Q. How did you become interested in focused ultrasound?
For my PhD, I worked on the imaging of mechanical properties of tissue using ultrasound, monitoring how the elasticity of tissue changes as a result of disease and exploring new ways of detecting tumors, especially in the breast. When I was looking for a post-doctorate position, I wanted to shift from imaging to therapeutics, and physicist Kullervo Hynynen was looking for a post-doc at Brigham and Women’s in Boston.
When you burn tissue with focused ultrasound ablation, you change its elasticity. In Hynynen’s lab, I started developing new ways of monitoring focused ultrasound ablation using ultrasound-based elasticity imaging. This was before MRI was prominent as a guidance tool. At that time, we could burn tissue with focused ultrasound ablation, but we did not have a clear idea where we were burning.
Q. How has your work changed over time, and how do you use ultrasound now?
We work on both imaging with ultrasound and on therapeutic applications for focused ultrasound. In therapy, we are exploring not only the thermal burning of ablation, but the mechanical effects of vibrating tissue with sound to monitor lesion formation and tumor differentiation. We have done preclinical studies opening the BBB to enable drug delivery to treat neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These diseases are deep in the brain, so they are good candidates for non-invasive treatment with focused ultrasound, and they are rising in prevalence. We are also interested in focused ultrasound ablation of both benign and cancerous tumors in the breast and pancreas.
Q. What is the goal of your work?
The common thread of our work is non-invasive, bloodless, non-ionizing radiation, and translational research. I can’t believe that invasive surgery is still the sole option for treating benign tumors, for example. We need alternatives, and focused ultrasound could prove to be the best alternative. Also, we are engineers and scientists, but we are not basic scientists. It will take a long time to understand how the human brain works, but you don’t have to fully understand how a treatment works (i.e., mechanisms), and we want to develop therapies.
Q. Have there been any exciting results?
A lot. In the beginning, we asked, “Can we open the BBB through the intact skull?” And we did. Then we wondered, “Once you open it, how long does it take to close?” and “Can it be safe?” We’ve been enchanted every step of the way. Not only can you open the BBB without harming, you can potentially treat the brain in doing so.
And the most exciting findings are counterintuitive, because you don’t really expect them. To open the BBB, we activate microbubbles with focused ultrasound. Not only do we need to activate these microbubbles through the intact skull, but we need to detect their reaction back through the skull -so we must both transmit and receive waves through the skull. But activating microbubbles is a mechanical effect, not a thermal effect, and MR imaging and elasticity imaging do not provide us with the monitoring information that we need. However, we discovered that we can actually listen to microbubble activity through the intact skull and we can detect whether bubbles are oscillating because they scatter back ultrasound. This is cavitation monitoring.
Q. Who do you collaborate with? What benefits have come from your collaborations?
I have about 25 lab members, and we are fortunate to work with departments throughout Columbia: pathology, neurology, neurosurgery, radiology, cardiology, vascular surgery, oncology, and more. Outside of Columbia, I have been able to collaborate with Paul Dayton at the University of North Carolina. Paul developed the nanodroplets that we are using in some aspects of our BBB work. These droplets are small and compact when they enter the bloodstream through an intravenous line. We then use focused ultrasound to expand them into microbubbles at their target. Microbubbles outside the focal spot can cause shadowing – and prevent ultrasound transmission. So, it’s exciting that you can induce your own microbubbles selectively, where you need them.
Q. What’s next?
We are building clinical systems for the brain, breast, and pancreas and will work to get them through regulatory approvals so that we can pursue clinical trials. We are also investigating whether we can inject nanoparticles intranasally for brain applications. We need to find the right drugs to treat the brain. After a drug crosses the BBB, it still needs to be active and potent. We need a drug that works and that is either affordable, or that pharma can make available to us. But it’s not straightforward. Drugs have failed for Alzheimer’s disease, and they’ve failed for a reason. Is it only because they failed to cross the BBB, or is there another reason?
Q. How has the Focused Ultrasound Foundation supported you?
As we transitioned our BBB research into our second stage of preclinical trials, we needed funding, and the Foundation supported us, which was very important. I also attended the Foundation’s workshop on the BBB and have met other researchers through the Foundation with whom I continue to exchange ideas.
Q. What do you need now?
In addition to a drug, we don’t currently work with any medical device companies. We assemble in-house, which means we have full control, but our system is bulky and is not ready for clinical use. We need funding to build a suitable, dedicated clinical system. Our prototype will come out of pocket, but the second generation will need external funding.
Key Focused Ultrasound Publications
Choi J, Selert K, Vlachos F, Wong A, Konofagou EE. Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles, Proc Natl Acad Sci (PNAS) 2011;108(40):16539-44.
Konofagou EE. Optimization of the ultrasound-induced blood-brain barrier opening. Theranostics 2012; 2(12):1223-37.
Marquet F, Teichert T, Wu S-Y, Tung Y-S, Downs ME, Wang S, Chen CC, Ferrera VP, Konofagou EE. Real-Time, Transcranial Monitoring of Safe Blood-Brain Barrier Opening in Non-Human Primates, PLoS One, Volume 9, Number 2, February 2014.
Chen H, Konofagou EE. The size of BBB opening induced by FUS is dictated by the acoustic pressure. J Cereb Flow and Metab 2014 Jul;34(7):1197-204.
Wang S, Olumolade O, Sun T, Samiotaki G, Konofagou EE. Non-invasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus, Gene Therapy 2015.