Method for manufacturing connector for sensing and stimulating multiple intracerebral neural signal through formation of liquid metal wiring on surface of living body

Abstract

The present invention relates to a method for forming a stretchable wire that connects a neural probe with a wireless device through high-resolution direct printing of a liquid metal on a biological surface. More specifically, the present invention relates to: a method for manufacturing a connector capable of sensing and stimulating signals in various regions of the brain by forming a stretchable wire at a high resolution directly on a biological surface such as the skull through 3D printing with an ink containing a gallium-based liquid metal alloy, wherein the connector connects a neural probe for sensing and stimulating intracranial neural signals with a wireless device; and a multi-channel intracranial neural signal detection and stimulation connector manufactured by the manufacturing method.

Description

Method for manufacturing a connector for detecting and stimulating multiple intracranial neural signals by forming liquid metal wiring on a biological surface

[0001] The present invention relates to a method for forming a direct flexible wiring on a biological surface using a high-resolution liquid metal printing method, and to a connector for detecting and stimulating multiple intracranial neural signals manufactured by the method.

[0002] The brain is a complex, three-dimensional structure that communicates through the constant generation and transmission of signals between neurons. These neural activity and firing patterns control bodily functions, consciousness, and memory formation. Subtle abnormalities in neural activity in the brain can lead to neurological disorders such as epilepsy, Parkinson's disease, Alzheimer's disease, depression, and chronic pain. Therefore, a flexible intracranial sensing and stimulation system, including electrodes implanted into the body, is needed to detect abnormalities in neural activity or to confirm and regulate functional connectivity for normal brain function.

[0003]

[0004] In the case of connectors applied to existing brain detection and stimulation systems, 1) they must be able to be inserted directly, so the electrodes are in a rigid form (mainly made of Si and solid electrodes), 2) they are manufactured based on pre-fabricated PCBs, so there is no design flexibility, and the positions of the electrodes are mostly fixed, which limits their ability to be manufactured to fit the size of the skull and brain of each individual, 3) during electrode insertion surgery, a hole must be drilled according to the structure of the PCB, and there is the inconvenience of having to change the structural design of the PCB from the beginning in order to target various diseases depending on the individual, and 4) since the brain signal detection / stimulation wireless device and the PCB must be inserted into the brain in a pre-assembled state, the connection between the device and the PCB is mostly manufactured in an inflexible (rigid) form, making it difficult to handle (bulky), which can restrict the individual's behavior and has limitations that can affect the results of behavioral experiments.

[0005]

[0006] Meanwhile, various conductive inks and printable liquid materials, such as mercury, are attracting attention as next-generation flexible wiring electrode materials due to their excellent flexibility and stretchability due to their liquid nature. However, additional heat treatment or UV exposure and drying processes are required after printing. Furthermore, mercury, a representative liquid metal, is toxic. These limitations restrict the direct use of these materials on animals, making it impossible to form circuits directly on surfaces.

[0007]

[0008] Accordingly, the inventors of the present invention have made efforts to develop a new connector to overcome the limitations of the existing connectors described above, and as a result, they have completed the present invention by confirming that by forming a flexible wire directly on a biological surface such as a skull using a high-resolution printing method with a gallium-based liquid metal alloy, it is easy to form a desired design, can be manufactured to match the differences in the shape and size of the skull and brain of each individual, and can be utilized as a connector that does not restrict the movement of an animal due to its small volume by forming it directly on the biological surface, and is capable of sensing and stimulating various regions of the brain.

[0009]

[0010] [Prior Art Literature]

[0011] [Patent Document]

[0012] Republic of Korea Patent No. 10-1608209

[0013]

[0014] [Non-patent literature]

[0015] Gustavo Rios et al., Nano Lett. 16, 11, 6857-6862, 2016 (https: / pubs.acs.org / doi / 10.1021 / acs.nanolett.6b02673)

[0016] Ashley L Juavinett et al., Elife 8, e47188, 2019 (https: / elifesciences.org / articles / 47188)

[0017] Mihaly Voroslakos et al., Elife 10, e65859, 2021 (https: / elifesciences.org / articles / 65859)

[0018]

[0019] The purpose of the present invention is to provide a method for manufacturing a connector capable of detecting and stimulating signals in various regions of the brain by forming a flexible wiring directly on a biological surface such as a skull using 3D printing with a gallium-based liquid metal alloy at high resolution, thereby connecting a neural probe for detecting and stimulating signals in the brain and a wireless device.

