Device for enhancing permeability of vascular wall

Abstract

To provide a negative pressure focused acoustic wave generation device which generates the pulse-like focused acoustic waves of the negative pressure.SOLUTION: A negative pressure focused acoustic wave generation device includes: a pulse-like voltage generator 20 that generates the single pulse-like voltage; an acoustic wave-generating element 10 that is made of a piezoelectric material and is distorted to generate the pulse-like acoustic waves when being applied with the pulse-like voltage; and a focusing element 30 that focuses the pulse-like acoustic waves generated from a front surface 12 of the acoustic wave-generating element 10 onto a focal point F, and generates the pulse-like focused acoustic waves at the focal point F. In order to generate the pulse-like focused acoustic waves of the negative pressure at the focal point F, the pulse-like voltage has the polarity of displacing in the direction where a front surface 12 retreats when viewed from the focal point when the pulse-like voltage is applied to the acoustic wave-generating element 10.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a negative pressure focused ultrasound generator and a vascular wall permeability enhancing device, and more specifically, to a negative pressure focused ultrasound generator that generates negative pressure pulsed focused ultrasound waves, and a vascular wall permeability enhancing device that generates negative pressure pulsed focused ultrasound waves and enhances the permeability of the vascular wall of a blood vessel to which the waves are irradiated. [Background technology]

[0002] Conventionally, various ultrasound contrast methods have been used in clinical ultrasound diagnosis. One known ultrasound contrast method is to administer an ultrasound contrast agent (hereinafter referred to as "microbubbles") to perform ultrasound contrast. Microbubbles are small spheres with a diameter of about 1 to 10 μm, which are air or perfluorocarbons covered with lipids or albumin, and enhance ultrasound echoes. Furthermore, when low-intensity ultrasound is applied to microbubbles, they vibrate by repeatedly contracting and expanding due to the sound pressure of the ultrasound. By utilizing this phenomenon and emphasizing the harmonic components caused by the vibration of microbubbles contained in the ultrasound echo, it is possible to obtain ultrasound contrast images with high contrast.

[0003] In addition, when high-intensity ultrasound is applied, microbubbles not only vibrate but also collapse. Research is being conducted into the use of microbubble vibration and collapse not only for ultrasound diagnosis but also for drug delivery and disease treatment. Non-Patent Document 1 describes that the permeability of blood vessel walls can be increased minimally invasively by utilizing the vibration and collapse of microbubbles caused by ultrasound irradiation, and further suggests the possibility of opening the blood-brain barrier (BBB). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] “Theranostics using ultrasound and microbubbles”, Drug Delivery System, 2018, Vol. 33, No. 3, p.190 - 196 [Patent documents]

[0005] [Patent Document 1] Patent No. 5557800 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the ultrasound emitted by the ultrasound oscillator used in the conventional ultrasound imaging method is a continuous wave, and when such continuous wave ultrasound is irradiated to biological tissue, heat is generated. Therefore, when the permeability of the vascular wall is increased using microbubbles and ultrasound as in the above-mentioned Non-Patent Document 1, if the intensity of the ultrasound is too high, tissues such as blood vessels may be damaged by heat generation. For example, even if the intention is to temporarily open the BBB for drug delivery into the brain, if the intensity of the ultrasound is too high, the BBB and its surrounding tissues may be irreversibly damaged by heat generation. In particular, when focused ultrasound is irradiated, the ultrasound energy is concentrated and the temperature becomes high locally, which may result in severe thermal damage.

[0007] On the other hand, the inventor of the present application has proposed a focused ultrasound therapy device in the above-mentioned Patent Document 1, which irradiates a single pulse of focused ultrasound waves to a treatment target once or repeatedly, instead of continuous ultrasound waves. The shock waves of the focused ultrasound waves are used for breaking up stones, treating pain, etc. This device irradiates the treatment target with a single pulse of focused sound waves, making it possible to efficiently concentrate sound energy on the target area while suppressing heat generation.

[0008] The inventor of the present application conducted tests based on the idea that by using this focused ultrasound therapy device to irradiate focused ultrasound waves onto blood vessels, it would be possible to concentrate ultrasound energy while suppressing heat generation, thereby enhancing the permeability of the blood vessel walls.

