Patent Application
20140356967
The present invention relates to a phantom for displaying a treatment area of ultrasonic wave radiated from an ultrasonic device used for measurement, diagnosis, treatment, and the like, and to a device for carrying out calibration of the ultrasonic device.
Recently, in treatment of diseases, Quality of Life of a patient who underwent operation has been considered to be important. Even in such heavy diseases as cancers, social needs for treatment methods with lower invasiveness than conventionally have been required. Currently, low invasive treatment mainly used clinically includes treatment such as endoscopic operation, laparoscopic operation, which includes insertion of a tubular guide into a body, or treatment such as radio frequency ablation treatment, which includes insertion of a needle-like treatment device into a body, any of which are accompanied with invasiveness of devices. On the contrary, ultrasonic waves can be converged in a region having a size of 1 cm×1 cm or less in a body from the outside of the body without inserting a device into the body, based on the relation between the wavelength and the attenuation in the body. By using the characteristics, clinical applications of low invasive ultrasonic treatment methods have been started. Ultrasonic treatment which is the most used clinically at present is High Intensity Focused Ultrasonic (HIFU) treatment subjected to uterine fibroid and breast cancer, which ablates an affected site tissue by raising a temperature of the affected site by irradiation with HIFU to at temperature equal to or higher than a coagulation temperature of protein for several seconds.
In treatment using an ultrasonic wave, since an ultrasonic wave generator is not brought into contact with a treatment region, it is necessary to monitor a region at which treatment is carried out by using a diagnostic imaging device, or the like. Furthermore, in order to carry out selective treatment more reliably, in addition to the monitoring, it is also important to schedule a treatment plan in advance, and to control the amount of ultrasonic waves so that the treatment region is irradiated with an appropriate amount of ultrasonic waves and that regions other than the treatment region is not irradiated with an inappropriately excessive amount of ultrasonic waves.
Important steps of the treatment plan in the ultrasonic treatment include verification of whether or not a device in which setting for treatment is carried out works as expected. Such verification can be achieved before application to a human body by irradiating an ultrasonic phantom (tissue mimicking phantom), which has been configured so as to be able to simulate a living body, to display the extent and range of the biological effect generated by ultrasonic irradiation inside thereof, with ultrasonic wave, and observing and analyzing the results.
As the above-mentioned ultrasonic phantom, one for visualizing not energy of an ultrasonic wave itself but a secondary effect generated by an ultrasonic wave is mainly used. Examples thereof include a phantom shown in NPL 1, which uses soluble protein as an indicator agent and detects temperature rise due to irradiation with an ultrasonic wave. This phantom uses the phenomena that when protein undergoes heat denaturation, the protein is coagulated and molecules are aggregated to each other, and scattering intensity is increased to cause optical change as compared with before the denaturation, in particular, whitening occurs.
A conventionally used tissue mimicking phantom for HIFU treatment detects the protein appearance change from translucent to opaque due to denaturation by visual check or an optical technique. However, there is a problem that the phantom cannot carry out controlling of ultrasonic intensity in which the optical change occurs, as well as controlling of optical turbidity and nucleus of cavitation, independently. That is because determination of the strength of ultrasonic intensity necessary for optical change is carried out inclusively based on the effect as a criteria of buffers such as lower alcohol and tris-(hydroxymethyl)-aminomethane (hereinafter, which is abbreviated as “Tris”), or the like. Specific buffers such as lower alcohol and Tris change a three-dimensional structure of bovine serum albumin and deteriorates dissolution stability in a solution. Therefore, albumin forms an aggregated body, but such an aggregated body is in a semi-denatured state. When temperature is increased due to ultrasonic irradiation or the like, the aggregated body of albumin is more susceptible to denaturation as compared with a simple substance of albumin. Such an effect that denaturation of protein easily occurs by ultrasonic irradiation is remarkably found in Tris. However, a protein solution including an aggregated body has higher turbidity than a solution in a state in which protein completely dissolved, which poses a problem when a phantom having a particularly large size is prepared.
Furthermore, the protein in such an aggregated body state works as nucleus of acoustic cavitation mentioned below, but since the phantom includes a region in which an aggregated body is generated and a region in which an aggregated body is not generated, nuclei are scattered, and as a result, denaturation is not generated uniformly in the phantom. Furthermore, since Tris or lower alcohol is a low molecule, there is a problem that Tris or lower alcohol has a property of easily passing through a network structure of hydrogel as base material of an tissue mimicking phantom, so that Tris or lower alcohol easily leaks out from the phantom. Therefore, as in, for example, a phantom-bed integral type large ultrasonic irradiation device, when it is necessary to use a phantom in a state in which it is brought into direct contact with an ultrasonic device, the component concentration is changed over time. Therefore, it is highly likely that properties as the phantom may be deteriorated.
Note here that an acoustic cavitation denotes a phenomenon in which minutes air bubbles are generated from a substance as a nucleus generated by irradiation with respect to liquid, organisms, or the like, with ultrasonic waves, is grown and finally collapsed by ultrasonic vibration.
