WO2023108348A1 - Meningeal lymphatic vessel stimulation device - Google Patents

Meningeal lymphatic vessel stimulation device Download PDF

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Publication number
WO2023108348A1
WO2023108348A1 PCT/CN2021/137470 CN2021137470W WO2023108348A1 WO 2023108348 A1 WO2023108348 A1 WO 2023108348A1 CN 2021137470 W CN2021137470 W CN 2021137470W WO 2023108348 A1 WO2023108348 A1 WO 2023108348A1
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meningeal lymphatic
ultrasonic
ultrasonic transducer
photon
module
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PCT/CN2021/137470
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French (fr)
Chinese (zh)
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牛丽丽
郑海荣
孟龙
邹俊杰
易沙沙
林争荣
周伟
陈厚民基
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深圳先进技术研究院
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Priority to PCT/CN2021/137470 priority Critical patent/WO2023108348A1/en
Publication of WO2023108348A1 publication Critical patent/WO2023108348A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy

Definitions

  • the application belongs to the technical field of biomedicine, and in particular relates to a meningeal lymphatic vessel stimulating device.
  • the brain is an important control center of the human body.
  • the functional activities of the brain are inseparable from the various activities of the human body.
  • the brain When the brain is active, it will produce various metabolites. These metabolites can flow back into the blood through the cerebrospinal fluid circulation. Lymphatic endothelial cells are present, and the central nervous system lacks lymphatic structures.
  • Neuromodulation technology is a key technology that can regulate neural activity based on various physical factors including electricity, magnetism, light, and sound.
  • ultrasonic neuromodulation technology is a new generation of neuromodulation technology with high precision and non-invasiveness. It has been confirmed that it can regulate neuron activity like electricity, magnetism and light.
  • ultrasound can also regulate other tissues and organs.
  • due to the special location of the meningeal lymphatic vessels there is a lack of direct observation methods.
  • the depth of focus of the current ultrasonic transducer is too deep to cover the meningeal lymphatic vessels close to the skull. Here comes the big problem.
  • ultrasonic radiation force is one of the important factors to regulate nerve and cell activities.
  • the acoustic energy of ultrasonic waves is transformed into kinetic energy, which affects the The force exerted by the medium of propagation.
  • Ultrasonic radiation force can cause slight changes in the morphology of the cell membrane, activate ion channels on the cell membrane, secrete related proteins, and affect the overall functional activities.
  • This application provides a meningeal lymphatic vessel stimulation device.
  • the present application provides a meningeal lymphatic vessel stimulation device, including a sequentially connected two-photon imaging module, a precise regulation module and a feedback evaluation module, the feedback evaluation module is connected to the two-photon imaging module;
  • the two-photon imaging module is used to locate, mark and image the meningeal lymphatic vessels, and transmit the image to the feedback evaluation module.
  • the precise control module is used for precise control of the meningeal lymphatic vessels. Changes in lymphatic vessel function, adjust the parameters of the precise regulation module through observation results.
  • the two-photon imaging module is a two-photon perspective imaging module
  • the two-photon perspective imaging module includes a two-photon microscope
  • the precise control module includes an ultrasonic stimulation unit
  • the ultrasonic stimulation The unit includes an ultrasonic transducer
  • the feedback evaluation module includes an image processor, a data storage and a display connected in sequence
  • the image processor is connected to the display
  • the two-photon microscope is connected to the image processor
  • the two-photon microscope is connected with the ultrasonic transducer.
  • the two-photon microscope is provided with a high-permeability lithium sulfate lens, and the excitation light of the two-photon microscope passes through the high-permeability lithium sulfate lens, so that the excitation light passes through without damage and enhances the stimulation of meningeal lymphatic vessels. imaging effect.
  • the ultrasonic transducer is connected to a coupling carrier
  • the coupling carrier includes several resistance circuits
  • the coupling carrier provides a fixed carrier for the ultrasonic transducer
  • the coupling carrier Matching circuit for adjusting resistors.
  • the ultrasonic transducer is made of piezoelectric material, and the ultrasonic transducer converts electrical energy into mechanical vibration through the piezoelectric effect to generate ultrasonic waves.
  • the precise control module further includes an ultrasonic signal control unit connected to the ultrasonic transducer.
  • the ultrasonic signal control unit includes an ultrasonic signal generator and an ultrasonic power amplifier connected to each other, and the ultrasonic signal generator is connected to the ultrasonic transducer.
  • the fundamental frequency of the ultrasonic transducer is 200kHz-4MHz, and the ultrasonic transducer uses magnetically compatible materials.
  • the two-photon microscope is a high-energy mode-locked pulsed laser
  • the pulse width of the two-photon microscope is 100 femtoseconds
  • the frequency of the two-photon microscope can reach 80 to 100 MHz.
  • the ultrasonic transducer is a pMUT novel plane wave ultrasonic transducer, and the ultrasonic transducer is based on lithium sulfate, and the piezoelectric material is fixed by photolithography.
  • the beneficial effect of the meningeal lymphatic vessel stimulation device lies in:
  • the meningeal lymphatic vessel stimulation device provided by this application can quickly locate the meningeal lymphatic vessel and visually observe the curative effect and safety of ultrasound regulation.
  • the meningeal lymphatic vessel stimulation device provided in this application is a visual wearable meningeal lymphatic vessel stimulation device.
  • the meningeal lymphatic vessel stimulation device provided by the present application is easy to use and real-time, and can identify meningeal lymphatic vessels more quickly and accurately, guide ultrasound to regulate them, and at the same time, observe changes in their functional activities in real time.
  • Fig. 1 is a schematic diagram of the workflow of the meningeal lymphatic vessel stimulating device of the present application
  • Fig. 2 is a schematic structural diagram of the meningeal lymphatic vessel stimulating device of the present application.
