The vaporization of a superheated droplet emulsion into gas bubbles using ultrasound – termed acoustic droplet vaporization (ADV) – has potential therapeutic applications in embolotherapy and drug delivery. The optimization of ADV for therapeutic applications can be enhanced by understanding the physical mechanisms underlying ADV, which are currently not clearly elucidated. Acoustic cavitation is one possible mechanism. This paper investigates the relationship between the ADV and inertial cavitation (IC) thresholds (measured as peak rarefactional pressures) by studying parameters that are known to influence the IC threshold. These parameters include bulk fluid properties such as gas saturation, temperature, viscosity, and surface tension; droplet parameters such as degree of superheat, surfactant type, and size; and acoustic properties such as pulse repetition frequency and pulse width. In all cases the ADV threshold occurred at a lower rarefactional pressure than the IC threshold indicating that the phase-transition occurs before IC events. The viscosity and temperature of the bulk fluid are shown to influence both thresholds directly and inversely, respectively. An inverse trend is observed between threshold and diameter for droplets in the 1 to 2.5 μ range. Based on a choice of experimental parameters, it is possible to achieve ADV with or without IC.

Previously, passive cavitation imaging has been described in the context of continuous-wave high-intensity focused ultrasound thermal ablation. However, the technique has potential use as a feedback mechanism for pulsed-wave therapies, such as ultrasound-mediated drug delivery. In this paper, results of experiments and simulations are reported to demonstrate the feasibility of passive cavitation imaging using pulsed ultrasound insonations and how the images depend on pulsed ultrasound parameters. The passive cavitation images were formed from channel data that was beamformed in the frequency domain. Experiments were performed in an in vitro flow phantom with an experimental echo contrast agent, echogenic liposomes, as cavitation nuclei. It was found that the pulse duration and envelope have minimal impact on the image resolution achieved. The passive cavitation image amplitude scales linearly with the cavitation emission energy. Cavitation images for both stable and inertial cavitation can be obtained from the same received data set.

Ultrasound-mediated delivery systems have mainly focused on microbubble contrast agents as carriers of drugs or genetic material. This study utilizes micron-sized, perfluoropentane (PFP) emulsions as carriers for chlorambucil (CHL), a lipophilic chemotherapeutic. The release of CHL is achieved via acoustic droplet vaporization (ADV), whereby the superheated emulsion is converted into gas bubbles using ultrasound. Emulsions were made using an albumin shell and soybean oil as the CHL carrier. The ratio of the PFP to soybean oil phases in the droplets, as well as the fraction of droplets that vaporize per ultrasound exposure were shown to correlate with droplet diameter. A 60-minute incubation with the CHL-loaded emulsion caused a 46.7% cellular growth inhibition, whereas incubation with the CHL-loaded emulsion that was exposed to ultrasound at 6.3 MHz caused an 84.3% growth inhibition. This difference was statistically significant (p < 0.01), signifying that ADV can be used as a method to substantially enhance drug delivery.

Passive cavitation detection has been an instrumental technique for measuring cavitation dynamics, elucidating concomitant bioeffects, and guiding ultrasound therapies. Recently, techniques have been developed to create images of cavitation activity to provide investigators with a more complete set of information. These techniques use arrays to record and subsequently beamform received cavitation emissions, rather than processing emissions received on a single-element transducer. In this paper, the methods for performing frequency-domain delay, sum, and integrate passive imaging are outlined. The method can be applied to any passively acquired acoustic scattering or emissions, including cavitation emissions. In order to compare data across different systems, techniques for normalizing Fourier transformed data and converting the data to the acoustic energy received by the array are described. A discussion of hardware requirements and alternative imaging approaches are additionally outlined. Examples are provided in MATLAB.

Acoustic droplet vaporization (ADV) shows promise for spatially and temporally targeted tissue occlusion. In this study, substantial tissue occlusion was achieved in operatively exposed and transcutaneous canine kidneys by generating ADV gas bubbles in the renal arteries or segmental arteries. Fifteen canines were anesthetized, among which 10 underwent laparotomy to externalize the left kidney and 5 were undisturbed for transcutaneous ADV. The microbubbles were generated by phase conversion of perfluoropentane droplets encapsulated in albumin or lipid shells in the blood. A 3.5 MHz single-element therapy transducer was aligned with an imaging array in a water tank with direct access to the renal artery or a segmental artery. In vivo color flow and spectral Doppler imaging were used to identify the target arteries. Tone bursts of 1 kHz pulse repetition frequency with 0.25% duty cycle vaporized the droplets during bolus passage. Both intracardiac (IC) and intravenous (IV) injections repeatedly produced ADV in chosen arteries in externalized kidneys, as seen by B-mode imaging. Concurrent with this in two cases was the detection by pulse wave Doppler of blood flow reversal, along with a narrowing of the waveform. Localized cortex occlusion was achieved with 87% regional flow reduction in one case using IC injections. Vaporization from IV injections resulted in a substantial echogenicity increase with an average half-life of 8 minutes per droplet dose. Gas bubbles sufficient to produce some shadowing were generated by transcutaneous vaporization of intra renal artery or IV administered droplets, with a tissue path up to 5.5 cm.

