One of the main interaction mechanisms that occur during the propagation of an ultrasonic wave through tissues is the possibility of acoustic cavitation. Cavitation is a complex phenomenon that involves creation, oscillation, growth and collapse of bubbles within a liquid medium to local pressure variation. A consequence of the cavitation process is the release of an enormous amount of energy in the form of an acoustic shock wave, temperature, pressure, and as visible light. When the acoustic cavitation bubble collapses close to or on a solid surface, it can collapse asymmetrically and produce high-speed jets of liquid being driving into the surface of the solid have been observed at speeds close to 400 km/h [1]. This can seriously damage the impact zone and create a newly exposed surface. This fact makes cavitation one of the important mechanism in shock wave lithotripsy for kidney stone destruction. Cavitation can also injure tissue during lithotripsy [2]. Studies [3–5] have provided indirect evidence that tissue injury response during shock-wave lithotripsy corresponds to cavitation. A number of studies have been attempted to control cavitation to obtain accelerated fragmentation while minimizing cell lysis and tissue injury [2]. Furthermore, cloud cavitation (bubble cloud) which is produced during lithotripsy is potentially the most destructive form of cavitation [2]. It has been shown that cloud cavitation is more destructive to high-speed turbo-pumps and ship propellers than the individual bubbles collapse [2]. The effect of cavitation on tissue has made a potential non-invasive therapy application of ultrasound for tissue fractionation and treatment of benign disease and cancer [6, 7]. It has been estimated that rapid adiabatic compression of gases and vapours within the bubbles or cavities produces hot spots with extremely high temperature and pressure approaching 5000 °C and 1000 atm during this collapse. As ultrasound propagates through tissue, part of its energy is absorbed by tissue which is converted to heat and energetic microbubbles that can result in cellular destruction. Damage to red blood cells [8], lung damage in mice by pulsed ultrasound in the diagnosis imaging range [9], lung lesions of pig, mice, rabbits, rats, monkey and dogs during ultrasound [3, 10–17] bring concern in ultrasonography. Furthermore, high intensity focused ultrasound treatment (HIFU) in which the ultrasound is focused into a small focal zone can damage tissue as a result of the very high temperature inside the bubbles produced, the collapse that creates a shock wave and jets, and also time duration of tissue exposure. The high temperature produced at the focal point HIFU leads to instantaneous cell death and coagulative necrosis at the focal point and with the margin of six to ten cells between live and dead cells at the edge [18]. Since the onset of cavitation and the resulting tissue damage is not predictable, high acoustic intensity is generally avoided in clinic, however cavitation is under investigation to be used as a means to enhance HIFU ablation. Another application of cavitation is in a relatively new field of medical therapy [19, 20] in which cavitation in HIFU is used for drug delivery in selectively permeable regions of tissue [21, 22]. Direct evidence of cavitation bubbles within the tissue is crucial for further development and refinement of such applications. In HIFU, gas generation, caused by cavitation, abruptly changes the pattern of heat transfer induced by ultrasound, which results in the extension of lesion from targeted area to surrounding healthy tissues [23]. The lack of cavitation bubble field probes is one of the reasons that limit the clinical development of cavitation. Consequently, it is essential to conduct a fundamental study for cavitation detection and cloud cavitation control to improve the safety and application of ultrasound therapy (such as lithotripsy and HIFU) and possibly for ultrasonography which is pervasively used for neonatal imaging.
The variation in bubble characteristics inside the cavitation field is one of the causes that make the study of cavitation characteristics so complex [24]. Once the cavitation bubbles are generated, they may undergo nonlinear oscillations during many cycles of the acoustic wave, called “stable cavitation”, or they may grow and collapse more or less violently, called “inertial cavitation” [24]. The cavitation state induced in liquid is seldom studied in most experiments. It is important to develop monitoring methods to correlate the cavitation state induced in a liquid to the biological effects observed. Since visualization of cavitation bubble field has been quite complex, workers have used some other indirect observations of macroscopic criteria to describe the induced cavitation state in a liquid [24]. However, the easiest way to study cavitation is the direct observation of the bubble field. In addition, to study the cavitation field in the body, a technique that enables detection of cavitation bubbles in tissue is required.
