JPH0678889A - Integrated composite electrode - Google Patents
Integrated composite electrodeInfo
- Publication number
- JPH0678889A JPH0678889A JP4236998A JP23699892A JPH0678889A JP H0678889 A JPH0678889 A JP H0678889A JP 4236998 A JP4236998 A JP 4236998A JP 23699892 A JP23699892 A JP 23699892A JP H0678889 A JPH0678889 A JP H0678889A
- Authority
- JP
- Japan
- Prior art keywords
- electrode
- electrodes
- integrated composite
- insulating layer
- composite electrode
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Investigating Or Analysing Biological Materials (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
- Non-Insulated Conductors (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、生体活動の電気的計
測、特に神経細胞の電気的活動を計測する神経電気生理
の分野で用いる、多電極を有する一体化複合電極に関す
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an integrated composite electrode having multiple electrodes, which is used in the field of electrical measurement of biological activity, particularly in the field of neuroelectrophysiology for measuring electrical activity of nerve cells.
【０００２】[0002]
【従来の技術】近年、神経細胞の医学的検討や電気素子
としての適用の可能性の検討などが活発に行われてきて
いる。神経細胞が活動する際には、活動電位が発生す
る。活動電位は、神経細胞のイオン透過性の変化に伴
い、細胞膜内外のイオン濃度が変わることによって生じ
るものである。そして電極により、神経細胞近傍のイオ
ン濃度変化（すなわちイオン電流）に伴う電位変化を測
定することによって、神経活動の検出、検討が行われて
いる。2. Description of the Related Art In recent years, medical examination of nerve cells and possibility of application as an electric element have been actively conducted. When nerve cells are activated, action potentials are generated. The action potential is caused by a change in ion concentration inside and outside the cell membrane with a change in ion permeability of nerve cells. Nerve activity is being detected and studied by measuring potential changes associated with changes in ion concentration (that is, ion current) in the vicinity of nerve cells using electrodes.
【０００３】従来、神経細胞の電気的活動を計測するに
は、ガラス電極等からなる記録電極と、金属電極等から
なる刺激電極とを各々細胞内または細胞間に挿入し、刺
激電極より刺激電流（または電圧）を印加した際の、神
経細胞の電気的活動を記録電極により計測するのが普通
であった。Conventionally, to measure the electrical activity of nerve cells, a recording electrode made of a glass electrode or the like and a stimulation electrode made of a metal electrode or the like are inserted inside or between cells, and a stimulation current is applied from the stimulation electrode. The electrical activity of nerve cells when (or voltage) was applied was usually measured by a recording electrode.
【０００４】これ以外にも、例えば細胞体を細管状のガ
ラス吸引電極で突き刺し、細胞帯の内部をガラス吸引電
極中の液で還流し、このガラス吸引電極から電気信号を
与えて細胞を観察するいわゆる細胞内還流法等多数の変
法がある。In addition to this, for example, the cell body is pierced with a glass suction electrode having a thin tube shape, the inside of the cell band is circulated with the liquid in the glass suction electrode, and an electric signal is applied from this glass suction electrode to observe the cells. There are many variations such as the so-called intracellular perfusion method.
【０００５】さらには、絶縁性の基盤上にＩＴＯ（酸化
インジウム錫）等の導電性物質で直径（または１辺）１
５〜２０μｍの電極を形成し、この上で神経細胞を培養
することにより、細胞に電極を刺入する事なく、細胞に
電気的刺激を印加し、また神経細胞の電気的活動を記録
する方法についても本発明者等が別途提案している。Further, a conductive material such as ITO (indium tin oxide) has a diameter (or one side) of 1 on an insulating base.
A method of forming an electrode of 5 to 20 μm and culturing a nerve cell on the electrode to apply an electrical stimulus to the cell and record the electrical activity of the nerve cell without inserting the electrode into the cell The inventors of the present invention have also separately proposed.
【０００６】[0006]
【発明が解決しようとする課題】上述した従来の技術お
よびその変法においては、ガラス電極など、細胞に比べ
てかなりの大きさにならざるを得ない電極を用いるの
で、主に空間的な制約と操作精度上の制約で、１つのサ
ンプル中に一度に２本以上の記録電極を挿入し、神経細
胞の電気的活動を記録する多点同時計測は非常に困難で
あるという課題があった。In the above-mentioned conventional technique and its modified method, an electrode such as a glass electrode, which has a size larger than that of a cell, is used. Due to the restriction on the operation accuracy, there is a problem that it is very difficult to perform multipoint simultaneous measurement in which two or more recording electrodes are inserted into one sample at a time to record the electrical activity of nerve cells.
【０００７】神経回路網全体の働きを検討するために
は、多くの神経細胞の活動を同時に記録する必要もあ
り、測定点が増えるに従って、困難さの度合が増加し、
多細胞間の観察ができ難いという課題があった。In order to examine the action of the entire neural network, it is necessary to record the activity of many nerve cells at the same time, and as the number of measurement points increases, the degree of difficulty increases,
There was a problem that it was difficult to observe between multiple cells.
【０００８】さらには、ガラス・金属等の電極を細胞内
に刺入する必要があるために、細胞に与える損傷が大き
く、数時間以上の長時間にわたる測定ができ難いという
問題点があった。Further, since it is necessary to insert an electrode of glass, metal or the like into the cells, there is a problem that the cells are seriously damaged and it is difficult to carry out the measurement for a long time of several hours or more.
