KR102568398B1 - Muti Channel Array Element Using Hybrid Graphene Electrode Brain Inserted - Google Patents

Abstract

The present invention relates to a multi-channel array device using graphene composite electrodes for brain implantation, each graphene composite electrode that contacts the surface of the cerebral cortex to measure a signal generated in the brain or transmits an external stimulus to the brain; Connection parts made of each gold electrode electrically connected to each graphene composite electrode to transmit an electric signal; and a communication pad connected to each gold electrode and connected to a circuit board for measurement and stimulation outside the brain. Each graphene composite electrode includes a first carbon structure, a metal layer, and a second carbon structure.

Description

Multi-channel array element using a graphene composite electrode for brain insertion {Muti Channel Array Element Using Hybrid Graphene Electrode Brain Inserted}

The present invention relates to a multi-channel array device using a brain-implanted graphene composite electrode.

A brain implantable medical device is a device that includes multiple microelectrodes that obtain nerve signals or deliver electrical impulses, and serve as a neural interface that connects neurons to electronic circuits.

Electrical stimulation has fewer side effects than drug therapy or ablation, and has the advantage of being reversible and adjustable.

In the case of commercially available brain implantable medical devices that deliver electrical stimulation, since they use penetrating electrodes that stimulate the deep brain, there is a problem of causing serious damage and infection in the deep brain.

Korean Registered Patent No. 10-1237052

In order to solve the above problems, the present invention provides a multi-channel array device using a low-noise graphene composite electrode for brain implantation, which can minimize skull opening when inserted into the brain and has excellent adhesion to living tissue.

In order to achieve the above technical problem, the present invention

Each graphene composite electrode that contacts the surface of the cerebral cortex to measure a signal generated in the brain or transmits an external stimulus to the brain;

Connection parts made of each gold electrode electrically connected to each graphene composite electrode to transmit an electric signal; and

It includes a communication pad connected to each gold electrode and connected to a circuit board for measurement and stimulation from outside the brain, and each graphene composite electrode is graphene for brain insertion composed of a first carbon structure, a metal layer, and a second carbon structure. Provided is a multi-channel array device using a composite structure electrode.

The first carbon structure and the second carbon structure are graphene, and the metal layer is made of gold.

The thickness of the first graphene and the second graphene is formed to be 0.335 nm, and the thickness of the metal layer is formed to be 6 nm.

The present invention provides a multi-channel array device using a graphene composite structure electrode for brain implantation, and has excellent flexibility and mechanical properties, and can be injected only by opening a very small area of the skull, making it a device for measuring brain signals and electrical stimulation with low noise. can function

The present invention lowers the electrochemical impedance by thinly depositing gold between the graphenes, shows high transmittance (70.64%), and has excellent effects on long-term stability in the living body.

1 and 2 are views showing the configuration of a multi-channel array device using a graphene composite electrode for brain implantation according to an embodiment of the present invention.
3 is a view showing a side layer structure of a multi-channel array element using a graphene composite electrode according to an embodiment of the present invention.
4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain implantation according to an embodiment of the present invention.
5 is a diagram showing transmittance of a graphene composite electrode according to an embodiment of the present invention.
6 is a diagram showing impedance results according to 4 nm, 6 nm, and 8 nm gold thicknesses according to an embodiment of the present invention.
FIG. 7 is a graph showing sheet resistance and transmittance of a graphene composite electrode according to an embodiment of the present invention and other previous materials.
8 is a diagram showing electrochemical impedance spectroscopy of a graphene composite electrode according to an embodiment of the present invention.
9 and 10 are diagrams illustrating long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to embodiments of the present invention.
11 is a diagram showing the signal-to-noise ratio (SNR) of a graphene composite electrode according to an embodiment of the present invention and the signal-to-noise ratio of other materials beforehand.
12 is a diagram showing comparison of measurement of brain signals in vivo of neural activity using a graphene composite electrode and a gold electrode according to an embodiment of the present invention.
13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using a graphene composite electrode in an awake model according to an embodiment of the present invention.

