Biosensing Using SERS Active Gold Nanostructures

Abstract

Surface-enhanced Raman spectroscopy (SERS) has become a powerful tool for biosensing applications owing to its fingerprint recognition, high sensitivity, multiplex detection, and biocompatibility. This review provides an overview of the most significant aspects of SERS for biomedical and biosensing applications. We first introduced the mechanisms at the basis of the SERS amplifications: electromagnetic and chemical enhancement. We then illustrated several types of substrates and fabrication methods, with a focus on gold-based nanostructures. We further analyzed the relevant factors for the characterization of the SERS sensor performances, including sensitivity, reproducibility, stability, sensor configuration (direct or indirect), and nanotoxicity. Finally, a representative selection of applications in the biomedical field is provided.

Keywords: SERS; biosensing; gold nanoparticles.

Figure 6

Panel (a) shows the schematic of the principle of SERS detection of biomolecules using optical force. Panel (b) shows the comparison between Raman spectra and SERS spectra of BSA and Phenylalanine in phosphate buffer solution. Reproduced with permission from Springer Nature Publications of ref. [67]. Panel (c,d) are the schematic of the experimental procedure of indirect protein sensing platform and the SERS spectra of monoclonal anti-tau functionalized hybrid nanoparticles exposed to BSA (500 nM), IgG (500 nM), tau (500 nM), and a solution with equal amounts (500 nM) of BSA, IgG, and tau. Reprinted (adapted) with permission from ref. [114], Copyright 2013 American Chemical Society.

Figure 7

Panel (a) shows the illustration of paper-based SERS substrate and SERS examination of the exfoliated cells obtained from oral-cancer patients. Panel (b) represents the SERS spectra from the exfoliated cells: normal tissue (top) and cancerous tissue (down) [116]. Panel (c) shows the methodology of super-lattice SERS substrate fabrication and its SEM image and Vis-NIR spectra are shown in panel (d). Panel (e) shows the comparison of Raman and SERS spectra for kynurenine (Kyn) and tryptophan (Trp). Reproduced with permission from Wiley publications of ref. [120].

Figure 8

TEM and AFM image of a P. multistriata single valve is shown in panels (a,b). Panel (c,d) shows the optical image of REH LCs over a single metalized diatom valve and the conventional Raman spectrum of a single REH cell. Reprinted (adapted) with permission from ref. [121], Copyright 2018 American Chemical Society. The schematic diagram of hybrid nanosystem (diatomite nanoparticles-AuNPs-LY@Gel) synthesis and internalization in colorectal cancer (CRC) cells have been shown in panel (e). Panel (f,g) show optical image and Raman mapping images showing the internalization of DNP-AuNPs-LY@Gel (50 μg mL⁻¹) into CRC cells after 0, 18, and 24 h of incubation (scale bar = 10 μm) and time-dependent LY SERS signal from the hybrid nanocomplex in living CRC cells. Reproduced with permission from Wiley publications of ref. [124].

Figure 1

The schematics of (a) localized surface plasmon resonances (LSPR) from plasmonic nanoparticles, (b) numerical simulation of the electric field distribution of isolated AuNP and its dependence of SERS enhancement on the distance from nanoparticle surfaces, (c) the normal Raman scatting process, (d) two-step EM enhancement mechanism in SERS, and (e) chemical enhancement in SERS (HOMO: highest occupied molecular orbital and LUMO: lowest unoccupied molecular orbital).

Figure 2

Scheme of the different procedures of SERS substrate fabrication, (a) nanoparticles in suspension and immobilized on the solid substrate [6], (b) e-beam lithography [32], (c) soft lithography [33].

Figure 3

SEM images of metallic periodic nanostructures nanohole arrays (a), diamond-shaped nanoparticle arrays (b), arrays of cylindrical nanoparticles (c) fabricated by different development times 95 s, 110 s, and 165 s, respectively. Reproduced from ref. [73] with permission from the Royal Society of Chemistry. (d) 45° tilt view of nanostructure arrays with Au coating thickness 60 nm. Reproduced with permission from Springer Nature Publications of ref. [49]. (e) nanohole array with 500 nm diameter, the inset shows the magnified image of one of the holes. Reprinted (adapted) with permission from ref. [70], Copyright 2010 American Chemical Society. (f) the cavity array substrate of 2 μm fabricated applying polystyrene microsphere template approach [33].

Figure 4

Schematic of the nanosphere periodic hexagonal patterns of CPA (a), SA (b), and SR (c). [Dimension: CPA (p = 500 nm, d = 500 nm, tAu = 30 nm), SA, (p = 500 nm, d = 350 nm, tAu = 30 nm), and SR, (tAu = 30 nm). Focused ion beam micrographs of CPA (d), SA (e), and SR (f) gold structures featuring a 500 nm period and hexagonal tile. Raman spectrum (green) of BPT (g), BSA (h), and RBC (i) and mean SERS spectra of BPT (g), BSA (h), and RBC (i) on the CPA (black), SA (red), and SR (blue) substrates [88].

Figure 5

Panel (a) is the schematic of the synthesis of plasmonic nanopores process. SEM image of the gold plasmonic nanopores is shown in panel (b). Panel (c) represents SERS spectra of A translocating through gold plasmonic nanopores with a bias potential of −1 V, from low to high 10⁻⁹ to 10⁻⁴ M, respectively. Panel (d) represents the SERS-based nonresonant molecules detection of the four nucleobases (G, A, T, and C). The scheme of measurement setup (inset). Reprinted (adapted) with permission from ref. [106], Copyright 2019 American Chemical Society. Panel (e) shows the Au nanostars are functionalized with a Cy3-tagged beacon DNA, creating the SERS-active nanostar probes (B), and then hybridized with a complementary oligonucleotide (B + C). Upon exposure to the viral RNA targets, the complementary oligonucleotide dehybridizes from the beacon and hybridizes with the viral RNA (B + C + T), returning the beacon to its original hairpin conformation and leading to SERS signal recovery (B + C + R), Panel (f) is the SERS signal “ON-OFF-ON” switching: ON with beacon in hairpin conformation (B); OFF when the beacon is hybridized with 500 nM complementary oligo (B + C); then ON again upon exposure of SANSPs to 500 nM target viral RNA (B + C + T); Signal recovery was not observed after a random RNA sequence (500 nM) was introduced (B + C + R). Reprinted (adapted) with permission from ref. [111], Copyright 2020 American Chemical Society.