A Review of Fiber-Optic Biosensors

Sensors and Actuators B 125 (2007) 688703
Review
A review of ber-optic biosensors
Angela Leung
a
, P. Mohana Shankar
b
, Raj Mutharasan
a,
a
Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104, United States
b
Department of Electrical and Computer Engineering, Drexel University, Philadelphia, PA 19104, United States
Received 21 December 2006; accepted 12 March 2007
Available online 15 March 2007
Abstract
Fiber-optic biosensors (FOBS) are optical ber-derived devices which use optical eld to measure biological species such as cells, proteins, and
DNA. Because of their efciency, accuracy, low cost, and convenience, FOBS are promising alternatives to traditional immunological methods for
biomolecule measurements. Tapered ber-optic biosensors (TFOBS) are a type of FOBS which rely on special geometries to expose the evanescent
eld to interact with samples. In order to amplify sensitivity and selectivity, TFOBS are often used with various optical transduction mechanisms
such as changes in refractive index, absorption, uorescence, and Surface Plasmon Resonance. In this review, the basic principles of TFOBS are
summarized. Various common geometries for evanescent sensing and the inuence of geometric parameters on optical principles are reviewed.
Finally, a detailed account of the studies done to date for biomolecules detection using TFOBS will be provided.
2007 Elsevier B.V. All rights reserved.
Keywords: Biosensor; Evanescent eld; Transmission; Immunosensors; Refractive index
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
2. Fiber optic evanescent sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
2.1. Effects of tapering on the evanescent eld . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
2.2. Effects of bending on evanescent eld. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
2.3. Effect of launch angle on evanescent eld . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
2.4. Effect of wavelength on evanescent eld . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
2.4.1. Tapered ber geometries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
2.4.2. Detection principles in tapered ber optic sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3. Applications of tapered ber optic sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.1. Cell concentration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.1.1. Pathogen detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
3.1.2. Clinical measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.2. Proteins or biomolecule concentration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.2.1. Biochemical measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.2.2. Toxins measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.2.3. Clinical measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
3.3. DNA hybridisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
3.3.1. Pathogen detection via DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
4. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Corresponding author. Tel.: +1 215 895 2236; fax: +1 215 895 5837.
E-mail address: mutharasan@drexel.edu (R. Mutharasan).
0925-4005/$ see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.snb.2007.03.010
A. Leung et al. / Sensors and Actuators B 125 (2007) 688703 689
1. Introduction
Biosensors are electrical, optical, chemical, or mechani-
cal devices with the capability to detect biological species
selectively. They are often modied with biological entities to
enhance their selectivity. Examples of biological recognition
molecules include enzymes, antibodies, and oligonucleotides.
The ideal biosensor not only has to respond to low concentra-
tions of analytes, but also must have the ability to discriminate
among species according to the recognition molecules that
are immobilized on its surface. Biosensors have wide applica-
tions, including biomarker detection for medical diagnostics,
and pathogen and toxin detection in food and water. Fiber-optic
biosensors (FOBS) use optical bers as the transduction ele-
ment, and rely exclusively on optical transduction mechanisms
for detecting target biomolecules. One reliable and sensitive
optical method is evanescent sensing. A majority of evanes-
cent FOBS are tapered ber-optic biosensors (TFOBS). This
review paper examines the transmission properties of TFOBS,
the different types of geometries, optical transduction mech-
anisms used with evanescent sensing, and the various studies
reported to date using TFOBS. The performances of TFOBS
are compared in terms of their detection capabilities. Apart
from the limit of detection (LOD) and selectivity, it is important
to recognize the advantages of ber-optic biosensors including
chemical-inertness, their compatibility to a wide range of sur-
face modication, the potential for remote sensing, lowcost, and
the ready availability of inexpensive lasers and photodetectors.
2. Fiber optic evanescent sensors
Optical bers consist of a cylindrical core and a surrounding
cladding, both made of silica, as illustrated in Fig. 1a. The core
is generally doped with Germanium to make its refractive index
Fig. 1. (A) Step-index SM ber. Typical diameter of the core is 812 m and
the overall diameter is 125 m. Light is transmitted in a single mode, meaning a
single path. (B) Step-index MMber. Typical diameter of the core is 50200 m
and the overall diameter is 125400 m. Light propagation occurs via many
paths. Total internal reection occurs when the incident angle is greater than the
critical angle.
slightly higher than the cladding refractive index, which results
inlight propagationbytotal internal reection(TIR). Light prop-
agating through an optical ber consists of two components:
the guided eld in the core and the exponentially decaying
evanescent eld in the cladding. In a uniform-diameter ber,
the evanescent eld decays to almost zero within the cladding.
Thus, light propagating in uniform-diameter cladded bers can-
not interact with the bers surroundings.
While optical bers were originally intended for light propa-
gation with minimal loss, it was not long before that they found
use in sensing, which requires light to interact with the bers
surroundings. One way to achieve this interaction is to expose
the evanescent eld of the transmitted light. For example, if
the cladding of a ber is reduced or removed, the evanescent
eld can interact with the surroundings. The distance to which
the evanescent eld extends beyond the core-cladding interface
is described by the penetration depth, which is the distance
where the evanescent eld decreases to 1/e of its value at the
core-cladding interface and is mathematically described as [1]:
E(x) = E
0
exp
x
d
p
(2-1)
where x is distance from the ber core, starting at x =0 at the
core-cladding interface, E
0
is the magnitude of the eld at the
interface, and d
p
is the penetration depth.
The penetration depth is given by [1]:
d
p
=

2
n
2
co
sin
2
n
2
cl
(2-2)
where is the wavelength of the light source, is the angle of
incidence of the light at the core/cladding interface, n
co
and n
cl
are the refractive indices (RI) of the core and cladding, respec-
tively. Fig. 2 is a cross-sectional view of a ber cut at the long
axis, and provides a graphical representation of the penetration
depth, angle of incidence, and a hypothetical ray of light prop-
agating along the ber. If the cladding of the ber is removed,
the optical output of the ber is then a measure of the changes
in magnitude of the evanescent eld.
The earliest studies of FOBSinvolvedthe simple designnoted
above, where the cladding was removed uniformly over a dis-
tance of the ber and replaced by the analyte, as shown in Fig. 3a.
Fig. 2. The cross-section prole of an optical ber cut along the long axis. The
thick arrow represents one mode of light entering in multimode with an angle of
incidence . Even though most of the light is propagated, there is a small portion
known as the evanescent eld that decays to 1/e of its value at the core-cladding
interface at a distance of d
p
. Typical SM bers that operate at 13101550 nm
have a core of of 8 m and an overall diameter of 125 m.
690 A. Leung et al. / Sensors and Actuators B 125 (2007) 688703
Fig. 3. (A) De-cladded optical ber. (B) Tapered optical ber. (C) U-shape probe. (D) Tapered tip.
Unfortunately, the penetration depth is typically far too small for
sensing. For example, analytes in biosensing applications usu-
ally have refractive indices (RI) n
aq
of 1.331.34. The ber core
typically has a refractive index of 1.45. If the cladding of the
ber was removed and the aqueous medium served as cladding,
the critical angle at the boundary (sin
1
(n
aq
/n
co
)) is 67
. For TIR
to occur, the angle of incidence must be greater than the critical
angle; therefore assuming that the angle of incidence is 80
, Eq.
(2-2) predicts the penetration depth is 0.145 m with 470 nm
light. In general, characteristic dimension of bacterial cells are
on the order of 1 m, while that of proteins are on the order of
10 nm. Therefore, depending on the size of the target analyte it
may be necessary to increase the penetration depth.
Apart from the penetration depth, light propagation through
an optical ber can be described in more detail by the wave
theory. The properties of light in the ber core are determined
by the number of modes N. In a multimode ber, there is a one-
to-one relationship between modes and angles of incidence. The
number of modes is directly related to a dimensionless parameter
known as the V number, given as [2]:
V
core
=
2
[n
2
core
n
2
clad
]
1/2
(2-3)
where is the radius of the core, is the wavelength of
the light, n
core
is the refractive index of the core, and n
clad
is
the refractive index of the cladding. The number of modes in a
multimode ber, N, is proportional to V
2
[3]:
N V
2
(2-4)
In a uniform-diameter single mode ber, Eq. (2-4) breaks
down and the light only propagates in one mode. However, if V
changes along the ber due to geometry or local RI changes, the
single mode ber becomes multimode, and coupling of modes
take place so that transmission by many modes occur, which
increases the evanescent portion. The increase in evanescent
eld forms the basis for increased sensitivity. In addition, several
investigators have attempted to increase the penetration depth
of the evanescent eld and facilitate mode coupling by bending
[47], tapering [812], altering the light launching angle [13],
and increasing the wavelength [14].
