Integrated Refractive Index Optical Ring
Resonator Detector for Capillary Electrophoresis
Hongying Zhu,†Ian M. White,†Jonathan D. Suter,†Mohammed Zourob,‡and Xudong Fan*,†
Department of Biological Engineering, 240D Life Sciences Center, University of Missouri-Columbia, Columbia, Missouri
65211, and Institute of Biotechnology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, UK
We developed a novel miniaturized and multiplexed, on-
capillary, refractive index (RI) detector using liquid core
optical ring resonators (LCORRs) for future development
of capillary electrophoresis (CE) devices. The LCORR
employs a glass capillary with a diameter of ∼100 µm and
a wall thickness of a few micrometers. The circular cross
section of the capillary forms a ring resonator along which
the light circulates in the form of the whispering gallery
modes (WGMs). The WGM has an evanescent field
extending into the capillary core and responds to the RI
change due to the analyte conducted in the capillary, thus
permitting label-free measurement. The resonating nature
of the WGM enables repetitive light-analyte interaction,
significantly enhancing the LCORR sensitivity. This LCORR
architecture achieves dual use of the capillary as a sensor
head and a CE fluidic channel, allowing for integrated,
multiplexed, and noninvasive on-capillary detection at any
location along the capillary. In this work, we used electro-
osmotic flow and glycerol as a model system to demon-
strate the fluid transport capability of the LCORRs. In
addition, we performed flow speed measurement on the
LCORR to demonstrate its flow analysis capability. Finally,
using the LCORR’s label-free sensing mechanism, we
accurately deduced the analyte concentration in real time
at a given point on the capillary. A sensitivity of 20 nm/
RIU (refractive index units) was observed, leading to an
RI detection limit of 10-6RIU. The LCORR marries
photonic technology with microfluidics and enables rapid
on-capillary sample analysis and flow profile monitoring.
The investigation in this regard will open a door to novel
high-throughput CE devices and lab-on-a-chip sensors in
Capillary electrophoresis (CE) is a rapid, high-resolution
analytical tool and has been used extensively in many chemical
and biomedical applications,1,2ranging from genome sequencing,3
proteomics,4and clinical and environmental sample analysis5,6to
chemical cytometry.7Detection of CE is typically carried out at
the terminal end of the capillary.1,2However, in this detection
scheme, only the final separated analyte is analyzed, and the
detailed information regarding how samples move in the capillary
is completely lost.8,9To take full advantage of the high resolution
and low sample volume achieved by CE, on-capillary detection is
highly desirable.8,9As compared to end-capillary detection, on-
capillary detection can analyze sample separation by providing
vital information about the flow profile, such as flow rate and
dispersion, while also permitting detection with low sample
volume.10,11In particular, for CE modes that exhibit self-concentra-
tion and self-focusing effects, such as capillary isoelectric focusing,
on-capillary detection becomes critical due to its capability of direct
monitoring of self-focusing dynamics and fast sample analysis.12
On-capillary detection has been accomplished using UV
absorption and laser-induced fluorescence (LIF) spectroscopy;2,8,13,14
however, the sensitivity in UV absorption is generally low due to
the short light absorption path and small sample volume. In
addition, UV absorption suffers from nonlinear response to sample
concentration.9Although LIF is the most sensitive detection
technique, this method requires the presence of chromophores
that are either inherent to the analyte or introduced through
labeling. In the former case, intrinsic chromophores may not
readily fit the laser lines available in the lab, and their fluorescence
is normally weak, leading to the poor signal-to-noise ratio. In the
latter situation, labeling processes are laborious and may interfere
with the analyte’s biochemical functions.
Recently, refractive index (RI) has been used in CE for on-
capillary detection9,11-20and end-capillary detection,21as well as
* To whom correspondence should be addressed. Phone: 573-884-2543.
Fax: 573-884-9676. E-mail: email@example.com.
†University of Missouri-Columbia.
‡University of Cambridge.
(1) Kraly, J.; Fazal, M. A.; Schoenherr, R. M.; Bonn, R.; Harwood, M. M.; Turner,
E.; Jones, M.; Dovichi, N. J. Anal. Chem. 2006, 78, 4097-4110.
(2) Landers, J. P. Handbook of Capillary Electrophoresis, 2nd ed.; CRC Press:
Boca Raton, 1996.
(3) Dovichi, N. J.; Zhang, J. Angew. Chem., Int. Ed. 2000, 39, 4463-4468.
(4) Guzman, N. A.; Phillips, T. M. Anal. Chem. 2006, 77, 60A-67A.
(5) Hu, S.; Dovichi, N. J. Anal. Chem. 2002, 74, 2833-2850.
(6) Thormann, W.; Lurie, I. S.; McCord, B.; Marti, U.; Cenni, B.; Malik, N.
Electrophoresis 2001, 22, 4216-4243.
(7) Krylow, S. N.; Starke, D. A.; Arriaga, E. A.; Zhang, Z.; Chan, N. W. C.; Palcic,
M. M.; Dovichi, N. J. Anal. Chem. 2000, 72, 872-877.
(8) Bruno, A. E.; Gassmann, E.; Pericles, N.; Anton, K. Anal. Chem. 1989, 61,
(9) Bruno, A. E.; Krattiger, B.; Maystre, F.; Widmer, H. M. Anal. Chem. 1991,
(10) Staller, T. D.; Sepaniak, M. J. Electrophoresis 1997, 18, 2291-2296.
