principle and bioeffects of focused ultrasound
Basic definitions
We define ultrasound as a mechanical wave that has a spectrum in the order of several hundreds of kHz to several MHz. Focused Ultrasound refers to the convergence of the mechanical wave in a specific point in the space. This focusing can be achieved mainly by three mechanisms:
Mechanical focusing, by shaping the ultrasound source with a geometry that make converges the wave. i.e., a spherical cap.
Diffraction by using a lens, just like in optics.
Electronic focusing. In this scenario we have a multi-element source where each element can be excited independently. It is possible to program the phase of the single in each element and then make converge the wave in a desired point in the space.
Each mechanism has its advantages and limitations. The mechanical focusing has the evident limitation of having a fixed location where ultrasound converges, but the source can be relatively simple to build and its cumbersomeness is small. The use of lens simplifies the construction of the source (it requires a flat source instead of a curved one) and allows some flexibility in the choice of the location of the focusing. In the other hand, as in optics, placing of lens is delicate and imply higher cumbersomeness when compared to the naturally focused sources. A multi-element source gives the maximum degree of freedom in terms of location of the focusing but its fabrication is complicated, it requires independent signal generation and amplification, and the cumbersomeness can be much more when compared to mechanical focusing and lens due to the complex connectivity of the elements.
The interest of focused ultrasound in biomedical applications
In the scope of biomedical applications, focused ultrasound is bringing a quite interested approach to treat localized diseases such as cancer. This is due to the following combination of factors:
Use of simple monochromatic waves in the frequency range of 300 KHz to 10 MHz.
The physical properties of the tissue, mostly the attenuation and absorption.
The amount of energy that can delivered by the current materials
All these factors have made possible that we can concentrate important amounts of energy inside the human tissue in a very small volume (a few cubic millimeters) and thus far from the device. By example, it is quite feasible to concentrate an intensity of 1000 W/cm2 all inside a volume of soft tissue of 40 mm3. The center of this volume can be located as far as several centimeters for the emitting source. The surrounding tissue to the "focal spot" receive much less energy dose (below 100 W/cm2). In the context of soft tissue such as muscle, prostate or liver, this scenario of energy concentration results in the formation of a small necrosis lesion by coagulation at the focal spot after 5 s of ultrasound exposure. The name of High Intensity Focused Ultrasound (HIFU) comes from this feasibility of concentrating such high levels of mechanical energy in a very small volume.
The main interest in medicine of HIFU comes then from this feasibility to concentrate mechanical energy. The first application of HIFU has been the destruction of well-targeted disease tissue such as localized prostate cancer or even brain tumors. Nevertheless, this concentration of energy can be also used in more moderate schema where the energy levels are much inferior and other therapeutic effects can be induced. Some of the most notable effects that be induced are the opening of the brain blood barrier to allow the passage of drugs into the brain tissue or the sonoporation effect to allow the passage of targeted drugs to specific cancer cells.
In the scope of biomedical applications, HIFU offers several important advantages for energy delivery inside the human body with the purpose of therapy:
It can penetrate deep in tissue
It is not ionizing
It does not have a maximal dose
It can focus energy in a very small volume (a few cubic millimeters) and this focusing can be controlled electronically
The energy concentrated at focus can be high enough to induce a well defined coagulation lesion by rising the temperature at focus around 80 degrees C after a few seconds. This feasibility of targeted lesion formation has been proposed for the ablation of localized tumours.
After introducing some micron-sized scatterers in the blood stream (contrast-agent), the energy level can be adjusted to be low enough to induce moderate effects in the cells to allow the passage of drugs otherwise impossible to deliver
The choice of mechanism of focusing depends a lot on the application. For proof-of-concept, it is not uncommon that a simple naturally focused source is more than enough, but there are commercial devices in treatment of localized cancer that uses a simple focused device, such as in the Ablatherm system. In the case of prostate cancer, it was the combination of several factors that allowed the use of a simple device: having a good access to the target; the mobility of the region to treat is minimal; and the feasibility of covering the treatment region with simple mechanical displacement of the source.
In the other hand, the main disadvantages of HIFU are:
Ultrasound does not travel through air. We need always to avoid air structures
Ultrasound needs for the most that tissue is compacted enough to allow a good passage of the wave. "Holes" or "gaps" in the interfaces of different tissues can compromise the effectiveness of the focusing.
Bone interfaces previous to the target are difficult to handle since bone diffracts a lot the ultrasound. However, the handling of bone interfaces is something that has received a lot of attention in the last years and the use of multi-elements devices allows to compensate the diffraction effects caused by the bone (i.e. treatment of brain tumours)
Cavitation effects can be induced and may not be desired (but may be desired depending on the application). This point deserves a special development, just read below.
The importance of cavitation in HIFU
Cavitation refers to the phenomenon of creating very small bubbles (micron size) under the effect of high pressure waves. Depending of the application, the presence of bubbles can be something positive if they oscillate moderately (non-inertial cavitation). Sometimes, bubbles are even injected previously under the form of contrast agent and the interaction of the acoustic waves and the bubbles allows therapeutic effects such as sonoporation. However, if bubbles are oscillating under very high pressure levels, the bubbles can collapse violently and produce destructive effects that are for the most difficult to control. Nevertheless, there are interesting and controlled situations of inertial cavitation that can be interesting for therapy. If very high-pressure waves are sent to the tissue but of very short duration, it is possibly to use inertial cavitation under well controlled environment (histotripsy)