WO2007117010A1

WO2007117010A1 - Probe for generating ultrasonic wave

Info

Publication number: WO2007117010A1
Application number: PCT/JP2007/057878
Authority: WO
Inventors: Tetsuya Kodama; Shiro Mori
Original assignee: Japan Material Co., Ltd.
Priority date: 2006-04-12
Filing date: 2007-04-10
Publication date: 2007-10-18
Also published as: JP2009165499A

Abstract

Exogenous molecules are introduced to a predetermined location by oscillating a high frequency wave generation plate and generating a large number of needle-shaped ultrasonic waves containing high frequency components over the substantially entire surface of the high frequency wave generation plate, thereby breaking countless hollow micro spherical bodies efficiently over the substantially entire surface of the high frequency wave generation plate. The probe for generating ultrasonic wave is characterized by comprising (a) a probe body (1) having an opening (9) for fixing the high frequency wave generation plate, and (b) a high frequency wave generation plate (2) having outer edge (2G) bonded to the opening (9) for fixing the high frequency wave generation plate and generating two or more high frequency waves from different positions through application of a voltage.

Description

Specification

Ultrasonic wave generation probe

Technical field

The present invention can generate two or more different position forces of a high frequency generator plate to generate high frequency waves and destroy hollow microspheres having acousticity over almost the entire surface of the high frequency generator plate, in other words, ultrasonic waves. The present invention relates to a medical ultrasonic wave generation probe capable of efficiently breaking the hollow microspheres, and can be applied to cleaning and sterilization outside of the medical field. For example, cleaning of lake water, seawater, and dams It also relates to an ultrasonic probe that can be used to sterilize food (oysters and laver).

Background art

[0002] The ultrasonic molecule introduction method utilizes the characteristics of ultrasonic waves, and the probe force generated ultrasonic waves (1) increase in percutaneous absorption, (2) hollow microspheres (acoustic nanobubbles or // And introduction of physiologically active substances into cells using a composition or mixture containing microbubbles and exogenous molecules, (3) enhancement of drug effects in vivo, etc. The device is also inexpensive and can introduce exogenous molecules into the affected area non-invasively. Currently, it is used for treatment of cardiovascular diseases including the heart, digestive diseases or malignant tumors. Play an important role.

[0003] This conventional ultrasonic wave generation probe (B) is as shown in FIG. 3, and is attached roughly to the cylindrical probe body (1 ') and the tip opening of the probe body (1'). Connected to the metal plate (6 ′) and the piezoelectric element (2 ′) disposed on the entire inner surface of the metal plate (6 ′) by direct bonding and electrodes provided on the piezoelectric element (2 ′) It consists of a feed cord (4 ') and (5'). In the probe (B) having such a structure, the entire lower surface of the piezoelectric element (2 ') is bonded to a relatively thick metal plate (6') through the adhesive layer (Κ ') to form the entire outer edge. [Non-adhesive] [The gap between the two is shown by. When an AC voltage or pulse voltage is applied to the piezoelectric element (2 ′), one Gaussian distribution (= normal distribution) waveform is generated from the metal surface (6a ′) that is the contact surface to the skin etc. Only ultrasound (PG) is generated [see Figure 3 (b)]. In FIG. 3 (b), the effective bubble-breaking range of the hollow hollow sphere to be described later of the ultrasonic wave (PG) of the Gaussian distribution waveform is indicated by (YG). And this one Gaussian The distribution of ultrasound (PG) was used to introduce the following exogenous molecules (drugs and genes) into predetermined locations in the living body.

[0004] Patent Document 1 relates to a composition for delivering a biologically active agent which is an exogenous molecule to a specific site of a living body, ie, a biologically active agent introduction composition containing micro hollow spheres. By applying a sound wave, micro hollow spheres are broken at a specific site so that the biologically active agent (in this case, a gene) is incorporated into the specific site by the impact pressure at the time of the broken foam.

[0005] More specifically, Patent Document 1 uses albumin-derived acoustic hollow microspheres (nano or micron bubbles) containing perfluorinated carbon as an internal gas, in which hollow microspheres are used. The frequency is close to the resonance frequency, and the hollow microspheres can be reliably broken at a lower sound pressure. The 1 MHz high frequency ultrasonic wave is acted to cause the breakage, and the shock pressure causes biological activity in the living body. A method is disclosed for introducing a drug. Although this method aims at introducing biologically active agents into specific areas of the living body, such as brain, digestive tract, blood vessels, muscles, and in particular, specific areas of the living body such as cancer tissue, the ultrasonic generation surface of the probe [ In the prior art shown in FIG. 3, from the outer surface (6a ') of the metal plate (6'), the sound pressure gradually decreases three-dimensionally as the central portion (YG) of the surface moves outward with the highest sound pressure. We use one that generates ultrasonic waves at a fixed frequency like Gaussian distribution. In this case, the narrow central portion (YG) of the ultrasonic wave generation surface [As described above, FIG. 3 (b) schematically shows the effective range in which the bubbles can be broken as (YG). ] Is the effective area that vibrates and breaks up the hollow microspheres, and the peripheral part that occupies most of the area hardly works to break up the bubbles, and there is a problem that the amount of biologically active agent introduced to a specific site is very small. was there.

[0006] Reference 2 describes an acute myocardial angioplasty treatment that contains hollow microspheres (acoustic nanobubbles or! ヽ and / or microbubbles) whose internal gas is perfluorocarbon and contains a therapeutic gene. In the invention relating to “gene transfer agent”, hollow microspheres in the gene transfer agent introduced into the myocardium are ruptured under ultrasound irradiation by injecting the gene transfer agent into blood, and the impact thereof is It is possible to introduce the HGF gene (= therapeutic gene) into the myocardium by The ultrasonic frequency used is the above-mentioned fixed frequency in the form of the normal distribution, which is the highest at the center of the surface from the ultrasonic generation surface of the ultrasonic generation probe also for hollow microsphere rupture. There is a problem that the effective range is narrow as described above, and the amount of biologically active agent introduced to a specific site is very small.

