Surface-enhanced Raman spectroscopy

for chemical and biological sensing

using nanoplasmonics: The relevance
of interparticle spacing and surface
morphology
Cite as: Appl. Phys. Rev. 7, 031307 (2020); https://doi.org/10.1063/5.0015246
Submitted: 26 May 2020 • Accepted: 17 August 2020 • Published Online: 18 September 2020

Vasyl Shvalya, Gregor Filipič, Janez Zavašnik, et al.

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Appl. Phys. Rev. 7, 031307 (2020); https://doi.org/10.1063/5.0015246 7, 031307

© 2020 Author(s).
 Applied Physics Reviews REVIEW scitation.org/journal/are

Surface-enhanced Raman spectroscopy

for chemical and biological sensing using
nanoplasmonics: The relevance of interparticle
spacing and surface morphology
Cite as: Appl. Phys. Rev. 7, 031307 (2020); doi: 10.1063/5.0015246
Submitted: 26 May 2020 . Accepted: 17 August 2020 .
Published Online: 18 September 2020

Vasyl Shvalya,1 Gregor Filipič,1 Janez Zavasnik,1 Ibrahim Abdulhalim,2 and Uros Cvelbar1,a)

AFFILIATIONS
1
ef Stefan Institute, Ljubljana SI-1000, Slovenia, European Union
Joz
2
Department of Electrooptics and Photonics Engineering and the Ilse Katz Center for Nanoscale Science and Technology, School of
Electrical and Computer Engineering, Ben-Gurion University of the Negev, Beersheba 84105, Israel

a)
Author to whom correspondence should be addressed: uros.cvelbar@ijs.si

ABSTRACT
In this review, the weightiest decadal developments of surface-enhanced Raman scattering (SERS) and nanoplasmonic materials in sensing
applications are discussed. Today, there are several well-established research directions where plasmonic detection is employed extensively,
namely, food and water quality monitoring, viruses, pathogenic bacteria and hazardous toxin investigations for theranostic applications, and
explosive substance detection for military and civil protection purposes. A combination of vibrational spectroscopy and surface nanoengin-
eering has gained a reputation as a powerful weapon for rapid and accurate determination of submolecular quantities of nanoanalytes. Signal
enhancement achieved by employing various metallic nanoparticles and nanostructures can be amplified significantly due to the electromag-
netic field confinement effect. Localized surface plasmon waves, which are responsible for the phenomenon, promote light absorption at
nanovolume, generating ‘hot spots’ with an incredibly intense and confined electromagnetic field close to the nanosculptured metallic sur-
face. However, the formation of the hot spot network is heavily dependent on morphology, size, and spatial arrangement of plasmonic nano-
materials. Under optimal excitation conditions, the interaction between the optically induced electromagnetic field in the hot spot region and
a probing analyte attached to the nanosculptured metallic substrate enlarges photon scattering cross section, increasing signal intensity by
106–1010. As a result, fast single-molecule vibrational fingerprint recording is possible. This focused review collects recent state-of-the-art
developments in nanoplasmonic SERS sensing, highlighting the most efficient surface morphology designs that hold the most promise for
future developments.
C 2020 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://
V
creativecommons.org/licenses/by/4.0/). https://doi.org/10.1063/5.0015246

TABLE OF CONTENTS B. Interparticle gaps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

I. INTRODUCTION AND MOTIVATION. . . . . . . . . . . . . .
II. FUNDAMENTAL REMARKS ON SURFACE-
ENHANCED RAMAN SCATTERING . . . . . . . . . . . . . . .
A. How Raman becomes SERS . . . . . . . . . . . . . . . . . . .
B. Chemical mechanism in SERS . . . . . . . . . . . . . . . . .
C. Electromagnetic mechanism in SERS . . . . . . . . . . .
D. Field confinement ‘hot spots,’ the limit of
detection (LOD) and sensitivity . . . . . . . . . . . . . . . .
III. KEY HOT SPOT FACTORS . . . . . . . . . . . . . . . . . . . . . . .
A. Shape and arrangement . . . . . . . . . . . . . . . . . . . . . . .
2 IV. SERS-SENSING WITH PLASMONIC
NANOPARTICLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2 A. Proper laser wavelength and complex surface
2 morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3 B. Cancer diagnostic and theranostic applications . . . 14
4 C. Kinetic chemical reaction monitoring . . . . . . . . . . . 15
D. Metal ion detection in aqueous environments. . . . 18
4 E. Detection of explosives and hazardous agents . . . . 19
7 F. Pathogenic bacteria detection . . . . . . . . . . . . . . . . . . 21
7 G. Viruses and SERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

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V. 3D-PLASMONIC NANOSTRUCTURES WITH
COMPLEX MORPHOLOGY. . . . . . . . . . . . . . . . . . . . . . . .
A. General peculiarities . . . . . . . . . . . . . . . . . . . . . . . . . .
B. Pillar-like plasmonic structures. . . . . . . . . . . . . . . . .
C. Porous-like plasmonic structures . . . . . . . . . . . . . . .
D. Nanoplasmonics with wrinkles, pyramids,
and grains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VI. SUMMARY AND FUTURE OUTLOOK. . . . . . . . . . . . .
I. INTRODUCTION AND MOTIVATION
Humanity is facing a number of grand challenges that threaten
the fabric of society and require a global response. For example, micro-
plastics are polluting our seas and soils; morphing viruses are creating
new pandemic threats; and terrorism and war remain constant dan-
gers to communities around the world. The first step toward tackling
these threats is to quantify them, but even this remains a significant
challenge. Portable and reliable sensing systems allowing rapid detec-
tion and accurate identification of different harmful microorganisms
and other hazardous contaminants at low concentrations are required.
New technical approaches and analytical tools are needed to solve
these tasks, providing labeled or label-free sensing abilities and satisfy-
ing four critical criteria: quick response, pronounced sensitivity, high
selectivity, and reliable reproducibility. Among various diagnostic devi-
ces based on electrical, magnetic, or optical properties, inelastic Raman
light scattering (optical nature) combined with nanostructured plas-
monic substrates (electronic nature) seems to be one of the most
promising tools for such applications in the near future. This tech-
nique is commonly known as surface-enhanced Raman scattering
(SERS) spectroscopy.
After the first experimental work conducted by Fleischmann in
1974 on vibrational spectra of pyridine adsorbed at a roughened Ag
electrode1 and a theoretical description provided later by Jeanmaire
and Van Duyne,2 SERS spectroscopy was applied in the development
of novel plasmonic sensors. The origin of improved vibrational scatter-
ing signal relies on multiple interactions between the incident irradia-
tion, metallic surface morphology, and an analyte, resulting in an
enlarged effective Raman cross section for the latter. Discovering the
nature of the plasmon resonance phenomenon brought the method to
a qualitative and quantitative new level, allowing vibrational finger-
print identification and offering potential for single-molecule detec-
tion.3 However, the quality of the output Raman signal depends on the
optical features of the surface defined by plasmon resonance
FIG. 1. The application area of nanoplasmonic SERS optical sensors, bridging the most significant research fields related to a general public wellbeing.
Appl. Phys. Rev. 7, 031307 (2020); doi: 10.1063/5.0015246
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properties. By modifying nanomaterial composition, morphology,
24 size, and spatial arrangement, it is possible to provide controllable tun-
24 ing of surface plasmonicity, thus opening an avenue for its effective
24 implementation in biological (food quality inspection, water purity
26 monitoring, pathogenic bacteria detection, and discrimination), medi-
cal (cancer cell diagnostic, drug delivery monitoring, theranostics,
28 viruses detection), chemical (kinetic reaction probing, metal ions), and
30 military (toxic vapors, explosives) applications (Fig. 1).
Widespread exploitation of this analytical tool has provoked tre-
mendous research interest devoted to improving SERS-based detection
devices. Within the last decade, there has been a huge surge in nano-
plasmonic sensing research as demonstrated by the publication of
numerous excellent experimental, theoretical, and review articles.4–12
The plasmonic SERS sensing progress achieved along the last decade
need to be consistently summarized, highlighting recent developments
within the area. The ultimate advantage of a SERS-based detection
approach is that the technique possesses seemingly unlimited practical
potential in terms of being an ultra-sensitive, reliable, portable, cost-
effective analytical tool.8 The current review deals with recent advances
in the research field of nanoplasmonic detection with the help of
Raman spectroscopy in chemical, biological, public protection, and
medical applications, touching on theoretical, experimental, and engi-
neering aspects of the subject. It is, therefore, intended to bring readers
a broad insight into the concept of plasmonic SERS analysis, giving an
understanding of its huge potential and practical value for humanity
both now and in the future.
II. FUNDAMENTAL REMARKS ON SURFACE-
ENHANCED RAMAN SCATTERING
A. How Raman becomes SERS
An interaction between matter and light gives rise to photon scat-
tering by the intrinsic molecular and lattice vibrations of the material.
Most photons are scattered elastically without changing their initial
frequency (Rayleigh scattering), but approximately one in a million
undergoes a frequency change (Raman scattering) by losing or gaining
some energy after interacting with the material. An energy drop in
favor of material vibrations excited from the ground state is known as
the Stokes Raman component, while the opposite situation where scat-
tered photons gain additional energy is called the anti-Stokes Raman
component. Even if Stokes bands are considerably more intense than
anti-Stokes ones, it is still a weak phenomenon, much less efficient
than fluorescence. However, it contains unique information on the
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structural features of a material. Normally, the signal intensity of the
Raman vibrations depends on several factors and can be described by
the following expression: PRaman¼INKrj,13 where PRaman is the
recorded Raman signal by a detecting device, I is the power of incident
irradiation, N is the total quantity of excited molecular vibrations, K is
a constant related to the proportion of generated photons that were
converted to electrons and recorded by the detector, and rk is the
Raman cross section of the particular jth normal band integrated over
all emission directions within a sample. For fluorescence, rk is about
1016 cm2/molecule. For Rayleigh scattering, this value is signifi-
cantly lower 1026, and for Stokes Raman scattering rk is typically
as low as 1029 cm2/molecule.13,14 From the formula, it is seen that I
and K relate to instrumental specifications, and N is linked to the
amount of material. Thus, these parameters cannot be influenced
strongly. The only parameter that can be externally affected is rk. Here
SERS stars, via the application of plasmonic nanomaterials as a source
of hybrid optically induced electromagnetic excitation. Using this tech-
nique, scattering cross section can be enlarged up to several orders of
magnitude, resulting in more intense Raman scattering. In essence, the
simple light-matter interaction is enhanced by additional light–metal
surface interaction.15–17 As a result, the intensity of the Raman modes
can be characterized by a formula: PSERS ¼ PRaman  GSERS ¼ PRaman
 GSERSCM  GSERSEM.18 In this equation, PSERS means enhanced
Raman signal, PRaman is normal Raman scattering, and GSERS is an
enhancement factor (EF) provided by the nanoplasmonic substrate
and consisting of the GSERSCM chemical and GSERSEM electromag-
netic mechanisms. These two mechanisms define mode intensity
amplification, making them essential for accurate detection and
analysis. For a better understanding of the nature of SERS, a gen-
eral description of both mechanisms is presented in the rest of the
chapter. For readers who are interested in a detailed theoretical
and mathematical description, we recommend specific review
articles4,18 for further reading.
B. Chemical mechanism in SERS
The first mechanism is associated with molecular orbital interac-
tion between the analyte and metal nanoparticles (NPs) deposited on
the sensing platform.19 Following Jensen et al.,20 chemical enhance-
ment consists of three aspects (Fig. 2):
(a) Non-resonance Raman caused by ground-state chemical
interactions between an analyte and sensing platform (not
related to the excitation, Fig. 2 panel I);
(b) resonance conditions of an adsorbate molecule and irradia-
tion wavelength k provoking resonance Raman enhancement
(Fig. 2 panel II),
(c) laser illumination being in resonance with photoinduced elec-
tron transfer transitions from the Fermi level of a metal sur-
face to vacant states of the adsorbate (Fig. 2 panel III).
Figure 2 represents a schematic explanation of the three factors
involved in the chemical mechanism of inelastic Raman scattering
enhancement. The contribution of the charge-transfer (CT) mode to
SERS is considerably stronger than the other two and mainly relies on
changes of molecule polarizability attached to the nanosculptured sur-
face, which can lead to new metal–analyte complex formation. The
electronic orbitals of a newly created chemical coupling are drastically
altered with respect to the original orbital configuration of the analyte,
which opens the door to intrinsic electron transitions inside the mole-
cule–metal surface complexes.21 From the electronic point of view,
this effect takes place because of the energy difference occurring
between the highest occupied states in a metal (HOMO) and the low-
est unoccupied energy states (LUMO) of the attached molecule. The
EF of this mechanism can be reasonably estimated as (xX/xje),4 where
xX is the energy difference of analyte HOMO–LUMO levels and xje is
excitation energy between LUMO of the adsorbed molecule and
HOMO of the metal. It is expected that organic molecules, revealing a
substantial stabilization of HOMO–LUMO energy gaps and favoring

FIG. 2. Mechanisms of chemical enhancement in SERS. Panel I: Ground state enhancement (non-resonance); Panel II: Resonance condition for an analyte being under illumi-
nation; and Panel III: Charge transfer resonance provoking electron movement from a metal to an analyte highest occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) of a probe molecule; E is the local electromagnetic field, x is the excitation frequency, and EF is the Fermi level for metal. Reproduced with permis-
sion from Jensen et al., Chem. Soc. Rev. 37, 5 (2008). Copyright 2008 Royal Society of Chemistry.20 Inset represents a four orbitals energy diagram depicting SERS favorable
p-backbonding formation between an adsorbed molecule and metal NPs. Reproduced with permission from Morton et al., J. Am. Chem. Soc. 131, 11 (2009). Copyright 2009
American Chemical Society.22

