PALO ALTO, CA, United States
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Mankos M.,KLA Tencor | Mankos M.,Electron Optica, Inc. | Spasov V.,KLA Tencor | Munro E.,MEBS Ltd.
Advances in Imaging and Electron Physics | Year: 2010

Several novel electron-optical components and concepts have been developed that improve the throughput and extend the applications of low-energy electron microscopes (LEEM). When the substrate is immersed in the magnetic field of the cathode objective lens, a substantial reduction in the e-e interactions and the associated blur can be seen compared with conventional purely electrostatic and nonimmersion magnetic lenses. The immersion nature of the objective lens introduces a twist in the mirror mode, which causes a serious degradation of resolution. This twist effect vanishes when the cathode of the electron gun is immersed in a rotationally symmetric magnetic field that is appropriately matched to the magnetic field at the substrate. A similar effect can be obtained when a partially mirrored beam and overlapping UV beam are used. Similar results were obtained when a laser beam was used to mitigate the charging effects. At or near glancing incidence, large shadows are formed on even the smallest topographic features, easing their detection.


Mankos M.,Electron Optica, Inc. | Shadman K.,Electron Optica, Inc. | Kolarik V.,Delong Instruments
Journal of Vacuum Science and Technology B: Nanotechnology and Microelectronics | Year: 2016

A mirror electron monochromator has been developed for reducing the energy spread of commonly used high brightness electron sources from the characteristic range of 0.3-1 eV to values below 100 meV. The monochromator utilizes mirror optics and thereby exploits the symmetry inherent in reversing the electron trajectory to monochromatize the primary beam with a knife edge instead of a conventional slit. The performance of the key electron-optical components of the monochromator has been simulated. These components include the combination of an electron mirror with a magnetic prism array. In initial testing, the monochromator has demonstrated the ability to reduce the energy spread of a 5 keV electron beam that was generated by a Schottky electron emitter from its initial value of 0.65-0.75 eV to 180 meV with an exit beam current exceeding 1 nA and to 100 meV with an exit beam current of 50 pA. Here, the attainable energy resolution was found to be limited by the noise on the power supply. The monochromator is designed to attach to scanning and transmission electron microscopes thus making them suitable for enhancing the study of the structure, composition, and bonding states of new materials at the nanoscale. For scanning electron microscopy, the monochromator will increase the spatial resolution of the acquired images of specimens, in particular, at low landing energies where the chromatic aberrations become dominant. For transmission electron microscopy, the monochromator will refine the spectra extracted from electron spectrometers, where the energy spread of the electron source limits the achievable energy resolution. © 2016 American Vacuum Society.


Mankos M.,Electron Optica, Inc.
Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment | Year: 2011

Dual-beam low energy electron microscopy (LEEM) is a novel imaging technique that extends LEEM applications to non-conductive substrates. In dual-beam LEEM, two flood beams with opposite charging characteristics illuminate the field of view in order to mitigate the charging effects occurring when substrates with insulating or floating surfaces are imaged in a LEEM. The negative charging effect, created by a partially absorbed mirror beam, is compensated by the positive charging effect of either a higher energy electron beam with an electron yield exceeding 1, or a photon beam. The electron-optical designs of existing and novel dual-beam LEEM approaches are reviewed and compared. © 2010 Elsevier B.V. Allrights reserved.


Mankos M.,Electron Optica, Inc. | Shadman K.,Electron Optica, Inc.
Ultramicroscopy | Year: 2013

The monochromatic, aberration-corrected, dual-beam low energy electron microscope (MAD-LEEM) is a novel instrument aimed at imaging of nanostructures and surfaces at sub-nanometer resolution that includes a monochromator, aberration corrector and dual beam illumination. The monochromator reduces the energy spread of the illuminating electron beam, which significantly improves spectroscopic and spatial resolution. The aberration corrector utilizes an electron mirror with negative aberrations that can be used to compensate the aberrations of the LEEM objective lens for a range of electron energies. Dual flood illumination eliminates charging generated when a conventional LEEM is used to image insulating specimens. MAD-LEEM is designed for the purpose of imaging biological and insulating specimens, which are difficult to image with conventional LEEM, Low-Voltage SEM, and TEM instruments. The MAD-LEEM instrument can also be used as a general purpose LEEM with significantly improved resolution. The low impact energy of the electrons is critical for avoiding beam damage, as high energy electrons with keV kinetic energies used in SEMs and TEMs cause irreversible change to many specimens, in particular biological materials. A potential application for MAD-LEEM is in DNA sequencing, which demands imaging techniques that enable DNA sequencing at high resolution and speed, and at low cost. The key advantages of the MAD-LEEM approach for this application are the low electron impact energies, the long read lengths, and the absence of heavy-atom DNA labeling. Image contrast simulations of the detectability of individual nucleotides in a DNA strand have been developed in order to refine the optics blur and DNA base contrast requirements for this application. © 2013 Elsevier B.V.


