Surface-enhanced Raman Scattering Biosensor Research Articles

Development of ratiometric DNA biosensors with improved accuracy, precision, and signal-to-noise ratio

Ratiometric DNA biosensors, which utilize DNA as the recognition element and integrate dual signals from diverse sensing platforms including fluorescence, electrochemistry, and surface-enhanced Raman scattering (SERS), have demonstrated remarkable proficiency in detecting a wide range of targets. In this review, we showcase the significant progress achieved by ratiometric biosensors. Firstly, ratiometric biosensors have made notable advancements in analyzing real samples. These include the analysis of pH values near cancer cells, quantification of miRNA in human cell lysates, detection of human telomerase RNA in cell extracts, and performing DNA logic-gated in situ bioimaging on cell membranes. Secondly, excellent sensitivity has been attained through the utilization of effective amplification methods such as RCA, HCR, and CHA, among others. Thirdly, the construction of stable reference signals has resulted in significantly improved precision for ratiometric biosensors. This breakthrough has overcome matrix effects, enabling reliable detection in real samples with high selectivity. This review provides a comprehensive overview of recent advancements in strategies employed by ratiometric DNA biosensors. We present three types of biosensors based on distinct sensing platforms: fluorescent, electrochemical, and SERS biosensors. Additionally, we discuss future directions and primary challenges in the development of ratiometric DNA biosensors.

Tailorable janus plasmonic SERS platform with hotspots integrating and analytes enriching property for multiple sensing

Electromagnetic hotspot engineering plays a crucial role in surface-enhanced Raman scattering (SERS) biosensors. However, the construction of optical hotspots with high density and the concentration of analytes into hotspot centers remain challenging tasks. Additionally, achieving high sensitivity and signal reproducibility in SERS biosensors is an ongoing challenge. In this study, we utilise Janus micro/nano arrays to develop a superhydrophobic SERS platform. The high roughness of these arrays facilitates the distribution of rich hotspots ranging from nano to microscale and encourages the concentration of analytes within hotspot centers. The Janus plasmonic micro/nano arrays were meticulously crafted through the synergy of site-specific growth and instant interfacial assembly of nanoparticles (NPs). In the realm of SERS measurements targeting organic dyes in river water, our sensing platform demonstrates high sensitivity (limit of detection (LOD): 10−9 M) and signal reproducibility (relative standard deviation (RSD)=4.25%). Furthermore, the SERS platform exhibited remarkable sensitivity to multiple dyes in river water. Thus, our superhydrophobic SERS platform lays the groundwork for sensitive analysis in diverse fields such as environmental analysis and healthcare monitoring.

SERS biosensor with plastic antibodies for detection of a cancer biomarker protein

Surface-enhanced Raman scattering (SERS) is a powerful method for detecting breast cancer-specific biomarkers due to its extraordinary enhancement effects obtained by localized surface plasmon resonance (LSPR) in metallic nanostructures at hotspots. In this research, gold nanostars (AuNSs) were used as SERS probes to detect a cancer biomarker at very low concentrations. To this end, we combined molecularly imprinted polymers (MIPs) as a detection layer with SERS for the detection of the biomarker CA 15–3 in point-of-care (PoC) analysis. This required two main steps: (i) the deposition of MIPs on a gold electrode, followed by a second step (ii) antibody binding with AuNSs containing a suitable Raman reporter to enhance Raman signaling (SERS). The MPan sensor was prepared by electropolymerization of the monomer aniline in the presence of CA 15–3. The template molecule was then extracted from the polymer using sodium dodecyl sulfate (SDS). In parallel, a control material was prepared in the absence of the protein (NPan). Surface modification for the control was performed using electrochemical techniques such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The performance of the sensor was evaluated using the SERS technique, in which the MPan sensor is first incubated with the protein and then exposed to the SERS probe. Under optimized conditions, the device showed a linear response to CA 15–3 concentrations from 0.016 to 248.51 U mL−1 in a PBS buffer at pH 7.4 in 1000-fold diluted serum. Overall, this approach demonstrates the potential of SERS as an optical reader and opens a new avenue for biosensing applications.Graphical

Combining multisite functionalized magnetic nanomaterials with interference-free SERS nanotags for multi-target sepsis biomarker detection