【０００９】一方、絶縁性の基盤上にＩＴＯ等の導電性
物質で直径（または１辺）１５〜２０μｍの円形（また
は正方形）の電極を形成したものを用いれば、多細胞間
に渡る信号伝達の観察が可能となる。しかしながら、電
極面積が１７７μｍ2 〜４００μｍ2 と小さいため、培
養液界面での電極抵抗は数ＭΩとなり、通常刺激は定電
流で与えられるので、電気抵抗が大きいと電極間には極
めて大きな電位差が発生することになり、かかる大きな
電圧で長期に渡り電気刺激を与えるとＩＴＯの破壊がお
き、このため長期に渡る観察が困難であるという問題点
があった。On the other hand, if a circular (or square) electrode having a diameter (or one side) of 15 to 20 μm is formed on an insulating substrate by using a conductive substance such as ITO, signal transmission between multi-cells is achieved. Can be observed. However, since the electrode area is small and 177μm 2 ~400μm 2, the electrode resistance is the number MΩ next culture liquid interface, usually stimulating because given by a constant current, between the electrical resistance is large electrode extremely large potential difference is generated Therefore, when the electrical stimulation is applied for a long period of time with such a large voltage, the ITO is destroyed, which makes it difficult to observe for a long period of time.
【００１０】本発明は、かかる従来の問題点を解決し、
神経細胞などの多点同時刺激・計測を簡便に行い、多細
胞間に渡る信号伝達観察を数時間以上の長期に渡り可能
ならしめる一体化複合電極を提供することを目的とす
る。The present invention solves the above conventional problems,
It is an object of the present invention to provide an integrated composite electrode that enables simultaneous multi-point stimulation and measurement of nerve cells and the like, and enables observation of signal transmission between multiple cells over a long period of several hours or longer.
【００１１】[0011]
【課題を解決するための手段】上記課題を解決するた
め、本発明の一体化複合電極は、絶縁基盤上に、最近接
の電極間距離が相等しい複数個の電極を備え、前記電極
からリード線を略放射状に配設した配線部と、前記リー
ド線をカバーする絶縁層とを設け、かつ電極が、正方形
もしくは円形であって、１辺の長さ若しくは直径が２０
μｍよりも大きく、且つ２００μｍ以下である構成を有
する。In order to solve the above-mentioned problems, an integrated composite electrode of the present invention comprises a plurality of electrodes having the same closest distance between electrodes on an insulating substrate, and leads from the electrodes. A wiring portion in which wires are arranged in a substantially radial shape and an insulating layer that covers the lead wires are provided, and the electrodes are square or circular and each side has a length or a diameter of 20.
It has a structure of larger than 200 μm and larger than 200 μm.
【００１２】更に、前記本発明の一体化複合電極におい
ては、最近接の電極間距離が、１０〜１０００μｍであ
ることが好ましい。また、前記本発明の一体化複合電極
においては、リード線をカバーする絶縁層が、各電極上
に孔を有し、かつリード線の外部回路との接点部近傍を
除いて前記絶縁基盤のほぼ全面に設けられた絶縁層であ
ることが好ましい。Further, in the integrated composite electrode of the present invention, the distance between the closest electrodes is preferably 10 to 1000 μm. Further, in the integrated composite electrode of the present invention, the insulating layer that covers the lead wire has a hole on each electrode, and is substantially the same as the insulating substrate except near the contact portion of the lead wire with the external circuit. It is preferably an insulating layer provided on the entire surface.
【００１３】更にまた、前記本発明の一体化複合電極に
おいては、複数個の電極中心部が、８×８の格子上の各
交点に位置することが好ましい。Furthermore, in the integrated composite electrode of the present invention, it is preferable that a plurality of electrode central portions are located at respective intersections on an 8 × 8 grid.
【００１４】[0014]
【作用】本発明の一体化複合電極は、絶縁基盤上に、最
近接の電極間距離が相等しい複数個の電極を備え、前記
電極からリード線を略放射状に配設した配線部と、前記
リード線をカバーする絶縁層とを設け、かつ電極が、正
方形もしくは円形であって、１辺の長さ若しくは直径が
２０μｍよりも大きく、且つ２００μｍ以下であるの
で、本発明の一体化複合電極上に培養した神経細胞に信
号を与え、同時に細胞間の信号の伝達を計測する際に、
最近接の電極間距離を測定対象の神経細胞（すなわち細
胞体と樹状突起と軸索突起）の長さとほぼ等しく調整
し、しかもこの電極間を等間隔で並ばせることにより、
一細胞体が電極上に配置し、この細胞体から伸びた細胞
突起を介した細胞体が、隣合う電極上に位置する確立が
高くなる。したがって、隣合う細胞体間の信号の伝達を
検知できる。The integrated composite electrode of the present invention comprises a plurality of electrodes having the same distance between the closest electrodes on the insulating base, and a wiring portion in which lead wires are arranged in a substantially radial manner from the electrodes, An insulating layer covering the lead wire is provided, and the electrode is square or circular, and the length or diameter of one side is larger than 20 μm and not larger than 200 μm. When giving signals to cultured nerve cells and measuring the transmission of signals between cells at the same time,
By adjusting the distance between the nearest electrodes to be approximately equal to the length of the nerve cell to be measured (that is, the cell body, dendrites, and axons), and evenly arranging these electrodes at equal intervals,
There is a high probability that one cell body will be placed on the electrode and that the cell body via the cell process extending from this cell body will be located on the adjacent electrode. Therefore, signal transmission between adjacent cell bodies can be detected.
【００１５】しかも、電極から伸ばしたリード線を略放
射状に配置したので、例えばリード線を平行に配置した
場合に比べて、リード線間の容量成分（キャパシタン
ス）が少なくなり、電気信号であるパルス信号波形の崩
れを小さくでき、回路の時定数が小さくなるため、早い
パルス信号に対する応答性が向上し、神経細胞活動の速
い成分に対する追従性が向上する。Moreover, since the lead wires extended from the electrodes are arranged in a substantially radial pattern, the capacitance component (capacitance) between the lead wires is smaller than that in the case where the lead wires are arranged in parallel, and a pulse which is an electric signal is obtained. Since the collapse of the signal waveform can be reduced and the time constant of the circuit is reduced, the responsiveness to a fast pulse signal is improved and the followability to a fast component of nerve cell activity is improved.
