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Raman Spectroscopy in Biosensing
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This entry is adapted from the peer-reviewed paper 10.3390/bios11120512

The effect of Raman scattering is a result of inelastic light scattering processes, which lead to the emission of scattered light with a different frequency associated with molecular vibrations of the identified molecule. Spontaneous Raman scattering is usually weak, resulting in complexities with the separation of weak inelastically scattered light and intense Rayleigh scattering. These limitations have led to the development of various techniques for enhancing Raman scattering, including resonance Raman spectroscopy (RRS) and nonlinear Raman spectroscopy (coherent anti-Stokes Raman spectroscopy and stimulated Raman spectroscopy). Furthermore, the discovery of the phenomenon of enhanced Raman scattering near metallic nanostructures gave impetus to the development of the surface-enhanced Raman spectroscopy (SERS) as well as its combination with resonance Raman spectroscopy and nonlinear Raman spectroscopic techniques. The combination of nonlinear and resonant optical effects with metal substrates or nanoparticles can be used to increase speed, spatial resolution, and signal amplification in Raman spectroscopy, making these techniques promising for the analysis and characterization of biological samples.

Raman spectroscopy surface-enhanced Raman spectroscopy (SERS) optical sensors

1. Recent Advances of Raman Spectroscopy in Biosensing

To date, the SERS technique is a promising analytical tool that provides a nondestructive and minimally invasive method for in vitro and in vivo analysis, requiring minimal sample preparation. The first and most widespread application of the SERS method for bioanalytical purposes is the immunoassay of various protein markers in biofluids [1][2]. Table 1 summarizes the recent research on the application of indirect SERS-based techniques in homogeneous and heterogeneous formats of biosensors. The homogeneous format of SERS detection implies a mandatory stage of separation of immune complexes and unreacted components, including the unbound SERS nanotag. For this purpose, magnetic nanoparticles are usually used [3][4]. Recently, a new scheme of SERS-based biosensor was proposed, in which the SERS active product is synthesized as a result of the formation of an immunocomplex [3]. The use of nanoparticles simultaneously with enzymes allowed for combining the functions of the carrier of active components of immunoassay (antibodies, antigens) and the enzymatic transformation of substrates [5]. The substrate of alkaline phosphatase, the so-called 5-bromo-4-chloro-3-indolyl phosphate (BCIP), in the immunoassay is hydrolyzed to the inorganic phosphate and sole active compound 5-bromo-4-chloro-3-indole (BCI) [6][7]. The resulting product of the reaction has characteristic bands detected during the SERS immunoassay.
Pham et al. proposed an enzyme-amplified SERS immunoassay for the detection of IgG and prostate-specific antigen. The principle of the method is based on the enzyme-catalyzed reduction of silver in the form of a shell on Au NP-assembled silica NPs modified by a Raman molecule. In the presence of the target analyte, the immune complex labeled with the enzyme alkaline phosphatase triggered the reaction of 2-phospho-l-ascorbic acid into ascorbic acid (AA). In turn, ascorbic acid reduces Ag+ to Ag, forming hot spots that enhance the signal from the SERS of the sample solution. Another example of the formation of the SERS active product is described as the highly sensitive detection of allergens by the SERS-based ratiometric enzyme-linked