KR20230037439A - Intracerebral implantable bioelectrode for sensing and stimulation of intracerebral nerve signals using room temperature liquid metal and manufacturing method thereof - Google Patents
Intracerebral implantable bioelectrode for sensing and stimulation of intracerebral nerve signals using room temperature liquid metal and manufacturing method thereof Download PDFInfo
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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
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/25—Bioelectric electrodes therefor
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- 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
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- A—HUMAN NECESSITIES
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0526—Head electrodes
- A61N1/0529—Electrodes for brain stimulation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F10/00—Additive manufacturing of workpieces or articles from metallic powder
- B22F10/20—Direct sintering or melting
- B22F10/22—Direct deposition of molten metal
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
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- A—HUMAN NECESSITIES
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- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
- A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B2562/16—Details of sensor housings or probes; Details of structural supports for sensors
- A61B2562/164—Details of sensor housings or probes; Details of structural supports for sensors the sensor is mounted in or on a conformable substrate or carrier
Abstract
Description
본 발명은 뇌내 삽입형 생체전극 및 이의 제조 방법에 관한 것으로서, 보다 상세하게는 상온 액체 금속을 이용한 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극 및 이의 제조 방법에 관한 것이다.The present invention relates to an implantable bioelectrode in the brain and a method for manufacturing the same, and more particularly, to an implantable bioelectrode for detecting and stimulating nerve signals in the brain using liquid metal at room temperature and a method for manufacturing the same.
뇌는 3차원의 복잡한 구조로 되어 있고, 뉴런간의 끊임없는 신호 생성 및 전달을 통해 의사소통을 하고, 이러한 신경 활동과 발화 패턴은 신체 기능, 의식 및 기억 형성을 제어한다. 뇌의 신경 활동의 미묘한 이상은 간질, 파킨슨병, 알츠하이머병, 우울증 및 만성 통증과 같은 신경 장애로 이어질 수 있다. 따라서, 신경 활동의 이상 발견, 또는 뇌의 정상적인 작동을 위한 기능적 연결성을 확인하기 위해 신경 이온 신호를 전자 신호로 변환하는 생체 내부로 삽입되는 유연한 생체전극이 필요하다.The brain is a complex three-dimensional structure, communicates through constant signal generation and transmission between neurons, and these neural activity and firing patterns control bodily functions, consciousness and memory formation. Subtle abnormalities in neural activity in the brain can lead to neurological disorders such as epilepsy, Parkinson's disease, Alzheimer's disease, depression and chronic pain. Therefore, a flexible bioelectrode inserted into a living body that converts a nerve ion signal into an electronic signal is required to detect abnormalities in neural activity or to confirm functional connectivity for normal brain operation.
기존의 유연한 생체전극으로써 연구개발 되고 있는 물질은 금속나노와이어, 카본나노튜브, 전도성 고분자, 얇은 고체 noble 전극 (Au, Pt) 등이 있지만, 이런 물질들도 생체에 비하면 매우 높은 영률(Young's modulus)을 가지기 때문에, 생체 삽입 시 면역반응을 일으키게 되고, 삽입 후에도 뇌의 미세한 움직임에 따른 추가적인 손상이 일어나 장기적인 신호 측정이 불가능하게 된다.There are metal nanowires, carbon nanotubes, conductive polymers, and thin solid noble electrodes (Au, Pt) that are being researched and developed as existing flexible bioelectrodes, but these materials also have a very high Young's modulus compared to living organisms. Since it has an immune response when inserted into a living body, additional damage occurs due to minute movements of the brain even after insertion, making long-term signal measurement impossible.
수은 등의 일반적인 액체 금속은 액체의 특성상 신축성이 매우 뛰어나 차세대 신축성 배선 전극 재료 각광 받고 있지만, 생체 내에 삽입하기에는 독성이 있다.Common liquid metals, such as mercury, are highly flexible due to the nature of the liquid and are in the limelight as next-generation stretchable wiring electrode materials, but are toxic to be inserted into the living body.