【００１６】さらに、電極の直径（または１辺）を２０
μｍより大きく２００μｍ以下の範囲で調整することに
より、数時間以上の長時間に渡り細胞に電気的刺激を与
え、かつ細胞の電気的活動を測定することができる。Furthermore, the diameter (or one side) of the electrode is set to 20.
By adjusting in the range of more than 200 μm and more than 200 μm, electrical stimulation can be applied to cells for a long time of several hours or more, and electrical activity of cells can be measured.
【００１７】また、前記本発明の一体化複合電極におい
て、最近接の電極間距離が、１０〜１０００μｍである
好ましい態様とすることにより、一般的に神経細胞の長
さがこの範囲内であるので、細胞体が電極上に位置し、
且つ神経突起を介して結合する可能性が高く、神経細胞
の測定に好都合な電極間距離となる。In the integrated composite electrode of the present invention, the distance between the nearest electrodes is preferably 10 to 1000 μm, so that the nerve cell length is generally within this range. , The cell body is located on the electrode,
In addition, there is a high possibility that they will be bound via neurites, and the inter-electrode distance is convenient for measurement of nerve cells.
【００１８】また、前記本発明の一体化複合電極におい
て、リード線をカバーする絶縁層が、各電極上に孔を有
し、かつリード線の外部回路との接点部近傍を除いて前
記絶縁基盤のほぼ全面に設けられた絶縁層である好まし
い態様とすることにより、絶縁層をリード線上のみに選
択的に設ける場合に比べ、感光性樹脂からなる絶縁材料
を使用して、ほぼ全面にこの樹脂を塗布し、フォトエッ
チング手法により、各電極上の絶縁層を除去して電極が
露出するように孔を開けるなどのフォトエッチングで容
易に必要な絶縁層が形成でき、生産を容易にすることが
できるし、絶縁不良の確率を小さくできるので好まし
い。Further, in the integrated composite electrode of the present invention, the insulating layer covering the lead wire has holes on each electrode, and the insulating substrate is provided except in the vicinity of a contact portion of the lead wire with an external circuit. By adopting a preferable mode in which the insulating layer is provided on substantially the entire surface of the resin, compared with the case where the insulating layer is selectively provided only on the lead wire, an insulating material made of a photosensitive resin is used and By applying the photo-etching method, the insulating layer on each electrode can be removed and the necessary insulating layer can be easily formed by photo-etching, such as making holes so that the electrodes are exposed. It is preferable because the probability of insulation failure can be reduced.
【００１９】更にまた、前記本発明の一体化複合電極に
おいては、複数個の電極中心部が、８×８の格子上の各
交点に位置することにより、前記本発明の電極からリー
ド線を略放射状に配設できる最高の電極数とすることが
できるので好ましい。Furthermore, in the integrated composite electrode of the present invention, a plurality of electrode center portions are located at respective intersections on an 8 × 8 grid, so that the lead wires are substantially omitted from the electrode of the present invention. It is preferable because the maximum number of electrodes that can be arranged radially can be obtained.
【００２０】[0020]
【実施例】本発明に供される絶縁基盤材料としては、細
胞培養後顕微鏡観察する必要があるため透明な基盤が好
ましく、石英ガラス、鉛ガラス、ホウ珪酸ガラス等のガ
ラス、若しくは石英等の無機物質、または、ポリメタク
リル酸メチルまたはその共重合体、ポリスチレン、ポリ
塩化ビニル、ポリエステル、ポリプロピレン、尿素樹
脂、メラミン樹脂などの透明性を有する有機物質等が挙
げられるが、機械的強度と透明性とを加味すると無機物
質が好ましい。EXAMPLES As the insulating substrate material used in the present invention, a transparent substrate is preferable because it needs to be observed under a microscope after cell culture. Glass such as quartz glass, lead glass, borosilicate glass, or inorganic such as quartz. Substances, or polymethylmethacrylate or its copolymer, polystyrene, polyvinyl chloride, polyester, polypropylene, urea resin, transparent organic substances such as melamine resin, and the like, mechanical strength and transparency and Inorganic substances are preferable in consideration of.
【００２１】本発明に供される電極材料としては、例え
ば酸化インジウム錫（ＩＴＯ）、酸化錫、Ｃｒ、Ａｕ、
Ｃｕ、Ｎｉ、Ａｌ等が使用可能である。特に、ＩＴＯ若
しくは酸化錫を用いると、電極はわずかに黄色を帯びた
透明なものとなり、神経細胞の顕微鏡下での視認性が良
く、実験操作上有利であるが、とりわけＩＴＯが良導伝
性であるため望ましい。Examples of the electrode material used in the present invention include indium tin oxide (ITO), tin oxide, Cr, Au,
Cu, Ni, Al, etc. can be used. In particular, when ITO or tin oxide is used, the electrode becomes slightly yellowish and transparent, and the visibility of nerve cells under a microscope is good, which is advantageous in experimental operation, but ITO is particularly good in conductivity. Therefore, it is desirable.
