Device for noninvasive regulation and control of blood brain barrier in non-invasive pulsed electric field

Abstract

The invention discloses a device for noninvasive regulation and control of a blood brain barrier in a non-invasive pulsed electric field. The device comprises a high-voltage pulse generator, a plurality of treatment electrodes and a fixing device. The connection tightness of endothelial cells is adjusted through a high-voltage short-pulse electric field, local regulation and control of the brain area are achieved in combination with electrode design, pulse parameters are flexibly adjusted to balance the effect and damage, and a new non-invasive physical treatment means is provided for assisting drug cross-blood-brain-barrier delivery. Compared with focused ultrasound, the multi-mechanism synergistic effect (electroporation effect and bioelectrochemical effect) is utilized instead of depending on the mechanical effect of exogenous microbubbles, so that the safety risk is remarkably reduced. The system has the advantages of noninvasiveness, safety and space flexibility, and can be opened for a long time. The non-invasive electrode is used for delivering instantaneous high-voltage electric pulses, which is different from conventional low-voltage long-time electric stimulation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of brain disease treatment, and particularly relates to a device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier. BACKGROUND

[0002] Focused Ultrasound (FUS) can temporarily and reversibly open the blood-brain barrier (BBB) by generating biological effects in the target area through high-intensity sound waves combined with microbubbles. FUS usually uses an ultrasonic transducer to emit high-frequency sound waves (usually 0.2-1.5 MHz), focuses on the target point (focal spot diameter about 1-3 mm) through the skull, and forms a high-intensity sound field (peak negative pressure 0.5-3 MPa). Microbubbles undergo inertial cavitation or stable cavitation in the sound field, generating mechanical forces to destroy the tight junctions (occludin, claudin-5) of vascular endothelial cells, increase the permeability of the BBB, and open for about 2-6 hours.

[0003] FUS requires strict control of sound pressure / microbubble dose, and the microbubble cavitation effect threshold is narrow. Excessive amount can easily lead to capillary rupture. Its opening time window is short, usually less than 6 hours, which is difficult to match the release period of slow-release drugs. The focal spot area is small (millimeter level), and multiple scans are required for large-scale opening, prolonging the treatment time.

[0004] Tumor Treating Fields (TTF) indirectly affect the permeability of the BBB (possibly by regulating tight junction proteins) through low-frequency alternating electric fields (100-300 kHz), but there is insufficient research on regulating the permeability of the BBB, and the mechanism of regulating the BBB is not clear. The effect is uncontrollable. In addition, TTF requires long-term wearing for treatment, which can easily cause skin inflammation.

[0005] The existing electrode scheme of pulsed electric field is mostly minimally invasive design (needle electrode), which cannot achieve completely non-invasive treatment. SUMMARY

[0006] The purpose of the present application is to provide a device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, comprising: a high-voltage pulse generator, a plurality of treatment electrodes, and a fixing device.

[0007] The high-voltage pulse generator is used to generate a pulse signal and transmit the pulse signal to the treatment electrodes.

[0008] The voltage amplitude of the pulse signal is greater than or equal to 500V, and the pulse width is less than 100us.

[0009] The treatment electrode is attached to the outer surface of the brain of the organism to form a pulsed electric field in the brain of the organism to regulate the blood-brain barrier of the organism.

[0010] The fixing device is used to fix the organism and the treatment electrode.

[0011] Further, the high-voltage pulse generator comprises a human-computer interaction interface, an FPGA module, a Marx generator, a low-voltage power supply module and a high-voltage power supply module.

[0012] The human-computer interaction interface is used to obtain pulse parameters and transmit the pulse parameters to the FPGA module.

[0013] The FPGA module is used to generate pulse control signals and transmit the pulse control signals to the Marx generator.

[0014] The Marx generator is used to generate pulse signals.

[0015] The low-voltage power supply module supplies power to the human-computer interaction interface, the FPGA module and the Marx generator.

[0016] The low-voltage power supply module provides a voltage amplitude range of 0-24V.

[0017] The high-voltage power supply module supplies power to the Marx generator.

[0018] The high-voltage power supply module provides a voltage amplitude range of 0-1kV.

[0019] Further, the pulse parameters include pulse field strength, pulse width, frequency and action time.

[0020] Further, the pulse field strength is less than or equal to 10kV / cm.

