A novel phase-sensitive SPR biosensor array based on prism phase

modulator
Gaoao Ye, Wei Yang, Li Jiang, Jun Qian and Sailing He*1

Centre for Optical and Electromagnetic Research, Zhejiang Provincial Key Laboratory for Sensing
Technologies, JORCEP [Joint Research Centre of Photonics of the Royal Institute of Technology
(Sweden), Lund University (Sweden), and Zhejiang University], Zhejiang University, Zijingang
Campus, 310058 Hangzhou, China.

ABSTRACT

Phase modulators in surface plasmon resonance phase-differential imaging (SPR-PI) sensing systems reported so far are
sensitive to temperature fluctuations or mechanical vibrations and thus their applications are limited. In this paper, we
propose a novel prism phase modulator (PPM) to replace a traditional modulator. The PPM consists of a parallel prism, a
rotation stage and a mirror. The PPM shows great stability in our experiment, and helps achieve high detection sensitivity
in our SPR-PI system. Moreover, the cost of our PPM is much lower than that of a traditional modulator and is thus suitable
for commercialization. A polydimethylsiloxane (PDMS) microfluidic chip is fabricated to control the flow velocity and
realize parallel detection in our experiment. Measured result of glycerine solution shows that the resolution of our SPR
biosensor array is about 9.11×10-7 refractive index unit (RIU). Real time monitoring of interaction between bovine IgG and
anti-bovine IgG is also realized. The proposed PPM-based microfluidic SPR-PI biosensor array is promising for future
practical applications.

Keywords: surface plasmon resonance, phase-sensitive SPR, SPR-PI, microfluidics, high throughput, prism phase
modulator

1. INTRODUCTION
Over the last decade, surface plasmon resonance (SPR) based sensing techniques has been widely applied to monitor the
interaction between biomolecules like protein bindings, DNA hybridization and antigen recognition1-6. By monitoring a
tiny refractive index change on the sensing interface, information of interactions between biomolecules could be observed
from the variation of reflected light characteristics including intensity7, wavelength8, angle9 and phase difference10 . The
major advantage of SPR biosensors is their ability for real-time and label-free detection compared to fluorescence11-13 and
SERS14 spectral detections. Moreover, SPR biosensors are suitable for integration with microfluidics as an on-chip lab15, 16,
which has already showed considerable potential for automation and real world applications. Microfluidics applied into
sensing devices can not only decrease the analyte consumptions, but also remarkably improve the detection performance
and system integration19, 20. With combined advantages of SPR sensing and microfluidics, multi-channel SPR biosensor
has become an important tool for molecules interaction analysis with high throughput 21-25 and has shown a great potential

1
[email protected]

Smart Photonic and Optoelectronic Integrated Circuits XVI, edited by Louay A. Eldada, El-Hang Lee,
Sailing He, Proc. of SPIE Vol. 8989, 89890Q · © 2014 SPIE · CCC code: 0277-786X/14/$18
doi: 10.1117/12.2047367

Proc. of SPIE Vol. 8989 89890Q-1

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 for clinical diagnostic like DNA mutation and early cancer detection.
Recently, SPR sensors based on phase-differential imaging (SPR-PI) have been dramatically progressed26-30 for its
excellent sensitivity and suitability for high throughput detection compared with angular or spectral interrogation SPR
sensors. In recently reported SPR-PI sensing systems, the incident light was usually modulated in phase or in polarization
statues. Depending on the system configuration, the modulator could be a liquid crystal modulator (LCM)27, a piezoelectric
transducer (PZT)29, or a wedge retardance plate (WRP)30. However, the performances of these devices are sensitive to
mechanical vibrations or temperature fluctuations, which in turn limit them from practical applications. In this paper, a
novel SPR-PI sensor based on a prism phase modulator (PPM) is proposed. Since the refractive index of glass is stable
under fluctuated temperature environment, the performance of PPM shows great resistance to various temperature
conditions. A common light-path (for both polarizations) configuration is adopted to reduce the background noise due to
the intensity fluctuation of laser and the mechanical vibration of optical devices. Integrated with microfluidics, a biosensor
array with four independent micro-channels is fabricated to monitor multi-channel analyte interactions with economical
analyte consumptions. Furthermore, the application of our PPM can notably reduce the cost of a SPR-PI sensing system
because of the low-cost and feasibility of the prism. With these distinct advantages, the proposed PPM shows remarkable
potential for practical applications.