[0009] However, even when blood vessels were irradiated with focused ultrasound waves using the focused ultrasound therapy device described in Patent Document 1, no test results were obtained that indicated increased permeability of the blood vessel walls. The inventor of the present application believes that the reason for this test result is that the pulsed focused sound waves generated by the focused sound therapy device are positive pressure shock waves that apply crushing pressure to the treatment target area, and that positive pressure shock waves have difficulty in causing a phenomenon such as the crushing of microbubbles, etc.

[0010] Therefore, as a result of various tests and investigations, the inventor of the present application came up with the idea that if negative pressure sound waves, rather than positive pressure shock waves, are irradiated onto a blood vessel as focused sound waves, an explosive expansion pressure will be applied to the focal point rather than a crushing pressure, and the permeability of the blood vessel wall may be increased, thus conceiving the present invention.

[0011] The present invention has been made in consideration of the above circumstances, and aims to provide a negative pressure focused ultrasound generator that generates negative pressure pulsed focused ultrasound waves, and a vascular wall permeability enhancement device that generates negative pressure pulsed focused ultrasound waves, suppresses heat generation, and enhances the permeability of the vascular wall of a blood vessel. [Means for solving the problem]

[0012] The negative pressure focused sound wave generator of the present invention comprises a pulsed voltage generator that generates a single pulsed voltage, a sound wave generating element made of a piezoelectric material that distorts to generate a pulsed sound wave when the pulsed voltage is applied, and a focusing element that focuses the pulsed sound wave generated from the front surface of the sound wave generating element at a focal point to generate a pulsed focused sound wave at the focal point, and is characterized in that the pulsed voltage has a polarity such that when the pulsed voltage is applied to the sound wave generating element, the front surface is displaced in a direction receding from the focal point, so as to generate the negative pressure pulsed focused sound wave at the focal point.

[0013] According to the negative pressure focused sound wave generating device of the present invention, a pulsed voltage having a polarity such that the front surface of the sound wave generating element is displaced in a direction receding from the focal point can be applied to the sound wave generating element to generate a negative pressure pulsed focused sound wave at the focal point.

[0014] In addition, the blood vessel wall permeability enhancing device of the present invention comprises an acoustic wave generating element made of a piezoelectric material that generates acoustic waves by displacement of its front surface, a pulsed voltage generator that generates a single pulsed voltage to be applied to the acoustic wave generating element, and a focusing element that focuses the acoustic waves generated by the acoustic wave generating element to which the pulsed voltage has been applied, to a focal point to generate a pulsed focused acoustic wave at the focal point, wherein the pulsed voltage has a polarity such that the front surface is displaced in a direction receding from the focal point when the pulsed voltage is applied to the acoustic wave generating element, so as to generate the negative pressure pulsed focused acoustic wave at the focal point, and the blood vessel positioned at the focal point is repeatedly irradiated with the negative pressure pulsed focused acoustic wave to enhance the permeability of the blood vessel wall of the blood vessel.

[0015] According to the blood vessel wall permeability enhancing device of the present invention, a pulsed voltage having a polarity such that the front surface of the acoustic wave generating element is displaced in a direction receding from the focal point can be applied to the acoustic wave generating element to generate a negative pressure pulsed focused acoustic wave at the focal point. By repeatedly irradiating a blood vessel at the focal point with this negative pressure pulsed focused sound wave, it is possible to increase the permeability of the blood vessel wall. Increasing the permeability of the blood vessel wall is expected to have the effect of causing drugs inside the blood vessel to leak out of the blood vessel, enhancing the effectiveness of the drug. This means that even a low concentration of drug can be expected to have the same effect as a high concentration drug, and it is also expected to have the effect of reducing the side effects of the drug. Effect of the Invention

[0016] According to the negative pressure focused ultrasound generator of the present invention, it is possible to generate a negative pressure pulsed focused ultrasound wave, and according to the vascular wall permeability enhancing device of the present invention, it is possible to enhance the permeability of the vascular wall by generating a negative pressure pulsed focused ultrasound wave and irradiating it to the blood vessel. The increase in permeability of the vascular wall according to the present invention increases the permeability of only the blood vessels at the site irradiated with sound waves. [Brief description of the drawings]

