Page 22 - Spring2019

Theracoustic Cavitation
Making Bubbles
An ultrasound field of sufficient intensity can produce bub- bles through either mechanical or thermal mechanisms or a combination of the two. However, the energy that is theo- retically required to produce an empty cavity in pure water is significantly higher than that needed to generate bubbles using ultrasound in practice. This discrepancy has been ex- plained by the presence of discontinuities, or nuclei, that provide preexisting surfaces from which bubbles can evolve. The exact nature of these nuclei in biological tissues is still disputed, but both microscopic crevices on the surfaces of tissue structures and submicron surfactant-stabilized gas bubbles have been identified as likely candidates (Fox and Hertzfeld, 1954; Atchley and Prosperetti, 1989).
The energy required to produce cavitation from these so- called endogenous nuclei is still comparatively large, and so, for safety reasons, it is highly desirable to be able to induce reproducible cavitation activity in the body using ultrasound frequencies and amplitudes that are unlikely to cause significant tissue damage. Multiple types of syn- thetic or exogenous nuclei have been explored to this end. To date, the majority of studies have employed coated gas microbubbles widely used as contrast agents for diagnos- tic imaging (see article in Acoustics Today by Matula and Chen, 2013). A primary disadvantage of microbubbles is that their size (1-5 μm) prevents their passing out of blood vessels (extravasating) into the surrounding tissue. As a consequence, cavitation is restricted to the blood stream. The bubbles are also relatively unstable, having a half-life of about 2 minutes once injected.
There has consequently been considerable research into alter- native nuclei. These include solid nanoparticles with hydro- phobic cavities that can act as artificial crevices (Rapoport et al., 2007; Kwan et al., 2015). Such particles have much longer circulation times (tens of minutes) and are small enough to diffuse out of the bloodstream into the surrounding tissue. Nanoscale droplets of volatile liquids, such as perfluorocar- bons, have also been investigated as cavitation nuclei (see Acoustics Today article by Burgess and Porter, 2015). These are similarly small enough to circulate in the bloodstream for tens of minutes and to extravasate. On exposure to ultra- sound, the liquid droplet is vaporized to form a microbubble. A further advantage of artificial cavitation nuclei is that they can be used as a means of encapsulating therapeutic material to provide spatially targeted delivery. This can significantly reduce the risk of harmful side effects from highly toxic che- motherapy drugs.
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Figure 1. Illustrations of bubble emission behavior as a function of driving pressure. At moderate pressures, harmonics (integer mul- tiples of the driving frequency [fo]) are produced, followed by frac- tional harmonics at higher pressures and eventually broadband noise (dashed lines indicate that the frequency range extends beyond the scale shown). Microbubbles (top left) will generate acoustic emissions even at very low pressures, whereas solid and liquid nuclei (top right) require significant energy input to activate them and so typically pro- duce broadband noise. The representative frequency spectra showing harmonic (bottom left) and broadband (bottom right) components were generated from cavitation measurements with f0 = 0.5 MHz.
Cavitation agents also have an advantage over many other drug delivery devices because their acoustic emissions can be detected from outside the body, enabling both their loca- tion and dynamic behavior to be tracked. Even at relatively low-pressure amplitudes such as those used in routine diag- nostic ultrasound, microbubbles respond in a highly nonlin- ear fashion and hence their emissions contain harmonics of the driving frequency (Arvanitis et al., 2011). As the pressure increases so does the range of frequencies in the emission spectrum, which will include fractional harmonics and even- tually broadband noise (Figure 1). More intense activity, which is normally associated with more significant biologi- cal effects, will produce broadband noise. Liquid and solid cavitation nuclei require activation pressures that are above the threshold for violent (inertial) bubble collapse and thus these agents always produce broadband emissions.
Mapping Bubbles
In both preclinical in vivo and clinical studies, a broad spectrum of bubble-mediated therapeutic effects has been demonstrated, ranging from the mild (drug release and in- tracellular delivery, site-specific brain stimulation) to the malevolent (volumetric tissue destruction). This sizable