Hereinafter, with reference to the drawings, the present invention will be described in detail so that those skilled in the art can easily practice it. In describing the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description will be omitted.

In addition, in this application, terms such as "comprise" or "have" are intended to designate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, but one or more other It should be understood that the presence or addition of features, numbers, steps, operations, components, parts, or combinations thereof is not precluded. In this application, singular expressions may include plural expressions unless the context clearly dictates otherwise.

The multi-channel array device using the graphene composite electrode for brain implantation according to the present invention is used as a graphene composite electrode having excellent flexibility and mechanical properties and excellent brain signal measurement characteristics.

Previously studied platinum and gold electrodes are opaque and limit a wide range of biological applications such as optogenetics.

In the case of PEDOT:PSS electrodes, there are difficulties in long-term use in vivo due to their water-soluble properties. In addition, transparent materials such as ITO (Indium Tin Oxide) are also used as electrode materials for transparent microelectrode arrays, but are vulnerable to cracking and mechanical degradation when used in flexible neural interfaces.

On the other hand, the graphene composite electrode of the present invention lowers electrochemical impedance by thinly depositing 6 nm thick gold between graphenes, shows high transmittance (70.64%), and has excellent long-term stability in vivo.

Since the total thickness of the multi-channel array element is only 6 to 6.5 μm, there is an advantage in that contact force is strong and conformal contact is formed on the surface of the cerebral cortex.

Devices based on these graphene composite structures and structures are planted on the surface of the cerebral cortex for a long period of time in an actual rat model to measure brain signals in real time and provide electrical stimulation without the influence of anesthetics to alleviate epilepsy. Based on this, clinical applications for therapeutic intervention in many brain diseases can be made possible.

1 and 2 are views showing the configuration of a multi-channel array element using a graphene composite electrode for brain implantation according to an embodiment of the present invention, and FIG. 3 is a multi-channel array device using a graphene composite electrode according to an embodiment of the present invention. It is a diagram showing the side layer structure of the channel array element.

A multi-channel array device 100 using a graphene composite electrode for brain implantation according to an embodiment of the present invention includes a contact part 110, a connection part 120, and a communication pad 130.

The contact portion 110 forms a plurality of hybrid graphene electrodes 111 and through holes at regular intervals. Here, the through hole is a hole through which liquid material present on the brain surface is discharged, and serves to help the graphene composite electrode 111 contact the brain surface.

The multi-channel array element 100 is provided with each graphene composite electrode 111 that contacts the surface of the cerebral cortex to measure a signal generated in the brain or transmits an external stimulus to the brain, and each graphene composite electrode 111. A connection part 120 made up of each gold electrode 121 electrically connected to transmit an electrical signal, and a communication pad 130 connected to each gold electrode 121 and connected to a circuit board for measurement and stimulation outside the brain ).

Each graphene composite electrode 111 is formed in a quadrangular shape and spaced apart from each other by a predetermined distance, and is a portion that contacts the surface of the cerebral cortex.

The contact unit 110 contacts the surface of the cerebral cortex to measure signals generated in the brain or transmit external stimuli to the brain.

The communication pad 130 may be fixed to the surface of the scalp or drawn out of the brain. The communication pad 130 is a contact board connected to a circuit board (eg, FPCB, etc.) for measurement and stimulation outside the brain.

The communication pad 130 is extended to a certain length from each gold electrode 121 to form multiple channels, and is formed wider than the width of the connection part 120 to facilitate coupling of FPCBs.

The communication pad 130 is connected to the FPCB from the outside of the brain, and the FPCB is connected to an external PC through a connection member to analyze and display the received brain signal with a built-in program.

The connection part 120 connects the contact part 110 and the communication pad 130 with the gold electrode 121 that is a wiring electrode connected to each graphene composite electrode 111 .

