Focus Feature: Histotripsy




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FOCUS FEATURE: HISTOTRIPSY
 
 

This special report highlights a lesser known area of focused ultrasound: a form of mechanical tissue destruction called histotripsy. With more than ten years of basic science groundwork, researchers have made advances to the point where histotripsy may quickly catch up to the clinical progress made with the ablative techniques of focused ultrasound.

After its invention (and naming!) at the University of Michigan more than 10 years ago, scientists there and at the University of Washington have advanced the technology to the point where we are wondering: Is it ready to tip? The stories below may convince you. Read about:

Michigan's Tissue Thresholds for Histotripsy and Liver Cancer

New Histotripsy Research: Dissolving Blood Clots

The Washington-Russian Collaboration

Histotripsy Development Milestones

A Start-up Histotripsy Company: HistoSonics




 
Has Histotripsy Reached A Tipping Point?

Have you seen a bubble cloud? How about shock wave boiling?

Although the most clinically advanced focused ultrasound therapies use heat to destroy unhealthy tissue, histotripsy is a non-thermal ultrasonic method that mechanically destroys target tissue.

Histotripsy can be classified by the method used to produce tissue-disrupting bubble cloud, and by the intensity and length of the "generator" acoustic pulse. The three approaches that have been developed are:



"Histotripsy" was Invented at the University of Michigan


"I coined the term histotripsy some 10 years ago to differentiate it from thermal therapy. In Greek, histo can refer to soft tissues (hence histology) and tripsy suggests breaking something. In a similar way, lithotripsy refers to breaking stones (as in the kidney)."

- Charles A. Cain, PhD, University of Michigan Biomedical Engineering Department

1. Shock Scattering Histotripsy: The original method developed at the University of Michigan (UM) that uses high intensity pulses from 2 to 20 microseconds in length (2 to 10 cycles of a tone burst pulse).

2. Intrinsic Threshold Histotripsy: A recent UM development that uses very high intensity pulses from 0.1 to 2 microseconds in length (a single negative half cycle can generate a dense bubble cloud!).

3. Boiling Histotripsy: The University of Washington method that uses medium intensity pulses of about 1000 microseconds in length. This hybrid thermal/acoustic method is more easily adapted from currently available thermal ablation technology.

A detailed explanation of these methods is described in an article co-written by the two teams in the October 2012 issue of Acoustics Today. This article, along with many others, shows that the work that has accumulated on this technique has reached a critical mass: Important clinical breakthroughs are imminent.

 

Visit our website to see an informative histotripsy video produced at the University of Michigan and learn how they are developing the technique to help newborn babies with heart defects.

 
 
 
 
 






Histotripsy showing its smaller-than-a dime accuracy



"Others have been slow to adopt histotripsy, but the technology is there. The tipping point can be easily reached."
- Charles A. Cain, PhD
 
Michigan Histotripsy Update: Tissue Thresholds and Liver Cancer Breakthroughs


The Histotripsy Group in the University of Michigan's Department of Biomedical Engineering invented and has been pioneering the development of focused ultrasound histotripsy for more than 12 years. Starting with their earliest work in the use of microbubbles to cause tissue damage, this group led by Charles A. Cain, PhD, and including Zhen Xu, PhD, Timothy L. Hall, PhD, J. Brian Fowlkes, PhD, and William Roberts, MD has grown to a team of 13 scientists who have developed histrotripsy into a highly controlled and predictable tool to remove unwanted tissue with microscopic precision. In fact, the lesions produced with histotripsy are much smaller and more precise than those that can currently be produced with thermal ablation.

Tissue Thresholds

 
 

The Michigan group's first published measurement of histotripsy bubble cloud thresholds in different types of biological tissues was recently included in the journal IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. This important work could serve as the baseline for initiating clinical use of the technique. Researchers found a relationship between the tissue type and its elasticity, and their findings will improve understanding of the effect of histotripsy in tissues with different mechanical properties and could also provide a rational basis to make parameter recommendations when treating different tissues. Read the abstract and gain access to the entire research paper. In fact, the Michigan group had three papers in the same issue, including one on microtripsy (cover photo) and one on dual-beam histotripsy.

Is Histotripsy Better for Liver Cancers?

 
 
Dr. Charles Cain and colleagues in his histotripsy laboratory
 

Histotripsy may be a better option to treat liver cancers because liver tissue is vascular, making it harder to heat than other tissue. Also, the ribs surrounding the liver may cause less interference with histotripsy than with ablation. In their August 2013 technical research report published in Ultrasound in Medicine and Biology, University of Michigan scientists suggested that focused ultrasound histotripsy could be successfully used to treat hepatocellular carcinoma because their noninvasive in vivo results proved that:

  • The liver tissue was fractionated with sharp margins.
  • The ribs and overlying tissue did not interfere with treatment.
  • Nearby major blood vessels and organs (gall bladder) remained intact and were not affected by the treatment.

The use of histotripsy to treat liver cancer has been studied for several years and may be getting very close to becoming a reality. Clinical trials for patients with primary liver cancer or liver metastases would be the next step, but none are yet planned. We look forward hearing the latest developments in this technology during the histotripsy presentations at our upcoming international symposium.

