The temporal flickering of contrast agents that labels a biological sample is a unique modality for cellular imaging with single molecule sensitivity. It improves the signal-to-noise ratio statistics associated with the noisy in vivo environment and has promising applications in single particle tracking and super-resolution microscopy techniques. The flickering can be triggered either statistically through the mechanism of temporal fluctuations of the emitter or through external modulation. The enriching toolbox of contrast agents that are feasible for biomedical imaging for the flickering methods will be discussed, with emphasis on the emerging field of flickering gold nanoparticles and the lock-in detection mechanism. WIREs Nanomed Nanobiotechnol 2016, 8:439-448. doi: 10.1002/wnan.1375 For further resources related to this article, please visit the WIREs website.
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