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Invited Paper
The use of planar fluidic devices for performing small-volume To simplify the job of the analytical chemist, the TAS con-
chemistry was first proposed by analytical chemists, who coined cept proposed the full incorporation of analytical procedures
the term miniaturized total chemical analysis systems (TAS) for into flowing systems. Carrier streams of fluids, rather than
this concept. More recently, the TAS field has begun to encom-
pass other areas of chemistry and biology. To reflect this expanded human hands, take over the role of sample transport between
scope, the broader terms microfluidics and lab-on-a-chip are different sample manipulation steps. Flow paths are defined
now often used in addition to TAS. Most microfluidics researchers by interconnected pieces of tubing, arranged in such a way
rely on micromachining technologies at least to some extent to pro- that the desired analysis can be performed. The TAS is a
duce microflow systems based on interconnected micrometer-di- smaller, faster version of this, with analyses taking place
mensioned channels. As members of the microelectromechanical
systems (MEMS) community know, however, one can do more with
in flow systems having L and even sub- L volumes, to
these techniques. It is possible to impart higher levels of function- achieve times on the order of seconds rather than many min-
ality by making features in different materials and at different levels utes. The devices used are small and monolithic in nature.
within a microfluidic device. Increasingly, researchers have con- Three-dimensional (3-D) tubing-based systems are replaced
sidered how to integrate electrical or electrochemical function into by networks of microchannels integrated into planar sub-
chips for purposes as diverse as heating, temperature sensing, elec-
strate surfaces, with cross-sectional dimensions generally
trochemical detection, and pumping. MEMS processes applied to
new materials have also resulted in new approaches for fabrication on the order of micrometers. Though still in its infancy, the
of microchannels. This review paper explores these and other devel- interest in this technology has grown explosively over the
opments that have emerged from the increasing interaction between last decade, with an increasing number of special symposia
the MEMS and microfluidics worlds. and conferences dedicated to the subject. Researchers from
KeywordsLab-on-a-chip, microfluidics, microfabrication, many disciplines other than analytical chemistry have also
micromachining, miniaturized total chemical analysis systems wholeheartedly embraced the fundamental fluidic principle
(TAS), review . of TAS as a way of developing new research tools for
chemical and biological applications. This has led, among
I. INTRODUCTION other things, to the emergence of TAS-like fluidic struc-
tures in microreactor technology. It has also resulted in the
Though there exist early, pre-1990 examples of microelec- introduction of new terminologies and concepts. Microflu-
tromechanical systems (MEMS)-type microfluidic devices idics, or alternatively, lab-on-a-chip (LOC), are recent
for chemical applications, it was the groundbreaking paper monikers that have entered the TAS jargon, and are in-
of Manz et al. [1] in 1990 that established the field of minia- creasingly used in place of TAS as general terms for the
turized total chemical analysis systems ( TAS). The TAS field. This development is in fact a tacit acknowledgment,
concept is an extension of the total chemical analysis system perhaps, that the use of microflow systems has long since
concept (TAS), which was put forth in the early 1980s to ceased to be the domain of the analytical chemist alone.
address the issue of automation in analytical chemistry [2]. The ability to make networks of interconnecting channels
is what lies at the heart of microfluidics, and makes it so
powerful. The crucial enabling technologies came first from
Manuscript received February 26, 2003; revised April 4, 2003. the world of MEMS, where the use of photolithographic
E. Verpoorte was with the Institute of Microtechnology, University of processes to obtain micrometer features in silicon and other
Neuchtel, CH-2007 Neuchtel, Switzerland. She is now at the Groningen
Research Institute of Pharmacy, University of Groningen, 9713 AV substrates was well established. The first successful demon-
Groningen, The Netherlands (e-mail: S.Verpoorte@farm.rug.nl). stration of chip-based analysis in the early nineties involved
N. F. de Rooij is with the Institute of Microtechnology, Uni- the fast separation of fluorescent dyes [3], [4] and fluores-
versity of Neuchtel, CH-2007 Neuchtel, Switzerland (e-mail:
nico.derooij@unine.ch). cently labeled amino acids [5] by capillary electrophoresis
Digital Object Identifier 10.1109/JPROC.2003.813570 (CE). This technique, based on the separation of charged
that can be used, as long as it is available in the form of developed by Grtillat et al. [48] and has become standard in
smooth, planar substrates. Microfluidic devices made in our work [49][51]. Channels are etched into a 10-cm Pyrex
fused silica (quartz) have also been reported. This material 7740 wafer using HF, using a 200- or 400-nm-thick layer
is attractive because it is UV-transparent, a characteristic of polysilicon as a masking layer over areas where etching
which makes it superior to glass. Photolithographic pro- is not desired. A typical process flow would proceed as
cesses similar to those used for silicon can be employed follows. After deposition of the polysilicon by low-pressure
for the patterning and subsequent transfer of channels into chemical vapor deposition (LPCVD), wafers are dehydrated
planar glass and quartz wafer surfaces. at 200 C for 30 min and exposed to hexamethyldisilazane
The glass micromachining method established in our lab- (HMDS) vapor for 15 min to improve photoresist adhe-
oratory is shown in Fig. 4(a). This is based on a process first sion. A 1.8- m-thin layer of AZ1518 (Clariant, Muttenz,
zoidal cross sections with aspect ratios 1. There is little the freedom of channel layout afforded by isotropic etching
freedom in channel network design, since possible layout of glass, a nickel master can be prepared directly from a
geometries are dictated by crystalline orientation. To retain structured glass wafer by growing a relatively thick (3-mm)
performing chemical reactions or processes requiring tem- Several of these use integrated heaters to achieve denatu-
perature control, since the high heat transfer rates in these ration of double-stranded DNA [150], [151]. An in-depth
systems lead to easier implementation of uniform tempera- review of the general topic of nucleic acid analysis with
ture conditions [146]. This section will examine microfluidic micromachined devices is presented by Mastrangelo (in this
devices incorporating resistive heating in one form or another issue).