immunosorbent assay [8]. In the current study, antibody-modified AuNPs doped with a covalent organic framework were applied as the SERS nanotag. This SERS nanotag showed the properties of nanozymes and catalyzed the reduction of a 4-nitrothiophenol substrate with further reduction in the presence of sodium borohydride to 4-aminothiophenol. The latter formed the Au–S bond with gold nanostars, resulting in the formation of Raman hotspots. The concentration of the analyte under study was determined from the ratio of the signal intensities of the characteristic bands of 4-aminothiophenol and 4-nitrothiophenol, respectively. Compared to fluorescence and luminescence, the Raman peaks are narrower, which contributes to the implementation of the multiplex format of SERS analysis [2]. In particular, a multiplex SERS-based immunoassay for pathogen [9], cancer marker [10][11], and toxin [12] detection has been implemented recently. New platforms and advances are discussed below that expand the potential application of SERS biosensors for rapid and point-of-care analysis.
Table 1. Indirect biosensing using SERS nanotags.
Table
Analyte SERS Substrate/Receptor Molecule Assay SERS Nanotag LOD Sample Features Year, Ref.
Gp51 antigen of bovine leukemia virus Magnetic gold nanoparticles (AuNPs)/the native (anti-gp51) and fragmented anti-gp51 antibody (Ab) Homogenous SERS-based sandwich immunoassay Gold nanorods modified with 5-thio-nitrobenzoic acid (DTNB) and specific anti-gp51 Ab 0.95 μg/mL Milk Oriented and random Ab immobilization, application of two kinds of nanoparticles 2013,
[13]
Escherichia coli (E. coli) Gold-coated magnetic spherical nanoparticles/polyclonal antibody (pAb) Homogenous SERS-based sandwich immunoassay Rod shaped AuNPs modified with DTNB, avidin, and biotin-labeled Ab 8 cfu/mL Real water samples Two kinds of AuNPs 2011,
[14]
E. coli and Staphylococcus aureus (S. aureus) Magnetic beads (400 nm)/anti-E. coli2, anti-S. aureus2 monoclonal antibody (mAb) Homogenous SERS-based sandwich immunoassay Poly-l-lysine-coated triple-bond-coded AuNPs modified with 4-cyanobenzenethiol (MBN) 10 and 25 cfu/mL Bottled water and milk Simultaneous detection with “hot spot” effect resulting in a significant enhancement of the Raman signal at 2105 and 2227 cm−1 2020,
[15]
Human immunoglobulin (hIgG) 100 nm thick gold film evaporated on microscope slide or silicon wafer/goat anti-human IgG Ab SERS immunoassay of human immunoglobulin 60 nm gold nanoparticles modified with 4-nitrobenzenethiol (4-NBT) and anti-human IgG Ab 3 pM on silicon and 28 pM on gold Standard solution Comparison of Si wafer and tradition gold surface 2020,
[16]
Human IgG, prostate-specific antigen (PSA) 2D arrays of Au (42 nm-core)@Ag (4.5 nm-shell) NPs on ITO substrate/polyclonal anti H-IgG, PSA mAb Heterogenous SERS-based sandwich immunoassay SH-PEG-COOH-coated AuNPs modified with 4-mercaptobenzoic acid (MBA) and anti H-IgG or PSA mAb 0.3 pg/mL (10 fM) for PSA and 0.05 pg/mL (0.3 fM) for H-IgG Standard solution Comparison of the size of AuNPs in SERS nanotag (26, 53, 110 nm) 2017,
[17]
Escherichia coli (E. coli) Spherical gold coated magnetic nanoparticles/pAb Homogenous SERS-based sandwich immunoassay Gold nanorods labeled
with alkaline phosphatase (ALP) enzyme and also modified with 5-bromo-4-chloro-3-indolyl phosphate (BCIP) and E. coli Ab		 10 cfu mL−1 Standard solution ALP activity; BCIP was hydrolyzed to SERS-active product; 5-bromo-4-chloro-3-indole (BCI) 2018,
[3]
IgM and IgG to SARS-CoV-2 No SERS substrate/mouse anti-human IgM and IgG capture Abs SERS-based LFIA Gap-enhanced Raman nanotags (GERTs) with 4-nitrobenzenethiol (4-NBT) between core and shell, modified with COVID-19 recombinant antigens (CN97) 1 ng/mL (IgM), 0.1 ng/mL (IgG) Standard solution Simultaneous determination of IgM and IgG 2021,
