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Low-dimensional van der Waals (vdW) materials can harness tightly confined polaritonic waves to deliver unique advantages for nanophotonic biosensing. The reduced dimensionality of vdW materials, as in the case of two-dimensional graphene, can greatly enhance plasmonic field confinement, boosting sensitivity and efficiency compared to conventional nanophotonic devices that rely on surface plasmon resonance in metallic films. Furthermore, the reduction of dielectric screening in vdW materials enables electrostatic tunability of different polariton modes, including plasmons, excitons, and phonons. One-dimensional vdW materials, particularly single-walled carbon nanotubes, possess unique form factors with confined excitons to enable single-molecule detection as well as in vivo biosensing. We discuss basic sensing principles based on vdW materials, followed by technological challenges such as surface chemistry, integration, and toxicity. Finally, we highlight progress in harnessing vdW materials to demonstrate new sensing functionalities that are difficult to perform with conventional metal/dielectric sensors.

A label-free, non-dispruptive, and real-time analytical device to monitor the dynamic features of biomolecules and their interactions with neighboring molecules is an essential prerequisite for biochip- and diagonostic assays. To explore one of the central questions on the lipid-lipid interactions in the course of the liquid-ordered (l o ) domain formation, called rafts, we developed a method of reconstituting continuous but spatially heterogeneous lipid membrane platforms with molayer-bilayer juntions (MBJs) that enable to form the l o domains in a spatiotemporally controlled manner. This allows us to detect the time-lapse dynamics of the lipid-lipid interactions during raft formation and resultant membrane phase changes together with the raft-associated receptor-ligand binding through the surface plasmon resonance (SPR). For cross-validation, using epifluorescence microscopy, we demonstrated the underlying mechanisms for raft formations that the infiltration of cholesterols into the sphingolipid-enriched domains plays a crucial roles in the membrane phase-separation. Our membrane platform, being capable of monitoring dynamic interactions among lipids and performing the systematic optical analysis, will unveil physiological roles of cholesterols in a variety of biological events., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Poloxamer 188 (P188), a poly(ethylene oxide)- b-poly(propylene oxide)- b-poly(ethylene oxide) triblock copolymer, protects cell membranes against various external stresses, whereas poly(ethylene oxide) (PEO; 8600 g/mol) homopolymer lacks protection efficacy. As part of a comprehensive effort to elucidate the protection mechanism, we used surface plasmon resonance (SPR) to obtain direct evidence of binding of the polymers onto supported lipid bilayers. Binding kinetics and coverage of P188 and PEO were examined and compared. Most notably, PEO exhibited membrane association comparable to that of P188, evidenced by comparable association rate constants and coverage. This result highlights the need for additional mechanistic understanding beyond simple membrane association to explain the differential efficacy of P188 in therapeutic applications.

We present quantitative, spectroscopic polarization interferometry phase measurements on plasmonic surfaces for sensing applications. By adding a liquid crystal variable wave plate in our beam path, we are able to measure phase shifts due to small refractive index changes on the sensor surface. By scanning in a quick sequence, our technique is extended to demonstrate real-time measurements. While this optical technique is applicable to different sensor geometries-e.g., nanoparticles, nanogratings, or nanoapertures-the plasmonic sensors we use here consist of an ultrasmooth gold layer with buried linear gratings. Using these devices and our phase measurement technique, we calculate a figure of merit that shows improvement over measuring only surface plasmon resonance shifts from a reflected intensity spectrum. To demonstrate the general-purpose versatility of our phase-resolved measurements, we also show numerical simulations with another common device architecture: periodic plasmonic slits. Since our technique inherently measures both the intensity and phase of the reflected or transmitted light simultaneously, quantitative sensor device characterization is possible.

Characterization of binding kinetics and affinity between a potential drug and its receptor are key steps in the development of new drugs. Among the techniques available to determine binding affinities, surface plasmon resonance has emerged as the gold standard because it can measure binding and dissociation rates in real-time in a label-free fashion. Surface plasmon resonance is now finding applications in the characterization of molecules for treatment of neurodegenerative diseases, characterization of molecules associated with pathogenesis of neurodegenerative diseases and detection of neurodegenerative disease biomarkers. In addition it has been used in the characterization of a new class of natural autoantibodies that have therapeutic potential in a number of neurologic diseases. In this review we will introduce surface plasmon resonance and describe some applications of the technique that pertain to neurodegenerative disorders and their treatment.

