WO2004021907A1 - Ultrasonic therapy apparatus - Google Patents

Abstract

An ultrasonic therapy apparatus for increasing the temperature of an affected part under treatment with high efficiency while reducing to a minimum the influence on other tissues than the part under treatment. The ultrasonic therapy apparatus comprises ultrasonic applying means for applying an ultrasonic wave to a tumor part. An ultrasonic wave is applied by the ultrasonic applying means to a tumor part of a subject to whom microbubbles are administered. As a result, the temperature of the tumor part is increased because of the heat generated from the microbubbles in vessels in the tumor part, thereby necrosing the tumor cells. In a preferred mode, the apparatus includes an ultrasonograph in which microbubbles are used as an ultrasonic contrast medium.

Description

Technical field

 The present invention relates to an ultrasonic therapy device using micro purple. Light

Background art

 Itoda

 Today's methods of treating tumors can be broadly divided into three categories: surgical treatment, drug treatment, and radiation therapy. In addition to such treatment methods, there is a treatment method using ultrasound as one of means for realizing noninvasive treatment. Ultrasound treatment includes high-intensity focused ultrasound (HIFU) using localized heating only in the tumor area by focusing strong ultrasound inside the body, and activation by ultrasound. Sonochemotherapy using drugs that exhibit antitumor effects is known. However, conventional ultrasonic treatment has the following problems.

 Ultrasound is strongly attenuated in the subcutaneous fat layer, so it is necessary to increase the output of the ultrasound from the ultrasound therapy device in order to obtain a temperature rise in the deep affected area. However, there is also a danger that the temperature of the body tissue which is not intended for treatment may increase in the propagation region of the ultrasonic wave before reaching the affected part.

 Irradiation of relatively high-power ultrasonic waves into the body also induces cavitation phenomena in the body, resulting in temperature rise due to ultrasonic scattering by cavitation bubbles and cavitation. Collapse may cause unintended damage to body tissue.

Contributes not only to the generation of cavitation bubbles but also to the temperature rise in the tumor area However, its mechanism of occurrence is complex and its effective use is extremely difficult technically, given its uncertainty, instability, and danger to normal tissues as mentioned above. is there. Therefore, a technique for coagulating a tumor with an ultrasonic output that is weak enough not to generate cavitation bubbles is desired.

 An object of the present invention is to provide an ultrasonic treatment apparatus capable of efficiently raising the temperature of a treatment site while minimizing the influence on other body tissues other than the treatment site. Things.

 Another object of the present invention is to perform safer and more accurate treatment by performing ultrasonic diagnosis at all stages before, during, and after treatment using a part of the configuration of the ultrasonic treatment apparatus. It is in. Disclosure of the invention

 The technical means adopted by the present invention is an ultrasonic treatment apparatus provided with an ultrasonic irradiation means for irradiating an ultrasonic wave to a tumor area, wherein the ultrasonic irradiation means applies an ultrasonic wave to the tumor area of a subject to which microvaple is administered by the ultrasonic irradiation means. By irradiating a sound wave, heat is emitted from a micropable in a blood vessel in the tumor region to raise the temperature of the tumor region and kill tumor cells. The present invention has been made by focusing on two points. One is that microbubbles are an excellent transducer from “ultrasonic energy” to “thermal energy”. Second, the vascular system develops abnormally in tumor cells compared to those near normal cells. Figure 3 shows the blood vessels of normal cells and cancer cells.

There are three factors that make microbubbles a transducer from “ultrasonic energy” to “thermal energy”. The first factor is that microbubbles oscillated by ultrasonic waves generate heat as viscous dissipation to surrounding media. Is to give. The second factor is that ultrasonic waves are scattered and reflected by the presence of micro-purples, and the viscous dissipation of the ultrasonic waves near the region where micro-bubbles exist is relatively increased, increasing the temperature. That is. The third factor is that ultrasonic vibration effectively stores heat energy inside the bubble, and the effect of heat conduction on the wall of the bubble increases the temperature around the bubble. The third factor seems to be the most dominant effect of temperature rise due to micro-pulverization.