갈륨 기반 액체금속이 생체에 비교적 무해함이 알려져 있으나, 이를 생체 내에 삽입할 수준의 작은 크기 및 기계적 안정성을 갖도록 제작되기 어렵다.Although it is known that gallium-based liquid metal is relatively harmless to living organisms, it is difficult to manufacture it to have a small size and mechanical stability at the level of inserting it into a living body.
이에, 본 발명자들은 이러한 문제들을 해결하기 위해, 잘 알려진 생체적합성과, 조직과 비슷한 영률, 추가적인 어닐링 공정없이 우수한 전도성을 갖는 갈륨 기반의 액체금속(EGaIn; 75.5% 갈륨, 24.5% 인듐 wt %)을 사용하여 액체금속의 고해상도 프린팅 방식을 이용해, 액체금속 기반 생체전극을 제작하였고, 추가적으로 생체와 맞닿는 부분의 신호 향상을 위해, platinum을 전기도금 방식으로 코팅을 진행하여 임피던스를 낮춤으로써, 본 발명을 완성하였다.Therefore, in order to solve these problems, the present inventors have developed a gallium-based liquid metal (EGaIn; 75.5% gallium, 24.5% indium wt %), which has well-known biocompatibility, Young's modulus similar to tissue, and excellent conductivity without an additional annealing process. A liquid metal-based bioelectrode was fabricated using a high-resolution printing method of liquid metal, and additionally, in order to improve the signal of the part in contact with the living body, the present invention was completed by coating platinum with an electroplating method to lower the impedance. did
본 발명의 목적은 수 마이크로미터의 선폭으로 형성된 갈륨 기반의 액체 금속 합금을 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극을 제공하는 것이다.An object of the present invention is to provide an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain including a gallium-based liquid metal alloy formed with a line width of several micrometers.
본 발명의 또다른 목적은 3D 프린팅 공정을 통해 갈륨 기반의 액체 금속 합금을 최소 수 마이크로미터의 선폭으로 형성함으로써 생체의 국부 조직에서 발생하는 신호를 감지하거나 자극할 수 있는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to detect and stimulate nerve signals in the brain that can detect or stimulate signals generated from local tissues of a living body by forming a gallium-based liquid metal alloy with a line width of at least several micrometers through a 3D printing process. It is to provide a method for manufacturing an implantable bioelectrode in the brain.
본 발명의 다른 목적은 상기 본 발명에 따른 갈륨 기반의 액체 금속을 포함하는 생체전극 및 외부 계측기를 포함하는 뇌내 신경신호 감지 및 자극용 시스템을 제공하는 것이다.Another object of the present invention is to provide a system for detecting and stimulating nerve signals in the brain including a bioelectrode containing a gallium-based liquid metal and an external instrument according to the present invention.
상기 목적을 달성하기 위하여, 본 발명은 상온 액체 금속 합금인 공융 갈륨-인듐(Eutectic Gallium-Indium; EGaIn)을 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극을 제공한다.In order to achieve the above object, the present invention provides an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain including eutectic gallium-indium (EGaIn), which is a liquid metal alloy at room temperature.
또한, 본 발명은In addition, the present invention
1) 액체 금속 합금인 공융 갈륨-인듐(Eutectic Gallium-Indium; EGaIn)을 원하는 길이 및 두께로 3D 프린팅하는 단계;1) 3D printing a liquid metal alloy, Eutectic Gallium-Indium (EGaIn), to a desired length and thickness;
2) 생체적합성을 갖는 물질로 캡슐화(encapsulation)하는 단계;2) encapsulation with a biocompatible material;
3) 생체와 맞닿는 부분의 전극을 오픈시키기 위해, 포토리소그래피 공정을 통해 패터닝하는 단계; 및3) patterning through a photolithography process to open electrodes in contact with a living body; and
4) 패터닝 후, 반응성 이온식각(reactive ion etching)을 하는 단계;를 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극의 제조방법을 제공한다.4) performing reactive ion etching after patterning; to provide a method for manufacturing an implantable bioelectrode for detecting and stimulating nerve signals in the brain.
