Focused Ultrasound Therapy

In this page, i will first examine high intensity focused ultrasound using heat. (Section A). In the second section, i will look at the same ultrasound therapy system, but without the use of heat, what is called histotripsy. (Section B). In section C, a case in point with liver cancer will be presented. (Section C)

Section A


Part of General Surgery is moving toward minimally-invasive procedures, using laparoscopic approaches with instruments inserted through tiny incisions or catheters placed in blood vessels through puncture sites. These techniques minimize the risks to the patient such as bleeding complications or infection dur- ing surgery.

Taken a step further, high-intensity focused ultrasound (HIFU) can provide a tool to accomplish many of the same procedures without any incision at all. (1-5)

High Intensity Focused Ultrasound

With HIFU, an ultrasound transducer can be positioned outside the body and focused through the skin and overlying tissue to deliver high-amplitude ultrasound to a target structure such as a tumor (Cf Exhibit A). Absorption of acoustic energy within the focal volume is high enough to rapidly heat the tissue, effectively ‘cooking’ it within seconds or even a fraction of a second. This procedure also removes the need for a sterile operating room: without the risk of infection, HIFU noninvasive therapy could be done in the doctor’s office or outpatient clinic.

While thermal ablation is the dominant interaction at lower HIFU focal intensities, higher intensities can introduce other bioeffects. If the temperature rises to 100o C during sonication, boiling bubbles appear in the tissue, inducing additional mechanical as well as thermal damage. At higher focal intensities, mechanical effects of the ultrasound wave itself become significant. 7,8

The large tension phase of the wave can cause sporadic inertial cavitation or even a cloud of cavitation bubbles in the focal region in tissue—a process where the small gas bubbles grow and violently collapse, creating destructive effects on the tissue. Nonlinear propagation effects result in formation of high-amplitude shock waves around the focus which themselves create mechanical stress in the tissue. In addition, significantly enhanced heat deposition at the shocks can induce boiling in tissue in millisec- onds, much faster than typical HIFU exposures. Extracorporeal shockwave lithotripsy uses such focused shock waves and cavitation to break up kidney stones.    9

Recent HIFU studies have shown that the presence of shocks and cavities, induced by HIFU either as a cavitation cloud or boiling, can be also used to break up or mechan- ically fractionate soft tissues to tiny debris—an outcome similar to disintegration in a “remote” blender.

Section B


This ultrasound-induced tissue disintegration opens a new direction in development of HIFU medical technology. The technique has been dubbed ‘histotripsy’ (the prefix histo- translated from Greek to mean tissue), as an analog to lithotripsy. Two separate techniques to perform histotripsy with ultrasound shock waves have been demonstrated thus far: one using a cloud of cavitation bubbles and another that uses boiling bubbles. The cavitation-based approach has been developed over the last 11 years at the University of Michigan,10-12 while the boiling-based method was discovered a few years ago at the University of Washington.13-15 The mechanisms of generating bubbles through each mode are quite different, but surprisingly, both techniques produce similar lesions through tissue disintegration.

Histotripsy could be employed as a noninvasive treat- ment for many diseases, such as malignant tumors, benign prostatic hyperplasia (BPH), deep vein thrombosis, and congenital heart defects. The unique ability of histotripsy to actually liquefy the tissue (rather than just thermally destroying it) means that the lesion content can be passed out of natural body orifices or easily reabsorbed by sur- rounding tissue. For instance, excess prostate tissue for BPH can be passed through the urinary system, offering imme- diate decompression and relief of symptoms. Thus far, both cavitation and boiling techniques have been demonstrated in animal studies.16-18

Although the most clinically advanced focused ultrasound therapies use heat to destroy unhealthy tissue, an innovative technique called  histotripsy  has been developed thanks to which non-thermal ultrasonic  mechanically destroys target tissue. This  Nonlinear physics mechanisms appears to be based on  the interaction of shock waves with tissue material. 

“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

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.

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:

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 others, shows that the work that has accumulated on this technique has reached a critical mass: Important clinical breakthroughs may be imminent. OUT

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 and one on dual-beam histotripsy.

 These results support our hypothesis, improve our understanding of the effect of histotripsy in tissues with different mechanical properties, and provide a rational basis to tailor acoustic parameters for fractionation of specific tissues. (Source)    19.  (1)

Section C

Is Histotripsy Better for Liver Cancers?

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.