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p-backbonding formation (Fig. 2 panel III), are the best candidates for
significant chemical enhancement.22,23 The resulting charge transfer
(CT) exchange determines an increase in the inelastic Raman light
scattering cross section (specifically, in the case of those vibrations
where electronic transitions are directly involved). The largest CT
SERS enhancement is expected to be obtained when the energy of
excitation photons falls within a range of energy differences between
the HOMO of an analyte and the Fermi level of a plasmonic metal.
By modifying the electrochemical potential of a metal/probe mol-
ecule system, owing to the electron exchange mechanism, it is possible
to manipulate, to a certain extent, an enhancement of Raman scatter-
ing signal.24,25 It is worth mentioning that the chemical enhancement
does not depend significantly on substrate morphology properties. On
the contrary, it fundamentally relies on the intrinsic polarization ability
of the attached analyte probe. Usually, inelastic vibrational spectros-
copy driven by charge transport enhancement reveals an overall signal
amplification factor in the range of EF  102–103).26 Interesting find-
ings were observed recently by Shegai et al.,27 showing that the chemi-
cal enhancement mechanism can further increase SERS intensity
simply by applying a periodic saw-shaped negative electric voltage to
the metallic electrode in the range of 0 to 1.2 V. This effect is related
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The first process occurs in the nanoscale proximity of metal NP
surfaces, while they are illuminated by a laser beam with an incident
frequency x0. This irradiation excites plasmonic waves (collective
oscillation of electrons) affecting the EM field near the metal-dielectric
interface (Fig. 3). At this stage, the plasmonic NPs (usually made of a
noble metal such as Au, Ag) play the role of receiving antenna, con-
verting the optically induced EM far-field E0 into a near-field Elocal,
which, in turn, is concentrated in the close vicinity of the nanosculp-
tured substrate. The second process arises from the emission of inelas-
tically scattered photons (with frequency xR) modified by additional
EM field excitation that originates from localized surface plasmons
(LSPs). In this case, the ‘nanoplasmonic antenna’ works in radiation
mode, transferring a near-field to a far-field and exciting the molecule
at the same wavelengths as Raman scattering occurs providing reso-
nance conditions. Further, during the third step, the resulting mutual
excitation induces a direct charge exchange between metal nanomate-
rial and HOMO states of a probe molecule (see energy diagram in
Fig. 2), enlarging polarizability of the latter as well its Raman cross sec-
tion. Under the aforementioned modeling conditions, the enhance-
ment coefficient EF is roughly defined as a product of the local field
contribution M1 and the radiation enhancement M230–32
to a broad CT resonance, which can be attributed to the contribution    
Elocal ðx0 Þ2 Elocal ðxR Þ2
of conductive electrons located below the Fermi level of the metal to EFtotal ¼ M1 ðx0 ÞM2 ðxR Þ ¼  2  2 : (1)
the CT transitions.27 It is worth pausing briefly here to make some
general remarks on resonant chemical enhancement:
(i) It is a short-range effect: very tight contact or separation
approximately up to several Angstroms (order of chemical
bonds) between the substrate and analyte.
(ii) It strongly depends on the polarizability of the particular
molecules and the ability of their electronic states to conduct
E0 ðx0 Þ E0 ðxR Þ
Taking into consideration an assumption that the frequencies of
inelastically scattered photons xR are close enough to the incident one
x0 (xR  x0), which is the case for low-frequency molecular vibra-
tions, it is reasonable to write M1(x0)  M2(xR). As a result, the total
EF can be estimated using the well-known power four approximation
EF  jEj4,32
electron transfer via interaction with a metal surface.  
Elocal ðxR Þ4
(iii) Depending on the CT regime (resonant or non-resonant), the EFtotal    : (2)
overall enhancement can be as high as 102–104.
C. Electromagnetic mechanism in SERS
The impact of the chemical mechanism on total SERS enhance-
ment is much lower in comparison with the EM one, which reveals an
amplification factor as high as EF  106–1010 and even more.28 This
mechanism, which typically dominates in SERS, arises from the inter-
action of the optically excited collective electron oscillation (plasmons)
and the probe molecule under study. Coupling the laser beam and
conductive electrons considerably affects local EM field distribution in
the proximity of the nanostructured metallic surface, increasing
Raman scattering cross section and, hence, improving the output sig-
nal.29 The important thing is that SERS based on the EM mechanism
does not rely on adsorbate polarizability or its capability to chemically
interact with a sensing substrate, making the method more selective
and attractive for practical implementation.
Let us briefly consider a problem related to the EM improvement
of SERS, introducing some physical concepts into the description. By
neglecting the chemical mechanism’s contribution, it is widely
accepted that classical EM enhancement can be explained fairly well
by a model including a two-step process: local field enhancement (M1)
and radiation enhancement (M2).30–33 Figure 3 provides a simplified
graphical explanation of the EM enhancement process.32
Appl. Phys. Rev. 7, 031307 (2020); doi: 10.1063/5.0015246
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E0 ðx0 Þ4
It is important to emphasize that apart from a field dependency, EF is
also a position-dependent function. This means that the spatial loca-
tion of an analyte with respect to the plasmonic NPs plays a significant
role in SERS as well. In other words, to get maximal signal amplifica-
tion, a molecule has to be as close as possible to the hot spot of EM
field distribution provided by metal NPs.
Electromagnetic enhancement has the following general
properties:
(i) It is a long-range effect. Tenths of nanometers are still accept-
able for achieving a strong enhancement.
(ii) It is independent of molecule specifications, but depends on
substrate morphology.
(iii) It produces a wide range of enhancement factors (104–1010)
depending on light localization and EM field confinement.
D. Field confinement ‘hot spots,’ the limit of detection
(LOD) and sensitivity
Ultra-high Raman enhancement can be achieved when the most
intense EM field is confined at a certain finite volume near a metal NP
surface. This field confinement can be created when plasmon modes
[propagating surface plasmons (PSPs), LSPs] strongly interact with
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FIG. 3. Schematic representation of plasmon enabled Raman scattering enhancement via the electromagnetic mechanism. Conduction electrons in metal or metal-like nano-
materials can be coherently excited by incident light to oscillate collectively at metal/dielectric interfaces forming surface plasmons waves: the longitudinal waves in the case of
an extended flat metal surface (panel I) or the localized ones in a case of nanostructured particles or nanoscale crevices (panel II). The molecules attached to the plasmonic
surface are irradiated by a newly created electromagnetic field that forces electron injection providing an additional excitation of the analyte vibrational modes.

one another. For a broad physical and mathematical overview of plas-
monic surface lattice resonances and coupling between PSP and LSP
modes, we recommend comprehensive review articles.4,34
Following,4,34 the most intense EM field is localized at the gaps or
crevices between metallic NPs or between a metallic NP and metal sur-
face. These special areas are known as ‘hot spots,’31,35–38 which can be
classified in the following manner:
(i) First-generation hot spots appear as a result of interaction
between a single nano-object and incident irradiation (Fig.
4 panel I, a1, a2).
(ii) Second-generation hot spots are produced by coupled plas-
monic nano-objects with controllable inter-particle distan-
ces (Fig. 4 panel I, b1, b2, and e1, e2).
(iii) Third-generation hot spots are a product of superposition of
EM field originating from metal NPs and EM field scattered
from the backing platform, which can be formed of conduc-
tive or insulator material (Fig. 4 panel I, c1, c2, d1, d2, and
e1, e2).
In general, the SERS signal intensity produced by second-
generation hot spots is up to four orders of magnitude larger in com-
parison with that generated by a single NP (Fig. 4 panel I, b1, b2),
making them more favorable for analyte fingerprint identification by
SERS. Also, the hot spot-specific volume of coupled nano-objects is
quite small, with an approximate diameter of 1–5 nm.37,39 In the
case of third-generation hot spots, the output signal relies heavily on
dielectric properties of the material from which the substrate is made.
For example, the resulting EF for a structure consisting of an Au nano-
sphere placed on a silicon plate (AuNP ! Si) is about one order of
magnitude lower compared to a platform constructed of the same Au
NP but located on Pt thin films (AuNP ! Pt).32 Considering the same
backing material (Fig. 4 panel I, c1, c2, d1, d2) but different NP geome-
try, the SERS amplification factor generated from a single Au nano-
sphere is more than 100-fold lower than that of a single Au nanocube
due to more concentrated EM field at the cube’s corners. Note that for
all these comparisons, the excitation wavelength was kept at a
fixed value. The common connecting obstacle of the second- and the

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FIG. 4. Panel I: Formation of first, second, and third-generation hot spots. The table displays the contribution of hot spots with high EM field amplification to overall SERS
intensity, indicating quality > quantity. Reproduced with permission from Ding et al., Nat. Rev. Mater. 1, 6 (2016). Copyright 2016 Springer Nature.32 Reproduced with per-
mission from Fang et al., Science 321, 5887 (2007). Copyright 2008 The American Association for the Advancement of Science.44 Panel II: (A) SERS intensity of a band
located at 1362 cm1 as a function of Raman marker (Rhodamine) concentrations. Error bars indicate standard deviations from at least 20 spectra. (B) Probability of
obtaining readable SERS fingerprint at different analyte concentrations. Reproduced with permission from Yang et al., PNAS 113, 2 (2016). Copyright 2020 National
Academy of Sciences.45

third-generation hot spot is their small volume size. One way to make
a situation better by increasing the number of near-field enhancement
regions is combined cooperation of 0D nanoparticles to form a closed
geometry as demonstrated on an example of gold nanospheres that
form chamomile type assembling40 or empty nano-spherical trimers,
quadrumers, and other aggregates.41,42 Another solution is the use of
one-dimensional plasmonics [nanowire, nanorods (NRs)] that create
narrow gaps with intense field confinement along the substrate-
nanoparticle and between the nanoparticles. As a result, a hot spot
volume size can be enlarged up to 104 times with respect to conven-
tional ones (Fig. 4 panel I c1, c2), benefiting SERS properties
significantly.43
The importance of cavity, gap, and crevice geometry has been
discussed in theoretical articles46–48 and has found further support in
some experimental work.3,44,49 In particular, Fang et al. have investi-
gated a contribution of hot spots to the SERS signal. As was demon-
strated in a report,44 despite the fact that hot spots with an EF in the
range 107–109 take up less than 1% of the total surface area, they

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contribute almost 50% of overall SERS intensity (see table incorpo-
rated in Fig. 4). It is, therefore, better to have a small amount of hot
spots with higher enhancement than a large quantity of hot spots with
lower enhancement. However, in real cases, some compromise might
occur, and optimal experimental signal amplification is related to a
distance between hot spots, EM field strength, and excitation wave-
length. Arranging a series of plasmonic NPs on top of the substrate
may lead to the appearance of a network consisting of spatially narrow
regions that generate a large EM field enhancement. When consider-
ing a general SERS scaling rule PSERS  jE( Local)j2jE( Raman)j2 [where
E( Local) and E( Raman) are the local field enhancement factors at the
excitation and Raman scattering wavelengths], the separate use of
these terms and their explicit consideration are needed when interpar-
ticle distances are reduced down to several nanometers, namely, gaps
below 10 nm.50 Theoretically, with decreasing gap size, the EM field
should increase as jEj4  1/a4 (where a is the gap size).37 However,
more recent developments holding strict electrodynamic conditions
reveal that the EM field does not follow this predicted behavior. In
fact, the field enhancement as a function of cavity size variation
satisfies universal behavior, yielding an expression jEj4  1/ap
(p  1.2–1.5), which is weaker in comparison to the 1/a4 approxima-
tion.51 This discrepancy is associated with currents that start to flow
between the particles as the gap size becomes less than 2 nm. Once the
interparticle distances reach sub-nm (<1 nm) size, the classical elec-
tromagnetic approach fails, and the nonlocal effects come into play.
Due to the extra-strong EM-field confinement, the optical response
becomes non-linear, and the properties of molecule-nanoplasmonics
complex undergo changes caused by the generation of hot electrons in
the vicinity of the nanoparticle surface. This can result in alteration of
the photophysical, photochemical features of the adsorbed analyte,
boosting chemical reactions and providing changes in the excitation
dynamics accompanied by the emergence of molecular optomechani-
cal effects. The competing fundamental processes that are not relevant
at a larger scale (>10 nm) become significant at subnano-levels, pico-
cavities, and gaps requiring consideration of “the weak coupling”
assumption based on quantum-mechanical approaches, thus helping
to model SERS substrates with desirable optical performance.52,53
Recently, a new scheme was proposed to obtain even higher
SERS EFs using the coupling between localized and extended or prop-
agating surface plasmon waves.34 The idea is that exciting the
electron-spin polarization (ESP) wave produces enhanced field EFex
 100, near the metal surface, which in turn excites the LSP wave on
metal NPs located in its neighborhood. The LSP excited from a free
space gives EFlsp  10–50. The resulting factor with ESP–LSP coupling
geometry is expected to be EF  EFex  EFlsp, which is at least two
orders of magnitude higher than with ESP excitation alone. This con-
figuration can be implemented by using the Kretschmann-Raether,
grating or waveguide coupling configurations. In principle, the concept
can be generalized to a coupling between any extended surface EM
waves and LSPs, such as Bloch and Tamm waves.34,54
By combining resonance Raman effects—in particular, the CT
mechanism and EM enhancement originating from the plasmonic
nature of a material—the Raman photon scattering cross section can
be considerably improved, reaching a value of about 1014 per mole-
cule, allowing the vibrational spectrum from one single molecule to be
obtained (for comparison, normal inelastic scattering cross section is
approximately 14–15 orders of magnitude lower than that
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accumulated by SERS). For a deeper understanding of hot spot phys-
ics, the reader can refer to specific reports.54–57
The Raman cross section enlargement results in a higher signal/
noise ratio as well as better sensitivity of this optical method pushing
the limit of detection toward the single-molecule level. Analytical
parameters such as the limit of detection (LOD) and quantification
range (sensitivity) are of vital importance in SERS analysis. The first
one is related to a minimal amount of a single analyte (concentration
in the case of solution) that can be detected by monitoring a position
of the most dominant characteristic vibration band. The sensitivity of
SERS can be defined from a slope of a concentration dependence as
presented in Fig. 4, (panel II a “orange zone”).45 The LOD is defined
as a rule of thumb by the ratio of the noise of the measuring system to
the sensitivity, assuming the minimum detectable variation in the
measured signal is the noise level. From the same figure, other “grey”
and “red” regions do not reveal concentration dependency and repre-
sent a single-molecule detection and the saturation level (region, where
a custom Raman technique can be utilized to a certain extent).
Following a trend of sensitivity curve, the probability of obtaining
nicely featured spectra reduces with lower concentrations (Fig. 4, panel
II b), which requires to collect more spectra around the measurement
spot. The additional important parameter is the limit of identification
(LOI), which is applicable when dealing with a set of samples or a mix-
ture of several similar analytes. LOI is intended for accurate discrimi-
nation of the smallest analyte concentration by comparing its
vibrational spectra to a defined database. LOI depends on LOD and is
typically higher due to the difference in Raman peak intensity of
samples.58
Highlights:
(a) Chemical enhancement is much weaker than EM
enhancement.
(b) The most intense EM field is confined in tiny sub-nm spaces
between plasmonic NPs.
(c) Combining localized and extended plasmons can generate
ultra-high enhancement because of significantly enlarged
Raman cross section.
III. KEY HOT SPOT FACTORS
A. Shape and arrangement
In the current section, an overview of theoretical investigations
related to the problem of NP morphology highlighting the importance
of size, shape, spatial arrangement, and cavity geometry in connection
to hot spot formation is introduced.59 The realization of highly sensi-
tive 2D and 3D structures, including dense hot spot meshes, has
become a huge challenge in recent years. By using the Kretschmann-
Raether configuration,60 which is a basic setup for investigating plas-
monic phenomena, Li et al. showed that it is possible to obtain an
additional 1–3 order increment of local EM field by exciting LSPs via
ESPs if the incident angle coincides with that for ESPs; hence, maximal
EM intensity is achieved.54 In another work,57 the influence of Au NP
diameter on EM distribution was presented. Theoretical modeling
provided the setup configuration, exhibiting optimal field enhance-
ment properties with the following specifications: inter-particle dis-
tance 1300 nm, particle diameter 80–100 nm, and irradiation
wavelength 785 nm.57 For green laser excitation with k ¼ 532 nm and
normal incident angle, Li et al. calculated that ideal arrangement for a
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square array of Au NPs deposited directly on top of a thin Ag film: NP
diameter 80 nm and grid distance 75 nm.61 Later on, Abutoama
et al.62 suggested a promising strategy for EM field improvement over
a wide spectral range (400–2000 nm) using a grating plasmonic struc-
ture. This setup offered the possibility of reaching up to three orders of
magnitude increase in EM intensity, simply by varying the grating
dimensions. This significant field increment and spectral interval wid-
ening are attributed to coupling of two regimes: extended surface plas-
mon resonance and cavity resonance modes. Common to all these
investigations54,57,61,62 is that theoretical simulations were performed
only on spherically shaped Au NPs located on top of a thin Ag film.
Planarly arranged spherical plasmonic NPs have a crucial disadvantage
with respect to more complex particle geometries like nano-disks
which reveal much narrower and more intense plasmon resonance
peak due to stronger EM confinement along the edges.63 By varying
disks’ diameter or interparticle spacing, or introducing a disorder, the
broadband features can be extended to a wider spectral range.
In Ref. 34, a comprehensive review of this excitation approach was
given, and some additional simulations were presented as well for nano-
rods (NRs) instead of spheres, showing even higher EFs on the tip of the
NRs. When plasmonic nanospheres are substituted by Au nano-disks,64
nanorods,27,65 nano-triangular prisms,66 nano-bipyramides,67 or their
dimeric coupling,68 the collective electron oscillation is affected by the
presence of sharp edges or facets. This is usually reflected as a redshift of
the resonance frequency or plasmonic mode splitting, altering the local
EM distribution. Hao and Schatz39 investigated this problem, presenting
comprehensive research describing EM field behavior around Ag mono-
mers and dimers made of triangular nanoprisms, NRs, and oblate sphe-
roids. In order to provide a meaningful comparison, NP sizes were
optimized by way of having resonance conditions at similar incident
laser wavelength (in that study k was chosen to be 700 nm, with an
exception for spheroidal NPs, where k ¼ 695 nm; see Fig. 5)
In the case of monomers, the largest enhancement was observed
for NRs (Fig. 5, panel I, c). In contrast, considering dimer structures, it
was observed that EM enhancement heavily depends on the wave-
length and interparticle distance.39 For instance, a triangular nanoprism
dimer ‘tip-to-side’ has maximal field amplification at k ¼ 852 nm,
reaching an EF of 5  104, while for ‘tip-to-tip’ structures, the optimal
excitation length is k ¼ 932 nm with corresponding enhancement
about 5  104 (Fig. 5, panel II). In turn, nanospherical dimers support
optimal EM enhancement at ‘greenish’ wavelength, with EF close to
104 (k ¼ 520 nm).

