Low-Intensity Ultrasound Induces Thermodynamic Phase Separation of Cell Membranes through a Nucleation–Condensation Process

Membrane fluidity, a broad term adopted to describe the thermodynamic phase state of biological membranes, can be altered by local pressure variations caused by ultrasound exposure. The alterations in lipid spatial configuration and dynamics can modify their interactions with membrane proteins and activate signal transduction pathways, thus regulating several cellular functions. Here fluidity maps of murine fibroblast cells are generated at a sub-micrometric scale during ultrasound stimulation with an intensity and frequency typical of medical applications. Ultrasound induces a phase separation characterized by two-step kinetics leading to a time-dependent decrease in fluidity. First, nucleation of liquid crystallin domains with an average dimension of ∼1 μm occurs. Then, these domains condense into larger clusters with an average dimension of ∼1.5 μm. The induced phase separation could be an important driving force critical for the cellular response connecting the ultrasound-induced mechanical stress and signal transduction.