아울러, 본 발명은 상기 본 발명에 따른 생체전극; 외부 계측기; 및 상기 생체전극 끝부분과 상기 외부 계측기와 연결 가능한 커넥터;를 포함하는 뇌내 신경신호 감지 및 자극용 시스템을 제공한다.In addition, the present invention is the bioelectrode according to the present invention; external instruments; and a connector connectable to the end of the bioelectrode and the external instrument.
본 발명은 갈륨 기반의 액체 금속 합금을 최소 수 마이크로미터의 선폭으로 형성함으로써 생체의 국부 조직에서 발생하는 신호를 감지하거나 자극할 수 있고, 생체조직에 유발하는 상처나 염증을 최소화할 수 있다.According to the present invention, by forming a gallium-based liquid metal alloy with a line width of at least several micrometers, it is possible to sense or stimulate a signal generated in a local tissue of a living body and minimize wounds or inflammation caused to the living tissue.
본 발명에 따른 상온 액체 금속을 이용한 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극은 유연하고, 장기적으로 삽입되어 있을 수 있으며, 뇌내 자극 전극, 뇌내 감지 전극, 심장 페이스메이커 전극, 기타 의생명공학 및 컴퓨터공학 분야의 뉴럴 인터페이스에 적용 가능하여 파킨슨병, 통증질환, 정신질환 등의 다양한 뇌신경계 질환 치료에 사용될 수 있다.The intracerebral implantable bioelectrode for detecting and stimulating intracerebral nerve signals using liquid metal at room temperature according to the present invention is flexible and can be inserted for a long period of time, and can be used for intracerebral stimulation electrodes, intracerebral sensing electrodes, cardiac pacemaker electrodes, other biomedical engineering and Applicable to neural interfaces in the field of computer engineering, it can be used for the treatment of various neurological diseases such as Parkinson's disease, pain disorders, and mental disorders.
도 1은 기존의 뇌내 신경조절 전극 및 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극의 차이점을 보여주는 그림이다.
도 2는 본 발명에 사용된 상온 액체 금속을 보여주는 그림이다.
도 3은 본 발명에 따른 3D 프린팅을 이용한 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극을 제조하는 과정을 보여주는 그림이다.
도 4는 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극을 제조하는 과정에서, 액체금속을 원하는 길이 및 두께로 프린팅하는 것을 보여주는 그림이다.
도 5는 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극을 제조하는 과정에서, 파릴렌, 액체금속 프린팅, 나노크기의 다공성(nanoporous)의 Pt(platinum) 전기도금을 이용하여 제작하는 것을 보여주는 그림이다.
도 6은 본 발명에 따라 제작된 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극에 대해 주사현미경으로 관찰한 실제 이미지를 보여주는 그림이다.
도 7은 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극을 주사기로 뇌내에 삽입하는 방식을 보여주는 그림이다.
도 8은 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극을 마우스의 해마 부위(Hippocampus region)에 삽입한 후, 마우스의 행동에 따른 신호 감지(움직일 때 왼쪽/가만히 있을 때 오른쪽)를 측정한 결과를 보여주는 그림이다.
도 9는 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극이 마우스의 뇌내에 삽입된 이미지를 보여주는 그림이다.
도 10은 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극이 마우스의 뇌내에 삽입된 후 약 8개월 동안 신경신호 감지가 유지됨을 측정한 결과를 보여주는 그림이다.
도 11은 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극이 기존의 잘 알려진 Pt 금속 기반의 전극과 비교하여 임피던스 측정 결과를 보여주는 그림이다.
도 12는 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극이 기존의 고체 noble 전극(Au, Pt)과 달리 끊어진 후에 다시 연결을 진행하였을 때 자가 치유 특성이 있음을 보여주는 그림이다.
도 13은 본 발명에 따른 상온 액체 금속 기반 뇌내 삽입형 신경조절 전극이 기존의 전극들과 달리 탄성계수가 뇌의 조직과 비숫한 영률을 가지고 있음을 보여주는 그림이다.1 is a diagram showing the difference between a conventional intracerebral neuromodulation electrode and a room-temperature liquid metal-based implantable intracerebral neuromodulation electrode according to the present invention.