[18]
IgM and IgG to SARS-CoV-2 No SERS substrate/anti-human IgM and anti-human IgG Abs SERS-based LFIA Ag shell on SiO2 core (SiO2@Ag) 5,5-dithiobis-(2-nitrobenzoic acid) modified with dual layers of DTNB and SARS-CoV-2 spike (S) protein 1.28 × 107-fold dilution by the IUPAC standard method, which is 800 times lower than that of the visualization results Clinical serum samples (n = 68) Simultaneous determination of IgM and IgG 2021,
[19]
Ferritin (FER) Hydrophilic AgNPs onto the specific area of the hydrophobic polydimethylsiloxane (PDMS)–hydrophilic/hydrophobic Ag/PDMS/anti-FER Ab SERS-based LFIA Raspberry-like AuNPs modified with 4-MBA and anti-FER Ab 0.41 pg/mL Standard solution Combination of SERS substrate and SERS nanotag in LFIA format 2020,
[20]
Carcinoembryonic antigen (CEA) Hydrophilic AgNPs with polymethylmethacrylate (PMMA)/anti-CEA Ab SERS-based LFIA Flower-shaped Ag nanoplates modified with crystal violet and anti-CEA Ab 4.92 pg/mL Standard solution Combination of SERS substrate and SERS nanotag in LFIA format 2021,
[21]
α-Fetoprotein (AFP) Few layers of MoS2 nanosheets exfoliated by NaK alloys/capture mAb SERS-based sandwich immunoassay Au@AgNCs and R6G–mAb complex 0.03 pg/mL Human blood serum samples The sandwich immunocomplex “capture probe/target/SERS tag” was deposited on a silicon wafer and decorated with silver-coated gold nanocubes to increase the density of “hot spots” on the surface of the immunosensor 2021,
[22]
Human immunoglobulin (hIgG) AuNP array (AuA)-coated solid substrate/rabbit anti-human IgG Ab SERS-based sandwich immunoassay AuNPs modified with 4-aminothiophenol (4-ATP) and rabbit anti-human IgG Ab 0.1 μg mL−1 Human serum samples The combination of a SERS substrate based on AuNP array with SERS nanotag resulted in sensitive detection 2021,
[23]
Pancreatic cancer marker MUC4 Immobilization of gold nanoflowers onto thiol-functionalized silicon wafer/Anti-MUC4 Ab SERS-based sandwich immunoassay Gold nanoflowers modified with 4-mercaptobenzoic acid and anti-MUC4 Ab 0.1 ng mL−1 Standard solution Raman mapping was applied for a large substrate area to decrease a “spot-to-spot” variation of SERS signal 2020,
[24]
IgG/PSA No SERS substrate/anti-rabbit IgG/anti-PSA Ab Homogeneous enzyme-amplified SERS immunoassay AuNP-assembled silica NPs (SiO2@Au-RLC@Ag) with Ag shell modified with 4-aminothiophenol (4-ATP)
Polyclonal alkaline phosphatase (AP)-conjugated goat anti-rabbit IgG or AP-streptavidin-biotin-conjugated anti-PSA Ab were used as a tracer Ab to produce ascorbic acid for reduction of Ag+ to Ag		 0.09 ng/mL for IgG and 0.006 ng/mL for PSA Human serum samples Enzyme-induced Ag growth on the surface of SERS nanotag to produce the amplification of the SERS signal 2020,
[25]
Carcinoembryonic antigen (CEA) Silver shell magnetic nanoparticles Fe3O4@Ag MNPs/anti-CEA monoclonal antibody SERRS-based sandwich immunoassay Silver-coated gold nanorods (Au@AgNRs) modified with diethylthiatricarbocyanineiodide (DTTC), coated with mPEG-SH and conjugated with anti-CEA antibodies 4.75 fg/mL Human serum samples Au@AgNRs were in resonance with the resonant Raman dye DTTC at 785 nm excitation laser 2016,
[26]
Mannose-capped lipoarabinomannan (ManLAM) Resonance Raman-enhanced adlayer of cyanine 5 on a smooth gold surface/polyclonal rabbit antibody for Mycobacterium tuberculosis SERRS-based sandwich immunoassay AuNPs modified with 5,5′-dithiobis (succinimidyl-2-nitrobenzoate; DSNB) and MAb to ManLAM 1.1 ng/mL Human serum samples Cy5 modified gold substrates were characterized; the SERRS performance was compared with SERS and revealed a ≈9.3 gain in sensitivity of immunoassay 2019,
[27]

