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Abstract
Technological innovation, cost effectiveness, and miniaturization are key factors that determine the commercial adaptability and sustainability of sensing platforms. Nanoplasmonic biosensors based on nanocup or nanohole arrays are attractive for the development of various miniaturized devices for clinical diagnostics, health management, and environmental monitoring. In this review, we discuss the latest trends in the engineering and development of nanoplasmonic sensors as biodiagnostic tools for the highly sensitive detection of chemical and biological analytes. We focused on studies that have explored flexible nanosurface plasmon resonance systems using a sample and scalable detection approach in an effort to highlight multiplexed measurements and portable point-of-care applications.
© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement
1. Introduction
Surface plasmon resonance (SPR) biosensors have emerged as powerful analytical tools for sensitive and real-time detection in numerous important fields, including fundamental biological studies, health science research, medical diagnostics, environmental monitoring, and food safety and security [1–3]. SPR can monitor the dynamic kinetics and affinity of bimolecular binding with distinct advantages, such as no damage to analytes, less reagent consumption, cost effectiveness, direct measurement of binding constant, and affinity [4,5]. Therefore, conventional prism-coupled SPR biosensor instruments have already entered the commercial market (Fig. 1(a),(d)) [6]. However, complex prism-coupling instrumentation limits further development of conventional SPR biosensor platforms for high-throughput screening for multiplexed analysis and integration into portable devices to achieve point-of-care applications [7,8]. Metasurfaces based on resonant subwavelength photonic structures enable novel methods for wavefront control and light focusing, underpinning a new generation of flat-optics devices [9]. Yesilkoy et al. combined dielectric metasurfaces and hyperspectral imaging to develop an ultrasensitive label-free analytical platform for biosensing [10]. Yang proposed the utilization of metasurfaces with freeform meta-atoms for on-chip ultraspectral imaging, thus, improving spectral imaging performance [11]. SPR technology takes advantage of metal-dielectric interfaces for interesting light–matter interactions at surfaces [12]. Therefore, the specific binding reaction between the species immobilized on the surface of the film and the analyte results in a change in the response signal, and any physical change on the surface that changes the refractive index (RI) causes the reaction [13]. As different concentrations of analytes bind to different types of glass, the RI fluctuates [14,15]. Localized surface plasmon resonance (LSPR) is the result of the collective oscillations of electrons in the conduction band of metal nanoparticles or nanostructures at wavelengths comparable to or smaller than the incident light wavelength (Fig. 1(b),(e)) [16]. Meta-Surface Plasmon Resonance (Meta-SPR) technology combines SPR and LSPR in a single geometry. A nanoarray with the characteristic period acts as a grating and matches the incoming light's momentum to the surface plasmons [17,18]. It is based on metallic nanostructures in dielectric media and can be interchanged with hollow or dielectric nanostructures in metallic media via electrostatic approximation (Fig. 1(c),(f)) [19]. Therefore, the nanoarray confines the incident electromagnetic field to its perimeter without requiring a complex optical instrument to act as an inverted hollow nanostructure. Surface-enhanced Raman scattering (SERS) generated by SPR local electromagnetic field enhancement is also a common point-of-care test technology that uses diagnostics [20–22]. This method measures samples adsorbed on the surface of colloidal metal particles, such as silver, gold, and copper, or on the rough surfaces of these metal sheets [23]. In addition, we list the four technologies, SPR, LSPR, SERS, and Meta-SPR-extraordinary optical transmission (EOT) [24,25], in a comparison table to better understand them (Table 1) and show a schematic illustration of SPR, LSPR, and Meta-SPR in Fig. 1.
Fig. 1. Schematic illustration of SPR, LSPR, and Meta-SPR. (a) Schematic illustration of SPR in the Kretschmann configuration. (b) Schematic illustration of LSPR in as gold Nanoparticles. (c) Schematic illustration of Meta-SPR for biosensing. (d) Representative angular reflectivity response curve of SPR for baseline and sample signals. (e) Representative shift in extinction spectrum of LSPR for baseline and sample signals. (f) Representative shift in Meta-SPR wavelength for baseline and sample signals.
Table 1. Characteristics of four technologies
Recently, nanoplasmonic biosensors characterized by nanostructures (e.g., nanohole and nanocup arrays) have received considerable attention because of their strong optical properties and controllable manipulation capabilities [26–31]. SPR biosensors based on nanoarrays have been widely demonstrated to have unique capabilities for multiplexed and label-free biological sensing in a highly compact manner owing to their outstanding EOT effect [32–35]. The EOT phenomenon is attributed to the strong field-enhanced plasma excitation in the vicinity of the nanoarrays, induced by grating light coupling at normal incidence illumination, which can simplify the optical system design and yield high sensitivity to minute local RI changes [34,36]. Based on this advantage of EOT, nanoarray-based sensors can not only respond to the binding of infinitesimal molecules on the sensor surface quickly and sensitively but can also be readily recorded by identifying variations in transmission spectra or peaks [34,37]. Therefore, similar to conventional SPR sensors, nanoarray-based biosensors can enable the direct monitoring of biomolecular interactions in real time and accurate quantification of analytes without requiring labels or signal amplification strategies.