[0007] Patent Document 3 introduces or adheres hollow microspheres into or on the surface of a tumor, and the hollow microspheres are ruptured with ultrasound to form at least a portion of tumor cells constituting the tumor. In the tumor treatment apparatus to be killed, the tumor treatment apparatus comprises: a first ultrasonic transducer for emitting a first ultrasonic wave for confirming the presence of the hollow microspheres administered in vivo; And a second ultrasonic transducer for oscillating a second ultrasonic wave for causing bubbles in the sphere, and information obtained by reflection of the first ultrasonic wave by ultrasonic control means in the tumor treatment apparatus. The second ultrasonic wave is controlled based on the first ultrasonic wave and the second ultrasonic wave (frequency = 100 kHz to 10 MHz, ultrasonic wave output = 0. 1 to 30 WZ cm). ² ) are controlled so that their output and Z or frequency are different, Ru. In this case as well, from the ultrasonic wave generation surface of the ultrasonic wave generation probe, one that generates ultrasonic waves with a fixed frequency in the form of Gaussian distribution with the highest in the center of the surface is used. Also in this case, as in the above case, the effective area of ultrasonic waves is very narrow, and only hollow microspheres located within a small area of the entire area of the ultrasonic transducer can be ruptured, which takes time for treatment. There was a problem that.

As described above, in this type of device using hollow microspheres having acousticity, that is, nanobubbles or microbubbles, the ultrasonic wave generation surface force of the ultrasonic wave generation probe is the central portion (YG) of the surface. It uses ultrasonic waves with a regular distribution like fixed frequency where the sound pressure decreases gradually in three dimensions as the sound pressure goes up to the highest, and all use ultrasonic waves from the probe for ultrasonic wave generation. With respect to the entire generation surface, the effective surface for hollow microsphere breaking is limited to a very small area (YG) in the central portion, and it is not possible to break in a wide peripheral portion, and the amount of drug introduced etc. It can not overcome the shortcoming that it is small (patent documents 1-3).

Patent Document 1: Japanese Patent Application Laid-Open No. 2002-145784

Patent Document 2: Japanese Patent Application Laid-Open No. 2004-210774

Patent Document 3: Japanese Patent Application Laid-Open No. 2004-223175

Disclosure of the invention Problem that invention tries to solve

[0010] As described above, according to the conventional technique · method, a hollow microsphere having acousticity is used using a probe that emits a single ultrasonic wave of Gaussian distribution shape at a certain fixed frequency, and an external source is placed at a predetermined location of a living body. The basic concept has been to introduce sexual molecules.

On the other hand, the present invention

1) A high frequency generation plate or a thin plate made of piezoelectric elements alone is made to vibrate a high frequency generation plate in which a thin plate of piezoelectric ceramic is attached to a metal plate, and a large number of needle-like ultrasonic waves including high frequency components are generated. Or almost all over the

2) By using a high frequency generating plate in which a plurality of piezoelectric ceramic thin plates are attached to a thin metal plate, a large number of needle-like ultrasonic waves are generated on corresponding portions of each piezoelectric ceramic thin plate. Generate several times of needle-like ultrasonic waves on the entire surface, or

3) By bonding the mesh-like insulating plate to the high frequency generating plate, the regions surrounded by the mesh are made independent of each other, and a large number of ultrasonic waves with force needle-like each region are generated. The hollow microspheres are efficiently ruptured on almost the entire surface of the high frequency generating plate, and the impact pressure of the innumerable cavity bubbles generated by the collapse of the innumerable hollow microspheres is effectively used for extrinsic molecules at predetermined places of the living body. The basic concept is a probe that is particularly effective for medical use, which makes it possible to introduce molecules or to cause the impact pressure of the cavity bubbles to act on a predetermined place of the living body. In addition to medical fields, it can also be applied to cleaning and sterilization, for example, it can be used to clean lake water, sea water, dams and dams, and sterilize food (oysters and laver). Hereinafter, medical applications will be described as a representative example.

Means to solve the problem

In the present invention, the high frequency generation plate (2) is

(I) In the case of a high frequency generating plate (2) constituted by one piezoelectric element alone (claim 1),

(Mouth) When it is formed of one or more piezoelectric elements (2a) and a metal plate (2M) (claim 2 or 3),

(Port 1) In this case, when the number of the piezoelectric elements (2a) is one, the whole circumference or a part of the outer edge (2G) is fixed, and (Claim 2),

(Port-2) There are a plurality of piezoelectric elements (2a) and their outer edges (2G) are fixed and they are separated There is a case where a gap (L) is provided (claim 3).

In addition, the shape of the high frequency generation plate mounting opening (9) can take any shape as required, such as circular, oval or quadrilateral (rectangular or square). When the shape of the high frequency wave generating plate (2) or the piezoelectric element (2a) is also circular, it can be elliptical or quadrilateral (rectangular or square).

[0012] The probe (A) of claim 1 uses a high frequency generating plate (2) composed of only one piezoelectric element as shown in FIG. 1, and the high frequency generating plate (2) is In the case where the entire outer periphery is fixed, or in the case of a quadrilateral, of course, the opposite side may be fixed. Good luck,

(a) a probe body (1) having a high frequency generation plate mounting opening (9),

(b) The outer edge (2G) is fixed to the high frequency generating plate mounting opening (9) and is provided, and is constituted by a high frequency generating plate (2) that generates high frequency of 2 or more different position force by voltage application. It is characterized by

As described above, the probe main body (1) can have a shape according to need, such as in the case of a circular, elliptical or quadrilateral shape of the high frequency generating plate mounting opening (9). This point is the same as in the case of claims 2 and 3.

