RESEARCH ARTICLE

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Printed in the United States of America

Advanced Science Letters

Vol. 4, 150155, 2011

Application of Microuidics
Technology in Bioanalysis
B. Liu1
, Y. Deng1
2
, B. B. Qin1 , and Z. Y. Li1
1

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, P.R. China
2
Hunan Key Laboratory of Green Packaging and Application of Biological Nanotechnology,
Hunan University of Technology, Zhuzhou 412008, China

Microuidics technology which includes continuous-ow microuidics technology and digital microuidics technology is widely used in bioassays today. It holds high promise to facilitate the progress of bioassay by enabling
miniaturization and upgrading of current biological research tools due to its advantages such as low sample
consumption, reduced analysis time, high-throughput and compatible sizes with most biological samples. In this
article, we describe the recent applications of microuidics in biological researches at the molecular and cellular
levels, including their implementation, and associated design issues. Although the maturity of microuidics is
not favoured in some reviews about the microuidics technology, we still predict that the future is bright for this
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Keywords: Microuidics, PCR, Sequencing Analysis, Drug Delivery, Cell Sorting.

1. INTRODUCTION
Microuidics technologies can be divided into two classes:
continuous-ow microuidics technology and digital microuidics technology. Traditional (continuous-ow) microuidics
technologies are based on the continuous ow of liquid through
microfabricated channels.1 Continuous-ow systems are inherently difcult to integrate because the parameters that govern
ow eld (e.g., pressure, uid resistance, electric eld strength)
vary along the ow-path, making the ow at any location dependent upon the properties of the entire system.
The concept of digital microuidics (DMF) arose in the
late 1990s and involves the manipulation of discrete volumes of liquids on a surface. Manipulation of droplets can
occur through various mechanisms, including electrowetting,2
dielectrophoresis,3 thermocapillary transport4 and surface acoustic wave transport.5 In the early 2000s, this technology was popularized by Fair and his coworkers6 and Kim and his coworkers7
at Duke and UCLA, respectively.
The microuidics technique was explained as being a phenomenon driven by surface tension, and was called electrowetting or electrowetting on-dielectric (EWOD). A detailed
review of electrowetting basics can be found in the work of
Mugele.8 In addition, work on simulation and modeling of
droplet-based electrowetting has been reported by Biddut and
Homayoun Najjaran.9

Authors to whom correspondence should be addressed.

150

Adv. Sci. Lett. Vol. 4, No. 1, 2011

Compared to traditional biochips, microuidic biochips platform is under software-driven electronic control, eliminating the
need for mechanical tubes, pumps, and valves. Moreover, because
each droplet can be controlled independently, these digital
systems also have dynamic recongurability, whereby groups
of cells in a microuidic array can be recongured to change
their functionality during the concurrent execution of a set of
bioassays.
The advent of microuidic systems has revolutionized
the methodology for biological researches.10 Applications of
microuidic chips in biology are growing fast. In this article, the
recent applications of microuidic chips in biological researches
at the molecular and cellular levels are overviewed from the perspective of biology. As the next-generation platform, microuidic
chips will certainly open up new avenues for high-throughput
biological analysis, facilitating the understanding of biology at
the molecule-level.

2. ANALYSIS AT MOLECULE LEVEL

Since the discovery of DNA double-helix structure by Watson
and Crick in 1953,11 molecular level understanding of biology started. Especially, with the post genome area coming,
microuidics based methods will play an important role in highthroughput genomic studies.
2.1. Polymerase Chain Reaction
Microuidics technology has been successfully applied for
numerous nucleic acid assay applications. One promising
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Adv. Sci. Lett. 4, 150155, 2011

