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J. Biophotonics 1–19 (2012) / DOI 10.1002/jbio.201200015

Journal of

BIOPHOTONICS

REVIEW ARTICLE
Surface plasmon resonance based biosensor technique:
A review
Xiaowei Guo*; 1; 2
1
School of Electrical Engineering and Computer Science, and College of Engineering, Seoul National University, 599 Gwanangno,
Gwanak-gu, Seoul 151-744, South Korea
2
School of Optoelectronic and Information, University of Electronic Science and Technology, Chengdu, China, No. 4 sect. 2,
North Jianshe road, Chengdu, 610054 China

Received 4 February 2012, revised 10 March 2012, accepted 11 March 2012

Published online 2 April 2012

Key words: Optical biosensor, surface plasmon resonance, microfluidics, optical fiber, nanoparticles

Optical Surface plasmon resonance (SPR) biosensors re-

present the most advanced and developed optical label-
free biosensor technology. Optical SPR biosensors are a
powerful detection and analysis tool that has vast appli-
cations in environmental protection, biotechnology, med-
ical diagnostics, drug screening, food safety and security.
This article reviews the recent development of SPR bio-
sensor techniques, including bulk SPR and localized
SPR (LSPR) biosensors, for detecting interactions be-
tween an analyte of interest in solution and a biomole-
cular recognition. The concepts of bulk and localized
SPs and the working principles of both sensing techni- SPR biosensing principle: the analyte of interest is de-
ques are introduced. Major sensing advances on biore- tected by measuring the change of the refractive index
cognition elements, measurement formats, and sensing in the target solution.
platforms are presented. Finally, the discussions on both
biosensor techniques as well as comparison of both SPR
sensing techniques are made.

1. Introduction ment has been a fascinating and fast-paced area

because they are immune to electromagnetic inter-
A biosensor is an analytical device for the analysis ference, capable of performing remote sensing, and
of biomaterial samples to gain an understanding of can provide multiplexed detection within a single de-
their bio-composition, structure and function by con- vice. Various optical sensing methods have been
verting a biological response into an electrical signal exploited in biosensors including chemiluminescence
[1]. It should basically consist of a transducer (elec- [5, 6], fluorescence [7], light absorption and scatter-
trochemical [2], piezoelectric [3], or optical [4]) and ing [8, 9], reflectance [10], and SPR [11], which can
a recognition element which captures a specific ana- be classified into two categories: label-based (the
lyte. In the past two decade, optical sensor develop- two formers) and label-free (the others). While

* e-mail: [email protected], Tel.: +82-02-3285-1738, Fax: +82-02-885-4459

# 2012 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

 Journal of

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2 X. Guo: Surface plasmon resonance based biosensor technique: A review

Figure 1 (online color at:

www.biophotonics-journal.org) A
SPR concept (a) and simulated
SPs (b).

label-based detection is extremely sensitive, with the tely trace the technique advances in SPR biosensors.
detection limit down to a single molecule [12], it suf- Finally we will provide the future scope of research
fers from laborious labeling processes that may also and development of optic SPR biosensors.
interfere with the function of a biomolecule. Quanti-
tative analysis is challenging due to the fluorescence
signal bias, as the number of fluorophores on each
molecule cannot be precisely controlled [13]. In con- 2. Bulk SPR and localized SPR
trast, label-free detection behaves in their natural
forms and relies on the measurement of binding-in- SPs were widely recognized in the field of surface
duced refractive index changes. As a result, this type science following the pioneering work of Ritchie in
of detection is relatively easy and cheap to perform, the 1950s [19]. SPs are coherent electron oscillations
and allows for quantitative and kinetic measurement that exist at the interface between any two materials
of molecular interactions. where the real part of the dielectric function changes
In this review, we will focus on optical SPR bio- sign across the interface, typically on a metal-dielec-
sensors because optical SPR biosensors have be- tric interface. These are essentially light waves that
come a central tool for molecular interactions and are trapped on the surface because of their interac-
provide a fast, specific and sensitive alternative to tion with the free electrons of the metal. In this in-
traditional laboratory analytical techniques. All the teraction, the free electrons respond collectively by
biosensors associated with SPR will be included in oscillating in resonance with the light wave. But the
the review. While presenting this review, we note electron oscillations decay exponentially into both
that there are several important reviews in the re- materials and the decay length is about wavelength
lated areas [14–18]. Homola presented bulk SPR order. The excitation of SPs by light is denoted as a
biosensors and summarized main application areas bulk SPR or SPR in terms of conventional usage for
in chemical and biological species [16]. Another re- planar surfaces (Figure 1) or LSPR for metallic na-
view concerns towards integrated SPR biosensors in noparticles (Figure 2) or metallic nanostructures,
which fiber and waveguide SPR biosensors are men- which are of interest to a wide spectrum of scientists,
tioned [17]. The LSPR biosensors were reviewed by ranging from physicists, chemists and materials scien-
Haes [18]. However, a comprehensive review for op- tists to biologists [20, 21]. For researchers in the field
tical SPR sensors is absent. On the other side, recent of chemistry and biology, one of the most attractive
advances in SPR biosensors need replenishments. aspects of SPs is the way in which these oscillations
Also, this review emphasizes on the sensing techni- are very sensitive to any change of this boundary
ques rather than applications. The purpose of the and therefore can be used as a sensing method for
present review tries to give out a clear understand- detection of external medium.
ing of SPR biosensor techniques. In bulk SPR case, the interaction between the
To this end, we will start out from bulk and loca- surface charge density and the electromagnetic field
lized SPR concept, and then sensing principle. Based results in the momentum of the SP mode, kSP, being
on the sensing principle, we will briefly but comple- greater than that of a free-space photon of the same

Figure 2 (online color at:

www.biophotonics-journal.org) A
LSPR concept (a) and simulated
LSPs (b).

# 2012 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.biophotonics-journal.org

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J. Biophotonics (2012) 3

Figure 4 (online color at: www.biophotonics-journal.org)

