Single nanoparticle detectors for biological applications

Abstract

Nanoparticle research has become increasingly important in the context of bioscience and biotechnology. Practical use of nanoparticles in biology has significantly advanced our understanding about biological processes in the nanoscale as well as led to many novel diagnostic and therapeutic applications. Besides, synthetic and natural nanoparticles are of concern for their potential adverse effect on human health. Development of novel detection and characterization tools for nanoparticles will impact a broad range of disciplines in biological research from nanomedicine to nanotoxicology. In this article, we discuss the recent progress and future directions in the area of single nanoparticle detectors with an emphasis on their biological applications. A brief critical overview of electrical and mechanical detection techniques is given and a more in-depth discussion of label-free optical detection techniques is presented.

Fig. 1

Nanoconstriction based detection of single nanoparticles and viruses. (a) The schematic demonstrating the device layout: external voltage bias electrodes (H and L) and sensing electrode (S); embedded filters (F); fluid resistor (FR); nanoconstriction (NC); pressure regulated fluidic ports (P1–P6). Nanoparticles in saline suspension flow in the direction of the arrows, and changes in the electrical potential of the fluid adjacent to the nanoconstriction are detected by the sensing electrode S. (b) Analysis of a nanoparticle solution mixture containing 51 nm, 75 nm and 117 nm polystyrene nanoparticles. Left panel shows the output voltage read as a function of time as the nanoparticles pass through the nanoconstriction. Right panel shows the histogram of effective diameter of the nanoparticles detected. (c) Analysis of T7 bacteriophage viruses with an admixture of 117 nm calibration nanoparticles. Left and right panels show the time-trace plot of output voltage and the histogram of effective diameter of detected particles. The dashed lines correspond to DLS measurement of the mixtures. Adapted from ref. . ©2011 Macmillan Publishers Ltd: Nature Nanotechnology.

Fig. 2

SMR based detection of gold nanoparticles. (a) Optical micrograph of the fabricated structure. (b) SEM image of the cutaway view of the structure showing the buried nanofluidic channel. (c) Resonance frequency shift of the cantilever when 50 nm diameter gold nanoparticles flow through the resonator. (d) Resonance frequency shift steps as individual gold nanoparticles are trapped at the tip of the cantilever. (e) The histogram showing the measured mass distribution of 50 nm gold nanoparticles in flow-through mode. The baseline noise is also demonstrated for comparison. Adapted from ref. . © 2011 American Chemical Society.

Fig. 3

Interferometric Reflectance Imaging Sensor (IRIS). (a) Schematic of the optical setup. The setup consists of a multi-wavelength LED light source that is set up in Kohler illumination with a 50 × 0.8NA objective. The sample is imaged at a single wavelength using a CCD camera. (b) The close-up schematic of the object space where the scattered and reflected fields are shown. (c) IRIS image of immobilized virus on the surface with the same field of view as the SEM image. (d) SEM image of the immobilized virus on the surface. (e) Size distribution of single particles on different chips. (f) Measured size distribution of the immobilized virus using IRIS. Adapted from ref. . © 2010 American Chemical Society.

Fig. 4

Morphology measurement of nanoparticles using IRIS. (a) Optical image of three gold nanorods (nominally 30 nm by 70 nm) for two orthogonal polarization of incident light. (Arrows show the polarization of the incident light.) (b) Comparison of IRIS and SEM measurements for two gold nanospheres (nominally, d = 46 nm) and two nanorods (nominally, 30 nm by 70 nm). The data points and the solid curves show the experimental values and numerical fit to data points for dimension analysis, respectively. (c) High-throughput analysis of nanorod and nanosphere populations on a scatter chart.

Fig. 5

Flow-based Heterodyne Interferometric Detector. (a) Schematic of the heterodyne interferometric technique. The nanoparticle (yellow) is detected as it traverses the focused spot. The scheme employs an excitation laser (E_exc) with frequency that is reflected off a beamsplitter and focused via an objective into a nanofluidic channel. The scattered light (E_sca) from the nanoparticle is superimposed onto a reference beam (E_ref) with frequency (ω + Δω) and directed onto a differential detector. (b) Particle size distributions for a mixture of 50 and 75 nm polystyrene nanoparticles. (c) Size distribution for a mixture of 30, 40, and 50 nm gold nanoparticles. Size distributions for (d) HIV (ADA strain) and (e) Sindbis virus. (f) Size distribution for a mixture of HIV and Sindbis viruses. Adapted from ref. . © 2010 American Chemical Society.

Fig. 6

Material specific detection of nanoparticles using IRIS. (a) Background normalized peak response for 52 nm gold (red) and 70 nm silver (black) nanoparticles is shown as a function of defocus. (b) Interferometric image at 525 nm at a defocus of 250 nm. The scale bar denotes 2 micron. (c) High-throughput material based classification of 52 nm Au and 70 nm Ag particles. The measurements were done on separate chips. (d) Simultaneous detection of 52 nm Au and 70 nm Ag particles.

Fig. 7

Surface Plasmon Resonance Microscopy (SPRM). (a) Schematic of the SPRM experimental setup. (b) SPRM images of H1N1 influenza A virus and three different silica nanoparticle populations in PBS buffer. For comparison with experiments insets in the images are nanoparticle images generated by numerical simulation. The SPR intensity profiles of selected particles along X (c) and Y (d) directions (indicated by dashed lines in (b)), respectively. The insets in the graph are the corresponding profiles from simulated images. Adapted from ref. . © 2010 National Academy of Sciences.

Fig. 8

High Sensitivity Optical Microcavity based detector. (a) Experimental setup for nanoparticle detection using a temperature-stabilized reference interferometer. The output of a tunable laser is split into two branches by a 90/10 coupler. One branch is coupled into/out of a microtoroid resonator in a cooled aqueous environment. The other branch is coupled into a reference interferometer to monitor the laser optical frequency in real time. The reference interferometer is immersed in ice-water to improve the stability. (Inset) SEM micrograph of an R = 25 nm bead binding on the surface of a microtoroid. (b) The resonance wavelength shift (scan A) and splitting frequency shift (scan B) are shown for a microtoroid immersed in a 1 pMInfA solution. The insets I and II show that the same resonance wavelength shift event can also be detected as a split frequency shift, respectively. (c) The histogram of the resonance wavelength-shift steps in scan A and an inset of the largest wavelength step recorded of 11.3 fm. Adapted from ref. . © 2011 National Academy of Sciences.

Fig. 9

Mode splitting in an Ultrahigh-Q microresonator. (a) Schematic of the experimental setup. DMA, differential mobility analyser; PD, photo-diode. The inset shows an SEM image of a microtoroid. (b) Illustration of the coupled nanoparticle–microtoroid system. k₁, microtoroid–taper coupling rate; k₀, intrinsic damping rate (material and radiation losses); g, coupling coefficients of the light scattered into the resonator; GR, additional damping rate due to scattering losses. CW, clockwise modes; CCW, counter-clockwise modes. (c) Series of normalized transmission spectra taken at a 1550 nm wavelength band and the corresponding optical images recorded without nanoparticles (top trace) and with four successive depositions of KCl nanoparticles. The spectral baseline is vertically shifted for clarity. (d) Normalized splitting 2g/ω_c (2g, splitting frequency; ω_c, resonance frequency) versus particle number for KCl nanoparticles. Each discrete step corresponds to a single nanoparticle binding event. The inset shows an enlarged plot for nanoparticles of R = 40 nm. Adapted from ref. . © 2010 Macmillan Publishers Ltd: Nature Photonics.