Investigator Profile — Zhen Xu, PhD

This pioneer seeks to ultimately see the translation of this discovery to the medical clinic, providing life-changing non-invasive treatment for diseases such as blood clots, liver tumors, brain cancer, and congenital heart disease. We interviewed her in July 2015 for a closer look at her research:

Zhen Xu_smFocused Ultrasound Work
Q. When and how did you get interested in FUS?
A. For my PhD in biomedical engineering, I became interested in the work of Charles Cain’s laboratory. A pediatric cardiologist, Achi Ludomirsky, asked us to find a non-invasive, non-thermal way to perforate the atrial septum, a membrane separating the left and right atrium in the heart. Dr. Cain asked me to investigate of the use of ultrasound to remove tissue by controlling cavitation, which is the formation and activity of microbubbles. Luckily, I didn’t know enough about the field to know that it was practically impossible, and I didn’t know enough to be afraid. So I tried a lot of new parameters that have never been tried before, and I was able to find something that could create tissue fractionation. What I tried was outside the range of what people would do. These early experiments became the beginning of many more by the co-inventors of histotripsy at the University of Michigan (Charles Cain, Timothy Hall, Brian Fowlkes, William Roberts, and me). Our entire team has contributed to each aspect of the invention: from building the device to understanding the mechanism to the continuation of its clinical translation.

Q. What are your areas of interest in focused ultrasound? What mechanisms and clinical indications do you study?
A. I use histotripsy cavitation and microtripsy for thrombolysis in treating blood clots and plaque, congenital heart disease (atrial septal defects), liver cancer, and brain tumors. My two focus areas in the brain are brain tumors and intracerebral hemorrhage.

Q. How large is your research staff/team?
A. Currently there are 13 researchers in my laboratory--I have two post-doctoral fellows, five doctoral students, four undergraduate students, and one visiting scholar (Lifang Jin, MD from China, who is a diagnostic radiologist for ultrasound imaging).

Xu research_group_smQ. What is the goal of your work?
A. Overall my goal is to see histotripsy used in the clinic to treat patients. I believe it will improve the standard of care for many different diseases.

Q. What have been your results so far?
A. We found that we can use histotripsy with real-time imaging guidance to precisely and non-invasively fractionate and destroy target tissue. We have demonstrated this in vitro and in vivo in many different animal models. Clinically, it’s already being ed for benign prostatic hyperplasia (BPH) by HistoSonics.

Q. What are your funding sources?
A. The National Institutes of Health, American Cancer Society, Focused Ultrasound Foundation, The Hartwell Foundation, American Heart Association, the Department of Defense, and National Science Foundation.

Research Details
Xu InfographicQ. Who are your internal and external collaborators?
A. At the University of Michigan, our histotripsy group has three laboratories (Charles Cain’s, Tim Hall’s, and mine). We work together in Biomedical Engineering, but we each have our own laboratory space and our own students. In addition, Brian Fowlkes has his group in Radiology, and William Roberts has his group in Urology. I have clinical collaboration with Gabe Owens (Pediatric Cardiology), Hitinder Gurm (Interventional Cardiology), Theodore Welling (Surgery - liver cancer), and Aditya Pandey (Neurosurgery). Furthermore, the University also has a large group of ultrasound researchers.

Q. Any major disappointments?
A. My major disappointment is always in terms of getting funding – the wrong cycles, etc. I have been especially disappointed in the lack of support for translational research. Where do you go for that? The federal sources are not willing to do this. Now I am a scientist who is looking for investors. There is really a gap in between, and that is why the Focused Ultrasound Foundation is so great – the translational research funding that you provide is really helpful. This type of funding represents a real unmet need in getting the technology to the patients who need it.

Q. What is on your research wish list?
A. A lot of things! For the brain applications, we want to transcranially treat all of the locations in the brain and treat them fast – a large volume at a fast rate. For liver cancer and really just overall, I want to be able to cover the range of locations that we want to treat with great efficacy and safety.

Looking Ahead
Q. What are your plans for the near future?
A. We have the NIH grant as mentioned in the project summary. I cannot give details, but hope to have news to announce soon about meetings we are having with industry representatives. Clinically, through a University of Michigan spinoff company, HistoSonics, histotripsy is being investigated in a clinical study for treatment of benign prostatic hyperplasia (BPH). We recently held a principle investigator meeting for congenital heart disease because we are hoping to start human clinical trials in one year.

Past Coverage
Focus Feature: Histotripsy
2013 Fourth Quarter Research Awards

Key FUS Publications
Vlaisavljevich E, Maxwell A, Warnez M, Johnsen E, Cain CA, Xu Z. Histotripsy-induced cavitation cloud initiation thresholds in tissues of different mechanical properties. IEEE Trans Ultrason Ferroelectr Freq Control 2014;61(2):341-52.

Vlaisavljevich E, Lin KW, Warnez MT, Singh R, Mancia L, Putnam AJ, Johnsen E, Cain C, Xu Z. Effects of tissue stiffness, ultrasound frequency, and pressure on histotripsy-induced cavitation bubble behavior. Phys Med Biol 2015;60(6):2271-92.

Zhang X, Miller RM, Lin KW, Levin AM, Owens GE, Gurm HS, Cain CA, Xu Z. Real-time feedback of histotripsy thrombolysis using bubble-induced color Doppler. Ultrasound Med Biol 2015;41(5):1386-401.

Devanagondi R, Zhang X, Xu Z, Ives K, Levin AM, Gurm HS, Owens GE. Hemodynamic and hematological effects of histotripsy of free-flowing blood: Implications for US-mediated thrombolysis. J Vasc Intervent Radiol 2015. Epub.

Xi Z, Owens GE, Gurm HS, Yu D, Cain CA, Zhen X. Noninvasive thrombolysis using histotripsy beyond the intrinsic threshold (microtripsy). Ultrasonics, Ferroelectrics, and Frequency Control, IEEE Transactions on. 2015;62(7):1342-1355.