for both chemical and biochemical applications. Yamamoto et al. contacted a PDMS chip containing a mi-
1) Biochemical Applications: There have been many croreactor array with a glass temperature control chip for
publications describing the application of MEMS tech- cell-free protein synthesis [152]. The glass chip had heaters
nologies to the development of devices for DNA analysis. and sensors structured in a 500-nm-thick layer of indium tin
A significant number have focused on the integration of oxide (ITO) by etching in a 1:1 HNO :HCl solution at 50 C
the polymerase chain reaction (PCR), used to increase the for about 20 min using a patterned resist layer as etch mask.
amount of DNA from a sample for analysis, into micro- Contact electrodes were then formed by liftoff, and the en-
machined chambers. Microchip PCR provides an attractive tire surface passivated by a 500-nm layer of SiO . Because
alternative because the low thermal mass of these devices the ITO layer is optically transparent, optical detection was
allows the reduction of cycle times from several minutes to possible through both chip surfaces. Thermal time constants
30 s or less. Another DNA-related topic that has received a for heating and cooling were 170 ms and 3 s, respectively,
lot of attention in recent years is the use of microchip gel and uniform temperature gradients could be achieved across
electrophoresis for DNA analysis (see, e.g., [147][149]). each reactor. The cell-free synthesis of green and blue fluo-
which a PtTi thin-film heater and RTD had been made idic systems. One early example using a stacked system of
[see Fig. 14(a) and (b)]. These contained either a packed silicon chips focused on the analysis of phosphate using the
bed of catalytic particles or structured microchannels with Molybdenum Blue method to form a blue-colored phosphate
staggered arrays of columns, 50 m in diameter, 300 m complex which could easily be detected by absorbance [38],
tall, with nearly 20 000 columns in all, to act as catalyst [157]. This example was interesting in that it was the first to
support [see Fig. 14(c)]. It was pointed out that while the use silicon-based micro pumps for controlling liquids within
high thermal conductivity of silicon allowed excellent heat the valveless system. However, a smaller flow system did not
dissipation and hence good thermal control by the heaters, mean enhanced reaction, since the kinetics of the reaction
large amounts of heat were lost to the environment. In used for phosphate analysis are slow and proved to be the
addition, heater performance was very dependent on how limiting factor for analysis. A more recent example of FIA,
the chip was packaged. using much smaller chips, was developed for analysis of am-
3) Other Microchemical Reaction Applica- monia in waste and drinking waters. It used the Berthelot re-
tions: Classical wet chemical analytical methods are action to convert ammonia through reaction with phenol to
generally based on the chemical conversion of the analyte a blue indophenol dye. Again, the kinetics of this reaction
of interest through derivatization, complexation, or other are slow, with maximum absorbance achieved only after 15
means to make it more visible to a detector. Many of minutes or so at 25 C. Since a sensitive measurement was
these methods lend themselves well to automation by desired in 5 min or less, and because reaction rates increased
flow injection analysis (FIA). In this technique, sample is significantly at 35 C and 45 C, the three-layer microflu-
injected into a flowing carrier stream and subjected to idic device used had a 50-nm-thick ITO layer sputtered on
various sample handling steps, such as dilution, reagent one surface for resistive heating [44]. An all-glass version of
addition, mixing, and finally, detection. Reaction times are the three-layer chips for this application, complete with ITO
defined by the residence time of the reacting sample zone in layer, has also been reported [51].
the flow system, and hence can be adjusted to some extent Fast derivatization is especially important when analytes
by flow-rate variation. Precise flow control is crucial to are to be labeled on-line just before or after a separation.
obtaining reproducibility in FIA, since measurements are Eijkel et al. micromachined a heated chemical reactor for
done under nonequilibrium conditions. precolumn chemical derivatization of amino acids with the
A number of publications have described the integration fluorescent agent, 4-fluoro-7-nitrobenzofurazan (NBD-F)
of classical wet chemical methods into micromachined flu- before separation in a conventional high-performance