Physical methods and devices for modulating molecular transport in the extracellular space of the brain

Abstract

A physical method for regulating molecular transport in the extracellular space of the brain includes applying an external pressure to the brain tissue of an animal, and the rhythm of applying the external pressure is associated with the automaticity of the animal. A device for regulating molecular transport in the extracellular space of the brain includes a detection mechanism, a pressure mechanism, and a control mechanism. The detection mechanism is capable of detecting the automaticity of the animal. The pressure mechanism is capable of applying an external pressure to the brain tissue of the animal. The control mechanism is capable of controlling the pressure mechanism based on the detection result of the detection mechanism such that the rhythm of applying the external pressure of the pressure mechanism is associated with the automaticity of the animal. The method and device can effectively regulate molecular transport in the extracellular space of the brain.

Description

[Technical Field]

[0001] The present patent relates to physical methods and devices for modulating molecular transport in the extracellular space of the brain. [Background technology]

[0002] The extracellular space (ECS) of the brain is a tortuous space that exists between brain cells and between cells and blood vessels, and there are two modes of transport of substances within this space: convection and diffusion. Novel administration methods via the ECS route have successfully circumvented the blood-brain barrier, which prevents most drugs from entering the brain, and offer new hope for many drugs that have failed in research and development via traditional oral and intravenous routes.

[0003] The factors affecting substance transport in the ECS are complex. Both neural excitation and the subsequent release of neurotransmitters induce changes in the transport rate of substances in the ECS (Y. Li et al., 2020; Shi et al., 2015). Various factors, such as sleep (Xie et al., 2013), anesthesia (Zhao et al., 2020), neural excitation (Shi et al., 2015), and development (R. Wang et al., 2021), may exert forward or reverse control over the drainage of brain interstitial fluid (ISF) in the brain ECS. These findings provide important theoretical foundations and technological approaches for exploring the treatment of stroke via the ECS pathway. For example, pain stimulation (Shi et al., 2015) and olfactory stimulation can slow ISF drainage, light irradiation can treat Alzheimer's disease (AD) by accelerating ISF drainage and promoting the excretion of abs from the brain (Yue et al., 2019), and different days of simulated weightlessness (Gao et al., 2021) and different types of anesthesia (Zhao et al., 2020) can control ISF drainage in either a forward or reverse direction.

[0004] Currently, there is a need for more effective methods of modulating molecular transport in the extracellular space of the brain. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel method that can effectively regulate molecular transport in the extracellular space of the brain.

[0006] Another object of the present invention is to provide a device that can effectively regulate molecular transport in the extracellular space of the brain. [Means for solving the problem]

[0007] The physical method of regulating molecular transport in the extracellular space of the brain according to the present invention involves applying external pressure to the brain tissue of an animal, the rhythm of which is associated with the motility of the animal.

[0008] The physical method for modulating molecular transport in the extracellular space of the brain can effectively modulate molecular transport in the extracellular space of the brain.

[0009] In another exemplary embodiment of the physical method of modulating molecular transport in the extracellular space of the brain, the automaticity is respiratory rhythm, cardiac rhythm, cerebral pulsation rhythm or vascular pulsation rhythm.

[0010] In yet another exemplary embodiment of a physical method for modulating molecular transport in the extracellular space of the brain, external pressure is applied to the brain tissue of the animal outside the dura mater of the animal.

[0011] The device for regulating molecular transport in the extracellular space of the brain according to the present invention includes a detection mechanism, a pressure mechanism, and a control mechanism. The detection mechanism is capable of detecting the automaticity of an animal. The pressure mechanism is capable of applying external pressure to the brain tissue of the animal. The control mechanism is capable of controlling the pressure mechanism based on the detection result of the detection mechanism so that the rhythm of applying the external pressure by the pressure mechanism is associated with the automaticity of the animal. The device for regulating molecular transport in the extracellular space of the brain can effectively regulate molecular transport in the extracellular space of the brain by a physical method.

[0012] In another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the automaticity is respiratory rhythm, cardiac rhythm, cerebral pulsation rhythm or vascular pulsation rhythm.

