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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.

Refractometric sensors utilizing surface plasmon resonance (SPR) should satisfy a series of performance metrics, bulk sensitivity, thin-film sensitivity, refractive-index resolution, and high-Q-factor resonance, as well as practical requirements such as manufacturability and the ability to separate optical and fluidic paths via reflection-mode sensing. While many geometries such as nanohole, nanoslit, and nanoparticles have been employed, it is nontrivial to engineer nanostructures to satisfy all of the aforementioned requirements. We combine gold nanohole arrays with a water-index-matched Cytop film to demonstrate reflection-mode, high- Q -factor ( Q exp = 143) symmetric plasmonic sensor architecture. Using template stripping with a Cytop film, we can replicate a large number of index-symmetric nanohole arrays, which support sharp plasmonic resonances that can be probed by light reflected from their backside with a high extinction amplitude. The reflection geometry separates the optical and microfluidic paths without sacrificing sensor performance as is the case of standard (index-asymmetric) nanohole arrays. Furthermore, plasmon hybridization caused by the array refractive-index symmetry enables dual-mode detection that allows distinction of refractive-index changes occurring at different distances from the surface, making it possible to identify SPR response from differently sized particles or to distinguish binding events near the surface from bulk index changes. Due to the unique combination of a dual-mode reflection-configuration sensing, high-Q plasmonic modes, and template-stripping nanofabrication, this platform can extend the utility of nanohole SPR for sensing applications involving biomolecules, polymers, nanovesicles, and biomembranes.

A multitude of biological processes are enabled by complex interactions between lipid membranes and proteins. To understand such dynamic processes, it is crucial to differentiate the constituent biomolecular species and track their individual time evolution without invasive labels. Here, we present a label-free mid-infrared biosensor capable of distinguishing multiple analytes in heterogeneous biological samples with high sensitivity. Our technology leverages a multi-resonant metasurface to simultaneously enhance the different vibrational fingerprints of multiple biomolecules. By providing up to 1000-fold near-field intensity enhancement over both amide and methylene bands, our sensor resolves the interactions of lipid membranes with different polypeptides in real time. Significantly, we demonstrate that our label-free chemically specific sensor can analyze peptide-induced neurotransmitter cargo release from synaptic vesicle mimics. Our sensor opens up exciting possibilities for gaining new insights into biological processes such as signaling or transport in basic research as well as provides a valuable toolkit for bioanalytical and pharmaceutical applications.

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.

Single-molecule techniques are being developed with the exciting prospect of revolutionizing the healthcare industry by generating vast amounts of genetic and proteomic data. One exceptionally promising route is in the use of nanopore sensors. However, a well-known complexity is that detection and capture is predominantly diffusion limited. This problem is compounded when taking into account the capture volume of a nanopore, typically 10(8)-10(10) times smaller than the sample volume. To rectify this disproportionate ratio, we demonstrate a simple, yet powerful, method based on coupling single-molecule dielectrophoretic trapping to nanopore sensing. We show that DNA can be captured from a controllable, but typically much larger, volume and concentrated at the tip of a metallic nanopore. This enables the detection of single molecules at concentrations as low as 5 fM, which is approximately a 10(3) reduction in the limit of detection compared with existing methods, while still maintaining efficient throughput.

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 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.

We report on the conformal surface passivation of photonic crystal (PC) laser devices with an ultrathin dielectric layer. Air-bridge-type Γ-point band-edge lasers (BELs) are fabricated by forming a honeycomb lattice two-dimensional PC structure into an InGaAsP multiple-quantum-well epilayer. Atomic layer deposition (ALD) is employed for conformal deposition of a few-nanometer-thick SiO2 layer over the entire device surface, not only on the top and bottom surfaces of the air-bridge membrane but also on the air-hole sidewalls. Despite its extreme thinness, the ALD passivation layer is found to protect the InGaAsP BEL devices from harsh chemicals. In addition, the ALD-SiO2 is compatible with the silane-based surface chemistry, which allows us to use ALD-passivated BEL devices as label-free biosensors. The standard streptavidin-biotin interaction shifts the BEL lasing wavelength by ∼1 nm for the dipole-like Γ-point band-edge mode. A sharp lasing line (<0.2 nm, full width at half-maximum) and a large refractive index sensitivity (∼163 nm per RIU) produce a figure of merit as high as ∼800 for our BEL biosensor, which is at least an order of magnitude higher than those of more common biosensors that rely on a broad resonance peak, showing that our nanolaser structures are suitable for highly sensitive biosensor applications.

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 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.

We demonstrate precise three-dimensional integration of smooth bumps, grooves, and apertures in optically thick metal films using template stripping. Patterned silicon wafers are used as high-quality, reusable templates. The heights or depths of the metallic features are controlled to within 2 nm, giving continuously tunable optical properties with sharp and intense plasmonic resonances. Furthermore, we demonstrate a pick-and-place template stripping method in situ, enabling versatile three-dimensional micromanipulation, imaging, and characterization of nanoscale devices.

This perspective gives an overview of recent developments in surface-enhanced Raman scattering (SERS) for biosensing. We focus this review on SERS papers published in the last 10 years and to specific applications of detecting biological analytes. Both intrinsic and extrinsic SERS biosensing schemes have been employed to detect and identify small molecules, nucleic acids, lipids, peptides, and proteins, as well as for in vivo and cellular sensing. Current SERS substrate technologies along with a series of advancements in surface chemistry, sample preparation, intrinsic/extrinsic signal transduction schemes, and tip-enhanced Raman spectroscopy are discussed. The progress covered herein shows great promise for widespread adoption of SERS biosensing., (This journal is © the Owner Societies 2011)

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.