Excitation of SPs based on (a) a prism and (b) a grating
coupler.
Figure 3 Dispersive curves for light in vacuum and SPs.
with a frequency. For noble spherical nanoparticles,
frequency, k0, as shown in Figure 3. There are two e.g. Au or Ag, with diameters less than 30 nm,
main techniques by which the missing momentum mainly dipole plasmon resonance is involved; how-
can be provided. One is utilizing prism coupler to ever, for larger particles, quadrupole plasmon reso-
enhance the momentum of the incident light [22]. nance from two negatively charged poles and two
This method is referred to as the attenuated total re- positively charged poles may be observed. The mag-
flection (ATR) method (Figure 4a). From ray optics nitude, peak wavelength and spectral bandwidth of
viewpoint, use of waveguide or fiber structure to ex- the plasmon resonance associated with a nanoparti-
cite SPs is also based on the ATR method [23]. The cle are dependent on the particle’s size, shape, and
dispersive relation of SPs can be expressed as below material composition, as well as its local dielectric
environment.
kSP ¼ nk0 sin q ð1Þ
with n is the refractive index in incidence medium
and q is the incidence angle.
The other is based on a periodic corrugation in 3. Bulk SPR biosensors
the metallic surface, typically metallic grating (Fig-
ure 4b) [24]. For one dimension grating, the disper- Figure 5 shows the basic principle of an affinity SPR
sive relation of SPs can be written as biosensor [15]. Biomolecular recognition elements on
kSP ¼ kx  mG ð2Þ the surface of metal recognize and capture analyte
present in a liquid sample producing a local increase
where kx is the wave vector along the grating plane in the refractive index at the metal surface. The re-
and its value is nk0 sin q, G is the reciprocal lattice fractive index increase gives rise to an increase in the
vectors and m is integer. G equals to 2p/L and L is propagation constant of SPs propagating along the
the pitch. metal surface which can be accurately measured by
In LSPR case, the light scatters from a topologi- different optical means, such as intensity modulation,
cal defect on the surface, such as a metallic nano- angular modulation, wavelength modulation, phase
structures or nanoparticles, which provides a conveni- modulation, and even polarization modulation. The
ent way to generate LSPs [25]. Light interacts with excitation of SPs at metal-dielectric interface results
metallic particles or nanostructures much smaller in the transfer of energy from incident photons to
than the incident wavelength, which leads to a plas- SPs. If the normalized reflection intensity is measured
mon that oscillates locally around the nanoparticle as a function of incident angle or wavelength by

Figure 5 SPR biosensing princi-

ple. Biomolecular recognition ele-
ments on the surface of metal (a)
recognize and capture analyte
present in a liquid sample (b) pro-
ducing a local increase in the re-
fractive index at the metal sur-
face. The refractive index increase
induces a SPR signal shift (c).

www.biophotonics-journal.org # 2012 by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

 Journal of

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4 X. Guo: Surface plasmon resonance based biosensor technique: A review

keeping other parameters unchanged, then a sharp accessible functional groups of exposed amino acids
dip is observed at resonance angle or wavelength. For e.g., lysine (amine group), cysteine (thiol group),
sensor applications, the refractive index change of a with suitable types of derivatized surfaces, e.g. car-
thin layer in contact with the metal surface of the sen- boxylic acid, aldehyde, maleimide, vinyl sulfone [34,
sor is monitored by measuring the spectral shift of 35]. However, chemical binding via side chains of
the resonance dip (Figure 5c). amino acids is often random, since it is based upon
The first suggestion of SPR for biosensor purposes residues typically present on the exterior of the pro-
was 1983 [27]. Liedberg et al. demonstrated the poten- tein. In order to ensure that all the biomolecules are
tial of SPR based on prism coupler for immunology. In oriented in such a way that their binding sites are
their experiments, a He-Ne laser was used for probe exposed to the sample solution, uniform alignment
light and detected by a simple recorder. The antigen onto the surface should be achieved. Different site-
or antibody has simply been adsorbed to the metal sur- specific immobilization techniques, e.g., Diels-Alder
face prior to measurement. For example, Human IgG cycloaddition [36], “click” chemistry [37], peptide li-
was adsorbed to the metal surface and then the solu- gation [38], have therefore been presented in recent
tion of anti-IgG was injected into the cell. Anti-IgG years. Another approach for site specific immobiliza-
binding to IgG resulted in a 0.3 shift of the resonance tion is based on biochemical affinity reaction, e.g.
angle. Since that, SPR biosensors have made vast ad- biotin-avidin/streptavidin reaction [39], histidine-che-
vances in terms of both development of the technol- lated metal ion interaction [40] or DNA hybridiza-
ogy and its applications [14–16, 28, 29]. A large num- tion [41]. This approach provides not only oriented
ber of papers have been published using SPR for and homogeneous attachment, but possible to de-
various analytical studies in such areas environmental tach proteins and make repeated use of the same
protection, biotechnology, medical diagnostics, drug surface.
screening, food safety and security. A detailed sum- Peptides are short polymers of amino acid mono-
marization of the applications is given in Homola’s mers linked by peptide bonds. In comparison with
2008 review [16]. The following section is dedicated to antibodies, peptides have been less used. In SPR
the technique advances in SPR biosensors. biosensors, peptides have been applied mainly for
the study of protein structure and function, e.g., anti-
bodies against hepatitis G, herpes simplex virus, and
Epstein-Barr virus [42–44]. They also were used for
3.1 Advances in biorecognition elements the detection of heavy metals and small ligand [45,
46]. Immobilization of peptides can follow strategies
Various types of biorecognition elements and immo- similar to those developed for proteins, including
bilization methods are available to allow biosensor electrostatic attraction and amine- or thiol-based
platforms to be tailored for specific detection, mainly covalent coupling [45]. Small molecules with func-
including antibodies, peptides and aptamers [30]. tional groups (aliphatic amines, thiols, aldehydes, or
Antibodies are large Y-shaped proteins used by carboxylic groups) can be covalently linked to suit-
the immune system to identify and neutralize foreign able corresponding groups on the sensor surface.
objects such as bacteria and viruses. Antibody recog- Small molecules without suitable functional groups
nition elements make use of the sensitivity and spe- need to be derivatized [46]. Very recently, one step
cificity of bimolecular antibody-antigen interactions. immobilization of peptides and proteins was re-
The major advantage of antibody sensor biorecogni- ported through the covalent bonding of the formyl
tion elements is that the immunogen need not be group with the primary amine groups of peptides
purified prior to detection. Besides conventional and proteins [47].
polyclonal and monoclonal antibodies, recombinant The newly used one is aptamers. Aptamers
antibodies consisting of genetically manipulated are nucleic acid ligands (RNA, ssDNA, modified
fused antigen binding domains of common antibo- ssDNA, or modified RNA) that are isolated from li-
dies are another source for biosensor [31]. A num- braries of oligonucleotides by an in vitro selection
ber of recombinant antibodies have been shown to process called SELEX (Systematic Evolution of Li-
be useful for detection and identification of HIV, gands by Exponential enrichment) [48]. Since they
Hepatitis B and C, Simian immunodeficiency, Ebola, are short, single-stranded oligonucleotides, they are
Rabies, Epstein–Barr, and Measles viruses as well as capable of folding into three-dimensional structures
biological agents such as botulinum neurotoxin A/B due to their self-annealing properties. Although ap-
[32, 33]. The early immobilization of protein on the tamers have been long applied as molecular recogni-
gold surface is mainly via physical adsorption or tion probes for a variety of sensor techniques such
electrostatic interactions, which may undergo confor- as electrochemical [49], piezoelectric [50], and opti-
mational changes or adsorb with weak attachment cal sensors [51], SPR biosensors was rarely reported
[27]. The stable immobilization of proteins is via a to use aptamers until 2001 [52]. This is due to the
covalent bond formed on the sensor surface through fact that the change in SPR signal resulting from the