[0013] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the pressurizing mechanism includes a flexible bag, a fluid container, and a fluid filling and discharging unit. The flexible bag is filled with a fluid, thereby applying external pressure to the animal's brain tissue. The fluid container stores a fluid. The fluid filling and discharging unit is connected to the flexible bag and the fluid container, and is capable of filling the flexible bag with the fluid stored in the fluid container and discharging the fluid in the flexible bag. The control mechanism is capable of controlling the fluid filling and discharging unit.

[0014] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the detection mechanism is an electrocardiograph, the control mechanism is capable of extracting QRS waves and T waves from the detection results of the detection mechanism, and the control mechanism is capable of controlling the fluid filling and discharging unit to fill the flexible bag with fluid at the start of the QRS wave and to discharge the fluid from the flexible bag at the end of the T wave.

[0015] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the fluid filling and discharging unit includes an intake tube, a gas compressor, an exhaust tube, and an exhaust valve. One end of the intake tube is connected to a flexible bag and the other end is connected to an outlet of the gas compressor. The inlet of the gas compressor is connected to a fluid container. One end of the exhaust tube is connected to the flexible bag and the other end is connected to the exhaust valve. The control mechanism is capable of controlling the gas compressor and the exhaust valve.

[0016] In yet another exemplary embodiment of the device for modulating molecular transport in the extracellular space of the brain, the fluid filling and discharging unit further includes an intake valve disposed between the gas compressor and the fluid container.

[0017] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the fluid filling and discharging unit further includes a flow meter connected to the control mechanism. The flow meter is provided in the intake pipe and the exhaust pipe and detects the volume of fluid flowing through the intake pipe and the exhaust pipe. The control mechanism is capable of integrating the total intake volume and / or the total exhaust volume based on the detection results of the flow meter. The device further includes a display unit connected to the control mechanism, and the control mechanism is capable of controlling the display unit to display the detection results of the detection mechanism, the total intake volume and / or the total exhaust volume.

[0018] In yet another exemplary embodiment of the device for modulating molecular transport in the extracellular space of the brain, the pressure mechanism includes a motor and a pressure plate. The control mechanism is capable of controlling the operation of the motor. The pressure plate is connected to an output end of the motor, and the motor is capable of driving the pressure plate to move and apply external pressure to brain tissue of an animal.

[0019] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the device further includes a pressure sensor. The pressure sensor is provided in the pressurizing mechanism and detects the pressure applied to the brain tissue from the pressurizing mechanism. The pressure sensor is connected to a control mechanism, and the control mechanism is capable of controlling the pressurizing mechanism based on the detection result of the pressure sensor so that the maximum value of the external pressure applied to the animal's brain tissue from the pressurizing mechanism satisfies a set value.

[0020] In yet another exemplary embodiment of the device for regulating molecular transport in the extracellular space of the brain, the device further includes an input mechanism connected to the control mechanism and capable of inputting operating parameters and on / off signals to the control mechanism, the operating parameters including a maximum set value for the external pressure applied to the animal's brain tissue by the pressure mechanism.

[0021] The following drawings are merely illustrative and explanatory of the present invention and are not intended to limit the scope of the present invention. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a schematic diagram illustrating an exemplary embodiment of a device for modulating molecular transport in the extracellular space of the brain. [Figure 2] FIG. 1 is a schematic diagram illustrating an exemplary embodiment of a device for modulating molecular transport in the extracellular space of the brain. [Figure 3] FIG. 2 is a schematic diagram of the pressurizing mechanism of the device shown in FIG. 1 that regulates molecular transport in the extracellular space of the brain. [Figure 4A] This is a nuclear magnetic resonance scan image from an effect experiment. [Figure 4B] This is a nuclear magnetic resonance scan image from an effect experiment. [Figure 4C] This is a nuclear magnetic resonance scan image from an effect experiment. [Figure 4D] This is a nuclear magnetic resonance scan image from an effect experiment. [Figure 5] This is a histogram of the feature values ​​of the brain ECS structure in the effect experiment. [Figure 6] This is a histogram of the feature values ​​of the brain ECS structure in the effect experiment. [Figure 7] This is a histogram of the feature values ​​of the brain ECS structure in the effect experiment. [Figure 8] This is a histogram of the feature values ​​of the brain ECS structure in the effect experiment. [Figure 9A] FIG. 1 is a two-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 9B] FIG. 1 is a two-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 9C] FIG. 1 is a two-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 9D] FIG. 1 is a two-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 10A] FIG. 1 is a three-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 10B] FIG. 1 is a three-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 10C] FIG. 1 is a three-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. [Figure 10D] FIG. 1 is a three-dimensional diagram reflecting molecular diffusion coefficients in the brain ECS. DETAILED DESCRIPTION OF THE INVENTION

