Cells have a complex composition that yields an intricate rheological behavior, appealing for measurements over a wide frequency range. However the existing techniques cannot exceed the kHz range, and rely for most on injected or contacting functionalized microprobes. Here, we report on an innovative non-contact optoacoustic probing of the mechanical properties of single cells at GHz acoustic frequencies under physiological conditions. We culture cells on a biocompatible Ti6Al4V metal alloy. Low-energy femtosecond laser pulses are focused at the cell-Ti6Al4V interface to a sub-µm spot. The ensuing ultrafast thermal dilatation of the metal launches a high-frequency sound pulse in the cell. Acoustic propagation is measured remotely with an ultrafast laser probe through Brillouin light scattering. This all-optical non-invasive technique offers a broad frequency range, extending up to 1 THz, a sub-µm lateral resolution and a nanometer in-depth resolution. For illustration, we here concentrate on the cell nucleus. Using the laser-generated GHz acoustic waves, we probe the stiffness and viscosity of the nuclei of various cell types. We demonstrate for the first time that, at GHz frequencies, the nucleus stiffness tends to a unique value, much larger than that observed at kHz frequencies. We demonstrate that this universal stiffness reflects the compressional dynamics of the nucleus components. We also show that the evolution of the mechanical properties of the nucleus during cell differentiation is correlated with a specific gene expression pattern. In the frame of soft glass rheology, we project the GHz mechanical properties of the differentiated nuclei to the kHz range. Comparison with the kHz data obtained by alternative techniques suggests the existence of a new absorption process appearing at GHz frequencies. This innovative technique defines a new class of experiments to enlighten cell mechanics in physiological conditions at a subcell scale.
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