Advances in Colloid and Interface Science 233 (2016) 255–270

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Advances in Colloid and Interface Science

journal homepage: www.elsevier.com/locate/cis

Historical perspective

Recent progress on colloidal metal nanoparticles as signal enhancers

in nanosensing
Sara Abalde-Cela a, Susana Carregal-Romero b,c, João Paulo Coelho d, Andrés Guerrero-Martínez d,⁎
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
b
Bionanoplasmonics Laboratory, CIC biomaGUNE, Paseo de Miramón 182, 20009 Donostia-San Sebastián, Spain
c
Oncology Area, Biodonostia Research Institute, Donostia-San Sebastián 20014, Spain
d
Departamento de Química Física I, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Available online 11 June 2015 Colloidal metal nanoparticles present very special optical and electromagnetic properties at the nanoscale range.
Such plasmonic properties have derived in a huge research field that encompasses the understanding of nanopar-
Keywords: ticle formation mechanisms for the ultimate goal of developing novel materials for real-life applications. Plas-
Colloidal metal nanoparticle monic sensing is experiencing a rapid transition by taking advantage of the characteristic properties of
Nanoplasmonics colloidal metal nanoparticles. However, a rational design of novel nanoplasmonic substrates, which gathers as
Surface-enhanced spectroscopy
much as the required properties for a substrate to be a ‘good’ sensor is critical through the development of appli-
SEF
SERS
cations that can be effectively transferred as applied technologies. Also, the chosen sensing technique is a key
Sensing factor when planning the design of a new plasmonic-based sensor. Several factors such as composition, shape,
size, particle interactions or stability among others will define the final quality of the nanomaterial as sensing
platform. Herein, we review the latest and most promising state-of-the art of nanoplasmonic-based sensors in
four differentiated areas regarding the surface-enhanced spectroscopy detection technique being LSPR-, SERS-
and SEIRA-, and SEF based platforms.
© 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
2. LSPR-based colloidal plasmonic nanosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
2.1. LSPR principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
2.2. LSPR-based nanosensing using colloidal metal NPs in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
2.3. LSPR-based nanosensing using colloidal metal NPs on substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
3. SERS- and SEIRA-based colloidal plasmonic nanosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.1. SERS and SEIRA principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.2. SERS and SEIRA-based nanosensing using colloidal metal NPs in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
3.3. SERS- and SEIRA-based nanosensing using colloidal metal NPs on substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
4. SEF-based colloidal plasmonic nanosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
4.1. SEF principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
4.2. SEF-based nanosensing using colloidal metal NPs in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
4.3. SEF-based nanosensing using colloidal metal NPs on substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

1. Introduction

⁎ Corresponding author. Noble metals, gold and silver in particular, exhibit interesting optical
E-mail address: [email protected] (A. Guerrero-Martínez). properties at the nanoscale that markedly differ from those of the bulk

http://dx.doi.org/10.1016/j.cis.2015.05.002
0001-8686/© 2015 Elsevier B.V. All rights reserved.
256 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

material and the isolated atomic constituents, due to the excitation of desired LSPR response can be achieved through wet chemical synthesis
localized surface plasmon resonances (LSPRs) [1]. These optical re- of NPs [12]. The most successful methodology for controlling size and
sponses can be tuned by changing different parameters such as the shape of gold nanoparticles (AuNPs) is the seed-mediated growth
size, shape, and composition of the nanoparticles (NPs). The intense method, which comprises the reduction of a gold salt precursor with a
and highly confined electromagnetic fields induced by the LSPR at the weak reducing agent in the presence of preformed seeds, including
NPs provide a very sensitive tool to detect small changes in their dielec- stabilizing molecules in aqueous solution [13]. For example, highly
tric environments, property that is particularly attractive for sensing monodisperse gold nanospheres ranging from 15 to 100 nm have
applications (Fig. 1) [2]. Therefore, building (bio)chemical sensors been recently synthesized following this strategy [14]. The same proce-
with NPs have evolved into a relevant research direction with special- dure is used for the synthesis of gold nanorods, where aspect ratios
ized journals and recent news focus in major journals [3]. ranging from 2 to 5 can be efficiently achieved [15]. In the case of silver
The excitation of LSPRs is accompanied by strong subwavelength NPs (AgNPs), the high reactivity of silver precursors and the relatively
confinement and resonant enhancement of light near the NP boundary low chemical stability of silver seeds have severely limited the use of
[4], distance-dependent effects that find many applications in surface- the seed-mediated growth method in the direct synthesis of AgNPs
enhanced spectroscopies [5]. In this context, surface-enhanced Raman with controlled size and shape [11]. Therefore, novel strategies compris-
scattering (SERS), surface-enhanced infrared absorption (SEIRA) and ing the kinetic control of the seeded growth method by combination of
surface-enhanced fluorescence (SEF) spectroscopies are three of the several reducing agents or the controlled reduction of a silver shell on
most powerful analytical techniques for the identification of molecular pre-formed AuNPs as cores have been recently used to synthesize
species at low concentrations, which can even reach single-molecule AgNPs with several morphologies [16].
detection [6]. Additionally, SERS, SEIRA and SEF provide complete vibra- Most of the times, to make use of NPs for applied sensing research,
tional and electronic information of the molecular system under study, access to well-stabilized colloidal NP samples in solution is necessary.
since the outputs are essentially infrared absorption (IR), Raman scat- Through careful choice of surface functionalization processes, such as
tering and fluorescence spectra, respectively [7,8]. The enhancement silica [17], polymer [18], and protein [19] coating procedures, one can
of the spectroscopic signal is mainly achieved by coupling of the vibra- handle stable aqueous- or organic-soluble NPs tailored to possess
tional and electronic modes of the analyte with the LSPR generated at desired chemical and optical properties in solution. The rational
the surface of the NP, upon excitation with light of appropriate energy. search for functionalized NP surfaces with appropriate supramolecu-
Moreover, particle aggregates have been found to provide much higher lar hosts [20] and antibodies [21] has opened the possibility of sensing
enhancement due to coupling between the LSPRs of adjacent particles, guest analytes through specific physicochemical and biochemical
resulting in significantly higher electromagnetic fields so-called hot- interactions.
spots [9]. All together, these features make NP aggregates extremely Following molecular concepts at the nanoscale, nanocrystals coated
interesting nanoplasmonic structures for the sensing of chemical analytes, with selected molecules have been arranged to build up solid aggre-
such as pollutants with environmental and biomedical impacts [10]. gates of NPs with different levels of crystallinity [12]. Thus, the idea
Currently, the advances in wet chemical synthesis allow the prepa- that molecules self-assemble in different fashions as they change from
ration of colloidal plasmonic NPs with different metal compositions the disordered isotropic liquid state to the ordered crystalline phase
(mainly gold and silver), morphologies (spheres, rods, stars and polyhe- has been explored in the field of plasmonic supercrystals, showing in-
dra), and nanocrystal sizes (10–100 nm) [11]. Therefore, almost any teresting collective sensing responses [22]. Amphiphilic molecules

