WO2024117828A1

WO2024117828A1 - Ultrasonic ventricle stimulation device

Info

Publication number: WO2024117828A1
Application number: PCT/KR2023/019600
Authority: WO
Inventors: 이은희; 한문; 권기현; 최우혁; 최종률; 최효진; 신재우; 전소연; 정재영; 김예진; 김종한
Original assignee: 재단법인 대구경북첨단의료산업진흥재단
Priority date: 2022-11-30
Filing date: 2023-11-30
Publication date: 2024-06-06

Abstract

The present invention relates to an ultrasonic ventricle stimulation device. According to the present invention, the device comprises: an ultrasound generation unit for generating ultrasound waves; an ultrasound guide unit for guiding the ultrasound generated by the ultrasound generation unit to irradiate the ventricular region of a subject; a computation unit for adjusting an ultrasound variable generated by the ultrasound generation unit; and a control unit for controlling the generation and output of ultrasound waves by the ultrasound generation unit and the operation of the ultrasound guide unit. Thus, according to the present invention, ventricle stimulation, which does not use microbubbles but solely non-invasive ultrasound stimulation, can be used to increase the circulation of cerebrospinal fluid to increase the delivery of medications to the brain, thereby reducing the risk of damage to brain tissue, and can be performed directly by a patient. Therefore, this technology can be used in combination with brain disorder treatment medications to increase the effectiveness of treatment.

Description

ultrasonic ventricle stimulation device

The present invention relates to an ultrasonic ventricular stimulation device, and more specifically, to an ultrasonic ventricular stimulation device that stimulates the patient's ventricle using ultrasound waves to enhance brain drug delivery.

The ventricle is an empty space in the brain filled with cerebrospinal fluid (CSF). The ventricle consists of the lateral ventricle, third ventricle, and fourth ventricle located on the left and right, and each ventricle is connected to each other. Each ventricle has a choroid plexus that produces cerebrospinal fluid. This cerebrospinal fluid circulates around the brain and tissues and performs functions such as supplying nutrients to the central nervous system or discharging metabolites.

When cerebrospinal fluid flows around the arteries, a flow of cerebrospinal fluid that moves around the veins is formed through AQP-4 (water transport protein) at the end of astrocytes. Through this flow (Connective flow),

The system that removes waste products in the brain, such as tau and tau, through veins has been named the glymphatic system, and research is being conducted to improve brain drug delivery using the glymphatic system.

Meanwhile, drug delivery using the blood-brain barrier (BBB) opening technology using conventional focused ultrasound uses microbubbles to open the blood-brain barrier existing in the brain parenchymal area, allowing the drug to enter the brain tissue. Makes transmission possible.

This technology requires intravenous administration of microbubbles, so for actual clinical application, it is inconvenient for patients to visit the hospital in person, and it has the disadvantage of differences in the degree of blood-brain barrier opening depending on the characteristics of the microbubbles.

In addition, there is an advantage that drugs present in the blood can be delivered to the brain parenchyma area due to the opening of the blood-brain barrier, but there are concerns about inflammatory reactions such as albumin present in the blood.

According to the present invention, the object is to provide an ultrasonic ventricular stimulation device that stimulates the ventricle of a patient using ultrasound waves to enhance drug delivery to the brain.

According to an embodiment of the present invention for achieving this technical problem, an ultrasonic ventricular stimulation device includes an ultrasonic generator that generates ultrasonic waves; an ultrasonic wave guiding unit that guides the ultrasonic waves generated by the ultrasonic wave generator to be irradiated to the ventricular area of the subject; a calculation unit that adjusts ultrasonic variables generated by the ultrasonic generator; and a control unit that controls the generation and output of ultrasonic waves by the ultrasonic generator and the operation of the ultrasonic guide.

According to the present invention, the circulation of cerebrospinal fluid is promoted through ventricular stimulation using only ultrasonic stimulation without using microbubbles, thereby increasing brain drug delivery, thereby lowering the possibility of damage to brain tissue and allowing patients to perform the procedure themselves. The treatment effect can be increased by combining this technology with brain disease treatment drugs.

