WO2023234231A1

WO2023234231A1 - Ultrasound therapy device for cardiac disease

Info

Publication number: WO2023234231A1
Application number: PCT/JP2023/019826
Authority: WO
Inventors: 宏明下川; 孝岡田
Original assignee: サウンドウェーブイノベーション株式会社
Priority date: 2022-05-30
Filing date: 2023-05-29
Publication date: 2023-12-07

Abstract

The purpose of the present invention is to provide an ultrasound therapy device for cardiac disease that enables ultrasound irradiation of the entire heart. The present invention provides an ultrasound therapy device characterized by including: at least two ultrasound transducers that transmit and receive ultrasound waves; and a holding unit that controls the irradiation of ultrasound beams from the at least two ultrasound transducers and holds the ultrasound transducers. Said device is also characterized in that the at least two ultrasound transducers irradiate ultrasound beams so that the irradiated ultrasound waves are irradiated over the entire heart.

Description

Ultrasonic treatment device for heart disease

The present invention relates to an ultrasound treatment device for heart disease.

With the aging of society, the prevalence of cardiovascular diseases such as angina pectoris, heart failure, and arrhythmia, especially heart diseases, continues to increase.

A serious problem in the cardiovascular field is the rapid increase in the number of heart failure patients worldwide, which is referred to as the "heart failure pandemic." ) is reported to be 290,000 people (Non-Patent Document 1). In particular, heart failure (heart failure with preserved ejection fraction, HFpEF), which occurs when the contractile capacity of the heart is maintained but the diastolic capacity is reduced, has become a problem, especially among elderly people. According to an epidemiological study conducted by the present inventors, currently more than 50% of chronic heart failure patients have HFpEF (Non-Patent Document 2). HFpEF patients easily experience acute exacerbation of heart failure under mild stress, are hospitalized and hospitalized several times a year, have a decreased quality of life, have a poor prognosis, and are the cause of increased medical costs. While effective drug treatments have been developed for heart failure with decreased contractility (HFrEF), there is no effective treatment for HFpEF, so the development of safe and effective treatments for HFpEF is long-awaited. There is.

Furthermore, the number of patients with angina pectoris (ischemic heart disease excluding hypertension) in Japan is said to be 720,000 annually (according to the 2018 edition of the Health, Labor and Welfare White Paper on the number of patients with ischemic heart disease), and temporary treatments such as nitroglycerin, etc. Although there are existing treatments such as drug therapy to improve symptoms, percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) for the purpose of complete treatment, Approximately 40% of patients remain with severe angina, and their QOL continues to be poor, requiring continuous drug therapy, with a prognosis of 2 to 5 years. There are virtually no treatment options for patients with severe angina who have not seen improvement after radical treatment with revascularization, and there is a large unmet need.

Furthermore, although the number of patients with pulmonary arterial hypertension (PAH) is small at 2,587 (2013 Intractable Disease Information Center), the vascular endothelium and vascular smooth muscle of the pulmonary artery wall proliferate abnormally, narrowing the lumen of the pulmonary artery. ~It is an intractable disease (designated intractable disease 86) in which complete occlusion increases pulmonary vascular resistance and pulmonary artery pressure, and patients ultimately die from right heart failure due to chronic pressure overload (5-year survival rate: approx. 50%). PAH includes (1) idiopathic PAH, (2) hereditary PAH, (3) drug-induced PAH, (4) PAH associated with collagen disease, (5) PAH associated with HIV infection, and (6) portal vein. PAH is classified into PAH associated with hypertension, (7) PAH associated with congenital heart disease, and (8) PAH associated with schistosomiasis, but in each case, the cause of onset is unknown and is considered an "intractable disease." is specified. Three types of drugs have been approved for treatment: prostacyclin preparations, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors that enhance the action of nitric oxide NO, which dilate pulmonary arteries and suppress proliferation, but their effectiveness remains limited. As it is an intractable disease with a poor prognosis, the development of new treatments is awaited.

The world's first practical ultrasound transducer was invented by P. Langevin in 1917, and since then ultrasound has been used for both medical diagnosis and treatment (non-patented). Reference 3).

In ultrasound medical diagnosis, an ultrasound transducer that transmits and receives ultrasound waves is placed in close contact with the body surface, and the ultrasound waves reflected from internal objects such as organs are received, and the time it takes for the reflected waves to reach the ultrasound transducer is measured. The principle used is to calculate the distance from to the object and create an image of the object.

The first successful examples of clinical application of ultrasound diagnosis include the detection of brain tumors by H.T. Ballantine in 1950 (Non-Patent Document 4) and the detection of gallstones by G.D. Ludwig (Non-Patent Document 5). In the 1950s, imaging of mammary glands, breast cancer, the heart, and blood vessels, tomographic imaging of the heart and eyes, and measurement of blood flow using Doppler ultrasound were reported. In the 1960s, D.W. Baker proposed the pulsed Doppler method (Non-Patent Document 6) in place of the classic continuous wave Doppler method, and the era of practical use of ultrasound diagnosis began in earnest. In the 1970s, research was conducted on scanning methods to achieve more precise imaging, and since the 1980s, ultrasound diagnostic technology has continued to make dramatic advances thanks to the benefits of digital signal processing. .