[0013] The probe (A) of claim 2 corresponds to [where the outer edge (2G) of one or more metal plates (2M) is fixed]], as shown in FIG. 4 and FIG. 2 or FIG. 5 (b). It is shown. That is,

(b) a thin plate for vibration (2M), the outer edge (2MG) of which is fixed to the high frequency generation plate attachment opening (9);

(c) One or more piezoelectric ceramic thin plates (2a) or (2al) ... whose outer edge (2G) is fixed to the high frequency generating plate mounting opening (9) and is stuck to the thin plate (2M) It is characterized by being composed of Also in this case, as described above, when the high frequency generation plate mounting opening (9) is circular, it can be shaped as needed, such as in the case of an ellipse or in the case of a quadrilateral. In the case where the piezoelectric ceramic thin plate is composed of one single piece, it is indicated by (2a), and in the case of plural pieces, it is indicated by (2al) ′ (2an).

FIG. 4 shows claims 2 and 3 at the same time. In the case of claim 2, one or more of If the piezoelectric ceramic thin plate (2a) or (2al) "'outer edge of (2a _n) (2G) [the piezoelectric ceramic thin plate (2a) is plural rectangular, outer edge (2G) it is in the short side. ] Is bonded to the high frequency generating plate mounting opening (9) (In addition, the long side of the piezoelectric ceramic thin plate is not bonded to the high frequency generating plate mounting opening (9).)

In the case of the next claim 3 (in this case, there is not one case), gaps (L) are provided at the outer edges (2G) of the plurality of piezoelectric ceramic thin plates (2al).

The probe (A) of claim 3 (as described above and shown in FIG. 4 and FIG. 5 (a) together with the claim 2.) A plurality of piezoelectric ceramic thin plates (2al) ′ ′ ′ (2a _n ) Is the inner circumferential surface force separation of the probe body (1) [this portion is indicated by a gap (L)].

(c) The inner circumferential surface force of the probe main body (1) is also composed of a plurality of piezoelectric ceramic thin plates (2al) '-(2a _n ) attached to the thin plate (2M) with a gap (L). It is characterized by

[0016] A fourth aspect of the present invention is the probe (A) according to any one of the first to third aspects, wherein "the generated high frequency has a needle-like shape".

The probe (A) of claim 5 is the probe (A) according to claim 2 or 3, as shown in FIG.

"(A) 1 of piezoelectric ceramic thin plate (2 ') forms ultrasonic wave (PG) of Gaussian distribution waveform, (b) other piezoelectric ceramic thin plate (2al) forms ultrasonic wave (P) of needle waveform It is characterized by

The probe (A) of claim 6 is the probe (A) according to any of claims 1 to 5, as shown in FIG. The mesh plate (2e) is further attached to the outer surface of the ceramic thin plate (2M).

Effect of the invention

According to the probe of the present invention, since the high frequency generating plate vibrates by generating high-order waves (two or more waves), if the high frequency generating plate is vibrated by voltage application, the high frequency generating plate A large number of vibration antinodes are formed on almost the entire surface of the Many sound waves are generated. In other words, a large number of needle-like ultrasonic waves are generated over almost the entire surface of the high frequency generation plate, thereby causing the high frequency generation plate of the probe to be a skin-coated gel sheet or cream (or (Jiel) simply by pressure bonding or contacting, the innumerable hollow microspheres are broken intermittently and continuously over almost the entire surface of the high frequency generating plate, and the extrinsic molecules are generated in the high frequency generating plate by the innumerable impact pressure at the time of the break. It will be intermittently and continuously hit the required part efficiently and in a short time over almost the entire surface of the This has made it possible to obtain higher pharmacological effects than ever before.

[0020] In addition, a plurality of piezoelectric ceramic thin plates are used. The piezoelectric ceramic thin plate 1 forms ultrasonic waves (Gas) of Gaussian distribution waveform, and the other piezoelectric ceramic thin plates have needle waveform ultrasonic waves. In the case of forming (P) (FIG. 7), ultrasonic wave (PG) of Gaussian distribution waveform is used to search for and identify a specific site such as an affected area, and then the specific site is detected by needle waveform ultrasonic wave (P). The hollow microspheres concentrated in the above are ruptured as described above, and with the impact pressure, the surrounding exogenous molecules are efficiently bombarded into surrounding cells or surrounding blood vessels. In this case, if needle waveform ultrasound (P) is generated around ultrasonic (PG) of Gaussian distribution waveform, ultrasound (PG) force needle waveform ultrasound (P) is simply generated. By switching to, the affected area can be tapped at that point, and treatment can be performed more efficiently.

Brief description of the drawings

FIG. 1 is a cross-sectional view of a first embodiment of the present invention and a drawing showing a state of ultrasonic wave generation thereof.

[FIG. 2] A cross-sectional view of the second embodiment of the present invention and a drawing showing the state of ultrasonic wave generation

[Fig. 3] ... A sectional view of a conventional example and a drawing showing the state of ultrasonic wave generation

[FIG. 4] A cross-sectional view of the third embodiment of the present invention and a drawing showing the state of ultrasonic wave generation

[FIG. 5] A drawing showing Embodiment 3 of the present invention and its modification

[Fig. 6] ... an exploded perspective view of the probe of the present invention attached with a net

[FIG. 7] A perspective view and a sectional view of Embodiment 4 of the present invention

[Fig. 8] ... Comparison of needle-like ultrasonic waves (a), (b) ( _C ) of the present invention and Gaussian-distributed ultrasonic waves (d) of the conventional example [FIG. 9] A sectional view of Embodiment 1 of the hollow microspheres used in the present invention

[FIG. 10] A sectional view of Embodiment 2 of the hollow microspheres used in the present invention

[Fig. 11] · · · 'Cross-sectional view of the hollow microspheres used in the present invention in Example 3

[FIG. 12] Cross section of Embodiment 4 of hollow microspheres used in the present invention

[FIG. 13] An imaginary view showing hollow microsphere breaking state by the probe of the present invention

[FIG. 14] An imaginary view showing hollow fine sphere breaking action by the needle-like ultrasonic wave (a) of the present invention and the Gaussian-distributed ultrasonic wave (b) of the prior art

[Fig. 15] · · An imaginary figure showing the hollow microsphere breaking state and the introduction function of the exogenous molecule

[Fig. 16] ... Diagram of the probe applied voltage

[Fig. 17] ... A picture as a substitute for a drawing showing the effect of introducing exogenous molecules (fluorescent molecules) by hollow microsphere rupture of ultrasonic waves according to the present invention

