10 Jul 2025
Abstract
Many essential cellular functions depend on the viscoelastic properties of the cytoplasm. While techniques such as optical tweezers and atomic force microscopy can measure these properties, their reliance on localized probes prevents intracellular imaging and perturbs native cellular behaviour. Label-free microscopy offers a non-invasive alternative for observing intracellular dynamics. However, limitations in signal-to-noise ratio and imaging speed typically restrict analysis to diffusivity, leaving cellular viscous properties inaccessible. Here, we introduce rheoSCAT, a label-free, phase-sensitive microscope engineered with ultra-low phase noise. This system enables measurements of intracellular dynamics at frequencies up to 50 kHz, twenty times faster than previous label-free approaches. Applied to live cancer cells, this technique establishes a connection between label-free microscopy and rheology. The high speed of our technique reveals viscoelastic behaviours that were previously inaccessible, which we show are consistent with probe-based microrheology observations. The rheological images produced distinguish intra- and extracellular regions with high contrast, resolve spatial variations in cellular mechanics, and enable monitoring of cellular state and stress over time. The ability to quantitatively map intracellular energetics and viscoelasticity offers a powerful tool for advancing fundamental cell biology, cancer research, clinical diagnostics, and drug development.
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