Each of the gold electrodes 121 is formed long with a predetermined length, and is connected to correspond to one side of each graphene composite electrode 111 .

1 and 2, the multi-channel array element 100 of the present invention has 32 channels, 64 channels, 128 channels, etc. through a plurality of graphene composite electrodes 111 and a plurality of gold electrodes 121. It can be composed of multiple channels of

As shown in FIG. 3, the multi-channel array device 100 includes a polyimide substrate 101 on a glass substrate (not shown) and a graphene composite electrode (Hybrid Graphene) on the polyimide substrate 101. An electrode 111 and a gold electrode 121 are formed, and an insulating layer 102 formed on the graphene composite electrode 111 and the gold electrode 121 is included.

The polyimide substrate 101 has a thickness of 4.2 μm, serves as a support substrate for supporting the graphene composite electrode 111, and is made of a material having a flexible property in order to achieve the object of the present invention. . In addition, since only the open graphene electrode portion of the device should be attached to living tissue, it is preferable to be an insulator.

Therefore, although not limited thereto, Parylene, PET (Polyethylene terephthalate), PC (Polycarbonate), PES (Polyethersulfone), PDMS (Polydimethylsiloxane), PVP (Polyvinylpyrrolidone), PEN (Polyethylene naphthalate), PVC (Polyvinyl chloride), and these It may be any one selected from the group consisting of mixtures of. In the device of the present invention, it is preferable to use PI (polyimide) as the material of the substrate in terms of excellent chemical resistance to various chemicals used in the manufacturing process and excellent mechanical properties capable of withstanding mechanical deformation even at a thickness of several μm. do.

The insulating layer 102 is an SU-8 passivation layer and is etched to expose a portion of the graphene composite electrode 111, and a portion of the graphene composite electrode 111 and a portion of the gold electrode 121 are adjacent to each other. to be connected In other words, each gold electrode 121 has a thickness of 40 nm, and connects the graphene composite electrode 111 to one end to transmit the brain signal measured by the graphene composite electrode 111 or send a stimulus signal to the brain. plays a role in conveying

The insulating layer 102 has a thickness of 2 μm and is etched to expose a portion of the graphene composite electrode 111 .

Each graphene composite electrode 111 is stacked in the order of the first carbon structure 111a, the metal layer 111b, and the second carbon structure 111c, and preferably has a thickness of 6.67 nm.

The size of the graphene composite electrode 111 is approximately square and 250×250 μm ² .

The first carbon structure 111a is made of N-layer graphene, carbon nanotubes, or the like. The first carbon structure 111a of the present invention is formed of graphene with a thickness of 0.335 nm.

The metal layer 111b may be made of one of various metal materials such as Novel Metal, such as gold, platinum, silver (Ag), copper (Cu), nickel (Ni), iron (Fe), and pt. , with a thickness of 4 to 10 nm. Preferably, the metal layer 111b of the present invention is formed of gold with a thickness of 6 nm.

The second carbon structure 111c is made of N-layer graphene, carbon nanotubes, or the like. The second carbon structure 111c of the present invention is formed of graphene with a thickness of 0.335 nm.

Hereinafter, the first carbon structure 111a and the second carbon structure 111c of the present invention may be referred to as a first graphene 111a and a second graphene 111c for convenience of explanation.

The first graphene 111a or the second graphene 111c is a portion that directly contacts the surface of the cerebral cortex. The reason why graphene is used is to prevent oxidation-reduction reactions of the metal layer 111b, to suppress electrical reactions of the metal, to minimize noise signals when measuring brain signals, and to prevent corrosion of the metal.

As another embodiment, the graphene composite electrode 111 of the present invention is composed of first graphene 111a, gold 111b, and second graphene 111c, but is not limited thereto, the first graphene, Various layer configurations such as gold, second graphene, and gold may be applied.