Rationale and Objectives Acoustic droplet vaporization (ADV) shows promise for spatial control and acceleration of thermal lesion production. Our hypothesis was that microbubbles generated by ADV could enhance high intensity focused ultrasound (HIFU) thermal ablation by controlling and increasing local energy absorption. Materials and Methods Thermal lesions were produced in tissue-mimicking phantoms using focused ultrasound (1.44 MHz) with a focal intensity of 4000 W·cm-2 in degassed water at 37°C. The average lesion volume was measured by visible change in optical opacity and by T2-weighted MRI. In addition, in vivo HIFU lesions were generated in a canine liver before and after an intravenous injection of droplets with a similar acoustic setup. Results Thermal lesions were seven-fold larger in phantoms containing droplets (3×105 droplets/mL) compared to phantoms without droplets. The mean lesion volume with a 2 s HIFU exposure in droplet-containing phantoms was comparable to that made by a 5 s exposure in phantoms without droplets. In the in vivo study, the average lesion volumes without and with droplets were 0.017 ± 0.006 cm3 (n = 4, 5 s exposure) and 0.265 ± 0.005 cm3 (n = 3, 5 s exposure), respectively – a factor of 15 difference. The shape of ADV bubbles imaged with B-mode ultrasound was very similar to the actual lesion shape as measured optically and by MRI. Conclusion ADV bubbles may facilitate clinical HIFU ablation by reducing treatment time or requisite in situ total acoustic power, and provide ultrasonic imaging feedback of the thermal therapy.

The aim of this study was to characterize the frequency-dependent acoustic attenuation of three phospholipid-shelled ultrasound contrast agents (UCAs): Definity, MicroMarker and echogenic liposomes. A broadband through-transmission technique allowed for measurement over 2 to 25 MHz with a single pair of transducers. Viscoelastic shell parameters of the UCAs were estimated using a linearized model developed by N. de Jong, L. Hoff, T. Skotland and N. Bom (Ultrasonics 1992; 30:95–103). The effect of diluent on the attenuation of these UCA suspensions was evaluated by performing attenuation measurements in 0.5% (w/v) bovine serum albumin and whole blood. Changes in attenuation and shell parameters of the UCAs were investigated at room temperature (25°C) and physiologic temperature (37°C). The attenuation of the UCAs diluted in 0.5% (w/v) bovine serum albumin was found to be identical to the attenuation of UCAs in whole blood. For each UCA, attenuation was higher at 37°C than at 25°C, underscoring the importance of conducting characterization studies at physiologic temperature. Echogenic liposomes exhibited a larger increase in attenuation at 37°C versus 25°C than either Definity or MicroMarker.

Ultrasound is known to enhance recombinant tissue plasminogen activator (rt-PA) thrombolysis. In this study, occlusive porcine whole blood clots were placed in flowing plasma within living porcine carotid arteries. Ultrasonically induced stable cavitation was investigated as an adjuvant to rt-PA thrombolysis. Aged, retracted clots were exposed to plasma alone, plasma containing rt-PA (7.1 ± 3.8 μg/mL) or plasma with rt-PA and Definity® ultrasound contrast agent (0.79 ± 0.47 μL/mL) with and without 120-kHz continuous wave ultrasound at a peak-to-peak pressure amplitude of 0.44 MPa. An insonation scheme was formulated to promote and maximize stable cavitation activity by incorporating ultrasound quiescent periods that allowed for the inflow of Definity®-rich plasma. Cavitation was measured with a passive acoustic detector throughout thrombolytic treatment. Thrombolytic efficacy was measured by comparing clot mass before and after treatment. Average mass loss for clots exposed to rt-PA and Definity® without ultrasound (n = 7) was 34%, and with ultrasound (n = 6) was 83%, which constituted a significant difference (p < 0.0001). Without Definity® there was no thrombolytic enhancement by ultrasound exposure alone at this pressure amplitude (n = 5, p < 0.0001). In the low-oxygen environment of the ischemic artery, significant loss of endothelium occurred but no correlation was observed between arterial tissue damage and treatment type. Acoustic stable cavitation nucleated by an infusion of Definity® enhances rt-PA thrombolysis without apparent treatment-related damage in this ex vivo porcine carotid artery model.