FIG. 5. Panel I. Contour maps showing EM-field distribution around nano-plasmonic monomers: (A) and (B) are triangular prisms with two options for incident light polarization;
(C) and (D) are colored contours with EM field increment for a nanorod and spheroid, respectively. Panel II. E-field enhancement distribution for different dimer structures: (A)
“tip-to-side” prism coupling; (B) “tip-to-tip” prism coupling; and (C) “side-by-side” nanospherical structure. The separation distance between individual particles was kept as
2 nm. Reproduced with permission from J. Chem. Phys. 120, 1 (2004). Copyright 2004 AIP Publishing.39

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B. Interparticle gaps
The NP interaction on the surface may create a more complex
dimer structure, providing variations in the interparticle gap morphol-
ogy and appearance of nanocrevices,69–71 nanofacets,72–75 or even
nanobridges.76–78 When nanoplasmonics are in contact through a
conductive junction, it opens a door for direct exchange of free elec-
trons, giving rise to the bonding dipole plasmon mode (BDP), charge
transfer plasmon mode (CTP), or longitudinal antenna plasmon mode
(LAP).79 In the case of a dimer consisting of two ideal 50 nm Au
spheres connected via a nanobridge with diameter 2–15 nm, the result-
ing peak position and intensity of EF wavelength spectra are strongly
influenced by bridge dimensions (Fig. 6 a1, a2). As clearly seen from
the graph, the maximal enhancement drops drastically from 108 down
to 105, when junction diameter changes from 2 to 10 nm, also reveal-
ing a slight blueshift of the BDP resonance peak (solid gray circle in
Fig. 6 b2).79 Similar behavior occurs when Au dimer is brought into
metallic contact by crevices (Fig. 6 b1, b2) but with one significant dif-
ference. Before the BDP mode exhibits monotonically decreasing
behavior, the EF trend overcomes a large jump, exceeding the idealized
separated dimer. A 5 nm crevice produces 1010 field magnification,
which is about 30 times larger in comparison to a ‘non-contact’ Au
nanosphere pair. Blueshifting of the BDP mode was observed as
well.79 It should be pointed out that the CTP mode starts playing an
important role as bridge/crevice size increases (10–15 nm), manifest-
ing as a peak at the long-wavelength part of the spectrum. However,
tiny crevices are more beneficial for achieving efficient hot spot regions
than nanobridges of the same size.
FIG. 6. The influence of cylindrical nanobridges [(A1) and (A2)] and nanocrevices [(B1) and (B2)] on the electromagnetic enhancement factor EF. Gray solid outline S (A1) dis-
plays the volume of EF calculations for connected spheres with R ¼ 50 nm [(A1) and (B1)]. Abbreviations BDP and CTP stand for bonding dipole plasmon mode and charge
transfer plasmon mode, respectively. Reproduced with permission from Huang et al., J. Mater. Chem. 6, 36 (2018). Copyright 2018 The Royal Society of Chemistry.79
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When metallic NPs with sharp facets are in the vicinity of each
other showing facet-to-facet coupling, a new type of plasmon mode
activity can be observed. Instead of a typical blueshift, the BDP reso-
nance frequency drifts to a near-infrared spectral region starting from
695 nm for 2 nm facets and moving toward 765 nm for 15 nm ones
[Figs. 7(a1) and 7(a2)]. Simultaneously, the average SERS intensity
falls by almost 75% from the initial enhancement obtained for non-
contact Au nanospheres.79 In the same work, Huang et al. additionally
investigated the influence of plasmonic NP roughness on hot spot
intensity distribution. As seen in Fig. 7(b), an increase in hemisphere
radius r leads to a slight improvement (from 7  109 to 9  109) in
total field magnitude, with an evident blueshift of the BDP mode. The
threshold limit of local EM field enhancement induced by smooth
plasmonic NPs may break down due to the features generated by nar-
row crevices.
Let us briefly discuss how EF will behave under gap distance vari-
ation. In the case of spherically shaped Au NPs with diameter 60 nm,
field enhancement undergoes a drastic decrease of about 4–5 orders of
magnitude, while the gap distance increases from 1 to 30 nm [Fig.
8(a)]. BDP resonance frequency shifts almost 150 nm downward to
shorter wavelengths. A significant decrease in EF with gap distance is
attributed to the fact that the spatial energy distribution of evanescent
EM waves induced by surface plasmons provides a strong exponential
reduction with respect to proximity to a metal surface.80,81 Taking into
account that noble metals are more efficient candidates to support
SERS activity, it is interesting to compare the influence of interparticle
distance for nanospherical dimers made of Ag or Au. As was
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FIG. 7. The influence of nanofacets [(A1) and (A2)] and nanoroughness [(B1) and (B2)] on the electromagnetic enhancement factor EF for gold spheres with R ¼ 50 nm.
Abbreviation BDP is the dipole plasmon mode. Reproduced with permission from Huang et al., J. Mater. Chem. 6, 36 (2018). Copyright 2018 The Royal Society of Chemistry.79

demonstrated by Huang et al.,82 the average field enhancement coeffi-
cient for both Ag and Au dimers also dramatically shrinks with
increasing gap size, showing nearly linear dependence with similar
negative slopes presented on a double logarithmic scale [see Fig. 8(b)].
Typical blueshifting of BDP resonance wavelength is present for
both metal NP couplings as well. The interesting finding here is
that the EF decreases when the Au sphere diameter reduces from
60 nm to 30 nm. The opposite behavior was observed for an Ag
dimer, where EF increased almost by one order of magnitude when
the diameter doubled.82 An important finding was observed: for
Ag NPs larger than 50 nm, the EF undergoes ‘flattening’ in the visi-
ble spectral range [Fig. 8(c)], which can be explained as follows.
For relatively large NPs not in the main dipole resonance mode,
multiple resonances can be excited as well. Thus, in the case of
dimeric coupling, a constant merging of bonding multipole reso-
nances (shorter wavelengths) and bonding dipole resonances
(longer wavelengths) might provoke the appearance of a flat pla-
teau on the EF spectra.

FIG. 8. (A) Calculated EF spectra for Au nanospherical dimers with different separation distances 1–30 nm. (B) Comparison of the maximal EF for Au and Ag dimers consisting
of spheres with diameter 30 and 60 nm, taken at the corresponding near-field bonding dipole resonance wavelengths: 390 nm for r ¼ 30 nm Ag nanosphere, 470 nm for
r ¼ 60 nm Ag nanosphere, 535 nm for r ¼ 30 nm Au nanosphere, 565 nm for r ¼ 60 nm Au nanosphere, respectively. (C) EF spectra flatten upon Ag sphere diameter incre-
ment. Reproduced with permission from Huang et al., Phys. Chem. Chem. Phys. 17, 43 (2015). Copyright 2015 Royal Society of Chemistry.82

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Together with interparticle size, the intensity of EM field distribu-
tion is also affected by the gap curvature. Indeed, the EF might be sig-
nificantly improved by the presence of sharp-edged NPs due to the
‘lightning rod effect’. When conductive electrons are concentrated at
the NP vertices, corners, or tips, the charge density considerably
increases. As a result, the local EM field reaches its maximal magnitude
in close proximity to the sharp structures. Recently, a prospective
SERS-sensitive substrate consisting of tip-to-tip coupled nanostars
(NSs) was proposed to take advantage of the lightning rod effect.83 And
complete theoretical support of the problem was received from research
published by Lee and Yoon.84 The calculations were performed for a
dimer containing two Au nanospheres, where one of them had a fixed
radius, while the second was replaced by a nanocube with different cor-
ner sharpness (a radius of inner rc curvature of a cube Fig. 9 panel I).
Considering gaps created by two types of coupling (nanosphere–nano-
sphere and nanocube–nanosphere), it was observed that large EM field
intensity occurs for a ‘sharp edge–round surface’ geometry with the
strongest confinement in close proximity to the cube vertex. The most
important finding is an extreme EF reduction as inner curvature r
increases (Fig. 9 panel II). For example, in the case of rc ¼ 0.5 nm, max-
imal field amplification was found to be about 1013, while at rc
¼ 42 nm the EF is two orders of magnitude lower (1011).84
Lee et al. also provided proof that sharp structure is a driving
force in field magnification. Substituting a sphere with different
diameters instead of a nanocube led to a rapid decrease in local EM
field intensity between plasmonic NPs. A nice practical example of
using the dimeric coupling of plasmonic nanomaterials is given in Ref.
85, where hybrid Au–Ag nano-mushrooms were employed for multi-
plex SERS detection of DNA and RNA targets, revealing the ability to
clearly differentiate one from another.
Highlights:
(a) Size and geometry of Au and Ag NPs play an important role in
hot spot formation.
(b) Tiny sub-nm interparticle gaps between metal NPs are the best
options to achieve an advanced level of near-field
magnification.
(c) Sharp edges and tips of plasmonic NPs are able to produce
highly intense EM field due to the lightning rod effect.
IV. SERS-SENSING WITH PLASMONIC
NANOPARTICLES
A. Proper laser wavelength and complex surface
morphology
The theoretical predictions regarding the optimal level of
enhancement are reasonable when a selected experimental laser wave-
length matches the plasmon resonance conditions. Once the excitation

FIG. 9. Panel I: Numerical simulations revealing the effect of nanogap curvature radius on electromagnetic field distribution confined between two nanomaterials. Interparticle
spacing was kept at a fixed value of 1 nm. The curvature radius increases from left to right. Panel II: The influence of nanoparticle corner sharpness on the SERS enhancement
factor in comparison with round surfaces coupling. A scheme depicted on panel II represents a general trend of enhancement factor with respect to plasmonic corner sharpen-
ing. Reproduced with permission from Lee et al., J. Phys. Chem. C 120, 37 (2016). Copyright 2016 American Chemical Society.84

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wavelength does not coincide with a “color” (absorbance peak) of nano-
plasmonic materials, the nearfield enhancement vanishes. A proper laser
wavelength is directly correlated with particle size86 (Fig. 10 panel I). In
the case of 3D SERS templates, selection of “a right” laser can be esti-
mated by dark-field microscopy as demonstrated by Asiala et al.87 They
found that black-silicon decorated with a vapor-deposited silver film
with thicknesses of 25 and 50 nm results in an increase in discrete scat-
tering at “green” and “red” frequencies associated with localized surface
plasmon resonances. In comparison, the thickest layer of 100 nm scat-
ters a broadband region with a significantly increased portion of blue
wavelengths. According to their research, the best SERS signal was
achieved when an incident laser wavelength corresponds to the most
dominant color of scattered photons that are detected by dark-field
microscopy. Since the Raman cross section depends on the absorption
of the molecule which is a function of the wavelength, and so does the
emission efficiency, there could be a shift for the optimum laser wave-
length to be used from the localized surface plasmon resonance (LSPR)
wavelength. For example, McFarland et al. found that the maximum
SERS enhancement occurred at excitation wavelengths slightly shorter
than the LSPR, such that both the incident photon and the Raman scat-
tered photon are strongly enhanced.88
The discovery and further improvement of the huge potential
locked within sharp-edged plasmon active nanoparticles (SEPANs)
with developed complex geometries has opened the door to designing
sophisticated SERS sensors that are going to supplement or even
replace some of the existing sensing devices in biological, chemical,
and medical areas. NRs,89–91 nanopyramids,92,93 nanotriangles,94–97
nanocubes,98–101 NSs,102–108 or shell-coated nanomaterials91,109–111 are
of great interest and recognized as the most desirable geometries for
obtaining optimal plasmonic properties due to their tunable size and
shape. This is because the large curvature area at the tips accumulates
electrons while simultaneously increasing the charge density. As a
result, intense EM field distribution can be easily produced. A wonder-
ful visualization of the lightning rod effect is given in Fig. 10 through a
set of numerical simulations performed by Rodrıguez-Oliveros and
Sanchez-Gil112 and by Yuan et al. for Au NSs with a developed ‘arms’
morphology fabricated by a surfactant-free wet-chemistry method
with different Agþ concentrations.113 SERS performance of separated
plasmonic Au nanospheres, Au NSs, hybrid hollow Au/Ag nanoshells,
and Au/Au core/satellite particles was compared recently by Tran and
co-workers through theoretical as well experimental investigations,
confirming their huge potential for single-molecule vibrational finger-
print analysis.114
The EM field near the tips dramatically enlarges the incident light
absorption beam and Raman scattering cross section. Thus, it signifi-
cantly improves the signal-to-noise ratio during measurement. In this

FIG. 10. Panel I: Correlation between size of colloidal gold nanoparticles [scanning electron microscopy (SEM) images and size distribution graphs] and surface plasmon reso-
nance frequency defined as the absorbance peak position shift. Reproduced and adapted with permission from Hong and Li, J. Nanomater. 2013, 9. Copyright 2013 Author(s),
licensed under a Creative Commons Attribution 3.0 Unported License.86 Panel II: [(A)–(F)] 3D representation showing the electromagnetic field distribution in the vicinity of tips
for multibranched Au nanostars at the localized surface-plasmon resonance frequency. (G) Absorption spectra calculated by following 3D Green’s theorem method for corre-
sponding gold nanostars [(A)–(F)]. Reproduced with permission from Rodrıguez-Oliveros and Sanchez-Gil, Opt. Express 20, 1 (2012). Copyright 2012 The Optical Society.112

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section, we are going to briefly introduce some peculiarities related to
SEPAN sensitivity performance, focusing mostly on SERS measure-
ments conducted with the assistance of common Raman probe mole-
cules such as Rhodamine-6G (R6G), crystal violet (CRV), 4-
Mercaptobenzoic acid (4-MBA), Nile blue (NB), and probenecid (PB)
(Table I). We skip the matter of the selectivity of a method to a partic-
ular type of bio-/chemo-/medical task, which is a specific objective of
Secs. IV B–IV F.
The discussion starts by considering the most complex shape
(NS) because it fits the majority of plasmonic features associated with
other NP geometries. Garcia-Leis and co-workers103 were one of the
first researchers to utilize Ag NSs to monitor SERS efficiency by using
PB as a probe-analyte. Surprisingly, they were able to detect PB at a
final concentration level of 5  107 M with an EF as high as
1.7  105. The EF achieved was quite high, considering the fact that no
additional active agent was used during analyte preparation. It is worth
noting that there was practically no signal obtained from spherically
shaped Ag NPs.103 SERS activity of three types of NSs each with
approximately the same core diameter of about 22 nm but different tip
lengths—20, 13, and 7 nm—were compared in another publication.115
The designed plasmonic substrates were employed to investigate con-
tamination of two Raman target analytes, R6G and Nile blue A
(NBA), dispersed in a water solution—an interesting finding related to
the performance capability of the designed sensing unit. Under equal
experimental conditions, the structure assembled by NSs with the lon-
gest arms produced the highest EF.115
The size effect of NS branches was again put to the test by Sheen
Mers and coworkers.116 Two different types of SERS platforms based
on ITO glass were activated by long-spiked gold nanostars (Au-LSNS)
and short-spiked gold nanostars (Au-SSNS), which were produced by
utilizing a hexagonal lyotropic liquid crystalline (LLC) phase as a tem-
plate.116 For inelastic light scattering measurements as well for sensing
performance evaluation, glutathione (GSH) and CRV served as probe
biomarkers. In contrast to results published in Ref. 115, the authors of
Ref. 116 observed quite surprising behavior, showing that the Au-
SSNS structure exhibits significantly larger signal amplification with
respect to that of Au-LSNS. The main reason for this unusual behavior
was attributed to the core size difference of NSs, which plays a relevant
role in plasmon resonance properties. In the case of ‘short-arm’ Au-
NS, the core diameter was 50 nm, which is approximately two times
smaller in comparison to ‘long-arm’ Au-NS. As a result, it enables
more light absorption at the excitation wavelength chosen in their
study, which is also supported by absorbance spectra.116
Hollow or porous hybrid NPs are also well-recognized plasmonic
nanomaterials showing considerably high SERS activity.117,118 For
instance, porous alloyed Au-Ag spherically shaped NPs can send the
limit of detection (LOD) for 4-aminothiophenol (4-ATP) as low as
1010 M.119 Bimetallic hollow AuAg@Ag core@shell nanocubes
reveals a remarkable SERS detection ability, reaching the attomolar
level for 4-mercaptothiophenol (4-MPh).120 In some rare cases, porous
Ag NPs can exceed the SERS performance of NSs.121 An additional
conductive or insulating coating layer may also have a strong influence

TABLE I. SERS performance of some selected SEPANs. For the sake of clarity: NSs-nanostars, NCs-nanocubes, NRs-nanorods, NTs-nanotriangles, GO-graphene oxide, and
G-graphene.