2. THEORETICAL ANALYSIS
The Kretschmann configuration is the most widely used method to excite SPR. A right angle prism is employed to
enhance the momentum of incident light to match the surface plasmon wave (SPW). The wave vector of SPW is
determined by k0 , ns and nm ,
na nm (1)
k spw = k 0
n a2 + n m2
where k0 is the wave vector of the incident light in air, na and nm are the refractive indices of the analyte and metal layer.
Typically, a 50 nm gold film was coated on the surface of a right angle prism. The strongest SPR wave was excited while
the component of k0 parallel to the gold/analyte interface equals kspw.

k0 ng sinθinc = kspw (2)

where ng is the refractive index of the right angle prism, and θinc is the incident angle on the gold/analyte interface. Once
the SPR wave was excited, the component of p polarization light undergoes dramatic intensity attenuation and phase jump,
while those characteristics of s polarization light remain unchanged. As a result, a phase difference between p and s
polarization light, defined as φspr, is created by SPR. φspr is determined by the effective refractive index of analyte as well
as other system conditions, e.g., wavelength of incident light, thickness of gold film, incident angle in SPR sensor, and so
on. If other conditions are fixed, the refractive index of analyte could be obtained by extracting the φspr from detection
results.
To reduce the unwanted noise and enhance the detecting ability, the phase difference between p and s polarization light
is usually modulated in common light-path SPR-PI sensors. In our proposed system (Fig. 2), total internal reflection (TIR)
in a parallel prism is applied to modulate phase difference, the modulated angle φm is determined by the refractive index of
the parallel prism ng and the TIR angle θTIR according to Fresnel reflection equation,

Proc. of SPIE Vol. 8989 89890Q-2

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 an oven at 65℃ to produce an inverse PDMS duplication of the mold. The duplication was carefully released from mold

and served as the PDMS micro-channel. Before the oxygen plasmon treatment, the PDMS micro-channel was punched and
cleaned with acetone, isopropanol and water in an ultrasonic cleaner. Then both the PDMS micro-channel and SPR sensing
array were treated by an oxygen plasmon cleaner for 1min before irreversible assembling. The structure of the PDMS
micro-channel and SPR sensing array should be aligned precisely during the assembly to prevent alignment error.
The fabricated microfluidics biosensor array is shown in the inset of Fig. 1. It contains 4 independent reaction chambers.

Each chamber is 1×3×0.02 mm3 large, and is linked with an inflow and an outflow channel. Medical syringes are used to

pump analyte into the chambers. The microfluidics biosensor array shows great potential in high throughput detection with
analyte consumption down to 60nL.

3.4 System setup

Fig. 2 shows the setup of our SPR phase-differential imaging system. In our system, a He-Ne laser (632.8nm) is applied
as the light source. The light goes through a linear polarizer and a beam splitter, then incidents into a BK7 parallel prism.
The modulated phase difference φm has been proved to be determined by the TIR angle and the refractive index of the prism
aforementioned in this paper. To realize the scanning of the TIR angle, we fix the parallel prism on a stage. The stage could
be rotated by a step motor driven by a controller. A LabVIEW program (National Instruments, Austin, TX, USA) is
developed to manipulate the rotation of the stage. A mirror is employed to reflect the light back into the parallel prism to
compensate the horizontal displacement and thus keep the modulated light propagating in the same path while the parallel
prism is rotated.