2.1. Effects of tapering on the evanescent eld
Tapering not only exposes the evanescent eld to the sur-
roundings, but also increases the evanescent eld magnitude and
penetration depth. Tapering was shown to enhance the potential
of the optical ber as a sensor [812]. Tapering can be performed
by removing the cladding and then tapering the core, or keeping
both the core and cladding in place and tapering the entire ber.
Fig. 3b illustrate the prole of a tapered ber where both the
core and the cladding were tapered.
The original evanescent FOBS consisted of uniform removal
of the cladding over a section of the ber. In a study by Mignani
et al., the optical characteristics of a de-cladded uniform-core
ber were compared to that of a de-cladded tapered core ber
in the context of evanescent absorption. Fractional power () is
dened as the fraction of power in the evanescent eld compared
to the total power in the ber. While absorption characteristics
of both bers followed the LambertBeers Law, the fraction
of power () differed signicantly. Considering a uniform ber
with a 200 m diameter, ranged from 4 10
4
to 8 10
4
.
On the other hand, in a tapered ber was much higher and
ranged from 6 10
3
to 8 10
3
. Sensitivity is proportional
to , which indicates that tapered core bers are 10 times more
sensitive [8]. Villatoro et al. used the ratio (R) of the power in the
evanescent eld to the total power of guided light to characterize
tapers [9]. Nano-sized bers had an Rof 100%, while de-cladded
uniformcores or tapered optical bers with larger diameters had
an Rof less than 20%[9]. In another similar study by Mackenzie
et al., adiabatic tapers as small as 1 m in diameter produced an
optical power intensity in the evanescent eld of 100 times than
what was achieved with a similarly polished ber [11].
2.2. Effects of bending on evanescent eld
Bending of optical ber results in loss in light and increase
in evanescent eld [4,5], and it is usually performed on a uni-
formly de-cladded ber. A schematic of a U probe is shown in
Fig. 3c. Fiber bending creates higher order modes which results
in the evanescent eld having greater penetration depth [5]. One
absorption study by Khijwania et al. demonstrated clearly the
superior sensingabilityof a Uprobe comparedtoa straight probe
of similar dimensions [4]. The absorption coefcient was found
to be larger in a U probe, which indicates that the U probe had a
larger evanescent eld. The reason for the smaller absorption in
a straight probe is that the number of ray reections as well as the
evanescent absorption coefcient is inversely proportional to the
core radius, and depends only on radius because the angle of ray
propagation is constant. However, the angle of ray propagation is
not constant but decreases in U probes. The effect of a decrease
in the angle of propagation is penetration depth increases. In
a follow up study by Khijwania et al. [6], it was reported that
there is an optimum bending angle. Sensitivity increases when
bending radius decreases, but only up to a certain value, after
which the sensitivity decreases. This decrease in sensitivity at
small bending radius is due to the evanescent eld overlap result-
ing in power transfer between the two arms without propagating
through the bent sensing region. In a similar absorption study
by Littlejohn et al., optical bers were de-cladded, bent, and
coiled by heat [5]. It was shown that sensors with more than one
bend were more sensitive. Using absorption of water bands, the
authors observed signal enhancements of up to 9 in bent bers
over straight bers.
2.3. Effect of launch angle on evanescent eld
In a single mode ber, light is launched over a very small
angle because onlythe lowest order mode is supported. However,
in multimode bers light can be launched at different angles
since these angles correspond to modes, and several modes are
supported simultaneously. The evanescent wave penetration was
shown by Ahmad et al. to be enhanced by as much as 300% in
certain designs of tapered bers [13]. However, further work on
this approach has not appeared and is not discussed in this report.
2.4. Effect of wavelength on evanescent eld
According to Eq. (2-2), penetration depth increases with
wavelength of the transmitted light. Some research has been
done on the use of bers at near-IR or IR wavelengths, but
mostly as H
2
sensors [9]. Very few reports have appeared in this
area for biosensing because most evanescent sensors depend on
absorption of light by biomolecules in the sensing region, and
only limited data is available on long wavelength absorption by
biomolecules. Furthermore, most biomolecules are suspended
in aqueous buffers, and the use of absorption at IR wavelengths
is complicated due to strong absorption by water. The applica-
tion of IR wavelengths with intensity-based tapered ber optic
biosensors (TFOBS) was investigated in our laboratory and was
showntoresult inhighsensitivityat lowconcentrations. Amodel
protein was detected at 10 fg/mL, using a 1550 nm source, even
though the protein did not absorb light at 1550 nm. Although a
direct comparison of evanescent absorption was not carried out
between IR and visible wavelengths, such low detection lim-
its have not been previously achieved in our laboratory using
TFOBS of similar dimensions with visible wavelengths [15].
2.4.1. Tapered ber geometries
Although there are various geometric methods to increase
the evanescent eld of FOBS, the most versatile geometry used
both in laboratory and industrial settings is the tapered FOBS
(TFOBS). There are two types of tapered ber geometries cur-
rently used in biosensing: tapered tips and continuous tapered
bers. A tapered tip consists of an optical ber which gradually
decreases in diameter until it becomes a tiny tip, and the tip is the
sensing element (see Fig. 3d). The tip itself can transmit the light
back to a detector for measurement. It is also possible to have an
external ber collecting the light from the tip for measurement.
A continuous tapered ber consist of an optical ber gradually
decreasing in diameter, which reaches a constant-diameter waist
region, and then gradually increases back to the original diam-
eter (see Fig. 3b). Light enters a continuous taper from one end
and is transmitted through the taper to the detector.
2.4.1.1. Tapered tips. Tapered tips are used extensively in
biochemical and clinical applications [1619]. Sensing using
tapered tips is usually aided by uorescence, which is discussed
in Section 2.4.2. Tapered tips can be further divided into the most
commonly used geometries: step-etched, conical, and combina-
tion tapers.
A step-etched tapered tip is fabricated by immersing a ber
into hydrouoric acid to etch it chemically, resulting in a ber tip
that abruptly decreases in diameter. It was found that this type
of ber loses a lot of power due to V number mismatch over
the step change in diameter and had low sensitivity when used
with uorescence sensing [20,21]. The diameter of a conical
tapered tip decreases continuously until it becomes a nanometer-
radius tip [20]. It is made by exposing different sections of the
ber to etching for different amounts of time, usually achieved
automatically by mounting the ber on a motor. The diameter of
a combination tapered tip decreases in a nonlinear fashion with
length, such that the Vnumber is matched. Thus the combination
taper ber has little loss in signal [20].
2.4.1.2. Continuous biconical tapers. A continuous biconical
taper consists of three regions (see Fig. 3b): a convergent region
of decreasing diameter, a region of almost xed diameter (waist),
and a divergent region of increasing diameter [22]. The waist
region is used as the sensing region because the evanescent
eld is at its maximum in the region of the smallest diameter.
Absorption, scattering, uorescence, and resonance can occur in
the waist region. Light resulting from uorescence is collected
along with the transmitted and scattered light in the divergent
region [23].
Although uniformly de-cladded tips and bers are not of
tapered geometry, they are predecessors to the development
of TFOBS. Because they are similar to tapered bers in opti-
cal behavior, they are included here as one type of TFOBS for
completeness.
2.4.2. Detection principles in tapered ber optic sensors
Changes of sensor response arising from the evanescent eld
are very versatile because they can be detected alone, amplied,
or detected in conjunction with various optical methods. Often
times, because the penetration depth is small in relation to the
target analyte, the use of additional transduction mechanisms
is imperative for amplication of response signals. The mecha-
nisms used in evanescent sensing depend on the analytes and the
application of the sensor. The use of evanescent sensing has been
previously investigated with many different sensing principles,
and include:
Changes inoutput power due torefractive indexchanges alone
(intensity-based TFOBS),
Evanescent eld absorption (absorption TFOBS),
Fluorescence (uorescence TFOBS),
Surface Plasmon Resonance (SPR).