[FIG. 18] Comparison graph of the exogenous molecule introduction effect of the probe of the present invention and the conventional probe

[Fig. 19] · · 'A graph comparing gene expression (left) and cell damage rate (right) in cell experiments with the probe of the present invention (Fig. 4) and a conventional Gaussian-distributed ultrasound probe

Explanation of sign

(A) Probe of the present invention

(B) Conventional probe

(P) Needlelike ultrasound

(PG) Ultrasonic of Gaussian waveform

(1) Probe body

(2) Ultrasonic wave generation plate (Piezoelectric element serving as ultrasonic wave generation plate alone (piezoelectric ceramic)) (2a) Single piezoelectric element forming ultrasonic wave generation plate with thin plate (piezoelectric ceramic) (2al) to (2an) Multiple piezoelectric elements (piezoelectric ceramics) that form an ultrasonic wave generation plate with a thin plate

(2M) A thin plate that will constitute an ultrasonic wave generation plate with the piezoelectric element

(3a) (3b) electrode

(4) Feeder

(5) Feeder (6) Metal plate

(10) Hollow microspheres

(11) Outer shell

(11a) Cavitation bubble

(12) Gel sheet

(13) Exogenous molecule

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be sequentially described according to the illustrated embodiments. The “microspheres (10) having acoustic properties” used in the present invention are hollow microspheres having a shell (nano bubbles = micro bubbles at the nano micron level or micro bubbles at the micro bubble = micro bubbles at the micro level). When it is administered to the body, a substance that becomes gaseous (gaseous) is enclosed at the temperature of the living body (around 37 ° C). Such substances (filling gas) include, for example, air, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas such as helium, argon, xenon, krypton, sulfur hexafluoride, sulfur difluoride, trifulf Sulfur fluoride such as trifluoromethyl sulfur pentafluoride, low molecular weight such as methane, ethane, pronone, butane, pentane, cyclopropane, cyclobutane, cyclobutane, cyclopentane, ethylene, propylene, propylene glycol, propylene oxide, propadiene, butene, acetylene and propyne Perfluoro, which is a polymer gas such as hydrocarbons or their halides, CF.

3 8

Carbon (in addition, 1, 1, 2, 2, 3, 3, 3-octafluoropropane), ethers such as dimethyl ether, ketones, esters, etc. And the powers that can be used in combination of one or more of these, particularly sulfur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane, etc. are preferred. . Strong hollow microspheres (10) exert high stability in living organisms.

Also, as a material constituting the hollow microsphere membrane (outer shell (11)), for example, a protein such as albumin, a polycationic lipid, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanol amine, phosphatidal Various lipids such as phospholipids such as ethanolamine, higher fatty acids such as palmitic acid and stearic acid, saccharides such as galactose, cholesterol, sterols such as cholesterol, sitosterol, surfactant, natural or synthetic Molecules, etc., and one or two or more of these may be used in combination It is possible to

The average particle size of the hollow microspheres (10) is not particularly limited, and is generally about 10011111 to 10 m, but the smaller the minimum diameter is, the more desirable it is actually 0. 05. It is preferably about 10 to 10 / ζπι. Since the inner diameter of the capillary is about 7 m, it is more preferable that the inner diameter is about 0.55 to 7 / 5〜πζ.

The hollow microspheres (10) may be composed of only the outer shell (11) (FIG. 9), or a water film (10a) containing an exogenous molecule (13) (for example, a drug) inside. May be formed (FIG. 10), or may contain an exogenous molecule (13) in or on the shell (11) of the hollow microsphere (10) (in the case of FIG. 11) or attached (FIG. 10) Alternatively, a water film (10a) containing an exogenous molecule (13) may be formed in the shell (11) (FIG. 12). Of course, the whole hollow space of the hollow microspheres (10) may be filled. In addition, exogenous molecules (13) may be contained in the gas in the sphere. As the type of exogenous molecule (13), appropriate ones such as drugs and genes are adopted depending on the treatment subject.

Since the hollow microspheres (10) are acoustic, they are vibrated by the application of an external force such as an ultrasonic wave, and furthermore, they are resonated or the intensity of the ultrasonic wave depending on the frequency to which the ultrasonic wave is applied. It is crushed and broken by (sound pressure). Then, in the case of rupture, a large number of cavity air bubbles (11a) are generated with the fragments of the hollow microspheres (10) as the core, thereby generating an impact pressure around (FIG. 15). Then, with this impact pressure, the permeability of the cell membrane of the cells (eg, skin (20) and blood vessels or visceral organs) in the vicinity of the cavity (11a) is changed. An exogenous molecule (13), for example, a drug or gene (nucleic acid) present in the vicinity of the cavity (11a) from the cell membrane causing the permeability change penetrates into the cells and blood vessels of the affected area. The exogenous molecule (13) will circulate throughout the body. The hollow microspheres (10) and the exogenous molecule (13) are, in the case of transdermal, from a liquid medium (120) applied to a gel sheet (12) described later or a cream (121) applied to the skin (20). It is supplied to the affected area, for example by injection, in the case of subcutaneous or visceral.

[0028] The gel sheet (12) is used to transmit the extrinsic molecule (13) to the body as well as the skin (20), and is a viscous body similar in acoustic impedance to living tissue, and is formed of, for example, silicon. In the past, innumerable hollow microspheres (10) or extrinsic substances on the adhering surface (12a) to the skin (20) The liquid medium (120) containing molecules (13) is attached by immersion or application. Because hollow microspheres (10) and extrinsic molecules (13) are fine particles, some of the substances attached to the gel sheet (12) may enter the inside, and the gel sheet (12) is soft, or For this reason, hollow microspheres (10) and exogenous molecules (13) may be previously incorporated into the gel sheet (12) in advance. Also, although not shown, the gel sheet (12) may be perforated and the pores may be filled with the exogenous molecule (13). The exogenous molecules (13) are prepared separately from the hollow microspheres (10) and, in the case as described above, are separately attached by immersion or deposition as described above.