[0017] [Figure 1] 1 is an explanatory diagram of a negative pressure focused ultrasound generator and a vascular wall permeability enhancing device according to a first embodiment of the present invention. FIG. [Diagram 2] 2A and 2B are schematic diagrams of the main part of the device shown in FIG. 1, where (a) is a cross-sectional view and (b) is a rear view. [Diagram 3] 1A is a waveform diagram showing a pulsed voltage waveform and a pulsed sound wave waveform when generating a positive pressure shock wave, and FIG. 1B is a waveform diagram showing a pulsed voltage waveform and a pulsed sound wave waveform when generating a negative pressure focused wave. [Figure 4] 13 is a photograph showing the state of a mouse ear after irradiation with negative focused wave. [Diagram 5] FIG. 1 is an explanatory diagram of increased permeability of the vascular wall of a blood vessel irradiated with a negative pressure focused wave. [Figure 6] 5A and 5B are explanatory diagrams of a negative pressure focused ultrasound generator and a vascular wall permeability enhancing device according to a second embodiment of the present invention, where (a) is a cross-sectional view and (b) is a rear view. [Figure 7] 1 is a schematic diagram showing the traveling direction of sound waves generated at the front surface of a sound wave generating element. FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Hereinafter, a negative pressure focused ultrasound generator and a vascular wall permeability enhancing device according to an embodiment of the present invention will be described with reference to the drawings. In the following embodiments, the negative pressure focused ultrasound generator and the vascular wall permeability enhancing device have the same structure, and will be referred to as "this device" hereinafter.

[0019] [First embodiment] The structure of the device according to the first embodiment will be described with reference to FIGS. This device comprises an acoustic wave generating element 10 made of a piezoelectric material that generates acoustic waves by displacement of the front surface 12, a pulsed voltage generator 20 that generates a single pulsed voltage to be applied to the acoustic wave generating element 10, and a focusing element 30 that focuses the acoustic waves generated by the acoustic wave generating element 10 to which the pulsed voltage has been applied, at a focal point F, thereby generating a pulsed focused acoustic wave at the focal point F.

[0020] The sound wave generating element 10 is made of a ceramic piezoelectric material and has a circular outline when viewed from the rear surface 14 side opposite the focal point F, as shown in Fig. 2(b). The front surface 12 of the sound wave generating element 10 is a curved member, as shown in Fig. 2(a), and the front surface 12 is a concave surface having a spherical shape centered on the focal point F, and the rear surface 14 is a convex surface.

[0021] A ground line 42 for applying a voltage is connected to the front surface 12, and a signal line 44 is connected to the rear surface 14. The reason why the ground line 42 is connected to the front surface 12 is to prevent a high voltage from being transmitted to the patient in the event of a malfunction. It is sufficient that a voltage is applied between the front surface 12 and the rear surface 14 of the sound wave generating element 10, and the signal line 44 may be connected to the front surface 12 side, and the ground line 42 may be connected to the rear surface 14 side. In addition, a conductive film is provided on each of the front surface 12 and the rear surface 14 of the sound wave generating element 10 so that the applied pulse voltage is reliably transmitted to the entire surface.

[0022] The thickness of the sound wave generating element 10 is about 6 mm, and since the applied voltage is high, there is no significant difference in the electric potential between the central part and the periphery of the sound wave generating element 10. Therefore, each position of the sound wave generating element 10 is distorted by an amount corresponding to the strength of the applied voltage, and sound waves are generated at each position on the front surface 12 in the direction perpendicular to the front surface.

[0023] The pulsed voltage generator 20 generates a single pulsed voltage to be applied to the sound wave generating element 10. The pulsed voltage has a polarity such that, when the pulsed voltage is applied to the sound wave generating element 10, the front surface 12 is displaced in a direction receding from the focal point F (in other words, in a direction moving away from the focal point F). As a result, when the pulsed voltage is applied, a negative pressure pulsed sound wave is generated at each position on the front surface 12 in the direction perpendicular to the front surface.

[0024] Here, with reference to FIG. 3, the relationship between the pulse voltage applied to the sound wave generating element 10 and the waveform of the generated sound wave will be described. First, for comparison, Fig. 3(a) shows the waveform of the pulsed voltage applied to the integrated concave element in the focused acoustic therapy device described in the above Patent Document 1, and the waveform of the pulsed acoustic wave, which is a positive pressure shock wave generated. The upper part of Fig. 3(a) shows the waveform of the pulsed voltage, and the lower part shows the waveform of the pulsed acoustic wave.

