Making Hidden Cell Particle Interactions Visible by Thermal Noise Frequency Decomposition

Thermal noise drives cellular structures, bacteria, and viruses on different temporal and spatial scales. Their weak interactions with their environment can change on subsecond scales. However, particle interactions can be hidden or invisible-even when measured with thermal noise sensitivity, leading to misconceptions about their binding behavior. Here, it is demonstrated how invisible particle interactions at the cell periphery become visible by MHz interferometric thermal noise tracking and frequency decomposition at a spectral update rate of only 0.5 s. The particle fluctuations are analyzed in radial and lateral directions by a viscoelastic modulus G(ω,t_ex ) over the experiment time t_ex , revealing a surprisingly similar, frequency dependent response for different cell types. This response behavior can be explained by a mathematical model for molecular scale elasticity and damping. The method to reveal hidden interactions is tested at two examples: the stiffening of macrophage filopodia tips within 2 s with particle contact invisible by the fluctuation width. Second, the extent and stiffness of the soft cell glycocalyx is measured, which can be sensed by a particle only on microsecond-timescales, but which remains invisible on time-average. This concept study shows how to uncover hidden cellular interactions, if particle motions are measured at high-speed.