When the hollow microspheres (10) contain the exogenous molecule (13) as shown in FIGS. 10 to 12, the hollow microspheres (10) are attached to the adhesion surface (12a) of the gel sheet (12). Application by immersion or application of a liquid medium (120) containing When not using the exogenous molecule (13) and using only the impact pressure of the cavity air bubble (11a) (eg, when the impact pressure of the cavity air bubble (11a) damages and kills the cells in the vicinity) The hollow microspheres (10) alone are attached to the adhesive surface (12a) of the gel sheet (12) and used or injected into the affected area, and two or more exogenous molecules (13) are introduced. If necessary, attach an exogenous molecule (13) of the same species or different species (especially to the adhesive surface (12a) in contact with the skin (20)) as appropriate, or subcutaneously (or in a predetermined position in the viscera) Can also be injected. These combinations are appropriately selected as necessary. Also. It is also possible to use cream (121) or gel in place of the gel sheet (12). In this case, it is preferable to knead the hollow microspheres (10) and Z or the exogenous molecule (13) in a necessary amount in advance into the cream (121) or gel.

The basic type (example 1) of the probe (A) according to the present invention (ie, a device for generating a plurality of high-order ultrasonic waves (P) intermittently or with a phase difference) is shown in FIG. The first embodiment will be described below. The first embodiment is generally configured of a cylindrical probe main body (1) and an ultrasonic wave generation plate (2) (in the present embodiment, it is constituted by a single piezoelectric element). The feed cords (4) and (5) are connected to the electrodes (3a) and (3b) respectively provided on the front and back of the ultrasonic wave generation plate (2) composed of the piezoelectric ceramic alone. [The electrode positions in the figure are conceptual and do not represent accurate positions. Then, the outer edge (2G) of the ultrasonic wave generation plate (2) contacts, for example, the inner peripheral surface or outer end of the tip cylindrical portion (la) of the probe main body (1), ie, the high frequency generation plate mounting opening (9) It is fixed by wearing. The tip cylindrical portion (la) is screwed off to the probe grip (lb). It is screwed so it can be worn. The probe main body (1) need not be cylindrical as long as it has the high frequency generation plate mounting opening (9), but may be a plate, for example. The shape of the high frequency generation plate attachment opening (9) is not particularly limited, either.

[0031] The characteristic of the cylindrical probe (A) is that the outer edge (2G) of the disk-like ultrasonic wave generating plate (2) made of a single piece of piezoelectric ceramic is located on the entire circumference (or opposite side in some cases) (A part of the arc or side) is fixed to the RF generator plate attachment opening (9) of the end cylindrical part (la) by adhesion [The adhesion site is shown by (K). ], When applying a pulse voltage of a certain duty ratio, the ultrasonic wave generation plate (2) [= single piezoelectric ceramic material] causes surface vibration (high-order vibration) in a wave form concentrically and along the concentric circle, ultrasonic wave Each abdominal force of surface vibration on the generation surface (2S) is also a point where a large number of ultrasonic waves (P) of needle-like waveform are generated intermittently [Fig. L (b) (c)]. Figure l (a ') shows surface vibration on the ultrasonic wave generation surface (2S).

The frequency of the ultrasonic wave (P) is the same as the natural frequency f of the ultrasonic wave generation plate (2), and a large number of ultrasonic waves (P) having a needle waveform are generated from each antinode of the surface vibration. The main frequency is the same as the natural frequency f of the ultrasonic wave generation plate (2) as described above, but also includes harmonic components of 2f, 3f, 41 ···. (Ie, the natural frequency f is a harmonic Wave components 2f, 3f, 41 "· · · are superimposed.;). The number of nodal diameters, the number of nodal circles, the peripheral fixing condition of the disc-like ultrasonic wave generation plate (2) [= bonding site Figure 1 (c) shows that the disc-shaped ultrasonic wave generation plate (2) emits a large number of pulse wave ultrasonic waves (P) intermittently. The above-mentioned probe (A) has a cylindrical shape. Of course, the probe (A) may be a square tube type shown later, or an elliptical surface type (not shown) or any other suitable shape.

FIG. 2 shows another example of FIG. 1 (Example 2) in which the ultrasonic wave generation plate (2) is formed of a piezoelectric ceramic thin plate (2a) and a thin plate (2M) 2M) is formed of metal or resin. Aluminum is preferred for metal plates. The reason is that (a) the acoustic impedance is close to the acoustic impedance of water, and (b) it is light, and the ability to prevent corrosion by water by using an anodizing treatment. The piezoelectric ceramic thin plate (2a) is bonded to the thin plate (2M), and the front and back of the piezoelectric ceramic thin plate (2a) is an electrode (3a) (3b) provided on the piezoelectric ceramic thin plate (2a) and the thin plate (2M) respectively. Power supply cords (4) and (5) are connected to). And, the outer circumference of the thin plate (2M) and the piezoelectric ceramic thin plate (2a) For example, it is fixed to the opening (9) by adhesion. The other points are the same as in Figure 1.

Example 3 [see FIG. 4 and FIG. 5 (a) and its modification, FIG. 5 (b)], the ultrasonic wave generation surface (2S) is a square (square or rectangle), and for one side, hereinafter. In the case where the other side is a rectangle slightly longer than the other side is a representative example) probe (A), in order to change (further increase) the number of nodes restricted by the fixed condition of the above-mentioned disc, A plurality of independent piezoelectric ceramic flakes (2al) (2a2) ′ ′ ′ is used, that is, the entire periphery of the outer edge (2G) or the two opposite sides are adhesive [the adhesive layer is indicated by (K) The rectangular piezoelectric ceramic flakes (2al) and (2a2) are attached in parallel to each other on the thin plate (2M) (8 in this embodiment, one of which will be described later as a modified example thereof; Example 3 In the case of [Fig. 5 (a)], the strip-like piezoelectric ceramic flakes (2al) (2a2) ... are separated from each other, and their short sides (2G) are also attached to the high frequency generating plate Opening (9) Force Separation A gap (L) is formed at the relevant part, while the deformation wedge 5 (b)] is the piezoelectric ceramic thin piece (2al) (2a2) ... the short side (2G) is a high frequency generating plate mounting opening Bonded to (9) The adhesive layer is indicated by (K).