[0025] As shown in Fig. 3(a), in the focused acoustic therapy device described in Patent Document 1, for example, when one pulsed voltage 1A of +4 kV with a pulse width of t = 3 μS is applied, the integrated concave element generates one positive pressure pulsed acoustic wave 1A' with a predetermined delay. Similarly, when one pulsed voltage 1B is applied in the next second, a corresponding one positive pressure pulsed acoustic wave 1B' is generated, and positive pressure pulsed acoustic waves are repeatedly generated. In addition, the positive pressure pulsed acoustic waves nA', nB' generated when multiple pulsed voltages nA, nB are applied in one second are shown by dashed lines. In this way, in the focused acoustic therapy device described in Patent Document 1, it is necessary to generate positive pressure shock waves that apply crushing pressure to the treatment target area as pulsed focused acoustic waves at the focal point, so positive pressure pulsed acoustic waves 1A', nA', 1B', nB' are generated in the integrated concave element.

[0026] Next, Fig. 3(b) shows the pulse voltage applied to the sound wave generating element 10 in the device of this embodiment (i.e., the voltage of the signal line 44 relative to the voltage of the ground line 42) and the waveform of the pulse sound wave of the generated negative pressure. The upper part of Fig. 3(b) shows the waveform of the pulse voltage, and the lower part shows the waveform of the pulse sound wave.

[0027] In this device, negative pressure pulsed focused sound waves are generated at the focus F rather than positive pressure shock waves, so the pulsed voltage has a polarity such that when the pulsed voltage is applied to the sound wave generating element 10, the front surface 12 is displaced in a direction receding from the focus F.

[0028] For this reason, as shown in FIG. 3(b), the pulsed voltage generator 20 generates, for example, a pulsed voltage of −4 kV with a pulse width of t=3 μS. When one pulsed voltage 1C is applied to the sound wave generating element 10, the sound wave generating element 10 generates one negative pressure pulsed sound wave 1C' with a predetermined delay. Similarly, when one pulsed voltage 1D is applied in the next second, a corresponding negative pressure pulsed sound wave 1D' is generated, and pulsed sound waves are repeatedly generated. In addition, the negative pressure pulsed sound waves nC', nD' generated on the front surface 12 of the sound wave generating element 10 when multiple pulsed voltages nC, nD are applied in one second are shown by dashed lines. In this manner, in this device, negative pressure pulsed acoustic waves 1C', nC', 1D', and nD' are generated on the front surface 12 of the acoustic wave generating element 10 so as to generate negative pressure pulsed focused acoustic waves at the focal point F.

[0029] The focusing element 30 is composed of the concave front surface 12 of the sound wave generating element 10 and a sound wave-transmitting gel pad 50 provided on the front surface 12 side of the sound wave generating element 10. The sound wave-transmitting gel pad 50 is composed of a first gel pad 52 that fills the recess of the concave front surface 12 and a cone-shaped or truncated cone-shaped second gel pad 54 provided on the first gel pad 52. The negative pressure pulsed sound waves generated on the front surface 12 of the sound wave generating element 10 propagate through the sound-transmitting gel pad 50 in a direction perpendicular to the front surface 12 at each position on the concave front surface 12 and are focused toward a focal point F located at the center of the spherical surface of the front surface 12. As a result, a negative pressure pulsed focused sound wave is generated at the focal point F.

[0030] In this way, according to this device, a negative pressure pulsed focused sound wave can be generated at the focal point F. In addition, since the pulsed focused sound wave is not a continuous wave, it is possible to suppress the generation of heat that occurs when ultrasonic waves are irradiated.