Surface-enhanced Raman scattering (SERS) is an ultra-sensitive vibration spectroscopy technology, with the advantages of multi-index and non-destructive quantitative detection, has attracted much attention in the joint detection of biomarkers. A novel SERS biosensor with multisite capture and interference-free quantification was designed for the joint detection of the sepsis biomarker interleukin-6 (IL-6) and procalcitonin (PCT). This biosensor had two interference-free core-shell SERS probes with highly efficient electromagnetic enhancement and a multisite functionalized magnetic nanomaterial with high adsorption capacity. They formed sandwich structure with the targets through boronic affinity and immunoreaction, and the multi-target quantitative analysis of biomarkers in serum was performed using a portable Raman spectrometer in the Raman-silent region. The SERS biosensor was exhibited highly sensitive with detection limits of 0.584 and 2.99 pg/mL for IL-6 and PCT, respectively. In addition, it exhibited excellent selectivity and specificity even with the interference of other proteins. As this SERS method showed excellent performance in the detection of sepsis, it has great potential for multi-index detection in clinical diagnosis of major diseases.

Graphene Quantum Dot-Enabled Nanocomposites as Luminescence- and Surface-Enhanced Raman Scattering Biosensors

Graphene quantum dots (GQDs) are a zero-dimensional (0D) carbon-based nanomaterial with a unique quantum confinement effect that have captured the eyes of many researchers. In addition to their luminescence properties, a high biocompatibility and large surface area have enabled GQDs to be used for many applications, and even be integrated with either organic or inorganic materials to produce GQD nanocomposites to enhance the application performances and broaden the application scope. In this review, we aim to highlight the exquisite properties and synthesis methods of GQDs, recent advances in the fabrication of GQD nanocomposites with both organic and inorganic materials, and their corresponding luminescence-based and surface enhanced Raman scattering (SERS)-based biosensing applications. Finally, this review article concludes with a summary of current challenges and prospects.

Plasmonic nanostructure-enhanced Raman scattering for detection of SARS-CoV-2 nucleocapsid protein and spike protein variants

Epidemiological control and public health monitoring during the outbreaks of infectious viral diseases rely on the ability to detect viral pathogens. Here we demonstrate a rapid, sensitive, and selective nanotechnology-enhanced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection based on the surface-enhanced Raman scattering (SERS) responses from the plasma-engineered, variant-specific antibody-functionalized silver microplasma-engineered nanoassemblies (AgMEN) interacting with the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins. The three-dimensional (3D) porous AgMEN with plasmonic-active nanostructures provide a high sensitivity to virus detection via the remarkable SERS signal collection. Moreover, the variant-specific antibody-functionalization on the SERS-active AgMEN enabled the high selectivity of the SARS-CoV-2 S variants, including wild-type, Alpha, Delta, and Omicron, under the simulated human saliva conditions. The exceptional ultrahigh sensitivity of our SERS biosensor was demonstrated via SARS-CoV-2 S and N proteins at the detection limit of 1 fg mL−1 and 0.1 pg mL−1, respectively. Our work demonstrates a versatile SERS-based detection platform can be applied for the ultrasensitive detection of virus variants, infectious diseases, and cancer biomarkers.

Multistage nucleic acid amplification induced nano-aggregation for 3D hotspots-improved SERS detection of circulating miRNAs

Circulating miRNAs in the blood can regulate disease development and thus indicate disease states via their various expression levels. For these reasons, circulating miRNAs constitute useful biomarkers, and an approach to the accurate detection of circulating miRNAs is attractive in the diagnosis and treatment of diseases. However, methods for clinical detecting of circulating miRNA that take both sensitivity and practicality into account are still needed. Therefore, we aimed herein to solve some inherent problems in the actual detection using a robust surface-enhanced Raman scattering (SERS) platform with integrated nucleic acid amplification and nanoparticle aggregation to construct 3D hotspots for improving performance of analyzing circulating miRNAs. After target recognition and initial signal amplification by DNAzyme, we observed that release triggered an open hairpin DNA on gold nanoparticles (AuNPs), which then promote AuNP aggregation, causing the accumulation of a large number of hotspots in three-dimention. The SERS biosensor achieved a better performance than the sandwich-type separation detection, with a low detection limit (0.37 fM) and a broad linear range (1 fM–10 nM) in liquids. This SERS platform can be used as a powerful tool for the detection of circulating miRNAs, and it can be used to improve the sensitivity and accuracy of various clinical-disease diagnoses.Graphical

An ultrasensitive and dual-recognition SERS biosensor based on Fe3O4@Au-Teicoplanin and aptamer functionalized Au@Ag nanoparticles for detection of Staphylococcus aureus