RESEARCH ARTICLE

(CAE) was rst introduced by Woolley and Mathies.19
20 for

application is for DNA amplication by using the polymerase
DNA sequencing using microuidic channel arrays in 1994.
chain reaction (PCR). Recently, a microwave heating system
Next-generation sequencing (NGS) platforms have transformed
which is described for performing PCR in a microuidic device
genetic variation studies by a massive reduction of cost and
is reported by Shaw et al.12 The heating system, in combination
sequencing effort. But the lack of efcient high-throughput methwith air impingement cooling, provides rapid thermal cycling
ods for enrichment of specic sequences from genomic DNA
with heating and cooling rates of up to 65  C s1 and minirepresents a key bottleneck in exploiting the enormous potential
mal over-or under-shoot (0.1  C) when reaching target temof next-generation sequencers.
peratures. Experiments showed that the fast thermal transition
Daniel Summerer et al. reported a strategy to multiply the
capability enabled 28 cycles to be performed in 42 minutes.
enrichment performance and consequently improve depth and
This represents a considerable time saving on previously reported
breadth of coverage for desired target sequences by applying
microwave PCR systems where 33 cycles took 127 minutes. To
two iterative cycles of hybridization with microuidic Geniom
demonstrate the functionality of the system, the author successbiochips.21 The use of microuidic array architecture can not
fully performed PCR for the amplication of the Amelogenin
only shorts the overall processes time, but also makes the
locus using heating rates and quantities an order of magnitude
processes highly automated, reduces contamination risk and
faster. PCR instrument with microwave heating system will be
increases reproducibility. With associated short hybridization
the tendency in the future. B. Maria Portia et al. validates the
times and a high level of automation throughout the HybSelect
microuidics-based method of post-polymerase chain reaction
procedure enables fast processing and easy handling, despite the
(PCR) analysis by hybridization and simultaneous size separation
use of two enrichment cycles. Recently, Chen et al. reported the
of DNA.13 The microuidic device with serpentine microchanproof of concept of a novel DNA sequencing technology called
nel pattern accommodated laminar ow and laminar secondary
sequencing by denaturation (SBD).22 They have designed and
ow which enabled hybridization and separation of probe-bound
fabricated a device with integrated temperature, uidic control,
DNA. Through evaluated by comparison with pp65 antigeneand uorescence imaging for sequencing application. Although
mia assay, this method shows high reliability of cytomegalovirus
due to the small differences between the melting temperatures of
detection as well as its potential as an alternative to antigenemia.
DNA fragments, the read length of SBD is expected to be limCompared with the conventional PCR assays, the concept
ited, perhaps as long as 20 bases in a single run. SBD also offers
of miniaturizing and automating PCR systems through digigreat reduction in genome sequence cost that can be combined
tal microuidics and advanced microfabrication techniques has
with other methods to achieve higher-throughput and lower-cost
attracted a great deal of attention because of the potential
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genome sequencing.
to dramatically improve the speed, portability, cost, sensitivity
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User
and specicity. For example, Zhishan Hua et al. success2.3. Preconcentration
IP : 203.113.130.216
fully developed a multiplexed real-time PCR system
using
Preparation
of proteins is usually a prerequisite step in proteomic
14
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08
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2011
08:56:53
electrowetting-based digital microuidics. In contrast to constudies. When working with natural low-abundance proteins, preventional benchtop real-time PCR instruments, this digital
concentration is necessary to bring target proteins into detectable
microuidic platform offers a high reproducibility and sensitivrange. The droplet-based (digital) microuidic platform has been
ity. It provides many advantages in terms of automation, cost and
developed to prepare and purify protein samples for measurement
time. Yung Tony et al. developed a digital PCR-based method for
by matrix-assisted laser desorption/ionization mass spectrometry
the quantitative detection of the two common epidermal growth
(MALDI-MS). Chatterjee et al. showed that a complete intefactor receptor mutations in the plasma and tumor tissues of
grated sequence of protein processing steps could be performed
patients suffering from non-small cell lung cancers.15 The senon droplet-based microuidic platform, including disulde reducsitive detection and accurate quantication of low abundance
tion, alkylation, and enzymatic digestion, followed by cocrystalEGFR mutations in tumor tissues and plasma by microuidics
lization with a MALDI matrix and analysis of the sample in situ
digital PCR would be useful for predicting treatment response,
by MALDI-MS.23
monitoring disease progression and the early detection of treatIn 2009, Jebrail et al. reported the development of an automent failure associated with acquired drug resistance. Lun et al.
mated microuidic method for extracting proteins from heterogefocus on comparing the imprecision of microuidics digital PCR
neous uids by precipitation.24 The structure of device consists
with that of a well-established non digital PCR assay for meaof four reagent reservoirs, the waste reservoir, and extraction
suring male fetal DNA in maternal plasma.16 They prove that
electrode. Frames from a movie depicted the extraction and
microuidics digital PCR represents an improvement over prepurication of BSA (50 mg/mL) in 20% TCA (precipitant) and
vious methods for quantifying fetal DNA in maternal plasma,
washing with 70/30 v/v chloroform/acetonitrile (rinse solution).
enabling diagnostic and research applications requiring precise
In the nal frame, the precipitated protein is redissolved in a
quantication. They predicated that this approach may also
droplet of 100 mM borate buffer containing 1% SDS. It is the
impact other diagnostic applications of plasma nucleic acids, e.g.,
rst microuidic method for extracting proteins from heteroin oncology and transplantation.
geneous uids by precipitation. The digital microuidics used
2.2. Sequencing Analysis
Capillary array electrophoresis (CAE) has been the golden standard for genome sequencing purposes,7
18 where multiple capillaries are used in parallel for high-throughput sequencing of
target DNAs. With the development of microfabrication technology, microfabricated capillary array electrophoresis device