[0031] [Increased permeability of vascular walls] Next, the results of a test on increased permeability of the vascular walls of mouse blood vessels using this device will be described. The test was performed as follows to irradiate negative pressure pulsed focused sound waves onto the mouse ear, which is thin and easy to observe, and has a network of peripheral blood vessels. (1) Based on the body weight of the mice immediately before administration, 2 mg / mL of sodium pentobarbital solution was administered intraperitoneally at 15 mL / kg per body weight. (2) Evans blue solution (dissolved in saline at a concentration of 10 mg / mL, then sterilized by filtration through a 0.2 μm filter) was administered to mice at 10 mL / kg body weight via the tail vein, and the mice were then anesthetized by inhalation of sevoflurane. (3) The anesthetized mouse was laid on its side on a cork board for dissection, and ultrasound diagnostic jelly was applied to the inside and outside of the right auricle. The device was then positioned so that the tip of the sound-transmitting gel pad 50 of the device was located 2 mm from the outside of the mouse's right auricle. (4) Five minutes after administration of the Evans blue solution, the right outer ear of the mice was irradiated with focused sound waves for 10 minutes (600 seconds), and the left ear was used as a control. (5) Ten and 30 minutes after irradiation with pulsed focused ultrasound, the irradiated site was observed with the naked eye to confirm whether or not Evans blue had leaked out of the blood vessels.

[0032] The test results are shown in Table 1 below. [Table 1]

[0033] As shown in Table 1 above, (1) In mice in which negative-pressure pulsed focused sound was irradiated to the right auricle under conditions No. 2 and No. 4, Evans blue was found to have leaked out of the blood vessels only in the irradiated area, the right auricle, 10 and 30 minutes after irradiation. In addition, the color of the Evans blue that had leaked out of the blood vessels in the right auricle became darker and the area of ​​leakage was larger 30 minutes after irradiation compared to 10 minutes after irradiation. Furthermore, when negative pressure pulsed focused sound waves were irradiated to the right auricle of another mouse under the same irradiation conditions as Condition No. 2, leakage of Evans blue outside the blood vessels was observed only in the irradiated site, the right auricle, 10 minutes and 30 minutes after irradiation, similar to the results above for Condition No. 2, confirming reproducibility.

[0034] Here, Fig. 4 shows a photograph of the mouse's auricle 30 minutes after irradiation under condition No. 4. The photograph in Fig. 4 was taken from below near the mouse's head, with the auricle on the right side of the photograph being the right auricle irradiated with negative pressure pulsed focused sound waves, and the auricle on the left side being the control left auricle. As shown in the photograph in Fig. 4, leakage of Evans blue was observed only in the right auricle irradiated with negative pressure pulsed focused sound waves, and no leakage of Evans blue was observed in the control left auricle.

[0035] (2) In mice in which negative pressure pulsed focused sound was irradiated to the right auricle under condition No. 3, no leakage of Evans blue was observed 10 minutes after irradiation, but 30 minutes after irradiation, leakage of Evans blue outside the blood vessels was observed only in the irradiated area, the right auricle.

[0036] (3) In mice exposed to negative-pressure pulsed focused sound waves under condition No. 1, no leakage of Evans blue outside the blood vessels was observed in the right auricle, the irradiated site, either 10 or 30 minutes after irradiation.

[0037] There are two possible reasons why Evans blue leaked from blood vessels exposed to negative pressure pulsed focused sound waves. 1. As shown in Figure 5, it is possible that cavitation occurred within blood vessel V due to the irradiation of negative pressure pulsed focused sound waves, and that tight junctions were opened by the effects (collapse, etc.) of the generated cavitation bubbles. 2. It is possible that the application of negative pressure pulsed focused sound waves stretched the vascular wall of blood vessel V millions of times, opening the tight junctions. It is also possible that the release was due to both possibilities 1 and 2 above, or that the two interacted to result in the release. Therefore, the results shown in Table 1 above show that under irradiation conditions No. 2 to 4 (e.g., applied voltage of -300 V, pulse width of 1 μS or less, oscillation frequency of 10,000 times / second or more), the permeability of the vascular wall of blood vessels irradiated with negative pressure pulsed focused sound waves was increased. According to the results shown in Table 1, in order to increase the permeability of the vascular wall, it is preferable that the pulse voltage generating means generates a pulse voltage having a width of, for example, 0.5 to 1.0 μS. It is also preferable that the pulse voltage generating means generates a pulse voltage 10,000 to 20,000 times per second.

[0038] In this manner, by using the device as in this embodiment, it is possible to enhance the permeability of the vascular wall VW regardless of the presence or absence of microbubbles. In addition, this device does not irradiate continuous ultrasound waves, but instead repeatedly irradiates single, negative pressure pulses of focused sound waves, which makes it possible to efficiently concentrate sound energy on the target area while suppressing heat generation.

