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The main objective is related to the capability of integrating into minimally invasive and ultra-thin disposable micro-endoscopic tool, a modality of realizing high-resolution imaging through scattering medium such as blood while performing medical procedure. In this research we aim for the first time to present a time-multiplexing super-resolving approach exhibiting enhanced focus sensitivity, generated by 3D spatial filtering, for significant contrast increase in images collected through scattering medium.Our innovative method of imaging through scattering media provides imaging of only one specific object plane in scattering medium's volume while suppressing the noise coming from all other planes. The method should be assisted with axial scanning to perform imaging of the entire 3D object's volume. In our developed optical system noise suppression is achieved by 3D spatial filtering approach while more than an order of magnitude of suppression is experimentally demonstrated. The sensitivity to defocus and noise suppression is dramatically enhanced by placing an array of micro-lenses combined with pinholes raster positioned between two modules of telecentric lenses.We present our novel conceptual designs for the enhanced signal-to-noise ratio (SNR) when imaging through scattering medium and present preliminary experimental results demonstrating both quality imaging performed on resolution bars target as well as SNR quantified results in which SNR enhancement of more than one order of magnitude was obtained.In this paper, to the best of our knowledge, we present the first ever design of time-multiplexing-based approach for super-resolved imaging through scattering medium. The approach includes a time-multiplexing optical design significantly increasing the depth of focus sensitivity and after performing axial scanning yielding a significant enhancement of the SNR of the 3D object that is being imaged through the scattering medium. Right after the contrast (the SNR) enhancement we scan the object with the projected array of spots (raster) and map it continuously and with high imaging resolution.

Single sensor (pixel) signals require scanning of the sample in order to obtain spatial information. In this paper we show that using interference, optically induced signals can be reconstructed when recorded using interference pattern excitation, rather than a point illumination. This method reduces the need for dense scanning and requires a small number of scans, or can eliminate the need for scanning in some cases. It is shown that this method can be used in particular in 2D photo-acoustic imaging.

In this chapter, we present a summary of research that uses silicon to enhance the imaging resolution and to push it toward the region of nanoscopy. The silicon has a nonlinear effect called the plasma dispersion effect (PDE), which can be used instead of the fluorescent dye in order to realize a stimulated emission depletion (STED) like microscopic imaging configuration. The silicon can be encapsulated into nanoparticles while the encapsulation may be biocompatible and yield the first step toward label-free bioimaging. The encapsulation may even be metallic to enhance the obtainable effect and to yield resolution enhancement at lower requirements from the pump beam. The silicon can even be used directly as a wafer but then the super-resolving imaging is mainly aimed at failure analysis of micro-electronic circuitry. When the silicon is encapsulated with metallic layer or when it is in the form of a wafer, while being illuminated with a pump beam (in visible wavelength being absorbed by the silicon) it modifies the imaging point spread function (PSF) of the probe beam (a near infra-red wavelength) into a doughnut-like shape, through the utilization of the PDE. This modified PSF has spatial components smaller than the diffraction limit, and by scanning the sample with it, super resolution can be achieved.

Gold nanoparticles are widely exploited in phototherapy. Owing to their biocompatibility and their strong visible-light surface plasmonic resonance, these particles also serve as contrast agents for cell image enhancement and super-resolved imaging. Yet, their optical signal is still insufficiently strong for many important real-life applications. Also, the differentiation between adjacent nanoparticles is usually limited by the optical resolution and the orientations of non-spherical particles are unknown. These limitations hamper the progress in cell research by direct optical microscopy and narrow the range of phototherapy applications. Here we demonstrate exploiting the optical anisotropy of non-spherical nanoparticles to achieve super-resolution in live cell imaging and to resolve the intracellular nanoparticle orientations. In particular, by modulating the light polarization and taking advantage of the polarization-dependence of gold nanorod optical properties, we realize the ‘lock-in amplification’, widely-used in electronic engineering, to achieve image enhancement in live cells and in cells that undergo apoptotic changes.

We report a novel optical single-emitter-localization methodology that uses the phase induced by path length differences in a Mach-Zehnder interferometer to improve localization precision. Using information theory, we demonstrate that the localization capability of a modified Fourier domain signal generated by photon interference enables a more precise localization compared to a standard Gaussian intensity distribution of the corresponding point spread function. The calculations were verified by numerical simulations and an exemplary experiment, where the centers of metal nanoparticles were localized to a precision of 3 nm.

