Low dose scanning transmission electron microscopy of organic crystals by scanning moiré fringes

S'ari, Mark; Cattle, James; Hondow, Nicole; Brydson, Rik; Brown, Andy

doi:10.1016/j.micron.2019.01.014

Cited by 21 publications

(22 citation statements)

References 55 publications

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“…There are two general approaches towards the unavoidable beam interactions; mitigating the effects or exploiting them. High fluence has been reported to damage organic crystals in a conventional TEM setup 22 , however, the high input energy from the electron beam can also induce nucleation and enable crystal growth by radiolysis of the solvent 23 . The beam effects can be reduced by minimising the dose absorbed by the sample by using a low-dose rate and restricted exposure time; radiolysis can also be mitigated by providing a constant flow of undisturbed solvent through the liquid cell 24,25 .…”

Section: Resultsmentioning

confidence: 99%

Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron microscopy

Cookman

Hamilton

Hall

et al. 2020

Sci Rep

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Non-classical crystallisation (NCC) pathways are widely accepted, however there is conflicting evidence regarding the intermediate stages of crystallisation, how they manifest and further develop into crystals. Evidence from direct observations is especially lacking for small organic molecules, as distinguishing these low-electron dense entities from their similar liquid-phase surroundings presents signal-to-noise ratio and contrast challenges. Here, Liquid Phase Electron Microscopy (LPEM) captures the intermediate pre-crystalline stages of a small organic molecule, flufenamic acid (FFA), a common pharmaceutical. High temporospatial imaging of FFA in its native environment, an organic solvent, suggests that in this system a Pre-Nucleation Cluster (PNC) pathway is followed by features exhibiting two-step nucleation. This work adds to the growing body of evidence that suggests nucleation pathways are likely an amalgamation of multiple existing non-classical theories and highlights the need for the direct evidence presented by in situ techniques such as LPEM.

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Section: Resultsmentioning

confidence: 99%

Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron microscopy

Cookman

Hamilton

Hall

et al. 2020

Sci Rep

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“…A further technique that has been used to obtain high-resolution, atomic lattice information at low electron fluence is the formation of scanning Moiré fringes (SMFs) in STEM (78)(79)(80). Scanning Moiré fringes arise from the interference between the atomic plane spacings in a crystal lattice and spacings in a similarly sized reference lattice, produced by the scanning of the electron beam.…”

Section: Low Dose Stem Approachesmentioning

confidence: 99%

“…Effectively the Moiré pattern produces a magnified image of the crystal lattice, including any imperfections, and allows lower magnification acquisitions and therefore larger areas to be imaged at a lower electron fluence than would normally be required. S'ari et al (54,79) have applied this to molecular crystalline materials and highlighted the ability to image, albeit indirectly, crystalline defects and surface strain, as shown in Figure 7.…”

Section: Low Dose Stem Approachesmentioning

confidence: 99%

Analysis of complex, beam-sensitive materials by transmission electron microscopy and associated techniques

Ilett

S'ari

Freeman

et al. 2020

Phil. Trans. R. Soc. A.

Self Cite

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We review the use of transmission electron microscopy (TEM) and associated techniques for the analysis of beam-sensitive materials and complex, multiphase systems in-situ or close to their native state. We focus on materials prone to damage by radiolysis and explain that this process cannot be eliminated or switched off, requiring TEM analysis to be done within a dose budget to achieve an optimum dose-limited resolution. We highlight the importance of determining the damage sensitivity of a particular system in terms of characteristic changes that occur on irradiation under both an electron fluence and flux by presenting results from a series of molecular crystals. We discuss the choice of electron beam accelerating voltage and detectors for optimizing resolution and outline the different strategies employed for low-dose microscopy in relation to the damage processes in operation. In particular, we discuss the use of scanning TEM (STEM) techniques for maximizing information content from high-resolution imaging and spectroscopy of minerals and molecular crystals. We suggest how this understanding can then be carried forward for in-situ analysis of samples interacting with liquids and gases, provided any electron beam-induced alteration of a specimen is controlled or used to drive a chosen reaction. Finally, we demonstrate that cryo-TEM of nanoparticle samples snap-frozen in vitreous ice can play a significant role in benchmarking dynamic processes at higher resolution. This article is part of a discussion meeting issue ‘Dynamic in situ microscopy relating structure and function’.

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“…We have fitted each two-dimensional (2D) reciprocal space maps (RSMs) of the {110} reflections to determine the fading curves of the diffraction intensity using a symmetrical 2D Gaussian function. The {110} reflections contain four peaks: (110), (-110), (-1-10) and (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).…”

Section: Fig 1a Illustrates a Pulsed Electron Beam Generated By The Nmentioning

confidence: 99%

“…Less common inelastic scattering from electron-electron interactions can cause ionization damage (radiolysis). Both scattering processes contribute to electrostatic charging, hydrocarbon contamination and heating of the sample [3][4][5] . Radiolysis in particular rapidly damages organic and biological crystal structure; intensity and contrast in diffraction patterns will fade as the same area of the sample is exposed to an increasing dose of beam electrons 3,6 .…”

Section: Introductionmentioning

confidence: 99%

Mitigation of radiation damage in biological macromolecules via tunable picosecond pulsed transmission electron microscopy

Choe

Пономарев

Montgomery

et al. 2020

Preprint

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We report mitigation of electron-beam-induced radiation damage in biological macromolecules using rapid, low-dose transmission electron microscopy (TEM) with a new, tunable, retrofittable stroboscopic pulser. Damage mitigation strategies historically consisted of sample cryoprotection and ultra-low beam current; ultrafast laser-pulsed systems have shown promise, but with day-long acquisition times. We show the first practical, fast, laser-free tunable system, with acquisition of diffraction series in minutes at 5.2 GHz and 10 pA. This is the largest study to date: two materials (C 36 H 74 paraffin and purple membrane), two beam energies (200 keV and 300 keV), two independent microscopes (Schottky and LaB 6 ), two modes (pulsed and continuous), and unsurpassed repetition rate tunability. Critical dose at room temperature doubled versus continuous beam for~100 MHz single-electron repetition rates. Results herald a new class of highly-tunable, ultrafast pulsers with future applications in cryogenic electron microscopy (CryoEM), high resolution single particle imaging, and rapid low-dose TEM.

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Low dose scanning transmission electron microscopy of organic crystals by scanning moiré fringes

Abstract: This is a repository copy of Low dose scanning transmission electron microscopy of organic crystals by scanning moiré fringes.

Cited by 21 publications

References 55 publications

Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron microscopy

Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron microscopy

Analysis of complex, beam-sensitive materials by transmission electron microscopy and associated techniques

Mitigation of radiation damage in biological macromolecules via tunable picosecond pulsed transmission electron microscopy

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