Microfluidics Meets MEMS - Semantic Scholar€¦ · Microfluidics Meets MEMS ELISABETH VERPOORTE AND NICO F. DE ROOIJ, FELLOW, IEEE Invited Paper The use of planar fluidic devices

Microfluidics Meets MEMS

ELISABETH VERPOORTEAND NICO F. DE ROOIJ, FELLOW, IEEE

Invited Paper

The use of planar fluidic devices for performing small-volumechemistry was first proposed by analytical chemists, who coinedthe term “miniaturized total chemical analysis systems” (�TAS) forthis concept. More recently, the�TAS field has begun to encom-pass other areas of chemistry and biology. To reflect this expandedscope, the broader terms “microfluidics” and “lab-on-a-chip” arenow often used in addition to�TAS. Most microfluidics researchersrely on micromachining technologies at least to some extent to pro-duce microflow systems based on interconnected micrometer-di-mensioned channels. As members of the microelectromechanicalsystems (MEMS) community know, however, one can do more withthese techniques. It is possible to impart higher levels of function-ality by making features in different materials and at different levelswithin a microfluidic device. Increasingly, researchers have con-sidered how to integrate electrical or electrochemical function intochips for purposes as diverse as heating, temperature sensing, elec-trochemical detection, and pumping. MEMS processes applied tonew materials have also resulted in new approaches for fabricationof microchannels. This review paper explores these and other devel-opments that have emerged from the increasing interaction betweenthe MEMS and microfluidics worlds.

Keywords—Lab-on-a-chip, microfluidics, microfabrication,micromachining, miniaturized total chemical analysis systems(�TAS), review .

I. INTRODUCTION

Though there exist early, pre-1990 examples of microelec-tromechanical systems (MEMS)-type microfluidic devicesfor chemical applications, it was the groundbreaking paperof Manzet al. [1] in 1990 that established the field of minia-turized total chemical analysis systems (TAS). The TASconcept is an extension of the total chemical analysis systemconcept (TAS), which was put forth in the early 1980s toaddress the issue of automation in analytical chemistry [2].

Manuscript received February 26, 2003; revised April 4, 2003.E. Verpoorte was with the Institute of Microtechnology, University of

Neuchâtel, CH-2007 Neuchâtel, Switzerland. She is now at the GroningenResearch Institute of Pharmacy, University of Groningen, 9713 AVGroningen, The Netherlands (e-mail: [email protected]).

N. F. de Rooij is with the Institute of Microtechnology, Uni-versity of Neuchâtel, CH-2007 Neuchâtel, Switzerland (e-mail:[email protected]).

Digital Object Identifier 10.1109/JPROC.2003.813570

To simplify the job of the analytical chemist, the TAS con-cept proposed the full incorporation of analytical proceduresinto flowing systems. Carrier streams of fluids, rather thanhuman hands, take over the role of sample transport betweendifferent sample manipulation steps. Flow paths are definedby interconnected pieces of tubing, arranged in such a waythat the desired analysis can be performed. TheTAS is asmaller, faster version of this, with analyses taking placein flow systems having L and even sub-L volumes, toachieve times on the order of seconds rather than many min-utes. The devices used are small and monolithic in nature.Three-dimensional (3-D) tubing-based systems are replacedby networks of microchannels integrated into planar sub-strate surfaces, with cross-sectional dimensions generallyon the order of micrometers. Though still in its infancy, theinterest in this technology has grown explosively over thelast decade, with an increasing number of special symposiaand conferences dedicated to the subject. Researchers frommany disciplines other than analytical chemistry have alsowholeheartedly embraced the fundamental fluidic principleof TAS as a way of developing new research tools forchemical and biological applications. This has led, amongother things, to the emergence ofTAS-like fluidic struc-tures in microreactor technology. It has also resulted in theintroduction of new terminologies and concepts. “Microflu-idics,” or alternatively, “lab-on-a-chip” (LOC), are recentmonikers that have entered theTAS jargon, and are in-creasingly used in place ofTAS as general terms for thefield. This development is in fact a tacit acknowledgment,perhaps, that the use of microflow systems has long sinceceased to be the domain of the analytical chemist alone.

The ability to make networks of interconnecting channelsis what lies at the heart of microfluidics, and makes it sopowerful. The crucial enabling technologies came first fromthe world of MEMS, where the use of photolithographicprocesses to obtain micrometer features in silicon and othersubstrates was well established. The first successful demon-stration of chip-based analysis in the early nineties involvedthe fast separation of fluorescent dyes [3], [4] and fluores-cently labeled amino acids [5] by capillary electrophoresis(CE). This technique, based on the separation of charged

0018-9219/03$17.00 © 2003 IEEE

930 PROCEEDINGS OF THE IEEE, VOL. 91, NO. 6, JUNE 2003

Fig. 1. Video imaging of sample loading, injection, and separationby micellar electrokinetic capillary chromatography (MECC) in asimple cross injector geometry. Separation is effected by interactionof the analyte with micelles composed of the surfactant, sodiumdodecyl sulfate (SDS), which was added to the run buffer. Withtheir hydrophobic interiors and charged surfaces, the micellesare aggregates which act as a pseudostationary phase transportedelectrokinetically in the electric field. Channels are�40�m wideand 10�m deep, so that the injected plug volume is�20 pL. Thevertical channel is filled with sample containing�2 mM eachof glycine (Gly) and arginine (Arg), both fluorescently labeledwith fluorescein isothiocyanate (FITC). The horizontal channelcontains MECC buffer [75-mM SDS, 10-mM NaHPO , and6-mM Na B O (pH 9.2)]. Arrows indicate direction and relativemagnitudes of the flows induced by application of voltages at theends of these channels. The spot visible in the intersection in imagesC and D is due to reflection of laser light from an imperfection inthe microchannel surface. (Reprinted with permission from [7].Copyright 1996 American Chemical Society.)

species according to their different mobilities in an appliedelectric field, is performed in liquid-filled capillaries. CEis particularly well suited to the chip format for a numberof reasons. For one thing, the electric fields used to sepa-rate species electrophoretically also generate a bulk flow ofliquid, known as electroosmosis [6]. Electroosmotic flow(EOF) is thus the mechanism by which liquids are movedfrom one end of the separation capillary to the other, ob-viating the need for mechanical pumps and valves. Thismakes this technique very amenable to miniaturization, asit is far simpler to make an electrical contact to a chip viaa wire immersed in a reservoir than it is to make a robustconnection to a pump. More important, however, is that allthe basic fluidic manipulations that a chemist requires formicrochip electrophoresis, or any other liquid handling forthat matter, have been adapted to electrokinetic microfluidicchips. This is illustrated in Fig. 1, which shows the forma-tion of a 20–pL injection plug containing two fluorescentspecies and the subsequent separation of the two analytesin just 160 ms [7].

Precise liquid pumping and handling may also be accom-plished using applied pressure or centrifugal force. As anillustration, Fig. 2 shows the squeezing or “hydrodynamicfocusing” of a fluorescent sample stream at a channel inter-section using two buffer flows from side channels [8]. Pres-sures were applied at the ends of the inlet and side channelsto generate liquid flows. The width of the resulting focusedsample stream is determined by the ratio of pressures appliedto the side channel and to the inlet. Widths as small as 50 nmwere observed, ensuring fast diffusion of molecules in theside streams across the sample stream to achieve ultrafast

s mixing. It is also clear that controlleds dilution may

Fig. 2. (a) Fluorescence microscope image of hydrodynamicfocusing in an intersection of microchannels made in silicon (thechannels are outlined with a dashed line). The side and outletchannels are 10�m wide, while the inlet channel terminates in a2-�m nozzle. All channels are 10�m deep. The sample contained5-carboxyfluorescein, a fluorescent dye.w is the width of thechannel;w is the width of the focused inlet stream. Inlet pressureis 5 psi; side pressure is 5.5 psi. (b) Images of the 3-D structure ofthe focused sample stream as a function of side pressure, obtainedby confocal scanning microscopy. Inlet pressure is 5 psi. Sidepressure of (a) is 2.5 psi; (b), 5.0 psi; (c), 5.5 psi; and (d), 6.0 psi.(Reprinted with permission from [8]. Copyright 1998 AmericanPhysical Society.)

be carried out in this fashion. As this example proves, pres-sure-driven flow may also be effectively used to carry outthe necessary liquid handling required for chemical applica-tions, though it is somewhat more difficult to implement inconjunction with microfluidic devices. The use of capillaryforces or well-defined surface tension gradients is also at-tracting more attention, as this is a passive means of movingliquids in small channels.

One of the most evident trends in the microfluidics worldis that of increasing complexity in the microchannel archi-tectures being used. Since the majority of devices do not fea-ture on-board valves, this requires very precise control in allbranches of the networks, a very challenging aspect of thistechnology. Some novel valving approaches have been pro-posed, which may facilitate development of these systems.

The true TAS or LOC, however, is still a long way off,for a number of reasons. First of all, the ability to work withreal samples from start to finish in a microfluidic device,in a hands-off sort of way, is usually very difficult. This isbecause many “real” samples are inherently incompatiblewith small channels, due to the presence of large particles orwall-adsorbing molecular species that could lead to clogging.The other issue holding back the development of sample pre-

VERPOORTE AND DE ROOIJ: MICROFLUIDICS MEETS MEMS 931

treatment on chips is the sheer variety of samples with whichthe chemist or biologist is confronted. There will be no oneuniversal approach to solving this problem on microfluidicdevices, just as there has been no universal solution in theconventional chemistry laboratory.

