Label-free Detection Of Biomolecules Research Articles

Advances in Label-Free Glucose Detection Using Self-Assembled Nanoparticles and Surface-Enhanced Raman Spectroscopy.

In the landscape of biomolecular detection, surface-enhanced Raman spectroscopy (SERS) confronts notable obstacles, particularly in the label-free detection of biomolecules, with glucose and other sugars presenting a quintessential challenge. This study heralds the development of a pioneering SERS substrate, ingeniously engineered through the self-assembly of nanoparticles of diverse sizes (Ag1@Ag2NPs). This configuration strategically induces 'hot spots' within the interstices of nanoparticles, markedly amplifying the detection signal. Rigorous experimental investigations affirm the platform's rapidity, precision, and reproducibility, and the detection limit of this detection method is calculated to be 6.62 pM. Crucially, this methodology facilitates nondestructive glucose detection in simulated samples, including phosphate-buffered saline and urine. Integrating machine learning algorithms with simulated serum samples, the approach adeptly discriminates between hypoglycemic, normoglycemic, and hyperglycemic states. Moreover, the platform's versatility extends to the detection and differentiation of monosaccharides, disaccharides, and methylated glycosides, underscoring its universality and specificity. Comparative Raman spectroscopic analysis of various carbohydrate structures elucidates the unique SERS characteristics pertinent to these molecules. This research signifies a major advance in nonchemical, label-free glucose determination with enhanced sensitivity via SERS, laying a new foundation for its application in precision medicine and advancing structural analysis in the sugar domain.

Simulation and modeling of high-sensitive JL-TFET based biosensor for label free detection of biomolecules

Simulation and modeling of high-sensitive JL-TFET based biosensor for label free detection of biomolecules

Trench Dual Gate Junctionless Field Effect Transistor

Diversified biomolecules sensing is turning out to be the most promising area of research due to ever decreasing healthy lifestyle. Field effect transistorized biosensing approach puts its signature as label free, portable and also very careful pathway. In this present work a trench structured dielectric modulated double gate junction-less field effect transistor (TG-DMJLFET) is urbanized using SILVACO ATLAS simulator for label free detection of biomolecules. The developed structure has two vertically positioned gates in distinct trenches. For immobilizing biomolecules, two cavities are formed in the gate oxide region for dielectric modulation. The dielectric constant (k) has been varied over a wide range of 1.54 (Uricase) to 12(Gelatin) signifying the sensing of diverse charged biomolecules. The sensitivity is evaluated in terms of threshold voltage shift and transconductance . The in-depth electrostatic analysis is illustrated in terms of central potential ,energy band diagram ,drive current and also by the depiction of the electric field .In case of charged biomolecules, the shift in threshold voltage is obtained as 350 mV for change in the di-electric constant (k) ranging from 1.54 to 12. The transconductance alteration is observed as 1.94×10-5 when the k is changed from 3.46 to 12 .The device has showed excellent performance in biomolecules sensing.

Label-free detection of biomolecules using inductively coupled plasma mass spectrometry (ICP-MS).

Bioassays using inductively coupled plasma mass spectrometry (ICP-MS) have gained increasing attention because of the high sensitivity of ICP-MS and the various strategies of labeling biomolecules with detectable metal tags. The classic strategy to tag the target biomolecules is through direct antibody-antigen interaction and DNA hybridization, and requires the separation of the bound from the unbound tags. Label-free ICP-MS techniques for biomolecular assays do not require direct labeling: they generate detectable metal ions indirectly from specific biomolecular reactions, such as enzymatic cleavage. Here, we highlight the development of three main strategies of label-free ICP-MS assays for biomolecules: (1) enzymatic cleavage of metal-labeled substrates, (2) release of immobilized metal ions from the DNA backbone, and (3) nucleic acid amplification-assisted aggregation and release of metal tags to achieve amplified detection. We briefly describe the fundamental basis of these label-free ICP-MS assays and discuss the benefits and drawbacks of various designs. Future research is needed to reduce non-specific adsorption and minimize background and interference. Analytical innovations are also required to confront challenges faced by in vivo applications.