  • the present application provides a meningeal lymphatic vessel stimulation device, which includes a sequentially connected two-photon imaging module, a precise control module and a feedback evaluation module 4, and the feedback evaluation module 4 is connected to the two-photon imaging module;
  • the two-photon imaging module is used to locate, mark and image the meningeal lymphatic vessels 5, and transmit the images to the feedback evaluation module 4.
  • the precise control module is used to precisely control the meningeal lymphatic vessels 5.
  • the feedback assessment module 4 It is used to observe the functional changes of meningeal lymphatic vessels 5 in real time, and adjust the parameters of the precise control module through the observation results.
  • the meningeal lymphatic vessel 5 is positioned and marked by the two-photon imaging module, and the meningeal lymphatic vessel 5 is precisely regulated by exciting ultrasound through the precise control module. At the same time, the activity of the meningeal lymphatic vessel 5 is observed by the two-photon imaging module.
  • the feedback evaluation module 4 transmits the image to the upper computer processing system in real time through the two-photon imaging module, and evaluates the curative effect of ultrasound regulating meningeal lymphatic vessels 5 in real time.
  • the two-photon imaging module is a two-photon perspective imaging module 1, the two-photon perspective imaging module 1 includes a two-photon microscope, the precise control module includes an ultrasonic stimulation unit 3, and the ultrasonic stimulation unit 3 includes an ultrasonic transducer energy device 8, the feedback evaluation module 4 includes an image processor 11, a data memory and a display connected in sequence, the image processor 11 is connected to the display, the two-photon microscope is connected to the image processor 11, The two-photon microscope is connected with the ultrasonic transducer.
  • the meningeal lymphatic vessels are located and marked by a two-photon microscope, and the meningeal lymphatic vessels are precisely regulated by exciting ultrasound through the ultrasonic transducer 8.
  • the personnel can modify the ultrasound stimulation parameters by their efficacy to obtain the best effect.
  • the two-photon microscope is provided with a high permeability lithium sulfate lens 7, and the excitation light of the two-photon microscope passes through the high permeability lithium sulfate lens 7, so that the excitation light passes through without damage, and the imaging effect to the meningeal lymphatic vessels 5 is enhanced.
  • the ultrasonic transducer 8 is connected to the coupling carrier 6, the coupling carrier 6 includes several resistance circuits, the coupling carrier 6 provides a fixed carrier for the ultrasonic transducer, and the coupling carrier 6 adjusts the resistance matching circuit.
  • the coupling carrier 6 is an important part of the ultrasonic stimulation unit 3 , which can adjust the resistance of the circuit of the ultrasonic transducer 8 to maximize its performance and provide a good carrier for the ultrasonic transducer 8 .
  • the fixed base of the coupling carrier 6 is preferably made of lithium sulfate as the main material, but not limited to other types of materials.
  • the preferred resistance range of the coupling carrier 6 material is 50 ⁇ .
  • the ultrasonic transducer 8 is made of piezoelectric material, and the ultrasonic transducer 8 converts electrical energy into mechanical vibration through the piezoelectric effect to generate ultrasonic waves.
  • the precise regulation module also includes an ultrasonic signal control unit 2 connected to the ultrasonic transducer 8 .
  • the ultrasonic signal control unit 2 includes an ultrasonic signal generator and an ultrasonic power amplifier connected to each other, and the ultrasonic signal generator is connected to the ultrasonic transducer 8 .
  • the ultrasonic parameters are controlled by a signal generator and the output power is adjusted by a power amplifier.
  • the ultrasonic signal generator band preferably has a frequency range of 20 kHz to 40 MHz, but is not limited to ultrasonic signal generators in other frequency ranges.
  • the fundamental frequency of the ultrasonic transducer 8 is 200kHz-4MHz, and the ultrasonic transducer 8 is made of magnetically compatible materials.
  • ultrasonic transducers with different frequencies, different focusing effects, different output energies, and different focal spot sizes and focal lengths can be selected, and ultrasonic transducers with a fundamental frequency of 200kHz to 4MHz are preferred. 8, but not limited to the above parameters.
  • the material of the ultrasonic transducer 8 is preferably a magnetically compatible material, but not limited to other materials.
  • the two-photon microscope is a high-energy mode-locked pulsed laser
  • the pulse width of the two-photon microscope is 100 femtoseconds
  • the frequency of the two-photon microscope can reach 80 to 100 MHz.
  • the ultrasonic transducer 8 is a new pMUT plane wave ultrasonic transducer, the ultrasonic transducer 8 is based on lithium sulfate, and the piezoelectric material is fixed by photolithography.
  • the ultrasonic transducer 8 preferably uses the pMUT novel plane wave ultrasonic transducer, but is not limited to other types of ultrasonic transducers that can meet the usage requirements.
  • the material of the ultrasonic transducer 8 is preferably based on lithium sulfate, and the piezoelectric material is fixed by photolithography, but it is not limited to other types of piezoelectric materials and processing techniques.
  • the two-photon perspective imaging module 1 includes a two-photon microscope and a high-permeability lithium sulfate lens 7.
  • the excitation light of the two-photon microscope reaches the meningeal lymphatic vessels through the high-permeability lithium sulfate lens 7 to achieve precise positioning.
  • Ultrasonic signal control unit 2 researchers can set ultrasonic parameters and output power through the ultrasonic signal control unit 2, complete precise positioning in the two-photon perspective imaging module 1 and trigger the work of the ultrasonic signal control unit 2, and set the preset ultrasonic parameters and The corresponding output power is transmitted to the ultrasound stimulation unit 3 .
  • the ultrasonic stimulation unit 3 includes an ultrasonic transducer 8 and a coupling carrier 6.
  • the ultrasonic transducer 8 After receiving the signal from the ultrasonic signal control unit 2, the ultrasonic transducer 8 converts the electrical signal into an ultrasonic signal, and transmits the ultrasonic parameters together with the coupling carrier 6. To the meningeal lymphatic vessels, regulate the function of meningeal lymphatic vessels.