Figure 2 is a picture showing room temperature liquid metal used in the present invention.
3 is a diagram showing a process of manufacturing a room-temperature liquid metal-based implantable neuromodulation electrode in the brain using 3D printing according to the present invention.
Figure 4 is a picture showing the printing of liquid metal to a desired length and thickness in the process of manufacturing a room-temperature liquid metal-based implantable neuromodulation electrode in the brain according to the present invention.
Figure 5 shows that in the process of manufacturing room temperature liquid metal-based intracerebral neuromodulation electrodes according to the present invention, they are manufactured using parylene, liquid metal printing, and nanoporous Pt (platinum) electroplating. It is a picture.
6 is a diagram showing actual images observed with a scanning microscope for the room-temperature liquid metal-based intracerebral implantable neuromodulation electrode manufactured according to the present invention.
7 is a diagram showing a method of inserting a room-temperature liquid metal-based intracerebral neuromodulation electrode according to the present invention into the brain using a syringe.
Figure 8 is a measurement of signal detection (left when moving / right when standing still) according to the behavior of the mouse after inserting the room temperature liquid metal-based intracerebral neuromodulation electrode according to the present invention into the hippocampus region of the mouse. Here is a picture showing the result.
9 is a picture showing an image of a room-temperature liquid metal-based intracerebral implantable neuromodulation electrode according to the present invention inserted into the brain of a mouse.
FIG. 10 is a diagram showing the result of measuring that the neural signal detection is maintained for about 8 months after the room-temperature liquid metal-based intracerebral neuromodulatory electrode is inserted into the brain of a mouse according to the present invention.
11 is a diagram showing impedance measurement results of a room temperature liquid metal-based intracerebral neuromodulatory electrode according to the present invention compared with a conventional well-known Pt metal-based electrode.
12 is a diagram showing that the room-temperature liquid metal-based intracerebral neuromodulation electrode according to the present invention has self-healing characteristics when reconnected after being disconnected, unlike conventional solid noble electrodes (Au, Pt).
13 is a diagram showing that the room temperature liquid metal-based intracerebral neuromodulation electrode according to the present invention has a Young's modulus similar to that of brain tissue in elastic modulus, unlike conventional electrodes.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 상온 액체 금속 합금인 공융 갈륨-인듐(Eutectic Gallium-Indium; EGaIn)을 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극을 제공한다.The present invention provides an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain including eutectic gallium-indium (EGaIn), which is a liquid metal alloy at room temperature.
상온 액체 금속은, 상온에서, 예를 들어 20℃ 내지 30℃ 범위의 온도에서, 액상을 나타내는 금속을 포함할 수 있다. 상기 상온 액체금속은, 갈륨, 인듐, 주석, 금, 은, 구리, 수은, 납, 비스무트, 카드뮴 및 이들의 합금을 포함할 수 있고, 갈륨, 인듐, 갈린스탄(Galinstan), EGaIn(eutectic gallium and indium), 금, 은, 주석, 구리, 수은, 납, 비스무트, 카드뮴, 및 이들의 합금 중 적어도 어느 하나를 포함할 수 있다. 상기 갈린스탄은 갈륨, 인듐, 주석의 합금으로서, 예를 들어 68.5%의 갈륨, 21.5%의 인듐, 및 10%의 주석을 포함한 합금일 수 있다.The room temperature liquid metal may include a metal that exhibits a liquid phase at room temperature, for example at a temperature in the range of 20° C. to 30° C. The liquid metal at room temperature may include gallium, indium, tin, gold, silver, copper, mercury, lead, bismuth, cadmium, and alloys thereof, and gallium, indium, gallinstan, EGaIn (eutectic gallium and indium), gold, silver, tin, copper, mercury, lead, bismuth, cadmium, and at least one of alloys thereof. The gallinstan is an alloy of gallium, indium, and tin, and may be, for example, an alloy containing 68.5% gallium, 21.5% indium, and 10% tin.
상기 상온 액체 금속은, 상온에서 액체 상태인 인장에 제약 없는 전기적 및 광학적 소재로서 액체 상태이기 때문에 stretchable하고 self-healable한 특징을 가진다.The room-temperature liquid metal is an electrical and optical material that is free from tension in a liquid state at room temperature and has stretchable and self-healable characteristics because it is in a liquid state.
