Low-Fouling Substrates for Plasmonic Sensing of Circulating Biomarkers in Biological Fluids

Abstract

The monitoring of biomarkers in body fluids provides valuable prognostic information regarding disease onset and progression. Most biosensing approaches use noninvasive screening tools and are conducted in order to improve early clinical diagnosis. However, biofouling of the sensing surface may disturb the quantification of circulating biomarkers in complex biological fluids. Thus, there is a great need for antifouling interfaces to be designed in order to reduce nonspecific adsorption and prevent inactivation of biological receptors and loss of sensitivity. To address these limitations and enable their application in clinical practice, a variety of plasmonic platforms have been recently developed for biomarker analysis in easily accessible biological fluids. This review presents an overview of the latest advances in the design of antifouling strategies for the detection of clinically relevant biomarkers on the basis of the characteristics of biological samples. The impact of nanoplasmonic biosensors as point-of-care devices has been examined for a wide range of biomarkers associated with cancer, inflammatory, infectious and neurodegenerative diseases. Clinical applications in readily obtainable biofluids such as blood, saliva, urine, tears and cerebrospinal and synovial fluids, covering almost the whole range of plasmonic applications, from surface plasmon resonance (SPR) to surface-enhanced Raman scattering (SERS), are also discussed.

Keywords: LSPR; SERS; SPR; biological fluids; circulating biomarkers; low-fouling; nanoplasmonics.

Figure 1

Clinical (plasma/serum/saliva/urine) biomarkers, including virus particles, nucleic acids, proteins and antibodies, that can be monitored by surface plasmon resonance (SPR)-based biosensors. The scheme in the box below represents a plasmonic sensing system based on the Kretschmann configuration. The incident light passes through a glass prism before being reflected by the sensing surface and captured by a detector. The refractive index at the interface and the surface plasmon wave frequency will change upon the binding of analytes. The amount of bound molecules can be measured in real time at a fixed incident angle or by tracking angle–SPR-resolved responses. The inset in the background depicts the generation of a surface plasmon wave that will propagate along the conductor–dielectric interface upon interaction with an incident plane-polarized light. Adapted with permission from Fehran et al. [10] (Copyright © (2018) Elsevier), Rapisuwon et al. [5] (under the terms and conditions of the Creative Commons CC BY License) and Chen et al. [15] (Copyright © (2019) Elsevier).

Figure 2

(a) Representation of the localized surface plasmon on nanoparticles and absorbance spectra obtained for binding events on nanoparticles. (b) Schematic diagram depicting the electromagnetic enhancement of surface-enhanced Raman scattering (SERS). Incoming radiation of resonant wavelength (hν_exc) interacts with the nanoparticle, exciting a localized surface plasmon resonance (LSPR). The near-field interaction between the Raman scatterer (i.e., analyte) and the plasmonic nanostructure increases the intensity of the scattered light (hν_scat). Adapted with permission from Masson et al. [24] (Copyright © (2020) Royal Society of Chemistry) and Strobbia et al. [17] (under the terms and conditions of the Creative Commons CC BY License).

Figure 3

(a) Scanning electron microscopy (SEM) image of an array of nanoholes in a gold film; (b) experimental setup of a plasmonic-based nanohole array biosensor. Adapted with permission from Gordon et al. [29] (Copyright © (2008) American Chemical Society).

Figure 4

Illustration of chain hydration and chain flexibility of (a) hydrophilic polymers, (b) zwitterionic polymers and (c) SAMs, which have different attributes of surface resistance and nonspecific protein adsorption. Reproduced with permission from Chen et al. [42] (Copyright © (2010) Elsevier).

Figure 5

(a) Schematic illustration of low-fouling SPR biosensor for high-sensitivity detection of miRNA in complex matrix based on DNA tetrahedron. (b) Effect of surface density of DNA tetrahedron probes (DTPs) on nonspecific adsorption (the amount of protein adsorption decreased with the increase of surface density until the surface density of 5.22 × 10¹² molecules per cm² in 100% serum and 100% plasma). (c) Detection of let-7a in 100% human serum (green histogram) and buffer (red histogram). Adapted with permission from Nie et al. [40] (Copyright © (2018) American Chemical Society).

Figure 6

(a) Schematic representation showing the detection procedure of the SPR biosensor consisting of a Ti₃C₂-MXene-based sensing platform and a multiwalled carbon nanotube (MWCNT)–polydopamine (PDA)–Ag nanoparticle (AgNP) signal enhancer (Ab: antibody; APA: staphylococcal protein A). (b) Analytical results of carcinoembryonic antigen (CEA) in human serum. Adapted with permission from Wu et al. [74] (Copyright © (2019) Elsevier).

Figure 7

(a) Scheme of the synthesis route of single-layer MoS₂; (b) single-layer carboxyl-MoS₂ nanocomposites; (c) the carboxyl-MoS₂-based SPR chip; (d) the carboxyl-MoS₂-based SPR sensing mechanism to detect the lung cancer biomarker CYFRA21-1. SPR sensorgrams were analyzed for the CYFRA21-1 protein in spiked human serum samples using the carboxyl-MoS₂-based chip, showing (e) different serum concentrations that were used to assess interference analysis during the test and (f) comparisons of different serum ratios in SPR biosensing for interference analysis. Adapted with permission from Chiu et al. [78] (under the terms and conditions of the Creative Commons CC BY License).

Figure 8

(a) Schematic illustration of the detection of Alzheimer’s disease (AD) serum by loop-displaying peptoid nanosheets in combination with 3D surface plasmon resonance imaging (SPRi) sensor chip. The AD peptoid 3 (ADP3) loop-displaying peptoid nanosheets were immobilized on the 3D sensor chip with carboxylated poly(OEGMA-co-HEMA) brushes fabricated on the gold surface by surface-induced polymerization (SIP). As the serum sample flow passed through the chip, Aβ42 in the serum was captured by the ADP3 loop in the nanosheet, generating SPRi binding signals. (b) Evaluation of the sensitivity of the ADP3 loop-displaying peptoid nanosheets to detect AD sera. SPRi binding signals of nanosheets with 100% ADP3 loop to AD and normal sera at different dilution ratios are shown. Error bars represent the standard deviation (n = 14). (c) Representative SPRi sensorgram showing the binding of nanosheets with 100% ADP3 loop to AD serum at different dilution ratios. Reproduced with permission from Zhu et al. [81] (Copyright © (2017) WILEY-VCH).

Figure 9

(a) SPR procedure for ABH antigen detection in saliva. (b,c) SPR sensorgrams of ABH antigen detection in red blood cells (direct assay) (b) and saliva (sandwich assay) (c). Adapted with permission from Peungthum et al. [94] (Copyright (2017) © Royal Society of Chemistry).