(a) He -Ne laser

SPR sensor

(b)

Probe channel

rc
Reference channel

Fig. 2 (a) Schematic diagram for the setup of the proposed microfluidic biosensor array based on a prism phase modulator (PPM). BS
stands for beam splitter. Detailed optical path in the parallel prism is shown in the inset (middle-bottom). (b) The image of the fabricated
microfluidic biosensor array (before the analyte liquid flows into the reaction chambers) with the selected pair of probe and reference
channels indicated. The deformation of rectangle may be due to some co-location error between the SPR chip and PDMS micro-channel.

Proc. of SPIE Vol. 8989 89890Q-5

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 to leave non-deposited regions for later PDMS assembling. A gold film with a thickness of 50nm was deposited by
magnetron sputtering coating equipment. The coating mask was then carefully peeled off from the substrate after gold

deposition. The fabricated SPR sensing array contains 4 rectangle gold spots. Each spot covers an area of 1×3mm2 and

serves as an individual sensing region. The number of sensing regions could be amplified by decreasing the sizes of gold
spots and arranging them to be closer. It has to be taken into consideration that with the increasing pattern complexity of the
gold film, the structure diffraction, which is deleterious for imaging, will also become more obvious in captured pictures
with an imaging system with limited depth of field. If a large number of sensing regions are employed in one SPR chip, it
is necessary to precisely align the optical devices, including the collimating lens and imaging lens, to maintain a high
imaging quality and signal to noise ratio.

/ ,
4, Gold coating
UV Exposure

//
4,Mold fabrication
Coating mask

/ Glass substrate

® Mold mask
SU -8 layer

Silicon substrate

PDMS duplication PDMS

4, Peel off mask I

Punching and assembling

Lay out of the Microfluidic

biosensor array

Fig. 1 Fabrication procedure of our biosensor array. The phtographe of a fabricated microfluidic biosensor array is shown in the inset
(right-bottom).

3.3 PDMS microfluidic chip

The biosensor array was assembled with the SPR sensing array and the PDMS microfluidic chip. To fabricate the PDMS
microfluidic chip, SU-8 negative photoresist was employed to produce the mold of the micro-channel. A silicon wafer was
spin coated with SU-8 2015 photoresist at a speed of 500rpm for 15s and 1000rpm for 29s. The coated wafer was baked at

65℃ for 15min and 95℃ for 30min with a hot plate. As illustrated in Fig. 1, a mold mask was applied in the standard

lithography process to make the pattern of the SU-8 structure coordinate well with that of the SPR sensing array. The

intensity of exposure was adjusted to 19.5mW/cm2. After 20s exposure, the wafer was baked again at 65℃ for 15min and

95℃ for 30min. After that, the silicon wafer was immersed in SU-8 developer and followed by isopropanol and water

rinsing to clean the SU-8 structure. The thickness of the SU-8 structure is about ~24um.
The PDMS elastomer and curing agents (mixed at a ratio of 10:1) were poured onto the SU-8 mold and baked for 12h in

Proc. of SPIE Vol. 8989 89890Q-4

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 an oven at 65℃ to produce an inverse PDMS duplication of the mold. The duplication was carefully released from mold

and served as the PDMS micro-channel. Before the oxygen plasmon treatment, the PDMS micro-channel was punched and
cleaned with acetone, isopropanol and water in an ultrasonic cleaner. Then both the PDMS micro-channel and SPR sensing
array were treated by an oxygen plasmon cleaner for 1min before irreversible assembling. The structure of the PDMS
micro-channel and SPR sensing array should be aligned precisely during the assembly to prevent alignment error.
The fabricated microfluidics biosensor array is shown in the inset of Fig. 1. It contains 4 independent reaction chambers.

Each chamber is 1×3×0.02 mm3 large, and is linked with an inflow and an outflow channel. Medical syringes are used to

pump analyte into the chambers. The microfluidics biosensor array shows great potential in high throughput detection with
analyte consumption down to 60nL.

