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Nanophotonic devices, which control light in subwavelength volumes and enhance light-matter interactions, have opened up exciting prospects for biosensing. Numerous nanophotonic biosensors have emerged to address the limitations of the current bioanalytical methods in terms of sensitivity, throughput, ease-of-use and miniaturization. In this Review, we provide an overview of the recent developments of label-free nanophotonic biosensors using evanescent-field-based sensing with plasmon resonances in metals and Mie resonances in dielectrics. We highlight the prospects of achieving an improved sensor performance and added functionalities by leveraging nanostructures and on-chip and optoelectronic integration, as well as microfluidics, biochemistry and data science toolkits. We also discuss open challenges in nanophotonic biosensing, such as reducing the overall cost and handling of complex biological samples, and provide an outlook for future opportunities to improve these technologies and thereby increase their impact in terms of improving health and safety., (© 2022. Springer Nature Limited.)

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 rapid, label-free, and broadly applicable chemical analysis platform for nanovesicles and subcellular components is highly desirable for diagnostic assays. We demonstrate an integrated nanogap plasmonic sensing platform that combines subvolt dielectrophoresis (DEP) trapping, gold nanoparticles (AuNPs), and a lineated illumination scheme for real-time, surface-enhanced Raman spectroscopy (SERS) imaging of biological nanoparticles. Our system is capable of isolating suspended sub-100 nm vesicles and imaging the Raman spectra of their cargo within seconds, 100 times faster than conventional point-scan Raman systems. Bare AuNPs are spiked into solution and simultaneously trapped with the nanovesicles along the gap to boost local optical fields. In addition, our platform offers simultaneous and delay-free spatial and temporal multiplexing functionality. These nanogap devices can be mass-produced via atomic layer lithography and provide a practical platform for high-speed SERS analysis of biological nanoparticles.

We combine atomic layer lithography and glancing-angle ion polishing to create wafer-scale metamaterials composed of dense arrays of ultrasmall coaxial nanocavities in gold films. This new fabrication scheme makes it possible to shrink the diameter and increase the packing density of 2 nm-gap coaxial resonators, an extreme subwavelength structure first manufactured via atomic layer lithography, both by a factor of 100 with respect to previous studies. We demonstrate that the nonpropagating zeroth-order Fabry-Pérot mode, which possesses slow light-like properties at the cutoff resonance, traps infrared light inside 2 nm gaps (gap volume ∼ λ(3)/10(6)). Notably, the annular gaps cover only 3% or less of the metal surface, while open-area normalized transmission is as high as 1700% at the epsilon-near-zero (ENZ) condition. The resulting energy accumulation alongside extraordinary optical transmission can benefit applications in nonlinear optics, optical trapping, and surface-enhanced spectroscopies. Furthermore, because the resonance wavelength is independent of the cavity length and dramatically red shifts as the gap size is reduced, large-area arrays can be constructed with λresonance ≫ period, making this fabrication method ideal for manufacturing resonant metamaterials.

A plasmonic nanohole sensor for virus-like particle capture and virucidal drug evaluation is reported. Using a materials-selective surface functionalization scheme, passive immobilization of virus-like particles only within the nanoholes is achieved. The findings demonstrate that a low surface coverage of particles only inside the functionalized nanoholes significantly improves nanoplasmonic sensing performance over conventional nanohole arrays., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, we present an infrared plasmonic biosensor for chemical-specific detection and monitoring of biomimetic lipid membranes in a label-free and real-time fashion. Lipid membranes constitute the primary biological interface mediating cell signaling and interaction with drugs and pathogens. By exploiting the plasmonic field enhancement in the vicinity of engineered and surface-modified nanoantennas, the proposed biosensor is able to capture the vibrational fingerprints of lipid molecules and monitor in real time the formation kinetics of planar biomimetic membranes in aqueous environments. Furthermore, we show that this plasmonic biosensor features high-field enhancement extending over tens of nanometers away from the surface, matching the size of typical bioassays while preserving high sensitivity.

The biochemical processes of cell membranes are sensitive to the geometry of the lipid bilayer. We show how plasmonic "nanowells" provide label-free real-time analysis of molecules on membranes with detection of preferential binding at negative curvature. It is demonstrated that norovirus accumulate in invaginations due to multivalent interactions with glycosphingolipids.