The mainstream method of ultrasound treatment is to remove blood clots, crush stones, and destroy cancerous tissue by emitting powerful ultrasound waves from outside the body and concentrating the energy at the target area within the body. There have also been many reports on its pain-relieving effects.

In 1939, R. Pohlman et al. produced an ultrasonic therapy device and reported its effectiveness in reducing sciatica (Non-Patent Document 7). Later, in 1942, L.G. Lynn et al. reported tissue destruction using focused ultrasound (Non-Patent Document 8), and in 1952, Oka et al. reported the effects of ultrasound irradiation on diseased areas of arthritis, trauma sequelae, and neuralgia, and the effect of analgesia and recovery of motor function. (Non-Patent Document 9), followed by a report by W.D. Mulvancy in 1953 on the effectiveness of stone fragmentation using focused ultrasound (Non-Patent Document 10).

In the late 1980s, studies began on new clinical applications of ultrasound, such as hyperthermia therapy for cancer using focused ultrasound and promotion of drug effects using low-intensity ultrasound. Among these, the development of treatment technology using High Intensity Focused Ultrasound (HIFU) has become active in recent years because it does not require skin incisions, does not involve tissue invasion like surgery, and is less physically burdensome. ing.

Low Intensity Pulsed Ultrasound (LIPUS) technology also developed in the late 1990s when Teijin Pharma launched Safus (registered trademark) and Exogen (registered trademark) as ultrasonic fracture treatment devices. It has become popular as a treatment technique that shortens the healing time for fractures of the lower leg and clavicle by about 40%. This treatment device uses a flat plate vibrator with a diameter of about 30 mm to irradiate fractures of about the same diameter, but because it treats bones that are relatively close to the superficial parts of the body, such as the feet and hands, it can only be used in a limited manner at the targeted location. This is a treatment device that is specific to the site and bone fracture. Because its mechanism of action is said to be ``promotion of bone union through physical stimulation,'' its indications have not expanded.

In 2000, the present inventors took advantage of Mariotto's conference presentation (Non-Patent Document 11) that shock wave irradiation of cultured human umbilical vein endothelial cells (HUVEC) enhances the expression of endothelial nitric oxide synthase (Non-Patent Document 11). In 2004, he discovered that irradiating cultured human umbilical vein endothelial cells (HUVEC) with low-energy shock waves enhanced the expression of vascular endothelial growth factor (VEGF). Patent Document 12). Subsequently, the present inventor discovered that increased expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) induces angiogenesis and anti-inflammatory effects. After discovering this, in 2006 they began developing a low-power external shock wave therapy device specifically for heart disease, and are now contributing to the treatment of angina pectoris through joint development with Storz of Switzerland. However, shock wave therapy devices applied to the heart have the following problems: (1) alignment of irradiation is somewhat complicated (risk of lung damage), and (2) treatment takes time (heartbeat synchronization). To solve this problem, a treatment device using low-power pulsed wave ultrasound was developed that (1) allows easy irradiation positioning (no damage to the lungs) and (2) shortens treatment time.

In 2010, the present inventors conducted basic research using cultured human umbilical vein endothelial cells (HUVEC) and found that VEGF expression was not enhanced even when irradiated with standing waves of ultrasound; Based on the idea of irradiating the skin in chunks, ultrasound was irradiated in chunks with different transmission wave numbers, such as 1 wave, 16 waves, 32 waves, 48 waves, and 64 waves, and the expression levels of VEGF were compared. As a result, it was found that LIPUS irradiation with 32 waves particularly enhances the expression of VEGF (Non-Patent Document 13).

The present inventors have elucidated that the expression mechanism of eNOS and VEGF brought about by LIPUS is a mechanotransduction mechanism mediated by physical stimulation of caveolin-1 (Figure 1, Non-Patent Document 14), and this This study demonstrated the possibility of expanding LIPUS to applications other than fracture treatment.

The present inventors first investigated angina pectoris (ischemic heart disease), which is a heart disease, as a new indication expansion for LIPUS.

Past attempts to treat the heart by irradiating ultrasound include a method in which a drug is administered to a localized target area such as the myocardium, and absorption of the substance into cells is enhanced by vibrational energy from ultrasound irradiation (Patent Document 1); In HIFU treatment, a treatment device equipped with a motion tracking method synchronized with the heartbeat (Patent Document 2) is equipped with an ultrasonic transducer for image acquisition inside the annular array transducer, and the treatment position can be determined in real time using tomographic images. An ultrasonic treatment device that emits therapeutic focused ultrasound from an annular array ultrasonic transducer while confirming the above (Patent Document 3); An example is a sonic device (Patent Document 4).

In a non-clinical study using myocardial infarction model mice, the present inventors compared the microvessel density and expression of VEGF and eNOS between the LIPUS irradiation group and the control group, and found that the LIPUS irradiation group was significantly lower than the control group. It was also confirmed that cardiac function indicators such as LVEF were significantly improved (Non-Patent Document 15).

Next, in a non-clinical study using a pig model of chronic myocardial ischemia, we compared microvessel density and expression of VEGF and eNOS between the LIPUS irradiation group and the control group. All were shown to significantly increase or accelerate, and cardiac function indicators such as LVEF also significantly improved. Furthermore, when comparing ischemic and non-ischemic areas, the density of microvessels and the expression of VEGF and eNOS were increased in ischemic areas (pathological tissues), but there were no changes in non-ischemic areas (normal tissues). It has been found that LIPUS acts specifically on pathological conditions (ischemic sites) (Non-Patent Document 16, Patent Documents 5 and 6).