2. Microfluidic SERS-Based Biosensors

One of the directions for improving SERS technique is the combination of detecting devices with microfluidic approaches [28]. Microfluidics allow the researcher to increase analysis productivity by separating reagent streams and simultaneously detecting multiple analytes on a single chip. In addition, the use of microchannels minimizes sample volumes, and the complex configuration of interlaced channels allows for controlled flows, the uniform mixing of reagents, and improved reproducibility of results [29][30]. On the one hand, volume minimization is an obvious improvement in analytical techniques. On the other hand, it imposes more stringent requirements on the sensitivity of tag detection. Therefore, the combination of microfluidics with such a highly sensitive method as SERS seems to be the most logical option. In addition, microchannel detection allows for a high surface-to-volume ratio to be achieved, which is critical for efficient SERS measurements, whereas in-stream analysis reduces sample heating, which is one of the significant limitations of Raman techniques [28][31]. This harmonious combination of the two technologies has given rise to growing interest in the development of microfluidic analytical devices with SERS detection.
To date, such analytical devices are successfully adapted for the detection of a wide range of analytes, including medicines and drugs [30][32], pesticides [33][34], hormones [35], antibiotics [36], disease markers [29][37][38][39], nucleic acids [40], whole cells [41], and others [31]. Figure 1, drawn in the review, represents the basic principle of measurements that is used in the listed above developments and its application to multi-analysis cases. When individual compounds are detected, the detection limit reaches the fg/mL range, and when detecting cells—single cells in milliliters [41]. The capabilities of separating streams and creating capillary matrices in microfluidic systems are perfectly combined with the capabilities of the simultaneous detection of multiple tags (thanks to the characteristic “fingerprints” of SERS nanotags). This opens up wide possibilities for creating systems for the multiplex detection of various analytes. Chen et al. developed a microfluidic matrix for the simultaneous detection of four markers of inflammation: C reactive protein, interleukin-6, serum amyloid A, and procalcitonin, using labels with SERS-encoded core-surface structures [37]. Multiplex detection can be useful for other tasks as well. For example, Wang et al. simultaneously used three different SERS-labeled molecular probes targeting different epitopes of the same pathogen to ensure the detection of pathogenic targets at the level of individual cells with subspecies specificity [41].
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Figure 1. SERS microfluidic chip with AgNPs in microchannels, functionalized with capture antibodies. After injection of analyzed samples and SERS nanotags, the sandwich complexes are formed in microchannels, and SERS signals indicate presence of corresponding analytes.