Second, if one defines the LOC to be an entity that shouldbe able to perform all chemical functions and detection ina monolithic device that fits in the palm of your hand(or smaller), then existing devices are generally still quiteunderdeveloped. This miniaturization will require increasedintegration of not only fluidic elements, but also electrical,optical, or other types of elements into microfluidic devices.The MEMS world has amply demonstrated the integration ofmechanical and electrical functionality into small structuresfor diverse applications. The aim of this review is to examinemore closely the role that MEMS technologies have playedto date not only in the fabrication of microchannels indifferent substrate materials, but also in the integration ofelectrical function into microfluidic devices.

II. PASSIVE MICROFLUIDIC ELEMENTS

The most basic elements of a microfluidic device are themicrochannels and microchambers themselves. These arepassive fluidic elements, formed in the planar surface ofthe chip substrate, which serve only to physically confineliquids to nL- or pL-volume cavities. Interconnection ofchannels allows the realization of networks along whichliquids can be transported from one location to another on adevice surface. In this way, small volumes of solution maybe introduced from one channel into another, and controlledinteraction of reactants is made possible.

Analytical chemists turned to microfabrication tech-niques to be able to design and construct the microchannelmanifolds required to satisfy the very stringent volumedemands of TAS. This technology, the foundation onwhich the MEMS field has been built, includes basic ICtechniques, namely, film formation, doping, lithography,and etching, developed four decades ago for the microelec-tronics industry. In addition, special etching and bondingprocesses that permit the sculpting of 3-D microstructureswith micrometer resolution have been and continue tobe developed [9]–[12]. Micromachining technologies areprimarily silicon-based, due both to the traditional roleof this semiconductor in IC technology and its excellentmechanical properties [13]. Silicon is thus unique, as itmakes the combination of mechanical and electrical functionin single devices possible, providing the impetus for theenormous activity over the past almost three decades in thearea of MEMS. In a parallel development, the high precisionobtainable with micromachining processes has led to theirapplication in the patterning of materials other than silicon.Thus, ceramics, plastics, quartz, and glass are graduallybecoming accepted complementary materials to silicon,widening the potential range of applications of microfab-ricated components and systems. This section considerssome examples of micromachining methods that have beenused for the formation of micrometer-dimensioned fluidicchannels in various substrate materials.

A. Microchannels in Silicon

Silicon micromachining can be divided into two cate-gories, depending on what region of the wafer is beingworked. Bulk micromachining refers to those processeswhich lead to structures in the single-crystal wafer, whereassurface micromachining results in structures located onthe wafer surface. Bulk micromachining methods fall intofour categories, namely wet isotropic, wet anisotropic, dryisotropic, and dry anisotropic [11], [12]. Isotropic methodsare those characterized by etch rates which are more orless equal in all directions. Anisotropic methods, on theother hand, have etch rates which are significantly fasterin a particular direction or directions. Wet etching involvesdipping the silicon wafer into a solution containing theetchant. The etchant may etch certain crystal planes fasterthan others (e.g., KOH, tetramethylammonium hydroxide).In this case, the side walls of the resulting structure aredefined by the slowest etching crystal planes. For wafersof 100 orientation, for example, channel geometries aretrapezoidal, with side walls corresponding to the111planes. For 110 wafers, the different orientation of the111 planes makes deep, rectangular channels possible.

The isotropic wet etching solution most commonly usedis known as HNA, and contains hydrofluoric acid (HF),HNO , and acetic acid. The resulting channels have roundedside walls, and are wider than they are deep, since etch ratesare equal for all crystal planes. A discussion of the furtherintricacies of silicon micromachining using wet etchingtechniques is beyond the scope of this review. Ampledetailed examples are given in [9]–[12].

Reactive-ion etching (RIE) processes are dry, relying onexternal RF power applied to a pair of plates to acceleratestray electrons in the gas between them. The kinetic energyof the electrons is augmented in this way to levels that allowchemical bonds in the reactant gases to be broken, leadingto the formation of reactive ions and radicals. The waferto be etched is placed between the plates to be exposed tothis reactive plasma. Depending on the conditions, etchingcan be achieved chemically, by reaction of fluorine freeradicals with the surface, for example, or physically, throughbombardment of the surface with high-energy ions [11],[12]. These processes can be fully or partially isotropicor anisotropic. One type of RIE, termed deep reactive-ionetching (DRIE), has gained in popularity in recent years.DRIE is a very high-aspect-ratio etching method for silicon,with aspect ratios of up to 30:1 (height:width) possible.This is because the plasma is highly dense. In addition, thereactive ions are accelerated by applying a bias voltage to thewafer, so that they bombard the wafer surface vertically. Asa result, very thin, tall structures and trenches can be formedwith this technique, at typical etch rates of 2–3m/min[14]–[16].

Microfluidic channels in silicon made by wet or dryetching processes are generally sealed using a glass coverchip, since this facilitates visual interrogation of fluidswithin the device. Bonding in this case is accomplished byfield-assisted or anodic bonding [11], [12]. This involves


applying a voltage of between 200 and 1000 V over thesilicon/glass assembly, with the cathode (negative electrode)on the glass side. The components to be bonded are heated atthe same time to a temperature between 180C and 500 C.Under these conditions, the glass becomes more conductive,and Na ions in the glass migrate more rapidly toward thecathode (that is, away from the glass–silicon interface).This results in a large electric field at this interface, whichpulls the two surfaces together. Covalent bonds between thesilicon and glass are formed due to the elevated temperatureand applied electric field, although the mechanism is stillnot so clearly understood. Pyrex 7740, a borosilicate glass,has been the material of choice for anodic bonding. Thisis because its thermal expansion coefficient nearly equalsthat of silicon. The use of glues or other adhesive layersto seal devices is not so common, as these approaches aregenerally not so clean and can result in contamination oreven clogging of channels.

It is not surprising that some of the first microfluidic chan-nels were made in silicon [17]–[19], given the role that siliconplays in MEMS. (In fact, the 2-in silicon gas chromatographdeveloped by Terryet al. [17] predated the introductionof the TAS concept by 11 years.) In [18], standard etchtechniques were used to form channels in100 -orientedmonocrystalline silicon, involving anisotropic etching usingeither KOH or ethylenediamine/pyrocatechol. However, theuse of silicon is generally incompatible with electroos-motic pumping (EOP), which quickly became the methodof choice for liquid transport in microfluidic devices in the1990s (see preceding text). Typical linear flowrates fall inthe range of micrometers per second to several millimetersper second, with the required electric fields usually quitehigh, corresponding to hundreds of volts per cm. Channellengths on the order of mm to cm thus necessitate appliedvoltages which often exceed 1000 V. The substrate usedmust therefore have excellent electrical insulating qualities.Since silicon itself is a semiconductor, its usage is lim-ited by the quality of the insulating layers of silicon oxideand/or nitride that can be deposited on the surface. Generallyspeaking, even good quality, pinhole-free insulating layerswith thicknesses up to 1 m suffer dielectric breakdownat applied voltages of 720 V or less [18]. Silicon has thusgenerally not been applied for electroosmotically controlledmicroflow manifolds.

There are a few notable exceptions in the literature,however, where silicon-based devices were used success-fully in conjunction with low field strengths (100 V/cm)for electrokinetic separations. These include demonstra-tions of free-flow electrophoresis of amino acids [20] andproteins [21] [see Fig. 3(a) and 3(b)], and DNA analysisby synchronized cyclic capillary electrophoresis [22] andgel electrophoresis [23], [24]. Recently, Petersenet al.reported microchip electrophoretic separation of caffeine,paracetamol, ketoprofen, and ascorbic acid in a siliconchannel sealed with glass, using an electric field strengthof 550 V/cm over a channel 3.5 cm long [25]. In this case,the silicon was coated with a waveguiding layer consistingof 15 m of thermal oxide, followed by 6 m of silicon

oxynitride, and finally 4 m of undoped silica. Channels(12 m deep) were etched into this layer by RIE, leaving a13- m-thick thermal oxide layer between the channel andthe silicon substrate.

Pressure-driven flow applications have also been imple-mented in silicon chips, notably liquid chromatography (LC)[see Fig. 3(c)–3(e)], [26]–[31], optical detection cells [32],[33], microreactors [34]–[37], and miniaturized flow injec-tion analysis ( FIA) [38], [39] (see also Section III-B3).Examples of gas chromatography (GC) chips may also befound in the literature [17], [40]–[43]. When high-aspectratio depth:width 1 channels in silicon are desired,DRIE is the method of choice. Daridonet al. used DRIEto fabricate a microflow system for ammonia analysis inglass/silicon/glass devices [44]. Deep, narrow channels30 m wide and 220 m deep made up the first part of thesilicon-based network, in which reagents were added to thesample zone. This was done in a side-on fashion, yieldingtwo 15- m-wide curtains of solution running side-by-sidedown the channel. Diffusion distances of sample and reagentmolecules were reduced in this way, allowing completemixing of solutions in less than 1 s by diffusion alone. Tobe able to perform absorbance detection of the chemicallyconverted ammonia compound, a small-volume, long-path-length optical cuvette was required. A small-diameter holewas etched by DRIE through the silicon wafer to form thiselement, which as a result had an optical pathlength equiva-lent to the wafer thickness. A recent publication by Junckeret al. describes a microfluidic capillary system formed byDRIE, designed to autonomously transport liquids fromone end to the other by capillary forces [45]. The principlewas demonstrated using a heterogeneous immunoassayfor a cardiac marker, which could be performed within 25min. DRIE has also been used to fabricate surface-areaenhancing structures in silicon microchannels for extractionand catalyzed reactions, in the form of arrays of staggered,narrow silicon columns (see also Section III-B2). Thesereplace packed-bed designs, in which a channel is packedwith particulate material. In one example, the columns wereused to extract DNA from solution in a sample pretreatmentstep [46]. Multiphase microreactor devices have also beenbased on this principle [34]. Of course, arrays of smallholes through a wafer are also possible, as Thiébaudet al.demonstrated in a device made for electrophysiologicalmeasurements of slices of rat brain [47]. Diffusion ofnutrient medium from a reservoir under the chip to the cellson top of the chip was assured in this way.

