System for noninvasive regulation and control of blood brain barrier permeability in transcranial pulsed electric field

Abstract

A system for noninvasive regulation and control of blood brain barrier permeability through a transcranial pulsed electric field comprises a high-voltage pulse generator and a plurality of treatment electrodes. 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 method has the advantages of noninvasiveness, high efficiency and safety, and can achieve a multi-mechanism synergistic effect. 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] This invention relates to the field of brain disease treatment technology, specifically to a system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields. Background Technology

[0002] Focused ultrasound (FUS) uses high-intensity sound waves to produce biological effects in the target area, and combined with microbubbles, it can temporarily and reversibly open the blood-brain barrier (BBB). FUS typically uses an ultrasound transducer to emit high-frequency sound waves (usually 0.2MHz–1.5MHz), which are focused behind the skull onto the target (focal spot diameter approximately 1mm–3mm), forming a high-intensity sound field (peak negative pressure 0.5MPa–3MPa). Microbubbles undergo inertial cavitation or stable cavitation in the sound field, generating mechanical forces that disrupt the tight junctions of vascular endothelial cells (occludin, claudin-5), increasing BBB permeability, with an opening time of approximately 2–6 hours.

[0003] Focused ultrasound requires strict control of sound pressure / microbubble dose to avoid excessive cavitation effect that could cause capillary rupture. Its open window is relatively short, usually closing within 6 hours, which limits the continuous release of drugs.

[0004] Tumor treating fields (TTFs) indirectly affect blood-brain barrier (BBB) ​​permeability through low-frequency alternating electric fields (100kHz–300kHz) (possibly by regulating tight junction proteins). However, research on their role in regulating BBB permeability is insufficient, the regulatory mechanism of BBB is unclear, and the effects are uncontrollable. Furthermore, TTFs require long-term wear for treatment, which can easily cause skin inflammation.

[0005] Existing pulsed electric field electrode designs are mostly minimally invasive (pin electrodes), which cannot achieve completely non-invasive treatment. Summary of the Invention

[0006] The purpose of this invention is to provide a system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, comprising: a high-voltage pulse generator and several therapeutic electrodes;

[0007] The high-voltage pulse generator is used to generate pulse signals and transmit the pulse signals to the treatment electrodes;

[0008] The voltage amplitude range of the pulse signal is -2kV to 2kV, and the pulse width range is 200ns to 2μs.

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

[0010] Furthermore, the system also includes a parameter controller;

[0011] The parameter controller is used to set pulse parameters and generate control signals based on the pulse parameters to control the high-voltage pulse generator to generate pulse signals.

[0012] Furthermore, the pulse parameters include pulse amplitude, pulse width, number of pulse trains, and frequency within the train.

[0013] Furthermore, the intra-string frequency is less than or equal to 1MHz.

[0014] Furthermore, the pulse signal includes a bipolar pulse signal.

[0015] Furthermore, the treatment electrode comprises a copper disc with a gold-plated surface.

[0016] Furthermore, when the treatment electrode is attached to the brain of a living organism, a conductive paste is evenly applied to the surface of the treatment electrode.

[0017] The technical effects of this invention are undeniable. This invention regulates the tightness of endothelial cell connections through a high-voltage short-pulse electric field (PEF), and achieves local brain region modulation by combining electrode design. The pulse parameters can be flexibly adjusted to balance the effect and damage, providing a new non-invasive physical therapy method to assist in drug delivery across the blood-brain barrier.

[0018] Compared to focused ultrasound (FUS), this invention utilizes a multi-mechanism synergistic effect (electroporation effect + bioelectrochemical effect) rather than relying on the mechanical effect of exogenous microbubbles, significantly reducing safety risks.

[0019] This invention utilizes non-invasive electrodes to deliver instantaneous high-voltage electrical pulses (amplitude 0-±2kV, pulse width 200ns-2μs, bipolar pulse output with an intra-series frequency up to 1MHz), which differs from the previous low-voltage long-term electrical stimulation of non-invasive electrodes (deep brain stimulation frequency 1Hz~10kHz, voltage 0.1V~10V / 1mA~20mA; tumor treatment electric field frequency 100kHz~300kHz, ±25V~100V sine wave).