【００２２】リード線材料にも同様の材料が適応でき、
やはり電極材料と同様の理由でＩＴＯが好ましい。特に
限定するものではないが、通常これらの電極やリード線
の厚みは、およそ５００〜５０００オングストローム程
度であり、通常これらの材料を絶縁基盤上に蒸着し、フ
ォトレジストを用いてエッチングにより所望のパターン
に形成できる。Similar materials can be applied to the lead wire material,
Again, ITO is preferable for the same reason as the electrode material. Although not particularly limited, the thickness of these electrodes and lead wires is usually about 500 to 5000 angstroms, and usually, these materials are vapor-deposited on an insulating substrate and a desired pattern is formed by etching using a photoresist. Can be formed into
【００２３】また、本発明に供されるリード線を絶縁す
るための絶縁層材料としては、例えばポリイミド（Ｐ
Ｉ）樹脂、エポキシ樹脂、アクリレート樹脂、ポリエス
テル樹脂、或はポリアミド樹脂等の透明な樹脂が挙げら
れる。The insulating layer material for insulating the lead wire used in the present invention is, for example, polyimide (P
Examples of the transparent resin include transparent resin such as I) resin, epoxy resin, acrylate resin, polyester resin and polyamide resin.
【００２４】これらの樹脂は、リード線上に通常の手法
によって塗布して絶縁層が構成される。なお、絶縁層材
料が光照射重合性等の感光性樹脂であると、前述したよ
うに電極を露出させるために電極上の絶縁層部分に孔を
開けるなどのパターン形成が可能となるため好ましい。These resins are applied on the lead wire by a usual method to form an insulating layer. In addition, it is preferable that the insulating layer material is a photosensitive resin such as a photopolymerizable resin because it is possible to form a pattern in the insulating layer portion on the electrode to expose the electrode as described above.
【００２５】特に、絶縁層材料がＰＩであり、培養する
細胞が神経細胞である場合には、良好な生育を示すため
望ましい。さらにＰＩの中でも、ネガティブフォトセン
シティブポリイミド（ＮＰＩ）が、配線部のパターン形
成と同様に、略全面にネガティブフォトセンシティブポ
リイミドを塗布した後フォトエッチングプロセスを用い
て電極上に孔を形成できるため好ましい。Particularly, when the insulating layer material is PI and the cells to be cultured are nerve cells, it is desirable because it shows good growth. Further, among PIs, negative photosensitive polyimide (NPI) is preferable because, like the pattern formation of the wiring portion, a hole can be formed on the electrode by using a photoetching process after coating the negative photosensitive polyimide on substantially the entire surface.
【００２６】また、絶縁層の厚みは絶縁性が付与できる
程度であればよく、特に限定するものではないが、通常
０．１〜１０μｍが好ましく、１〜５μｍ程度がさらに
好ましい。The thickness of the insulating layer is not particularly limited as long as it can impart insulating properties, but is usually 0.1 to 10 μm, preferably 1 to 5 μm.
【００２７】本発明の一体化複合電極は、直接細胞を培
養して細胞の電気活動を計測記録する。培養条件若しく
は細胞の種類によって、細胞体の大きさ若しくは樹状突
起や軸索などの細胞突起の長さが異なるが、一体化複合
電極の最近接の電極間距離は、１０〜１０００μｍが好
ましい。電極間距離が１０μｍ未満であると、互いに近
接し過ぎるため細胞体が細胞突起を介して相隣合う確立
が減り、またリード線の配線も困難となる。また、１０
００μｍを越えると、リード線の配線はしやすいが、細
胞突起が１０００μｍ程度も伸びることは稀なため、細
胞体が電極上に位置する確立が減る。一般の条件で培養
した細胞の長さは、哺乳動物の中枢神経細胞の場合、平
均２００〜３００μｍ程度であるため、電極間距離は２
００〜３００μｍ程度が望ましい。The integrated composite electrode of the present invention directly cultures cells and measures and records the electrical activity of the cells. Although the size of cell bodies or the length of cell projections such as dendrites and axons differ depending on the culture conditions or the type of cells, the closest interelectrode distance of the integrated composite electrode is preferably 10 to 1000 μm. If the distance between the electrodes is less than 10 μm, the cell bodies are too close to each other to reduce the probability that the cell bodies are adjacent to each other via the cell projections, and the wiring of the lead wire becomes difficult. Also, 10
If it exceeds 00 μm, it is easy to wire the lead wire, but it is rare that the cell projections extend by about 1000 μm, so that the probability that the cell body is located on the electrode is reduced. Since the length of cells cultured under general conditions is about 200 to 300 μm on average in the case of mammalian central nerve cells, the distance between electrodes is 2
It is desirable that the thickness is about 00 to 300 μm.
【００２８】電極の形状は、最近接の電極間距離を一定
にする要請のため、円形か正方形が好ましい。電極面積
については、長期に渡り細胞に電気刺激を印加する際の
電極破壊を避けるため、培養液との界面での抵抗を小さ
くする必要があるため、ある程度以上の大きさが要求さ
れる。しかしながら、電極面積が大きくなり培養液との
界面での抵抗が小さくなると、測定される細胞の電気的
活動は小さくなり、Ｓ／Ｎ比が低下する。すなわち、電
流値Ｉが一定とすると、Ｉ＝Ｖ／Ｒであるから、抵抗値
Ｒが小さくなると測定される電位Ｖの変化も小さくな
る。つまり測定される細胞の電気的活動が小さくなりＳ
／Ｎ比が低下する。このため、電極面積は慎重に調整さ
れる必要があり、円形状の電極の場合直径が２０μｍよ
り大きく２００μｍ以下、特に好ましくは１００〜２０
０μｍ、正方形状の電極の場合１辺が２０μｍより大き
く２００μｍ以下、特に好ましくは１００〜２００μｍ
が好ましい。The shape of the electrodes is preferably circular or square because of the requirement of keeping the distance between the nearest electrodes constant. The electrode area is required to have a certain size or more because it is necessary to reduce the resistance at the interface with the culture solution in order to avoid electrode destruction when applying electrical stimulation to cells for a long period of time. However, as the electrode area increases and the resistance at the interface with the culture medium decreases, the measured electrical activity of the cells decreases and the S / N ratio decreases. That is, when the current value I is constant, I = V / R, and therefore, the change in the measured potential V also decreases as the resistance value R decreases. In other words, the measured electrical activity of the cell is reduced and S
/ N ratio decreases. Therefore, the electrode area needs to be carefully adjusted, and in the case of a circular electrode, the diameter is more than 20 μm and 200 μm or less, particularly preferably 100 to 20.