상기 상온 액체 금속은, 일반적인 금속들과 비슷한 비저항(resistivity) 값을 가져 전기적 특성이 우수하고 (29.4 ×10-8 Ω·m), 일반적인 금속들에 비해 낮은 영률(Young’s modulus)을 가지며 (0.204 GPa), 공기 중에 노출된 액체 금속은 산소와 반응하여 얇은 산화막을 형성해 unique한 3차원 구조를 나타낼 수 있다.The room-temperature liquid metal has a resistivity value similar to that of common metals, excellent electrical properties (29.4 × 10 -8 Ω m), and a lower Young's modulus than common metals (0.204 GPa ), the liquid metal exposed to the air reacts with oxygen to form a thin oxide film, which can show a unique three-dimensional structure.
상기 산화막은 상기 상온 액체 금속의 표면에 즉각적으로 형성되거나 의도적으로 형성될 수 있으며, 상기 산화막의 두께는 0.1nm 내지 30nm 범위일 수 있다.The oxide film may be formed immediately or intentionally on the surface of the liquid metal at room temperature, and the thickness of the oxide film may be in the range of 0.1 nm to 30 nm.
상기 EGaIn는 갈륨 65 ~ 80 wt% 및 인듐 20 ~ 25 wt%를 포함하는 것이 바람직하며, 갈륨 75 ~ 76 wt% 및 인듐 24 ~ 25 wt%를 포함하는 것이 더욱 바람직하다.The EGaIn preferably contains 65 to 80 wt% of gallium and 20 to 25 wt% of indium, more preferably 75 to 76 wt% of gallium and 24 to 25 wt% of indium.
상기 생체전극은 생체적합성을 갖는 물질로 캡슐화(encapsulation)되어 있는 것이 바람직하며, 상기 생체적합성을 갖는 물질은 파릴렌(parylene)이 바람직하나 이에 한정되지 않는다.The bioelectrode is preferably encapsulated with a material having biocompatibility, and the material having biocompatibility is preferably parylene, but is not limited thereto.
상기 생체전극은 나노크기의 다공성의 Pt(platinum)로 도금되어 있는 것는 것이 바람직하다.Preferably, the bioelectrode is plated with nano-sized porous Pt (platinum).
또한, 본 발명은 갈륨 기반의 액체 금속 합금을 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극의 제조방법을 제공한다.In addition, the present invention provides a method for manufacturing an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain including a gallium-based liquid metal alloy.
상기 제조방법은 대한민국 등록특허 10-1608209의 3D 프린팅 장치를 이용하여 갈륨 기반의 액체 금속 합금을 최소 수 마이크로미터의 선폭으로 형성함으로써 제조할 수 있다.The manufacturing method can be manufactured by forming a gallium-based liquid metal alloy with a line width of at least several micrometers using the 3D printing device of Korean Patent Registration No. 10-1608209.
상기 제조방법은 The manufacturing method
1) 액체 금속 합금인 공융 갈륨-인듐(Eutectic Gallium-Indium; EGaIn)을 원하는 길이 및 두께로 3D 프린팅하는 단계;1) 3D printing a liquid metal alloy, Eutectic Gallium-Indium (EGaIn), to a desired length and thickness;
2) 생체적합성을 갖는 물질로 캡슐화(encapsulation)하는 단계;2) encapsulation with a biocompatible material;
3) 생체와 맞닿는 부분의 전극을 오픈시키기 위해, 포토리소그래피 공정을 통해 패터닝하는 단계; 및3) patterning through a photolithography process to open electrodes in contact with a living body; and
4) 패터닝 후, 반응성 이온식각(reactive ion etching)을 하는 단계;를 포함할 수 있다.4) after patterning, reactive ion etching; may be included.
상기 제조방법은 상기 4) 단계 이후, 5) 전기도금 방식을 이용하여, 오픈된 전극위에 나노크기의 다공성의 Pt(platinum)을 도금하는 단계;를 포함할 수 있다.The manufacturing method may include, after step 4), 5) plating nano-sized porous Pt (platinum) on the open electrode using an electroplating method.