The ability to localize precisely a single optical emitter is important for particle tracking applications and super resolution microscopy. It is known that for a traditional microscope the ability to localize such an emitter is limited by the photon count. Here we analyze the ability to improve such localization by imposing interference fringes. We show here that a simple grating interferometer can introduce such improvement in certain circumstances and analyze what is required to increase the localization precision further.

Recent microscopy techniques use nanoparticles as contrast agents that assist in realizing super resolved imaging of the inspected sample. While the sample itself is not labelled, its optical properties and form are revealed from the agent's location and movement. Gold nanoparticles are frequently used for compound cellular imaging due to their plasmonic resonance that occurs in the visible regime. While the effect dramatically enhances their effective absorption cross-section, additional enhancement techniques are still needed in order to reach adequate signal-to-noise levels and differentiate between adjacent nanoparticles. In this paper we demonstrate an effective way to image a sample using specialized eccentric gold nanoparticles while exploiting the polarization dependency of their plasmonic resonance. Temporal modulation of the illumination polarization induces a corresponding temporal flickering of the nanoparticles. The method enhances localization by eliminating noise that differs in frequency from the temporal modulation. Differentiation between nanoparticles is concurrently gained as the flickering is changed in relation with the angle between their eccentric axis and the polarization angle.

Single sensor (pixel) signals require scanning of the sample in order to obtain spatial information. In this paper we show that using interference, optically induced signals can be reconstructed when recorded using interference pattern excitation, rather than a point illumination. This method reduces the need for dense scanning and requires a small number of scans, or can eliminate the need for scanning in some cases. It is shown that this method can be used in particular in photo-acoustic imaging.

Three nanoparticle based structures are presented for the use of tunable surface enhanced Raman scattering effect. The tunability is obtained by change in the refractive index through illumination of silicon nanoparticles, and the result is a highly controllable enhancement factor and extinction cross section resonance wavelength. Intensity enhancements of up to 10^9 are demonstrated with induced modulation of enhancement of up to 48dB for certain structures.

In this paper, we present the concept of novel contact-free probe enabling to obtain high accuracy electrical characterizations of interconnection lines within working ULSI microchips. The probe consists of a tapered optical fiber and a certain structure of metallic nanorods (ferromagnetic and nonmagnetic) located within a hole drilled inside the fiber. Using the proposed probe, the waveform of electrical currents is reproduced from the change in the scattering cross section of two interacted metallic nanorods.

This work presents the use of flickering nanoparticles for imaging biological samples. The method has high noise immunity, and it enables the detection of overlapping types of GNPs, at significantly sub-diffraction distances, making it attractive for super resolving localization microscopy techniques. The method utilizes a lock-in technique at which the imaging of the sample is done using a time-modulated laser beam that match the number of the types of gold nanoparticles (GNPs) that label a given sample, and resulting in the excitation of the temporal flickering of the scattered light at known temporal frequencies. The final image where the GNPs are spatially separated is obtained using post processing where the proper spectral components corresponding to the different modulation frequencies are extracted. This allows the simultaneous super resolved imaging of multiple types of GNPs that label targets of interest within biological samples. Additionally applying the post-processing algorithm of the K-factor image decomposition algorithm can further improve the performance of the proposed approach.

Tissues are characterized by a strong scattering of visible optical radiation, which prevents one from achieving deep-tissue imaging. We propose a computational imaging technique for the inference of specific macroscopic, spatial phase distribution features of the scattering media. The spatial phase distribution is reconstructed from several defocused intensity images. We empirically demonstrate the method by reconstructing the location of two fibula chicken bones, embedded within chicken breast tissue. The suggested technique is safe, using visible laser illumination, and noninvasive. It is also cost-effective since a simple optical system is used and the images are acquired using a conventional camera, and it does not require interferometric detection as well as direct access to the object in absence of the layer.