0 μm, in the case of a square electrode, one side is more than 20 μm and 200 μm or less, particularly preferably 100 to 200 μm
Is preferred.
【００２９】さらに、本発明の前述した好ましい態様に
よれば、一体化複合電極の絶縁層中の孔は、一体化複合
電極上で培養した細胞体に電気刺激を与えると同時に、
隣合う細胞体から電気的活動を検知するため、電極を露
出する目的で形成し、電極中心部に位置する。この孔の
大きさは、電極の大きさ以下にすることが好ましく、一
辺または直径が１５〜１９５μｍ程度が好ましい。Further, according to the above-described preferred embodiment of the present invention, the pores in the insulating layer of the integrated composite electrode provide electrical stimulation to the cell bodies cultured on the integrated composite electrode, and at the same time,
In order to detect electrical activity from adjacent cell bodies, the electrodes are formed to expose the electrodes and are located at the center of the electrodes. The size of this hole is preferably equal to or smaller than the size of the electrode, and one side or diameter is preferably about 15 to 195 μm.
【００３０】また、本発明の一体化複合電極の電極中心
部が、同心円状若しくは８×８以下の格子状の各交点に
位置する構成であると、リード線を放射状に配線でき、
特に可能な限り多くの電極を構成し、多点同時刺激・記
録を行うという観点からは、８×８の格子状の各交点に
電極を設けることが望ましい。Further, when the electrode central portion of the integrated composite electrode of the present invention is located at each intersection of concentric circles or a lattice of 8 × 8 or less, the lead wires can be arranged in a radial pattern.
Particularly, from the viewpoint of configuring as many electrodes as possible and performing simultaneous stimulation / recording at multiple points, it is desirable to provide electrodes at each intersection of a 8 × 8 grid.
【００３１】以下具体的実施例で、本発明の一体化複合
電極をさらに詳細に説明する。 実施例１ 図１は絶縁基盤３上に電極１とリード線２を形成した本
発明の一体化複合電極の絶縁層のない状態の配線部のパ
ターンを示した平面図である。図２は図１で示した部材
の上に形成された絶縁層のみの平面図の一部切り欠き図
である。図３は本発明の一体化複合電極の一部の断面図
である。以下これらの図面を参照しながら説明する。The integrated composite electrode of the present invention will be described in more detail with reference to specific examples. Example 1 FIG. 1 is a plan view showing a pattern of a wiring portion of an integrated composite electrode of the present invention in which an electrode 1 and a lead wire 2 are formed on an insulating substrate 3 without an insulating layer. FIG. 2 is a partially cutaway view of a plan view of only the insulating layer formed on the member shown in FIG. FIG. 3 is a sectional view of a part of the integrated composite electrode of the present invention. Hereinafter, description will be given with reference to these drawings.
【００３２】まず、複合電極配線部の作製について述べ
る。一体化複合電極の絶縁基盤３は機械的強度の強い透
明な絶縁素材として、５０×５０×１ｍｍの硬質ガラス
（“ＩＷＡＫＩ ＣＯＤＥ ７７４０ ＧＬＡＳＳ”
［岩城硝子（株）製］以下同じ）を用いた。First, the production of the composite electrode wiring portion will be described. The insulating substrate 3 of the integrated composite electrode is made of 50 × 50 × 1 mm hard glass (“IWAKI CODE 7740 GLASS”) as a transparent insulating material having high mechanical strength.
The same applies hereinafter) (manufactured by Iwaki Glass Co., Ltd.).
【００３３】電極１およびリード線２の材料にＩＴＯを
用い、前記硬質ガラスの絶縁基盤３上の全面に約１００
０オングストローム厚に蒸着し、その後洗浄した。次
に、８×８の格子上の各交点（図２の５で示されたよう
な位置）に各電極１の中心部が位置し、各電極の最近接
の電極の中心間距離が等しく、しかもリード線２が放射
状に伸びた形状の電極１およびリード線２のパターンに
なるように、フォトレジストを用いて露光し、純水５
０、塩酸５０、硝酸１の体積比で混合した溶液中でＩＴ
Ｏをエッチングした後、フォトレジストを除去した。電
極１の直径は６０μｍ、リード線２の幅は３０μｍ、電
極中心間距離は３００μｍの配線部を形成した。ITO is used as a material for the electrode 1 and the lead wire 2, and about 100 is formed on the entire surface of the insulating substrate 3 made of hard glass.
It was vapor-deposited to a thickness of 0 angstrom and then washed. Next, the center of each electrode 1 is located at each intersection (the position as shown by 5 in FIG. 2) on the 8 × 8 lattice, and the distance between the centers of the nearest electrodes of each electrode is equal, Moreover, exposure is performed using a photoresist so that the lead wire 2 has a pattern of the electrode 1 and the lead wire 2 having a radially extended shape, and pure water 5
IT in a mixed solution of 0, 50 hydrochloric acid and 1 nitric acid in a volume ratio
After etching O, the photoresist was removed. A wiring portion was formed in which the diameter of the electrode 1 was 60 μm, the width of the lead wire 2 was 30 μm, and the distance between the electrode centers was 300 μm.
