【０００１】[0001]
【発明の属する技術分野】この発明は、バイオセンサに
関する。TECHNICAL FIELD The present invention relates to a biosensor.
【０００２】[0002]
【従来の技術】従来、この種のバイオセンサとしては、
図５（Ａ）、（Ｂ）に示すような構造のものが提案され
ている。このバイオセンサは、図に示すように、絶縁基
板１の上に、例えばスクリーン印刷法により導電性カー
ボンペーストを印刷してなる作用極（アノード電極）２
Ａと、同じく導電性カーボンでなる対極（カソード電
極）２Ｂと、が所定間隔を介して形成されている。作用
極２Ａは、矩形状であり、対極２Ｂはこの作用極２Ａの
三方を囲むような略コ字形状となっている。そして、作
用極２Ａの表面には、酸化還元酵素または、酸化還元酵
素およびメディエータの両者、からなる酵素反応層３が
形成されている。このバイオセンサを用いて試料液の基
質濃度を測定するには、このバイオセンサを試料液に浸
漬して、作用極２Ａと対極２Ｂとの間に試料液が存在す
る状態で行う。このとき、酸化還元酵素の触媒作用によ
り、基質が例えば酸化され、メディエータが還元され
る。そして、還元されたメディエータを電気化学的に酸
化し、そのとき得られるメディエータの酸化電流を検出
することにより、試料液中の基質濃度を求めるようにな
っている。2. Description of the Related Art Conventionally, as this type of biosensor,
The structure shown in FIGS. 5A and 5B has been proposed. As shown in the figure, this biosensor has a working electrode (anode electrode) 2 formed by printing a conductive carbon paste on an insulating substrate 1 by, for example, a screen printing method.
A and a counter electrode (cathode electrode) 2B, which is also made of conductive carbon, are formed with a predetermined interval. The working electrode 2A has a rectangular shape, and the counter electrode 2B has a substantially U-shape that surrounds the working electrode 2A on three sides. Then, on the surface of the working electrode 2A, an enzyme reaction layer 3 composed of a redox enzyme or both a redox enzyme and a mediator is formed. To measure the substrate concentration of the sample solution using this biosensor, the biosensor is immersed in the sample solution and the sample solution is present between the working electrode 2A and the counter electrode 2B. At this time, the substrate is oxidized, for example, by the catalytic action of the oxidoreductase, and the mediator is reduced. Then, the reduced mediator is electrochemically oxidized, and the oxidation current of the mediator obtained at that time is detected to determine the substrate concentration in the sample solution.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、このよ
うなバイオセンサを例えばグルコースセンサに適用した
場合、４０ｍｇ／ｄｌ以下のグルコース濃度に対する電
流応答が小さく、低濃度領域のグルコース測定が困難で
あった。また、還元性物質による妨害電流が生じ、還元
性物質（例えば、アスコルビン酸など）を多く含む試料
液の測定値が高くでるという問題点があった。なお、こ
のような問題は、グルコースセンサに限られるものでは
なく、他の基質濃度を測定する各種のバイオセンサにお
いても同様であった。However, when such a biosensor is applied to, for example, a glucose sensor, the current response to a glucose concentration of 40 mg / dl or less is small and it is difficult to measure glucose in a low concentration region. Further, there is a problem that an interfering current is generated by the reducing substance, and the measured value of the sample liquid containing a large amount of the reducing substance (such as ascorbic acid) becomes high. It should be noted that such a problem is not limited to the glucose sensor, and is the same in various biosensors that measure other substrate concentrations.
【０００４】この発明の課題は、所謂妨害物質を含んだ
試料液中の基質濃度の測定を可能にするバイオセンサを
得るにはどのような手段を講じればよいかという点にあ
る。An object of the present invention is what kind of means should be taken to obtain a biosensor capable of measuring a substrate concentration in a sample solution containing a so-called interfering substance.
【０００５】[0005]
【０００６】請求項１記載の発明は、バイオセンサにお
いて、スペーサにより互いに離間された一対の絶縁膜に
それぞれカソード電極及び白金からなるアノード電極が
対向して形成され、前記アノード電極表面に測定する試
料と化学反応を生じる酵素または酵素及びメディエータ
を含む酵素層が形成され、前記酵素層の少なくとも一側
面には、前記スペーサにより外部と連通されている試料
導入空間が形成されていることを特徴とする。According to a first aspect of the invention, in the biosensor, a cathode electrode and an anode electrode made of platinum are formed to face each other on a pair of insulating films separated by a spacer, and a sample to be measured on the surface of the anode electrode. An enzyme layer that contains a chemical reaction with an enzyme or an enzyme and a mediator is formed, and at least one side surface of the enzyme layer is formed with a sample introduction space that is communicated with the outside by the spacer. .
