WO2022203118A1 - Multi-channel array element using graphene composite electrode for brain insertion - Google Patents

Multi-channel array element using graphene composite electrode for brain insertion Download PDF

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WO2022203118A1
WO2022203118A1 PCT/KR2021/007177 KR2021007177W WO2022203118A1 WO 2022203118 A1 WO2022203118 A1 WO 2022203118A1 KR 2021007177 W KR2021007177 W KR 2021007177W WO 2022203118 A1 WO2022203118 A1 WO 2022203118A1
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graphene composite
graphene
brain
composite electrode
electrode
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PCT/KR2021/007177
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French (fr)
Korean (ko)
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안종현
임정식
양성구
이진호
이상원
임수호
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연세대학교 산학협력단
주식회사 지브레인
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Priority claimed from KR1020210073487A external-priority patent/KR102568398B1/en
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Publication of WO2022203118A1 publication Critical patent/WO2022203118A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • A61B5/293—Invasive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/37—Intracranial electroencephalography [IC-EEG], e.g. electrocorticography [ECoG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/372—Analysis of electroencephalograms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation

Definitions

  • 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 containing multiple microelectrodes that obtains neural signals or transmits electrical impulses, and serves as a neural interface that connects neurons to electronic circuits.
  • Electrical stimulation has fewer side effects compared to drug treatment or resection, and has the advantages of reversibility and controllability.
  • the present invention provides a multi-channel array device using a graphene composite electrode for brain insertion of low noise that can minimize skull opening when inserted into the brain and has excellent adhesion to living tissue.
  • each graphene composite electrode that contacts the cerebral cortex surface to measure a signal generated in the brain or transmit an external stimulus to the brain;
  • connection part made of each gold electrode electrically connected to each graphene composite electrode to transmit an electrical signal
  • each graphene composite electrode is graphene for brain insertion consisting of a first carbon structure, a metal layer, and a second carbon structure.
  • a multi-channel array device using a composite electrode is provided.
  • the first carbon structure and the second carbon structure are made of 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 electrode for brain insertion, has excellent flexibility and mechanical properties, and can be injected only by opening a very narrow skull area, making it a low-noise brain signal measurement and electrical stimulation device. can function.
  • the present invention lowers the electrochemical impedance by thinly depositing gold between graphene, and at the same time shows a high transmittance (70.64%), and has an excellent effect on long-term stability in vivo.
  • FIG. 1 and 2 are diagrams showing the configuration of a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
  • FIG 3 is a view showing a side layer structure of a multi-channel array device using a graphene composite electrode according to an embodiment of the present invention.
  • FIG. 4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
  • FIG. 5 is a view showing the transmittance of the graphene composite electrode according to an embodiment of the present invention.
  • FIG. 6 is a diagram showing impedance results according to gold thicknesses of 4 nm, 6 nm, and 8 nm according to an embodiment of the present invention.
  • FIG. 7 is a view showing the sheet resistance and transmittance of the graphene composite electrode according to an embodiment of the present invention and other materials before.
  • FIG. 8 is a view showing an electrochemical impedance spectroscopy method of a graphene composite electrode according to an embodiment of the present invention.
  • FIGS 9 and 10 are diagrams showing long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to an embodiment of the present invention.
  • SNR signal-to-noise ratio
  • FIG. 12 is a view showing a comparison of measurements of in vivo brain signals of neural activity with a graphene composite electrode and a gold electrode according to an embodiment of the present invention.
  • FIG. 13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using graphene composite electrodes in an awake model according to an embodiment of the present invention.
  • the multi-channel array device using the graphene composite electrode for brain insertion of the present invention is used as a graphene composite electrode having excellent flexibility and mechanical properties and excellent brain signal measurement properties.
  • ITO indium tin oxide
  • the graphene composite electrode of the present invention lowers the electrochemical impedance by thinly depositing 6 nm thick gold between graphene, and at the same time shows a high transmittance (70.64%), and is excellent in long-term stability in vivo.
  • the contact force is strong and there is an advantage of forming a conformal contact on the cerebral cortical surface.
  • This graphene composite material and structure-based device are planted on the cerebral cortical surface for a long period of time in a real mouse model to provide real-time brain signal measurement and electrical stimulation without the influence of anesthetics to alleviate epilepsy. Based on this, clinical applications for the therapeutic intervention of many brain diseases may be possible.
  • FIG. 1 and 2 are diagrams showing the configuration of a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention
  • 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.
  • the multi-channel array device 100 using a graphene composite electrode for brain insertion includes a contact part 110 , a connection part 120 , and a communication pad 130 .
  • the contact part 110 forms a plurality of graphene composite electrodes 111 and Thu Holes at regular intervals.
  • the through hole is a hole for discharging the liquid material present on the brain surface, and the graphene composite electrode 111 serves to help the brain surface contact.
  • the multi-channel array element 100 is in contact with the surface of the cerebral cortex to measure a signal generated in the brain or transmit an external stimulus to the brain.
  • Each graphene composite electrode 111, and each graphene composite electrode 111 A connection part 120 made of each gold electrode 121 that is electrically connected to transmit an electrical signal, and a communication pad 130 connected to each gold electrode 121 to connect to a circuit board for measurement and stimulation outside the brain ) is included.
  • Each graphene composite electrode 111 is formed to be spaced apart by a predetermined distance in a rectangular shape, and is a portion in contact with the cerebral cortical surface.
  • the contact unit 110 is in contact with the cerebral cortex surface to measure a signal generated in the brain or transmit an external stimulus to the brain.
  • the communication pad 130 may be formed by being 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.
  • a circuit board eg, FPCB, etc.
  • the communication pad 130 extends from each gold electrode 121 to a predetermined length to form a multi-channel, and is formed to be wider than the width of the connection part 120 to facilitate coupling of the FPCB.
  • 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 a brain signal received with a built-in program.
  • connection part 120 connects between the contact part 110 and the communication pad 130 with the gold electrode 121 which is a wiring electrode connected to each graphene composite electrode 111 .
  • Each of the gold electrodes 121 is formed to have a predetermined length and is connected to correspond to one side of each graphene composite electrode 111 .
  • the multi-channel array device 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. can be configured with multiple channels of
  • the multi-channel array device 100 includes a polyimide substrate 101 on a glass substrate (not shown), and a hybrid graphene electrode on the polyimide substrate 101 . 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 ⁇ m, serves as a support substrate for supporting the graphene composite electrode 111, and is made of a material having flexible properties in order to achieve the object of the present invention. .
  • it is preferably an insulator.
  • 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 a mixture of.
  • PI polyimide
  • the insulating layer 102 is etched to expose a part of the graphene composite electrode 111 with a SU-8 passivation layer, and a part of the graphene composite electrode 111 and a part of the gold electrode 121 are adjacent to each other. to be connected
  • each gold electrode 121 has a thickness of 40 nm, and by connecting the graphene composite electrode 111 to one end of the graphene composite electrode 111, the brain signal measured by the graphene composite electrode 111 is transmitted or a stimulus signal is applied to the brain. serves to transmit
  • the insulating layer 102 has a thickness of 2 ⁇ m and is etched to expose a portion of the graphene composite electrode 111 .
  • Each graphene composite electrode 111 is stacked in the order of a first carbon structure 111a, a metal layer 111b, and a 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 is 250 ⁇ 250 ⁇ m 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 having a thickness of 0.335 nm.
  • the metal layer 111b may be made of one of various metal materials such as Novel Metals such as gold, platinum, silver (Ag), copper (Cu), nickel (Ni), iron (Fe), and pt. , with a thickness of 4 to 10 nm.
  • Novel Metals such as gold, platinum, silver (Ag), copper (Cu), nickel (Ni), iron (Fe), and pt.
  • the metal layer 111b of the present invention is formed of gold having 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 having a thickness of 0.335 nm.
