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Review of Fluid Flow in Microfluidic Devices

A Report for

National Measurement System Directorate Department of Trade & Industry 151 Buckingham Palace Road

London, SW1W 9SS

Project No:FEKT02 Report No: 2005/32 Date: February 2005

The work described in this report was carried out under contract to the Department of Trade & Industry (‘the Department’) as part of the National Measurement System’s 2002-2005 Flow Programme. The Department has a free licence to copy, circulate and use the contents of this report within any United Kingdom Government Department, and to issue or copy the contents of the report to a supplier or potential supplier to the United Kingdom Government for a contract for the services of the Crown. For all other use, the prior written consent of TÜV NEL Ltd shall be obtained before reproducing all or any part of this report. Applications for permission to publish should be made to: Contracts Manager TÜV NEL Ltd Scottish Enterprise Technology Park East Kilbride G75 0QU E-mail: [email protected] Tel: +44 (0) 1355-272096 © TÜV NEL Ltd 2005

National Engineering Laboratory

Project No: FEKT02 Page 1 of 27 Report No: 2005/32

NEL East Kilbride

Glasgow G75 0QU Tel: 01355 220222 Fax: 01355 272999

Review of Fluid Flow in Microfluidic Devices

A Report for

National Measurement System Directorate Department of Trade & Industry 151 Buckingham Palace Road

London, SW1W 9SS

Prepared by: Mr Jim McNaught .................................................. 28 February 2005

Approved by: Mrs Jane Sattary .................................................. 28 February 2005 Date: February 2005 for Mr M Valente Managing Director



CONTENTS Page

EXECUTIVE SUMMARY ........................................................................ 3 1 INTRODUCTION .................................................................................... 4 2 FLOW IN MICROCHANNELS 2.1 Introduction ............................................................................................ 4 2.2 Microchannels ........................................................................................ 5 2.3 Electrokinetic Flow ................................................................................. 7 2.4 Bottleneck Effect .................................................................................... 7 2.5 Wall Roughness ..................................................................................... 7 3 FLOW DIAGNOSTICS 3.1 Introduction ............................................................................................. 8 3.2 Weighing ................................................................................................. 8 3.3 Micro Particle Image Velocimetry .......................................................... 9 3.4 Validation of PIV .................................................................................... 10 3.5 Commercial Micro PIV ........................................................................... 11 3.6 Electrokinetic Flows ............................................................................... 11 4 COMPUTATIONAL FLUID DYNAMICS ................................................. 12 5 NON-NEWTONIAN FLOWS .................................................................. 13 6 FLOW SENSORS 6.1 General .................................................................................................. 13 6.2 Suppliers of Microfluidic Flow Sensors .................................................. 15 7 MICROFLUIDICS AT NATIONAL MEASUREMENT INSTITUTES ....... 16 8 EUROPEAN CONSORTIA 8.1 Flow Map Project ................................................................................... 16 8.2 Licom ..................................................................................................... 18 8.3 Intellidrug ............................................................................................... 19 8.4 UK Lab on a Chip Consortium ............................................................... 19 9 OTHER APPLICATIONS OF MICROFLUIDIC SENSORS .................... 19 10 FUNDED RESEARCH IN THE UK 10.1 EPSRC ................................................................................................... 20 10.2 Faraday Partnership .............................................................................. 20 10.3 Other UK Research ................................................................................ 20 11 KEY SOURCES ..................................................................................... 21 12 CONTACTS ........................................................................................... 21 13 CONCLUSIONS ..................................................................................... 21 REFERENCES ...................................................................................... 22 APPENDIX I ........................................................................................... 24



EXECUTIVE SUMMARY The objective of this report is to review the current state of the art in relation to knowledge, experience and measurement of fluid flow in microfluidic systems. There has been significant growth in recent years in the development of microfluidic devices based on micro-electromechanical system (MEMS) technologies. These devices can combine electrical and mechanical components down to a characteristic length scale of 1 micron. The technology involves the fabrication of microscopic channels, nozzles, pumps and valves used to mix and regulate microscopic quantities of fluids. In one definition microfluidic devices have one or more fluid channels with at least one dimension less than 1 mm. MEMS microfluidic devices typically have channels with the smallest dimension of the order 1 – 100µm. The very small flow channels that arise in microfluidics have implications on the nature of the flow and on the type of flow and velocity measurements that are both needed and practical. The latest research indicates that liquid flows of Newtonian fluids are well represented by conventional theories of continuum fluid mechanics in channels with characteristic dimensions down to at least 50 µm and possibly much smaller. With gas flows the conventional assumption of no-slip at the wall starts to break down for air at room conditions at a characteristic dimension of about 70 µm. This means that gas flows in microfluidics devices are on the borderline of the point at which the no-slip condition at the wall breaks down. Computational Fluid Dynamics packages are available for the three–dimensional analysis of low in microfluidics devices, and the packages also incorporate the coupling of the equations describing electro-hydrodynamic, chemical and biological effects with the flow equations. The extent of validation of these packages for microfluidics is most probably very limited. Micro Particle Image Velocimetry (µPIV) is a fairly well advanced technique for flow diagnostics in microfluidics devices, but it is currently limited by particle size and limitations in optical resolution. Sophisticated flow sensors are available from a limited number of specialist companies for measurement of ultra low flows in capillaries and micro-channels. Currently it seems that a purchaser must rely on the manufacturer’s calibration.



