Liquid Phase Electron Microscopy: From the lab to the microscope and back again


Dr. Joseph P. Patterson

Department of Chemistry,
Department of Materials Science and Engineering,
University of California, Irvine, USA

Session 1

Date: Wednesday, July 29 2020
Time: 9 AM Pacific Daylight Time (PDT) | 6 PM Central European Summer Time (CEST)

Session 2

Date: Wednesday, July 29 2020 (PDT) | Thursday, July 29 2020 (CST)
Time: 8 PM Pacific Daylight Time (PDT) | 11 AM China Standard Time (CST)

This webinar will be given 2 times. Choose the time slot that best suits you.

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Chemistry, and its manifestation as self-assembly, provides an elegant strategy to create functional, highly complex, and hybrid materials for a myriad of applications.1 Through evolution, living systems, have achieved exquisite control over the deposition of both organic and inorganic building blocks to create hierarchical, composite materials with exceptional properties. Nature does this under ambient conditions, utilizing compartmentalization and confinement of chemical environments to control the pathway of formation, realizing structures and shapes that are not readily achievable in synthetic systems. If materials chemists are ever able to have this level of control, it will come from a deep understanding of general mechanisms and pathways that govern the self-assembly of hierarchical and hybrid structures in complex solution environments.2

Considering that materials synthesis in liquids, and deposition from liquids, pervades the vast majority of polymer science and soft matter research, imaging techniques that provide direct observations of structure and chemistry in solution with nanoscale resolution should be the leading analytical tools for driving self-assembly theory and experimental design. However, techniques such as Liquid Phase Electron Microscopy (LPEM) are still in their infancy and several key challenges must be overcome before its potential can be realized. Although many challenges exist, the current focus has been on understanding and controlling electron-beam sample interactions, which for LPEM experiments provides a unique challenge compared to conventional electron microscopy.

In conventional and cryoEM, electron-sample interactions have been well studied, and for new systems can readily be determined by the application of a dose series. Here, a series of images is recorded and changes in the structural features of interest can be measured with each additional image (corresponding to an increase in total dose). If there are changes to the structural features of interest then ‘low dose’ images should be recorded in which these changes are negligible.3 For liquid phase electron microscopy, electron-sample interactions present a unique challenge. Firstly, all liquids will undergo some degradation when exposed to an electron beam, even at very low doses.4 However, due to the high mobility of the system, the energy input from the electron beam can be rapidly dissipated. Therefore, it is now recognized that in LPEM, dose rate is often much more important than the total dose, as the dose rate establishes a steady-state of energy input/output. 45 This has been discussed in detail previously,4, 6, 7 but here it is important to note the differences in establishing dose limits for a system in conventional/cryo and liquid phase EM. In conventional/cryo EM, the sample is static and therefore measuring changes in an image series will provide information on how the electron beam is affecting the sample structure. Since the goal of the experiment is to capture the structure of the samples prepared outside of the microscope, any changes to the structure by the electron beam can be considered as ‘damage’.

In LPEM, the sample is inherently dynamic, meaning that changes to the structure with sequential images are not necessarily directly related to the interaction with the electron beam, although the electron beam is likely to have some effect on all dynamic processes. The important point here is to understand in what respect, and to what degree, the electron beam is influencing the observations.8 One way of achieving this is to perform a detailed analysis of all the dynamic processes in question, over a range of electron doses. For soft matter systems this has been most rigorously demonstrated by Parent et. al.67 where it was shown that although the electron beam had an influence on dynamic processes such as particle motion, the underlying mechanisms of motion, fusion and growth were related to the specific organization, composition and environment of the structures – thereby revealing useful information on their structural evolution. A second approach for understanding electron-sample interactions is by performing a series of control experiments and comparing in-situ and ex-situ observations, the design of which will be dependent on the specific system in question.9-11 An important third approach that is often overlooked is to ask, if my observation were to hold true in the absence of the electron beam, what would this mean for the theory of how this material forms? And, should we update this theory? If yes, can we design experiments with this new theory to form “better” or new materials? Ultimately, it will be our ability to translate the insights from LPEM into new theories about the chemistry and self-assembly of materials that dictates the future of this technique and its ultimate utility in science and engineering.


  1. Whitesides, G. M.; Grzybowski, B., Self-assembly at all scales. Science 2002, 295 (5564), 2418-2421.
  2. Patterson, J. P.; Xu, Y.;  Moradi, M. A.;  Sommerdijk, N.; Friedrich, H., CryoTEM as an Advanced Analytical Tool for Materials Chemists. Acc. Chem. Res. 2017, 50 (7), 1495-1501.
  3. Leijten, Z.; Keizer, A. D. A.;  de With, G.; Friedrich, H., Quantitative Analysis of Electron Beam Damage in Organic Thin Films. J Phys Chem C Nanomater Interfaces 2017, 121 (19), 10552-10561.
  4. Woehl, T. J.; Abellan, P., Defining the radiation chemistry during liquid cell electron microscopy to enable visualization of nanomaterial growth and degradation dynamics. J Microsc 2017, 265 (2), 135-147.
  5. Schneider, N. M.; Norton, M. M.;  Mendel, B. J.;  Grogan, J. M.;  Ross, F. M.; Bau, H. H., Electron-Water Interactions and Implications for Liquid Cell Electron Microscopy. J. Phys. Chem. C 2014, 118 (38), 22373-22382.
  6. Parent, L. R.; Bakalis, E.;  Proetto, M.;  Li, Y.;  Park, C.;  Zerbetto, F.; Gianneschi, N. C., Tackling the Challenges of Dynamic Experiments Using Liquid-Cell Transmission Electron Microscopy. Acc. Chem. Res. 2018, 51 (1), 3-11.
  7. Parent, L. R.; Bakalis, E.;  Ramirez-Hernandez, A.;  Kammeyer, J. K.;  Park, C.;  de Pablo, J.;  Zerbetto, F.;  Patterson, J. P.; Gianneschi, N. C., Directly Observing Micelle Fusion and Growth in Solution by Liquid-Cell Transmission Electron Microscopy. J. Am. Chem. Soc. 2017, 139 (47), 17140-17151.
  8. Ianiro, A.; Wu, H.;  van Rijt, M. M. J.;  Vena, M. P.;  Keizer, A. D. A.;  Esteves, A. C. C.;  Tuinier, R.;  Friedrich, H.;  Sommerdijk, N.; Patterson, J. P., Liquid-liquid phase separation during amphiphilic self-assembly. Nat Chem 2019, 11 (4), 320-328.
  9. Patterson, J. P.; Abellan, P.;  Denny, M. S., Jr.;  Park, C.;  Browning, N. D.;  Cohen, S. M.;  Evans, J. E.; Gianneschi, N. C., Observing the growth of metal-organic frameworks by in situ liquid cell transmission electron microscopy. J. Am. Chem. Soc. 2015, 137 (23), 7322-8.
  10. Smith, B. J.; Parent, L. R.;  Overholts, A. C.;  Beaucage, P. A.;  Bisbey, R. P.;  Chavez, A. D.;  Hwang, N.;  Park, C.;  Evans, A. M.;  Gianneschi, N. C.; Dichtel, W. R., Colloidal Covalent Organic Frameworks. ACS Cent Sci 2017, 3 (1), 58-65.
  11. Nielsen, M. H.; Aloni, S.; De Yoreo, J. J., In situ TEM imaging of CaCO3 nucleation reveals coexistence of direct and indirect pathways. Science 2014, 345 (6201), 1158-1162.