  • first carbon structure 111a and the second carbon structure 111c of the present invention may be described as a first graphene 111a and a second graphene 111c for convenience of description.
  • the first graphene 111a or the second graphene 111c is a portion in direct contact with the cerebral cortical surface.
  • the reason for using graphene is to prevent the oxidation-reduction reaction of the metal layer 111b, to minimize the noise signal when measuring the brain signal by suppressing the electrical reaction of the metal, and to prevent corrosion of the metal.
  • the graphene composite electrode 111 of the present invention includes, but is not limited to, the first graphene 111a, the gold 111b, and the second graphene 111c, and the first graphene, Various layer configurations such as gold, second graphene, and gold can be applied.
  • the first graphene 111a and the second graphene 111c may each be formed as a multilayer 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 a multi-layered metal layer, or a layer in which a graphene electrode layer is mixed may be formed on the metal layer 111b.
  • the multi-channel array device 100 includes a polyimide substrate 101 and a graphene hybrid electrode including first graphene 111a, gold 111b, and second graphene 111c.
  • the size and thickness of the 111 and the gold electrode 121 may be changed according to conditions.
  • FIG. 4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
  • the manufacturing method of the multi-channel array device 100 using the graphene composite electrode for brain insertion includes the first step (S100), the second step (S101), the third step (S102), and the fourth step Step S103, a fifth step S104, and a sixth step S105 are included.
  • a graphene single layer is grown on a copper substrate by passing hydrogen and methane gas through a furnace equipment using a chemical vapor deposition (CVD) method (graphene growth process).
  • CVD chemical vapor deposition
  • a PMMA (Polymethlymethacrylate) film is coated on two grown graphene monolayers, and then the copper substrate is etched using an APS (Ammonium Persulfate) solution (copper etching process).
  • APS Ammonium Persulfate
  • the copper substrate is etched by the APS solution, and impurities are washed using distilled water (DI Water) (washing process).
  • DI Water distilled water
  • the graphene monolayer of the third step (S102) and the PMMA of (1) are removed with acetone and transferred to a substrate requiring electrodes, and then a thin gold film (6 nm) is deposited (Physical Vapor Deposition method) .
  • the graphene monolayer and (2) of the third step (S102) are transferred onto the fourth step (S103).
  • the PMMA is removed using distilled water drying and acetone to complete the graphene composite electrode 111 of the graphene composite structure.
  • FIG. 5 is a diagram showing the transmittance of the graphene composite electrode according to an embodiment of the present invention
  • FIG. 6 is a diagram showing the impedance result according to the gold thickness of 4 nm, 6 nm, and 8 nm according to an embodiment of the present invention
  • FIG. 7 is this It is a view showing the sheet resistance and transmittance of the graphene composite electrode according to an embodiment of the present invention and other materials before.
  • the graphene composite electrode 111 is formed by thinly depositing gold (Au) 111b with a thickness of 6 nm between the first graphene 111a and the second graphene 111c to lower the electrochemical impedance and at the same time high transmittance. (70.64%), and has an excellent effect on long-term stability in vivo (FIG. 5).
  • FIG. 6 shows the impedance results according to the gold thickness of 4 nm, 6 nm, and 8 nm 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 (24.37 ⁇ /square).
  • the graphene composite electrode 111 is an important variable that determines the electrical and optical properties of the electrode depending on the thickness of the thin gold deposited between the graphene 111a and 111c.
  • the sheet resistance and transmittance were measured by changing the thickness (5 nm, 6 nm, 7 nm) of very thin gold within 10 nm between graphene.
  • the graphene composite electrode 111 has a sheet resistance of 24.37 ⁇ /square at a gold 6 nm thick point and a high transmittance (70.64%) in the 550 nm region.
  • the transmittance represents the transparency at which rate the graphene composite electrode 111 transmits when viewed with the human eye.
  • transmittance is an important factor because it is possible to know where the blood vessels on the brain surface are visible to know where it is installed.
  • FIG. 8 is a view showing an electrochemical impedance spectroscopy method of a graphene composite electrode according to an embodiment of the present invention.
  • the graphene composite electrode 111 For the graphene composite electrode 111, a very thin 6 nm gold electrode was deposited between graphene, 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 major epileptic discharge appears.
  • the impedance of the graphene composite electrode 111 exhibits a lower value within the low local field potential range compared to the nitrate-doped 4-layer graphene electrode and the gold electrode.
  • the graphene composite electrode 111 has the advantage that the lower the impedance, the less noise when measuring the brain signal, and the ability to accurately distinguish the brain signal.
  • the low impedance in the low frequency range can help the electrical signal flow efficiently and reduce electronic noise.
  • cyclic voltammetry (CV) was confirmed to investigate whether the excellent graphene composite electrode 111 showed better charge transfer performance and storage function.
  • the graphene composite electrode 111 has a specific capacitance of 1.65 mC cm -2 , which is much higher than that of the gold electrode 0.906 mC cm -2 .
  • FIGS 9 and 10 are diagrams showing long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to an embodiment of the present invention.
  • EIS electrochemical impedance spectroscopy
  • Electrochemical impedance of the graphene composite electrode 111 was measured on days 0, 13, and 31 to investigate long-term stability.
  • the graphene composite electrode 111 was observed to show a negligible level of degradation to 6.69% for about one month.
  • the relative impedance in the periodic electrical stimulation test 9 x 10 5 showed a slight change of about 4%.
  • FIG. 11 is a view showing the signal-to-noise ratio (SNR) of the graphene composite electrode according to an embodiment of the present invention and the signal-to-noise ratio in other materials before
  • FIG. 12 is a graphene composite electrode according to an embodiment of the present invention.
  • the graphene composite electrode 111 of FIG. 11 exhibits a higher SNR than other materials, and the high SNR helps to observe accurate brain activity on the brain surface.
  • the brain signals of the graphene composite electrode and the gold electrode were measured and compared.
  • 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 the brain nerve activity on the surface of the cerebral cortex.
  • FIG. 8 is a graph showing a comparison of measurements of in vivo brain signals of neural activity using the graphene composite electrode 111, nitrate-doped 4-layer graphene, and gold electrodes according to an embodiment of the present invention.
  • the brain signals of the graphene composite electrode 111, the nitrate-doped 4-layer graphene electrode, and the gold electrode were measured and compared.
  • the SNR value of the graphene composite electrode 111 was 51.68.
  • 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 it has a higher level value. This makes it possible to clearly detect brain neural activity on the surface of the cerebral cortex.
  • FIG. 13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using graphene composite electrodes in an awake model according to an embodiment of the present invention.
  • FIG. 13 is a view showing the insertion of the multi-array element 100 into the skull of the experimental animal.
  • the multi-array device 100 using the graphene composite electrode 111 is implanted in the cerebral cortical surface of a real mouse for a long period of time, enabling real-time brain signal measurement and electrical stimulation.
  • the miniaturized MEA and PCB board After inserting the miniaturized MEA and PCB board to the size suitable for planting on the head of the animal, fix it. After surgery, the patient undergoes a recovery period and injects drugs that induce epilepsy to observe behavior and EEG in real time.
  • the multi-array element 100 since noise caused by the movement of the animal is not measured, it is possible to detect a pure EEG according to the behavior of the animal.
  • the multi-array element 100 delivers therapeutic stimulation to the epilepsy-induced animal through the inserted MEA, and shows improvement in EEG and behavioral patterns.
  • the multi-array device 100 significantly reduced EEG in the alpha and theta wave regions, which are predominantly epilepsy-specific.
  • the present invention can be applied to a brain implantable medical device capable of real-time brain signal measurement and electrical stimulation for the therapeutic intervention of many brain diseases.