B. Microchannels in Glass and Quartz

Glass is a much better material, electrically speaking,for microfluidic devices utilizing electrokinetic sampletransport. This, combined with the fact that it is opticallytransparent, has made it one of the main materials used inmicrofluidics today. Pyrex 7740, a borosilicate glass foundin many cleanrooms, has been popular for glass microfluidicdevices. From a fabrication point of view, however, therehas been no limitation noted so far as to the type of glass


Fig. 3. (a) Free-flow electrophoresis device made in silicon and sealed anodically with glass. Thephotograph was taken through the glass cover. 1 marks the separation bed (50 mm long, 10 mm wide,50�m deep); 2, the array of 125 inlet channels; 3, the electrode chambers (50 mm long, 2 mm wide,50�m deep); 4, the arrays of 2500 channels separating electrode chambers from separation bed; 5,the array of 125 outlet channels; 6, the sample inlet; 7, the buffer inlets; 8, the buffer outlet; 9,common waste. (b) Scanning electron micrograph (SEM) of a corner of the separation bed whereboth inlet channels (left) and 2500-channel array (right) enter it. The inlet channels are 70�m wide(across the top) and 50�m deep; the channels to the electrode chamber are 12�m wide (acrossthe top), 10�m deep, and 1 mm long. (c) Assembled silicon/glass chip for small-volume liquidchromatography. The separation channel (long horizontal channel) is 20 mm long, 300�m wide, and100�m deep (490 nL); the injector is the channel element on the right; the detector cell (2.3 nL,1 mm long, designed for absorbance detection) is at the end of the separation channel on the left.(d) SEM showing the end of the separation column and entry into the detector cell. Two arraysof 58 fine channels serve as a frit to retain particles in the separation channel. Note that the deadvolume between the end of the column and the cell is about 140 pL, so that this dead volume isminimized. (e) SEM of a detail of the frit. These channels were 3.2�m wide, 1.4�m deep, 1.6�mapart, and 19�m long (volume of each channel: 59 fL). It was possible to retain particles largerthan 3�m in the column with this barrier.


Fig. 4. (a) Schematic diagram of the process flow used for glass micromachining in the authors’laboratory. This process differs from others in that a polysilicon etch mask is used, rather than a metalmask. (b) SEM of a double-T intersection etched in glass, used to perform volume-defined injectionin microchip electrophoresis (see Fig. 1). Channels are about 50�m wide across the top and 20�mdeep. The intersection is 200�m long, allowing the definition and injection of 165-pL sample plugs.(c) SEM showing a channel cross section, again about 20�m deep and 50�m wide at its widestpoint. The channel was thermally sealed with a second glass wafer. Note that there is no visiblebonding interface, indicating that the wafers have been hermetically sealed. (d) View of one full�FIA structure and partial views of two others. These devices consisted of three layers of glass,with interconnecting vias and holes made by spark-assisted etching. Channels were 200�m wideand 30�m deep. The networks are relatively complex, allowing reagents to be added to a samplestream, and sufficient time for reaction before passage through an integrated optical cuvette. (Photo:A. Daridon, IMT, University of Neuchâtel, Neuchâtel, Switzerland).

that can be used, as long as it is available in the form ofsmooth, planar substrates. Microfluidic devices made infused silica (quartz) have also been reported. This materialis attractive because it is UV-transparent, a characteristicwhich makes it superior to glass. Photolithographic pro-cesses similar to those used for silicon can be employedfor the patterning and subsequent transfer of channels intoplanar glass and quartz wafer surfaces.

The glass micromachining method established in our lab-oratory is shown in Fig. 4(a). This is based on a process first

developed by Grétillatet al.[48] and has become standard inour work [49]–[51]. Channels are etched into a 10-cm Pyrex7740 wafer using HF, using a 200- or 400-nm-thick layerof polysilicon as a masking layer over areas where etchingis not desired. A typical process flow would proceed asfollows. After deposition of the polysilicon by low-pressurechemical vapor deposition (LPCVD), wafers are dehydratedat 200 C for 30 min and exposed to hexamethyldisilazane(HMDS) vapor for 15 min to improve photoresist adhe-sion. A 1.8- m-thin layer of AZ1518 (Clariant, Muttenz,


Switzerland) positive photoresist is then spin-coated ontothe wafer at 4000 r/min for 40 s and prebaked on a hotplatefor 1 min at 100 C. The resist layer is then patternedphotolithographically by illumination through an opticalmask. Laser-plotted transparency films with a dot size of7 m (DIP SA Repro, Lausanne, Switzerland), mounted onblank 5-in glass plates, serve as photolithography masksfor rapid prototyping applications. When higher resolutionor fine structuring are required, Cr masks with 1- to 2-mresolution are used. In the case of transparency films, theexposure dose is increased to 60 mJ/cm, a value whichis 10% above the recommended value for the resist, tocompensate for the reduced transparency of the laser-plottedfilms. Wafers are then developed for 1 min in AZ351developer (Clariant), which has been diluted 1:4 withdeionized, 18-M (DI-18M) water. This is followed bya rinse in DI water and postbake at 125C for 30 min.RIE is used to transfer the pattern into the polysiliconlayer. After photoresist removal with acetone, the channelstructures are etched into the glass using 49% HF. Finally,the polysilicon layer is removed by dipping the wafer for5 min in 40% KOH solution at 60C. The channels are thenthermally sealed with glass cover-plates containing holesto access the microfluidic network. Once these holes havebeen aligned with the ends of the corresponding channelsin the lower wafer, the two-wafer assembly is placed inan oven for thermal bonding at 650C. After an initialtemperature ramp, the wafers are held at 650C for a coupleof hours. During this time, the wafers are fused together.A slow cooling process is then initiated to prevent thermalstress and the resulting cracking or breaking of wafers. Athorough cleaning procedure to remove both organic andinorganic residues (e.g., micrometer-sized particles fromthe hole-drilling process) from the wafers is critical forachieving good, void-free bonding. Fig. 4(b) shows a SEMof a 200- m-long double-T junction made in glass, socalled because each of the side channels forms a T-shapedintersection with the horizontal channel. An example of thehermetic seal between two wafers that is typically achievedwith thermal bonding is given in Fig. 4(c). Note that there isno visible interface between the wafer surfaces.

Glass etching with HF is isotropic in nature. The resultingchannels have rounded side walls, and widths which aretwice the channel depth plus the width of the initial line onthe etch mask [see Fig. 4(b) and 4(c)]. Channel depths aredetermined by etch times. Typical dimensions are widthsand depths of tens ofm, with channel lengths on the orderof a few cm. The etchants used in glass microfabricationmay vary in composition [52], [53], with mixtures of HF andHNO [54], NH F-buffered HF [55], or concentrated [56]or dilute HF baths being used. Metal etch masks composedof a thin layer of Cr covered by Au are most common [54],[56]. The Cr layer acts as an adhesion layer to better coat theAu onto the glass surface. Polysilicon [48] and amorphoussilicon [56] may also be used as etch mask layers, as de-scribed previously. For very shallow structures, photoresistalone may be adequate to protect the glass surface, althoughit quickly deteriorates in the more aggressive etch solutions

[55], [56]. Quartz devices have been fabricated using similartechniques as those described previously, though the thermalbonding must be carried out at higher temperatures, around1000 C or so [57]–[59].

Alternative glass-to-glass bonding methods are available.For instance, anodic bonding of glass to glass via an inter-mediate, 160-nm layer of silicon nitride at a temperatureof 400 C and a voltage of 100 V has been reported [60].Low-temperature glass-to-glass bonding is possible, using a1% HF solution, wicked in between the wafers, and pressure(1 MPa) at room temperature [61]. Another low-temperatureapproach involves a spin-on layer of sodium silicate solutionas adhesive layer [62], [63]. Spontaneous bonding of thor-oughly cleaned and hydroxylated wafers at room tempera-ture has also been described for both quartz and glass [64].

Generally speaking, channels are formed in one layer andsealed by a second. It is also possible to achieve symmetricalchannel cross sections by mating two surfaces containingchannels [51], [65]. The inclusion of special alignment markson the wafers to be bonded can yield an alignment precisionof 5 m, dictated only by the optical resolution of themask aligner used [65]. Three-layer glass devices forFIA,incorporating through-holes from one layer to the next, and a200- m-diameter optical cuvette formed through the middlewafer, have also been reported [51]. These were made andbonded in the same way as shown in Fig. 4(a). The challengein this case was the formation of holes small enough not tocause dispersion of the sample zone as it passed from onelevel to the next. Particularly critical in this regard was thefabrication of the optical cuvette. Spark-assisted etching,also known as electrical discharge machining, proved to bea valuable tool for making holes as small as 200m indiameter through the 525-m glass wafers. Fig. 4(d) showsseveral bonded devices still in wafer format, before dicing(cutting) of the individual chips. Multilayer glass deviceswith 3-D microchannel networks for chemical synthesisapplications have also been reported by Kikutaniet al.[66], [67]. The “pile-up” glass microreactor described in[67] contained ten layers of microchannel circuits, whichwere thermally bonded all at once in much the same wayas described previously.