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J. Biophotonics (2012) 5

binding process of aptamer with its target molecules 3.2 Advances in measurement formats
is not very large. In recent years, aptamers are pro-
posed as alternatives to antibodies as biorecognition
elements in analytical devices with ever increasing Various measurement formats have been developed
frequency. Aptamers have been produced against a in SPR biosensor to ensure that the monitored bind-
wide range of targets including drugs, proteins, and ing event produces a measurable sensor response
even supramolecular complexes such as viruses or [68]. The most frequently used measurement formats
bacteria [53–56]. The immobilization of aptamers are direct detection [69, 70], sandwich [71, 72], and
(oligonucleotides) is often based on chemical bond- competitive inhibition assay [73, 74].
ing of the thiol group on gold surface. The most Direct detection is usually preferred in applica-
straightforward approach is to use biotinylated deri- tions where direct binding of analyte of concentra-
vatives. The biotinylated aptamer is immobilized on tions of interest produces a sufficient response. In di-
the avidin or streptavidin layer through biotin-strep- rect detection format, analyte in a sample interacts
tavidin interaction. with a biomolecular recognition element immobi-
The ideal recognition surface should provide lized on the sensor surface. The resulting refractive
abundant immobilization sites and maintain the activ- index change is directly proportional to the concen-
ity of the recognition element without initiating non- tration of analyte. The lowest detection limits of the
specific interactions with other elements of the analy- direct SPR biosensors can be improved by using
tical media. There are lots of strategies for the sandwich assay and inhibit assay. In the sandwich as-
construction of highly effective recognition surface say format the measurement consists of two steps.
[57]. To maximize the density of active surface groups, Firstly, sample containing analyte is brought in con-
the technique of self-assembled monolayers (SAM), a tact with the sensor and the analyte molecules bind
kind of ordered molecular assemblies of different or- to the antibodies on the sensor surface. Then the
ganic materials, was used to separate the immobilized sensor surface is incubated with a solution contain-
molecules with a minimal distance [58]. For instance, ing “secondary” antibodies. The secondary antibo-
SAM of thiols group is an effective chemical treat- dies bind to the previously captured analyte further
ment to obtain highly ordered packed layer on the increasing the number of bound biomolecules and
gold surface although the main drawback is nonspeci- thus also the sensor response. However, the detec-
fic protein adsorption [59]. The use of this DNA tion and quantification of low-molecular-weight ana-
SAM was expected to realize efficient hybridization lytes in the two formats is powerless. Competitive as-
because the ds portion can generate a space for hybri- say provides potential to detect smaller molecules.
dization and this method is expected to immobilize In this detection format, a sample is initially mixed
the probe portion on a substrate without DNA dena- with respective antibodies and then the mixture is
turation [60]. To reduce nonspecific absorption, poly/ brought in contact with the sensor surface coated
oligo (ethylene glycol) (PEG)-modified and peptide- with analyte molecules. The concentration of the
based self-assembled monolayers have been devel- antibody is kept constant so that the response varia-
oped. Ploy (carboxybetaine methacrylate) was also tions are proportional to the amount of the analyte
proven to be highly resistant to nonspecific absorp- mixed with the antibody. An increase in the reso-
tion [61]. Peptide-based SAMs with complex biologi- nance angle occurs when the antibody binds with the
cal media such as cell lysate and crude serum seems conjugate immobilized on the surface. However,
to be a powerful tool to minimize nonspecific absorp- when an equilibrium mixture of antibody and ana-
tion [62, 63], decreasing nonspecific adsorption to lyte is allowed to flow over the conjugate, only the
nearly 20–40 ng cm2, in contrast to commonly used unbound antibody in the equilibrium mixture can be
PEG, which typically adsorbed 100 ng cm2 of pro- available for binding to the conjugate surface, and
teins. Another most commonly used method is to hence, a decrease in the resonance angle is observed.
block the exposed surface with bovine serum albumin The measured binding response is, therefore, inver-
(BSA) [64, 65]. To provide more binding sites for cap- sely proportional to the concentration of analyte in
ture molecules, three-dimensional matrices have been solution.
developed. The most widely used is carboxymethy- All the measurement efforts lead to a very lim-
lated dextran provided by BioCore company in 1990 ited change in SPR response. To increase the magni-
[66]. Agarose and aldehyde-agarose have been deri- tude of the response, a second specifically interacting
vatized with primary amino groups and poly- (ethyle- biomolecule is introduced as external label. Often
nimine) to improve immobilization performances this second molecule carries a high molecular weight
[67]. Hydrogels have the ability to hold water within or high refractive index tag. Consequently, a much
the porous spaces available among the polymeric larger change in SPR reflectivity can be observed.
chains through which the capture molecules can dif- Liposomes [75], latex particles [76, 77], and certain
fuse, showing a 100-fold superior capacity of immobi- proteins [78] have been tested as amplification tags.
lization compared to that of planar surfaces [57]. Following the idea, several kinds of metallic nano-

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 Journal of

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6 X. Guo: Surface plasmon resonance based biosensor technique: A review