in the method not only facilitates high throughput extraction

and screening of proteins, but also has reduced analysis time.
Experiment results suggested great potential for the development
of integrated, multi-step processes incorporating sample reduction, alkylation and digestion. Especially this work represents an
important rst step in efforts to develop fully automated microuidic methods for proteomic analyses.
151

RESEARCH ARTICLE

Adv. Sci. Lett. 4, 150155, 2011

mass production by techniques, such as injection molding and

2.4. Drug Analysis and Delivery
embossing are in great demand for practical applications.
Recent advances in molecular biology and genetic research have
(2) Multiplicity. The multiplexed assay will continue to be the
made possible the creation of more powerful and effective candominant method for commercialization of these microuidic
cer therapeutics, bringing about the realization of the century-old
immunoassays.
concept of magic bullets that can carry therapeutic drugs to
(3) Surface modication and immobilization. Nonspecic
target sites with high specicity.25
adsorption or binding to molecules rather than analytes is a key
Gao et al. developed a novel method based on uorescence
concern in immunoassays because it may greatly impair the sendetection of hydrogel encapsulated cells in microchannels for
anticancer drug analysis.26 Firstly, they fabricated poly (ethysitivity and selectivity.
lene glycol) (PEG) hydrogel microstructures with controlled mor(4) Purication and concentration. Due to the complexity and
phology and position to encapsulate mammalian cells inside
the low trace of analytes in biosamples, purication and concenmicrochannels with a simple and inexpensive photolithogratration steps are often required in microuidic immunoassays.
phy technique which is benecial for cell-based assays. Sec(5) Detection. Developing and integrating miniaturized, comondly, they immobilized human hepatoma HepG2 cells and
pact, portable, and inexpensive detection systems with an accepthuman lung epithelial A549 cells inside two different shapes of
able sensitivity onto microuidic devices are still in great
three-dimensional hydrogel microstructures using photolithogrademand.
phy approach on a same array simultaneously. By comparison
(6) Integration, packaging, and cost down issues. The ultimate
of quantitative analysis of intracellular glutathione (GSH) and
goal for practical commercialization is to develop fully intereactive oxygen species (ROS) contents between the cells encapgrated, well packaged, disposable, and cheap microuidic syssulated inside hydrogels and cultured on 96-well plate, it was
tems for immunoassays.
demonstrated that this simple method for selective encapsulation
(7) Storage of reagents. This is an important issue in portable
of single cells inside hydrogel microstructures in ordinary labdevices because most bioreagents are not durable under room
oratory is very useful for biomedical basic research and drug
temperature and some of them require special environments for
screening.
storage.
Kanaka Hettiarachchi and Lee reported the ability to generate
Besides immunization analysis, other applications of microufunctionalized multilayer gas lipospheres with precisely con27
idic
chips include microspheres separation and selection, quantrolled size and drug carrying capacity. Through their previous
tum
dot
preparation, and so on.
work, they demonstrated the application of multilayer lipospheres
Delivered
to:et al. introduced a microuidic device fabricated
Asmatulu
as drug delivery agents, although those vehicles were
produced by Ingenta
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via
UV
lithography
technique to separate non-magnetic uoreswith techniques that resulted in size and loading inconsistency.
brite
carboxy
microspheres
(4.5 m) in the pH 7 ferrouids
IP
:
203.113.130.216
Tatiana et al. reviewed the recent microuidics progress and
28
made
of magnetite nanoparticles (10 nm).31 This study may
They
applications in glycosaminoglycan and heparin research.
Tue, 08
Mar 2011
08:56:53
be useful for the separation of biological particles, which are
showed that digital microuidics may provide environments that
very sensitive to pH value of the solutions. Masato et al. synmore accurately mimic biological synthesis and can be manipthesized ZnS/CdSe/ZnS quantum dot quantum well (QDQW) by
ulated leading to new biosynthetic and biological screening
using a microuidic reactor.32 Experiment results demonstrated
designs. They predicted that the future should bring an improved
that high quality CdSe phase was embedded in the ZnS core
understanding of Golgi-based heparin/HS biosynthesis, its conand shell, and the layer thickness was controlled homogeneously
trol and scale-up. The rapid, microscale analysis of heparin/HS
will lead to the production of bioengineered anticoagulant hepby using the microuidic system. This method may be a useful
arin and a novel array of designer heparin-based therapeutics.
tool for controlling the multilayer nanocrystals such as QDQW.
Through simulating a nanoparticle focusing lens in a microu2.5. Immunization Analysis and Other Applications
idic channel, Lee et al. can estimate the path of randomly movImmunoassays and enzyme activity assays currently used in newing nanoparticles through a focusing lens.33 This method will
born screening have been translated to a disposable microchip
be efciently applicable to design the microuidic channel conprogrammed to dispense, transport, mix, wash, and incubate
taining various particles, molecules and so forth in the near
individual microdroplets from specimens, including dried blood
future.
spot extracts, and reagents all under software control. There
Juan Yan et al. developed a cancer protein chip with the help
are many characteristics which make microuidics technolof microuidic channel.34 By using the protein chip based on
ogy attractive to newborn screening, such as low volumes,
microuidic technology, they could detect carcinoma embryonic
direct translation of existing assays, automation, portability,
antigen (CEA) at a wide range of concentration (550000 ng/mL)
inexpensive manufacturing, sample compatibility, scalability and
and also had high sensitivity (LOD < 1 pM). Because of its
multifunctionality.
quick detection procedure and no need for high-cost instruments,
Millington et al. described a cost-effective new platform that
this protein chip showed potential use for point-of-care (POC)
reduced the time to result reporting and could perform multiplexdiagnostics.
ing assays requiring different platforms.29 Lin et al. presented a
brief introduction to microuidic immunoassays and showed the
critical issues which are important for microuidic immunoas3. ANALYSIS AT CELLULAR LEVEL
says and should be addressed properly.30 The critical issues are
There are several new techniques to analyze the cell, such as new
as follows:
capillary electrophoresis, molecular imaging,35
36 single walled
(1) Mass production. For commercial and disposability considcarbon nanotubes37 and microuidic chip. Conventional ow
erations, materials with similar properties and capabilities for
152

Adv. Sci. Lett. 4, 150155, 2011

cytometers which are routinely utilized for analyzing the physical and chemical properties of biological cells require a high
amount of reagent for analysis and furthermore are both bulky
and expensive and require trained personnel for operation and
maintenance.

RESEARCH ARTICLE
heater. Microheaters and suspended biocompatible microbridge
were integrated on a chip in which yeast-cell immobilization can
be performed by gelation of a PNIPAAm solution.

