Jongbum Seo

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.

Effects of contrast agent infusion rates on thresholds for tissue damage produced by single exposures of high-intensity ultrasound

Stabilized microbubble ultrasound contrast agents (UCA) have potential to aid tissue ablation during ultrasound surgery by enhancing both cavitational and thermal damage mechanisms. Previously, we showed UCA infused at a rate of 1 /spl mu/L/kg/min prior to ultrasound exposure could reduce the total energy required to produce tissue damage by up to two orders of magnitude. In this paper, we evaluate thresholds for macroscopic tissue damage with UCA infusion rates (IR) of 0.1, 0.3, 1, 3, and 10 /spl mu/L/kg/min to determine IR, potentially effective for ultrasound therapy. Canine kidneys were surgically externalized and insonified with single exposures of focused ultrasound. Incident exposures were 1.44 MHz tone bursts, either 250 ms in duration with intensity between 500 W/cm/sup 2/ and 3200 W/cm/sup 2/, or 100 /spl mu/s to 1 s in duration with intensity equal to 3200 W/cm/sup 2/. Probabilities of tissue damage occurrence were determined for each set of exposure conditions (intensity, duration, and IR). A threshold intensity and threshold duration, defined as the quantities for which tissue damage occurred with probability equal to 0.5, were estimated for each IR. Results show that, as IR increased from 0.1 to 10 /spl mu/L/kg/min, the threshold intensity decreased by up to a factor of 3, and threshold duration decreased by up to a factor of 200. Microbubble introduction at IR up to 10 /spl mu/L/kg/min thus may be effective in aiding ultrasound therapy.

Evaluation of ultrasound tissue damage based on changes in image echogenicity in canine kidney

Sufficiently high intensity ultrasound can create hyperechoic regions in an ultrasound image due to local bubble generation. We explore the link between the temporal extent of these hyperechoic regions and tissue damage caused by ultrasound therapy. The decay rate of increased echogenicity from the focal zone in insonated live exteriorized canine kidney was quantified and correlated to the spatial extent of tissue damage. The decay half-time, t/sub half/, defined as the time for echogenicity enhancement to decay by a factor of 2, was observed in all cases to be greater than 41 s in spatial zones in which extensive histological damage was observed. In cases in which the measured t/sub half/ was less than 11 s, the damage was limited to minor hemorrhage, or it was not detected. These t/sub half/ discrimination boundaries of 41 and 11 s were not statistically different for cases in which contrast agent was used to enhance therapeutic efficiency. This was true even though contrast agent infusion significantly reduced the therapy pulse duration threshold for damage production.

Microbubble enhanced threshold reductions for tissue damage using high intensity ultrasound

We show that introducing gas filled microbubbles (ultrasound contrast agent) reduces the threshold intensity and requisite duration of a single ultrasound burst for producing observable tissue damage in canine kidneys in-situ. The presence of microbubble contrast agent enhances the effects of acoustic cavitation in producing tissue damage, especially when short duration ultrasound exposures are used. Unlike thermal ablation mechanisms, acoustic cavitation can destroy tissue without heating overlying tissue layers. By developing approaches using the benefits of microbubbles in reducing both threshold intensity and burst duration, acoustic cavitation may become a more predictable and effective mechanism for non-invasive ultrasound surgery.