cation effect of aptamer-Au NPs conjugates by using

human immunoglobulin E as model analyte with a
lowest LOD of 1 ng mL1 [96]. In 2011, Gilad et al.
created a multifunctional AuNPs which was functio-
nalized with thiolated nucleic acid hairpin and imple-
mented fM detection of DNA, adenosine monopho-
sphate, and Hg2þ ions [97].
Recently, magnetic nanoparticle (MNP) labels
have been also employed in SPR biosensorsto in-
Figure 6 (online color at: www.biophotonics-journal.org) crease the binding-induced refractive index changes
Gold nanoparticles to push the delect limit. Reprinted with [98] and quick preconcentration and purification of
permission from (95). Copyright (2007) American Chemi- target analytes in complex samples [99]. In 2010,
cal Society. Wang et al. presented an amplification technique
using MNPs as external tags for an enhanced SPR
bioassay [98]. Subsequently, Knoll group reported a
particles (NPs) including Au NPs, [79–83] Pd NPs, SPR biosensor technology combining with use of ex-
[84] and Pt NPs [85] had been applied to increase ternal magnet to immobilize MNPs for detection and
the SPR sensitivity for detecting all kinds of biomo- manipulating molecular analytes on the sensor sur-
lecules, for example, the formation of antigen-anti- face [99]. The MNPs conjugated with antibodies spe-
body complexes, [86] DNA hybridization, [87] for- cific to different analyte epitopes served both as la-
mation of aptamer-substrate complexes, [88] or bels for enhancing refractive index changes and as
enzymatic transformations [89]. Among them, Au “vehicles” for the rapid delivery of analyte from a
NPs are most investigated in SPR biosensor due to sample solution to the sensor surface. A lowest
its noble property which supports LSPR on particle LOD of 0.45 pM was achieved.
surfaces. The strong coupling between the localized
NP SPs and bulk SPs on the Au substrate results in a
high sensitivity (Figure 6). Pollard-Knight et al. used
30 nm diameter colloidal Au nanoparticles in an im- 3.3 Advances in sensing platforms
munoassay to demonstrate the concept of this ampli-
fication technique [90]. Natan group has developed To increase the availability of analytes at a sensor’s
an Au-amplified SPR sandwich immunoassay and surface, SPR transducer is often used in conjunction
achieved a pM detection of human immunoglobulin with microfluidic flow channels, which allows use of
G [91], and conducted systematic studies of the effect small volumes of expensive reagents [100–102]. The
of particle size and surface coverage on SPR response typical progresses in sensing platforms were towards
[92, 93]. He et al. demonstrated that use of the Au improvement of the sensor performance and multi-
NP tags leads to a greater than 10-fold increase in an- ple analyte analysis.
gle shift in analysis of DNA hybridization, corre- High sensitivity and resolution can be obtained
sponding to a more than 1000-fold improvement in by increasing the fraction of SPs in solution or the
sensitivity for the target oligonucleotide as compared intensity of SPs at the sensor surface (Figure 7). For
to the unamplified binding event [94]. In 2007, Wark a thin metallic film sandwiched by two dielectric
et al. developed an ultrasensitive surface bioaffinity layers with a similar refractive index, there are two
sensors for DNA hybridization by the adsorption of surface plasmon modes called long-range surface
Au NPs onto gold diffraction gratings [95]. A limit of plasmon (LRSP) and short-range surface plasmon
detect (LOD) 10 fM for DNA hybridization was ob- (SRSP), which are bound to both metal-dielectric in-
tained. In 2009, Wang et al. demonstrated the amplifi- terfaces [103]. The electric and magnetic fields of an

Figure 7 LRSP and Conventional

SP. Reprinted with permission
from (106). Copyright 2009, Else-
vier.

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J. Biophotonics (2012) 7

LRSP are nearly perpendicular to the wave’s direc- fracted light. A refractive index resolution of this
tion of propagation with lateral confinement on the sensor was established at 3.5  107 RIU. In 2008,
order of several wavelengths. Because of these char- Guo et al. presented an SPR biosensor using both
acteristics, LRSPs can propagate the farthest of all LRSP and SRSP excited simultaneously on a prism
known metallic modes, for instance, centimeter dis- coupler with different angles [116]. This approach of-
tances at infrared wavelengths and millimeters at fers ability to distinguish sensor response caused by
visible wavelengths, making it suitable for large tar- bulk and surface refractive index changes.
get molecules. The use of LRSPs was first proposed Many sensitive SPR biosensors are being pre-
for sensing in 1990 by Matsubara et al. [104]. The sented but most of them only can detect one analyte.
use of LRSPs was shown to significantly improve For practical applications, there is an urgent need
both the sensor sensitivity and resolution. Nenninger for the development of SPR biosensors capable of
et al. demonstrated an teflon-based LSPR biosensor multi-analyte detection. SPR sensors based on multi-
capable of resolving refractive index changes as channel structures could provide a method for de-
small as 3  107 RIU [105]. In 2007, Slavik et al. de- tecting multiple analytes simultaneously. In 1991,
monstrated an even better RI resolution of 3108 Sjolander et al. presented an integrated fluid flow
RIU [106]. In 2011, Knoll group used LPSR-en- system with three sensing channels on the surface of
hanced fluorescence spectroscopy for the detection of a glass prism [117]. A divergent beam produced by
E. coli O157 : H7 [107]. The LOD below 10 cfu mL1 the LED was collimated and focused to produce a
was achieved. Generally, a silver film with a sharp wedge-shaped beam of light hitting the glass-gold in-
SPR curve may yield a higher imaging sensitivity terface, which enables the use of multichannel moni-
than a gold film since silver has a lower absorption toring. The reflected beams of light from the prism
of light [108]. However, the sensitivity of the SPR are collimated and projected onto the photodetector
biosensor has a potential limitation, because silver is array. By immobilizing different sample amounts in
highly susceptible to oxidation. To prevent the oxi- different flowing channel, it is therefore possible to
dation of the sliver film, Choi et al. used garphene create multiple-step ‘gradient’ surface and thus make
sheet on the sliver film [109] since the successful iso- it easy for detection of low-molecular-weight ana-
lation of single atomic planes of graphite [110]. In lytes and for characterization of weak interactions
particular, the graphene sheet is impermeable to [118]. The number of channels was later extended to
gases as small as He atom [111]. This is attributed to 6 [119] and 10 [120]. An alternative way is to use
the fact that the electron density of hexagonal rings multiple light beams irradiating parallel channels
is substantial enough to prevent atoms and mole- and the reflected signal is analyzed by multiple spec-
cules from passing through the ring structure [112]. trographs [121]. There were two interesting parallel
The recent numerical study by Wu et al. demon- architectures with wavelength modulation. One is to
strated that a graphene-on-gold SPR biosensor can deposit a dielectric overlayer over a part of the SPR-
be more sensitive than the conventional gold film- active surface [122]. The addition of the thin dielec-
based biosensors, due to the increased adsorption of tric film shifts the coupling wavelength to a longer
target biomolecules on graphene [113]. Furthermore, wavelength, the reflected light exhibits two dips as-
use of spectroscopy of multiple SPs contributes to sociated with the excitation of surface plasmons in
the improvement of the detection sensitivity. In the area with and without the overlayer. The other
2006, Homola group reported an SPR sensor based approach is to use a special prism coupler with a
on a special metallic grating with a profile composed tilted top surface [123]. The top surface reflects the
of multiple harmonics [114]. A polychromatic light incidence light onto different areas of the sensing
beam was made incident onto the grating, and the surface at different angles of incidence. The surface
reflected light contained multiple SPR dips, one for plasmons on different regions are excited with differ-
each grating period. The use of multiple surface plas- ent wavelengths which yielded an eight-channel SPR
mons of different field profiles can provide more de- sensor with a resolution around 1  106 RIU. Multi-
tailed information about the refractive index distri- channel sensors have been also realized using dif-
bution at the sensor surface. It is also suggested to fraction grating couplers [124]. In 2007, Jin et al.
use a polychromatic light incident on a special dif- used a mirror as a light relay element and realized
fraction grating acting as a SPR coupler and disper- two fluidic grating channels for biomolecule binding
ser (SPRCD) [115]. SPs was excited by the second [125]. In 2009, Partrik et al. reported a compact mul-
order of diffraction. Simultaneously, the light dif- tichannel biosensor based on SPRCD diffraction
fracted into the first diffraction order was dispersed grating-coupled SPR [126]. This approach provided
and the light components of different wavelengths potential to handle six independent sensing channels
were directed to different areas of a detector. The with temperature stabilization. A refractive index as
coupling of light into a surface plasmon resulted in a low as 2  107 RIU was demonstrated to detect the
drop in the intensity of diffracted light, which was binding of antibodies to the antigen-coated sensor
observed as a narrow dip in the spectrum of dif- surface. Zhang et al. also described a similar sensor

