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were intended to avoid thermally significant cavitation. This example shows the potential for real-time mapping of bubble activity in clinically relevant targets using PAM techniques.
Using Bubbles
Bubble Behaviors
The seemingly simple system of an ultrasonically driven bubble in a homogeneous liquid can exhibit a broad range of behaviors (Figure 4). In an unbounded medium, bubble wall motion induces fluid flow, sound radiation, and heating (Leighton, 1994) and may spur its own growth by rectified diffusion, a net influx of mass during ultrasonic rarefaction cycles. When a bubble grows sufficiently large during the rar- efactional half cycle of the acoustic wave, it will be unable to resist the inertia of the surrounding liquid during the com- pressional half cycle and will collapse to a fraction of its orig- inal size. The resulting short-lived concentration of energy and mass further enhances sound radiation, heating rate, fluid flow, and particulate transport and can lead to a chemical reac- tion (sonochemistry) and light emission (sonoluminescence). Regarding the spatially and temporally intense action of this “inertial cavitation,” it has been duly noted that in a simple laboratory experiment “...one can create the temperature of the sun’s surface, the pressure of deep oceanic trenches, and the cooling rate of molten metal splatted onto a liquid-helium- cooled surface!” (Suslick, 1990, p. 1439).
Further complexity is introduced when the bubble vibrates near an acoustic impedance contrast boundary such as a glass slide in an in vitro experiment or blood vessel wall in tissue. Nonlinearly generated circulatory fluid flow known as “microstreaming” is produced as the bubble oscillates about its translating center of mass (Marmottant and Hilgenfeldt, 2003) and can both en- hance transport of nearby therapeutic particles (drugs or sub- micron nuclei) and amplify fluid shear stresses that deform or rupture nearby cells (“microdeformation” in Figure 4).
Theracoustic Applications:
Furnace, Mixer, and Sniper Bubbles
Suitably nucleated, mapped, and controlled, all of the aforemen- tioned phenomena find therapeutically beneficial applications within the human body. Here, we present a subset of the ever- expanding range of applications involving acoustic cavitation.
One of the earliest, and now most widespread, uses of thera- peutic ultrasound is thermal, whereby an extracorporeal transducer is used to selectively heat and potentially destroy a well-defined tissue volume (“ablation”; Kennedy, 2005). A key challenge in selecting the optimal acoustic parameters to achieve this is the inevitable compromise between propaga-
Figure 3. Example of passive cavitation mapping during a clinical therapeutic ultrasound procedure. Left: axial CT slice showing tho- racic organs, including the tumor targeted for treatment, with red and blue arrows indicating the directions of therapeutic focused ultrasound (FUS) incidence and PAM data collection, respectively. Right: enlarged subregion (left, blue dashed-line box) in which a PAM image was generated. Maximum (red) and minimum (blue) color map intensities cover one order of magnitude. A video of six successive PAM frames spanning a total time period of 500 microsec- onds is available at (acousticstoday.org/gray-media).
Figure 4. Illustration of bubble effects and length scales. Green, in vivo measurement feasibility; jagged shapes indicate reliance on iner- tial cavitation; red dots, best spatial resolution; text around radial arrows, demonstrated noninvasive observation methods. SPECT, single photon emission computed tomography; US, ultrasound; a, ac- tive; p, passive; MRI, magnetic resonance imaging; CT, X-ray com- puted tomography; PET, positron emission tomography.
tion depth, optimally achieved at lower frequencies, and the local rate of heating, which is maximized at higher frequen- cies. “Furnace” bubbles provide a unique way of overcoming this limitation (Holt and Roy, 2001); by redistributing part of the incident energy into broadband acoustic emissions that are more readily absorbed, inertial cavitation facilitates highly localized heating from a deeply propagating low-fre- quency wave (Coussios et al., 2007).
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