Figure 1 is a diagram showing the configuration of an ultrasonic ventricular stimulation device according to an embodiment of the present invention.

Figure 2 is a diagram for explaining the configuration of an ultrasonic ventricular stimulation device according to an embodiment of the present invention.

Figure 3 is a diagram for explaining an ultrasonic generator according to an embodiment of the present invention.

Figure 4 is a diagram showing an example of a transduce according to an embodiment of the present invention.

Figure 5 is a configuration diagram of an ultrasonic guidance unit according to an embodiment of the present invention.

Figure 6 is an example of an ultrasonic ventricle stimulation device stimulating the ventricle through an ultrasonic guide unit.

Figure 7 is a diagram showing the ventricle.

Figure 8 is a diagram for explaining the flow of cerebrospinal fluid.

Figure 9 is a diagram for explaining the glymph system.

Figure 10 is a schematic diagram to explain the mechanism of glymphatic system stimulation by ultrasound stimulation.

Figure 11 is a diagram confirming that the drug delivery amount was increased through MRI contrast agent and Evans blue drug after ultrasound stimulation in the lateral ventricle of the animal's brain.

Hereinafter, preferred embodiments according to the present invention will be described in detail with reference to the attached drawings. In this process, the thickness of lines or sizes of components shown in the drawings may be exaggerated for clarity and convenience of explanation.

Additionally, the terms described below are terms defined in consideration of functions in the present invention, and may vary depending on the intention or custom of the user or operator. Therefore, definitions of these terms should be made based on the content throughout this specification.

FIG. 1 is a diagram illustrating the configuration of an ultrasonic ventricular stimulation device according to an embodiment of the present invention, FIG. 2 is a diagram illustrating the configuration of an ultrasonic ventricular stimulation device according to an embodiment of the present invention, and FIG. 3 is a diagram illustrating the configuration of an ultrasonic ventricular stimulation device according to an embodiment of the present invention. This is a diagram for explaining an ultrasonic generator according to an embodiment of the present invention, Figure 4 is a diagram showing an embodiment of a transduce according to an embodiment of the present invention, and Figure 5 is a diagram showing an embodiment of the transducer according to an embodiment of the present invention. This is a configuration diagram of the ultrasonic guidance unit, and Figure 6 is an example of an ultrasonic ventricle stimulation device stimulating the ventricle through the ultrasonic guidance unit.

1 to 6, the ultrasonic ventricular stimulation device 100 according to an embodiment of the present invention includes an ultrasonic generator 110, an ultrasonic guide unit 120, a facial recognition sensor unit 130, and a calculation unit 140. and a control unit 150.

The ultrasonic generator 110 is used to generate ultrasonic waves and may include one or more ultrasonic transducers.

According to one embodiment, when the ultrasound generator 110 is composed of four ultrasound transducers, two transducers can be used to stimulate the left ventricle and two transducers can be used to stimulate the right ventricle.

Additionally, as shown in FIG. 3, the ultrasonic generator 110 may be configured with a gyroscope structure.

More specifically, since the size and location of the ventricle are different for each person, the ultrasound generator 110 may be configured with a gyroscope structure that drives the transducer in the X, Y, and Z axes to accurately transmit energy. Movement of the X, Y, and Z axes of the transducer may be controlled by the control unit 150, which will be described later.

Additionally, the ultrasonic transducer may be a linear beamforming transducer that irradiates ultrasonic waves as a linear beam, as shown in FIG. 4.

Additionally, the ultrasonic transducer may be a single type transducer or a multi-array transducer. Here, multiple arrayed transducers have the advantage of having higher ultrasonic resolution and controlling the position of the ultrasonic beam. In this case, by simultaneously controlling the position of the ultrasonic beam of multiple arrayed transducers along with the mechanical movement by the ultrasonic guide unit 120, which will be described later, the movement of the ultrasonic beam can be controlled more freely and the ultrasonic wave can be irradiated to a desired location.

