High-intensity focused ultrasound
High intensity focused ultrasound (HIFU, or sometimes MRgFUS for magnetic resonance guided focused ultrasound) is a medical procedure that applies high intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation.
HIFU is a hyperthermia therapy, a class of clinical therapies that use temperature to treat diseases. HIFU is also one modality of therapeutic ultrasound, involving minimally invasive or non-invasive methods to direct acoustic energy into the body. In addition to HIFU, other modalities include ultrasound-assisted drug delivery, ultrasound hemostasis, ultrasound lithotripsy, and ultrasound-assisted thrombolysis.
Clinical HIFU procedures are typically performed in conjunction with an imaging procedure to enable treatment planning and targeting before applying a therapeutic or ablative levels of ultrasound energy. When Magnetic Resonance Imaging (MRI) is used for guidance, the technique is sometimes called Magnetic Resonance guided Focused Ultrasound, often shortened to MRgFUS or MRgHIFU.
Currently, HIFU is an approved therapeutic procedure to treat uterine fibroids in Asia, Australia, Canada, Europe, Israel and the United States. HIFU is approved for use in Bulgaria, China, Hong Kong, Germany, Italy, Japan, Korea, Malaysia, Mexico, Poland, Russia, Romania, Spain and the United Kingdom. Research for other indications is actively underway, including clinical trials evaluating the effectiveness of HIFU for the treatment of cancers of the brain, breast, liver, bone, prostate, as well as soft tissue tumors. At this time non-image guided HIFU devices are cleared to be on the market in the US, Canada, EU, Australia, and several countries in Asia for the purposes of body sculpting.
Therapeutic applications use ultrasound to bring heat or agitation into the body. Therefore, much higher energies are used than in diagnostic ultrasound. In many cases the range of frequencies used are also very different.
- Ultrasound sources may be used to generate regional heating and mechanical changes in biological tissue, e.g. in occupational therapy, physical therapy and cancer treatment. However the use of ultrasound in the treatment of musculoskeletal conditions has fallen out of favor.
- Focused ultrasound may be used to generate highly localized heating to treat cysts and tumors (benign or malignant), This is known as Magnetic Resonance guided Focused Ultrasound (MRgFUS) or High Intensity Focused Ultrasound (HIFU). These procedures generally use lower frequencies than medical diagnostic ultrasound (from 0.250 to 2 MHz), but significantly higher energies. HIFU treatment is often guided by MRI.
- Focused ultrasound may be used to break up kidney stones by lithotripsy.
- Ultrasound may be used for cataract treatment by phacoemulsification.
- Additional physiological effects of low-intensity ultrasound have recently been discovered, e.g. its ability to stimulate bone-growth and its potential to disrupt the blood–brain barrier for drug delivery.
- Procoagulant at 5–12 MHz
Development of this therapy significantly broadened the range of treatment options for patients suffering from uterine fibroids. HIFU treatment for uterine fibroids was approved by the Food and Drug Administration (FDA) in October 2004. This is a non-invasive treatment option for patients suffering from symptomatic fibroids. Most patients benefit from HIFU and symptomatic relief is sustained for two plus years. Up to 16-20% of patients will require additional treatment.
Other benign tumors
Echopulse was the first HIFU device to receive CE marking in 2007 for benign thyroid nodules and hypertrophic parathyroid glands ablation and in 2012 for breast fibroadenoma ablation. The first echotherapy treatments on neck were performed in 2004 and in 2011 for breast fibroadenomas. Echopulse applications are developed by Theraclion, a spin-off from EDAP, that conceived and commercialized the Ablatherm device.
Transcranial magnetic resonance guided focused ultrasound (tcMRgFUS surgery) is a promising new technology for the non-invasive treatment of various brain disorders. It is CE marked for the treatment of essential tremor, neuropathic pain and Parkinson’s Disease and available in medical centers in Europe and Asia.