3.4 System setup

Fig. 2 shows the setup of our SPR phase-differential imaging system. In our system, a He-Ne laser (632.8nm) is applied
as the light source. The light goes through a linear polarizer and a beam splitter, then incidents into a BK7 parallel prism.
The modulated phase difference φm has been proved to be determined by the TIR angle and the refractive index of the prism
aforementioned in this paper. To realize the scanning of the TIR angle, we fix the parallel prism on a stage. The stage could
be rotated by a step motor driven by a controller. A LabVIEW program (National Instruments, Austin, TX, USA) is
developed to manipulate the rotation of the stage. A mirror is employed to reflect the light back into the parallel prism to
compensate the horizontal displacement and thus keep the modulated light propagating in the same path while the parallel
prism is rotated.

(a) He -Ne laser

SPR sensor

(b)

Probe channel

rc
Reference channel

Fig. 2 (a) Schematic diagram for the setup of the proposed microfluidic biosensor array based on a prism phase modulator (PPM). BS
stands for beam splitter. Detailed optical path in the parallel prism is shown in the inset (middle-bottom). (b) The image of the fabricated
microfluidic biosensor array (before the analyte liquid flows into the reaction chambers) with the selected pair of probe and reference
channels indicated. The deformation of rectangle may be due to some co-location error between the SPR chip and PDMS micro-channel.

Proc. of SPIE Vol. 8989 89890Q-5

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 5. CONCLUSIONS
A novel SPR phase-differential imaging system has been introduced in this article. A prism phase modulator (PPM) has
been employed to modulate the phase difference between p light and s light in the common light-path SPR-PI system. The
application of the PPM helps to enhance the detection stability under various temperature conditions. The configuration of
the common light-path system can remarkably enhance the stability of system. A PDMS micro-channel has been applied to
realize four independent reaction channels. Our test results of glycerine solution have shown that the detection limit of our

biosensor array is about 9.11×10-7 RIU. Immunoassay with bovine IgG and anti-bovine IgG has also been carried out in

this system. Detection of 16.7pM anti bovine IgG has been realized. The microfluidics biosensor array has shown great
potential for high throughput monitoring by increasing the number of reaction channels. This can be achieved by reducing
the size of gold spots and the distances between two reaction chambers.
Moreover, due to the low-cost of the parallel prism, the cost of a SPR-PI system can be dramatically reduced by the
application of our PPM. With the combined advantages of low-cost, high stability, high sensitivity and high throughput, the
proposed PPM-based SPR-PI biosensor array has great potential for various practical applications.

ACKNOWLEDGEMENTS
This work was partially supported by the Science and Technology Department of Zhejiang Province, the National Basic
Research Program (973) of China (2011CB503700), the National Natural Science Foundation of China (60990322 and
61008052), and the Fundamental Research Funds for the Central Universities. Gaoao Ye is grateful to Qingkun Liu and
Yunpeng Zhu for their help in PDMS micro-channel fabrication.

REFERENCE

[1] Steiner, G., "Surface plasmon resonance imaging," Anal Bioanal Chem, 379, 328-331 (2004)
[2] Jin, W., Lin, X., Lv, S., Zhang, Y., Jin, Q., Mu, Y., "A DNA sensor based on surface plasmon resonance for
apoptosis-associated genes detection," Biosens Bioelectron, 24, 1266-1269 (2009)
[3] Jennifer, S., Shumaker-Parry, Ruedi, A. and Charles, T. C., "Parallel, Quantitative Measurement of Protein Binding to
a 120-Element Double-Stranded DNA Array in Real Time Using Surface Plasmon Resonance Microscopy," Anal
Chem , 76, 2071-2082 (2004)
[4] Law, W., Yong, K., Baev, A. and Prasad, P. N., "Sensitivity Improved Surface Plasmon Resonance Biosensor for
Cancer Biomarker Detection Based on Plasmonic Enhancement," Acs Nano, 5, 4858-4864 (2011)
[5] Goodrich, T. T., Lee, H. J. and Corn, R. M., "Direct Detection of Genomic DNA by Enzymatically Amplified SPR
Imaging Measurements of RNA Microarrays," J Am Chem Soc, 126, 4086-4087 (2004)
[6] Wang, Y., Li, Z., Li, H., Vuki, M., Xu, D. and Chen, H., "A novel aptasensor based on silver nanoparticle enhanced
fluorescence, " Anal Bioanal Chem, 389, 819-825 (2007)
[7] Manuel, M., Vidal, B., Lopez, R., Alegret, S. and Alonso-Chamarro, J., "Determination of probable alcohol yield in
musts by means of an SPR optical sensor," Sensors and Actuators B: Chemical, 11, 455-459 (1993)
[8] Jorgenson, R. C. and Yee, S. S., "A fiber-optic chemical sensor based on surface plasmon resonance," Sensors and
Actuators B: Chemical, 12, 213-220 (1993)

