Invited Paper

Breakthroughs in Photonics 2013:

Research Highlights on Biosensors Based
on Plasmonic Nanostructures
Volume 6, Number 2, April 2014
Yongkang Gao
Qiaoqiang Gan
Filbert J. Bartoli

DOI: 10.1109/JPHOT.2014.2311440
1943-0655 2014 IEEE

IEEE Photonics Journal

Breakthroughs in Photonics 2013

Breakthroughs in Photonics 2013:

Research Highlights on Biosensors Based
on Plasmonic Nanostructures
Yongkang Gao, 1 Qiaoqiang Gan, 2 and Filbert J. Bartoli 1
(Invited Paper)
1

Department of Electrical and Computer Engineering, Lehigh University, Bethlehem, PA 18015 USA
2
Department of Electrical Engineering, University of Buffalo, The State University of New York,
Buffalo, NY 14150 USA

DOI: 10.1109/JPHOT.2014.2311440
1943-0655 2014 IEEE. Translations and content mining are permitted for academic research only.
Personal use is also permitted, but republication/redistribution requires IEEE permission.
See http://www.ieee.org/publications_standards/publications/rights/index.html for more information.

Manuscript received February 9, 2014; revised March 3, 2014; accepted March 4, 2014. Date of
publication March 12, 2014; date of current version April 30,2014. Corresponding authors: Y. Gao
and F. J. Bartoli (e-mail: [email protected]; [email protected]).

Abstract: Label-free biomolecular sensing is by far the most common and successful
application area in the emerging field of nanoplasmonics. This review paper highlights the
latest progress and achievements made in this area. Key aspects of the nanoplasmonic
sensor development, including performance enhancement, efforts to increase multiplexing
capacity, and the progress in sensor integration and miniaturization, are discussed.
Index Terms: Biosensors, plasmonics, biophotonics, surface plasmon resonance.

1. Introduction
Over the past two decades, optical biosensors that employ the surface plasmon resonance (SPR)
in thin metal films have become the gold standard for label-free measurement of biomolecular
interactions [1]. SPR sensors allow fast, sensitive, real-time monitoring of biomolecular binding
kinetics, affinities, and specificities, all without the need of laborious labeling, and have found utility
in a wide range of applications in proteomics, drug discovery, diagnostics, and system biology.
However, despite its commercial success, this powerful sensing tool has found use mainly in
laboratory research applications, due largely to the complexity of the optical instrumentation and the
large size and high cost of the system. Nanoplasmonic biosensors, which utilize plasmonic effects
in engineered metal nanoparticles or nanostructures, have been proposed recently as a promising
alternative to conventional SPR techniques, greatly broadening the range of potential technological
applications [2][6]. Such nanoplasmonic biosensors eliminate the bulky prism-coupling geometry
used in current SPR instruments, using instead a simple collinear transmission or reflection
illumination geometry, which creates greater opportunities for sensor miniaturization, low-cost
production, and integration with microfluidic platforms [7]. Scalability of the sensor footprint down to
a few square micrometers also offers the possibility of massive multiplexing, which is difficult to
achieve using previous SPR techniques [8].
The general objective in this area of research is to preserve the virtues of SPR (real-time
biosensing, high sensitivity), while providing additional sensor advantages such as massive
multiplexing and device miniaturization. Enhancing the performance of nanoplasmonic sensors

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Fig. 1. (a) SEM image of the gold mushroom array biosensor [14, Fig. 1(e)]. (b) Conceptual illustration of
nanoplasmonic interferometric biosensor based on ring-hole nanostructures [21]. (c) Schematic of a
handheld plasmonic biosensor system, comprising a battery, LED light source, a plasmonic sensor
chip, and a CMOS imager [36, Fig. 1(b)].

through novel nanostructure design and optimization is an important research direction and also the
main focus of this paper. We also discuss recent achievements in sensor miniaturization for pointof-care diagnostics as well as extending their sensing capacity for high-throughput assays. For
possible applications of these new sensors in biological and biomedical assays and their
performance comparison, readers are suggested to refer to recently published papers [2] and [5].
While plasmonic effects also constitute the basis of surface enhanced Raman scattering (SERS),
this review concerns only refractometric-based plasmonic sensing.