“This work shows that histotripsy is capable of non-invasively fractionating liver tissue while preserving critical anatomic structures within the liver. Results suggest histotripsy has potential for the non-invasive ablation of liver tumors”. (Source) (2) 20

Sound waves prove to be viable for Prostate Cancer

High-intensity focused ultrasound therapy proved to be a highly-effective cancer treatment in various studies and clinical trials including prostate cancer. In this perspective, researchers at the University College Hospital in London examined 625 men with prostate cancer and found that 93 percent of patients who underwent HIFU alone remained cancer-free at five years following the treatment, without requiring surgery or radiotherapy. Data also showed that only one to two percent of patients who had HIFU treatment suffered long-term urinary incontinence, compared with 10 to 20 percent of patients who had surgery. In addition, only 15 percent of patients in the HIFU group developed erectile dysfunction compared with 30 to 60 percent of surgical patients.

“The results of this study are impressive and have the potential to transform prostate cancer treatment for many men in the future. It is extremely exciting technology and these results show that in men diagnosed early by prostate-specific antigen (PSA) blood testing, this targeted therapy could be as effective as surgery to remove the whole prostate gland or radiotherapy and cause far fewer side effects,” said study co-author Tim Dudderidge.

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Fig. 1. Diagram of HIFU surgery. The transducer emits a focused ultrasound beam through the overlying tissue layers to create a high intensity region within the organ. The focus can be translated to ablate the entire volume of interest.

Discussion and future Prospects

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. CLots, benign tu..arthirtism cancer and more.

The technique in question, known as histotripsy, uses ultrasound to mechanically destroy cancerous or other targeted tissues. This is a departure from traditional ultrasound therapy, which destroys tissues using heat.

Tumor-destroying technique uses currently available technology

In histotripsy, ultrasound-induced vibration leads to the production of bubbles formed from dissolved gases. If the vibration continues at high enough intensities, the bubbles eventually collapse, release a shock wave that can completely liquefy cells. A series of these collapses (known as inertial cavitation) can destroy a vast section of tissue, such as a tumor. Scientists can accelerate the process by injecting microbubbles into the tissue before the procedure.

Studies have shown that histotripsy can totally liquefy tumors, and can do so with remarkable precision and minimal impact on healthy surrounding tissue.

To date, three forms of histotripsy have been developed. The original method, shock scattering histotripsy, uses high intensity pulses ranging in length from 2 to 20 microseconds. More recently, researchers have developed an even more high intensity form, intrinsic threshold histotripsy, which uses pulses only 0.1 to 2 microseconds long.

The University of Washington researchers were experimenting with the third form, known as boiling histotripsy, which combines vibration and heat to produce the same effect as more conventional histotripsy. The main advantage of this technique is that it requires much less energy, and can be more easily produced by adapting existing technology.




High intensity focused ultrasound has been previously applied to ablate tissue noninvasively through absorption- induced heating. However, at very high focal pressure amplitudes, strong nonlinear effects manifest such as shock formation, cavitation, and rapid boiling resulting in mechanical effects. At their extreme, these phenomena can be applied to completely disintegrate tissue structures, i.e., to produce histotripsy. Both histotripsy technologies overviewed in this article may hold advantages over thermal therapy. While the dose must be tightly regulated in thermal therapy to control heat diffusion and collateral tissue dam- age, blood vessels can transfer heat away from the treatment site by convection, causing distortion of a thermal lesion. Cavitation clouds and shock-induced boiling are inherently self-limited to the focal volume by the processes described above. Because heat diffusion is not an essential component of histotripsy, the modalities described above may provide a much more compelling argument for the wider clinical acceptance of noninvasive, focused-ultrasound therapy. In addition, bubbles and tissue breakdown can also be visual- ized on ultrasound imaging as targeting feedback for the surgeon, while acoustic detection of heating is very diffi- cult. Finally, the ability to actually disintegrate tissue rather than just causing necrosis may aid reabsorption into the body and allows new clinical applications which cannot be accomplished with thermal HIFU.

It may be surprising that the same effect can be achieved by two completely separate paths, using different acoustic pulsing schemes. However, both of these schemes utilize relatively large cavities (0.1 – 1 mm) created in the tissue to achieve the effect, generated in different ways. It may be stress induced by expansion and collapse of the bub- bles or atomization that fractionate tissue. In reality, it is likely that each mechanism contributes in some degree to both cavitation and boiling histotripsy. Regardless, it is clear that nonlinear acoustic propagation and shock waves play a critical role in both the creation of the cavitation cloud and the vapor cavities of millisecond boiling, as well as provid- ing mechanisms of ultrasound interaction between tissue


“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




and bubbles. These studies reflect the importance of acoustic principles in understanding and predicting the interactions that drive this new medical technology.