【０００７】したがって、酵素層が形成されているアノ
ード電極を白金とすることにより、試料に含まれる被測
定対象である基質の酵素反応に伴う酸化還元電流を鋭敏
に検知すると共に試料に含まれる妨害物質に起因する電
流の検知を低減することができるので、より精度の高い
試料中の基質の測定を行なうことができる。また、試料
導入空間が酵素層の少なくとも一側面に形成されている
ので迅速に試料を酵素層に到達することができる。Therefore, by using platinum as the anode electrode on which the enzyme layer is formed, the redox current associated with the enzymatic reaction of the substrate to be measured contained in the sample can be sensitively detected and the interference contained in the sample can be prevented. Since the detection of the electric current caused by the substance can be reduced, the substrate in the sample can be measured with higher accuracy. Further, since the sample introduction space is formed on at least one side surface of the enzyme layer, the sample can quickly reach the enzyme layer.
【０００８】請求項２記載の発明は、前記力ソード電極
に対向して、前記酵素層と重ならない補正用アノード電
極を備えることを特徴とする。According to a second aspect of the present invention, there is provided a correcting anode electrode facing the force sword electrode and not overlapping the enzyme layer.
【０００９】したがって、補正用アノード電極を用いて
酵素反応と異なる反応により生じる電流を測定し、アノ
ード電極とカソード電極との間に発生する電流から差し
引くことにより、より精度の高いセンスを行なうことが
できる。Therefore, by using the correcting anode electrode to measure the current generated by a reaction different from the enzymatic reaction and subtracting it from the current generated between the anode electrode and the cathode electrode, more accurate sensing can be performed. it can.
【００１０】請求項３記載の発明は、前記酵素層は、柔
軟性を有する多孔性膜であり、前記酵素または酵素及び
メディエータは前記多孔性膜内に形成されている。According to a third aspect of the present invention, the enzyme layer is a flexible porous film, and the enzyme or the enzyme and the mediator are formed in the porous film.
【００１１】したがって、多孔質の酵素層であるので反
応を起こす表面積が大きいので高感度に測定することが
できる。また、試料導入空間を狭小にすることができる
ので微量な試料でセンスすることができる。Therefore, since it is a porous enzyme layer, it has a large surface area for causing a reaction, so that it can be measured with high sensitivity. Further, since the sample introduction space can be narrowed, it is possible to sense with a small amount of sample.
【００１２】請求項４記載の発明は、一部が外部に露出
している前記多孔性膜上にカソード電極表面が形成され
ていることを特徴とする。The invention according to claim 4 is characterized in that the surface of the cathode electrode is formed on the porous film, a part of which is exposed to the outside.
【００１３】したがって、カソード電極側にも試料が導
入することができ、迅速に測定することができる。Therefore, the sample can be introduced also to the cathode electrode side, and the measurement can be performed quickly.
【００１４】請求項５記載の発明では、前記試料はグル
コースを含み、前記酵素層はグルコースオキシターゼを
含むことを特徴とする。According to a fifth aspect of the present invention, the sample contains glucose, and the enzyme layer contains glucose oxidase.
【００１５】[0015]
【発明の実施の形態】以下、この発明に係るバイオセン
サの詳細を図面に示す実施形態に基づいて説明する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, details of a biosensor according to the present invention will be described based on embodiments shown in the drawings.
【００１３】（実施形態１）図１（Ａ）および（Ｂ）
は、この発明の実施形態１を示している。図１（Ａ）
は、この実施形態のバイオセンサの平面説明図であり、
図１（Ｂ）は同図（Ａ）のＢ−Ｂ断面図である。(Embodiment 1) FIGS. 1A and 1B
Shows Embodiment 1 of the present invention. FIG. 1 (A)
Is a plan view of the biosensor of this embodiment,
FIG. 1B is a sectional view taken along line BB of FIG.
【００１４】このバイオセンサの構成は、図１（Ｂ）に
示すように、上連続多孔性膜３１と下連続多孔性膜３２
とが、絶縁性材料でなる板状のスペーサ３３を介して接
合されている。これら上下連続多孔性膜３１、３２は、
ポリテトラフルオロエチレンでなり、その膜厚は例えば
２０〜〜２００μｍで、連続孔の孔径は０．２μｍに設
定されている。そして、下連続多孔性膜３２には、上連
続多孔性膜３１の一側縁部より外側に突出する延在部３
２Ａが形成されている。なお、スペーサ３３には、図１
（Ａ）に破線で示すような平面略Ｔ字形状の、試料液導
入空間としての中空部３４が形成されている。この中空
部３４は、下連続多孔性膜３２の延在部３２Ａの幅方向
の中央の位置から内側に向けてスペーサ３３を切り欠い
た試料液導入部３４Ａと、この試料液導入部３４Ａに連
通する、上下連続多孔性膜３１、３２の幅方向に沿って
スペーサ３３を切り欠いた検査空間３４Ｂと、から構成
されている。As shown in FIG. 1B, the structure of this biosensor has an upper continuous porous film 31 and a lower continuous porous film 32.