Fig. 1. Scheme showing the different types of optical interactions between NPs and molecules. (A) LSPR shift induced by adsorbed molecules without resonance absorption coupling.
(B) Resonance coupling between NP LSPRs and strong absorptions of adsorbed molecules. (C) Luminescence enhancement of fluorophores close to NPs.
From Ref. [33].
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 257

have gained popularity as a surface template in the formation of self- electrons. Therefore, when ε′ = −2εm condition is fulfilled, the wave-
assembled NP supercrystals [23], providing fine control over interparti- length absorption by the bulk metal is condensed into the LSPR at the
cle spacing that can be used to tune the plasmonic properties of the wavelength of the absorbing radiation λ. Therefore, not only in nano-
supercrystal over micrometer length scales [24]. Indeed, the types of spheres but also in NPs with other morphologies such as ellipsoids,
superlattices obtained in these assemblies have been controlled by tiny changes of εm caused by (bio)chemical analytes at the surroundings
varying the length and flexibility of the capping agents [25]. Such specif- of NPs may induce significant wavelength shifts of the LSPRs (Fig. 1A).
ic assembly of NPs has served as a platform for building-up devices Thus, LSPR-based plasmonic sensing relies on the fact that the plasmon
with applications in plasmonic sensing [23]. The fabrication of NP resonance frequency is highly sensitive to the molecular environment
supercrystals with high optical activity and long-range sensing areas [31], the proximity of another particle [4], and the NP surface charge
has been recently exploited to obtain enhanced electric field concentra- [32].
tion to maximize the spectroscopic signal of biorelevant chemical Recently, on the basis of molecular orbital theory, a plasmon hybrid-
analytes at ultralow concentrations [26]. ization model has been proposed that predicts how plasmon resonances
However, although colloid chemistry principles have emerged as vary upon molecular interaction [33] and clustering of plasmonic
powerful concepts for devising novel plasmonic nanosensors, becoming particles [34] (Fig. 1). The plasmon hybridization model has been a fun-
a natural starting point for the bottom-up fabrication of sensing analyt- damental concept in designing plasmon rulers [35], in which interparti-
ical devices in solution and on substrates [12], there are inherent diffi- cle distances and plasmon shifts are correlated through a simple
culties related to the colloidal stability and crystallization of NPs that mathematical expression. In practical terms, a plasmon ruler allows
still need to be overcome: monitoring single-molecule biophysics (e.g., transformation of biomol-
ecules) even in three dimensions (3D), which may have significant im-
(i) In colloidal solution, the relatively low enhancements of spectro-
pact on the future understanding of mechanisms behind biological
scopic signals in NP colloids, which are related to difficulties in
processes.
the tuning of distance between analytes and the NP surface
[27], added to problems of self-assembly control.
2.2. LSPR-based nanosensing using colloidal metal NPs in solution
(ii) As colloidal substrates, the low control of NP distances and pack-
ing within the aggregates and supercrystals as well as the ab-
Although the position of the LPSR in colloidal NPs is sensitive to
sence of macroscopic homogeneities of the nanoplasmonic
the environment dielectric constant, normally the LSPR shifts in the
substrates, which are directly related to non-controlled drying
presence of adsorbed analytes at low concentrations are typically in
effects of NP colloidal solutions on substrates [28].
the range of a few nanometers, thus limiting the sensitivity of the
nanosensors. In order to overcome such limitation, several groups
As a consequence of these experimental uncertainties, it should have demonstrated that molecules whose absorption bands match the
be pointed that there is a lack of general and versatile commercially LSPRs of AuNPs, within the red region of the visible spectrum, show
available LSPR-, SERS-, SEIRA- and SEF-based sensors fabricated from larger plasmon shifts (Fig. 1B) [33]. This resonance coupling effect has
colloidal NPs, being only few of them obtained through lithography been shown by Wang and co-workers [36], who constructed hybrid
techniques [29]. Additionally, the lack of reusability of almost all plas- nanostructures of red absorbing dyes and rod-shape AuNPs through
monic nanosensors considerably raises their prices and disposal needs, electrostatic interactions, in which wavelength shifts of ~100 nm were
limiting their uses in practical detection of real samples. Thus, in order observed. Interestingly, a maximum of ~ 3 nm distance between the
to achieve homogeneous and reliable detection of chemical analytes dyes and the AuNP surface was necessary to observe significant shifts
through surface-enhanced spectroscopies, novel nanosensors with of the LSPRs. The use of monodisperse colloidal AgNPs as LSPR-based
higher stabilities, macroscopic and nanoscopic homogeneities and reus- sensors through resonance coupling effects may broaden a variety of
able capability of sensing are needed, and may involve the search of opportunities of detection in solution of molecular species that absorb
novel methodological tools for NP preparation. Although many different at the blue and green edge of the visible spectrum.
LSPR-, SERS-, SEIRA- and SEF-based nanosensors have been explored so Of particular interest is the development of controlled self-
far, we intend to present herein an overview of the most recent activi- assembled NPs in solution, in which the interaction between close-
ties in this area, restricting ourselves to those that have been dedicated packed NPs offers an indirect analytical way of sensing of analytes at
to overcome such colloidal limitations in solution and substrates. the interparticle gaps. One of the most representative examples is the
aggregation-based immunoassay that makes use of NPs functionalized
2. LSPR-based colloidal plasmonic nanosensors with antibodies complementary to proteins, which induce the aggrega-
tion to create colorimetric responses [37], as in home pregnancy tests.
2.1. LSPR principle However, the control of self-assembly to produce arrays with defined
geometrical arrangements of the nanoparticles in solution remains a
Nanoplasmonic sensing is based on the oscillation of the conduction difficult task [38], being mainly focused on the preparation of dimers
electrons of NPs at the LSPR, which leads to intense light absorption and of NPs. Among them, the plasmon ruler concept can be considered as
scattering effects at visible wavelengths [4]. As a simplest example, the one of the most successful examples in terms of control and reproduc-
optical properties of spherical NP colloids with a radius R can be deter- ibility. Reinhard et al. have demonstrated experimentally this concept
mined by the Mie theory [30], through expressions for the extinction by separation of two AuNPs in solution using a conjugated DNA as linker
cross-section Cext (sum of absorption and scattering). For nanosized [35]. Accurate control over the AuNP separation at the nanometer range
particles with a frequency dependent, complex dielectric function was obtained by conjugating one colloidal solution with a single-strand
ε = ε′ + iε″, embedded in a medium of dielectric constant εm, Cext can DNA and conjugating a second colloidal solution with the complementa-
be calculated from: ry single-strand DNA. The obtained LSPR shifts of AuNPs can be directly
correlated to the flexibility of the molecular spacer and thus to its struc-
3
= tural conformation.
24πR3 εm 2 ε″
C ext ¼ : As an alternative approach, the changes of the LSPR shape during a
λ 2
ðε þ 2εm Þ þ ε0
″
chemical reaction have been used to determine the concentration of
analytes in solution. For example, Liz-Marzán and co-workers have
The surface polarization charge induced by the dipole created by developed a novel colorimetric assay for the detection of subnanomolar
the applied electric field of light acts as a restoring force for the free concentrations of biochemical inhibitors [39]. In this method, the
258 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