RIE of quartz has been employed to produce a liquidchromatographic chip with an array of 10-m-high,5- m 5- m rectangular columns to act as support forthe stationary phase in the 4.5-cm-long, 150-m-wideseparation channel [68]–[70]. Fig. 5 is a SEM of this typeof device, taken at the entrance to the separation column.It clearly shows how the inlet channel is bifurcated severaltimes to ensure even solution distribution over the arrayof diamond-shaped pillars at the top of the photo. Chro-matographic performance was good [68], and peptidesstemming from the tryptic digest of ovalbumin could beseparated [70]. DRIE of Pyrex has recently been wellcharacterized, with a 20-m-thick nickel mask being usedto achieve good verticality and aspect ratios greater than10 [71]. Ceriottiet al. also used a nickel mask to fabricate50- m-deep rectangular channels in quartz by inductivelycoupled plasma (ICP)-RIE, using the process flow shown


Fig. 5. SEM of structure designed for microchip chromatography,showing channel layout at the beginning of the column. All featureshave been etched by RIE to a depth of 10�m. (Reprinted in partwith permission from [68]. Copyright 1998 American ChemicalSociety).

in Fig. 6(a) [72]. Detection of fluorescently labeled aminoacids separated electrophoretically in a DRIE quartz channelmuch like that in Fig. 6(b), sealed with an elastomer chip,was demonstrated [73].

Photostructurable glasses such as FOTURAN (Schott)are also interesting materials forTAS, as they allow formicrostructures having aspect ratios of 20:1, and the possi-bility of transformation to a glass ceramic upon heating [74].These materials are inherently photosensitive, and hence donot require a photoresist layer for patterning. Exposure toUV results in the formation of microcrystallites, which cansubsequently be removed by etching in HF. Tips for atomicforce microscopy have been fabricated in this material [75].Channels having a minimum depth of 25m are also pos-sible [74]. Recently, Beckeret al. reported the fabricationof a microchip electrophoresis device in a new type ofphotostructurable glass [76]. A separation of fluorescentlylabeled amino acids was demonstrated in channels whichwere 500 m deep and 200 m wide.

C. Miniaturized Transparent Insulating Channels (TICs)

There are a number of alternative approaches for the fab-rication of insulated microchannels which still use silicon.One of these involves the formation of channels with ex-tremely thin walls ( 1 m) in silicon nitride or oxide, usinga thick ground plate to support these structures [77]–[80].The process used to produce the channels is shown in Fig.7(a). To start, channels are patterned and etched in silicon,using either wet or dry, anisotropic or isotropic methods.The structure on the right in Fig. 7(a) has a geometry whichis characteristic for an isotropic process. The middle and leftchannels, on the other hand, were formed with anistropicprocesses. (Note that the combination of all these channelgeometries in one Si wafer is unrealistic. The geometriesare given to indicate that there is some flexibility in thechoice of profile geometry available when using silicon.This is in contrast to glass, for which anisotropic processesare not yet well established.)

Fig. 6. (a) Process flow for ICP-RIE of 50-�m-deep rectangularchannels in quartz. (b) SEM showing the cross-sectional profile of adry-etched channel in quartz. Width across the top: 50�m. Depth:about 50�m. Conditions for etching had not been optimized in thiscase. It was possible in later experiments to achieve good wallverticality and smooth walls [72].

Once formed, the masking material used to form thechannels is removed from the silicon surface, and the chan-nels are coated with an insulating layer. The silicon wafer isthen anodically bonded via the insulating layer to a Pyrexwafer. After bonding, the silicon is etched away from the


backside using an isotropic etchant, leaving the freestanding,thin-walled microchannels. An early publication describedthe deposition first of a 50-nm-thick layer of silicon nitride,followed by an oxide layer of up to 600 nm [78], to facilitatebonding to the Pyrex. Later work used only silicon nitridelayers of 360 nm [79] or 390 nm [80] to form the channels. Inany case, these channels are electrically insulating, opticallytransparent, and demonstrate very efficient heat dissipation,making them ideal candidates for electrokinetically drivenmicrofluidic applications. Fig. 7(b) and (c) shows SEMs of

TICs molded in an isotropically etched Si channel, anda DRIE channel, respectively. As is evident in Fig. 7(c),

TICs do have the disadvantage that they are fragile. Thismay be overcome by covering the channels with a glue orother polymer layer [77]–[79]. This type of structure hasbeen used for microchip electrophoresis of small cations inconjunction with conductivity detection [79], and for thedemonstration of field-effect flow control in microfabricatedstructures [80].

D. Microchannels by Replication in Poly(Dimethylsiloxane)(PDMS)

Poly(dimethylsiloxane) (PDMS) is a polymer which is be-coming increasingly popular for microfluidic applications,because structures made in this material are inexpensive,easy to handle, and rapidly fabricated by replica moldingunder noncleanroom conditions. The special properties ofthis elastomer, and its use in soft lithography (replication)and micro contact printing (surface patterning by depositionof molecules using stamping techniques) to obtain mi-crometer-sized structures, are described in several reviews[81]–[83]. The use of microfluidic devices replicated insilicone rubber was reported as early as 1989 by Masudaet al. for a biological application involving cell fusion[84]. Fig. 8(a) is a schematic diagram of a typical castingprocedure for replication of microchannels in PDMS.Fabrication of microchannels involves casting a solutionof the PDMS prepolymer onto a master whose surfacehas been structured to yield a topography or surface reliefof some kind. When cured, PDMS faithfully replicates,with nm resolution, the surfaces with which it has been incontact. Microchannels are thus easily formed in PDMS ifthe corresponding master has a raised network of ridges toserve as microfluidic network mold. PDMS has a number ofintrinsic properties which make it interesting for microflu-idic applications. It is, for example, optically transparent inthe UV and visible, from 230 to 700 nm [72], [85]. The gaspermeability of PDMS means that bubbles created insidechannels by electrolysis of water or from other sources maybe dissipated through the material [86]. Gases can of coursealso penetrate the PDMS to enter microchannel structures,making it a suitable material for applications using live cells[83], [85]. Structures with flat surfaces made in this materialseal reversibly with glass, silicon, and PDMS. Alternatively,irreversible bonding can be accomplished by treatment ofthe surfaces to be bonded with an oxygen plasma [87], [88].

A variety of masters have been used for replication ofmicrochannels in PDMS. Anisotropic wet etching of100

Fig. 7. (a) Basic process used for the fabrication of�TICs.Cross-sectional views of�TICs made using (b) an isotropicallywet-etched silicon mold and (c) a DRIE silicon mold. [(b) Reprintedin part with permission from [78]. Copyright 1998 Elsevier ScienceLtd.; (c) Reprinted in part with permission from [79]. Copyright2001 Wiley-VCH Verlag GmbH].

silicon has been used to produce masters for plastic channelreplication [89]–[91], but the resulting channels had trape-


Fig. 8. (a) Schematic diagram of the steps involved in replication of microchannels in PDMS. (b) Athree-layer PDMS device for passive mixing by lamination of solution streams. (Reprinted withpermission from [85]. Copyright 2000 IEEE) (c) A 3-D PDMS network for a cell culture application.(Reprinted with permission from [100]. Copyright 2002 IEEE.)

zoidal cross sections with aspect ratios1. There is littlefreedom in channel network design, since possible layoutgeometries are dictated by crystalline orientation. To retain

the freedom of channel layout afforded by isotropic etchingof glass, a nickel master can be prepared directly from astructured glass wafer by growing a relatively thick (3-mm)


nickel layer onto it [92], [93]. Alternatively, resist reliefs onsilicon wafers made using the negative photoresist, EPONSU-8, can be used as masters. This approach is an attrac-tive choice in terms of fabrication time and layout flexibility[85], [87], [94], [95]. Moreover, features 5 to 1200m highare possible with aspect (height-to-width) ratios approaching20 [96]–[98]. To date, 1 : 1 aspect-ratio structures [negativechannel structures (i.e., ridges) with equal height and width]were used for PDMS molding, and they can be used indefi-nitely [83]. Masters realized by DRIE have the same advan-tage as those made in photoresist, namely, freedom to choosechannel layout [88], [99]. Curved relief patterns with verticalwalls and high aspect ratios are thus possible.

3-D PDMS structures have been reported by severalgroups. In one case, many thin (100 m thick) patternedPDMS layers were stacked to form 3-D channel paths [85].Each layer contained channels and openings, molded againstan SU-8 master using a sandwich-type molding configu-ration. Fig. 8(b) shows a photograph of an assembled 3-Dpassive micromixer made in this way. Andersonet al. useda similar approach yielding thin layers with through-holesand microstructuring on both sides, which were sealed withthicker PDMS slabs [95]. A microfluidic device for the cre-ation of a sheath flow of buffer to hydrodynamically confinea sample stream close to a sensor surface was realized inPDMS by Hofmannet al. [99]. This approach required theability to introduce a buffer flow onto the sample streamfrom above to compress it, a criterion which this 3-D devicefulfilled well. Fig. 8(c) shows a close-up SEM image of a3-D microchannel network formed in PDMS for culturingof human cancerous liver cells [100]. The 3-D approachtaken here could prove useful for more sophisticated tissueengineering applications.