 When microbubbles are injected into a subject, many of them are retained in tumor cells with developed vasculature. As described above, when ultrasonic waves are applied to the microvapules, heat energy is released from the microvapules. Therefore, when ultrasonic waves are irradiated to the tumor region, the ultrasonic waves are also irradiated to the micro-purples that remain in the blood vessels of the tumor cells, and the micro-purples vibrate to emit heat energy. In the present invention, by using a micropable, bubbles are oscillated by the ultrasonic wave even with an ultrasonic wave having a smaller output than the ultrasonic output which is applied in the existing ultrasonic therapy using the heating action. As a result, a highly efficient heat generation effect can be obtained. Therefore, it is possible to reduce the pressure amplitude of the ultrasonic wave applied to the ultrasonic wave propagation region in the body, and it is possible to minimize the influence on other body tissues.

 In summary, in the past, if the ultrasound output was weak, the treatment of the tumor would be inadequate, while if the ultrasound output was too strong, cavitation would occur, causing body tissue damage at unintended sites. was there. According to the present invention, treatment efficiency can be improved while ensuring safety by a combination of relatively weak ultrasonic waves and microbubbles.

 In addition, the bubble diameter of the microbubble, the type of gas in the bubble, the presence or absence of a bubble shell,

By appropriately selecting the combination with the DDS (Drug Delivery System), ultrasonic frequency, irradiation time, etc., it becomes possible to perform various types of controlled ultrasonic treatment. You. Examples of suitable microbubbles employed in the present invention include contrast agents. For microbubble contrast agents, the bubble size distribution can be grasped to some extent (appropriate ultrasonic frequency can be selected), and the gas inside the bubbles can be replaced.

 It is known that microbubbles are used as contrast agents in ultrasound diagnosis. Since the ultrasonic therapy apparatus of the present invention uses microbubbles, by combining the ultrasonic therapy apparatus with an ultrasound diagnostic apparatus using microbubbles as a contrast agent, tumors can be obtained before, after, and during treatment. Ultrasound diagnosis of the area can be performed.

 In other words, the other technical means adopted by the present invention are: a therapeutic ultrasonic irradiation unit that irradiates a therapeutic ultrasonic wave to the subject; and a diagnostic ultrasonic wave that is transmitted to the subject and the subject that administers the microbubbles. A diagnostic ultrasonic wave transmitting / receiving unit that receives the echo signal, an image processing unit that processes the echo signal to generate an image, and an image that displays the image generated by the image processing unit It is an ultrasonic diagnostic and treatment device having a display unit. The ultrasonic diagnostic / therapy device irradiates the ultrasonic region from the ultrasonic irradiation section to the tumor region of the subject to which the microbubbles are administered, and reduces the temperature of the tumor region by heat radiation from the microbubbles in the blood vessel in the tumor region. While raising and killing the tumor cells, the diagnostic ultrasonic waves are transmitted to the tumor region of the subject before and after or during and after the irradiation of the therapeutic ultrasonic waves from the ultrasonic irradiation section, and the image processing is performed. And displaying the image of the tumor region obtained by processing the echo signal by the unit on the image display unit.

Also, regarding the relationship between the therapeutic ultrasonic irradiation unit and the diagnostic ultrasonic transmission / reception unit in the ultrasonic diagnostic / therapy device, the following two configurations can be considered. One is a form in which the “ultrasonic transducer for treatment” and the “ultrasonic probe for diagnosis” are one unit. In this unit, the vibrator and probe are composed of a common member, and the vibrator and probe are separate bodies. However, both cases where both are integrated are included. Regarding the waveform generating device and the amplifier, depending on the waveform to be used, the therapeutic ultrasonic irradiation unit and the diagnostic ultrasonic transmitting / receiving unit may include a common waveform generating device and amplifier. The other is a configuration in which the "ultrasonic transducer for treatment" and the "ultrasonic probe for diagnosis" are driven independently of each other through separate waveform generators and amplifiers. . BRIEF DESCRIPTION OF THE FIGURES