  • the feedback evaluation module 4 includes a two-photon imaging processing system. When the ultrasonic stimulation unit 3 outputs ultrasound to regulate the activity of meningeal lymphatic vessels, the functional changes of meningeal lymphatic vessels are observed in real time through a two-photon microscope, and the results are transmitted to the display. effect, adjust the ultrasound parameters.
  • the coupling carrier 6 is mainly made of lithium sulfate, which contains different resistance circuits, and is used to provide a fixed carrier and a matching circuit for adjusting resistance for the ultrasonic transducer 8.
  • the high-permeability lithium sulfate lens 7 in the two-photon perspective imaging module has It is beneficial for the excitation light source of the two-photon microscope to pass through and reach the meningeal lymphatic vessel 5; the ultrasonic transducer 8 in the ultrasonic stimulation unit 3 converts the electrical signal into an ultrasonic signal, and transmits the ultrasonic energy to the meningeal lymphatic vessel; the skull 9 is for protecting The bony structure of the brain, the meningeal lymphatic vessels 5 are attached to the skull 9; the ultrasonic signal control unit 2, including an ultrasonic signal generator and a power amplifier, is used to generate regular electrical signals, enhance and amplify the electrical signals, and transmit energy to the ultrasonic transducer 8; the connecting cable 11 is used to connect the ultrasonic signal control unit 2 and the ultrasonic transducer 8; the image processing system 12 in the feedback evaluation module, including a computer, data storage and central processing unit, etc., can be online in real time The image signals collected by the two-photon microscope are processed,
  • This application is a device for ultrasonic intervention of meningeal lymphatic vessels, and develops a system and related research programs that combine with two-photon imaging technology to evaluate the effect of ultrasonic regulation in real time.

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Abstract

A meningeal lymphatic vessel stimulation device comprises a two-photon imaging module, a precise regulation and control module, and a feedback evaluation module (4) connected in sequence; the feedback evaluation module (4) is connected to the two-photon imaging module; the two-photon imaging module is used for positioning, marking and imaging meningeal lymphatic vessels (5), and transmitting images to the feedback evaluation module (4); the precise regulation and control module is used for precisely regulating and controlling the meningeal lymphatic vessels (5); and the feedback evaluation module (4) is used for observing functional changes of the meningeal lymphatic vessels (5) in real time, and adjusting parameters of the precise regulation and control module according to the observation result. According to the device, the morphology of a cell membrane can be slightly changed by means of ultrasonic radiation force, so that ion channels on the cell membrane are activated to secrete related proteins, thereby influencing the overall functional activities. The locations of the meningeal lymphatic vessels (5) can be quickly positioned, and the curative effect and safety of ultrasonic regulation and control can be visually observed.

Description

一种脑膜***刺激装置A meningeal lymphatic vessel stimulation device 技术领域technical field
本申请属于生物医学技术领域，特别是涉及一种脑膜***刺激装置。The application belongs to the technical field of biomedicine, and in particular relates to a meningeal lymphatic vessel stimulating device.
背景技术Background technique
大脑是人体重要的控制中枢，大脑的功能活动与人体的各项活动密不可分，大脑是活动的同时，会产生各种代谢产物，这些代谢产物可以通过脑脊液循环回流到血液中，既往认为大脑不存在淋巴内皮细胞，中枢神经***缺乏***结构。随着对大脑深入探索，目前研究发现并证实大脑中存在着***及淋巴循环***，对于大脑内的各种代谢废物的清除有着重要的意义。The brain is an important control center of the human body. The functional activities of the brain are inseparable from the various activities of the human body. When the brain is active, it will produce various metabolites. These metabolites can flow back into the blood through the cerebrospinal fluid circulation. Lymphatic endothelial cells are present, and the central nervous system lacks lymphatic structures. With the in-depth exploration of the brain, the current research has discovered and confirmed the existence of lymphatic vessels and lymphatic circulation system in the brain, which is of great significance for the removal of various metabolic wastes in the brain.
目前已经发现多种神经退行性疾病与代谢废物的清除有关，如目前给社会造成严重负担的阿尔兹海默氏病的病因之一是由于β淀粉蛋白的清除存在异常。研究发现，脑膜***是β蛋白清除的重要途径。It has been found that a variety of neurodegenerative diseases are related to the removal of metabolic waste. For example, one of the causes of Alzheimer's disease, which currently poses a serious burden to society, is due to the abnormal removal of β-amyloid protein. Studies have found that meningeal lymphatic vessels are an important way for β protein clearance.
随着对脑膜***的功能研究深入，针对脑膜***的开展治疗相关研究也是目前的研究热点之一，包括药物及物理因素都是重要手段。With the in-depth research on the function of meningeal lymphatic vessels, research on the treatment of meningeal lymphatic vessels is also one of the current research hotspots, including drugs and physical factors are important means.
神经调控技术是基于包括电、磁、光、声在内的多种物理因素构成可以调节神经活动的关键技术。其中，超声神经调控技术是具有高精度、无创性的新一代神经调控技术，目前已经证实与电、磁、光一样可以调节神经元活动。除了神经元之外，超声对其它组织及器官也同样具有调控作用。但是对于与脑膜***相关的疾病，目前还缺乏有效的调控方式。一方面，由于脑膜***位置特殊，缺乏直接的观察手段，另一方面，目前超声换能器聚焦深度较深，难以覆盖紧贴颅骨的脑膜***，给开展超声对脑膜***相关研究带来了重大难题。Neuromodulation technology is a key technology that can regulate neural activity based on various physical factors including electricity, magnetism, light, and sound. Among them, ultrasonic neuromodulation technology is a new generation of neuromodulation technology with high precision and non-invasiveness. It has been confirmed that it can regulate neuron activity like electricity, magnetism and light. In addition to neurons, ultrasound can also regulate other tissues and organs. However, there is still a lack of effective regulation methods for diseases related to meningeal lymphatic vessels. On the one hand, due to the special location of the meningeal lymphatic vessels, there is a lack of direct observation methods. On the other hand, the depth of focus of the current ultrasonic transducer is too deep to cover the meningeal lymphatic vessels close to the skull. Here comes the big problem.