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Abstract

The present invention relates to a multi-channel array element using a graphene composite electrode for brain insertion, the element comprising: graphene composite electrodes, each of which is in contact with the cerebral cortex surface and measures signals generated from the brain or transmits external stimuli to the brain; a connection part composed of gold electrodes that are electrically connected and transmit electrical signals to the graphene composite electrodes, respectively; and a communication pad connected to each of the gold electrodes and connected to a circuit board for measurement and stimulation outside the brain, wherein each of the graphene composite electrodes is composed of a first carbon structure, a metal layer, and a second carbon structure.

Description

뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자Multi-channel array device using graphene composite electrode for brain insertion
본 발명은 뇌주입형 그래핀 복합 전극을 이용한 다중 채널 어레이 소자에 관한 것이다.The present invention relates to a multi-channel array device using a brain-implanted graphene composite electrode.
뇌 삽입형 의료 기기는 신경 신호를 얻거나 전기 자극을 전달하는 다중 미세 전극을 포함하는 장치로, 뉴런을 전자 회로에 연결하는 신경 인터페이스 역할을 수행한다.A brain implantable medical device is a device containing multiple microelectrodes that obtains neural signals or transmits electrical impulses, and serves as a neural interface that connects neurons to electronic circuits.
전기 자극은 약물치료나 절제술에 비해 부작용이 적고 가역성과 조정 가능성의 장점을 갖는다.Electrical stimulation has fewer side effects compared to drug treatment or resection, and has the advantages of reversibility and controllability.
상업화되어 있는 전기 자극을 전달하는 뇌 삽입형 의료 기기의 경우, 뇌 심부를 자극하는 대뇌 침투형 전극봉을 이용하기 때문에 뇌 심부에 심각한 손상과 감염을 초래하는 문제점이 있었다.In the case of a commercially available brain implantable medical device that delivers electrical stimulation, there is a problem of causing serious damage and infection in the deep brain because it uses a cerebral penetrating electrode that stimulates the deep brain.
이와 같은 문제점을 해결하기 위하여, 본 발명은, 뇌에 삽입 시 두개골 개방을 최소화할 수 있으며, 생체 조직과의 부착력이 뛰어난 저잡음의 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자를 제공한다.In order to solve this problem, the present invention provides a multi-channel array device using a graphene composite electrode for brain insertion of low noise that can minimize skull opening when inserted into the brain and has excellent adhesion to living tissue.
상기 기술적 과제를 달성하기 위하여 본 발명은,The present invention in order to achieve the above technical problem,
대뇌 피질 표면과 접촉하여 뇌에서 발생한 신호를 측정하거나 외부의 자극을 뇌에 전달하는 각각의 그래핀 복합 전극;each graphene composite electrode that contacts the cerebral cortex surface to measure a signal generated in the brain or transmit an external stimulus to the brain;
각각의 그래핀 복합 전극에 전기적으로 연결되어 전기 신호를 전달하는 각각의 골드 전극으로 이루어진 연결부; 및a connection part made of each gold electrode electrically connected to each graphene composite electrode to transmit an electrical signal; and
각각의 골드전극에 연결되어 뇌 외부에서 측정 및 자극용 회로 보드와 연결하는 통신 패드를 포함하며, 각각의 그래핀 복합 전극은 제1 탄소 구조체, 금속층, 제2 탄소 구조체로 이루어진 뇌 삽입용 그래핀 복합구조 전극을 이용한 다중 채널 어레이 소자를 제공한다.It includes a communication pad connected to each gold electrode and connected to a circuit board for measurement and stimulation outside the brain, and each graphene composite electrode is graphene for brain insertion consisting of a first carbon structure, a metal layer, and a second carbon structure. A multi-channel array device using a composite electrode is provided.
제1 탄소 구조체와 제2 탄소 구조체는 그래핀(Graphene)이고, 상기 금속층은 금(Gold)으로 이루어진다.The first carbon structure and the second carbon structure are made of graphene, and the metal layer is made of gold.
제1 그래핀과 제2 그래핀의 두께는 0.335nm로 형성하고, 금속층의 두께는 6nm로 형성한다.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.
본 발명은 뇌 삽입용 그래핀 복합구조 전극을 이용한 다중 채널 어레이 소자를 제공하며, 유연성과 기계적 특성이 뛰어나, 아주 좁은 면적의 두개골 영역 개방만으로 주입 가능하여 저잡음의 뇌 신호 측정 및 전기 자극용 소자로 기능할 수 있다.The present invention provides a multi-channel array device using a graphene composite electrode for brain insertion, has excellent flexibility and mechanical properties, and can be injected only by opening a very narrow skull area, making it a low-noise brain signal measurement and electrical stimulation device. can function.
본 발명은 그래핀 사이에 금(Gold)을 얇게 증착하여 전기 화학적 임피던스를 낮추고, 동시에 높은 투과율(70.64%)를 보이며, 생체 내의 장기간 안정성에 뛰어난 효과가 있다.The present invention lowers the electrochemical impedance by thinly depositing gold between graphene, and at the same time shows a high transmittance (70.64%), and has an excellent effect on long-term stability in vivo.
도 1 및 도 2는 본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 구성을 나타낸 도면이다.1 and 2 are diagrams showing the configuration of a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
도 3은 본 발명의 실시예에 따른 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 측면 층구조를 나타낸 도면이다.3 is a view showing a side layer structure of a multi-channel array device using a graphene composite electrode according to an embodiment of the present invention.
도 4는 본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 제조 방법을 나타낸 도면이다.4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
도 5는 본 발명의 실시예에 따른 그래핀 복합 전극의 투과율를 나타낸 도면이다.5 is a view showing the transmittance of the graphene composite electrode according to an embodiment of the present invention.
도 6은 본 발명의 실시예에 따른 4nm, 6nm, 8nm 골드 두께에 따라 임피던스 결과를 나타낸 도면이다.6 is a diagram showing impedance results according to gold thicknesses of 4 nm, 6 nm, and 8 nm according to an embodiment of the present invention.
도 7은 본 발명의 실시예에 따른 그래핀 복합 전극과 이전의 다른 물질에서의 면저항과 투과율을 나타낸 도면이다.7 is a view showing the sheet resistance and transmittance of the graphene composite electrode according to an embodiment of the present invention and other materials before.
도 8은 본 발명의 실시예에 따른 그래핀 복합 전극의 전기 화학적 임피던스 분광법을 나타낸 도면이다.8 is a view showing an electrochemical impedance spectroscopy method of a graphene composite electrode according to an embodiment of the present invention.
도 9 및 도 10은 본 발명의 실시예에 따른 그래핀 복합 전극의 장기 안정성 및 주기적 전기 자극 테스트를 나타낸 도면이다.9 and 10 are diagrams showing long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to an embodiment of the present invention.
도 11은 본 발명의 실시예에 따른 그래핀 복합 전극의 신호 대 잡음비(SNR)와 이전의 다른 물질에서의 신호 대 잡음비를 나타낸 도면이다.11 is a view showing the signal-to-noise ratio (SNR) of the graphene composite electrode according to an embodiment of the present invention and the signal-to-noise ratio in other materials before.
도 12는 본 발명의 실시예에 따른 그래핀 복합 전극과 골드 전극으로 신경 활동의 생체 내 뇌 신호의 측정 비교를 나타낸 도면이다.12 is a view showing a comparison of measurements of in vivo brain signals of neural activity with a graphene composite electrode and a gold electrode according to an embodiment of the present invention.
도 13은 본 발명의 실시예에 따른 깨어있는 모델에서 그래핀 복합 전극을 이용하여 실시간 뇌 신호 측정 및 전기 자극을 주는 모습을 나타낸 도면이다.13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using graphene composite electrodes in an awake model according to an embodiment of the present invention.