enzyme acetylcholinesterase decomposes acetylthiocholine (a central be restricted to two distinct origins: (i) NPs with individual chirality
neurotransmitter widely distributed in our nervous system) to generate and (ii) collective interactions between 3D ordered NPs (Fig. 3). Recent-
a thiol-derivative compound that has been used to tune the growth of ly, interesting studies of Govorov and co-workers have shown the pos-
rod-shaped AuNPs. Thus, at different experimental conditions of the sibility of sensing peptides and proteins inducing LSPR-CDs in individual
enzymatic reaction, the final growth solution contained a mixture of chiral AuNPs [46]. Moreover, a recent report of Kotov and co-workers
AuNPs with different morphologies (rods, cubes and spheres) with has illustrated the promising potential of 3D chiral assemblies of rod-
controllable relative populations, strongly affecting the overall optical shape AuNPs to produce LSPR-CD signals of outstanding intensity [47],
response of the system. Therefore, by analyzing the LSPR of rod- which have been used in the detection of DNA at attomolar concentra-
shaped AuNPs, the concentration of paraoxon (a molecular inhibitor of tions (Fig. 3).
acetylcholinesterase that is used in nerve gas) can be determined at
the nanomolar regime (Fig. 2).
As the stability and aggregation of (bio)polymer-capped NPs are 2.3. LSPR-based nanosensing using colloidal metal NPs on substrates
highly sensitive toward external stimuli, due to the significant structural
modifications that such macromolecules register under tiny changes of To apply nanoplasmonic sensing on substrates, colloidal NPs have
the (bio)chemical environment [40], a high number of reports have been mainly investigated at the single particle level by dark-field
been devoted to LSPR-based nanosensing of parameters such as pH microscopy [48]. In this technique, the large light scattering efficiency
[41], heavy metals [42], and temperature [43], using NPs in colloidal at the LSPR makes the visualization of single NPs down to sizes of
solutions. In an elegant approach, Chanana and co-workers have de- about 10 nm in diameter. In this sense, Sönnichsen and co-workers
signed dual-responsive NPs coated by proteins and grafted with have detected single unlabeled proteins with extremely high temporal
thermosensitive polymer brushes that present pH- and thermo- resolution, allowing for monitoring the dynamic evolution of proteins
responsive behavior [41]. Such preparation led to AuNPs with lower [48]. In an advanced design, the same group has developed an efficient
critical solution temperatures of 42 °C in pure water and around 37 °C and cost-effective multiplexed sensor for proteins, in which the LSPR
under physiological conditions, which were followed by LSPR coupling. position of rod-shape AuNPs responds specifically to different proteins
Jointly, the pH-induced aggregation at the isoelectric point of the pro- [49]. The efficiency of this original method lies in the nanomolar sensi-
tein was completely reversible and could be repeated multiple times. tivity, the sensor recycling capability, and the potential to upscale to
Additionally, the same research group synthesized insulin-capped hundreds of targets.
AuNPs that showed highly sensitive and selective LSPR responses in Similar single NP approaches have been developed at the macroscop-
the presence of heavy metals, such as Fe2 +, Cu2 +, Pb2 +, and Hg2 +, ic level, in which label-free, chip-based biosensors have been fabricated
due to strong metal–protein interactions that favor the aggregation by random chemisorption of AuNPs onto mercaptosilane-modified glass
phenomena [42]. substrates, followed by conjugation of sensitive proteins. Chilkoti and
In connection to UV/Vis spectroscopy, circular dichroism (CD), co-workers have monitored the streptavidin binding to biotin by the
defined as the difference in extinction of left- and right-circularly polar- wavelength shift of the LSPR peak of immobilized rod-shape AuNPs
ized light, is one of the most commonly used spectroscopic techniques due to changes in local refractive index, obtaining a nanomolar detection
for the sensing of chiral systems such as organic compounds and bio- limit in serum [50]. An analogous substrate has been fabricated by Lin
molecules [44]. Within a nanoplasmonic context, CD has been explored et al., in which a fiber-based biosensor utilizing the LSPR effect is used
to date using chiral NPs resulting in intense LSPR-mediated circular to evaluate the amount of paraoxon in solution [51]. In this study, a bio-
dichroism (LSPR-CD) signals over a wide spectral range across the visi- active layer consisting of acetylcholinesterase is immobilized by cova-
ble (Fig. 3) [45]. Although in many examples the mechanisms behind lent coupling onto an AuNP layer, allowing the determination of
optical activity in NPs cannot be easily identified, it may in principle paraoxon at ppb limits by inhibition of acetylcholinesterase activity.

Fig. 2. (A) Scheme showing the inhibition of acetylcholinesterase activity by paraoxon. (B) Absorbance spectra of the growth products formed in the presence of 0.05 mM
acetylthiocholine, 0.5 mU mL−1 acetylcholinesterase and different concentrations of paraoxon. (C) Variation of the ratio between the maxima of the longitudinal and transverse LSPR
bands, as a function of paraoxon concentration. (D) TEM images of AuNPs that show the morphologies tuned by the addition of thiocholine at different concentrations.
From Ref. [39].
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 259

Fig. 3. (A) Molecular precursor of chiral fibers. (B–C) SEM images of nanofibers with P and M morphologies, respectively. (D) SEM micrograph of P nanofibers coated by gold nanorods.
(E) TEM micrograph of M nanofibers coated by gold nanorods. (F–G) CD and UV/Vis spectra of nanofibers with P and M morphologies coated by gold nanorods in solution, respectively.
(H) CD spectra for chiral gold nanorod assemblies obtained for different DNA concentrations. (I) Calibration plots obtained using UV/Vis and CD spectra of chiral gold nanorod side-by-side
assemblies. (J) Cryo TEM tomography images for a chiral assembly of gold nanorods (the scale bar is 25 nm).
From Refs. [45] and [47].

