JP2009165499A - Probe for generating ultrasonic wave - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To introduce exogenous molecules to a predetermined location by oscillating a high-frequency wave generation plate and generating a large number of needlelike ultrasonic waves containing high-frequency components over the substantially entire surface of the high-frequency wave generation plate, thereby breaking countless hollow microspherical bodies efficiently over the substantially entire surface of the high-frequency wave generation plate. <P>SOLUTION: 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. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention can generate a high frequency from two or more different positions of the high-frequency generating plate, and can destroy the hollow microspheres having acoustic properties over almost the entire surface of the high-frequency generating plate. It can be applied to medical ultrasonic probes and can be applied to cleaning and sterilization outside the medical field. For example, for purification of lake water, seawater, dams, and sterilization of food (oysters, laver) Also relates to an ultrasonic probe that can be used.

  The ultrasonic molecule introduction method uses the characteristics of ultrasonic waves, and the ultrasonic waves generated from the probe (1) increase percutaneous absorption, (2) hollow microspheres (acoustic nanobubbles and / or microbubbles) ) And exogenous molecules are used to introduce bioactive substances into cells using a composition or mixture, and (3) enhancement of drug effects in vivo has been reported. Since it can introduce exogenous molecules into the affected area non-invasively, it currently plays an important role in the treatment of cardiovascular diseases such as the heart, gastrointestinal diseases or malignant tumors.

  The conventional ultrasonic wave generation probe (B) is as shown in FIG. 3, and is roughly a cylindrical probe body (1 ′) and a metal mounted on the tip opening of the probe body (1 ′). The plate (6 ′), the piezoelectric element (2 ′) disposed by being directly adhered to the inner surface side of the metal plate (6 ′), and the feeding cord connected to the electrode provided on the piezoelectric element (2 ′) ( 4 ') and (5'). In the probe (B) having such a structure, the entire lower surface of the piezoelectric element (2 ′) is bonded to the relatively thick metal plate (6 ′) via the adhesive layer (K ′) to the entire outer edge. Non-adhesive [The gap between the two is indicated by (L '). Therefore, when an AC voltage or pulse voltage is applied to the piezoelectric element (2 ′), the shape of one Gaussian distribution is greater than the normal distribution from the metal surface (6a ′) that is the contact surface to the skin or the like. Only sound waves (PG) are generated [see FIG. 3 (b)]. The effective bubble breaking range of the micro hollow sphere described later of the ultrasonic wave (PG) having the normal distribution waveform is indicated by (YG). In addition, the following exogenous molecules (drugs and genes) have been introduced into a predetermined place in the living body by using the ultrasonic wave (PG) having this normal distribution waveform.

  Patent Document 1 exposes a composition for delivering a biologically active agent that is an exogenous molecule to a specific part of a living body, that is, a biologically active agent introduction composition containing a micro hollow sphere, to ultrasound. Thus, the micro hollow sphere is broken at a specific site, and the biologically active agent (in this case, a gene) is incorporated into the specific site by the impact pressure at the time of the bubble break.

  More specifically, Patent Document 1 uses an albumin-derived acoustic hollow microsphere (nano or micron bubble) containing perfluorocarbon as an internal gas, and has a frequency close to the resonance frequency of the hollow microsphere. A method of introducing a biologically active agent into a living body by using a 1 MHz high-frequency ultrasonic wave that can surely break the hollow microsphere with a lower sound pressure is used to break the bubble. It is disclosed. This method aims to introduce biologically active agents into specific areas of the living body, such as brain, digestive tract, blood vessels, muscles, especially cancer tissues, and other parts of the body. In the conventional example of 3, the outer surface (6a ') of the metal plate (6') is fixed in a normal distribution shape in which the sound pressure is highest in the central part (YG) and gradually decreases in three dimensions toward the outside. A device that generates ultrasonic waves at a frequency is used. In this case, the narrow central portion (YG) of the ultrasonic wave generation surface [As shown above, the effective range in which bubbles can be broken in FIG. 3 (b) is schematically shown as (YG). ] Is an effective region that vibrates and breaks the hollow microspheres, and the peripheral portion that occupies the majority hardly affects the bubble breakage, and the amount of biologically active agent introduced into a specific site is very small. there were.

  Citation 2 is an invention relating to a “gene transfer agent” for treating acute myocardial infarction containing hollow microspheres (acoustic nanobubbles and / or microbubbles) whose internal gas is perfluorocarbon and containing a therapeutic gene. , By injecting the gene introduction agent into the blood, the hollow microspheres in the gene introduction agent introduced into the myocardium are bubbled under ultrasonic irradiation, and the myocardium of the HGF gene (= therapeutic gene) by the impact It is possible to introduce to. The ultrasonic frequency used is the one that generates ultrasonic waves with the fixed frequency of the normal distribution with the highest center from the ultrasonic generation surface of the probe for generating ultrasonic waves due to the breakage of the hollow microspheres. As described above, there is a problem that the effective range is narrow and the amount of biologically active agent introduced into a specific site is very small.