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8 X. Guo: Surface plasmon resonance based biosensor technique: A review

method is used to detect ssDNA down to a con-

centration of 1 fM [147]. Campbell’s group demon-
strated some applications of the method for absolute
quantitative measurements to time- and spatially-re-
solved measurements of absolute coverages during
protein binding onto gold and onto dsDNA microar-
rays on gold [148–150]. With a He––Ne laser as a
source of light, their sensor was able to measure si-
multaneously in 120 sensing channels with a refrac-
tive index resolution of 210-5 RIU. In 2007, they
improved the sensor resolution down to 5  106
RIU [151].
A lot of efforts have been devoted to the im-
provement of the SPRI sensing platform. Employing
Figure 8 (online color at: www.biophotonics-journal.org) a highly coherent He––Ne laser as a source of illumi-
A SPRI biosensor. nation easily results in parasitic interference patterns
that were disturbing SPR measurements, an incoher-
chip with grating micro channels. Use of scanning ent light source with a NIR narrow band-pass filter
method enables the SPR sensing with more channels was introduced [152]. Being highly sensitive, SPRI
[127]. technique was affected by possible shape changes of
The multichannel analysis described above is not the resonance which can be caused by unexpected
suitable for high throughput detection. The SPR modification of the surface roughness or by light ab-
imaging (SPRI) technique is so far the most promis- sorbance. The diffracted or scattered light from the
ing tool for high throughput detection [128]. The neighboring area around a sensing spot can also in-
typical SPRI sensor is based on prism coupling (Fig- terfere with the radiation reflected from this spot. In
ure 8), in which monochromatic incident light is ex- 2005, Zybin et al. presented a dual-wavelength SPR
panded, passes through a prism and strikes the inter- imaging system [153]. The sensor output was defined
face of the thin film and a prism at the coupling as the difference of these two signals corresponding
angle, exciting a broad area of the sensing surface. to two different wavelengths. A refractive index re-
The reflected light is imaged on a CCD camera. Si- solution of 2  106 RIU was achieved. Wavelength-
milar to the microarray technique, in SPRI the sen- tunable SPRI biosensors were reported by Nelson
sing chip is divided into many small sensing spots for [154] and Fu [155]. Grating-based SPRI sensors have
detecting different analytes. Corn’s group has been also been attracted many attentions because of their
very active in the development and characterization compatibility with mass production [156–158]. In
of SPRI technique. They not only provided a wide 2001 Brockman et al. presented an SPRI grating de-
variety of robust surface chemistries to link biologi- vice with an array of 400 sensing channels was pre-
cal molecules (DNA, proteins, peptides, carbohy- pared on the chip by means of spatially resolved fic-
drates, RNA, etc.) to gold surfaces, and methods to tionalization. In 2005, Homola’s group used scanning
deposit these in array formats appropriate for high- method to obtain simultaneous measurements in
throughput applications using SPRI [129–135], but over 200 sensing channels with a refractive index re-
also demonstrated the application of DNA microar- solution of 5  106 RIU [157]. In 2008, they re-
rays for SPRI-based detection of oligonucleotides ported a two-dimensional SPRI sensor based on an
[136] and ribosomal RNA [137], for monitoring the array of metallic diffraction gratings. Each diffrac-
induced formation of hairpin structures [138], for tion grating on a sensor chip serves both as an SPR
studying the specific binding of two response regula- coupler and a sensing channel. Parallel measure-
tors proteins to DNA [139], and the application of ments with high-refractive index resolution of
array-based detection with SPRI to quantitatively 5  107 RIU was achieved in 120 sensing channels
monitor carbohydrate-protein, peptide-protein, and [158]. Another research effort in SPRI is phase-sen-
protein–protein interactions, as well as surface en- sitive SPR sensing, because the resonant phase beha-
zyme kinetics [140–146]. It is highlighted that the vior exhibits a steep jump, which leads to the poten-
enzyme chemistry enables SPRI technique to be an tial in achieving extremely high sensitivity [159, 160].
ultrasensitive platform. In 2011, they described a In the earlier technique, a Mach-Zehnder interfe-
method where the specific sequence-dependent ad- rometer with p-polarized as both signal and refer-
sorption of a target ssDNA template molecule onto ence beams was used. Measurement sensitivity as
an ssDNA-modified gold microarray is followed with good as 4  108 RIU was demonstrated with pure
the generation of multiple copies of ssRNA via in silver as the sensor surface [159]. In 2004, Wu. et al.
situ surface transcription by RNA polymerase. This presented a differential phase measurement techni-
RNA transcription-based dual element amplification que by using p polarization as signal light and s po-