This article discusses the acoustics of both types of histotripsy – including the processes of gener- ation and focusing of intense ultrasound, the formation of cavitation clouds and rapid boiling in tissue, and the inter- actions of ultrasound shock waves with bubbles leading to tissue disintegration

British J. Urol. Int. 106(7), 1004–1009 (2010).

UPdatea nd where to go Conslult


Fig. 2. Bioeffects of focused ultrasound at different focal intensity levels. At lower intensities, heating through acoustic absorption is the dominant mechanism, denaturing proteins within the tissue, leaving a blanched appearance. Boiling cavities form in the lesion when the temperature reaches 100oC. At higher intensities, heating combined with microbubble cavitation can cause mechanical trauma to the tissue structure. At very high intensities, shockwaves form at the focus and the wave itself can impart sig- nificant mechanical damage such as comminution of kidney stones (lithotripsy) or fractionation of soft tissues (histotripsy).

Disintegration of Tissue Using HIFU 25


1 F. Wu, W. Zhi-Biao, C. Wen-Zhi, Z. Hui, B. Jin, Z. Jian-Zhong, L. Ke-Quan, J. Cheng-Bing, X. Fang-Lin, and S. Hai-Bing, “Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma,” Ann. Surg. Oncol. 11,1061–1069 (2004).

2 T. J. Dubinsky, C. Cuevas, M. K. Dighe, O. Kolokythas, and J. H. Hwang, “High-intensity focused ultrasound: Current potential and oncologic applications, “Am. J. Roentgenol. 190, 191–199 (2008).

3 G. K. Hesley, K. R. Gorny, T. L. Henrichsen, D. A. Woodrum, and D. L. Brown, “A clinical review of focused ultrasound abla- tion with magnetic resonance guidance: An option for treating uterine fibroids,” Ultrasound Quarterly 24(2), 131–139 (2008).

4 S. Crouzet, F. J. Murat, G. Pasticier, P. Cassier, J. Y. Chapelon, and A. Gelet, “High intensity focused ultrasound (HIFU) for prostate cancer: current clinical status, outcomes and future per- spectives,” Int. J. Hyperthermia 26(8), 796–803 (2010).

5 R. W. Ritchie, T. Leslie, R. Phillips, F. Wu, R. Illing, G. ter Haar, “Protheroe A and Cranston D. Extracorporeal high intensity focused ultrasound for renal tumours: A 3-year follow-up,” British J. Urol. Int. 106(7), 1004–1009 (2010).

7 J. Tavakkoli, A. Birer, A. Arefiev, F. Prat, J. Chapelon, and D. A. Cathignol “Piezocomposite shock wave generator with electron- ic focusing capability: Application for producing cavitation- induced lesions in rabbit liver. Ultrasound Med. Biol 23(1), 107–115 (1997).

8 N. Smith and K. Hynynen, “The feasibility of using focused ultrasound for transmyocardial revascularization,” Ultrasound Med. Biol. 24(7), 1045–1054 (1998).

9 M. R. Bailey, J. A. McAteer, Y. A. Pishchalnikov, M. F. Hamilton, T. Colonius, “Progress in lithotripsy research,” Acoustics Today 2, 18–29 (2006).

10 J. E. Parsons, C. A. Cain, G. D. Abrams, and J. B. Fowlkes, “Pulsed cavitational ultrasound therapy for controlled tissue homogenization,” Ultrasound Med. Biol. 32, 115–129 (2006).

11 Z. Xu, A. Ludomirsky, L. Y. Eun, T. L. Hall, B. C. Tran, J. B. Fowlkes, C. A. Cain, “Controlled ultrasound tissue erosion,

12  Z. Xu, J. B. Fowlkes, E. D. Rothman, A. M. Levin, C. A. Cain,“Controlled ultrasound tissue erosion: The role of dynamic interaction between insonation and microbubble activity,” J. Acoust. Soc. Am. 117, 424–435 (2005).

13  M. Canney, V. Khokhlova, J. H. Hwang, T. Khokhlova, M. Bailey, L. Crum, “Tissue erosion using shock wave heating and mil- lisecond boiling in high intensity ultrasound field,” in: Proc. 9th International Symposium on Therapeutic Ultrasound (23–26 September 2009, Aix-en-Provence, France), pp.36–39.