Gate Engineered Ferroelectric Junctionless BioFET for Label-Free Detection of Biomolecules

Gate Engineered Ferroelectric Junctionless BioFET for Label-Free Detection of Biomolecules

Gold Nanorod Density-Dependent Label-Free Bacteria Sensing on a Flake-like 3D Graphene-Based Device by SERS.

Surface-enhanced Raman spectroscopy (SERS) is an effective technique for biosensing, enabling label-free detection of biomolecules with enhanced sensitivity. There is a tremendous probability of signal failure in Raman frequencies because of the scattering of the Raman radiation in liquids, effective SERS improvement is required to reduce this issue when considering liquid specimens. We examined a liquid bacterial sample, investigating the electrostatic interactions of the bacterial samples with gold nanorods (AuNRs) and graphene. We established a voltage-gated 3D graphene functionalized with an AuNR-based device on the silicon substrate for SERS measurements when the applied voltage ranges from 0 to 3 V. Moreover, AuNRs density-susceptible bacterial sample analysis with varied concentrations of bacterial samples has also been described. Using bacterial SERS analysis, the bacterial components amide II (1555-1565 cm-1) and amide III (1250-1350 cm-1) have been discovered for both bacteria, Gram-positive, Listeria monocytogenes and Gram-negative, Salmonella typhi. Our fabricated device affords an interesting label-free, rapid, and reproducible bacterial sample analysis based on the density of the AuNRs when functionalizing flake-like 3D graphene, which can help facilitate label-free bacteria sensing platforms.

A single gate Si1−xGex dopingless TFET functioned as an effective label-free biosensor

This paper examines the sensitivity of a newly presented heterojunction dopingless tunnel field effect transistor (HJ-DLTFET) biosensor for the label-free detection of biomolecules. The etched nanocavity is introduced in the source metal region for better sensing ability. The dielectric constants (k) of five neutral biomolecules are employed in this paper to test the sensitivity of the proposed biosensor. The electrostatic performance is investigated based on transfer characteristics, energy band, tunneling distance (λ) at source/channel (S/C) interface, drain current (ID) variation for different dielectric constant (k), drain to source voltage (VDS) variation and mole fraction (x) variation respectively. Further, the RF performance analysis includes gate/source capacitance (Cgs), total gate capacitance (Cgg), cut-off frequency (ft), and maximum frequency (fm) analysis. Similarly, sensitivity analysis consists of current sensitivity (SID), current ratio sensitivity (Sratio), average SS sensitivity (SSS), Cgs sensitivity, Cgg sensitivity, ft sensitivity, and fm sensitivity. The investigation is carried out with the variation of neutral biomolecules in terms of various k inside the cavity. Similarly, the impact of charged biomolecules on the sensitivity of the proposed biosensor is investigated. The HJ-DLTFET sensor provides the maximum sensitivity SID of 1.56 × 1010, Sratio of 5.95 × 109, and SSS of 0.80 for Gelatin (k = 12.00) at room temperature using the Silvaco TCAD simulation tool. Combining a low band gap Si0.6Ge0.4 source with a high band gap silicon channel and a high-k (HfO2) improves drain current sensitivity without impacting leakage current.

Electrokinetic Active Particles for Motion-Based Biomolecule Detection.

Detection of biomolecules is essential for patient diagnosis, disease management, and numerous other applications. Recently, nano- and microparticle-based detection has been explored for improving traditional assays by reducing required sample volumes and assay times as well as enhancing tunability. Among these approaches, active particle-based assays that couple particle motion to biomolecule concentration expand assay accessibility through simplified signal outputs. However, most of these approaches require secondary labeling, which complicates workflows and introduces additional points of error. Here, we show a proof-of-concept for a label-free, motion-based biomolecule detection system using electrokinetic active particles. We prepare induced-charge electrophoretic microsensors (ICEMs) for the capture of two model biomolecules, streptavidin and ovalbumin, and show that the specific capture of the biomolecules leads to direct signal transduction through ICEM speed suppression at concentrations as low as 0.1 nM. This work lays the foundation for a new paradigm of rapid, simple, and label-free biomolecule detection using active particles.