NPs type Raman probe LOD k (nm) NPs size, nm EF Ref.

–7 5
Ag-NSs PB 5  10 M 532 300 1.7  10 103
Ag-NSs R6G 1.0  10–9 633 400–500 3.0  107 124
Ag-NSs Congo Red 5.0  10–9 532 400 1.0  107 125
Au-NSs R6G 1.0  10–9 785 50 5.0  106 115
Au-NSs NB 5.0  10–11 785 50 2.0  105 115
AuNSs-GO-AuNSs R6G 5.0  10–13 785 75 6.6  107 110
Au-NSs CRV 1.0  10–9 633 60 1.0  104 116
Au-NSs 4-MBA 1.0  10–9 785 50 4.0  105 105
AgNCs R6G 1.0  10–12 633 100 8.7  1010 98
Au@AgNCs CRV 1.0  10–8 N/A 56 1.5  106 99
Au-NPyramidss R6G 1.0  10–8 633 1000–2000 6.0  106 92
Au/AgNRs R6G 1.0  10–12 785 d30, l 150–800 1  1011 89
AuNRs R6G 1.0  10–10 785 d30, l 150–800 1  109 89
Au/Ag/Au NRs R6G 1.0  10–8 785 d90, l 500 1  108 90
rGO-Au@AgNRs R6G 1.0  10–7 532 d14, l 90 5  108 109
Au@AgNRs R6G 1.0  10–7 532 d14, l 90 5  107 109
SiO2@AuNRs R6G 1.0  10–9 633 d30, l 170 1  108 111
Ag@Fe@SiO2-NRs CV 1.0  10–10 514 d20, l 100 1  109 126
G/AuNRs CV 1.0  10–9 532 d23, l 78 1  105 91
AuNRs R6G 1.0  10–13 532 d23, l 78 8  108 91
AuNRs CV 1.0  10–10 633 d27, l 105 5  105 127
Au@AgNRs CV 1.0  10–13 633 d16, l 53 N/A 123
Ag-NTs R6G 1.0  10–11 532 260 7  107 96

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on NP SERS sensitivity. An evident improvement was reported in
2018,109 where reduced graphene oxide (GO)-coated Au@Ag NRs
demonstrated 17 times higher Raman intensity of their R6G peaks
compared to non-coated Au@Ag NRs. The same observation was
made by Zhao et al., who found that graphene wrapping of Au NRs
provides at least a double enhancement of Raman signal originating
from R6G.91 Nanographene oxide covering Au NSs also magnifies
Raman signal as was reported in Ref. 122, exhibiting a 4.9- and 5.4-
fold increment, respectively, of R6G and CRV vibrational peaks when
compared with a non-graphene Au NS-based substrate.
Similar results are found when Au NPs are decorated with
another plasmonic metal. For instance, 7 nm thin Ag film can produce
an approximately two- and fivefold increment in EM field intensity on
transverse and longitudinal axes of Au NRs, respectively.123 This
enlargement may be related to plasmon resonance frequency position
optimization, resulting in a perfect match with excitation wavelength,
which is an ideal case for achieving a better SERS signal.
A detailed study of the effect of introducing a conductive Au
layer thickness on the SERS response of Au nanocubes was conducted
by Lin et al.99 Nicely faceted NPs with an approximate edge size of
40 nm (core Au cube) were decorated with 16, 28, and 42 nm Ag films
to demonstrate different R6G vibrational peak intensities under the
same experimental conditions. The calculated EF increased gradually
with Ag layer thickness reduction: 0.31  106, 0.45  106, and
1.45  106 for 42, 28, and 16 nm Ag coating, respectively.99 A combi-
nation of plasmonic SERS improvement originated from the coinable
film. Chemical enhancement ensured by graphene or GO coating may
further elevate Raman sensitivity of SEPANs. Toward a proof of con-
cept, in Ref. 128, researchers used a ternary functional complex hybrid
nanomaterial consisting of Ag wrinkled nanoballs covered with GO
and additionally decorated with Au NPs. This arrangement allowed
the identification of R6G Raman dye molecules at concentrations
reaching a value down to 1013 M. A similar effect was observed by
Zhao and colleagues,110 where GO served as a separation membrane
for a bilayer array of sharp-tip Au NSs. Again, GO acted as a source of
chemical enhancement while simultaneously preventing direct metal-
lic contact between lower and upper stacks of NSs. Just a quick
reminder: small sub-10 nm gaps strongly favor the highest EM field
intensity, enlarging total EF, while conductive nanobridges drastically
lower EF [see Figs. 6(a) and 8(a)]. The designed sandwich structure
provides a limit of R6G SERS detection with the same order of magni-
tude as reported in Ref. 128. Boosted Raman activity of plasmonic
NPs can also be achieved by adding an ultrathin sub-nm dielectric
SiO2 shell, as was suggested in a selection of publications.129–133
B. Cancer diagnostic and theranostic applications
In the next few years, the potential of NSs and other SEPANs will
be realized on a large scale for medical purposes. A decent number of
research papers can be found in the literature regarding cancer diag-
nostics, either directly or by measuring biomarkers using target-free
and antibody-tagged detection approaches.134–137 Here we consider
some applications of nanoplasmonics. As was shown by Yuan et al.,
silica-coated Au-NSs with an average size of about 50 nm (core
together with sharp branches) show significant potential in identifying
breast cancer cells.105 SERS mapping investigations with plasmon-
active NSs were reported in Ref. 138 where the authors examined the
influence of laser beam power on the degradation behavior of the
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breast cancer tumor marker HER2 (human epidermal growth factor
receptor 2).138 Another fabrication strategy was proposed by Bassi
et al.139 with the aim of designing a biocompatible prototype device
possessing HeLa cancer cell identification diagnostic capabilities. The
sensing ideology was based on a pretty simple approach, where the
surface of seed-grown Au NSs was functionalized by folic acid (FA).
This activating procedure forces selective binding between NPs and
HeLa cells membrane, greatly improving selectivity and sensitivity of
the SERS substrate in this cancer probe.139 Simultaneously, the plat-
form has a promising theranostic activity that can be effectively used
to target and thermally kill HeLa cancer cells.
A demonstration of the prospective utilization of sharp NPs in
oncology applications was presented by D’Hollander et al.,141 where a
combination of in vivo passive targeting and star-shaped nanosized
plasmon active Au species was used for the detection of an ovarian
cancer cell line molecule (SKOV3). Another exciting SERS detector
demonstrator was recently described in Ref. 140, where researchers
realized an Au NS-based sensor [Fig. 11(a)] that can significantly
improve recognition of a epithelial cell adhesion molecule (EpCAM
protein is a cancer biomarker). A nano-platform was constructed with
design specifications, allowing a quantitatively readable Raman spec-
trum of EpCAM to be obtained, revealing an impressive single-cell
detection limit of about 10 pM [Fig. 11(b)]. Moreover, a bio-adaptive
procedure ensured platform selectivity to capture two EpCAM positive
cancer cells, MCF-7 (breast cancer cell line) and PC-3 (prostate cancer
cell), but not HeLa cells, which are EpCAM-negative [Fig. 11(c)]. The
characteristic vibrational mode of 4-ATP at 1076 cm1 was signifi-
cantly enlarged only for PC-3 and MCF-7 cell lines, showing a linear
decrease in peak intensity as cell numbers reduced from 50 000 down
to 100 cells.140
Looking at a different application, excellent plasmonic properties
of NSs and other prominent sharp-edged metal NPs can be efficiently
used for conversion of laser light absorption into local heating for the
purpose of photothermal cancer therapy. A comprehensive investiga-
tion in this area was carried out by Liu and coworkers in 2015.142 In
that research, the authors put to the test radioactive iodine (I-131)-
enriched 30 and 60 nm Au NSs [Figs. 12(a) and 12(b)] in mice-
injected xenograft sarcoma cells [Fig. 12(f)] to judge their diagnostic
and therapeutic applicability. Both sets of NPs were found to have a
similarly high level of diagnostic sensitivity, revealing two distinct
characteristic Raman peaks with comparable intensities located at
1067 and 1588 cm1 [blue and black curves in Fig. 12(e)]. No peak
was detected on non-tumor injected healthy mouse muscletissue (pur-
ple and red curve on the same figure).142 A slightly modified approach
based on composite structure detection consisting of plasmonic NSs
and polystyrene beads was reported in Ref. 143, in which in vitro SERS
imaging was carried out for breast cancer (MCF-7), murine monocyte-
macrophage (J774), and human lung epithelial cancer (A549) cell
lines.
Effective photon-to-heat conversion is decisive in tumor ablation
photothermal therapy. As known from the literature, tumor cells can
be destroyed by local heating up to a temperature of 50  C.142 A com-
parison of measured photothermal conversion efficiency of 30 and
60 nm Au NSs with Au shells widely used for therapy applications144
indicated a substantial efficiency increase for both 30 (94%) and 60 nm
NSs (90%), while shell-coated particles exhibited an efficiency increase
in about 61%. Consequently, it was concluded that due to the
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FIG. 11. (A) Schematic illustration of fabrication steps of the SERS-active detector for selective capturing of EpCAM positive cancer cell lines. (B) SERS sensitivity probing
using EpCAM protein aptamer with LOD as low as 10 pM. (C) SERS spectra collected for breast cancer cells MCF-7, prostate cancer cells PC-3, and HeLa cells. Black line
represents no cancer cells. Reproduced with permission from Bhamidipati et al., Bioconjug. Chem. 29, 9 (2018). Copyright 2018 American Chemical Society.140

improved light-to-heat energy transformation142 injection of NSs into
cancer cells leads to more successful therapy under the calculated max-
imum permissible exposure 0.72 W/cm2 (MPE) while using laser irra-
diation with wavelength 980 nm142 (Fig. 13).
Most exciting was that just one day after therapy, tumor cells
incubated with Au NSs revealed a clear size regression down to an
undetectable level for both SERS and visual observations. In contrast,
aggressive cancer molecules without injected NSs that were laser
post-treated continued their rapid growth from one day to another
(Fig. 13). Just a few years ago, such high photothermal conversion effi-
ciency was a distant dream in cancer therapy, and little progress had
been made. Having now discovered the theranostic breakdown poten-
tial of SEPANs due to their outstanding ability to capture light and
concentrate heat near plasmonic spikes or corners, it seems that
humanity has obtained a powerful weapon with a decisive advantage
in the war against cancer cells. The theranostic effect and cancer cell
diagnostic ability of plasmonic NPs are highlighted in two comprehen-
sive review articles published recently.145,146
C. Kinetic chemical reaction monitoring
The background to the implementation of SERS instruments in
this research field was discussed in a review147 and book chapter.148
This review instead focuses on the mechanisms of implementation
and potential applications. Observation of real-time kinetic evolution
of chemical reactions is challenging but may bring new insight into
reaction mechanisms. Fortunately, in addition to plasmonic features,
Ag and Au metal NPs also possess good catalytic properties, which
can be used to solve the issue partially. Coinable nanomaterials as a
catalytic reactant for redox chemical reactions149,150 are of great inter-
est owing to their electron-enriched surfaces, which can play the role
of electron transmitter/exchanger between nucleophiles and electro-
philes. As was stated in Refs. 151–153, Au NP catalytic performance-
boosting originates from a concentration of low-coordinated atoms
that are responsible for particle size shrinking. Moreover, similar to
the hot spot formation mechanism, the contribution of sharp particle
tips, corners, or facets is a predominant factor causing high catalytic

FIG. 12. [(A)–(C)] TEM images for 30 and 60 nm Au NSs and 12 nm Au nanosphere, respectively. (D) Extinction spectra with corresponding plasmonic peak for NPs presented
in [(A)–(C)]. (E) In vivo Raman spectra collected for tumor injected muscle tissues (T) and non-injected ones (N) with the assistance of 30 and 60 nm Au NSs under 785 nm
laser excitation and using pMBA reporter. (F) A mouse with xenograft sarcoma cells in the leg (T) and without it (N). Reproduced with permission from Liu et al., Theranostics
5, 9 (2015). Copyright 2015 Ivyspring International Publisher.142

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FIG. 13. Top: NIR images of surface mice temperature during photothermal therapy collected at 0, 120, and 300 s. Three left pictures represent intravenous injection of 150 ll
tumor enriched phosphate buffered saline (PBS) solution without 30 nm Au NSs. Three right pictures represent post-injection of 30 nm Au NSs at a dose of 20 mg/25g. Bottom:
Digital and X-ray images of mouse leg taken before and after 7 days of photothermal treatment without incorporation of Au NSs (A), and taken before and after 3 days of ther-
apy with the incorporation of 30 nm Au NSs (C). (B) Difference between in vivo surface temperature profiles of primary xenograft sarcoma cells with and without Au NSs inside.
Reproduced with permission from Liu et al., Theranostics 5, 9 (2015). Copyright 2015 Ivyspring International Publisher.142

activity.152 Owing to the aforementioned geometrical advantages of
Au NSs, K€onig et al.154 successfully performed in situ label-free kinetic
SERS monitoring of the heterogeneous hydride reduction of 4-
nitrothiophenol to 4-aminothiophenol chemisorbed at a metal–solu-
tion interface. Similar research was published by Zheng et al.155 where
a simple filter paper coated with Au NPs was tested for the 4-NP into
4-AP chemical transformation. Briefly, an operando SERS monitoring
was performed as follows. During the reduction reaction, the charac-
teristic Raman peaks of 4-NP located at 1343 and 1571 cm1 con-
stantly reduced in intensity, simultaneously resulting in new peak
appearances at 1593 cm1 (originating from the 4-ATP phenyl ring
mode). Finally, after a certain amount of time, the 4-NP into 4-AP
transformation was completed as clearly demonstrated by the differ-
ence between the two SERS spectra [Fig. 14(b)] collected at the initial
time and after 15 min of reaction progress, respectively.155 The differ-
ence [Figs. 14(b)–14(d)] itself was highlighted as 1571 cm1 (4-NP)
into 1593 cm1 (4-AP) peak intensity pumping and the monotonic
disappearance of a peak at 1343 cm1. This chemical transformation
has also served as a model reaction for the successful testing of the
kinetic SERS monitoring ability of a plasmonic platform made of Si
wafer covered by a self-assembled array of bifunctional 15/56 nm
diameter Au NPs.156
In Ref. 157, 60 nm Au NPs were used to perform in vivo SERS
analysis of the O-phenylenediamine (OPD) oxidation reaction process
under the influence of Cu2þ ions. Another potential application of
NPs was reported in Ref. 158, where the photocatalytic degradation
process of NB was followed by SERS measurement carried out with
the assistance of a micro-scale Ag@AgCl hollow cube array. Raman
spectra time evolution of a model p-nitroaniline reduction reaction
was investigated by using a complex porous nanosized platform made
of glass coated with a discrete Ag layer forming separated faceted par-
ticles (100 nm).159 Regarding characteristic vibrational Raman peak
intensity changes as a result of reaction progression, it worth mention-
ing that a similar level of SERS imaging sensitivity was achieved in pre-
vious investigations.157,158
A step forward in the way of improving operando SERS imaging
of a catalytic reaction was recently demonstrated by Choi et al.160 To
achieve their goal of single-molecule Raman scattering probing of the
dimerization of 4-nitrobenzenethiol (NBT), the authors employed a
combination of a surface-immobilized Ag NPs (80 nm) array distrib-
uted on top of a Si wafer covered by a thin coinable Au film with thick-
ness 10 nm. This platform achieved a large EF near Ag particle
junctions, reaching a value of about 1.7  108, which was quite enough
to satisfy observation of single-molecule modifications. Time-resolved
SERS spectra revealed that a focused laser beam (632.8 nm) results in a
clear photoreduction trace of NBT into intermediate state 4,40 -dimer-
captoazobenzene (DMAB) (Fig. 15, panel I). Further increasing the
irradiation time provokes a transformation to 4-aminobenzenethiol
(ABT),160 which typically happens when dealing with this probe
chemical reaction.
Taking a different approach, Zong and colleagues conducted
research comparing catalytic properties of Au and Ag NPs through an
investigation of a plasmon-driven decarboxylation reaction where
para-mercaptobenzoic acid (PMBA) was converted to thiophenol