发明内容Contents of the invention
1.要解决的技术问题1. Technical problems to be solved
基于目前认为，超声辐射力是调控神经及细胞活动的重要因素之一，其是在超声波在传播过程中，由于介质的吸收、反射或者散射等作用，使超声波的声能向动能转化，对超声传播的介质产生的力。超声辐射力可以使细胞膜的形态发生微小变化，使细胞膜上的离子通道被激活，分泌相关蛋白，影响整体的功能活动的问题，本申请提供了一种脑膜***刺激装置。Based on current beliefs, ultrasonic radiation force is one of the important factors to regulate nerve and cell activities. During the propagation of ultrasonic waves, due to the absorption, reflection or scattering of the medium, the acoustic energy of ultrasonic waves is transformed into kinetic energy, which affects the The force exerted by the medium of propagation. Ultrasonic radiation force can cause slight changes in the morphology of the cell membrane, activate ion channels on the cell membrane, secrete related proteins, and affect the overall functional activities. This application provides a meningeal lymphatic vessel stimulation device.
2.技术方案2. Technical solution
为了达到上述的目的，本申请提供了一种脑膜***刺激装置，包括依次连接的双光子 成像模块、精准调控模块和反馈评估模块，所述反馈评估模块与所述双光子成像模块连接；所述双光子成像模块用于对脑膜***定位、标记和成像，并将图像传送至反馈评估模块，所述精准调控模块用于对脑膜***精准调控，所述反馈评估模块用于实时观察脑膜***功能变化，通过观察结果调节精准调控模块的参数。In order to achieve the above purpose, the present application provides a meningeal lymphatic vessel stimulation device, including a sequentially connected two-photon imaging module, a precise regulation module and a feedback evaluation module, the feedback evaluation module is connected to the two-photon imaging module; The two-photon imaging module is used to locate, mark and image the meningeal lymphatic vessels, and transmit the image to the feedback evaluation module. The precise control module is used for precise control of the meningeal lymphatic vessels. Changes in lymphatic vessel function, adjust the parameters of the precise regulation module through observation results.
本申请提供的另一种实施方式为：所述双光子成像模块为双光子透视成像模块，所述双光子透视成像模块包括双光子显微镜，所述精准调控模块包括超声刺激单元，所述超声刺激单元包括超声换能器，所述反馈评估模块包括依次连接的图像处理器、数据存储器和显示器，所述图像处理器与所述显示器连接，所述双光子显微镜与所述图像处理器连接，所述双光子显微镜与所述超声换能器连接。Another embodiment provided by the present application is: the two-photon imaging module is a two-photon perspective imaging module, the two-photon perspective imaging module includes a two-photon microscope, the precise control module includes an ultrasonic stimulation unit, and the ultrasonic stimulation The unit includes an ultrasonic transducer, the feedback evaluation module includes an image processor, a data storage and a display connected in sequence, the image processor is connected to the display, the two-photon microscope is connected to the image processor, and The two-photon microscope is connected with the ultrasonic transducer.
本申请提供的另一种实施方式为：所述双光子显微镜上设置有高透硫酸锂透镜，所述双光子显微镜激发光通过高透硫酸锂透镜，使得激发光无损通过，增强对脑膜***的成像效果。Another embodiment provided by the present application is: the two-photon microscope is provided with a high-permeability lithium sulfate lens, and the excitation light of the two-photon microscope passes through the high-permeability lithium sulfate lens, so that the excitation light passes through without damage and enhances the stimulation of meningeal lymphatic vessels. imaging effect.
本申请提供的另一种实施方式为：所述超声换能器与耦合载体连接，所述耦合载体包括若干电阻电路，所述耦合载体为所述超声换能器提供固定载体，所述耦合载体调节电阻的匹配电路。Another embodiment provided by the present application is: the ultrasonic transducer is connected to a coupling carrier, the coupling carrier includes several resistance circuits, the coupling carrier provides a fixed carrier for the ultrasonic transducer, and the coupling carrier Matching circuit for adjusting resistors.
本申请提供的另一种实施方式为：所述超声换能器采用压电材料制备，所述超声换能器通过压电效应将电能转化为机械振动，产生超声波。Another embodiment provided by the present application is: the ultrasonic transducer is made of piezoelectric material, and the ultrasonic transducer converts electrical energy into mechanical vibration through the piezoelectric effect to generate ultrasonic waves.
本申请提供的另一种实施方式为：所述精准调控模块还包括超声信号控制单元，所述超声信号控制单元与所述超声换能器连接。Another implementation manner provided by the present application is: the precise control module further includes an ultrasonic signal control unit connected to the ultrasonic transducer.
本申请提供的另一种实施方式为：所述超声信号控制单元包括相互连接的超声信号发生器和超声功率放大器，所述超声信号发生器与所述超声换能器连接。Another embodiment provided by the present application is: the ultrasonic signal control unit includes an ultrasonic signal generator and an ultrasonic power amplifier connected to each other, and the ultrasonic signal generator is connected to the ultrasonic transducer.
本申请提供的另一种实施方式为：所述超声换能器基频为200kHz～4MHz，所述超声换能器采用磁兼容材料。Another implementation manner provided by the present application is: the fundamental frequency of the ultrasonic transducer is 200kHz-4MHz, and the ultrasonic transducer uses magnetically compatible materials.
本申请提供的另一种实施方式为：所述双光子显微镜为高能量锁模脉冲激光器，所述双光子显微镜脉冲宽度为100飞秒，所述双光子显微镜频率能够达到80至100兆赫。Another embodiment provided by the present application is: the two-photon microscope is a high-energy mode-locked pulsed laser, the pulse width of the two-photon microscope is 100 femtoseconds, and the frequency of the two-photon microscope can reach 80 to 100 MHz.