Each of the first graphene 111a and the second graphene 111c may be formed as a multi-layer graphene electrode layer, or a layer in which the metal layer 111b is mixed with the graphene electrode layer may be formed.

The metal layer 111b may be composed of multiple metal layers or a layer in which a graphene electrode layer is mixed with the metal layer 111b may be formed.

The multi-channel array device 100 includes a polyimide substrate 101, a hybrid graphene electrode made of first graphene 111a, gold 111b, and second graphene 111c. The size and thickness of the electrode 111 and the gold electrode 121 may be changed according to conditions.

4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain implantation according to an embodiment of the present invention.

The manufacturing method of the multi-channel array element 100 using the graphene composite electrode for brain implantation according to an embodiment of the present invention includes the first step (S100), the second step (S101), the third step (S102), and the fourth step (S102). Step S103, a fifth step S104 and a sixth step S105 are included.

In the first step (S100), a graphene monolayer is grown on a copper substrate by passing hydrogen and methane gas through a furnace equipment using a CVD (Chemical Vapor Deposition) method (graphene growth process).

In the second step (S101), a polymethlymethacrylate (PMMA) film is coated on the two grown graphene monolayers, and then the copper substrate is etched using an aluminum persulfate (APS) solution (copper etching process).

In the third step (S102), the copper substrate is etched by the APS solution, and impurities are washed using distilled water (DI Water) (cleaning process).

In the fourth step (S103), a thin gold film (6 nm) is deposited after removing the graphene monolayer of the third step (S102) and the PMMA of (1) with acetone and transferring them to a substrate requiring an electrode (Physical Vapor Deposition method) .

In the fifth step (S104), the graphene monolayer of the third step (S102) and (2) are transferred onto the fourth step (S103).

In the sixth step ( S105 ), PMMA is removed using distilled water drying and acetone to complete the graphene composite electrode 111 having a graphene composite structure.

5 is a diagram showing transmittance of a graphene composite electrode according to an embodiment of the present invention, FIG. 6 is a diagram showing impedance results according to 4nm, 6nm, and 8nm gold thicknesses according to an embodiment of the present invention, and FIG. It is a diagram showing the sheet resistance and transmittance of the graphene composite electrode according to an embodiment of the present invention and other previous materials.

The graphene composite electrode 111 has low electrochemical impedance and high transmittance at the same time by thinly depositing 6 nm thick gold (Au) 111b between the first graphene 111a and the second graphene 111c. (70.64%), and has an excellent effect on long-term stability in vivo (FIG. 5).

6 shows impedance results according to 4 nm, 6 nm, and 8 nm gold thicknesses in the graphene composite electrode 111.

The graphene composite electrode 111 showed good results in electrical conductivity and transmittance (70.64%) based on sheet resistance (24.37Ω/square).

The thin gold thickness deposited between the graphene 111a and 111c in the graphene composite electrode 111 is an important variable in determining the electrical and optical characteristics of the electrode.

As shown in FIG. 7, sheet resistance and transmittance were measured while changing the thickness (5 nm, 6 nm, 7 nm) of very thin gold between graphenes within 10 nm.

As a result of confirming the electrical conductivity obtained based on the sheet resistance and the measured transmittance, the graphene composite electrode 111 has a sheet resistance of 24.37 Ω/square at a gold thickness of 6 nm and a high transmittance (70.64%) in the 550 nm region.

The reason why the thickness of the gold 111b was selected as 6 nm in the graphene composite electrode 111 of the present invention is that it exhibits transmittance of 70% or more and low impedance.

As shown in FIG. 12 below, the transmittance indicates the transparency at what rate the graphene composite electrode 111 is transmitted when viewed with the human eye.

When the graphene composite electrode 111 is installed on the surface of the brain, the transmittance is an important factor because it is necessary to see blood vessels on the surface of the brain to know where it is to be installed.

8 is a diagram showing electrochemical impedance spectroscopy of a graphene composite electrode according to an embodiment of the present invention.