E. Microchannels by Replication in Other Polymers

Masters made in silicon can be used to imprint or hot-emboss channels in hard plastic materials like poly(methylmethacrylate) (PMMA) at temperatures close to the soft-ening point of the plastic or, alternatively, at elevated pres-sures [101], [102]. Martynovaet al.used the former approachto make plastic microchannels [103], whereas Xuet al.wereable to do much the same but at room temperature and highapplied pressures [104]. McCormicket al.used a microma-chined silicon wafer to fabricate a metal stamp by electro-plating Ni onto the silicon, and using this electroform tocreate a second electroform [105]. The second form is thusa replica of the original silicon master. These researchersused forms made using this two-step electroplating process toboth imprint and injection-mold channels into plastic. Otherreports of injection molding for microfluidic chips may befound in [106] and [107]. Excellent discussions generallyabout the fabrication of polymer microfluidic devices aregiven by Becker and Gärtner in [101], and again by Beckerand Locascio in [102].

A more recent report describes the 3-D replication of struc-tures in UV-curable acrylates using a finely patterned siliconmaster, produced by a series of dry etching processes [108].

Though this technique has not been applied to microfluidicdevices yet, it offers a route to nanostructuring, and hencecould be an attractive tool for the microfluidics community.

F. Other Techniques for Fabrication of PolymerMicrofluidic Devices

Laser ablation was first introduced by Robertset al.for the fabrication of polymer microchannels [109]. Thistechnique involves directing laser pulses at the plastic sur-face in defined regions, which causes degradation of theplastic at those spots as a consequence of a combinationof photochemical and photothermal degradation processes.A UV excimer laser was used to produce channels in avariety of substrates, which were then subsequently sealedusing a low-cost plastic lamination technique. EOF in thesechannels was characterized, and shown to be a function ofablation conditions [109]. Henryet al.studied this aspect oflaser-ablated channels in more depth, using channels madein poly(ethylene terephthalate glycol) [110]. Johnsonet al.used laser ablation techniques to modify the surfaces ofchannels already hot-embossed into various polymer sub-strates [111], [112]. In one case, the surface structureswere designed to reduce broadening of sample plugs asthey passed around corners [111], whereas in the other, thepurpose of the modification was to create a rapid mixer[112]. CO -laser machining has also been used to rapidlywrite structures in PMMA [113], and has proven to be aneffective tool for rapid protoyping of devices for diagnosticapplications [114].

A simple method based on plasma etching was recentlypresented for producing both channels and electrodes inpolymer, starting with three-layer foil composed of 50m ofpolyimide sandwiched between two 5-m layers of copper[115]. Photoresist is used to pattern the copper layers, afterwhich the exposed copper is etched away chemically usingan aqueous solution of CuCl–H O . The foil is then placedin a reactive plasma chamber to transfer the desired patterninto the polyimide. After the plasma etch, the copper iseither removed or further patterned to produce conductivepads, which can be coated with Au by electroplating. Theprocess is shown in Fig. 9(a), along with some photos ofthe finished devices in Fig. 9(b). Implementation of suchdevices for microchemical analysis was demonstrated withvoltammetric detection in a 60-nL microchannel.

III. I NTEGRATION OFELECTRICAL AND ELECTROCHEMICAL

FUNCTION INTO MICROFLUIDIC DEVICES

One of the unique possibilities offered by MEMS tech-nology is the direct integration into microfluidic devices ofelements not having a fluidic functionper se. The fact thatthese technologies were developed for the microelectronicsindustry in the first place makes their use for fabrication offeatures with electrical function rather obvious. The abilityto deposit and structure thin metal or other conductive filmson wafer or channel surfaces is thus being exploited in mi-crofluidics for integrating electrochemical detection (ECD),resistive heating, and pumping elements into devices. This


Fig. 9. (a) Process flow for plasma etching microchannels inpolyimide foil. A) Channels are formed first, followed by a secondpatterning/etching step to form access holes. It is during this stepthat channels may be etched down to contact the underlyingCu layer. B) This copper layer may be further structured toyield electrodes and electrical contact pads. (b) Photographsof a four-electrode device made in polyimide foil. (Reprintedwith permission from [115]. Copyright 2002 Royal Society ofChemistry.)

section will consider examples which have an electrical el-ement somewhere on or in the chip for performing one ormore of these functions.

A. Electrochemical Detection in Microfluidic Chips

ECD, which includes amperometric, potentiometric, andconductometric detection, is the subject of an increasingnumber of research papers looking at its integration intomicrofluidic chips [116], [117]. This is because it scalesbetter upon miniaturization than absorbance or fluorescencedetection, since output signal is dependent on electrodesurface area rather than on available detection volume [118].As a result, limits of detection (in concentration terms)do not degrade as rapidly for electrochemical detection as

they would for optical techniques [119]. Electrochemicaltechniques are generally attractive for this reason, thoughthey will never compete with fluorescence in terms of sensi-tivity. The use of micromachining technologies to integrateelectrochemical sensing elements into microfluidic devicesbrings some unique advantages not possible in conventionalsystems. For instance, fabrication of electrodes directly inmicrofluidic channels means that these are aligneda priori,eliminating the need for often-difficult alignment proce-dures. Moreover, devices incorporating detection electrodesdo not require a large amount of peripheral equipment foracquisition of detector signal. This makes the developmentof portable instrumentation based on microfluidic deviceswith ECD a realistic possibility.

There have been a number of approaches reported in theliterature for integration of electrodes into chips. In the sim-plest case, grooves or channels whose purpose it is to simplyhold metal or carbon electrodes in place are formed in oneof the surfaces of the device, and sealed with the secondlayer. Electrodes are inserted into these channels before as-sembly of the devices. This approach has been reported forchips replicated in PDMS and utilizing 30-m carbon fiberelectrodes [120]–[122]. Pt wires 127m in diameter wereinserted in 130-m guide channels for contact conductivitydetection in chips which had been hot-embossed in PMMA[123], [124]. In [125], the end of an electrophoresis separa-tion channel in glass was widened by etching in HF, to fa-cilitate insertion of Pt, Au, or Cu wires for amperometricdetection. Alternatively, electrode channels were formed inPDMS and filled with carbon paste [126], or laser-ablated inpolyethylene terephthalate (PET) and filled with carbon ink[127]–[130].

More sophisticated means of integrating electrodes forECD involve deposition and patterning of metal layersaccording to established micromachining techniques. Thetechnique used will depend on the type of metal chosen.In the simplest case, glass devices for microchip elec-trophoresis were modified by cutting off the end of the chipperpendicularly through the separation channel to sever thewaste reservoir from the chip. In this way, the outlet of theseparation channel was directly at the flat end of the chip,rather than in a solution reservoir. Gold electrodes were thenformed around this channel outlet [131], [132]. In one case, athin gold film was sputtered around the outlet to a thicknessof 200 nm. Electrical contact was made using a lead gluedwith silver epoxy to the gold layer. The gold electrode pluslead was then coated with an electrically insulating ink,leaving a gold disk-shaped area of 78 mmexposed foruse in amperometric detection [131]. In the other example,electroless deposition of gold was carried out on the end ofthe chip, using formaldehyde as a chemical reducing agentto plate gold from solution onto the glass surface [132].Again, the actual active electrode surface was defined whenthe wire contact and gold surface were covered with aninsulating layer to leave only a small region bare.

In the previous examples, patterning using a photolitho-graphic process was not possible, since the electrodes werelocated on the edge of the devices, rather than on a planar


surface. More precise structuring of electrodes results whenphotolithographic patterning is used. The simplest procedureinvolves deposition of a uniform metal layer onto a planarsurface, followed by standard photolithography and transferof the electrode geometry in the metal layer. Generally, a thinlayer of one metal is first deposited to enhance the adhesionof a second, thicker metal layer to be used as electrode. Typ-ical adhesion layers for different metals include: 1) Cr (forAu); 2) Ta or Ti (for Pt); and 3) Ti (for Cu). This was the ap-proach followed by Martinet al.[133], who coated soda-limeglass squares sequentially with chromium (5 nm) and gold( 200 nm) using an evaporation technique. Chromium wasused as an adhesion layer for the gold. The Cr–Au layer wasthen patterned using a positive photoresist, and the under-lying Cr–Au layers removed in appropriate etchant solutionsin areas where the resist had been stripped during develop-ment. The result was an array of four parallel electrodes,40 m wide and with a pitch of 80 m. Because these elec-trodes protrude slightly from the surface, the wafer surfaceis no longer completely flat. Hence, hermetically sealing thissurface by thermal or anodic bonding to a second chip con-taining channels would not be possible if the second substratewere glass or silicon. Martinet al.used a PDMS substrate in-stead, since this material conforms well to a surface bearing atopography [133]. The PDMS and glass chips were alignedin such a way that the electrodes were positioned perpen-dicularly to the separation channel, just beyond the end ofthis channel. A similar procedure was used by Liuet al. toproduce a single-gold-electrode PDMS/glass device [134].In a microreactor application, interdigitated arrays of carbonmicroelectrodes were integrated into a silicon-based devicecontaining two flow chambers. The upstream chamber waspacked with enzyme-modified porous glass beads for glu-cose oxidation. The second chamber contained the electrodearrays for electrochemiluminescence (ECL) detection of thehydrogen peroxide produced, each consisting of 125 pairsof 1-mm-long, 3.2- m-wide electrodes, with an electrodespacing of 0.8 m. To obtain these detectors, the electrodeswere defined on a sputtered thin film of carbon with a stan-dard photolithographic procedure, followed by structuringof the carbon layer using an Oplasma [135], [136]. Theflow chambers were defined after electrode fabrication byphotolithography in a thick layer (300m) of Epon-SU 8[135]. Woolleyet al.presented a glass CE device with inte-grated Pt electrodes for indirect ECD of DNA [137]. As theSEM image of this device in Fig. 10 shows, photolithographymakes possible the positioning of the 10-m-wide, dual-lead,platinum working electrode just 30m beyond the end ofthe separation channel in the large reservoir. This is impor-tant, as this detection electrode finds itself just outside thehigh electric field used for separation, and is effectively de-coupled from this field as a result. In this case, 20 nm of Ti(adhesion layer) and 260 nm of Pt were sequentially sput-tered onto the substrate. Thick photoresist (ca. 10m) wasthen coated onto the wafer and patterned, and the exposed Ptremoved in hotaqua regia(personal communication with R.A. Mathies, University of California, Berkeley).