Universal Method for Label-Free Detection of Pathogens and Biomolecules by Surface-Enhanced Raman Spectroscopy Based on Gold Nanoparticles.

The detection of biomolecules is the key to basic molecular research, diagnostics, drug screening, and other biomedical applications. However, the existing detection techniques can only detect single classes of biomolecules, which warrant the development of a versatile biomolecule detection platform. Here, we developed a universal method for label-free detection of biomolecules via surface-enhanced Raman spectroscopy (SERS) by using sulfhydryl-modified gold nanoparticles as the substrate. The biomolecules can be adsorbed on the surface of gold nanoparticles cleaned by bromide ions to obtain initially enhanced Raman signals, and the aggregator (calcium ion) was further added to form a "hot spot", which enhanced the biomolecular signal again. Through the "two-step enhancement method", we were able to obtain fingerprints of DNA, RNA, amino acids, peptides, proteins, viruses, bacteria, and lipid molecules. This low-toxic, highly sensitive, and widely applicable technique has potential applications in biomedical research, clinical testing, and disease diagnosis and lays the foundation for the development of SERS technology in various fields.

Dual Cavity Dielectric Modulated Ferroelectric Charge Plasma Tunnel FET as Biosensor: For Enhanced Sensitivity.

This work reports a biosensor based on the dual cavity dielectric modulated ferroelectric charge plasma Tunnel FET (FE-CP-TFET) with enhanced sensitivity. By incorporating underlap and dielectric modulation phenomena, ultra sensitive, and label-free detection of biomolecules is achieved. The cavity is carved underneath the source-gate dielectric for the immobilization of the biomolecules. The ferroelectric (FE) material is used as a gate stack to realize a negative capacitance effect to amplify the low gate voltage. To avoid the issues with metallurgical doping such as random dopant fluctuations (RDFs), ambipolar conduction, and increased thermal budget, the charge plasma concept is deployed. Based on our exhaustive ATLAS 2D TCAD study, the electric field, hole concentration, and energy band diagram of the proposed device are critically analyzed to provide a better insight into the biosensor working mechanism. Here, two different figures-of merits (FOMs) for the proposed biosensor are investigated such as sensitivity and linearity. Sensitivity has been measured in terms of drain current, [Formula: see text] to [Formula: see text] ratio, electric field, and transconductance sensitivity. Linearity analysis of the proposed structure includes [Formula: see text] ratio. The reported biosensor is capable of detecting several biomolecules such as (neutral and charged as well) Streptavidin (2.1), 3-aminopropyltriethoxysilane (APTES) (K =3.57 ), Keratin (K =8 ), T7 (K =6.3 ) and Gelatin (K =12 ). It was observed that the optimized cavity structure demonstrates high drain current sensitivity ( 2.7×108 ) as well as high [Formula: see text] sensitivity ( 1.45×108 ). Further, the linearity analysis shows that the Pearson's coefficient of both structures have been achieved as ( r2 ≥ 0.8 ). It is conferred from the results that our biosensor can be a better alternative for the detection of the various neutral and charged biomolecules.

Dielectric Modulated Nanotube Tunnel Field-Effect Transistor as a Label Free Biosensor: Proposal and Investigation.