[0035] In each case, the ultrasonic wave generation status is slightly different, but the piezoelectric ceramic flakes (2al) (2 _a 2)-also show the long side force, and each piezoelectric ceramic flakes (2 al) (2 _a 2) '· · · The abdomen and nodes are formed to form multiple needle ultrasound waves (P). On the other hand, when viewed from the short side (2G) side of the piezoelectric ceramic flakes (2al) (2 _a 2) "', each piezoelectric ceramic flakes (2 al) (2 _a 2) is formed with only one needle-like ultrasonic wave. Needle-like ultrasonic waves (P) are formed side by side according to the number of piezoelectric ceramic flakes (2al), (2a2), etc. In the embodiment of the figure, a plurality of (in this case, eight) Piezoelectric ceramic thin film (2al) (2a2) '· · · Each of the electrodes (3al) (3a2)' · · · '(3b) feeder (4 1 × 42) ·-(5) extends, each feeder (41 ) (42) · · · (5) is integrated into one, and the input signal for ultrasonic wave generation is input intermittently or continuously simultaneously or with phase difference. By doing this, as described later, each piezoelectric ceramic thin film (2al) (2a2) ... is simultaneously or simultaneously with the input signal and intermittently or continuously with a phase difference between the ultrasonic waves (P) of a plurality of needle waveforms. The piezoelectric ceramic (2a) is thus divided into (2al) (2a2) ′ ′ and so on, almost on the entire surface of the ultrasonic wave generating surface (2s), which is the contact surface [eg, skin] of an elephant. As a result, the number of ultrasonic waves is doubled by the number of piezoelectric ceramic flakes (2al) ( _2a 2) ′ ′, and there is an advantage that generation can be performed continuously or intermittently or by providing a phase difference. Piezoelectric ceramic thin plate (2a) which is a modification of the third embodiment In the case of a sheet of Si, an example in which the entire periphery of the outer edge (2G) is fixed by the adhesive layer (K), in this case Is the same as in FIG. 2 described above.

FIG. 6 shows an example in which a reticulated insulation member (2e) is attached to the surface of the ultrasonic wave generation plate (2) or thin plate (2M) of the probe (A). The regions (2z) in the lattice of the member (2e) vibrate respectively, and a needle-shaped ultrasonic wave (P) is generated for each region (2z) in the lattice. The other points are the same as those of the first embodiment described above.

Although not shown, the piezoelectric ceramic (2a) can also be divided by the cylindrical probe (A) to generate ultrasonic waves as many as the number of thin pieces of piezoelectric ceramic. There is no limitation on the method of division, but as an example, it is also possible to arrange piezoelectric ceramic flakes of approximately isosceles triangle shape with a central force radially, as the oranges are cut in a circle!

Next, a method of applying a voltage to the ultrasonic wave generation plate (2) is as shown in FIG. 16. For one cycle (T), pulse voltage [or AC voltage for only time t] ] Is applied. At this time, by changing the intensity (pulse height), the duty ratio (t / T), and the number of applied cycles (X), a wider range of ultrasonic wave generation conditions can be set, which has further effects. It is appropriate that these be decided by the subject.

Also, unlike the case of using a disk-shaped ultrasonic wave generation plate (2) made of a single piezoelectric ceramic alone or a single piezoelectric ceramic thin plate (2a), a plurality of piezoelectric ceramic thin plates (2al) (2a2) When ...) is used, the input timing of the input signal can be changed to give a phase time, and the ultrasonic wave generation plate (2) changes the ultrasonic wave (P) according to the phase difference between different occurrence locations. The plurality of ultrasonic waves (P) having these phase differences cooperate with one another to effectively break the hollow microspheres (10). The frequency of the ultrasonic wave (P) affects the tissue of the skin (20) or the viscera to which it is applied, and the force is usually about 1 MHz because the hollow microspheres (10) are broken. Of course, as long as the above conditions are satisfied, when using a plurality of piezoelectric ceramic flakes (2al) (2a2) ..., it is possible to make the natural frequency of each piezoelectric ceramic flake (2a 1) (2) · · · · · · · · · · · · · · It is possible to generate even more complex ultrasound waves by changing the phase difference of the input signal. To change the sound pressure, change the applied voltage. FIG. 7 shows the fourth embodiment, in which a disc-like thin plate (2M) is provided around a central metal plate (6 ′), and a conventional piezoelectric ceramic (not shown) is formed on the central metal plate (6 ′). 2 ') is pasted, and a plurality of piezoelectric ceramics (2 _a l x 2 _a 2)''(2 _an ) are provided on the thin plate (2 M) around it, and all or one part of its outer end (2 G) In this example, the part is fixed to the partition wall (17) and the opening (9) by the adhesive layer (K). The ultrasonic wave (PG) of the Gaussian distribution waveform is formed from the central piezoelectric ceramic thin plate (2 '), and the piezoelectric ceramics (2 _a1 ) (2a2) ′ ′ (2 _an ) around it have a needle-like waveform. Form a sound wave (P).

In this case, while moving the probe (A), a specific region such as the affected area is searched and specified by ultrasonic waves (PG) of Gaussian distribution waveform, and if the affected area is found, the needle waveform ultrasonic wave ( P) rupture the hollow microspheres concentrated at the specific site, and the impact pressure efficiently strikes the surrounding exogenous molecules into surrounding cells or surrounding blood vessels. In this case, if needle waveform ultrasound (P) is generated around ultrasonic (PG) of the Gaussian distribution waveform, then the ultrasound (PG) force is simply needle waveform ultrasound (P By simply switching to), the affected area can be struck at that time, and treatment can be performed more efficiently.

