Volumetric Passive Acoustic Mapping and Cavitation Detection of Nanobubbles under Low-Frequency Insonation

Gas bubbles, commonly used in medical ultrasound (US), witness advancements with nanobubbles (NB), providing improved capabilities over microbubbles (MB). NBs offer enhanced penetration into capillaries and the ability to extravasate into tumors following systemic injection, alongside prolonged circulation and persistent acoustic contrast. Low-frequency insonation (<1 MHz) with NBs holds great potential in inducing significant bioeffects, making the monitoring of their acoustic response critical to achieving therapeutic goals. We introduce a US-guided focused US system comprising a one-dimensional (1D) motorized rotating imaging transducer positioned within a low-frequency therapeutic transducer (center frequencies of 105 and 200 kHz), facilitating precise monitoring of NB cavitation activity in three-dimensional (3D) and comparison with MBs. Passive cavitation detection (PCD) revealed frequency-dependent responses, with NBs exhibiting significantly higher stable and inertial cavitation doses compared to MBs of the same gas volume when excited at a center frequency of 105 kHz and peak negative pressures ranging from 100 to 350 kPa. At 200 kHz, MBs showed higher cavitation doses than NBs. PCD showed that 105 kHz enhanced both NBs' and MBs' oscillations compared to 200 kHz. The system was further used for 3D passive acoustic mapping (PAM) to provide spatial resolution alongside PCD monitoring. Two-dimensional PAM was captured for each rotation angle and used to generate a complete 3D PAM reconstruction. Experimental results obtained from a tube phantom demonstrated consistent contrast PAM full-width half-maximum (FWHM) as a function of rotation angle, with similar FWHM between MBs and NBs. Frequency-selective PAM maps distinguished between stable and inertial cavitation via the harmonic, ultraharmonic and broadband content, offering insights into cavitation dynamics. These findings highlight NBs' superior performance at lower frequencies. The developed 3D-PAM technique with a 1D transducer presents a promising technology for real-time, noninvasive monitoring of cavitation-based US therapies.