An alternative way of structuring electrodes in microflu-idic devices uses a microfabrication procedure known asliftoff. This approach is more involved than that describedpreviously, requiring several steps. However, it remainspopular, particularly when making electrodes in platinum,a metal which does not etch easily (see the previous text).The liftoff process is described in more detail in Hierlemannet al. (in this issue). Liftoff processes have been used toform microelectrode arrays in microfluidic devices in goldfor generation of ECL [138], [139], and platinum, foramperometric [135], [138] and conductivity [140] detection.Three images of a microdevice incorporating two arraysof Pt microelectrodes for glucose detection are shown inFig. 11 [138]. A microchip electrophoresis device in glassincorporating a single platinum electrode for wireless ECLdetection has also been reported [141].

As mentioned previously, electrodes formed on top ofplanar surfaces make good sealing with other planar sub-strates in hard materials difficult. A number of researchershave developed a variation of liftoff processing whichcircumvents this problem. The procedure starts much thesame, with a layer of photoresist being spin-coated onto awafer surface and electrode geometries defined. However, atthis point, shallow cavities (500 nm) are formed first in theregions where electrodes are to be deposited. Only then arethe metal layers deposited onto the wafer, with thicknessesthat just fill the cavities in the substrate. The resist is thenremoved as before by dissolution in an organic solvent,with liftoff of the metal occurring at the same time. In thisway, the chip surface containing the electrodes retains itsplanarity, and may be bonded to another silicon or glasssubstrate. This approach was taken to form 160-nm-thick Ptelectrodes in a silicon chip for use in coulometric nanoti-tration in stopped-flow [142] and continuous-flow systems[143]. Pt electrodes were made similarly in 200-nm recessesin glass for conductivity detection [79], and 300-nm recessesin glass for amperometric detection in conjunction withmicrochip electrophoresis [144]. The device in Fig. 12 wassomewhat different, in that 170-nm-thick Pt–Ta electrodeswere formed in 12-m-deep cavities [145]. The applicationin this case was contactless conductivity detection formicrochip CE. Good capacitive coupling into the detectionvolume over a thin glass wall was thus required, while atthe same time ensuring complete isolation of the electrodesfrom the solution in the analysis channel. Fig. 12 shows aphotograph of the finished device, focusing on the detectorregion.

B. Integrated Temperature Control

There are a number of ways to generate heat in MEMSdevices, which have been developed for a variety of appli-cations (see, e.g., Kovacs [11]). In microfluidics, the mostcommonly implemented approach involves integration of asimple resistor somewhere on the device. Passage of currentthrough a resistive element results in the generation of Jouleheat, , according to , where is electrical resis-tance and is current. Microfluidic devices are attractive for


Fig. 10. Microchip electrophoresis device with integrated Pt counter and working electrodesfor amperometric detection. (A) Overall layout of the device. (B) Detailed schematic diagram ofthe arrangement of electrodes at the end of the separation channel. A small Ag/AgCl referenceelectrode was immersed in the detection reservoir to complete the three-electrode setup. (C) Close-upSEM image of the photolithographically patterned Pt working electrode positioned just after theend of the separation channel. (Reprinted with permission from [137]. Copyright 1998 AmericanChemical Society.)

performing chemical reactions or processes requiring tem-perature control, since the high heat transfer rates in thesesystems lead to easier implementation of uniform tempera-ture conditions [146]. This section will examine microfluidicdevices incorporating resistive heating in one form or anotherfor both chemical and biochemical applications.

1) Biochemical Applications:There have been manypublications describing the application of MEMS tech-nologies to the development of devices for DNA analysis.A significant number have focused on the integration ofthe polymerase chain reaction (PCR), used to increase theamount of DNA from a sample for analysis, into micro-machined chambers. Microchip PCR provides an attractivealternative because the low thermal mass of these devicesallows the reduction of cycle times from several minutes to30 s or less. Another DNA-related topic that has received alot of attention in recent years is the use of microchip gelelectrophoresis for DNA analysis (see, e.g., [147]–[149]).

Several of these use integrated heaters to achieve denatu-ration of double-stranded DNA [150], [151]. An in-depthreview of the general topic of nucleic acid analysis withmicromachined devices is presented by Mastrangelo (in thisissue).

Yamamotoet al.contacted a PDMS chip containing a mi-croreactor array with a glass temperature control chip forcell-free protein synthesis [152]. The glass chip had heatersand sensors structured in a 500-nm-thick layer of indium tinoxide (ITO) by etching in a 1:1 HNO:HCl solution at 50 Cfor about 20 min using a patterned resist layer as etch mask.Contact electrodes were then formed by liftoff, and the en-tire surface passivated by a 500-nm layer of SiO. Becausethe ITO layer is optically transparent, optical detection waspossible through both chip surfaces. Thermal time constantsfor heating and cooling were 170 ms and 3 s, respectively,and uniform temperature gradients could be achieved acrosseach reactor. The cell-free synthesis of green and blue fluo-


Fig. 11. Three images of a microfluidic device designed tofunction as an enzymatic microreactor. The devices incorporate twoarrays of Pt microelectrodes formed by liftoff. (a) Optical imageof empty devices before wafer dicing. The microreactor geometrywas defined in a 300-�m-thick layer of EPON SU-8, and containstwo chambers separated by 11 posts. The chamber with the zigzagshape was packed with glass beads that had glucose oxidaseimmobilized on them. These were retained in this chamber behindthe posts. The HO produced when a glucose-containing samplewas reacted with the beads could pass the posts, to be detectedamperometrically at the electrode arrays, visible as light-reflectingsquares in this image. (b) SEM of a single microreactor after dicing.The two electrodes arrays are more visible in this image (upper left).(c) Close-up view of the posts and an electrode array, obtained byscanning electron microscopy. The Pt electrodes are 3.2�m wide,0.8�m apart, and about 1 mm long. [Fig. 11(a) and (b) reprintedwith permission from [138]. Copyright 2000 Kluwer AcademicPublishers; photographs courtesy of G.-C. Fiaccabrino, IMT.]

rescent proteins from their DNA templates was successfullydemonstrated.

Controlled protein crystal growth was the objectiveof studies carried out by Sanjohet al. with the help ofmicrofluidic silicon devices [153], [154]. The microfluidic

devices typically contained a crystal growth cell, reservoircell, and, for certain studies, heaters. The lower surface ofthe growth cell was patterned with fine features in either n-or p-type silicon layers, which serve as spatially selectivenucleation sites by electrostatically attracting dissolvedprotein molecules. The integrated heaters were used tocontrol the degree of supersaturation of protein in solution.Lysozyme crystals grown on n-type Si features are shownin Fig. 13. In Fig. 13(a), the features are narrow ridges, asshown in the inset, whereas in Fig. 13(b), they are trenches.Crystallization is well-defined and clearly selective for then-type Si.

2) Microreactors for Chemical Engineering:Miniaturi-zation, and hence MEMS technology, is attractive to thechemical engineering community for the realization of mi-crofluidic platforms for chemical process optimization. Ofparticular interest is the capability MEMS offers to integratecontrol, sensing, and reactor functions into the same device.It has also been proposed that reactions, once optimized,could be scaled out in arrays of microreactors rather thanscaled up to larger volumes in a single reactor. This wouldcertainly reduce the risks associated with handling partic-ularly explosive or exothermic reactions, making chemicalproduction safer. It also becomes conceivable to think ofon-site generation of hazardous chemicals, thereby forgoingthe need for special storage and transport conditions [146],[155].

Improved temperature control is ultimately one of themain advantages to be gained from downscaling. Microfabri-cated microreactors for chemical engineering purposes thushave often included elements for heating and temperaturesensing. A very simple example by McCreedyet al.saw theinsertion of a Ni–Cr wire, twisted into a serpentine shape,into a PDMS solution before it was cured, to serve as a heaterin the resulting polymer chip [156]. This chip was sealed toa glass base-plate that contained the microreactor channels.Sulfated zirconia was used as catalyst, and was immobilizedin the inner surface of the PDMS cover. The PDMS wasstable up to 180C, and it was possible to dehydrate hexanoland ethanol to hexene and ethene, respectively.

