Electron microscopy of specimens in liquid

Journal name:
Nature Nanotechnology
Year published:
Published online


Imaging samples in liquids with electron microscopy can provide unique insights into biological systems, such as cells containing labelled proteins, and into processes of importance in materials science, such as nanoparticle synthesis and electrochemical deposition. Here we review recent progress in the use of electron microscopy in liquids and its applications. We examine the experimental challenges involved and the resolution that can be achieved with different forms of the technique. We conclude by assessing the potential role that electron microscopy of liquid samples can play in areas such as energy storage and bioimaging.

At a glance


  1. Configurations for electron microscopy in liquid.
    Figure 1: Configurations for electron microscopy in liquid.

    a, TEM imaging with an open environmental chamber containing liquid and vapour. Differential apertures separate the microscope vacuum from the higher pressure at the sample. b, SEM imaging with an environmental chamber. The electron beam scans in x and y directions over the sample. c, TEM imaging of nanoparticles in a liquid fully enclosed between electron transparent windows. d, STEM imaging in a fully enclosed liquid, used to image nanoparticle labels on whole biological cells. e, SEM of a liquid sample under an electron transparent window. f, Combination of SEM and light microscopy of a liquid sample above an electron transparent window.

  2. Examples of electron microscopy systems for liquids.
    Figure 2: Examples of electron microscopy systems for liquids.

    a, Fabrication of a liquid cell from Si microchips (upper and lower wafers) with SiN windows, glass reservoirs, lids and three electrodes for electrochemical TEM experiments3. b, Photograph of an assembled liquid cell. c, A single Si microchip with an electron transparent SiN window25. The dimensions of the microchip are 2.0 × 2.3 × 0.3 mm. d, A microfluidic chamber formed from two of the microchips in c, showing the liquid flow direction. e, A capsule with an electron transparent window for imaging liquid samples in SEM43. The outer diameter is 16 mm. f, Cell culture dish with a microchip with a SiN window33, for combined light microscopy and SEM. g, The back (vacuum) side of the microchip for the culture dish. Panels reproduced with permission from: a,b, ref. 3, © 2003 NPG; c, ref. 25, © 2010 CUP; e, ref. 43, © 2004 Informa Healthcare; f,g, ref. 33, © 2010 Elsevier. Panel d modified with permission from ref. 4, © 2009 National Academy of Sciences.

  3. Electron microscopy of biological samples.
    Figure 3: Electron microscopy of biological samples.

    a, Human monocyte-derived macrophages imaged with SEM in a wet environment39 at 4.9 torr and 7 °C. Samples were fixed in glutaraldehyde and rinsed with deionized water before imaging. b, SEM image of H. pylori bacterium fully immersed in liquid, imaged using a capsule with a thin window. Samples were incubated with complexed biotinylated gastrin on streptavidin-coated 20 nm Au particles, followed by glutaraldehyde fixation. c, STEM image of Au-labelled epidermal growth factor receptors on whole fixed COS7 fibroblast cells in liquid. The Au labels are visible as yellow spots on the light blue cellular material. The background shows in dark blue. d, Endocytotic vesicles were formed in a second sample after a longer incubation. e, Fluorescence microscopy image of COS7 cells33. The cells were fixed, labelled with a fluorescent dye, and stained for contrast in SEM. f, SEM image of the cellular material in the rectangle in e imaged under fully hydrated conditions33. Panels reproduced with permission from: a, ref. 39, © 2009 Wiley; e,f, ref. 33, © 2010 Elsevier. Panels modified with permission from: b, ref. 2, © 2004 National Academy of Sciences; c,d, ref. 4, © 2009 National Academy of Sciences.

  4. Liquid cell electron microscopy in materials science.
    Figure 4: Liquid cell electron microscopy in materials science.

    a, Images and electrochemical data obtained during potentiostatic deposition of Cu on a polycrystalline Au electrode from 0.1M CuSO4/0.18M H2SO4. Cu has dark contrast whereas the Au (20 nm thick), SiN windows (80 nm thick) and electrolyte (1 μm thick) provide the grey background. The applied potential was −70 mV with respect to a Cu reference electrode, and the graph shows the total current versus time. The electrode area is 2 × 10−5 cm2. Red lines show the times of each image. b, Images acquired during Pt nanoparticle formation from a solution containing 10 mg mL−1 Pt(acetylacetonate)2 in a 9:1 mixture of o-dichlorobenzene and oleylamine. The images were recorded after 17.9, 18.7, and 22.3 s of beam exposure during which a coalescence event occurs. The graph shows the size of this (red circles) and another particle that appears to grow by addition of monomers (blue triangles). c, Energy filtered images at 16 s intervals during dendritic growth of Cu from the edge of an electrode6. Galvanostatic conditions were used with current density 40 mA cm−2 and average lateral growth rate 0.2 μm s−1. Panels modified with permission from: a, ref. 52, © 2006 ACS; b, ref. 6, © 2009 AAAS; c, ref. 104 © 2010 CUP.

  5. Resolution of different forms of electron microscopy in liquid.
    Figure 5: Resolution of different forms of electron microscopy in liquid.

    Theoretical maximal resolution versus water thickness for TEM, STEM and SEM. The resolution was calculated for typical TEM and STEM instrument parameters at 200 keV beam energy (see text), and for the imaging of Au nanoparticles at the bottom of a layer of water for TEM, and at the top of the layer for STEM. The resolution obtained in SEM just below the liquid-enclosing membrane does not depend on the liquid thickness (see text). Experimental data points are shown for Au nanoparticles in TEM31, STEM26 and SEM with a 30-nm-thick SiN window33, and for PbS nanoparticles in water imaged with STEM35. The error bars represent experimental errors.


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  1. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, Tennessee 37232, USA

    • Niels de Jonge
  2. IBM T. J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, New York 10598, USA

    • Frances M. Ross

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