 Fig. 1 is a schematic diagram of an ultrasonic therapy device; Fig. 2 is a diagram showing an ultrasonic therapy using micro purple; Fig. 3 is a diagram showing the vascular system of normal cells and cancer cells. FIG. 4 is a graph showing the difference in temperature rise depending on the presence or absence of microbubbles; FIG. 5 is an explanatory diagram of an in vivo experiment and experimental results; FIG. 6 is an explanatory diagram of an in vitro experiment and FIG. It is an experimental result. BEST MODE FOR CARRYING OUT THE INVENTION

 An embodiment of the present invention will be described with reference to the drawings as appropriate. FIG. 1 is a schematic diagram of an ultrasonic therapy apparatus. The ultrasonic apparatus has a therapeutic ultrasonic irradiation unit having a waveform generating device, an amplifier, and a therapeutic ultrasonic transducer. A drive signal is generated from the waveform generator by the control, and the drive signal is amplified by an amplifier and then input to the ultrasonic transducer for treatment. In one preferred example, the therapeutic ultrasonic transducer is a piezo element. The therapeutic ultrasonic irradiation means irradiates therapeutic ultrasonic waves in a focused manner to a treatment site of an organ of a subject during treatment.

Microbubbles are previously injected into the subject. It is known that the vascular system develops abnormally near cancer cells as compared to normal cells (see Fig. 3). Therefore, when micropurple is injected into a subject, for example, from a vein, At the tumor site, more micropurples will be lodged. Therefore, by irradiating the therapeutic ultrasonic wave to the tumor region by the therapeutic ultrasonic irradiation means, the temperature of the tumor region is increased by the heat radiation from the microbubbles in the blood vessels of the tumor region. Cells can be killed.

 As shown in FIG. 1, the ultrasonic therapy apparatus according to the present invention has an ultrasonic diagnostic apparatus using micro purple as a contrast agent. An ultrasonic diagnostic apparatus includes: a diagnostic ultrasonic probe that performs both transmission of diagnostic ultrasonic waves and reception of an echo signal reflected from a subject with respect to transmission of diagnostic ultrasonic waves; An image processing unit that obtains an image from the computer; and a monitor (image display unit) that displays the obtained image. Angiography with microvapure is also performed in current clinical practice. When microbubbles are injected into the subject and irradiated with diagnostic ultrasonic waves, an echo signal having a frequency component different from the frequency of the transmitted ultrasonic waves is returned from the MicroPurple. There is known a method of imaging using the non-fundamental component (harmonic component) of the echo signal. The diagnostic ultrasonic transmission means of the ultrasonic diagnostic apparatus can also be used as the aforementioned therapeutic ultrasonic irradiation means of the ultrasonic therapeutic apparatus. The microbubbles injected into the subject for the ultrasonic treatment according to the present invention can be used as a contrast agent in ultrasonic diagnosis.

A treatment method using such an ultrasonic treatment device will be described with reference to FIG. Figure 2 (A) shows before treatment (confirmation of tumor position), Figure 2 (B) shows treatment (tumor necrosis), and Figure 2 (C) shows after treatment (confirmation of tumor death). Inject the micro-purple into the subject and irradiate the subject with diagnostic ultrasound from the diagnostic ultrasound irradiating means. Injection of micro purple is performed using a syringe needle, a power catheter, or the like. A diagnostic image is acquired from an ultrasonic echo signal obtained when a diagnostic ultrasonic wave is irradiated on a microbubble to accurately obtain information on cancer cells before treatment. Then, the cancer cells are irradiated with therapeutic ultrasonic waves to oscillate the micro-bubbles in the blood vessels of the cancer cells, and the heat energy obtained therefrom raises the temperature of the cancer cells to death.

 During treatment, the state of treatment is ascertained by detecting echo signals from micro purple and cancer cells in real time. After the treatment, the condition of the affected area is diagnosed accurately using the ultrasonic echo signal.

 According to the present invention, by using a micropable as a contrast agent, the position, range, and state of cancer cells can be accurately grasped before treatment, and the state of cancer cells can be monitored in real time during treatment. After treatment, it is possible to confirm the death of cancer cells.