3.3. Cell Culture and Development

In order to better predict the clinical response to drug com3.1. Cell Sorting
pounds, a cell culture model that is faithful to in vivo behavior
is required. With the recent advances in microuidic technology,
Cell sorting is a preliminary step for cellular level investigathe utilization of a microuidic-based cell culture has several
tion of biology. In 2008, Barbulovic-Nad et al. introduced a new
advantages, making it a promising alternative to the conventional
method for implementing cell-based assays.38 This method is
cell culture methods.
based on digital microuidics which was used to actuate nanoLiu et al. developed a novel and robust microuidic chip with
litre droplets of reagents and cells on a planar array of electrodes.
combined functions of continuous culture and output of PC-3
Experiments demonstrated that this method is advantageous for
prostate cancer cells.49 With digital controls, polydimethylsiloxcell-based assays because of automated manipulation of multiple reagents in addition to reduced reagent and analysis time. In
ane (PDMS) exible diaphragms are able to apply hydrodynamic
2010, Ji et al. reviewed advances of nanotechnology in the stem
shear forces on cultures, detaching a fraction of attached cancer
cells research, including various micro/nanofabrication technolocells from the surface for output while leaving others for reuse in
gies, microgrooves technology and so on.39
subsequent cultures. The fractions of detached cells and remaining cells can be precisely controlled. The system has not only the
To circumvent the complexity of the detection systems of
advantages of small size, high cell culture efciency, and digital
microuidic devices, Hartley et al. recently reported on a CMOS
control, but also of simple fabrication at low cost, easy operation
optical active pixel sensor (APS) for near-eld detection and
and robust performance. The chip performs 9 passages during
counting of microscopic particles.40 To further enhance the dig30 days of continuous culture and shows promise as a durable
ital cytometric capabilities of the original sensor, Yahya et al.
design suitable for long-term cell output.
modied and utilized a dual APS-array scheme to facilitate the
Hwa Sung Shin et al. described a novel microuidic device
determination of the velocity and size of particles owing in
that is compatible with cells growing on a monolayer on a conmicrouidic channels.41 The experimental results suggested that
ventional tissue culture Petri dish.50 Through this device, they
the dual-array-APS arrangement offered a simplistic yet effective strategy for size measurements of microscopic
particles
in
investigated
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microuidic environments.
of lipoplex (DNA entangled with liposome) to primary neurons.
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In Comparison with viral methods, this method has signicantly
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3.2. Patterning and Immobilization
lower transfection rate which limited its use in neuroscience
Tue, 08 Mar 2011
08:56:53
research.
Immobilization of cells is usually necessary before analysis
Barbulovic-Nad et al. introduced the rst lab-on-a-chip platcan be effectively conducted on microuidic chips. One comform for complete mammalian cell culture.51 The new method
monly used method is cell patterning in microuidic channels
is powered by digital microuidics (DMF), a technique in which
by soft lithographic techniques,42 such asmicrocontact printing,
nanolitre-sized droplets are manipulated on an open surface of
patterning using microuidic channels, and laminar ow patternan array of electrodes. Three key innovations are required to
ing. There are many cell immobilization methods reported for
implement complete cell culture on a microuidic device: (1) a
microuidic systems in recent years, such as cell docking,43
44
technique for growing cells on patterned islands (or adhesion
acoustic trap45 and optical trap.46
pads) positioned on an array of DMF actuation electrodes; (2)