Patent Document 3 discloses a tumor in which at least a part of tumor cells constituting the tumor is killed by introducing or attaching hollow microspheres into or on the surface of the tumor and breaking the hollow microspheres with ultrasonic waves. In the treatment apparatus, the tumor treatment apparatus breaks the hollow microsphere by a first ultrasonic transducer that oscillates a first ultrasonic wave for confirming the presence of the hollow microsphere administered to the living body. Based on information obtained from the reflected wave of the first ultrasonic wave by the ultrasonic control means in the tumor treatment apparatus, The oscillation of the second ultrasonic wave is controlled, and the first ultrasonic wave and the second ultrasonic wave (frequency = 100 kHz to 10 MHz, ultrasonic output = 0.1 to 30 W / cm ² ) Are their power and / or frequency Are controlled differently. Also in this case, the ultrasonic wave generating probe generates ultrasonic waves with a fixed frequency having a normal distribution with the highest center from the ultrasonic wave generating surface. Also in this case, as described above, the effective area of the ultrasonic wave is very narrow, and only the hollow microspheres located within a small area of the total area of the ultrasonic transducer can be ruptured. there were.

  As described above, in this type of device using hollow microspheres having acoustic properties, that is, nanobubbles or microbubbles, the central portion (YG) is the most acoustic pressure from the ultrasonic generation surface of the ultrasonic generation probe. Is used, which generates ultrasonic waves of a fixed frequency with a normal distribution in which the sound pressure gradually decreases as it goes outwards. The effective surface for foam breakage of the hollow microspheres is limited to a very small area (YG) in the central part, and there is a disadvantage that foam cannot be broken in a wide peripheral part and the introduction amount of the drug is small. It could not be overcome (Patent Documents 1-3).

JP2002-145784 JP2004-210774 JP 2004-223175 A

As described above, in the conventional techniques and methods, an exogenous molecule is placed at a predetermined position of a living body using a hollow microsphere having acoustic properties using a probe that emits a single ultrasonic wave having a Gaussian distribution shape at a certain fixed frequency. The basic concept has been to introduce molecules.
In contrast, the present invention
1) A high frequency generating plate composed of a piezoelectric element alone or a high frequency generating plate in which a piezoelectric ceramic thin plate is bonded to a thin metal plate is vibrated in a high order to generate a large number of needle-like ultrasonic waves including high frequency components. In almost the entire surface, or
2) By using a high frequency generator 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 in the corresponding parts of each piezoelectric ceramic thin plate, resulting in almost the entire high frequency generating surface. To generate several times the acicular ultrasonic wave, or
3) By attaching a mesh-like insulating plate to the high-frequency generating plate, each region surrounded by the mesh is made an independent region, and many needle-like ultrasonic waves are generated from each region. Efficiently breaks the hollow microspheres on almost the entire surface of the high-frequency generator plate, and effectively utilizes the impact pressure of the countless cavitation bubbles generated by the countless collapse of the hollow microspheres. The basic concept is a probe that is particularly effective for medical use, which makes it possible to introduce molecules or to apply the impact pressure of the cavitation bubbles to a predetermined place of a living body. In addition to the medical field, the present invention can also be applied to cleaning and sterilization. For example, it can be used to purify lake water, seawater, dams, and sterilize food (oysters, seaweed). In the following, medical applications will be described as typical examples.

In the present invention, the high frequency generating plate (2) is
(A) In the case of a high frequency generating plate (2) composed of a single piezoelectric element (Claim 1),
(B) when formed from one or more piezoelectric elements (2a) and a metal plate (2M) (claim 2 or 3),
(B-1) In this case, when the number of the piezoelectric elements (2a) is one, the entire circumference or a part of the outer edge (2G) is fixed (Claim 2),
(B-2) There are a plurality of piezoelectric elements (2a) and the outer end edges (2G) are fixed, and there are cases where gaps (L) are provided apart from each other (Claim 3).
In addition, the shape of the high frequency generating plate mounting opening (9) can take a shape as necessary, such as a circular shape, an elliptical shape, or a quadrilateral shape (rectangular shape or square shape). The shape of the generator plate (2) or the piezoelectric element (2a) can be circular, oval or quadrilateral (rectangular or square).

The probe (A) of claim 1 uses a high frequency generating plate (2) constituted by a single piezoelectric element as shown in FIG. 1, and the high frequency generating plate (2) In the case where the circumference is fixed or in the case of a quadrilateral, not only the entire circumference but also the opposite side may be fixed. As described above, the probe main body (1) can have a shape as required, such as when the high frequency generating plate mounting opening (9) is circular, elliptical or quadrilateral. This also applies to the second and third aspects.
(a) a probe body (1) having a high frequency generator plate mounting opening (9);
(b) The high frequency generating plate mounting opening (9) is provided with an outer edge (2G) fixed thereto, and is configured by a high frequency generating plate (2) that generates two or more high frequencies from different positions by applying a voltage. It is characterized by having.

The probe (A) of claim 2 is a case where the outer edge (2G) of one or more metal plates (2M) is fixed, and is shown in FIG. 4 and FIG. 2 or FIG. 5 (b). Yes. That is,
(a) a probe body (1) having a high frequency generator plate mounting opening (9);
(b) a vibration thin plate (2M) having an outer edge (2MG) fixed to the high frequency generating plate mounting opening (9);
(c) One or more piezoelectric ceramic thin plates (2a) or (2a1) whose outer edge (2G) is fixed to the high frequency generating plate mounting opening (9) and attached to the thin plate (2M). It is composed of and. Also in this case, as described above, when the high frequency generating plate mounting opening (9) is circular, oval or quadrilateral, the shape can be taken as required. When the piezoelectric ceramic thin plate is constituted by a single piece, it is indicated by (2a), and when it is plural, it is indicated by (2a1)... (2an).

FIG. 4 shows claims 2 and 3 simultaneously. In the case of claim 2, the outer edge (2G) of one or more piezoelectric ceramic thin plates (2a) or (2a1). When the piezoelectric ceramic thin plate (2a) is rectangular and has a plurality, the outer edge (2G) is on the short side and the long side is free. ] Is bonded to the high frequency generating plate mounting opening (9).
According to the third aspect of the present invention (in this case, there is no single sheet), a gap (L) is provided on the outer edge (2G) of the plurality of piezoelectric ceramic thin plates (2a1).

