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Microfluidics with Droplets.

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Lab on a Chip
Microfluidics with Droplets**
Detlev Belder*
analytical methods · high-throughput screening ·
lab on a chip · microfluidics · microreactors
In analogy to miniaturization in microelectronics, the integration of chemical
processes on chips, where chemical
reactions are performed in microchannels and -cavities, is currently the focus
of significant research efforts. The ambitious aim is to shrink chemical laboratories to “lab-on-a-chip” systems. The
development of technologies and miniaturized components like reactors and
valves in order to realize such a handheld laboratory is currently a very active
research area. In this context microfluidics is of particular importance as microfluidic channels play a major role as
central elements of miniaturized labs in
analogy to the conducting paths in
microelectronics. Microfluidic channels
are utilized for transport, mixing, and
separation of reagents on the nanoliter
scale. While tremendous progress has
been made in the miniaturization of
individual construction units of potential lab chips, interfacing such tiny
devices to the macroscopic world is still
a big challenge.
Zheng und Ismagilov[1] reported recently a straightforward and economic
approach for handling and transfering a
large number of samples on the nanoliter scale into basic microfluidic systems
for subsequent screening assays. For this
purpose aqueous samples several nanoliters in volume are introduced into a
capillary using immiscible phases as
spacers to form a sample array. While
in classical flow injection analyses (FIA)
air bubbles are used to separate a series
[*] Dr. D. Belder
Max-Planck-Institut fr Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mlheim an der Ruhr (Germany)
Fax: (+ 49) 208-306-2275
[**] The figures were obtained from ref. [1].
Angew. Chem. Int. Ed. 2005, 44, 3521 –3522
of samples, Zheng and Ismagilov describe a three-phase liquid/liquid/gas
system. An array of different aqueous
samples is generated inside a capillary,
while the sample plugs are surrounded
by a fluorinated carrier fluid and additionally separated by gas bubbles (Figure 1).
Figure 1. An array of differently colored aqueous samples separated by air bubbles (dark
segments) in a capillary filled with a fluorocarbon.
Zheng and Ismagilov report that
such three-phase systems are much
more robust than the classical two-phase
gas/liquid[2] and liquid/liquid systems.[3]
This reduces coalescence and carry-over
of samples more efficiently. Preloaded
capillaries are even suitable for longterm storage of samples on the nanoliter
Such segmented flows, whereby
aqueous sample droplets are floating in
a hydrophobic liquid, are especially
attractive in mircrofluidics, as reagents
can be mixed within a droplet and
simultaneously sample dispersion is
minimized.[4] The mixing of compounds
in microfluidic channels is challenging
because of the low Reynolds numbers
and the corresponding laminar flows.
Significant research efforts have been
devoted to solving this problem, for
example, by the development of micromixers.[5]
By coupling a capillary to a microfluidic chip, Zheng and Ismagilov performed simple chemical reactions with
the sample array. For this purpose the
preformed samples are introduced into
a microfluidic system with a T-junction,
DOI: 10.1002/anie.200500620
where they meet a reagent stream
(Figure 2). In this type of microreactor,
which has already been described in
detail for two-phase systems,[6] the sam-
Figure 2. Schematic drawing of sample zones
merging with a reagent solution in a microfluidic chip.
ple droplets merge with the reagent
solution without distortion of the segmented flow. The reagent concentrations can be adjusted easily by regulating the flow rates.
This technique was illustrated with
two examples. In one case an assay was
performed in which a set of enzymes was
screened for phosphatase activity using
fluorescein diphosphate as a fluorogenic
substrate. An array of protein samples
(15 nL), preloaded in a capillary as
described above, was merged with the
reagent solution at the T-junction. The
presence of a phosphatase could be
evident from the fluorescence of the
hydrolyzed substrate (see Figure 3).
In a second example this approach
was successfully utilized for screening a
single protein against multiple crystal-
Figure 3. Schematic drawing and microscopic
image of an enzyme assay for phosphatase activity using a fluorogenic substrate.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
lization agents. For this purpose an
additional outlet capillary was coupled
to the chip in order to collect the
segmented crystallization solutions.
Such glass capillaries are much better
suited for time-consuming crystallization experiments than the solvent-permeable polydimethylsiloxane (PDMS)
Microfluidic chips prepared from
PDMS appear to be well suited for
coupling with capillaries and adapters
owing to the elasticity of the material. It
would be very attractive to extend this
concept also to chips manufactured
from glass or fused silica, which are
considered the materials of choice for
future chip laboratories because of their
excellent chemical resistance and optical properties.
Segmented flow is not optimal for
more complex chip laboratories since
successive operations would require a
homogeneous one-phase flow. In classi-
cal flow injection analyses, bubble gates
are used for that purpose. Hibara et al.[8]
have recently described a corresponding
microfluidic system for the removal of
air bubbles in aqueous flows that is
based on channel segments with different hydrophobicity. In this approach, gas
bubbles are removed utilizing hydrophobic channels, while the aqueous
phase is guided into hydrophilic channels. The application of this approach to
the system described by Zheng and
Ismagilov could allow online coupling
of succeeding analytical steps like electrophoresis. This would be a promising
step toward the goal of a “lab on a chip”.
Published online: May 13, 2005
[1] B. Zheng, R. F. Ismagilov, Angew. Chem.
2005, 117, 2576 – 2579; Angew. Chem. Int.
Ed. 2005, 44, 2520 – 2523.
[2] V. L. Linder, S. K. Sia, G. M. Whitesides,
Anal. Chem. 2005, 77, 64 – 71.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[3] H. Song, R. F. Ismagilov, J. Am. Chem.
Soc. 2003, 125, 14 613 – 14 619.
[4] a) H. Song, J. D. Tice, R. F. Ismagilov,
Angew. Chem. 2003, 115, 792 – 796; Angew. Chem. Int. Ed. 2003, 42, 768 – 772;
b) A. Gnther, S. A. Khan, M. Thalmann,
F. Trachsel, K. F. Jensen, Lab Chip 2004,
4, 278 – 286.
[5] J. M. Ottino, S. Wiggins, Science 2004,
305, 485 – 486.
[6] a) B. Zheng, J. D. Tice, R. F. Ismagilov,
Anal. Chem. 2004, 76, 4977 – 4982;
b) L. S. Roach, H. Song, R. F. Ismagilov,
Anal. Chem. 2005, 77, 785 – 796; c) I.
Shestopalov, J. D. Tice, R. F. Ismagilov,
Lab Chip 2004, 4, 316 – 321; d) B. Zheng,
L. S. Roach, R. F. Ismagilov, J. Am.
Chem. Soc. 2003, 125, 11 170 – 11 171.
[7] B. Zheng, J. D. Tice, L. S. Roach, R. F.
Ismagilov, Angew. Chem. 2004, 116,
2562 – 2565.
[8] A. Hibara, S. Iwayama, S. Matsuoka, M.
Ueno, Y. Kikutani, M. Tokeshi, T. Kitamori, Anal. Chem. 2005, 77, 943 – 947.
Angew. Chem. Int. Ed. 2005, 44, 3521 –3522
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