Another advantage of nanoarray-based sensors is their ability to be integrated with other bioanalytical tools and miniaturized into portable point-of-care devices [5,38]. Several studies have demonstrated the excellent performance of nanoarray-based biosensors for integration in a 96-well plate format [39,40], high-resolution SPR imaging [41–43], flow-through sensing [44,45], and lipid membrane–membrane protein integration [46–48], which have generated new insights into the optimization of various properties of nanoarray-based sensors for multiplexing and high-throughput analysis at low cost, ease of use, and portable platforms.
Several excellent review articles have expounded nanohole-based sensors using intensity-based measurement systems [49,50], integration with microfluidics using spectroscopy-based measurements [51], and plasmonic sensors for point-of-care applications [52,53]. This review article aims to elucidate the potential applications of nanoarray-based biosensors in biological and chemical detection, and outlines their status. The superior and unique functions of nanoarray-based sensors for biological sensing are discussed. This review encourages the biological sensor research community to consider further development of nanoarray-based sensors for chemical/biological agent detection, microbial detection, disease diagnosis, and clinical applications [54,55].
Nakamoto et al. developed a plasmonic nanohole array sensor using UV nanoimprinting technology [56,57]. By adjusting the hole depth topography, gold deposition thickness, and hole periodicity, the effects of various parameters of the nanohole array structure on RI change were investigated [58,59]. Figure 2(a) shows the reflectance spectrum of the nanopore array. With a hole depth of 100 nm and a periodicity of 500 nm, the gold film increased in thickness: Dip1 sharpness remained unchanged; however, Dip2 became wider and shallower. Three types of nanohole array structures with depths of 50, 100, and 150 nm (gold film thickness = 100 nm) were fabricated (Fig. 2(b)). When the hole depth increased, the exposed polymer substrate affected the SPR of the gold layer. Therefore, the resonance valley widened with increasing hole depth, and the sharpest peak was obtained when the hole depth was 50 nm. The periodicity of the nanoholes was subsequently investigated, and the designed period was changed from 400 to 600 nm while maintaining a hole depth of 50 nm and gold thickness of 100 nm. In Fig. 2(c), the slope became steeper with increasing periodicity and the sensitivity increased. By optimizing the above three parameters, normalized reflectance SPR spectra for various bulk refractive indices at 100 nm gold thickness, 50 nm hole depth, and 600 nm period were obtained. The RI of the solution ranged from 1.000 (air) to 1.700 (matched oil) (Fig. 2(d)). Materials with different microstructures have different physical and chemical properties [60]. Therefore, the material difference significantly affects the sensing performance of nanoarray sensors. Four types of material discoveries were evaluated: precious metals, refractory (high-temperature stable) metals, transition metal nitrides, and conductive oxides [61,62]. As shown in Fig. 2(e), silver outperformed all other materials, and silver as the material of the sensor was most conducive to the sensitivity of the sensor. However, silver is prone to oxidation and therefore unstable in performance, which results in unreliable sensing technology.
Fig. 2. (a) Reflection spectra with various gold thicknesses. (b) Relative reflectance spectra of deep gold nanohole arrays with different holes at 50, 100, and 150 nm. (c) Reflectance spectra of gold nanohole arrays with different periods at 400, 500, and 600 nm. (d) When the period, diameter, depth, and thickness of the gold nanohole array were 600 nm, 300 nm, 50 nm, and 100 nm, respectively, the reflectance spectra of various refractive indices were detected on the surface [56]. (e) RI sensitivity is calculated in terms of frequency and wavelength [61].
Another key reason that nanoarray biosensors affect sensitivity is the periodicity of the nanostructured arrays. The appropriate periodicity is related to the coupling strength between the arrayed nanostructures. The smaller the period, the closer the particles are spaced and the stronger is the electric field at the nanogap, which can create “hotspots”. Consequently, the electric field strength increases exponentially [63]. However, when many particles are in close proximity, which causes coupling or overlapping between adjacent formants, the formants form a broad formant. This is an influencing factor in guiding the rational control of particle spacing in the design of nanoarray biosensor chips.
According to the summary of Kurt et al., nanofabrication methods are divided into two categories: bottom-up and top-down [17]. Bottom-up fabrication techniques mainly include hole-mask colloidal lithography and nanosphere lithography. In Fig. 3(a), self-assembled monolayers utilizing colloidal crystals were used as scaffolds for sensor fabrication using colloidal lithography (CL). In this method, monodisperse PS, PMMA, or silica nanospheres were used as building blocks. Therefore, it is often referred to as nanosphere lithography (NSL) [64]. Alternatively, as shown in Fig. 3(b), plasmonic biosensors can be obtained by forming a hexagonal close-packed (HCP) monolayer of colloidal crystals on a substrate and then depositing a metal layer. Consequently, the metal vapor fills the gaps between the spheres. After removing the monolayer nanospheres by tape or chemical etching, triangular pyramidal nanostructures with hexagonal periodicity were obtained [65]. Top-down fabrication techniques include a) substrate patterning using photolithography, b) material deposition on the patterned substrate, and c) lift-off or etching processes, which are mainly divided into electron-beam lithography (EBL) and nanoimprint lithography (NIL). These steps alternate or repeat, depending on the structure and device design. Efficient nanofabrication requires a high spatial resolution, low cost, and high yield of defect-free nanostructure generation. Therefore, photolithography is one of the most critical steps in obtaining smooth structures. Cao et al. reported problems with different nanoparticle features fabricated by EBL followed by the exfoliation process shown in Fig. 3(c) [66]. In contrast to EBL, NIL is a cost-effective, high-resolution, and high yield technique for large surfaces. As demonstrated by Chou et al., nanohole-array-based structures can be fabricated using NIL techniques [67]. Several other groups later reported that structures of several nanometers can be fabricated using NIL [67,68]. Different types of molds have been used to obtain nanostructures using NIL techniques. The pattern generation step included coating the substrate with a liquid polymer and mechanical molding, as shown in Fig. 3(d). However, mechanical pressing can distort the transferred pattern. The substrate with patterned fluid underwent a hardening process. The final step was to remove the mold, leaving the substrate with the nanostructures.