아울러, 본 발명은 상기 본 발명에 따른 갈륨 기반의 액체 금속 합금을 이용한 생체전극을 포함하는 뇌내 신경신호 감지 및 자극용 시스템을 제공한다.In addition, the present invention provides a system for detecting and stimulating nerve signals in the brain including a bioelectrode using a gallium-based liquid metal alloy according to the present invention.
상기 시스템은 상기 본 발명에 따른 생체전극; The system includes the bioelectrode according to the present invention;
외부 계측기; 및 external instruments; and
상기 생체전극 끝부분과 상기 외부 계측기와 연결 가능한 커넥터;를 포함할 수 있다.A connector connectable to the end of the bioelectrode and the external instrument may be included.
상기 시스템은 외부자극기, 센싱-자극 인터페이싱을 위한 회로 수단, 및 무선전력전송 및 통신을 위한 디바이스 수단을 포함할 수 있다. The system may include an external stimulator, circuit means for sensing-stimulus interfacing, and device means for wireless power transmission and communication.
이하, 실시예 및 실험예를 통하여 본 발명을 보다 상세히 설명하기로 한다. Hereinafter, the present invention will be described in more detail through examples and experimental examples.
이들 실시예 및 실험예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예 및 실험예에 의해 제한되지 않는다는 것은 당 업계에서 통상의 지식을 가진 자에게 있어서 자명한 것이다.These examples and experimental examples are only for explaining the present invention in more detail, and it is common knowledge in the art that the scope of the present invention is not limited by these examples and experimental examples according to the gist of the present invention. It is self-evident for oneself.
<실시예 1> 3D 고해상도 프린팅을 이용한 생체전극 제조<Example 1> Manufacture of bioelectrode using 3D high-resolution printing
프린팅 시스템은, Ink reservoir, 6-axis stage, pneumatic controller로 구성되어 있다. Ink reservoir에는 액체금속이 포함되어 있으며, 6-axis stage는 3차원 이동 스테이지는 x, y, z 축으로 이동 및 x, y, z 방향의 회전과, 각 방향으로 100 nm 단위의 정밀한 이동이 가능하며, Pneumatic controller는 압력을 조절함으로써 액체금속이 흘러나오게 도와준다.The printing system consists of an ink reservoir, a 6-axis stage, and a pneumatic controller. The liquid metal is included in the ink reservoir, and the 6-axis stage is a 3-dimensional movement stage that can move in the x, y, and z axes, rotate in the x, y, and z directions, and move precisely in 100 nm increments in each direction. and the pneumatic controller helps the liquid metal flow out by controlling the pressure.
신경조절전극은 다음과 같이 제조되었다(도 4 ~ 도 6).Neuromodulation electrodes were prepared as follows (Figs. 4 to 6).
1. 액체금속을 원하는 길이, 두께로 프린팅을 진행한다.1. Print the liquid metal to the desired length and thickness.
2. 생체적합성을 갖는 물질인 파릴렌을 이용하여, encapsulation을 진행한다.2. Proceed with encapsulation using parylene, a material with biocompatibility.
3. 생체와 맞닿는 부분의 전극을 오픈시키기 위해, 포토리소그래피 공정을 통해 패터닝을 진행한다. 3. In order to open the electrodes in contact with the living body, patterning is performed through a photolithography process.
4. 패터닝 후, reactive ion etching을 진행한다. 4. After patterning, proceed with reactive ion etching.
5. 전기도금 방식을 이용하여, 오픈된 전극위에 porous한 platinum을 도금하여, 임피던스를 낮춘다.5. Using the electroplating method, the impedance is lowered by plating porous platinum on the open electrode.
<실시예 2> 생체전극을 이용한 마우스 뇌내 신호 감지<Example 2> Signal detection in mouse brain using bioelectrode
실험동물로는, Normal 종류인 C57BL/6, wild type, male, 4주령 마우스를 사용하였다.As the experimental animal, a normal type C57BL/6, wild type, male, 4-week-old mouse was used.