Proc. of SPIE Vol. 8989 89890Q-9

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 In order to test the detection resolution, we refilled the probe channel with glycerine solutions of different concentration
from 0% to 2%. The SPR signal of each glycerine solution was monitored in an approach described above. The relationship
between SPR signal and refractive index is plotted in Fig. 4. Due to the nonlinearity of the SPR phase response, the highest
RI detection sensitivity relies on the region from 0% to 0.1%, where the SPR signal changes from 0.0098 rad to -0.0645 rad.
The refractive index of pure water is about 1.3321 RIU at a wavelength of 633nm, while that of 0.1% glycerine is about

1.33222 RIU. Considering that the system stability is 5.64×10-4 rad, the detection resolution is calculated to be 9.11×10-7

RIU.

(a) -.- Probe Channel (b)

Reference Channel 0.0110
5.176

5.174
0.0105
Ñ 5.172
5.170 í0 0.0100
c 5.188
o To
Ñ 5.166 rn 0.0095
iT)
K 5.164
á 5.182
m
á1n 0.0090

E 5.180
0.0085
5.158

-10 0 10 20 30 40 50 60 70 -10 0 10 20 30 40 50 80 70

Time (min) Time (min)

Fig. 3 (a) The phase responses of the probe channel and reference channel, and their standard deviations are 2.48×10-3 rad and 2.51×10-3
rad, respectively. Note that the phase response fluctuations of the two channels are almost the same. (b) The SPR signal when the analyte
is pure water. The averaged SPR signal is 0.0098 rad with a standard deviation of 5.64×10-4 rad. The result is obtained by subtracting the
phase response of the reference channel from that of the probe channel.

0.05

0.00 0%

-0.05 \ 0.1%
0.3%
m -0.10
\ 0.5%
-0.15 N.0.7%
nf
-0.20 N1%
-0.25

-0.30
2%
-0.35

0.40
1.3320 1.3325 1.3330 1.3335 1.3340 1.3345 1.3350
Refractive Index (RIU)

Fig. 4 SPR signal curve when the concentration of the glycerine solution increases gradually.

4.2 Detection of anti-bovine IgG

To carry out the detection of the interaction between bovine IgG and anti-bovine IgG, the gold spots were assembled with
a membrane of bovine IgG. A DDA ethanol solution (5mmol/L) was injected into the probe channel at a speed of 0.5mL/h.

Proc. of SPIE Vol. 8989 89890Q-7

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 A mix solution of EDC and NHS, both with concentrations of 12.5mmol/L, was injected into the probe channel for
activation at 0.5mL/h for 75min. After washing, a bovine IgG solution (0.1mg/mL) was injected into the probe chamber at
0.5mL/h for 60min. Thereafter, the probe chamber was washed with PBS buffer. A BSA solution (10mg/mL) was injected

into the probe chamber at 1mL/h for blocking. All procedures were taken at constant room temperature of 25 ℃.