2.4.2.1. Changes in output power due to refractive index
changes alone. Intensity-based sensors were the earliest
reported and one of the most widely used to date [24]. Changes
in the magnitude of the evanescent eld are detected by mea-
suring the changes in output power in a de-cladded uniform
ber or TFOBS. The amount of evanescent eld propagating
depends on the refractive index difference between the core and
the sample. Geometric parameters dominate the performance of
intensity-based sensors. Factors which inuence the sensitivity
of an intensity-based TFOBS include bending, radius, length,
and taper ratio.
As mentioned in Section 2, bending of a tapered ber
increases the fraction of evanescent eld in the sensing region,
and therefore increases sensitivity [812,24]. In terms of the
radius, it was found that smaller diameters cause a larger evanes-
cent eld, which increases sensitivity. For example, Villatoro et
al. [9] demonstrated that in nano bers the percentage of power
in evanescent eld approaches 100%. A study by Diaz-Herrera
et al. on a ber-optic temperature sensor also showed that sen-
sitivity increases with decreasing waist diameter [10]. Chen et
al. show that longer bers can be used to overcome a small d
p
caused by short wavelength [25]. The tapered region in the dis-
tal end converts lower order modes to higher order modes that
couple deeply and more efciently into the cladding. In a study
by Ahmad et al., a ray model was used and an expression was
obtained to relate d
p
to refractive indices, numerical aperture,
taper ratio, length, launch angle, and position along the taper
axis [13]. It was shown that the longest taper (10 cm) gave the
largest d
p
. However, with the shorter tapers the penetration depth
depended strongly on launch angle and a clear trend between the
angle and d
p
was not observed. Another factor which affects the
performance of the sensor is the taper ratio. Taper ratio is the
ratio of the waist diameter of a tapered ber to the total diam-
eter of a uniform ber. According to Bures et al., when taper
ratio is large, the evanescent wave is negligible, whereas when
taper ratio is small, the mode is so highly spread out that it tends
towards a free-space wave [26]. Ahmad et al. [13] concluded
that a taper ratio of unity gave the minimum d
p
, while d
p
can
increase up to 300% for tapers of certain geometry at a suitable
launch angle.
2.4.2.2. Evanescent eld absorption. When light is transmitted
through a tapered ber and the evanescent eld interacts with
the analytes in the tapered region, the transmission decreases
if the analytes absorb in the wavelength used for transmission.
The magnitude of the transmission decreases and depends on
the analytes concentration. In order to use tapers for absorption
measurements, the light source must be at a wavelength which
is absorbed by the sample analyte.
In a uniform-core optical ber stripped of cladding,
absorbance is governed by the LambertBeers Law:
A = L (2-5)
where is the absorption coefcient, L is the length of interac-
tion, and is the fraction of light in the evanescent domain [8].
The absorption coefcient is given by:
= C (2-6)
where is the molar absorptivity, and C is the concentration of
the species. Sensitivity is given by:
S = L
+C
(2-7)
If the species is weakly absorbing,
S

= L (2-8)
In a uniform-core optical ber, is quite low. Considering a ber
with a 200 m diameter, is in the 10
4
range [8]. Geometric
factors which inuence the sensitivity of an absorption TFOBS
include radius, taper ratio, length, and bending.
Mignani et al. compared tapered core optical bers to the uni-
form core de-clad bers [8]. In the tapered ber, radius changes
as a function of the distance along the axis of the ber, such
that r = r(z), where z is the distance along the axis. The angle
of each guided rate, , is also not constant. The taper can be
considered as a sequence of uniform sensing regions, such that
A =
L
0
(z) dz (2-9)
It was found that reducing the core radius enhances
absorbance by increasing and increasing the integration range
of the angle of ray propagation. The average value for in a
tapered ber is 10 times that of a uniform core decladded ber
[8]. Radius affects the number of ray reections per unit length,
and therefore also affects the sensitivity in an absorption sen-
sor. Khijwania et al. found that for straight bers, the number of
reections increases when radius decreases [4]. When the num-
ber of reectionincreases, evanescent absorptioncoefcient also
increases. As in the case of intensity-based FOBS, taper ratio
also determines the sensitivity of an absorption FOBS. Guo et al.
studied the transmission property and evanescent wave absorp-
tion using cladded multimode tapers, and found that lower the
taper ratios resulted in higher absorbance [12]. Using Eq. (2-8) it
is reasonable to suggest that the sensitivity increases with taper
length. Experimentally this was found to be the case by Guo et
al. using a multimode cladded taper [12]. As mentioned above,
bending increases the penetration depth and consequently an
increase in absorption occurs. In a U probe (see Fig. 3c), the
angle of a guided ray decreases in the bent region, which causes
penetration depth to increase [4]. In a spectroscopic study which
compared bent bers with straight ones, it was concluded that
bending can lead to higher order modes and therefore higher per-
centage of power in the evanescent eld [5]. Using absorption of
water bands as a guide, it was observed that signal enhancements
of up to 9 times can be obtained compared to straight bers.
In addition, mode-dependent variation of evanescent interaction
withthe sample canleadtonon-linear absorbance behavior when
the ber mode structure is lled.
2.4.2.3. Evanescent wave uorescence. There are two general
methods for using uorescence with TFOBS. In the rst method,
the sandwich assay, a primary antibody is covalently bonded to
the surface of the ber. Then, the target biomolecule that binds
to the antibody is introduced. Presence of this biomolecule is
then conrmed using a secondary uorescent antibody, which
uoresces when excited by the incident light from the evanes-
cent wave. In the second method, known as the direct method,
a uorescent dye is rst attached on the surface of the taper.
When a molecule is near the surface of the taper, the uores-
cence quenching is measured. Hale et al. found that the detection
limit using uorescence with a ber loop was in the pg/mL
range [7].
V-number matching is a unique problem in uorescence
TFOBS [20,21,27]. Anderson et al. prepared an evanescent u-
orescence sensor by removing the cladding with the step-etched
design, such that the ber radius remains constant and then sud-
denly decreases to just the ber core radius. It was found that the
return of uorescent signal was inefcient in this design [28].
The inefciency was due to the V-number mismatch, expressed
as the difference in mode carrying capacity between the clad
and uncladded ber, which limits signal coupling. The results
from this study suggest that for uorescence sensing, a probe of
constant diameter is not ideal.
Other geometric factors which inuence the sensitivity of
uorescence TFOBS include length, angle of incidence, bend-
ing, and surface area. The effect of length on uorescence
FOBS was studied using tapered quartz rods, immersed in a
100 ppm tetracycline solution [25]. Signal from the evanescent
eld was reciprocally collected, passed through a beam splitter,
and collected by a PMT. It was found that a long taper can be
used to overcome the low penetration depth [25]. In a multi-
mode ber, the input angle of incidence affects the percentage
of light in the evanescent eld. When the angle is optimized
for obtaining the maximum percentage of light in the evanes-
cent eld, more light is available for uorescence excitation
and stronger emission signals are obtained. Similar to evanes-
cent absorption and scattering, bending and looping of optical
bers improve coupling and sensitivity in uorescence sens-
ing [25]. Hale et al. detected human IgG using a looped ber
in a two-step sandwich assay where uorophores were intro-
duced in the second step [7]. In terms of surface area, tapered
single mode bers suffer from having a small surface area and
possibly lower source collection efciency [29]. It was found
that with tapers greater than 10 m in diameter, the longer
tapers were found to have 510 times greater coupling efciency
[29].
2.4.2.4. Surface plasmon resonance. Surface plasmon reso-
nance (SPR) is a variation of the evanescent wave phenomenon
[30]. The geometry for a SPR sensor is a metal coated dielectric
in which light propagates. Instead of having the evanescent eld
interact directly with the sample or excite uorescent molecules,
optical energy is transferred to the surface of the metal layer as
packets of electrons called plasmons. SPR is an optical phe-
nomenon where a p-polarized light beam satises the resonance
condition and excites a charge density oscillation 100 nm above
and below the metal surface known as a surface plasmon wave
(SPW) [30,31]. When SPRoccurs, the intensity of reected light
is greatly reduced. The resonance condition depends on the inci-
dent angle, wavelength, and dielectric functions of the metal and
dielectric. The wavelength or angle at which resonance occurs
depends on the refractive index of the analyte. Shifts in res-
onance can be monitored by angle, wavelength, or reection
intensity changes. From the resonance angle or wavelength one
can obtain the RI of the analyte [32]. The most popular and
commercially available conguration for SPR is the Krestch-
mann conguration, which consists of a metallic layer deposited
directly on the base of a prism. More recently, the tapered ber
became another popular conguration for SPR[31]. Fibers have
certain advantages over prisms in that they are simple, exible,
small, and allows for multichannel and remote sensing [31].