The present inventors also considered expanding the application to diastolic heart failure (HFpEF). In a non-clinical study using an HFpEF mouse model, diastolic capacity was improved in terms of echocardiography, pressure-volume curves, and pressure measurements, and myocardial cross-sectional area, interstitial fibrosis, treadmill mileage (exercise tolerance), and blood pressure were improved. The therapeutic effect was confirmed from the middle BNP level, and the mechanism of improving left ventricular myocardial dilatation and fibrosis was shown to be due to activation of the NO-sGC-cGMP-PKG pathway (Figure 2, Non-Patent Document 17) .

The present inventors also considered expanding the indication to pulmonary arterial hypertension (PAH). In a nonclinical study using a right heart failure model animal (pulmonary artery coarctation (PAB) mouse model), LIPUS treatment activated the eNOS-NO-sGC-cGMP-PKG pathway (Figure 3), and echocardiography showed that the LIPUS treatment group Significant improvement in right ventricular function was observed (Non-Patent Document 18).

Special table 2002-521118 Special table 2006-519048 Special table 2019-514485 JP2020-185482 Patent No. 5603572 Patent No. 6653172

The present inventors have discovered that the irradiation area of a LIPUS irradiation device using the element arrangement (convex type, sector type, etc.) of the ultrasonic transducer described in the conventional ultrasonic treatment device and the above-mentioned Patent Documents 1 and 2 is as follows: The focused ultrasound beam is limited to the scanned cross-sectional plane, and can be used in cases where multivessel lesions spread throughout the coronary arteries as in severe angina, cases of left ventricular diastolic dysfunction as in HFpEF, and cases as in PAH. We found that in cases with right heart failure, areas that are not irradiated with ultrasound tend to occur, making it difficult to obtain sufficient therapeutic effects. In this case, it is possible to expand the irradiation area by increasing the number of tomographic planes that are irradiated with ultrasound, but increasing the number of tomographic planes increases the treatment time and increases the burden on patients and practitioners.

The present invention has been made in view of the above-mentioned problems, and its purpose is to provide an ultrasonic treatment device capable of irradiating the entire heart with LIPUS, which is used for the treatment of heart diseases such as HFpEF, PAH, and angina pectoris. Our goal is to provide the following.

As a result of intensive studies to solve the above problems, the present inventors have determined that at least two ultrasonic transducers capable of emitting non-focused ultrasonic beams (diffuse beams) are used, and one ultrasonic transducer is used for parasternal approach. We have discovered that another ultrasound transducer can irradiate the entire heart with LIPUS by irradiating an ultrasound beam from the intercostal approach to the apex of the heart, making it possible to treat various heart diseases such as HFpEF.

The present invention is based on this new knowledge, and relates to an ultrasonic treatment device used in the treatment method, and includes the following inventions.
[1] An ultrasound treatment device for treating heart disease,
at least two ultrasound transducers that direct unfocused ultrasound beams to the heart;
a transmitter that controls irradiation of unfocused ultrasound beams from the at least two ultrasound transducers;
a holder for holding the at least two ultrasonic transducers in place;
Equipped with
The transmitter controls the ultrasound transducer to sequentially irradiate the unfocused ultrasound,
The holder is capable of attaching and detaching the at least two ultrasonic transducers, and one of the at least two ultrasonic transducers is configured to transmit an unfocused ultrasonic beam including a long-axis section of the left sternal rim using a parasternal approach to the heart. and another one of the at least two ultrasound transducers to transmit ultrasound waves to the heart by transmitting an unfocused ultrasound beam including an apical long-axis tomographic plane from the intercostal to the apex approach. An ultrasonic treatment device that is held in a position where it can be irradiated.
[2] The transmitter has a transmission frequency of 0.1 to 3 MHz, is composed of a discontinuous wave with a cycle number of 1 to 64 cycles, and has a pulse repetition time (PRT) of 0. The ultrasonic treatment device according to [1], wherein the at least two ultrasonic transducers are controlled so as to continuously irradiate the unfocused ultrasonic waves with a duration of .25 to 2.56 ms for 1 to 80 minutes.
[3] The ultrasound treatment device according to [2], wherein the transmission frequency of the unfocused ultrasound is 0.5 to 1.875 MHz.
[4] The ultrasound treatment device according to [2], wherein the number of cycles of the unfocused ultrasound is 32 cycles.
[5] The ultrasonic treatment device according to [1], wherein the at least two ultrasonic transducers have convex transducer surfaces.
[6] The ultrasonic treatment device according to [1], wherein the at least two ultrasonic transducers have an acoustic lens on a transducer surface.
[7] The ultrasound treatment device according to [1], wherein the at least two ultrasound transducers are capable of switching between irradiation with a non-focused ultrasound beam and irradiation with a focused ultrasound beam.
[8] The ultrasonic treatment device according to [7], wherein the at least two ultrasonic transducers include removable acoustic lenses.
[9] The ultrasonic treatment device according to [7], wherein the plurality of ultrasonic transducers include a large number of vibration elements arranged two-dimensionally.
[10] After the at least two ultrasonic transducers emit focused ultrasonic beams, the image forming unit includes an image forming unit that obtains an ultrasonic reception signal from the treatment area as waveform information from the transmitting/receiving means. The ultrasonic treatment apparatus according to [7], which forms image data that creates B-mode tomographic image data from the waveform information.
[11] The ultrasonic treatment device according to [1], wherein the at least two ultrasonic transducers have a transducer surface having a size of 8 mm to 20 mm.
This specification includes the content described in the specification of Japanese Patent Application No. 2022-088027 filed on May 30, 2022, which is the basis of the priority of this application.
All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.