 Figure 4 is a graph showing that there is a difference in temperature rise between when microbubbles are present and where there are no microbubbles at the location where ultrasonic waves are irradiated.The horizontal axis is time, and the vertical axis is time. Temperature rise. 3.24 MHz ultrasonic waves were confined to water containing Levovisi: (a contrast agent consisting of micro-vapules, a trademark of SCHERING) confined in a closed space, and micro-purple also confined in a closed space. This is a rough showing the temperature change when irradiating water that does not have water. The one having a large gradient is water containing microvapules, and the one having a small gradient is water having no micropables. This indicates that the presence of micro-purple affects the temperature rise when irradiating ultrasonic waves.

The present invention uses micro-bubbles, and appropriately selects the bubble diameter of the micropable, the type of gas in the bubble, the presence or absence of a bubble shell, a combination with the DDS (Drug Delivery System), the frequency of the ultrasonic wave, the irradiation time, and the like. This enables various types of controlled ultrasound treatment. For example, at the time of treatment or diagnosis, the most suitable gas component in the microbubble can be selected according to the usage scene and purpose of the microbubble. Specifically, My When the gas inside the bubble is converted into a monoatomic molecule such as Ar, the thermal attenuation when the microbubble vibrates becomes large. On the other hand, if a polyatomic molecule such as SF ₆ is used for the gas in the micro purple, the thermal attenuation will be reduced.

 When a certain amplitude of ultrasonic pressure is applied to the micro-vaple, the micro-purple whose internal gas is a monatomic molecule has a large rate of thermal attenuation (conversion of ultrasonic energy to thermal energy). Microbubbles, in which the gas inside is multi-atomic molecules, have a high rate of acoustic attenuation (the conversion of ultrasonic energy to the vibrational energy of the micropaples). Here, "attenuating" means that the energy of a given ultrasonic wave is converted into another form of energy. In other words, here, it means that the energy of the ultrasonic wave is converted into another form of energy through the micro-bubble, and the energy is emitted toward the periphery of the micropable. In the case of a micropable in which the gas inside is a monatomic molecule, the thermal attenuation is large, so that a large amount of heat energy is released toward the microbubble, leading to an efficient temperature rise in the surrounding. On the other hand, in the case of a micropable in which the gas inside is a polyatomic molecule, the acoustic attenuation is large, and therefore, the vibration energy of the microparticle is large, and a stronger echo is returned. Basically, any monoatomic molecule or polyatomic molecule can be used as long as the gas inside the micro-bapule is a gas that does not adversely affect the human body.

By utilizing the above properties, those with large thermal attenuation, that is, those that increase the amount of heat given to the surroundings from the microscopic, are used in situations where thermal effects are expected (for example, during treatment). Those with low thermal damping and high acoustic damping are used in situations where bubbles are expected to reliably undergo non-linear oscillations (eg, during diagnostics). Furthermore, by selecting a plurality of bodies of the microbubbles and changing the mixing ratio, etc., the vibration mode of the microbubbles can be changed, and optimal use can be made according to the situation. Specifically, As if gas, a combination of A r and SF _6.

Individual experiments were performed in vivo and in vitro using rat liver based on the ultrasonic therapy apparatus according to the present invention. Figures 5 and 6 show the experimental illustration and the experimental results. The ultrasonic conditions were as follows: frequency: 2.174 MHz, amplifier output: 72 W, irradiation time: 60 sec. The diameter of the ultrasonic probe is 40 mm _{s and the} focal length is 40 mm.

 Fig. 5 shows an illustration of the in vivo experiment and the experimental results. The rat liver was injected with PBS (phosphate buffered saline) and Levovist-containing PBS from the aortic portal vein force, and the rat liver was irradiated with ultrasonic waves in a state of blood flow. In Case 1, Case 2, and Case 3, the maximum ablation size of the cross section (the maximum diameter of the ablation mark) was measured. As is clear from the table in Fig. 5, it was confirmed that the presence of Levovist increased the maximum diameter (coagulation range) of the ablation scar.