명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있는 것을 의미한다.Throughout the specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 발명의 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자는 유연성과 기계적 특성이 뛰어나고 뇌 신호 측정 특성이 우수한 그래핀 복합 전극으로 사용한다.The multi-channel array device using the graphene composite electrode for brain insertion of the present invention is used as a graphene composite electrode having excellent flexibility and mechanical properties and excellent brain signal measurement properties.
기존 연구 되었던 백금 및 골드 전극은 불투명성과 광 유전학과 같은 광범위한 생물학적 응용을 제한한다.The previously studied platinum and gold electrodes limit their opacity and wide range of biological applications such as optogenetics.
PEDOT:PSS 전극의 경우 수용성 특성으로 인해 생체 내 장기 사용에 어려움이 있다. 또한, ITO(Indium Tin Oxide)와 같은 투명 물질도 투명 미세 전극 어레이의 전극 물질로 사용하지만 유연한 신경 인터페이스에 사용될 때 균열 및 기계적 열화에 취약하다.In the case of the PEDOT:PSS electrode, it is difficult to use it for a long time in vivo due to its water-soluble properties. In addition, transparent materials such as indium tin oxide (ITO) are also used as electrode materials for transparent microelectrode arrays, but they are vulnerable to cracking and mechanical deterioration when used in flexible neural interfaces.
반면, 본 발명의 그래핀 복합 전극은 그래핀 사이에 6nm 두께의 금(Gold)을 얇게 증착하여 전기 화학적 임피던스를 낮추고, 동시에 높은 투과율(70.64%)를 보이며, 생체 내의 장기간 안정성에 뛰어나다.On the other hand, the graphene composite electrode of the present invention lowers the electrochemical impedance by thinly depositing 6 nm thick gold between graphene, and at the same time shows a high transmittance (70.64%), and is excellent in long-term stability in vivo.
다중 채널 어레이 소자의 총 두께가 6 내지 6.5μm에 불과하여 접촉력이 강하고 대뇌 피질 표면 위에 컨포멀(Conformal)한 접촉을 형성하는 장점이 있다.Since the total thickness of the multi-channel array element is only 6 to 6.5 μm, the contact force is strong and there is an advantage of forming a conformal contact on the cerebral cortical surface.
이러한 그래핀 복합구조 소재 및 구조에 기반한 소자를 실제 쥐 모델에서 대뇌 피질 표면 위에 장기간 심어 마취약의 영향없이 실시간 뇌 신호 측정 및 전기 자극을 주어 뇌전증을 완화한다. 이러한 바탕으로 많은 뇌 질환의 치료적 개입을 위한 임상적 응용을 가능하게 할 수 있다.This graphene composite material and structure-based device are planted on the cerebral cortical surface for a long period of time in a real mouse model to provide real-time brain signal measurement and electrical stimulation without the influence of anesthetics to alleviate epilepsy. Based on this, clinical applications for the therapeutic intervention of many brain diseases may be possible.
도 1 및 도 2는 본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 구성을 나타낸 도면이고, 도 3은 본 발명의 실시예에 따른 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 측면 층구조를 나타낸 도면이다.1 and 2 are diagrams showing the configuration of a multi-channel array device using a graphene composite electrode for brain insertion 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.
본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자(100)는 접촉부(110), 연결부(120) 및 통신 패드(130)를 포함한다.The multi-channel array device 100 using a graphene composite electrode for brain insertion according to an embodiment of the present invention includes a contact part 110 , a connection part 120 , and a communication pad 130 .
접촉부(110)는 일정한 간격마다 그래핀 복합 전극(Hybrid Graphene Electrode)(111)과 쓰루 홀(Thu Holes)을 복수개 형성한다. 여기서, 쓰루 홀은 뇌표면에 존재하는 액체물질을 배출하는 홀로서 그래핀 복합 전극(111)이 뇌표면의 접촉을 도와주는 기능을 수행한다.The contact part 110 forms a plurality of graphene composite electrodes 111 and Thu Holes at regular intervals. Here, the through hole is a hole for discharging the liquid material present on the brain surface, and the graphene composite electrode 111 serves to help the brain surface contact.
다중 채널 어레이 소자(100)는 대뇌 피질 표면과 접촉하여 뇌에서 발생한 신호를 측정하거나 외부의 자극을 뇌에 전달하는 각각의 그래핀 복합 전극(111)과, 각각의 그래핀 복합 전극(111)에 전기적으로 연결되어 전기 신호를 전달하는 각각의 골드 전극(121)으로 이루어진 연결부(120)와, 각각의 골드전극(121)에 연결되어 뇌 외부에서 측정 및 자극용 회로 보드와 연결하는 통신 패드(130)를 포함한다.The multi-channel array element 100 is in contact with the surface of the cerebral cortex to measure a signal generated in the brain or transmit an external stimulus to the brain. Each graphene composite electrode 111, and each graphene composite electrode 111 A connection part 120 made of each gold electrode 121 that is electrically connected to transmit an electrical signal, and a communication pad 130 connected to each gold electrode 121 to connect to a circuit board for measurement and stimulation outside the brain ) is included.
각각의 그래핀 복합 전극(111)은 사각형 형태로 일정 거리 이격되어 형성하고, 대뇌 피질 표면과 접촉하는 부분이다.Each graphene composite electrode 111 is formed to be spaced apart by a predetermined distance in a rectangular shape, and is a portion in contact with the cerebral cortical surface.
접촉부(110)는 대뇌 피질 표면과 접촉하여 뇌에서 발생한 신호를 측정하거나 외부의 자극을 뇌에 전달한다.The contact unit 110 is in contact with the cerebral cortex surface to measure a signal generated in the brain or transmit an external stimulus to the brain.
통신 패드(130)는 두피 표면에 고정되거나 뇌의 외부로 인출되어 형성될 수도 있다. 통신 패드(130)는 뇌 외부에서 측정 및 자극용 회로 보드(예를 들어, FPCB 등)와 연결되는 컨택 보드이다.The communication pad 130 may be formed by being 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.
통신 패드(130)는 각각의 골드 전극(121)으로부터 일정한 길이로 연장되어 다중 채널로 형성하고, 연결부(120)의 폭보다 넓게 형성하여 FPCB의 결합을 손쉽게 한다.The communication pad 130 extends from each gold electrode 121 to a predetermined length to form a multi-channel, and is formed to be wider than the width of the connection part 120 to facilitate coupling of the FPCB.
통신 패드(130)는 뇌 외부에서 FPCB에 연결되고, FPCB는 연결부재를 통해 외부의 PC에 연결되어 내장된 프로그램으로 수신된 뇌 신호를 분석하고 디스플레이 할 수 있다.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 a brain signal received with a built-in program.
연결부(120)는 각각의 그래핀 복합 전극(111)에 연결된 배선 전극인 골드 전극(121)으로 접촉부(110)와 통신 패드(130)의 사이를 연결한다.The connection part 120 connects between the contact part 110 and the communication pad 130 with the gold electrode 121 which is a wiring electrode connected to each graphene composite electrode 111 .
상기 각각의 골드 전극(121)은 일정한 길이로 길게 형성하고, 각각의 그래핀 복합 전극(111)의 일측에 대응되도록 연결된다.Each of the gold electrodes 121 is formed to have a predetermined length and is connected to correspond to one side of each graphene composite electrode 111 .
도 1 및 도 2에 도시된 바와 같이, 본 발명의 다중 채널 어레이 소자(100)는 복수의 그래핀 복합 전극(111)과 복수의 골드 전극(121)을 통해 32채널, 64채널, 128 채널 등의 다채널로 구성할 수 있다.1 and 2, the multi-channel array device 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. can be configured with multiple channels of
도 3에 도시된 바와 같이, 다중 채널 어레이 소자(100)는 유리 기판(미도시)의 위에 폴리이미드(Polyimide) 기판(101)과, 폴리이미드 기판(101) 상에 그래핀 복합 전극(Hybrid Graphene Electrode)(111)과 골드 전극(Gold Electrode)(121)을 형성하고, 그래핀 복합 전극(111)과 골드 전극(121) 상에 형성된 절연층(102)을 포함한다.As shown in FIG. 3 , the multi-channel array device 100 includes a polyimide substrate 101 on a glass substrate (not shown), and a hybrid graphene electrode on the polyimide substrate 101 . 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.