1 INTRODUCTION There has been significant growth in recent years in the development of microfluidic devices based on micro-electromechanical system (MEMS) technologies. These devices can combine electrical and mechanical components down to a characteristic length scale of 1 micron. The technology involves the fabrication of microscopic channels, nozzles, pumps and valves used to mix and regulate microscopic quantities of fluids. There is rapid growth in the fields of printing, medicine, chemistry, clinical analysis and forensics, and application areas include inkjet printing, and Lab-on-a-Chip. In one definition a microfluidic device is identified by the fact that it has one or more channels with at least one dimension less than 1 mm. MEMS microfluidic devices typically have channels with the smallest dimension of the order 1 – 100µm. Luff et al (2004) define microfluidics as the generic technology of manipulating fluids on a chip, including the integration of pumps, valves, mixers and reaction chambers that enable the fabrication of microreactors and lab-on-a-chip devices. They state that microfluidics offers the following advantages for sensor products:

• compactness • reduced reagent volumes (hence lower cost) • faster response times • well-controlled reaction conditions and delivery of reagents • low power consumption

Possible disadvantages of the technology that may impact its commercialisation in some areas are:

• how representative are small sample volumes? • device fouling • interfacing to the macro-world • high voltages required for electrophoresis pumping systems

The very small flow channels that arise in microfluidics have implications on the nature of the flow and on the type of flow and velocity measurements that are both needed and practical. The objective of this report is to review the current state of the art in relation to knowledge, experience and measurement of fluid flow in microfluidic systems. It does not consider materials, manufacturing or interaction of flow with chemical and other effects. 2 FLOW IN MICROCHANNELS 2.1 Introduction There are a number of assumptions underlying the conventional underlying theory of engineering fluid dynamics, two of which are:

1. The fluid can be represented as a continuum, i.e. the flow is analysed at a level where the smallest element of fluid considered is much larger than the mean free path length of a molecule, and that the fluid has a continuous structure. Continuum mechanics yields predictions of the velocity vector of a continuous fluid at a point in space.



2. There is no slip at the wall. Molecular attractive forces mean that the fluid

immediately adjacent to a solid surface is stationary. There is a velocity gradient from the surface to the bulk of the fluid

Fluid flow in channels can be characterised using the Reynolds number, defined by

ηρud

=Re (1)

where ρ is the fluid density, u is the mean velocity, η is the dynamic viscosity, and d is the most relevant length scale. In normal macro-channels the flow is laminar if Re < 2000, and there is a transition to turbulent flow somewhere between Re = 2000 and 4000. Laminar flow is amenable to analytical modelling in simple geometries using the Navier Stokes equations. For laminar flow of a Newtonian fluid with constant radial properties in a straight circular channel of length L the velocity profile is parabolic, and the pressure drop is given by

dLufp

24 2ρ

=∆ (2)

where

Re16

=f (3)

For laminar flow in macro-channels f is independent of the wall roughness. A number of authors have challenged the validity of the underlying theory and the results to microchannels. 2.2 Microchannels In microchannels the Reynolds number is normally very small and the flow is almost always laminar. However it is possible that the assumptions of continuum fluid mechanics and no slip at the wall may become invalid. Other factors such and the micropolar molecular structure of the fluid may become important. In a very small channel the roughness of the wall may be much more important than in larger channels. According to Tabeling (2001), for simple liquids and ideal gases at normal pressures, the classical continuum theory should apply down to channel dimension scales of 10 µm. On the other hand Tabeling questions the validity of the no-slip assumption and suggest that, with smooth surfaces, there is a certain amount of slip and therefore the potential for drag reduction. Sharp and Adrian (2004) state that continuum theory for liquids can be applied until the tube diameter drops well below 1 µm. They report a set of experiments in microtubes of diameters between 50 and 250 µm using Newtonian liquids of different polarities. The experiments were primarly directed at evaluating the transition Reynolds number for laminar to turbulent flow. They found that the transition Re lies in the same range as would be expected for normal channels, i.e. 1800 – 2300. They also found that, below the transition Reynolds number, equation (3) fitted their data very accurately. This implies that the continuum model with the no-slip boundary condition is applicable at least down to diameters of 50 µm.



The results of Sharp and Adrian (2004) are in contrast to some previous authors who have reported a transition to turbulence at much lower Reynolds numbers than 2000, and also large errors when using equation (3). However they claim that their 1500 carefully taken data points with 3 different liquids are conclusive evidence The situation with gases is described by Barber and Emerson (2002). For an ideal gas modelled as rigid spheres, the mean free path of the molecules, Lm can be expressed as

22 cm p

kTLσπ

= (4)

where k = Boltzmann's constant 1.380662 × 10-23 J/K T = Temperature (K) p = pressure (N/m2 ) and σc = collision diameter of the molecules (m) Continuum mechanics is valid provided the mean free path of the molecules is smaller than the characteristic dimension of the flow channel. If this condition is violated, velocity profiles, boundary wall shear stresses, mass flow rates and pressure differences will then be affected by non-continuum effects. In addition, the conventional no-slip boundary condition imposed at the solid-gas interface will begin to break down. The ratio between the mean free path Lm, and the characteristic dimension of the flow geometry d, is known as the Knudsen number, Kn, defined by:

dLm=Kn (5)

The value of the Knudsen number determines the validity of the continuum flow assumption. Barber and Emerson (2002) state: Kn ≤ 0.001 Continuum model and no-slip conditions apply 0.001≤ Kn <0.1 Continuum model applies but slip-flow boundary condition at

the wall is required 0.1≤ Kn <10 Continuum model starts to break down, and alternative model

required Kn >10 Continuum model breaks down completely, and regime is free

molecular flow Barber and Emerson (2002) describe a method to apply a boundary condition at the wall to account for the effects of slip at the wall in the regime 0.001≤ Kn<0.1 in numerical modelling. Since Lm ~70 nm at room conditions, the above table means that at atmosheric pressure both the continuum model and no-slip conditions apply down to characteristic dimensions of the order of 70 µm, at which point the no-slip condition starts to break down. The continuum model applies down to about 700 nm. Another point to be noted in relation to microchannels is that the pressure drop in laminar flow is proportional to 1/d4. Thus highly accurate measurement of d is required in any microfluidics work.