For the graphene composite electrode 111, a very thin 6 nm gold electrode was deposited between graphenes, and electrochemical properties of the gold electrode and the doped graphene electrode were tested. The impedance of the graphene composite electrode 111 showed the lowest value in the Local Field Potential range (1 to 100 Hz) where the main epileptic discharge appeared.

The impedance of the graphene composite electrode 111 is lower than that of the nitric acid-doped 4-layer graphene electrode and the gold electrode within a low local field potential range.

The lower the impedance of the graphene composite electrode 111, the lower the noise when measuring the brain signal, and has the advantage of accurately distinguishing the brain signal.

In the low frequency range, low impedance can help the flow of electric signals efficiently and reduce electronic noise. In addition, cyclic voltammetry (CV) was checked to investigate whether the superior graphene composite electrode 111 showed better charge transfer performance and storage function.

It is found that the graphene composite electrode 111 has a specific capacitance of 1.65 mC cm ⁻² , much higher than that of the gold electrode 0.906 mC cm ⁻² .

This indicates that the surface area of the graphene composite electrode 111 exceeds that of the gold film, thereby improving the amount of charge transfer delivered to nerve stimulation applications.

9 and 10 are diagrams illustrating long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to embodiments of the present invention.

In the present invention, in order to confirm the relatively long-term stability of the graphene composite electrode 111 in phosphate buffered saline (PBS pH 7.4), electrochemical impedance spectroscopy (EIS) was measured at 0, 13, and 31 days.

Electrochemical impedance of the graphene composite electrode 111 was measured on days 0, 13, and 31 to investigate long-term stability.

Impedance changes were observed in a specific frequency range (15 to 28 Hz), the most dispersive frequency range of electrical signal power when a seizure was detected.

When a seizure was detected, it was confirmed that the impedance change in a specific frequency range, which is the most dispersive frequency range of electrical signal power, did not change significantly at 6.69%.

It was observed that the graphene composite electrode 111 exhibited a negligible degradation of 6.69% for about one month. In addition, the relative impedance in the periodic electrical stimulation test 9 x 10 ⁵ showed a slight change of about 4%. These results show that the graphene composite electrode 111 of the present invention can be operated in the brain with stability lasting for a relatively long time.

FIG. 11 is a diagram showing the signal-to-noise ratio (SNR) of a graphene composite electrode according to an embodiment of the present invention and the signal-to-noise ratio of other previous materials, and FIG. 12 is a graphene composite electrode according to an embodiment of the present invention. It is a diagram showing the comparison of measurement of brain signals in vivo of neural activity with and gold electrodes.

The graphene composite electrode 111 of FIG. 11 exhibits a higher SNR than other materials, and the high SNR helps to accurately observe brain activity on the brain surface.

After injecting the epilepsy-inducing drug, the brain signals of the graphene composite electrode and the gold electrode were measured and compared. As a result, the SNR of the graphene composite electrode was 51.68, which is higher than that of the gold electrode. The gold electrode has an SNR value of 5.56. Due to this, the graphene composite electrode 111 of the present invention can clearly detect brain nerve activity on the surface of the cerebral cortex.

FIG. 12 is a diagram showing measurement comparison of in vivo brain signals of neural activity using a graphene composite electrode 111, nitric acid-doped 4-layer graphene, and a gold electrode according to an embodiment of the present invention.

After injecting epilepsy-inducing drugs, brain signals of the graphene composite electrode 111, the nitric acid-doped 4-layer graphene electrode, and the gold electrode were measured and compared. As a result, the SNR value of the graphene composite electrode 111 was 51.68. It has a higher level than the SNR value (34.50) of the 4-layer graphene electrode doped with nitric acid and the SNR value (5.66) of the gold electrode. This makes it possible to clearly detect brain nerve activity on the surface of the cerebral cortex.

13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using a graphene composite electrode in an awake model according to an embodiment of the present invention.