We experimentally demonstrate dielectrophoretic concentration of biological analytes on the surface of a gold nanohole array, which concurrently acts as a nanoplasmonic sensor and gradient force generator. The combination of nanohole-enhanced dielectrophoresis, electroosmosis, and extraordinary optical transmission through the periodic gold nanohole array enables real-time label-free detection of analyte molecules in a 5 μL droplet using concentrations as low as 1 pM within a few minutes, which is more than 1000 times faster than purely diffusion-based binding. The nanohole-based optofluidic platform demonstrated here is straightforward to construct, applicable to both charged and neutral molecules, and performs a novel function that cannot be accomplished using conventional surface plasmon resonance sensors.

Self-assembled plasmonic nanoring cavity arrays are formed alongside the curvature of highly packed metallic nanosphere gratings. The sub-10-nm gap size is precisely tuned via atomic layer deposition and highly ordered arrays are produced over a cm-sized area. The resulting hybrid nanostructure boosts coupling efficiency of light into plasmons, and shows an improved SERS detection limit. These substrates are used for SERS detection of the biological analyte, adenine, followed by concurrent localized surface plasmon resonance sensing., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We demonstrate a novel scheme for plasmonic nanofocusing with internally illuminated asymmetric metallic pyramidal tips using linearly polarized light. A wafer-scale array of sharp metallic pyramids is fabricated via template stripping with films of different thicknesses on opposing pyramid facets. This structural asymmetry is achieved through a one-step angled metal deposition that does not require any additional lithography processing and when internally illuminated enables the generation of plasmons using a Kretschmann-like coupling method on only one side of the pyramids. Plasmons traveling toward the tip on one side will converge at the apex, forming a nanoscale "hotspot." The asymmetry is necessary for these focusing effects since symmetric pyramids display destructive plasmon interference at the tip. Computer simulations confirm that internal illumination with linearly polarized light at normal incidence on these asymmetric pyramids will focus optical energy into nanoscale volumes. Far-field optical experiments demonstrate large field enhancements as well as angle-dependent spectral tuning of the reradiated light. Because of the low background light levels, wafer-scale fabrication, and a straightforward excitation scheme, these asymmetric pyramidal tips will find applications in near-field optical microscopy and array-based optical trapping.

With recent advances in high-throughput proteomics and systems biology, there is a growing demand for new instruments that can precisely quantify a wide range of receptor-ligand binding kinetics in a high-throughput fashion. Here we demonstrate a surface plasmon resonance (SPR) imaging spectroscopy instrument capable of simultaneously extracting binding kinetics and affinities from 50 parallel microfluidic channels. The instrument utilizes large-area (~ cm(2)) metallic nanohole arrays as SPR sensing substrates and combines a broadband light source, a high-resolution imaging spectrometer and a low-noise CCD camera to extract spectral information from every channel in real time with a refractive index resolution of 7.7 × 10(-6) refractive index units. To demonstrate the utility of our instrument for quantifying a wide range of biomolecular interactions, each parallel microfluidic channel is coated with a biomimetic supported lipid membrane containing ganglioside (GM1) receptors. The binding kinetics of cholera toxin b (CTX-b) to GM1 are then measured in a single experiment from 50 channels. By combining the highly parallel microfluidic device with large-area periodic nanohole array chips, our SPR imaging spectrometer system enables high-throughput, label-free, real-time SPR biosensing, and its full-spectral imaging capability combined with nanohole arrays could enable integration of SPR imaging with concurrent surface-enhanced Raman spectroscopy.

Multiple sclerosis is a progressive neurological disorder that results in the degradation of myelin sheaths that insulate axons in the central nervous system. Therefore promotion of myelin repair is a major thrust of multiple sclerosis treatment research. Two mouse monoclonal natural autoantibodies, O1 and O4, promote myelin repair in several mouse models of multiple sclerosis. Natural autoantibodies are generally polyreactive and predominantly of the IgM isotype. The prevailing paradigm is that because they are polyreactive, these antibodies bind antigens with low affinities. Despite their wide use in neuroscience and glial cell research, however, the affinities and kinetic constants of O1 and O4 antibodies have not been measured to date. In this work, we developed a membrane biosensing platform based on surface plasmon resonance in gold nanohole arrays with a series of surface modification techniques to form myelin-mimicking lipid bilayer membranes to measure both the association and dissociation rate constants for O1 and O4 antibodies binding to their myelin lipid antigens. The ratio of rate constants shows that O1 and O4 bind to galactocerebroside and sulfated galactocerebroside, respectively, with unusually small apparent dissociation constants (K(D) ≈ 0.9 nM) for natural autoantibodies. This is approximately one to 2 orders of magnitude lower than typically observed for the highest affinity natural autoantibodies. We propose that the unusually high affinity of O1 and O4 to their targets in myelin contributes to the mechanism by which they signal oligodendrocytes and induce central nervous system repair.

