A laser-based phase plate for cryo-electron microscopy

Transmission electron microscopy of vitrified biological macromolecules and cells (cryo-EM), which is becoming a preferred method in the area of high-resolution structural biology, is limited by low signal-to-noise ratio. This is because the samples only weakly modulate the phase, and not the amplitude of the transmitted electron beam. In addition, defocusing the images provides an incomplete conversion of this phase modulation to detectable intensity modulation. Phase plates have long been used to address a similar problem that exists in bright-field optical microscopy of unstained samples, but such devices have been difficult to realize in electron microscopy without causing unwanted wave-front aberrations or resolution loss due to charging or scattering.