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Label-free single-molecule all-optical
sensor
Andrea M. Armani, Scott E. Fraser, Richard C. Flagan
Andrea M. Armani, Scott E. Fraser, Richard C. Flagan, "Label-free single-
molecule all-optical sensor," Proc. SPIE 6852, Optical Fibers and Sensors for
Medical Diagnostics and Treatment Applications VIII, 68520A (7 February
2008); doi: 10.1117/12.761007
Event: SPIE BiOS, 2008, San Jose, California, United States
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Label-free, single-molecu
le all-optical sensor
Andrea M. Armani
1
, Scott E. Fraser
1,2
, and Richard C. Flagan
3
1
Department of Applied Physics, California Institute of Technology
2
Division of Biology, California Institute of Technology
3
Division of Chemistry and Chemical Engineering, California Institute of Technology
1200 E California Blvd, Pasadena, CA 91125
armani@caltech.edu
,
sefraser@caltech.edu
,
flagan@caltech.edu
ABSTRACT
Recently, quality factors greater than 100 million
were demonstrated using planar arrays of
silica microtoroid resonators. These high Q factor
s allow the toroidal resonators to perform
very sensitive detection experiments. By func
tionalizing the silica surface of the toroid with
biotin, the toroidal resonators become both sp
ecific and sensitive detectors for Streptavidin.
One application of this sensor is performing de
tection in lysates. To mimic this type of
environment, additional solutions of Streptavid
in were prepared which also contained high
concentrations (nM and
μ
M) of tryptophan.
1. INTRODUCTION
While single molecule experiments have made signi
ficant advances in understanding protein folding
kinetics[1], molecular transport,[2, 3] and aspects of DNA replication[4], all of these breakthrough
discoveries required labeling the target molecule.[5, 6]
In most experiments, this label behaves as an
amplifier for an otherwise undetectable single molecule
signal; however, it also r
estricts an experiment’s
scope, because there must be prior knowledge of the ta
rget’s presence and the target molecule must be
modified to incorporate the label. [7-12] There have b
een several attempts to overcome this need to label the
analyte by developing label-free sensing technol
ogies, ranging from fiber optic waveguides[13] and
nanowires[14] to nanoparticle prob
es[15], biochips[16] and mechani
cal cantilevers[17]; but none has
achieved single molecule sensitivity.
Optical microcavities have successfully
demonstrated label-free, single-molecule detection.[18] Sensitivity is
inherent to ultra-high-Q microcavities because of the
long photon lifetime within the microcavity which
results in an increase in sampling or amplification of
the signal without a label on the target molecule.[19]
Additionally, microcavity-based detection can be performed
in real-time, which allows for data to be taken
continuously while other biologically
relevant parameters (such as temperature, pH, salt) are changed.
Specificity is endowed to the microcavity through surface functionalization.[20]
Previous microcavity detection experiments have
been performed using a range of geometries and
materials.[21, 22] Silica resonant sensors fabr
icated from high-Q microspheres (Q~2 million) have
demonstrated the ability to distinguish between two st
rands of DNA and between ci
s/trans isomers based on a
resonant wavelength shift in real time. [23, 24]
The Q in these experiments was limited by the testing
wavelength and was not a fundamental limit of the cav
ity. Polymer devices have also performed similar
biological detection experiments. Polymer microring r
esonators have demonstrated detection of glucose and
bacteria.[25, 26] The techniques used to fabricate
these devices enable integration and multiplexing.[27]
Integrated polymer resonator sensors have also demonstr
ated detection of avidin[28] The quality factors of
the polymer devices were limited by the fabrication methods used.[29, 30]
Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications VIII,
edited by Israel Gannot, Proc. of SPIE Vol. 6852, 68520A, (2008) · 1605-7422/08/$18
doi: 10.1117/12.761007
Proc. of SPIE Vol. 6852 68520A-1
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Single molecule experiments using ultra-high-Q resonators
have been previously proposed using a variety of
detection techniques such as fluorescence [31], transmi
ssion variations [19] and polarizability changes[32].
However, these mechanisms assumed th
at the molecule was non-absorbing. As has been shown in previous
theoretical and experimental studies, an optically
absorbing monolayer will have significant effects on a
microcavity’s behavior [33-35]. These optical losses
interact with the whispering gallery mode of the
microcavity and, due to the high circulating intensiti
es present in the microcavity, are amplified. The
subsequent heating of the microcavity induces a resona
nt wavelength red-shift which can be described by the
thermo-optic effect. This effect has not been previ
ously proposed as a detection mechanism because of the
incorrect assumption that biological molecules were non-absorbing.
The resonant wavelength shift that molecule produces is
dependent on the optical absorption of the molecule,
which is easily determined using a commercially
available spectrophotometer, and on several other
parameters, such as input power, Q and mode volume.
In microcavity-based detection, the microcavity
directly detects the molecule. This direct detection is
in contrast to the previous single molecule experiments
based on fluorescent labels, where the emission of light
from the label is detected, not the molecule.