In order to solve the above-mentioned problem, an tissue mimicking phantom in accordance with the present invention is characterized by including an indicator agent which is denatured by temperature rise to simulate the effects of ultrasonic treatment, and a denaturation sensitivity controlling agent which is a different component from the indicator agent and which serves as a nucleus of cavitation and supports the temperature rise and the denaturation of the indicator agent at the time of irradiation with ultrasonic waves.
According to the ultrasonic phantom of the present invention, it is possible to independently control a degree at which optical changes occur by the irradiation with ultrasonic waves, optical transparency before the irradiation with ultrasonic waves, and a degree of serving as the nucleus of cavitation at a time of ultrasonic irradiation. Calibration of the strength of an ultrasonic treatment device can be carried out more stably than conventionally possible. Furthermore, the ultrasonic phantom of the present invention can be used in a state in which the phantom is taken out from a container and is closely brought into direct contact with an ultrasonic irradiation device. Thus, there is little limitation in usage forms.
In a conventional ultrasonic phantom, it was difficult to control the sensitivity at which denaturation occurs when irradiation with an ultrasonic wave is carried out, optical turbidity, and an effect as a nucleus of cavitation independently. This is because a component to be denatured is in a metastable state, thus improving sensitivity, with the effects of Tris and lower alcohol, when irradiation with an ultrasonic wave is carried out, but this metastable state increases optical turbidity and has an effect as a nucleus of cavitation. Furthermore, in such an existing phantom, since low molecules such as Tris are used for expressing the effects, the above-mentioned three effects easily disappear due to flowing of the low molecules such as Tris from the inside of the phantom having a gel form. Thus, the existing phantom lacks in stability over time.
From these viewpoints, we have devised a method of allowing a phantom to additionally contain material, which has a property that is substantially the same as in a state in which the component generating denaturation becomes a metastable state by the presence of Tris or the like, as a denaturation sensitivity controlling agent, in addition to the component generating denaturation when irradiation with ultrasonic waves is carried out, instead of using material which directly acts on a component, typically Tris, generating denaturation when irradiation with an ultrasonic wave is carried out. In particular, unlike conventional phantom, by using not a low molecule but a high molecule, phantom, which has taken stability over time into account, is achieved.
Specifically, the phantom is configured by including, as a denaturation sensitivity controlling agent, a high molecular compound whose turbidity in the wavelength of 600 nm when it is dispersed at 1 gram per 1 liter in a pure water and in a neutral state becomes 0.001 or more and 0.1 or less per 1 cm. The use of such a method can dissolve a problem that the turbidity of a phantom as a whole is increased when metastable state protein is used as conventionally.
As a result of study, as the high molecular compound used as the denaturation sensitivity controlling agent, we found that protein having low solubility in water, or protein whose solubility in water is lowered by pretreatment is preferred. More specifically, we have found that egg white albumin, milk albumin, globulin in general having lower solubility in water than that of serum albumin satisfy the purpose. Furthermore, regardless of the solubility in water, we have found that water-soluble protein, which was subjected to heat treatment, or ultrasonic treatment, or radiation irradiation in advance, satisfy the purpose.
Hereinafter, Test Examples and Examples of the present invention are described specifically, but the present invention is not limited to these Examples.
Firstly, in order to search material to be used as the denaturation sensitivity controlling agent, an effect of generating cavitation when the material is dispersed in water and irradiation with an ultrasonic wave is carried out is measured by using an experimental system shown in
The transducer 5 is connected to a waveform generator 6 and signal amplifier 7. Furthermore, in order to verify the position of the sample 101, an ultrasonic diagnostic device 8 and a diagnostic probe 9 are provided in the water. Furthermore, an acoustic signal generated from the sample 101 by ultrasonic irradiation is measured by using a hydrophone 100, and the acoustic signal is stored in an oscilloscope 102. The waveform generating device 6, the ultrasonic diagnostic device 8, and the oscilloscope 102 are connected to a control oriented computer 11, and set so that the acoustic signal taken by a hydrophone 100 in synchronization with ultrasonic irradiation from the waveform generating device 6.
Furthermore, each sample was prepared in a thickness of 2 cm, and a chicken breast meat piece, which had been cut in a size of 1 cm3, was disposed behind the sample. Then, when it was verified whether or not the shape of the chicken breast meat piece was able to be determined, it was shown that the shape was able to be clearly determined when the turbidity was not more than 0.1 per 1 cm.
Considering the above-mentioned experimental fact and considering that a denaturation indicator agent of the present invention is serum albumin having a concentration of about 10% and that the concentration of the denaturation sensitivity controlling agent is desirably not more than one-tenth of that of the denaturation indicator agent so that denatured regions are not spotted, it is desirable that the concentration of the denaturation sensitivity controlling agent is not more than about 1%. Thus, it is shown to be desirable that in the denaturation sensitivity controlling agent of the present invention, the turbidity in the wavelength of 600 nm is not more than 0.001 and not less than 0.1 when 10 gram per liter is dispersed.
Subsequently, an tissue mimicking phantom including serum albumin as a denaturation indicator agent which is denatured due to temperature rise and which simulates an ultrasonic treatment effect, and egg white albumin as a denaturation sensitivity controlling agent which becomes a nucleus of cavitation when irradiation with an ultrasonic wave is carried out and which controls the temperature rise and the denaturation sensitivity of the indicator agent is prepared, and the properties thereof are evaluated. The evaluation results are described.