[0021] Further, the treatment electrode comprises a gold-plated copper disc.

[0022] Further, when the treatment electrode is attached to the brain of the organism, the surface of the treatment electrode is uniformly coated with conductive paste.

[0023] Further, the regulation of the blood-brain barrier of the organism includes two-electrode regulation and multi-electrode regulation.

[0024] For two-electrode regulation, the fixing device adopts a two-end clamping type fixing device.

[0025] For multi-electrode regulation, the fixing device adopts a multi-electrode binding type fixing device.

[0026] Further, the two-end clamping type fixing device comprises four fixed columns, two movable columns and an operation table.

[0027] Four fixed columns are respectively fixedly installed at four corners of the operation table.

[0028] The organism is placed on the operation table, and the limbs of the organism are fixed to the four fixed columns through the live rope sleeves.

[0029] The treatment electrode is fixed on the two movable columns.

[0030] The height and the interval of the two movable columns are adjusted so that the treatment electrode is close to the two sides of the brain of the organism.

[0031] Further, the multi-electrode binding type fixing device comprises four fixed columns, a binding belt and an operation table.

[0032] Four fixed columns are respectively fixedly installed at four corners of the operation table.

[0033] The organism is placed on the operation table, and the limbs of the organism are fixed to the four fixed columns through the live rope sleeves.

[0034] The treatment electrode is fixed on the two movable columns.

[0035] The technical effect of the present application is self-evident. The present application adjusts the tightness of endothelial cell connection through high-voltage short-pulse electric field (PEF), realizes local regulation of brain area in combination with electrode design, flexibly adjusts pulse parameters to balance effect and damage, and provides a new non-invasive physical treatment method for assisting drug delivery across blood-brain barrier.

[0036] Compared with focused ultrasound (FUS), the present application utilizes multi-mechanism synergistic effect (electroporation effect + bioelectrochemical effect) instead of relying on the mechanical effect of exogenous microbubbles, thereby significantly reducing the safety risk.

[0037] The present application utilizes non-invasive electrodes to deliver transient high-voltage electric pulses (voltage greater than or equal to 500V, pulse width less than 100us), which is different from the low-voltage long-time electric stimulation (deep brain stimulation frequency 1Hz-10kHz, voltage 0.1V-10V / 1mA-20mA; tumor treatment electric field frequency 100kHz-300kHz, ±25V-100V sine wave) of the non-invasive electrodes in the past.

[0038] The present application has the following beneficial effects:

[0039] 1. Non-invasiveness: the pulse electric field delivery mode through the skin close to the electrode avoids brain tissue damage caused by needle electrodes.

[0040] 2. Long-term opening: BBB opening can be completed after several minutes of treatment, and the permeability window period is maintained for ≥12 hours.

[0041] 3. Safety: controllable electric field parameters, no risk of bleeding caused by microbubbles.

[0042] 4. Spatial flexibility: multiple target points can be simultaneously controlled through electrode array design. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 Figure is a schematic diagram of a high-voltage pulse delivery device;

[0044] Figure 2 Figure is a schematic diagram of a biological body fixing table and electrode fixing form; Figure 2 (a) is a schematic diagram of a two-side clamping type; Figure 2 (b) is a schematic diagram of a multi-electrode binding type;

[0045] Figure 3 Figure is a schematic diagram of EB staining results; Figure 3 (a) is a schematic diagram of 3h staining results; Figure 3 (b) is a schematic diagram of 12h staining results; Figure 3 (c) is a schematic diagram of 24h staining results. DETAILED DESCRIPTION

[0046] The application will be further described below in conjunction with the examples, but should not be understood as limiting the above-mentioned subject matter of the application only to the following examples. Various substitutions and modifications can be made according to ordinary technical knowledge and conventional means in the art without departing from the above-mentioned technical idea of the application, and all should be included in the protection scope of the application.

[0047] Example 1:

[0048] Reference Figures 1 to 3 A device for non-invasive pulse electric field non-invasive regulation of blood brain barrier, comprising: a high-voltage pulse generator, a plurality of treatment electrodes, and a fixing device.

[0049] The high-voltage pulse generator is used to generate a pulse signal and transmit the pulse signal to the treatment electrodes.

[0050] The voltage amplitude of the pulse signal is greater than or equal to 500V, and the pulse width is less than 100us.

