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A) B)
C)
Figure 5. A: Gene delivery through the BBB (BBB-opened; left) vs. contralateral (unopened; right) brain hemispheres in two separate regions of the brain (top and bot- tom). Green, virus-transduced cells. AAV, adeno-associated virus. Gene- transduced neurons (B; green) and astrocytes (C; green; 100×) in the BBB-opened region from the left panel. Scale bars, 150 μm.
without investigating long-term effects (Kovacs et al., 2017). However, several groups have repeatedly shown that such an inflammation can be reversed after the opening depending on the pressure used (Sun et al., 2015).
Over the past couple of decades, therapeutic ultrasound has morphed into a formidable technology that has impacted several fields from dental care and alleviation from Parkin- sonian tremors to cancer therapies and treatment of kidney stones (see article by Simon, Maxwell, and Bailey in this is- sue of Acoustics Today). The brain, similar to the lungs, has always been an organ remotely related to ultrasound because of the limitations in its imaging. Not anymore. Because of the transcranial capabilities of ultrasound and the advent of MRI and CT imaging, therapeutic ultrasound on the brain has not only been shown feasible but has also been integrat- ed in the clinic for ablation of essential tremors.
However, as described herein, therapeutic ultrasound could also prove pivotal in brain drug delivery. FUS currently con- stitutes the sole technique that can noninvasively, safely, and transiently open the formidable frontier in brain drug deliv- ery, the BBB. It has even been shown that it can stimulate the immune system to facilitate toxic protein reduction that is associated with Alzheimer’s and to induce immunotherapy of cancer. More importantly, it constitutes a technology that can be combined with any drug already available to treat neurological disease. Therefore, given the immense need of
treating these currently intractable diseases over the next few years, ultrasound is expected to be readily available and in- valuable in the clinic for patients suffering from these condi- tions. It will signify the dawn of an exciting, new era in both acoustics and healthcare.
Acknowledgments
The work shown here was performed by Babak Baseri, Cher- ry Chen, Hong Chen, James Choi, Thomas Deffieux, Karen Duff, Vincent Ferrera, Fabrice Marquet, Gesthimani Samio- taki, Oluyemi Olumolade, Scott Small, Tobias Teichert, and Shih-Ying Wu. The research was supported by Grants R01- EB-009041 from the National Institute of Biomedical Imag- ing and Bioengineering, R01-AG-038961 from the National Institute on Aging, and R21-EY-018505 from the National Eye Institute, National Institutes of Health; National Science Foundation CAREER Award 0644713; the Kinetics Founda- tion; and the Kavli Institute.
Biosketch
Elisa Konofagou is the Robert and Mar- garet Hariri Professor of Biomedical En- gineering, professor of radiology, and director of the Ultrasound and Elastic- ity Imaging Laboratory, Columbia Uni- versity, New York. Professor Konofagou has coauthored over 170 peer-reviewed
journal articles and is a recipient of the National Science Foundation-CAREER Award, the National Institutes of Health Nagy Award, and awards from the American Heart Association, Acoustical Society of America (ASA), Ameri- can Institute of Ultrasound in Medicine, Wallace H. Coulter Foundation, Bodossaki Foundation, and Radiological Soci- ety of North America. Elisa is a fellow of the ASA and the American Institute of Biological and Medical Engineering.
References
Abbott, N. J., Ronnback, L., and Hansson, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews in Neuroscience 7, 41-53.
Baseri, B., Choi, J. J., Tung, Y. S., and Konofagou, E. E. (2010). Safety assess- ment of blood-brain barrier opening using focused ultrasound and defin- ity microbubbles: A short-term study. Ultrasound in Medicine and Biology 36, 1445-1459.
Baseri, B., Choi, J. J., Deffieux, T., Samiotaki, G., Tung, Y. S., Olumolade, O., Small, S. A., Morrison, B., and Konofagou, E. E. (2012). Activation of signal- ing pathways following localized delivery of systemically administered neu- rotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles. Physics in Medicine & Biology 57(7), N65-N81.
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