本申请提供的另一种实施方式为：所述超声换能器为pMUT新型平面波超声换能器，所述超声换能器以硫酸锂为基底，通过光刻技术固定压电材料。Another embodiment provided by the present application is: the ultrasonic transducer is a pMUT novel plane wave ultrasonic transducer, and the ultrasonic transducer is based on lithium sulfate, and the piezoelectric material is fixed by photolithography.
3.有益效果3. Beneficial effect
与现有技术相比，本申请提供的脑膜***刺激装置的有益效果在于：Compared with the prior art, the beneficial effect of the meningeal lymphatic vessel stimulation device provided by the present application lies in:
本申请提供的脑膜***刺激装置，可以快速定位脑膜***位置及可视化观察超声调 控的疗效及安全性。The meningeal lymphatic vessel stimulation device provided by this application can quickly locate the meningeal lymphatic vessel and visually observe the curative effect and safety of ultrasound regulation.
本申请提供的脑膜***刺激装置，为一种可视化穿戴式脑膜***刺激装置。The meningeal lymphatic vessel stimulation device provided in this application is a visual wearable meningeal lymphatic vessel stimulation device.
本申请提供的脑膜***刺激装置，具有易用性及实时性，能够更快速、准确识别脑膜***，引导超声对其进行调控，同时，可以实时观察其功能活动变化。The meningeal lymphatic vessel stimulation device provided by the present application is easy to use and real-time, and can identify meningeal lymphatic vessels more quickly and accurately, guide ultrasound to regulate them, and at the same time, observe changes in their functional activities in real time.
附图说明Description of drawings
图1是本申请的脑膜***刺激装置工作流程示意图；Fig. 1 is a schematic diagram of the workflow of the meningeal lymphatic vessel stimulating device of the present application;
图2是本申请的脑膜***刺激装置结构示意图。Fig. 2 is a schematic structural diagram of the meningeal lymphatic vessel stimulating device of the present application.
具体实施方式Detailed ways
在下文中，将参考附图对本申请的具体实施例进行详细地描述，依照这些详细的描述，所属领域技术人员能够清楚地理解本申请，并能够实施本申请。在不违背本申请原理的情况下，各个不同的实施例中的特征可以进行组合以获得新的实施方式，或者替代某些实施例中的某些特征，获得其它优选的实施方式。Hereinafter, specific embodiments of the present application will be described in detail with reference to the accompanying drawings. According to these detailed descriptions, those skilled in the art can clearly understand the present application and can implement the present application. Without departing from the principle of the present application, the features in different embodiments can be combined to obtain new implementations, or some features in certain embodiments can be replaced to obtain other preferred implementations.
参见图1～2，本申请提供一种脑膜***刺激装置，包括依次连接的双光子成像模块、精准调控模块和反馈评估模块4，所述反馈评估模块4与所述双光子成像模块连接；所述双光子成像模块用于对脑膜***5定位、标记和成像，并将图像传送至反馈评估模块4，所述精准调控模块用于对脑膜***5精准调控，所述反馈评估模块4用于实时观察脑膜***5功能变化，通过观察结果调节精准调控模块的参数。Referring to Figures 1-2, the present application provides a meningeal lymphatic vessel stimulation device, which includes a sequentially connected two-photon imaging module, a precise control module and a feedback evaluation module 4, and the feedback evaluation module 4 is connected to the two-photon imaging module; The two-photon imaging module is used to locate, mark and image the meningeal lymphatic vessels 5, and transmit the images to the feedback evaluation module 4. The precise control module is used to precisely control the meningeal lymphatic vessels 5. The feedback assessment module 4 It is used to observe the functional changes of meningeal lymphatic vessels 5 in real time, and adjust the parameters of the precise control module through the observation results.
通过双光子成像模块定位脑膜***5并标记，通过精准调控模块激发超声波对脑膜***5实现精准调控，同时，通过双光子成像模块观察脑膜***5的活动。反馈评估模块4通过双光子成像模块将图像实时传输到上位计算机处理***，实时评估超声调控脑膜***5的疗效。The meningeal lymphatic vessel 5 is positioned and marked by the two-photon imaging module, and the meningeal lymphatic vessel 5 is precisely regulated by exciting ultrasound through the precise control module. At the same time, the activity of the meningeal lymphatic vessel 5 is observed by the two-photon imaging module. The feedback evaluation module 4 transmits the image to the upper computer processing system in real time through the two-photon imaging module, and evaluates the curative effect of ultrasound regulating meningeal lymphatic vessels 5 in real time.
进一步地，所述双光子成像模块为双光子透视成像模块1，所述双光子透视成像模块1包括双光子显微镜，所述精准调控模块包括超声刺激单元3，所述超声刺激单元3包括超声换能器8，所述反馈评估模块4包括依次连接的图像处理器11、数据存储器和显示器，所述图像处理器11与所述显示器连接，所述双光子显微镜与所述图像处理器11连接，所述双光子显微镜与所述超声换能器连8接。Further, the two-photon imaging module is a two-photon perspective imaging module 1, the two-photon perspective imaging module 1 includes a two-photon microscope, the precise control module includes an ultrasonic stimulation unit 3, and the ultrasonic stimulation unit 3 includes an ultrasonic transducer energy device 8, the feedback evaluation module 4 includes an image processor 11, a data memory and a display connected in sequence, the image processor 11 is connected to the display, the two-photon microscope is connected to the image processor 11, The two-photon microscope is connected with the ultrasonic transducer.
通过双光子显微镜定位脑膜***并标记，通过超声换能器8激发超声波对脑膜***实现精准调控，同时，通过双光子显微镜观察脑膜***5的活动并通过双方评估超声调控效果，使研究人员可以通过其疗效修正超声刺激参数以获得最佳效果。The meningeal lymphatic vessels are located and marked by a two-photon microscope, and the meningeal lymphatic vessels are precisely regulated by exciting ultrasound through the ultrasonic transducer 8. The personnel can modify the ultrasound stimulation parameters by their efficacy to obtain the best effect.
