The application of phase-shift nanoemulsion in high intensity focused ultrasound: an in vitro study

Abstract

High intensity focused ultrasound (HIFU) is a noninvasive alternative to open surgery for the cancer treatment, whereby high-intensity acoustic energy is transmitted transcutaneously by a focused transducer to heat and destroy diseased tissue by thermal coagulative necrosis. It has been well documented that the presence of microbubbles at the HIFU focus during sonication can increase the absorption of ultrasound energy and thus accelerate heating in tissue. As a result, the time and acoustic energy required for an effective treatment can be significantly reduced. However, uncontrolled bubble formation and activity can lead to unpredictable heating. The primary objectives of this study were to investigate the feasibility of using a custom developed nuclei agent to (1) reduce the pressure threshold for bubble formation, (2) localize bubble formation to the focal zone of the transducer, and (3) reduce the power and time required for HIFU thermal ablation. The nucleation agent, referred to as phase-shift nanoemulsion (PSNE), consists of dodecafluoropentane nanodroplets stabilized with an albumin or a phospholipid shell. These nanodroplets are pressure-sensitive and can be vaporized by a microsecond ultrasound pulse, provided the pressure exceeds a well-defined threshold. The vaporization threshold was found to be inversely proportional to the ambient temperature and independent of pulse length and PSNE concentration for the ranges used in these studies. Because PSNE vaporization is predictable, it is possible to nucleate bubbles and acoustic cavitation when needed. This allows for bubble-enhanced heating and lesion formation in a more controlled manner. By mixing PSNE into albumin-containing gel phantom, the effect of localized PSNE vaporization on ultrasound-mediated heating and lesion formation was investigated in vitro . The results show that the onset of bubble-enhanced heating could be controlled by choosing the vaporization time and that the cavitation location was confined to the HIFU focal region. A significant reduction (71.9%) in acoustic power was achieved by initiating cavitation and the cavitation-related lesion shapes maintained a symmetric cigar shape across a range of PSNE volume fractions investigated in this study. Thermocouple measurements of accelerated heating correlated with detected inertial cavitation (IC) activities, which suggests that IC is the primary mechanism for the PSNE-related heating enhancement. Furthermore, a model of single bubble dynamics based on Keller-Miksis equation was employed to explain the mechanisms behind the bubble-related heating.