This treatment is administered through a trans-rectal probe and relies on heat developed by focusing ultrasound waves into the prostate to kill the tumor. Promising results have been reported in people with prostate cancer. These treatments are performed under ultrasound imaging guidance, which allows for treatment planning and some minimal indication of the energy deposition. This is an outpatient procedure that usually lasts 1–3 hours.
Traditionally, the entire prostate is ablated, including the prostatic urethra. The urethra has regenerative ability because it is derived from a different type of tissue (bladder squamous-type epithelium) rather than prostatic tissue (glandular, fibrotic and muscular). While the urethra is an important anatomical structure, the sphincter and bladder neck are more important to maintaining the urinary function. During HIFU the sphincter and bladder neck are identified and avoided.
HIFU has been found to offer palliative care. CE approval has been given for palliative treatment of bone metastasis. Experimentally, a palliative effect was found in cases of advanced pancreatic cancer.
HIFU may be used to create high temperatures not necessarily to treat the cancer alone, but in conjunction with targeted delivery of cancer drugs. For example, HIFU and other devices may be used to activate temperature-sensitive liposomes, filled with cancer drug "cargo" to release the drug in high concentrations only at the tumor site(s) only where triggered to do so by the hyperthermia device (See Hyperthermia therapy).
HIFU devices have been cleared to treat subcutaneous adipose tissue for the purposes of body contouring (known colloquially, and incorrectly since there is no suction involved, as " non-invasive liposuction"). These devices are available in the US, Canada, the EU, Australia, and certain countries in Asia. HIFU is also cleared for eyebrow lifts, albeit with lower energy levels.
Method of use
In HIFU therapy, ultrasound beams are focused on diseased tissue, and due to the significant energy deposition at the focus, temperature within the tissue can rise to levels from 65° to 85 °C, destroying the diseased tissue by coagulation necrosis. Higher temperature levels are typically avoided to prevent boiling of liquids inside the tissue. Each sonication of the beams theoretically treats a precisely defined portion of the targeted tissue, although in practice cold spots (caused by, among other things, blood perfusion in the tissue), beam distortion, and beam mis-registration are impediments to finely controlled treatments. The entire therapeutic target is treated by moving the applicator on its robotic arm in order to juxtapose multiple shots, according to a protocol designed by the physician. This technology can achieve precise ablation of diseased tissue, therefore is sometimes called HIFU surgery. Because it destroys the diseased tissue non-invasively, it is also known as "Non-invasive HIFU surgery". Anesthesia is not required, but is generally recommended.
Mechanism of action
As an acoustic wave propagates through the tissue, part of it is absorbed and converted to heat. With focused beams, a very small focus can be achieved deep in tissues (usually on the order of milimeters, with the beam having a characteristic "cigar" shape in the focal zone, where the beam is longer than it is wide along the transducer axis). Tissue damage occurs as a function of both the temperature to which the tissue is heated and how long the tissue is exposed to this heat level in a metric referred to as "thermal dose". By focusing at more than one place or by scanning the focus, a volume can be thermally ablated. At high enough acoustic intensities, cavitation (microbubbles forming and interacting with the ultrasound field) can occur. Microbubbles produced in the field oscillate and grow (due to factors including rectified diffusion), and can eventually implode (inertial or transient cavitation). During inertial cavitation, very high temperatures inside the bubbles occur, and the collapse is associated with a shock wave and jets that can mechanically damage tissue. Because the onset of cavitation and the resulting tissue damage can be unpredictable, it has generally been avoided in clinical applications.
There are several ways to focus ultrasound -- via a lens (for example, a polystyrene lens), a curved transducer, a phased array, or any combination of the three. This concentrates it into a small focal zone; it is similar in concept to burning ants by focusing light through a magnifying glass. This can be determined using an exponential model of ultrasound attenuation. The ultrasound intensity profile is bounded by an exponentially decreasing function where the decrease in ultrasound is a function of distance traveled through tissue:
is the initial intensity of the beam, is the attenuation coefficient (in units of inverse length), and z is distance traveled through the attenuating medium (e.g. tissue).