Usually gold or silver is used as the coating for SPR sensors.
The use of gold results in increase in the shift of the resonance
parameter with respect to changes in the refractive index. The
use of silver narrows the resonance curve, thus gives a higher
signal-to-noise ratio (SNR). However, unlike gold, the problem
with silver is the lowchemical stability [31]. Recently it has been
suggested that there should be two metal layers, and that gold
should act as the outer layer while silver as the inner layer. The
total thickness of the metal layers were kept constant at 50 nm,
and it was found that when the silver layer increase in thickness,
SNR increases and sensitivity decreases [31]. Silver decreases
the width of the resonance curve whereas gold increases the sep-
arationbetweenresonance wavelength, thus increases sensitivity
[31].
Geometric factors which affect the performance of a SPR
sensor include the metal thickness, length, waist diameter, and
launch angle. It was previous stated that the metal coating thick-
ness must be on the order of the wavelength used [33]. In the
study done by Sharma et al., it was concluded that increas-
ing the length of the sensing region increases the number of
reections, and causes a broader SPR curve with lower SNR
[31]. Fabrication and modeling of a uniform-waist single mode
SPR sensor was examined by Villatoro et al. and it was found
that thicker waist diameters resulted in sharper resonance peaks,
which increases sensitivity [33]. Sharma et al. also found that
increasing the diameter decreases the number of reections,
which results in sharper resonance peaks [31]. Sharma et al.
studied launching of selected guided rays at desired angles, and
found that SNR for all guided ray launching is 1.5 times that of
selected rays launching [31].
3. Applications of tapered ber optic sensors
TFOBS have been widely used for the measurement of cells,
proteins, and DNA. Tables 2.12.3 summarize the biosensing
application to date including the target detected, matrix, the limit
of detection (LOD), sensor geometry, ber type, principle of
detection, and references.
3.1. Cell concentration
3.1.1. Pathogen detection
Ferreira et al. developed an intensity-based evanescent sen-
sor to detect the growth of Escherichia coli O157:H7 [34].
The sensor was fabricated by chemically etching a multimode
ber. Sensing is based on the interaction of the bacteria with
the evanescent eld as well as attenuation. The power loss is
Table 2.1
TFOBS for pathogen and toxin measurements
Target analyte LOD Matrix Taper geometry Fiber type Detection principle References
Bacillus anthracis 3.2E5 spores/mL Buffer BT Polystyrene MM Fluorescent sandwich
assay
[44]
Bacillus subtilis var. niger 8 10
4
spores/mL Buffer NA (chip) NA (chip) Leaky wave (SPR) [75]
LacZ DNA in Escherichia
coli
25 pM Buffer Uniform MM Fluorescent
intercalating agents
[73]
Staphylococcus aureus
Protein A
1 ng/mL ND ND MM plastic Fluorescent sandwich
assay
[52]
Escherichia coli O157:H7 0.016 dB/h/N
o
,
Initial number
(N
o
): 10-800*
Buffer BT MM Absorption [34]
Escherichia coli O157:H7 70 cells/mL Buffer BT SM Intensity [22]
Escherichia coli O157:H7 1 CFU/mL Ground beef samples Uniform MM polystyrene Fluorescent sandwich
assay
[36,37]
Salmonella 50 CFU/g irrigation water used
in the sprouting of
seeds
RAPTOR
uniform
Waveguide Fluorescent sandwich
assay
[39]
Salmonella 10
4
CFU/mL Hotdog samples RAPTOR
uniform
assay
[76]
Salmonella 10
4
CFU/mL Nutrient broth TT MM Fluorescent sandwich
assay
[40]
Staphylococcal enterotoxin
B
Min: 0.5 ng/mL
(buffer)
Buffer, human serum,
urine, and aqueous
extract of ham
CTT ND Fluorescent sandwich
assay
[50]
C. Botulinum toxin A,
Pseudexin toxin
Min: 30 pM (C.
Botulinum toxin
A), 60 pM
(Pseudexin)
ND CTT MM Fluorescent sandwich
assay
[77]
Clostridium-Botulinum
toxin A
5 ng/mL Buffer TT MM Fluorescent sandwich
assay
[53]
E. coli lipopolysaccharide
endotoxin
Min: 10 ng/mL Buffer and plasma CTT ND Fluorescent sandwich
assay
[55]
Ricin concentration Min: 100 pg/mL
(buffer) Max:
1 ng/mL (river
water)
Buffer, river water CTT MM (plastic clad
silica)
Fluorescent sandwich
assay
[54]
Listeria monocytogenes 5 10
5
CFU/mL Frankfurter sample RAPTOR
uniform
assay
[43]
Listeria monocytogenes 5.4 10
7
CFU/mL Hotdog samples RAPTOR
uniform
assay
[42]
Listeria monocytogenes 4.3 10
3
CFU/mL Buffer Uniform MM polystyrene Fluorescent sandwich
assay
[41]
Abbreviations: BT=biconical taper, TT=tapered tip, CTT=combination taper Tip, SM=single mode, MM=multimode, ND=not described, * =the change in dB
per hour per number of cells at inoculation, NA=not applicable.
Table 2.2
TFOBS in biochemical measurements
NADH, NADPH concentration Min: 0.2 M (NADH),
0.5 M (NADPH)
Buffer BT SM Absorption [45]
Chinese Hamster Ovary Cell
concentration
Min: 10
5
cells/mL Buffer BT SM Absorption [45]
Paraoxon Sub ppm Buffer TT MM Chemiluminescence [47]
STAT3 ND Buffer Uniform MM Fluorescent sandwich assay [49]
Abbreviations: BT=biconical taper, TT=tapered tip, CTT=combination taper Tip, SM=single mode, MM=multimode, ND=not described.
proportional to the intrinsic bulk absorption and scattering,
which depends on the concentration of the bacteria. The sen-
sitivity of this sensor was 0.016/dB/h/No, where No ranges
from 10 to 800 and is the initial number of bacteria. Simi-
larly, Maraldo et al. used TFOBS to detect the growth of E.
coli JM 101 [35]. Tapered surface was coated with poly-l-
lysine and E. coli JM 101 expressing green uorescent protein
was immobilized. Growth was monitored by light transmission
through the tapered ber. The transmission decreased exponen-
tially with cell growth on the tapered surface. In a follow up
study by Rijal et al., E. coli O157:H7 was covalently bonded to
the surface of a TFOBS via an antibody, and concentrations as
low as 70 cells/mL was detected by changes in intensity [22].
Detection of E. coli O157:H7 in real samples is of great interest
in pathogen detection and was investigated by DeMarco et al.
[36]. E. coli O157:H7 in seeded ground beef samples was pre-
pared and detected by a sandwich immunoassay using cyanine
5 dye-labeled polyclonal anti-E. coli O157:H7. Responses were
obtained within 20 min, and E. coli O157:H7 at 330 CFU/mL
were detected. Signals with Listeria monocytogenes, Salmonella
typhimurium, and E. coil non O157:H7 were negligible com-
pared to those observed with a similar concentration of E. coli
O157:H7. Asimilar study was recently conducted by Geng et al.,
where a sandwich uorescent antibody-based FOBS was devel-
oped to detect E. coli O157:H7 in ground beef [37]. The sensor
detected 10
3
CFU/mL of pure cultured E. coli O157: H7 cells
grown in culture broth. Articially inoculated E. coli O157: H7
at concentration of 1 CFU/mL in ground beef was detected after
4 h of enrichment.
Fluorescence resonance energy transfer (FRET) involves the
non-radiative energy transfer froma uorescent donor molecule
to an acceptor molecule due to the dipoledipole interactions
when the two are in close proximity. Ko et al. used the FRET
principle with an optical ber tip sensor to detect S. typhimurium
[38]. The tip was made by chemical etching using hydrouoric
acid (HF). Antibody to Salmonella was labeled with a FRET
donor uorophore (Alexa Fluor 546), and Protein G (PG) was
labeled with FRET acceptor uorophore (Alexa Fluor 594).
