【発明の詳細な説明】産業上の利用分野本発明は、血液中の特定成分を迅速、かつ容易に定量す
ることのできるバイオセンサに関するものである。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a biosensor that can quickly and easily quantify specific components in blood.
従来例の構成とその問題点近年、酵素の有する特異的触媒作用を利用した種々のバ
イオセンサが開発され、特に臨床検査分野への応用が試
みられている。検査項目及び検体数が増加している現在
、迅速に精度よく測定できるバイオセンサが望まれてい
る。Structures of Conventional Examples and Their Problems In recent years, various biosensors that utilize the specific catalytic action of enzymes have been developed, and attempts have been made to apply them particularly to the field of clinical testing. Currently, as the number of test items and specimens increases, a biosensor that can perform measurements quickly and accurately is desired.
グルコースセンサに例をとると、糖尿病の増加が激しい
今日、血液中の血糖値を測定し管理するには、以前のよ
うに血液を遠心分離し血漿にして測定するのでは非常に
時間がかかるため、全面で測定できるセンサが要求され
ている。簡易型としては、尿検査の時に使用されている
検査紙と同様に、スティック状の支持体に糖（グルコー
ス）にのみ反）ムする酵素および酵素反応時又は酵素反
応の生成物により変化する色素を含有する相体を設置し
７／コものがある０、この担体に血液を添加し、一定時
間後の色素の変化を目又は光により測定する方式である
が、血液中の色素による妨害が大きく精度は低い。Taking glucose sensors as an example, in today's world where diabetes is rapidly increasing, measuring and managing blood glucose levels requires a lot of time to centrifuge blood and convert it into plasma, as was done in the past. , a sensor that can measure the entire surface is required. A simple type, similar to the test strips used in urine tests, is a stick-shaped support containing an enzyme that reacts only with sugar (glucose) and a dye that changes during the enzyme reaction or by the products of the enzyme reaction. In this method, blood is added to this carrier and the change in pigment is measured by eye or light after a certain period of time, but there is interference from the pigment in the blood. It is large and the accuracy is low.
そこで、第１図のような多層式の分析担体が開発さね、
ている。透明な支持体１の上に試薬層２、展開層３、防
水層４、顔過層６が順に積層した構造となっている。血
液ザンプルを上部から滴下すると、捷ずρ渦層５により
血液中の赤血球、血小板などの固形成分が除去され、防
水層４にある小孔４ａから展開層３へ均一に浸透し、試
薬層２において反応が進行する。反応終了後、透明な支
持体１を通して矢印の方向から光をあて、分光分析によ
り基質濃度を測定する方式である。従来の簡易なスティ
ック状の担体にくらべ、複雑な構造であるが、血球除去
などにより精度は向上した。しかし、血液の浸透および
反応に時間がかがるため、ザンブルの乾燥を防ぐ防水層
４が必要とな−たり、反応を速めるだめに高温でインキ
ュベートスル必要があり、装置および担体が複雑化する
という問題かある。Therefore, a multilayer analytical carrier as shown in Figure 1 was developed.
ing. It has a structure in which a reagent layer 2, a spreading layer 3, a waterproof layer 4, and a face layer 6 are laminated in this order on a transparent support 1. When a blood sample is dropped from the top, solid components such as red blood cells and platelets in the blood are removed by the ρ vortex layer 5 without being strained, and the blood sample permeates uniformly into the spreading layer 3 through the small holes 4a in the waterproof layer 4, and the reagent layer 2 The reaction proceeds at . After the reaction is completed, light is irradiated through the transparent support 1 in the direction of the arrow, and the substrate concentration is measured by spectroscopic analysis. Although it has a more complex structure than the conventional simple stick-shaped carrier, it has improved accuracy due to blood cell removal. However, since it takes time for blood to permeate and react, a waterproof layer 4 is required to prevent the sample from drying out, and in order to speed up the reaction, it is necessary to incubate at a high temperature, which complicates the equipment and carrier. There is a problem.
最近、酵素反応と電極反応を結びっけて基質濃度を測定
するバイオセンサが開発されている。グルコースセンサ
に例をとると、第２図のように、グルコースオキシダー
ゼ固定化電極６を容器７に入わ７、緩衝液８で満たし、
スターテ９で撹拌している中に試料液を添加する。グル
コースオキシダーゼ固定化電極６には定電圧か印加され
ており、試料中のグルコースと反応して生成した過酸化
水素を検知して電流が流れグルコース濃度が測定できる
。この方式を用いバーば、血液中の色素なとに妨害され
ず迅速に測定できる。しかし、撹拌装置か不可欠なため
アワが発生したり、液の乱れが精度に影響するという問
題かあった。又希釈しているため、緩衝液の量や試料の
添加量に精度が要求され操作が複雑化する不都合があっ
た。Recently, biosensors have been developed that measure substrate concentration by combining enzyme reactions and electrode reactions. Taking a glucose sensor as an example, as shown in FIG. 2, a glucose oxidase immobilized electrode 6 is placed in a container 7 and filled with a buffer solution 8.