Fig. 3. Commonly used nanofabrication techniques in applications of nanoplasmonic biosensors. (a) Electron-beam lithography. (b) Hole-mask colloidal lithography. (c) Nanosphere lithography. (d) Nanoimprint lithography [17].
Moreover, in Table 2, we list quantitative comparisons, including enhancement technology, dynamic range, and sensitivity, of the nanoplasmonic sensors.
Table 2. Quantitative comparison of nanoplasmonic sensor technologies
2. Biological detection
2.1 Molecular interaction detection
The ability to measure the kinetics and affinities of biomolecular binding interactions is one of the main preoccupations of basic biology, biomarker discovery, proteomics, pharmaceutical development, and drug discovery [79,80]. Nanoplasmonics has emerged as an attractive surface-based technique because of its ability to sensitively sense the surface binding of biomolecules in a label-free manner, enabling the rapid quantification of association/dissociation rates and equilibrium constants for analytes binding to targets. Recently, our group integrated nanocup array-enhanced surface plasmon resonance with a standard 96-well plate and eight-pillar device, both of which can be developed to vary ready-to-use Meta-SPR biosensors to offer rapid, high-throughput, real-time, and label-free interaction analysis of the binding and dissociation processes for drug screening (Fig. 4). Meanwhile, a variety of ready-to-use NanoSPR biosensors were separately modified to demonstrate the high-quality binding kinetics of different biomolecular interactions, which pave the way for NanoSPR biosensors to achieve high-throughput and easy-to-use molecular interaction analysis with outstanding performance [40].
Fig. 4. (a) Schematic diagram of SARS-CoV-2 nucleocapsid protein (Np) detection. (b) Representative real-time curve of binding and dissociation of 104 nM SARS-CoV-2 Np detected by the SARS-CoV-2 Np antibody immobilized on the Meta-SPR chip. The binding dynamic fitting curve (c), dissociation fitting curve (d), and binding dissociation kinetic curve (e) between SARS-CoV-2 Np antibody and different concentrations of SARS-CoV-2 Np (0–208 nM) are shown [40].
Traditionally, natural IgM antibodies have been considered to have low affinity for targets. The equilibrium dissociation constants for IgM autoantibodies typically range from mM to 10 nM [81,82]. However, it is challenging to quantify the affinity of the interactions or kinetics of these antibodies with their primary antigens. Meta-SPR sensors can integrate lipid bilayers for label-free analysis of binding kinetics. Wittenberg et al. described a nanoscale myelin array based on a Meta-SPR sensor to measure both the association and dissociation rate constants of O1 and O4 antibodies (IgM isotype antibodies) binding to their myelin lipid antigens [83]. In this study, the ratio of rate constants showed that O1 and O4 could bind to galactocerebroside (GalC) and sulfated galactocerebroside (Sulf) with significantly greater affinity, which is at least one to two orders of magnitude greater than that of other natural autoantibodies. High-density vesicles and natural membrane arrays require no chemical modification of the substrate beyond microfabrication. These arrays can be applied to the detection of a large variety of medical and therapeutic molecules and their membrane-bound targets of action (Fig. 5). Cetin et al. also investigated the sensing properties of plasmonic nanohole array sensors for label-free detection of protein mono- and bilayers [84]. This Meta-SPR sensor, coupled with a protein bilayer composed of protein A/G and protein IgG, could achieve an experimentally minimum detectable protein concentration as low as 200 pg/mL.
Fig. 5. (a) Schematic representation of a supported lipid bilayer (SLB) on a gold nanohole array. The pentameric structures represent antibodies (IgM Abs), such as O1 and O4. (b) A full sensor gram from formation of an SLB containing 2% Sulf to IgM antibody binding to the SLB surface. The spectral position in minimum transmission around 700 nm was monitored to track changes on the surface. A 2.7 M MgCl2 solution was used to induce regeneration for serial kinetic measurements on the same membrane surface. (c) O4 binding to SLBs containing 2% Sulf. (d) O1 binding to SLBs with 2% GalC [83].
By combining highly parallel microfluidic technologies with periodic nanohole array chips, the Meta-SPR system enables high-throughput, label-free, real-time SPR biosensing, with promising applications in point-of-care and portable healthcare technologies. Ji et al. developed an integrated label-free, real-time sensing system for simultaneous monitoring of multiple biomolecular binding events based on nanohole-sensing arrays [85]. This system, combined with changes in EOT intensity, successfully obtained 25 separate binding curves between glutathione S-transferase (GST) and anti-GST simultaneously in real time with good sensitivity. This instrument has the potential to meet high-throughput, spatial, and temporal resolution and sensitivity requirements for drug discovery and proteomics studies. Subsequently, Lee at al. combined metallic nanohole-based SPR technologies with imaging spectroscopy to precisely quantify a wide range of receptor–ligand binding kinetics in a high-throughput fashion [86]. The instrument could simultaneously extract and quantify binding kinetics and affinities from 50 parallel microfluidic channels by coating with a biomimetic supported lipid membrane containing ganglioside (GM1) receptors in each parallel microfluidic channel. Moreover, Im et al. presented an affordable low-noise nanohole array-based SPR instrument to quantify antibody-ligand binding kinetic parameters [87]. This nanohole-based SPR instrument equipped with a 12-channel microfluidic flow cell could detect the concentrations between antigens and a panel of small 25 kDa single-chain antibodies down to 1 nM to achieve a broad range of binding kinetics with equilibrium dissociation constants ranging from 200 pM to 40 nM.
