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alone. In this context, “sniper”-collapsing bubbles come to tion nucleated by either microbubbles (Carlisle et al., 2013)
the rescue by producing fluid jets and shear stresses that kill or submicron cavitation nuclei (Myers et al., 2016) has been
cells or liquify extended tissue volumes (Khokhlova et al., shown to enable successful delivery of next-generation, larg-
2015). More recent approaches, such as in Figure 5, center er anticancer therapeutics to reach each and every cell within
row, have utilized gas-stabilizing solid nanoparticles to pro- the tumor, significantly enhancing their eflicacy.

mote and sustain inertial cavitation activity In_this example, An example is shown in Figure 5, bottom WW, Where a Pair
a pair of FUS sources initiate cavitation in an intervertebral . .

_ _ _ _ _ of FUS sources was used for in vivo treatment of a mouse tu-
disc of the spinal column while a pair of conventional ul- . . . . .

_ _ H ,_ mor using an oncolytic virus (140 nm) given intravenously.
trasound arrays is used to produce conventional ( B-mode ) I . . .

_ _ _ _ _ n the absence of microbubbles, the PAM image (Figure 5,

diagnostic and PAM u'nages during treatment. The region of . . . .
_ _ _ _ . bottum raw, center) indicates no cavitation, and only the
elevated cavitation activity (Figure 5, center raw, center, red .
treated cells (Figure 5 bottom raw center green) are those
. ; J ;
dm on the B-1-node wage) corresponds to sources fibroid‘ directl ad'acent to the blood vessel (Fi re 5 buttom raw
band emissions detected and localized by PAM and also centeryredl) However when mrcmbubililes Wgre madmin:
identifies the location and size of destroyed tissue. Critically, mere‘; wnn the virus) the enetmtron and dismbunon or
this theracoustic configuration has enabled highly localized ) P . .

_ _ _ _ _ treatment were greatly enhanced, correlating with broad-
dlsuflegmnon of muagenous ‘Issue m ‘he Cemral Part oflhe band acoustic emissions associated with inertial cavitation
disc without affecting the outer part or the spinal canal, po- . . . . . . .

_ _ _ _ _ in the tumor. Excitingly, noninvasively mapping acoustic
‘emlauy enabling the development on new mm”-“any mu‘ cavitation mediated b particles that are coadministered and
SW6 “Cam-‘em for lower back pain <M°1h-mri’ 2012)" similarly sized to theydrug potentially makes it possible to
Acoustic excitation is not always required to act as the pri- monitor and confirm successful drug delivery to target tu-
mary means of altering biology but can also be deployed mors during treatment for the very first time.
synergistically with a drug or other therapeutic agent to en-
hance its delivery and efficacy In this context, “mixer” bub- final Thuughr-3
bies have a rnaior role in niay; by imposing sneer siresses ai Acoustic cavitation demonstrably enables therapeutic mod-
tissue interfaces and by transferring momentum to the sur- “1“"°“ °f 3‘ “umber °f mherwlse maccesslble PhY51°1°S1C31
rounding rnedinrn) rhey can both increase ihe nerrneabiiiiy barriers, including crossing the skin, delivering drugs to tu-
and convectively transport therapeutic agents across other- “"0”, accessmg file b‘"““" and 55mm] “"V°“5 Sysiemi “nd
wise irnneneirabie biological interfaces‘ penetrating the cell. Much remains to be done, both in terms

_ _ _ of understanding and optimizing the mechanisms by which
one such barn“ 15 Presemed by ‘he Vasculature feed"-lg me oscillating bubbles mediate biological processes and in the
brain’ which’ lo Prevent ‘he ‘mnsm-mien ofinfedion’ exhibm development of advanced indication-specific technologies
very limited permeability that hinders the -delivery of drugs for nudemng, Pmmonng, imaging) and Controlling cavn
lo the_neW°us syS_tem‘ However’ n°mn_em‘a1 cflvmmon n_-my tation activity in increasingly challenging anatomical loca-
reversibly open fins smmued b1°°d'bmm barner (see amde tions. Suitabl nucleated, mapped, and controlled, therapeu-
in Acoustics Todn b Konofa ou 2017) A second such bar- Y

_ _ y Y 3 ’ ' _ _ _ tic cavitation enables acoustics to play a major role in shaping
rier is presented by the upper layer of the skin, which makes it ‘he future ofprecision medicine
challenging to transdermally deliver drugs and vaccines with-
out a needle. Recent studies have indicated that the creation of Acknowledgments
a “patch” containing not only the drug or vaccine but also iner- We gratefully acknowledge the continued support over 15 years
tial cavitation nuclei (Kwan et al., 2015) can enable ultrasound from the United Kingdom Engineering and Physical Sciences
to simultaneously permeabilize the skin and transport the Research Council (Awards EP/F01 1547/ 1, EP/I)024012/ 1,
therapeutic to hundreds of microns beneath the skin surface EP/K021729/ 1, and EP/I021795/ 1) and the National Institute
to enable need.le-free i.rnmunization (Bhatnagar et al., 2016). for Health Research (Oxford Biomedical Research Centre).
Last but not least, perhaps the most formidable barrier to Constantin-C. Coussios gratefully acknowledges support from
drug delivery is presented by tumors where the elewted in- the Acoustical Society of America under the 2002-2003 F. V.
ternal pressure, sparse vascularity, and dense extracellular Hunt Postdoctoral Fellowship in Acoustics. Last but not least,
matrix hinder the ability of anticancer drugs to reach cells we are hugely grateful to all the clinical and postdoctoral re-
far removed from blood vessels. Sustained inertial cavita- search fellows, graduate students, and collaboiators who have

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