We demonstrate an affordable low-noise surface plasmon resonance (SPR) instrument based on extraordinary optical transmission (EOT) in metallic nanohole arrays and quantify a broad range of antibody-ligand binding kinetics with equilibrium dissociation constants ranging from 200 pM to 40 nM. This nanohole-based SPR instrument is straightforward to construct, align, and operate, since it is built around a standard microscope and a portable fiber-optic spectrometer. The measured refractive index resolution of this platform is 3.1 × 10(-6) without on-chip cooling, which is among the lowest reported for SPR sensors based on EOT. This is accomplished via rapid full-spectrum acquisition in 10 ms followed by frame averaging of the EOT spectra, which is made possible by the production of template-stripped gold nanohole arrays with homogeneous optical properties over centimeter-sized areas. Sequential SPR measurements are performed using a 12-channel microfluidic flow cell after optimizing surface modification protocols and antibody injection conditions to minimize mass-transport artifacts. The immobilization of a model ligand, the protective antigen of anthrax on the gold surface, is monitored in real-time with a signal-to-noise ratio of ~860. Subsequently, real-time binding kinetic curves were measured quantitatively between the antigen and a panel of small, 25 kDa single-chain antibodies at concentrations down to 1 nM. These results indicate that nanohole-based SPR instruments have potential for quantitative antibody screening and as a general-purpose platform for integrating SPR sensors with other bioanalytical tools.

Inexpensive, reproducible, and high-throughput fabrication of nanometric apertures in metallic films can benefit many applications in plasmonics, sensing, spectroscopy, lithography, and imaging. Here we use template-stripping to pattern periodic nanohole arrays in optically thick, smooth Ag films with a silicon template made via nanoimprint lithography. Ag is a low-cost material with good optical properties, but it suffers from poor chemical stability and biocompatibility. However, a thin silica shell encapsulating our template-stripped Ag nanoholes facilitates biosensing applications by protecting the Ag from oxidation as well as providing a robust surface that can be readily modified with a variety of biomolecules using well-established silane chemistry. The thickness of the conformal silica shell can be precisely tuned by atomic layer deposition, and a 15 nm thick silica shell can effectively prevent fluorophore quenching. The Ag nanohole arrays with silica shells can also be bonded to polydimethylsiloxane (PDMS) microfluidic channels for fluorescence imaging, formation of supported lipid bilayers, and real-time, label-free SPR sensing. Additionally, the smooth surfaces of the template-stripped Ag films enhance refractive index sensitivity compared with as-deposited, rough Ag films. Because nearly centimeter-sized nanohole arrays can be produced inexpensively without using any additional lithography, etching, or lift-off, this method can facilitate widespread applications of metallic nanohole arrays for plasmonics and biosensing., (© 2011 American Chemical Society)

We demonstrate three-dimensional plasmonic nanofocusing of light with patterned metallic pyramids obtained via template stripping. Gratings on the faces of these pyramids convert linearly polarized light into plasmons that propagate toward and converge at a approximately 10 nm apex. Experiments and computer simulations confirm that optical energy is focused into a nanoscale volume (5 x 10(-5) wavelength(3)). Because these structures are easily and reproducibly fabricated, our results could benefit many applications, including imaging, sensing, lithography, and nonlinear spectroscopy.