[0023] In order to more clearly understand the technical features, objects and effects of the invention, specific embodiments of the present invention will be described with reference to the drawings, in which the same reference numerals designate elements that are the same or similar in structure but have the same function.

[0024] As used herein, "exemplary" means "serving as an example, instance, or illustration," and any illustration or embodiment described herein as "exemplary" is not to be construed as a preferred or more advantageous technical solution.

[0025] For the sake of simplicity, each drawing shows only the parts related to the present invention, but does not represent the actual structure of the product.

[0026] 1 is a schematic diagram illustrating an exemplary embodiment of a device for regulating molecular transport in the extracellular space of the brain. As shown in FIG. 1, the device for regulating molecular transport in the extracellular space of the brain includes a detection mechanism 10, a pressure mechanism 30, and a control mechanism 50.

[0027] The detection mechanism 10 can detect the automaticity of an animal. Regarding automaticity (abbreviated as automaticity), generally, when a particular system operates without external stimuli, the system has automaticity. In physiology, automaticity generally refers to the ability of a part or organ of a living organism to continue active activity without other stimuli. Examples of the automaticity of an animal include respiratory rhythm, heartbeat, brain pulsation rhythm, and vascular pulsation rhythm. When the automaticity is heartbeat, the detection mechanism 10 is, for example, an electrocardiograph.

[0028] The pressure mechanism 30 can apply external pressure to the animal's brain tissue. The external pressure refers to a force applied to the brain tissue from a structure other than the brain tissue. FIG. 3 is a schematic diagram of a specific structure of the pressure mechanism. Specifically, as shown in FIG. 3, in this exemplary embodiment, the pressure mechanism 30 includes a flexible bag 31, a fluid container 32 for storing a fluid, and a fluid filling / discharging unit 33. The flexible bag 31 can be filled with a fluid to apply external pressure to the animal's brain tissue. As shown in FIGS. 1 and 2, in use, the flexible bag 31 is disposed, for example, between the animal's skull 91 and the dura mater 92. However, this is not limiting. In other uses, the flexible bag 31 may be disposed, for example, on the side of the animal's dura mater 92 away from the skull 91. The flexible bag 31 is made of, for example, a polymer polyurethane material, has good flexibility, is sized to be disposed between the skull 91 and the dura mater 92, and is configured to be as thin as possible. FIG. 1 shows a state after fluid has been discharged from the flexible bag 31, and FIG. 2 shows a state after the flexible bag 31 is filled with fluid and pressure is applied to the brain tissue. The fluid is, for example, a gas, such as helium gas. In other exemplary embodiments, the fluid may be a liquid. A fluid filling and discharging unit 33 is connected to the flexible bag 31 and the fluid container 32. The fluid filling and discharging unit 33 can fill the flexible bag 31 with a fluid stored in the fluid container 32. The fluid filling and discharging unit 33 can also discharge the fluid in the flexible bag 31. In the exemplary embodiment, the fluid container 32 is, for example, a high-pressure gas storage tank.

[0029] 3 , in this exemplary embodiment, the fluid filling and discharging unit 33 includes, for example, an intake pipe 331, a gas compressor 332, an exhaust pipe 333, and an exhaust valve 334. One end of the intake pipe 331 is connected to the flexible bag 31. The gas compressor 332 has an outlet connected to the other end of the intake pipe 331 and an inlet connected to the fluid container 32. One end of the exhaust pipe 333 is connected to the flexible bag 31. The exhaust valve 334 is connected to the other end of the exhaust pipe 333, and the exhaust valve 334 is, for example, an electromagnetic valve.

