Development of an ultrasound guided focused ultrasound system for 3D volumetric low energy nanodroplet-mediated histotripsy.

Low pressure histotripsy is likely to facilitate current treatments that require extremely high pressures. An ultrasound guided focused ultrasound system was designed to accommodate a rotating imaging transducer within a low frequency therapeutic transducer that operates at a center frequency of 105 kHz. The implementation of this integrated system provides real-time therapeutic and volumetric imaging functions, that are used here for low-cost, low-energy 3D volumetric ultrasound histotripsy using nanodroplets. A two-step approach for low pressure histotripsy is implemented with this dual-array. Vaporization of nanodroplets into gaseous microbubbles was performed via the 1D rotating imaging probe. The therapeutic transducer is then used to detonate the vaporized nanodroplets and trigger potent mechanical effects in the surrounding tissue. Rotating the imaging transducer creates a circular vaporized nanodroplet shape which generates a round lesion upon detonation. This contrasts with the elongated lesion formed when using a standard 1D imaging transducer for nanodroplet activation. Optimization experiments show that maximal nanodroplet activation can be achieved with a 2-cycle excitation pulse at a center frequency of 3.5 MHz, and a peak negative pressure of 3.4 MPa (a mechanical index of 1.84). Vaporized nanodroplet detonation was achieved by applying a low frequency treatment at a center frequency of 105 kHz and mechanical index of 0.9. In ex-vivo samples, the rotated nanodroplet activation method yielded the largest lesion area, with a mean of 4.7 ± 0.5 mm, and a rounded shape. In comparison, standard fixed transducer nanodroplet activation resulted in an average lesion area of 2.6 ± 0.4 mm, and an elongated shape. This hybrid system enables to achieve volumetric low energy histotripsy, and thus facilitates the creation of precise, large-volume mechanical lesions in tissues, while reducing the pressure threshold required for standard histotripsy by over an order of magnitude.