From finite element modeling (FEM) of microtoroid res
onators, it has been shown that the majority of the
optical field intensity (over 90%) resides within the si
lica. Additionally, the c
onductivity of water and silica
are similar (0.6 and 1.38 W/m
°
K). Taking both of these into account, the theoretical wavelength shift
produced by a single bound molecule via the thermo-
optic mechanism can be shown to be given by the
expression below:
δλ
λ
⎡
⎣
⎢
⎤
⎦
⎥
SM
=
σλ
dn
dT
8
π
2
n
2
κ
V
QP
u
(
r
r
)
2
r
r
+
ε
∫
d
r
r
(1)
where
λ
is the wavelength,
σ
is the absorption cross section of a single molecule,
dn/dT
is the opto-thermal
constant of silica (1.3x10
-5
K
-1
),
κ
is thermal conductivity,
n
is the effective refractive index of the silica
toroid,
V
is the optical mode volume,
Q
is cavity Q-factor, and
P
is the coupled optical power. The integral in
this expression accounts for the spatial overlap
of the whispering gallery mode field (
u
(r)) with the
temperature profile created by the near
ly point-like molecular heat source.
The actual form of the temperature plume in the vicini
ty of the molecule is likely complex and has been
combined into a single empirical parameter,
ε
. In contrasting a perfect point source of heat with a molecule,
this parameter captures the essential fact
that the temperature profile is not singular at the source and instead
rises steadily until reaching some radius of order the mo
lecular size. This approximation is justified first
because the thermal transport process itself rapidly
smoothes nano-scale spatial variations created by
molecular shape, and second because the ensuing temperatur
e field created by the molecular hot spot is long-
range (i.e., 1/r dependence). For this reason, the tuni
ng shift is only a weak function of the parameter “
ε
”. In
fact, a variation in “
ε
” of 1 nm to 100 nm induces only a 16% change in resonant wavelength shift.
Therefore, the optical cross section
σ
is more significant to the thermo-optic induced heating that the physical
radius,
ε
. On the other hand, the size of “
ε
” strongly suggests a maximum temperature in the vicinity of the
molecule.
2. METHODOLOGY
To verify this effect, a single-mode, tunable external
cavity laser centered at 681.5nm was coupled to a single-
mode tapered optical fiber waveguide
. Tapered optical fibers are very low-loss/high-efficiency waveguides
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used for probing ultra-high-Q modes in microcavities (Figur
e 1).[36] To create the testing chamber, the ultra-
high-Q microtoroids were placed on a high-resolution tr
anslation stage and were monitored by two cameras
(top and side view) simultaneously. With the taper wa
veguide in close proximity to the microtoroid, pure
water was added and a cover slip was placed on top,
forming a water-filled microaquarium.[37] Solutions
were injected into the aquarium and removed from the a
quarium using a series of syringes at one end. Both
the intrinsic Q and resonant wavele
ngth were determined by monitoring
the power transmission spectra. The
intrinsic Q factor was determined by scanning the wavelength of the single-mode laser and measuring both
the resonant power transmission and the loaded line
width (full-width-half-maximum) in the under-coupled
regime. The intrinsic modal linewidth (and hence intrin
sic Q) is then computed using a resonator-waveguide
coupling model. [36, 38] The positio
n of the resonant frequency was dete
rmined by scanning the laser over a
0.03nm range and recording the res
onance position from an oscilloscope.
Figure 1: Artistic rendering of a toroidal resonato
r coupled to a tapered optical fiber waveguide.
A Biotin surface functionalization was used (Figure 2).
To detect Streptavidin, th
e surface of the toroid was
functionalized with 0.1
μ
M of Biotin. The large dissociation constant (K
D
) of the Streptavidin-Biotin bond
has increased its popularity among biologists and biochemists, and it is commonly used to functionalize
sensor surfaces.[39] Additionally, because antibodies ca
n be easily biotinylated, this technique creates a
“self-passivating” surface or one where only the antibody
with the Biotin-tag on it binds to the surface.
Finally, studies have shown that the Biotin-Streptavidi
n pair correctly align and orient antibodies on a silica
surface.[20] Therefore, this pair of functionalization
techniques forms a foundation for a vast array of future
experiments in this field.
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'ii,
V
Figure 2: The Biotin-Streptavidin surface functiona
lization consisted of four steps: 1) immerse
the toroid resonator in buffer, 2) coat with
Biotin, 3) introduce pure Tryptophan, and 4)
introduce Streptavidin. Step 3 was only
performed in the case of the Tryptophan
experiments.
To perform single molecule measurements, a 3x10
-16
M (300aM) solutions of the target molecule
(Streptavidin) were used. At this concentration leve
l, only a few molecular binding events on the whispering
gallery are expected. As this solution was added,
the resonance position was recorded using an automated
data acquisition system until the 1mL syringe was empty.
The solution around the toroid was then cleansed
by removing the ambient solution and replacing it with fresh
water. At this concentration, single molecule
detection experiments could be repeated
numerous times on a single microtoroid.