Mankos M.,Electron Optica, Inc. | Shadman K.,Electron Optica, Inc. | Ndiaye A.T.,Lawrence Berkeley National Laboratory | Schmid A.K.,Lawrence Berkeley National Laboratory | And 2 more authors.
Journal of Vacuum Science and Technology B:Nanotechnology and Microelectronics | Year: 2012

Monochromatic, aberration-corrected, dual-beam low energy electron microscopy (MAD-LEEM) is a novel imaging technique aimed at high resolution imaging of macromolecules, nanoparticles, and surfaces. MAD-LEEM combines three innovative electron-optical concepts in a single tool: a monochromator, a mirror aberration corrector, and dual electron beam illumination. The monochromator reduces the energy spread of the illuminating electron beam, which significantly improves spectroscopic and spatial resolution. The aberration corrector is needed to achieve subnanometer resolution at landing energies of a few hundred electronvolts. The dual flood illumination approach eliminates charging effects generated when a conventional, single-beam LEEM is used to image insulating specimens. The low landing energy of electrons in the range of 0 to a few hundred electronvolts is also critical for avoiding radiation damage, as high energy electrons with kilo-electron-volt kinetic energies cause irreversible damage to many specimens, in particular biological molecules. The performance of the key electron-optical components of MAD-LEEM, the aberration corrector combined with the objective lens and a magnetic beam separator, was simulated. Initial results indicate that an electrostatic electron mirror has negative spherical and chromatic aberration coefficients that can be tuned over a large parameter range. The negative aberrations generated by the electron mirror can be used to compensate the aberrations of the LEEM objective lens for a range of electron energies and provide a path to achieving subnanometer spatial resolution. First experimental results on characterizing DNA molecules immobilized on Au substrates in a LEEM are presented. Images obtained in a spin-polarized LEEM demonstrate that high contrast is achievable at low electron energies in the range of 1-10 eV and show that small changes in landing energy have a strong impact on the achievable contrast. The MAD-LEEM approach promises to significantly improve the performance of a LEEM for a wide range of applications in the biosciences, material sciences, and nanotechnology where nanometer scale resolution and analytical capabilities are required. In particular, the microscope has the potential of delivering images of unlabeled DNA strands with nucleotide-specific contrast. This simplifies specimen preparation and significantly eases the computational complexity needed to assemble the DNA sequence from individual reads. © 2012 American Vacuum Society.


Mankos M.,Electron Optica, Inc. | Shadman K.,Electron Optica, Inc. | Persson H.H.J.,Stanford University | N'Diaye A.T.,Electron Optica, Inc. | And 3 more authors.
Ultramicroscopy | Year: 2014

Monochromatic, aberration-corrected, dual-beam low energy electron microscopy (MAD-LEEM) is a novel technique that is directed towards imaging nanostructures and surfaces with sub-nanometer resolution. The technique combines a monochromator, a mirror aberration corrector, an energy filter, and dual beam illumination in a single instrument. The monochromator reduces the energy spread of the illuminating electron beam, which significantly improves spectroscopic and spatial resolution. Simulation results predict that the novel aberration corrector design will eliminate the second rank chromatic and third and fifth order spherical aberrations, thereby improving the resolution into the sub-nanometer regime at landing energies as low as one hundred electron-Volts. The energy filter produces a beam that can extract detailed information about the chemical composition and local electronic states of non-periodic objects such as nanoparticles, interfaces, defects, and macromolecules. The dual flood illumination eliminates charging effects that are generated when a conventional LEEM is used to image insulating specimens. A potential application for MAD-LEEM is in DNA sequencing, which requires high resolution to distinguish the individual bases and high speed to reduce the cost. The MAD-LEEM approach images the DNA with low electron impact energies, which provides nucleobase contrast mechanisms without organometallic labels. Furthermore, the micron-size field of view when combined with imaging on the fly provides long read lengths, thereby reducing the demand on assembling the sequence. Experimental results from bulk specimens with immobilized single-base oligonucleotides demonstrate that base specific contrast is available with reflected, photo-emitted, and Auger electrons. Image contrast simulations of model rectangular features mimicking the individual nucleotides in a DNA strand have been developed to translate measurements of contrast on bulk DNA to the detectability of individual DNA bases in a sequence. © 2014 Elsevier B.V.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 499.24K | Year: 2011