 Figure 6 shows an illustration of the in vitro experiment and the experimental results. First, PBS containing PBS and Levovist were injected into the rat liver from the aorta and portal vein, and then the liver was excised, fixed with a phantom imitating a living body, and irradiated with ultrasonic waves. In Case 1, the cautery size of the bottom surface (length x width x oblique), the cauterization distance in the depth direction of the cross section (cauterization size), and the maximum cauterization size of the cross section (maximum diameter of the cauterization mark) were measured. As is clear from the table in Fig. 6, it was confirmed that the presence of Levovist increased the ablation area. Industrial applicability

 INDUSTRIAL APPLICABILITY The present invention can be used for an ultrasonic therapy apparatus or an ultrasonic diagnostic / therapy apparatus using micro purple.

Claims

 Scope of Claim An ultrasonic treatment apparatus provided with an ultrasonic irradiation means for irradiating an ultrasonic wave to a tumor area, wherein the ultrasonic irradiation means irradiates an ultrasonic wave to a tumor area of a subject to which microbubbles are administered. An ultrasonic therapy apparatus characterized in that the temperature of the tumor region is increased by heat radiation from microbubbles in the blood vessel of the tumor region to kill the tumor cells. 2. The ultrasonic treatment device according to claim 1, wherein the microbubbles are an ultrasonic contrast agent. 3. The ultrasonic treatment apparatus according to claim 1, wherein the apparatus includes an ultrasonic diagnostic apparatus using micro purple as an ultrasonic contrast agent. A therapeutic ultrasound irradiator that irradiates the subject with therapeutic ultrasound, and a diagnostic ultrasound transceiver that transmits diagnostic ultrasound to the subject and receives echo signals from the subject to which the microbubbles are administered And an image processing unit for processing the echo signal to generate an image, and an image display unit for displaying an image generated by the image processing unit, and a tumor region of a subject to which microbubbles are administered. The ultrasonic irradiation section irradiates an ultrasonic wave to the tumor area, thereby radiating heat from micro-purples in the blood vessels in the tumor area to raise the temperature of the tumor area and kill the tumor cells, while treating with the ultrasonic irradiation section. Before and after or at the time of irradiation of the ultrasound for use, the diagnostic ultrasound is transmitted to the tumor area of the subject, and the image processing unit processes the echo signal to obtain the tumor area. Images on the image display Shimesuru ultrasonic diagnosis and treatment apparatus, characterized in that have configured on. . In Claim 4, a therapeutic ultrasonic transducer constituting a therapeutic ultrasonic irradiation unit and a diagnostic ultrasonic probe constituting a diagnostic ultrasonic transmitting / receiving unit are provided. Ultrasound diagnosis and treatment, wherein the microbubbles are ultrasound contrast agents, wherein the microbubbles are ultrasound contrast agents. . 7. An ultrasonic diagnostic and therapeutic apparatus according to claim 4, wherein microbubbles containing different types of gas at the time of treatment and at the time of diagnosis are used. 8. The ultrasonic diagnostic and therapeutic apparatus according to claim 7, wherein a micro-bubble having a large thermal attenuation is selected at the time of treatment, and a micro-bubble having a small thermal attenuation is selected at the time of diagnosis. In Claim 8, the microbubbles with large thermal attenuation contain gas of monoatomic molecules, and the ultrasonic diagnostic and therapeutic device according to Claims 8 and 9, wherein the microbubbles with small thermal attenuation are provided. Bull is an ultrasonic diagnostic and therapeutic device characterized by containing a gas of polyatomic molecules.  The ultrasonic diagnostic / therapeutic apparatus according to any one of claims 4 to 10, wherein the administered micropulps include a plurality of types of micropullets containing different types of gases as components. .  Administering micro-purple to the tumor area of the subject; irradiating the tumor area of the subject with the micro-vaple with ultrasound; and radiating heat from the microbubbles in the blood vessels of the tumor area. Elevating the temperature to kill the tumor cells. Administering microbubbles to the tumor area of the subject; and irradiating the ultrasound area to the tumor area of the subject to which the microphone-mouth bapule is administered And a step of increasing the temperature of the tumor region by heat radiation from microbubbles in blood vessels of the tumor region.