The antibody was immobilized on decladded tapered bers
by silanization. The rate of energy transfer is proportional to
1/r
6
o
, where r
o
is the distance between the donor and accep-
tor. PG binds specically to the F
c
portion of the antibody.
When binding of S. typhimurium to the antibody occurs, the
conformation of the antibody changes, which decreases the dis-
tance between the donor and acceptor, and results in increase in
uorescence. The limit of detection was determined by measur-
ing the lowest concentration that generated a signicant change
in signal over the baseline (three times the standard deviation
from the baseline). The best packing density of acceptor and
donor was 0.033 mg/mL, which results in a limit of detection
of 10
3
cells/mL with 8.2% change in uorescence. The ber
probes were shown to work in real samples as well by detect-
ing S. typhimurium at 10
5
CFU/g in homogenized pork samples
with a 6.67% change in uorescence within a 5-min response
time. Kramer et al. studied the detection of S. typhimurium
in sprout rinse water using the uorescence sandwich method
[39]. Alfalfa seeds contaminated with various concentrations
of S. typhimurium were sprouted. The sprout rinse water was
assayed with the RAPTOR
TM
, an evanescent uorescence sen-
sor developed by Research International, Monroe, Washington.
Using this method, S. typhimurium was identied for seeds
that were contaminated with 50 CFU/g. Zhou et al. is another
author who used a sandwich immunoassay to detect Salmonella
[40]. Tapered ber tips with different shapes and treatments
were studied and optimized, and Salmonella was detected at
10
4
CFU/mL.
An antibody-based sandwich uorescence FOBS was devel-
oped by Geng et al. to detect L. monocytogenes [41]. This sensor
was specic for L. monocytogenes as shown by the signicantly
lower signals caused by other Listeria species or microorgan-
isms. The LOD was 4.3 10
3
CFU/mL for a pure culture of L.
monocytogenes. In less than 24 h, this method could detect L.
monocytogenes in hot dog or bologna at 101000 CFU/g after
enrichment. Recently, Kim et al. also detected L. monocyto-
genes using the previously mentioned RAPTOR
TM
sensor [42].
Detection of L. monocytogenes in hotdog sample achieved a
LOD of 5.4 10
7
CFU/mL. RAPTOR
TM
detection of L. mono-
cytogenes in phosphate buffered saline (PBS) was performed
again by Nanduri et al. to evaluate the effect of ow on antibody
immobilization [43]. It was found that both the static and the
ow through mode method both resulted in a LOD of 1 10
3
CFU/mL in PBS. However, the effective disassociation con-
stant and the binding valences for static modes were higher than
for ow through method of antibody immobilization. The ow
through mode was chosen to test real samples, and the LODwas
found to be 5 10
5
CFU/mL of L. monocytogenes.
There are currently few rapid and sensitive methods to detect
Bacillus anthracis, which is a signicant threat to national secu-
rity. Tims et al. addressed this need by detecting B. anthracis at a
concentration of 3.2 10
5
spores/mg in spiked powders in less
Table 2.3
TFOBS in clinical measurements
Protein A 1 g/mL ND NA (chip) NA Leaky wave (SPR) [78]
BSA 10 fg/mL Buffer BT SM Intensity [15]
BSA 7.4 ng/mL Buffer Chip (NA) Chip (NA) SPR [79]
BSA 2.5 g/mL Buffer BT ND (plastic
clad silica)
Dye-protein complex absorption [58]
Ovalbumin 2.5 g/mL Buffer BT ND (plastic
clad silica)
Hemoglobin 2.5 g/mL Buffer BT ND (plastic
clad silica)
IgG 20 fM Buffer TT MM Fluorescent competitive assay [59]
IgG 75 pg/mL Serum and
jejunal uids
diluted with
buffer
BBT SM Fluorescent sandwich assay [7]
Protein C 0.1 g/mL Buffer TT ND Fluorescent sandwich assay [60]
Protein C 0.5 g/mL Plasma TT MM Fluorescent sandwich assay [61]
Protein C 0.5 g/mL Plasma Uniform MM Fluorescent sandwich assay [18]
Protein S 0.5 g/mL Plasma Uniform MM Fluorescent sandwich assay [18]
Antithrombin III (ATIII) 30 g/mL Plasma Uniform MM Fluorescent sandwich assay [18]
Plasminogen (PLG) 30 g/mL Plasma Uniform MM Fluorescent sandwich assay [18]
B-type natriuretic peptide
(BNP)
0.1 ng/mL Plasma Uniform MM Fluorescent sandwich assay [18]
Cardiac troponin I (cTnI) 1 ng/mL Plasma Uniform MM Fluorescent sandwich assay [18]
C-reactive protein (CRP) 1 g/mL Plasma Uniform MM Fluorescent sandwich assay [18]
Myoglobin (MG) 75 ng/mL Plasma Uniform MM Fluorescent sandwich assay [18]
L. donovani antibody
concentration
Min:
0.244 ng/mL
Serum CTT MM (plastic
clad silica)
Fluorescent sandwich assay [17]
Progesterone ng/mL Buffer ND ND Fluorescent sandwich assay [66]
Adriamycin 0.01 g/mL Blood Straight core tip MM Fluorescence quenching [16]
Cytochrome c ND Cell TT MM Fluorescent sandwich assay [67]
Cytochrome c 2.5 g/mL Buffer BT ND (plastic
clad silica)
Yersinia pestis fraction 1 50 ng/mL Buffer, serum,
plasma, and
whole blood
BT MM Fluorescent sandwich assay [68]
cTnI 31 pM Plasma TT MM quartz Nano gold particle enhanced
uorescence
[80]
BNP 26 pM Plasma TT MM quartz Nano gold particle enhanced
uorescence
[80]
Intracellular Benzopyrene
Tetrol
6.4 pM Cell TT ND Autouorescence [19]
Benzo\c\phenanthridinium
alkaoids
ND Buffer Chip NA SPR [81]
Fumonisin B
1
10 ng/mL Methanol/water-
extracted
corn
TT MM (plastic
clad silica)
Fluorescent sandwich assay [56]
Myoglobin 2.9 ng/mL Buffer Tip MM SPR [62]
Myoglobin 5 nmol/L Buffer Uniform probe MM Fluorescent Energy Transfer [63]
Thrombin 1 nM Buffer Spheres (NA) NA Fluorescent competitive assay [65]
Thrombin 1 nM Buffer Uniform MM Coagulation of uorescently
labeled brinogen to unlabelled
brinogen bound to the surface of
the bre optic
[64]
RNA pM Buffer TT SM Fluorescence [74]
DNA 70 fM Buffer Uniform MM Fluorescence [70]
interleukin-1 (IL-1),
interleukin-6 (IL-6), and
tumor necrosis factor-a.
(TNF-alpha)
1 ng/mL Buffer and
spiked cell
culture medium
(CCM)
ND MM Fiber-optic surface plasmon
resonance (SPR)
[69]
DNA 5 nM Buffer ND MM Fluorescence [71]
Abbreviations: BT=biconical taper, TT=tapered tip, CTT=combination taper Tip, SM=single mode, MM=multimode, ND=not described, NA=not applicable.
than 1 h [44]. The principle of detection is uorescent sandwich
assay used with a polystyrene tapered ber.
3.1.2. Clinical measurements
Although there are many potential benets to the detection
of whole cells for clinical measurements, little work has been
undertaken in this area using TFOBS. The reason is that mam-
malian cells are more difcult to culture than bacterial cells, and
small chemicals indicative of diseases are easier to detect with
TFOBS once isolated from the cells. However, there has been
very few reports to detect mammalian cells, and the methods
used are similar to the ones for bacterial cells detection. For
example, Haddock et al. measured the concentration of Chinese
Hamster Ovary (CHO) cells using absorption TFOBS[45]. They
found that the sensitivity in tapered ber is an order of magni-
tude higher than that obtained in a cuvette. The detection limit
of ber was 0.1 millions cells/mL. MIR spectra of mouse liver
tissues have been recorded using a chalcogenide glass ber in
contact with the tissue [46]. The measurements were based on
evanescent wave spectroscopy. The IRlight was absorbed by the
chemical bond vibrations with characteristic frequencies, which
gives rise to absorption peaks. The results were in agreement
with histological colorations.