3. Integration of SERS with Different Methods

Recently, there has been a tendency in which (i) the conditions for the analysis become more complicated, and (ii) it has become possible to use two methods for determining the analyte content at once. The proposed strategy is a dual detection approach that combines several methods for determining the content of the target analyte or cells, which enables the comparison of approaches under the same conditions in terms of sensitivity or detection limit. Recently, SERS-combined techniques have been summarized in a review by Zhang et al. [42]. Thus, SERS was experimentally integrated with electrochemical techniques [43], fluorescence detection [44], and the polymerase chain reaction (PCR) method [45]. Thus, in the work of Wang et al. [44], nanostars modified with antibodies and aptamers were used to identify circulating tumor cells. Gold nanoflowers were arranged in an orderly manner on the Au-ITO electrode as a substrate and then modified with an aptamer interacting with circulating tumor cells. Nanostars treated with polyethylene glycol followed by the immobilization of two hairpin trigger DNA molecules with fluorescent and reporter tags, as well as antibodies against the determined cells, were used as the SERS nanotag. After the complex was formed on the substrate, it was possible to estimate its amount by the fluorescence intensity or by the Raman shift. When comparing two analytical methods (fluorescence and SERS), the authors showed a twofold reduced limit achieved by SERS detection. Castaño-Guerrero et al. [43] combined the possibility of the simultaneous electrochemical and SERS detection of specific antigen–antibody interactions in the determination of cancer embryonic antigen. Here, the authors used a specific antigen–antibody interaction in a sandwich immunoassay format. The first capturing antibodies were covalently immobilized onto gold screen-printed electrodes modified with cysteamine to form accessible, functional groups for crosslinking with antibodies. The second antibodies were immobilized on gold nanostars together with a reporter molecule (4-ATP). Electrochemical impedance spectroscopy was performed by the authors prior to the addition of the Raman probe to assess the capabilities of electrochemical detection in this format. Thus, the analysis itself was carried out in two stages, and both methods of detection were separated in time. The authors point to a 10-fold gain in sensitivity when using SERS; however, when switching from buffer to serum containing the cancer embryonic antigen, the detection limit dropped by 10 times, which was probably due to the impossibility of avoiding the matrix effect of the blood serum sample.
The dual mode of determining three types of bacteria (Escherichia coli, Salmonella, Staphylococcus aureus) in contaminated milk, with the possibility of qualitative and quantitative determination, was demonstrated by Xu et al. [46]. In this work, two types of nanoparticles were applied: functionalized upconverting nanoparticles as a fluorescent probe and bimetallic (Au@Ag) magnetic nanoparticles modified with 4-mercaptophenylboronic acid (4-MPBA) as a SERS tag. Interestingly, for the interaction, the authors chose a phenylboronic acid derivative, which can be used for binding with the carbohydrate moiety of the wall bacteria. Here, 4-MPBA, as both a SERS reporter and bacteria capturer, was applied for the development, and there was no need to use additional reporters to form a Raman probe. Despite the fact that three different species of bacteria bind the same to the phenylboronic acid residue, the SERS reporter spectra differ for these species. The authors called this the fingerprints of bacteria, that is, the individual differences of bacteria made their own changes in the spectral characteristics of the bacteria used, which made it possible to use this parameter to identify the bacteria in the mixture. Thus, the above study does not so much show the advantage of fluorescence or SERS, but rather shows how this method and the corresponding reporter can be used, as well as how the signal changes depending on whether the bacterium is alive or killed.
Lee et al. [45] proposed the integration of PCR with paper-based SERS for the detection of the bacterial DNA of Mycoplasma pneumoniae as a model. At the first stage, it was necessary to accumulate bacterial DNA by PCR. Silver nanowires were applied to the surface of the paper-based device. In the presence of the target DNA, after several cycles of amplification (0–30), the applied EvaGreen dye was reversibly incorporated into the DNA structure. In this case, the observed SERS signal was low. If the desired DNA was not formed in the process, then the dye would adhere to the silver nanowires on the surface of the paper to form so-called hot spots, and the signal was amplified accordingly. In this case, the SERS signal was read from the surface of the paper. The difference between a positive and a negative result was observed when comparing the intensities at the test and control points.

