Application of analyzer based X-ray imaging technique for detection of ultrasound induced cavitation bubbles from a physical therapy unit
© Izadifar et al. 2015
Received: 6 July 2015
Accepted: 29 September 2015
Published: 19 October 2015
The observation of ultrasound generated cavitation bubbles deep in tissue is very difficult. The development of an imaging method capable of investigating cavitation bubbles in tissue would improve the efficiency and application of ultrasound in the clinic. Among the previous imaging modalities capable of detecting cavitation bubbles in vivo, 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.
The spatial distribution of cavitation bubbles, driven by 0.8835 MHz therapeutic ultrasound system at output power of 14 Watt, was studied in water using a synchrotron X-ray imaging technique, Analyzer Based Imaging (ABI). The cavitation bubble distribution was investigated by repeated application of the ultrasound and imaging the water tank. The spatial frequency of the cavitation bubble pattern was evaluated by Fourier analysis. Acoustic cavitation was imaged at four different locations through the acoustic beam in water at a fixed power level. The pattern of cavitation bubbles in water was detected by synchrotron X-ray ABI.
The spatial distribution of cavitation bubbles driven by the therapeutic ultrasound system was observed using ABI X-ray imaging technique. It was observed that the cavitation bubbles appeared in a periodic pattern. The calculated distance between intervals revealed that the distance of frequent cavitation lines (intervals) is one-half of the acoustic wave length consistent with standing waves.
This set of experiments demonstrates the utility of synchrotron ABI for visualizing cavitation bubbles formed in water by clinical ultrasound systems working at high frequency and output powers as low as a therapeutic system.
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 . 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 . 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 . Furthermore, cloud cavitation (bubble cloud) which is produced during lithotripsy is potentially the most destructive form of cavitation . It has been shown that cloud cavitation is more destructive to high-speed turbo-pumps and ship propellers than the individual bubbles collapse . 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 , lung damage in mice by pulsed ultrasound in the diagnosis imaging range , 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 . 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 . 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 . 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” . 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 . 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 . 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 , and in addition, the sound wave that produces the cavitation induces an acoustic-optic effect . Also, the presence of collapsing bubbles can be inferred from second harmonic generation . 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 . In this technique the volume of the sample is very small and unrestricted visual access at high magnification is required . 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)  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 . 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 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.
Tap water was used as the sample to produce ultrasound induced cavitation bubbles in it. The tap water was pre-boiled and let stand for 48 h in advance the experiment.
Imaging of therapeutic ultrasound induced cavitation bubbles was performed at the CLS synchrotron source (BMIT-BM 05B1-1). A highly collimated, monochromatic, X-ray beam with maximum horizontal beam size of 250 mm and maximum vertical beam size of 8.0 mm produced by a bend magnet (1.354 T) was used for imaging. The X-ray beam with photon energy of 40 keV was prepared by the double crystal monochromator reflection of Si (4,4,0) to provide high contrast images. Depending on the chosen photon energy, the X-ray beam with vertical beam size of 4.0 mm and horizontal beam size of 250 mm at the sample location and the detector was applied for imaging experiments. Images were collected by an X-ray camera (VHR-90, Photonic Science, Mountfield, East Sussex, UK) with gadolinium oxysulphide scintillator layer having a projected density of 7.5 mg/cm2 and area of 74.9 mm × 49.9 mm (4008 × 2672 pixels) with an effective pixel size of 18.5 μm. Pixel binning of 4 × 4 was applied (optical pixel size of 74 μm × 74 μm) and the region of interest of 100 × 77 pixels (7.4 × 5.7 mm) was selected. Planar ABI was performed for imaging of therapeutic ultrasound induced cavitation bubbles in this study. A schematic of the ABI system applied is shown in Fig. 2. The distance between the sample and the X-ray source was about 26 m and the distance between the double crystal monochromator and sample was approximately 13.5 m. The monochromator—analyzer used in ABI was a silicon (4,4,0) configuration. The analyzer was adjusted very close to the top of the rocking curve. The distance between the analyzer crystal and detector was 0.6 m, and the distance between the sample and the analyzer was 0.7 m as demonstrated in the Fig. 1.
Multiple image contrast technique was used for collection of images at each distance from the tip of the probe. In this technique a large number of images in sequence mode were collected to improve the signal to noise ratio and to minimize the effects of the small drift of the analyzer crystal. The imaging sequence contained 7000 on–off cycles. In each cycle 2 images were captured. First an image was collected when the ultrasound was turned on, immediately after that the ultrasound was turned off and after a 500 ms delay another image was collected. The time necessary to complete one cycle is small and both images were collected practically at same point of the analyzer rocking curve. More details on this method of imaging can be found of the previous work of authors . When the ultrasound was on, the output power of sonicator was set for 14 W. The sample area of 17.75–31.75 mm below the lowest point of the tip of the probe in the sample was imaged. The sample over 14 mm range was scanned by taking 4 frames and incrementing the position of the scanning stage by 3.5 mm between each frame (at four different locations of 19.5, 23, 26.5, and 30 mm below the tip of the probe). The exposure time for each frame was 2.5 s, selected based on the intensity of the X-ray beam. In total 7000 images with ultrasound on and 7000 images with ultrasound off were acquired. Then the two resulting summed image sets were divided by each other. The initial results were calculated and analyzed by ImageJ software program. Then, a dedicated program was written in Interactive data language (IDL) software program (Exelis Visual Information Solution, Inc., Boulder, Colorado, USA) and the final results were analyzed. The intensity ratio (on divided by off) was evaluated for each image set. At 40 keV the total radiation exposure was about 17 Gy for the 14,000 images.
Result and discussion
The pattern of cavitation bubbles in water driven by a 0.8835 MHz therapeutic ultrasound system at 14 watt output power were detected by synchrotron X-ray ABI. Since the flux of X-ray at 40 keV on the BMIT beamline is quite low, the imaging time was long. Although the acquisition time was somewhat long, the pattern of induced cavitation bubbles was revealed. The cavitation bubbles’ pattern was observed in repetitive lines. The calculated distance between intervals revealed that the distance of frequent cavitation lines (intervals) is one-half of the acoustic wave length consistent with standing waves. The presence of bubbles was observed as a time-averaged bubble region. The density and location of bubbles were inferred indirectly by measuring the ultra-small angle X-ray scattering distribution in the region of images where bubbles (cavitation) were formed. This set of experiments demonstrates the utility of synchrotron ABI for visualizing cavitation bubbles formed in water by clinical ultrasound systems working at high frequency and output powers as low as a therapeutic system. This can be the first step toward more detailed characterization of cavitation bubbles formation in other clinical acoustic systems such as HIFU and lithotripsy.
ZI carried out the design and perform of the experiment, acquisition, analysis and interpretation of data, image processing and writing the manuscript. GB has participated in experimental design and data acquisition. PB has contributed in reading and revising the manuscript. DC has contributed in experimental design, interpretation of data, reading and revising the manuscript. All authors read and approved the final manuscript.
This work was supported in part by a University of Saskatchewan Dean’s Scholarship program (ZI). The authors acknowledge the assistance of Western college of veterinary medicine in providing access to a therapeutic ultrasound system. The authors additionally acknowledge the Canadian Institutes of Health Research (CIHR) -Training in Health Research Using Synchrotron Techniques (THRUST) program (ZI) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant program (DC). Research described in this paper was performed at the Canadian Light Source, which is funded by the Canada Foundation for Innovation, NSERC, the National Research Council Canada, CIHR, the Government of Saskatchewan, Western Economic Diversification Canada, and the University of Saskatchewan.
The authors declare that they have no competing interests.
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