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FIG. 14. (A) Representation of 4-NTP to 4-ATP transformation on top of filter paper decorated with Au NPs. [(B) and (C)] In situ Raman spectra of 4-NTP to 4-ATP conversion.
(D) Kinetic intensity pumping of two characteristic vibrational bands: 1571 cm1 for 4-NTP and 1590 cm1 for 4-ATP, respectively. Solid lines display the best experimental
data. Reproduced with permission from Zheng et al., Chem. Commun. 51, 22 (2015). Copyright 2015 Royal Society of Chemistry.155

(TP).161 Self-assembled Au or Ag sharp NPs (15 and 80 nm, respec-
tively) were placed on a clean oxidized Si wafer. The observed chemi-
cal features of PMBA to TP transformation were attributed to
vibrational Raman spectra modifications. Initially, SERS measure-
ments of PMBA absorbed on the surfaces of the plasmonic particles
demonstrated two narrow bands located at about 1077 and
1588 cm1. Later, under continuous laser irradiation, new sharp vibra-
tional modes arose at 1003 and 1026 cm1 with evident shouldering of
the peak at 1588 cm1 (Fig. 15, panel II). Such alterations unequivo-
cally determined plasmon-induced decarboxylation of PMBA and for-
mation of thiophenol molecules on the surface of the NPs.161 What is
also interesting is that both metals revealed a similar level of catalytic
performance at 632.8 nm wavelength, with a slight benefit to using Ag.
The SERS signal of the peak ratio I1577/1588 ¼ 1.07 originating from the
Ag platform was found to be somewhat higher than that of the Au
particle monolayer I1577/1588 ¼ 0.75. Characteristic TP bands at 1003
and 1026 cm1 were also slightly more intense.
Recently, Weatherston and colleagues demonstrated quantitative
operando SERS kinetic probing of the base-catalyzed aldol condensa-
tion of surface-bound 4-(methylthio) benzaldehyde by using nicely
faceted Ag–Au core-shell-coated nanocubes with side size of about
100 nm as the plasmonic platform.162 In other research, El-Zahry and
Lendl163 presented SERS measurements of the fluoroquinolone antibi-
otic Ofloxacin degradation process under the influence of basic, acidic,

FIG. 15. Panel I. (A) Schematic illustration of single-molecule operando SERS kinetic monitoring for photoreduction of NTB to DMAB. (B) Transformation of NTB Raman spec-
tra under continuous exposure. The inset shows a dark-field scattering spectrum observed for a single junction of a AgNP-NBT-AuTF (Thin Film) sandwich structure.
Reproduced with permission from Choi et al., Chem. Commun. 138, 13 (2016). Copyright 2016 American Chemical Society.160 Panel II. (A)—Schematic representation of a
plasmon-driven catalyzed decarboxylation of PMBA under incident laser irradiation. [(B) and (D)]—SERS probing of PMBA collected before and after exposure. (C)—In situ
Raman band transformation during photoreduction of PMBA to TP. Reproduced with permission from Zong et al., RSC Adv. 4, 60 (2014). Copyright 2014 RSC Publishing.161

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and oxidative stimulators by exploiting a roughened Ag NP self-
assembled array as a plasmonic sensing substrate. One more example
of fruitful utilization of plasmonic Ag NPs for kinetic SERS imaging
was presented in Ref. 164, where the authors monitored off-line o-phe-
nylenediamine (OPD) to form benzotriazole (BTA) chemical transfor-
mation with the assistance of NO2 and on-line plasmon-driven
oxidation of the same OPD probe as well.
In comparison to other catalytic metals, Ag and Au plasmonic
nanomaterials continue to lead in situ SERS kinetic probing of pro-
gressing chemical reactions. Moreover, it looks like their core-shell
configurations are one of the optimal solutions for such types of
investigations.
D. Metal ion detection in aqueous environments
Heavy metal ion (Cu, Pb, Cd, Hg, Fe, Cr, etc.) trace detection in
aqueous media is of vital importance to clean water security. Recently,
a strategy was demonstrated where cysteine covered NSs served as a
sensing unit for recognizing hazardous Cu ions in a water environ-
ment.165 The extraordinary selectivity of the designed SERS platform
was ensured due to the strong coordination ability of cysteine mole-
cules to bind with Cu chemically. Such an interaction significantly
alters the intensity of the symmetric and asymmetric COOH stretch-
ing bands in Raman spectra, located in a range between 1600 and
1390 cm1 (Fig. 16, panel I). The limit of detection was as low as 106
M.165 In another report, Ma et al.166 proposed a sensing prototype
consisting of a self-assembled NS dimeric array with average diameter
50–60 nm, additionally covered by thiol-modified DNA for the realiza-
tion of selective and precise identification of Hg ions in water. SERS
performance of this sensing unit was excellent, revealing an impressive
Hg2þ LOD of 0.8 pg mL1. A similar approach based on the formation
of T-Hg2þ-T pairs was used in Ref. 167, where SiO2-coated Au NPs
were immobilized by vertically oriented DNA molecules. Another effi-
cient prototype for SERS detection of highly poisonous Cd2þ was
demonstrated by Yin et al.168 In their study, 40 nm-sized Au NPs were
FIG. 16. Illustration of two different pathways toward metal ion SERS detection in an aqueous environment using bio-functionalized plasmonic platforms. Panel I: Peak intensity
probing, when functionalization captures certain metal ions only. Panel II: Peak position probing when the biolayer is not assigned to a particular metal species. Reproduced
with permission from Ndokoye et al., Langmuir 30, 44 (2014). Copyright 2014 American Chemical Society.165 Reproduced with permission from Kim et al., Analyst 138, 10
(2013). Copyright 2013 Royal Society of Chemistry.
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supplemented with a dye molecule through a disulfide anchoring
group and a layer of Cd2þ-chelating polymer brush coating attached
on the plasmonic NPs by using surface-initiated atom transfer radical
polymerization. An alternative platform that can serve as a detecting
unit for cadmium trace identification in water is based on Au NPs
(13 nm) activated by a Alizarin dye molecule.169
The described detection investigation methodologies were based
on an approach where increased metal ion concentrations selectively
affect the peak intensity of particular vibrational bands. A modified
strategy of using SERS active metal particles for monitoring hazardous
metal was reported in 2013.170 Instead of using signal intensity
changes, identification was carried out by Raman peak position shift-
ing using a cyanide (CN)-activated Au NP platform. As is well-
known,171 transition metals, depending on their solubility, may form
stable bindings with CN due to the presence of lone-pair electrons in
N atoms. As a result, the CN stretching vibrational mode undergoes a
strong blueshift of about 26–35 cm1 in the presence of Mn2þ, Ni2þ,
and Fe2þ divalent ions, and an approximately twice as strong shift
under the influence of trivalent Cr3þ and Fe3þ metal ions (Fig. 16,
panel II).170 What is also important is that a CN-Au SERS platform
enables trace metal detection in a water solution at femtomolar con-
centrations. A similar principle was recently employed by Hanif
et al.,172 confirming organic cyanide (4-mercaptobenzonitrile, MBN)
to be an excellent precursor for capturing Fe3þ ions with its further
SERS recognition at the picomolar level. Plasmonic NSs activated with
carboxyl-terminated alkanethiols can also be efficiently utilized for
detecting radioactive uranium species.173,174
Recently, Safro et al.175 proposed a fast, sensitive recognition
strategy for selective detection of Pb (II) ion contamination in water
by using a nanostructured platform consisting of rough Au NPs (aver-
age size 100 nm) that were electrochemically deposited on the elec-
trode substrate made of Au. Selectivity was ensured through exploiting
aminobenzo-18-crown-6 (AB18C6) as a target molecule. After the
interaction between AB18C6 and Pb (II), the majority of vibrational
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Raman peaks were shifted uutward to higher wavenumbers.
Moreover, the Pb(II)-AB18C6 complex provoked the appearance of
new bands on the SERS spectra at 820, 958, 1149, 1284, 1440, 1458,
and 1483 cm1, from which the one located at around 820 cm1 can
be assigned to binding formation between the lead (II) and crown
ether.176 The rest of the peaks were caused by conformational changes
of the crown ether moiety under the influence of Pb ions.177
Therefore, by monitoring the highly sensitive 820 cm1 peak, the
research team175 was able to detect lead species in the water at concen-
trations down to 1  1012 M. Some other specific reviews articles are
recommended for readers requiring more comprehensive knowledge
of high-risk poisonous heavy metal ion detection in aqueous
environments.178–180
E. Detection of explosives and hazardous agents
To guarantee civil protection, rapid response and correct identifi-
cation are essential when dealing with highly explosive materials such
as DNT (2,4-Dinitrotoluene), TNT (2,4,6-Trinitrotoluene), RDX
(1,3,5-Trinitro-1,3,5-triazinane), PETN (Pentaerythritol tetranitrate),
tetryl (2,4,6-Trinitrophenylmethylnitramine), ANTA (5-amino3-
nitro-1H-1,2,4-triazole), NTO (3- nitro-1,2,4-triazole-5-one), picric
acid (PA), or other detonating chemicals. Due to the low saturating
vapor pressure under ambient conditions of PA (0.97 ppb) and DNT
(411 ppb) as well other explosives, it is difficult to perform rapid detec-
tion with custom gas sensing approaches.181
A mixed combination of Au/Ag NPs with a complex surface
loaded on a filter paper was successfully employed for quantitative and
qualitative recognition of multiple explosive molecules in water such
as PA (5 lM), DNT (1 lM), and NTO (10 lM) with the additional
aim of their clear differentiation from a dye probe molecule (methy-
lene blue, 5 nM) commonly used in SERS analysis.183 Quite recently,
Chen et al.182 prepared NPs made of 200 nm spherically shaped pol-
ydopamine (PDA) as a backing material covered by Au seeds. The
idea behind this was to obtain a developed nanowaxberry-like surface
FIG. 17. Example of DNT explosive detection in water with SEPANs. (A) Iodide ion induced fabrication process of spherically shaped plasmonic PDA@Au nanowaxberry. (B)
Series of SEM and TEM images of polydopamine nanospheres decorated with Au seeds. (C) Control Raman spectra of solid DNT. (D) SERS spectra of DNT spiked in water
and ethanol, curves (i) and (ii), respectively. Curve (iii) is a background spectrum collected from environmental water. Reproduced with permission from Chen et al., Anal.
Chem. 90, 15 (2018). Copyright 2018 American Chemical Society.182
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morphology (Fig. 17). Using these specifically shaped plasmonic NPs,
the researchers were able to detect DNT explosive in the water at con-
centrations as low as 108 mol/L.
In another report,184 researchers demonstrated the SERS poten-
tial of a plasmonic platform consisting of an ordered array of Au octa-
hedrons of size 40 nm separated by sub-10 nm interparticle gaps.
Sharp NP corners and tiny separating distance played a vital role in
achieving excellent enhancement, allowing detection of 2,4,6-trinitro-
toluene (TNT) nitroaromatic explosive at nanomolar concentrations
(109 M). The selectivity of the designed structure to TNT was
ensured through adding a bilayer of ethylhexadecyldimethyl ammo-
nium bromide (EHDAB), which stimulated good adsorption of TNT
on the NP surface, causing substantial growth of the inelastic light
scattering signal. A significant three order of magnitude sensitivity
improvement was observed in Ref. 185, where Ag NP decorated Ag
molybdate nanowires served as a testing platform when dealing with
the same TNT explosive. It should be emphasized that the authors in
Ref. 185 chose a different chemical reactant (p-aminothiophenol) for
capturing TNT molecules instead of EHDAB that was used by Liu
et al.184 Just a couple of years ago, Xu and coworkers186 compared the
SERS detection ability of mono-6-thio-b-CD activated nanospheres
and triangular nanoprisms (both made of Au with size 30 and
100 nm, respectively) by investigating the presence of 2,4-dinitroto-
luene (DNT) in water. The estimated EF observed for triangular plas-
monic nanoprisms (1.05  108) was found to be one order of
magnitude larger than the one originating from spherically shaped
NPs (2.13  107). This remarkable tenfold increase is definitely caused
by the intense EM field localized at the sharp particles tips, which in
turn is attributed to the specification of the absorption spectra.
Nanosphere diameter was much less than 100 nm; therefore, dipole
and quadrupole surface plasmon resonance modes were difficult to
distinguish. As a result, only one peak with a maximum of about
533 nm could be observed. In contrast, the absorption curve of trian-
gular Au prisms revealed two well-separated humps: the first placed
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around 533 nm, while the wide second peak fitted within a range of
700 and 900 nm. The lowest detection limit for a DNT explosive ana-
lyte achieved with this triangular NP array was 1011 M.186 Therefore,
close-packed distributed grainy Ag NPs sized 50–150 nm on top of a
glassy Si wafer in combination with p-aminobenzenethiol (PABT) as
an activator and an excitation laser wavelength of 514 nm can provide
reliable recognition of TNT in a water solution at concentrations of
107–1011 M.187
In another investigation,188 Ag–Cu bi-metal nanomaterials
prepared by femtosecond laser ablation were utilized for the pre-
cise identification of picric acid (PA) and ammonium nitrate (AN)
in an aqueous solution. The idea of mixing Ag NPs with Cu ones
opens an opportunity for plasmon resonance peak position tuning
in the absorption spectra, with the purpose of achieving a desirable
wavelength region to induce optimal light absorption (Fig. 18).
With such flexible NP configuration adjustment, the authors in
Ref. 188 observed an EF as high as 107, which in turn ensured pre-
cise recognition of PA and AN analytes at concentrations ranging
from 5  103 to 5  106 M.
The above-mentioned investigations have a characteristic com-
mon feature that connects them to form a complete puzzle. The SERS
plasmon-driven recognition of explosive chemicals was performed
with the assistance of aqueous media, requiring the use of an addi-
tional functionalization step. A more challenging and complex matter
is the rapid identification of these dangerous materials in a vapor envi-
ronment. Recently, Piorek et al.189 demonstrated a successful strategy
of continuous, fast real-time label-free Raman fingerprint recognition
of vapor phase 2,4-DNT, reaching exceedingly low concentrations
down to 1 ppb. To achieve this, the researchers implemented a
FIG. 18. (A) SERS performance of Cu, Ag, and Ag-Cu alloy NPs using a MB (methylene blue) target Raman probe. [(B) and (C)] Raman spectra of picric acid (PA) and ammo-
nium nitrate (AN) in a water solution taken with Ag-Cu alloy NPs. [(D)–(F)] TEM images of Cu, Ag, and Ag-Cu alloy NPs complemented by their size distributions depicted in
insets. (G) UV-Vis absorbance spectra for three types of nanomaterials with indicated peak positions. Reproduced with permission from Satya Bharati et al., RSC Adv. 9, 3
(2019). Copyright 2019 Royal Society of Chemistry.188
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free-surface microfluidics/SERS detection system complemented by
Au NPs of average size 35 nm and with an excitation wavelength of
658 nm. A similar study was performed in 2017, where Ben-Jaber
et al.98 utilized Ag nanocubes with the average size 100 nm as a plas-
monic material to record Raman spectra of 1,3,5-trinitroperhydro-
1,3,5-triazine (RDX) and 2,4-dinitrotoluene (DNT) at nanomolar and
femtomolar concentrations, respectively. Another interesting realiza-
tion of DNT detection in vapor phase was reported by Wang,190 where
an ordered array of well-separated plasmonic clusters served as a SERS
sensing platform. The clusters were formed by coupling 80 nm Ag
nanospheroids into a plasmonic complex consisting of two, three,
four, or five individual particles. Despite difficulties and the high cost
of the platform preparation process, this methodology recognizes
DNT at concentrations reaching a detection minimum of 100 ppb.
In Ref. 191, a sensing substrate was presented consisting of an Al
plate with cylindrically-shaped pores (d  240 nm, l  60 lm), deco-
rated by Ag nanocubes with edge length 40 nm. The authors demon-
strated that different agglomeration types of Ag NPs within the pore
sidewalls significantly altered the total EF, thus having a crucial influ-
ence on the lowest detection limit when dealing with explosive binder
N-methyl-4-nitroaniline (MNA) and benzenethiol (BT). It was
observed that denser nanocubes packing provides the highest SERS
sensitivity, providing a detection limit of about 3 and 500 ppb for
vapor traces of MNA and BT, respectively. For comparison, a similar
plasmonic platform formed of nanospheres instead of cubic NPs pos-
sesses at least one order of magnitude lower SERS activity, giving clear
evidence that SEPANs are critical in detecting explosive materials in
vapor phase or prepared as an aqueous solution. Further on, Chou
et al. have demonstrated the ability of femtosecond laser proceeded
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gold-coated sapphire surface to accurately detect four different nitroar-
omatic vapors (2,4- dinitrotoluene, 2,4-dinitrochlorobenzene, p-
nitroaniline and nitrobenzene) at room temperature revealing a
response within a concentration range of 0.05–15 lM. An eightfold
signal increase was observed for nanopatterned substrate with respect
to the smooth gold-covered sapphire surface.192 More detailed over-
views of plasmonic SERS identification of explosive chemicals can be
found in other focused reviews.193–195
F. Pathogenic bacteria detection
Approximately 4%–5% of global deaths are caused by common
waterborne bacteria (Salmonella, Bacillus, Staphylococcus, Vibrio chol-
era, Rotavirus, Dysentery, Escherichia coli, Hepatitis A and E…)196,197
that can reach our bodies in our lunch, drinking water, or any other
food or liquids we consume. Water and food (fruits, vegetables, meat,
and so on) are excellent environments for a rapid population increase
in pathogenic microorganisms. The journey from farm to table suffer-
ing from a lack of reliable and cost-effective instruments that can
quickly improves safety inspection. Plasmonic SERS sensing based on
the implementation of sharp-featured Ag or Au NPs which have the
ability to interact with microorganisms through their membrane is
one technique that can provide in situ recognition of most common
Gram-negative and Gram-positive stamps within a short period of
time (5–15 min).198,199
In 2016, Wu et al.200 published results where they showed SERS
sensing potential of Ag NR arrays aligned on a Si slab with a tilting
angle of approximately 73 . The average particle size was as follows:
length 500 nm and diameter 50 nm. The prepared plasmonic plat-
form was furthermore functionalized by immersion into 1 nM vanco-
mycin solution for 12 h. This step was essential to ensure selectivity of
the designed system in detecting target organelles such as Salmonella
and Escherichia coli O157:H7. By using a filtration method and inelas-
tic light scattering spectroscopy, the researchers were able to precisely
identify the presence of Salmonella Poona in cantaloupe cube samples
and Escherichia coli in lettuce at concentrations 100 and 1000 CFU/
mL, respectively. Later on, a label-free approach based on the
Bacteria@AgNPs colloid solution prepared for in situ SERS detection
of a series of both Gram-negative and Gram-positive bio-organelles in
water (E. coli, M. morganii, E. lactis, L. case) was introduced201 as well
as the resulting excellent recognition sensitivity; the researchers made
two important findings. The first relates to improving fundamental
differentiation between two groups of pathogens: Gram-positive and
Gram-negative. The second concerns the experimental process: the
researchers discovered that long incubation time of Ag NPs leads to
their agglomeration. As a result, the plasmon resonance maximum
can be redshifted, forcing the application of an excitation laser with a
longer wavelength to achieve optimal signal-to-noise ratio while per-
forming SERS measurements.
Another effective tactic to exploit Ag NPs with complex surface
morphology was reported in 2018.202 The designed platform was pri-
marily activated by adding a layer of amino sites via glass surface sila-
nization and amino-PEG-ylation, following the pathway proposed by
Wolter et al.203 Afterward, positively charged NH3þ groups were
formed by immersion of a sensing substrate into a diluted 7.5% HCl
water solution. Such surface protonation automatically gave the plat-
form the ability to capture Gram-negative pathogens only. After that,
the SERS-based chip was fruitfully employed to identify three
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uropathogenic bacteria straight from their culture environment
(Pseudomonas aeruginosa, Proteus mirabilis PRM1, and Escherichia
coli CFT 073 PAO1) at concentrations that satisfy the required mini-
mum level for clinical diagnostics (105 cells ml1). From the absorp-
tion curve with a narrow peak located in the violet region of the
spectrum (Fig. 19), the estimated size of plasmonic Ag NPs is 25 nm
(a He-Ne laser with an excitation wavelength of 633 nm was used).202
An alternative strategy for designing a SERS biosensor for micro-
bial detection was proposed by Pan et al.,204 where they used a porous
anodic aluminum oxide membrane to fabricate an ordered array of
faceted Ag nanodots with controllable diameter and interparticle gap
distances. Three different platforms were prepared and put to the test
in order to identify a fungus bacteria Alternaria alternata, which can
provoke upper respiratory tract diseases and asthma in humans with
poor immunity.205 For each substrate, gap distances were approxi-
mately 31, 26, and 17 nm, while nanodots were sized 69, 73, and
83 nm, respectively. After having obtained primary results, the
researchers experimented with NP patterns that possessed smaller
interparticle distances, achieving three and five times larger signal with
respect to 26 and 31 nm gaps platforms, respectively. Later on, they
played with Ag dot heights, which were 20, 30, and 50 nm. The best
configuration had a dot height of 50 nm, allowing the accurate detec-
tion of Alternaria alternata bacteria at concentrations ranging from
1.0  105 down to 1.0  103 CFU mL1.204 It has to be emphasized
that no additional biofunctionalization of Ag NPs was performed with
the purpose of adapting the selectivity of the system for a particular
sort of organelle.
Widespread use of common antibiotics in clinical applications
causes increased drug resistance to harmful bacteria. For instance,
over time, Escherichia coli can become insensitive to highly effective
antimicrobial medicines such as carbapenem, which is typically used
to treat severe bacterial infections. The rapid spread of carbapenem-
resistant Escherichia coli bacteria in humans provokes an increased
mortality rate in hospitalized patients.206 In a report,207 Li and cow-
orkers demonstrated a strategic pathway for clear differentiation of
carbapenem-sensitive (CSEC) and carbapenem-resistant (CREC)
Escherichia coli pathogens by using enhanced Raman spectroscopy
with assistance from plasmonic Au NRs with the approximate size of
70  17 nm2 and coated in a thin 7 nm Ag shell. The Ag layer depos-
ited on the surface of the NRs tunes a longitudinal plasmon resonance
(LPR) peak to slightly shorter wavelength regions of the absorbance
spectra. The purpose of this tuning is SERS signal optimization, which
is achieved by matching the LPR frequency with a 785 nm excitation
laser (Fig. 20). Based on the Raman spectra signal difference analysis,
the authors had remarkable success in distinguishing all 48 strains of
CREC out of a total 89 strains of microorganisms tested, demonstrat-
ing a near 100% discrimination precision.207
Toward a deeper understanding, some other configurations of
plasmonic NPs were investigated as well. For instance, the SERS signal
originating from Ag-coated Au NRs was found to be at least 4.5
times stronger in comparison to simple Au NR arrays and roughly
twofold stronger than that of spherically shaped Ag NPs. Raman peak
intensities collected using an Au@Ag NRs platform were estimated to
be 50% stronger compared to those obtained from a mix of Au@Ag
NPs,207 showcasing the excellent SERS detection ability of plasmonic
Au@Ag NRs. Moreover, the increased number of distinct peaks
observed while employing Ag-coated NRs can provide complete
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FIG. 19. (A) Fabrication steps for preparing an Ag NP-based SERS-active portable platform for selective recognition of Gram-negative waterborne bacteria. (B) UV-Vis absor-
bance spectra of Ag NPs with a plasmonic peak about 400 nm. [(C)–(E)] Raman spectra of Gram-negative strains: Escherichia coli, Proteus mirabilis, and Pseudomonas aeru-
ginosa, respectively. Reproduced with permission from Yang et al., R. Soc. Open Sci. 5, 9 (2018). Copyright 2018 The Royal Society.202
fingerprint information for accurate recognition of Escherichia coli
molecules among other pathogenic organelles.
Plasmonic nanocubes made of Ag and functionalized with an
additional antibody capturing a 4-aminothiophenol layer were an
object of interest for Xiao et al. in Ref. 208, where they applied SERS
methodology to recognize two pathogenic strains: Listeria monocyto-
genes and Escherichia coli. The designed nanoprobing platform allows
accurate identification of target molecules at concentrations of about
102–103 CFU mL1, which is more than enough for clinical diagnos-
tics. A similar approach was documented in Ref. 209, where the nano-
structured plasmonic substrate was decorated by a 4-aminothiophenol
thin film, enabling accurate single bacterium identification of
Escherichia coli from a water droplet probe. In another investigation
conducted by Chen et al.,210 the researchers proposed label-free SERS
discrimination of several harmful strains including Pseudomonas aeru-
ginosa, Escherichia coli, methicillin-resistant Staphylococcus aureus
(MRSA), Listeria monocytogenes, and Listeria innocua by imple-
menting roughened colloidal Ag NPs as a plasmonic source. The
achieved limit of detection was found to be high, reaching a value of
103 CFU mL1.
Zhang and colleagues211 designed two sensing platforms that
showed a clear SERS response when a particular food-associated path-
ogen was attached to the surface of the NPs. The first detection unit,
which consisted of mercaptobenzoic acid (MBA) immobilized Au NP
(15 nm) arrays, revealed high SERS activity while Salmonella typhi-
murium was attached to the plasmonic surface. The second one, which
is also built from the same sort of NPs but modified with DNTB
[5,50 -Dithiobis (2-nitrobenzoic acid)], revealed a great Raman signal
sensitivity while dealing with Staphylococcus aureus bacteria. Both
organelles S. typhimurium and S. aureus interact with MBA and
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DNTB Raman probes, significantly altering their characteristic vibra-
tional bands located at around 1582 and 1333 cm1, respectively. This
method identifies S. typhimurium and S. aureus at concentrations
falling within the range 102–107 CFU mL1 with LOD of 15 and 35
CFU mL1, respectively. The selectivity of the methods was unambig-
uously confirmed by testing other common microorganisms that pro-
voke a number of diseases such as Escherichia coli, Bacillus cereus,
Shigella dysenteriae, and Vibrio parahaemolyticus with a pretty clear
conclusion that only Salmonella and Staphylococcus alter SERS peak
intensities of probe molecules MBA and DNTB183 significantly.
In the above discussion, we highlighted the most effective strate-
gies that are going to be employed in the near future for accurate rec-
ognition and precise discrimination between various types of harmful
foodborne and waterborne organelles. For more specific information
about labeled or label-free plasmonic SERS sensing of different patho-
genic bacteria, we direct readers to short review articles.212,213
G. Viruses and SERS
Viruses are the source of the greatest genetic diversity on the
planet, and as a class of biological species, they are the most abundant
around the world including ground, air, and water, much more plenti-
ful than archaea and bacteria merged together.214 These biological
nanocreations are the driving force of global geochemical changes and
the main cause of human mortality. With an increased thread of
spreading different viruses that bring health-harming effect to world
population such as deadly dangerous HIV, enteric virus infections, or
a variety of respiratory diseases, the importance of developing detec-
tion techniques grows as well. In particular, the influenza respiratory
viruses are significant human pathogens that can provoke seasonal,
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FIG. 20. Tuning plasmonic properties for accurate determination of carbapenem-sensitive (CSEC) and carbapenem-resistant (CREC) Escherichia coli pathogens. [(A) and (B)]
TEM images of Au NRs and Ag-shell@Au NRs. (C) Absorbance spectra of Ag-coated and non-coated Au NRs with an evident blueshift of plasmon resonance peak for perfect
matching with a 785 nm laser. (D) Averaged Raman band intensities for 41 carbapenem-sensitive and 48 carbapenem-resistant bacterial strains. Solid blue line is a vertically
shifted subtracted baseline, and t-dashed line is the standard deviation. (E) SERS performance of Au NRs, Au@Ag NRs, Au@Ag core-shell nanoparticles (Au@Ag NPs), and
common Ag NPs upon 785 nm incident wavelength. (F) 2D orthogonal partial least squares discriminant analysis (OPLS-DA) scheme representing nearly 100% accuracy of
CSEC and CREC strain discrimination relying on SERS spectra. Reproduced with permission from Li et al., RSC Adv. 8, 9 (2018). Copyright 2018 Royal Society of
Chemistry.207