And are joined via a plate-shaped spacer 33 made of an insulating material. These upper and lower continuous porous membranes 31, 32 are
It is made of polytetrafluoroethylene, and its film thickness is, for example, 20 to 200 μm, and the diameter of the continuous holes is set to 0.2 μm. Then, in the lower continuous porous membrane 32, the extending portion 3 protruding outward from one side edge portion of the upper continuous porous membrane 31.
2A is formed. It should be noted that the spacer 33 has a structure shown in FIG.
A hollow portion 34 as a sample liquid introduction space having a substantially T-shape in plan view as shown by a broken line in (A) is formed. The hollow portion 34 communicates with the sample liquid introducing portion 34A in which the spacer 33 is cut inward from the center position in the width direction of the extending portion 32A of the lower continuous porous membrane 32, and the sample liquid introducing portion 34A. And the inspection space 34B in which the spacer 33 is cut out along the width direction of the upper and lower continuous porous membranes 31, 32.
【００１５】そして、下連続多孔性膜３２の下面には、
白金（Ｐｔ）でなるカソード電極３５が全面に亙って形
成されている。また、このカソード電極３５の下面に
は、全面に亙って下絶縁膜３６が形成されている。一
方、上連続多孔性膜３１の上面には、図１（Ａ）に示す
ように、白金でなるアノード電極３７が形成されてい
る。このアノード電極３７の一端部には、例えば径寸法
が２．５ｍｍの円形状の検査部３７Ａが形成されてい
る。なお、アノード電極３７における検査部３７Ａ以外
の部分は、幅寸法が１ｍｍの線状パターン３７Ｂに形成
されている。また、検査部３７Ａは、スペーサ３３と上
下連続多孔性膜３１、３２とで形成される検査空間３４
Ｂに、上連続多孔性膜３１を介して臨むように配置され
ている。ところで、アノード電極３７およびカソード電
極３５を形成するには、マグネットスパッタリング法で
白金膜を成膜する。この白金膜からアノード電極３７を
パターン形成するには、例えばメタルマスクまたはフォ
トリソグラフィー技術およびエッチング技術を用いれば
よい。そして、図１（Ａ）に示すように、検査空間３４
Ｂに対応する部分の上連続多孔性膜３１には、グルコー
スオキシダーゼ（ＧＯＤ）と牛血清アルブミン（ＢＳ
Ａ）とが固定化されて、酵素固定化層３１Ａが形成され
ている。この酵素固定化層３１Ａは、上連続多孔性膜３
１の連続孔を酵素で塞いでしまうものではなく、基性で
あるグルコースがアノード電極１７に到達し得るように
連続孔が連通した状態を保つように固定化されている。
このような酵素の固定化方法としては、架橋法や包括法
などが知られている。本実施形態では、上下連続多孔性
膜３１、３２をスペーサ３３を介して張り合わせる前
に、グルコース酸化酵素であるグルコースオキシダーゼ
（ＧＯＤ）と牛血清アルブミン（ＢＳＡ）との混合溶液
を、上連続多孔性膜３１の検査空間３４Ａに臨む部分
に、適量滴下し、乾燥後、グルタルアルデヒド蒸気中で
架橋反応を行って酵素を固定化した。アノード電極３７
を覆うように上連続多孔性膜３１の上面に上絶縁膜３９
が全面に亙って設けられている。On the lower surface of the lower continuous porous membrane 32,
A cathode electrode 35 made of platinum (Pt) is formed over the entire surface. A lower insulating film 36 is formed on the entire lower surface of the cathode electrode 35. On the other hand, an anode electrode 37 made of platinum is formed on the upper surface of the upper continuous porous film 31, as shown in FIG. A circular inspection portion 37A having a diameter of 2.5 mm, for example, is formed at one end of the anode electrode 37. The portion of the anode electrode 37 other than the inspection portion 37A is formed into a linear pattern 37B having a width of 1 mm. In addition, the inspection part 37A includes an inspection space 34 formed by the spacer 33 and the upper and lower continuous porous films 31, 32.
It is arranged so as to face B through the upper continuous porous membrane 31. By the way, in order to form the anode electrode 37 and the cathode electrode 35, a platinum film is formed by a magnet sputtering method. To pattern the anode electrode 37 from this platinum film, for example, a metal mask or photolithography technique and etching technique may be used. Then, as shown in FIG.
The upper continuous porous membrane 31 corresponding to B has glucose oxidase (GOD) and bovine serum albumin (BS
A) and (A) are immobilized to form an enzyme immobilization layer 31A. The enzyme immobilization layer 31A is an upper continuous porous membrane 3
The continuous hole of No. 1 is not blocked with an enzyme, but is immobilized so that the continuous hole is kept in communication so that basic glucose can reach the anode electrode 17.