[0051] The treatment electrodes are attached to the outer surface of the brain of the biological body, forming a pulse electric field in the brain of the biological body, and regulating the blood brain barrier of the biological body.

[0052] The fixing device is used to fix the biological body and the treatment electrodes.

[0053] Example 2:

[0054] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is seen from embodiment 1, further, the high-voltage pulse generator includes a man-machine interface, an FPGA module, a Marx generator, a low-voltage power supply module and a high-voltage power supply module.

[0055] The man-machine interface is used for acquiring pulse parameters and transmitting the pulse parameters to the FPGA module.

[0056] The FPGA module is used for generating pulse control signals and transmitting the pulse control signals to the Marx generator.

[0057] The Marx generator is used for generating pulse signals.

[0058] The low-voltage power supply module supplies power to the man-machine interface, the FPGA module and the Marx generator.

[0059] The low-voltage power supply module provides a voltage amplitude range of 0-24V.

[0060] The high-voltage power supply module supplies power to the Marx generator.

[0061] The high-voltage power supply module provides a voltage amplitude range of 0-1kV.

[0062] Embodiment 3:

[0063] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is seen from any one of embodiments 1 to 2, further, the pulse parameters include pulse field strength, pulse width, frequency and action time.

[0064] Embodiment 4:

[0065] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is seen from any one of embodiments 1 to 3, further, the pulse field strength is less than or equal to 10kV / cm.

[0066] Embodiment 5:

[0067] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is seen from any one of embodiments 1 to 4, further, the treatment electrode includes a gold-plated copper disc.

[0068] Embodiment 6:

[0069] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is seen from any one of embodiments 1 to 5, further, when the treatment electrode is attached to the brain of a living body, the surface of the treatment electrode is uniformly coated with conductive paste.

[0070] Embodiment 7:

[0071] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is any one of embodiments 1-6, further, the biological blood-brain barrier regulation mode includes two-electrode regulation and multi-electrode regulation.

[0072] For two-electrode regulation, the fixing device adopts a two-end clamping type fixing device.

[0073] For multi-electrode regulation, the fixing device adopts a multi-electrode binding type fixing device.

[0074] Embodiment 8:

[0075] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is any one of embodiments 1-7, further, the two-end clamping type fixing device includes four fixed columns, two movable columns, and an operation table.

[0076] The four fixed columns are respectively fixedly installed at the four corners of the operation table.

[0077] The organism is placed on the operation table, and the four limbs of the organism are respectively fixed to the four fixed columns through the live rope sleeve.

[0078] The treatment electrode is fixed on the two movable columns.

[0079] The height and spacing of the two movable columns are adjusted so that the treatment electrode closely contacts the two sides of the brain of the organism.

[0080] Embodiment 9:

[0081] The device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier, the main technical content is any one of embodiments 1-8, further, the multi-electrode binding type fixing device includes four fixed columns, a binding belt, and an operation table.

[0082] The four fixed columns are respectively fixedly installed at the four corners of the operation table.

[0083] The organism is placed on the operation table, and the four limbs of the organism are respectively fixed to the four fixed columns through the live rope sleeve.

[0084] The treatment electrode is fixed on the two movable columns.

[0085] Embodiment 10:

[0086] Referring to Figures 1 to 3 A device for non-invasive pulsed electric field non-invasive regulation of blood-brain barrier includes a high-voltage pulse generator, a plurality of treatment electrodes, and a fixing device.

[0087] The high-voltage pulse generator is configured to generate a pulse signal and transmit the pulse signal to the treatment electrode.

[0088] The pulse signal has a voltage amplitude greater than or equal to 500 V and a pulse width less than 100 us.

[0089] The treatment electrode is attached to the outer surface of the brain of the living body to form a pulse electric field in the brain of the living body, regulate the blood-brain barrier of the living body, and increase the intercellular space and permeability of the brain microvascular endothelial cells in the pulse electric field effect zone. After the electric field ends, the function of the blood-brain barrier will recover in a certain period of time.

[0090] The living body can be any living body, but the output voltage amplitude of the high-voltage pulse needs to be adjusted accordingly to generate an effective field strength in the brain.

[0091] The fixing device is configured to fix the living body and the treatment electrode.

