Regulating microbubble clusters for improving temporal uniformity of stable cavitation intensity under rapid short-pulse ultrasound

Stable cavitation induced by rapid short-pulse (RaSP) ultrasound produces more uniform bioeffects in the treatment region than traditional long-pulse sequences. However, temporal non-uniformity of stable cavitation intensity (SCI)-either within a single RaSP or across multiple RaSPs-compromises the efficiency and biosafety of cavitation-based therapies. This study investigates the causes of temporal non-uniformity in SCI and proposes strategies to enhance uniformity. Monodisperse microbubbles, that were generated using a flow-focusing microfluidic device, were exposed to a single RaSP (frequency: 1 MHz; pulse repetition frequency: 1 kHz; peak negative pressure (PNP): 150-250 kPa; pulse length (PL): 20-150 μs; total number of pulses: 100) in a polydimethylsiloxane-gel flowing phantom. Synchronized high-speed microscopic imaging (4000 fps) and cavitation detection systems were used to simultaneously record the bubble population dynamics and SCI evolution. The SCI gradually decayed to a stable level during RaSP ultrasound excitation, with bubble aggregation and clustering progressing exponentially under the earlier pulses, eventually forming stable large clusters. Both the rates of bubble aggregation and SCI decay correlated positively with PNP and PL. Statistical analysis confirmed that cluster formation was the primary cause of SCI decay. Optimizing the PNP and PL only marginally improved the temporal stability of the SCI because cluster formation was not completely suppressed. To address this, an ultrafast feedback controller was developed to regulate the PNP of RaSP in real-time, achieving significantly improved temporal uniformity of SCI. These findings provide fundamental insights into bubble dynamics during RaSP ultrasound and a practical approach for optimizing cavitation-mediated therapies.