Challenges and opportunities in cryo-EM with phase plate.

Not long after the invention of transmission electron microscope (TEM), phase plate was proposed as a novel electron-optical apparatus at the back-focal plane of the objective lens to modulate the magnified specimen images with enhanced contrast, especially in cryo-electron microscopy (cryo-EM) application of biological specimens. In the past two decades, novel phase plates of different kinds were designed and fabricated for cryo-EM application. Some of them such as the Volta phase plate have already been proved very useful in single particle cryo-EM and cryo-electron tomography (cryo-ET) analysis. In this review, we discuss the current progress, challenges and opportunities of cryo-EM with phase plate.