J.B. Fowlkes

Controlled ultrasound tissue erosion

The ability of ultrasound to produce highly controlled tissue erosion was investigated. This study is motivated by the need to develop a noninvasive procedure to perforate the neonatal atrial septum as the first step in treatment of hypoplastic left heart syndrome. A total of 232 holes were generated in 40 pieces of excised porcine atrial wall by a 788 kHz single-element transducer. The effects of various parameters [e.g., pulse repetition frequency (PRF), pulse duration (PD), and gas content of liquid] on the erosion rate and energy efficiency were explored. An Isppa of 9000 W/cm/sup 2/, PDs of 3, 6, 12, and 24 cycles; PRFs between 1.34 kHz and 66.7 kHz; and gas saturation of 40-55% and 79-85% were used. The results show that very short pulses delivered at certain PRFs could maximize the erosion rate and energy efficiency. We show that well-defined perforations can be precisely located in the atrial wall through the controlled ultrasound tissue erosion (CUTE) process. A preliminary in vivo experiment was conducted on a canine subject, and the atrial septum was perforated using CUTE.

Microbubble-enhanced cavitation for noninvasive ultrasound surgery

Experiments were conducted to explore the potential of stabilized microbubbles for aiding tissue ablation during ultrasound therapy. Surgically exteriorized canine kidneys were irradiated in situ using single exposures of focused ultrasound. In each experiment, tip to eight separate exposures were placed in the left kidney. The right kidney was then similarly exposed, but while an ultrasound contrast agent was continually infused. Kidneys were sectioned and examined for gross observable tissue damage. Tissue damage was produced more frequently, by lower intensity and shorter duration exposures, in kidneys irradiated with the contrast agent present. Using 250-ms exposures, the minimum intensity that produced damage was lower in kidneys with microbubbles than those without (controls) in 10 of 11 (91%) animals. In a separate study using /spl sim/3200 W/cm/sup 2/ exposures, the minimum duration that produced damage was shorter after microbubbles were introduced in 11 of 12 (92%) animals. With microbubbles, gross observable tissue damage was produced with exposure intensity /spl ges//spl sim/800 W/cm/sup 2/ and exposure duration /spl ges/10 /spl mu/s. The overall intensity and duration tissue damage thresholds were reduced by /spl sim/2/spl times/ and /spl sim/100/spl times/, respectively. Results indicate that acoustic cavitation is a primary damage mechanism. Lowering in vivo tissue damage thresholds with stabilized microbubbles acting as cavitation nuclei may make acoustic cavitation a more predictable, and thus practical, mechanism for noninvasive ultrasound surgery.

The role of inertial cavitation in acoustic droplet vaporization

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 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 mum range. Based on a choice of experimental parameters, it is possible to achieve ADV with or without IC.

In vivo droplet vaporization for occlusion therapy and phase aberration correction

The objective was to determine whether a transpulmonary droplet emulsion (90%, <6 /spl mu/m diameter) could be used to form large gas bubbles (>30 /spl mu/m) temporarily in vivo. Such bubbles could occlude a targeted capillary bed when used in a large number density. Alternatively, for a very sparse population of droplets, the resulting gas bubbles could serve as point beacons for phase aberration corrections in ultrasonic imaging. Gas bubbles can be made in vivo by acoustic droplet vaporization (ADV) of injected, superheated, dodecafluoropentane droplets. Droplets vaporize in an acoustic field whose peak rarefactional pressure exceeds a well-defined threshold. In this new work, it has been found that intraarterial and intravenous injections can be used to introduce the emulsion into the blood stream for subsequent ADV (Band M-mode on a clinical scanner) in situ. Intravenous administration results in a lower gas bubble yield, possibly because of filtering in the lung, dilution in the blood volume, or other circulatory effects. Results show that for occlusion purposes, a reduction in regional blood flow of 34% can be achieved. Individual point beacons with a +24 dB backscatter amplitude relative to white matter were created by intravenous injection and ADV.

Rapid elastic image registration for 3-D ultrasound

A Subvolume-based algorithm for elastic Ultrasound REgistration (SURE) was developed and evaluated. Designed primarily to improve spatial resolution in three-dimensional compound imaging, the algorithm registers individual image volumes nonlinearly before combination into compound volumes. SURE works in one or two stages, optionally using MIAMI Fuse/spl copy/ software first to determine a global affine registration before iteratively dividing the volume into subvolumes and computing local rigid registrations in the second stage. Connectivity of the entire volume is ensured by global interpolation using thin-plate splines after each iteration. The performance of SURE was quantified in 20 synthetically deformed in vivo ultrasound volumes, and in two phantom scans, one of which was distorted at acquisition by placing an aberrating layer in the sound path. The aberrating layer was designed to induce beam aberrations reported for the female breast. Synthetic deformations of 1.5-2.5 mm were reduced by over 85% when SURE was applied to register the distorted image volumes with the original ones. Registration times were below 5 min on a 500-MHz CPU for an average data set size of 13MB. In the aberrated phantom scans, SURE reduced the average deformation between the two volumes from 1.01 to 0.30mm. This was a statistically significant (P=0.01) improvement over rigid and affine registration transformations, which produced reductions to 0.59 and 0.50 mm, respectively.