An ultrasensitive and dual-recognition surface-enhanced Raman scattering (SERS) biosensor for Staphylococcus aureus (S. aureus) was constructed, which was based on teicoplanin (Tcp) functionalized gold-coated magnet nanoparticles (Fe3O4@Au-Tcp NPs) as capture probe and S. aureus aptamer (Apt) functionalized silver coated gold nanoparticles (Au@Ag-DTNB-Apt NPs) as signal probe. Both Au NPs and Au@Ag NPs were prepared by a green synthesis method. Especially, the synthesis method of Au@Ag NPs reduced by chitosan (CS) was first reported in this work. Due to the great SERS enhancement based on the hot spot effect between Au NPs and Au@Ag NPs, and the dual-recognition ability based on Tcp and Apt, the SERS biosensor was ultrasensitive and specific. A detection limit of 1.09 CFU mL−1 with a broad dynamic linear (7.6 × 101–7.6 × 107 CFU mL−1) was achieved within 50 min without interference by other bacteria. Moreover, the SERS biosensor could be applied for detection of S. aureus in milk and orange juice samples. This study provides a green, rapid and ultrasensitive method to detect S. aureus, and also explores the high utilization value of CS and Tcp, which has a broad application prospect in detection of pathogenic bacteria.

Sensitive SERS detection of melamine and cyromazine in raw milk using aptamer-based in situ silver nanoparticles synthesis

In this paper, we develop a simple design for simultaneous detection of melamine (MEL) and cyromazine (CYR) by surface-enhanced Raman scattering (SERS) with the formation of well-defined MEL or CYR-aptamer-AgNPs. This detection will take only 10 min, and SERS signals generated by MEL-aptamer-AgNPs exhibits a linear dependence on melamine (R2 = 0.998) concentration ranging from 0.1 to 0.5 ppm on melamine. The detection limit is sensitive down to 43.5 ppb. SERS signals generated by CYR-aptamer-AgNPs exhibits a linear dependence on cyromazine (R2 = 0.997) concentration ranging from 0.1 to 0.5 ppm on cyromazine. The detection limit is sensitive down to 23.6 ppb. This SERS biosensor was first reported for the simultaneous detection of melamine and cyromazine by using aptamer-based in situ silver nanoparticles synthesis. So we expected that the development of this biosensor could provide a good platform for the rapid detection of other pollutants in raw milk.

A Review of Graphene-Based Surface Plasmon Resonance and Surface-Enhanced Raman Scattering Biosensors: Current Status and Future Prospects.

The surface plasmon resonance (SPR) biosensor has become a powerful analytical tool for investigating biomolecular interactions. There are several methods to excite surface plasmon, such as coupling with prisms, fiber optics, grating, nanoparticles, etc. The challenge in developing this type of biosensor is to increase its sensitivity. In relation to this, graphene is one of the materials that is widely studied because of its unique properties. In several studies, this material has been proven theoretically and experimentally to increase the sensitivity of SPR. This paper discusses the current development of a graphene-based SPR biosensor for various excitation methods. The discussion begins with a discussion regarding the properties of graphene in general and its use in biosensors. Simulation and experimental results of several excitation methods are presented. Furthermore, the discussion regarding the SPR biosensor is expanded by providing a review regarding graphene-based Surface-Enhanced Raman Scattering (SERS) biosensor to provide an overview of the development of materials in the biosensor in the future.

Modification of CR39 surfaces by 193 nm ArF laser for biomaterial sensing

Abstract Ultrasensitive detection of biological and chemical species is significant in a wide range of scientific and technological fields. In this work, a surface enhanced Raman scattering (SERS) substrate is engineered upon 193 nm ArF (Argon Fluoride) excimer laser irradiation that produces an output energy of 160 mJ/pulse in 10 ns. It induces a periodic surface structures which is commonly known as Laser Induced Periodic Surface Structures (LIPSS) of grooves like nanostructures on surface of Allyl diglycol carbonate (ADC) or CR39 polymer due to irradiation of 2400 J/cm2 energy dose. Then the produced nanostructured surface is coated with gold layer. The potential of the produced substrate as a SERS biosensor is investigated through methylene blue (MB) that gave an enhancement factor of 0.5*104. The biosensor sensitivity is characterized by detecting low concentration of MB with a detection limit of 0.1 μMolar (μM).

Plasmonic SERS Biosensor Based on Multibranched Gold Nanoparticles Embedded in Polydimethylsiloxane for Quantification of Hematin in Human Erythrocytes.