NPs coated with rationally selected (bio)molecules have been formation of polyrotaxanes at the nanoparticle surface in the presence
arranged to build up organized plasmonic aggregates, showing interest- of the macrocycle α-cyclodextrin [54]. The self-assembly between the
ing collective optical and sensing LSPR-based responses [12]. Natan and surface supramolecules provides large and homogeneous supercrystals
co-workers have prepared 3D AuNP and AgNP multilayered films by with hexagonal close packing of nanoparticles (Fig. 4). Once formed, the
using successive treatments of NP monolayers with a bifunctional self-assembled supercrystals can be fully redispersed in water. There-
cross-linker and colloidal solutions [52]. Such plasmonic substrates fore, the reversibility of the crystallization process may offer an excel-
have shown highly sensitive LSPRs under immersion in solvents with lent reusable material to prepare gold nanoparticle inks and optical
different types of analytes, which depend on the Au or Ag composition sensors with the potential to be recovered after use. In other example,
of NPs, the number of NP layers and the length of the molecular bifunc- cationic gemini surfactants were used for the reproducible and con-
tional cross-linkers. Similarly, Ye et al. have fabricated 3D self-assembled trolled synthesis of monodisperse Au and Ag nanorods, focusing on
AuNP multilayer structures by the alternate deposition of a bifunctional the role of the chemical structure of these surfactants on the self-
cross-linker and AuNPs, improving the refractive index sensitivity of the assembly of highly ordered, robust 2D and 3D NP superlattices with
LSPR sensor [53]. The investigations show that the number of AuNP de- directional optical properties (Fig. 4) [23,24]. The optimization on
position cycles has a strong effect on the sensitivity of the sensor and the the preparation of colloidal supercrystals was carried out by drop
multilayer structure fabricated from four NP deposition cycles exhibits casting the colloidal solution at controlled temperature and humidity
maximum sensitivity to the change of the environmental refractive conditions.
index.
These studies are showing promise, however all substrates present 3. SERS- and SEIRA-based colloidal plasmonic nanosensors
relatively low nanoscopic homogeneities in terms of the low control of
NPs packing within the aggregates, which may render to broad and 3.1. SERS and SEIRA principle
non-uniform LSPR bands. With the aim of solving that issue, Guerrero-
Martínez and co-workers have developed methods of syntheses of Surface-enhanced Raman scattering (SERS) is currently recognized
large and homogeneous substrates of supercrystals with close packing as one of the most sensitive spectroscopic techniques, and has been ex-
of AuNPs following supramolecular [54] and colloidal [23,24] strategies. tensively exploited for ultrasensitive (bio)chemical detection [55]. SERS
Such plasmonic substrates show highly reproducible LSPR bands spectroscopy basically occurs when the LSPR of a NP enhances the
within long-range areas (~ cm2) of the substrates (Fig. 4). Within a Raman signal of a molecule being close to the nanostructure (Fig. 5)
supramolecular context, the use of thiol-functionalized nonionic [5]. From the early studies of the SERS effect, the experimental observa-
surfactants to stabilize AuNPs in water induces the spontaneous tions showed that more than one mechanism should contribute to the
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Fig. 4. (A) NP thiolated stabilizer (up) and reversible supercrystals of stabilized AuNPs in water by supramolecular approaches (down). (B) TEM micrograph of a hexagonally packed bi-
layer of stabilized AuNPs. (C) SEM micrograph of the stabilized AuNP supercrystal. (D) Normalized UV/Vis spectra of depositions of stabilized AuNPs (1), and conventional types of AuNPs
(2, 3), at the ring (solid lines) and inner (dashed lines) of the drop patterns. (E) Normalized UV/Vis spectra of the stabilized AuNP solutions before (black) and after (red) redispersion of
supramolecular supercrystals in water. (F) SEM micrographs of Au@Ag nanorods deposited at optimized drop casting conditions. (G) Drop profile and SERS mapping of an analyte evap-
orated on Au@Ag nanorod and Au nanorod deposits. (H) Comparisons between SERS intensities on Au@Ag nanorod and Au nanorod supercrystals at the different pattern regions.
From Refs. [54] and [24].

enhancement of the Raman signal. Two mechanisms are commonly and the emitted radiation. According to that, the SERS electromagnetic
considered for SERS, one of which involves enhancements in the electric enhancement factor (EF) can be simply expressed as:
near field intensity as a result of surface plasmon resonance excitation,
which is called electromagnetic mechanism (EM, Fig. 5). On the other E F ≈ MLoc ðωL ÞMdRad ðωR Þ
hand, the enhancement in polarizability due to chemical effects such
as charge-transfer excited states gives rise to the so-called chemical where MLoc(ωL) is the local field intensity enhancement factor and
effect or charge transfer effect (CT, Fig. 5) [56]. Nowadays, it is recog- MdRad(ωR) corresponds to the directional radiation enhancement factor
nized that although EM is essential for SERS, CT plays a key role in the (related to a given position). MLoc defines how stronger the field inten-
truly ultrasensitive application of the technique, such as single molecule sity is with respect to the intensity in the absence of metal substrate,
detection [6]. and can be found by solving the electromagnetic problem under specific
The obtained SERS spectrum is the vibrational fingerprint of the sys- external excitation conditions with an incident field EInc, which yields
tem under study, and thus provides crucial information about the struc- the local field ELoc everywhere.
ture, conformation and dynamics of the analyte. Therefore, much of the Estimating MdRad is a priori a more difficult task, but in order to avoid
impetus behind the research in SERS relies on its potential applications. further complications, it is often assumed that MdRad(ω) ≈ MLoc(ω),
The signal enhancement provided by metallic nanostructures resolves which means that the SERS enhancement can then be expressed as:
the problem of the low cross-section of the Raman process [5,6],
combining the ultrasensitive potential of this technique with the rich jELoc ðωL Þj2 jELoc ðωR Þj2
SMEF ðωL ; ωR Þ ≈ MLoc ðωL ÞMLoc ðωR Þ ≈ :
chemical and structural information characteristic of the vibrational jEInc j2 jEInc j2
spectroscopy. In fact, nowadays enhancement factors have been report-
ed up to 1014–1015 fold [57]. The enhancement factor strongly depends Latter expression has been widely used in the literature, and pro-
on both the structure (size, shape and composition) of the metallic vides a fairly simple way of estimating the electromagnetic enhance-
nanostructure as well as on the nature of the molecular probe. Usually, ment factor from a calculation of the local field at the excitation and
the enhancement factor expression is simplified by the so-called E4 ap- Raman frequencies [6].
proximation (fourth power of field enhancement at the NP surface). Since SERS can be carried out under environmental or biological con-
This model is commonly used to explore the EM enhancement and con- ditions [58], it appears as an ideal detection platform for (bio)chemical
siders the Raman scattering in the vicinity of the defined metallic sensing, diagnostics, (bio)analytical chemistry or environmental moni-
nanosurface. A more detailed explanation of this model can be given toring, among other applications [59]. Although much work is still
by separately taking into account the enhancement of both the incident being carried out in terms of the fundamental understanding of the
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 261

Fig. 5. Schematic representation of SERS effect in: (A) an individual NP. (B) An interparticle gap, so-called hot-spot, area with further enhanced Raman signal. (C) Schematic representation
of the interaction between the electromagnetic radiation and a spherical NP, explanation of the electromagnetic (EM) mechanism in SERS phenomenon. (D) Diagram depicting the
chemical transfer (CT) mechanism showing the energy levels for a ‘metal–molecule’ system and the possible Raman resonance processes involving molecular states (path a) and molecular
and metallic states (paths b and c).