As a method for immobilizing such an enzyme, a crosslinking method, an entrapment method, and the like are known. In the present embodiment, a mixed solution of glucose oxidase (GOD) and bovine serum albumin (BSA) is mixed with the upper continuous pores before the upper and lower continuous porous membranes 31, 32 are bonded together via the spacer 33. An appropriate amount was dropped on the portion of the permeable film 31 facing the inspection space 34A, and after drying, a crosslinking reaction was performed in glutaraldehyde vapor to immobilize the enzyme. Anode electrode 37
To cover the upper insulating film 39 on the upper surface of the upper continuous porous film 31.
Is provided over the entire surface.
【００１６】そして、図１（Ｂ）に示すように、カソー
ド電極３５は、リード線４０を介して電圧印加回路４１
および電流測定回路４２に接続されている。また、アノ
ード電極３７は、リード線４３を介して電圧印加回路４
１および電流測定回路４２に接続されている。Then, as shown in FIG. 1B, the cathode electrode 35 is connected to the voltage applying circuit 41 via the lead wire 40.
And a current measuring circuit 42. Further, the anode electrode 37 is connected to the voltage applying circuit 4 via the lead wire 43.
1 and the current measuring circuit 42.
【００１７】このような構成のグルコースセンサを用い
て、試料液に対する電流応答を測定した。試料液として
は、低濃度のグルコース標準溶液を１０μｌ滴下して用
いた。なお、試料液の滴下位置は、下連続多孔性膜３２
の延在部３２Ａ中央の試料液導入部３４Ａの入口位置で
ある。このような位置に滴下すると、標準溶液は毛細管
現象により、試料液導入部３４Ａに沿って検査空間３４
Ｂに取り込まれ、アノード電極３７側に標準溶液が拡散
して行く。そして、酵素固定化層３１Ａで酵素反応が起
こり、グルコースが酸化されるとともに、過酸化水素が
生成される。標準溶液が、対向するアノード電極３７
（検査部３７Ａ）とカソード電極３５との間に十分染み
込むのを待って、所定時間経過後、電極間に０．７Ｖの
電圧を電圧印加回路４１によって印加した。電圧印加に
より、電極間に過酸化水素の電解電流が流れる。電圧印
加してから５秒後の電解電流を電流測定回路４２により
検出した。図２は、グルコース濃度０のときのバイアス
電流キャンセル後の、グルコース濃度に対する電解電流
値をプロットしたグラフである。このグラフから、グル
コース濃度０〜６０ｍｇ／ｄｌの低濃度領域で、非常に
良い直線性が得られた。また、１００ｍｇ／ｄｌのアス
コルビン酸溶液に対する応答は、約０．２μＡとなり、
従来のカーボンペースト電極の応答の約２．２μＡより
１０分の１以下となり、アスコルビン酸の影響を著しく
削減できた。Using the glucose sensor having such a structure, the current response to the sample solution was measured. As the sample solution, 10 μl of a low-concentration glucose standard solution was dropped and used. The sample liquid is dropped at the lower continuous porous membrane 32.
It is the inlet position of the sample liquid introducing section 34A at the center of the extending section 32A. If the standard solution is dropped at such a position, the standard solution is moved along the sample liquid introducing section 34A by the capillary phenomenon to cause the inspection space 34 to flow.
The standard solution is taken in by B and diffuses toward the anode electrode 37 side. Then, an enzyme reaction occurs in the enzyme-immobilized layer 31A to oxidize glucose and generate hydrogen peroxide. The standard solution is the opposite anode electrode 37
After a sufficient time soaked between the (inspection unit 37A) and the cathode electrode 35, a voltage of 0.7 V was applied between the electrodes by the voltage application circuit 41 after a predetermined time had elapsed. By applying a voltage, an electrolytic current of hydrogen peroxide flows between the electrodes. The electrolysis current 5 seconds after applying the voltage was detected by the current measuring circuit 42. FIG. 2 is a graph in which the electrolytic current value with respect to the glucose concentration is plotted after the bias current cancellation when the glucose concentration is 0. From this graph, very good linearity was obtained in the low concentration region of glucose concentration of 0 to 60 mg / dl. The response to a 100 mg / dl ascorbic acid solution was about 0.2 μA,
The response of about 2.2 μA of the conventional carbon paste electrode is 1/10 or less, and the influence of ascorbic acid can be significantly reduced.
【００１８】本実施形態では、電極材料に白金を用いた
ことにより、例えばアスコルビン酸などの妨害物質の影
響を受けずに、低濃度の基質の濃度測定が可能となる。In the present embodiment, by using platinum as the electrode material, it is possible to measure the concentration of the low-concentration substrate without being affected by interfering substances such as ascorbic acid.