Dielectric modulated (DM) field-effect transistors (FET) have gained significant popularity for label-free detection of biomolecules. However, the inherent short channel effects limit their sensitivity, scalability and energy-efficiency. Therefore, to realize the true potential of the DMFET based biosensors, in this work, we propose a highly scalable, extremely sensitive and energy-efficient DM nanotube tunnel FET (NT-TFET) biosensor for label-free detection of biomolecules by modifying the structure of the conventional NT-TFET. The modified architecture facilitates the realization of a nanocavity at the source-channel tunneling junction and also provides stability to the immobilized biomolecules. We have performed an extensive analysis of the performance of the proposed DM NT-TFET biosensor in the presence of different representative target biomolecules characterized by different dielectric constants, and/or ionized charge densities using calibrated TCAD simulations. Our results indicate that the proposed DM NT-TFET exhibits an extremely high threshold voltage sensitivity ( SVth ) of 0.44, a high selectivity exceeding four orders of magnitude, ON-state current sensitivity ( SION ) of more than five orders of magnitude and could be a promising alternative to the conventional FET based dielectric modulated biosensors. Moreover, the sensitivity of the proposed DM NT-TFET could be further improved by utilizing alternate source materials with lower bandgap or by probing the transient response of the drain current and exploiting the difference in the settling time for different biomolecules with different dielectric constant ( κ ).

Plasmonic Biosensors Based on Deformed Graphene

Rapid, accurate, and label-free detection of biomolecules and chemical substances remains a challenge in healthcare. Optical biosensors have been considered as biomedical diagnostic tools required in numerous areas including the detection of viruses, food monitoring, diagnosing pollutants in the environment, global personalized medicine, and molecular diagnostics. In particular, the broadly emerging and promising technique of surface plasmon resonance has established to provide real-time and label-free detection when used in biosensing applications in a highly sensitive, specific, and cost-effective manner with small footprint platform. In this study we propose a novel plasmonic biosensor based on biaxially crumpled graphene structures, wherein plasmon resonances in graphene are utilized to detect variations in the refractive index of the sample medium. Shifts in the resonance wavelength of the plasmon modes for a given change in the RI of the surrounding analyte are calculated by investigating the optical response of crumpled graphene structures on different substrates using theoretical computations based on the finite element method combined with the semiclassical Drude model. The results reveal a high sensitivity of 4990 nm/RIU, corresponding to a large figure-of-merit of 20 for biaxially crumpled graphene structures on polystyrene substrates. We demonstrate that biaxially crumpled graphene exhibits superior sensing performance compared with a uniaxial structure. According to the results, crumpled graphene structures on a titanium oxide substrate can improve the sensor sensitivity by avoiding the damping effects of polydimethylsiloxane substrates. The enhanced sensitivity and broadband mechanical tunability of the biaxially crumpled graphene render it a promising platform for biosensing applications.

Fiber-Based Surface Plasmon Resonance Biosensor for Leptospira DNA Detection

Fiber-based surface plasmon resonance (SPR) sensors are the ideal configuration for rapid and label-free biomolecule detection. Gold-coated tapered optical fiber was used to excite the SPR mode that propagates at the metal–dielectric interface. By forming self-assembled monolayers (SAMs) of active chemical functional groups, the deoxyribonucleic acid (DNA) probe targeting the secY gene of Leptospira was immobilized onto the sensor surface. Red shifts in the SPR wavelengths were observed at different concentrations of leptospiral DNA target against the immobilized DNA probe due to the ability of plasmonic interaction to sensitively detect the binding of biomolecules on the sensor area. The developed sensor showed satisfactory linear responses at two target concentration ranges; low (1.0 fM to 1.0 pM) and high (0.1 nM to <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$1.0~\mu \text{M}$ </tex-math></inline-formula> ), with the highest sensitivity of 1.22 nm per log M. The negative control test also revealed high sensor specificity toward the complementary DNA strand. This sensor will represent a significant step toward laboratory-free diagnosis of leptospirosis.

Performance assessment of cavity on source dual material split gate GaAs/InAs/Ge junctionless TFET for label-free detection of biomolecules

Performance assessment of cavity on source dual material split gate GaAs/InAs/Ge junctionless TFET for label-free detection of biomolecules

Vertical gate cavity bulk-planar junctionless FET-based biosensor for label-free detection of biomolecules