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J. Biophotonics (2012) 9

larization as reference light, which eliminates com- struments make use of index matching oils between
mon-mode measurement fluctuations [161]. The SPR a prism and an exchangeable glass plate with metal
phase can be extracted by comparing the phase dif- films. Such instruments therefore tend to suffer from
ference between the interference signals of p polari- mechanical wear and require extensive optical main-
zation and s polarization. In 2007, their experimental tenance and technical service.
sensor resolution was 9.8  105 RIU [162]. Until One technical route to overcome this challenge is
now, SPR imaging in the phase domain has been based on integrating the light source, the prism and
mainly focused on analyzing the fringe pattern of in- detector array in one disposable SPR sensor system
terferograms [163, 164]. Spatial resolution over the [168–172]. For instance, a concept of the miniature
sensor surface is limited and this makes it difficult SPR sensor is based on integration of all electro and
to implement high-throughput microarray applica- optical components in a monolithic platform, Spree-
tions. Furthermore, phase detection is well known ta 2000 SPR sensor, developed by Texas Instruments
to be extremely sensitive to environmental vibration. in the mid-1990s [168]. Thirstrup et al. integrated the
Some of recent efforts focus on improvement of in- traditional prism and focusing optics in an injection
terrogation ability of SPRI instruments. To improve moulded SPR sensor chip by means of diffractive
the addressability of individual spots, Luo et al. in optical coupling elements [173]. As an alternative,
2008 designed two dimensional crossed-flow archi- integrated SPR waveguide biosensors have been also
tecture with dedicated valves for each channel inter- investigated [174]. In 2001, Homola’s group demon-
section to prevent cross-talk between horizontal or strated that the SPR waveguide sensor was capable
vertical channels [165]. While this approach added of measuring bulk refractive index changes smaller
an additional level of control, entire microchannels than 1.2  106 [175]. It consists of a channel wave-
were still exposed to the same analyte stream, limit- guide locally covered with a metallic layer structure
ing the number of interaction conditions. In 2010, supporting surface plasmons. Light propagates
Ouellet et al. developed an integrated microfluidic through the waveguide and excites surface plasmons
array for high-throughput SPRI-based detection and in the multilayer structure. In conjunction with speci-
determination of binding affinities of antibodies fic bimolecular recognition elements, monoclonal
against protein targets [166]. The device consists of antibodies, the sensor was capable of detecting 2 ng
264 element-addressable chambers isolated by mi- of hCG present in 1 ml of 1% bovine serum albumin
crovalves. The use of element-addressable chambers solution. In 2004 another SPR waveguide biosensor
allows the interrogation of multiple ligand spots with the capability of bipolarization wavelength in-
through multiple analyte streams, the device features terrogation was presented [176]. In the conventional
a dilution network capable of simultaneous interro- SPR biosensors, only the transverse magnetic (TM)-
gation of up to six different analyte concentrations polarized light wave can couple with the surface
in a single experiment without the need for lengthy plasma wave. The proposed SPR biosensor can
surface regeneration, and controlled recovery of rare make both the TM- and the transverse electric (TE)-
samples is possible. Finally, the microfludic material polarized light wave to produce the SPR. Therefore,
on SPRI biosensors is being investigated. It is well two kinds of biomaterials can be separately detected
known that PDMS devices perform poorly with the by the signals from the TM- and the TE-polarized
introduction of organic solvents into the channels, modes, and the number of detectable materials in a
resulting in solvent leakage or swelling. An alterna- single chip can be doubled. Human serum albumin
tive material is necessary to develop organic-phase- is coated on the device to sense the concentration of
based microfluidic devices. In 2011, Sheppard et al. beta-blocker. Experimental results showed that the
presented Thiolene-based microfluidic devices have concentration of beta-blocker was related to the
been coupled with SPRI to provide an integrated SPR wavelength shift at a rate of 0.08 and 0.027 nm/
platform to study interfacial interactions in both aqu- ppm for the TM- and the TE-polarized modes, re-
eous and organic solutions [167]. spectively.
More convenient route is use of optical fiber as
biosensor element that is very useful for remote sens-
ing, point of care analysis and in situ monitoring.
4. Waveguide and fiber SPR biosensor The development of optical fiber sensor can be
dated back to the earlier 1990s. Jorgenson et al. re-
Most existing commercial SPR instruments rely on placed the traditional prism-based systems by a fiber
excitation of optical evanescent waves by prism-cou- optic design [177]. To generate SPs, they removed a
pling of various designs. The prism-based instru- segment of the cladding on a multimode fiber and
ments comprise several mechanical interfaces requir- coated a silver film around the exposed fiber core.
ing a rather delicate mechanical system. In addition, In the meantime, Maria et al. used a fiber tip to ex-
since it is not practical to replace the whole prism cite SPs for microprobe [178]. After that, many types
when exchanging sensor surfaces, most of these in- of optical fiber SPR sensors have been proposed in-

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10 X. Guo: Surface plasmon resonance based biosensor technique: A review

Figure 9 Side polished fiber SPR biosensor. Reprinted

with permission from (190). Copyright 2001, Elsevier. Figure 10 (online color at: www.biophotonics-journal.org)
TFBG SPR biosensor. Reprinted with permission from
(200). Copyright (2011) American Chemical Society.
cluding side-polished or D-type [178–181], hetero-
core structure [182], tapered [183, 184], fiber grating a nonzero electric field in the cladding-sample inter-
[185–187], and metallic nanostructure or nanoparti- face. For example, long-period fiber gratings
cles [188, 189]. Nevertheless, most of them were re- (LPFGs) couple light from the core mode to a for-
ported for chemical sensing purposes. ward-propagating cladding mode [196]. Short-period
In 2001, R. Slavik et al. applied side-polished tilted fiber Bragg gratings (TFBGs) reflect the core
SPR fiber (Figure 9) for detection of IgG proteins field directly onto the cladding-sample interface
via respective monoclonal antibodies immobilized on through tilted grating surface [198], which is analo-
the SPR sensor surface [190]. The polished sensor gous to that in prism-based biosensors. By coating a
surface was functionalized with a double-layer of metal layer on the fiber claddings, it was shown that
anti-IgG molecules by glutaraldehyde. The depolar- it is possible to excite a particular cladding mode
ized light and spectral interrogation was used to whose effective index is perturbed by a plasmon re-
overcome the limit of adverse sensitivity to fiber de- sonance of a metal coating on the fiber under the
formations. The sensor was operated using a flow in- phase-matching conditions [199]. In 2006, Tang et al.
jection system and mild acid was used to regenerate presented a LPFG biosensor on which self-as-
the surface for replicate analyses, and the sensor has sembled gold colloids was coated [198]. The trans-
been proved to be able to measure refractive index mission spectra and optical properties of gold col-
variations as small as 5  107. In a continuation of loids change with the different refractive index of
this research, they used the same fiber optic SPR the environment near the surface of gold colloids.
sensor for the detection of staphylococcal enterotox- The sensor response of gold colloids increases line-
in B [191]. The SPR biosensor was demonstrated to arly with solvents of increasing refractive index.
be able to detect ng mL1 concentrations of SEB in When the colloidal gold surface was modified with a
less than 10 min. In 2009, Jang et al. combined the dinitrophenyl (DNP) compound, experimental re-
side-polished SPR fiber and the sandwich assay sults showed that the signal increase linearly with
mode for the detection of prostate specific antigen increasing concentration of the analyte, and the de-
[192]. The optical sensitivity of the SPR sensor was tection limit of the sensor for anti-DNP is 0.95 nM.
determined as 2.5  106 RIU. Pollet et al. used a In 2011, Y. Shevchenko et al. demonstrates that a
SPR fiber biosensor for measuring DNA hybridiza- TFBG-SPR sensor manufactured from an single
tion and DNA-protein interactions [193]. A fiber mode fiber can be used as a biosensor to detect a
with a diameter of 400 mm and a numerical aperture bimolecular target at varying concentrations from
of 0.39 allowed a specific incidence angle to excite 0.1 mM to 5 mM [200]. The TFBG biosensor is de-
SPs. A detection limit of 0.5 mM and 2 nM was ob- scribed in Figure 10. In their experiments, the throm-
served for DNA hybridization and DNA-protein as- bin aptamer immobilized on the surface of the sen-
says, respectively. sor is used as a recognition element for binding of
The methods mentioned above require total or the thrombin protein. There is a unique advantage
partial removal of the fiber cladding or tapering associated with the use of TFBG is the elimination
down the fiber to allow core guided light to escape of the effect of temperature cross-sensitivity from
into the cladding, which excites the surface plasmons the sensor readings.
at the fiber core-metal layer interface. Therefore,
one should carefully design and fabricate the SPR
biosensors. These problems have resulted in a rise in
cost. To overcome the disadvantages, fiber grating 5. Localized SPR biosensors
biosensors have been suggested [194–198, 200].
These fiber grating biosensors were realized by The sensing principle of the LSPR method is based
photo-writing a grating in fiber core which produces on the fact that the absorption and scattering spectra