2.2 Immunological detection
The development of immunoassays using specific antibodies to detect antigens plays a crucial role in disease diagnosis, water analysis, foodborne pathogen detection, food safety monitoring, and environmental monitoring [88]. The detection of the total SARS-CoV-2 NA level can be used for COVID-19 serodiagnosis, convalescent plasma therapy, vaccine development, and assessment. In another recent work of our team, we developed a novel nanoplasma immunosorbent assay (NanoPISA) platform for the high-throughput rapid quantification of COVID-19 antibodies to evaluate vaccine effectiveness on a large scale. The novel nanocup sensor platform, enhanced by coupling of nanoporous hollow gold nanoparticles, was able to detect SARS-CoV-2 NA within 15 min and a detection limit of 0.2 pM without washing steps. And the testing capacity can be improved to simultaneous detection of up to 96 samples. This work demonstrated that the NanoPISA platform would help vaccine development for SARS-CoV-2 variants and suppress the SARS-CoV-2 variants epidemic. (Fig. 6) [89].
Fig. 6. Nanostructure-coupled biosensor platform for one-step high-throughput quantification of serum neutralizing antibody after COVID-19 vaccination. (a) One-step rapid quantification of total SARS-CoV-2 NAs with the novel nanoparticle-coupled biosensor platform. (b) SEM images of the nanoplasmonic sensor chip surface. (c) Differential spectra of SARS-CoV-2 NAs at different concentrations (2–400 pM) at 600 and 650 nm. (d) Dynamic binding curves of SARS-CoV-2 NAs at different concentrations (2–400 pM) [89].
Meta-SPR immunoassays for the detection of C-reactive protein (CRP), a well-recognized biomarker used for the clinical diagnosis of acute inflammatory diseases. Recently, our group developed a label-free nanosensor integrated in the standard 96-well plate format for dynamic measurements of CRP and anti-CRP antibody binding kinetics and quantification of CRP concentration in buffer and blood serum using a generic microplate reader [39]. Our low-cost label-free nanosensor plate could monitor the binding kinetics of immobilized protein interactions based on changes in the intensity of the transmission optical density (OD) value at specific wavelengths. The relative end-point OD value changes showed a good linear response with changes in protein concentrations (from 0.05 to 50 µg/mL). The unique nanosensor plate combined with a generic microplate reader opens new opportunities for biomolecular interaction and kinetic studies (Fig. 7(a)–7(c)). In addition, another study reported a label-free and highly sensitive imaging sensor based on plasmonic–photonic interaction in a gold-titanium dioxide gold metal (insulator) plasmonic nanocup array, which could detect proteins and exhibits superior performance in visible light sensing [90]. This device could detect and image the inflammation biomarker CRP with an LOD of 2.36 ng/mL using a common microscope, which provides a promising platform for future portable optical sensing with visible light illumination and imaging (Fig. 7(d)).
Fig. 7. (a) Camera image of water-scale MIM nanocup array with 90-nm bottom and top Au layers and an 80 nm TiO2 cavity layer and top-down SEM image of the device; (b) Integration of the Au-TiO2 -Au nanocup array chip with a homemade 96-well plate. (c) CRP molecular interaction and kinetic assay results [39]. (d) Illustration of the detection mechanism of the metal-insulator-metal (MIM) nanocup biosensor [90].
Plasmonic nanostructures offer unique advantages for colorimetric sensing. Recently, our group engineered a self-referenced portable smartphone-based nanoplasmonic imaging platform integrated with an internal reference sample, along with an image-processing method for colorimetric biomolecule sensing [69]. The platform was able to provide a 30 times improvement in the LOD for simulated urine testing using simple smartphone imaging and color analysis, compared with a traditional colorimetric assay such as using urine testing strips. In addition, the platform could also precisely identify simulated urine samples with high protein concentrations, which showed potential for point-of-care and early detection of kidney disease with the smartphone nanocup-based sensing system (Fig. 8).
Fig. 8. (a) Smartphone-based portable colorimetric sensing platform. (b) Real image of optical detection setup. (c) Color images taken for urine sample testing and corresponding intensity (×4) of the red channel in the gray scale. (d) Bar chart of normalized intensity in the red channel for different urine samples [61].