In Example 4, the structure as described above is illustrated in FIG. 7, but the structure of Example 4 is of course not limited to this, and the structure shown in Examples 1 to 3 may be obtained. It can apply. For example, in FIG. 7, the peripheral piezoelectric ceramic plates (2al) to (2an) are circular, and a part of the outer peripheral edge (2G) is the inner peripheral surface of the partition wall (17) or the opening (9) The piezoelectric ceramic plates (2al) to (2an) fixed to the end face may be formed into a fan shape, and the entire outer peripheral edge (2G) may be fixed, or the thin plate (2MG) is excluded. Then, the piezoelectric ceramic plates (2al) to (2an) may be directly fixed in the same manner as in Example 1. Since the piezoelectric ceramic plate can be formed into any shape, it is not shown, but it is formed in a ring shape, and the thin plate (2MG) and the partition wall (17) and the inner periphery of the opening (9) are formed in the same ring shape. It may be fixed to a surface, or a ring-shaped unitary piezoelectric ceramic plate may be attached directly without a thin plate (2MG).

[0044] Next, the foam-breaking action of ultrasound (P) will be described. As shown in Figs. 14 (a) and 14 (b), the sound pressure at the central part of the ultrasonic wave (P) is high, and the sound pressure gradually decreases as it goes to the periphery.

In other words, the pressure (sound pressure) is also directed outward at the central force. On the other hand, hollow microspheres (10) It exists innumerably in the liquid medium (120) or cream (121) containing the exogenous molecule (13) applied to the gel sheet (12) under the ultrasonic wave generation surface (2s), and it is liquid because of ultrafine particles. It is moving in the medium (120) or cream (121).

As shown in FIG. 14 (b), when ultrasonic waves (PG) of the Gaussian distribution waveform are applied to the gel sheet (12) or the cream (121) with the conventional probe (B), the ultrasonic waves are generated as described above. The sound pressure of (PG) gradually decreases toward the central part force. It is estimated as follows that V, and not clearly, of the bubble-breaking action of hollow microspheres by ultrasonic wave.

[0047] In the conventional ultrasonic probe (B), the metal plate (6) has an entire surface so that the pressure distribution of the ultrasonic wave (PG) obtained as described above has a clear mountain shape (Gaussian distribution). I'm glued. In this case, the central part (YG) is the largest and the lower it goes to the periphery. Then, this ultrasonic wave (PG) is applied at a certain duty ratio and intermittently outputted from the ultrasonic wave generation plate (2).

On the other hand, innumerable hollow microspheres (10) migrate in the liquid medium (120) and the like. When ultrasound (PG) of the conventional Gaussian distribution waveform is output, the hollow microspheres (10) located in the central portion (YG) of the ultrasound (PG) are ruptured by the strong sound pressure. And, as described above, the surrounding exogenous molecules (13) will be driven into surrounding tissues. In the vicinity of the central part (YG) of the ultrasonic wave (PG), the hollow microsphere (10) of the ultrasonic wave (PG) is in the central part (YG). ) Force The central part (YG) force is also pushed away by the decreasing pressure in the peripheral direction. Therefore, in the case of the ultrasonic (PG) of the conventional Gaussian distribution waveform, when the ultrasonic (PG) is output, only the hollow microspheres (10) which happen to be in the range of the central portion (YG) burst It is bad and the bubble breaking efficiency is bad.

On the other hand, in the probe (A) of the present invention, when a pulse voltage is applied to the ultrasonic wave generation plate (2), the ultrasonic wave generation plate (2) causes surface vibration, but the number of nodes of surface vibration and diameter The number of nodal circles is determined by the radius of the ultrasonic wave generation plate (2) [piezoelectric element], plate thickness, density, bending synthesis, natural angular frequency, and the generated ultrasonic waves are antinodes of higher order vibration modes. These components are synthesized +12 + 13 + to + & 1 + 1 n and output from the ultrasonic wave generation surface (2s) of the probe (A). The harmonic component is generated in this ultrasonic wave (P). (See Fig. 8 (a) to (c)) and the level may be a much higher peak if the same energy as in the prior art is applied in some cases. Note that Fig. 8 (d) shows the conventional planar ultrasonic wave (Gaussian distributed wave). Form).

Furthermore, in the probe (A) of the present invention, a plurality of (in other words, two or more) ultrasonic waves (P) generate an ultrasonic wave generation surface (2S) force, so one ultrasonic wave (P) is generated. The hollow microspheres (10), which are located around the central part (Y) of the core and force-pushed out of the central part (Y) without bursting, are the other ultrasonic waves (P ) And it is broken at the central part (Y) of its ultrasonic wave (P) (see Fig. 13 and Fig. 14 (a)).

In addition, when the ultrasonic wave (P) is needle-like, the peak value of the needle-like ultrasonic wave (P) (compared to the peak value of the ultrasonic wave (PG) of the conventional Gaussian distribution waveform for the same input energy If so, the sound pressure is considered to have a higher probability of breaking the hollow microspheres (10) that have penetrated into the high ultrasonic waves (P). In addition, since a plurality of ultrasonic waves (P) of the present invention can be generated, the liquid medium (120) containing an infinite number of hollow microspheres (10) and an infinite number of exogenous molecules (13) is stirred in a wide range. It can be considered that the migration of hollow microspheres (10) can be made more active to increase the breakage probability (see FIG. 14 (a)).

[0052] Furthermore, ultrasonic transducer plurality of piezoelectric ceramic elements (2al) consists of (2a _n), their respective is pulsed voltage is applied with a phase if Ru, one ultrasound (P) When the density of the hollow microspheres (10) in the periphery increases and the density of the hollow microspheres (10) in the periphery increases, another ultrasonic wave (P) is generated with a phase difference in the periphery. It is considered that the above-mentioned stirring effect is further enhanced since the bursting of the hollow microspheres (10) in the peripheral part is naturally performed at high density when produced.