In this model,  is a measure of the power density of the heat absorbed from the ultrasound field. Sometimes, SAR is also used to express the amount of heat absorbed by a specific medium, and is obtained by dividing Q by the tissue density. This demonstrates that tissue heating is proportional to intensity, and that intensity is inversely proportional to the area over which an ultrasound beam is spread -- therefore, focusing the beam into a sharp point (i.e. increasing the beam intensity) creates a rapid temperature rise at the focus.
The amount of damage caused in the tissue can be modeled using Cumulative Equivalent Minutes (CEM). Several formulations of the CEM equation have been suggested over the years, but the equation currently in use for most research done in HIFU therapy comes from a 1984 paper by Dewey and Sapareto:
with the integral being over the treatment time, R=0.5 for temperatures over 43 °C and 0.25 for temperatures between 43 °C and 37 °C, a reference temperature of 43 °C, and time in minutes. This formula is an empirical formula derived from experiments performed by Dewey and Sapareto by measuring the survival of cell cultures after exposure to heat.
The ultrasound beam can be focused in these ways:
- Geometrically, for example with a lens or with a spherically curved transducer.
- Electronically, by adjusting the relative phases of elements in an array of transducers (a "phased array"). By dynamically adjusting the electronic signals to the elements of a phased array, the beam can be steered to different locations, and aberrations in the ultrasound beam due to tissue structures can be corrected.
High Intensity Focused Ultrasound requires a location tracking position to ensure safety and to verify that currents are going to the proper place. This allows lesion formation to be controlled where tissues are destroyed. Examples of this include x-ray, MRI, and Diagnostic Ultrasound. The most basic method of this is Visual monitoring. X-rays were the earliest form of guidance. MRI allows tissue contrast for localization of target volume, characterization of diffusion, perfusion, flow, and temperature, enabling detection of tissue damage. Diagnostic Ultrasound can indicate treatment progress by showing the area as hyper echoic images in real time during the scan. 
The first investigations of HIFU for non-invasive ablation were reported by Lynn et al. in the early 1940s. Extensive important early work was performed in the 1950s and 1960s by William Fry and Francis Fry at the University of Illinois and Carl Townsend, Howard White and George Gardner at the Interscience Research Institute of Champaign, Ill., culminating in clinical treatments of neurological disorders. In particular High Intensity ultrasound and ultrasound visualization was accomplished stereotaxically with a Cincinnati precision milling machine to perform accurate ablation of brain tumors. Until recently, clinical trials of HIFU for ablation were few (although significant work in hyperthermia was performed with ultrasonic heating), perhaps due to the complexity of the treatments and the difficulty of targeting the beam noninvasively. With recent advances in medical imaging and ultrasound technology, interest in HIFU ablation of tumors has increased.
The first commercial HIFU machine, called the Sonablate 200, was developed by the American company Focus Surgery, Inc. (Milipitas, CA) and launched in Europe in 1994 after receiving CE approval, bringing a first medical validation of the technology for benign prostatic hyperplasia (BPH). Comprehensive studies by practitioners at more than one site using the device demonstrated clinical efficacy for the destruction of prostatic tissue without loss of blood or long term side effects. Later studies on localized prostate cancer by Murat and colleagues at the Edouard Herriot Hospital in Lyon in 2006 showed that after treatment with the Ablatherm (EDAP TMS, Lyon, France), progression-free survival rates are very high for low- and intermediate- risk patients with recurrent prostate cancer (70% and 50% respectively) HIFU treatment of prostate cancer is currently an approved therapy in Europe, Canada, South Korea, Australia, and elsewhere. Clinical trials for the Sonablate 500 in the United States are currently ongoing for prostate cancer patients and those who have experienced radiation failure.
Use of magnetic resonance-guided focused ultrasound was first cited and patented in 1992. The technology was later transferred to InsighTec in Haifa Israel in 1998. The InsighTec ExAblate 2000 was the first MRgFUS system to obtain FDA market approval in the United States.
The International Society for Therapeutic Ultrasound (ISTU), founded in 2001, aims to promote clinical, academic and industrial advancement in therapeutic ultrasound.
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