2. Performance Enhancement
For nanoplasmonic biosensors to meet future sensing needs and achieve market significance, the
first major challenge is improving sensor performance. Conventional SPR systems are widely used
as a benchmark, permitting sensitive detection of refractive index changes down to 1 10 7 RIU or
a surface mass coverage of biomolecules as low as 0.1 pg/mm2 [1]. Such sensors outperform early
nanoplasmonic biosensors by one to two orders of magnitude [2], [3], illustrating the need for
continued sensor improvement.
Nanoplasmonic biosensors that employ extraordinary optical transmission (EOT) in metallic
nanoaperture arrays or the localized surface plasmon resonance (LSPR) in metal nanoparticles
typically exhibit broad resonances due to strong radiative and non-radiative losses, which severely
limit the sensor performance [9]. An attractive approach for narrowing the plasmon linewidth is to
design hybrid plasmonic nanostructures that couple broadband plasmon radiant modes with
different resonant modes that possess much narrower linewidths [9][12]. For example, Cetin et al.
demonstrated an asymmetric ring/disk nanocavity system, which supports a Fano-like resonance
arising from the coupling between super- and sub-radiant modes of the disk and ring cavities [12].
They achieved a narrow linewidth of 9 nm and a figure of merit (FOM) of 72, where FOM is defined
as the refractive index sensitivity divided by the resonance linewidth [13]. In a later work, Shen et al.
fabricated a gold mushroom array [see Fig. 1(a)] and demonstrated a resonance linewidth of 10 nm
with a high FOM of 108, due to the coupling of a LSPR with the spectrally narrow Woods anomaly
[14]. The high FOM demonstrated is comparable to the theoretically predicted upper limit for
conventional prism-based SPR system (108 [15]). However, care must be taken in designing
coupled plasmonic systems not to achieve narrower resonance linewidths if they also incur greatly
reduced resonance peak intensities or modulation depth, which in fact can greatly degrade the
overall sensor performance [16], [17]. Also, while FOM is a convenient metric for evaluating
nanoplasmonic sensor performance, it does not take into consideration the instrumentation noise or
temperature fluctuations. Sensor resolution, defined as the smallest detectable refractive index
change or surface mass coverage of biomolecules may provide a more realistic estimate of the
overall system performance. Another way to narrow the resonance linewidth is to decrease the
radiative loss from surface-roughness scattering by improving the quality of the fabricated
nanostructures. Using the template stripping method [17][20], Lee et al. demonstrated a nanohole
array sensor platform with an ultrasmooth metal surface with a roughness below 1 nm, resulting in a

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narrow EOT peak linewidth of 9 nm [17]. A fundamentally different approach to control plasmon
lineshape is to introduce surface plasmon polariton (SPP) spectral interference [16], [21][23]. Such
plasmonic interferometric sensing platforms, employing simple slit-groove or ring-hole structures
[see Fig. 1(b)], allow flexible tailoring of the plasmon lineshapes through control of the amplitude
and phase properties of SPPs, hence reducing loss associated with the resonant nanostructures.
Sensor resolutions of 0.4 pg/mm2 [21] and 3 10 7 RIU [23] have been demonstrated using this
approach, which compare favorably with conventional SPR systems.
The performance of nanoplasmonic biosensors also depends strongly on instrumentation noise
and the detection methods employed. Wu et al. has employed a multispectral detection method to
improve the sensor signal-to-noise ratio (SNR), by integrating the magnitude of the relative intensity
changes at all wavelengths to form the sensor output [24]. This integration approach takes into
account more SPP-mediated data than the common single-peak tracking method and provided a
three-times higher SNR for their sensing platform. The reduction of instrumentation noise, such as
light source fluctuations, mechanical vibration, temperature instability, and detector noise, is
another important way to enhance sensor performance [1], [25]. Dahlin et al. summarized several
common methods for reducing instrumentation noise in their recent work [26].
For most applications, the nanoplasmonic biosensors monitor surface biomolecular binding
events rather than the bulk refractive index changes. Understanding the SPP field distribution and
maximizing its overlap with the biomolecules thus become crucial to optimize the biosensor
performance [27], [28]. Through site-selective surface chemistry, Feuz et al. placed the target
biomolecules exclusively in the gap between the fabricated gold nanodisk dimers, where the SPP
field is the strongest, and achieved four-fold increase in sensor signal per bound molecule
compared to cases where the biomolecules are bound to the surfaces of the gold nanodisks [29]. In
a later work, Gao et al. studied the sensor response upon molecular adsorption at different positions
in an EOT-based nanoslit array, and demonstrated improved sensor performance by directing the
target molecules to the most sensitive sensor regions [30]. Interestingly, this spatially selective
sensing method has the potential for integration with recently proposed flow-through biosensor
platforms [31], [32], where the biomolecules flow through nanoaperture channels, potentially
achieving faster sensor response and enhanced sensitivity. The strong overlap between the
plasmonic hot spot, biomolecular binding sites, and flow-through nanochannels may lead to new
opportunities for optimizing the performance of nanoplasmonic sensors.