In this paper, we propose a vertical gate bulk-planar junctionless field-effect transistor (VGC-BPJLFET)-based biosensor for the label-free detection of neutral and charged target biomolecules. The vertical gate structure exhibits better performance due to high gate controlability in the channel region, which improves the drain current of the device. The enhancement in drain current significantly increases the sensing capability of the biosensor. To sense the neutral (APTES, biotin, streptavidin, protein, etc) and charged (deoxyribonucleic acid (DNA)) target biomolecules, the VGC-BPJLFET biosensor includes a vertical nanogap cavity in between the gate electrodes of the device in which HfO2 behaves as the functionalization layer. However, for the detection of both neutral and charged biomolecules, the two electric parameters (dielectric constant (K) and the charge density (ρ)) are considered in the etched nanogap cavity. Furthermore, to see the potentiality of the VGC-BPJLFET biosensor, the proposed biosensor has been compared to the lateral gate cavity BPJLFET biosensor in terms of drain current, sensitivity, linearity and signal-to-noise ratio characteristics. From the comparison, it has been observed that the proposed device has a higher sensitivity of ∼104 and ∼103 with the conjugation of neutral (APTES (K = 3.57)) and charged (DNA (ρ = −1 × 1011 cm−2)) biomolecules, respectively. The VGC-BPJLFET biosensor also carries the better sensing capability to sense the target biomolecules with the presence of unwanted (air) biomolecules in the etched nanogap cavity.

Sensitivity Assessment of Electrically Doped Cavity on Source Junctionless Tunnel Field-Effect Transistor-Based Biosensor

The tunnel field-effect transistor (TFET) has emerged as a promising device for biosensing applications due to band-to-band tunneling (BTBT) operation mechanism and a steep subthreshold swing. In this paper, an electrically doped cavity on source junctionless tunnel field-effect transistor (ED-CS-JLTFET)-based biosensor is proposed for label-free detection of biomolecules. In the proposed model, the electrically doped concept is enabled to reduce fabrication complexity and cost. In order to create a nano-cavity at the source region, some portion of the dielectric oxide of the polarity gate terminal is etched away. To perceive the presence of biomolecules, two important properties of biomolecules, such as dielectric constant and charge density, are incorporated throughout the simulation. The sensing performance of the proposed ED-CS-JLTFET-based biosensor has been analyzed in terms of transfer characteristics, threshold voltage and subthreshold swing. In addition, the sensitivity of the proposed biosensor has also been analyzed with respect to different fill factors (FFs), varying nano-cavity dimension and work-function of the control gate. It is found from the simulated results that the proposed ED-CS-JLTFET-based biosensor offers higher current sensitivities with neutral, positively charged and negatively charged biomolecules of [Formula: see text] (at k [Formula: see text]), [Formula: see text] (at [Formula: see text] and [Formula: see text] C[Formula: see text]cm[Formula: see text]) and [Formula: see text] (at k [Formula: see text] and [Formula: see text] C[Formula: see text]cm[Formula: see text]), respectively.

Wafer-Scale LSPR Substrate: Oblique Deposition of Gold on a Patterned Sapphire Substrate.

Label-free detection of biomolecules using localized surface plasmon resonance (LSPR) substrates is a highly attractive method for point-of-care (POC) testing. One of the remaining challenges to developing LSPR-based POC devices is to fabricate the LSPR substrates with large-scale, reproducible, and high-throughput. Herein, a fabrication strategy for wafer-scale LSPR substrates is demonstrated using reproducible, high-throughput techniques, such as nanoimprint lithography, wet-etching, and thin film deposition. A transparent sapphire wafer, on which SiO2-nanodot hard masks were formed via nanoimprint lithography, was anisotropically etched by a mixed solution of H2SO4 and H3PO4, resulting in a patterned sapphire substrate (PSS). An LSPR substrate was finally fabricated by oblique deposition of Au onto the PSS, which was then applied to label-free detection of the binding events of biomolecules. To the best of our knowledge, this paper is the first report on the application of the PSS used as an LSPR template by obliquely depositing a metal.

Highly sensitive biosensor based on an all-dielectric asymmetric ring metasurface.