폴리이미드 기판(101)은 4.2㎛ 두께를 가지고, 그래핀 복합 전극(111)을 지지하는 지지 기판의 역할을 하며, 본 발명의 목적을 달성하기 위하여 플렉서블(flexible)한 특성을 갖는 재료로 구성된다. 또한, 소자의 오픈된 그래핀 전극 부분만 생체조직에 부착되어야 하므로 절연체인 것이 바람직하다.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 flexible properties in order to achieve the object of the present invention. . In addition, since only the open graphene electrode portion of the device has to be attached to the living tissue, it is preferably an insulator.
따라서, 이에 한정되는 것은 아니나, Parylene, PET(Polyethylene terephthalate), PC(Polycarbonate), PES(Polyethersulfone), PDMS(Polydimethylsiloxane), PVP(Polyvinylpyrrolidone), PEN(Polyethylene naphthalate), PVC(Polyvinyl chloride), 및 이들의 혼합물로 구성된 군에서 선택되는 어느 하나일 수 있다. 본 발명의 소자에서 기판의 재료는 제작 공정 내에서 사용되는 다양한 케미컬들에 대한 우수한 내화학성 및 수 μm의 두께에서도 기계적 변형을 버틸 수 있는 우수한 기계적 물성의 측면에서 PI(polyimide)를 사용하는 것이 바람직하다.Accordingly, but 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 a mixture of. For the material of the substrate in the device of the present invention, it is preferable to use PI (polyimide) in terms of excellent chemical resistance to various chemicals used in the manufacturing process and excellent mechanical properties that can withstand mechanical deformation even at a thickness of several μm. do.
절연층(102)은 SU-8 패시베이션 레이어(Passivation Layer)로 그래핀 복합 전극(111)의 일부가 노출되도록 식각되며, 그래핀 복합 전극(111)의 일부와 골드 전극(121)의 일부가 인접하여 연결된다. 다시 말해, 각각의 골드 전극(121)은 40nm 두께를 가지고, 일측 끝단에 그래핀 복합 전극(111)을 연결하여 그래핀 복합 전극(111)에서 측정된 뇌 신호를 전달하거나 외부에 자극 신호를 뇌에 전달하는 역할을 한다.The insulating layer 102 is etched to expose a part of the graphene composite electrode 111 with a SU-8 passivation layer, and a part of the graphene composite electrode 111 and a part 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 by connecting the graphene composite electrode 111 to one end of the graphene composite electrode 111, the brain signal measured by the graphene composite electrode 111 is transmitted or a stimulus signal is applied to the brain. serves to transmit
절연층(102)는 2㎛ 두께를 가지고, 그래핀 복합 전극(111)의 일부가 노출되도록 식각된다.The insulating layer 102 has a thickness of 2 μm and is etched to expose a portion of the graphene composite electrode 111 .
각각의 그래핀 복합 전극(111)은 제1 탄소 구조체(111a), 금속층(111b), 제2 탄소 구조체(111c)의 순서로 적층되어 있으며, 바람직하게는 6.67nm의 두께를 형성한다.Each graphene composite electrode 111 is stacked in the order of a first carbon structure 111a, a metal layer 111b, and a second carbon structure 111c, and preferably has a thickness of 6.67 nm.
그래핀 복합 전극(111)의 크기는 대략 정사각형으로 250×250μm2이다.The size of the graphene composite electrode 111 is approximately square and is 250×250 μm 2 .
제1 탄소 구조체(111a)는 N-layer 그래핀(Graphene), 카본 나노튜브(Carbon Nanotube) 등으로 이루어져 있다. 본 발명의 제1 탄소 구조체(111a)는 0.335nm 두께의 그래핀으로 형성한다.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 having a thickness of 0.335 nm.
금속층(111b)은 금(Gold), 플래티늄(Platinum), 은(Ag), 구리(Cu), 니켈(Ni), 철(Fe), pt 등 Novel Metal 종류 등의 다양한 금속물질 중 하나로 이루어질 수 있으며, 두께가 4 내지 10nm로 형성된다. 바람직하게는, 본 발명의 금속층(111b)은 6nm의 두께의 금(Gold)으로 형성한다.The metal layer 111b may be made of one of various metal materials such as Novel Metals 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 having a thickness of 6 nm.
제2 탄소 구조체(111c)는 N-layer Graphene, 카본 나노튜브(Carbon Nanotube) 등으로 이루어져 있다. 본 발명의 제2 탄소 구조체(111c)는 0.335nm 두께의 그래핀으로 형성한다.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 having a thickness of 0.335 nm.
이하에서는 본 발명의 제1 탄소 구조체(111a)와 제2 탄소 구조체(111c)는 설명의 편의를 위해서 제1 그래핀(111a)과 제2 그래핀(111c)으로 기재할 수 있다.Hereinafter, the first carbon structure 111a and the second carbon structure 111c of the present invention may be described as a first graphene 111a and a second graphene 111c for convenience of description.
제1 그래핀(111a) 또는 제2 그래핀(111c)은 대뇌 피질 표면에 직접적으로 접촉하는 부분이다. 그래핀을 사용하는 이유는 금속층(111b)의 산화 환원 반응을 방지하고, 금속의 전기적 반응을 억제하여 뇌 신호 측정 시 잡음 신호를 최소화하며, 금속의 부식을 방지하기 위한 것이다.The first graphene 111a or the second graphene 111c is a portion in direct contact with the cerebral cortical surface. The reason for using graphene is to prevent the oxidation-reduction reaction of the metal layer 111b, to minimize the noise signal when measuring the brain signal by suppressing the electrical reaction of the metal, and to prevent corrosion of the metal.
다른 실시예로서, 본 발명의 그래핀 복합 전극(111)은 제1 그래핀(111a), 골드(111b) 및 제2 그래핀(111c)으로 구성하고 하지만 이에 한정하지 않으며, 제1 그래핀, 골드, 제2 그래핀, 골드 등 다양한 층 구성을 적용할 수 있다.As another embodiment, the graphene composite electrode 111 of the present invention includes, but is not limited to, the first graphene 111a, the gold 111b, and the second graphene 111c, and the first graphene, Various layer configurations such as gold, second graphene, and gold can be applied.
제1 그래핀(111a)과 제2 그래핀(111c)은 각각 다층의 그래핀 전극층으로 형성하거나, 그래핀 전극층에 금속층(111b)을 혼합하는 층을 형성할 수 있다.The first graphene 111a and the second graphene 111c may each be formed as a multilayer graphene electrode layer, or a layer in which the metal layer 111b is mixed with the graphene electrode layer may be formed.
금속층(111b)은 다층의 금속층으로 구성하거나, 금속층(111b)에 그래핀 전극층을 혼합하는 층을 형성할 수 있다.The metal layer 111b may be composed of a multi-layered metal layer, or a layer in which a graphene electrode layer is mixed may be formed on the metal layer 111b.
다중 채널 어레이 소자(100)는 폴리이미드(Polyimide) 기판(101)과, 제1 그래핀(111a), 골드(111b) 및 제2 그래핀(111c)으로 이루어진 그래핀 복합 전극(Hybrid Graphene Electrode)(111)과, 골드 전극(Gold Electrode)(121)이 조건에 따라 크기와 두께를 변경할 수 있다.The multi-channel array device 100 includes a polyimide substrate 101 and a graphene hybrid electrode including first graphene 111a, gold 111b, and second graphene 111c. The size and thickness of the 111 and the gold electrode 121 may be changed according to conditions.
