Multi-pass microscopy – approaching Heisenberg limited sensitivity in optical and electron microscopy
The number of biological macromolecules with a structure solved by cryogenic-electron microscopy (cryo-EM) increases dramatically each year. However, many small and weakly scattering protein structures remain out of reach, as electron dose induced specimen damage limits the achievable spatial resolution .
Improved sensitivity and spatial resolution can be obtained employing quantum measurement strategies. A quantum optimal approach to measuring small phase shifts, as induced by a thin protein, is to pass each probe particle through the specimen multiple times .
Employing self-imaging cavities, this idea can be applied to widefield microscopy . We show post-selected optical birefringence and absorption measurements beyond the shot-noise limit and discuss the applicability of multi-pass microscopy to cryo-EM. Our EM simulations  show that multi-pass TEM allows for a tenfold damage reduction in imaging small proteins.
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