After the IgG functionalization, the probe chamber was filled with anti-bovine IgG. Three different anti IgG solution
with concentrations of 2.5ng/mL, 25ng/mL and 250ng/mL was injected into the probe channel separately. The flow
velocity was keep to be 1mL/h and the reaction time for each concentration was set to be about 50min. Before another anti
IgG solution was injected, the probe chamber was injected with air to pump out excess anti IgG solution.

Measured Result
-0.70 - Fit Curve

-0.75- PBS

-0.80 -
'
VL anti IgG (2.5ng /mL)

cß
-0.85-
anti IgG (25ng /mL)
-0.90-

-0.95 - PBS
û_ anti IgG (250ng /mL)
(/)
-1.00-

-1.05 , , , , , , , , , , , , ,

-20 0 20 40 60 80 100 120 140 160 180 200 220

Time (min)

Fig. 5 Kinetic result of the SPR signal after adding anti bovine IgG solution with different concentrations. The measured reaction results
are fitted with exponential-like curves.

The kinetic response curve of SPR signal is shown in Fig. 5. The SPR signal of PBS was linearly fitted, and those of anti
IgG solutions were fitted into exponential-like curves. As illustrated in Fig. 5, the PBS solution was tested as the base line
of the SPR signal. The signal clearly descends after injecting solution of 2.5ng/mL anti IgG, which indicates the interaction
between IgG and anti IgG. The high uncertainty of measured results may be due to the random association and
disassociation of IgG and anti IgG on the gold surface. The disassociation of conjugated molecules could be decreased by
slowing down the flow velocity in the channel and optimizing the reaction temperature.
The fit curve shows that the SPR signal descends faster when the concentrations of anti IgG solution gets higher,
indicating a higher association ability of anti IgG with IgG membrane. The jump of SPR signal between different IgG
solutions may be due to the disassociation of the loosely conjugated IgG and anti IgG immune-complex during the analyte
draining and injecting processes.
The detection limit of anti IgG is hard to calculate due to the nonlinearity and high instability of the SPR signal. More
experiments of anti IgG solutions with gradient concentration are required to find a reliable relationship between SPR
signal variations and anti IgG concentrations. Since the SPR signal variation of 2.5ng/mL anti IgG solution is much greater
than the residual RMS of the fit curve, the detection resolution of anti IgG was demonstrated to be much lower than
2.5ng/mL, or 16.7pM (molecular weight of anti-bovine IgG ~150kDa).

Proc. of SPIE Vol. 8989 89890Q-8

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 5. CONCLUSIONS
A novel SPR phase-differential imaging system has been introduced in this article. A prism phase modulator (PPM) has
been employed to modulate the phase difference between p light and s light in the common light-path SPR-PI system. The
application of the PPM helps to enhance the detection stability under various temperature conditions. The configuration of
the common light-path system can remarkably enhance the stability of system. A PDMS micro-channel has been applied to
realize four independent reaction channels. Our test results of glycerine solution have shown that the detection limit of our

biosensor array is about 9.11×10-7 RIU. Immunoassay with bovine IgG and anti-bovine IgG has also been carried out in

this system. Detection of 16.7pM anti bovine IgG has been realized. The microfluidics biosensor array has shown great
potential for high throughput monitoring by increasing the number of reaction channels. This can be achieved by reducing
the size of gold spots and the distances between two reaction chambers.
Moreover, due to the low-cost of the parallel prism, the cost of a SPR-PI system can be dramatically reduced by the
application of our PPM. With the combined advantages of low-cost, high stability, high sensitivity and high throughput, the
proposed PPM-based SPR-PI biosensor array has great potential for various practical applications.

ACKNOWLEDGEMENTS
This work was partially supported by the Science and Technology Department of Zhejiang Province, the National Basic
Research Program (973) of China (2011CB503700), the National Natural Science Foundation of China (60990322 and
61008052), and the Fundamental Research Funds for the Central Universities. Gaoao Ye is grateful to Qingkun Liu and
Yunpeng Zhu for their help in PDMS micro-channel fabrication.

