Tackling the Challenges of Dynamic Experiments Using Liquid-Cell Transmission Electron Microscopy Published as part of the Accounts of Chemical Research special issue “Direct Visualization of Chemical and Self- Assembly Processes with Transmission Electron Microscopy”. Lucas R. Parent, †,‡,§,∥ Evangelos Bakalis, ⊥ Maria Proetto, †,‡,§,∥,†,# Yiwen Li, ∥,# Chiwoo Park, ∇ Francesco Zerbetto, ⊥ and Nathan C. Gianneschi* ,†,‡,§,∥ † Department of Chemistry, ‡ Department of Materials Science & Engineering, and § Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States ∥ Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, California 92093, United States ⊥ Dipartimento di Chimica “G. Ciamician”, Universita ̀ di Bologna, Bologna BO, Italy 40126 # College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China ∇ Department of Industrial and Manufacturing Engineering, Florida State University, Tallahassee, Florida 32306, United States * S Supporting Information CONSPECTUS: Revolutions in science and engineering frequently result from the development, and wide adoption, of a new, powerful characterization or imaging technique. Beginning with the first glass lenses and telescopes in astronomy, to the development of visual-light microscopy, staining techniques, confocal microscopy, and fluorescence super-resolution microscopy in biology, and most recently aberration-corrected, cryogenic, and ultrafast (4D) electron microscopy, X-ray microscopy, and scanning probe microscopy in nanoscience. Through these developments, our perception and understanding of the physical nature of matter at length-scales beyond ordinary perception have been fundamentally transformed. Despite this progression in microscopy, techniques for observing nanoscale chemical processes and solvated/hydrated systems are limited, as the necessary spatial and temporal resolution presents significant technical challenges. However, the standard reliance on indirect or bulk phase characterization of nanoscale samples in liquids is undergoing a shift in recent times with the realization (Williamson et al. Nat. Mater. 2003, 2, 532−536) of liquid-cell (scanning) transmission electron microscopy, LC(S)TEM, where picoliters of solution are hermetically sealed between electron-transparent “windows,” which can be directly imaged or videoed at the nanoscale using conventional transmission electron microscopes. This Account seeks to open a discussion on the topic of standardizing strategies for conducting imaging experiments with a view to characterizing dynamics and motion of nanoscale materials. This is a challenge that could be described by critics and proponents alike, as analogous to doing chemistry in a lightning storm; where the nature of the solution, the nanomaterial, and the dynamic behaviors are all potentially subject to artifactual influence by the very act of our observation. 1. INTRODUCTION Over the past decade, in situ liquid-cell (scanning) transmission electron microscopy (LC(S)TEM) experiments have revealed numerous new nanoscale phenomena or provided direct evidence for processes that had previously only been postulated from static microscopy, indirect techniques, or theoretical modeling. 1−3 While key instrumentation developments and critical limitations of LCTEM have been considered, and in some publications, systematic experiments into LCTEM radiolysis chemistry have been conducted for specific systems, the field lacks a set of experimental or video-data analysis Received: July 5, 2017 Article pubs.acs.org/accounts Cite This: Acc. Chem. Res. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.accounts.7b00331 Acc. Chem. Res. XXXX, XXX, XXX−XXX