2.3 Electrokinetic Flow The above theory applies to flows that are driven by a pressure difference created by, for example, a pump or a syringe. Another common technique for pumping microfluids is that of electro-osmosis. If the walls of a microchannel have an electric charge, as most surfaces do, an electric double layer of counter ions will form at the walls. When an electric field is applied across the channel, the ions in the double layer move towards the electrode of opposite polarity. This creates motion of the fluid near the walls which transfers via viscous forces into convective motion of the bulk fluid. The velocity profile across the channel is nearly uniform across the entire width. This is known as “plug flow”, and is in contrast to the parabolic velocity profile that results from pressure-driven flow. Plug flow may have advantages in some applications. In electrokinetic flow, pumping and valving are achieved without moving parts. 2.4 Bottleneck Effect Tabeling (2001) describes the so-called “bottleneck effect” that can arise when a liquid is driven through a microchannel using a syringe pump. If the liquid can be regarded as incompressible then liquid displaced by the piston in the syringe chamber is instantaneously ejected from the microchannel. However, because of the compressibility of the liquid, the system takes time to reach steady state. The time taken can be shown to be inversely proportional to the channel diameter raised to the power 4. With a 1 µm capillary the time required is stated to be several minutes. Whilst in practice the compliance of the tube outweighs this effect, this example is used by Tabeling to illustrate the fact that there counter-intuitive effects can arise in flow in microchannels. 2.5 Wall Roughness The roughness of the wall is likely to be much more important in microchannels than in larger channels. The roughness may affect the friction factor even in laminar flow, and the degree of liquid slip at the wall. Eason et al (2004) investigate the manufacturing of a variety of microchannels, produced by wet and dry etching in silicon, as well as precision mechanical sawing in silicon and thermoset plastic. They also describe the experimental equipment and methods used to measure the pressure drop characteristics of the channels. The mass flow rate through the system is measured by weighing the flow from the system in a given time. The measured pressure flow behaviour was compared with theoretical values as calculated from macro scale theory. The deep reactive ion etched (DRIE) channels show the most significant lack of correlation with theoretical predictions from macro-scale methods.



3 FLOW DIAGNOSTICS 3.1 Introduction

According to Devasenathipathy and Santiago (2004), “As on-chip electroosmotic and electrophoretic systems grow in complexity and designs are optimized, the need for a detailed understanding of the underlying flow physics of such systems grows ever more critical. Experimental studies of these flows as well as experimentally-validated flow models are needed to facilitate the development of microfabricated electroosmotic systems”. The need for validated flow models would seem appropriate for pressure-driven flows as well. There may be a need for detailed modelling of, for example, flow around a blood cell, as well as overall flowrate measurements in channels. 3.2 Weighing Figure 1 shows the laboratory apparatus used by Sharp and Adrian (2004) to measure flow rate in a capillary tube. A constant pressure source is used to maintain a steady flowrate in the capillary. Measurements were obtained with capillary inside diameters between 50 and 247 µm, and Reynolds number ranges of 20 – 400 and 400 – 2,900.

Figure 1: Schematic of equipment used in flow resistance study of Sharp and Adrian (2004) The authors claim an uncertainty of ±2.5% rms in the measured friction factor. Another system for electrokinetic flows is described by Devasenathipathy and Santiago (2004). Figure 2 shows a schematic of the apparatus, in which the weight of liquid pumped from one reservoir to another. A schematic of a typical weighing setup is shown in Figure 3.6. The configuration shown in the figure was applied by VanDeGoor (1992). The grounded electrolyte reservoir is placed on an analytical balance and an electric field is applied using a high voltage power supply with special care taken to ensure that the electrode in the grounded reservoir does not influence the weighing. The weight of one electrode reservoir/vessel is monitored with the analytical micro-balance at time intervals ranging from 1 –10 s. Measurements were taken for flows in both directions by reversing the polarities of the electrodes, and a simple average was calculated to yield the electroosmotic flow rate. Devasenathipathy and Santiago advise that losses due to evaporation are particularly critical in weighing experiments, and that they should be minimized and estimated to



quantify uncertainty. They also make the points that consideration of evaporation losses is especially critical for the low volume flow rates (of order 100 nl/min) typically encountered in electrokinetic flows, and that environmental parameter controls such as temperature and humidity may help to mitigate this effect. Other limitations in the resolution obtainable from weighing are the sensitivity of the balance and the effects of room air currents on the balance. Some steps must also be taken to de-gas liquids in on-chip applications.

Figure 2: Schematic of weighing setup for electroosmotic mobility measurement, VanDeGoor (1992) 3.3 Micro Particle Image Velocimetry Particle Image Velocimetry (PIV) is a technique for the measurement of instantaneous velocities in a flow field. The flow must be seeded with small particles. From the TSI website (http://www.tsi.com/), PIV systems measure velocity by determining particle displacement over time using a double-pulsed laser technique. A laser light sheet illuminates a plane in the flow, and the positions of particles in that plane are recorded using a digital or film camera. A fraction of a second later, another laser pulse illuminates the same plane, creating a second particle image. From these two particle images, analysis algorithms obtain the particle displacements for the entire flow region to be imaged, and generate velocity information at hundreds or thousands of locations. Other properties, such as mean velocity, turbulence intensity, and higher order flow statistics can also be obtained. The first application of PIV to microfluidics is by Santiago et al (1998). The seed particles were 300 nm diameter, and velocity vector fields were measured with spatial resolutions down to 6.9 x 6.9 x 1.5 µm. The technique was used to measure velocities in flow around a 30 µm diameter cylinder with a bulk velocity of around 50 µm/s. Figure 3 shows an averaged measured PIV velocity vector field from Santiago et al (1998).



Figure 3: Averaged PIV velocity field in Hele-Shaw flow around a 30mm wide obstacle, from Santiago et al (1998) Wereley and Meinhart (2004) provide a comprehensive state-of the-art review of micro PIV. They conclude that, by applying advanced experimental and analytical techniques the maximum spatial resolution of the µPIV technique stands at approximately 1 µm. They state that the use of smaller seed particles that fluoresce at shorter wavelengths could reduce this limit by a factor of 2 to 4, and that spatial resolutions an order of magnitude smaller still could be obtained by adding a particle tracking step after the correlation-based PIV. 3.4 Validation of PIV Meinhart et al (1999) describe PIV measurements in a rectangular microchannel of cross section 30 µm x 300 µm. It is claimed that the technique can provide measurements of velocity fields with spatial resolutions approaching 0.9 µm. It was found that the PIV measurements agreed to within 2% of the analytical solution for laminar flow in a rectangular channel. Adrian et al (2004) describe micro PIV measurements in laminar Newtonian flows in various microchannel geometries, and evaluate their accuracy by comparing the results with CFD computations. The micro PIV technique that they use is described as “high image intensity”. It relies on the depth of the flow field being small enough to limit the background glow of the out-of-focus particles by limiting their volume, in which case the PIV interrogation becomes virtually identical to conventional macro-scale PIV. Measurement volumes are typically 10 µm cubes with this technique, which is therefore limited to channels that are of the order of several hundred microns. The “high image intensity” technique is an alternative to the technique described by Santiago et al (1999) and Meinhart et al (1999) in which resolutions as small as 1 µm3 can be achieved, though it is restricted to flow fields that are both deep in the direction of the microscope axis and the same in each frame. Adrian et al (2004) state it turns out to be surprisingly difficult to perform high quality experiments in microfluidic flows, even though the flow is steady, laminar and Newtonian in simple geometries. Experimental problems include uncontrolled transients in the flows and fouling of the micro-channels by impurities, bubbles, and the