The ultrasonic guidance unit 120 is intended to guide the ultrasonic waves generated by the ultrasonic generator 110 to be irradiated to the ventricular area of the subject. According to one embodiment, it consists of a helmet mounted on the head as shown in FIG. 5. It can be.

In this case, the four ultrasonic transducers constituting the ultrasonic generator 110 may be placed two each on the left and right sides of the helmet, and according to one embodiment, as shown in FIG. 6, each ultrasonic transducer irradiates It is coupled to a helmet so that direction and angle can be changed, so that ultrasound is focused on the subject's ventricular area and stimulates the ventricular area.

The facial recognition sensor unit 130 is intended to support the installation of the ultrasonic guidance unit 120 through facial recognition of the subject, and provides guidance through a display as to whether the ultrasonic guidance unit 120 is correctly mounted at a predetermined position.

Specifically, the facial recognition sensor unit 130 determines whether the ultrasonic guidance unit 120 is mounted in the correct position through facial recognition of the subject.

As a result of the determination, if the mounting position of the ultrasonic guidance unit 120 is misaligned, the correct mounting position is guided through the display, and if it is accurately mounted in the predetermined position, the display informs the subject that ultrasonic ventricular stimulation is possible.

The calculation unit 140 is for controlling ultrasonic variables generated by the ultrasonic generator 110, and controls the ultrasonic variables by adjusting the duty cycle.

The control unit 150 controls the generation and output of ultrasonic waves by the ultrasonic generator 110 and controls the operation of the ultrasonic guidance unit 120.

At this time, the control unit 150 has information measuring the subject's ventricle already input, and controls the operation of the ultrasound generator 110 and the ultrasound guide unit 120 according to the previously input information on the subject's ventricle to control the subject's ventricle. Change the irradiation direction and angle of the ultrasonic transducer so that the ultrasonic waves are focused on the area.

Hereinafter, with reference to FIGS. 7 to 11, the principle of ventricular stimulation according to an embodiment of the present invention and the resulting effect of increasing drug delivery will be described.

FIG. 7 is a diagram illustrating the ventricle, FIG. 8 is a diagram illustrating the flow of cerebrospinal fluid, and FIG. 9 is a diagram illustrating the glymphatic system.

Referring to FIG. 7, the ventricle refers to an empty space in the brain filled with cerebrospinal fluid, and is called by various names depending on its location.

Specifically, the ventricle consists of the lateral ventricles, the third ventricle, and the fourth ventricle located on the left and right. The four ventricles are connected to each other, and each ventricle has a choroid plexus that produces cerebrospinal fluid.

There is a lateral ventricle in the left and right cerebral hemispheres, and the third ventricle is connected to the interventricular foramina. The lateral ventricle is composed of four parts: the anterior horn in the frontal lobe, the central part in the parietal lobe, the olfactory horn in the occipital lobe, and the inferior horn in the temporal lobe. The third and fourth ventricles are connected through the cerebral aqueduct in the midbrain. The fourth ventricle is a space surrounded by the dorsal parts of the peduncle, the dorsal part of the cerebellum, and the lower part of the cerebellum. It connects downward to the central canal of the spinal cord and connects the entire spinal cord.

The inner surface of the ventricle is covered with ependymal cells. Part of the ventricle wall contains a choroid plexus formed by blood vessels in the pia mater, where cerebrospinal fluid is produced and secreted into the ventricle. This cerebrospinal fluid circulates around the brain and tissues and performs roles such as supplying nutrients to the central nervous system or discharging metabolites.

As shown in Figure 8, cerebrospinal fluid produced in the lateral ventricle flows through the third ventricle to the fourth ventricle. And the cerebrospinal fluid flows from the fourth ventricle into the subarachnoid space and travels around the brain. Cerebrospinal fluid flows out through sac-like structures called arachnoid granules and joins the blood. This cerebrospinal fluid plays a role such as supplying nutrients to the central nervous system and discharging metabolites.

Referring to Figure 9, the glymphatic system is a system that removes metabolites from the central nervous system, and removes metabolites by circulating cerebrospinal fluid in the ventricle while the brain is resting.