【００３４】ついで、絶縁層４としてネガティブフォト
センシティブポリイミド（以下ＮＰＩと略す）を、乾燥
後の厚みが１μｍとなるようにスピンコートし、図２に
示すように配線部の各電極の中心に一辺５０μｍの正方
形の孔５ができるように、絶縁層パターンを露光形成し
た。Next, negative photosensitive polyimide (hereinafter abbreviated as NPI) is spin-coated as the insulating layer 4 so that the thickness after drying is 1 μm, and one side is formed at the center of each electrode of the wiring portion as shown in FIG. An insulating layer pattern was formed by exposure so that square holes 5 of 50 μm were formed.
【００３５】リード線２の電極１と反対方向の端部近傍
の部分の外部回路との接点は、金７およびニッケル８で
コートし、耐久性を向上させた。さらに、絶縁層４の孔
５の部分の電極１の部分を１％の塩化白金酸六水和物と
０．０１％酢酸鉛の混合水溶液中に電極を浸漬し、５０
ｍＡ／ｃｍ2 の電流を３０秒間通電し電極表面に白金黒
６を析出させることで、インピーダンスを低下させた
後、以下の実験に供した。The contacts with the external circuit in the vicinity of the ends of the lead wire 2 in the direction opposite to the electrode 1 were coated with gold 7 and nickel 8 to improve the durability. Further, the electrode 1 portion of the hole 5 portion of the insulating layer 4 is immersed in a mixed aqueous solution of 1% chloroplatinic acid hexahydrate and 0.01% lead acetate, and 50
A current of mA / cm 2 was applied for 30 seconds to deposit platinum black 6 on the electrode surface to reduce the impedance, and then the following experiment was performed.
【００３６】なお、本実施例では電極１およびリード２
の部分にＩＴＯ、絶縁層にＮＰＩを用いたが、用いる材
料はこれらに限定されないことは既に述べた。また、本
発明の一体化複合電極を構成するためのプロセスは本実
施例の方法に限定されない。In this embodiment, the electrode 1 and the lead 2 are
Although ITO is used for the portion and NPI is used for the insulating layer, the material used is not limited to these. Further, the process for forming the integrated composite electrode of the present invention is not limited to the method of this embodiment.
【００３７】実施例２ 次に、一体化複合電極上での神経細胞の培養について述
べる。実施例１のようにして構成した一体化複合電極上
で、神経細胞としてラット大脳視覚皮質を培養した。Example 2 Next, the culture of nerve cells on the integrated composite electrode will be described. On the integrated composite electrode configured as in Example 1, rat cerebral visual cortex was cultured as nerve cells.
【００３８】以下、培養法について詳細に述べる。 （イ）妊娠後１６〜１８日を経過したＳＤラットの胎児
の脳を摘出し、氷冷したハンクス平衡塩液（以下ＨＢＢ
Ｓと略す）に浸す。The culture method will be described in detail below. (A) 16 to 18 days after the gestation, the brain of the SD rat fetus was extracted and ice-cooled Hanks balanced salt solution (hereinafter referred to as HBB).
Immerse in S).
【００３９】（ロ）氷冷ＨＢＢＳ中の脳から視覚皮質を
切り出し、イーグル最小必須培地（以下ＭＥＭと略す）
液中に移す。 （ハ）ＭＥＭ液中で、視覚皮質をできるだけ細かく、最
大でも０．２ｍｍ角となるように切断する。(B) A visual cortex was cut out from the brain in ice-cold HBBS, and Eagle's minimum essential medium (hereinafter abbreviated as MEM).
Transfer into liquid. (C) In the MEM solution, the visual cortex is cut as finely as possible to be 0.2 mm square at the maximum.
【００４０】（ニ）細かく切断した視覚皮質を遠沈管
（遠心分離用試験管）に入れ、カルシウムおよびマグネ
シウムを含まないＨＢＢＳ（以下ＣＭＦ−ＨＢＢＳと略
す）で３回洗浄した後、適量の同液中に分散する。(D) The finely cut visual cortex was placed in a centrifuge tube (test tube for centrifugation), washed three times with calcium- and magnesium-free HBBS (hereinafter abbreviated as CMF-HBBS), and then an appropriate amount of the same solution. Disperse inside.
【００４１】（ホ）上記（ニ）の遠沈管中に、トリプシ
ンのＣＭＦ−ＨＢＢＳ溶液（０．２５重量％）を加え、
全量を倍にする。緩やかに撹拌しながら、３７℃で１５
分から２０分間恒温状態に保ち酵素反応をおこなわせ
た。(E) A CMF-HBBS solution of trypsin (0.25% by weight) was added to the centrifuge tube of the above (d),
Double the total amount. 15 at 37 ° C with gentle stirring
The enzyme reaction was performed by keeping the temperature constant for 20 minutes.
【００４２】（ヘ）牛胎児血清（ＦＣＳ）１０％を含む
ダルベッコ変更イーグル培地（ＤＭＥＭ）とＨａｍＦ−
１２培地を１対１の体積比で混合したＤＭＥＭ／Ｆ−１
２混合培地を、上記（ホ）を経た遠沈管中に加え、全量
をさらに倍にする。先端をバーナーであぶり口径を小さ
くしたパスツールピペットで、緩やかにピペッティング
を繰り返し（最大２０回程度）、細胞をほぐす。(F) Dulbecco's modified Eagle medium (DMEM) containing 10% fetal calf serum (FCS) and HamF-
DMEM / F-1 in which 12 media were mixed at a volume ratio of 1: 1
2) Mixed medium is added into the centrifuge tube that has been subjected to the above (e), and the total amount is further doubled. Using a Pasteur pipette with a small tip, use a Pasteur pipette and gently repeat pipetting (up to about 20 times) to loosen the cells.