REFERENCE

[1] Steiner, G., "Surface plasmon resonance imaging," Anal Bioanal Chem, 379, 328-331 (2004)
[2] Jin, W., Lin, X., Lv, S., Zhang, Y., Jin, Q., Mu, Y., "A DNA sensor based on surface plasmon resonance for
apoptosis-associated genes detection," Biosens Bioelectron, 24, 1266-1269 (2009)
[3] Jennifer, S., Shumaker-Parry, Ruedi, A. and Charles, T. C., "Parallel, Quantitative Measurement of Protein Binding to
a 120-Element Double-Stranded DNA Array in Real Time Using Surface Plasmon Resonance Microscopy," Anal
Chem , 76, 2071-2082 (2004)
[4] Law, W., Yong, K., Baev, A. and Prasad, P. N., "Sensitivity Improved Surface Plasmon Resonance Biosensor for
Cancer Biomarker Detection Based on Plasmonic Enhancement," Acs Nano, 5, 4858-4864 (2011)
[5] Goodrich, T. T., Lee, H. J. and Corn, R. M., "Direct Detection of Genomic DNA by Enzymatically Amplified SPR
Imaging Measurements of RNA Microarrays," J Am Chem Soc, 126, 4086-4087 (2004)
[6] Wang, Y., Li, Z., Li, H., Vuki, M., Xu, D. and Chen, H., "A novel aptasensor based on silver nanoparticle enhanced
fluorescence, " Anal Bioanal Chem, 389, 819-825 (2007)
[7] Manuel, M., Vidal, B., Lopez, R., Alegret, S. and Alonso-Chamarro, J., "Determination of probable alcohol yield in
musts by means of an SPR optical sensor," Sensors and Actuators B: Chemical, 11, 455-459 (1993)
[8] Jorgenson, R. C. and Yee, S. S., "A fiber-optic chemical sensor based on surface plasmon resonance," Sensors and
Actuators B: Chemical, 12, 213-220 (1993)