SERS effect, many more publications are now entirely dedicated to its can theoretically be achieved by SEIRA (101–104) are considerably
applications and the development of new substrates such as colloids, lower than the ones obtained by SERS (108–1014), the higher cross-
thin films, self-assembled or hybrid materials [60]. The design of effi- section of infrared versus Raman, pushed researchers to explore further
cient and flexible nanostructured substrates for SERS detection is one on the SEIRA technique.
of the main challenges to be achieved before the technique can be wide- Therefore, metals, semimetals, conductors, polar dielectric nano-
ly applied. Therefore, the preparation of optical substrates with opti- structures and composite materials can show SEIRA effect. Following
mized properties is a very dynamic field of research, and, as there is metals are the most used by far for the fabrication of SEIRA substrates:
no universal ‘best’ SERS platform, careful consideration of the analytical Au, Ag, Cu and Pt, presumably because of the higher understanding on
problem is required before choosing/designing a SERS sensor platform the spectroscopies behind such metals associated to the higher develop-
[10]. ment of SERS compared to SEIRA [65]. Regarding the supporting mate-
Soon after the discovery of SERS in the early 1970s, the parallel asso- rials, SEIRA substrates are mainly designed as thin films, and in turn,
ciation to the phenomenon at longer wavelengths regarding vibrational thin films fabricated by lithographic methods [66]. However, as this
energy changes, SEIRA (surface-enhanced infrared absorption spectros- review is focused on colloidal substrates, we will just cover the state-
copy) was realized. Generally speaking, it is possible to attribute to of-the-art on colloidal-based SEIRA materials.
SEIRA similar mechanisms than SERS, being both complementary tech-
niques. Electromagnetic and chemical effects play a crucial role in the 3.2. SERS and SEIRA-based nanosensing using colloidal metal NPs in solution
SEIRA as well. Nevertheless, latter affirmation is quite general, and spe-
cific differences in SEIRA and SERS have been extensively studied by One of the highest obstacles of SERS sensing in colloidal solution
Osawa [61]. The main difference between both phenomena is that is the limited achievable sensitivity, directly related to the inability of
SERS happens when there is a change in the polarizability of the mole- forming stable and reproducible hot-spots (interparticle gaps with
cule close to the nanosurface, whereas in SEIRAS there is a need of a enhanced SERS effect due to the coupling of LSPRs). Strategies like
change in the dipole moment perpendicular to the substrate surface magnetic optical accumulation by using hybrid materials [67], nanopar-
[62]. We would also like to refer the reader to reviews about SEIRA ticle assemblies in liquid–liquid or liquid–air interfaces [68,69] or
and a book about SEVS (surface-enhanced vibrational spectroscopy) microfluidics and microdroplets techniques [70,71], have effectively
that extensively explain the mechanism behind the SEIRA phenomenon demonstrated to overcome such sensitivity issue. SERS ultradetection
in comparison to SERS [63,64]. Although the enhancement factors that of a Raman molecular probe (1-naphthalenethiol) was possible by
262 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

concentrating core–shell γ-Fe2O3@SiO2 coated with rod-shape AuNPs in platform for sensing [75]. Automation, miniaturization and high
a small spot of the sample containing the multifunctional material by throughput are unique properties desired by companies investing in
applying a magnetic field [72]. A portable Raman system was used in novel sensing technologies [29]. The lack of reproducibility among
this work, validating their application for on-field detection of analytes SERS substrate batches obtained within conventional bench-top tech-
at trace concentrations. The same principle, adapted by different niques can be avoided by automating the synthetic process; miniaturi-
research groups varying the hybrid material components and the mole- zation in microfluidics offers higher enhancement factors due to the
cule of study, allowed DNA-sequencing and pollutants ultradetection in decrease of volume and thus an improved sensitivity; and finally, the
liquid phase. Specifically, pNIPAM, a thermosensitive coating hydrogel, high throughput ability of microfluidics technology leads to a rapid
was used to trap hydrophobic molecules with low affinity for Au or Ag and accurate analysis of liquid samples. For example, Cecchini et al. de-
surfaces [67]. The combination of hydrophobic trapping in the hydrogel veloped a microdroplet-based detection tool by coupling the enhancing
matrix, with the collapsing ability to form hot-spots allowed for the power of aggregated AgNPs with the high-throughput screening ability
trace detection of pentachlorophenol, an elusive chlorinated ubiquitous of microdroplet technique (Fig. 6) [76]. The SERRS (surface-enhanced
environmental pollutant. resonance Raman scattering) signals from the silver aggregates within
Also, supramolecular chemistry has shown to be effective for the de- the microdroplets were used for sensitive and high-throughput analysis
tection of small molecules or analytes with low affinity for plasmonic of a Raman reporter. Multiplexing is also one of the most important ca-
surfaces by means of SERS [20]. For example, Baumberg's research pabilities when developing analytical sensors. In this line, Abalde-Cela
group uses the macrocyclic host cucurbit[n]uril to form very controlled et al. used a simple approach by co-flowing AgNPs and complex liquid
subnanometer gaps between AuNPs [73]. By this method, not only the samples through a microfluidic chip (Fig. 6) [70].
cavity of the macrocycle traps small molecules, but also the created Compared to the broad bibliography on SERS colloidal platforms, it is
hot-spots are highly controllable in terms of interparticle distance and quite challenging to design SEIRA probe particles for analysis in solution.
reproducibility among experiments. They have reported on the quanti- In order to be able to acquire the IR spectra of an analyte, all other con-
fication of several molecules by this method, and remarkably of some tributions from matrix or media need to be avoided, as they would over-
small molecules being difficult to detect by SERS (Fig. 6) [74]. The crea- lap the analyte signal. As an example, water exhibits a strong IR pattern
tion of hot-spots by this method opens up new possibilities for liquid owed to the OH− bending vibrational mode. According to this, the de-
SERS substrates, as overcomes the sensitivity issue when using dis- sign of liquid SEIRA colloidal platforms would be quite challenging.
persed nanoparticles and the low reproducibility of hot-spots in solu- However, it is worth mentioning that novel studies have shown that
tion regarding conventional aggregation techniques. the matrix or media contribution to the spectrum can be distinguished
Recently, microfluidic and microdroplet techniques are starting to from the analyte contribution in SEIRA platforms by adjusting their in-
rise up as promising platforms for NP synthesis as well as a detection ternal reflections, absorptions and scatterings [77]. Latter approach

Fig. 6. (A) Schematic of host–guest SERS analysis using ternary complexation with cucurbit[8]uril-based hot-spot. (B) SERS spectra of (i) CB[8] (5 μM) and (ii)–(v) CB[8] complexes with
different molecules. (C) Real-time multiplex SERS detection in microfluidics; (i) +-shaped microfluidic device for dual multiplex online monitoring of two flows of different sources, where
each flow contains a mixture of two different analytes, either CV and NB or AB and TB (CV + NB, pink; AB + TB, light green; CV, purple; NB, red; AB, blue; and TB, yellow). (ii, iii) Optical and
SERS images of the microchannel showing the distribution of the analytes (experimental: dotted black line; spectral references: colored solid lines). Dye concentration, 1 mM; scan time,
70 ms.
From Refs. [70] and [74].
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 263

