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To be visualized by an electron microscope, either transmission or scanning, biological samples need to be fixed (stabilized) so the electron beam does not destroy them and dried thoroughly (desiccated/dehydrated) so the vacuum does not affect them. Fixation needs to be done as quickly as possible because the sample properties will start changing as soon as it is removed from its natural environment. For example, in a tissue sample, the oxygen levels begin decreasing, causing an altered...

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Related Experiment Video

Updated: Jan 19, 2026

Optimizing Sample Preparation for Cryogenic Electron Microscopy

Optimizing Sample Preparation for Cryogenic Electron Microscopy

Published on: April 11, 2025

Current outcomes when optimizing 'standard' sample preparation for single-particle cryo-EM.

B Carragher¹, Y Cheng², A Frost³

¹Simon Electron Microscopy Center, New York Structural Biology Center, New York, U.S.A.

Journal of Microscopy

|September 26, 2019

Summary

This summary is machine-generated.

Preparing high-quality frozen-hydrated samples for cryo-electron microscopy (cryo-EM) is challenging. This work shares experiences to help optimize cryo-EM sample preparation for better structural biology insights.

Keywords:

Air-water interface biological cryo-EM sample preparation

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Published on: January 31, 2022

Area of Science:

Structural Biology
Biophysics
Biochemistry

Background:

High-resolution cryo-electron microscopy (cryo-EM) requires optimal frozen-hydrated samples.
Standard sample preparation methods can compromise sample integrity, hindering structural analysis.

Purpose of the Study:

To share collective experiences in optimizing sample preparation for cryo-EM.
To provide guidance for researchers, especially those new to the field, facing sample preparation challenges.
To encourage the development of more broadly applicable cryo-EM sample preparation techniques.

Main Methods:

Summarizing collective experiences across diverse biochemical samples.
Reviewing commonly used grid preparation variations.
Identifying preferred first steps for specific sample preparation problems.

Main Results:

Sample preparation for cryo-EM remains a significant challenge.
No single method is universally optimal for all samples.
Experience-based recommendations can guide optimization efforts.

Conclusions:

Optimizing cryo-EM sample preparation requires empirical testing and tailored approaches.
Sharing practical experiences is crucial for advancing cryo-EM methodology.
Further development of robust sample preparation techniques is needed for broader cryo-EM application.