【００１９】（実施形態２）図３（Ａ）はこの実施形態
の平面図、図３（Ｂ）は同図（Ａ）のＡ−Ａ断面図であ
る。本実施形態では、図に示すように、上連続多孔性膜
１１と下連続多孔性膜１２とが、絶縁性材料でなる板状
のスペーサ１３を介して接合されている。なお、下連続
多孔性膜１２は、上連続多孔性膜１１の一側縁部より外
側に突出する延在部１２Ａが形成されている。なお、ス
ペーサ１３には、図３（Ａ）に破線で示すような平面略
Ｔ字形状の、試料液導入空間としての中空部１４が形成
されている。この中空部１４は、下連続多孔性膜１２の
延在部１２Ａの幅方向の中央の位置から内側に向けてス
ペーサ１３を切り欠いた試料液導入部１４Ａと、この試
料液導入部１４Ａに連通する、上下連続多孔性膜１１、
１２の幅方向に沿ってスペーサ１３を切り欠いた検査空
間１４Ｂと、から構成されている。(Embodiment 2) FIG. 3A is a plan view of this embodiment, and FIG. 3B is a sectional view taken along line AA of FIG. 3A. In the present embodiment, as shown in the figure, the upper continuous porous film 11 and the lower continuous porous film 12 are joined via a plate-like spacer 13 made of an insulating material. In addition, the lower continuous porous membrane 12 is formed with an extending portion 12A protruding outward from one side edge portion of the upper continuous porous membrane 11. In addition, the spacer 13 is provided with a hollow portion 14 as a sample liquid introduction space, which is substantially T-shaped in plan view as shown by a broken line in FIG. The hollow portion 14 communicates with the sample liquid introducing portion 14A in which the spacer 13 is cut inward from the central position in the width direction of the extending portion 12A of the lower continuous porous membrane 12 and the sample liquid introducing portion 14A. The upper and lower continuous porous membranes 11,
The inspection space 14B is formed by notching the spacer 13 along the width direction of the reference numeral 12.
【００２０】そして、下連続多孔性膜１２の下面には、
例えば対向電極として導電性カーボンでなるカソード電
極１５が全面に亙って形成されている。また、このカソ
ード電極１５の下面には、全面にわたって下絶縁膜１６
が形成されている。一方、上連続多孔性膜１１の上面に
は、図３（Ａ）に示すように、所定距離を介して、長手
方向に沿って形成された、作用電極として白金でなるア
ノード電極１７と、同じく白金でなる補正用アノード電
極１８とが形成されている。これらアノード電極１７と
補正用アノード電極１８のそれぞれの一端部には、円形
状の検査部１７Ａ、１８Ａが形成されている。この検査
部１７Ａ、１８Ａは、スペーサ１３と上下連続多孔性膜
１１、１２とで形成される検査空間１４Ｂに、上連続多
孔性膜１１を介して臨むように配置されている。そし
て、図３（Ａ）に示すように、検査空間１４Ｂのアノー
ド電極１７側の半分に対応する部分の上連続多孔性膜１
１には、グルコースオキシダーゼ（ＧＯＤ）と牛血清ア
ルブミン（ＢＳＡ）とが固定化されて、酵素固定化層１
１Ａが形成されている。また、検査空間１４Ｂの補正用
アノード電極１８側の半分に対応する部分の上連続多孔
性膜１１には、牛血清アルブミン（蛋白質）のみが固定
化されてなる非酵素固定化層１１Ｂが形成されている。
なお、これら酵素固定化層１１Ａ、非酵素固定化層１１
Ｂは、上連続多孔性膜１１の連続孔を酵素等で塞いでし
まうものではなく、基質であるグルコースがアノード電
極１７、補正用アノード電極１８に到達し得るように連
続孔が連通した状態を保つように固定化されている。そ
して、図３（Ｂ）に示すように、アノード電極１７およ
び補正用アノード電極１８を覆うように上連続多孔性膜
１１の上面に上絶縁膜１９が全面に亙って設けられてい
る。On the lower surface of the lower continuous porous membrane 12,
For example, a cathode electrode 15 made of conductive carbon is formed as an opposite electrode over the entire surface. Further, the lower insulating film 16 is formed on the entire lower surface of the cathode electrode 15.
Are formed. On the other hand, as shown in FIG. 3A, on the upper surface of the upper continuous porous membrane 11, an anode electrode 17 made of platinum as a working electrode is formed along a longitudinal direction with a predetermined distance, and A correction anode electrode 18 made of platinum is formed. Circular inspection parts 17A and 18A are formed at one end of each of the anode electrode 17 and the correction anode electrode 18. The inspection parts 17A and 18A are arranged so as to face the inspection space 14B formed by the spacer 13 and the upper and lower continuous porous films 11 and 12 with the upper continuous porous film 11 interposed therebetween. Then, as shown in FIG. 3 (A), the upper continuous porous membrane 1 corresponding to a half of the inspection space 14B on the anode electrode 17 side.