has been reported for lithographic materials, but we just wanted to electromagnetism, conductivity, biocompatibility or reusability. For ex-
highlight that it would be theoretically possible to adapt this method ample, a hybrid material comprising silver aggregates supported on the
to colloidal–SEIRA substrates. porous structure of a free-standing carbon nanotube film [87], has
allowed the filtration of large volumes of fluids retaining active analytes
3.3. SERS- and SEIRA-based nanosensing using colloidal metal NPs for its direct identification of multiple analytes at the attomolar regime.
on substrates It is also worth mentioning the new current of flexible, portable and
user-friendly SERS sensors being developed very recently, especially
The use of colloid nanoparticles for the preparation of SERS sensors those supported in paper [88]. A very interesting work was released
demands some methodological requirements. Specifically, the analyte by Polavarapu et al. demonstrating the use of plasmonic inks made of
of interest must have affinity for the plasmonic sensing platform, thus different NPs to write SERS arrays. Impressive attomolar detection limits
the Raman signal of the molecule can be effectively enhanced. However, of dye molecules were achieved by the use of such substrate [89].
a wide range of molecular functional groups shows low affinity toward Finally, Tian and co-workers reported on a novel 3D hot-spot matrix
Au or Ag surfaces, the most commonly used metals in SERS substrates achieved by evaporating a droplet of citrate-AgNPs on a fluorosilylated
[78]. Furthermore, the sensitivity achieved with average SERS may not silicon wafer (Fig. 7) [81]. Interparticle gaps were formed in the 3D ma-
be enough when detection of trace concentrations of analytes is pursued. trix as water evaporates until the AgNPs were uniformly deposited on
Although polymer trapping, optical accumulation, and microfluidics- the wafer. Interestingly, they have made a theoretical and experimental
based sensing in liquid substrates has remarkably evolved in the last study of the evolution of the hot-spots during the evaporation process.
years, sensor engineering plays a key role in the design of more flexible, Peak SERS intensities were found for several analytes with different
functional and ultra-sensitive SERS substrates [59]. affinities for the plasmonic surface. Moreover, they demonstrate the ap-
In this section, we will focus on SERS substrates based on NPs depos- plicability of the technique for both Ag and AuNPs. Authors claim on the
ited or embedded within a supporting substrate, being thin films or universality of the platform as its use can be either extended to other
solid polymer/hydrogel particles, which can effectively address the lim- plasmonic structures as well as along with different sensing techniques
itations of SERS liquid sensors. Initially, amorphous assemblies of NPs or analytes of different chemical nature. It is noteworthy, that this 3D
over substrates (glass, silicon, ITO) were obtained by simple casting a platform theoretically gathers all the premises for a sensor to be ex-
drop of the colloidal NPs over the substrate and forcing the aggregation traordinary: controllable, reproducible, ultra-sensitive, homogeneous,
of the NPs by adding a salt solution to destabilize the colloidal suspen- portable and universal.
sion and cause random hot-spots, or either by tuning the capping SEIRA solid substrates are mainly produced by lithographic tech-
agent coating the specific NPs [79]. However, the assembly of the NPs niques as mentioned above [65]. However, the issue of this review
in such cases ended up in random crystal formation very difficult to covers analytical substrates based on colloidal metallic particles. One
reproduce from one experiment to another. The next generation of of the first reports on SEIRA with colloidal particles included a compar-
substrates benefited from the accurate control and variation of external ison on the efficiency of gold films versus gold colloids for the detection
factors, such as temperature, pressure or humidity implemented to of Salmonella antibody/antigen complexes. Authors developed a com-
slightly control the reproducibility of hot-spot formation [24,80,81]. bined method involving the filtration of gold colloids into polyethylene
Later, not only to improve the control over aggregation but also to membranes after attachment to specific antibodies [90]. Even there is
increase the size and homogeneity of substrate areas, hierarchical as- not an extensive bibliography on SEIRA, majority of the applied works
sembly of NPs over different substrates started to be a pursued strategy. report on protein–protein interactions, as a subtle change in the confor-
The assembly of NPs in specific geometries allows the effective coupling mation and orientation to the surface is translated into spectral changes.
of electromagnetic fields, thus controlling the nanoantenna effects of In this line, Polissiou and co-workers have used dry films of colloidal
the engineered substrate [82]. However, it is not technically straightfor- gold to study the spectra of protein A and the changes after its conjuga-
ward to build homogeneous, large size-range and reproducible hierar- tion to immunoglobulin G. Also, Halas and co-workers have made a
chical assemblies. Recently, strong interest on plasmonic supercrystals remarkable progress on the fundamental study, development and sens-
as SERS substrates is an expanding area of research [83]. Gómez-Graña ing applications of SEIRA solid substrates [91]. More specifically, they
et al. reported on a refined supercrystal arrangement based on rod- have developed a substrate based on the aggregation of Au nanoshells
shape AgNPs vertically aligned over a substrate acting as SERS antennas over silicon films. The generation of infrared ‘hot-spots’ allowed for
(Fig. 4) [84]. By controlling the capping molecules surrounding the an enhancement factor in SEIRA of 104 for the molecular probe 4-
nanoplasmonic surface, a novel and highly optically active SERS sensor mercaptoaniline, one of the highest EFs in SEIRA reported up-to-date
for ultrasensitive screening of analytical targets relevant to medical [92]. Another study of the same group describes the use of these sub-
and environmental science was developed. Within the same type of strates for combined SERS and SEIRA, analyzing the spectra of CTAB
substrates, NPs deposited with different morphologies such as Au nano- and p-mercaptoaniline with both enhancing spectroscopies [93]. More
rods, Au nanostars, Au-spiked nanoparticles or Ag nanoplates have been recently, Cai et al. have applied a novel composite material to SEIRA.
explored aiming a homogeneous enhancing surface [26,84,85]. The con- They have designed Fe3O4/Au nanocomposites allowing both magnetic
trol of the assembly properties, interparticle distances, composition, manipulation of the material as well as spectroscopic enhancing of the
size, shape or surface area coverage determines the final properties of infrared absorption [94].
the solid substrate. Specifically, a recent work presented by Hamon
et al. reports on a novel one-step patterning method achieving critical 4. SEF-based colloidal plasmonic nanosensors
substrate aspects mentioned above [80]. Remarkably, by this method,
homogeneous assemblies of rod-shape AuNPs in the millimeter scale 4.1. SEF principle
range area were possible due to the confinement of the colloidal sus-
pensions in micron-sized cavities and further evaporation (Fig. 7). Fluorescence-based techniques which are key tools for labeling and
Hybrid materials also deserve special mention in this section. The sensing in analytical chemistry, biotechnology and biochemistry can
combination of polymers, hydrogels or carbon nanotubes as supporting also be benefited from the interaction between the free electrons of
materials for dense NP hot-spot matrixes has attracted the attention of plasmonic substrates or particles and fluorophores [95]. In general,
worldwide researchers. Both in films or beads fashion, hybrid materials this interaction can trigger the quenching or enhancement (i.e. SEF) of
offer several advantages as SERS sensors [86]. By choosing the appropri- fluorescence but concretely, parameters such as distance between the
ate non-plasmonic component, several functionalities can be added to fluorophore and the metal [27], nature [96] and geometry of the plas-
the final material, such as sensitivity to external triggers, magnetism, monic material (e.g., size and shape) [97], spectral overlap [98] and
264 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

Fig. 7. (A) Tilted SEM characterization of patterned substrates to form supercrystals at rod-shape AuNP concentration of 375 mM. (B) Optical microscopy images of (left) AuNP
supercrystals (the scale bar is 10 μm) and corresponding SERS images (right — in red) obtained by mapping the intensity of the crystal violet vibrational peak integrated over
1618–1632 cm−1. (C) Average SERS spectra of crystal violet at a concentration of 10−6 M in ethanol, drop-casted on the substrate and dried under ambient conditions. Spectra were ac-
quired on supercrystals with different shapes: drops (blue), circles (black), and squares (red). (D) (I–III) 3D hotspot matrix of noble-metal sols generated in the water evaporation process.
(E) (I) Time-course SERS mapping of a 1 μL sample with 50 amol of R6G (3 × 107 molecules) and ~1010 AgNPs placed on a hydrophobic-treated silicon wafer. (II) Line SERS mapping at
610 cm−1 for the dried sample in a range of −100 to 100 μm centered on the position used for time-course mapping.
From Refs. [80] and [81].