All operations hereinafter were carried out at 4° C. An aqueous solution (86.5 ml) of containing 15% bovine serum albumin and 5 ml of pure water in which 0.1% egg white albumin had been dispersed and 25 ml of 40% solution of acrylamide (acrylamide:bisacrylamide=39:1) were sufficiently mixed with each other, followed by degasification. Then, the mixture was poured into a rectangular parallelepiped container. While the mixture was mildly stirred with a stirrer, 5 ml of 10% solution of ammonium persulfate and 5 ml of N,N,N′,N′-tetramethyl ethylenediamine were rapidly added. When they were mixed homogeneously, the stirring was stopped, a stirrer bar was removed, and a cover was put on the rectangular parallelepiped container and the container was stood still for 20 minutes. From the above-mentioned operations, substantially transparent gel was prepared and used as a tissue mimicking phantom. Furthermore, a gel which does not contain egg white albumin was prepared and used as a control phantom.
The below-mentioned tests were carried out by using an experimental system shown in
Calculation of a denatured region in a phantom in the below-mentioned tests was carried out by the following procedure.
(Cutting Out of Still Picture from Moving Picture)
Pixel values of the pictures which had undergone binarization processing were multiplied in the direction of the ultrasonic irradiation, and a region showing the highest value was made to be a central axis in which denaturation occurred.
Integration processing is carried out assuming rotational symmetry around the above-mentioned central axis. Note here that by applying the actual distance (unit: millimeter) in the image between the neighboring pixels which had been calculated, the results of the integration processing are made into a cubic millimeter unit.
Firstly, a phantom was prepared according to the above-mentioned gel preparation method (1). An experimental system shown in
Study at room temperature assuming the use of phantom in a simple configuration without increasing temperatures was carried out. Firstly, phantom was prepared according to the above-mentioned gel preparation method (1). An experimental system shown in
According to
Since the visual observation becomes easier and error in carrying out quantification becomes smaller as the volume is larger, the effect of the phantom into which a denaturation sensitivity controlling agent is filled is obvious as shown in
Furthermore, the same was true to the case in which milk albumin, blood globulin, and ultrasonic wave-denatured serum albumin were used as the denaturation sensitivity controlling agent. Note here that the denaturation sensitivity controlling agent shows an effect when the turbidity shown in
In order to verify that the size of the denatured region can be controlled by varying the concentration of the indicator agent, phantom was prepared according to the above-mentioned phantom preparation method (1) with the concentration of the serum albumin varied. An experimental system shown in
According to
Note here that when the same experiment was carried out with the ultrasonic frequency varied from 1 to 6 MHz, similar to
From the above-mentioned tests, the effectiveness of the tissue mimicking phantom in accordance with the present invention is shown. Hereinafter, Examples in which it is actually used are described.
An example of a phantom for evaluating ultrasonic-wave organism action is described. Hereinafter, one Example of the present invention is described with reference to
At the use time as the phantom, an ultrasonic irradiation source to be evaluated is brought into close contact with the acoustic window 15 for ultrasonic irradiation and is irradiated with ultrasonic wave, and the result is observed from the window 16 for observing ultrasonic irradiation results. When the ultrasonic irradiation source and the acoustic window 15 for ultrasonic irradiation cannot be brought into contact with each other, irradiation with an ultrasonic wave can be carried out in a state in which the phantom and the ultrasonic irradiation source are placed into a water tank. Furthermore, irradiation can be carried out in a state in which a portion between the acoustic window 16 for ultrasonic irradiation and the ultrasonic irradiation source is filled with an acoustic coupling agent such as acoustic jelly.
Note here that in the preparation method (1), a homogeneous phantom is prepared, but the property of the phantom to be placed and used in the outer frame shown in
An example of a calibration device of an ultrasonic treatment device is described. Hereinafter, one Example of the present invention is described with reference to
The phantom holding portion 9 holds a phantom shown in
Furthermore, when a parameter is input in advance, a function of setting information of whether or not the denatured region and the center position of the denaturation are included in the set range can be transferred to the treatment device, and a function of issuing an alarm when the obtained result is out of the set range or a function of disabling ultrasonic irradiation of the treatment device can be provided.
In carrying out the calibration device of this Example, for example, the following procedure is carried out. Firstly, in a treatment plan scheduled based on the a diagnostic image of an affected site to be treated, conditions such as an irradiation position of ultrasonic wave for treatment and irradiation time at each point are determined. In carrying out treatment, immediately before ultrasonic irradiation to the affected site, by using a calibration device including phantom according to forms and properties of the affected site of the present invention, ultrasonic irradiation is carried out in the same conditions in which treatment is carried out. When the denatured region is included in the assumed range, treatment is started. When the denatured region is not included in the assumed range, maintenance is carried out with respect to abnormality of the treatment device.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2011-287368 | Dec 2011 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2012/083191 | 12/21/2012 | WO | 00 | 6/27/2014 |