[0020] Another object of the present invention is to provide a connector capable of detecting and stimulating signals in various regions of the brain, comprising flexible wiring formed by direct printing of a gallium-based liquid metal alloy onto a biological surface, such as the skull, at high resolution using 3D printing.

[0021] Another object of the present invention is to provide a brain signal detection and stimulation system, which is configured by connecting a neural probe and a wireless device to a flexible wiring according to the present invention.

[0022]

[0023] In order to achieve the above object, the present invention provides a method for manufacturing a connector for detecting and stimulating multiple intracranial neural signals, comprising a process of forming wiring by directly printing on a biological surface of an animal other than a human through 3D printing using ink containing eutectic gallium-indium (EGaIn), a room-temperature liquid metal alloy, and characterized in that the wiring is formed to be connected to a neural probe and a wireless device.

[0024] In addition, the present invention provides a connector for detecting and stimulating multiple intracranial neural signals, characterized in that it includes wiring formed by directly printing on a biological surface of an animal other than a human through 3D printing using ink containing eutectic gallium-indium (EGaIn), a room-temperature liquid metal alloy, and the wiring is formed such that a neural probe and a wireless device are connected.

[0025] In addition, the present invention provides a multiple intracranial neural signal detection and stimulation system including a connector for multiple intracranial neural signal detection and stimulation according to the present invention.

[0026] In addition, the present invention provides a system for preventing and treating a brain nervous system disease, including a connector for detecting and stimulating multiple brain neural signals according to the present invention.

[0027] In addition, the present invention provides a method for preventing and treating a brain nervous system disease using a connector for detecting and stimulating multiple brain nerve signals according to the present invention.

[0028] The present invention can manufacture multiple connectors for detecting and stimulating intracranial neural signals by using a method for forming flexible wiring connecting a neural probe for detecting and stimulating intracranial signals and a wireless device through high-resolution direct printing of liquid metal on a biological surface such as a skull.

[0029] The present invention has the advantages of 1) being formed by directly printing on a biological surface, so that it can be easily formed into a desired design, and can be freely changed in real time to fit the shape and size of the skull and brain, which are different for each individual, and can be customizable according to the shape and size of the skull and brain, which are different for each individual, 2) inserting a neural probe into a desired target brain area and connecting a wireless device to the corresponding location does not require an additional process for design change, and freely designing the wiring according to the size and shape of the skull, 3) forming it by directly printing along the curvature of the skull and brain, so that it can be formed conformally using a high-resolution printing method, and having a small volume that does not restrict the movement of the animal, and 4) forming the wiring with liquid metal, so that it can maintain its shape and be passivated by an oxide film formed when exposed to the air without additional processing.

[0030] The present invention develops a patient-specific connector capable of detecting and stimulating neural signals in multiple brain regions on a biological surface, and can be usefully used for the prevention and treatment of various neurological diseases such as stroke, dementia, Parkinson's disease, pain diseases, and mental illness.

[0031] Figure 1 is a schematic diagram of a 3D printer for forming liquid metal direct stretchable wiring used in one embodiment of the present invention.

[0032] FIG. 2 is a drawing showing a process of forming a flexible wiring directly on the skull of an experimental animal using a high-resolution printing method according to one embodiment of the present invention:

[0033] Left: High-resolution liquid metal direct printing scene of a mouse skull;

[0034] Center: Image of liquid metal flexible wiring formed on the mouse skull; and

[0035] Right: A close-up of the center image.

[0036] FIG. 3 is a schematic diagram showing that electrical connection between a neural probe for detecting brain signals and a wireless device is possible by directly printing liquid metal on a skull according to one embodiment of the present invention.

[0037] FIG. 4 is a drawing showing a diffuse wiring formed on the skull of an experimental animal according to one embodiment of the present invention:

[0038] Left: Image of flexible wiring formed via direct liquid metal printing on the mouse skull, connecting a neural probe and a wireless device;

[0039] Center: Schematic illustration of the liquid metal flexible wiring connecting 12 neural probes to a wireless device on the mouse skull; and

[0040] Right: Impedance verified through 12 liquid metal flexible wires.