Evaluation of ultrasound tissue damage based on changes in image echogenicity

Sufficiently high intensity ultrasound can create hyperechoic regions in an ultrasound image due to local bubble generation. We explore the link between the temporal extent of these hyperechoic regions and tissue damage caused by ultrasound therapy. The decay rate of increased echogenicity from the focal zone in insonated live exteriorized canine kidney was quantified and correlated to the spatial extent of tissue damage. The decay half-time, t/sub half/, defined as the time for echogenicity enhancement to decay by a factor of 2, was observed in all cases to be greater than 41 s in spatial zones in which extensive histological damage was observed. In cases in which the measured t/sub half/ was less than 11 s, the damage was limited to minor hemorrhage, or it was not detected. These t/sub half/ discrimination boundaries of 41 and 11 s were not statistically different for cases in which contrast agent was used to enhance therapeutic efficiency. This was true even though contrast agent infusion significantly reduced the therapy pulse duration threshold for damage production.The rate of decay of increased echogenicity of the focal zone insonified in vivo canine kidney was quantified and parameterized to evaluate tissue damage. High intensity focused sonification was conducted at high mechanical index in order to assure onset of cavitation. A 2D local correlation method was applied to trace temporal change at each location and for motion compensation. The decay half time of increased echo, t/sub half/, defined as the time for echo enhancement to decay by a factor of 2, was measured. The average t/sub half/ determined from 23 occurrences of tissue damage, characterized by coagulation necrosis, pitting, and/or blanching, was approximately 45 seconds. On the other hand, when increased echogenicity decayed significantly faster, the observed damage, if present at all, was limited to minor hemorrhage. In 18 cases where increased echogenicity was observed and associated tissue damage was not found, the average was approximately 13 seconds. The correlation between the decay half time and the observed tissue damage is presented and may provide a useful method for both pre-treatment localization and post-treatment evaluation for non-invasive ultrasound surgery.

In vivo comparison of multiple pulse and CW strategies for microbubble-enhanced ultrasound therapy

Stabilized microbubble (ultrasound contrast agent) introduction can effectively reduce the propagated energy required to produce tissue damage in vivo. Acoustic parameter adjustment can also produce therapeutic gains. We found that exposures containing multiple, short duration pulses produced more tissue damage than single, CW exposures of the same amplitude and propagated energy, both with and without contrast agent. We suspect the increased tissue damage resulted from the initiation of cavitation and maintenance of a highly dynamic microbubble population during insonation. Results suggest that active adjustment of acoustic parameters may make cavitation more controllable.

Aberration correction by nonlinear beam mixing: generation of a pseudo point sound source

Nonlinear beam mixing with microbubbles was explored to create a pseudo point source for aberration correction of therapeutic ultrasound. A damping coefficient for a bubble driven by a dual frequency sound field was derived by revisiting Prosperettis linearized damping model. As a result, the overall damping term for dual frequency was obtained by linear summation of two damping terms for each frequency. The numerical simulation based on the bubble model suggests that the most efficient size range to generate a 1 MHz frequency from 4 MHz and 5 MHz sound sources is 2.6 to 3.0 /spl mu/m. Furthermore, this size range constitutes the primary distribution of a specific ultrasound contrast agent. When a chamber of 0.1% of the diluted agent is sonified by 4 MHz and 5 MHz sound beams with 80/spl deg/ incident angle between them, an approximately 100 Pa, 1 MHz difference frequency signal can be measured approximately 10 cm away. In addition, the received 1 MHz difference frequency signal shows omni-directional characteristics, even though the overlap zone of the two sound beams is on the order of the difference frequency wavelength. Therefore, the induced sound source can be considered as a pseudo point source and is expected to be useful for aberration correction for therapeutic ultrasound.

Aberration correction by nonlinear beam-mixing: generation of a pseudo point sound source

Nonlinear beam-mixing with microbubbles was explored to create a pseudo point source for aberration correction of therapeutic ultrasound. A damping coefficient for a bubble driven by a dual frequency sound field was derived by revisiting Prosperettis linearized damping model. As a result, the overall damping term for dual frequency was obtained by linear summation of two damping terms for each frequency. The numerical simulation based on the bubble model suggests that the most efficient bubble radius to generate a 1 MHz frequency from 4 MHz and 5 MHz sound sources is 2.6-3.0 /spl mu/m. Furthermore, this size range constitutes the primary distribution of a specific ultrasound contrast agent: Optison (Amersham Health, Princeton, NJ). When a chamber of 0.1% diluted Optison was insonified by 4 MHz and 5 MHz sound beams with 80/spl deg/ incident angle between them, an approximately 100 Pa, 1 MHz difference frequency signal was measured approximately 10 cm away. In addition, the received 1 MHz difference frequency signal shows omnidirectional characteristics, even though the overlap zone of the two sound beams is on the order of the difference frequency wavelength. Therefore, the induced sound source can be considered as a pseudo point source and is expected to be useful for aberration correction for therapeutic ultrasound.