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Surface plasmon resonance (SPR) and localized SPR (LSPR) effects have been shown as the principles of some highlysensitive sensors in recent decades. Due to the advances in nano-fabrication technology, the plasmon nano-array sensors based on SPR and LSPR phenomena have been widely used in chemical and bioloical analysis. Sensing with surface-enhanced field and sensing for refractive index changes are able to identify the analytes quantitatively and qualitatively. With the newly developed ultrasensitive plasmonic biosensors, platforms with excellent performance have been built for various biomedical applications, including point-of-care diagnosis and personalized medicine. In addition, flexible integration of plasmonics nano-arrays and combining them with electrochemical sensing have significantly enlarged the application scenarios of the plasmonic nano-array sensors, as well as improved the sensing accuracy.

Exosomal microRNAs (miRNAs) have considerable potential as pivotal biomarkers to monitor cancer development, dis‐ease progression, treatment effects and prognosis. Here, we report an efficient target recycling amplification process (TRAP) for the digital detection of miRNAs using photonic resonator absorption microscopy. We achieve multiplex digital detection with sub‐attomolar sensitivity in 20 minutes, robust selectivity for single nucleotide variants, and a broad dynamic range from 1 aM to 1 pM. Compared with traditional qRT‐PCR, TRAP showed similar accuracy in profiling exosomal miRNAs derived from cancer cells, but also exhibited at least 31‐fold and 61‐fold enhancement in the limits of miRNA‐375 and miRNA‐21 detection, respectively. The TRAP approach is ideal for exosomal or circulating miRNA biomarker quantification, where the miRNAs are present in low concentrations or sample volume, with potentials for frequent, low‐cost, and minimally invasive point‐of‐care testing. [ABSTRACT FROM AUTHOR]

One of the frontiers in the field of biosensors is the ability to quantify specific target molecules with enough precision to count individual units in a test sample, and to observe the characteristics of individual biomolecular interactions. Technologies that enable observation of molecules with "digital precision" have applications for in vitro diagnostics with ultra-sensitive limits of detection, characterization of biomolecular binding kinetics with a greater degree of precision, and gaining deeper insights into biological processes through quantification of molecules in complex specimens that would otherwise be unobservable. In this review, we seek to capture the current state-of-the-art in the field of digital resolution biosensing. We describe the capabilities of commercially available technology platforms, as well as capabilities that have been described in published literature. We highlight approaches that utilize enzymatic amplification, nanoparticle tags, chemical tags, as well as label-free biosensing methods. [ABSTRACT FROM AUTHOR]

We demonstrate a rapid, 2-step, and ultrasensitive assay approach for quantification of target protein molecules from a single droplet test sample. The assay is comprised of antibody-conjugated gold nanoparticles (AuNPs) that are "activated" when they are mixed with the test sample and bind their targets. The resulting liquid is passed through a microfluidic channel with a photonic crystal (PC) biosensor that is functionalized with secondary antibodies to the target biomarker, so that only activated AuNPs are captured. Utilizing recently demonstrated hybrid optical coupling between the plasmon resonance of the AuNP and the resonance of the PC, each captured AuNP efficiently quenches the resonant reflection of the PC, thus enabling the captured AuNPs to be digitally counted with high signal-to-noise. To achieve a 2-step assay process that is performed on a single droplet test sample without washing steps or active pump elements, controlled single-pass flow rate is obtained with an absorbing paper pad waste reservoir embedded in a microfluidic cartridge. We use the activate capture and digital counting (AC + DC) approach to demonstrate HIV-1 capsid antigen p24 detection from a 40 μL spiked-in human serum sample at a one thousand-fold dynamic range (1–103 pg mL−1) with only a 35-minute process that is compatible with point-of-care (POC) analysis. The AC + DC approach allows for ultrasensitive and ultrafast biomolecule detection, with potential applications in infectious disease diagnostics and early stage disease monitoring. [ABSTRACT FROM AUTHOR]