4. SERS-Based Lateral Flow Immunoassay

The development of rapid point-of-care systems for the determination of various compounds is a priority direction in life science research. Among the existing approaches, lateral flow immunoassay (LFIA) tests based on antigen–antibody interactions in a flow of reagents on a membrane carrier with the formation of visually detectable nanoparticle-labeled immune complexes are in demand. The indisputable advantages of LFIA are its low cost and ease of testing. However, insufficient sensitivity and insufficiently high-quality (“yes/no”) results reduce the effectiveness of test systems. In this regard, the integration of LFIA with SERS detection is of great interest because capture antibodies immobilized in the test zone concentrate the SERS nanotag, and the lateral flow format of assay allows the study to be carried out without additional washing and separation steps [47]. The recent applications of SERS-based LFIA for target marker detection are shown in Table 1.
The schematic illustration of SERS-based LFIA is given in Figure 2. For the assembly of SERS-based LFIA, antibodies and aptamers (oligonucleotide sequences) are used as receptor molecules to interact with the target compound. The choice of antibodies is preferable because it provides high-affinity specific binding to the target analyte. Nanoparticles of noble metals (most often gold nanoparticles), which are used in traditional LFIA as a detectable label and in SERS immunoassay as part of the nanotag, combine these two analytical methods. This is because the modification of nanoparticles with a reporter and receptor molecules leads to the formation of a SERS nanotag. The result of the interaction of the selected receptor molecules with the analyte will be a change (increase or decrease) in the amount of SERS nanotags bound in the test zone. The spectra of reporter molecules from SERS nanotags make it possible to identify the content of analytes during the formation of an immune complex. Previously, the strategies to design high-performance SERS-based LFIA systems and prospects for their application were summarized in the review by Khlebtsov et al. [48].
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Figure 2. Principle of SERS-based LFIA.
In the design of the SERS-based LFIA, an important parameter is the shape of the metal nanoparticles in the SERS nanotag [49]. Sánchez-Purrà et al. [49] provided the comparison of gold nanoparticles of different shapes for the detection of viruses in LFIA. According to the study, nanoflowers, nanostars, and other particles with sharp spikes and corners potentially have advantages for use in SERS-based LFIA because they can have higher signal amplification due to the redistribution of electric fields at the ends. In this regard, it is preferable to use the formed nanoparticles in systems with low sensitivity to improve the performance of the analysis. For example, Lin et al. compared the performance of SERS-based LFIA for the determination of biphenol A using the SERS nanotags based on star-shaped and spherical gold nanoparticles of the same size (40 nm) [50]. The authors showed that the use of SERS nanotags, including gold nanostars modified with 4-ATP and anti-BPA antibodies, can increase the visual and quantitative detection limit of bisphenol A by 20 and 205 times, respectively, compared to gold nanospheres.
A similar efficiency of star-shaped gold nanoparticles was shown for the determination of the nucleoprotein of the influenza virus by the SERS-LFIA method [51]. In this work, the star-shaped nanoparticles with a size of about 100 nm, modified with 4-ATP and monoclonal antibodies specific to nucleoproteins, were used as a SERS nanotag. The detection limit for the influenza virus nucleoprotein was 37 and 300 times better than the characteristics of fluorescent and standard LFIA, correspondingly. The size of nanoparticles also plays an important role in the development of SERS-based LFIA. Chen et al. [18] demonstrated that it is preferable to use particles larger than 40 nm due to the stronger effect of surface electromagnetic amplification and as a result of the higher SERS signal. However, in the synthesis and selection of the SERS nanotag, the most important factors are the stability of the nanoparticles, the quality of the coating, the size of the gap, and the number of reporter molecules per particle, which can be detected using Raman spectrometers.
Thus, Khlebtsov et al. synthesized gold nanorods covered with a gold shell with a gap between the core and shell of 1 nm and the included reporter molecule 1,4-nitrobenzenthiole (NBT), which, after conjugation with specific antibodies, were used as a SERS nanotag in the SERS-LFIA of troponin I [52]. The authors compared the sensitivity of the developed SERS-LFIA and the standard LFIA assembled with the same immunoreagents and showed a 30-fold gain in sensitivity when using the SERS nanotag in conjunction with the SERS signal registration. The efficiency of a 1 nm gap between the metal core and the shell was confirmed in another work [18], where the so-called gold “nanomatreshki” were obtained, consisting of a spherical gold core and a shell with a 4-NBT reporter molecule inserted between the layers. Gap-enhanced nanoparticles were functionalized with a recombinant antigen and used to develop SERS-LFIA for the simultaneous detection of anti-SARS-CoV-2 IgM and IgG antibodies. The sensitivity for IgM and IgG antibodies detection was two orders of magnitude higher than the characteristics of commercial LFIA tests for antibodies to SARS-CoV-2.
Tang and coauthors [21] proposed a new approach for improving the sensitivity of SERS-LFIA that consists in integrating a sandwich scheme of SERS immunoassay with LFIA. Thus, hydrophobic and hydrophilic regions were formed on the analytical membrane in the test and control zones, consisting of a hydrophobic polymethyl methacrylate layer with a sprayed hydrophilic silver layer on which antibodies to carcinoembryonic antigen (anti-CEA) were immobilized. The flower-shaped silver nanoplates modified with a crystal violet reporter molecule and anti-CEA antibodies were used as a SERS nanotag. Ultrasensitive analysis of carcinoembryonic antigen was achieved using the developed SERS-LFIA.

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Subjects: Biotechnology & Applied Microbiology; Biochemical Research Methods; Spectroscopy
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Ksenia Serebrennikova
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Update Date: 07 Jan 2022
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