전극 투입 방법은 syringe injection 방식을 이용하였다. Glass capillary 를 pipette puller 장비를 이용하여 얇게 뽑아낸 후, glass capillary 안에 PBS를 채운 후, neural probe를 끝부분에 위치시켰다. 보유하고 있는 프린팅 시스템을 이용하여, brain 내부 원하는 위치에 도달한 후에, 일정한 유량을 흘려보내면서 동시에 Z 축으로 일정한 속도로 들어올려 원하는 위치에 neural probe를 위치시켰다. The electrode insertion method used a syringe injection method. After pulling out the glass capillary thinly using a pipette puller equipment, after filling the glass capillary with PBS, a neural probe was placed at the tip. After reaching the desired location inside the brain using the printing system in place, the neural probe was positioned at the desired location by lifting at a constant speed along the Z axis while flowing a constant flow rate.
액체금속 기반의 생체전극을 두개골에 삽입 후, 액체금속의 고해상도 프린팅을 이용하여, 생체전극 끝부분과 외부 계측기와 연결 가능한 커넥터와 전기적으로 연결을 시켜주었다. 쥐 머리위에 달려있는 커넥터와 외부 계측기(Tucker-Davis Technologies) 와 연결시킴으로써, 신호를 읽어들이고 자극하였다.After inserting the liquid metal-based bioelectrode into the skull, high-resolution printing of the liquid metal was used to electrically connect the tip of the bioelectrode to a connector that could be connected to an external instrument. Signals were read and stimulated by connecting a connector on the head of the mouse to an external instrument (Tucker-Davis Technologies).
TDT 사의 synapse software를 이용하여, local field potentials(LFPs)과 single unit potentials(SU)에 해당하는 주파수를 설정 후에 신호를 읽어들이고 자극하였다. 신호 감지의 경우, LFP : 0.5 Hz - 300 Hz / SU : 3000 Hz - 6000 Hz에 해당하였다. 자극의 경우, voltage 기반이 아닌 전류 기반으로 150 μA에 해당하는 biphasic한 pulse를 주어 실험을 진행하였다.After setting the frequencies corresponding to local field potentials (LFPs) and single unit potentials (SU), signals were read and stimulated using TDT's synapse software. In the case of signal detection, LFP: 0.5 Hz - 300 Hz / SU: 3000 Hz - 6000 Hz. In the case of stimulation, the experiment was conducted by giving a biphasic pulse corresponding to 150 μA based on current, not voltage.
그 결과, 액체금속 기반 생체전극을 이용해서 신경신호를 감지했고, 약 8개월 동안 신호가 유지됨을 확인하였다(도 7 ~ 도 10).As a result, the nerve signal was detected using the liquid metal-based bioelectrode, and it was confirmed that the signal was maintained for about 8 months (FIGS. 7 to 10).
<실시예 3> 생체전극을 포함하는 뇌신경 질환 치료 시스템 구성<Example 3> Configuration of a treatment system for cranial nerve disease including a bioelectrode
생체전극-외부 계측기와의 연결을 통해, mouse의 움직임에 따른 다양한 신호를 측정하였다. 다양한 움직임에 따른 신호 변화를 감지하여 뇌의 기능적 연결성을 확인하기 위한 분석 및 해석을 할 수 있었다.Through the connection between the bioelectrode and an external instrument, various signals according to the movement of the mouse were measured. By detecting signal changes according to various movements, it was possible to analyze and interpret to confirm the functional connectivity of the brain.
<실시예 4> Pt 금속 기반의 전극과 성능 비교 <Example 4> Performance comparison with Pt metal-based electrode
상온액체가 아닌 기존의 잘 알려진 Pt 금속 기반의 전극과 임피던스를 측정을 비교해보았을 때, 약 3배 정도 차이가 남을 확인하였다. 신호 감지 측면에서 신호의 품질이 향상됨을 알 수 있다(도 11).When comparing the measurement of the impedance with the existing well-known Pt metal-based electrode, which is not a liquid at room temperature, it was confirmed that about 3 times the difference remains. It can be seen that the signal quality is improved in terms of signal detection (FIG. 11).