14  M. S. Canney, V. A. Khokhlova, O. V. Bessonova, M. R. Bailey, L. A. Crum, “Shock-induced heating and millisecond boiling in gels and tissue due to high intensity focused ultrasound,” Ultrasound Med. Biol. 36, 250–267 (2010).

15  T. D. Khokhlova, M. S. Canney, V. A. Khokhlova, O. A. Sapozhnikov, L. A. Crum, M. R. Bailey, “Controlled tissue emul- sification produced by high intensity focused ultrasound shock,” J. Acoust. Soc. Am. 130, 3498–3510 (2011)

16  W. W. Roberts, T. L. Hall, K. Ives, J. S. Wolf Jr., J. B. Fowlkes, and C. A. Cain, “Pulsed cavitational ultrasound: A noninvasive tech- nology for controlled tissue ablation (histotripsy) in the rabbit kidney,” J. Urol. 175(2), 734–738 (2006).

17  Z. Xu, G. Owens, D. Gordon, C. Cain, A. Ludomirsky, “Noninvasive creation of an atrial septal defect by histotripsy in a canine model,” Circulation 121, 742–749 (2011).

18  T. D. Khokhlova, J. Simon, Y-N. Wang, V. A. Khokhlova, M. Praun, F. Starr, P. Kaczkowski, L. A. Crum, J-H. Hwang, M. R. Bailey, “In vivo tissue emulsification using millisecond boiling induced by high intensity focused ultrasound,” J. Acoust. Soc. Am. 129, 2477(A) (2011).


” Histotripsy is an ultrasound ablation method that depends on the initiation and maintenance of a cavitation bubble cloud to fractionate soft tissue. This paper studies how tissue properties impact the pressure threshold to initiate the cavitation bubble cloud. Our previous study showed that shock scattering off one or more initial bubbles, expanded to sufficient size in the focus, plays an important role in initiating a dense cavitation cloud. In this process, the shock scattering causes the positive pressure phase to be inverted, resulting in a scattered wave that has the opposite polarity of the incident shock. The inverted shock is superimposed on the incident negative pressure phase to form extremely high negative pressures, resulting in a dense cavitation cloud growing toward the transducer. We hypothesize that increased tissue stiffness impedes the expansion of initial bubbles, reducing the scattered tensile pressure, and thus requiring higher initial intensities for cloud initiation. To test this hypothesis, 5-cycle histotripsy pulses at pulse repetition frequencies (PRFs) of 10, 100, or 1000 Hz were applied by a 1-MHz transducer focused inside mechanically tunable tissue-mimicking agarose phantoms and various ex vivo porcine tissues covering a range of Young’s moduli. The threshold to initiate a cavitation cloud and resulting bubble expansion were recorded using acoustic backscatter detection and optical imaging. In both phantoms and ex vivo tissue, results demonstrated a higher cavitation cloud initiation threshold for tissues of higher Young’s modulus. Results also demonstrated a decrease in bubble expansion in phantoms of higher Young’s modulus. These results support our hypothesis, improve our understanding of the effect of histotripsy in tissues with different mechanical properties, and provide a rational basis to tailor acoustic parameters for fractionation of specific tissues. (Source) (1)

(20).  Hepatocellular carcinoma (HCC), or liver cancer, is one of the fastest growing cancers in the United States. Current liver ablation methods are thermal based and share limitations resulting from the heat sink effect of blood flow through the highly vascular liver. In this study, we explore the feasibility of using histotripsy for non-invasive liver ablation in the treatment of liver cancer. Histotripsy is a non-thermal ablation method that fractionates soft tissue through the control of acoustic cavitation. Twelve histotripsy lesions ∼1 cm3 were created in the livers of six pigs through an intact abdomen and chest in vivo. Histotripsy pulses of 10 cycles, 500-Hz pulse repetition frequency (PRF), and 14- to 17-MPa estimated in situ peak negative pressure were applied to the liver using a 1-MHz therapy transducer. Treatments were performed through 4–6 cm of overlying tissue, with 30%–50% of the ultrasound pathway covered by the rib cage. Complete fractionation of liver parenchyma was observed, with sharp boundaries after 16.7-min treatments. In addition, two larger volumes of 18 and 60 cm3 were generated within 60 min in two additional pigs. As major vessels and gallbladder have higher mechanical strength and are more resistant to histotripsy, these remained intact while the liver surrounding these structures was completely fractionated.

Disclaimer: Nothing in this educational blog should be construed as medical advise
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