Srinivasanet al.described a more sophisticated, Si-basedmicroreactor [37]. Pt–Ti heaters and sensors for temper-ature and flow were formed by liftoff on a 1-m siliconnitride layer deposited on silicon. The T-shaped reactorchamber was then etched from the other side down to thenitride membrane, and a thin Pt catalyst film deposited byshadow-mask evaporation on the inside surface of the mem-brane. The highly exothermic, Pt-catalyzed partial oxidationof ammonia was considered, and the safe investigation ofignition-extinction behavior demonstrated. Pt–Ti heatersand resistance temperature detectors (RTDs) were incorpo-rated by the same group into a Pd membrane reactor, forpurification of hydrogen, or alternatively, for hydrogenationand dehydrogenation reactions [146]. The gas–liquid–solidreaction of cyclohexene with Hin the presence of a Ptcatalyst was chosen as the model reaction in another setof three-layer microfluidic devices [34]. Two structuredlayers of silicon were topped off by a glass cover-plate, onto


Fig. 12. Layout of a microchip electrophoresis device designed for small-ion analysis usingcontactless conductivity detection. The inset on the right shows a photograph of the detector region.Electrical connections to the electrodes were made via round contact pads at the end of the metallines. All metal structures were placed in 12-�m-deep recesses to prevent problems during thermalbonding due to uneven surface topography. (Reprinted with permission from [145]. Copyright2002 Wiley-VCH Verlag GmbH.)

which a Pt–Ti thin-film heater and RTD had been made[see Fig. 14(a) and (b)]. These contained either a packedbed of catalytic particles or structured microchannels withstaggered arrays of columns, 50m in diameter, 300 mtall, with nearly 20 000 columns in all, to act as catalystsupport [see Fig. 14(c)]. It was pointed out that while thehigh thermal conductivity of silicon allowed excellent heatdissipation and hence good thermal control by the heaters,large amounts of heat were lost to the environment. Inaddition, heater performance was very dependent on howthe chip was packaged.

3) Other Microchemical Reaction Applica-tions: Classical wet chemical analytical methods aregenerally based on the chemical conversion of the analyteof interest through derivatization, complexation, or othermeans to make it more visible to a detector. Many ofthese methods lend themselves well to automation byflow injection analysis (FIA). In this technique, sample isinjected into a flowing carrier stream and subjected tovarious sample handling steps, such as dilution, reagentaddition, mixing, and finally, detection. Reaction times aredefined by the residence time of the reacting sample zone inthe flow system, and hence can be adjusted to some extentby flow-rate variation. Precise flow control is crucial toobtaining reproducibility in FIA, since measurements aredone under nonequilibrium conditions.

A number of publications have described the integrationof classical wet chemical methods into micromachined flu-

idic systems. One early example using a stacked system ofsilicon chips focused on the analysis of phosphate using theMolybdenum Blue method to form a blue-colored phosphatecomplex which could easily be detected by absorbance [38],[157]. This example was interesting in that it was the first touse silicon-based micro pumps for controlling liquids withinthe valveless system. However, a smaller flow system did notmean enhanced reaction, since the kinetics of the reactionused for phosphate analysis are slow and proved to be thelimiting factor for analysis. A more recent example ofFIA,using much smaller chips, was developed for analysis of am-monia in waste and drinking waters. It used the Berthelot re-action to convert ammonia through reaction with phenol toa blue indophenol dye. Again, the kinetics of this reactionare slow, with maximum absorbance achieved only after 15minutes or so at 25C. Since a sensitive measurement wasdesired in 5 min or less, and because reaction rates increasedsignificantly at 35 C and 45 C, the three-layer microflu-idic device used had a 50-nm-thick ITO layer sputtered onone surface for resistive heating [44]. An all-glass version ofthe three-layer chips for this application, complete with ITOlayer, has also been reported [51].

Fast derivatization is especially important when analytesare to be labeled on-line just before or after a separation.Eijkel et al. micromachined a heated chemical reactor forprecolumn chemical derivatization of amino acids with thefluorescent agent, 4-fluoro-7-nitrobenzofurazan (NBD-F)before separation in a conventional high-performance


Fig. 13. Photographs show lysozyme crystals that have beengrown in a growth cell with n-Si features patterned in the bottom.(a) The n-Si nucleation sites take the form of ridges, whereas in (b),they are narrow trenches. In both cases, crystals clearly prefer toform on these sites. Solution pH: 4.7. (Reprinted with permissionfrom [153]. Copyright 1999 Elsevier Science Ltd.)

liquid chromatography system (HPLC) [158]. The devicecontained on-chip Pt–Cr thin-film metal resistors as heaters,which were recessed into the silicon chip by sputtering themetals into a 1.5-m-deep groove. These elements couldheat a 50-L volume to a maximum of about 90C at arate of 2 C/s, using 2 W of power. In addition, there weretwo temperature-sensitive resistors on board for temperaturemeasurement.

4) Other Examples Using Integrated Temperature Con-trol: Analysis of gaseous analytes often requires their pre-concentration by adsorption onto a solid surface, followed bya thermal desorption step once enough sample has been col-lected for further detection. Microfluidic devices designedfor this purpose and incorporating thin-film resistive heatershave been reported. In one case, airborne benzene, toluene,ethylbenzene, and xylenes were of interest [159]. A Pt heaterwas formed by sputter deposition and liftoff on the bottomof a Pyrex wafer, which then had a trench machined into itand was sealed by anodic bonding to a second Pyrex wafer.The trench was packed with adsorbent particles, and gaseoussamples passed through the packed bed. Gases preconcen-trated in this device were desorbed by ramping the tempera-ture at about 2C/s, and collected in a second micromachineddetection cell. A preconcentration factor of 100 could be ob-tained this way, and parts-per-million (ppm) levels of toluenecould be determined. The same researchers (Uenoet al.) later

Fig. 14. (a) Schematic overview of a three-layer silicon–glassdevice for multiphase mixing and reaction. The thin-film metalheater and temperature sensor pattern is superimposed onto thechannel layout. (b) Photograph of the device, corresponding to theschematic in (a). (c) SEM of a small portion of the 20 000-columnarray in the reactor bed, each of which is 300�m high and 50�min diameter. These structures serve as catalyst supports within themicroreactor. (Reprinted with permission from [34]. Copyright2002 IEEE.)

used this device for measurements of mixtures containingbenzene, toluene, and o-xylene at the 10-ppm level [160].Manginell et al. reported a microfabricated planar precon-centrator for integration with a silicon-based gas chromato-graphic column [161]. This silicon-based device consistedof a flow-through chamber formed by through-wafer etchingdown to a silicon nitride membrane, onto which a thin-filmPt heater had been previously patterned. The heater servedas the hotplate, and was covered by a porous sol-gel adsor-bent layer. Preconcentration factors of between 100 and 500were achieved for the analyte of interest, dimethyl methylphosphonate (DMMP), a nerve gas simulant. Heating rates


of 10 C/s were possible, which represented a thousandfoldimprovement over conventional systems. At the same time,power consumption, which was 100 mW for a typical des-orption temperature of 200C, was a thousandfold lower.

Increased temperatures are also beneficial in GC forseparating less volatile compounds (i.e., compounds that arestrongly retained on the stationary phase). Nohet al.recentlypresented a gas chromatographic column micromachined inparylene, a polymer exhibiting a low heat capacity and goodchemical inertness [162]. Parylene was deposited from thegas phase onto a DRIE mold, followed by an intermediatelayer of Pt, and finally a second layer of parylene. A Pyrexwafer was then coated with parylene, and bonded to thecoated Si wafer under high pressure and temperature. TheSi was then etched away, leaving a freestanding parylenecolumn attached to the Pyrex wafer. Gold was evaporatedonto the tops of the column to serve as a heater. The purposeof the intermediate layer of Pt in the parylene walls wastwofold: namely, it reduced gas permeation through the wallsof the column, in addition to diffusing the heat uniformlythroughout the column. Simulation and experiment showedthat this polymer material showed much faster heating andcooling than chip-based silicon-glass columns.

A unique micro liquid handling method was reported byHandiqueet al., who used an integrated heater and RTD tothermally generate air pressure inside a microfluidic channelfor pumping discrete droplets [163]. The hybrid device con-tained a lower Si chip with Pt electrodes formed by liftoff andcoated by oxide, and an upper glass chip with the microflu-idic channels and air trapping chambers (see Fig. 15). Thechamber containing the heater and trapped air is connectedto the microfluidic channel via a small channel. It is throughthis channel that heated, expanding air pushes its way fromthe chamber into the liquid-containing channel, displacing aplug of liquid before it. Droplets of nL volume could be pre-cisely defined using this system at flow rates of 20 nL/s usingair heating rates of 6C/s.