orientation of the fluorophore [7] rule the final characteristics of the ra- respect to the fluorophore. Considering the following expressions for
diative decay of dyes. Usually, SEF can occur at distances between 5 and the fluorophore quantum yield (Q0) and lifetime (τ0):
30 nm. At shorter distances, fluorescence would be quenched. Another
relevant issue is the spectral overlap (Fig. 1C). The enhancement of Γ
Q0 ¼
fluorescence is more efficient when the emission of the fluorophore is Γ þ knr
red-shifted with respect to the metal plasmon band spectra and it can
−1
be quenched if it is blue-shifted [99]. It is also noteworthy that SEF τ0 ¼ ðΓ þ knr Þ
takes place with all types of fluorophores, regardless if they are organic
molecules, quantum dots or lanthanides [27,100]. where knr is the non-radiative decay rate. The Qm and τm of the
The presence of NPs near fluorophores at nanoscale distances in- fluorophore–metal complex are given by:
fluences the excitation/emission process of fluorophores in two ways
[101]. On one hand, the excitation process can be affected by the Γ þ Γm
Qm ¼
plasmonically-enhanced electromagnetic field near the NPs, espe- Γ þ Γm þ knr
cially at the hot-spots [102]. This may increase the absorbed light
−1
by the fluorophores. On the other hand, the emission process and τ0 ¼ ðΓ þ Γm þ knr Þ :
non-radiative decay rates are strongly influenced by metals due to the
coupling between the emission of the fluorophore and the NP LSPR Often, the efficiency of fluorescence enhancement is characterized
modes [103], and as consequence, the quantum yield and life time of by the enhancement factor according to:
fluorophores change [104].
Excited-state fluorophores can create plasmons near metals, I f ‐m
EF ¼
which can radiate with the same emission spectra than the original If
fluorophore but with shorter lifetimes (τ). The increase of the radiative
decay rate (Γ = τ−1) is produced by the shorter lifetimes of plasmons where If–m represents the emission intensity of the fluorophore–metal
(~50 fs) compared with fluorophores (~1 ns) [7]. Because the emission complex and If represents the emission intensity of the free fluorophore,
properties are a combination of both the fluorophore and the metal, the whose concentration matches with the concentration of fluorophores in
fluorophore–metal complex can be regarded as the emitting specie the complex. The effect of SEF can be dramatic and quantum yields
characterized by a new quantum yield (Qm) and lifetime (τm) with can reach almost the unity, lifetimes can decrease up to 105-fold and
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 265

enhancement factors of three orders of magnitude can be obtained molecule. The detection of the target molecule triggers the reversible re-
[105]. Furthermore, shorter lifetimes increase the photostability of storing of the fluorescence of the quenched dye [112]. Small metal
the fluorophore–metal complex, since it can undergo more excitation/ nanoparticles (~ 2 nm) were firstly applied in such hairpin probes as
emission cycles, and enhances in parallel its brightness. mere quenchers due to their high absorption cross-sections (Fig. 8)
These features, explain why platforms based on SEF are attractive for [113]. However, sensors based on SEF can be designed if the colloidal
analytical sensing. However, the design of sensors based on SEF is chal- NP is large enough. Cheng et al. developed a SEF sensor with thiolated
lenging. The sensitivity of the coupling between the fluorophore and the hairpin oligonucleotides that undergo quenching/SEF in the absence/
LSPR modes of the metallic nanostructure is exploited for sensing, how- presence of a target oligonucleotide (Fig. 8) [114]. The influence of the
ever many parameters in the environment that are not under control distance between the fluorophore and the metallic surface was studied
may affect simultaneously the fluorescence emission. For example, using hairpin oligonucleotides of different lengths. Moreover, the influ-
changes of solvent or adsorption of proteins in physiological fluids mod- ence of the NP size (from 20 to 100 nm) was demonstrated experimen-
ify the refractive index and consequently, the coupling [106]. This tally and theoretically. The largest AuNPs (100 nm) produced the
would produce misleading signals. Moreover, the fact that SEF platforms highest enhancement factor (~1.5), which was in any case lower than
require a controlled distance between the metal and the fluorophore the typical values obtained with SEF platforms in substrates.
involves the use of spacers. These spacers have as well their own limita- Recently, molecular beacons involving SEF have been applied for the
tions, for example in terms of synthesis and stability [107]. detection of mercuric ions using thymine (T) containing probes. In this
However, recently, promising examples of sensors based on SEF case, the hairpin structure opened in the presence of ions due to the
substrates had shown high sensitivity, specificity and reproducibility, formation of a T–Hg2+–T complex. Enhancement factors around 7 and
even for multiplexed sensing in complex systems such as blood, which a high specificity were reached using this approach [115]. The design
can boost further applications in the field and the development of com- of molecular beacons based on SEF can be extended to various targets
mercial devices in the best case [108]. In the following, applications of such as proteins or microRNAs [116]. However, though it could be in
several sensing platforms based on SEF will be discussed and compared. principle feasible to use such sensors for in vivo detection [117], the
We refer the reader to an excellent previous report for more details need of a relatively high-sized NP well stabilized to avoid agglomera-
about the physical aspects of SEF and the production of SEF platforms, tion, and the probable non-specific adsorption of proteins in physiolog-
both in solution and substrates [7]. ical medium, would complicate the practical use of these sensors. There
are more examples in the literature where SEF sensors are designed to
4.2. SEF-based nanosensing using colloidal metal NPs in solution undergo an enhancement in fluorescence due to a controlled increase/
decrease of the spacer length or distance. Polymers can be also used as
There are only few examples of SEF platforms for analysis in solution. responsive spacers [118]. The main limitation of such design is the
Nevertheless, they could have broad applications in life science and an- lack of a fine control over the fluorophore–metal distance in some
alytical chemistry. The impact of improvements in this field could be cases and the difficulties to achieve multiplexing.
noteworthy since fluorescent probes are the main tools for real-time Non-invasive detection with fluorophore–metal complexes in solu-
imaging of live cells and NPs can increase their quantum yield and tion has more chances to reach commercial applications as compared
photostability. For SEF nanosensing in solution, the size of colloidal to invasive sensing. Recently, Hakonen and Strömberg developed an
NPs is particularly important. In very small metallic nanoparticles, ammonium optode sensor to study tissue decomposition with AuNPs
absorption is higher than scattering of light, and quenching of the emis- and a ratiometric fluorophore entrapped in hydrogel/ether droplets
sion of the fluorophore will predominate over its enhancement. There- (Fig. 9) [119]. In this case, the droplets are used to concentrate both
fore, larger nanoparticles and geometries with higher scattering cross- fluorophore and metal nanoparticles. The obtained limits of detection
sections are preferred [109]. and signal-to-noise ratios were reduced as compared with other con-
One of the first reported SEF sensors in solution was based on AgNPs ventional analytical techniques. Moreover, this sensor configuration
coated with a silica shell [110]. Such proof of concept demonstrated that could be modified to sense theoretically all ions.
the binding of fluorescently labeled streptavidin to avidin-functionalized
AgNPs reduced the lifetime of the fluorophore 1.3-fold (enhancement 4.3. SEF-based nanosensing using colloidal metal NPs on substrates
factor ~4). The main limitations of such sensor were the polydispersity
and inhomogeneous shape of AgNPs, the inhomogeneous silica shell The most advanced SEF platforms for single molecule detection and
thickness and the non-controlled and non-reversible agglomeration of designing of highly efficient multiplexed sensors have been built on
the NPs upon streptavidin binding. These factors produce low sensitivi- substrates [105]. Here, it is worth differentiating between three differ-
ties and reproducibilities. The quality of NPs and silica shells in terms ent kinds of substrates: i) metal nanoparticles bound or deposited
of monodispersity and thickness homogeneity can be improved using onto inert surfaces; ii) metallic thin films with nanoscale thickness;
new synthetic strategies in order to tailor the fluorescence enhancement and iii) lithographically fabricated nanoantennas with controlled for-
[27]. However, sensors based on the streptavidin-mediated binding mation of hot-spots [7]. The three kinds of substrates produce different
suffer from an intrinsic drawback. Due to non-specific adsorption, interactions between fluorophores and metals and all of them can be
streptavidin-functionalized NPs tend to agglomerate even in the absence used for sensing [120]. Typically thin films do not modify dramatically
of biotin or avidin [40]. This non-specific adsorption is probably one of the lifetime and emission intensity of fluorophores. In contrast, litho-
the main drawbacks for recognition using some biological linkers. Other- graphically prepared substrates can trigger the largest enhancement
wise proteins can be directly attached to the metal surface and act as factors but they are not cost-effective. This section will focus on the
spacers within the fluorophore–metal complex [111]. first kind of substrates that typically result in enhancement factor of
The production of robust sensors for analytical purposes should fluorescence in the range of 1–100 [12].
avoid non-specific interactions. Specificity in the detection process can AgNP and AuNP island films are the SEF platforms more broadly
be substantially increased for SEF sensors in solution using oligonucleo- applied for sensing [108]. The formation of NP islands on a dielectric
tides. For example, molecular beacons have been extensively studied substrate concentrates optical fields due to the LSPRs of NPs and the
(Fig. 8). These hairpin shaped oligonucleotides contain a quenched presence of gaps between the particles that lead to enormous field am-
dye, a quencher and an oligonucleotide sequence that act as a probe. plifications and fluorescence enhancement factors (~100-fold), higher
Such sensors can detect DNAs or RNAs that are complementary to than those obtained with NPs in solution. Protein microarrays on
their probe in a very specific manner, due to the opening of the hairpin AuNP island films have been utilized for high-throughput protein anal-
structure upon the hybridization between the probe and the target ysis. Fig. 10 schematically shows the configuration of the sensors based
266 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

