Page 22 - Spring 2019
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'n"9"9‘=°'-'3'5l'= c*'Vi‘73‘5l°“ Gas micruhubblas Solid/liguld narmgrliclss
- 1 1 i i
E 4.0 - . Mid
Making Bubbles E 35 . ‘ g_,,m,.,,, 0
An ultrasound field of suflicient intensity can produce bub- E  3 gm‘ -. 9
bles through either mechanical or thermal mechanisms or § 2'0 _ _ _ gym
a combination of the two. However, the energy that is theo- :’ L5 . . -
retically required to produce an empty cavity in pure water § 1 o - u . a
is significantly higher than that needed to generate bubbles E 0-5 ' I ;
using ultrasound in practice. This discrepancy has been ex- 0 —_\ D,“/mg mssm
plained by the presence of discontinuities, or nuclei, that 2 nae av \'
provide preexisting surfaces from which bubbles can evolve. Eeee, ”
The exact nature of these nuclei in biological tissues is still E... W.
disputed, but both microscopic crevices on the surfaces of gs/Hi,‘ ""’
tissue structures and submicron surfactant-stabilized gas .3 ., l V ‘_ 1 ‘
bubbles have been identified as likely candidates (Fox and "°‘“‘°"“Y”"““ "°‘“‘”""V""“’
Henzfeld, 1954;Atch1ey and Prospereni, 1989). Figure 1. Illustrations ef bubble emission behevier as e fimctiwi ef
. _ _ driving pressure. At moderate pressures. harmonics (integer mul-
The energy required to produce cavitation from these so- “PIES Hf the dfivingfiequency (U) are Pwduced fgunwed byfilm
Called €nd0g€n°“S nuclei is 51111 C°mPmtiVe1Y large» and tionalhmmoriics uthigher pressures undeventuully lzrnmilzund noise
so, for safety reasons, it is highly desirable to be able to (dashed lines indicate that the frequency range extends beyond the
induce reproducible cavitation activity in the body using scule shnwn). Micralzulzbles (mp left) will generate ucaustic emissinns
ultrasound frequeueles and empllludes ll,“ are unlikely even_ut very_lnwpressures,_whereas solid and liquid nuclei (top right)
to cause significant tissue damage. Multiple types of syn- Sq“? '“g:£fi”:i"ter'ergjy_h'"P"t ta acttllgmftfem and ‘W filcagypra’
me you an nmse. e re resen :1 ve e uenc ec us Uwln
thetic or exogenous nuclei have been explored to this end. hmmanic (hmom left) and bpmadlmmi (bagom IQZ) mmpnnenf:
T0 dale» ‘he meiofiw °f “"5195 have €mP1°Y€d mated S35 were generated frem cavitation measurements with Q, = 0.5 MHz.
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 Cavitation agents also have an advantage over many other
that their size (1-5 pm) prevents their passing out of blood drug delivery devices because their acoustic emissions can
vessels (extravasating) into the surrounding tissue. As a be detected from outside the body, enabling both their loca-
consequence, cavitation is restricted to the blood stream. tion and dynamic behavior to be tracked. Even at relatively
The bubbles are also relatively unstable, having a half-life of low-pressure amplitudes such as those used in routine diag-
about 2 minutes once injected. nostic ultrasound, microbubbles respond in a highly nonlin-
f h‘ d h th ' ' ' t ' h ' f
There has consequentlybeen considerable research into alter- ear as. lon an ems elf efxllsslons con am armomcs 0
. . . . . . the driving frequency (Arvanitis et al., 2011). As the pressure
native nuclei. These include solid nanoparticles with hydro- _ . . . .

. . . . . . increases so does the range of frequencies in the emission
phobic cavmes that can act as amficml crevices (kapopon ct s ectrum which will include fractional harmonics and even
al., 2007; Kwan et al., 2015). Such particles have much longer ‘San bngadbmd noise (Pi II" 1) More imense acfivi
circulation times (tens of minutes) and are small enough to _ Y . . g . ' . . . 

. . . . which is normally associated with more significant biologi-
diffuse out of the bloodstream into the surrounding tissue. _ . . . .
_ _ _ cal effects, will produce broadband noise. Liquid and solid
Nmoscale droplets of Volatile liquids’ such as Perfluomcap cavitation nuclei re uire activation ressures that are above
bons, have also been investigated as cavitation nuclei (see _q _ _ P
. _ the threshold for violent (inertial) bubble collapse and thus
Acoustics Today article by Burgess and Porter, 2015). These . .

. . . . these agents always produce broadband emissions.
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. Nlapping Bubbles
Afurther advantage of artificial cavitation nuclei is that they In both preclinical in vivo and clinical studies, a broad
can be used as a means of encapsulating therapeutic material spectrum of bubble-mediated therapeutic effects has been
to provide spatially targeted delivery. This can significantly demonstrated, ranging from the mild (drug release and in-
reduce the risk of harmful side effects from highly toxic che- tracellular delivery, site-specific brain stimulation) to the
motherapy drugs. malevolent (volumetric tissue destruction). This sizable
an 1 AI:uulI:l:l Tbday 1 Spring 2019

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