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J. Biophotonics (2012) 11

of noble metal nanoparticles have a high sensitivity possible to distinguish perfectly complementary tar-
to the change of the nanoparticle shape [201, 202], get sequences from those that had single base pair
size [203, 204], interparticle distance [205], dielectric mismatches, detecting as small as 10 fmol of oligonu-
properties of the nanoparticle material [206], and cleotide. The DNA duplex melting characteristics
the dielectric properties of the surrounding medium were further exploited by Nam et al. to distinguish
[207–210]. Therefore, there are many tricks used for antibody targets [213]. Specific oligonucleotide se-
determining a sample concentration. quences were encoded onto the gold nanoparticles,
Gold and silver colloids display strong colors as a and a complementary oligonucleotide modified with
result of the plasmon absorption. This absorption is a biomolecule target binding partner was prehybri-
dependent on colloid-colloid proximity, which can be dized to the nanoparticle-bound sequence. Upon in-
monitored by using UV-Vis spectroscopy. In 1996, troduction of the appropriate biomolecule target, the
Mirkin et al. made use of this simple concept to Au nanoparticles aggregate and a color change is
demonstrate DNA-directed assembly of colloidal seen. With judicious choice of the complementary
gold as shown in Figure 11 [211]. In this work, two oligonucleotide sequences, it was possible to control
separate batches of 13nm-diameter gold nanoparti- the melting behavior of the aggregated nanoparti-
cles were labeled with noncomplementary single- cles. Sequences with greater cytosine/guanine con-
stranded thiol-capped DNA 8-mers. Upon adding a tent have higher melting transitions. Accordingly,
DNA duplex with eight base-pair-long ‘sticky ends’ after a color change demonstrated that a biomole-
that were complementary to each of the two pre- cule target was detected, a melting analysis revealed
pared DNA/Au conjugates, colloidal assembly oc- which target was detected. In 2001, the simple col-
curred, and the solution color changed as the nano- orimetric technique was described for the detection
particle electromagnetic coupling character of small concentrations of aqueous heavy metal ions,
increased. This assembly was reversible; by increas- including toxic metals such as lead, cadmium, and
ing the solution temperature above the DNA melt- mercury [214]. Functionalized gold nanoparticles are
ing transition and then reducing it again, both the aggregated in solution in the presence of divalent
spectroscopic signal for DNA hybridization and that metal ions by an ion-templated chelation process;
for nanoparticle aggregation cycled to reveal colloi- this causes an easily measurable change in the ab-
dal disassembly and reassembly. In related work, El- sorption spectrum of the particles. The chelation/ag-
ghanian et al. demonstrated that the nanoparticle/ gregation process is reversible via addition of a
DNA/nanoparticle assembly time could be greatly strong metal ion chelator.
shortened if the mixture was either heated to 50  C Sensing based on scattering detections was re-
or frozen in dry ice and isopropyl alcohol [212]. ported in recent years [215–218]. In 2003, Roll et al.
Even though the complete dissociation of the DNA suggested the resonant Raleigh scattering detection
strands (melting) is somewhat slow, as molecular as- approach for solution phase molecules using the
sociations weaken before duplex disassembly occurs, light scattering properties of colloids with LED irra-
disassembly of the nanoparticle aggregate is quite diation [215]. In this work, colloid aggregation was
fast, leading to sharp melting transitions when mon- induced by avidin-biotin interactions, which shifted
itoring the LSPR. By considering both solution color the plasmon absorption to longer wavelengths. It
changes and melting transition characteristics, it was was found the spectral shift results in changes in the

Figure 11 DNA-based colloide Au

nanoparticle assembly (a) and
Absorbance versus temperature
profile for DNA/colloid hybri-
dized materials (b). Reprinted
with permission from (211). Copy-
right (1996) Nature Publishing
Group.

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 Journal of

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12 X. Guo: Surface plasmon resonance based biosensor technique: A review

scattering at different incident wavelengths. By meas-

uring the ratio of scattered intensities at two inci-
dent wavelengths, this measurement was made inde-
pendent of the total colloid concentration. The high
scattering efficiency of the colloids resulted in inten-
sities equivalent to fluorescence when normalized by
the optical density of the fluorophore and colloid. In
2007, Mie scattering was used for spectroscopic Figure 12 Biomolecular binding at the surface of the func-
study of the kinetic interaction between protein and tionalized gold monolayer results in a absorption shift in
gold nanoparticles [216]. The influence of the geo- peak wavelength. Reprinted with permission from (223).
metrical shape and size of the nanoparticles regard- Copyright (2002) American Chemical Society.
ing the binding of a protein was investigated. Spheri-
cal nanoparticles of 60 and 100 nm diameters as well
as ellipsoidal particles of dimension 20 by 60 nm for refractive index changes shown in Figure 12. These
the minor and major axes respectively have been nanoscale biosensors based on LSPR spectroscopy
used. The nanoparticles were mounted in a quartz operate in a manner totally analogous to their SPR
suprasil cuvette in a solution of millipore water. counterparts by transducing small changes in refrac-
Light was incident on the cuvette and scattering by tive index near the noble metal surface into a mea-
the particles was recorded by a monochromator. To surable wavelength shift response. In 2000, Okamoto
each of the nanoparticle samples protein human ser- et al. have demonstrated red-shifting of the LSPR
um albumin was added, and a series of spectra were band of gold nanoparticles immobilized on a glass
immediately recorded to observe the expected shift substrate when the gold nanoparticles are coated
in wavelength of the scattering maxima. By fitting with a dielectric layer several nanometers thick
the experimental data with theoretical predictions, [221]. Himmelhaus et al. reported a highly sensitive
the size of the nanoparticle and the distribution in biosensor using LSPR in cap-shaped gold nanoparti-
the sample, the shape, the influence of sedimentation cles immobilized on a dielectric substrate [222]. Nath
and the necessary kinetic parameters have been de- et al. have also reported affinity biosensor using a
termined. Two-photon Rayleigh scattering (TPRS) glass substrate covered with gold nanoparticles,
[217–220] was used by Adria et al. in 2009 for detec- by measuring transmission absorption spectra [223,
tion of tau protein which plays a vital role in occur- 224]. A solvent refractive index sensitivity of
rence of Alzheimer’s dementia in cerebrospinal fluid 76.4 nm RIU1 and a detection of 16 nM streptavi-
[217]. The TPRS approach is based on the fact that, din were achieved. Van Duyne group have exploited
the monoclonal ani-tau antibody-conjugated gold triangular silver nanoparticles based sensing techni-
nanoparticles can readily and specifically identify ques [226–231]. In 2002, a detailed study was pre-
Tau protein, through antibody–antigen interaction sented demonstrating that triangular silver nanopar-
and recognition. For a Tau protein, there are many ticles function as extremely sensitive and selective
surface antigens available for specific recognition nanoscale affinity biosensors [227–229]. The biotin-
with monoclonal ani-tau antibody-conjugated nano- streptavidin system was chosen to illustrate the attri-
particles. Therefore, in the presence of Tau protein, butes of these LSPR-based nanoscale affinity biosen-
several nanoparticles can bind to each protein, sors. Amplification of the LSPR nanobiosensor
thereby producing nanoparticle aggregates. As a re- response was demonstrated using biotinylated Au
sult, a colorimetric change has been observed from colloids. In 2006, the effect of interacting molecular
red to bluish color and a new broad band appears resonances and nanoparticle LSPRs was investigated
around 150 nm far from their plasmon absorption [231]. It has been demonstrated that the LSPR peak
band. This bioassay is rapid and takes less than shift and line shape induced by a resonant molecule
35 minutes from protein binding to detection and vary with wavelength, and, in most instances, the os-
analysis and it can be three orders of magnitude cillatory dependence of the peak shift on wavelength
more sensitive than the usual colorimetric techni- tracks with the wavelength dependence of the real
que. It have demonstrated two-photon scattering as- part of the refractive index.
say for the detection of Alzheimer’s tau protein in An effective method to improve the LOD of the
1 pg mL1 level. LSPR sensing system is to reduce the number of na-
The disadvantage of aggregation-based colori- noparticles probed. The method, however, requires a
metric sensing technique is irreversible in most in- high sensitive detection instrument because the ab-
stances, and difficult to quantitate. An alternative sorbance of a single nanoparticle is very close to the
method to circumvent the issue of irreversible com- shot noise-governed LOD. In 2003, Van Duyne
plex formation is to synthesize nanoparticles bound group has demonstrated that by using dark-field mi-
to substrates [221–230]. In this method, these wave- croscopy, single Ag nanoparticles can be used to
length shifts are caused by adsorbate-induced local sense local refractive index changes induced via bulk