Belushkin et al. also presented a bright-field imaging plasmonic biosensor that allows the visualization of single-subwavelength gold nanoparticles (NPs) on large-area gold nanohole arrays (Au-NHAs) [92]. The technique, implemented in a one-step sandwich immunoassay, could detect the lowest concentrations of biotinylated bovine serum albumin (bBSA) and human CRP at 10 pg/mL and 27 pg/mL, respectively, which are at least four orders of magnitude lower than the clinically relevant concentrations (Fig. 9(a)–9(c)). In another study, they utilized a portable digital nanoparticle-enhanced plasmonic imager for rapid detection of procalcitonin (PCT) and CRP directly from blood serum [93]. As shown in Fig. 9(d) and 9(e), the unique nanoplasmonic imaging mechanism is based on gold nanoparticle (Au-NP) binding to Au-NHA, which enables the quantification of individual molecule binding on the sensor surface in complex media. The bioassay was performed in a single step without signal amplification or washing procedures, and plasmonic detection was robust against variations in the optical properties of the samples. The results showed that The device achieved ultrahigh detection sensitivities with LOD values of 21 and 36 pg mL−1 for PCT and CRP levels, respectively, and a wide dynamic range of at least three orders of magnitude (Fig. 9(d),(e)).
Fig. 9. Portable digital nanoparticle-enhanced plasmonic imager for biomarker detection. (a) Strong local suppression in the transmission by Au-NPs creates intensity dips (i.e., red spots) at the corresponding locations of the captured image. (b) SEM image and plasmonic image of an Au-NHA area after a bioassay showing the bound NPs. (c) PCT and CRP, which are blood-circulating protein biomarkers secreted by the host body in response to systemic inflammation, are detected using DENIS. A single-step bioassay directly in human serum produces rapid molecular results, critical for the early diagnosis of sepsis, by detecting individual Au-NP binding to Au-NHA. (d) Antigen is recognized by capture antibodies immobilized on the Au-NHA and then by detection antibodies tethered to Au-NPs. (e) A prototype DENIS reader developed for highly sensitive and multiplexed detection of biomarkers. The device uses a CMOS camera and a narrow-band LED source to record the transmitted images from a nanoplasmonic chip [92,93].
In addition, a simple and mass-producible plasmonic nanohole array device was developed to detect tumor necrosis factor-a (TNF-α) via real-time immunoreaction [56]. As a result, the device integrated with a microfluidic device achieved a LOD of 21 ng/mL using streptavidin–gold and 45 ng/mL with direct immunoassay, which improved by approximately three times compared with the result obtained using Flexchip. This device, based on a plasmonic nanohole array, has potential for use in clinical and practical point-of-care testing sensors. Feuz et al. demonstrated how a specially designed nanoplasmonic sensor based on nanohole arrays can be used to direct specific proteins bound to the most sensitive regions of the sensor [94]. This sensor could increase the response time by a factor of almost 20, which was achieved by applying material-selective poly (ethylene glycol)-based surface chemistry. This concept may be applicable to all types of miniaturized sensors that allow for selective surface modification.
In another study, a protein with unknown function in Leishmania infantum (hypothetical C1 protein or C1 protein) was selected as a recognition biomolecule to construct an immunosensor [95]. Considering the high motivation to continue with this study, immobilization of the recombinant C1 protein on a multivalent platform was performed to construct an SPR-based immunosensor for anti-L. infantum antibodies [96]. The results demonstrated that immobilization of the C1 protein on the platform formed by the combination of a thiol SAM (cysteamine) and the PAMAM(G4) dendrimer amplified the SPR signal, suggesting an increased number of immobilized biomolecules because the tridimensional structure of the dendrimer molecules provides a broader surface area for interaction with the C1 protein. These findings indicated the increased efficiency of the multivalent film used for the construction of the SPR immunosensor.
2.3 Nucleic acid detection
The reverse transcription and quantitative polymerase Chain Reaction (RT-qPCR) method is the current standard test for the detection of viral RNA or DNA [97–99]. And the recombinase polymerase amplification (RPA) assay is another main method for nucleic acid detection [100]. To the best of our knowledge, studies based on nanopores, and Au-NPs are helpful for enhancing the detection effect. However, there have been few studies on the use of nanoarrays to enhance isothermal amplification. Recently, our group developed a nanoplasmonic-enhanced isothermal nucleic acid amplification (NanoPEIA) strategy that combines a nanoplasmonic sensor with isothermal nucleic acid amplification (Fig. 10). A nanocup array chip was used for the nucleic acid detection of SARS-CoV-2 virus. This novel strategy provides an ideal easy-to-operate detection platform for obtaining accurate, ultra-fast, and high-throughput (96 samples can be tested together) data. The efficient NanoPEIA detection strategy facilitates real-time detection and visualization within ultrashort durations and can be applied for POCT diagnosis in resource-poor and highly populated areas [70]. A schematic representation of the proposed assay is shown in Fig. 10. Applying this platform to novel coronavirus detection showed that the NanoPEIA platform was 100% sensitive to N and orf1ab genes, higher than RT-qPCR (88.9% and 90.0%, respectively). N gene specificity was 92.3%, whereas orf1ab gene specificity was 91.7%, and LOD of N and Orf1ab genes was 28.3 and 23.3 copies/mL, respectively.
Fig. 10. Schematic diagram of high-throughput and point-of-care testing nanoplasmonic-enhanced isothermal amplification (NanoPEIA) for SARS-CoV-2 [70].