[0030] The control mechanism 50 can control the pressurizing mechanism 30 based on the detection result of the detection mechanism 10 so that the rhythm of applying external pressure by the pressurizing mechanism 30 is associated with the automaticity of the animal. Specifically, in this exemplary embodiment, the control mechanism 50 can control the fluid charging / discharging unit 33, and further, the control mechanism 50 can control the gas compressor 332 and the exhaust valve 334.

[0031] The device for regulating molecular transport in the extracellular space of the brain is capable of applying external pressure to the brain tissue of an animal, and the rhythm of applying the external pressure is associated with the motility of the animal.

[0032] In the exemplary embodiment, fluid filling / draining unit 33 further includes an intake valve 336 disposed between gas compressor 332 and fluid container 32 .

[0033] In this exemplary embodiment, the detection mechanism 10 is, for example, an electrocardiograph, and the control mechanism 50 can extract, for example, a QRS wave and a T wave from the detection results of the detection mechanism 10. The control mechanism 50 can control the fluid filling and discharging unit 33 to fill the flexible bag 31 with fluid at the onset of the QRS wave and to discharge the fluid from the flexible bag 31 at the end of the T wave, which is advantageous for accurate control. Specifically, in this exemplary embodiment, the control mechanism 50 includes, for example, a preamplifier 51, a high-pass filter 52, a pulse amplitude and frequency extraction circuit 53, and a microcontroller 54. The electrocardiogram signal measured by the electrocardiograph has its baseline removed by the preamplifier 51 and the high-pass filter 52, and then enters the pulse amplitude and frequency extraction circuit 53, where it is shaped into a digital pulse and transmitted to the microcontroller 54, which can control the exhaust valve 334 and the intake valve 336.

[0034] 3 , in the exemplary embodiment, the fluid charging / discharging unit 33 further includes a flow meter 335. The flow meter 335 is provided in the intake pipe 331 and the exhaust pipe 333 to detect the volume of fluid flowing through the intake pipe 331 and the exhaust pipe 333. The flow meter 335 is connected to the control mechanism 50. The control mechanism 50 can calculate the total intake volume and / or the total exhaust volume based on the detection result of the flow meter 335. This makes it easier for the user to monitor the operating status of the device.

[0035] 1 , in an exemplary embodiment, the device for regulating molecular transport in the extracellular space of the brain further includes a display unit 60 connected to the control mechanism 50. The control mechanism 50 can control the display unit 60 to display the detection results of the detection mechanism 10, the total intake volume, the total exhaust volume, etc., to facilitate the user's monitoring of the operating status of the device.

[0036] 1 , in an exemplary embodiment, the device for regulating molecular transport in the extracellular space of the brain further includes a pressure sensor 70 that is provided in the pressure applying mechanism 30 and detects the pressure applied to the brain tissue from the pressure applying mechanism 30. The pressure sensor 70 is connected to the control mechanism 50. Based on the detection result of the pressure sensor 70, the control mechanism 50 can control the pressure applying mechanism 30 so that the maximum value of the external pressure applied to the animal's brain tissue from the pressure applying mechanism 30 satisfies a set value. This makes it easier to control the magnitude of the applied pressure.

[0037] As shown in FIG. 1 , in an exemplary embodiment, the device for regulating molecular transport in the extracellular space of the brain further includes an input mechanism 80 connected to the control mechanism 50. The input mechanism 80 allows operating parameters and on / off signals to be input to the control mechanism 50, and the operating parameters include a maximum setting value for the external pressure applied to the animal's brain tissue from the pressure mechanism 30. The input mechanism 80 is, for example, a key. However, without being limited thereto, in other exemplary embodiments, the input mechanism 80 may be, for example, a knob or a touch mechanism (e.g., a touch keyboard). This makes it easier for the user to control the device.

[0038] In an exemplary embodiment, the device for modulating molecular transport in the extracellular space of the brain further comprises a battery to provide the electrical energy required for operation.