In this proof-of-concept study, we proposed a dual detection method for heavy metal ions based on nanostructured sensor device. This sensor device, named nano Lycurgus cup array, was characterized with hybrid structure of nano-scaled cups and gold nanoparticles. The hybrid periodic nanostructure could trigger localized surface plasmon resonance (LSPR) phenomenon, which was highly sensitive to refractive index changes. Then electrochemical measurement of anodic stripping voltammetry (ASV) was combined with LSPR for synchronous heavy metal ions detection, i.e., galvanizing metal ions onto the surface of the nanodevice whilst quantitatively recording electrochemical signals. Combining the electrochemical method with LSPR measurement, the dual detection system demonstrated a detection limit of part-per-billion level for aqueous heavy metal ions, such as lead, copper, and zinc. The LSPR measurement demonstrated a higher signal to noise rate (SNR) than electrochemical measurement and promising accuracy even with the presence of mixed solution, and was proved immune to the mechanical fluidic disturbance during the stripping phase which would deteriorate electrochemical signal in traditional electrochemical voltammogram. By presenting electrochemical signals on the dimension of LSPR, our method could be applied in highly integrated detection systems for on-spot detection. [ABSTRACT FROM AUTHOR]

In recent years, the biosensor research community has made rapid progress in the development of nanostructured materials capable of amplifying the interaction between light and biological matter. A common objective is to concentrate the electromagnetic energy associated with light into nanometer-scale volumes that, in many cases, can extend below the conventional Abbé diffraction limit. Dating back to the first application of surface plasmon resonance (SPR) for label-free detection of biomolecular interactions, resonant optical structures, including waveguides, ring resonators, and photonic crystals, have proven to be effective conduits for a wide range of optical enhancement effects that include enhanced excitation of photon emitters (such as quantum dots, organic dyes, and fluorescent proteins), enhanced extraction from photon emitters, enhanced optical absorption, and enhanced optical scattering (such as from Raman-scatterers and nanoparticles). The application of photonic metamaterials as a means for enhancing contrast in microscopy is a recent technological development. Through their ability to generate surface-localized and resonantly enhanced electromagnetic fields, photonic metamaterials are an effective surface for magnifying absorption, photon emission, and scattering associated with biological materials while an imaging system records spatial and temporal patterns. By replacing the conventional glass microscope slide with a photonic metamaterial, new forms of contrast and enhanced signal-to-noise are obtained for applications that include cancer diagnostics, infectious disease diagnostics, cell membrane imaging, biomolecular interaction analysis, and drug discovery. This paper will review the current state of the art in which photonic metamaterial surfaces are utilized in the context of microscopy. [ABSTRACT FROM AUTHOR]

The interaction between nanoparticles and the electromagnetic fields associated with optical nanostructures enables sensing with single-nanoparticle limits of detection and digital resolution counting of captured nanoparticles through their intrinsic dielectric permittivity, absorption, and scattering. This paper will review the fundamental sensing methods, device structures, and detection instruments that have demonstrated the capability to observe the binding and interaction of nanoparticles at the single-unit level, where the nanoparticles are comprised of biomaterial (in the case of a virus or liposome), metal (plasmonic and magnetic nanomaterials), or inorganic dielectric material (such as TiO2 or SiN). We classify sensing approaches based upon their ability to observe single-nanoparticle attachment/detachment events that occur in a specific location, versus approaches that are capable of generating images of nanoparticle attachment on a nanostructured surface. We describe applications that include study of biomolecular interactions, viral load monitoring, and enzyme-free detection of biomolecules in a test sample in the context of in vitro diagnostics. [ABSTRACT FROM AUTHOR]

Based on the special electrical and optical properties resulted from periodic nanostructure, localized surface plasmon resonance (LSPR) sensors have been widely used for various chemical and biological detections. Utilizing uniform alignment nanocups, an electrophoresis-enhanced LSPR sensor was designed for sensitive thrombin detection. The nanocup array was composed of nano-scaled funnel shaped cups with nanoparticles along the side walls. Through self-assembly, polyethylene glycol, thrombin-specific peptide, and bovine serum albumin were successively immobilized on the nanocup array. The results demonstrated that the synchronous implementation of electrophoresis and LSPR measurement could lead to obvious peak shifts in optical transmission spectra for detecting thrombin. The detection limit was as low as 10 −11 M. With the high sensitivity and well linearity, the electrophoresis-enhanced LSPR sensing offered a novel design perspective for chemical and biological sensors with specific modifications on the nanosensor surfaces. [ABSTRACT FROM AUTHOR]