The probe (A) of claim 3 is shown in FIGS. 4 and 5 (a) together with claim 2 as described above. A plurality of piezoelectric ceramic thin plates (2a1). ) Separated from the inner circumferential surface [this portion is indicated by a gap (L). ]
(a) a probe body (1) having a high frequency generator plate mounting opening (9);
(b) a vibration thin plate (2M) having an outer edge (2MG) fixed to the high frequency generating plate mounting opening (9);
(c) It is composed of a plurality of piezoelectric ceramic thin plates (2a1) (2an) that are attached to the thin plate (2M) with a gap (L) from the inner peripheral surface of the probe body (1). It is characterized by.

  A fourth aspect is characterized in that "in the probe (A) according to any one of the first to third aspects, the generated high frequency has a needle shape".

The probe (A) according to claim 5 is, as shown in FIG. 7, “a plurality of piezoelectric ceramic thin plates (2a1)... (2an) are used. A)
(a) One of the piezoelectric ceramic thin plates (2a1) forms an ultrasonic wave (PG) with a Gaussian distribution waveform,
(b) Others form a needle-shaped ultrasonic wave (P) ”.

  As shown in FIG. 6, the probe (A) according to claim 6 is a probe (A) according to any one of claims 1 to 5, comprising a thin plate (2M) or a high-frequency generator plate (2). Further, a net plate (2e) is further adhered to the outer surface.

  According to the probe of the present invention, the high-frequency generating plate vibrates by generating higher-order waves (two or more waves). Therefore, if the high-frequency generating plate is vibrated by voltage application, A large number of anti-vibration portions are formed on almost the entire surface, and many needle-like ultrasonic waves are generated from these portions. In other words, a large number of needle-like ultrasonic waves are generated over almost the entire surface of the high-frequency generator plate, whereby the high-frequency generator plate of the probe is applied to the skin-attached gel sheet or cream (or gel) carrying exogenous molecules and hollow microspheres. The infinite number of hollow microspheres are intermittently and continuously bubbled over almost the entire surface of the high-frequency generating plate simply by being crimped or brought into contact with each other. In other words, it is intermittently and continuously driven at a necessary place efficiently in a short time. Thereby, higher pharmacological effects can be obtained than ever.

  In addition, in a probe using a plurality of piezoelectric ceramic thin plates, one of the piezoelectric ceramic thin plates forms an ultrasonic wave (PG) having a Gaussian distribution waveform, and the other forms an ultrasonic wave (P) having a needle-like waveform ( FIG. 7), a specific part such as an affected part is probed and identified by ultrasonic waves (PG) of a Gaussian distribution waveform, and then hollow microspheres concentrated on the specific part by needle-like waveform ultrasonic waves (P) are described above. It is ruptured like this, and the surrounding exogenous molecule is efficiently driven into the surrounding cells or the surrounding blood vessels by the impact pressure. In this case, if the ultrasonic wave (P) is generated around the ultrasonic wave (PG) of the Gaussian distribution waveform, the ultrasonic wave (P) is simply converted from the ultrasonic wave (PG). By simply switching to, it is possible to strike the affected area at that time, and the treatment work can be performed more efficiently.

Hereinafter, the present invention will be described in order according to the illustrated embodiments. “Acoustic microsphere (10)” used in the present invention is a hollow microsphere having a shell (nanobubble = nanomicron level microbubble or microbubble = micron level microbubble). When administered, a substance that becomes gaseous (gaseous) at the temperature of the living body (around 37 ° C.) is enclosed. Examples of such substances (encapsulated gas) include air, nitrogen, oxygen, carbon dioxide, hydrogen, helium, argon, xenon, krypton, inert gas, sulfur hexafluoride, disulfur decafluoride, Low molecular weight hydrocarbons such as sulfur fluoride such as fluoromethyl sulfur pentafluoride, methane, ethane, propane, butane, pentane, cyclopropane, cyclobutane, cyclopentane, ethylene, propylene, propadiene, butene, acetylene, propyne Alternatively, perfluorocarbon which is a polymer gas such as these halides and C ₃ F ₈ (one of preferred examples is 1,1,1,2,2,3,3,3-octafluoropropane) , Ethers such as dimethyl ether, ketones, esters and the like, and one or more of these are combined Can be used, in particular, sulfur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane are preferred. Such hollow microspheres (10) exhibit high stability in the living body.

  The material constituting the hollow microsphere membrane (outer shell (11)) includes, for example, proteins such as albumin, polycationic lipids, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and phosphatidylethanolamine. Various lipids such as phospholipids, higher fatty acids such as palmitic acid and stearic acid, sugars such as galactose, sterols such as cholesterol and sitosterol, surfactants, natural or synthetic molecules, etc. 1 type or 2 types or more can be used in combination.

  The average particle diameter of the hollow microsphere (10) is not particularly limited, and is generally about 100 nm to 10 μm, but the smaller the minimum diameter, the more desirable, and actually about 0.05 to 10 μm. Is preferred. Since the inner diameter of the capillary is about 7 μm, it is more preferably about 0.05 to 7 μm.