C. Pumping

As mentioned previously, EOF has been a popular meansof pumping liquids in microfluidic devices. In most cases,this is still achieved by immersing wire electrodes intoopen reservoirs at the ends of the channels. The resultingelectrolytically generated gas bubbles are easily removed, asthey simply drift to the surface of the liquids in the reservoirand vanish into the air. Smaller, more compact devices couldbe realized by integration of the pumping electrodes into themicrochannels themselves. However, this would result inthe formation and trapping of gas bubbles in the channels,which would interrupt the applied electric field and halt theEOF unless gas dissipation was facilitated in some way. Toavoid this problem, electrodes integrated into the reservoirsthemselves have been described by Figeyset al. [164].After 30- m-deep channels and reservoirs had been etchedinto the glass wafer, Au electrodes were vacuum-depositedin the reservoirs. The electrode pads were connected byan 80- m-wide metal line to contact pads, at which thehigh voltage was applied. Jeonget al. also integrated Au

Fig. 15. (a) Schematic of the discrete drop pumping device.(b)–(e) How the pump operates: (b) Liquid is introduced at the inlet,and drawn into the device by capillary forces up to the hydrophobicpatch (channel surface is not conducive to capillary flow). Air istrapped in the chamber during this process. (c) The heater is turnedon, and the air inside the chamber is heated to the point that itexceeds a threshold pressure and enters the liquid channel to push awell-defined liquid droplet past the hydrophobic patch. (d) Furtherheating leads to continued expansion of air, and further motion ofthe liquid droplet as a result. (e) The air pressure is vented as thedroplet passes the vent channel. (Reprinted with permission from[163]. Copyright 2001 American Chemical Society.)

electrodes into their Si–glass device for synchronized cyclicCE [22]. McKnight et al. photolithographically patternedand etched a Au–Ti layer on glass to form electrodes[86]. A channel in PDMS was positioned perpendicularto these electrodes, which extended across the channel. Inthis case, gas dissipation through the gas-permeable PDMSlayer ensured that the electric field was not interrupted. Itwas possible to generate EOF in just a short segment of amicrochannel in this way, causing solution to be hydraulicallydisplaced on either side of the pair of electrodes.

In fact, bubbles generated by electrolysis may be usedbeneficially in a microfluidic device for pumping purposes.Böhm et al. described a microfluidic device comprising a


channel/reservoir structure in silicon, capped by a Pyrexglass cover onto which a set of Pt electrodes had beenfabricated [165], [166]. The interdigitated electrodes serveda dual purpose, since the bubbles were generated and theirvolume simultaneously measured by impedance at theseelectrodes. The bubbles displaced liquid in reservoir chan-nels connected to the gas generation chamber as they grew,which in turn dispensed the liquids into a third channel forfurther use upstream. Flow rates in the order of nL/s werepossible with this system [165], [166].

IV. CONCLUSION

Clearly, micromachining technologies have played a cru-cial role in the development of microfluidics from the verybeginning. The realization of sub-L flow systems with fea-tures precise enough to achieve the desired performance formost applications is difficult if not impossible without a pho-tolithographic process involved somewhere in device fab-rication. Hence, micromachined channel devices have be-come inherent to the microfluidics field. The association ofmicrofluidics with MEMS has extended beyond the fabri-cation of simple microchannels, however, as has been dis-cussed. The MEMS field has utilized the ability to work withdifferent materials to construct devices with an increasingnumber of functions. The microfluidics world is learning todo the same.

One area of increasing interest is the integration of opticalelements into microfluidic devices, a subject which wasnot dealt with in this paper. Both early and more recentpapers have focused on small-volume, long-pathlengthdetector cells for application to absorbance detection [27],[32], [33], [44], [51], [167]. Other groups have investigatedthe direct microfabrication into microfluidic devices ofmicrolenses [168]–[171], integrated waveguides [25], [172],and photodiodes [139], [173]–[176]. A dc microplasma on achip has also been reported as an optical emission detectorfor GC [177]–[179]. Besides the possibility of smaller,more portable devices, the integrated approach also has thepotential to alleviate problems associated with the alignmentof external detection elements with the microfluidic chip.Increased sensitivity may also result if the number of opticalinterfaces can be minimized through integration.

The advantages of microchip electrophoresis especiallyfor nucleic acid analysis have been widely touted. Gen-erally, the increase in speed reported is on the order oftenfold to a hundredfold relative to capillaries and slab-gelformats, respectively (see, e.g., [180], [181]). Resolutionof peaks in the electropherogram obtained on the chip,though sometimes lower than that observed in fused-silicacapillaries [181], [182], is comparable in all cases to theequivalent experiments done in conventional CE systems.Throughput can be increased even further by resortingto multicapillary arrays in glass, as has been put forthparticularly by the Mathies group [149], [183]–[187], butalso described by Sassiet al. [188] and Huanget al. [189].The most recent example from the Mathies group describesa 384-lane capillary array electrophoresis bioanalyzer forultrahigh-throughput genetic analysis [190]. This device

was fabricated on a 20-mm-diameter glass wafer, and had384 sample reservoirs and 96 common buffer reservoirs.Fabrication of such a system represents a challenge, as all384 lanes need to be exactly the same. Moreover, gettingsolutions onto the device requires some form of automatedsample addition step. Improving the interface between themicrofluidic device and the macroscopic world for thisand many other applications is an area in which MEMStechnologies could provide some advances in the future.

Last but not least, the trend toward the integration ofmore sample pretreatment onto microfluidic devices is nowestablished, particularly in the area of genetic analysis.A number of researchers have reported the (almost) totalintegration of nucleic acid analysis, including samplepretreatment, onto polymer-based [191]–[193], glass-based[194], and silicon-based [23], [24] devices. Of these, thedevices emerging from the Burns group [23], [24] are themost sophisticated from a MEMS point of view, incorpo-rating micromachined elements for micro liquid handling,thermal reaction, electrophoretic separation, and detectiononto a single device. With batch-type processing, it may bepossible to scale out these types to large arrays for highlyparallel analysis. However, control of liquids in multibranchsystems will ultimately require the development of newvalving concepts. This is because present valveless conceptsbased on electroosmotic flow or hydrophobic patches, whileappropriate for many simpler applications, are somewhatlimited due to their tendency toward leakiness. Microfab-ricated valves based on pneumatically actuated elastomermembranes have recently been proposed for array appli-cations in biochemistry [195], [196]. Thorsenet al. haveextended this concept to realize high-density microfluidicchips with thousands of valves and hundreds of individuallyaddressable microchambers [197]. These truly impressivedevices, designed to be analogous to electronic ICs, provethe feasibility of very large-scale valving in complex mi-crofluidic systems. Here too, MEMS technologies will playan important role in the future development of microfluidics.

ACKNOWLEDGMENT

The authors would like to thank all the members, pastand present, of theTAS team in the Sensors, Actuators,and Microsystems Laboratory (SAMLAB), at the Instituteof Microtechnology, University of Neuchâtel, Neuchâtel,Switzerland, for their valuable efforts. Their contributions tothis paper in the form of photos and figures are of particularnote. The authors would also like to thank G. C. Fiaccabrino(SAMLAB), R. Guijt-van Duijn (Technical University ofDelft), T. Fujii (University of Tokyo), H. Minhas (RSCJournals), and J. Rossier (Diagnoswiss S.A., Monthey,Switzerland) for photos and figures.

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Elisabeth Verpoorte received the Ph.D. in analytical chemistry from theUniversity of Alberta, Edmonton, AB, Canada, in 1990. Her dissertationfocused on the use of AC impedance analysis for studying the permeabilityand behavior of dissociable species in PVC-based ion selective membranes.

She was in the Corporate Analytical Research department of Ciba Ltd.,Basel, Switzerland, first in a postdoctoral position, and later in a permanentposition as Research Scientist. There, she worked on the development ofminiaturized total analysis systems (�TAS). In July 1996, she assumed aposition as Team Leader in the group of Prof. N. F. de Rooij at the Instituteof Microtechnology (IMT), University of Neuchâtel, Switzerland, where herresearch interests concentrated in the area of�TAS (Lab-on-a-Chip) for bio-analytical and environmental applications. She led a research team of abouteight Ph.D. students and researchers while at IMT. Recently, she accepteda Chair of Pharmaceutical Analysis at the Groningen Research Institute ofPharmacy, University of Groningen, Groningen, The Netherlands. She holdsthree patents and has published over 40 peer-reviewed papers.

Nico F. de Rooij (Fellow, IEEE) received the M.Sc. degree in physicalchemistry from the State University of Utrecht, Utrecht, The Netherlands,in 1975, and the Ph.D. degree from Twente University of Technology,Enschede, The Netherlands, in 1978.

From 1978 to 1982, he worked at the Research and Development De-partment of Cordis Europa NV, Roden, The Netherlands. In 1982, he joinedthe Institute of Microtechnology of the University of Neuchâtel, Neuchâtel,Switzerland (IMT UNI-NE), as Professor and Head of the Sensors, Actua-tors and Microsystems Laboratory. From 1990 to 1996 and since October2002, he is Director of the IMT UNI-NE. He has lectured at the Swiss Fed-eral Institute of Technology, Zurich (ETHZ), and since 1989, he has been apart-time professor at the Swiss Federal Institute of Technology, Lausanne(EPFL). He is a Member of the editorial boards for the journalsSensors andActuatorsandSensors and Materials. His research activities include micro-fabricated sensors, actuators, and microsystems.

Dr. de Rooij was a Member of the steering committee of the Interna-tional Conference on Solid-State Sensors and Actuators and of Eurosensors.He acted as European Program Chairman of Transducers ’87 and GeneralChairman of Transducers ’89. He is a Member of the editorial board of theIEEE JOURNAL OF MICROELECTROMECHANICALSYSTEMS.


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Microfluidics Meets MEMS - Semantic Scholar€¦ · Microfluidics Meets MEMS ELISABETH VERPOORTE AND NICO F. DE ROOIJ, FELLOW, IEEE Invited Paper The use of planar fluidic devices