seed particles. Uncertainty also arises from the method used to fabricate the micro-channels. 3.5 Commercial Micro PIV Commercial Micro PIV systems are marketed by the following organisations: TSI Inc: http://www.tsi.com/fluid/products/piv/micropiv.htm Oxford Lasers: http://www.oxfordlasers.com/hsi/hsih.htm LaVision Gmbh: http://www.piv.de/ Dantec: http://www.dantecdynamics.com/ TSI claim that the technique of using ensemble averaging of correlation maps helps improve vector spatial resolution substantially (of the order of 1 micron) when proper seed particles are used, and that consequently, the technique is very suitable for near wall measurements. Dantec Dynamics quote a smallest field of view of 131 x 105 µm, and a typical particle size of 1 µm. They also quote an application with a resolution of 3.6 × 3.6 × 3.2 µm. Oxford Lasers state: ” If you study flows in millimeter sized channels, micro-PIV will measure velocities with unprecedented accuracy and precision. Using your existing microscope (or one we supply) we can measure velocities with a resolution of a few tens of microns” 3.6 Electrokinetic Flows Devasenathipathy and Santiago (2004) describe a number of methods for measuring velocities and flow rates in electrokinetic flow. Their conclusions appear to be sufficiently authoritative to merit quotation in full: “The field of electrokinetic flow diagnostics is developing rapidly. This development is largely due to a surge of interest in microfabricated electrokinetic systems with applications to bioanalytical devices. Earlier bulk flow methods of flow characterization include weighing of effluent, conductivity cell monitoring, streaming potential, and current monitoring. These relatively simple techniques are very important as they will probably always form the basis of initial characterizations of electrokinetic microsystems and, indeed, provide a reference for comparison with more than a century of electrokinetic measurements activity. The value of these techniques is being complemented by that of more complex flow diagnostics with higher spatial resolution, higher temporal resolution, and the ability to analyze two- and three-dimensional flow fields.” “The simplest of the multi-dimensional, high temporal resolution techniques are simple visualization of the temporal development of fluorescent dye fields. These visualizations form the simple, initial thrust in the direction of field-based diagnostic techniques. In particular, experiments such as the tracking and imaging of sample plugs in electrophoretic systems are today shedding new light on sample band dispersion rates and the coupled problem of sensitivity in microfluidic systems. The application (and validation) of neutral marker imaging promises to yield further insight into the electroosmotic (i.e., bulk) liquid motion independent of the effects of tracer electromigration. Such visualizations are direct and relatively robust since they avoid



problems of high intensity and short duration laser illumination, as well as the adsorption and/or flow disturbance problems associated with particle flow seeding. Further along the evolution of field-based flow diagnostic systems are the methods that provide more quantitative and/or spatially resolved flow field information. For example, scalar line writing techniques such as photo-bleached fluorescence and caged fluorescence imaging allow for the simultaneous measurement of advection and diffusion processes in microfluidic electrokinetic systems”. “Although probably the most complex to implement, particle-based diagnostics offer measurements resolved in the depthwise direction which can be applied in three dimensional flow fields and which offer the highest available spatial and temporal resolutions. This feature is in sharp contrast to the line-of-sight averaged measurements provided by scalar techniques. Another contrast is that the particle tracking methods are not really model systems for scalar development visualizations where diffusion of molecular species is of primary interest. In the end, the choice of visualization should and often is determined by the phenomena of interest and, ultimately, the application of interest. Most diagnostics offer some relative set of advantages ranging from simplicity to resolution.” “The future of electrokinetic diagnostics is tied to the future of electrokinetic systems. One key characteristic of their development is that electrokinetic systems and the applications which they target are inherently multiphysics oriented (i.e. multidisciplinary). This characteristic is unlike much of the development of modern fundamental fluid mechanics and, in particular, turbulence research where the major goals of diagnostics have been in providing higher spatial and temporal resolution measurements of the gradients of unsteady, three-dimensional velocity fields. In contrast, the development of electrokinetic systems is much more diverse in that the key issues are the interplay between electrostatics, electrodynamics, molecular and particle transport, fluid motion, reactive systems, and functionalities of biological systems. As such, an important area in the development of electrokinetic flow diagnostics will probably be the development of simultaneous measurements of scalar and vector fields of interest. The merits of, for instance, simultaneous measurements of temperature and concentration fields together with velocity fields in efforts to study fundamental flow/macromolecule interactions should be significant. Clearly, the multiphysics field of electrokinetics will need multiphysics measurements and our work has just begun”. 4 COMPUTATIONAL FLUID DYNAMICS Some of the research studies described above have applied computational fluid dynamics to microfluidics. Commercial CFD packages claim capability for microfluidics. For example the CFD-ACE+ product of CFD Research Corporation (www.cfdrc.com) is claimed to offer, in relation to microfluidics:

• Hydrophobic/Hydrophilic Filling and Dispensing with Chemistry • Fluid-Structure Interaction • Pressure Driven Flow • Heat Transfer • Electric Field • Dynamic Contact Angle • Hele-Shaw Models • CD – Based µFluidic Devices



The Fluent website (www.fluent.com) states “analysis of the fluid flow and heat transfer inside microelectromechanical systems (MEMS) requires specialized models. Fluent software provides advanced features such as fluid/structure interaction, free surface tracking with the volume of fluid method (VOF), and electrohydrodynamics. Typical applications include microfluidics, ink jets and ink jet actuators (including piezoelectric effects), and electrophorectic transport of tiny fluid samples.” 5 NON-NEWTONIAN FLOWS Much of what is written above applies to Newtonian fluids, in which the viscosity is independent of the shear rate. Fluids which do not obey this rule are known as non-Newtonian. Blood is one important fluid in microfluidics applications such as lab-on-a-chip which is non-Newtonian. Bitsch et al (2003) describe the application of micro PIV to blood flow in a microchannel. Velocity profiles were measured in a channel of roughly rectangular cross section of size 28 µm by 360 µm. Particular measurement issues with blood flow are the low transparency, highly non-Newtonian behaviour, and the fact that the diameter of a red blood cell (8 µm) is comparable with the channel dimension of 28 µm. The measured velocity profiles across the channel were rather flat in contrast to the parabolic profile for a Newtonian fluid. http://www.ansys.com/applications/mems/mems_applications/app_micro_fluidic.htm provides a link to a CFD study of blood flow in microfluidic channels. The analysis capabilities of the CFD package are reported as:

• Determine pressure drop across device. • Determine velocity profile. • Incorporate non-newtonian flow • Incorporate turbulent flow/ vortex formation effects • Compute pressure applied to walls and structural deformation • Ability to transfer heat from fluid to structure and vica-versa.