Liu Zongbin et al. developed a microuidic silicon chip
a method for rapidly and efciently exchanging media and other
with poly(ethylene glycol) (PEG) hydrogel microarray on the
reagents on cells grown on adhesion pads; and (3) a system capananoporous anodized aluminum oxide (AAO) membrane which
ble of detachment and collection of cells from an (old) origin
was fabricated to form cell based microarray with controlled drug
site and delivery to a (new) destination site for subculture. These
delivery.47 The PEG hydrogel microstructures were fabricated
new methods may be useful for a wide range of applications in
using photolithography on nanoporous alumina surface modied
cell biology, tissue engineering, screening and beyond.
with a 3-(trimethoxysilyl)propyl methacrylate (TPM) monolayer.
During the photopolymerization reaction, 1010 hydrogel arrays
3.4. Patch Clamp and Electroporation
were covalently bonded to the substrate via the TPM monolayer
Patch clamp and electroporation has been widely used in genetics
for cell patterning.
and molecular biology to deliver chemical and biological agents
Yamanishi et al. described the fabrication of a temperaturesuch as DNA into cells. Microuidics-based cell electroporation
controlled microuidic chip for cell immobilization using
has many advantages in delivering small molecules into cells.
a thermosensitive hydrogel of poly (N-isopropylacrylamide)
Zhu et al. developed a simple microuidic chip with hydrody(PNIPAAm).48 A mixture of PNIPAAm solution, yeast cells, and
namic focusing52 and it can produce high through-put (more than
Calcein-AM uorescent dye was owed in the microchannel, and
the indium-tin-oxide (ITO) microheaters fabricated by microma104 cells min1 ) of cellular electroporation under low voltage
chining technology heated a PNIPAAm gel. In order to avoid
(<3 V) charge of continuous DC power. By controlling the velocblocking the observation of the culturing cells and reduce the
ity ratio, the uid focusing can produce very thin layer to allow
signal-to-noise ratio (SNR), they fabricated a suspended microcells to sequentially pass through so that high quality electroperbridge above the microheater that limits the height of the gel,
meation can be performed for each cell as moving in the focusing
ensuring that it forms a thin and transparent layer above the
region, where the electrical pulse is provided as the potential
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RESEARCH ARTICLE
charge during the passing time. Simulation results showed that
an input voltage of only 1.5 V could generate an electric eld
intensity of about 1.17 kV cm1 across the cell suspension ow
in the squeezed area. The electropermeation of yeast cell was
observed, showing a permeabilization percentage up to 70%.
Adrian et al. developed a novel open-access microuidic
patch-clamp array chip by combining both a microscale softlithography and a macroscale polymer fabrication method.53
They demonstrated the capability of using such an openaccess uidic system for patch-clamp measurements. Experiments showed that the system was capable of performing whole
cell measurements and drug proling in a more efcient manner
than the traditional patch-clamp set-up.
Botzolakis et al. developed a novel microuidic approach54
to solution switching that allows for precise temporal control
over the neurotransmitter transient while substantially increasing experimental throughput, exibility, reproducibility, and costeffectiveness. When this system was used to apply ultra-brief
(similar to 400 s) GABA pulses to recombinant GABA
(A) receptors, members of the cys-loop family of LGICs,
the resulting currents resembled hippocampal inhibitory postsynaptic currents (IPSCs) and differed from currents evoked by
longer, conventional pulses, illustrating the importance of evaluating LGICs on a synaptic timescale. This methodology should
therefore allow the effects of disease-causing mutations and
allosteric modulators to be evaluated in vitro under physiologically relevant conditions.