Glucose oxidase (GOD) and bovine serum albumin (BSA) are immobilized on the surface of the enzyme immobilization layer 1.
1A is formed. Further, a non-enzyme immobilization layer 11B in which only bovine serum albumin (protein) is immobilized is formed on the upper continuous porous membrane 11 of a portion corresponding to the half of the inspection space 14B on the side of the correcting anode electrode 18 side. ing.
In addition, these enzyme immobilization layer 11A, non-enzyme immobilization layer 11
In B, the continuous pores of the upper continuous porous membrane 11 are not blocked with an enzyme or the like, and the continuous pores are connected so that glucose as a substrate can reach the anode electrode 17 and the correction anode electrode 18. It is fixed to keep. Then, as shown in FIG. 3B, an upper insulating film 19 is provided on the entire upper surface of the upper continuous porous film 11 so as to cover the anode electrode 17 and the correcting anode electrode 18.
【００２１】なお、上記した酵素固定化層１１Ａ、非酵
素固定化層１１Ｂを形成する方法としては、それぞれの
領域の上連続多孔性膜１１に、グルコースオキシダーゼ
と牛血清アルブミンとの混合溶液、または牛血清アルブ
ミン溶液を滴下し、乾燥を行った後、グルタルアルデヒ
ド蒸気中で架橋反応を行って固定化する。As a method of forming the above-mentioned enzyme-immobilized layer 11A and non-enzyme-immobilized layer 11B, a mixed solution of glucose oxidase and bovine serum albumin is formed on the upper continuous porous membrane 11 of each region, or A bovine serum albumin solution is dropped, and after drying, a cross-linking reaction is performed in glutaraldehyde vapor to immobilize.
【００２２】そして、図３（Ｂ）に示すように、カソー
ド電極１５は、リード線２２を介して電圧印加回路２３
および電流測定回路２４に接続されている。また、アノ
ード電極１７は、リード線２０を介して電圧印加回路２
３および電流測定回路２４に接続されている。さらに、
補正用アノード電極１８は、リード線２１を介して電圧
印加回路２３および電流測定回路２４に接続されてい
る。またさらに、電流測定回路２４は、演算手段２５お
よび表示手段２６に接続されている。Then, as shown in FIG. 3B, the cathode electrode 15 is connected to the voltage applying circuit 23 via the lead wire 22.
And a current measuring circuit 24. Further, the anode electrode 17 is connected to the voltage applying circuit 2 via the lead wire 20.
3 and the current measuring circuit 24. further,
The correction anode electrode 18 is connected to a voltage application circuit 23 and a current measurement circuit 24 via a lead wire 21. Furthermore, the current measuring circuit 24 is connected to the computing means 25 and the display means 26.
【００２３】本実施形態では、アノード電極１７に接触
する部分の上連続多孔性膜１１のみに酵素を固定化した
ため、電圧印加により例えば尿酸の酸化電流が生じて
も、アノード電極１７と補正用アノード電極１８との両
方に流れ、酵素反応後に生じる過酸化水素の酸化電流は
アノード電極１７のみに流れるため、２つの電流の差を
取れば、尿酸やその他の還元性物質による影響を除去す
ることができる。具体的には、尿酸１００ｍｇ／ｄｌ、
グルコース１０ｍｇ／ｄｌの混合溶液に対する電流応答
とグルコース１０ｍｇ／ｄｌ溶液に対する電流応答の差
は０．１μＡとなり、グルコースの１０倍濃度の尿酸を
含むに拘わらず、その影響は著しく削減された。In the present embodiment, since the enzyme is immobilized only on the upper continuous porous membrane 11 in contact with the anode electrode 17, even if an oxidation current of uric acid is generated by voltage application, for example, the anode electrode 17 and the correcting anode are corrected. Since the oxidation current of hydrogen peroxide that flows to both the electrode 18 and the enzymatic reaction flows only to the anode electrode 17, if the difference between the two currents is taken, the effect of uric acid and other reducing substances can be removed. it can. Specifically, uric acid 100 mg / dl,
The difference between the current response to the mixed solution of glucose 10 mg / dl and the current response to the glucose 10 mg / dl solution was 0.1 μA, and the effect was remarkably reduced regardless of containing 10 times the concentration of uric acid as glucose.
【００２４】また、作用電極であるアノードで１７が白
金でなるため、アスコルビン酸１００ｍｇ／ｄｌ溶液に
対する応答は、約０．２μＡとなり、従来のカーボンペ
ースト電極の応答の約２．２より１０分の１以下とな
り、アスコルビン酸に起因する電流の影響を著しく低減
することができた。Further, since the anode 17 which is the working electrode is made of platinum, the response to a 100 mg / dl solution of ascorbic acid is about 0.2 μA, which is about 10 minutes from 2.2 of the response of the conventional carbon paste electrode. It was 1 or less, and the influence of electric current due to ascorbic acid could be significantly reduced.