DNA methylation is associated with the development and progression of inherited genetic diseases, neurological disorders, and cancers. Detection of DNA methylation is crucial because of its key role in the regulation of gene expression, eukaryotic development, and cellular differentiation [101–103]. Meta-SPR sensors are outstanding label-free and straightforward tools for DNA analysis with high sensitivity and specificity. Luo et al. designed a nanohole array sensor combined with surface-enhanced Raman spectroscopy (SERS) for DNA methylation detection [104]. This Meta-SPR platform with well-controlled hot spots has an open surface topology, which could be used as a SERS substrate to detect DNA molecules and exhibits sensitivity for detecting methylation changes of 1%. Moreover, this work demonstrated the ability of the Meta-SPR sensor-based SERS device for the sensitive and highly reproducible detection of DNA methylation, as well as the measurement of methylation levels and discrimination of methylation sites such as 5-methylcytosine and N6-methyladenine.
2.4 Cell secretion detection
Supervising cellular functions is beneficial for obtaining a better understanding of physiological and pathological processes, thereby improving the diagnosis and treatment of diseases [91,105,106]. Quantifying the number and real-time dynamics of cell secretions offers important information for basic research and clinical applications [106–109]. Recently, Meta-SPR biosensors have shown potential for sensitively detecting cell biomarker concentrations. Our group presented a plasmonic nanocup array sensor design and sensing method based on plasmonic–photonic interactions to detect the cancer biomarker carcinoembryonic antigen (CEA) [110]. This device exhibits highly sensitive detection of RI changes along with transmission peak intensity changes without a shift in the resonance wavelength. In addition, this nanocavity plasmonic sensor design successfully achieved a label-free limit of detection (LOD) of 1 ng/mL for CEA, which is clinically relevant for human CEA levels and represents a significant improvement over the current typical EOT sensors and commercially available SPR systems. Escobedo et al. also demonstrated a nanohole array-based biosensor integrated into a microfluidic concentration gradient generator for the imaging detection and quantitative assessment of ovarian cancer biomarkers [111]. Biosensors functionalized with ovarian cancer marker antibodies were used to quantify the ovarian cancer marker, r-PAX8. The LOD for the r-PAX8 protein was approximately 5 nM, within a dynamic range of approximately one order of magnitude. Furthermore, the current system combined with the microfluidic platform can generate calibration curves, which represents a further step toward the development of lab-on-chip biomedical diagnostics based on nanohole array technology.
Generally, the investigation of cell secretion dynamics is particularly important in physiological and disease processes because of its temporal variability [108]. Li et al. developed a nanoplasmonic biosensor platform composed of gold nanohole arrays supporting EOT for the real-time monitoring of cellular secretion in a label-free configuration [71]. The nanoplasmonic biosensor was equipped with an adjustable microfluidic cell module and a readily implementable nanohole array-based biosensor, which enabled the sensitive and high-throughput analysis of live cells under well-controlled culture conditions (Fig. 11). This study achieved an outstanding sensitivity of 145 pg/mL (∼5 pM) for the direct detection of vascular endothelial growth factor (VEGF) levels in live cancer cells in complex cell media. This technology may provide new insights into cell biology and facilitate the development of lab-on-chip biomedical diagnostic devices.
Fig. 11. (a) The biosensor system consists of a microfluidic cell module and an optical detection module. Cancer cells grow in a zigzag single-channel PDMS unit, and the secreted cytokines are directly delivered to the adjacent detection module. The detection module illustrates the three in-line nanohole arrays in one microfluidic channel. Two arrays are functionalized with specific anti-VEGF antibodies (blue), and the third without antibodies serves as a negative control sensor. A beam of collimated broadband light illuminates the microarrays at normal incidence. (b) Schematic design of the microfluidic-integrated biosensor for real-time cytokine secretion analysis. (c) The illustration shows the surface chemistry utilized for specific VEGF detection [71].
Exosomes can deliver various effectors or signaling macromolecules between specific cells, which shows potential for disease diagnosis. The detection and molecular analysis of exosomes is a technical challenge that often requires extensive sample purification and labeling [112,113]. Meta-SPR sensors are particularly useful for the on-chip probing of exosomes. A new SPR chip, named nanoplasmonic exosome (nPLEX) sensor, for a label-free, high-throughput approach for quantitative analysis of exosomes was reported by Hyungsoon et al. [114]. The nanoplasmonic exosome (nPLEX) assay is based on SPR transmission through periodic nanohole arrays, which are functionalized with antibodies to enable binding between exosome surface proteins and proteins present in exosome lysates. Compared with conventional instruments, nPLEX technology can realize highly sensitive and label-free exosome detection and enables continuous and real-time monitoring of molecular binding, as the probing depth (<200 nm) of plasmonic nanoholes can be readily matched to exosome size. To improve the throughput, the authors further designed an nPLEX imaging system by combining nanohole chips with a miniaturized imaging setup, which represents a significant step forward for massively parallel measurements.
2.5 Microbial detection
The ongoing COVID-19 pandemic has led to infections in millions of people and the loss of many lives [115,116]. Rapid, accurate, and convenient microbial (e.g., viruses and bacteria) detection is crucial for controlling and stopping severe and prolific infectious diseases. Meta-SPR sensors are an acceptable method for the effective detection of single virus-like particles. Recently, our group developed a method for the rapid and direct optical measurement of whole SARS-CoV-2 virus particles in one step without sample preparation using a spike protein-specific nanoplasmonic resonance sensor (Fig. 12) [117]. In our study, concentrations as low as 370 vp/mL were detected in one step within 15 min, and the virus concentration was quantified linearly in the range of 0 to 107 vp/mL. SARS-CoV-2 virus concentrations in the range of 102–107 vp/mL can also be quantified by this assay with simultaneous measurements of diluted standard samples using the same microplate reader. A similar sensing capability was demonstrated using low-cost handheld optical equipment controlled by a smartphone application. Ultrasensitive SARS-CoV-2 virus detection and early diagnosis of COVID-19 are potential point-of-care applications in clinics, roadside triage sites, and even home settings.