[0039] In other exemplary embodiments, the pressure mechanism may further include, for example, a motor and a pressure plate. The control mechanism may control the operation of the motor. The pressure plate may be connected to an output end of the motor, and the motor may drive the pressure plate to move and apply external pressure to the animal's brain tissue. However, without being limited thereto, the pressure mechanism may be any other structure capable of applying external pressure to the animal's brain tissue.

[0040] Hereinafter, external pressure will be applied to the brain tissue of an animal, and the effect of the rhythm of the applied external pressure, which is associated with the animal's automaticity, on molecular transport in the extracellular space of the brain will be verified experimentally.

[0041] Effect experiment In this experiment, external pressure was applied to the rat's brain tissue using the rat's own arterial pulsation so that the rhythm of the applied external pressure was the same as the arterial pulsation rhythm.

[0042] According to the experimental requirements, the rats were randomly divided into four groups. Control group (Group A): No arterial patch was performed. Arterial patching group (group B): Arterial patching was performed and ipsilateral contrast medium was injected. Contralateral arterial patching group (group C): Arterial patching was performed and contrast medium was injected on the contralateral side. Group D: Arterial patch followed by gelatin sponge pad. Arterial patch was applied, ipsilateral contrast medium was injected, and gelatin sponge was applied.

[0043] 1. Treatment of experimental animals Arterial attachment: A rat's own artery is attached to the right epidural space of the brain. Ipsilateral contrast agent: The contrast agent is present in the right caudate nucleus of the rat. Contralateral contrast agent: Contrast agent is present in the left caudate nucleus of the rat. Gelatin sponge patch: To suppress the effects of arterial pulsation, a gelatin sponge is placed under the artery of the arterial patch.

[0044] 2. Nuclear magnetic resonance scanning and data post-processing The rats were placed in a prone position and subjected to nuclear magnetic resonance scanning. Images were collected until the contrast agent had completely diffused. The collected images are shown in Figure 4A, 4B, 4C, and 4D, corresponding to groups A, B, C, and D, respectively. In the figures, Cor: coronal image of the rat brain, Axi: axial image of the rat brain, Sag: sagittal image, Pre: image without contrast agent, and 15 to 240 min: time point of image collection.

[0045] The results of the nuclear magnetic resonance scans were post-processed using NanoDetect analysis software to obtain the following parameters: contrast agent half-life (T1 / 2), molecular diffusion coefficient in the brain ECS (D*), tortuosity of the brain ECS (λ), and volume fraction of the brain occupied by the brain ECS (α).These results are shown in Figures 5, 6, 7, and 8, respectively.

[0046] 3.Result analysis As shown in Figures 4A-4D, the contrast agent diffuses into the ipsilateral superficial cortex in the caudate nucleus region. The bright white contrast agent spots in Figures 4A-4D disappear at essentially the same rate, which is likely due to the insufficient resolution of the magnetic resonance imaging.

[0047] As can be seen from Figures 5-8, the arterial patch group (Group B) had a shorter contrast half-life (T1 / 2), a higher molecular diffusion coefficient (D*) in the cerebral ECS, a smaller tortuosity (λ) of the cerebral ECS, and a higher volume fraction (α) of the cerebral ECS compared to the other groups on days 1, 3, 7, and 15. These results suggest that arterial patching can accelerate ISF drainage in rat brain tissue, increase the diffusion of micromolecules, reduce tortuosity, and expand the cerebral ECS space. However, the contralateral arterial patch group (Group C) and the post-arterial patch gelatin sponge pad group (Group D) showed no statistically significant differences in the above parameters compared to the control group (Group A).

[0048] The conclusion that arterial patching can increase the molecular diffusion coefficient in the cerebral ECS is also evident from the D-mapping visualization graph of the molecular diffusion coefficient in the cerebral ECS. Figures 9A, 9B, 9C, and 9D are two-dimensional maps reflecting the molecular diffusion coefficient in the cerebral ECS, corresponding to groups A, B, C, and D, respectively. Figures 10A, 10B, 10C, and 10D are three-dimensional maps reflecting the molecular diffusion coefficient in the cerebral ECS, corresponding to groups A, B, C, and D, respectively. The color distribution in Figures 9A-9D and the height of the three-dimensional columns in Figures 10A-10D both reflect the magnitude of the molecular diffusion coefficient in the cerebral ECS. As shown in the figures, the arterial patching group (group B) had the highest molecular diffusion coefficient in the cerebral ECS compared to the other three groups, i.e., it had the strongest molecular diffusion capacity in the cerebral ECS.