We propose an all-dielectric asymmetric ring-cylindrical metasurface. Based on the analysis of transmission characteristics and the calculation of electromagnetic field distribution of the metasurface with this element structure, it is found that the high Q resonance of the ultra-narrowband can be realized when the symmetry of the ring-cylindrical structure is broken. Meanwhile, it is found that the degree of asymmetry of the ring, the refractive index of the material, the radius of the ring, and the substrate have great influence on the Q value and resonant frequency of the metasurface. Our proposed metasurface structure is applied to the detection of biological molecules based on the change in refractive index of biomolecular solutions. The designed metasurface with high sensitivity to detect biomolecules with different refractive indices, the Q value can reach 365.03, and the sensitivity is increased by 90.36 GHz/RIU compared to that without substrate, while the figure of merit value is as high as 100.56, providing label-free detection of biomolecules.

Atomistic Simulations of Functionalized Nano-Materials for Biosensors Applications.

Nanoscale biosensors, a highly promising technique in clinical analysis, can provide sensitive yet label-free detection of biomolecules. The spatial and chemical specificity of the surface coverage, the proper immobilization of the bioreceptor as well as the underlying interfacial phenomena are crucial elements for optimizing the performance of a biosensor. Due to experimental limitations at the microscopic level, integrated cross-disciplinary approaches that combine in silico design with experimental measurements have the potential to present a powerful new paradigm that tackles the issue of developing novel biosensors. In some cases, computational studies can be seen as alternative approaches to assess the microscopic working mechanisms of biosensors. Nonetheless, the complex architecture of a biosensor, associated with the collective contribution from “substrate–receptor–analyte” conjugate in a solvent, often requires extensive atomistic simulations and systems of prohibitive size which need to be addressed. In silico studies of functionalized surfaces also require ad hoc force field parameterization, as existing force fields for biomolecules are usually unable to correctly describe the biomolecule/surface interface. Thus, the computational studies in this field are limited to date. In this review, we aim to introduce fundamental principles that govern the absorption of biomolecules onto functionalized nanomaterials and to report state-of-the-art computational strategies to rationally design nanoscale biosensors. A detailed account of available in silico strategies used to drive and/or optimize the synthesis of functionalized nanomaterials for biosensing will be presented. The insights will not only stimulate the field to rationally design functionalized nanomaterials with improved biosensing performance but also foster research on the required functionalization to improve biomolecule–surface complex formation as a whole.

Highly sensitive plasmonic nanorod hyperbolic metamaterial biosensor

Plasmonic sensing based on nanostructures is a powerful analytical tool for ultrasensitive label-free biomolecule detection that holds great potential in the field of clinical diagnostics and biomedical research. Here, we report the fabrication, the characterization, and the principle of operation of gold nanorod hyperbolic metamaterials (NHMMs) along with ultrasensitive bulk refractive index and label-free biomolecular detection. By combining electron-beam lithography and nanoscale electroplating, we demonstrate the fabrication of a highly ordered, height-controllable, and vertical array of nanorods. By exciting the bulk plasmon–polariton mode in the NHMM using a prism-coupling technique and integrating the sensor in microfluidics, we demonstrate that the bulk sensitivity and figure of merit of our device could reach 41,600 nm/RIU and 416 RIU-1, respectively. The physical mechanism of this high bulk sensitivity is revealed through theoretical and experimental studies. Moreover, by bio-functionalizing the surface of the NHMM sensor, monitoring the binding of streptavidin at dilute concentrations is performed in real time. We test different concentrations of streptavidin ranging from 200 to 5 µg/mL, and the NHMM biosensor exhibits a 1 nm wavelength shift for a 5 µg/mL streptavidin detection. By fitting the Hill equation of the NHMM biosensor and taking into account the level of noise (0.05 nm) as the minimum wavelength shift of the detectable limit, the limit of detection of the NHMM biosensor to streptavidin can be estimated to be 0.14 µg/mL (2.4 nm). As a direct comparison, a 0.5 nm wavelength shift for 20 µg/mL of streptavidin is reported when using a conventional gold film sensor under identical experimental conditions. The developed plasmonic NHMM sensor shows tremendous potential for highly sensitive bulk solutions and biomolecule detection and provides a promising avenue for free-label biosensing applications in the future.