[0020] This invention is the first to propose a non-invasive transcranial directional pulsed electric field system for modulating blood-brain barrier permeability, which has the following beneficial effects:

[0021] 1. Non-invasive: The pulsed electric field delivery method, which delivers the electrode close to the skin, avoids surgical trauma and has a high patient acceptance rate.

[0022] 2. High efficiency: BBB opening can be completed in minutes.

[0023] 3. Synergistic effect of multiple mechanisms: It opens the BBB through a dual mechanism of physical effects dominated by electroporation and regulation by bioelectrochemical signals, which has the advantages of being fast and precise.

[0024] 4. Reduced safety risks: It does not rely on microbubbles or nanoparticles, thus reducing the risk of immune responses. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of a high-voltage electrical pulse delivery system;

[0026] Figure 2 This is a schematic diagram of fluorescence intensity at Ex620nm / Rx680nm. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments, but it should not be construed that the scope of the present invention is limited to the following embodiments. Various substitutions and modifications made based on ordinary technical knowledge and common practices in the art without departing from the above-described technical concept of the present invention should be included within the scope of protection of the present invention.

[0028] Example 1:

[0029] See Figures 1 to 2 A system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, comprising: a high-voltage pulse generator and several therapeutic electrodes;

[0030] The high-voltage pulse generator is used to generate pulse signals and transmit the pulse signals to the treatment electrodes;

[0031] The voltage amplitude range of the pulse signal is -2kV to 2kV, and the pulse width range is 200ns to 2μs.

[0032] The therapeutic electrode is attached to the outer surface of the brain of the organism and is used to form a pulsed electric field in the brain of the organism to regulate the blood-brain barrier of the organism.

[0033] Example 2:

[0034] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in Example 1, further includes a parameter controller;

[0035] The parameter controller is used to set pulse parameters and generate control signals based on the pulse parameters to control the high-voltage pulse generator to generate pulse signals.

[0036] Example 3:

[0037] The system for non-invasively modulating the permeability of the blood-brain barrier via transcranial pulsed electric field, the main technical contents of which are described in any one of Examples 1 to 2, further wherein the pulse parameters include pulse amplitude, pulse width, number of pulse trains, and frequency within the train.

[0038] Example 4:

[0039] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 1 to 3, further wherein the frequency within the series is less than or equal to 1MHz.

[0040] Example 5:

[0041] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 1 to 4, further wherein the pulse signal includes a bipolar pulse signal.

[0042] Example 6:

[0043] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 1 to 5, further wherein the therapeutic electrode comprises a copper disc plated with gold.

[0044] Example 7:

[0045] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 1 to 6, further wherein when the treatment electrode is attached to the brain of a living organism, conductive paste is uniformly applied to the surface of the treatment electrode.

[0046] Example 8:

[0047] See Figures 1 to 2 A system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, comprising: a high-voltage pulse generator and several therapeutic electrodes;

[0048] The high-voltage pulse generator is based on a solid-state Marx circuit and is used to generate pulse signals and transmit the pulse signals to the treatment electrode.

[0049] The voltage amplitude range of the pulse signal is -2kV to 2kV, and the pulse width range is 200ns to 2μs.

[0050] The therapeutic electrode is attached to the outer surface of the brain of the organism and is used to form a pulsed electric field in the brain of the organism to regulate the blood-brain barrier of the organism.

[0051] Conductive paste is applied to the surface of the treatment electrode and it is tightly attached to the brain, thereby forming a pulsed electric field effect zone near the electrode. Considering the energy attenuation of the electrical pulse by the skin and skull, the pulse parameters (mainly amplitude and pulse width) need to be flexibly adjusted according to the target penetration depth.

[0052] In the region affected by the pulsed electric field, the stable connections of tight junction proteins (such as occludin, claudin-5, and ZO-1) are disrupted, increasing the intercellular spaces between brain microvascular endothelial cells. The electric field stimulates endothelial cells to release NO and prostaglandins, leading to local vasodilation and increased permeability. After the electric field ends, the blood-brain barrier function recovers within a certain period of time.

[0053] Example 9:

[0054] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in Example 8, further includes a parameter controller;

[0055] The parameter controller is used to set pulse parameters and generate control signals based on the pulse parameters to control the high-voltage pulse generator to generate pulse signals.

[0056] Example 10:

[0057] The system for non-invasively modulating the permeability of the blood-brain barrier via transcranial pulsed electric field, the main technical contents of which are described in any one of Examples 8 to 9, further wherein the pulse parameters include pulse amplitude, pulse width, number of pulse trains, and frequency within the train.