3.2. Proteins or biomolecule concentration
3.2.1. Biochemical measurements
Nicotinamide adenine dinucleotide (NADH) and nicoti-
namide adenine dinucleotide phosphate (NADPH) at various
concentrations were successfully detected by Haddock et al.
using a tapered ber sensors drawn by a ame [45]. The power
output of the ber depends on the amount of light absorbed
by the solute, which depends on the concentration. An impor-
tant parameter in evanescent absorption is the product of the
extinction coefcient and light path, and is used to character-
ize sensitivity. In a tapered ber, the interaction length and
extinction coefcient cannot be separated. A comparison was
made between the LOD using the taper and cuvette measure-
ments. It was found that the LOD of the taper was 0.2 M of
NADH and 0.5 m of NADPH. On the other hand, the limit
of detection for the cuvette was 3 M for both NADH and
NADPH.
Chen et al. developed a chemiluminescent-based ber optic
sensor to detect a multilayer of enzyme alkaline phosphatase
[47]. The enzyme was immobilized by chemical crosslinking to
the optical ber surface. Then, chemiluminescence, ellipsome-
try, and SPR were used to characterize the structure and activity
of the assembly. The chemiluminescence method was also used
for the detection of organophosphorus-based pesticides at sub-
ppm levels. The detection takes advantage of the competition
between the OP-based pesticide and the chemiluminescent sub-
strate for the enzyme, which results in partial inhibition of the
chemiluminescence signal. Boththe multilayer thickness andthe
RI conrmed with ellipsometry and SPR. Detection at sub-ppm
levels was achieved for paraoxon.
Kishen et al. developed a FOBS to monitor Mutans strepto-
cocci activityinhumansaliva [48]. The M. streptococci mediated
reaction with sucrose is monitored using a photosensitive indi-
cator, which is immobilized within a porous glass coating on the
surface of the de-cladded ber.
Kapoor et al. used a uorescent sandwich FOBS to detect
trophic factor activated signaling molecules in cells [49].
Quantitative detection of signal transducers and activators of
transcription 3 (STAT3) phosphorylation in neuroblastoma cells
was achieved. The method is two orders of magnitude more
sensitive than the Western blotting technique.
3.2.2. Toxins measurement
Staphylococcal enterotoxins are a major cause of food
poisoning. Tempelman et al. quantied Staphyloccoccal Entero-
toxin B (SEB) in a ber optic biosensor using a uorescent
sandwich immunoassay [50]. Light from a 635 nm diode laser
was launched to the taper to excite the labeled antibody. The uo-
rescence was measured and gave a detection limit of 0.5 ng/mL.
Shriver-Lake et al. used an array biosensor to detect SEB in
buffer and six different types of food samples [51]. It was found
that the LOD was 0.5 ng/mL of SEB. In addition, Staphylo-
coccus aureus is the only species which produces protein A,
and was detected by Chang et al. using a uorescent sandwich
FOBS [52]. The LOD was 1 ng/mL. Similar to SEB, Clostrid-
ium botulinum toxin A was detected by a uorescent sandwich
FOBS [53]. Antibody to C. botulinum was covalently attached
to the surface of the tapered ber, and the toxin was detected at
concentrations of 5 ng/mL.
Narang et al. reported a uorescent TFOBS for the detection
of ricin [54]. Antibody to ricin was immobilized onto tapered
ber surface using two methods: silanization and avidinbiotin
linkage. Then, ricinwas introducedintothe vicinityof the sensor.
Finally, a Cy5-labeled secondary antibody was used to complete
the sandwich immunoassay. The avidinbiotin method showed
higher sensitivity and had a wider linear dynamic range. In the
avidinbiotin sensor, the response was linear in the concen-
tration range of 100 pg/mL to 250 ng/mL. The LOD for ricin
in buffer solution was 100 pg/mL, and in river water it was
1 ng/mL. At concentrations of ricin greater than 50 ng/mL, there
was strong interaction of ricin with the avidin due to the lectin
activity of ricin. This interaction was signicantly reduced using
bers coated with neutravidin or by adding galactose to the ricin
samples.
James et al. developed a method to detect lipopolysaccharide
(LPS) endotoxin, which is the most powerful immune stimu-
lant and causes sepsis [55]. In the study, LPS from E. coli was
detectedat concentrations as lowas 10 ng/mLusinguorescence
TFOBS based on the competitive assay. Polymyxin B was used
as a recognition molecule. It was covalently immobilized onto
the surface of the probe. Fluorescent labeled LPS was intro-
duced to the ber and attached to the Polymyxin B. Unlabeled
LPS was then introduced and competed with the labeled LPS
for the binding sites on the Polymyxin B. As the unlabeled LPS
concentration increases, uorescence decreases. The detection
limit of this sensor in buffer and plasma samples was 10 ng/mL.
Thompson et al. developed a evanescent ber optic
immunosensor to detect fumonisin B-1 (FB1) [56]. Antibody
to FB1 was covalently bonded to the ber surface via a
heterobifunctional silane. Acompetitive assay was used to mea-
sure unlabeled FB1. Fluorescein isothiocyanate (FTIC) labeled
FB1 was added to the ber, and then unlabeled FB1 was
added. Competition between FB1 and FB1-FITC determines
the uorescence signal. The uorescence was inversely pro-
portional to the concentration of unlabeled FB1. The sensor
had a working range of 101000 ng/mL of FB1. The sen-
sor response was specic and was not affected by a sample
matrix of methanol/water-extracted corn. In a follow up to
Thompsons study, Maragos et al. used the uorescent sen-
sor to detect fumonisins and aatoxins in maize [57]. Unlike
Thompsons study, here both competitive and non-competitive
assays were used. The competitive assay was used to measure
fumonisin B-1 (FB1) in both spiked and naturally contami-
nated maize samples. Antibody to FB1 was covalently bonded
to the ber, and the antibody binding sites were exposed to
the competition between FB1 and FITC-labeled FB1. The
uorescence signal was inversely proportional to the concen-
tration of FB1. The immunosensor results for the naturally
contaminated samples agreed with detection with the HPLC
method, except when there is a large amount of contami-
nating fumonisins that cross-reacted with the immunosensor.
The mycotoxin aatoxin B-1 (AFB(1)) was detected using a
non-competitive assay because the AFB(1) uoresces. The u-
orescent signal in this case was directly proportional to the
concentration of AFB(1). The detection limit was 2 ng/mL of
AFB(1).
3.2.3. Clinical measurements
Medical diagnostics based on protein concentrations often
dependonimmunological methods. TFOBSis anattractive alter-
native because of the quick response time and sensitivity. Effort
is focused on detecting clinically-relevant proteins such as car-
diac markers and anticoagulants. However, investigators have
also detected a variety of model proteins in order to characterize
TFOBS potential for detection. Preejith et al. detected model
proteins using ber optic evanescent wave spectroscopy [58].
They immobilized a dye, Comassie Blue, in a porous glass coat-
ing, which was coated on the surface of a multimode optical
ber. Comassie Blue normally absorbs at 467 nm, but it forms
a dye-protein complex with the protein when it is in an acidic
environment, and such a complex absorbs at 590 nm. The con-
centration of the protein is inversely proportional to the output
power at 590 nm, because increase in protein levels increases the
evanescent light absorption. Calibration curves were obtained
for BSA, hemoglobin, ovalbumin, and cytochrome c in the
range of 020 g/mL. In our laboratory, BSA has recently been
detected at 10 fg/mL using intensity-based TFOBS modied
with antibody under stagnant condition [15]. Tromberg et al.
detected antibody to IgG on a uorescent FOBS tip using a
competitive assay [59]. Rabbit IgG was immobilized on the tip
of a ber, and exposed to uorescein isothiocyanate (FITC)
labeled and unlabeled anti-IgG. The response was inversely
proportional to the amount of unlabeled anti-IgG, because the
unlabeled anti-IgG displaced the labeled one. Using this sen-
sor, 20 fM of unlabeled antibody was detected in 20 min. Hale
et al. developed a uorescent optical bre loop sensor to detect
antibody to IgG [7]. A bent TFOBS was used with a two-step
sandwich assay. IgG was labeled with the uorescent dyes uo-
rescein isothiocyanate or tetramethyl rhodamine. In the rst step
of the assay, the tapered ber was silanized so that unlabeled
IgG attaches to the sensing region covalently. Then, antibody
to IgG binds to the sensing region due to the presence of the
attached IgG. Finally, labeled IgGwas introduced, and the argon
ion laser enters the evanescent region to excite the uorescent
dye. The uorescence emitted by the dye was coupled back
into the ber and is a direct measurement of the IgG concen-
tration. A concentration of 75 pg/mL was detected with this
method.