 
 
 
 


Zhen Xu, PhD will be using histotripsy to remove blood clots in the deep veins of the legs

 
New Histotripsy Research: Dissolving Blood Clots


Dr. Zhen Xu, one of the researchers in the University of Michigan group will take the lead with a new project that was recently funded by the Foundation. Entitled "Image-guided non-invasive ultrasonic thrombolysis using histotripsy," this project will attempt to create a new way to treat deep vein thrombosis (DVT) using the histotripsy effect of focused ultrasound. This preclinical study will determine whether or not histotripsy is safe and effective in dissolving blood clots that are found in the deep veins of the legs.

 

 

"Nonlinear physics of histotripsy based on interaction of shock waves with tissue is beautiful."
- Vera A. Khokhlova, DrSc

"Histotripsy addresses many of the limitations of thermal ablation--it uses the same instrumentation in a different way, adding more breadth to the field of focused ultrasound."- Larry A. Crum, PhD

 
Washington-Russian Collaboration Sends Shock Waves through Focused Ultrasound

 


The University of Washington research team led by Vera A. Khokhlova, DrSc, and Lawrence A. Crum, PhD (not pictured)
 

An alternative method of tissue fractionation--boiling histotripsy--has been developed in a unique collaboration between and the University of Washington (UW) in Seattle and Moscow State University (MSU) in Russia. Drs. Vera A. Khokhlova, Lawrence A. Crum, and the growing UW/MSU teams have developed the method that uses longer (millisecond instead of microsecond) duration focused ultrasound pulses to generate a millimeter-sized boiling bubble (instead of a cavitation cloud) through tissue heating by shocks. Two papers that detailed their groundbreaking work were published in Ultrasound in Medicine and Biology and the Journal of the Acoustical Society of America.

Last year, the team successfully collaborated with Dr. A. Partanen from Philips Healthcare to determine the feasibility of using the Sonalleve clinical MR-HIFU system for boiling histotripsy. Accurate characterization of the system was performed using acoustic holography and nonlinear modeling methods, showing its capability to generate high-amplitude shock wave fields in the focus. These results were published in the August 2013 issue of IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control.

READ MORE ABOUT ONGOING PROJECTS AND THE TECHNICAL DETAILS OF THIS WORK ►

 
 
 
A Histotripsy Timeline


Key publications of the milestones in the development of histotripsy include:

February 2014

August 2013

August 2013

October 2012

November 2011 February 2010 June 2004
IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control
Ultrasound in Medicine and Biology IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control
Acoustics Today Journal of the Acoustical Society of America Ultrasound in Biology and Medicine  IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control
Histotripsy-induced cavitation cloud initiation thresholds in tissues of different mechanical properties. Image-guided non-invasive ultrasound liver ablation using histotripsy: Feasibility study in an in vivo porcine model.
Character-
ization of a multi-element clinical HIFU system using acoustic holography and nonlinear modeling.
Disintegration of tissue using high intensity focused ultrasound: two approaches that utilize shock waves. Controlled tissue emulsification produced by high intensity focused ultrasound shock waves and millisecond boiling. Shock-induced heating and millisecond boiling in gels and tissue due to high intensity focused ultrasound.
Controlled ultrasound tissue erosion.
UM group published tissue thresholds that can be used to plan clinical treatments. UM's feasibility study for using histotripsy to treat hepatocellular carcinoma. UW's histotripsy method can be successfully performed on the Philips Sonalleve clinical system. Comprehen-
sive comparison of histotripsy written by collaboration between researchers at UM and UW.
This UW study showing boiling histotripsy as "an effective and reliable way to emulsify tissue." UW proved that shocked focal waveforms produced boiling in as little as 3 milliseconds. The first publication to describe histotripsy, published by the UM group.
 

Tom Davison, PhD, Chairman & CEO of HistoSonics

 
Company Profile: HistoSonics

Patients who are interested in participating in the pilot study, which is currently enrolling in Ann Arbor, Michigan and Toledo, Ohio, should go to www.bphresearchstudy.com

HistoSonics, Inc. is a Michigan-based company that is using the non-thermal histotripsy mechanism of focused ultrasound to treat benign prostatic hyperplasia (BPH). Although BPH causes an enlarged prostate, it does not lead to cancer-the unwanted cells need to be removed when they cause irritation or obstruction. Vortx RX is the company's investigational, image-guided, system for treating BPH. A pilot clinical trial is currently underway in North America to test the system's safety and initial effectiveness.

Q&A With HistoSonics Chairman & CEO Tom Davison, PhD

Q. How did you get involved in starting HistoSonics?
I was introduced to the University of Michigan (UM) Department of Tech Transfer in late 2007. UM asked me to help evaluate several medical device technologies in their patent portfolio, including histotripsy. Because of my experience in therapeutic ultrasound businesses (UltraCision and Sontra), UM asked me to review the histotripsy program to determine whether it should be licensed or had the potential to support a stand-alone business. At the completion of the consulting assignment, I acquired an option to license the histotripsy technology and intellectual property. After several years of planning, HistoSonics was founded in December 2009.

READ MORE ►

 
 
 
 
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