The ability to track single fluorescent particles within a three dimensional (3D) cellular environment can provide valuable insights into cellular processes. In this paper, we present a modified nonlinear image decomposition technique called K-factor that reshapes the 3D point spread function (PSF) of an XYZ image stack into a narrow Gaussian profile. The method increases localization accuracy by ~60% with compare to regular Gaussian fitting, and improves minimal resolvable distance between overlapping PSFs by ~50%. The algorithm was tested both on simulated data and experimentally. This work presets a novel use of the nonlinear image decomposition technique called K-factor that reshapes the three dimensional (3D) point spread function (PSF) of an XYZ image stack into a narrow Gaussian profile. The experimentally obtained PSF of a Z-stack raw data that is acquired by a widefield microscope has a more elaborate shape that is given by the Gibson and Lanni model. This shape increases the computational complexity associated with the localization routine, when used in localization microscopy techniques. Furthermore, due to its nature, this PSF spreads over a larger volume, making the problem of overlapping emitters detection more pronounced. The ability to use Gaussian fitting with high accuracy on 3D data can facilitate the computational complexity, hence reduce the processing time required for the generation of the 3D superresolved image. In addition it allows the detection of overlapping PSFs and reduces the effects of the penetration of out of focus PSFs into in focused PSFs, therefore enables the increase in the activated fluorophore density by ~50%. The algorithm was tested both on simulated data and experimentally, where it yielded an increase in the localization accuracy by ~60% with compare to regular Gaussian fitting, and improved the minimal resolvable distance between overlapping PSFs by ~50%, making it extremely applicable to the field of 3D biomedical imaging

The goal of this paper is to immobilize gold nanoparticles uniformly on a glass substrate. In order to attach gold-nanorods (GNRs) to an area of a few squared microns surface of glass substrate without preliminary coating of the GNR, 3-(Mercaptopropyl)trimethoxysilane molecules were used as linker while using different methods. These methods included placing the glass slide and the GNR (1) inside a tube without any motion; (2) inside a shaker; (3) in a fan setup. The fan setup included a tube containing the GNR solution and the glass slide at a vertical position, when the fan blows above the tube, producing turbulations in the liquid. Each method was evaluated according to the density and the homogeneousness of the GNR monolayer on the surface. The uniformity of the monolayer was demonstrated using AFM images of different areas on the slides, and the effectiveness of the protocol was demonstrated by calculating the average density of the GNR on the surface using image processing and analysis software. It was found that while both the shaker and the fan setups improved the monolayer density, the fan setup improved the density by a factor of more than two than the density found using the shaker.

We applied nonlinear optimization to convert a cannula into a high-resolution computational-fluorescence microscope. The microscope was used to image fluorescent microspheres, genetically-encoded mouse-brain slices, genetically-encoded and fluorescent-stained C. elegans nematodes (both living and dead animals).

Two new directions are presented. The first uses modified nonlinear image decomposition to reshapes the 3D point spread function of an XYZ Z-stack and improves the localization accuracy. The second improves the localization accuracy by labeling the specimens with GNPs and their subsequent flickering at different temporal frequencies.

We show that the localization precision of single nanoparticles can be improved by imposing an interference pattern on the Point-Spread-Function. Localization precision of 0.1nm for a single emitter was obtained.

We applied nonlinear optimization to convert a rigid cannula into a high-resolution computational-fluorescence microscope. The prototype cannula microscope was used to image fluorescent microspheres and genetically-encoded mouse-brain slices and produced quality images comparable to a conventional widefield microscope.

Utilizing the surface plasmon resonance effect in gold nanoparticles enables their use as contrast agents in a variety of applications for compound cellular imaging. However, most techniques suffer from poor signal to noise ratio (SNR) statistics due to high shot noise that is associated with low photon count in addition to high background noise. We demonstrate an effective way to improve the SNR, in particular when the inspected signal is indistinguishable in the given noisy environment. We excite the temporal flickering of the scattered light from gold nanoparticle that labels a biological sample. By preforming temporal spectral analysis of the received spatial image and by inspecting the proper spectral component corresponding to the modulation frequency, we separate the signal from the wide spread spectral noise (lock-in amplification).

We present a fast wide-field holography system for detecting the photothermally excited gold nanospheres in a QPI scheme. An interferometric optical lock-in approach was shown to improve SNR for detecting nanoparticles on multiple substrates.

Interference of signal in Fourier space, emitted from single probes, is used to localize it by recording and computing the phase of the fringes. Such system has applications in super resolution localization microscopy.

Noble metal nanoparticles exhibit enhanced scattering and absorption at specific wavelengths due to a localized surface plamson resonance. This unique property can be exploited to enable the use of plasmonic nanoparticles as contrast agents in optical imaging. A range of optical techniques have been developed to detect nanoparticles in order to implement imaging schemes. Here we review several different approaches for using optical interferometry to detect the presence and concentration of nanoparticles. The strengths and weaknesses of the various approaches are discussed and quantitative comparisons of the achievable signal to noise ratios are presented. The benefits of each approach are outlined as they relate to specific application goals.