Next, in the photograph instead of the drawing for demonstrating the percutaneous introduction effect by the hollow microspheres (10) of the probe (A) of the present invention (FIG. 17), the “Control (photograph)” shows the hollow microspheres (10). B) without using the probe of the present invention (A) for percutaneous introduction of the exogenous molecule (13), and “NB + U Sj is a photograph showing the effect of percutaneous introduction by hollow microspheres (10) The demonstration method is as follows: The perforated gel sheet (12) was attached to the skin, and in the “control”, the exogenous molecule (13) was carried in this hole without hollow microspheres (10). The liquid medium (120) is filled with the liquid medium (120) carrying the hollow microspheres (10) and the exogenous molecule (13) in "NB + US", and this filling portion is the probe of the present invention shown in FIG. It is the result of applying at high frequency (P) in A). As can be seen by comparing “control” and “NB + US”, “NB + US” is a fluorescent molecule (TEXAS-R It can be seen that the exogenous molecule introduction effect of the hollow microspheres (10) having many portions stained with ED (extrinsic molecule) is clear.

The method of using the liquid medium (120) carrying the hollow microspheres (10) and the extrinsic molecule (13) is the adhesion surface of the liquid medium (120) to the skin of the gel sheet (12). 12a), and this gel sheet (12) is adhered to the skin surface (20), and even if pulse voltage is applied in this state to generate ultrasonic waves, the nature of the gel sheet (12) It is believed that similar effects can be obtained. Also, because of the above-mentioned relationship, the cream (121) or the like (not shown) such as a gel includes hollow microspheres (10) and exogenous molecules (13) (exogenous molecules (13) carrying hollow microspheres (10) ) May be included.

[0055] FIG. 18 differs from FIG. 17 in that a luciferase plasmid was injected into the skeletal muscle of a non-transdermal mouse to introduce an exogenous molecule, and ultrasound was applied to the exogenous molecular injection site, and 4 days elapsed. The later data show the relationship between the sample mouse and the number of input pulses applied to it (horizontal axis) and the value of gene expression (expression amount of introduced exogenous molecule) (vertical axis). Note that "R" and "L" are codes indicating whether the sample is the left foot or the right foot of the mouse. The number of pulses (Pulse) is 10, 100, 1000, 2, 20, 200, 50, 500, and the duty ratio is shown by 10%, 20%, 50% in the upper row. The probes of the present invention are mouse Nos. (Mouse No.) 1 to 13, and the conventional probes are mouse Nos. (Mouse No.) 14 to 20.

According to FIG. 18, according to the probe of the present invention shown in FIG. 1, the tendency of the probe of the present invention as a whole generally slightly exceeds the exogenous molecule introduction effect of the conventional probe, and the mouse No. 11 has a duty ratio of 20% to 200 pulses, mouse In the case of No. 12 with a duty ratio of 50% -50 pulses, a high exogenous molecule introduction effect is shown. The variation in the extrinsic molecule introduction effect is considered to be due to the variation in the experimental method due to individual differences and irradiation.

[0057] FIG. 19 shows that the piezoelectric ceramic elements (2al) (2ab) ′ ′ (2a8) shown in FIG. 4 and FIG. 5 (a) are extrinsic in comparison with the present invention probe and the conventional probe of eight types. Luciferase plasmid was used as the molecule EMT 6 mouse breast cancer cells and C26 mouse colon cancer cells were used The data described as "patent" are the probes of the present invention, and they are "planar" or "commercially available". The data described are conventional probes. On the horizontal axis, “Control (= 0, 20, 50, 80)” is described as [duty ratio (%)], and the vertical axis on the left is the gene expression strength (the expression of the exogenous molecule The current effect (1 MHz) is shown, and the vertical axis in the right figure shows the cell damage rate (1 MHz). The pulse voltage of the probe of the present invention applied a pulse voltage of the same frequency simultaneously to the misaligned piezoelectric ceramic element (2al) (2ab) '·' (2a8). In the probe of the present invention shown in FIG. 4 etc., a plurality of needle-like ultrasonic waves (P) are generated even when the piezoelectric ceramic elements (2al) (2a2) '·' (2a8) are displaced. The number of ultrasonic waves (P) generated is the number of ultrasonic waves generated in one piezoelectric ceramic element X the number of piezoelectric ceramic elements, and the number of needle ultrasonic waves (P) in the probe of the present invention shown in FIG. It is estimated that the number of occurrences of all needle ultrasonic waves (P) is significantly and stably contributes to the extrinsic molecule introduction effect, as compared with the case of the present invention. The pulse voltage applied to both probes (A) and (B) is the same.

According to the present invention, a plurality of needle-like ultrasonic waves are generated simultaneously and continuously at substantially the entire surface of the contact surface of the probe, and a wide range and a large amount of hollow microspheres are continuously broken in a short time. Alternatively, it was possible to implant the exogenous molecules into the surrounding cells in an unprecedented amount, and it was possible to make the conventional ultrasound exogenous molecule introduction more efficient. This significantly reduced the burden on patients and contributed to the advancement of medical care.

Claims

The scope of the claims

[1] (a) A probe body having a high frequency generation plate mounting opening,

(b) A probe characterized in that the outer edge thereof is fixed to the high frequency generation plate attachment opening and configured by a high frequency generation plate that generates two or more high frequencies from different positions by voltage application. .

[2] (a) A probe body having a high frequency generating plate mounting opening,

(b) a thin plate for vibration, the outer edge of which is fixed to the high frequency generation plate attachment opening;

(c) A probe characterized in that its outer edge is constituted by one or a plurality of piezoelectric ceramic thin plates fixed to the high frequency generation plate mounting opening and stuck to the thin plate.

[3] (a) A probe body having a high frequency generating plate mounting opening,

(c) Inner peripheral surface force of probe main body A probe characterized by comprising a plurality of piezoelectric ceramic thin plates attached to the thin plate with a gap.

[4] The waveform according to any one of claims 1 to 3, characterized in that the generated high frequency waveform has a needle shape. , Probe described in any place.

[5] (a) 1 of the piezoelectric ceramic thin plate forms ultrasonic waves of Gaussian distribution waveform,

(b) The probe according to claim 2 or 3, characterized in that the other piezoelectric ceramic thin plate forms a needle waveform ultrasonic wave.

[6] The probe according to any one of claims 1 to 5, wherein a mesh plate is further attached to the outer surface of the high frequency generation plate or the piezoelectric ceramic thin plate.