도 4는 본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자의 제조 방법을 나타낸 도면이다.4 is a view showing a method of manufacturing a multi-channel array device using a graphene composite electrode for brain insertion according to an embodiment of the present invention.
본 발명의 실시예에 따른 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자(100)의 제조 방법은 제1 단계(S100), 제2 단계(S101), 제3 단계(S102), 제4 단계(S103), 제5 단계(S104) 및 제6 단계(S105)를 포함한다.The manufacturing method of the multi-channel array device 100 using the graphene composite electrode for brain insertion 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 Step S103, a fifth step S104, and a sixth step S105 are included.
제1 단계(S100)는 CVD(Chemical Vapor Deposition) 공법을 이용하여 퍼니스 장비에 수소와 메탄 가스를 통과시켜 구리기판 위에 그래핀 단층을 성장한다(그래핀 성장 과정).In the first step (S100), a graphene single layer is grown on a copper substrate by passing hydrogen and methane gas through a furnace equipment using a chemical vapor deposition (CVD) method (graphene growth process).
제2 단계(S101)는 2개의 성장된 그래핀 단층 위에 PMMA(Polymethlymethacrylate) 막을 코팅한 후, APS(Ammonium Persulfate) 용액을 이용하여 구리기판을 에칭한다(구리 에칭 과정).In the second step (S101), a PMMA (Polymethlymethacrylate) film is coated on two grown graphene monolayers, and then the copper substrate is etched using an APS (Ammonium Persulfate) solution (copper etching process).
제3 단계(S102)는 APS 용액에 의하여 구리기판이 에칭되고, 증류수(DI Water)를 이용하여 불순물을 세척한다(세척 과정).In the third step (S102), the copper substrate is etched by the APS solution, and impurities are washed using distilled water (DI Water) (washing process).
제4 단계(S103)는 제3 단계(S102)의 그래핀 단층과 (1)의 PMMA를 아세톤으로 제거 및 전극이 필요한 기판으로 전사한 후에 얇은 금막(6nm)을 증착한다(Physical Vapor Deposition 공법).In the fourth step (S103), the graphene monolayer of the third step (S102) and the PMMA of (1) are removed with acetone and transferred to a substrate requiring electrodes, and then a thin gold film (6 nm) is deposited (Physical Vapor Deposition method) .
제5 단계(S104)는 제4 단계(S103) 위에 제3 단계(S102)의 그래핀 단층과 (2)를 전사한다.In the fifth step (S104), the graphene monolayer and (2) of the third step (S102) are transferred onto the fourth step (S103).
제6 단계(S105)는 증류수 건조 및 아세톤을 이용하여 PMMA를 제거하여 그래핀 복합 구조의 그래핀 복합 전극(111)을 완성한다.In the sixth step (S105), the PMMA is removed using distilled water drying and acetone to complete the graphene composite electrode 111 of the graphene composite structure.
도 5는 본 발명의 실시예에 따른 그래핀 복합 전극의 투과율를 나타낸 도면이고, 도 6은 본 발명의 실시예에 따른 4nm, 6nm, 8nm 골드 두께에 따라 임피던스 결과를 나타낸 도면이고, 도 7은 본 발명의 실시예에 따른 그래핀 복합 전극과 이전의 다른 물질에서의 면저항과 투과율을 나타낸 도면이다.5 is a diagram showing the transmittance of the graphene composite electrode according to an embodiment of the present invention, FIG. 6 is a diagram showing the impedance result according to the gold thickness of 4 nm, 6 nm, and 8 nm according to an embodiment of the present invention, FIG. 7 is this It is a view showing the sheet resistance and transmittance of the graphene composite electrode according to an embodiment of the present invention and other materials before.
그래핀 복합 전극(111)은 제1 그래핀(111a)와 제2 그래핀(111c)의 사이에 6 nm 두께의 골드(Au)(111b)를 얇게 증착하여 전기 화학적 임피던스를 낮추고, 동시에 높은 투과율(70.64%)를 보이며, 생체 내의 장기간 안정성에 뛰어난 효과가 있다(도 5).The graphene composite electrode 111 is formed by thinly depositing gold (Au) 111b with a thickness of 6 nm between the first graphene 111a and the second graphene 111c to lower the electrochemical impedance and at the same time high transmittance. (70.64%), and has an excellent effect on long-term stability in vivo (FIG. 5).
도 6은 그래핀 복합 전극(111)에서 4nm, 6nm, 8nm 골드 두께에 따라 임피던스의 결과를 나타낸 것이다.6 shows the impedance results according to the gold thickness of 4 nm, 6 nm, and 8 nm in the graphene composite electrode 111.
그래핀 복합 전극(111)은 면 저항(24.37Ω/square)을 바탕으로 한 전기 전도도와 투과율(70.64%)에서 좋은 결과를 보였다.The graphene composite electrode 111 showed good results in electrical conductivity and transmittance (70.64%) based on sheet resistance (24.37Ω/square).
그래핀 복합 전극(111)은 그래핀(111a, 111c) 사이에 증착된 얇은 골드 두께의 따라 전극의 전기적 및 광학적 특성을 결정하는 중요한 변수이다.The graphene composite electrode 111 is an important variable that determines the electrical and optical properties of the electrode depending on the thickness of the thin gold deposited between the graphene 111a and 111c.
도 7에 도시된 바와 같이, 그래핀 사이에 매우 얇은 골드 10nm 이내 두께(5nm, 6nm, 7nm)를 바꿔가며 면 저항 및 투과율을 측정했다.As shown in FIG. 7 , the sheet resistance and transmittance were measured by changing the thickness (5 nm, 6 nm, 7 nm) of very thin gold within 10 nm between graphene.
그래핀 복합 전극(111)은 면 저항을 바탕으로 얻은 전기 전도도와 측정한 투과율을 확인한 결과, 골드 6nm 두께 지점에서 면 저항 24.37Ω/square와 550nm 영역에서의 높은 투과율(70.64%)을 가진다.As a result of checking the electrical conductivity obtained based on the sheet resistance and the measured transmittance, the graphene composite electrode 111 has a sheet resistance of 24.37Ω/square at a gold 6 nm thick point and a high transmittance (70.64%) in the 550 nm region.
본 발명의 그래핀 복합 전극(111)에서 골드(111b)의 두께를 6nm로 선택한 이유는 70% 이상의 투과율과 낮은 임피던스를 나타내기 때문이다.The reason why the thickness of the gold 111b is 6 nm in the graphene composite electrode 111 of the present invention is that it exhibits a transmittance of 70% or more and a low impedance.
이하의 도 12와 같이, 투과율은 그래핀 복합 전극(111)을 사람의 눈으로 보았을 때, 어느 정도 비율로 투과를 하는지 투명도를 나타낸다.As shown in FIG. 12 below, the transmittance represents the transparency at which rate the graphene composite electrode 111 transmits when viewed with the human eye.
그래핀 복합 전극(111)은 뇌 표면에 설치하는 경우, 뇌 표면의 혈관이 보여야 어느 위치에 설치하는지 알 수 있기 때문에 투과율이 중요한 요소이다.When the graphene composite electrode 111 is installed on the brain surface, transmittance is an important factor because it is possible to know where the blood vessels on the brain surface are visible to know where it is installed.
도 8은 본 발명의 실시예에 따른 그래핀 복합 전극의 전기 화학적 임피던스 분광법을 나타낸 도면이다.8 is a view showing an electrochemical impedance spectroscopy method of a graphene composite electrode according to an embodiment of the present invention.