[0049] 4. Experimental conclusions The above experimental results showed that cerebral ISF drainage was faster in rats in the arterial patching group (group B) compared with the control group (group A), and this change was detected on postoperative day 1 and persisted until postoperative day 15. However, no significant difference was observed in the contralateral arterial patching group (group C), indicating that arterial patching can effectively improve ISF drainage from the deep part of the ipsilateral brain to the cerebral surface for a long period of time, while no significant improvement was observed in ISF drainage in the contralateral brain, demonstrating the effect of regional control.

[0050] The results of the above experiment showed that the cerebral ISF drainage in the gelatin sponge pad group (Group D) after arterial patching was not significantly different from that in the control group (Group A). ​​That is, after suppressing the influence of arterial pulsation, cerebral ISF drainage returned to normal. As can be seen from the results in Figures 5 to 10, arterial patching can accelerate the cerebral ISF drainage rate, increase the cerebral ECS space occupancy rate, reduce tortuosity, and improve molecular diffusion capacity.

[0051] This indicates that epidural arterial attachment can promote molecular diffusion in the brain ECS and change the structure of the brain ECS.

[0052] In the above-mentioned efficacy experiments, external pressure was applied to the rat's brain tissue using the rat's own arterial pulsation. However, instead of arterial pulsation, external pressure was applied to the rat's brain tissue using the device for regulating molecular transport in the brain's extracellular space shown in Figure 1. The rhythm of the applied external pressure was made to match the animal's arterial pulsation rhythm, achieving the same effects as in the arterial patching group (Group B) in the above-mentioned efficacy experiments, namely, increasing the cerebral ISF drainage rate, increasing the cerebral ECS space occupancy rate, reducing tortuosity, and enhancing molecular diffusion capacity. This device for regulating molecular transport in the brain's extracellular space can effectively regulate molecular transport in the brain's extracellular space.

[0053] The physical method of the present invention for regulating molecular transport in the extracellular space of the brain comprises applying external pressure to the brain tissue of an animal, and the rhythm of the applied external pressure is associated with the automaticity of the animal. Examples of automaticity include respiratory rhythm, cardiac rhythm, cerebral pulsation rhythm, and vascular pulsation rhythm. The site at which the external pressure is applied is, for example, outside the dura mater of the animal. The method for applying the external pressure is, for example, the arterial patching method used in the above-mentioned efficacy experiment. The external pressure may be applied using the device for regulating molecular transport in the extracellular space of the brain shown in FIG. 1.

[0054] As can be seen from the above effect experiments, the physical method for regulating molecular transport in the extracellular space of the brain can effectively regulate molecular transport in the extracellular space of the brain.

[0055] The detailed description set forth above is merely a specific description of possible embodiments of the present invention, and does not limit the scope of protection of the present invention. Any equivalent embodiment or modification made without departing from the technical idea of ​​the present invention, such as a combination, division or duplication of features, should be included in the scope of protection of the present invention. [Explanation of symbols]

[0056] 10 Detection mechanism 30 Pressure Mechanism 31 Flexible Bag 32 Fluid container 33 Fluid filling and discharging unit 331 Intake pipe 332 Gas Compressor 333 Exhaust pipe 334 Exhaust valve 335 Flow meter 336 Intake valve 50 Control Mechanism 51 Preamp 52 High-pass filter 53 Pulse amplitude and frequency extraction circuit 54 Microcontrollers 60 display units 70 Pressure Sensor 80 Input mechanism 91 Skull 92 Dura mater 93 Pia mater