[0039] Next, Table 2 below shows the test results in which the device was used to generate "positive pressure" pulsed focused sound waves, and the "positive pressure" pulsed focused sound waves were irradiated onto the right auricle of a mouse under irradiation conditions equivalent to those for the "negative pressure" pulsed focused sound waves under conditions No. 1 to 4.

[0040] [Table 2]

[0041] As shown in Table 2 above, in mice exposed to "positive pressure" pulsed focused sound waves under conditions No. 5 to 8, no leakage of Evans blue outside the blood vessels was observed in the right auricle, the irradiated site, either 10 minutes or 30 minutes after irradiation. Therefore, the results shown in Tables 1 and 2 indicate that irradiating a blood vessel with a pulsed focused sound wave of "positive pressure" does not increase the permeability of the blood vessel wall, but that irradiating a blood vessel with a pulsed focused sound wave of "negative pressure" increases the permeability of the blood vessel wall.

[0042] In this manner, the present device can generate a pulsed focused sound wave of negative pressure at the focal point by applying a pulsed voltage to the sound wave generating element having a polarity such that the front surface of the sound wave generating element is displaced in a direction receding from the focal point.Then, by repeatedly irradiating the blood vessel positioned at the focal point with the pulsed focused sound wave of negative pressure, the permeability of the blood vessel wall can be increased.

[0043] [Second embodiment] The structure of the device according to the second embodiment will be described with reference to FIGS. The second embodiment of the device differs from the first embodiment in that the sound wave generating element has a planar front surface and the focusing element is an acoustic lens, and detailed descriptions of the components that are identical to those of the first embodiment will be omitted.

[0044] This device comprises an acoustic wave generating element 10a made of a piezoelectric material that generates acoustic waves by displacement of its planar front surface 12a, a pulsed voltage generator (not shown in Figure 6) that generates a single pulsed voltage to be applied to the acoustic wave generating element 10a, and a focusing element 30 that focuses the acoustic waves generated by the acoustic wave generating element 10a to which the pulsed voltage has been applied, to a focal point F to generate pulsed focused acoustic waves at the focal point F, and an acoustic lens 30a provided on the front surface 12a of the acoustic wave generating element 10a.

[0045] The acoustic lens 30a is composed of a first member 32 provided on the front surface 12a and a second member 34 in which sound waves travel at a different speed than the first member 32, and the joint surface between the first member 32 and the second member 34 forms a curved surface that is concave on the focal point F side. In this embodiment, the first member 32 is made of epoxy resin in which sound waves travel at a speed of 2600 m / s, and the second member 34 is made of silicone rubber in which sound waves travel at a speed of 1000 m / s. The radius of curvature of the curved surface that is the joint surface between the first member 32 and the second member 34 is 108 mm.

[0046] The principle of focusing sound waves by the acoustic lens 30a will be described with reference to FIG. 7. In the figure, the traveling direction of each sound wave group generated on the front surface 12a of the sound wave generating element 10a is shown by a solid line. The sound waves generated at each point on the planar front surface 12a of the sound wave generating element 10a are synthesized while spreading to describe a hemispherical surface, and as a result, travel in the direction shown by the solid line. In the acoustic lens 30a, which is shown in the figure as a convex lens, the sound waves are refracted according to the traveling speed ratio of the sound waves between the first member 32 and the second member 34 and the curvature of the contact surface, and as a result, the sound waves are focused to the focal point F.

[0047] In this device of the present embodiment, as in the first embodiment, a pulsed voltage having a polarity that displaces the front surface 12a in a direction receding from the focal point F when applied to the sound wave generating element 10a is applied to the sound wave generating element 10a, and a negative pressure pulsed focused sound wave is generated at the focal point F. As a result, in the device of this embodiment, a pulsed voltage is applied to the sound wave generating element 10a under conditions similar to those of the first embodiment, a negative pressure pulsed focused sound wave is generated, and the negative pressure pulsed focused sound wave is irradiated to a blood vessel positioned at the focus F, thereby increasing the permeability of the vascular wall of the blood vessel.