그래핀 복합 전극(111)은 그래핀 사이에 매우 얇은 6nm 골드 전극을 증착하고, 골드 전극 및 도핑된 그래핀 전극의 전기 화학적 특성을 테스트를 하였다. 그래핀 복합 전극(111)의 임피던스는 주요 Epileptic Discharge가 나타나는 Local Field Potential 범위(1 내지 100Hz)에서 가장 낮은 값을 나타냈다.For the graphene composite electrode 111, a very thin 6 nm gold electrode was deposited between graphene, 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 major epileptic discharge appears.
그래핀 복합 전극(111)의 임피던스는 질산 도핑된 4층 그래핀 전극과 골드 전극에 비해 낮은 지역장 전위 범위 내에서 더 낮은 값을 나타낸다.The impedance of the graphene composite electrode 111 exhibits a lower value within the low local field potential range compared to the nitrate-doped 4-layer graphene electrode and the gold electrode.
그래핀 복합 전극(111)은 임피던스가 낮으면 낮을수록 뇌 신호 측정 시 노이즈가 줄어들고, 뇌 신호를 정확하게 구분할 수 있는 장점이 있다.The graphene composite electrode 111 has the advantage that the lower the impedance, the less noise when measuring the brain signal, and the ability to accurately distinguish the brain signal.
저주파 범위에서 낮은 임피던스는 효율적으로 전기 신호의 흐름을 돕고 전자 노이즈를 줄일 수 있다. 또한, 우수한 그래핀 복합 전극(111)이 더 나은 전하 전달 성능 및 저장 기능이 보였는지 조사하기 위해 순환 전압 전류법(CV)를 확인했다. The low impedance in the low frequency range can help the electrical signal flow efficiently and reduce electronic noise. In addition, cyclic voltammetry (CV) was confirmed to investigate whether the excellent graphene composite electrode 111 showed better charge transfer performance and storage function.
그래핀 복합 전극(111)은 1.65 mC cm-2의 비 정전 용량을 가진다는 것을 발견하고, 골드 전극 0.906 mC cm-2 보다 훨씬 높다.It was found that the graphene composite electrode 111 has a specific capacitance of 1.65 mC cm -2 , which is much higher than that of the gold electrode 0.906 mC cm -2 .
이는 그래핀 복합 전극(111)의 표면적이 골드 필름의 표면적을 능가하여 신경 자극 응용에 전달되는 전하 이동량을 향상시킬 수 있음을 나타낸다.This indicates that the surface area of the graphene composite electrode 111 can exceed the surface area of the gold film to improve the amount of charge transfer delivered to nerve stimulation applications.
도 9 및 도 10은 본 발명의 실시예에 따른 그래핀 복합 전극의 장기 안정성 및 주기적 전기 자극 테스트를 나타낸 도면이다.9 and 10 are diagrams showing long-term stability and periodic electrical stimulation tests of graphene composite electrodes according to an embodiment of the present invention.
본 발명은 인산 완충 생리 식염수(PBS pH 7.4)에서 그래핀 복합 전극(111)의 비교적 장기간 안정성을 확인하고자 전기 화학 임피던스 분광법(EIS)을 0일, 13일 및 31일에서 측정하였다.In the present invention, electrochemical impedance spectroscopy (EIS) was measured on days 0, 13 and 31 to confirm the relatively long-term stability of the graphene composite electrode 111 in phosphate buffered saline (PBS pH 7.4).
그래핀 복합 전극(111)은 장기(Long-Term) 안정성을 조사하기 위해 0일, 13일 및 31일에 전기 화학 임피던스를 측정하였다.Electrochemical impedance of the graphene composite electrode 111 was measured on days 0, 13, and 31 to investigate long-term stability.
발작이 감지되었을 때 전기 신호 전력의 가장 분산된 주파수 범위인 특정 주파수 범위(15 내지 28Hz)에서 임피던스 변화를 관찰했다.When seizures were detected, impedance changes were observed in a specific frequency range (15 to 28 Hz), which is the most dispersed frequency range of electrical signal power.
발작이 감지되었을 때, 전기 신호 전력의 가장 분산된 주파수 범위인 특정 주파수 범위의 임피던스 변화는 6.69%로 큰 변화가 없는 걸 확인했다.When a seizure was detected, it was confirmed that there was no significant change in the impedance change in a specific frequency range, which is the most dispersed frequency range of electrical signal power, at 6.69%.
그래핀 복합 전극(111)은 약 한 달 동안 6.69%로 무시할 수 있는 수준의 저하를 보이는 것으로 관찰했다. 또한, 주기적 전기 자극 테스트 9 x 105에서의 상대 임피던스는 약 4%로 미세한 변화를 보였다. 이러한 결과는 본 발명의 그래핀 복합 전극(111)이 비교적 장시간 지속되는 안정성으로 뇌에서 구동할 수 있음을 보여준다.The graphene composite electrode 111 was observed to show a negligible level of degradation to 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 driven in the brain with a relatively long-lasting stability.
도 11은 본 발명의 실시예에 따른 그래핀 복합 전극의 신호 대 잡음비(SNR)와 이전의 다른 물질에서의 신호 대 잡음비를 나타낸 도면이고, 도 12는 본 발명의 실시예에 따른 그래핀 복합 전극과 골드 전극으로 신경 활동의 생체 내 뇌 신호의 측정 비교를 나타낸 도면이다.11 is a view showing the signal-to-noise ratio (SNR) of the graphene composite electrode according to an embodiment of the present invention and the signal-to-noise ratio in other materials before, and FIG. 12 is a graphene composite electrode according to an embodiment of the present invention. A diagram showing a comparison of measurements of in vivo brain signals of neural activity with gold electrodes.
도 11의 그래핀 복합 전극(111)은 다른 물질보다 높은 SNR을 나타내고, 높은 SNR은 뇌 표면에서 정확한 뇌 활동을 관찰하는데 도움이 된다.The graphene composite electrode 111 of FIG. 11 exhibits a higher SNR than other materials, and the high SNR helps to observe accurate brain activity on the brain surface.
간질 유도 약물을 주입한 후, 그래핀 복합 전극, 골드 전극의 뇌 신호를 측정하여 비교한 결과, 그래핀 복합 전극의 SNR의 값이 51.68로 골드 전극의 비해 높은 수준의 값을 가진다. 골드 전극은 SNR의 값이 5.56이 된다. 이로 인해 본 발명의 그래핀 복합 전극(111)은 대뇌 피질 표면의 뇌 신경 활동을 명확하게 감지할 수 있다.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 the brain nerve activity on the surface of the cerebral cortex.
도 8은 본 발명의 실시예에 따른 그래핀 복합 전극(111), 질산 도핑된 4층 그래핀과 골드 전극으로 신경 활동의 생체 내 뇌 신호의 측정 비교를 나타낸 도면이다.8 is a graph showing a comparison of measurements of in vivo brain signals of neural activity using the graphene composite electrode 111, nitrate-doped 4-layer graphene, and gold electrodes according to an embodiment of the present invention.
간질 유도 약물을 주입한 후, 그래핀 복합 전극(111), 질산 도핑된 4층 그래핀 전극과 골드 전극의 뇌 신호를 측정하여 비교한 결과, 그래핀 복합 전극(111)의 SNR의 값이 51.68로 질산 도핑된 4층 그래핀 전극의 SNR 값(34.50), 골드 전극의 SNR 값(5.66)에 비해 높은 수준의 값을 가진다. 이로 인해 대뇌 피질 표면의 뇌 신경 활동을 명확하게 감지할 수 있다.After injecting the epilepsy-inducing drug, the brain signals of the graphene composite electrode 111, the nitrate-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. Compared to 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, it has a higher level value. This makes it possible to clearly detect brain neural activity on the surface of the cerebral cortex.
도 13은 본 발명의 실시예에 따른 깨어있는 모델에서 그래핀 복합 전극을 이용하여 실시간 뇌 신호 측정 및 전기 자극을 주는 모습을 나타낸 도면이다.13 is a diagram illustrating real-time brain signal measurement and electrical stimulation using graphene composite electrodes in an awake model according to an embodiment of the present invention.