Deciency in Protein C (PC), if left untreated, may result
in thrombotic complications, such as major clotting problems,
and thus presents an important clinical challenge. Traditionally,
the presence of PC is detected by ELISA, but that method is
time-consuming, expensive, and requires skilled technicians to
perform. Spiker et al. detectedPCinreal-time usinga uorescent
ber optic sensor [60]. Monoclonal antibody to PC was immo-
bilized on a tapered quartz ber. The system was probed with
a uorophore-tagged secondary antibody against PC. When PC
was introduced, the immobilized antibody, PC, and secondary
antibodyforma sandwichcomplex, anduorescence levels were
detected and corresponded to the concentration of PC. Using this
system, the authors detected 0.1 g/mL in pure buffer. Regen-
eration of the ber was achieved using CaCl
2
, because in the
presence of the Calcium, the conguration of PC changes such
that it can no longer bind to the antibody. Using the Calcium
buffer at pHof 9.4, a signicant increase in the ber lifetime was
achieved, averaging in 6.3 assays per ber. Real-time detection
of PC in plasma is an important challenge in the clinical setting.
Convective ow plays a vital role in the transport of PC in a
viscous media such as plasma, as demonstrated by a study by
Tang et al. who concluded that uorescent sandwich FOBS can
detect PC in plasma at 0.5 g/mL [61].
The cardiac markers myoglobin (MG) and cardiac tropinin
I (cTnI) are released from cardiac muscles when they are
damaged, and therefore their concentrations can predict the
occurrence of myocardial infarction. A ber-optic SPR sensor
to detect markers of MG and cTnI at 3 ng/mL was devel-
oped by Masson et al. [62]. A direct uorescence FOBS was
also used to detect myoglobin [63]. Cascade Blue-labeled
antibody was entrapped in the sensing element. Fluorescence
quenching occurred when myoglobin bound to labeled anti-
body. Using this method, myoglobin was detected at 5 nM.
A recent study by Tang et al. developed a ber-optic multi-
analyte system which simultaneously quanties the above two
groups of multi-biomarkers related to cardiovascular diseases
(CVD): anticoagulants (protein C, protein S, antithrombin
III, and plasminogen) for deciency diagnosis; and cardiac
markers (B-type natriuretic peptide, cardiac troponin I, myo-
globin, and C-reactive protein) for coronary heart disease
diagnosis.
An interesting assay was developed by Garden et al. to
detect thrombin using uorescence [64]. Unlabelled brinogen
was rst bound to the surface of the evanescent FOBS. Then,
coagulation of solution phase uorescently labeled brinogen
to unlabelled brinogen bound to the surface was observed.
Thrombin concentrations down to 1nM were detected. Lee et
al. detected thrombin using a uorescent ber-optic biosensor
immobilized with an antithrombin DNA aptamer receptor [65].
The aptamer was immobilized on the surface of silica micro-
spheres, which were distributed in microwells on the distal tip
of an imaging ber. A similar type of silica microspheres was
preparedwitha different oligonucleotide tomeasure the nonspe-
cic binding. The distal end of the imaging ber was incubated
with uorescein-labeled thrombin (F-thrombin). Then, non-
labeled thrombin was detected using the competitive method.
The imaging ber was coupled to a modied epiuorescence
microscope system. The limit of detection was 1 nM of non-
labeled thrombin.
Protein is commonly measured by analytical methods like gas
chromatographymass spectroscopy (GCMS) and high perfor-
mance liquidchromatographymass spectroscopy(HPLCMS),
which requires pre-concentration of samples by orders of mag-
nitude to achieve detectable amounts [66]. Immunoanalytical
methods at very low limit of detection (LOD) and low limit
of quantication (LOQ) are becoming increasingly important
for environmental analysis. Based on animal studies, Proges-
terone was found to have evidence of carcinogenicity, and can
be found in various surface waters, which is used for drinking
water. In a study by Tschmelak et al., a uorescence optical
biosensor was immobilized with a labeled-antibody and used
successfully with evanescent eld and binding inhibition to
obtain detection of progesterone at concentrations lower than
ng/L [66].
A ber tip uorescence sensor was used to measure adri-
amycin (ADM) in vivo [16]. A polymeric uorescent D-70
membrane with pore sizes of 12 m was immobilized on the
ber tip. The signal uorescence was quenched by ADM in
the blood, and the uorescence signal was detected by a pho-
tomultiplier tube (PMT) at a wavelength of 530 nm. Light was
emitted from a xenon lamp and directed into one branch of a
bifurcated optical ber, and was transmitted to a probe inserted
into the blood vessel. This method has a detection limit of
10 ng/mL.
Another protein, cytochrome c, which is involved in apopto-
sis, was detected by a uorescent nanobiosensor fabricated by
Song et al. [67]. -Aminolevulinic acid (5-ALA), a photody-
namic therapy (PDT) drug, was activated by a HeNe laser to
induce apoptosis in MCF-7 human breast carcinoma cells. When
mitochondria are damagedbyPDT, cytochrome c is releasedinto
the cytoplasm, which means that cytochrome c concentration is
indicative of apoptosis. In this study, antibody to cytochrome c is
immobilized on a nanoprobe. The nanoprobe was inserted inside
a cell where binding of cytochrome c to the antibody occurs.
Then, enzyme-linked immunosorbent assay (ELISA) was per-
formed on the nanosensor outside the cell. Results indicate
that 5-ALA PDT-treated cells show a much higher uorescence
intensity, which indicates that the cytochrome c concentration
is much higher in the treated cells.
Yersinia pestis is an etiologic agent of plague. An opti-
cal system devised by Cao et al. was used to detect Yersinia
pestis Fraction 1 antigen [68]. Antibody was immobilized
on the core surface, and then antigen was added. Then,
tetramethylrhodamine-labeled anti-plague antibody was added
and formed a sandwich uorescent complex with the immo-
bilized antibody and antigen. An argon ion laser at 514 nm
launched light into a long-clad ber and the uorescence was
produced by the immunouorescent complex formed in the
evanescent wave region. This system detected 50400 ng/mL
of protein in serum, with a limit of 5 ng/mL. The results were in
excellent agreement with ELISA results.
Nath et al. developed a uorescent ber optic sensor to detect
L. donovani specic antibodies [17]. The sensor was made by
decladding an optical ber so that the evanescent wave prop-
agated outside the tapered region. Cell surface protein of L.
donovani was immobilized covalently on the sensing region.
Then, the sensor was incubated with patient serum for 10 min,
followed by incubation with goat anti-human IgG tagged with
FTIC. The amount of L. donovani specic antibodies in the
patient serum was proportional to the uorescence. There were
no false positive results from leprosy, tuberculosis, typhoid, and
malaria serum.
Cullum et al. detected a metabolite of benzo[a]pyrene in
mammary carcinoma cells using a uorescence ber-optic
nanosensor tip [19]. The tip was coated with antibodies and
sensing was based on the uorescence of a secondary antibody.
The sensor was used to detect concentration of benzo[a]pyrene
tetrol (BPT), a metabolite of benzo[a]pyrene, within the cells
of two different cell lines, human mammary carcinoma and rat
liver epithelial cells. By plotting the increase in uorescence
from one concentration to the next, versus the concentration of
BPT, and tting the relationship with a straight line, one is able
to calibrate the sensor and obtain an unknown concentration by
observing the level of uorescence. This technique is useful for
cancer screening since carcinogens bind to DNA and form sub-
stances such as BPT. The detection limit was 6.4 1.7 E pM of
BPT.
Three cytokines related to chronic wound healing are
interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis
factor- (TNF-alpha) [69]. The surface of a ber-optic SPR
sensor was modied with antibodies specic to the cytokine
of interest, and detected these proteins with LOD of 1 ng/mL in
buffered saline solution and spiked cell culture medium (CCM).