【００４３】（ト）９８０６．６５ｍ／ｓｅｃ2 （すな
わち１０００ｇ）で約５分間遠心分離をおこなう。遠心
分離終了後、上清を捨て、沈澱をＦＣＳ５％を含むＤＭ
ＥＭ／Ｆ−１２混合培地に懸濁する。(G) Centrifugation is performed at 9806.65 m / sec 2 (that is, 1000 g) for about 5 minutes. After the centrifugation, discard the supernatant and precipitate the precipitate with 5% FCS in DM.
Suspend in EM / F-12 mixed medium.
【００４４】（チ）上記（ト）および（チ）をあと２回
（計３回）繰り返す。 （ヌ）最終的に得られた沈澱を、５％ＦＣＳを含むＤＭ
ＥＭ／Ｆ−１２混合培地に懸濁し、懸濁液中の細胞濃度
を赤血球計数盤を用いて計測する。同様の培地を用いて
細胞濃度を２〜４×１０6 個／ｍｌになるように調整す
る。(H) The above (G) and (H) are repeated two more times (three times in total). (G) The finally obtained precipitate was added to DM containing 5% FCS.
The cells are suspended in an EM / F-12 mixed medium, and the cell concentration in the suspension is measured using a red blood cell counter. The cell concentration is adjusted to 2-4 × 10 6 cells / ml using the same medium.
【００４５】（ル）一体化複合電極上に直径２５ｍｍ、
高さ６ｍｍのプラスティック製円筒を、複合電極の中心
とプラスティック円筒の中心を合わせて接着することに
より構成した細胞培養用ウェル中に、あらかじめ５％Ｆ
ＣＳを含むＤＭＥＭ／Ｆ−１２混合培地５００μｌを加
え、ＣＯ2 インキュベータ内（Ｏ2 濃度９５％、ＣＯ 2
濃度５％、湿度９７％、温度３７℃）で暖めておく。(L) 25 mm diameter on the integrated composite electrode,
Place a 6 mm high plastic cylinder at the center of the composite electrode.
And glue the center of the plastic cylinder together
5% F in advance in the well for cell culture
Add 500 μl of DMEM / F-12 mixed medium containing CS.
Eh, CO2In the incubator (O295% concentration, CO 2
Warm at a concentration of 5%, humidity of 97%, and temperature of 37 ° C).
【００４６】（ヲ）上記（ル）のウェル中に細胞濃度を
調整した懸濁液１００μｌを静かに加え、再びＣＯ2 イ
ンキュベータ内に静置する。 （ヨ）上記（ル）の操作より３日後に、培地の半量を新
しいものと交換する。交換培地はＦＣＳを含まないＤＭ
ＥＭ／Ｆ−１２混合培地を用いる。(2) 100 μl of the suspension having the adjusted cell concentration is gently added to the well of (l) above, and the suspension is again placed in the CO 2 incubator. (Y) After 3 days from the operation in (L), replace half of the medium with a new one. Exchange medium is DM without FCS
EM / F-12 mixed medium is used.
【００４７】（タ）以降、４〜５日毎に上記と同様の培
地交換をおこなう。 これら一連の操作により、一体化複合電極上でラット大
脳皮質の神経細胞を培養することができた。After (ta), the same medium exchange as above is performed every 4 to 5 days. By these series of operations, the nerve cells of rat cerebral cortex could be cultured on the integrated composite electrode.
【００４８】細胞は絶縁層（ＮＰＩ）上でも白金黒を析
出させた電極上でも良好に生育した。したがって、適切
な位置にある電極を刺激電極または記録電極として用い
れば、神経細胞電気活動の同時多点計測が可能であっ
た。The cells grew well both on the insulating layer (NPI) and on the electrode on which platinum black was deposited. Therefore, if an electrode at an appropriate position is used as a stimulating electrode or a recording electrode, simultaneous multipoint measurement of nerve cell electrical activity was possible.
【００４９】また、ウェルにＤＭＥＭ／Ｆ−１２培養液
を満たした状態で、２個の電極を通じ、一方を正極他方
を負極として１００μＡの定電流刺激を０．２Ｈｚで４
８時間以上与えても、電極の破壊はみられなかった。Further, while the well was filled with the DMEM / F-12 culture solution, a constant current stimulation of 100 μA was performed at 0.2 Hz for 4 hours through two electrodes, one of which was a positive electrode and the other was a negative electrode.
No destruction of the electrodes was observed even after application for 8 hours or more.
【００５０】したがって、神経細胞電気活動の同時多点
計測を４８時間以上の長期に渡り連続的におこなうこと
が可能であった。なお、神経細胞の培養法は本実施例以
外にも多くの変法があり、本実施例に限定されるもので
はない。Therefore, it was possible to continuously perform simultaneous multipoint measurement of electrical activity of nerve cells for a long period of 48 hours or more. The method for culturing nerve cells is not limited to this example because there are many modified methods other than this example.
【００５１】[0051]
【発明の効果】本発明は、神経細胞の培養が可能で、従
来不可能または非常に困難であった神経細胞電気活動の
同時多点計測および多細胞に渡る信号伝達の数時間以上
の長期観察が実現でき、また、応答性の優れた一体化複
合電極を提供できる。INDUSTRIAL APPLICABILITY The present invention is capable of culturing nerve cells, and has been impossible or extremely difficult in the past. Simultaneous multipoint measurement of electrical activity of nerve cells and long-term observation of signal transmission over multiple cells for several hours or more. And an integrated composite electrode having excellent responsiveness can be provided.