Add the sample solution while stirring with Starter 9. A constant voltage is applied to the glucose oxidase immobilized electrode 6, and hydrogen peroxide produced by reaction with glucose in the sample is detected, and a current flows to measure the glucose concentration. Using this method, measurements can be made quickly without being interfered with by pigments in the blood. However, since a stirring device was required, there were problems such as bubbles occurring and turbulence of the liquid affecting accuracy. Furthermore, since the method is diluted, precision is required in the amount of buffer solution and the amount of sample added, making the operation complicated.
発明の目的本発明は、上記の問題点を克服し、血液中の特定成分を
簡易に、迅速かつ精度よく測定できるバイオセンサを１
号ることを目的とする。Purpose of the Invention The present invention overcomes the above problems and provides a biosensor that can easily, quickly, and accurately measure specific components in blood.
The purpose is to issue a message.
発明の構成本発明のバイオセンサは、絶縁性の基板上に少なくとも
測定極と対極からなる電極系を有し、前記電極系を少な
くとも酸化還元酵素および酸化還とする。Structure of the Invention The biosensor of the present invention has an electrode system consisting of at least a measurement electrode and a counter electrode on an insulating substrate, and the electrode system includes at least a redox enzyme and a redox enzyme.
本発明ノバイオセンサを用いることに」＝す、血液中の
特定成分の測定を簡易に、精度よく測定することかでき
る、実施例の説明本発明のバイオセンサの１つとして、グルコースセンサ
を例に説明する。第３図にグルコースセンサの一実施例
の模式図を示す。塩化ビニル樹脂からなる絶縁性の基板
１０に白金を埋め込み、測定極１１と対極１２とする。By using the biosensor of the present invention, specific components in blood can be easily and accurately measured.Description of Examples As one of the biosensors of the present invention, a glucose sensor is used as an example. Explain. FIG. 3 shows a schematic diagram of an embodiment of a glucose sensor. Platinum is embedded in an insulating substrate 10 made of vinyl chloride resin to form a measurement electrode 11 and a counter electrode 12.
前記電極系を覆うように、ナイロン不織布１３を設置す
る。このナイロン不織布１３は、酸化還元酵素としてグ
ルコースオキシダーゼ１４と酸化還元酵素と共役する酸
化型色素としてフェリシアン化カリウム１５を、溶解含
浸後乾燥状態で担持している。このナイロン不織布１３
の上部に、多孔性（孔径１μｍ）のポリカーボネートか
らなるｐ渦層１６を設置する。A nylon nonwoven fabric 13 is placed so as to cover the electrode system. This nylon nonwoven fabric 13 supports glucose oxidase 14 as an oxidoreductase and potassium ferricyanide 15 as an oxidized pigment conjugated with the oxidoreductase in a dry state after being dissolved and impregnated. This nylon nonwoven fabric 13
A p-vortex layer 16 made of porous (pore diameter 1 μm) polycarbonate is installed on top of the p-vortex layer 16 .
このセンサに血液を滴下して含浸させると、沖過層によ
り赤血球などの大きな分子が沖過され、ナイロン不織布
１３からなる反応層において血液中のグルコースがグル
コースオキシダーゼ１４により酸化される際、フェリシ
アン化カリウム１５か共役して還元されフェリシアン化
カリウムが生成する。このフェリシアン化カリウムを、
対極１２を基準に測定極１１の電位をｏＶから＋０．５
Ｖ寸でｏ、１Ｖ ７秒の速度で掃引することにより酸化
する。この時間られる酸化電流は、フェリシアン化カリ
ウムの濃度に比例し、フェロシアン化カリウムは基質濃
度に比例して生成するため、酸化電流を測定することに
より基質であるグルコースの濃度が検知できる。得られ
た電流値は、グルコースの標準液で測定したところ、８
００ｍｇ／ｄ７１Ｉまでグルコースの濃度とよい直線性
を示した。酵素と酸化型色素からなる反応層および濾過
層は、測定毎に交換しだが、標準液および血液のサンプ
ル両方において再現性は良好であった。又、血液の添加
量を２０μβ〜１４０μｌまで変化させだが、酸化型色
素及び酵素量が充分々だめ、添加量に関係なく一定の値
を示した。When this sensor is dripped with blood and impregnated, large molecules such as red blood cells are filtered out by the overlayer, and when glucose in the blood is oxidized by glucose oxidase 14 in the reaction layer made of nylon nonwoven fabric 13, potassium ferricyanide 15 is conjugated and reduced to produce potassium ferricyanide. This potassium ferricyanide,
The potential of the measurement electrode 11 is +0.5 from oV with respect to the counter electrode 12.