[0092] When the pulse is applied, the system outputs the electric field in stages according to the preset parameters. For example, a low field strength (0.5 kV / cm) and a short pulse width (50 us) are used for pre-stimulation, and after evaluating the physiological response of the living body, the treatment field strength (1-3 kV / cm) is gradually increased. The current measurement is used to feedback the electrode-skin contact state in real time throughout the process. If the current abnormally increases, the output is paused and the electrode position is adjusted.

[0093] Embodiment 11:

[0094] A device for non-invasive pulse electric field non-invasive regulation of the blood-brain barrier, the main technical content is shown in embodiment 10, further, the high-voltage pulse generator comprises a human-computer interaction interface, an FPGA module, a Marx generator, a low-voltage power supply module, and a high-voltage power supply module.

[0095] The human-computer interaction interface is configured to obtain pulse parameters and transmit the pulse parameters to the FPGA module.

[0096] The FPGA module is configured to generate a pulse control signal and transmit the pulse control signal to the Marx generator.

[0097] The Marx generator is configured to generate a pulse signal.

[0098] The low-voltage power supply module supplies power to the human-computer interaction interface, the FPGA module, and the Marx generator.

[0099] The low-voltage power supply module provides a voltage amplitude ranging from 0 to 24 V.

[0100] The high-voltage power supply module supplies power to the Marx generator.

[0101] The high-voltage power supply module provides a voltage amplitude range of 0-1 kV.

[0102] Embodiment 12:

[0103] A device for non-invasive pulsed electric field non-invasive regulation of the blood-brain barrier, the main technical content of any one of embodiments 10 to 11, further, the pulse parameters include pulse field strength, pulse width, frequency and action time.

[0104] Embodiment 13:

[0105] A device for non-invasive pulsed electric field non-invasive regulation of the blood-brain barrier, the main technical content of any one of embodiments 10 to 12, further, the pulse field strength is less than or equal to 10 kV / cm.

[0106] Embodiment 14:

[0107] A device for non-invasive pulsed electric field non-invasive regulation of the blood-brain barrier, the main technical content of any one of embodiments 10 to 13, further, the treatment electrode includes a gold-plated copper disc with a diameter of 2-10 mm.

[0108] Embodiment 15:

[0109] A device for non-invasive pulsed electric field non-invasive regulation of the blood-brain barrier, the main technical content of any one of embodiments 10 to 14, further, when the treatment electrode is attached to the brain of the organism, the surface of the treatment electrode is uniformly coated with conductive paste, thereby forming a pulsed electric field effect zone near the electrode. Considering the energy attenuation of the skin and skull to the electric pulse, the pulse parameters (mainly amplitude and pulse width) need to be adjusted flexibly according to the penetration depth target.

[0110] Embodiment 16:

[0111] A device for non-invasive pulsed electric field non-invasive regulation of the blood-brain barrier, the main technical content of any one of embodiments 10 to 15, further, the method of regulating the blood-brain barrier of the organism includes two-electrode regulation and multi-electrode regulation.

[0112] Opening the blood-brain barrier site is to expand towards the deep brain near the electrode, and multi-electrode can realize larger range of blood-brain barrier opening, in addition, selecting large size electrode sheet to increase contact area can increase the range of regulation.

[0113] For two-electrode regulation, the fixing device adopts a two-end clamping type fixing device.

[0114] For multi-electrode regulation, the fixing device adopts a multi-electrode binding type fixing device.

[0115] Embodiment 17:

[0116] A device for non-invasive pulsed electric field non-invasive regulation of blood brain barrier, the main technical content is seen in any one of embodiments 10 to 16, further, the two-end clamping type fixing device includes four fixed columns, two movable columns, and an operation table.

[0117] The four fixed columns are respectively fixedly installed at the four corners of the operation table.

[0118] The organism is placed on the operation table, and the limbs of the organism are respectively fixed to the four fixed columns through the live rope sleeve.

[0119] The treatment electrode is fixed on the two movable columns.

[0120] The height and spacing of the two movable columns are adjusted so that the treatment electrode closely contacts the two sides of the brain of the organism.

[0121] Embodiment 18:

[0122] A device for non-invasive pulsed electric field non-invasive regulation of blood brain barrier, the main technical content is seen in any one of embodiments 10 to 17, further, the multi-electrode binding type fixing device includes four fixed columns, a binding belt, and an operation table.

[0123] The four fixed columns are respectively fixedly installed at the four corners of the operation table.