This work reports a plasmonic surface-enhanced Raman scattering (SERS) biosensor that allows for quantitative analysis of hematin in erythrocytes without the need of separating it from hemoglobin (Hb). The biosensor exploits the tunable localized surface plasmon resonance (LSPR) characteristics of multibranched gold nanoparticles (M-AuNPs) and the strong plasmon coupling between an Au thin film and a flexible substrate consisting of M-AuNPs embedded in polydimethylsiloxane (PDMS) (i.e., M-AuNP-embedded PDMS substrate). In the assay, the hematin (or hematin-containing erythrocyte hemolysate) was deposited on Au film surface and covered with M-AuNP-embedded PDMS. Strong SERS signals were generated under excitation at 785 nm; the signals were sensitive to hematin concentration but not to several common coexisting biological substances. The intensities of the SERS signal (at 1623 cm-1) displayed a wide linear range using hematin concentrations in a range of at least ∼1.5 nM-1.1 μM; the limit of detection (LOD) was ∼0.03 ± 0.01 nM at a signal/noise (S/N) of 3. This assay is simple and sensitive without tedious separation procedures, thereby saving time and enhancing efficiency. This biosensor can be used to determine hematin concentration in human erythrocyte cytosols giving concentrations of ∼18.5 ± 4.5 (by averaging eight samples) and 51.5 ± 6.2 μM (by averaging three samples) for healthy and sickle erythrocytes, respectively, making it a potential application in clinical detection.

Graphene Oxide-Assisted and DNA-Modulated SERS of AuCu Alloy for the Fabrication of Apurinic/Apyrimidinic Endonuclease 1 Biosensor.

Fabrication of high-performance surface-enhanced Raman scattering (SERS) biosensors relies on the coordination of SERS substrates and sensing strategies. Herein, a SERS active AuCu alloy with a starfish-like structure is prepared using a surfactant-free method. By covering the anisotropic AuCu alloy with graphene oxide (GO), enhanced SERS activity is obtained owing to graphene-enhanced Raman scattering and assembly of Raman reporters. Besides, stability of SERS is promoted based on the protection of GO to the AuCu alloy. Meanwhile, it is found that SERS activity of AuCu/GO can be regulated by DNA. The regulation is sequence and length dual-dependent, and short polyT reveals the strongest ability of enhancing the SERS activity. Relying on this phenomenon, a SERS biosensor is designed to quantify apurinic/apyrimidinic endonuclease 1 (APE1). Because of the APE1-induced cycling amplification, the biosensor is able to detect APE1 sensitively and selectively. In addition, APE1 in human serum is analyzed by the SERS biosensor and enzyme-linked immunosorbent assay (ELISA). The data from the SERS method are superior to that from ELISA, indicating great potential of this biosensor in clinical applications.

SERS Nanotags and Their Applications in Biosensing and Bioimaging

Owing to the unique advantages of surface enhanced Raman scattering (SERS) in high sensitivity, specificity, multiplexing capability and photostability, it has been widely used in many applications, among which SERS biosensing and bioimaging are the focus in recent years. The successful applications of SERS for non-invasive biomarker detection and bioimaging under in vitro, in vivo and ex vivo conditions, offer significant clinical information to improve diagnostic and prognostic outcomes. This review provides recent developments and applications of SERS, in particular SERS nanotags in biosensing and bioimaging, describing case studies in which different types of biomarkers have been investigated, as well as outlining future challenges that need to be addressed before SERS sees both pathological and clinical use.

Realistic FDTD Simulations of Plasmonic Properties on Ag Columnar Thin Films as SERS Biosensor

Noble metal sculptured thin films are of great interest during last decade as excellent surface-enhanced Raman scattering (SERS) substrates due to remarkable plasmonic properties in the visible and near-infrared range. In this work, Ag columnar thin films (Ag-CTFs) have been prepared by the glancing angle deposition technique. Finite-difference time-domain simulations has been utilized to study plasmonic properties of Ag-CTFs with a more accurate model based on binary scanning electron microscope (SEM) images by taking account of the shape irregularities, size distributions and random arrangement. The calculated absorption spectra based on the model of binarized SEM images show the best agreement with the measured spectra compared with models of periodic array with a regular shape. The near-field plasmonic properties are simulated based on the verified model. The distributions of electric field enhancement and hot spots are confirmed to be spectral and polarization dependent. There are multiple resonance peaks from visible to near-infrared and multiple eigenmodes coexist at the same wavelength and electric field enhancement are mainly excited by the polarized light vertical to the gap orientation. The electric field enhancement is found to distribute unevenly in the films with surface-localized feature. The equations to calculate the simulation SERS enhancement factor (EF) and total number of hot spots (tHN) are modified according to the above discussions. The experimental SERS EFs are on the order of 107–108, which indicates the high sensitivity of the films and the simulation SERS EFs and tHNs show good agreement with the experimental EFs. It is found that the SERS performance of Ag-CTFs is decided by both the cross-section structural characteristics and film thickness, which affect the electric filed enhancement and number of adsorbed molecules, respectively. Our work could be helpful in understanding the SERS mechanism and useful to the optimization of metal sculptured thin films for designing SERS biosensor.