【００２５】以上、実施形態２について説明したが、本
実施形態においては、酵素を固定化したアノード電極１
７と、固定化しない補正用アノード電極１８との電流応
答の差を取ることにより、還元性物質の電解酸化電流を
除去できるため、高濃度の妨害物質を含んだ試料液、例
えば唾液中のグルコース濃度の正確な測定が可能とな
る。また、酵素を固定化したアノード電極１７と固定化
しない補正用アノード電極１８との電流応答の差を取る
ことにより、基質濃度０のときに生じるバイアス電流を
自動的に除去できるため、基質濃度０での応答を別に測
定して、バイアス電流をキャンセルする必要がないとい
う利点がある。Although the second embodiment has been described above, in the present embodiment, the enzyme-immobilized anode electrode 1 is used.
7 and the correction anode electrode 18 which is not immobilized, the electrolytic oxidation current of the reducing substance can be removed by taking the difference in the current response, so that the glucose in the sample solution containing a high concentration of the interfering substance, for example, saliva. Accurate measurement of concentration is possible. Further, by taking the difference in current response between the anode electrode 17 on which the enzyme is immobilized and the correction anode electrode 18 on which the enzyme is not immobilized, the bias current generated when the substrate concentration is 0 can be automatically removed. There is an advantage that there is no need to cancel the bias current by separately measuring the response at.
【００２６】なお、上記実施形態では、アノード電極１
７の電流応答のそれぞれを検出し、その差を算出した
が、それぞれの電流検出回路の後段に引き算回路を設
け、直接差電流を検出するようにしても勿論よい。ま
た、酵素の種類を変えることで、グルコース以外の基質
のセンサとすることも可能である。さらに、酵素固定化
層１１Ａは、酵素としてグルコースオキシダーゼのみを
固定したが、これに加えてメディエータを共存させる構
成としも勿論よい。この場合、酵素およびメディエータ
の酸化還元反応に伴う還元型メディエータの酸化電流を
検出するバイオセンサを構築することができる。このバ
イオセンサでは、図４に示すように、グルコースを酸化
させて還元型に変化した酵素ＧＯＤred２７が元の酸化
型酵素ＧＯＤox２８に戻る際、メディエータが酵素から
電子を奪い還元型メディエータＭred２９となる。そし
て、この還元型メディエータが電極反応によって酸化さ
れ、元の酸化型メディエータＭox３０となる。すなわ
ち、酵素とメディエータとが固定化されたアノード電極
近傍に基質が存在すれば、酵素とメディエータとを仲介
して電子がアノード電極へ移動し、グルコース濃度に応
じた電流が流れる。従って、この電流を検出すればグル
コース濃度を測定することができる。このようなバイオ
センサの場合は、酵素とメディエータとをアノード電極
近傍に共存させて固定化されているため、試料液中に溶
存酸素が全くないか、あるいはその量が少ないときで
も、グルコース濃度に応じた電流が流れるため、溶存酸
素濃度に依存しないバイオセンサとすることができる。
また、メディエータを介して電極と電子の授受を行うの
で、メディエータが無い場合に比べて印加電圧を低く抑
えることができる。In the above embodiment, the anode electrode 1
Although each of the current responses of 7 is detected and the difference between them is calculated, it is needless to say that a subtraction circuit may be provided in the subsequent stage of each current detection circuit to directly detect the difference current. It is also possible to use a sensor for a substrate other than glucose by changing the type of enzyme. Furthermore, although the enzyme immobilization layer 11A has only immobilized glucose oxidase as an enzyme, it may of course have a configuration in which a mediator coexists in addition to this. In this case, it is possible to construct a biosensor that detects the oxidation current of the reduced mediator associated with the redox reaction of the enzyme and the mediator. In this biosensor, as shown in FIG. 4, when the enzyme GODred 27, which has been converted to a reduced form by oxidizing glucose, returns to the original oxidized enzyme GODox 28, the mediator takes electrons from the enzyme and the reduced mediator M. It will bered 29. Then, the reduced mediator is oxidized by the electrode reaction to become the original oxidized mediatorMox 30. That is, if the substrate exists near the anode electrode on which the enzyme and the mediator are immobilized, the electrons move to the anode electrode via the enzyme and the mediator, and a current corresponding to the glucose concentration flows. Therefore, the glucose concentration can be measured by detecting this current. In the case of such a biosensor, since the enzyme and the mediator are coexistent and immobilized in the vicinity of the anode electrode, there is no dissolved oxygen in the sample solution, or even when the amount is small, the glucose concentration is Since a corresponding current flows, the biosensor can be made independent of the dissolved oxygen concentration.