  The hollow microsphere (10) may be composed only of the outer shell (11) (FIG. 9), and a water film (10a) containing an exogenous molecule (13) (for example, a drug) is formed inside. Alternatively, the exogenous molecule (13) is contained in the shell (11) of the hollow microsphere (10) or the surface thereof (if it is contained) or attached (or adsorbed). Alternatively, a water film (10a) containing an exogenous molecule (13) may be formed in the shell (11) (FIG. 12). Of course, the entire hollow space of the hollow microsphere (10) may be filled. In addition, exogenous molecules (13) may be included in the gas in the sphere. As the type of exogenous molecule (13), an appropriate one, for example, a drug or a gene, is used depending on the treatment target.

  Since the hollow microsphere (10) is acoustic, it vibrates when an external force such as an ultrasonic wave is applied, and further resonates depending on the applied frequency of the ultrasonic wave or the intensity of the ultrasonic wave (sound pressure). It is crushed by and is broken. When ruptured, a large number of cavitation bubbles (11a) are generated with the fragments of the hollow microspheres (10) as nuclei, thereby generating an impact pressure around them (FIG. 15). The impact pressure changes the permeability of the cell membrane of cells (for example, the skin (20), blood vessels or internal organs) in the vicinity of the cavitation bubbles (11a). Exogenous molecules (13) existing near the cavitation bubbles (11a), such as drugs and genes (nucleic acids), permeate the affected cells and blood vessels from the permeabilized cell membrane. Sex molecules (13) circulate throughout the body. These hollow microspheres (10) and exogenous molecules (13) are transdermal, from the liquid medium (120) applied to the gel sheet (12) described later or the cream (121) applied to the skin (20). In the case of subcutaneous or visceral, it is supplied to the affected area by injection, for example.

  The gel sheet (12) is used for permeation of exogenous molecules (13) from the skin (20), and is a viscous body having an acoustic impedance approximate to that of a living tissue. ) Is attached to the surface (12a) by immersion or application of a liquid medium (120) containing countless hollow microspheres (10) and exogenous molecules (13). Since hollow microspheres (10) and exogenous molecules (13) are fine particles, some of those attached to the gel sheet (12) may enter the inside, and since the gel sheet (12) is soft, Necessary hollow microspheres (10) and exogenous molecules (13) may be kneaded into the gel sheet (12). Although not shown, a hole may be formed in the gel sheet (12) and the hole may be filled with exogenous molecules (13). When the exogenous molecule (13) is prepared separately from the hollow microsphere (10), it is attached separately by dipping or coating as described above.

  When the exogenous molecule (13) is contained in the hollow microsphere (10) as shown in FIGS. 10 to 12, the liquid medium containing the hollow microsphere (10) on the sticking surface (12a) of the gel sheet (12) ( It is attached by immersion or coating of 120). When excluding exogenous molecules (13) and wanting to use only the impact pressure of the cavitation bubble (11a) (for example, when the impact pressure of the cavitation bubble (11a) damages and kills nearby cells) In this case, only the hollow microspheres (10) are attached to the adhesive surface (12a) of the gel sheet (12) for use or injected into the affected area, and two or more exogenous molecules (13) are to be introduced. In some cases, exogenous molecules (13) of the same or different components are attached to (especially the affixing surface (12a) in contact with the skin (20)) or injected subcutaneously (or in a predetermined position on the internal organs) as necessary. You can also do it. These combinations are appropriately selected as necessary. Also. It is also possible to use cream (121) or gel instead of the gel sheet (12). In this case, a necessary amount of hollow microspheres (10) and / or exogenous molecules (13) are kneaded in advance in the cream (121) or gel.

  The basic type (Example 1) of the probe (A) according to the present invention (that is, a device that generates a plurality of high-order ultrasonic waves (P) intermittently or with a phase difference) is as shown in FIG. Hereinafter, the first embodiment will be described. Example 1 is roughly constituted by a cylindrical probe body (1) and an ultrasonic wave generation plate (2) (in this example, it is constituted by a single piezoelectric element). The feeding 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 exact positions. Then, the outer edge (2G) of the ultrasonic wave generation plate (2) is bonded, for example, to the inner peripheral surface or outer end of the tip cylindrical portion (1a) of the probe body (1), that is, the high frequency generation plate mounting opening (9). It is fixed by. The tip cylindrical portion (1a) is detachably screwed to the probe grip portion (1b) with a screw. The probe main body (1) only needs to have a high frequency generating plate mounting opening (9), and does not need to be cylindrical, and may be, for example, a plate. The shape of the high frequency generating plate mounting opening (9) is not particularly limited.

  The characteristic of the cylindrical probe (A) is that the entire circumference of the outer edge (2G) of the disk-shaped ultrasonic wave generation plate (2) composed of piezoelectric ceramic alone (in some cases, an arc or side located on the opposite side) ) Is fixed to the high-frequency generating plate mounting opening (9) of the tip cylindrical portion (1a) by bonding [the bonding site is indicated by (K). ], When a pulse voltage of a certain duty ratio is applied, the ultrasonic wave generation plate (2) [= single piezoelectric ceramic] causes surface vibration (higher order vibration) concentrically and in a wave shape along the concentric circle. This is a point where many needle-like ultrasonic waves (P) are generated intermittently from each antinode of the surface vibration on the generation surface (2S) [FIGS. 1 (b) (c)]. FIG. 1 (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 generating plate (2), and many needle-like ultrasonic waves (P) are generated from each antinode of the surface vibration. As described above, the main frequency is the same as the natural frequency f of the ultrasonic wave generation plate (2), but includes harmonic components 2f, 3f, 4f,... (That is, the natural frequency f includes the harmonic component 2f). , 3f, 4f ... are superimposed.) The number of nodal diameters and the number of nodal circles are determined by the peripheral fixing condition of the disc-shaped ultrasonic wave generation plate (2) [= the state of adhesion at the adhesion site (K)]. FIG. 1 (c) is an imaginary view showing a state where a large number of needle-like ultrasonic waves (P) are intermittently emitted from the disk-like ultrasonic wave generation plate (2). The above-described probe (A) has been shown to be cylindrical, but of course, it is possible to use a rectangular tube type shown later, or an elliptical type or other optimal shape (not shown).