[0058] Example 11:

[0059] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 8 to 10, further wherein the frequency within the string is less than or equal to 1MHz.

[0060] Example 12:

[0061] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 8 to 11, further wherein the pulse signal includes a bipolar pulse signal.

[0062] Example 13:

[0063] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 8 to 12, further wherein the therapeutic electrode comprises a copper disc plated with gold.

[0064] Example 14:

[0065] The system for non-invasively modulating the permeability of the blood-brain barrier using transcranial pulsed electric fields, the main technical contents of which are described in any one of Examples 8 to 13, further wherein when the treatment electrode is attached to the brain of a living organism, conductive paste is uniformly applied to the surface of the treatment electrode.

[0066] Example 15:

[0067] The system for non-invasively modulating the permeability of the blood-brain barrier via transcranial pulsed electric field, the main technical contents of which are described in any one of Examples 8 to 14, further wherein 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.

[0068] The human-computer interaction interface is used to acquire pulse parameters and transmit the pulse parameters to the FPGA module.

[0069] The FPGA module is used to generate pulse control signals and transmit the pulse control signals to the Marx generator.

[0070] The Marx generator is used to generate pulse signals.

[0071] The low-voltage power supply module provides power to the human-computer interaction interface, FPGA module, and Marx generator.

[0072] The low-voltage power supply module provides a voltage range of 0 to 24V.

[0073] The high-voltage power supply module supplies power to the Marx generator.

[0074] The voltage amplitude range provided by the high-voltage power supply module is 0 to 1kV.

[0075] Example 16:

[0076] See Figures 1 to 2 A system for non-invasive modulation of blood-brain barrier permeability via transcranial pulsed electric fields, the main technical contents of which include:

[0077] System components:

[0078] A high-voltage pulse generator, based on solid-state Marx circuitry, is used to generate bipolar pulse outputs with amplitudes of 0-±2kV, pulse widths of 200ns-2μs, and intra-series frequencies up to 1MHz.

[0079] Therapeutic electrodes are used to deliver pulsed electric fields to the brain.

[0080] Working principle:

[0081] The pulse generator output pulse parameters are set by the controller, and bipolar pulses are output to the treatment electrode.

[0082] Conductive paste is applied to the surface of the treatment electrode and it is tightly attached to the brain, thereby forming a pulsed electric field effect zone near the electrode. Considering the energy attenuation of the electrical pulse by the skin and skull, the pulse parameters (mainly amplitude and pulse width) need to be flexibly adjusted according to the target penetration depth.

[0083] In the region affected by the pulsed electric field, the stable connections of tight junction proteins (such as occludin, claudin-5, and ZO-1) are disrupted, increasing the intercellular spaces between brain microvascular endothelial cells. The electric field stimulates endothelial cells to release NO and prostaglandins, leading to local vasodilation and increased permeability. After the electric field ends, the blood-brain barrier function recovers within a certain period of time.

[0084] Example 17:

[0085] See Figures 1 to 2 A system for non-invasive modulation of blood-brain barrier permeability via transcranial pulsed electric fields, the main technical contents of which include:

[0086] See appendix Figure 1 This is a component of the non-invasive transcranial directional pulsed electric field system. In the initial stage, the optimal configuration of treatment pulse parameters is determined based on the electrode placement scheme and the desired therapeutic effect, and the recommended treatment parameters are input into the integrated human-machine interface. This interface can precisely control the pulse output to ensure it remains within a safe range and meets the treatment requirements.

[0087] See appendix Figure 2 This is a non-invasive transcranial directional pulsed electric field system. The system comprises a parameter controller, a high-voltage pulse generator, and treatment electrodes. The parameter controller stores optimal parameter configurations for different treatment plans, which can be set according to specific treatment conditions, and transmits control signals to the high-voltage pulse generator. The high-voltage pulse generator receives signals from the parameter controller and outputs them accordingly. The output terminal has an expansion port that can support pulse output from up to four electrodes. The treatment electrodes are gold-plated copper discs. When applied to the brain, conductive gel must be applied to ensure good electrical contact, thereby better delivering the pulsed electric field.