Further, since the electrons are transferred to and from the electrodes via the mediator, the applied voltage can be suppressed lower than that in the case without the mediator.
【００２７】また、上下連続多孔性膜１１、１２および
上下絶縁膜１９、１６を柔軟性および可撓性を有する材
料で形成することにより、例えば瞼の下に挿入したり、
歯に被せるなど、狭小な場所や凹凸のある場所での使用
を可能にすることができる。さらに、連続多孔性膜の連
続孔の径寸法を適宜設定することにより、例えばヘモグ
ロビンや蛋白質のなどの高分子がアノード電極に到達す
ることを防止することができる。このようにすれば、酵
素固定化層内で発生した過酸化水素を効率よく検出する
ことができる。By forming the upper and lower continuous porous films 11 and 12 and the upper and lower insulating films 19 and 16 with a material having flexibility and flexibility, for example, they can be inserted under the eyelid,
It can be used in narrow places or uneven places such as covering teeth. Furthermore, by appropriately setting the diameter of the continuous pores of the continuous porous membrane, it is possible to prevent polymers such as hemoglobin and proteins from reaching the anode electrode. By doing so, hydrogen peroxide generated in the enzyme-immobilized layer can be efficiently detected.
【００２８】以上、実施形態１および実施形態２につい
て説明したが、この発明はこれらに限定されるものでは
なく、構成の要旨に付随する各種の設計変更が可能であ
る。例えば、上記実施形態１においてアノード電極、補
正用アノード電極およびカソード電極を白金で形成した
が、アノード電極のみを白金で形成する構成としても勿
論よい。また、上記実施形態１において、アノード電極
全体を白金で形成したが、少なくとも酵素固定化層に接
する電極表面だけに白金薄膜を形成する構成としてもよ
い。なお、上記実施形態１において、酵素固定化層は酵
素としてグルコースオキシターゼのみを固定したが、こ
れに加えてメディエータを共存させてもよい。Although the first and second embodiments have been described above, the present invention is not limited to these, and various design changes associated with the gist of the configuration can be made. For example, although the anode electrode, the correction anode electrode, and the cathode electrode are formed of platinum in the first embodiment, it is of course possible that only the anode electrode is formed of platinum. Further, in the first embodiment, the entire anode electrode is formed of platinum, but a platinum thin film may be formed only on at least the electrode surface in contact with the enzyme immobilization layer. In the first embodiment, the enzyme immobilization layer immobilized only glucose oxidase as an enzyme, but in addition to this, a mediator may coexist.
【００２９】[0029]
【発明の効果】以上の説明から明らかなように、この発
明によれば、高濃度の妨害物質を含んだ試料液中の基質
濃度の測定が可能となる。また、この発明によれば、試
料液が微量での基質濃度の測定を可能にするという効果
を奏する。As is apparent from the above description, according to the present invention, it is possible to measure the substrate concentration in a sample solution containing a high concentration of interfering substance. Further, according to the present invention, there is an effect that it is possible to measure the substrate concentration with a small amount of the sample liquid.
【図１】（Ａ）はこの発明の実施形態１の平面説明図、
（Ｂ）は（Ａ）のＡ−Ａ断面図。FIG. 1A is a plan explanatory view of a first embodiment of the present invention,
(B) is an AA sectional view of (A).
【図２】実施形態１の測定結果を示すグラフ。FIG. 2 is a graph showing the measurement result of the first embodiment.
【図３】（Ａ）はこの発明の実施形態２の平面説明図、
（Ｂ）は（Ａ）のＢ−Ｂ断面図。FIG. 3A is an explanatory plan view of Embodiment 2 of the present invention,
(B) is BB sectional drawing of (A).
【図４】メディエータを用いた酵素反応を示す説明図。FIG. 4 is an explanatory diagram showing an enzymatic reaction using a mediator.
【図５】（Ａ）は従来例の平面説明図、（Ｂ）は従来例
の断面図。5A is a plan view of a conventional example, and FIG. 5B is a sectional view of the conventional example.
１１ 上連続多孔性膜 １２ 下連続多孔性膜 １３ スペーサ １４ 中空部 １５ カソード電極 １７ アノード電極 １８ 補正用アノード電極 11 Upper continuous porous film 12 Lower continuous porous film 13 Spacer 14 Hollow part 15 Cathode electrode 17 Anode electrode 18 Correcting anode electrode
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| JP7282363AJPH09101280A (en) | 1995-10-05 | 1995-10-05 | Biosensor |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7282363AJPH09101280A (en) | 1995-10-05 | 1995-10-05 | Biosensor |
| Publication Number | Publication Date |
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| JP7282363APendingJPH09101280A (en) | 1995-10-05 | 1995-10-05 | Biosensor |
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