More specifically, when cerebrospinal fluid flows around the arteries, a flow of cerebrospinal fluid that moves around the veins is formed through AQP-4 (water transport protein) at the end of astrocytes. The glymphatic system is formed through this flow (connective flow).

It refers to a system that removes waste products in the brain, such as Tau, through veins.

Figure 10 is a schematic diagram to explain the mechanism of stimulation of the glymphatic system by ultrasound stimulation, and Figure 11 is a diagram confirming that the drug delivery amount was increased through MRI contrast agent and Evans blue drug after ultrasound stimulation in the lateral ventricle of the animal's brain.

Referring to Figure 10, the space surrounding the vein, such as the perivascular space (PVS) and subarachnoid space (SAS), showing local glymphatic outflow after opening the blood-brain barrier using focused ultrasound in patients with neurodegenerative diseases. By observing patterns of increased diffusion of contrast agents in MRI, it was confirmed that the effects of proteinopathy and drug delivery through the glymphatic system could be increased.

Referring to FIG. 11, it can be seen that the amount of drug delivery increases when the animal's ventricle is stimulated with focused ultrasound (ultrasound stimulation group) after administering the MRI contrast agent and Evans blue drug compared to the case where the animal's ventricle is not stimulated (ultrasonic stimulation group).

In this way, according to the present invention, the circulation of cerebrospinal fluid is promoted through ventricular stimulation using only ultrasound stimulation without using microbubbles, thereby increasing brain drug delivery, thereby reducing the possibility of damage to brain tissue and allowing patients to perform the procedure themselves. Therefore, the treatment effect can be increased by combining this technology with brain disease treatment drugs.

The present invention has been described with reference to the embodiments shown in the drawings, but these are merely illustrative, and those skilled in the art will understand that various modifications and other equivalent embodiments are possible therefrom. will be. Therefore, the true technical protection scope of the present invention should be determined by the technical spirit of the patent claims below.

Claims

An ultrasonic generator that generates ultrasonic waves;

an ultrasonic wave guiding unit that guides the ultrasonic waves generated by the ultrasonic wave generator to be irradiated to the ventricular area of the subject;

a calculation unit that adjusts ultrasonic variables generated by the ultrasonic generator; and

An ultrasonic ventricular stimulation device comprising a control unit that controls the generation and output of ultrasonic waves by the ultrasonic generator and the operation of the ultrasonic induction unit.
According to claim 1,

The ultrasonic generator,

An ultrasonic ventricular stimulation device comprising one or more ultrasonic transducers.
According to claim 2,

The transducer,

Ultrasound ventricular stimulation devices with single type transducers or multiple arrayed transducers.
According to claim 2,

The ultrasonic generator,

An ultrasonic ventricular stimulation device consisting of a gyroscope structure that drives the ultrasonic transducer in X, Y, and Z axes.
According to claim 2,

The ultrasonic guide unit,

An ultrasonic ventricle stimulation device configured in the form of a helmet mounted on the subject's head.
According to claim 5,

The ultrasonic transducer is,

An ultrasonic ventricle stimulation device coupled to the helmet to enable changes in irradiation direction and angle.
According to claim 5,

An ultrasonic ventricular stimulation device further comprising a facial recognition sensor unit that supports mounting of the ultrasonic guidance unit through facial recognition of the subject.
According to claim 7,

The facial recognition sensor unit,

An ultrasonic ventricle stimulation device that guides the mounting position through a display when the mounting position of the ultrasonic guidance unit is misaligned.
According to claim 1,

The calculation unit is,

An ultrasonic ventricle stimulation device that controls the ultrasonic variables by adjusting the duty cycle.
According to claim 6,

The control unit,

An ultrasonic ventricular stimulation device that controls the operations of the ultrasound generator and the ultrasound guide unit according to previously input information about the ventricle of the subject and changes the irradiation direction and angle of the ultrasonic transducer so that the ultrasonic waves are focused on the subject's ventricle area.