[0048] The above describes the embodiments of the negative pressure focused ultrasound generator and vascular wall permeability enhancing device of the present invention, but the present invention is not limited to the above-mentioned embodiments, and various modifications can be made within the scope of the present invention. For example, in the above-described embodiment, the sound wave generating element is made of a ceramic piezoelectric material. However, in the present invention, a piezo element may be used as the piezoelectric material. [Industrial Applicability]

[0049] The increase in vascular wall permeability caused by the negative pressure focused sound wave generator and vascular wall permeability increasing device of the present invention increases the permeability only in the blood vessels at the site irradiated with negative pressure pulsed focused sound waves. This indicates the possibility of concentrating the delivery of drugs to only the affected area for diseases in which the affected area is localized. Current drug treatments target the entire body even in the case of cancer and other localized diseases, and the amount of drug administered is increasing. If the administered drug can be effectively delivered locally, there is a possibility that the total amount of drug administered can be reduced. This indicates the possibility of reducing the side effects of the drug and improving the therapeutic effect.

[0050] In addition, although dementia is a brain disease, no therapeutic drug or treatment has been developed for the purpose of a complete cure. Many therapeutic drugs have undergone Phase III clinical trials, but no therapeutic drug has been proven to be effective. It is believed that the main reason why drugs that were expected to be effective in animal experiments do not work in the human body is the presence of the blood-brain barrier (BBB), and the administered drugs cannot pass through the BBB, so the therapeutic drugs cannot work. The negative pressure focused ultrasound generator and vascular wall permeability enhancing device of the present invention may also be used to open the BBB, and if the permeability of the BBB is increased so that the drug can pass through the BBB, the drug may be effective in the brain.

[0051] Furthermore, current anticancer drug treatments that utilize the EPR effect (Enhanced Permeation and Retention Effect) are not intended to provide localized cancer treatment. However, if it were possible to improve the permeability of the vascular walls of new blood vessels in a tumor using the negative pressure focused acoustic wave generator and vascular wall permeability enhancement device of the present invention, it may be possible to greatly advance the possibilities of anticancer drug treatments and may even contribute to the realization of localized cancer treatment. [Explanation of symbols]

[0052] 10, 10a Sound wave generating element 12 Front 14 Back 20 Pulse voltage generator 30 Focusing elements 30a Focusing element, acoustic lens 32 First component: Epoxy resin 34 Second component: Silicone rubber 42 Ground Line 44 Signal Line 50, 50a Sound-transmitting gel pad 52 First gel pad 54 Second Gel Pad B Evans Blue F focus V blood vessel VW blood vessel wall

Claims

1. a pulse voltage generator that generates a single pulse voltage; an acoustic wave generating element made of a piezoelectric material, which distorts when the pulse voltage is applied to generate a pulsed acoustic wave; A focusing element for focusing the pulsed acoustic waves generated from a front surface of the acoustic wave generating element at a focal point to generate a pulsed focused acoustic wave at the focal point; Equipped with The pulsed voltage has a polarity such that the front surface is displaced in a direction receding from the focal point when the pulsed voltage is applied to the acoustic wave generating element so as to generate the pulsed focused acoustic wave of negative pressure at the focal point. A negative pressure focused sound wave generating device characterized by:

2. The focusing element comprises: the concave front surface of the acoustic wave generating element; a sound-transmitting gel pad provided on the front surface of the sound-generating element; It is made up of 2. The negative pressure focused acoustic wave generator according to claim 1 .

3. The acoustic wave generating element has a planar front surface, The focusing element is an acoustic lens provided on the front surface of the acoustic wave generating element and configured to focus the pulsed acoustic wave generated from the front surface to the focal point.

2. The negative pressure focused sound wave generating device according to claim 1.

4. an acoustic wave generating element made of a piezoelectric material, which generates acoustic waves by displacement of its front surface; a pulse voltage generator that generates a single pulse voltage to be applied to the sound wave generating element; A focusing element that focuses the pulsed sound waves generated by the sound wave generating element to which the pulsed voltage is applied, to a focal point to generate a pulsed focused sound wave at the focal point; Equipped with the pulsed voltage has a polarity such that the front surface is displaced in a direction receding from the focal point when the pulsed voltage is applied to the acoustic wave generating element so as to generate the pulsed focused acoustic wave of negative pressure at the focal point; Repeatedly irradiating a blood vessel positioned at the focal point with the pulsed focused acoustic waves at a negative pressure to increase the permeability of a blood vessel wall of the blood vessel. A device for increasing the permeability of a blood vessel wall.

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