【００５２】また、最近接の電極間距離が、１０〜１０
００μｍである本発明の好ましい態様とすることによ
り、各細胞体が各電極上に位置し、且つ神経突起を介し
て結合する可能性が高くでき、神経細胞の測定に好都合
な一体化複合電極を提供できる。Further, the distance between the closest electrodes is 10 to 10
By adopting a preferred embodiment of the present invention having a size of 00 μm, it is possible to increase the possibility that each cell body is located on each electrode and bind via neurites, and an integrated composite electrode convenient for nerve cell measurement is provided. Can be provided.
【００５３】また、リード線をカバーする絶縁層が、各
電極上に孔を有し、かつリード線の外部回路との接点部
近傍を除いて前記絶縁基盤のほぼ全面に設けられた絶縁
層である本発明の好ましい態様とすることにより、感光
性樹脂からなる絶縁材料を使用して、ほぼ全面にこの樹
脂を塗布し、フォトエッチング手法により、容易に必要
な絶縁層パターンが形成でき、生産が容易で、絶縁不良
の確率の小さい一体化複合電極を提供できる。The insulating layer covering the lead wire is an insulating layer which has holes on each electrode and is provided on almost the entire surface of the insulating substrate except for the vicinity of the contact portion of the lead wire with the external circuit. According to a preferred embodiment of the present invention, an insulating material made of a photosensitive resin is used, and this resin is applied to almost the entire surface, and the required insulating layer pattern can be easily formed by a photoetching method, and the production is improved. An integrated composite electrode that is easy and has a low probability of insulation failure can be provided.
【００５４】また、複数個の電極中心部が、８×８の格
子上の各交点に位置する本発明の好ましい態様とするこ
とにより、電極からリード線を略放射状に配設できる最
高の電極数を有する一体化複合電極を提供できる。Further, by adopting a preferred embodiment of the present invention in which a plurality of electrode central portions are located at respective intersections on an 8 × 8 grid, the maximum number of electrodes in which lead wires can be arranged substantially radially from the electrodes. It is possible to provide an integrated composite electrode having
【００５５】[0055]
【００５６】[0056]
【図１】本発明の一実施例の絶縁基盤上に電極とリード
線を形成した本発明の一体化電極の絶縁層のない状態の
配線部のパターンを示した平面図である。FIG. 1 is a plan view showing a pattern of a wiring portion of an integrated electrode of the present invention in which an electrode and a lead wire are formed on an insulating substrate of an embodiment of the present invention without an insulating layer.
【００５７】[0057]
【図２】本発明の一体化複合電極の一実施例の絶縁層の
みの平面図の一部切り欠き図である。FIG. 2 is a partially cutaway view of a plan view of only an insulating layer of an embodiment of an integrated composite electrode of the present invention.
【００５８】[0058]
【図３】本発明の一体化複合電極の一実施例の一部の断
面図である。FIG. 3 is a partial cross-sectional view of one embodiment of the integrated composite electrode of the present invention.
【００５９】[0059]
１ 電極 ２ リード線 ３ 絶縁基盤 ４ 絶縁層 ５ 孔 ６ 白金黒 ７ 金 ８ ニッケル 1 electrode 2 lead wire 3 insulating substrate 4 insulating layer 5 hole 6 platinum black 7 gold 8 nickel
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｇ０１Ｎ 27/26 Ｕ 7235−2Ｊ 27/30 Ｆ 7235−2Ｊ 27/416 // Ｈ０１Ｂ 5/14 Ｚ 7235−2Ｊ Ｇ０１Ｎ 27/46 ３４１ Ｍ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification number Office reference number FI technical display location G01N 27/26 U 7235-2J 27/30 F 7235-2J 27/416 // H01B 5/14 Z 7235-2J G01N 27/46 341 M
Claims (4)
等しい複数個の電極を備え、前記電極からリード線を略
放射状に配設した配線部と、前記リード線をカバーする
絶縁層とを設け、かつ電極が、正方形もしくは円形であ
って、１辺の長さ若しくは直径が２０μｍよりも大き
く、且つ２００μｍ以下である一体化複合電極。1. A wiring part having a plurality of electrodes having the same closest distance between electrodes on an insulating base, and lead wires arranged substantially radially from the electrodes, and an insulating layer covering the lead wires. And an electrode having a square or circular shape with a side length or diameter of more than 20 μm and not more than 200 μm.
μｍである請求項１記載の一体化複合電極。2. The distance between the closest electrodes is 10 to 1000.
The integrated composite electrode according to claim 1, which has a thickness of μm.
上に孔を有し、かつリード線の外部回路との接点部近傍
を除いて前記絶縁基盤のほぼ全面に設けられた絶縁層で
ある請求項１または２に記載の一体化複合電極。3. An insulating layer for covering the lead wire, wherein the insulating layer has holes on each electrode and is provided on substantially the entire surface of the insulating substrate except in the vicinity of a contact portion of the lead wire with an external circuit. The integrated composite electrode according to claim 1 or 2.
の各交点に位置する請求項１〜３のいずれかに記載の一
体化複合電極。4. The integrated composite electrode according to claim 1, wherein a plurality of electrode central portions are located at respective intersections on an 8 × 8 grid.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23699892A JP3193471B2 (en) | 1992-09-04 | 1992-09-04 | Integrated composite electrode |
| DE1993633945 DE69333945T2 (en) | 1992-09-04 | 1993-09-02 | Flat electrode |
| EP19930114091 EP0585933B1 (en) | 1992-09-04 | 1993-09-02 | Planar electrode |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23699892A JP3193471B2 (en) | 1992-09-04 | 1992-09-04 | Integrated composite electrode |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0678889A true JPH0678889A (en) | 1994-03-22 |
| JP3193471B2 JP3193471B2 (en) | 2001-07-30 |
Family
ID=17008876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23699892A Expired - Fee Related JP3193471B2 (en) | 1992-09-04 | 1992-09-04 | Integrated composite electrode |
Country Status (1)
| Country | Link |
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