High Speed Imaging of Bubble Clouds Generated in Pulsed Ultrasound Cavitational Therapy - Histotripsy

Our recent studies have demonstrated that mechanical fractionation of tissue structure with sharply demarcated boundaries can be achieved using short (< 20 mus), high intensity ultrasound pulses delivered at low duty cycles. We have called this technique histotripsy. Histotripsy has potential clinical applications where noninvasive tissue fractionation and/or tissue removal are desired. The primary mechanism of histotripsy is thought to be acoustic cavitation, which is supported by a temporally changing acoustic backscatter observed during the histotripsy process. In this paper, a fast-gated digital camera was used to image the hypothesized cavitating bubble cloud generated by histotripsy pulses. The bubble cloud was produced at a tissue-water interface and inside an optically transparent gelatin phantom which mimics bulk tissue. The imaging shows the following: 1) Initiation of a temporally changing acoustic backscatter was due to the formation of a bubble cloud; 2) The pressure threshold to generate a bubble cloud was lower at a tissue-fluid interface than inside bulk tissue; and 3) at higher pulse pressure, the bubble cloud lasted longer and grew larger. The results add further support to the hypothesis that the histotripsy process is due to a cavitating bubble cloud and may provide insight into the sharp boundaries of histotripsy lesions.

Initial Investigation of Acoustic Droplet Vaporization for Occlusion in Canine Kidney

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 five 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 min per droplet dose. Gas bubbles sufficient to produce some shadowing were generated by transcutaneous vaporization of intrarenal artery or IV-administered droplets, with a tissue path up to 5.5 cm.

Acoustic droplet vaporization threshold: effects of pulse duration and contrast agent

The use of superheated liquid perfluorocarbon droplets encased in albumin shells has been proposed as a minimally invasive alternative to current treatment of cancer by means of occlusion therapy. In response to an applied acoustic field, these droplets, which are small enough to pass through capillaries, vaporize into large gas bubbles that subsequently lodge in the vasculature. This technique, known as acoustic droplet vaporization (ADV) has been shown to successfully reduce blood flow in vivo, but for in situ conditions where attenuation is present, lower acoustic frequency and ADV threshold may be desirable. Thus, two methods to lower the ADV threshold at a lower 1.44 MHz were explored. The first part of this study investigated the role of pulse duration on ADV. The second part investigated the role of inertial cavitation (IC) external to a droplet by lowering the IC threshold in the host liquid with the presence of Definityreg contrast agent (CA). The threshold was found to be 5.5-5.9 MPa for short microsecond pulses and decreased for millisecond pulses (3.8-4.6 MPa). When CAs were present and long millisecond pulses were used, the ADV threshold decreased to values as low as 0.41 MPa

Registration of three-dimensional compound ultrasound scans of the breast for refraction and motion correction

Use of multiple look directions, that is, compound imaging, has been shown previously to increase detection of specular reflectors and averaging of speckle noise in gray-scale images, often at the expense of spatial resolution and other misregistration errors. In color flow imaging, additional view angles can fill in vessels missed due to Doppler angle dropout and increase quantitative and visual Doppler accuracy by triangulation or a simple peak-frequency-shift combination algorithm. Image registration and unwarping throughout multiple three-dimensional (3D) volume sets should correct for many refraction artifacts, motion between and during compounded image sets and even, possibly, positioning errors between image sets, acquired months apart, to display growth of abnormalities. The registration described here does not provide sufficient accuracy for formation of enhanced coherent apertures, but shows promise in some cases to provide superior compound images and possibly comparisons of current and prior studies. In this study, the breast is stabilized by mild compression between a flat plate and a scanning membrane. Registration and unwarping is performed retrospectively on two separate volumetric data sets by defining pairs of corresponding points and, in some cases, line and plane segments. Three-dimensional linear affine transforms are performed using identified points, lines and planes. 3D nonlinear warped transforms are also possible given adequate numbers of identifiable points. More than two data sets are registered by selecting one as the standard, and registering the remainder to match. The most appropriate algorithm, such as averaging or maximum amplitude, may be used to combine the data sets for display. Significant success has been achieved in compound display of a test object and of the breast in vivo, even when there was relative motion or warping between image sets. In pulse-echo imaging, homologous feature registration for compounding appears to have advantages over mechanically registered compounding methods previously employed in the breast and significant increases in lesion and structural conspicuity are noted due to a reduction in speckle noise. The improvements from compounding in 3D, surface-rendered Doppler imaging of vasculature are striking.

Acoustic droplet vaporization for temporal and spatial control of tissue occlusion: a kidney study

Acoustic droplet vaporization (ADV) has been introduced with the potential application of tumor treatment via occlusion and subsequent necrosis. New Zealand White rabbits were anesthetized, and their left kidney was externalized. An imaging array and single-element transducer were positioned in a tank with direct access to the kidneys vasculature and renal artery. Filtered droplet emulsions (diameter < 6 /spl mu/m) were injected intra-arterially (IA) into the left heart during insonification of the renal artery, and the extent of blood flow reduction by ADV was compared to the untreated right kidney. Flow cytometry (using colored microspheres) of kidney tissue samples and reference blood from the femoral artery allowed the quantitative estimation of regional blood flow. A maximum regional blood flow reduction in the treated region of >90% and an average organ perfusion reduction of >70% was achieved using ADV. After treatment of the left kidney, the control kidney on the contralateral side showed a maximum decrease in regional blood flow of 18% relative to the pre-ADV baseline. Image-based hyper-echogenicity from ADV of IA injections was monitored for approximately 90 minutes, and cortex perfusion was reduced by >60% of its original value for more than 1 hour. This could be enough time for the onset of cell death and possible tumor treatment via ischemic necrosis. Moreover, currently used radiofrequency tissue ablation-based tumor treatment could benefit from ADV due to the decreased heat loss via vascular cooling.