Localization of a single fluorescent particle with sub-diffraction limit accuracy is a key merit in fluorescence microscopy. Implementation of nonlinear filtering algorithms prior the localization process can improve the localization accuracy of standard existing methods and also enable the localization of overlapping particles, allowing the use of increased fluorophore activation density, and thereby increased data collection speed. In this paper we present the use of an image decomposition algorithm termed K-factor which reduces an image into a nonlinear set of contrast-ordered decompositions whose joint product reassembles the original image. The K-factor technique is implemented on the images, prior to the localization of the fluorescent probes. Numerical simulations of fluorescence data with random probe positions, and especially at high densities of activated fluorophores demonstrated an improvement in the localization precision with compare to single fitting techniques. Implanting the proposed concept also on experimental data of cellular structures yielded the theoretically predicted resolution enhancement.

Metal nanoparticles are used for different applications in holographic configurations. The metal nanoparticles are placed close to an object and encode it by a time varying random mask. A decoding mask is computed and used to obtain super-resolution digital hologram and eliminate the twin image and DC from a digital hologram. The method is also shown to be applicable for other optical methods.

A multilayer photonic XOR gate is presented. The XOR is implemented by the interconnect layers of a microelectronic chip and is suitable for fabrication in a standard VLSI fabrication process. The proposed device features an inherent insertion loss compensation mechanism by utilization of nanometric holes, making it possible to implement an optic memory cell without the need of additional complex compensation devices. The structure of such a memory cell, implemented by utilization of two proposed XOR gates, configured to perform the NOT function, is shown. The unique structure of the proposed device allows us to significantly reduce sensitivity to process variations and therefore makes it possible to utilize the memory cell in state-of-the-art nanoscale processes. The proposed memory can be integrated with conventional electronics on the same VLSI chip.

A method for eliminating the unwanted terms in an on axis hologram is presented. Free randomly distributed nanoparticles are used to encode and later on to decode/separate the desired term from the unwanted aberrations.

An all optical Viterbi decoder on a silicon chip was designed. The device is composed of an optical memory cell and two interfering input arms that use QPSK modulation to encode the incoming bits. The device has a shape of a ring resonator with a size of just a few micrometers and relies on the coupling of modes. Data processing of a few picoseconds is within the ability of the device.

A method for eliminating the unwanted terms in an on axis hologram is presented. In this method, free randomly distributed nanoparticles are in proximity to the object and their Brownian motion encodes the spatial features of the object in the recorded hologram. The nanoparticles are localized and a decoding pattern is calculated for each frame. This decoding pattern is then used to remove the reference beam and the conjugate beam in the reconstruction of the hologram.

Spatial diffusion reflection (DR) measurements of gold nanorods (GNR) were recently suggested as a simple and highly sensitive non-invasive and non-ionizing method for real-time cancer detection. In this paper we demonstrate that wavelength dependent DR measurements enable the spectral red-shift observation of highly concentrated GNR. By conjugating targeting moieties to the GNR, large density of GNR can specifically home onto cancer cells. The inter-particle plasmon resonance pattern of the highly concentrated GNR leads to an extension and a red-shift (Δλ) in the absorption spectrum of the concentrated GNR. Dark-field microscopy was used in order to measure the expected Δλ in different GNR concentrations in vitro. Double-wavelength DR measurements of tissue-like phantoms and tumor bearing mice containing different GNR concentrations are presented. We show that the DR profile of the highly concentrated GNR directly correlate with the spectral extension and red-shift. This presented work suggests that wavelength dependent DR method can serve as a promising tool for real-time superficial tumor detection. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Localization microscopy provides valuable insights into cellular structures and is a rapidly developing field. The precision is mainly limited by additive noise and the requirement for single molecule imaging that dictates a low density of activated emitters in the field of view. In this paper we present a technique aimed for noise reduction and improved localization accuracy. The method has two steps; the first is the imaging of gold nanoparticles that labels targets of interest inside biological cells using a lock-in technique that enables the separation of the signal from the wide spread spectral noise. The second step is the application of the K-factor nonlinear image decomposition algorithm on the obtained image, which improves the localization accuracy that can reach 5nm and enables the localization of overlapping particles at minimal distances that are closer by 65% than conventional methods.

We propose an approach to Brillouin optical frequency domain analysis for measuring temperature or strain along an optical fiber. In this approach, we modulate the pump by a cosine function over a range of frequencies. By measuring only the probe power at the edge of the fiber for each modulation frequency, we obtain the cosine transform of the Brillouin gain coefficient of the fiber. We describe the operation principle of the proposed method, introduce additional advantages of the frequency domain analysis, such as compressed representation of the spatial information and better field of view, and use simulations and experimental work to demonstrate the capabilities of the proposed technique.