Fig. 8. (A) Schematic representation of a molecular beacon based on metallic NPs. SEF can occur at appropriated NP–fluorophore distances and NP size. (B) Schematic representation of a
molecular beacon for SEF using AuNPs and thiolated hairpin oligonucleotides of different sizes.
From Ref. [114].

on antibodies (Ab) that bind specifically small proteins (e.g., cytokines) analytes triggered by the presence of AgNPs. Multiplexing in such de-
and bigger protein biomarkers (e.g., 1° human Ab) for the detection of vices is in principle possible which may increase the number of feasible
defects in the immune system and type 1 diabetes, respectively [121]. applications of SEF nanotechnology.
This approach allows for multiplexing and has higher sensitivity and
specificity than the ELISA assay. 5. Concluding remarks
The size and shape of NPs within the aforementioned substrates are
not homogeneous, which could compromise the reproducibility of the In this review, we have analyzed the potential of using colloidal
sensor. Recently, the formation of SEF planar platforms via the assembly metal nanoparticles as advanced sensing platforms, both in solution
of colloidal NPs with controlled geometry onto substrates has gained and on solid substrates, applied to surface-enhanced spectroscopies.
increasing interest. There are many possible designs such substrates As shown, research in the field accomplished the design of high quality
based on AuNPs and quantum dots [122], Langmuir–Blodgett arrays of nanoplasmonic sensors showing impressively low detection limits
AuNPs [123], or copper arrays [124]. However, for detection the recog- while also being reproducible, reliable, portable and reusable. According
nition event between the SEF platform and the analyte determines the to the latter, some of the colloidal sensing platforms described in this
specificity and sensitivity of the sensor. As in the case of SEF sensors in review could be translated into products or technologies for industrial
solution the most utilized molecules for this purpose are oligonucleo- applications [126]. In fact, even though most of the commercial devices
tides and proteins [107]. Therefore, the appropriated choice of oligonu- based on surface-enhanced spectroscopies integrate planar substrates
cleotides or proteins and their effective linkage (avoiding non-specific produced by photolitography, several companies have already devel-
adsorption) to the substrate are key factors for the further technique oped detection systems based on colloidal particles. For example, ag-
implementation. glomerated silver nanoparticles are being used on SERRS substrates
In a similar context to SERS, the design and development of for nucleic acid detection.
microfluidic devices for sensing involving SEF will influence the future Considering the high intensity of LSPR-mediated circular dichroism
application of such platforms. Recently, Wang et al. successfully built a signals that have been registered by NPs both in the visible-near infra-
highly efficient micro/nanofluidic SEF sensor [125]. Reactive oxygen red region, using versatile and generic self-assembly strategies, we an-
species within a flow were detected via the enhanced fluorescence of ticipate the use of such plasmonic nanoantennas as powerful chirality
 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270 267

Fig. 9. (A) Schematic representation of an optode sensor involving SEF with AuNPs and ratiometric dyes entrapped in hydrogel/ether droplets. On the right, false color images show the
ammonium concentrations after 10 days. Concentrations are indicated on the color bar in mM. (B) Sensor without Au NPs. (C) Sensor with AuNPs.
From Ref. [119].

probes upon specific attachment to proteins and DNA for in situ struc- species. Similarly, an analogous combination has already shown very
ture determination by selecting the appropriate nature, dimensions, high enantioselectivity toward (bio)analytes detection through surface
morphology and functionalization of the nanocrystals. In such scenario, enhanced Raman optical activity spectroscopy (SEROA) [128].
the fluorescence detected–circular dichroism (FD–CD), based on the The chemical and physical properties of the analytes to be detected
measurement of the differential emission of light from a sample excited are still some factors that limit the implementation of surface-enhanced
with circular polarized radiation and still in its infancy at the nanoscale spectroscopies based on colloidal particles, specially in the case of
[127], coupled to the surface enhanced fluorescence spectroscopy may SEIRA-based nanosensing. In this regard, the (bio)functionalization of
emerge as a prominent technique for generation of individual and col- the particles rules the quality of the target binding between their sur-
lective chiroptical activity in fluorophores with enhanced FD–CD, face and the analyte, which is key for the development of sensors with
which might be a powerful analytical technique for detection of chiral practical applications. The challenges in this approach are related to

Fig. 10. (A) Electron microscopy image of a gold island film. Schematic representation of plasmonic chips for detection based on protein binding: (B) the substrate is functionalized with an
Ab that captures the analyte and (C) the substrate is functionalized with an antigen of the 1° Ab that acts as biomarker of type 1 diabetes.
From Ref. [121].
268 S. Abalde-Cela et al. / Advances in Colloid and Interface Science 233 (2016) 255–270

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