We present a simple and massively parallel nanofabrication technique to produce self-assembled periodic nanohole arrays over a millimeter-sized area of metallic film, with a tunable hole shape, diameter, and periodicity. Using this method, 30 x 30 microm(2) defect-free areas of 300 nm diameter or smaller holes were obtained in silver; this area threshold is critical because it is larger than the visible wavelength propagation length of surface plasmon waves ( approximately 27 microm) in the silver film. Measured optical transmission spectra show highly homogeneous characteristics across the millimeter-size patterned area, and they are in good agreement with FDTD simulations. The simulations also reveal intense electric fields concentrated near the air/silver interface, which was used for surface-enhanced Raman spectroscopy (SERS). Enhancement factors (EFs) measured with different hole shape and excitation wavelengths on the self-assembled nanohole arrays were 10(4)-10(6). With an additional Ag electroless plating step, the EF was further increased up to 3 x 10(6). The periodic nanohole arrays produced using this tunable self-assembly method show great promise as inexpensive SERS substrates as well as surface plasmon resonance biosensing platforms.

Technologies based on surface plasmon resonance (SPR) have allowed rapid, label-free characterization of protein-protein and protein-small molecule interactions. SPR has become the gold standard in industrial and academic settings, in which the interaction between a pair of soluble binding partners is characterized in detail or a library of molecules is screened for binding against a single soluble protein. In spite of these successes, SPR is only beginning to be adapted to the needs of membrane-bound proteins which are difficult to study in situ but represent promising targets for drug and biomarker development. Existing technologies, such as BIAcoreTM, have been adapted for membrane protein analysis by building supported lipid layers or capturing lipid vesicles on existing chips. Newer technologies, still in development, will allow membrane proteins to be presented in native or near-native formats. These include SPR nanopore arrays, in which lipid bilayers containing membrane proteins stably span small pores that are addressable from both sides of the bilayer. Here, we discuss current SPR instrumentation and the potential for SPR nanopore arrays to enable quantitative, high-throughput screening of G protein coupled receptor ligands and applications in basic cellular biology.

We propose a method of optical data storage that exploits the small dimensions of metallic nano-particles and/or nano-structures to achieve high storage densities. The resonant behavior of these particles (both individually and in small clusters) in the presence of ultraviolet, visible, and near-infrared light may be used to retrieve pre-recorded information by far-field spectroscopic optical detection. In plasmonic data storage, a very short (approximately few femtoseconds) laser pulse is focused to a diffraction-limited spot over a small region of an optical disk containing metallic nano-structures. The digital data stored in each bit-cell, comprising multiple bits of information, modifies the spectrum of the incident light pulse. This spectrum is subsequently detected, upon reflection/transmission, with the aid of an optical spectrum analyzer. We present theoretical as well as preliminary experimental results that confirm the potential of plasmonic nano-structures for high-density optical data storage applications.

We present nanohole arrays in a gold film integrated with a six-channel microfluidic chip for parallel measurements of molecular binding kinetics. Surface plasmon resonance effects in the nanohole arrays enable real-time, label-free measurements of molecular binding events in each channel, while adjacent negative reference channels can record measurement artifacts such as bulk solution index changes, temperature variations, or changing light absorption in the liquid. With the use of this platform, streptavidin-biotin specific binding kinetics are measured at various concentrations with negative controls. A high-density microarray of 252 biosensing pixels is also demonstrated with a packing density of 10(6) sensing elements/cm(2), which can potentially be coupled with a massively parallel array of microfluidic channels for protein microarray applications.

We present nanohole arrays in thin gold films as sub-micron resolution surface plasmon resonance (SPR) imaging pixels in a microarray format. With SPR imaging, the resolution is not limited by diffraction, but by the propagation of surface plasmon waves to adjacent sensing areas, or nanohole arrays, causing unwanted interference. For ultimate scalability, several issues need to be addressed, including: (1) as several nanohole arrays are brought close to each other, surface plasmon interference introduces large sources of error; and (2) as the size of the nanohole array is reduced, i.e. fewer holes, detection sensitivity suffers. To address these scalability issues, we surround each biosensing pixel (a 3-by-3 nanohole array) with plasmonic Bragg mirrors, blocking interference between adjacent SPR sensing pixels for high-density packing, while maintaining the sensitivity of a 50 x larger footprint pixel (a 16-by-16 nanohole array). We measure real-time, label-free streptavidin-biotin binding kinetics with a microarray of 600 sub-micron biosensing pixels at a packing density of more than 10(7) per cm(2).