PtB/EGaIn은 기존의 고체 noble 전극(Au, Pt)과 달리 끊어진 후에 다시 연결을 진행하였을 때, EGaIn의 self-healing 특성 때문에 전기적인 특성이 유지됨을 확인하였다. 생체내에서 전극이 끊어졌을 때의 문제를 해결할 수 있음을 알 수 있다(도 12). Unlike conventional solid noble electrodes (Au, Pt), it was confirmed that PtB/EGaIn maintains electrical characteristics due to the self-healing characteristics of EGaIn when reconnected after disconnection. It can be seen that the problem of electrode breakage in vivo can be solved (FIG. 12).
기존의 전극들과 Elastic modulus를 비교하였다. Si, Pt, Au, Pt와 달리 아주 낮은 영률을 갖고 있음을 확인하였다. 이는 뇌 조직과 비슷한 영률을 갖고, 면역 반응을 최소화하여 장기간 감지가 가능함을 알 수 있다(도 13).Elastic modulus was compared with conventional electrodes. Unlike Si, Pt, Au, and Pt, it was confirmed that it had a very low Young's modulus. It can be seen that it has a Young's modulus similar to that of brain tissue and can be detected for a long period of time by minimizing the immune response (FIG. 13).
Claims (7)
An intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain containing eutectic gallium-indium (EGaIn), a liquid metal alloy at room temperature.
상기 EGaIn는 갈륨 65 ~ 80 wt% 및 인듐 20 ~ 25 wt%를 포함하는 것을 특징으로 하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극.
According to claim 1,
The EGaIn is an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain, characterized in that it contains 65 to 80 wt% of gallium and 20 to 25 wt% of indium.
상기 생체전극은 생체적합성을 갖는 물질로 캡슐화(encapsulation)되어 있는 것을 특징으로 하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극.
According to claim 1,
The bioelectrode is an intracerebral implantable bioelectrode for detecting and stimulating nerve signals in the brain, characterized in that the bioelectrode is encapsulated with a material having biocompatibility.
상기 생체전극은 나노크기의 다공성의 Pt(platinum)로 도금되어 있는 것을 특징으로 하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극.
According to claim 1,
The bioelectrode is an implantable bioelectrode in the brain for detecting and stimulating nerve signals in the brain, characterized in that it is plated with nano-sized porous Pt (platinum).
2) 생체적합성을 갖는 물질로 캡슐화(encapsulation)하는 단계;
3) 생체와 맞닿는 부분의 전극을 오픈시키기 위해, 포토리소그래피 공정을 통해 패터닝하는 단계; 및
4) 패터닝 후, 반응성 이온식각(reactive ion etching)을 하는 단계;를 포함하는 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극의 제조방법.
1) 3D printing a liquid metal alloy, Eutectic Gallium-Indium (EGaIn), to a desired length and thickness;
2) encapsulation with a biocompatible material;
3) patterning through a photolithography process to open electrodes in contact with the living body; and
4) a method of manufacturing an implantable bioelectrode for detecting and stimulating nerve signals in the brain, including the step of performing reactive ion etching after patterning.
상기 4) 단계 이후, 전기도금 방식을 이용하여, 오픈된 전극위에 다공성의 Pt(platinum)을 도금하는 단계;를 더 포함하는 것을 특징으로 하는, 뇌내 신경신호 감지 및 자극용 뇌내 삽입형 생체전극의 제조방법.
According to claim 5,
After step 4), plating porous Pt (platinum) on the open electrode using an electroplating method; manufacturing an implantable bioelectrode for detecting and stimulating nerve signals in the brain, characterized in that it further comprises method.
외부 계측기; 및
상기 생체전극 끝부분과 상기 외부 계측기와 연결 가능한 커넥터;를 포함하는 뇌내 신경신호 감지 및 자극용 시스템.The bioelectrode according to any one of claims 1 to 4;
external instruments; and
A system for detecting and stimulating nerve signals in the brain comprising a connector connectable to the end of the bioelectrode and the external instrument.
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