进一步地，所述双光子显微镜上设置有高透硫酸锂透镜7，所述双光子显微镜激发光通 过高透硫酸锂透镜7，使得激发光无损通过，增强对脑膜***5的成像效果。Further, the two-photon microscope is provided with a high permeability lithium sulfate lens 7, and the excitation light of the two-photon microscope passes through the high permeability lithium sulfate lens 7, so that the excitation light passes through without damage, and the imaging effect to the meningeal lymphatic vessels 5 is enhanced.
进一步地，所述超声换能器8与耦合载体6连接，所述耦合载体6包括若干电阻电路，所述耦合载体6为所述超声换能器提供固定载体，所述耦合载体6调节电阻的匹配电路。耦合载体6是超声刺激单元3重要组成部分，可以有将调节超声换能器8电路的电阻，使其实现效能最大化，同时，给超声换能器8提供良好的载体。Further, the ultrasonic transducer 8 is connected to the coupling carrier 6, the coupling carrier 6 includes several resistance circuits, the coupling carrier 6 provides a fixed carrier for the ultrasonic transducer, and the coupling carrier 6 adjusts the resistance matching circuit. The coupling carrier 6 is an important part of the ultrasonic stimulation unit 3 , which can adjust the resistance of the circuit of the ultrasonic transducer 8 to maximize its performance and provide a good carrier for the ultrasonic transducer 8 .
耦合载体6固定基底优选采用硫酸锂作为主要材料，但不限于其它类型的材料。The fixed base of the coupling carrier 6 is preferably made of lithium sulfate as the main material, but not limited to other types of materials.
耦合载体6材料优选的电阻范围为50Ω。The preferred resistance range of the coupling carrier 6 material is 50Ω.
进一步地，所述超声换能器8采用压电材料制备，所述超声换能器8通过压电效应将电能转化为机械振动，产生超声波。Further, the ultrasonic transducer 8 is made of piezoelectric material, and the ultrasonic transducer 8 converts electrical energy into mechanical vibration through the piezoelectric effect to generate ultrasonic waves.
进一步地，所述精准调控模块还包括超声信号控制单元2，所述超声信号控制单元2与所述超声换能器8连接。Further, the precise regulation module also includes an ultrasonic signal control unit 2 connected to the ultrasonic transducer 8 .
进一步地，所述超声信号控制单元2包括相互连接的超声信号发生器和超声功率放大器，所述超声信号发生器与所述超声换能器8连接。通过信号发生器控制超声参数并通过功率放大器调节输出功率。Further, the ultrasonic signal control unit 2 includes an ultrasonic signal generator and an ultrasonic power amplifier connected to each other, and the ultrasonic signal generator is connected to the ultrasonic transducer 8 . The ultrasonic parameters are controlled by a signal generator and the output power is adjusted by a power amplifier.
超声信号发生器带优选频率范围在20kHz到40MHz，但不限于其它频率范围的超声信号发生器。The ultrasonic signal generator band preferably has a frequency range of 20 kHz to 40 MHz, but is not limited to ultrasonic signal generators in other frequency ranges.
进一步地，所述超声换能器8基频为200kHz～4MHz，所述超声换能器8采用磁兼容材料。Further, the fundamental frequency of the ultrasonic transducer 8 is 200kHz-4MHz, and the ultrasonic transducer 8 is made of magnetically compatible materials.
刺激超声换能器8根据研究与治疗需要，可以选择不同频率、不同聚焦效果，不同输出能量和不同焦斑大小和焦距的超声换能器，优选的使用基频为200kHz～4MHz的超声换能器8，但不限于上述的参数。在超声换能器8材料上，优选为磁兼容材料，但不限于选择其它材料。Stimulating ultrasonic transducer 8 According to the needs of research and treatment, ultrasonic transducers with different frequencies, different focusing effects, different output energies, and different focal spot sizes and focal lengths can be selected, and ultrasonic transducers with a fundamental frequency of 200kHz to 4MHz are preferred. 8, but not limited to the above parameters. The material of the ultrasonic transducer 8 is preferably a magnetically compatible material, but not limited to other materials.
进一步地，所述双光子显微镜为高能量锁模脉冲激光器，所述双光子显微镜脉冲宽度为100飞秒，所述双光子显微镜频率能够达到80至100兆赫。Further, the two-photon microscope is a high-energy mode-locked pulsed laser, the pulse width of the two-photon microscope is 100 femtoseconds, and the frequency of the two-photon microscope can reach 80 to 100 MHz.
进一步地，所述超声换能器8为pMUT新型平面波超声换能器，所述超声换能器8以硫酸锂为基底，通过光刻技术固定压电材料。Further, the ultrasonic transducer 8 is a new pMUT plane wave ultrasonic transducer, the ultrasonic transducer 8 is based on lithium sulfate, and the piezoelectric material is fixed by photolithography.
超声换能器8优选的使用pMUT新型平面波超声换能器，但不限于使用可以达到使用需求的其它类型超声换能器。超声换能器8材料优选的是以硫酸锂为基底，通过光刻技术固定压电材料，但不限于使用其它类型的压电材料及加工工艺。The ultrasonic transducer 8 preferably uses the pMUT novel plane wave ultrasonic transducer, but is not limited to other types of ultrasonic transducers that can meet the usage requirements. The material of the ultrasonic transducer 8 is preferably based on lithium sulfate, and the piezoelectric material is fixed by photolithography, but it is not limited to other types of piezoelectric materials and processing techniques.