[0124] The organism is placed on the operation table, and the limbs of the organism are respectively fixed to the four fixed columns through the live rope sleeve.

[0125] The treatment electrode is fixed on the two movable columns.

[0126] Embodiment 19:

[0127] See Figures 1 to 3 A device for non-invasive pulsed electric field non-invasive regulation of blood brain barrier, the main technical content includes:

[0128] Device composition:

[0129] High-voltage pulse generator, based on all-solid-state Marx pulse generation circuit to provide high-voltage electric pulse. As Figure 1 shown, including human-computer interaction interface, field programmable gate array (FPGA), low-voltage power supply module, high-voltage power supply module and Marx main circuit.

[0130] Treatment electrode, for delivering pulsed electric field to the brain, including a gold-plated conductive disc with a diameter of 2-10mm.

[0131] Mouse and electrode fixing device, for fixing the mouse and the treatment electrode. The fixing method is as Figure 2As shown in the figure, the mouse limbs are fixed to four movable columns by a live rope sleeve; two ends are clamped, the electrode sheet is fixed to two columns, and the column height and spacing are adjusted to closely adhere to the two sides of the mouse brain; the multi-electrode binding type is fixed to the binding band at a certain interval, and then the binding band is wound around the mouse brain.

[0132] Working principle:

[0133] The pulse parameters are set through the human-computer interaction interface and transmitted to the FPGA, and then the FPGA controls the Marx circuit to generate high-voltage pulse output to the treatment electrode.

[0134] The surface of the treatment electrode is smeared with conductive paste and closely adheres to the brain, so as to form a pulse electric field effect zone near the electrode. Considering the energy attenuation of the skin and skull to the electric pulse, the pulse parameters (mainly amplitude and pulse width) need to be flexibly adjusted according to the penetration depth target.

[0135] In the pulse electric field effect zone, the stability of the tight junction is disrupted, the intercellular space of the brain microvascular endothelial cells is increased, and the permeability is increased. After the electric field ends, the function of the blood-brain barrier will recover in a certain period of time.

[0136] Example 20:

[0137] Reference Figures 1 to 3 A device for non-invasive pulse electric field non-invasive regulation of blood-brain barrier, the main technical content includes:

[0138] Reference to the attached Figure 1 The pulse electric field regulation device of the application mainly consists of a high-voltage pulse generator, a treatment electrode and a mouse fixing device. In the initial stage, the operator needs to input the optimized treatment parameters on the human-computer interaction interface according to the electrode arrangement scheme and the BBB regulation target (such as local or whole brain opening), including pulse field strength, pulse width, frequency and action time. The interface has a parameter checking function to ensure that the output pulse is within a safe range (such as field strength ≤10kV / cm, pulse width ≤10ms), while meeting different experimental needs.

[0139] The high-voltage pulse generator adopts a full-solid Marx circuit design, which is precisely controlled by the FPGA to generate high-stability high-voltage pulses. The treatment electrode is a gold-plated copper disc with a diameter of 2-10mm, which is connected to the generator through flexible wires. Before applying the pulse, conductive paste needs to be evenly applied to the electrode contact surface to reduce the skin-electrode interface impedance and ensure efficient delivery of the pulse electric field to the target brain area.

[0140] Reference to the attached Figure 2The treatment electrode of the system supports multiple arrangement schemes. For bilateral target regulation, a two-end clamping type fixation method can be used to fix the electrode sheet on an adjustable stand, and the micro-adjusting mechanism is used to make it closely fit the two sides of the mouse skull (e.g. 2 mm behind the fontanel, 1.5 mm away from the midline). For large-scale regulation, a multi-electrode bandage type design can be used, in which the electrode array is arranged on the elastic bandage at a fixed interval (e.g. 3-5 mm), and the target brain area is covered by winding.

[0141] When the pulse is applied, the system outputs the electric field in stages according to the preset parameters. For example, first, pre-stimulation is performed with low field strength (0.5 kV / cm) and short pulse width (50 μs), and after evaluating the physiological response of the mouse, the treatment field strength (1-3 kV / cm) is gradually increased. Throughout the process, the current measurement is used to feedback the electrode-skin contact state in real time, and if the current abnormally increases, the output is suspended and the electrode position is adjusted.

[0142] After the treatment is completed, Evans Blue or fluorescent labeled antibody can be injected through the tail vein to verify the BBB opening effect. Experiments show that the device can maintain the BBB open for ≥12 hours under non-invasive conditions.