도 13은 실험 동물의 머리뼈 내부에 다중 어레이 소자(100)를 삽입한 모습이다.13 is a view showing the insertion of the multi-array element 100 into the skull of the experimental animal.
그래핀 복합 전극(111)을 이용한 다중 어레이 소자(100)로 실제 쥐의 대뇌 피질 표면에 장기간 심어 실시간 뇌 신호 측정 및 전기 자극이 가능하다.The multi-array device 100 using the graphene composite electrode 111 is implanted in the cerebral cortical surface of a real mouse for a long period of time, enabling real-time brain signal measurement and electrical stimulation.
동물의 머리에 심기 적합한 사이즈로 소형화된 MEA와 PCB 보드를 실험 동물의 머리에 삽입한 후 고정한다. 수술 후 회복기를 거치고, 뇌전증을 유도하는 약물을 주입해 행동과 뇌파를 실시간으로 관측한다.After inserting the miniaturized MEA and PCB board to the size suitable for planting on the head of the animal, fix it. After surgery, the patient undergoes a recovery period and injects drugs that induce epilepsy to observe behavior and EEG in real time.
뇌전증을 유도하는 약물을 동물에 주입하면, 안면 떨림, 고개 끄덕임, 움직이지 않는 응시, 전신 발작 등 심각한 병변이 발생한다.When an animal is injected with a drug that induces epilepsy, serious lesions such as facial tremors, nodding, stationary gaze, and generalized seizures occur.
다중 어레이 소자(100)는 동물의 움직임에 의한 노이즈가 측정되지 않아 동물의 행동에 따른 순수한 뇌파를 검출하는 것이 가능하다.In the multi-array element 100 , since noise caused by the movement of the animal is not measured, it is possible to detect a pure EEG according to the behavior of the animal.
다중 어레이 소자(100)는 뇌전증이 유도된 동물에게 삽입된 MEA를 통하여 치료 자극을 전달하게 되고, 뇌파와 행동 양상이 호전되었음을 보인다.The multi-array element 100 delivers therapeutic stimulation to the epilepsy-induced animal through the inserted MEA, and shows improvement in EEG and behavioral patterns.
다중 어레이 소자(100)는 뇌전증 특이적으로 우세를 보이는 알파파와 쎄타파 영역의 뇌파가 크게 감소됨을 확인할 수 있었다.It was confirmed that the multi-array device 100 significantly reduced EEG in the alpha and theta wave regions, which are predominantly epilepsy-specific.
이상에서 본 발명의 실시예에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본 발명의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본 발명의 권리범위에 속하는 것이다.Although the embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto. is within the scope of the right.
본 발명은 많은 뇌 질환의 치료적 개입을 위하여 실시간 뇌 신호 측정 및 전기 자극이 가능한 뇌 삽입용 의료 기기에 적용할 수 있다.The present invention can be applied to a brain implantable medical device capable of real-time brain signal measurement and electrical stimulation for the therapeutic intervention of many brain diseases.

Claims (8)

  1. 대뇌 피질 표면과 접촉하여 뇌에서 발생한 신호를 측정하거나 외부의 자극을 뇌에 전달하는 각각의 그래핀 복합 전극;each graphene composite electrode that contacts the cerebral cortex surface to measure a signal generated in the brain or transmit an external stimulus to the brain;
    상기 각각의 그래핀 복합 전극에 전기적으로 연결되어 전기 신호를 전달하는 각각의 골드 전극으로 이루어진 연결부; 및a connection part made of each gold electrode electrically connected to each of the graphene composite electrodes to transmit an electrical signal; and
    상기 각각의 골드전극에 연결되어 뇌 외부에서 측정 및 자극용 회로 보드와 연결하는 통신 패드를 포함하며, 상기 각각의 그래핀 복합 전극은 제1 탄소 구조체, 금속층, 제2 탄소 구조체로 이루어진 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.A communication pad connected to each of the gold electrodes and connected to a circuit board for measurement and stimulation outside the brain, wherein each graphene composite electrode is for brain insertion consisting of a first carbon structure, a metal layer, and a second carbon structure Multi-channel array device using graphene composite electrode.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 제1 탄소 구조체와 상기 제2 탄소 구조체는 그래핀(Graphene)이고, 상기 금속층은 금(Gold)으로 이루어진 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.The first carbon structure and the second carbon structure are graphene, and the metal layer is a multi-channel array device using a graphene composite electrode for brain insertion made of gold.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 각각의 그래핀 복합 전극은 사각형 형태로 일정 거리 이격되어 형성하고, 상기 각각의 골드 전극은 일정한 길이로 길게 형성하고, 상기 각각의 그래핀 복합 전극의 일측에 대응되도록 연결하고, 상기 통신 패드는 상기 각각의 골드 전극으로부터 일정한 길이로 연장되어 다중 채널로 형성하고, 상기 연결부의 폭보다 넓게 형성하는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.Each of the graphene composite electrodes is formed to be spaced apart by a predetermined distance in a rectangular shape, each of the gold electrodes is formed to have a predetermined length, and is connected to correspond to one side of each of the graphene composite electrodes, and the communication pad includes A multi-channel array device using a graphene composite electrode for brain insertion that extends from each of the gold electrodes to a predetermined length to form multiple channels and to be wider than the width of the connection part.
  4. 청구항 1에 있어서,The method according to claim 1,
    상기 금속층의 두께는 4 내지 10nm로 형성하는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.A multi-channel array device using a graphene composite electrode for brain insertion, wherein the metal layer has a thickness of 4 to 10 nm.
  5. 청구항 1에 있어서,The method according to claim 1,
    상기 제1 그래핀과 상기 제2 그래핀의 두께는 0.335nm로 형성하고, 상기 금속층의 두께는 6nm로 형성하는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.A multi-channel array device using a graphene composite electrode for brain insertion, wherein the first graphene and the second graphene have a thickness of 0.335 nm, and the metal layer has a thickness of 6 nm.
  6. 청구항 1에 있어서,The method according to claim 1,
    기판 상에 상기 각각의 그래핀 복합 전극와, 상기 각각의 그래핀 복합 전극의 일측에 상기 각각의 골드 전극을 전기적으로 연결하고, 상기 각각의 그래핀 복합 전극과 상기 각각의 골드 전극 상에 절연층을 형성하며, 상기 절연층은 상기 그래핀 복합 전극의 일부가 노출되도록 식각되는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.Each of the graphene composite electrodes and the respective gold electrodes are electrically connected to one side of each of the graphene composite electrodes on a substrate, and an insulating layer is formed on each of the graphene composite electrodes and each of the gold electrodes. A multi-channel array device using a graphene composite electrode for brain insertion, wherein the insulating layer is etched to expose a portion of the graphene composite electrode.
  7. 청구항 2에 있어서,3. The method according to claim 2,
    상기 제1 그래핀과, 상기 제2 그래핀은 하나 이상의 다층의 그래핀 전극층을 형성하거나, 상기 그래핀 전극층에 금속층을 혼합하는 층을 형성하는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.The first graphene and the second graphene form one or more multi-layered graphene electrode layers, or a multi-channel array device using a graphene composite electrode for brain insertion that forms a layer in which a metal layer is mixed with the graphene electrode layer. .
  8. 청구항 2에 있어서,3. The method according to claim 2,
    상기 금속층은 다층의 금속층을 형성하거나, 상기 금속층에 상기 그래핀 전극층을 혼합하는 층을 형성하는 뇌 삽입용 그래핀 복합 전극을 이용한 다중 채널 어레이 소자.The metal layer is a multi-channel array device using a graphene composite electrode for brain insertion to form a multi-layer metal layer, or to form a layer in which the graphene electrode layer is mixed with the metal layer.
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