[0041] FIG. 5 is a drawing showing the results of measuring neural signals in the brain read from 12 neural probes connected to the diffuse wiring formed on the skull of an experimental animal according to one embodiment of the present invention:

[0042] Left: Image of neural signals in the brain read from 12 neural probes connected to liquid metal flexible wiring formed on the mouse skull; and

[0043] Right: Spike images detected from 12 neural probes.

[0044] FIG. 6 is a drawing showing a flexible wiring formed on the skull of an experimental animal and an NFC chip connected thereto according to one embodiment of the present invention:

[0045] Left: SEM image of a 3D-structured liquid metal stretchable wire formed on a mouse skull and an NFC chip connected to it; and

[0046] Right: Actual photo of the 3D structure of liquid metal stretchable wiring formed on the mouse skull and the NFC chip connected to it.

[0047] FIG. 7 is a diagram showing stable signal detection of a wireless system comprising a flexible wiring formed on the skull of an experimental animal, 12 neural probes, and an NFC chip according to one embodiment of the present invention:

[0048] Left: Photo of a mouse with a system formed on the skull consisting of a neural probe, liquid metal wiring of 3D structure, and an NFC chip;

[0049] Center: Image of identifying neural signal data in the brain via an NFC-based system through cell phone tagging; and

[0050] Right: Image of neural signals read by the system.

[0051] Hereinafter, the present invention will be described in detail. In describing the present invention, detailed descriptions of related known structures or functions may be omitted.

[0052] Terms or words used in this specification and claims should not be interpreted as limited to their usual or dictionary meanings, but should be interpreted with meanings and concepts that are consistent with the technical aspects of the present invention.

[0053] The embodiments described in this specification and the configurations illustrated in the drawings are preferred embodiments of the present invention, and do not represent all of the technical ideas of the present invention, so there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0054]

[0055] The present invention

[0056] A process for forming wiring by directly printing on the biological surface of an animal other than a human being through 3D printing using ink containing eutectic gallium-indium (EGaIn), a room-temperature liquid metal alloy.

[0057] The above wiring is characterized in that it is formed to be connected to a neural probe and a wireless device.

[0058] A method for manufacturing a connector for detecting and stimulating multiple intracranial neural signals is provided.

[0059] In the above manufacturing method, the room temperature liquid metal is an electrical and optical material that is in a liquid state at room temperature and is not subject to tensile restrictions, and thus has stretchable and self-healable characteristics because it is in a liquid state. The room temperature liquid metal has excellent electrical properties with a resistivity value similar to that of general metals, and has a lower Young's modulus than general metals. The liquid metal exposed to air can react with oxygen to form a thin oxide film to exhibit a unique three-dimensional structure. The oxide film can be formed immediately on the surface of the room temperature liquid metal or its thickness can be intentionally controlled, and the thickness of the oxide film can be in the range of 0.1 nm to 30 nm. The EGaIn preferably contains 65 to 80 wt% of gallium and 20 to 25 wt% of indium, and more preferably contains 75 to 76 wt% of gallium and 24 to 25 wt% of indium.

[0060] In the above manufacturing method, it is preferable to use the ink containing the eutectic gallium-indium in its pure state without subsequent processing in order to maintain high electrical conductivity and biocompatibility.

[0061] In the above manufacturing method, the 3D printing can be performed by a 3D printing device including a nozzle, a 6-axis stage, and a pneumatic pressurization unit. In the 3D printing device, the nozzle is a part from which liquid metal ink is ejected, and the wiring thickness can be determined according to the inner diameter of the nozzle. The 6-axis stage can have x, y, z directions and two tilting axes and one rotating axis, and the pneumatic pressurization unit can provide a constant pressure to the nozzle containing the liquid metal ink to eject the liquid metal. Using the 3D printing device, a gallium-based liquid metal alloy can be formed as a wiring with a line width of at least several micrometers on a living surface.