(11) Pawliszyn, J. Anal. Chem. 1988, 60, 2796-1801.
(12) Wu, X.-Z.; Pawliszyn, J. Electrophoresis 2002, 23, 542-549.
(13) Schrum, K. F.; Lancaster, J. M., III; Johnston, S. E.; Gilman, S. D. Anal.
Chem. 2000, 72, 4317 - 4321.
(14) Swinney, K.; Bornhop, D. J. Electrophoresis 2000, 21, 1239-1250.
(15) Bornhop, D. J.; Dovich, N. J. Anal. Chem. 1987, 59, 1632-1636.
(16) Markov, D.; Dotson, S.; Wood, S.; Bornhop, D. J. Electrophoresis 2004, 25,
(17) Wang, Z.; Bornhop, D. J. Anal. Chem. 2005, 77, 7872-7877.
Anal. Chem. 2007, 79, 930-937
Analytical Chemistry, Vol. 79, No. 3, February 1, 2007
10.1021/ac061279q CCC: $37.00© 2007 American Chemical Society
Published on Web 12/19/2006
system is highly compatible with current CE technology and can
further be implemented with integrated optical designs for
instrument miniaturization.47Moreover, the LCORR is capable of
detecting flow at multiple locations, which provides high accuracy
in tracking the flow profile in the capillary. In a futuristic design,
detection can be performed along the entire capillary so that the
sample separation can be monitored en route to the terminal end
of a capillary, which will enhance the CE effectiveness in resolution
and detection speed.
In addition to conventional CE, the LCORR may also be an
excellent platform for immunoaffinity CE (IACE)4,48and capillary
isoelectric focusing (CIEF).12IACE can potentially utilize the
LCORR’s capability of detecting the binding of the molecules to
the interior surface. We recently showed that the detection limit
for protein binding is on the order of 10 pg/mm2.47,49For IACE,
the inlet of the LCORR will be patterned with different capture
molecules for multianalyte detection.50,51Thus, the binding and
elution processes of analytes, as well as subsequent sample
separation, can be monitored using the same LCORR technology.
CIEF takes advantage of the high-density, multiplexed, on-capillary
detection capability of the LCORR that permits real-time analyte
concentration gradient monitoring and fast analyte detection.12
Much work has to be done to develop the LCORR into a full-
fledged technology. To increase the detection channel density and
to integrate and miniaturize the detection system, optical waveguide
arrays fabricated with photolithography will be used in replace-
ment of fiber tapers, as has been demonstrated in our recent
work.47These optical waveguides can be mass-produced with well-
defined spacing. High detection channel density in combination
with high detection resolution will produce tremendous informa-
tion regarding the flow in a capillary. Furthermore, a few strategies
will be implemented to improve the detection limit. For example,
we will introduce a reference channel in the proximity of the
detection channel on the same LCORR, which will significantly
reduce the common-mode noise.17,26Sensitivity will be increased
by using an even thinner-walled LCORR, as indicated in Figure
2. Switching the operating wavelength from 980 nm to a longer
wavelength, such as 1550 nm, will also enhance the sensitivity.
For example, the same LCORR with 2.3-µm-thick wall will yield a
sensitivity of 150 nm/RIU when working at 1550 nm, according
to our simulation tool based on eq 2. In a longer term, photonic
crystal structures using multiple concentric layers coated onto the
LCORR will be employed to further expose more light into the
core,52,53thus increasing the light-analyte interaction. With all
these implementations, the detection limit of 1 × 10-7RIU or lower
can be reasonably expected, which makes the LCORR a competi-
tive technology for high-throughput CE development.
The authors thank the support from a 3M Non-Tenured Faculty
Award, the Wallace H. Coulter Foundation, a MU Research
Council Award, and a Life Sciences Postdoctoral Fellowship.
Received for review July 14, 2006. Accepted November 9,
(47) White, I. M.; Oveys, H.; Fan, X.; Smith, T. L.; Zhang, J. Appl. Phys. Lett.
2006, 89, 191106-1-191106-3.
(48) Guzman, N. A. Anal. Bioanal. Chem. 2004, 378, 37-39.
(49) White, I. M.; Zhu, H.; Suter, J. D.; Oveys, H.; Fan, X. Proc. SPIE 2006,
6380, 63800F-1 - 63800F-7.
(50) Balakirev, M. Y.; Porte, S.; Vernaz-Gris, M.; Berger, M.; Arie, J.-P.; Fouque,
B.; Chatelain, F. Anal. Chem. 2005, 77, 5474-5479.
(51) Ligler, F. S.; Breimer, M.; Golden, J. P.; Nivens, D. A.; Dodson, J. P.; Green,
T. M.; Haders, D. P.; Sadik, O. A. Anal. Chem. 2002, 74, 713-719.
(52) Xu, Y.; Liang, W.; Yariv, A. Opt. Lett. 2003, 28, 2144-2146.
(53) Hart, S. D.; Maskaly, G. R.; Temelkuran, B.; Prideaux, P. H.; Joannopoulos,
J. D.; Fink, Y. Science 2002, 296, 510-513.
Analytical Chemistry, Vol. 79, No. 3, February 1, 2007