endemic infections and periodic, unpredictable worldwide pandemic
outbreaks, like it happened in 1918, 1957, and 2009 with H1N1 and
H5N1 viruses featured with an increased mortality rate.215,216
Nowadays, the quantification and identification of this type airborne
diseases can be provided using enzyme-linked immunosorbent assay
(ELISA),217 real-time reverse transcription-polymerase chain reaction
PCR method,218 or rapid techniques like immune–chromatography
strips.219 These approaches are considered as a useful tool in a fight
against virus surveillance and tracking; however, they require a certain
amount of time, complex sample treatment, and in-depth knowledge
of the strains. With the advancement of SERS, it becomes possible to
provide accurate detection and investigation of nanopathogens.220
Recently, a research team from Russia221 has designed a sandwich-like
plasmonic aptasensor build on Si-SiO2 wafer decorated with silver
nanoislands, which were functionalized with an aptamer RHA0385
the biomaterial, that is, specifically suitable to recombinant hemagglu-
tinin from the series of influenza viruses (IV) H1N1, H3N2, and
H5N1 strains.222 Upon excitation of 532 nm laser wavelength, the per-
formance of the optical nanosensor demonstrated the limit of detec-
tion LoD at the level of 104 virus particles per sample or 104 HAU
per sample, that is, approximately one order of magnitude lower than
of polymerase chain reaction. Also, the analysis time needed for
accurate identification of seasonal (H3N2), pandemic (H1N1), and
rare outbreaks (H5N1 and others) of influenza viruses was reduced
down to 10–15 min,221 which is again much faster in comparison to
widely used PCR method. Recently, a platform based on vertically
aligned nitrogen-doped carbon nanotubes array decorated with Au
nanoparticles has been utilized for label-free detection of enriched rhi-
novirus, influenza virus, and parainfluenza viruses, revealing a high
90% real-time recognition.223 Neng et al. prepared a combination of
Au nanoparticles (GNPs) and paramagnetic nanoparticles (PMPs)
conjugated with polyclonal antibodies forming GNP/antigen/PMP
complexes to distinguish Raman fingerprints of viral zoonotic patho-
gens West Nile virus (WNV) and Rift Valley fever virus (RVFV).224
Moon and coworkers developed SERS antibody probes by mixing gold
nanoparticles, gold binding peptide-protein G, and an anti-pH1N1
monoclonal antibody to detect pathogen pH1N1 with a sensitivity
down to 4.1  103 TCID per mL (65 ng mL1).225 Silver nanorod
SERS-active arrays prepared by an oblique angle deposition were uti-
lized to investigate molecular vibrational signatures of Rotavirus226
related to human enteric virus infections as well as rhinovirus, and
HIV viruses.227
The respiratory viruses have an ability to create new forms and
strains, therefore becoming more dangerous for humankind. Because