Claims

1. a detection mechanism (10) capable of detecting the motility of an animal, said detection mechanism (10) being an electrocardiograph; a pressure mechanism (30) capable of applying external pressure to the animal's brain tissue; a control mechanism (50) capable of controlling the pressure applying mechanism (30) based on the detection result of the detection mechanism (10) so that the rhythm of applying external pressure by the pressure applying mechanism (30) is associated with the automaticity of the animal, the control mechanism (50) being capable of extracting QRS waves and T waves from the detection result of the detection mechanism (10), and the control mechanism (50) being capable of controlling the pressure applying mechanism (30) to apply external pressure to the animal's brain tissue at the onset of the QRS wave, and being capable of controlling the pressure applying mechanism (30) to release the external pressure at the end of the T wave; 1. A device for regulating molecular transport in the extracellular space of the brain, comprising:

2. The device for regulating molecular transport in the extracellular space of the brain according to claim 1 , wherein the automaticity is respiratory rhythm, heart beat, cerebral pulsation rhythm or vascular pulsation rhythm.

3. The pressure mechanism (30) a flexible bag (31) that is filled with a fluid and thereby capable of applying external pressure to the animal's brain tissue; a fluid container (32) for storing a fluid; a fluid filling and discharging unit (33) connected to the flexible bag (31) and the fluid container (32); Including, 2. The device for regulating molecular transport in the extracellular space of the brain as described in claim 1, wherein the fluid filling and discharging unit (33) is capable of filling the flexible bag (31) with fluid stored in the fluid container (32), the fluid filling and discharging unit (33) is also capable of discharging the fluid in the flexible bag (31), and the control mechanism (50) is capable of controlling the fluid filling and discharging unit (33).

4. 4. The device for regulating molecular transport in the extracellular space of the brain as described in claim 3, wherein the control mechanism (50) is capable of controlling the fluid filling and discharging unit (33) to fill the flexible bag (31) with fluid at the start of the QRS wave and to discharge fluid from the flexible bag (31) at the end of the T wave.

5. The fluid filling and discharging unit (33) an intake pipe (331) whose one end is connected to the flexible bag (31); a gas compressor (332) whose outlet is connected to the other end of the intake pipe (331) and whose inlet is connected to the fluid container (32); an exhaust pipe (333) having one end connected to the flexible bag (31); an exhaust valve (334) connected to the other end of the exhaust pipe (333); Including, 4. The device for regulating molecular transport in the extracellular space of the brain according to claim 3, wherein the control mechanism (50) is capable of controlling the gas compressor (332) and the exhaust valve (334).

6. The fluid charging / discharging unit (33) further includes a flow meter (335), which is provided in the intake pipe (331) and the exhaust pipe (333) and detects the volume of fluid flowing through the intake pipe (331) and the exhaust pipe (333), and the flow meter (335) is connected to the control mechanism (50), which is capable of integrating a total intake volume and / or a total exhaust volume based on the detection result of the flow meter (335); 6. The device for regulating molecular transport in the extracellular space of the brain as described in claim 5, wherein the device further includes a display unit (60) connected to the control mechanism (50), and the control mechanism (50) is capable of controlling the display unit (60) to display the detection results of the detection mechanism (10), the total intake volume and / or the total exhaust volume.

7. The pressure mechanism (30) a motor whose operation is controllable by said control mechanism (50); a presser plate connected to an output end of the motor; Including, 2. The device for regulating molecular transport in the extracellular space of the brain of claim 1, wherein the motor is capable of driving the pressure plate so as to move and apply external pressure to brain tissue of an animal.

8. 2. The device for regulating molecular transport in the extracellular space of the brain as described in claim 1, further comprising a pressure sensor (70) provided in the pressure applying mechanism (30) and detecting the pressure applied from the pressure applying mechanism (30) to the brain tissue, the pressure sensor (70) being connected to the control mechanism (50), and the control mechanism (50) being capable of controlling the pressure applying mechanism (30) based on the detection result of the pressure sensor (70) so that the maximum value of the external pressure applied from the pressure applying mechanism (30) to the animal's brain tissue satisfies a set value.

9. 9. The device for regulating molecular transport in the extracellular space of the brain as described in claim 8, further comprising an input mechanism (80) connected to the control mechanism (50), wherein the input mechanism (80) allows operating parameters and on / off signals to be input to the control mechanism (50), and the operating parameters include a set value for a maximum external pressure applied to the animal's brain tissue from the pressure mechanism (30).

Images