The present invention provides a new ultrasound treatment device that can irradiate the entire heart with ultrasound. According to the present invention, the entire heart including the ventricles and atria can be irradiated with ultrasound, and even cases where multivessel lesions have spread throughout the heart can be efficiently treated. Further, according to the present invention, the production of endothelial nitric oxide synthase (eNOS) and the promotion of vascular endothelial growth factor (VEGF) can be promoted by irradiating ultrasound. It can increase blood flow and promote angiogenesis in myocardial tissue, increasing the therapeutic effect of ischemic tissue.

FIG. 1 shows a schematic diagram of the mechanism of increased expression of eNOS and VEGF brought about by LIPUS (Non-Patent Document 14). FIG. 2 shows a schematic diagram of the mechanism of improving left ventricular myocardial dilatation and fibrosis by activation of the NO-sGC-cGMP-PKG pathway (Non-Patent Document 17). FIG. 3 shows a schematic diagram of the mechanism of improving right heart failure by activation of the NO-sGC-cGMP-PKG pathway. FIG. 4 shows a schematic diagram of an exemplary embodiment of the ultrasound treatment device of the present invention. FIG. 5 shows a schematic diagram of an exemplary embodiment of a convex ultrasound transducer that emits an unfocused ultrasound beam (divergent beam). FIG. 6 shows a schematic diagram of another exemplary embodiment of an ultrasound transducer that uses an acoustic lens to emit a non-focused ultrasound beam (divergent beam). FIG. 7 shows an image of irradiating ultrasound through the intercostal space from the transthoracic wall using the apex approach. FIG. 8 shows a schematic diagram of another typical embodiment of the ultrasonic treatment device of the present invention, including a transmitting/receiving section, an image forming section, and the like. FIG. 9 shows a schematic diagram of an exemplary embodiment of emitting an unfocused ultrasound beam (divergent beam) with a sector-scanning one-dimensional array ultrasound transducer. (Left) shows the time in diagnosis mode, (right) shows the time in treatment mode. FIG. 10 shows a schematic diagram of an exemplary embodiment in which a sector-scanning two-dimensional array type ultrasound transducer emits an unfocused ultrasound beam (diffuse beam). (Right) shows the treatment mode. FIG. 11 shows a schematic diagram of an example of the arrangement of ultrasound transducers for irradiating the entire heart with ultrasound in a typical embodiment of the treatment method using the ultrasound treatment device of the present invention. FIG. 12 is a photographic diagram showing an example of a holder for an ultrasound transducer for irradiating the entire heart with ultrasound in a typical embodiment of the treatment method using the ultrasound treatment device of the present invention.

Hereinafter, the present invention will be explained with reference to the drawings. In addition, in the present invention, the "ultrasonic treatment device" means a treatment device that irradiates "LIPUS".

The ultrasound treatment device of the present invention is a device for treating heart disease, and includes:
at least two ultrasound transducers that direct a non-focused ultrasound beam (divergent beam) to the heart;
a transmitter that controls irradiation of the ultrasonic beam from the ultrasonic transducer;
a holder for holding the at least two ultrasonic transducers in a predetermined position,
The present invention is characterized in that the plurality of ultrasound transducers sequentially irradiate ultrasound beams so that the entire heart is irradiated with the irradiated ultrasound beams.

The ultrasound treatment device of the present invention can treat ischemic heart diseases such as angina pectoris, myocardial infarction, and microvascular angina (MVA), heart failure such as diastolic heart failure (HFpEF) and systolic heart failure (HFrEF), Cardiomyopathy such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), pressure overload heart disease such as pulmonary arterial hypertension (PAH), hypertensive heart disease, and secondary myocardial diseases such as cardiac amyloidosis and Fabry disease. It is suitable for the treatment of heart disease consisting of symptoms.

FIG. 4 shows a schematic diagram of the overall configuration of a typical embodiment of the ultrasonic treatment device of the present invention. The ultrasonic treatment device 2 of the present invention includes two ultrasonic transducers 1 capable of emitting non-focused ultrasonic beams (diffuse beams). Ultrasonic transducers are equipped with one vibrating element or a vibrator with multiple vibrating elements arranged to emit ultrasonic waves, and can be of the convex scanning type, sector scanning type, linear scanning type, or two-dimensional array arranged in a matrix. A mold etc. can be used as appropriate.

The ultrasound transducer 1 receives a transmission signal for irradiating ultrasound from the transmitter 3, converts it into ultrasound at the ultrasound transducer 1, and sends a non-focused ultrasound beam (diffuse beam) from the transducer surface to the entire heart. irradiate the area. The ultrasonic transducer 1 is held in place using a holder (not shown), and one is inserted into the sternum from the third or fourth intercostal space on the left sternum, or near it (parasternal approach). An unfocused ultrasound beam is irradiated to the entire heart in the direction of the long-axis cross-section of the left edge, and another one is directed from the intercostal area (apex) where the apex pulsation is felt at the bottom of the papilla to the apex long-axis cross-section. A non-focused ultrasound beam is directed toward the entire heart to irradiate ultrasound waves. Therefore, both ventricles and atria of the heart receive ultrasound irradiation.