We integrate periodic nanohole arrays in a thin gold film with lipid membranes in a microfluidic channel. Surface plasmon-enhanced light transmission through the periodic nanohole arrays enables real-time label-free sensing of molecular binding on the lipid membrane surface. This membrane biosensor can potentially act as a natural platform for studying binding kinetics of proteins with their binding partners anchored in the lipid membrane. We also present the concept of using nanopore arrays for kinetic assays of transmembrane proteins in a free-standing lipid membrane.

Surface plasmon resonance (SPR) imaging is a powerful technique for high-throughput, real-time, label-free characterization of molecular interactions in a microarray format. In this paper, we demonstrate SPR imaging with nanohole arrays illuminated by a laser source. Periodic nanoholes couple incident photons into SPs, obviating the need for the prism used in conventional SPR instruments, while a laser source provides the intensity, stability and spectral coherence to improve the detection sensitivity. The formation of a self-assembled monolayer of alkanethiolates on gold changed the laser transmission by more than 35%, and binding kinetics were measured in parallel from a 5 x 3 microarray of nanohole sensors. These results demonstrate the potential of nanohole sensors for high-throughput SPR imaging on microarrays.

Optical biosensors based on surface plasmon resonance (SPR) in metallic thin films are currently standard tools for measuring molecular binding kinetics and affinities – an important task for biophysical studies and pharmaceutical development. Motivated by recent progress in the design and fabrication of metallic nanostructures, such as nanoparticles or nanoholes of various shapes, researchers have been pursuing a new generation of biosensors harnessing tailored plasmonic effects in these engineered nanostructures. Nanoplasmonic devices, while demanding nanofabrication, offer tunability with respect to sensor dimension and physical properties, thereby enabling novel biological interfacing opportunities and extreme miniaturization. Here we provide an integrated overview of refractometric biosensing with nanoplasmonic devices and highlight some recent examples of nanoplasmonic sensors capable of unique functions that are difficult to accomplish with conventional SPR. For example, since the local field strength and spatial distribution can be readily tuned by varying the shape and arrangement of nanostructures, biomolecular interactions can be controlled to occur in regions of high field strength. This may improve signal-to-noise and also enable sensing a small number of molecules. Furthermore, the nanoscale plasmonic sensor elements may, in combination with nanofabrication and materials-selective surface-modifications, make it possible to merge affinity biosensing with nanofluidic liquid handling.

The ability to precisely control the topography, roughness, and chemical properties of metallic nanostructures is crucial for applications in plasmonics, nanofluidics, electronics, and biosensing. Here a simple method to produce embedded nanoplasmonic devices that can generate tunable plasmonic fields on ultraflat surfaces is demonstrated. Using a template-stripping technique, isolated metallic nanodisks and wires are embedded in optical epoxy, which is capped with a thin silica overlayer using atomic layer deposition. The top silica surface is topographically flat and laterally homogeneous, providing a uniform, high-quality biocompatible substrate, while the nanoplasmonic architecture hidden underneath creates a tunable plasmonic landscape for optical imaging and sensing. The localized surface plasmon resonance of gold nanodisks embedded underneath flat silica films is used for real-time kinetic sensing of the formation of a supported lipid bilayer and subsequent receptor-ligand binding. Gold nanodisks can also be embedded in elastomeric materials, which can be peeled off the substrate to create flexible plasmonic membranes that conform to non-planar surfaces. [ABSTRACT FROM AUTHOR]

We investigate thin Ag films incorporating plasmonic nanohole arrays as transparent conducting electrodes for organic photovoltaic cells. Plasmonic electrodes are fabricated using nanosphere lithography to create hexagonal nanohole arrays over centimeter-sized areas. Devices constructed using a nanopatterned Ag anode show power conversion efficiencies that exceed those of devices constructed on conventional indium-tin-oxide, independent of light polarization. In comparison to cells constructed on unpatterned Ag, the power conversion efficiency is noted to double with patterning. [ABSTRACT FROM AUTHOR]

Enhanced optical transmission and surface plasmon resonant cavity effects are studied for subwavelength aperture arrays surrounded by rectangular-shaped Bragg mirrors. A circular nanohole array with a surrounding rectangular Bragg resonator exhibits the introduction of polarization-dependent enhanced optical transmission by constructive and destructive interference effects generated within the cavity. The feasibility for high-density packing of several individually distinct nanohole arrays is demonstrated by also using the Bragg mirrors to block surface plasmon interference between multiple such neighboring devices spaced 5 μm apart. [ABSTRACT FROM AUTHOR]