[0143] The experimental parameters E1: voltage 1 kV, pulse width 2 μs, 25 positive and negative pulses, positive and negative pulse interval 5 μs, 200 pulse strings 1 Hz. After the pulse treatment is completed, Evans Blue (2% in PBS, 4 mL / kg) is injected into the tail vein of all mice at 2, 11, and 23 hours, the circulation time is 1 hour, and the brain is taken after heart perfusion. The staining results are shown in Figure 3 As shown in the figure, at t=3h, the staining area of the mouse is obvious, and the blood-brain barrier has been opened; at t=3h, the staining area of the mouse is reduced; at t=24h, the staining area of the mouse is very weak, and the blood-brain barrier is almost closed.

Claims

1. A device for non-invasive modulation of the blood-brain barrier using pulsed electric fields, characterized in that, include: High-voltage pulse generator, several treatment electrodes, and fixation device; The high-voltage pulse generator is used to generate pulse signals and transmit the pulse signals to the treatment electrodes; The voltage amplitude of the pulse signal is greater than or equal to 500V, and the pulse width is less than 100µs; The therapeutic electrode is attached to the outer surface of the brain of the organism, forming a pulsed electric field inside the brain of the organism, thereby regulating the blood-brain barrier of the organism. The fixation device is used to fix the organism and the therapeutic electrode.

2. The device for non-invasive modulation of the blood-brain barrier using pulsed electric fields according to claim 1, characterized in that, The high-voltage pulse generator includes a human-machine interface, an FPGA module, a Marx generator, a low-voltage power supply module, and a high-voltage power supply module. The human-computer interaction interface is used to acquire pulse parameters and transmit the pulse parameters to the FPGA module; The FPGA module is used to generate pulse control signals and transmit the pulse control signals to the Marx generator; The Marx generator is used to generate pulse signals; The low-voltage power supply module provides power to the human-machine interface, FPGA module, and Marx generator. The low-voltage power supply module provides a voltage amplitude range of 0 to 24V; The high-voltage power supply module supplies power to the Marx generator; The voltage amplitude range provided by the high-voltage power supply module is 0 to 1kV.

3. The device for non-invasive modulation of the blood-brain barrier using a pulsed electric field according to claim 2, characterized in that, The pulse parameters include pulse field strength, pulse width, frequency, and duration.

4. The device for non-invasive pulsed electric field modulation of the blood-brain barrier according to claim 3, characterized in that, The pulse field strength is less than or equal to 10 kV / cm.

5. The device for non-invasive modulation of the blood-brain barrier using pulsed electric fields according to claim 1, characterized in that, The therapeutic electrode comprises a copper disc plated with gold.

6. The device for non-invasive modulation of the blood-brain barrier using pulsed electric fields according to claim 1, characterized in that, When the therapeutic electrode is attached to the brain of a living organism, a conductive paste is evenly applied to the surface of the therapeutic electrode.

7. The device for non-invasive modulation of the blood-brain barrier using a pulsed electric field according to claim 1, characterized in that, The blood-brain barrier is regulated in organisms through two-electrode regulation and multi-electrode regulation. For two-electrode control, the fixing device adopts a two-end clamping type fixing device; For multi-electrode control, a multi-electrode binding type fixing device is adopted.

8. The device for non-invasive modulation of the blood-brain barrier using a pulsed electric field according to claim 7, characterized in that, The two-end clamping type fixing device includes four fixed columns, two movable columns, and an operating table; Four fixed columns are respectively fixedly installed at the four corners of the operating table; The organism was placed on the operating table, and its limbs were fixed to four fixed pillars using rope loops. The treatment electrodes are fixed to two movable columns; Adjust the height and spacing of the two movable columns so that the treatment electrodes are in close contact with both sides of the patient's brain.

9. The device for non-invasive modulation of the blood-brain barrier using a pulsed electric field according to claim 7, characterized in that, The multi-electrode binding type fixing device includes four fixing columns, straps, and an operating table; Four fixed columns are respectively fixedly installed at the four corners of the operating table; The organism was placed on the operating table, and its limbs were fixed to four fixed pillars using rope loops. The treatment electrodes are fixed to the strap at a set interval, and the strap is wrapped around the brain of the organism so that the treatment electrodes are in close contact with the brain.

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