The transmitter 3 controls the ultrasound transducer 1 by outputting a transmission signal for the ultrasound transducer 1 to emit ultrasound. The transmitter 3 generates a transmission signal for irradiating ultrasound based on the ultrasound transmission frequency, wave number, and PRT set by the controller 4.

The control unit 4 controls the entire ultrasound treatment device 2. The controller 4 outputs to the transmitter 3 a transmission control signal that controls the transmission frequency, wave number, PRT, switching between a plurality of ultrasound transducers, etc. of the ultrasound emitted from the ultrasound transducer 1 .

The operation unit 5 accepts operations from the user, and the received instructions are output to the control unit 4 and reflected in the control within the ultrasound treatment device 2.

The transmitting units 3 are each realized by hardware such as an FPGA, a processor, or an electric circuit. Further, the operation unit 5 is configured of at least a portion of, for example, a touch panel, a keyboard, a trackball, switches, and the like. The control unit 4 is constituted by hardware such as a microprocessor or a personal computer, and the functions of the control unit 4 are realized through cooperation between the hardware and software (program) that defines its operation.

FIG. 5 shows a schematic diagram of a typical embodiment of an ultrasound transducer that emits a non-focused ultrasound beam (diffuse beam) according to the present invention. The ultrasonic transducer 1 includes one vibrating element or a vibrator (not shown) in which a plurality of vibrating elements are arranged for emitting ultrasonic waves, a cable 10 connected to a transmitter (not shown), and a cable 10 that emits ultrasonic waves. It is composed of a vibrator surface protection film 8 that covers a vibrator surface 9 which is an irradiation surface. The transducer surface 9 has a convex curved surface in order to irradiate a non-focused ultrasound beam (diffuse beam). The convex curved surface can be formed by making the ultrasonic irradiation surface a convex curved shape or by arranging a plurality of vibration elements in a convex curved shape. By forming the ultrasound irradiation surface into a convex curved shape, a non-focused ultrasound beam (diffuse beam) can be efficiently irradiated. Note that in this specification, the term "unfocused ultrasound beam" or "diffuse beam" refers to an ultrasound beam that is diffused without being focused on one point or line. In the present invention, as shown in Fig. 7 (image of irradiation using the apex approach), ultrasound is irradiated from the intercostals and the entire heart is irradiated with ultrasound, so that the unfocused ultrasound beam gradually radiates toward the heart. It is preferable to diffuse in a reverse tapered shape that expands in diameter. It is preferable that the angle at which the inclined plane of the inversely tapered unfocused ultrasonic beam expanding in diameter spreads is from 50° to 100°, more preferably from 60° to 90°. Since the transducer surface 9 emits ultrasonic waves from between the ribs, it is preferable that its longest dimension (or diameter if the surface is circular) is 8 mm to 20 mm. The transducer surface protective film 8 is adhered or attached to the transducer surface 9, and prevents damage to the transducer surface due to collision with objects around the treatment device, and prevents unfocused ultrasound from the ultrasound transducer. Any material may be used as long as it does not interfere with beam irradiation, and it is composed of a thin film made of a material such as resin (noryl resin, polyacetal, ionomer resin, urethane resin, etc.).

FIG. 6 shows a schematic diagram of another typical embodiment of an ultrasound transducer that emits a non-focused ultrasound beam (diffuse beam) according to the present invention. The ultrasonic transducer 1 includes a vibrating element (not shown) that transmits and receives ultrasonic waves or a vibrator (not shown) in which a plurality of vibrating elements are arranged, a cable 10 that is connected to a transmitter (not shown), and a cable 10 that transmits and receives ultrasonic waves. It is composed of an acoustic lens 11 attached to a vibrator surface 9' which is an irradiation surface. The acoustic lens 11 is provided to diffuse the ultrasound generated from the transducer and irradiate it as a non-focused ultrasound beam (diffuse beam). The acoustic lens 11 only needs to be made of a material (for example, ABS, Pebax) that can propagate ultrasonic waves at a faster sound speed than the sound speed of the ultrasonic waves generated from the vibrator. It can be spread out over a wide angle without converging.

FIG. 8 shows a schematic diagram of the overall configuration of another typical embodiment of the ultrasonic treatment device of the present invention. The ultrasonic treatment device 22 of the present invention includes two plurality of ultrasonic transducers 21. The ultrasonic transducer 21 is a sector scanning array probe capable of emitting a non-focused ultrasonic beam (diffuse beam), and may include an acoustic lens adapter that is a detachable acoustic lens.

The ultrasonic treatment device 22 has an ultrasonic treatment function and an ultrasonic diagnostic function, and the ultrasonic transducer 21 can transmit and receive diagnostic ultrasonic waves and therapeutic ultrasonic waves. The ultrasound transducer 21 may include a transducer capable of transmitting and receiving both diagnostic ultrasound and therapeutic ultrasound, or may include separate transducers that transmit and receive each of them.