[0062] In the above manufacturing method, the animal other than a human may be any one selected from the group consisting of a mouse, rat, guinea pig, rabbit, hamster, dog, cat, cow, pig, horse, sheep, goat, monkey, and ape, but is not limited thereto, and small animals such as a mouse, rat, and rabbit are preferred.

[0063] In the above manufacturing method, the biosurface may be various surface areas of the brain or skull.

[0064] In the above manufacturing method, it is preferable that the wiring form a two-dimensional pattern, a three-dimensional pattern, or a pattern in which two-dimensional and three-dimensional structures are mixed, and the wiring pattern can be freely designed to match the area of ​​the brain where a neural signal is to be detected.

[0065] In the above manufacturing method, the wiring can form one or more multiple wirings for connection with one or more multiple neural probes, and can be designed to enable detection and stimulation in various brain regions by inserting a neural probe into a desired target brain region and connecting a wireless device to the location.

[0066]

[0067] In addition, the present invention

[0068] Includes wiring formed by direct printing on the biological surface of an animal other than a human through 3D printing using ink containing eutectic gallium-indium (EGaIn), a room temperature liquid metal alloy;

[0069] The above wiring is characterized in that it is formed so that a neural probe and a wireless device are connected.

[0070] Provides a connector for detecting and stimulating multiple intracranial neural signals.

[0071] The above EGaIn preferably contains 65 to 80 wt% of gallium and 20 to 25 wt% of indium, and more preferably contains 75 to 76 wt% of gallium and 24 to 25 wt% of indium.

[0072] It is preferable to use the ink containing the above eutectic gallium-indium in its pure state without subsequent processing to maintain high electrical conductivity and biocompatibility.

[0073] The animal other than the human may be any one selected from the group consisting of, but not limited to, mice, rats, guinea pigs, rabbits, hamsters, dogs, cats, cows, pigs, horses, sheep, goats, monkeys, and apes, and small animals such as mice, rats, and rabbits are preferred.

[0074] The above biosurface may be various surface areas of the brain or skull.

[0075] It is preferable that the above wiring form a two-dimensional pattern, a three-dimensional pattern, or a pattern in which two-dimensional and three-dimensional structures are mixed, and the wiring pattern can be freely designed to match the area of ​​the brain where a neural signal is to be detected.

[0076] The above wiring can form one or more multiple wirings for connection with one or more neural probes, and can be designed to enable detection and stimulation in various brain regions by inserting a neural probe into a desired target brain region and connecting a wireless device to the location.

[0077]

[0078] In addition, the present invention provides a multiple intracranial neural signal detection and stimulation system including a connector for multiple intracranial neural signal detection and stimulation according to the present invention.

[0079] The system may include bioelectrodes, external measuring devices, external stimulators, wireless power transmitters, and / or devices for communication.

[0080]

[0081] In addition, the present invention provides a system for preventing and treating a brain nervous system disease, including a connector for detecting and stimulating multiple brain neural signals according to the present invention.

[0082] In addition, the present invention provides a method for preventing and treating a brain nervous system disease using a connector for detecting and stimulating multiple brain nerve signals according to the present invention.

[0083] The above-mentioned neurological disease is preferably one selected from the group consisting of stroke, dementia, epilepsy, Parkinson's disease, pain disease, mental illness, peripheral neuropathy, and brain tumor, but is not limited thereto.

[0084]

[0085] Hereinafter, the present invention will be described in detail through the following examples and experimental examples.

[0086] However, the following examples and experimental examples are only illustrative of the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

[0087]

[0088] <Example 1> Formation of a connector on an animal's biosurface using high-resolution liquid metal printing

[0089] <1-1> Preparation of ink including gallium-based room-temperature liquid alloy

[0090] A gallium-based alloy ink was prepared with a composition of 75.5% gallium and 24.5% indium by weight, respectively.

[0091]

[0092] <1-2> Preparing the 3D printer

[0093] The printing system used to form liquid metal direct stretchable wiring consists of a nozzle, a 6-axis stage, and a pneumatic pressurization unit. The nozzle is the part where the liquid metal ink is ejected, and the wiring thickness is determined by the inner diameter of the nozzle. The 6-axis stage is a self-made system that combines two commercially available stages and has x, y, z directions and two tilting axes and one rotating axis. The pneumatic pressurization unit is the part that provides a constant pressure to the nozzle containing the liquid metal ink to eject the liquid metal.