  FIG. 2 is another example (Example 2) of FIG. 1, in which the ultrasonic wave generation plate (2) is formed of a piezoelectric ceramic thin plate (2a) and a thin plate (2M), and the thin plate (2M) is a metal. Or it is formed with resin. In the case of a metal plate, aluminum is preferable. The reason for this is that corrosion by water can be prevented by anodizing at two points: (a) the acoustic impedance is close to the acoustic impedance of water, and (b) it is light. The piezoelectric ceramic thin plate (2a) is bonded to the thin plate (2M), and is attached to the front and back of the piezoelectric ceramic thin plate (2a) or the electrodes (3a) (3b) provided on the piezoelectric ceramic thin plate (2a) and the thin plate (2M), respectively. The power feeding cords (4) and (5) are connected. The outer peripheries of the thin plate (2M) and the piezoelectric ceramic thin plate (2a) are fixed to the high frequency generating plate mounting opening (9) of the probe body (1) by, for example, adhesion. The other points are the same as in FIG.

  In 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 rectangular). In order to change (further increase) the number of nodes limited by the above-mentioned disk fixing conditions, the piezoelectric ceramics independent of each other can be used. A plurality of slices (2a1) (2a2) are used. That is, the entire circumference of the outer edge (2G) or two opposite sides are bonded [the adhesive layer is indicated by (K). The rectangular piezoelectric ceramic thin pieces (2a1), (2a2),... Are attached in parallel to the thin plate (2M) (in this embodiment, there are eight pieces, one of which will be described later as a modification thereof). . In the case of Example 3 [FIG. 5 (a)], the strip-shaped piezoelectric ceramic thin pieces (2a1), (2a2)... Are separated from each other, and the short side (2G) also has a high frequency generating plate mounting opening (9 ), And a gap (L) is formed in the part. On the other hand, in the deformation [FIG. 5 (b)], the short sides (2G) of the piezoelectric ceramic flakes (2a1), (2a2)... Are bonded to the high frequency generating plate mounting opening (9). The adhesive layer is indicated by (K).

  In either case, the ultrasonic wave generation situation is slightly different, but when viewed from the long side of the piezoelectric ceramic flakes (2a1) (2a2) ..., each of the piezoelectric ceramic flakes (2a1) (2a2) ... A plurality of needle-like ultrasonic waves (P) are formed. On the other hand, when viewed from the short side (2G) side of the piezoelectric ceramic flakes (2a1) (2a2)..., Each piezoelectric ceramic flake (2a1) (2a2). Needle-shaped ultrasonic waves (P) corresponding to the number of 2a1) (2a2)... Are formed side by side. In the embodiment shown in the figure, each of the electrodes (3a1), (3a2),... (3b) of a plurality (eight in this case) of piezoelectric ceramic flakes (2a1), (2a2). ... (5) is extended, and each feed line (41) (42) ... (5) is combined into one, and the input signals for ultrasonic generation are intermittent or continuous at the same time or with a phase difference. Input. In this way, as will be described later, each piezoelectric ceramic flake (2a1) (2a2)... Is formed with a plurality of needle-like ultrasonic waves (P) simultaneously with the input signal or intermittently or continuously with a phase difference. Is generated on almost the entire ultrasonic wave generation surface (2s) which is the contact surface [for example, skin] of the object. Thus, when the piezoelectric ceramic (2a) is divided as (2a1) (2a2) ..., the ultrasonic waves are doubled by the number of piezoelectric ceramic flakes (2a1) (2a2) ... There is an advantage that it can be generated.

  In the case of a single piezoelectric ceramic flake (2a) as a modification of Example 3, the entire outer edge (2G) of the piezoelectric ceramic flake (2G) is fixed by the adhesive layer (K). It is the same as FIG.

  FIG. 6 shows an example in which a net-like insulating member (2e) is attached to the surface of the ultrasonic wave generating plate (2) or thin plate (2M) of the probe (A). By doing so, the insulating member (2e) Each region (2z) in the lattice vibrates, and a needle-like ultrasonic wave (P) is generated for each region (2z) in the lattice. The other points are the same as in the first embodiment.

  Although not shown, the cylindrical probe (A) can also generate ultrasonic waves by dividing the piezoelectric ceramic (2a) by the number of piezoelectric ceramic flakes. Although the method of division is not limited, for example, piezoelectric ceramic flakes having a substantially isosceles triangle shape may be arranged radially from the center as if the mandarin orange was cut.

  Next, a method of applying a voltage to the ultrasonic wave generation plate (2), as shown in FIG. 16, a pulse voltage [or AC voltage] is applied for one cycle (T) for (t) time. . At this time, by changing the intensity (pulse height), the duty ratio (t / T = 100), and the number of applied cycles (X), it is possible to set a wider range of ultrasonic generation conditions, which has a further effect. These are appropriately determined depending on the object.