3. Multiplexing and Miniaturization

Extending the sensing capacity of nanoplasmonic sensors to high-throughput assays is another
promising research direction with important biomedical applications. Simultaneous screening of
multiple biomolecular interactions could not only improve the sensing accuracy by referencing but
also enable high-throughput sensing applications in proteomics, drug discovery, and cell biology.
SPR imaging is a well-established label-free technique for such applications, where a CCD camera
is employed to measure the intensity distribution of light reflected from an SPR surface containing
multiple sensing spots [33]. However, the prism-coupling scheme in conventional SPR imaging
results in a tilted image plane and prohibits the use of high numerical aperture optics, limiting the
sensor throughput and performance [8], [16]. On the other hand, the small footprint of
nanoplasmonic sensors, as little as a few square micrometers, and the simple optical transmission
or reflection geometries constitute two unique advantages for highly-multiplexed sensing.
Ruemmele et al. have demonstrated a multiplexed nanoplasmonic sensor chip using LSPR in
metal nanoparticles [34]. In that work, a liquid crystal tunable filter was used to filter the white light
illuminating the sensor chip and a CCD camera was employed to record the images whose intensity
maps were then correlated with wavelength. Using this spectral imaging method, they were able to
extract the LSPR spectra for each nanoparticles and enable nanoplasmonic sensing with high
throughput. Another approach for multiplexed plasmonic sensing is to use intensity-based detection
with narrow-band illumination, and measure the intensity change instead of spectral shift; this can
significantly improve the time resolution for kinetic measurements by eliminating wavelength

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scanning [35]. While promising, this intensity-interrogated sensing method typically lags in
performance compared to spectrally-interrogated sensing since less analytical data is collected due
to the much narrower spectral range [1]. To address this issue, several methods were proposed
recently to improve the performance of intensity-interrogated nanoplasmonic sensors. Gao et al.
used a self-referenced method in which two plasmonic interferometers were specifically designed to
exhibit similar initial transmitted intensities but have positive and negative intensity-change
sensitivities [16]. By measuring the intensity difference between the two sensors, they have
achieved a two-fold improvement in sensor sensitivity and a significantly reduced background
noise. The resulting sensor resolution of 5 10 5 RIU was 6 times better than that of a single
sensor element. Another attractive approach proposed by the same authors utilized nanoplasmonic
interferometers that were carefully designed to achieve a balanced destructive interference
between SPPs and free-space light, leading to an extremely low optical transmission through the
sensor in the quiescent state [21]. This delicate interference balance can be easily disrupted by a
small change in the local refractive index, and yields a pronounced increase in relative intensity.
They experimentally demonstrated a superior sensitivity of 14 600%/RIU using this low-background
intensity-modulation sensing method.
Besides massive multiplexing, the potential as miniaturized portable devices for point-of-care
applications is another strong driving force behind nanoplasmonic sensor research. For example,
use of a simple light emitting diode (LED) and photodetector, rather than a spectrometer, should
greatly reduce the cost and size of nanoplasmonic sensors. Cetin et al. have recently demonstrated
a handheld nanoplasmonic sensor system that is only 60 g in weight and 7.5 cm in height [36]. As
shown in Fig. 1(c), they used a LED as the light source, a nanohole array-based plasmonic sensor
chip, and a CMOS detector for image recording. Compared to commercial SPR systems, and
previously demonstrated nanoplasmonic sensors that used high-end light sources and detectors,
the reported sensor system employed no costly instruments and represents an important step
toward the development of simple, low-cost, point-of-care diagnostic tools. Other potential
improvements include the integration with compact microfluidic platforms, which would facilitate
easy sample handling and low-cost sensing measurements. Another interesting research direction
is the integration of nanoplasmonic sensor chip with portable smartphones, for both image
acquisition and data processing [37]. The wireless communication enabled by the smartphones
could also expand the use of nanoplasmonic sensors in field settings for remote diagnostics,
environmental monitoring and disease control applications.

4. Conclusion
In summary, we have briefly reviewed the progress in research on nanoplasmonic biosensing
reported mainly in 2013. Significant improvements in sensor performance, throughput, and
integration have been reported by several groups, showing its great potential for future widespread
use as commercial biosensor devices. While most works have focused on the development of novel
plasmonic nanostructures to improve sensing performance, future research should also
concentrate on sensing of target molecules in complex solutions, integration of nanoplasmonic
chips with functional microfluidic platforms for sample preparation, and further decrease in the size
and cost of nanoplasmonic sensor devices.

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