Innovation and Partnerships Office

Nanometer Resolution TEM Imaging of Biological Samples in Liquid 2013-165

Transmission electron microscopy (TEM) for

  • Pharmaceuticals
  • Biomedical research


  • Enables imaging of label free, near-native-state biological samples
  • Nanometer resolution imaging capability
  • Compatible with existing, industry standard TEM instruments and equipment
  • Controllable, adjustable liquid layer thickness
  • Efficient, simple operation


Berkeley Lab researchers led by Gang Ren and Ed Wong have developed a new, low cost microchamber and associated tools and procedures for positioning and securing liquid biological samples in Transmission Electron Microscopy (TEM) imaging. The holding apparatus permits researchers to manipulate the thin level of liquids within the microchamber to accommodate different types of cells and proteins so they can be imaged, without dehydration or freezing, in their near-natural state.

The apparatus works by sealing a thin liquid layer between two transparent plastic films, enabling direct visualization through TEM of the structure of proteins, viruses, bacteria, and cells. The device is designed to be easy to operate and mountable on most general purpose TEM sample holders. The ability to control thickness of the liquid layer allows a thicker layer to provide more space for cellular motion or a thinner layer to reduce electron scattering and/or absorption that can limit motion or even kill the cells.

The ability to directly visualize proteins with nanometer resolution in liquids can dramatically advance our mechanistic understanding of protein function and cellular activity. Current optical techniques for imaging proteins, bacteria, and cells in liquid are limited by micron-scale resolution and the need for fluorescent labeling, dehydration, fixing, staining, or freezing. Using nanofabricated, hermetically sealed microchambers, TEM images of biological specimens at nanometer scales have been made, but at relatively low-resolution and at great cost, requiring custom-designed TEM holders. Using TEM technology, researchers have achieved high resolution imaging of hard, nanoscale materials in liquid solution; the Berkeley Lab technique will bring the power of those imaging techniques to the analysis of “soft” biological samples, without having to compromise them by freezing, tagging, or staining.

DEVELOPMENT STAGE:  Bench scale prototype

STATUS:  Patent pending.  Available for licensing or collaborative research.