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of this, it is of significant interest to investigate possible Raman finger-
prints evolutions. An example of such viral RNA mutations of influenza
A virus was sensed recently by using self-assembled silica-coated gold
nanostar probes (d  90 nm), functionalized with Cy3-tagged beacon
DNA via Au-thiol covalent bonding.228 Lim and colleagues analyzed and
differentiated three different sets of viruses, noninfluenza (displaying
VSVG), influenza (displaying CAL HA and NA or WSN HA and NA),
and shuffled influenza (displaying WSN HA and CAL NA) viruses by
utilizing SERS and 80 nm gold nanoparticles.229 The further development
of several nanotextured plasmonic chips such as hollow nanocones at the
bottom of microbowls for exploring Adenovirus Type 5 (Ad5) and cox-
sackievirus type 3 (Cv3),230 gold nanopopcorn-attached graphene oxide
hybrid for detection human immunodeficiency virus (HIV),231 nanoscale
porous silver nanofilms for testing rabbit myxomatosis virus, canine dis-
temper virus, tobacco mosaic virus, and potato virus X232 highlights a
huge potential of nanoplasmonic optical sensoring.
Furthermore, the nanoplasmonic optical sensors can be used for
fast screening in any global pandemic outbreak like recent SARS-
CoV-2 (COVID-19) for identification, monitoring, or investigation.
For example, silver nanorods (diameter  211 6 45 nm and
lengths  737 6 52 nm) operating in a fingerprint region <1800 cm1
of SARS-CoV-2 spike proteins revealed a promising result with the
indication of false-positive and false-negative samples based on a
vibrational band shift of Amide III for C-N stretching and N-H bend-
ing. Majority of samples with SARS-CoV-2 demonstrated an observ-
able redshift of a vibrational band located at 1189 cm1 downward to
1182 cm1 allowing to use this feature as a biomarker with a reported
discriminating accuracy higher than 90%.233 The avian influenza virus
A (H7N9) has been SERS probed by using core-shell AuAg nanopar-
ticles of approximate size about 50 nm that were additionally function-
alized by 4-aminothiophenol (4-ATP) and antibodies. A silver shell
layer covering the Raman reporter prevented the probes from aggre-
gating at high concentrations and provided plasmonic response tun-
ing. Under this SERS strategy, the sensitivity was three orders of
magnitude improved regarding a custom hemagglutination HA assays
method.234 Once widespread detection is settled, the following
research regarding a deeper investigation of virus proteins spectral
data will help scientists to develop new antiviral vaccines and drugs.
Highlights:
(a) Maximal SERS effect is achieved when the excitation wave-
length matches the plasmon resonance conditions.
(b) NPs with complex geometry may have the greatest practical
potential for labeled and label-free biosensing using SERS.
(c) SEPANs possess a thermoplasmonic effect that is of use for effi-
cient cancer cell thermal killing.
(d) Catalytic properties of SEPANs have found application in in
situ monitoring of chemical product kinetic transformations.
(e) Biofunctionalization is essential to ensure detection specificity.
(f) Plasmonic optical nanosensors can be a powerful tool for fast
recognition of viruses.
V. 3D-PLASMONIC NANOSTRUCTURES WITH
COMPLEX MORPHOLOGY
A. General peculiarities
SERS-active platforms can be more efficient and resilient by uti-
lizing robust nanosculptured surfaces. SERS-active substrates possess
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some unique advantages with respect to colloidal nanoplasmonics
such as uniform and more stable NPs aggregation on the surface, bet-
ter adhesion for analytes, and much greater ability to capture incident
laser illumination. Additionally, the nano-featured surface can be rela-
tively better tailored regarding their wetting properties by applying
plasma, laser, or wet chemical preprocessing. By precise hydrophilic
and hydrophobic features alterations, the analyte-surface interaction
contact area can be controllably customized, allowing to achieve one-
order of magnitude SERS signal improvement and advancing the mol-
ecule trace detection.235,236 Furthermore, 3D nanostructures decorated
with continuous noble metal nanolayers or their nano-colloids are
known as good plasmonic media because they provide the additional
dimension (depth) needed to generate specific regions with an intense
EM field confinement. In the case of continuous films, Raman inten-
sity typically increases with metallic film thickening as was demon-
strated for Ag, Au-covered Si-pillars,87,237 Au/Pd alloy deposited
Cu2O/CuO chestnut template,238 and black-CuO covered with gold
films.239 However, Raman signal intensity does not follow plasmonic
film thickness linearly in an entire range. It increases rather rapidly in
the beginning because of surface roughness which leads to enhanced
light scattering and then reaches saturation with thicker layers which
add no benefit to SERS. Later, it occurs due to surface smoothing,
which hinders the formation of hot spots region between the bulging
nano-features.237,238 Optimizing the spacing between metal decorated
surface nano-features can enable a precise formation of hotspots areas.
Complex 3D plasmonic substrates decorated with aggregated nano-
clusters on sidewalls typically produce higher SERS activity, but unfor-
tunately produce non-uniform response due to non-homogeneous
nanoparticle distribution on the substrates. Up to now, a huge number
of articles have appeared in the literature, regarding different types of
complex 3D plasmonic structures, but the most popular and effective
ones can be broadly merged to build three well-separated categories
with fundamentally different morphological specifications: nanopillars,
nonporous and sharp-edged (wrinkles, pyramids or grains) structures.
In addition, ultrahigh enhancement using coupling between propagat-
ing and localized plasmons is worth mentioning as a newly emerging
approach with significant potential.34
B. Pillar-like plasmonic structures
The nanopillar-like pattern is a nice example to demonstrate a
surface ‘plasmonic’ improvement that is straightforwardly assigned to
sharp tiny tips around where intense EM field is localized. In this sec-
tion, we discuss several types of structures having similar morphologi-
cal features such as pillars, rods, nanofingers, nanowires, and urchin-
like platforms. Among a variety of methodologies reported in the liter-
ature, there are several approaches that most successfully produce
free-standing rods or pillars: electron-beam lithography,240 colloidal
lithography,241 interference lithography,242 metallization of natural
surfaces,243 porous anodized alumina templates,244 and mask-less
reactive ion etching.245–247 Hakonen and coworkers recently reported
Au-on-Si substrates (obtained through mask-less lithography comple-
mented by reactive ion etching), exhibiting remarkable plasmonic
properties that allowed them to detect the hazardous nerve gases VX
and Tabun, with LOD of 13 and 670 fmol.246 They also produced
an Ag-on-Si pillar-like platform for accurate recognition of explosive
PA at a concentration of 20 ppt.247 In the same study, the researchers
found that the Ag-based platform has less hydrophobicity in
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comparison to the Au-based one, which is important for easier han-
dling of an analyte droplet on top of a sensing unit while performing
Raman analysis.247 A similar synthesis methodology using SF6 and O2
ions as a source of reactive etching species was described in Ref. 248,
where the plasmonic substrate was used for trace detection of trans-
1,2-bis (4-pyridyl) ethylene with LOD of 4  1013 M. Mask-less
lithography synthesis was also applied to construct a pillar-like plas-
monic sensing device for accurate quantification of p-coumaric acid
(pHCA) produced by Escherichia coli bacteria.249 A one-step phase-
shift interference lithography method was employed to fabricate a ver-
tically oriented highly periodic (500 nm) ‘pagoda-like nanopillar’
structure which was covered by a continuous 20 nm thin Ag film for
the purpose of performing SERS detection of a benzenethiol (BT)
monolayer. The achieved final EF  3  108 was sufficiently high to
support single-molecule recognition.250 In another investigation, a
nanoimprint lithography technique using porous anodic aluminum
oxide (AAO) template was employed to form nanopillar featured mor-
phologies on a 0.3 mm thick polycarbonate (PC) plate. Among differ-
ent nanosculptured substrates prepared in their study, the one that
possessed gaps spacing of 20 nm, and Au film thickness and pillar
diameter of 90 nm, characterized a maximal Raman scattering signal
amplification reaching a value of about 1.4  108, hence allowing SERS
recognition of the trans-1,2-bis(4-pyridyl)ethylene (BPE) probe at
concentrations down to 1010 M.251 Li and colleagues performed a
study where deep ultraviolet (DUV) immersion lithography and a
spattering technique were merged to build a vertically oriented
lollipop-like plasmonic structure (inter-gap distances 10 nm and
head sizes 80 nm). This structure demonstrated excellent SERS activ-
ity under 633 and 785 nm laser excitations approaching EF  108.252
In 2018, Hackett and coworkers developed a novel multi-layered met-
al–insulator–metal (MIM; Au@bottom–TiO2–Au@top) plasmonic
superstructure prepared by a nanoreplica molding process used to
form the polymer nanopillar dense matrix, sputtering technique, and
e-beam evaporation for the insulator and metal layer deposition,
respectively.253 The main benefit of using complex MIM geometry is
that it opens unique opportunities for tuning plasmonic properties by
independently varying the thickness of each layer separately. After
having investigated 36 different substrate configurations, the authors
claimed that the top Au layer has the strongest influence on SERS per-
formance. While increasing the width of the top Au layer from 90 nm
to 150 nm, the experimental EF was enlarged from 7.3  106 up to
3.2  107. Simultaneously, they observed that increasing the dielectric
(cavity) layer thickness caused a slight redshift of the plasmon reso-
nance dip in reflectance spectra which was mirrored as a signal-to-
noise ratio improvement. From this, they discerned that the optimal
TiO2 layer thickness was 80 nm. Bringing these insights together, the
team designed a platform with the best plasmonic properties
(90–80–150 nm for Au@bottom–TiO2–Au@top) to test Raman finger-
print recognition (633 nm excitation laser) of trans-1,2-bis(4-pyridyl)-
ethylene (BPE) probe at concentrations down to100 lm and a cancer
biomarker anti-CA-125 (Fig. 21).253
A nanoimprint lithography methodology has been employed to
produce flexible Au-coated (50–80 nm) polymer nanofingers
(500 nm tall), forming assembled clusters of digon (2-mer), trigon

FIG. 21. (A) Schematic drawing representing a skeleton of nanopillar-like metal-insulator-metal SERS-active substrate. [(B) and (C)] Tilted SEM images showing the morphol-
ogy of closely packed nanopillars. (D) 3D-FEM modeling of the plasmonic platform. (E) Electric jEj field intensity contour map in the proximity of an individual nanopillar in con-
tact with air and excited with a wavelength of 633 nm. (F) SERS spectra of BPE taken with the assistance of Au@bottom–TiO2–Au@top structure having different top layer
thicknesses. (G) Vibrational spectra of the cancer biomarker CA-125 collected with a substrate configuration of 90–80–150 nm. Reproduced with permission from Hackett
et al., J. Phys. Chem. C 122, 11 (2018). Copyright 2018 American Chemical Society.253

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FIG. 22. Panel I. SEM images of the top (90 ) and tilted (45 ) views of the contacted nanopillar assemblies: [(A) and (B)] for digon, [(C) and (D)] for trigon, [(E) and (F)] for tet-
ragon, [(G) and (H)] for pentagon, and [(I) and (J)] for hexagon structures, respectively. Panel II. (A) SERS performance of different nanofinger configurations using BPE as a
probe molecule and 785 nm laser irradiation. (B) Normalized intensity of a Raman peak at 1600 cm1 for different structures under 633, 785, and 1064 nm incident excitations.
Panel III. Electric field jEj2 distribution map of all nanofinger assemblies [(A)–(J)] calculated for two orthogonal in-plane polarizations at 785 nm wavelength. Reproduced with
permission from Ou et al., Nano Lett. 11, 6 (2011). Copyright 2011 American Chemical Society.254

(3-mer), tetragon (4-mer), pentagon (5-mer), hexagon (7-mer), and
ordered dot array shapes (Fig. 22, panel I).254,255 Due to capillary
forces,256,257 the nano-heads of designed pillars come into contact with
each other, creating small gaps which increase the intensity of the EM
field. By using trans-1,2-bis (4-pyridyl)-ethylene BPE analyte probe
and numerical simulations based on the discrete dipole approximation
(DDA) approach,258 authors have shown that a nano-cluster consist-
ing of five individually coupled pillars exhibits maximal SERS activity,
approaching an EF value of about 1011 under 785 nm laser excitation
(Fig. 22, panel II and III).
Recently, Tang and co-workers have also achieved a 1013 M
limit of SERS detection for R6G dye and 108 M for parathion-methyl
by using a complex urchin-like substrate, consisting of Ag NP covered
ZnO NRs constructed on a polyacrylonitrile nanopillar array film.259
In another study, ZnO pillars—400 and 600 nm long, prepared by the
hydrothermal method and covered by an Au layer with thicknesses of
100 and 200 nm—were served as a plasmonic unit for vibrational fin-
gerprint recognition of breast cancer cell line MDA-MB-231. It was
found that under 785 nm laser irradiation the platform with 600 nm
rods and 200 nm Au film produced the largest Raman enhance-
ment.260 Tao et al. reported a radial 3D SERS substrate constructed of
high-density ZnO NR arrays grown by a hydrothermal method on top
of a pre-textured Si wafer. Its soaking further decorated the prepared
platform with Ag NP colloidal solution for 1, 2, 4, and 5 min,
respectively. By probing R6G dye, the structure being in contact for
5 min with plasmonic solution revealed the best Raman performance,
producing a LOD of 108 M and EF of 107.261 Metal oxide-coated Ag
NR array-based substrates prepared by the oblique angle deposition
technique also possess remarkable SERS performance, easily reaching
EFs of 107 order of magnitude.262 In 2018, Xu and colleagues came up
with a similar hedgehog-like SERS-active morphology obtained by
laser ablation texturing of Cu sheets with further thermal annealing at
450  C for 2 h and decorating with Ag NPs by an electron-beam evap-
orating technique.263 The designed substrate demonstrated a 15-fold
increment of Raman signal in comparison to a simple Cu plate coated
with a 15 nm thin Ag layer. Another group of SERS substrates that
may fall in this category is nanosculptured thin films made of Ag or
Au in the form of straight, slanted, or zigzag-shaped nanopatterns pre-
pared by oblique or glancing angle deposition techniques. These struc-
tures have shown high EF (108), can be prepared in a large area,
and exhibit high stability and durability.54
C. Porous-like plasmonic structures
The second class of nanostructured platform is also widely used
in vibrational fingerprint analysis. Multiple pores are excellent loca-
tions for adhesion of small Au or Ag nanomaterial because they can
provide highly uniform distribution of plasmonic NPs forming a dense

