Abstract
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.
Highlights
High resolution microscopy technologies such as electron beam microscopy and confocal fluorescence microscopy, including super-resolution methods (structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), photo-activated localization microscopy (PALM), and stochastic optical reconstruction microscopy (STORM)) that enable observation of fluorophore-tagged features with sizes below the diffraction limit of light offer the ability to observe nanometer-scale objects [1,2,3]
Digital resolution sensing of the presence of specific biomolecules is an enabling capability for the most demanding applications for in vitro diagnostics such as liquid biopsies for cancer via detection of circulating DNA, messenger RNA or microRNA [46,47,48,49], where the test sample volume may be limited to only several microliters, combined with analyte concentrations that extend below 1 pg/mL
Factors, even slight changes to the Whispering gallery mode (WSG) sensor’s effective refractive index will affect the modal frequency of the traveling wave, which can be measured by a shift in the wavelength of light optimally coupled from an adjacent waveguide to the WSG ring
Summary
High resolution microscopy technologies such as electron beam microscopy and confocal fluorescence microscopy, including super-resolution methods (structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), photo-activated localization microscopy (PALM), and stochastic optical reconstruction microscopy (STORM)) that enable observation of fluorophore-tagged features with sizes below the diffraction limit of light offer the ability to observe nanometer-scale objects [1,2,3]. Digital resolution sensing of the presence of specific biomolecules (such as proteins, DNA, or RNA) is an enabling capability for the most demanding applications for in vitro diagnostics such as liquid biopsies for cancer via detection of circulating DNA, messenger RNA (mRNA) or microRNA (miRNA) [46,47,48,49], where the test sample volume may be limited to only several microliters (such as a droplet of serum from a fingerstick), combined with analyte concentrations that extend below 1 pg/mL For such scenarios, the number of available target molecules may be between 100–10,000, and approaches that require aggregation of many captured molecules into a compact region, such as a microarray spot, will no longer reliably generate features that can be recognized and quantified [50]. The entire transducer surface can be considered as “active” for sensing, and different regions within the field of view can be designated as experimental controls or as regions for multiplexed detection of many analytes
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