  Unlike the case of using a disk-shaped ultrasonic wave generation plate (2) or a single piezoelectric ceramic flake (2a) composed of a single piezoelectric ceramic, a plurality of piezoelectric ceramic flakes (2a1) (2a2) ... When used, the phase timing can be given by changing the input timing of the input signal, and the ultrasonic wave generation plate (2) generates ultrasonic waves (P) according to the respective phase differences at different generation locations. Thus, the plurality of ultrasonic waves (P) having the phase difference can cooperate with each other to effectively break the hollow microsphere (10). The frequency of the ultrasonic wave (P) is usually about 1 MHz in order to cause the hollow microsphere (10) to bubble without affecting the applied skin (20) or internal tissue. Of course, as long as the above conditions are satisfied, when using a plurality of piezoelectric ceramic flakes (2a1) (2a2) ..., it is possible to change the natural frequency of each piezoelectric ceramic flake (2a1) (2a2) ... Further, by changing the phase difference of the input signal, it is possible to generate a more complicated ultrasonic wave. Moreover, what is necessary is just to change an applied voltage in order to change a sound pressure.

  FIG. 7 shows a fourth embodiment in which a disk-shaped thin plate (2M) is provided around a central metal plate (6 ′), and a conventional piezoelectric ceramic (2 ′) is formed on the central metal plate (6 ′). A plurality of piezoelectric ceramics (2a1) (2a2) ... (2an) are provided on the thin plate (2M) around it, and all or part of its outer end (2G) is an adhesive layer (K) This is an example of being fixed to the partition wall (17) and the opening (9). An ultrasonic wave (PG) with Gaussian distribution waveform is formed from the piezoelectric ceramic thin plate (2 ') in the center, and the surrounding piezoelectric ceramics (2a1) (2a2) ... (2an) generate ultrasonic waves (P) with a needle-like waveform. Form.

  In this case, the probe (A) is moved and the specific part such as the affected part is searched and specified by the ultrasonic wave (PG) of the Gaussian distribution waveform, and when the affected part is found, the specific part is detected by the acicular waveform ultrasonic wave (P). The hollow microspheres concentrated at the site are ruptured, and the surrounding exogenous molecules are efficiently driven into the surrounding cells or the surrounding blood vessels by the impact pressure. In this case, if the ultrasonic wave (P) is generated around the ultrasonic wave (PG) of the Gaussian distribution waveform, the ultrasonic wave (P) is simply converted from the ultrasonic wave (PG). By simply switching to, it is possible to strike the affected area at that time, and the treatment work can be performed more efficiently.

  In addition, although the structure as above-mentioned in Example 4 is illustrated in FIG. 7, the structure of Example 4 is not restricted to this naturally, All the structures shown in Examples 1-3 can be applied. . For example, in FIG. 7, the surrounding piezoelectric ceramic plates (2a1) to (2an) are circular and part of the outer peripheral edge (2G) is the inner peripheral surface of the partition wall (17) or the opening (9) (not shown, but the end surface) However, the piezoelectric ceramic plates (2a1) to (2an) can be formed in a fan shape so that the entire outer periphery (2G) can be fixed, and the thin plate (2MG) can be eliminated. Then, the piezoelectric ceramic plates (2a1) to (2an) may be directly fixed as in the first embodiment. Since the piezoelectric ceramic plate can be formed into any shape, it is not shown in the figure, but it is formed in a ring shape, and the inner surface of the thin plate (2MG) and the partition wall (17) and the opening (9) formed in the ring shape as described above. The ring-shaped single piezoelectric ceramic plate may be directly attached without a thin plate (2MG).

  Next, the bubble breaking action of ultrasonic waves (P) will be described. As shown in FIGS. 14 (a) and 14 (b), the ultrasonic wave (P) having a needle shape or a Gaussian waveform has a high sound pressure at the central portion, and the sound pressure gradually decreases toward the periphery.

  In other words, the pressure (sound pressure) is outward from the center. On the other hand, the hollow microsphere (10) is a liquid medium (120) or cream containing a hollow microsphere (10) or an exogenous molecule (13) coated on the gel sheet (12) under the ultrasonic wave generation surface (2s). 121) are innumerable and migrate in the liquid medium (120) or cream (121) due to ultrafine particles.

  As shown in Fig. 14 (b), when a Gaussian waveform ultrasonic wave (PG) is applied to the gel sheet (12) or cream (121) with the conventional probe (B), the sound of the ultrasonic wave (PG) as described above. The pressure gradually decreases from the central part toward the periphery. Although it is not clear about the bubble-breaking effect by the ultrasonic wave of a hollow microsphere, it estimates as follows.

  In the conventional ultrasonic probe (B), the metal plate (6) is adhered to the entire surface so that the pressure distribution of the ultrasonic wave (PG) obtained as described above becomes a gentle mountain shape (Gaussian distribution). In this case, the central portion (YG) is maximum and decreases toward the periphery. The ultrasonic wave (PG) is applied at a certain duty ratio and is intermittently output from the ultrasonic wave generation plate (2).

  On the other hand, countless hollow microspheres (10) migrate in the liquid medium (120) and the like. When ultrasonic waves (PG) with a conventional Gaussian waveform are output, the hollow microsphere (10) located in the central part (YG) of this ultrasonic wave (PG) bursts due to its strong sound pressure, Thus, the surrounding exogenous molecule (13) is driven into the surrounding tissue. However, the hollow microsphere (10) in the vicinity of the central part (YG) of the ultrasonic wave (PG) and the hollow microsphere (10) trying to approach the ultrasonic wave (PG) are moved from the central part (YG) to the peripheral direction. It is pushed out in the direction away from the central part (YG) by the gradually decreasing pressure. Therefore, in the case of ultrasonic (PG) with a conventional Gaussian waveform, when the ultrasonic (PG) is output, only the hollow microsphere (10) that happens to be in the range of the central part (YG) bursts. Therefore, the bubble breaking efficiency is poor.