[0094]

[0095] <1-3> Preparation of experimental animals

[0096] Eight-week-old mice (C57BL / 6N) were used. Mice were raised in an environment of 23°C, 50% humidity, and a 12 / 12 light / dark cycle.

[0097]

[0098] <1-4> Forming connectors by printing on animals

[0099] A nozzle containing liquid metal was applied with a constant pressure of 60 psi on the mouse skull and moved at a speed of 80 μm / s to perform printing. To obtain neural signals from 12 neural probes on the mouse skull, namely 4 points in the visual cortex (top row), 4 points in the hippocampus (middle row), and 4 points in the motor cortex (bottom row), a flexible wiring was formed (Figs. 2 and 4). By forming the wiring of the 3D structure, an NFC chip and a neural probe were connected to form an NFC-based system on the skull (Fig. 5).

[0100]

[0101] <Experimental Example 1> Measurement of electrical connection and stable signal detection

[0102] Impedance, which represents the electrical characteristics of wiring, was measured using a potentiostat. The resistance value was measured considering the phase difference between the voltage and current that occurs when an AC voltage is applied. In the case of electrodes and wiring that obtain signals within the brain, it was important to determine the impedance at 1 kHz, which is the frequency band of the signal, and this was determined. It represents a single unit potential, a neural signal generated within the mouse brain that contains a signal of 300 to 5,000 Hz. A single unit potential is a signal that represents the electrophysiological activity of a neuron, and when a peak greater than five times the standard deviation of the entire signal occurred, it was detected as a spike. Spikes that occurred in 12 regions were organized.

[0103] As a result, we confirmed that the NFC-based system reliably reads brain signals. This confirmed the functionality of direct stretchable wiring on a biosurface using high-resolution liquid metal printing (Figs. 5 and 7).

Claims

1. A process for forming wiring by directly printing on a biological surface of an animal other than a human being through 3D printing using ink containing eutectic gallium-indium (EGaIn), a liquid metal alloy at room temperature. The above wiring is characterized in that it is formed to be connected to a neural probe and a wireless device. A method for manufacturing a connector for detecting and stimulating multiple intracranial neural signals.

2. A method for manufacturing a connector for detecting and stimulating multiple brain neural signals, characterized in that in the first paragraph, the eutectic gallium-indium is an alloy containing 75 to 76 wt% of gallium and 24 to 25 wt% of indium.

3. A method for manufacturing a connector for detecting and stimulating multiple brain neural signals, characterized in that in paragraph 1, the animal other than a human is any one selected from the group consisting of a mouse, a rat, a guinea pig, a rabbit, a hamster, a dog, a cat, a cow, a pig, a horse, a sheep, a goat, a monkey, and a simian.

4. A method for manufacturing a connector for detecting and stimulating multiple brain neural signals, characterized in that the biological surface in the first paragraph is the brain or skull.

5. A method for manufacturing a connector for detecting and stimulating multiple brain neural signals, characterized in that in the first paragraph, the wiring forms a two-dimensional pattern, a three-dimensional pattern, or a pattern in which two-dimensional and three-dimensional structures are mixed.

6. A method for manufacturing a connector for detecting and stimulating multiple brain neural signals, characterized in that in the first paragraph, the wiring forms one or more multiple wires for connection with one or more multiple neural probes.

7. Includes wiring formed by direct printing on the biological surface of an animal other than a human, using 3D printing using ink containing eutectic gallium-indium (EGaIn), a liquid metal alloy at room temperature. The above wiring is characterized in that it is formed to be connected to a neural probe and a wireless device. Connector for detection and stimulation of multiple intracranial neural signals.

8. A brain neural signal detection and stimulation system including a connector according to Article 7.

9. A system for prevention and treatment of brain and nervous system diseases including a connector according to Article 7.

10. A system for preventing and treating a brain nervous system disease, characterized in that in paragraph 9, the brain nervous system disease is any one selected from the group consisting of stroke, dementia, epilepsy, Parkinson's disease, pain disease, mental illness, peripheral neuromuscular disease, and brain tumor.

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