Graphene-Gold Nanoparticles Hybrid-Synthesis, Functionalization, and Application in a Electrochemical and Surface-Enhanced Raman Scattering Biosensor.

Graphene is a single-atom-thick two-dimensional carbon nanosheet with outstanding chemical, electrical, material, optical, and physical properties due to its large surface area, high electron mobility, thermal conductivity, and stability. These extraordinary features of graphene make it a key component for different applications in the biosensing and imaging arena. However, the use of graphene alone is correlated with certain limitations, such as irreversible self-agglomerations, less colloidal stability, poor reliability/repeatability, and non-specificity. The addition of gold nanostructures (AuNS) with graphene produces the graphene–AuNS hybrid nanocomposite which minimizes the limitations as well as providing additional synergistic properties, that is, higher effective surface area, catalytic activity, electrical conductivity, water solubility, and biocompatibility. This review focuses on the fundamental features of graphene, the multidimensional synthesis, and multipurpose applications of graphene–Au nanocomposites. The paper highlights the graphene–gold nanoparticle (AuNP) as the platform substrate for the fabrication of electrochemical and surface-enhanced Raman scattering (SERS)-based biosensors in diverse applications as well as SERS-directed bio-imaging, which is considered as an emerging sector for monitoring stem cell differentiation, and detection and treatment of cancer.

Disordered array of Au covered Silicon nanowires for SERS biosensing combined with electrochemical detection.

We report on highly disordered array of Au coated silicon nanowires (Au/SiNWs) as surface enhanced Raman scattering (SERS) probe combined with electrochemical detection for biosensing applications. SiNWs, few microns long, were grown by plasma enhanced chemical vapor deposition on common microscope slides and covered by Au evaporated film, 150 nm thick. The capability of the resulting composite structure to act as SERS biosensor was studied via the biotin-avidin interaction: the Raman signal obtained from this structure allowed to follow each surface modification step as well as to detect efficiently avidin molecules over a broad range of concentrations from micromolar down to the nanomolar values. The metallic coverage wrapping SiNWs was exploited also to obtain a dual detection of the same bioanalyte by electrochemical impedance spectroscopy (EIS). Indeed, the SERS signal and impedance modifications induced by the biomolecule perturbations on the metalized surface of the NWs were monitored on the very same three-electrode device with the Au/SiNWs acting as both working electrode and SERS probe.

Detection of Mercury with a Surface-Enhanced Raman Scattering Biosensor

There is a risk that toxic heavy metals are released from dental amalgams. This study has demonstrated a sensitive and selective biosensor based on surface-enhanced Raman scattering (SERS), which is capable of measuring mercury(II) ions in human saliva from ppt up to ppb level. In the biosensor system, the SERS probe and the solid-state chip were functionalized with complementary single-stranded DNA, respectively, except for three artificially designed T-T mismatches. Only in the presence of mercury ions can the SERS probe be captured by the chip due to hybridization of ssDNA, rendering the specific detection of mercury ions. Finite Difference Time Domain (FDTD) simulations have showed that the excellent performance of the SERS biosensor is attributed to the strong coupling between SERS probe and the chip with a high enhancement factor.

Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing

Multimodal imaging provides complimentary information that is advantageous in studying both cellular and molecular mechanisms in vivo, which has tremendous potential in pre‐clinical research and clinical translational imaging. It is desirable to design probes for multimodal imaging that can be administered minimally but provides multifaceted information. Herein, we demonstrate the complementary dual functional ability of a nanoconstruct for molecular imaging in both photoacoustic (PA) and surface‐enhanced Raman scattering (SERS) biosensing simultaneously in tandem. To realize this, a group of NIR active organic molecules are designed and synthesized that possess both SERS and PA activity. Nanoconstructs realized by anchoring such molecules onto gold nanoparticles are demonstrated for targeting cancer biomarkers in vivo while providing complimentary information about biodistribution and targeting efficiency. In future, such nanoconstructs could play a major role in identifying surgical margins and also for disease monitoring in translational medicine.

Detection of Cancer Biomarker With Surface-Enhanced Raman Scattering Biosensor

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