The ultrasonic transducer 21 is held in a predetermined position using a holder (not shown), receives an electric signal for emitting ultrasonic waves from the transmitting/receiving unit 23, converts it into ultrasonic waves with a transducer, and enters the treatment mode. Sometimes, a non-focused ultrasound beam (diffuse beam), which is therapeutic ultrasound, is irradiated from the transducer surface onto a treatment area (for example, the heart, etc.). On the other hand, in the diagnosis mode, a focused ultrasound beam, which is diagnostic ultrasound, is irradiated from the transducer surface onto a treatment area (for example, the heart). After irradiation, the ultrasonic transducer 21 also receives reflected waves from the treatment area, converts them into reception signals using a vibrator, and outputs the signals to the transmission/reception section 23 .

The transmitting/receiving unit 23 controls the ultrasonic transducer 21 by outputting a transmission signal for irradiating an ultrasonic beam to a vibrator included in the ultrasonic transducer 21. The transmitting/receiving unit 23 generates a transmission signal for irradiating an ultrasound beam based on the ultrasound transmission frequency, wave number, and PRT in the treatment mode or diagnosis mode, which are set by the control unit 26 . In addition, the transmitting/receiving unit 23 obtains a received signal by performing phasing and addition processing on the electric signals obtained from the vibrator included in the ultrasound transducer 21, converts it into waveform information, and outputs it to the waveform forming unit 24 in the treatment mode. , is output to the image forming section 212 in the diagnosis mode.

The waveform forming unit 24 generates image data from the waveform information input from the transmitting/receiving unit 23 and outputs it to the display unit 25.

The image forming unit 212 performs signal processing to create B-mode tomographic image data from the waveform information input from the transmitting/receiving unit 23, and then converts the data into image data and outputs it to the display unit 25.

The display unit 25 displays the received ultrasound signal based on the image data input from the waveform forming unit 24, and displays a B-mode tomographic image based on the image data input from the image forming unit 28.

The control unit 26 controls the entire ultrasound treatment device 22. The control unit 26 transmits the transmission frequency, wave number, PRT, switching information between a plurality of ultrasound transducers, transmission/reception switching information, etc. of the ultrasound emitted from the ultrasound transducer 21 in the treatment mode or diagnosis mode. A transmission/reception control signal to be controlled is output to the transmission/reception section 23. Further, the control section 26 outputs a waveform display control signal to the waveform forming section 24 , an image display control signal to the image forming section 212 , and a display control signal to the display section 25 .

The operation unit 27 accepts operations from the user, and the received instructions are output to the control unit 26 and reflected in the control within the ultrasound treatment device 22.

The transmitting/receiving unit 23, the waveform forming unit 24, and the image forming unit 212 are each realized by hardware such as an FPGA, a processor, or an electric circuit. Further, the display section 25 is realized by, for example, a liquid crystal display. Further, the operation unit 27 is configured of at least a portion of, for example, a touch panel, a keyboard, a trackball, switches, and the like. The control unit 26 is constituted by hardware such as a microprocessor or a personal computer, and the functions of the control unit 26 are realized through cooperation between the hardware and software (program) that defines its operation.

FIG. 9 shows a typical sector scanning one-dimensional array type ultrasonic transducer that emits a non-focused ultrasonic beam (diffuse beam) as an ultrasonic transducer used in the ultrasonic treatment device shown in FIG. 8. Figure 3 shows a schematic diagram of an embodiment. The ultrasonic transducer 21 includes a vibrator (not shown) in which a plurality of vibrating elements for transmitting and receiving ultrasonic waves are arranged, a cable 210 connected to a transmitting/receiving section (not shown), and a vibration irradiation surface that is an ultrasonic irradiation surface. It consists of a child surface 29 and an acoustic lens adapter 211 which is a detachable acoustic lens. In the diagnostic mode (left in FIG. 9), the acoustic lens adapter 211 is not attached, and the transmitting and receiving unit controls the irradiation timing of each vibrating element arranged on the transducer surface 29 to generate a focused ultrasound beam, which is diagnostic ultrasound. irradiate. On the other hand, in the treatment mode (right side of FIG. 9), the acoustic lens adapter 211 is attached to the transducer surface 29, and the irradiation timing of each transducer element arranged on the transducer surface 29 is controlled by the transmitter/receiver section to transmit therapeutic ultrasonic waves. A non-focused ultrasound beam (diffuse beam) is irradiated.

FIG. 10 shows a typical sector scanning two-dimensional array type ultrasonic transducer that emits a non-focused ultrasonic beam (diffuse beam) as an ultrasonic transducer used in the ultrasonic treatment device shown in FIG. Figure 3 shows a schematic diagram of an embodiment. The ultrasonic transducer 21' includes a large number of transducer elements 213 arranged two-dimensionally on a transducer surface 29', a cable 210' connected to a transmitting/receiving section (not shown), and a transducer surface that is an ultrasonic irradiation surface. 29'. In the diagnostic mode, the transmitter/receiver unit controls the irradiation timing of each transducer element arranged on the transducer surface, and irradiates a focused ultrasonic beam, which is a diagnostic ultrasonic wave (not shown). On the other hand, in the treatment mode (right side of FIG. 10), the irradiation timing of each transducer element arranged on the transducer surface 29' is controlled by the transmitter/receiver section, and a non-focused ultrasound beam (diffuse beam) that is therapeutic ultrasound is generated. irradiate.