[0088] Example 18:

[0089] See Figures 1 to 2 A system for non-invasive modulation of blood-brain barrier permeability via transcranial pulsed electric fields, the main technical contents of which include:

[0090] 1. Preoperative preparation

[0091] Anesthesia: Mice were anesthetized with isoflurane to ensure depth of anesthesia (no toe reflexes);

[0092] Skin preparation: Use hair removal cream to remove hair from the top and sides of the head, and disinfect the skin with iodine;

[0093] Fixation: The mouse's limbs are tied to the fixation table, with its abdomen facing down and its back facing up.

[0094] 2. Electrode placement and pulse processing

[0095] Conductive paste and electrodes: Apply conductive paste evenly to both sides of the skull, and place the electrode pads tightly against the skin.

[0096] Pulse parameters (variations in parameter values ​​involve pulse width, number of pulses within the string, and number of pulses outside the string).

[0097] Experimental parameters E1: voltage 1kV, pulse width 2μs, 20 positive and negative pulses, positive and negative pulse interval 5μs, 100 pulse trains @1Hz;

[0098] Experimental parameters E2: voltage 1kV, pulse width 0.5μs, 160 positive and negative pulses, positive and negative pulse interval 5μs, 100 pulse trains @1Hz;

[0099] Experimental parameters E3: voltage 1kV, pulse width 0.2μs, 400 positive and negative pulses, positive and negative pulse interval 5μs, 100 pulse trains @1Hz;

[0100] Experimental parameters E4: voltage 1kV, pulse width 0.2μs, 200 positive and negative pulses, positive and negative pulse interval 5μs, 200 pulse trains @1Hz.

[0101] Control group C1: Only electrodes are attached, no electric field is applied (the influence of conductive paste / electrode itself needs to be excluded).

[0102] 3. Evans Blue Injection and Circulation

[0103] Injection timing: 2 hours after the pulse treatment, all mice were injected into the tail vein with Evans Blue (2% in PBS, 4 mL / kg).

[0104] Circulation time: 1 hour (maintain body temperature at 37℃ to avoid deviation in circulation time).

[0105] 4. Pouring and Material Sampling

[0106] Cardiac perfusion: After circulation is complete, perfuse the heart with normal saline (approximately 50 mL).

[0107] Brain removal: Complete removal of brain tissue.

[0108] 5. Evans Blue Quantitative Analysis

[0109] Brain tissue processing: The tissue was homogenized and ground using a homogenizer, and 50% trichloroacetic acid (1:10 w / v) was added.

[0110] Centrifuge (10,000 rpm, 10 min, 4℃) and collect the supernatant.

[0111] Detection: Fluorescence was read using an ELISA reader (Ex / Em: 620 / 680nm).

[0112] from Figure 2It can be seen that, compared with the control group, Evans blue dye crossed the blood-brain barrier into the mouse brain parenchyma in the experimental group, proving that the method can effectively open the blood-brain barrier.

Claims

1. A system for non-invasive modulation of blood-brain barrier permeability using transcranial pulsed electric fields, characterized in that, include: High-voltage pulse generator, several therapeutic electrodes; The high-voltage pulse generator is used to generate pulse signals and transmit the pulse signals to the treatment electrodes; The voltage amplitude range of the pulse signal is -2kV to 2kV, and the pulse width range is 200ns to 2μs. The therapeutic electrode is attached to the outer surface of the brain of the organism and is used to form a pulsed electric field in the brain of the organism to regulate the blood-brain barrier of the organism.

2. The system for non-invasive modulation of blood-brain barrier permeability using transcranial pulsed electric fields according to claim 1, characterized in that, The system also includes a parameter controller; The parameter controller is used to set pulse parameters and generate control signals based on the pulse parameters to control the high-voltage pulse generator to generate pulse signals.

3. The system for non-invasive modulation of blood-brain barrier permeability using transcranial pulsed electric fields according to claim 2, characterized in that, The pulse parameters include pulse amplitude, pulse width, number of pulse trains, and frequency within the train.

4. The system for non-invasive modulation of blood-brain barrier permeability using transcranial pulsed electric fields according to claim 3, characterized in that, The frequency within the string is less than or equal to 1 MHz.

5. The system for non-invasive modulation of blood-brain barrier permeability using transcranial pulsed electric fields according to claim 1, characterized in that, The pulse signal includes a bipolar pulse signal.

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

7. The system for non-invasive modulation of blood-brain barrier permeability using transcranial 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.

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