We present a fast, wide-field holography system for detecting photothermally excited gold nanospheres with combined quantitative phase imaging. An interferometric photothermal optical lock-in approach (POLI) is shown to improve SNR for detecting nanoparticles (NPs) on multiple substrates, including a monolayer of NPs on a silanized coverslip, and NPs bound to live cells. Furthermore, the set up allowed for co-registered quantitative phase imaging (QPI) to be acquired in an off-axis holographic set-up. An SNR of 103 was obtained for NP-tagging of epidermal growth factor receptor (EGFR) in live cells with a 3 second acquisition, while an SNR of 47 was seen for 20 ms acquisition. An analysis of improvements in SNR due to averaging multiple frames is presented, which suggest that residual photothermal signal can be a limiting factor. The combination of techniques allows for high resolution imaging of cell structure via QPI with the ability to identify receptor expression via POLI.

Localization of a single fluorescent particle with sub-diffraction-limit accuracy is a key merit in localization microscopy. Existing methods such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM) achieve localization accuracies of single emitters that can reach an order of magnitude lower than the conventional resolving capabilities of optical microscopy. However, these techniques require a sparse distribution of simultaneously activated fluorophores in the field of view, resulting in larger time needed for the construction of the full image. In this paper we present the use of a nonlinear image decomposition algorithm termed K-factor, which reduces an image into a nonlinear set of contrast-ordered decompositions whose joint product reassembles the original image. The K-factor technique, when implemented on raw data prior to localization, can improve the localization accuracy of standard existing methods, and also enable the localization of overlapping particles, allowing the use of increased fluorophore activation density, and thereby increased data collection speed. Numerical simulations of fluorescence data with random probe positions, and especially at high densities of activated fluorophores, demonstrate an improvement of up to 85% in the localization precision compared to single fitting techniques. Implementing the proposed concept on experimental data of cellular structures yielded a 37% improvement in resolution for the same super-resolution image acquisition time, and a decrease of 42% in the collection time of super-resolution data with the same resolution.

An all optical Viterbi decoder, realized on a silicon chip was designed. The device relies on mode coupling inside a ring resonator, and is composed of an optical memory cell and two interfering input arms that use QPSK modulation to encode the incoming bits. The device has a dimension of a few micrometers, and is capable of processing bits with a length of just a few picoseconds. The approach chosen in this research demonstrates the capability to design all-optical processing units which are not composed of single building blocks.

An all-optical XOR gate was designed to take advantage of the previously unused silicon dioxide (SiO2) interconnect layers in a microelectronic chip. The device relies on the coupling of modes between parallel waveguides and the interaction of the modes with the metal interconnects of a silicon chip to obtain a phase difference between input arms. When the signals from the two input arms interfere, the result is a logic XOR operation due to the phase difference. The design was numerically implemented, and a contrast of 18.7 dB was obtained with a 13.2-μm-long logic gate. © 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). (DOI: 10.1117/1.JNP.6.061607)

The hybrid optically and electrically controllable field effect transistor is a novel device whose current-voltage ( I-V ) curve can be controlled by optical or electrical modulation of metallic nanoparticles. The basic structure of this transistor is similar to that of a junction gate field effect transistor, where the conventional gate contact is replaced by an array of nanoparticles located on the upper side of the p-n junction and parallel to the channel direction, whereas the source and the drain contacts remain the same. The deposition of the nanoparticles is achieved by self-assembly using the focused-ion-beam technology. The displacement of the nanoparticles along the air gap is performed either optically or electrically. Optical control is based on a special type of optical tweezers realized by guiding and confining light into a nanosize void structure in which the nanoparticle is placed. Electrical control via an external electric field tunes the nanoparticles. Control of the I-V curve controls the logic function of the device.

We designed a nanoscale optical communication device for use as an electro-optical modulator, an all-optical modulator, or an all-optical cascadable logic gate. The device is based on electrostatic forces and has the shape of a parallel plate capacitor. Careful planning of the dimensions allows for operation frequencies of up to hundreds of megahertz and a contrast of more than 3 dB. The device can be implemented for AND, NOT, and NAND gates.

We present a method to improve the localization precision of nanoparticles over Gaussian fitting by imposing an interference pattern on the Point-Spread-Function. Localization precision of 0.1nm for a single emitter was obtained.

Localization precision of single emitters can be fundamentally improved by imposing interference fringes on the Point-Spread-Function. We show that this interference effect can be used for coherent and incoherent signals for sub nanometer localization.