DESCRIPTION (provided by applicant): Significant demand exists for the development of novel technologies capable of low-cost, high quality DNA sequencing. Established sequencing techniques based on capillary array electrophoresis and cyclic array sequencing offer such analytical capability, and next generation commercial sequencers deliver at a cost approaching 10,000/genome. One drawback is that these technologies identify in one segment (read) only about 10 to 1000 sequential base pairs out of the total3 Gb in the human genome. The complex repetitive nature of DNA makes it costly and time consuming to completely and accurately reassemble a full genome. Recently, transmission electron microscopy (TEM) techniques have been proposed that label specific DNAbases with heavy atoms (e.g., osmium) and thus have the promise of significantly extending the length of individual reads. However, the accurate determination of the complete DNA sequence is complicated by the need for labeling and correlating the labeledand unlabeled bases. In addition, the relatively high electron energy used in high resolution TEMs causes radiation damage that leads to read errors and limits the usable electron dose. Electron Optica proposes to develop a novel electron microscope capable of imaging a DNA base sequence of unlimited length at a cost of 1,000/genome with the high accuracy needed for full-scale sequencing. In this technique, which we call monochromatic aberration-corrected dual-beam low energy electron microscopy, two beams illuminate the sample with electrons having energies from 0 to a few 100 eV, and the reflected electrons are utilized to form a magnified image. The microscope includes a monochromator and aberration corrector, and has the potential of delivering imagesof unlabeled DNA with nucleotide-specific contrast. This simplifies sample preparation and eases the computational complexity needed to assemble the sequence from individual reads. In addition, at low landing energies there is no radiation damage, so highelectron doses needed for high throughput and low cost can be used. The proposed research will focus on the feasibility of the key aspects required for this approach, i.e., achieving high spatial resolution, high throughput and DNA base-specific contrast. A detailed analysis of the column optics including the aberration corrector and monochromator will be performed using state-of-the-art simulation software. Analysis of the electronic structure of DNA bases will be carried out theoretically and experimentally and the achievable contrast will be evaluated. The proposed research will develop a new approach to low cost, high quality genome sequencing needed to enable the use of genomic information in individual health care. PUBLIC HEALTH RELEVANCE: Electron Optica proposes to develop a novel electron microscope capable of reading DNA sequences of unlimited length at affordable cost without labeling the bases with heavy atoms and without radiation damage. An instrument of such capability makes comprehensive genomic sequence information available for individual health care and makes personalized medicine a reality. It promises to greatly improve our understanding of human diseases, make diagnosis a more precise procedure and opens a wide field of applications for sub-nanometer resolution imaging in the biosciences.


PubMed | Stanford University, Lawrence Berkeley National Laboratory and Electron Optica, Inc.
Type: Journal Article | Journal: PloS one | Year: 2016

DNA sequencing by imaging in an electron microscope is an approach that holds promise to deliver long reads with low error rates and without the need for amplification. Earlier work using transmission electron microscopes, which use high electron energies on the order of 100 keV, has shown that low contrast and radiation damage necessitates the use of heavy atom labeling of individual nucleotides, which increases the read error rates. Other prior work using scattering electrons with much lower energy has shown to suppress beam damage on DNA. Here we explore possibilities to increase contrast by employing two methods, X-ray photoelectron and Auger electron spectroscopy. Using bulk DNA samples with monomers of each base, both methods are shown to provide contrast mechanisms that can distinguish individual nucleotides without labels. Both spectroscopic techniques can be readily implemented in a low energy electron microscope, which may enable label-free DNA sequencing by direct imaging.


PubMed | Stanford University, Lawrence Berkeley National Laboratory and Electron Optica, Inc.
Type: | Journal: Ultramicroscopy | Year: 2014

Monochromatic, aberration-corrected, dual-beam low energy electron microscopy (MAD-LEEM) is a novel technique that is directed towards imaging nanostructures and surfaces with sub-nanometer resolution. The technique combines a monochromator, a mirror aberration corrector, an energy filter, and dual beam illumination in a single instrument. The monochromator reduces the energy spread of the illuminating electron beam, which significantly improves spectroscopic and spatial resolution. Simulation results predict that the novel aberration corrector design will eliminate the second rank chromatic and third and fifth order spherical aberrations, thereby improving the resolution into the sub-nanometer regime at landing energies as low as one hundred electron-Volts. The energy filter produces a beam that can extract detailed information about the chemical composition and local electronic states of non-periodic objects such as nanoparticles, interfaces, defects, and macromolecules. The dual flood illumination eliminates charging effects that are generated when a conventional LEEM is used to image insulating specimens. A potential application for MAD-LEEM is in DNA sequencing, which requires high resolution to distinguish the individual bases and high speed to reduce the cost. The MAD-LEEM approach images the DNA with low electron impact energies, which provides nucleobase contrast mechanisms without organometallic labels. Furthermore, the micron-size field of view when combined with imaging on the fly provides long read lengths, thereby reducing the demand on assembling the sequence. Experimental results from bulk specimens with immobilized single-base oligonucleotides demonstrate that base specific contrast is available with reflected, photo-emitted, and Auger electrons. Image contrast simulations of model rectangular features mimicking the individual nucleotides in a DNA strand have been developed to translate measurements of contrast on bulk DNA to the detectability of individual DNA bases in a sequence.

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