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network of hot spot regions. In 2018, Zhong et al.264 demonstrated the
SERS ability of Ag-coated porous p-type Si substrate treated by an
anodic electrochemical etching method. They used this technique to
identify Raman modes of PA, reaching a concentration of 108 mol/L
that was two orders of magnitude better than that of Ag nanotriangle-
loaded filter paper substrate previously reported in the literature.95 A
photoelectrochemical method and chemical reduction of HAuCl4
were employed to fabricate an Au@porous Si platform that success-
fully rapidly recognized Penicillin antibiotic at ultra-low concentra-
tions (109 M), with an EF around 5  107.265 A similar
photoelectrochemical etching process was used by Alwan et al.266 for
the fabrication of a porous–macroporous Si/Au NP decorated SERS
platform that provided an EF of the same order of magnitude (107).
Silicon oxide wafers and p- or n- doped Si plates are most frequently
used to produce microporous, mesoporous, or macroporous templates
for SERS application.267 Nevertheless, materials can be applied for the
same purpose. In recent research, Novara’s group compared the detec-
tion abilities of silver-decorated porous silicon (Ag-pSi) and silver-
polydimethylsiloxane (Ag-PDMS) systems, which were prepared by
electrochemical and thermochemical etching methodologies, respec-
tively. Under 514.5 nm laser irradiation the Si-based platform identi-
fied a 4-MBA Raman probe at molar concentrations of 5  108,
while the polymer-based one showed a LOD of 107 with EFs of about
2  106 and 106, respectively. Nevertheless, the Ag-PDMS sub-
strate was characterized by excellent repeatability supported by small
inter- and into-substrate standard error deviation while performing
Raman measurements, which plays a relevant role when conducting
quantitative SERS analysis and data treatment.268
Freshly published research by Jiang and co-workers269 reports a
novel synthesis strategy to construct uniform porous-featured Ag
nanostructures with controllable gap distances falling within a range
20–400 nm (Fig. 23). The fabrication process was based on the soft-
template surfactant-directed (dodecyltrimethylammonium bromide;
FIG. 23. SEM imaging showing the morphology of Ag nanoporous structures with controlled pore sizes prepared at different synthesis temperatures: (A) Ambient temperature
(200 nm), (B) 50  C (150 nm), (C) 70  C (80 nm), (D) 85  C (50 nm), (E) 105  C (20 nm), and (F) 120  C (400 nm). (G) Pore size as a function of synthesis temperature. (H)
Raman spectra of thiram in purchased orange juice as a series of diluted concentrations with the assistance of Ag porous substrate and a 532 nm wavelength laser.
Reproduced with permission from Jiang et al., New J. Chem. 42, 21 (2018). Copyright 2018 Royal Society of Chemistry.269
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DTAB) method optimized by utilizing a solution approach with dode-
cylamine (DA) as a reduction reagent. Pore size control was ensured
by heating substrates at a fixed temperature for 24 h upon constant
magnetic stirring. Under increasing solution temperature, gap sizes
monotonically reduced from 200 nm at 20  C to 20 nm at 105  C with
an abrupt pore morphology change 400 nm after reaching boiling
point at 120  C. Prepared Ag substrates exhibited extraordinarily high
enhancement for vibrational peak intensities, with a LOD for R6G of
1016 M (EF  1014) and 106 M (0.03 ppb) for trace pesticide thiram,
which is more than 200 times lower than the suggested maximal resi-
due limit (MRL) in fruits.269
Luo and co-workers reported a thin porous C film obtained
through a template-driven route, which was SERS functionalized with
Ag NPs (20 nm) by self-assembling via a hydrophobic interaction
with a substrate. By using a designed structure and CV as a Raman
probe, with an excitation laser wavelength of 633 nm, a remarkable
LOD (1014) and EF (2  106) were achieved.270 Just as for the nano-
pillar morphology, a supporting layer of zinc oxide can be prepared in
the form of a porous structure by using a film-scraped methodology as
was reported in Ref. 271. Such a platform decorated with colloidal Ag
NPs with average size 75 nm can reach a LOD for R6G of 1011 and
Raman signal amplification as high as 2  108 under 532 nm incident
wavelength. Martynova et al.272 employed an electrochemical deposi-
tion technique using chloride Au electrolyte to decorate a porous poly-
styrene membrane with an array of 2D inverse opals with an average
diameter of 400 nm. Raman spectra collected with a custom R6G dye
probe revealed a LOD of 107 M with signal amplification of 2  106.
Recently Duy Vu and co-workers presented an exceptionally mechani-
cally durable AgNP loaded nickel foam platform that was able to rec-
ognize an R6G Raman fingerprint at a molar concentration of 0.1 nM,
exhibiting an EF of about 2.5  108.273 In 2018, Wu et al. reported a
quasi-3D porous Ag and Ag-NiO nanofiber SERS system obtained by
a simple two-step electrospinning-calcination synthesis process. Final
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structure formation was completed by a 3 h long annealing at a tem-
perature of 500  C. While dealing with Rhodamine as an analyte and
upon laser excitation at 785 nm, designed porous and fibre-like sub-
strates revealed Raman peak intensity amplification of 1.5  105 and
2.9  104, approaching the LOD around 5  108 and 3  107,
respectively.274 A large-scale hybrid heterogeneous Au/SnO/Ag mem-
brane prepared by continuous incorporation of SnO nanomaterials
with further Ag coating of a pre-textured commercial porous
Au35Ag65 (at atomic %) alloy film (100 nm) supports a quite large EM
amplification (EF  1010) that can be sufficiently applied for single-
molecule recognition of resonant and non-resonant analytes.275
Comprehensive investigative efforts have been made by Okeil
and Schneider in Ref. 276, where they provided a systematic study
related to the influence of radio frequency plasmas (oxygen, nitrogen,
argon, and hydrogen) on the controllable synthesis of porous struc-
tures by utilizing Ag deposited glass plates with film thicknesses of 5,
10, 20, 50, and 200 nm. Constructed porous systems demonstrated a
wide range of Raman peak intensity amplifications falling within a
range of 1.9  102 to 2.3  105. In addition to fabrication abilities, the
researchers showed that plasmas also possess excellent cleaning skills,
which is an excellent finding for real practical implementations.
D. Nanoplasmonics with wrinkles, pyramids,
and grains
The last category in the list of SERS-active platforms is textured
in the way of having sharp morphological features, such as nanopyra-
mids, nanograins, or certain sorts of elongated surface wrinkles. In a
similar manner to tips, abrupt facets and edges are effective in produc-
ing LSPs that can efficiently support high-intensity EM field. There are
two main pathways to engineering grainy or wrinkle-like substrates.
The first is related to direct texturing of Au or Ag films,277,278 while
the second imposes a plasmonic decoration of already nanosculptured
backing material.279
In 2011, Zhang et al. engineered a wrinkled SERS substrate fabri-
cated from a thin porous Au film with the assistance of thermal con-
traction under annealing at 160  C for 6 min.280 The designed
FIG. 24. (A) SEM images representing the morphology change of thermally shrunken and buckled Au films on polystyrene, coated with 10 to 290 nm thick metal films: (B)
Raman spectra of thiophenol self-assembled monolayer from thermally treated polystyrene with different Au film thicknesses; (C) SERS intensity of the most dominating thio-
phenol peak located at about 990 cm1 as a function of plasmonic film thickness. Reproduced with permission from Balčytis et al., Nanoscale 9, 2 (2017). Copyright 2017 The
Royal Society of Chemistry.281
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platform was characterized by a uniform distribution of wrinkles with
a biaxial periodicity of small gaps along the whole sample surface,
which resulted in a large Raman intensity increment reaching an EF
up to 109. Balčytis et al.281 designed a wrinkle-type SERS substrate by
nano-rescaling of the gold films on pre-stretched 2D polystyrene (PS)
sheets. Under a short-term treatment at elevated temperature
(150  C), the continuous noble metal film gradually transformed and
reproduced the morphology of polymer sheets. During the testing of
different plasmonic layer thicknesses, the highest enhancement was
obtained for a 100 nm Au film (Fig. 24).281
Later on, Kim and co-workers presented a three-step synthesis
process employed to build a “hot spots on grain boundaries” (HOGs)
texture. At the beginning, a 100 nm thick Au layer was deposited onto
a glass substrate by using an e-beam evaporating technique. Next, a
low-molecular-weight polymer PDMS (polydimethylsiloxane) was
imprinted on top of the Au and served as an ultrathin insulating gap.
Finally, a second e-beam evaporation stage created small (20–30 nm)
Au nuclei, which were grown along grain boundaries due to “atomic
force masking” (Fig. 25, panel I a). Strong EM confinement predicted
by numerical simulations (Fig. 25, panel II a) was well supported by an
experimentally observed vibrational signal increment for the
Rhodamine R6G probe (Fig. 25, panel II b). The SERS performance of
the complex Au/PDMS/Au substrate was at least ten times better a
substrate consisting of 100 nm continuous Au film, allowing finger-
print recognition at single-molecule level.282
In a study conducted by Liu and colleagues,283 the team imple-
mented selective etching of a hard Al2O3–TiC template by using Ar
and C2H4 gas mixture plasma to produce a grainy-like morphology on
the surface, which was further covered by Ag film (with thicknesses
ranging from 10 to 100 nm) and an ultrathin ta-C layer. Experimental
investigations carried out upon 514 nm laser excitation indicated that
texture with a 30 nm thick Ag layer possesses the highest EF, about
2  106. Decreasing the layer thickness provokes a monotonic reduc-
tion of EF, which the researchers attributed to a redshift of plasmon
resonance peak position. The minimum EF of 1  104 was
observed for 10 nm film, which can be easily explained. At so tiny
Ag layer thicknesses, interparticle gaps are too wide. Therefore,
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FIG. 25. Panel I. (A) Schematic representation of a plasmonic substrate with HOGs morphology. [(B)–(D)] Normal (90 ) SEM images of the HOGs structures after the second
stage of Au film deposition with thickness 2, 4, and 8 nm, respectively. Panel II. (A) Numerical simulations of EM field intensity in a cavity of HOGs texture. (B) Vibrational
modes of Rhodamine 6G dye at various concentrations using HOGs plasmonic platform (from bottom to top: 108, 107, 106, 105, and 104 M). Reproduced with permis-
sion from Kim et al., ACS Appl. Mater. Interfaces 8, 47 (2018). Copyright 2018 American Chemical Society.282

there is little interference between EM fields produced by separated
plasmonic NPs. Hence, amplification is much smaller. By utilizing
an RF magnetron spattering technique284 and performing a direct
nitridation of the sol-gel derived titanium dioxide film annealed at
1000  C in ammonia atmosphere,285 a uniform grainy-like morphol-
ogy was synthesized on titanium nitride films with EF  6  103 and
EF  1  104, respectively.
Kreno et al. demonstrated a polycrystalline metal-organic frame-
work (MOF)-based activation methodology by constructing a ZIF-
8 (Zeolitic imidazolate framework)-coated Ag FON (films-over-nano-
spheres) platform, which revealed an excellent Raman fingerprint
recording ability for different vapors. In their study, it was shown that
the LOD for benzene approaches a value of 540 ppm, which is
unreachable for most extant analytical detection techniques.286
Nanopyramid-like texturing to achieve maximal Raman scatter-
ing signal amplification has been a subject of interest for many
research groups. Mathematical support provided by Li et al. is a strong
base to begin to understand how geometrical parameters may influ-
ence total EM near-field distribution.287 In Ref. 288, ordered pyrami-
dal arrays were replicated on plastic polymethyl methacrylate
(PMMA) by using a roll-to-roll (R2R) UV embossing methodology
that exhibited up to 11-fold SERS performance increment over that
provided by a platform based on inverse pyramids. The same polymer
was successfully employed for manufacturing a flexible SERS-active
system, as was reported by Zhao and colleagues.289 They used a com-
plex multistep synthesis approach involving several procedures: textur-
ing of Si by anisotropic wet chemical etching ! deposition of Ag by
thermal evaporation ! annealing at 500  C for 30 min ! coating
with PMMA ! chemical etching ! spin-coating GO. The resulting
substrate with inverse pyramid arrays was able to reproduce most
representative R6G Raman bands at concentrations as low as 109 M,
showing an EF close to 2  107. A similar synthesis approach was
repeated in Ref. 290, with a slightly modified fabrication process,
where MoS2 NPs were introduced as an additional mechanism of
Raman scattering enhancement. By using Rhodamine as an analyte
probe (Fig. 26; see graph on the right), the calculated signal amplifica-
tion of the improved substrate was found to be 5.9  109, which is
more than two orders of magnitude larger than that for the substrate
reported in Ref. 289.
In a similar manner to structures with inversely shaped
pyramids,290 MoS2 can be effectively used for boosting SERS per-
formance of Ag decorated pyramid arrays created on Si wafer, as
was suggested by Jiang et al. in Ref. 291, where a hybrid
MoS2@AgNPs@Pyramidal-Si system revealed an experimental EF
as high as 9.5  106, which is more than 10 times larger than that
for a MoS2@AgNPs@Flat-Si platform (7.3  103) and 90 times
higher than Ag-coated pyramids without MoS2. Bimetallic Au@Ag
coating of analogous Si pyramids may bring EFs up to even higher
values 1.2  109.292
Recently published research by Roy and co-workers describes a
novel thermally assisted galvanic displacement approach employed for
the decoration of a chemically etched pyramidal Si plate. Prepared
platforms were additionally modified by annealing in N2 and O2
atmospheres at elevated temperature (550  C); reflected in the different
plasmonic activity of the systems. The substrate, kept in an oxygen
environment, possessed higher SERS response and exhibited a better
signal reproducibility even after 28 d.293 Guo et al. proposed to use
thin (few nm) GO film to prevent natural oxidation of Ag NPs depos-
ited on Pyramidal-Si, and improve the adhesive ability of the substrate
as well as mechanical and physical stability.294

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FIG. 26. Left: Schematic illustrating a fabrication pathway for a flexible plasmonic 3D AgNPs@MoS2/pyramidal structure. Right: SERS sensitivity comparison for
AgNPs@MoS2/flat polymer (1# platform), annealed AgNPs@MoS2/pyramidal polymer (2# platform), AgNPs/pyramidal polymer (3# platform), and AgNPs@MoS2/pyramidal
polymer (4# platform) using R6G Raman probe at diluted concentration (105 M). Reproduced with permission from Li et al., Adv. Mater. Technol. 3, 11 (2018). Copyright 2018
John Wiley and Sons.290
Highlights:
(a) 3D substrates are characterized by better adhesion for analytes
and much better ability to capture incident laser light.
(b) Plasmonic 3D platforms have the advantage of multiple
reusability.
(c) Porous and pillar-like textures may provide additional room
for hot spot formation, inducing volume-enhanced Raman
scattering.
VI. SUMMARY AND FUTURE OUTLOOK
Localized and extended surface plasmon resonance modes can
significantly boost the sensing potential of Raman spectroscopy, allow-
ing precise analyte recognition at the single-molecule level. Enhanced
Raman scattering is already a well-established tool that can be imple-
mented with great success to address some of society’s greatest medical
(cancer cell diagnostics, theranostics), biological (food quality inspec-
tion, water purity monitoring, pathogenic bacteria strain separation),
and chemical (kinetic reaction monitoring, detection of explosives,
metal ions, toxic vapors) challenges. Alongside the fact that excited
plasmons are extremely useful for SERS analysis due to their natural
ability to capture light, they have also found a practical application in a
couple of other analytical instruments such as SEF (Surface Enhanced
Fluorescence)295 and SEIRA (Surface Enhanced Infra-Red
Absorption),296 extending their utility. SEF and SEIRA would be an
apt focus for another review to complete the picture of surface plas-
mon driven bio-detection techniques.
In this review, a key focus of the discussion has been SERS sens-
ing based on noble-metal surface activation (EM enhancement), with
a clear separation from noble-metal free substrates because of their dif-
ferent working principle (chemical enhancement). Moreover, those
types of platforms do not rely strongly on geometrical and morpholog-
ical specifications of the detecting surface, which is a crucial problem
for plasmon-driven sensing systems. The spatial arrangement, size,
shape, and nano-gap distances are decisive variables that need to be
under control to achieve optimal plasmonic properties and maximal
Raman signal amplification. An assembly of a closely packed colloidal
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hollow or dense Ag/Au NPs shaped like triangles, cubes, rods, and
NSs can reach a remarkable level of SERS activity, approaching LODs
in the range 109–1013 M. In addition, solid 3D plasmonic substrates
can provide an additional dimension to ensure more uniform spatial
distribution of ‘hot spots on the surface, characterized by better stabil-
ity and reproducibility of SERS measurements. Among a variety of
configurations, platforms with multiple pores, pillar, or sharp grain
surface morphology specifications are at the top of the list of plas-
monic substrates with the best SERS performance, exhibiting EFs as
high as 105–109. Combined with ultrahigh SERS signal are the recent
technological advancements in efficient miniature optoelectronic and
computing components; thus, miniature, low cost, and powerful SERS
devices can be built for the different applications mentioned.
However, for the successful realization of reliable mass-produced
plasmonic substrates, there is still a stumbling block that must be over-
come. A well-known ‘stick with two ends’ dilemma is related to the
cost of the fabrication process needed to synthesize NPs or supporting
substrates with desirable morphologies. The techniques providing con-
trollable synthesis are characterized by high production price, while
cheaper techniques are not achievable certain pre-inscribed NP geom-
etries, or they require too many steps during the preparation
procedure.
In recent years, several research groups have noticed that among
the vast number of fabrication pathways, a plasma-assisted synthesis
methodology might have the capabilities required to resolve this
dilemma. First, synthesis parameters (power, time, plasma type, gas
flow, contamination…) could be easily tailored297 in order to construct
the desired surface structure. Second, the methodology can be applied
to nanosculpt different materials, both metals276,298,299 and non-
metallic materials.283,300,301 Third, alongside substrate texturization,
plasma has the potential to bring significant improvements in designed
surface decoration, making it possible to simplify plasmonic activation
pathways. This improvement can be reflected in better uniformity of
NP distribution and enhanced NP adhesion to a backing platform,
which increases the reliability and reusability of SERS-active devices.
Furthermore, plasma can clean the plasmonic substrate platforms276
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and even retailor them at the atomic level,302 which is useful for practi- 24
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ACKNOWLEDGMENTS I. Abdulhalim, Nanophotonics 7, 1891 (2018).
35
G. Haran, Acc. Chem. Res. 43, 1135 (2010).
The authors would like to acknowledge the support of the 36
H. Xu, E. J. Bjerneld, M. K€all, and L. B€ orjesson, Phys. Rev. Lett. 83, 4357
Slovenian Research Agency—Israeli Ministries of Science (1999).
37
collaboration project ARRS Grant Nos. NI-0001 and N2-0091. J. M. McMahon, S. Li, L. K. Ausman, and G. C. Schatz, J. Phys. Chem. C 116,
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38
DATA AVAILABILITY B. Pettinger, P. Schambach, C. J. Villag omez, and N. Scott, Annu. Rev. Phys.
Chem. 63, 379 (2012).
The data that support the findings of this study are available 39
E. Hao and G. C. Schatz, J. Chem. Phys. 120, 357 (2004).
from the corresponding author upon reasonable request. 40
Y. Zheng, L. Rosa, T. Thai, S. H. Ng, S. Juodkazis, and U. Bach, Sci. Rep. 9,
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