So far there have been a number of techniques for direct observation of the bubble field such as high speed photography [25–28], laser scattering of single bubbles, and acoustic detection of bubbles [29]. The high speed photography techniques are only applicable in in vitro systems and it is virtually impossible to capture all the bubbles considering the range of temporal and spatial scales. This technique has a very limited depth of field due to the camera [30], and in addition, the sound wave that produces the cavitation induces an acoustic-optic effect [24]. Also, the presence of collapsing bubbles can be inferred from second harmonic generation [29]. With laser scattering method, most of the temporal and spatial scales related to the dynamics of a cavitation bubble can be captured; however this method is not able to give qualitative information about bubbles or non-spherical bubbles. In addition, the theory behind this method is only applied to spherical shape bubbles considering that all forms of bubbles, spherical and non-spherical, are produced in clinical application of ultrasound [30]. In this technique the volume of the sample is very small and unrestricted visual access at high magnification is required [30]. The acoustic detection technique has the positive aspect of in vivo application, however the size of the initial cavitation bubble and the amplitude of the ultrasound that produced the cavitation bubbles, affect the timing and amplitude of the cavitation bubbles’ emissions.
Analyzer-based X-ray imaging (ABI) [31] has the potential to detect and visualize ultrasound cavitation bubbles in thick, optically opaque materials such as in vivo tissue relying on the high penetration of X-rays and a sensitivity to small angle refraction. As such, ABI can visualize and characterize properties of the cavitation bubbles in vivo without having any influence on the bubbles or vice versa.
The present authors have used ABI for visualizing cavitation bubbles from a high intensity sonochemistry system [32]. In that work, the operating conditions are well beyond that used for any physical therapy or imaging application (130 W and 20 kHz). The system relies on generating cavitation bubbles for cell disruption. The present paper addresses cavitation bubble formation in a type of ultrasound system commonly used for physical therapy applications (14 W and 0.88 MHz) where one might not expect to observe cavitation bubbles. Again, the use of an X-ray method can allow observation of cavitation in opaque systems without interacting with the cavitation process.
X-ray ABI
X-ray ABI is a phase sensitive imaging technique that can detect subtle projected density and thickness variations in materials such as tissue. As a collimated X-ray beam travels through the object being imaged, it may be refracted, scattered or absorbed. Small structures such as a bubble in tissue or water will refract the X-rays through very small angles. With ABI, these small angles can create contrast based on the very narrow reflectivity curve of the analyzer crystal placed after the object. Thus the ABI technique is particularly well suited to visualize interfaces between features within soft tissues such as bubbles. This leads to very high contrast for some tissues such as lung particularly when the analyzer is placed at the peak position. The alveoli appear as a “bubbly” structure which very effectively refracts the X-rays and thus create contrast. The effect of multiple refraction events by several alveolar interfaces creates a scatter distribution (ultra-small angle X-ray scattering) of the X-rays which effectively removes X-rays from their original collimated trajectory. This scatter distribution can be very effectively interrogated by the analyzer crystal.
Detecting ultrasound cavitation bubbles in tissues can be simplified by ABI. The bubbles will be of a transient nature and should provide enough contrast to be imaged in a time averaged exposure. For example, a single air bubble the same size as a detector pixel can generate ~20 % contrast compared to a region not containing a bubble. Applying ABI the density of stationary and moving bubbles in the tissue and intravascular can be indirectly inferred by measuring the ultra-small angle X-ray scattering distribution in the zone of images where bubbles are formed. However, at the top or peak spot of the analyzer, there is a recognizable loss of intensity due to scattering from the bubbles. With ABI, the X-ray imaging beam is prepared, or collimated, by Bragg diffraction from a perfect crystal monochromator which is typically made with silicon crystals (see Fig. 1). A double crystal arrangement is applied so that the imaging energy can be varied while the exit beam is in the same direction as the incident synchrotron beam. The imaging energy is usually selected based on the sample’s composition, thickness and features of interest. The object is located in the beam with an analyzer crystal downstream of the object before the detector. The analyzer is parallel to the double monochromator crystals and is of the same direction, reflection and crystal type. In this arrangement, as the analyzer is locked in angle near the Bragg angle for the energy and lattice plans selected, the intensity profile is called a rocking curve. When the X-ray beam passes through the sample being imaged, the X-rays are refracted at the interfaces of features or structures in the sample through angles of a few nanoradians to microradians. The analyzer can be adjusted over these angular ranges and the character of the image is greatly affected by the angular setting. The analyzer at the peak setting is sensitive to X-rays redirected in angle such as scatter and removes it from the image. The ABI experimental procedure is explained in more detail in other publications [31] [33, 34]. ABI has demonstrated a noticeable ability to image structures that have interfaces between materials of various density such as that between air and water in a bubble. The cavitation bubble will be of a transient nature; however, they are continuously created and may provide enough contrast to be imaged in a time averaged exposure.