Adv. Sci. Lett. 4, 150155, 2011

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Like most new technologies, microuidics has obviously short08 Mar
coming in the previous years. As some articlesTue,
reported,
most 2011 08:56:53
4. CONCLUSION

microuidic platforms built to date are highly specialized and

designed to fulll the requirements of a single particular application within a limited set of operations. The detection techniques
should be able to circumvent the limitations of hydrophobic surfaces and exploit the advantages of the array format, high droplet
transport speeds and rapid mixing schemes.
As the applications discussed in this article, we propose
that the ever-expanding community of microuidics researchers
(including academics, all, and others) will solve some of
the mechanistic and practical problems that remain, such that
microuidics will become a widely practiced technique in the
next decade.

Acknowledgments: This research is nancially supported

by the National Natural Science Foundation of China (NO.
60971045), the China National Science and Technology Major
Projects (2009ZX10004-311) and the University Creative Group
Project of Hunan Education Department.

References and Notes

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(2003).
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(2003).
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100, 116101 (2006).
6. M. G. Pollack, R. B. Fair, and A. D. Shenderov, Appl. Phys. Lett. 77, 1725
(2000).

154

RESEARCH ARTICLE

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50. S. S. Hwa, J. K. Hyung, J. S. Sang, and L. J. Noo, J. Nanosci. Nanotechnol.

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53. Y. L. Adrian, J. H. Paul, R. W. Angela, and P. L. Luke, Lab Chip 6, 1510

(2006).
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Received: 8 May 2010. Revised/Accepted: 10 September 2010.

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