Analysis of 4D-STEM methods for detecting metallic nanoparticles in amorphous ice: A numerical study

Metallic nanoparticles play important roles in contrast enhancement and medical therapeutics. Understanding the mechanisms of nanoparticle-cell interactions is critical to the future development and utility of nanoparticles in medicine. Cryo-scanning transmission electron microscopy is suitable for collecting data from beam-sensitive biological systems. Detection of nanoparticles in these biological systems in bright-field cryo-scanning transmission electron microscopy is hindered by the vitrified ice surrounding them. Here, we demonstrate the detection of metallic nanoparticles embedded in slabs of ice with different thicknesses of ice for several electron beam fluxes, using the extended ptychographic iterative engine, non-negative matrix factorisation and virtual dark field imaging algorithms.