Fig. 12. (a) Schematic diagram of the nanoplasmonic resonance sensor for SARS-CoV-2 pseudovirus concentration measurement. (b) The illustration shows the detection process of the sensor chip cartridge for specific SARS-CoV-2. (c) SARS-CoV-2 mAb-labeled Au-NP enhanced binding curves with different concentrations of the SARS-CoV-2 pseudovirus over the range of 0–1.0 × 107 vp/mL [117].
Recently, our group designed a multi-metal-layer NanoSPR chip, including titanium, silver, and gold with unique additional surface nanostructures, to improve the capturing efficiency and detection sensitivity of the biosensor. A novel nanoplasmon biosensor with nanorobot hand (NanoRHB) integration was created as a virus capturing platform for rapid quantification of adenovirus nanoparticles and efficient large-scale assessment of virus viability (Fig. 13). This NanoRHB platform displays great potential for quality control in vaccine and delivery vector research and production within several minutes and without signal amplification and washing procedure. Furthermore, the NanoRHB integrated with gold particles can achieve one-step sandwich method for ultrasensitive detection of adenovirus with a limit of detection of 100 copies/mL. The platform allows for simple operation in practical applications, real-time monitoring of vaccine quantity and quality, and evaluation of vaccine viability; thus, it provides a convenient and rapid evaluation method for monitoring and accurate detection of other viral vectors [118].
Fig. 13. One-step rapid quantification of virus particles using the NanoRHB platform. (a) NanoSPR sensor modified by highly sensitive nanorobot hands. (b) NanoSPR sensor immobilized receptor proteins or antibodies to form a NanoRBH platform with specific capture capabilities. (c) Schematic diagram of minute time scale of the NanoRHB platform used to detect virus vectors within 5 min. (d) Schematic diagram of the super-sensitivity scale of the NanoRHB platform for the detection of viral vectors using a one-step sandwich method within 15 min [118].
Yanik et al. presented a label-free optofluidic nanoplasmonic sensor that could directly detect intact virus particles from biological media with little to no sample preparation [119]. This sensing platform can utilize group-specific antibodies to rapidly capture and detect different types of viruses based on the extraordinary light transmission effect in plasmonic nanoholes. The results demonstrated that a dynamic concentration range spanning three orders of magnitude for small, enveloped RNA viruses, such as vesicular stomatitis virus, pseudotyped Ebola virus, and large, enveloped DNA vaccinia virus, was obtained in the experimental measurements corresponding to virion concentration within a window relevant to clinical testing. However, the penetration depths of the surface plasmon polaritons are comparable to the sizes of the pathogens, which remains a question regarding the possible limitations of virus detection technology (Fig. 14).
Fig. 14. (a) VSV attaches only to the antibody-immobilized sensor. (b) Gold deposition results in suspended plasmonic nanohole sensors without any lift-off process. No clogging of the nanohole openings is observed (inset). (c) Immunosensor surface functionalization is illustrated in the schematics. Antiviral immunoglobulins are attached at their Fc region to the surface through a protein A/G layer [119].
Jackman et al. developed a plasmonic nanohole sensor to capture virus-like particles and evaluate virucidal drug candidates [120]. The nanohole array platform was fabricated with suitable nanohole dimensions to host viruses and virus-like particles according to the size distribution of dengue virus particles before and after treatment with a virucidal drug candidate. Based on this platform, a lower surface coverage of particles inside the functionalized nanoholes could be detected compared to that of the nonfunctionalized nanoholes, which suggests a significant improvement in the nanoplasmonic sensing performance (e.g., high sensitivity and specificity).
The Meta-SPR sensor has also been identified as a rapid and multiplexed diagnostic tool for the detection of bacteria to address current epidemic diseases. Soler et al. introduced a novel nanoplasmonic biosensor for the simultaneous detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in urine samples [121]. The plasmonic microarray can capture and identify the bacteria present in urine samples and provide rapid diagnosis in a label-free configuration by combining a microfluidic system with selectively functionalized nanohole arrays with specific antibodies (Fig. 15). The multiplexing capability of the biosensor successfully detected, identified, and quantified the levels of the two bacteria in a one-step assay and achieved outstanding sensitivities of 300 colony forming units (CFU)/mL for CT and 1500 CFU/mL for NG for direct immunoassay of urine samples. Furthermore, compared with conventional SPR, EOT can be achieved by normal light incidence, and it is compatible with the use of light-emitting diode (LED)-and complementary metal oxide semiconductor (CMOS)-based imagers, all owing to supernormal miniaturization and a broad field-of-view for multiplexing. This work elucidates broad potential biosensing applications of EOT phenomena in point-of-care biosensors that enable fast, simple, and efficient diagnosis of infectious diseases.