Several applications in health diagnostics, food, safety, and environmental monitoring require rapid, simple, selective, and quantitatively accurate viral load monitoring. Here, we introduce the first label-free biosensing method that rapidly detects and quantifies intact virus in human saliva with single-virion resolution. Using pseudotype SARS-CoV-2 as a representative target, we immobilize aptamers with the ability to differentiate active from inactive virions on a photonic crystal, where the virions are captured through affinity with the spike protein displayed on the outer surface. Once captured, the intrinsic scattering of the virions is amplified and detected through interferometric imaging. Our approach analyzes the motion trajectory of each captured virion, enabling highly selective recognition against nontarget virions, while providing a limit of detection of 1 × 10 3 copies/mL at room temperature. The approach offers an alternative to enzymatic amplification assays for point-of-collection diagnostics.

Rapid, sensitive, and selective detection of nucleic acid biomarkers for health diagnostic applications becomes feasible for point of care scenarios when the detection instrument is inexpensive, simple, and robust. Here, we report the design, implementation, and characterization of a point of care instrument for photonic resonator absorption microscopy (PRAM) that takes advantage of resonant optical coupling between plasmonic gold nanoparticle tags and a photonic crystal (PC) surface. Matching the PC resonant wavelength to the gold nanoparticle's surface plasmon wavelength generates localized and efficient quenching of the PC resonant reflection intensity, resulting in the ability to clearly detect and count individual gold nanoparticles when they are captured on the PC surface. Surface-captured nanoparticles are observed by illuminating the PC at normal incidence with polarized light from a low-intensity red LED, and recording of PC reflected intensity on an inexpensive CMOS image sensor. A contrast limited adaptive histogram equalization (CLAHE) image processing algorithm was applied to derive counts of captured nanoparticles. The instrument is utilized in the context of an activate capture + digital counting (AC + DC) assay for a specific miRNA sequence, using nucleic acid toehold probes applied to gold nano-urchin (AuNU) nanoparticles to achieve 160 aM detection limits in a 30 min. assay., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Circulating exosomal microRNA (miR) represents a new class of blood-based biomarkers for cancer liquid biopsy. The detection of miR at a very low concentration and with single-base discrimination without the need for sophisticated equipment, large volumes, or elaborate sample processing is a challenge. To address this, we present an approach that is highly specific for a target miR sequence and has the ability to provide "digital" resolution of individual target molecules with high signal-to-noise ratio. Gold nanoparticle tags are prepared with thermodynamically optimized nucleic acid toehold probes that, when binding to a target miR sequence, displace a probe-protecting oligonucleotide and reveal a capture sequence that is used to selectively pull down the target-probe-nanoparticle complex to a photonic crystal (PC) biosensor surface. By matching the surface plasmon-resonant wavelength of the nanoparticle tag to the resonant wavelength of the PC nanostructure, the reflected light intensity from the PC is dramatically and locally quenched by the presence of each individual nanoparticle, enabling a form of biosensor microscopy that we call Photonic Resonator Absorption Microscopy (PRAM). Dynamic PRAM imaging of nanoparticle tag capture enables direct 100-aM limit of detection and single-base mismatch selectivity in a 2-h kinetic discrimination assay. The PRAM assay demonstrates that ultrasensitivity (<1 pM) and high selectivity can be achieved on a direct readout diagnostic., Competing Interests: The authors declare no conflict of interest.

The interaction between nanoparticles and the electromagnetic fields associated with optical nanostructures enables sensing with single-nanoparticle limits of detection and digital resolution counting of captured nanoparticles through their intrinsic dielectric permittivity, absorption, and scattering. This paper will review the fundamental sensing methods, device structures, and detection instruments that have demonstrated the capability to observe the binding and interaction of nanoparticles at the single-unit level, where the nanoparticles are comprised of biomaterial (in the case of a virus or liposome), metal (plasmonic and magnetic nanomaterials), or inorganic dielectric material (such as TiO 2 or SiN). We classify sensing approaches based upon their ability to observe single-nanoparticle attachment/detachment events that occur in a specific location, versus approaches that are capable of generating images of nanoparticle attachment on a nanostructured surface. We describe applications that include study of biomolecular interactions, viral load monitoring, and enzyme-free detection of biomolecules in a test sample in the context of in vitro diagnostics., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.