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.

The template-stripping method can yield smooth patterned films without surface contamination. However, the process is typically limited to coinage metals such as silver and gold because other materials cannot be readily stripped from silicon templates due to strong adhesion. Herein, we report a more general template-stripping method that is applicable to a larger variety of materials, including refractory metals, semiconductors, and oxides. To address the adhesion issue, we introduce a thin gold layer between the template and the deposited materials. After peeling off the combined film from the template, the gold layer can be selectively removed via wet etching to reveal a smooth patterned structure of the desired material. Further, we demonstrate template-stripped multilayer structures that have potential applications for photovoltaics and solar absorbers. An entire patterned device, which can include a transparent conductor, semiconductor absorber, and back contact, can be fabricated. Since our approach can also produce many copies of the patterned structure with high fidelity by reusing the template, a low-cost and high-throughput process in micro- and nanofabrication is provided that is useful for electronics, plasmonics, and nanophotonics.

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 a template-stripping fabrication technique, we demonstrate the mass fabrication of high-quality, uniform, ultrasharp (10 nm) metallic probes suitable for single-molecule fluorescence imaging, tip-enhanced Raman spectroscopy (TERS), and other near-field imaging techniques. We achieve reproducible single-molecule imaging with sub-20-nm spatial resolution and an enhancement in the detected fluorescence signal of up to 200. Similar results are obtained for TERS imaging of carbon nanotubes. We show that the large apex angle (70.5°) of our pyramidal tip is well suited to scatter the near-field optical signal into the far-field, leading to larger emission enhancement and hence to a larger quantum yield. Each gold or silver pyramidal probe is used on-demand, one at a time, and the unused tips can be stored for extended times without degradation or contamination. The high yield (>95%), reproducibility, durability, and massively parallel fabrication (1.5 million identical probes over a wafer) of the probes hold promise for reliable optical sensing and detection and for cementing near-field optical imaging and spectroscopy as a routine characterization technique.

A simple route to flat, large-area, single-crystalline films for plasmonics is demonstrated by sputter deposition of silver onto mica substrates at elevated temperatures. The films exhibit improved dielectric properties and allow more precise patterning of high-quality nanostructures for plasmonic applications., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

Fabricating plasmonic nanostructures with robust optical and chemical properties remains a challenging task, especially with silver, which has superior optical properties but poor environmental stability. In this work, conformal atomic layer deposition (ALD) of thin alumina overlayers is used to precisely tune the optical transmission properties of periodic nanohole arrays made in gold and silver films. Experiments and computer simulations confirm that ALD overlayers with optimized thicknesses tune and enhance the transmitted intensity due to refractive index matching effects and by modifying the dielectric properties of each nanohole. Furthermore, encapsulating silver nanohole arrays with thin alumina overlayers protects the patterned surfaces against unwanted oxidation and contamination. The ability to precisely tune the optical properties while simultaneously providing robust chemical stability can benefit a broad range of applications, including biosensing and fluorescence imaging.

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.

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.

Surface plasmons are electromagnetic waves that can exist at metal interfaces because of coupling between light and free electrons. Restricted to travel along the interface, these waves can be channeled, concentrated, or otherwise manipulated by surface patterning. However, because surface roughness and other inhomogeneities have so far limited surface-plasmon propagation in real plasmonic devices, simple high-throughput methods are needed to fabricate high-quality patterned metals. We combined template stripping with precisely patterned silicon substrates to obtain ultrasmooth pure metal films with grooves, bumps, pyramids, ridges, and holes. Measured surface-plasmon-propagation lengths on the resulting surfaces approach theoretical values for perfectly flat films. With the use of our method, we demonstrated structures that exhibit Raman scattering enhancements above 10(7) for sensing applications and multilayer films for optical metamaterials.

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.

Metallic nanostructures now play an important role in many applications. In particular, for the emerging fields of plasmonics and nanophotonics, the ability to engineer metals on nanometric scales allows the development of new devices and the study of exciting physics. This review focuses on top-down nanofabrication techniques for engineering metallic nanostructures, along with computational and experimental characterization techniques. A variety of current and emerging applications are also covered. [ABSTRACT FROM AUTHOR]