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alone. In this context, “sniper”-collapsing bubbles come to the rescue by producing fluid jets and shear stresses that kill cells or liquify extended tissue volumes (Khokhlova et al., 2015). More recent approaches, such as in Figure 5, center row, have utilized gas-stabilizing solid nanoparticles to pro- mote and sustain inertial cavitation activity. In this example, a pair of FUS sources initiate cavitation in an intervertebral disc of the spinal column while a pair of conventional ul- trasound arrays is used to produce conventional (“B-mode”) diagnostic and PAM images during treatment. The region of elevated cavitation activity (Figure 5, center row, center, red dot on the B-mode image) corresponds to sources of broad- band emissions detected and localized by PAM and also identifies the location and size of destroyed tissue. Critically, this theracoustic configuration has enabled highly localized disintegration of collagenous tissue in the central part of the disc without affecting the outer part or the spinal canal, po- tentially enabling the development of a new minimally inva- sive treatment for lower back pain (Molinari, 2012).
Acoustic excitation is not always required to act as the pri- mary means of altering biology but can also be deployed synergistically with a drug or other therapeutic agent to en- hance its delivery and efficacy. In this context, “mixer” bub- bles have a major role to play; by imposing shear stresses at tissue interfaces and by transferring momentum to the sur- rounding medium, they can both increase the permeability and convectively transport therapeutic agents across other- wise impenetrable biological interfaces.
One such barrier is presented by the vasculature feeding the brain, which, to prevent the transmission of infection, exhibits very limited permeability that hinders the delivery of drugs to the nervous system. However, noninertial cavitation may reversibly open this so-called blood-brain barrier (see article in Acoustics Today by Konofagou, 2017). A second such bar- rier is presented by the upper layer of the skin, which makes it challenging to transdermally deliver drugs and vaccines with- out a needle. Recent studies have indicated that the creation of a “patch” containing not only the drug or vaccine but also iner- tial cavitation nuclei (Kwan et al., 2015) can enable ultrasound to simultaneously permeabilize the skin and transport the therapeutic to hundreds of microns beneath the skin surface to enable needle-free immunization (Bhatnagar et al., 2016). Last but not least, perhaps the most formidable barrier to drug delivery is presented by tumors where the elevated in- ternal pressure, sparse vascularity, and dense extracellular matrix hinder the ability of anticancer drugs to reach cells far removed from blood vessels. Sustained inertial cavita-
tion nucleated by either microbubbles (Carlisle et al., 2013) or submicron cavitation nuclei (Myers et al., 2016) has been shown to enable successful delivery of next-generation, larg- er anticancer therapeutics to reach each and every cell within the tumor, significantly enhancing their efficacy.
An example is shown in Figure 5, bottom row, where a pair of FUS sources was used for in vivo treatment of a mouse tu- mor using an oncolytic virus (140 nm) given intravenously. In the absence of microbubbles, the PAM image (Figure 5, bottom row, center) indicates no cavitation, and only the treated cells (Figure 5, bottom row, center, green) are those directly adjacent to the blood vessel (Figure 5, bottom row, center, red). However, when microbubbles were coadmin- istered with the virus, the penetration and distribution of treatment were greatly enhanced, correlating with broad- band acoustic emissions associated with inertial cavitation in the tumor. Excitingly, noninvasively mapping acoustic cavitation mediated by particles that are coadministered and similarly sized to the drug potentially makes it possible to monitor and confirm successful drug delivery to target tu- mors during treatment for the very first time.
Final Thoughts
Acoustic cavitation demonstrably enables therapeutic mod- ulation of a number of otherwise inaccessible physiological barriers, including crossing the skin, delivering drugs to tu- mors, accessing the brain and central nervous system, and penetrating the cell. Much remains to be done, both in terms of understanding and optimizing the mechanisms by which oscillating bubbles mediate biological processes and in the development of advanced, indication-specific technologies for nucleating, promoting, imaging, and controlling cavi- tation activity in increasingly challenging anatomical loca- tions. Suitably nucleated, mapped, and controlled, therapeu- tic cavitation enables acoustics to play a major role in shaping the future of precision medicine.
Acknowledgments
We gratefully acknowledge the continued support over 15 years from the United Kingdom Engineering and Physical Sciences Research Council (Awards EP/F011547/1, EP/L024012/1, EP/K021729/1, and EP/I021795/1) and the National Institute for Health Research (Oxford Biomedical Research Centre). Constantin-C. Coussios gratefully acknowledges support from the Acoustical Society of America under the 2002-2003 F. V. Hunt Postdoctoral Fellowship in Acoustics. Last but not least, we are hugely grateful to all the clinical and postdoctoral re- search fellows, graduate students, and collaborators who have
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