FIG. 11 shows a schematic diagram of an example of the arrangement of ultrasound transducers for irradiating the entire heart with ultrasound in a typical embodiment of the treatment method using the ultrasound treatment device of the present invention. In the present invention, two ultrasound transducers are placed at different positions and irradiate a non-focused ultrasound beam (diffuse beam), thereby realizing ultrasound irradiation over a wide range, preferably the entire heart. It is. As illustrated in Figure 11, one ultrasound transducer emits an unfocused ultrasound beam (diffuse beam) that includes the long-axis section of the left sternal edge through a parasternal approach, and another ultrasound transducer emits a non-focused ultrasound beam (diffuse beam) from the intercostal A non-focused ultrasound beam including an apical long-axis tomogram is irradiated using an apical approach. This makes it possible to achieve ultrasonic irradiation over a wide range, preferably over the entire heart including the ventricles and atria. When using three or more ultrasound transducers, in addition to the above locations, the apical, suprasternal, left parasternal border (long and short axis), and epigastric approaches are well known in the art. Each ultrasound transducer can also be placed separately at multiple locations selected from , as well as other approaches.

In the treatment method, a holder is used to place and fix the ultrasonic transducer in a predetermined position. FIG. 12 shows an example of a typical holder in the ultrasonic treatment device of the present invention, but the holder is not particularly limited to this form as long as it can place and fix the ultrasonic transducer in a predetermined position. It's not something you can do. The holder shown in FIG. 12 is composed of a chest belt and an ultrasonic transducer fixing belt, and the chest belt is wrapped around the patient's chest so that the ultrasonic transducer installation window is aligned with the desired fixing position. Next, the ultrasonic transducer is placed in this ultrasonic transducer installation window, and the transducer is fixed with an ultrasonic transducer fixing belt. Similarly, other ultrasonic transducers are also placed and fixed at predetermined positions. In a typical embodiment using the ultrasound treatment device of the present invention, the chest belt is wrapped around the chest with the ultrasound transducer installation window of the chest belt aligned with the left edge of the sternum (at this time, the belt is wrapped around the chest near the apex approach). Next, place the ultrasonic transducer in the ultrasonic transducer installation window and secure the ultrasonic transducer with the ultrasonic transducer fixing belt. Furthermore, use another chest belt to wrap the ultrasound transducer placement window around the chest with the position of the apical approach, and then place another ultrasound transducer in the ultrasound transducer placement window. , fix the ultrasonic transducer with the ultrasonic transducer fixing belt. Thereby, two ultrasound transducers can be placed and fixed in the parasternal approach and the apical approach, respectively.

In addition, in the treatment method, the transducer surface of the ultrasound transducer and/or the ultrasound Appropriate gel (also referred to as echo gel, echo jelly, etc.) may be applied to the patient's site where the sonic transducer is to be placed.

In the treatment method using the ultrasonic treatment device of the present invention, the ultrasonic transmission frequency (frequency) of the unfocused ultrasonic beam can be appropriately set in the range of 0.1 to 3 MHz, preferably 0. .5 to 1.875MHz. By irradiating ultrasound at a frequency of this order, it is possible to effectively vibrate the tissue at the irradiation site, promoting eNOS expression, angiogenesis, etc., and making the treatment more effective.

Furthermore, in the present invention, the unfocused ultrasound beam is a discontinuous wave, and the number of cycles thereof can be appropriately set in the range of 1 to 64 cycles, for example, 1 cycle, 16 cycles, 32 cycles, 48 cycles. cycle, 64 cycles, etc., preferably 16 to 48 cycles, more preferably 32 cycles. Here, the number of cycles of ultrasound refers to the number of waves of transmitted waves within the range from the start of ultrasound irradiation to the end of ultrasound irradiation. By setting the number of ultrasound cycles to about 32, the expression of factors related to angiogenesis (e.g. VEGF) can be particularly enhanced (Patent No. 6653172, PLOS ONE, August 2014, Volume 9, Issue 8), the effectiveness of treatment can be obtained.

In the present invention, by using a plurality of ultrasonic transducers and emitting unfocused ultrasonic beams from different locations, ultrasonic irradiation over a wide range, preferably the entire heart, is achieved. In the present invention, from the viewpoint of safety, more specifically, from the viewpoint of suppressing the redundant irradiation of the heart with ultrasound waves irradiated from multiple locations and the transmission of excessive ultrasound energy, Unfocused ultrasound is sequentially irradiated between multiple ultrasound transducers. In the present invention, "sequentially irradiating unfocused ultrasound among a plurality of ultrasound transducers" means that first, among the plurality of ultrasound transducers, a certain ultrasound transducer generates ultrasound, and during that time, Another ultrasonic transducer does not generate ultrasonic waves, then another ultrasonic transducer generates ultrasonic waves, and during that time, other ultrasonic transducers do not generate ultrasonic waves, and so on. , out of a plurality of ultrasonic transducers, only one ultrasonic transducer is generating ultrasonic waves at the same time; in other words, two or more ultrasonic transducers do not generate ultrasonic waves at the same time. In the present invention, the interval between unfocused ultrasonic irradiations by a plurality of ultrasonic transducers can be expressed as PRT, and it is preferable to set PRT appropriately in the range of 0.25 to 2.56 ms. In the present invention, by setting PRT within this range, the irradiated ultrasound is attenuated (preferably to about 1/100) before the next unfocused ultrasound energy irradiation, and the Excessive ultrasound stimulation due to duplication of sound wave energy can be avoided or reduced. However, if the irradiation areas of unfocused ultrasound do not overlap between a plurality of ultrasound transducers, it is also possible to irradiate them simultaneously.