3.3. DNA hybridisation
Kleinjung et al. detected DNA hybridization by a uorescent
multimode FOBS with 13-mer probe attached to the de-cladded
core [70]. The complementary strands were labeled and detected
when introduced to the sensor. The sensor was reported as capa-
ble of detecting concentrations as low as 3.2 attomoles (70 fM).
This sensors performance was selective as it distinguished
between matching sequences, single nucleotide mismatch, and
mismatch caused by additional deviations.
Zeng et al. examined the interfacial hybridization kinetics
of oligonucleotides immobilized onto silica using a uores-
cent FOBS [71]. Probe DNA dT20 was used as recognition
molecules, while target uorescein-labeled non-complementary
DNA (ncDNA) dT20 and uorescein-labeled dA20 were
detected. The target DNA concentrations were 5 nM0.1 M.
The kinetic response of the sensor was shown to follow second
order Langmuir model.
Molecular beacons (MB) are oligonucelotide probes that
become uorescent upon hybridization with target DNAor RNA
molecules [72]. Liu et al. immobilized MB on a uorescence
FOBSand examined the effects of ionic strength and target DNA
concentration on hybridization kinetics. It was found that the
limit of detection was 1.1 nMof DNA. The sensor showed selec-
tivity by distinguishing between 100 nM of ncDNA, 100 nM of
one-base mistmatch, and 100 nM of cDNA.
3.3.1. Pathogen detection via DNA
Aber optic uorescence biosensor was developed by Alma-
didy et al. to detect short sequences of oligonucleotides that
indicate the presence of E. coli microbial contamination [73].
This biosensor detectedgenomic targets fromE. coli at pMlevels
within minutes. First, oligonucleotide probes were immobilized
to silica surface via a silane reagent. Then, stepwise synthesis
of oligonucleotides by the -cyanoethyl-phosphoramidite pro-
tocol was performed on the surface. Experiments were done with
both fully complementary (cDNA) and non-complementary
(ncDNA) 20-mers, in addition to genomic DNAfromE.coli. The
cDNA and ncDNA were introduced at a concentration of about
1.7 nM, whereas genomic DNA was introduced at 1.7170 pM.
Fluorescent intercalating dye was used to detect hybridization.
Quantities as low as 100 fM provided signals at three times the
standard deviation levels. The bers were washed and regener-
ated using a 90
C water and 90% formamide solution in TE

buffer between samples.
Pilevar et al. detected Helicobacter pylori total RNA using
a uorescence TFOBS [74]. Probe oligonucleotides were
cross-linked to the tapered surface. IRD-41 is a near-infrared
uorophore excited by 785 nm light. Real-time hybridization
of IRD 41-labeled oligonucleotide at various concentrations to
the surface bound probes was performed. Light was launched at
785 nm, and the sensor used the evanescent wave at the tapered
region to excite the IRD41. Using 20-mers as probes, comple-
mentary oligonucleotides at lower than nM concentration were
detected. Sandwich assays were performed with Helicobacter
pylori total RNA to determine if the sensor can detect bacterial
cells using rRNA as the target, and it was found that this sensor
can detect H. pylori RNA in a sandwich assay at 25 pM.
4. Conclusions and future directions
In the past 20 years, the design of FOBS has evolved from
the use of simple de-cladded bers to tapered geometries with
surface modications. FOBS have been used for many biolog-
ical applications such as the detection of pathogens, medical
diagnosis based on protein or cell concentration, and real-time
detection of DNA hybridization.
In terms of detection principles, it appears that intensity-
based sensors have been used to a limited extent in the detection
of cells. However, for the protein and DNA detection, the use
of uorescence TFOBS have been widespread because ampli-
cation is often necessary to detect low levels of biomolecules
at UV and visible wavelengths. Perhaps due to the small size of
these molecules, intensity or absorption based sensors are not
sensitive enough. More recently, SPR has evolved to become
one of the most commonly used methods for protein characteri-
zation. SPR was originally used with a chip but there have been
a few successful studies combining SPR and optical bers. The
ng/mL sensitivity provided by SPR suits many clinical appli-
cations. While uorescence provides an attractive platform in
terms of selectivity, its sensitivity is surpassed by SPR. In addi-
tion, uorescence methods require multiple steps for sensor or
sample preparation.
As for applications, one possible area of growth is the use of
SPR or intensity-based FOBS for the detection of protein and
DNA. The DNA-based detection is increasingly being used for
pathogen detection, and most methods reported to date use uo-
rescent labeled DNA. Another area of growth is drug screening
using TFOBS by making chemical modication on the ber sur-
face. Because of recent concerns of security, there will likely to
be signicant development in the detection of bio-threat agents.
Detection of pathogens also remains important in maintaining a
safe environment and food supply. In addition, clinical applica-
tions of TFOBS will continue to ourish along the advancement
of medical diagnostics. After surveyingthe large number of stud-
ies on TFOBS, it appears that detection of cells using antibodies
as recognition molecules is lacking across all platforms, and this
is one important area that is likely to grow in the future.
There are many challenges in the development of FOBS. One
challenge is the high LOD faced by intensity-based TFOBS.
Thus far the most popular method to overcome this challenge is
to utilize uorescent labels to amplify the signal associated with
the presence of the target. However, the disadvantage of uo-
rescence is the limited lifetime of uorescent molecules and the
need to prepare a second labeled target or antibody for detec-
tion. SPR is an attractive method because it does not require
any labeling. As a result, there has been a shift in protein and
increasingly DNA detection to using SPR; however, some dis-
advantages of SPR include its large size and high cost. The
development of ber optic-based SPR should alleviate some of
these problems provided that the high sensitivity is retained. One
area of TFOBS which has been investigated to a limited extent
is the use of longer wavelengths. The use of longer wavelengths
has been used with some success in chemical sensing, but has
not caught on in biosensing because of the challenges associated
with water absorption at long wavelengths. If long wavelengths
are to be used in TFOBS, it is necessary to functionalize the
surface of the TFOBS so that water is excluded, or detection
is carried out at a wavelength where absorption of water is
minimal.
As FOBS evolves, new effort will be focused on enhancing
the sensitivity and selectivity. It appears that methods based on
SPR and uorescence have reached a plateau in terms of detec-
tion limit, and one possible future direction is to combine the two
methods so that the SPR signal is enhanced. Improved surface
chemical modication and stability of the recognition molecule
can also increase the sensitivity and robustness of TFOBS, espe-
cially for intensity-based TFOBS because it is the most sensitive
when molecules are bound to its surface. As was shown in this
review, there is a solid foundation of work to support the use of
TFOBS in a wide variety of applications. Given its promising
advantages, it is likely that TFOBS will remain a popular choice
among researchers and practitioners for detection of biological
agents.
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Biographies
Angela Leung received her BASc in Biomedical Engi-
neering from University of Toronto in 2003. She
is currently a nal year doctoral student in Drexel
University, where she is anticipating a PhDin Chemical
and Biological Engineering in June 2007. Her research
area is in biosensors, particularly low concentration
protein and DNA detection and design and fabrication
of tapered ber optic sensors and devices. Her interest
also includes development of validation methods for
bioprocesses and biomedical devices.
P.M. Shankar received his M.Sc (1972) in Physics
from Kerala University, India, M.Tech (1975) in
Applied Optics and PhD in Electrical Engineering
(1980) from Indian Institute of Technology, Delhi,
India. He was a visiting scholar at the School of Electri-
cal Engineering, University of Sydney, Australia, from
1981 to 1982. He joined Drexel University in 1982 and
is currently the Allen Rothwarf Professor and Interim
Department Headof Electrical andComputer Engineer-
ing. He is the author of the textbook Introduction to
Wireless Systems, published by John Wiley & Sons,
2002. His research interests are in Wireless communications, Fiber sensors,
Biosensors, and Statistical signal processing for medical applications.
Raj Mutharasan received his BS degree (1969) in
Chemical Engineering from IIT Madras (India) and
a PhD (1973) in Chemical Engineering from Drexel
University. He joined the faculty ranks at Drexel Uni-
versity in 1974 after a post doctoral year at University
of Toronto, Canada. He was appointed to the position
of Frank A. Fletcher Professor of Chemical and Bio-
logical Engineering in 1995. His research interests are
in biophysics, biophotonics and cantilever for sensor
development, and process biotechnology. He has pub-
lished extensively and is the author of several patents.
He is a Fellow of American Institute of Chemical Engineers and American
Institute for Medical and Biological Engineering.

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