Fig. 15. (a) Cross-sectional overview of the nanoplasmonic biosensor setup. (b) Schematics of the sensor surface biofunctionalization. The different nanohole arrays are modified with different antibodies: anti-Neisseria gonorrhoeae (NG) (green), anti-Chlamydia trachomatis (CT) (blue), and a control antibody (red). Each microfluidic channel (black arrows) covers three in-line sensor arrays; therefore, it includes the two specific sensors for the different bacteria plus the negative control sensor. The zoom-in section illustrates the surface chemistry strategy employed for the functionalization of the sensors [121].
3. Chemical detection
Meta-SPR sensors can be readily developed into miniaturized devices for point-of-care environments and healthcare monitoring, particularly for explosives, heavy metals, and gases.
3.1 2,4,6-Trinitrotoluene (TNT)
2,4,6-Trinitrotoluene (TNT) is the prime constituent of most landmines and exhibits toxic, mutagenic, and carcinogenic effects. Our group has developed a nanocup array (nanoCA)-based biosensor for detecting explosives, in which a TNT-specific peptide was immobilized on a nanocup by Au–S covalent linkage [122]. The peptide-modified nanocup device was able to monitor the binding of TNT at concentrations as low as 3.12 × 10−7 mg/mL in the presence of 2,4-dinitrotoluene (DNT) and 3-nitrotoluene (3-NT), which showed high sensitivity and specificity and provided novel approaches to design versatile biosensor assays based on Meta-SPR for chemical molecules (Fig. 16(a), 16(b)).
Fig. 16. (a) The nanoCA device and its optical measurement system. (b) Schematic diagram of the peptide immobilization on the nanoCA with covalent Au–S linkage (Au nanoparticles are deposited everywhere in nanocups). (c) Schematic illustration of experimental apparatus of the heavy metal detection system. The electrochemical detection component is composed of a three-electrode system and a perfusion system. NanoCA serves as working electrode (WE). The NanoCA is placed against the chamber wall and perpendicular to the light pathway [122,123].
3.2 Heavy metals
In another study, a dual detection method combining LSPR and anodic stripping voltammetry was proposed to analyze heavy metal ions using a nanocup array sensor device [123]. The dual detection system, combined with the electrochemical method and LSPR measurement, demonstrated an LOD of the part-per-billion level for aqueous heavy metal ions such as lead, copper, and zinc. In combination with electrochemical methods, Meta-SPR sensors can be applied in highly integrated detection systems for on-spot detection (Fig. 17(c)).
3.3 Gases
Recently, significant efforts have been made to develop miniaturized Meta-SPR sensors for the detection of a wide variety of gases. Zhao et al. reported a miniaturized nanoarray-based plasmonic platform for the detection of acetone and ethanol vapor [124]. The developed nanohole-based SPR sensor, which is coated with a Cu-benzenetricarboxylate metal organic framework (MOF), is promising for the detection of 500 nmol/mol (ppb) acetone or ethanol vapors at room temperature (Fig. 17). The developed miniaturized Meta-SPR sensor, a readily integrated sensing device, exhibits great potential for the monitoring of indoor or outdoor air quality and the quality of food or beverages and the detection of breath biomarkers (such as acetone and ethanol) for the diagnosis of different diseases.
Fig. 17. (a) Schematic image of the Meta-SPR sensor. (b) Image of one sensor chip. Each chip has four nanohole array windows with an area of 300 µm × 300 µm. (c) Schematic diagram of the sensing mechanism [124].
4. Conclusions
Owing to their unique nanostructures, nanoarray-based biosensors have superior advantages over conventional SPR sensors. In the past several years, nanoarray-based biosensors have been widely explored for biosensing applications because they can be manipulated in a simplified optical system, thus allowing integration into low-cost, easy-to-use, and portable platforms. We assert that robust nanosensor chips paired with universal equipment or novel biospecific modification strategies could improve the performance of nanoarray-based SPR biosensors, leading to the rapid, sensitive, and specific detection of chemical and biological analytes in complex samples. Other plasmonic structures, such as nanoparticle arrays [125], hyperbolic metamaterial multilayers [126], and split-ring resonators [127], can also be used for chemical and biological analytes. These biosensor systems are expected to be flexible platforms for highly sensitive measurements in various settings, including clinical and point-of-care applications and home-use diagnostics. In addition, the detection of nanoarray sensors in chemical aspects can be used as a new research direction. However, some limitations of Meta-SPR biosensors, including the improvement of sensitivity and LOD, specificity in complex biological samples, and miniaturization for point-of-care applications, should be addressed to achieve their full potential. In addition, whether using a PSPR or LSPR sensor, it is difficult to directly detect species at extremely dilute concentrations (less than 1 pmol/L) or with a very small molecular weight (less than 8 Da); therefore, improving the sensitivity and selectivity of SPR has become a popular topic and a big challenge [128,129]. Moreover, Meta-SPR systems, such as protein A ligand, anti-His labeled, and avidin biosensors, can be expected to enter the commercial market in the coming years for food control, medical diagnosis, environment monitoring, and life science research.
Notation
EOT | Extraordinary optical transmission |
LOD | Limit of detection |
LSPR | Local surface plasmon resonance |
PSPR | Propagating surface plasmon resonance |
SPR | Surface plasmon resonance |
Funding
National Natural Science Foundation of China (82072735, 91959107); Fundamental Research Funds for the Central Universities (2019kfyXMPY002, 2020kfyXGYJ111); Key Technologies Research and Development Program (2020YFC0861900).
Disclosures
The authors declare no competing financial interests.
Data availability
No data were generated or analyzed in the presented research.
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