The website shows an animation of the development of calculated velocity profiles in a microchannel block. 6 FLOW SENSORS 6.1 General A presentation on the working principles of different types of micro-flow sensors is given by Ducree and Zengerle in http://www.myfluidix.com/. Flow sensors area classified into the following types:

• Thermal o Principle: transfer of thermal energy depend on velocity and flowrate o Requires heaters and thermometer o Must be thermally insulated o Suitable for microfabrication o For measurement of minute flow rates



• Static pressure o Differential measurement of pressure o For measurement of high flow rates

• Mechanical o Principle: force or torque o Deflection of cantilever o Torsion of flow channel by Coriolis force

• Direct velocity measurement o Time intervals of suspended particles o Laser-Doppler-Anemometry (LDA)

Examples of each type are described. The greatest emphasis is on some variants of the thermal type. The approach can be calorimetric or “time of flight”, or a combination of the two to cover different flow rate ranges. The calorimetric approach will require calibration for the specific fluid used since the small temperature rise is confined to the boundary layer and therefore depends on the fluid transport properties (viscosity, thermal conductivity). Figure 4 shows an example of a thermal flow sensor used for dosage measurement.

Figure 4: Special configuration of thermal flow sensor for dosage tools (from Ducree and Zengerle, http://www.myfluidix.com/) Another interesting development is a “Micro Differential Flow Sensor” which is a probe (Figure 5) of diameter 6mm and length 20 mm that measures differential pressure within the flow, therefore avoiding the need for impulse lines to the exterior of the metering pipe. The sensor includes a chip measuring 3 x 3 x 0.5 mm and the pressure membrane is etched with 2 x 2 mm surface and 8 µm thickness. The application is flow measurement of non-aggressive liquids like water, for example fresh and hot water consumption in households. The technical data presented indicate flows down to about 20 l/h.

Figure 5: Micro differential flow sensor (from Ducree and Zengerle, http://www.myfluidix.com/)



6.2 Suppliers of Microfluidic Flow Sensors ISSYS Inc (http://www.mems-issys.com/html/microfluidfam.html) This company offers precision microfluidic products and is ISSYS is developing advanced density and flow meters “that could dramatically improve accuracy, reduce costs, and change the way numerous industries quantify fluid flows”. ISSYS has produced prototype Micro-Coriolis Mass Flow meters that provide accuracy and improved low flow capability, with flow tube diameters ranging from 50 microns to 500 microns. Low flow capabilities below 1 microgram per second are anticipated. Bronkhorst High-Tech B.V. (http://www.bronkhorst.com/pdf/muflow_leaflet.pdf) A new generation of thermal liquid mass flow meters/controllers of the µ-FLOW Series is a small, compact instrument with ranges from 25...500 nanolitres per minute (1,5...30 mg/h) up to 0,1...2 g/h. HORIBA STEC (http://www.horibastec.com/STEC) This company supplies liquid flow controllers and meters for low flowrates down to 0.02 ml/min. CSEM (http://www.csem.ch/) CSEM has developed silicon microfluidics devices to act as flow meters in biomedical implants. Sensirion AG (www.sensirion.com) This company has developed thermal mass flow sensors directed at lab-on-a-chip applications. The company’s new CMOSens® technology integrates this basic physical measuring principle in an “extremely fast, miniaturized thermal sensor with all of the high-precision signal-conditioning circuitry on a single CMOS microchip. A heating element on the microchip adds a minimal amount of heat to the medium for the thermal flow measurement. Two temperature sensors, symmetrically positioned upstream and downstream of the source of the heat, detect even the slightest temperature differences, thus providing the basic information about the spread of the heat, which itself is directly related to the flow rate. Integration on a single chip ensures that the sensitive analog sensor signals can be amplified with high precision, digitalized and further processed. Semiconductor technology also allows small, battery-operated sensor modules to run very well.” Sensirion claim repeatability at flows down to 1 nl/min. A complete “Labkit” with micro mass flow sensor, software, interface cable and power supply etc is available. The Sensirion website gives further details of the sensor CMOS technology, known as CMOSens®. Figure 6 illustrates the principle of the Sensirion thermal flow sensor. The link http://www.slatersoft.com/Sensirion/Rapport.pdf describes a calibration procedure for the Sensirion flow sensor.



Figure 6: Operating Principle of Sensirion Thermal Flow Sensor 7 MICROFLUIDICS AT NATIONAL MEASUREMENT INSTITUTES The websites of the major European National Measurement Institutes PTB (Germany), BNM (France), NMi (Holland), and Metas (Switzerland) revealed no work programmes in microfluidics. The website of IMGC (Italy) refers to a project on accurate measurements of flows between 10-12 mol/s and 10-3 mol/s. There do not appear to be ultra-low flow calibration facilities at these institutes. 8 EUROPEAN CONSORTIA 8.1 FlowMap Project The FlowMap project is based on the cooperation between four European partners. Three of them are presently co-operating in a Europractice competence centre on microfluidics - Liquid Control and Measurement "LICOM", and the fourth has carried out various technology and market studies on microfluidics. The four partners are

• IMTEK - Institute for Microsystem Technology, University of Freiburg (Germany), Chair for MEMS Applications

o WTC - Wicht Technologie Consulting (subcontractor to IMTEK), Munich (Germany)

• CBC - Cranfield Biotechnology Centre, Cranfield University (UK) • HSG-IMIT - Hahn-Schickard-Gesellschaft, Institute for Micro- and Information

Technology (Germany) • Yole Développement Lyon (France)

Further information can be found on the website http://www.microfluidics-roadmap.com/pages/consortium/index.html. The objective of the project is to create a microfluidics technology “roadmap” for the life sciences.