To demonstrate that the microtoroid sensor’s sing
le molecule detection capabilities are not negatively
impacted by the presence of additional materials, a
set of complementary single molecule detection
experiments were performed using 300aM Streptavid
in solution containing additional Tryptophan (Sigma-
Aldrich, 99.9% pure L-Tryptophan) at either 1nM or 1
μ
M. Tryptophan (Trp) is a commonly found amino
acid in lysates.
While the Biotin surface functionalization may leave bi
nding sites open on the surface of the toroid for the
Trp, the toroid can overcome this limitation because
of the detection mechanism. Unlike conventional
techniques, such as fluorescence which detects a single
signal, the toroid is c
ontinuously detecting the
resonant wavelength and is providing
information about its environment. Therefore, after the Biotin was
physisorbed onto the toroid surface, the microtoroid was exposed to the Trp solution (1
μ
M Trp). Because
testing was performed at 680nm which is significantly away from the fluorescent maximum of Trp (278nm),
the binding of the Trp to the surface
of the toroid did not significantly impact the Q factor or change the
sensitivity of the toroid. Finally, the zero point is re-
set and the single molecule detection of Streptavidin is
performed.
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0.8
—,—-. Trp (1 ,LM)
Sire plavidin
0.8
Sirp etavi din
lip (1iM)
Strepiavidin
Streptavidin
Strpetavidin
a
=
(0
0
0
=
Co
=
0
(0
0
0.30
0.15
0.00
0
20 40
Time (sec)
(a)
80
0
IC
Time (see)
(b)
20
3. RESULTS
Figure 3 shows the resonance shifts which occurre
d as the microtoroid was exposed to the 300aM
Streptavidin solutions and the 1
μ
M Trp solution. Because testing was performed sufficiently away from the
absorption maximum for Trp, the quality factor of the microtoroid was not impacted by Trp binding during
the first injection.
It is important to compare the total resona
nce shift for each of the different solutions
(Figure 3a). The total
resonance shift is approximately the same, whether the toro
id is exposed to pure Streptavidin or a Streptavidin
solution containing additional Trp. The second injection of
Trp induced a resonance shift that is negligible in
comparison with the Streptavidin induced shifts and
is of the same order of magnitude as noise-induced
fluctuations.
Figure 3: Single molecule detection of pure Streptavidin (black squares), pure Trp (blue inverted
triangles), and mixed solutions containing both Streptavidin and Trp (red circles, green
triangles) using the microtoroid sensor. a) As molecules bind to the surface, the resonant
wavelength red-shifts. Note that the Trp
has a negligle effect on the detection of
Streptavidin. b) The first 20 seconds of de
tections. The steps created by individual
molecules binding throughout the whispering gallery mode are easily identifiable at this
time scale.
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0
I
IiMTrp
.
I
•
I
•
I
000
0.01
0.02
0.03
4
2
0
000
001
002
0.03
4
2
I
ISA+nMTrp
iIFIflI..,HIL
0.00
0.01
IRk 4HTh
0.02
003
0
Resonance Shift (pm)
4
2
0
I
ISA+MTrp
IIELllmr11IIInH
0.01
0.02
0.03
Figure 4: A series of histograms created from the
resonant wavelength shif
t data shown in Figure
3. The largest shift results from a molecule
binding at the highest intensity region of the
microtoroid. In the histograms containing Stre
ptavidin data, all resonant wavelength shifts
below 0.001pm were considered noise. In the 1
μ
M Trp data, all resona
nt wavelength shifts
fell below this threshold, therefore, they were
included in the histogram. It is important to
note that the largest resonant wavelength shif
t is the same in all of the Streptavidin
histograms. Additionally, approximately th
e same number of Streptavidin molecules
bound (note y-axis).
The histogram showing the resonant wavelength shifts of
the single molecule binding events is contained in
Figure 4. The largest shift which occurred was the sa
me in all of the solutions, except for the pure Trp
solution. This value agrees very well with the theo
retically predicted value based upon the toroid’s Q factor
and the absorption cross section of Streptavidin. In
the pure Trp solution, only noise was recorded. In the
histograms containing Streptavidin, shifts below 0.0
01pm were considered noise and not included. Because
all of the shifts in the Trp data we
re below 0.001pm, these shifts were included the Trp histogram. It is also
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important to note that the number of molecules that bi
nd is approximately constant, regardless of the amount
of Trp in the solution.
4. CONCLUSION
In the present work, ultra-high-Q toroid
al resonators have demonstrated label-free, single molecule detection
of Streptavidin using a Biotin surface functionalization.
The proposed thermo-optic detection mechanism was
also verified.
Additional experiments were performed in more comple
x environments to explore the microtoroid sensor’s
sensitivity in a more realistic environment. These e
xperiments in the presence of high concentrations of
Tryptophan, the dominant component of lysates, demons
trated that the sensor’s
single molecule detection
capabilities are not significantly affected. The experiment
al resonant wavelength shifts were in excellent
agreement with the thermo-optic mechanism.
Future work will focus on integration and
improvements to surface functionalization.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Rajan Kulkarni
for numerous helpful discussions. A.M. Armani is
supported by a Clare Boothe Luce Post-doctoral Fellowshi
p. This work was supported by the DARPA Center
for OptoFluidic Integration.
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