实施例Example
如图1所示，双光子透视成像模块1，包含双光子显微镜及高透硫酸锂透镜7，双光子显微镜激发光通过高透硫酸锂透镜7到达脑膜***实现精准定位。超声信号控制单元2，研究人员可以通过超声信号控制单元2设置超声参数，并设置输出功率，在双光子透视成像模块1完成精准定位并触发超声信号控制单元2工作，将预设的超声参数及对应的输出功率传输到超声刺激单元3。超声刺激单元3，包括超声换能器8及耦合载体6，在接收到超声信号控制单元2的信号后，超声换能器8将电信号转化为超声信号，与耦合载体6一起将超声参量传送到脑膜***上，调控脑膜***的功能。反馈评估模块4包含双光子成像处理***，在超声刺激单元3输出超声调控脑膜***活动时，通过双光子显微镜实时观察脑膜***功能变化，将结果在传送到显示器，研究人员通过观察超声刺激效果，调节超声参数。As shown in FIG. 1, the two-photon perspective imaging module 1 includes a two-photon microscope and a high-permeability lithium sulfate lens 7. The excitation light of the two-photon microscope reaches the meningeal lymphatic vessels through the high-permeability lithium sulfate lens 7 to achieve precise positioning. Ultrasonic signal control unit 2, researchers can set ultrasonic parameters and output power through the ultrasonic signal control unit 2, complete precise positioning in the two-photon perspective imaging module 1 and trigger the work of the ultrasonic signal control unit 2, and set the preset ultrasonic parameters and The corresponding output power is transmitted to the ultrasound stimulation unit 3 . The ultrasonic stimulation unit 3 includes an ultrasonic transducer 8 and a coupling carrier 6. After receiving the signal from the ultrasonic signal control unit 2, the ultrasonic transducer 8 converts the electrical signal into an ultrasonic signal, and transmits the ultrasonic parameters together with the coupling carrier 6. To the meningeal lymphatic vessels, regulate the function of meningeal lymphatic vessels. The feedback evaluation module 4 includes a two-photon imaging processing system. When the ultrasonic stimulation unit 3 outputs ultrasound to regulate the activity of meningeal lymphatic vessels, the functional changes of meningeal lymphatic vessels are observed in real time through a two-photon microscope, and the results are transmitted to the display. effect, adjust the ultrasound parameters.
如图2所示，颅骨下脑膜***5，脑膜***5处在颅骨骨缝下方，为超声调控的作用目标。耦合载体6，主要材料为硫酸锂，内包含不同的电阻电路，用于为超声换能器8提供固定载体及调节电阻的匹配电路，双光子透视成像模块中的高透硫酸锂透镜7，有利于双光子显微镜的激发光源通过并到达脑膜***5；超声刺激单元3中的超声换能器8，将电信号转化为超声信号，并将超声能量传送到脑膜***上；颅骨9为保护大脑的骨性结构，脑膜***5贴附于颅骨9上；超声信号控制单元2，包含超声信号发生器及功率放大器，用于产生规律的电信号及将电信号增强放大，并将能量传送到超声换能器8上；连接电缆11用于连接超声信号控制单元2及超声换能器8；反馈评估模块中的图像处理***12，包含计算机，数据存储及中央处理器等，可以在线实时处理双光子显微镜采集到的图像信号，数据直观显示在显示器上，研究人员可以评估超声作用效果；连接光纤13将双光子显微镜采集到的数据传送到反馈评估模块4上。As shown in FIG. 2 , the meningeal lymphatic vessels 5 under the skull, the meningeal lymphatic vessels 5 are located below the suture of the skull, and are the targets of ultrasound regulation. The coupling carrier 6 is mainly made of lithium sulfate, which contains different resistance circuits, and is used to provide a fixed carrier and a matching circuit for adjusting resistance for the ultrasonic transducer 8. The high-permeability lithium sulfate lens 7 in the two-photon perspective imaging module has It is beneficial for the excitation light source of the two-photon microscope to pass through and reach the meningeal lymphatic vessel 5; the ultrasonic transducer 8 in the ultrasonic stimulation unit 3 converts the electrical signal into an ultrasonic signal, and transmits the ultrasonic energy to the meningeal lymphatic vessel; the skull 9 is for protecting The bony structure of the brain, the meningeal lymphatic vessels 5 are attached to the skull 9; the ultrasonic signal control unit 2, including an ultrasonic signal generator and a power amplifier, is used to generate regular electrical signals, enhance and amplify the electrical signals, and transmit energy to the ultrasonic transducer 8; the connecting cable 11 is used to connect the ultrasonic signal control unit 2 and the ultrasonic transducer 8; the image processing system 12 in the feedback evaluation module, including a computer, data storage and central processing unit, etc., can be online in real time The image signals collected by the two-photon microscope are processed, and the data are visually displayed on the monitor, and researchers can evaluate the effect of ultrasound; the optical fiber 13 is connected to transmit the data collected by the two-photon microscope to the feedback evaluation module 4 .
首先实现超声对脑膜***5的调控，为相关疾病的研究、治疗提供可靠的装置；另一方面，本装置具有先进的理念，通过结合双光子成像技术，实现脑膜***5可视化，并实时评估超声调控的作用效果，可以为相关研究提供简单、直观的体验。First, realize the regulation of meningeal lymphatic vessels 5 by ultrasound, and provide a reliable device for the research and treatment of related diseases; on the other hand, this device has an advanced concept. Assessing the effect of ultrasound modulation can provide a simple and intuitive experience for related research.
本申请为一种超声干预脑膜***的装置，并且开发一套与双光子成像技术结合，实时评估超超声调控效果的***及相关研究方案。This application is a device for ultrasonic intervention of meningeal lymphatic vessels, and develops a system and related research programs that combine with two-photon imaging technology to evaluate the effect of ultrasonic regulation in real time.
尽管在上文中参考特定的实施例对本申请进行了描述，但是所属领域技术人员应当理解，在本申请公开的原理和范围内，可以针对本申请公开的配置和细节做出许多修改。本申请的保护范围由所附的权利要求来确定，并且权利要求意在涵盖权利要求中技术特征的等同物文字意义或范围所包含的全部修改。Although the present application has been described above with reference to specific embodiments, those skilled in the art should understand that many modifications can be made to the configurations and details disclosed in the present application within the principles and scope disclosed in the present application. The protection scope of the present application is determined by the appended claims, and the claims are intended to cover all modifications included in the equivalent literal meaning or scope of the technical features in the claims.

