Dynamics and mechanisms of intracellular calcium waves elicited by tandem bubble-induced jetting flow

Significance Ultrasound-induced microbubble oscillation can lead to cell injury or mechanotransduction via calcium signaling processes such as intracellular calcium waves (ICWs). However, the mechanisms by which microbubbles stimulate ICWs remain unknown. Using a microfluidic system with highly controlled bubble−cell interaction, we identified two distinct types of ICWs: a fast response correlating with significant membrane poration, and a slow response triggered by calcium influx through stretch-activated ion channels. The fast ICWs, distinguished from those under physiological conditions, are associated with cell injuries. We further elicited ICWs without cell injury by displacing integrin-binding beads on the cell membrane under mild cavitation conditions. This study provides mechanistic insights into ICWs for guiding ultrasound therapy in tissue modification, drug delivery, and cell mechanotransduction.