A Report from the FlowMap project has now been made available at 100 euros. The Executive Summary of this report follows: “Microfluidics has become one of the most dynamically emerging disciplines of microtechnology, supplying some of the key hardware to enable the rapid growth and commercialization of the life sciences in the recent decade. Microfluidic devices can be characterized by their capability to accurately control minute volumes of fluid – mostly liquids – well below the microliter range. Modern inkjet technology with global turnover beyond 10 billion euros p.a. represents an impressive example of how microfluidics has leveraged a mature and commercially very successful field of business. By significantly reducing reagent volumes and thus the decisive costs per test, microfluidics-based liquid handling equipment has emerged from inkjet technology, already enabling modern high-throughput technologies for pharmaceutical drug discovery. Apart from the accurate delivery of small droplets, the behavior of fluids in the microworld is governed by peculiar effects such as

• fast response times, • well-controlled reaction conditions, • small power consumption, • low dead volumes • and the possibility to manipulate liquids by means of electric fields, heating or

ultrasonic waves.” “Making explicit use of these unique microfluidic effects, compact, often stand-alone systems have been designed featuring full process integration and automation to carry out complex tasks in a hands-off fashion. These portable or point-of-use systems leverage applications such as so-called ”labs-on-a-chip” for medical diagnostics or other analytical purposes like ecological monitoring. Other promising markets comprise miniaturized therapeutical devices, e.g. for implantable, stand-alone drug delivery units. On behalf of research and development, it has also become evident that microfluidics provides a unique access to the nanoworld of biomolecular chemistry thus setting the pace for many leading edge biotechnological innovations.” “In the course of the ”FlowMap”, a consortium of strong European partners comprising IMTEK (D), HSG-IMIT (D), Cranfield Biotechnology Center (UK) and Yole D´eveloppement (F) has analyzed existing and future markets, products and technologies for microfluidics in the life sciences. During this one-year project, more than 150 external experts have been involved in FlowMap by a series of designated workshops, personal interviews and a world-wide questionnaire action. As a result, we have quantified the economic development and pinpointed important market drivers. Furthermore, the paramount technology drivers which will determine the present and expected capabilities have been identified. This way, the roadmap provides a solid basis for decision makers planning investments in the life science arena.” “Various technological advantages are associated by the participants of the study with the use of microfluidic technologies, the most frequently mentioned are

• the reduced amounts of reagents, • the small size and weight of devices • and the short time-to-results as well as enhanced system integration and

automation.”



“The most cited demands on microfluidic technologies comprise • the amenability to

– point-of-care – point-of-use – portable applications

• and novel technologies for centralized laboratories.” “The main market drivers have been identified as

• cost reduction, • reduced analysis time • and increased throughput.”

“Being asked for major hurdles presently impeding the commercial proliferation of microfluidic technologies, the experts involved in the FlowMap project mentioned

• the cost of associated equipment, • the cost of microfluidic components, • the strength of competing / substitutive technologies, • and the lack of

– commercial suppliers, – infrastructure – and industrial standards.”

“To tackle these serious techno-economical obstacles, we encourage to agree on a small number of broadly accepted microfluidic platforms for a given group of applications, each equipped with a full-fledged set of components, instead of developing discontiguous component technologies.” “The majority of participants expect an overall annual growth rate for micro-fluidic technologies in the life sciences of more than 30% per annum with drug discovery, medical diagnostics and therapeutic devices representing the most promising fields. In a systematic market analysis based on the data acquired during the FlowMap project, our partner Yole D´eveloppement has estimated the global market of microfluidics in the life sciences to approximately 500 million euros, increasing with an assumed annual growth rate of 19% to 1.4 billion euros in 2008. The FlowMap report presents a detailed breakdown of this turnover in each microfluidics segment identified in Life Sciences.” 8.2 Licom LICOM is short for The European Liquid Handling Competence Centre which was established in 2000 within the frame of EUROPRACTICE. LICOM represents the combined expertise of four institutes: HSG-IMIT, IMTEK, Chair for MEMS Applications, Cranfield Biotechnology Centre, Cranfield University and CSEM. The consortium claims to be among the international leading development providers in microfluidics, to be one of Europe's largest R&D (research and development) groups working in the field of microfluidics. It provides R&D, design, manufacturing, consultancy and training services. It ran a 1st LICOM Microfluidic Symposium in Hanover on April 22nd 2004, and one contribution by Kleinlogel (2004) of the Swiss company Sensirion AG was on flow sensors. Further details of the Symposium and downloads are available from http://www.licom.net/index.asp.



8.3 Intellidrug The Intellidrug project (www.intellidrug.org) is aimed at developing an intelligent micro- and nano- system to provide an alternative approach for the treatment of addiction and chronic diseases. It is proposed to developing an intraoral micro-system, which contains a medication replacement reservoir and releases the medication in a controlled, intelligent manner in periods lasting days, weeks or months. The micro-system comprises a medication release mechanism, a built-in intelligence, micro-sensors to monitor the rate of release, micro-actuators, and a remote control. The project partners are: Assuta Medical Centres (IL) Fraunhofer IBMT (D) Relsoft Systems Ltd. (IL) Hahn-Schickard-Gesellschaft – Institute for Micromachining and Information

Technology – HSG-IMIT (D) Valtronic SA, Les Charbonnieres (CH) Warsaw University of Technology, Faculty of Chemical and Process Engineering (PL) University of Palermo (I) Karma Pharm (IL) Medical Technology-Promedt Consulting GmbH (D) ASM – Market Research and Analysis Centre Ltd. (PL) Hospital Clinico San Carlos, Madrid (E) Charite – Universitaetsmedizin Berlin (D) Federico II University of Naples, The Department of Odontostomatological and

Maxillofacial Sciences (I) Israel Anti Drug Authority – IADA (IL) 8.4 UK Lab on a Chip Consortium Lab on a Chip is a Foresight LINK-funded collaborative research project on miniaturisation of chemical analysis and synthesis to improve throughput, performance and accessibility and significantly reduced costs. It involves a UK consortium of eleven companies and seven universities, coordinated by LGC with the University of Hull. The Royal Society of Chemistry Lab on a Chip Network, at http://www.chemsoc.org/networks/locn/, contains more general information and links. 9 OTHER APPLICATIONS OF MICROFLUIDIC SENSORS Much of the impetus for development of micro-scale sensor has naturally come from microfluidics applications such as lab-on-a-chip. However there are also macro-scale situations in which a micro-scale sensor can be applied, for example, measurement in confined spaces or where minimal intrusion into a flow or low pressure drop are required. The BAe Systems (http://www.baesystems.com/engineering/examples/mems.htm) website describes the development of micro-sensors using MEMS. One application is flow sensors for monitoring a pilot's breathing and measuring the supersonic flows of his aircraft.