Proc. of SPIE Vol. 8989 89890Q-9

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 [9] Liedberg, B. and Lundstrom, I., "Principles of biosensing with an extended coupling matrix and surface plasmon
resonance," Sensors and Actuators B: Chemical, 11, 63-72 (1993)
[10] Nelson, S. G., Johnston, K. S. and Yee, S. S., "High sensitivity surface plasmon resonace sensor based on phase
detection," Sensors and Actuators B: Chemical, 35,187-191 (1996)
[11] Zhan, Q. Q., Qian, J., Liang, H. J., Somesfalean, G., Wang, D., He, S. L., Zhang, Z. G. and Andersson-Engels, S.,
"Using 915 nm laser excited Tm3+/Er3+/Ho3+-doped NaYbF4 upconversion nanoparticles for in vitro and deeper in
vivo bioimaging without overheating irradiation," Acs Nano, 5, 3744-3757 (2011)
[12] Qian, J., Jiang, L., Cai, F. H., Wang, D. and He, S. L., "Fluorescence-surface enhanced Raman scattering
co-functionalized gold nanorods as near-infrared probes for purely optical in vivo imaging," Biomaterials, 32,
1601-1610 (2011)
[13] Wang, D., Qian, J., He, S. L., Park, J. S., Lee, K. S., Han, S. H. and Mu. Y., "Aggregation-enhanced fluorescence in
PEGylated phospholipid nanomicelles for in vivo imaging," Biomaterials, 32, 5880-5888 (2011)
[14] Jiang, L., Qian, J., Cai, F. and He, S., "Raman reporter-coated gold nanorods and their applications in multimodal
optical imaging of cancer cells," Anal Bioanal Chem, 400, 2793-2800 (2011)
[15] Krishnamoorthy, G., Carlen, E. T., Berg, A. V. D., Schasfoort, R. B. M., "Surface plasmon resonance imaging based
multiplex biosensor: Integration of biomolecular screening, detection and kinetics estimation," Sensors Actuators B:
Chemical, 148 (2), 511-521 (2010)
[16] Ouellet, E., Lausted, C., Lin, T., Yang, C. W. T., Hood, L. and Lagally, E. T., "Parallel microfluidic surface plasmon
resonance imaging arrays," Lab Chip, 10, 581-588 (2010)
[17] Fang, X. and White, I. M., "Optofluidic microsystems for chemical and biological analysis," Nat Photonics, 5,
591-597 (2011)
[18] Monat, C., Domachuk, P. and Eggleton, B. J., "Integrated optofluidics: A new river of light," Nat Photonics, 1,
106-114(2007)
[19] Yin, D., Deamer, D. W., Schmidt, H., Barber, J. P. and Hawkins, A. R., "Single-molecule detection sensitivity using
planar integrated optics on a chip," Opt Lett, 31(14), 2136-2138 (2006)
[20] Huang, M., Yanik, A. A., Chang, T-Y. and Altug, H., "Sub-wavelength nanofluidics in photonic crystal sensors," Opt
Express, 17 (26), 24224-24233 (2009)
[21] Luo, Y., Yu, F. and Richard, N. Z., "Microfluidic device for immunoassays based on surface plasmon resonance
imaging," Lab chip, 8, 694-700 (2008)
[22] Lee, K. H., Su, Y. D., Chen, S. J., Tseng., F. G. and Lee, G. B., "Microfluidic systems integrated with two-dimensional
surface plasmon resonance phase imaging systems for microarray immunoassay," Biosens Bioelectron, 23, 466-472
(2007)
[23] Wegner, G. J., Lee, H. J. and Corn, R. M., "Characterization and optimization of peptide arrays for the study of
epitope-antibody interactions using surface plasmon resonance imaging," Anal Chem, 74 (20), 5161-5168 (2002)
[24] Kanda, V., Kariuki, J. K., Harrison, D. J. and McDermott, M. T., "Label-free reading of microarray-based
immunoassays with surface plasmon resonance imaging," Anal Chem, 76 (24), 7257-7262 (2004)
[25] Lee, H. J., Goodrich, T. T. and Corn, R. M., "SPR Imaging Measurements of 1-D and 2-D DNA Microarrays Created
from Microfluidic Channels on Gold Thin Films," Anal Chem, 73 (22), 5525-5531 (2001)
[26] Piliarik, M., Vaisocherova, H. and Homola, J., "A new surface plasmon resonance sensor for high-throughput
screening applications," Biosens and Bioelectronics, 20 (10), 2104-2110 (2005)

Proc. of SPIE Vol. 8989 89890Q-10

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms

 [27] Hooper, I. R., Sambles, J. R., Pitter, M. C. and Somekh, M. G., "Phase sensitive array detection with polarisation
modulated differential sensing," Sensors and Actuators B: Chemical, 119 (2), 651-655 (2006)
[28] Patskovsky, S., Jacquemart, R., Meunier, M., Crescenzo, G. D. and Kabashin, A. V., "Phase-sensitive
spatially-modulated surface plasmon resonance polarimetry for detection of biomolecular interactions," Sensors and
Actuators B: Chemical, 133 (2), 628-631 (2008)
[29] Wong, C. L., Ho, H. P., Suen, Y. K., Kong, S. K., Chen, Q. L., Yan, W. and Wu, S. Y., "Real-time protein biosensor
arrays based on surface plasmon resonance differential phase imaging," Biosens and Bioelectronics, 24 (4), 606-612
(2008)
[30] Halpern, A. R., Chen, Y., Corn, R. M. and Kim, D., "Surface Plasmon Resonance Phase Imaging Measurements of
Patterned Monolayers and DNA Adsorption onto Microarrays," Anal Chem, 83 (7), 2801-2806 (2011)

Proc. of SPIE Vol. 8989 89890Q-11

Downloaded From: http://proceedings.spiedigitallibrary.org/ on 05/14/2015 Terms of Use: http://spiedl.org/terms