  On the other hand, 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. Are determined by the radius, thickness, density, bending composition, and natural angular frequency of the ultrasonic wave generation plate (2) [piezoelectric element], and the generated ultrasonic waves are generated at the antinodes of the higher-order vibration mode. Are combined (f + f2 + f3 +... + Fm + fn) and output from the ultrasonic wave generation surface (2s) of the probe (A). This ultrasonic wave (P) includes harmonic components and has a needle shape parallel to each other. In some cases, the level may show a much higher peak value when the same energy as in the conventional example is applied.

  Furthermore, in the probe (A) of the present invention, a plurality of (in other words, two or more) ultrasonic waves (P) are generated from the ultrasonic wave generation surface (2S). The hollow microspheres (10) that exist around (Y) and are pushed out from the central part (Y) without breaking are in the other ultrasonic waves (P) that are generated adjacently with that momentum. It is pushed in and bubbles are broken at the central part (Y) of the ultrasonic wave (P).

  In addition, when the ultrasonic wave (P) is needle-shaped, the peak value of the needle-shaped ultrasonic wave (P) compared to the peak value of the ultrasonic wave (PG) of the conventional Gaussian waveform for the same input energy (in other words, , Sound pressure) is high, and it is considered that the probability of bubble breakage of the hollow microsphere (10) that has entered the ultrasonic wave (P) is higher. 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 exogenous molecules (13) can be stirred in a wide range. It is considered that the migrating action of the hollow microspheres (10) can be made more active and the bubble breaking probability can be increased.

  Furthermore, when the ultrasonic wave generation source is composed of a plurality of piezoelectric ceramic elements (2a1) (2an) and each is applied with a pulse voltage with a phase, the above-described stirring effect is further enhanced (in other words, When the density of the hollow microspheres (10) is pushed out from the ultrasonic wave (P) and the hollow microspheres (10) are scattered around the periphery and the density of the hollow microspheres (10) in the peripheral area increases, another ultrasonic wave has a phase difference in the peripheral area. When (P) is produced, it is considered that the hollow microspheres (10) in the periphery thereof are naturally broken at a high density).

  Next, a photograph (FIG. 17) instead of a drawing for demonstrating the transdermal introduction effect by the hollow microsphere (10) of the probe (A) of the present invention, the `` control photograph '' does not use the hollow microsphere (10), FIG. 5 is a photograph of the probe (A) of the present invention for transdermal introduction of an exogenous molecule (13), and “NB + US” is a photograph for demonstrating the effect of transcutaneous introduction by a hollow microsphere (10). The verification method is as follows. A gel sheet (12) with a hole is affixed to the skin. In “Control”, a liquid medium (120) carrying exogenous molecules (13) without hollow microspheres (10) in this hole is used. In “NB + US”, As a result of filling the liquid medium (120) carrying the hollow microsphere (10) and the exogenous molecule (13), and applying this filled portion at high frequency (P) with the probe (A) of the present invention in FIG. is there. As can be seen by comparing “Control” with “NB + US”, “NB + US” is more stained with fluorescent molecules (TEXAS-RED = exogenous molecules) and introduces exogenous molecules into hollow microspheres (10). It can be seen that the effect is obvious.

  The method of using the liquid medium (120) carrying the hollow microsphere (10) and the exogenous molecule (13) is to attach the liquid medium (120) to the skin adhesion surface (12a) of the gel sheet (12), Even if this gel sheet (12) is attached to the skin surface (20) and a pulse voltage is applied in this state to generate ultrasonic waves, the same effect can be obtained on the properties of the gel sheet (12). It is done. Further, from the above-mentioned relationship, the cream (121) or the gel (not shown) includes a hollow microsphere (10) and an exogenous molecule (13) (exogenous molecule (13) -carrying hollow microsphere (10). ) May be dispersed and contained.

  FIG. 18 differs from FIG. 17 in that it is not transcutaneous, and the exogenous molecule is introduced into the mouse skeletal muscle by injection of luciferase plasmid, and ultrasonic waves are applied to the exogenous molecule injection site, and the data after 4 days have passed. The mouse, which is a sample, the number of input pulses applied thereto (horizontal axis), and the vertical axis are the relationship between the value of gene expression (expression amount of the introduced exogenous molecule). In addition, it is a code | symbol which shows the mouse | mouth left leg | foot which is R * L sample, or a right leg | foot. The number of pulses (Pulse) is 10, 100, 1000, 2, 20, 200, 50, 500, and the duty ratio is indicated by 10%, 20%, 50% in the upper stage. The probe of the present invention is 1 to 13, and the conventional probe is 14 to 20.

  In FIG. 18, the probe of the present invention shown in FIG. 1 generally shows a slight increase in the exogenous molecule introduction effect of the conventional probe, with a duty ratio of 20% -200 pulses for mouse No. 11 and duty for mouse No. 12 The ratio of 50% -50 pulses shows a high exogenous molecule introduction effect. The variation in the exogenous molecule introduction effect is thought to be due to individual differences and variations in the experimental technique associated with irradiation.