13 is a view showing the multi-array device 100 inserted into the skull of an experimental animal.

The multi-array device 100 using the graphene composite electrode 111 is implanted on the surface of the cerebral cortex of an actual rat for a long period of time, and real-time brain signal measurement and electrical stimulation are possible.

The MEA and PCB board, which are miniaturized to a size suitable for planting on the animal's head, are inserted into the experimental animal's head and then fixed. After undergoing a recovery period after surgery, drugs that induce epilepsy are injected to observe behavior and brain waves in real time.

When animals are injected with drugs that induce epilepsy, serious lesions such as facial tremors, head nodding, motionless staring, and generalized seizures occur.

The multi-array device 100 does not measure noise caused by the movement of the animal, so it is possible to detect pure brain waves according to the behavior of the animal.

The multi-array device 100 transmits treatment stimuli through the MEA inserted into the animal in which epilepsy was induced, and it is shown that the brain waves and behavior patterns are improved.

In the multi-array device 100, it was confirmed that the brain waves of the alpha wave and theta wave regions, which are predominantly specific to epilepsy, were greatly reduced.

The above description is merely an example of the technical idea of the present invention, and various modifications and variations can be made to those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments described in the present invention are for explaining the technical idea of the present invention, and the technical idea of the present invention is not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all technical ideas within the equivalent range should be construed as being included in the scope of the present invention.

100: multi-channel array element
101: polyimide substrate
102: insulating layer
110: contact
111: graphene composite electrode
111a: first carbon structure, first graphene
111b: metal layer, gold, gold
111c: first carbon structure, second graphene
120: connection part
121: gold electrode
130: communication pad

Claims (8)

Graphene composite electrodes that contact the surface of the cerebral cortex to measure signals generated in the brain or transmit external stimuli to the brain;
a connection portion made of each gold electrode electrically connected to each of the graphene composite electrodes to transmit an electrical signal; and
It includes a communication pad connected to each of the gold electrodes and connected to a circuit board for measurement and stimulation from outside the brain, and each of the graphene composite electrodes is stacked in the order of a first carbon structure, a metal layer, and a second carbon structure. A multi-channel array device using a graphene composite electrode for brain implantation. The method of claim 1,
The first carbon structure and the second carbon structure are graphene, and the metal layer is a multi-channel array element using a graphene composite electrode for brain insertion made of gold. The method of claim 1,
Each of the graphene composite electrodes is formed in a quadrangular shape and spaced apart from each other by a predetermined distance, and each of the gold electrodes is formed long with a predetermined length and connected to one side of each graphene composite electrode, and the communication pad is A multi-channel array element using a graphene composite electrode for brain insertion that extends from each of the gold electrodes to a certain length to form a multi-channel and is wider than the width of the connecting portion. The method of claim 1,
The thickness of the metal layer is a multi-channel array device using a graphene composite electrode for brain insertion to form a thickness of 4 to 10 nm. The method of claim 1,
The first carbon structure and the second carbon structure have a thickness of 0.335 nm, and the metal layer has a thickness of 6 nm. The method of claim 1,
Electrically connecting each of the graphene composite electrodes on a substrate and each of the gold electrodes to one side of each of the graphene composite electrodes, and forming an insulating layer on each of the graphene composite electrodes and each of the gold electrodes. And the insulating layer is a multi-channel array device using a graphene composite electrode for brain insertion in which a portion of the graphene composite electrode is etched to be exposed. The method of claim 1,
The first carbon structure and the second carbon structure form one or more multi-layer graphene electrode layers, or a multi-channel array element using a graphene composite electrode for brain implantation to form a layer in which a metal layer is mixed with the graphene electrode layer. . The method of claim 2,
The metal layer is a multi-channel array element using a graphene composite electrode for brain implantation to form a multi-layer metal layer or to form a layer in which a graphene electrode layer is mixed with the metal layer.

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