Claims (10)

  1. 一种脑膜***刺激装置，其特征在于：包括依次连接的双光子成像模块、精准调控模块和反馈评估模块，所述反馈评估模块与所述双光子成像模块连接；所述双光子成像模块用于对脑膜***定位、标记和成像，并将图像传送至反馈评估模块，所述精准调控模块用于对脑膜***精准调控，所述反馈评估模块用于实时观察脑膜***功能变化，通过观察结果调节精准调控模块的参数。A meningeal lymphatic vessel stimulation device, characterized in that: it includes a sequentially connected two-photon imaging module, a precise control module and a feedback evaluation module, the feedback evaluation module is connected to the two-photon imaging module; the two-photon imaging module is used It is used to locate, mark and image the meningeal lymphatic vessels, and transmit the images to the feedback evaluation module. The precise control module is used for precise regulation of the meningeal lymphatic vessels. Observe the results to adjust the parameters of the fine-tuning module.
  2. 如权利要求1所述的脑膜***刺激装置，其特征在于：所述双光子成像模块为双光子透视成像模块，所述双光子透视成像模块包括双光子显微镜，所述精准调控模块包括超声刺激单元，所述超声刺激单元包括超声换能器，所述反馈评估模块包括依次连接的图像处理器、数据存储器和显示器，所述图像处理器与所述显示器连接，所述双光子显微镜与所述图像处理器连接，所述双光子显微镜与所述超声换能器连接。The meningeal lymphatic vessel stimulation device according to claim 1, characterized in that: the two-photon imaging module is a two-photon perspective imaging module, the two-photon perspective imaging module includes a two-photon microscope, and the precise control module includes ultrasonic stimulation unit, the ultrasonic stimulation unit includes an ultrasonic transducer, the feedback evaluation module includes an image processor, a data storage and a display connected in sequence, the image processor is connected to the display, and the two-photon microscope is connected to the The image processor is connected, and the two-photon microscope is connected with the ultrasonic transducer.
  3. 如权利要求2所述的脑膜***刺激装置，其特征在于：所述双光子显微镜上设置有高透硫酸锂透镜，所述双光子显微镜激发光通过高透硫酸锂透镜，使得激发光无损通过，增强对脑膜***的成像效果。The meningeal lymphatic vessel stimulation device according to claim 2, characterized in that: the two-photon microscope is provided with a high-permeability lithium sulfate lens, and the excitation light of the two-photon microscope passes through the high-permeability lithium sulfate lens, so that the excitation light passes through without damage , to enhance the imaging effect of meningeal lymphatic vessels.
  4. 如权利要求2所述的脑膜***刺激装置，其特征在于：所述超声换能器与耦合载体连接，所述耦合载体包括若干电阻电路，所述耦合载体为所述超声换能器提供固定载体，所述耦合载体调节电阻的匹配电路。The meningeal lymphatic vessel stimulating device according to claim 2, characterized in that: the ultrasonic transducer is connected to a coupling carrier, the coupling carrier includes several resistance circuits, and the coupling carrier provides a fixation for the ultrasonic transducer. carrier, the matching circuit of the coupling carrier adjustment resistor.
  5. 如权利要求2所述的脑膜***刺激装置，其特征在于：所述超声换能器采用压电材料制备，所述超声换能器通过压电效应将电能转化为机械振动，产生超声波。The meningeal lymphatic vessel stimulating device according to claim 2, wherein the ultrasonic transducer is made of piezoelectric material, and the ultrasonic transducer converts electrical energy into mechanical vibration through piezoelectric effect to generate ultrasonic waves.
  6. 如权利要求2～5中任一项所述的脑膜***刺激装置，其特征在于：所述精准调控模块还包括超声信号控制单元，所述超声信号控制单元与所述超声换能器连接。The meningeal lymphatic vessel stimulating device according to any one of claims 2 to 5, characterized in that: the precise control module further includes an ultrasonic signal control unit connected to the ultrasonic transducer.
  7. 如权利要求6所述的脑膜***刺激装置，其特征在于：所述超声信号控制单元包括相互连接的超声信号发生器和超声功率放大器，所述超声信号发生器与所述超声换能器连接。The meningeal lymphatic vessel stimulation device according to claim 6, wherein the ultrasonic signal control unit includes an ultrasonic signal generator and an ultrasonic power amplifier connected to each other, and the ultrasonic signal generator is connected to the ultrasonic transducer .
  8. 如权利要求6所述的脑膜***刺激装置，其特征在于：所述超声换能器基频为200kHz～4MHz，所述超声换能器采用磁兼容材料。The meningeal lymphatic vessel stimulating device according to claim 6, characterized in that: the fundamental frequency of the ultrasonic transducer is 200kHz-4MHz, and the ultrasonic transducer is made of magnetically compatible materials.
  9. 如权利要求6所述的脑膜***刺激装置，其特征在于：所述双光子显微镜为高能量锁模脉冲激光器，所述双光子显微镜脉冲宽度为100飞秒，所述双光子显微镜频率能够达到80至100兆赫。The meningeal lymphatic vessel stimulation device according to claim 6, wherein the two-photon microscope is a high-energy mode-locked pulsed laser, the pulse width of the two-photon microscope is 100 femtoseconds, and the frequency of the two-photon microscope can reach 80 to 100 MHz.
  10. 如权利要求6所述的脑膜***刺激装置，其特征在于：所述超声换能器为pMUT新型平面波超声换能器，所述超声换能器以硫酸锂为基底，通过光刻技术固定压电材料。The meningeal lymphatic vessel stimulating device according to claim 6, characterized in that: the ultrasonic transducer is a pMUT novel plane wave ultrasonic transducer, and the ultrasonic transducer is based on lithium sulfate, and the pressure is fixed by photolithography technology. electrical material.
PCT/CN2021/137470 2021-12-13 2021-12-13 Meningeal lymphatic vessel stimulation device WO2023108348A1 (en)

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