The irradiation conditions of these unfocused ultrasound beams are controlled by the controller via the transmitter.

In the treatment method using the ultrasound treatment device of the present invention, the treatment time for irradiation with unfocused ultrasound energy may be appropriately determined depending on factors such as, for example, the patient's symptoms and the irradiation conditions for the unfocused ultrasound beam. The irradiation time per treatment can be appropriately determined in the range of preferably 1 to 80 minutes, more preferably 15 to 25 minutes, and particularly preferably 20 minutes. Furthermore, the number of irradiations with unfocused ultrasound energy per day (i.e., the number of irradiations in one day treatment) can be performed multiple times, and is not particularly limited; It can be set appropriately in the range of 4 times, preferably 2 to 3 times, and more preferably 3 times. Each session can be carried out at appropriate intervals, and although not particularly limited, it is preferable to carry out the sessions at intervals of at least 5 minutes or more. The treatment method of the present invention can be carried out continuously at an appropriate frequency as long as no adverse events occur.

Note that the focused ultrasound beam, which is the diagnostic ultrasound, can be of the same level as the ultrasound used for diagnosis with conventionally known general ultrasound diagnostic devices.

Although the present invention has been described above based on the drawings showing specific embodiments, it is clear that the present invention is not limited to these embodiments. For example, the number of ultrasonic transducers may be two as shown in FIGS. 4, 8, etc., or may be more than that (for example, 3, 4, 5, etc.). The connection between the ultrasonic transducer and the transmitter may be wired as shown in FIGS. 4, 8, etc., or may be wireless. Further, the shape of the ultrasonic transducer, especially the shape of the transducer surface which is the ultrasonic irradiation surface, is sufficient as long as it can irradiate ultrasonic waves in all directions, and may be circular as shown in FIGS. It may be approximately circular, approximately elliptical, polygonal (triangle, quadrilateral (square, rectangle, parallelogram, trapezoid, etc.), pentagon, hexagon, heptagon, octagon, etc.), or the like. The present invention includes various modifications without departing from its essence.

1, 21, 21' Ultrasonic transducer 2, 22 Ultrasonic treatment device 3, 23 Transmitting/receiving section 24 Waveform forming section 25 Display section 4, 26 Control section 5, 27 Operation section 8 Transducer surface protective film 9, 9', 29, 29' Vibrator surface 10, 210, 210' Cable 11 Acoustic lens 211 Acoustic lens adapter 212 Image forming section 213 Vibrating element

Claims

An ultrasound treatment device for treating heart disease,
at least two ultrasound transducers that direct unfocused ultrasound beams to the heart;
a transmitter that controls irradiation of unfocused ultrasound beams from the at least two ultrasound transducers;
a holder for holding the at least two ultrasonic transducers in place;
Equipped with
The transmitter controls the ultrasound transducer to sequentially irradiate the unfocused ultrasound,
The holder is capable of attaching and detaching the at least two ultrasonic transducers, and one of the at least two ultrasonic transducers is configured to transmit an unfocused ultrasonic beam including a long-axis section of the left sternal rim using a parasternal approach to the heart. holding another one of the at least two ultrasound transducers in a position where it can irradiate the heart with an unfocused ultrasound beam that includes an apical long-axis tomographic plane from the intercostal approach to the apex of the heart; An ultrasonic treatment device that can be held in any position.
The transmitter has a transmission frequency of 0.1 to 3 MHz, is composed of a discontinuous wave with a cycle number of 1 to 64 cycles, and has a pulse repetition time of 0.25 to 2.56 ms. The ultrasonic treatment device according to claim 1, wherein the at least two ultrasonic transducers are controlled to continuously irradiate focused ultrasonic waves for 1 minute to 80 minutes.
The ultrasound treatment device according to claim 2, wherein the transmission frequency of the unfocused ultrasound is 0.5 to 1.875 MHz.
The ultrasound treatment device according to claim 2, wherein the number of cycles of the unfocused ultrasound is 32 cycles.
The ultrasonic treatment device according to claim 1, wherein the at least two ultrasonic transducers have convex transducer surfaces.
The ultrasonic treatment device according to claim 1, wherein the at least two ultrasonic transducers have an acoustic lens on a transducer surface.
The ultrasound treatment device according to claim 1, wherein the at least two ultrasound transducers are capable of switching between irradiation with an unfocused ultrasound beam and irradiation with a focused ultrasound beam.
The ultrasonic treatment device according to claim 7, wherein the at least two ultrasonic transducers include removable acoustic lenses.
The ultrasonic treatment device according to claim 7, wherein the at least two ultrasonic transducers include a large number of vibration elements arranged two-dimensionally.
After the at least two ultrasonic transducers emit focused ultrasound beams, the image forming unit includes an image forming unit that obtains an ultrasonic reception signal from the treatment area as waveform information from the transmitting/receiving means, and the image forming unit receives the waveform information. The ultrasonic treatment apparatus according to claim 7, wherein image data is formed to create B-mode tomographic image data.
The ultrasonic treatment device according to claim 1, wherein the at least two ultrasonic transducers have transducer surfaces with a size of 8 mm to 20 mm.