10 FUNDED RESEARCH IN THE UK 10.1 EPSRC The following EPSRC funded project is related to microfluidics: Fluid Flow and Heat Transfer in Gas Microsystems Principal Investigator: Professor JM Reese (University of Strathclyde) Other Investigators: Dr DR Emerson, Dr RW Barber (Daresbury) Abstract: Microengineering is set to revolutionise the control and analysis of biological, chemical, aerodynamic and other industrial processes. However, a range of important micron-scale gas flows cannot be effectively modelled at present: the Navier-Stokes equations with no-slip boundary conditions do not apply to these far-from-equilibrium systems. The applicants propose, therefore, constructing and exploring a new mathematical model built upon higher order governing equations derived from fundamental kinetic theory. We will also investigate novel forms of the slip boundary conditions for solid surfaces. After testing this model against published experimental data, we will use it to examine a range of gas flows in industrially-relevant MEMS geometries, focussing on uncovering new phenomenological information. Starts: 1 January 2004 Ends: 31 December 2006 £ Value: 197,521 10.2 Faraday Partnership Multiphase flows in flexible channels Industrial collaborators: Unilever Academic collaborators: University of Nottingham Initiated : 28/06/04 The aim of this Faraday Partnership project is to develop theoretical models to describe multiphase flows in flexible microchannels found in biological and engineered networks. Asymptotic and numerical techniques appropriate to free surface flows and flow-structure interactions will be exploited to understand the complex dynamics of instabilities in these systems. The work is directed towards improved design of high-throughput microfluidic devices and improve understanding of drug delivery and the release of nutrition or flavour from foods in the small intestine. 10.3 Other UK Research According to Luff et al (2004), the following other research groups in the UK area developing microfluidic technologies for sensor applications:

• The University of Hull, Department of Chemistry: Glass microfluidic devices for immunoassays and immobilised cell sensors. Reactions are interrogated electrically and optically (absorption).

• The University of Wales, Microengineering and Laboratory-on-a-Chip Research

Group: Techniques for the real time monitoring of the toxicity of chemical agents against microorganisms and biofilms, and assays for detecting the presence of micro-organisms in water.



• The University of Southampton, Department of Electronics and Computer Science: Microfluidic pumps, valves, flow meters and mixers in silicon.

• The University of Birmingham: Simulations and experimental studies of

microfluidic flow 11 KEY SOURCES The website http://www.myfluidix.com/ provides an extensive set of lecture notes in PowerPoint form covering all aspects of microfluidics in considerable depth. http://www.microfluidics-roadmap.com/ is the website of the Flowmap project. http://www.microfluidics.de/index.asp is the website of the Licom consortium. A link to the Stanford Laboratories, with many other links to PIV is http://microfluidics.stanford.edu/piv.htm. The following book is about to be published: Microscale Diagnostic Techniques Breuer, Kenny (Ed.) 2005, Approx. 280 p., Hardcover, Springer, ISBN: 3-540-23099-8 Due: November 16, 2004 12 CONTACTS Key contacts in the UK in relation to the fluids aspects of microfluidics are:

• Cranfield Biotechnology Centre, Cranfield University, Silsoe (partner in FlowMap project)

• University of Hertfordshire (Dr Mark Tracey)

• University of Southampton:

http://www.micro.ecs.soton.ac.uk/activities/mems/fluid/

• Daresbury Laboratory (Dr David Emerson). Contacts from the DTI UK MNT Directory (http://www.mnt-directory.org/, search on Microfluidics) are listed in the Appendix. 13 CONCLUSIONS The latest research indicates that liquid flows of Newtonian fluids are well represented by conventional theories of continuum fluid mechanics in channels with characteristic dimensions down to at least 50 µm and possibly much smaller. With gas flows the conventional assumption of no-slip at the wall starts to break down for air at room conditions at a characteristic dimension of about 70 µm. This means that gas flows in microfluidics devices are on the borderline of the point at which the no-slip condition at



the wall breaks down. An EPSRC-funded project at Strathclyde University and Daresbury is addressing the modeling of gas flows in this regime. In relation to flow diagnostics it appears that Micro PIV is fairly well advanced, but that it is currently limited by particle size and limitations in resolution. Computational Fluid Dynamics packages are available for the three–dimensional analysis of low in microfluidics devices, and the packages also incorporate the coupling of the equations describing electro-hydrodynamic, chemical and biological effects with the flow equations. The extent of validation of these packages for microfluidics is most probably very limited. Sophisticated flow sensors are available from a limited number of specialist companies for measurement of ultra low flows in capillaries and micro-channels. Currently it seems that a purchaser must rely on the manufacturer’s calibration. REFERENCES Adrian, R.J., Yamaguchi, E, Vanka, P., Plattner, T. and Lai, W. (2004) “Validation of Micro PIV Measurements in PDMS Micro-channel Flow Geometries”, 12th International Symposium on Applications of Laser Techniques to Fluid Mechanics, Lisbon, 12-15 July 2004, paper 05_02. Barber, R.W. and Emerson, D. R. (2002) “The influence of Knudsen number on the hydrodynamic development length within parallel plate micro-channels”. Advances in Fluid Mechanics IV, WIT Press, pages 207-216. Devasenathipathy, S. and Santiago, J.G. (2004) “Electrokinetic Flow Diagnostics”, in “Micro- and Nano-Scale Diagnostic Techniques,” Ed. K.S. Breuer, Springer Verlag, New York. Eason, C., Dalton, T., O'Mathuna, C., Davies, M. and Slattery, O. (2004), “Direct Comparison Between a Variety of Microchannels: Part 2 - Experimental Description and Flow Friction Measurement”, ICMM2004-2330, Microchannels and Minichannels – 2004, June 2004, Rochester, New York USA Kleinlogel, C. (2004) “Flow Sensors for Microfluidic Applications based on CMOSens Technology”, Sensirion AG, Zürich, Switzerland, 1st Microfluidic Symposium, Hannover Fair 2004. Luff, J., Cumpson, P., Cross, M. and Brook, R. (2004) “SENSCOPE Strategic Scoping Study on the Convergence of Enabling Technologies: Microsystems, Nanotechnology and Sensors, Report and Roadmap”, Sira Ltd., 2004. Meinhart, C.D, Wereley, S.T. and Santiago, J.G. (1999) “PIV Measurements of a micro-channel flow,” Experiments in Fluids, Volume 27, pages 316 -319. Santiago, J.G., Wereley, S.T., Meinhart, C.D., Beebe, D.J. and Adrian, R.J. (1998), “A particle image velocimetry system for microfluidics”, Experiments in Fluids, Volume 25, pages 414-419. Sharp, K.V. and Adrian, R.J. (2004) “Transition from laminar to turbulent flow in liquid filled microtubes”, Experiments in Fluids, Vol. 36, pages 7410747