  FIG. 19 shows that the piezoelectric ceramic elements (2a1), (2ab)... (2a8) shown in FIG. 4 and FIG. It was used. As the cells, EMT6 mouse breast cancer cells and C26 mouse colon cancer cells were used. Data indicated as “patent (higher order)” is the probe of the present invention, and data indicated as “plane” is a conventional probe. In the horizontal axis, “control (= 0), 20, 50, 80” is described as [duty ratio%], and the vertical axis in FIG. 19 (a) on the left indicates gene expression strength (exogenous molecule Expression effect (1 MHz)), and the vertical axis of FIG. 19 (b) on the right shows the cell damage rate (1 MHz). As for the pulse voltage of the probe of the present invention, a pulse voltage having the same frequency was simultaneously applied to any of the piezoelectric ceramic elements (2a1), (2ab), ... (2a8). In the probe of the present invention shown in FIG. 4 and the like, a plurality of acicular ultrasonic waves (P) are generated in each of the piezoelectric ceramic elements (2a1), (2a2)... (2a8). ) Is the number of ultrasonic waves generated by one piezoelectric ceramic element × the number of piezoelectric ceramic elements, and the number of needle-like ultrasonic waves (P) of the probe of the present invention shown in FIG. It is presumed that the increase in the number of all needle-like ultrasonic waves (P) increases stably and contributes greatly and stably to the effect of introducing exogenous molecules. The pulse voltage applied to both probes (A) and (B) is the same.

  In the present invention, a plurality of needle-shaped ultrasonic waves are continuously generated simultaneously from almost the entire contact surface of the probe, and hollow microspheres are continuously broken in a short time in a wide range and in a large amount. Incorporated exogenous molecules can be injected into surrounding cells in an unprecedented amount, and the introduction of ultrasonic exogenous molecules, which has been conventionally performed, can be made more efficient. This greatly reduced the burden on patients and contributed to medical progress.

... Cross-sectional view of the first embodiment of the present invention and drawings showing the ultrasonic generation state thereof ... Cross-sectional view of the second embodiment of the present invention and a drawing showing the state of ultrasonic generation ... Cross sectional view of the conventional example and drawings showing the ultrasonic generation status ... Cross-sectional view of the third embodiment of the present invention and the drawing showing the ultrasonic wave generation state -Drawing which shows Example 3 of the present invention, and its modification ... Disassembled perspective view of the probe of the present invention with a net attached ... Perspective view and sectional view of embodiment 4 of the present invention. ... Comparison drawing of acicular ultrasonic wave (a) (b) (c) of the present invention and Gaussian distributed ultrasonic wave (d) of conventional example ... Cross sectional view of Example 1 of hollow microsphere used in the present invention ... Sectional view of Example 2 of hollow microsphere used in the present invention ... Sectional view of Example 3 of hollow microsphere used in the present invention ... Sectional view of Example 4 of hollow microsphere used in the present invention ... Imaginary view showing hollow microsphere breakage state by probe of the present invention ... Imaginary diagram showing the bubble breaking action of hollow microspheres by the acicular ultrasonic wave of the present invention and the conventional Gaussian distributed ultrasonic wave … Imaginary view showing the state of foam breakage of hollow microspheres and introduction of exogenous molecules ... Figure of probe applied voltage ... Photos substituted for drawings showing the effect of introduction of exogenous molecules (fluorescent molecules) by the breakage of hollow microspheres of the present invention ... Comparison graph of exogenous molecule introduction effect of probe of the present invention and conventional probe ... Comparison graph of gene expression (left) and cell damage rate (right) in cell experiments using the square probe of the present invention (FIG. 4) and a conventional Gaussian ultrasonic probe

Explanation of symbols

(A) Probe of the present invention
(B) Conventional probe
(P) acicular ultrasound
(PG) Gaussian waveform ultrasound
(1) Probe body
(2) Ultrasonic wave generation plate (piezoelectric element (piezoelectric ceramics) that becomes a single ultrasonic wave generation plate)
(2a) Single piezoelectric element (piezoelectric ceramics) that forms an ultrasonic wave generating plate with a thin plate
(2a1)-(2an) Multiple piezoelectric elements (piezoelectric ceramics) that form an ultrasonic wave generation plate with a thin plate
(2M) Thin plate that forms an ultrasonic wave generation plate with a piezoelectric element
(3a) (3b) Electrode
(4) Feed line
(5) Feed line
(6) Metal plate
(10) Hollow microsphere
(11) Outer shell
(11a) Cavitation bubbles (11a)
(12) Gel sheet
(13) Exogenous molecules

Claims (6)

(a) a probe body having a high frequency generator plate mounting opening;
(b) A probe having a high frequency generating plate that is provided with an outer edge fixed to the high frequency generating plate mounting opening and generates two or more high frequencies from different positions by applying a voltage. (a) a probe body having a high frequency generator plate mounting opening;
(b) a vibration thin plate having an outer edge fixed to the high frequency generating plate mounting opening;
(c) A probe characterized in that the outer end edge is composed of one or more piezoelectric ceramic thin plates fixed to the high frequency generating plate mounting opening and attached to the thin plate. (a) a probe body having a high frequency generator plate mounting opening;
(b) a vibration thin plate having an outer edge fixed to the high frequency generating plate mounting opening;
(c) A probe comprising a plurality of piezoelectric ceramic thin plates attached to the thin plate with a gap (L) from the inner peripheral surface of the probe body (1). The probe according to any one of claims 1 to 3,
A probe characterized in that the generated high frequency has a needle shape. The probe according to any one of claims 1 to 3, wherein a plurality of piezoelectric ceramic thin plates are used.
(a) One of the piezoelectric ceramic thin plates forms an ultrasonic wave with a Gaussian distribution waveform,
(b) A probe characterized in that the other forms an ultrasonic wave having a needle-like waveform. The probe according to any one of claims 1 to 5,
A probe characterized in that a net plate is further adhered to the outer surface of a thin plate or a high frequency generating plate.