identifications secondS&T science and technologySIMM slit interdigital micro mixerSME small or medium sized enterpriset tonne (metric ton) = 1,000 kgT telephoneTFI Technology for Industry Ltd (UK)TNO Nederlandse Organisatie voor Toegepast-Natuurwetenschappelijk Onderzoek –

Netherlands Organisation for Applied Scientific ResearchTU Technische Universiteit – Technical University (University of Technology)UK United KingdomUS(A) United States (of America)UV-VIS ultraviolet-visible (radiation)VC venture capital

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VDI Verein Deutscher Ingenieure eV – Association of German EngineersVDMA Verband Deutscher Maschinen- und Anlagenbau – German Engineering

Federationvs versusW watt – unit of power = 1 J/sWh watt-hour = 3,600 Jy yearZEMI Zentrum für Mikrosystemtechnik – Centre for Microsystems Technology

(Germany)ZMN Zentrum für Mikro- und Nanotechnologien – Centre for Micro- and

Nanotechnologies (Technical University of Ilmenau, Germany)ZVEI Zentralverband Elektrotechnik- und Elektronikindustrie eV – Electrical and

Electronic Manufacturers’ Association (Germany)

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Grant for Research and Development – is available through the nine English RegionalDevelopment Agencies. The Grant for Researchand Development provides funds for individualsand SMEs to research and develop technologicallyinnovative products and processes. The grant isonly available in England (the DevolvedAdministrations have their own initiatives).www.dti.gov.uk/r-d/

The Small Firms Loan Guarantee – is a UK-wide, Government-backed scheme that providesguarantees on loans for start-ups and youngbusinesses with viable business propositions.www.dti.gov.uk/sflg/pdfs/sflg_booklet.pdf

Knowledge Transfer Partnerships – enableprivate and public sector research organisations to apply their research knowledge to importantbusiness problems. Specific technology transferprojects are managed, over a period of one tothree years, in partnership with a university,college or research organisation that has expertise relevant to your business.www.ktponline.org.uk/

Knowledge Transfer Networks – aim to improvethe UK’s innovation performance through a singlenational over-arching network in a specific field oftechnology or business application. A KTN aims to encourage active participation of all networkscurrently operating in the field and to establishconnections with networks in other fields thathave common interest. www.dti.gov.uk/ktn/

Collaborative Research and Development –helps industry and research communities worktogether on R&D projects in strategicallyimportant areas of science, engineering andtechnology, from which successful new products,processes and services can emerge.www.dti.gov.uk/crd/

Access to Best Business Practice – is availablethrough the Business Link network. This initiativeaims to ensure UK business has access to bestbusiness practice information for improvedperformance.www.dti.gov.uk/bestpractice/

Support to Implement Best Business Practice

– offers practical, tailored support for small andmedium-sized businesses to implement bestpractice business improvements.www.dti.gov.uk/implementbestpractice/

Finance to Encourage Investment in Selected

Areas of England – is designed to supportbusinesses looking at the possibility of investingin a designated Assisted Area but needingfinancial help to realise their plans, normally in the form of a grant or occasionally a loan.www.dti.gov.uk/regionalinvestment/

Other DTI products that help UK businesses acquire andexploit new technologies

Global Watch Information

Global Watch Online – a unique internet-enabled service delivering immediate andinnovative support to UK companies in theform of fast-breaking worldwide business andtechnology information. The website providesunique coverage of UK, European andinternational research plus businessinitiatives, collaborative programmes andfunding sources.Visit: www.globalwatchservice.com

Global Watch magazine – distributed freewith a circulation of over 50,000, this monthlymagazine features news of overseasgroundbreaking technology, innovation andmanagement best practice to UK companiesand business intermediaries.Contact:[email protected]

Global Watch Missions – enabling teams ofUK experts to investigate innovation and itsimplementation at first hand. The technologyfocused missions allow UK sectors andindividual organisations to gain internationalinsights to guide their own strategies forsuccess.Contact:[email protected]

Global Watch Technology Partnering –providing free, flexible and direct assistancefrom international technology specialists toraise awareness of, and provide access to,technology and collaborative opportunitiesoverseas. Delivered to UK companies by anetwork of 23 International TechnologyPromoters, with some 8,000 currentcontacts, providing support ranging frominformation and referrals to more in-depthassistance with licensing arrangements andtechnology transfer.Contact: [email protected]

For further information on the Global WatchService please visitwww.globalwatchservice.com

The DTI Global Watch Service provides support dedicatedto helping UK businesses improve their competitivenessby identifying and accessing innovative technologies andpractices from overseas.

Printed in the UK on recycled paper with 75% de-inked post-consumer waste content

First published in July 2006 by Pera on behalf of the Department of Trade and Industry

© Crown copyright 2006

URN 06/1220

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