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J. Biophotonics (2012) 13

mous and widely used SPR biosensors. For high

throughput analysis, prism-based SPRI instruments
such as SPRimagerII ARRAY (GWC Technologies),
Lumera SPRI, IBIS SPRI, and SPRiLab (GenOp-
tics), and Grating-based SPRI instruments such as
BioRad’s ProteOn XPR and Biacore’s FlexChip, are
available. Especially in the past few years, the per-
formance of SPR biosensors increases quickly. The
SPR and SPRI biosensors have been applied in mo-
lecular biology for the detection of proteins with a
LOD ranging from picomolar to nanomolar [235–
240], and detection of DNA molecules [130, 241–
Figure 13 (online color at: www.biophotonics-journal.org)
Single Ag nanoparticle biosensor. Reprinted with permis-
243] with the LOD as low as 54 fM with a flow injec-
sion from (232). Copyright (2003) American Chemical So- tion device and as low as 1 fM when aided by signal
ciety. amplification through gold nanoparticles [147, 244].
SPR also provides sensitive and fast detection of
cancer biomarkers [245–248] and other biomarkers
solvent changes and a monolayer of alkanethiols [249–251] with the LOD at ng mL1 level for medi-
[232]. In this work, a low density of chemically cal diagnosis. Additionally, SPR biosensors have
synthesized Ag nanoparticles was dispersed onto a been used for bacterial detection for environmental
clean glass coverslip. After recording the resonant monitoring, food safety and homeland security with
Rayleigh scattering spectrum of an individual Ag na- a LOD ranging from 10 to 106 cfu mL1 [107, 252–
noparticle in an N2 environment, a 1.0 mM alka- 254].
nethiol solution in ethanol was injected into the flow However, many challenges remain ahead. For an
cell. After incubation in the analyte solution, the example, that ideal recognition surface is still not
flow cell was flushed several times with ethanol, achieved. Many researchers suggest the range of
methanol, and hexane to ensure that a maximum of SPR sensing applications is still hampered by the
one monolayer had adsorbed. Finally, the nanoparti- tricky issue of surface functionalization especially for
cle was dried under N2 and a scattering spectrum array applications. Use of PEG or peptide or DNA
was recorded. The LSPR extinction maximum re- SAM monolayer provides highly resistant to nonspe-
sponse of individual Ag nanoparticles to the adsorp- cific absorption, but for SPR biosensor it can’t offer
tion of less than 60,000 hexadecanethiol molecules is enough reliable sensing signals. Three-dimension
about 40 nm (Figure 13). Using the same method, strategy provides more binding sites but simulta-
the detection of <100 streptavidin molecules per na- neously creates more chance for nonspecific absorp-
noparticle in a solution concentration of 1 pM by tion and thus results in high background signals. For
using nanoparticle array sensing was also demon- another example, the LOD of the commercial SPR
strated [233]. In 2010, the detection of a single mole- biosensors used in the fields of medical diagnosis
cule immunoassay was achieved using bipyramid and food safety is still low, typically in ng mL1 level
gold nanoparticles by Mayer et al. Bipyramid gold for most cases. For practical applications, further im-
nanoparticles have different LSPR spectrums from provement is necessary. Au NPs conjugates and
sphere nanoparticles [234]. Instead of monitoring LRSPs provides possible solutions.
antibody (Rabbit IgG)-antigen (Goat anti-Rabbit For optical fiber SPR biosensor, the sensitivity
IgG) binding, they measured antibody-antigen un- limit is usually around 105 to 106 RIU [175, 255].
binding events. The unbinding of single antigen mo- Although the detection performance is far below
lecule results in small, discrete <0.5 nm blue-shifts of that of prism-based SPR biosensors, it enables porta-
the plasmon resonance. ble sensing and low cost. TFBG biosensor seems a
promising tool to obtain high sensitivity, but there is
a long way to go.
LSPR biosensor provides much lower sensitivity
6. Closing remarks and conclusions to changes in the bulk refractive index than SPR
biosensor, but LSPR biosensors can be powerfully
Over the past two decade, optical SPR biosensors complementary to SPR biosensors. The response of
have achieved great advances which lead to many the two techniques becomes comparable when meas-
commercial SPR instruments. Most of them are uring short-range changes in the refractive index
based on prism coupling design, such as Biocore ser- owing to a molecular adsorption layer [256]. It is
ies (Biocore X to Biocore 4000), SR series (7000 highlighted that single-nanoparticle LSPR spectro-
and 7500), Autolab SPR, Plasmonic, Spreeta, Nano- scopy is an option, offering ability to detect pM
film, Multiskop. The Biocore series are the most fa- [233], even possible tens of fM sample concentration

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 Journal of

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14 X. Guo: Surface plasmon resonance based biosensor technique: A review

[257]. The most pronounced advantage for LSPR [12] H. T. Li, L. M. Ying, J. J. Green, S. Balasubrama-
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