Rapidly dissolving polymeric microbubbles promote supersaturation and in-situ formation of acoustic nanobubbles capable of dynamic pressure sensing

• A pH-responsive polymeric microbubble system allows a novel method to generate acoustic nanobubbles in situ on demand. • The mechanism of dissolution of microbubbles is elucidated, and triggered dissolution of microbubbles enable supersaturation. • In situ generated nanobubbles enable high-sensitivity dynamic pressure sensing using focused ultrasound in ex vivo heart model. Developing noninvasive methods for monitoring intravascular and intracardiac pressures is crucial for advancing the diagnosis and management of cardiovascular diseases. Here we report an approach utilizing pH-responsive polymeric microbubbles (PMBs) as precursors to produce in situ generated nanobubbles (NBs) as acoustic pressure sensors. Upon exposure to physiologic pH, PMBs rapidly dissolve their gas core, inducing gas supersaturation and transient formation of acoustically active NBs with cavitation thresholds characteristic of their sizes. In situ generated NBs exhibit subharmonic emission inversely correlated with hydrostatic pressure. As proof of concept, we show in an ex vivo Langendorff working heart model in situ generated NBs achieve excellent linear sensitivity to monitor intracardiac pressures (R 2 0.94 and 0.2 dB/mmHg) using focused ultrasound, highlighting the potential of the current system for noninvasive pressure monitoring. Moreover, this work introduces a new concept of on-demand in situ NB generation, which may allow expand NB applications among various fields.