Tabeling, P. (2001) “Some basic problems of microfluidics”, 14th Australasian Fluid Mechanics Conference, Adelaide, 10-14 December 2001. VanDeGoor, A. A. A. M. (1992) “Capillary Electrophoresis of Biomolecules; Theory, Instrumentation and Applications.” Ph.D. thesis, Eindhoven University of Technology, The Netherlands. Wereley, S.T. and Meinhart, C.D. (2004) “Micron-Resolution Particle Image Velocimetry”, in “Micro- and Nano-Scale Diagnostic Techniques,” Ed. K.S. Breuer, Springer Verlag, New York.



APPENDIX I



Contacts from the DTI UK MNT Directory (http://www.mnt-directory.org/) search on Microfluidics) are as follows: Dr David Anderson TTP Dr John Attard Xaar Plc Mr Glenn Barrowman Photonics Cluster (UK) Prof Jeremy Baumberg School of Physics & Astronomy

University of Southampton Dr Mark Baxendale Physics

Queen Mary, University of London Dr Mark Begbie Design Group, Institute for System Level Integration [ISLI] Mr Edward Bell Crown Bio Systems Mrs Nicola Booton-Mander

Services Business Unit Oxford Gene Technology (Operations) Limited

Prof Robert Brown Queen's University Belfast Mr Steve Byars Innos Limited Mr Richard Carter INEX Dr Brendan Casey Kelvin Nanotechnology Ltd Mr Geoffrey Clark Patterning Technologies Limited Dr Alison Crossley Oxford University

Oxford Materials Characterisation Service Dr David Cullen Institute of BioScience and Technology

Cranfield University Dr Keith Davies Markab Mr Mike Day Advanced Microsystems Engineering, QinetiQ Ltd Dr Marc Desmulliez MicroSystems Engneering Centre, Heriot Watt University Dr Resham Dhariwal Electrical, Electronic and Computer Eng, Heriot-Watt

University Mrs Sue Dunkerton Advanced Materias and Processes Group, TWI Ltd Dr Steve Dunn Nanotechnology, Cranfield Uniersity Mr Barry Eggington Photoelectroforming & Microstructures, Tecan Ltd Mr Leslie Embury Gwent Electronic Materials Ltd. Dr David Emerson Computational Science and Engineering

Centre for Microfluidics & Microsystems Modelling Mr Tom Empson The Generics Group Mr Geraint Evans Manufacturing Engineering Centre, Cardiff University Dr Alan Ferguson Oxford Lasers Ltd Mr Alan Finlay Microsaic Systems Ltd Mr Colin Freeland Elliot Scientific Ltd



Dr Yiton Fu Corporate Research, Unilever R&D Prof Julian Gardner School of Engineering, Warwick University Mr John Gilbert JEOL (UK) Ltd. Mr Andrew Gurnell Research & Industry Office, University of York Mr Robert Gusthart Innovation Architects Prof John Hay Chemistry, University of Surrey Mr Roger Hazelden Advanced Sensing and Control, TRW Conekt Dr Mike Holmes Inst. for Bioelectronic and Molecular Microsystems Mr Stephen Holton The Centre for Integrated Photonics Prof John Barry Hull Business Development Unit

Nottingham Trent University Mr Iain Hyslop SSTRIC Ltd Dr Michael Johnson Engineering & Instrumentation

CCLRC, Rutherford Appleton Laboratory Prof Richard Jones University of Sheffield Mr Christopher Lamaison Cambridge Resolution Ltd Mr Simon Lau Lasers Are Us Dr Simon Lawson Industrial Centre of Particle Science & Engineering

University of Leeds Mr Len Lewell Microsytems & Nanotechnology Professional Network Mr Darian Mauger Centre of Excellence, Taylor Hobson Precision Dr Alastair McGibbon National Microelectronics Institute Prof Kevin O'Grady Physics, University of York Mr Andrew Pacey AdvoTek Ltd Dr Jed Place Medical Device Technology Consultants Prof Alan Purvis Engineering, University of Durham Dr Philip Rayner Tecray Dr Andrew Richardson Engineering, Lancaster University Dr Clive Roberts School of Pharmacy, The University of Nottingham Dr Tim Ryan Epigem Limited Mr Rob Santilli Appled Microengineering Ltd (AML) Mr Derek Sharp AZoNano - The A to Z of Nanotechnology Dr Carolyn Short Surface Technology Systems plc Dr Keith Simons Crystal Faraday Dr Ian Sturland MEMS DEvices Group

BAESystems plc, Advanced Technology Centre Mr Harry Swan Carbon Nanomaterials, Thomas Swan & Co. Ltd. Mr David Tolfree Commercial Technoprenur Ltd Mr Ian Tonge IDC Dr Mark Tracey Science and Technology Research Institute



University of Hertfordshire Mr Amer Vohora First Stage Capital Dr Nicholas Walker iXscient limited Prof Anthony Walton School of Engineering and Electronics

Institute for Integrated Micro and Nano Systems Prof Roger Webb Advanced Technology Institute

Surrey Ion Beam Centre Prof Roger Whatmore Advanced Materials

Cranfield University Mr Nick White Qudos Technology Ltd,eg. Quick Design On Silicon Prof Richard Williams Leeds Institute of Nanomanufacturing

University of Leeds

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