Oxidize by sweeping at a speed of 1 V and 7 seconds with V dimension. This time-consuming oxidation current is proportional to the concentration of potassium ferricyanide, and since potassium ferrocyanide is produced in proportion to the substrate concentration, the concentration of the substrate glucose can be detected by measuring the oxidation current. The obtained current value was measured with a glucose standard solution and was 8.
It showed good linearity with the glucose concentration up to 00 mg/d71I. Although the reaction layer and filtration layer consisting of enzyme and oxidized dye were replaced after each measurement, reproducibility was good for both standard solutions and blood samples. Furthermore, although the amount of blood added was varied from 20 μ.beta. to 140 μl, the amounts of oxidized pigment and enzyme were sufficiently reduced and remained constant regardless of the amount added.
濾過層１６として、ポリカーボネートの多孔体を用いる
ことにより、血液中の血球や粘性の物質があらかじめ濾
過でき、電極の汚れを少なくすることができた。濾過層
が々いと、長期間使用しているうちに電極上に血球が付
着し、得られる電流値が低下するだめ、電極をアルコー
ルで洗浄する必要があったが、濾過層により電極を水洗
だけで応答が再現性よく保持できるようになった。又、
ポリカーボネートの多孔体を界面活性剤で処理すること
により親水性をもだせることができる。界面活性剤とし
て例えばポリエチレングリコールアルキルフェニルエー
テル（商品名ニトリトンｘ）の１％溶液中に浸漬後乾燥
して使用すると、血液の濾過かすみやかになり、再現性
がさらに向上した。By using a polycarbonate porous body as the filtration layer 16, blood cells and viscous substances in the blood could be filtered out in advance, and staining of the electrodes could be reduced. If the filtration layer is too thick, blood cells will adhere to the electrode after long-term use, reducing the current value obtained, so it was necessary to wash the electrode with alcohol, but with the filtration layer, it is now possible to simply wash the electrode with water. The response can now be maintained with good reproducibility. or,
Hydrophilicity can be imparted to a porous polycarbonate body by treating it with a surfactant. When used as a surfactant, for example, by immersing it in a 1% solution of polyethylene glycol alkyl phenyl ether (trade name Nitriton
さらに、濾過層に抗凝血剤であるフッ化ナトリウム溶液
を含浸後乾燥して担持させたところ、血液がわずか１０
秒で濾過できだ。血液は粘性が高いだめ濾過に時間がか
かりすぎると凝血が始まり濾過層を通過できなくなると
いう問題があった。Furthermore, when the filtration layer was impregnated with a sodium fluoride solution, which is an anticoagulant, and then dried to support it, only 10
It can be filtered in seconds. Since blood is highly viscous, there is a problem that if it takes too long to filter, blood will start to coagulate and will not be able to pass through the filter layer.
抗凝血剤を用いることにより濾過かすみやかになり、常
に安定に測定でき、測定の迅速化にも大きな効果があっ
た。The use of an anticoagulant made the filtration hazy, allowing stable measurements at all times, and had a significant effect on speeding up measurements.
測定極および対極に白金を用いて２電極系で測定する場
合は、対極の面積を測定極のよりより十分大きくした方
か、対極の分極が少なくなり、良好な応答が得られる。When measuring with a two-electrode system using platinum for the measurement electrode and the counter electrode, a good response can be obtained by making the area of the counter electrode sufficiently larger than that of the measurement electrode, or the polarization of the counter electrode will be reduced.
又、対極を銀塩化銀にすると、電位は安定する。Furthermore, when silver chloride is used as the counter electrode, the potential becomes stable.
第４図のように、塩化ビニル樹脂からなる基板１ｏに白
金を埋め込み、測定極１１．対極１２、および参照極１
７からなる３電極で電極系を構成した。参照極を用いだ
３電極とすることにより、２電極に比較して、応答再現
性が向上した。また、上記に述べた様に対極面積を大き
くする必要もなくなり小型化できた。又、白金を基板上
にスノくツタ法や蒸着法により白金層を形成して電極系
とすることも可能である。As shown in FIG. 4, platinum is embedded in a substrate 1o made of vinyl chloride resin, and measurement electrodes 11. Counter electrode 12, and reference electrode 1
The electrode system was composed of three electrodes consisting of 7. By using three reference electrodes, response reproducibility was improved compared to two electrodes. Furthermore, as mentioned above, there is no need to increase the area of the counter electrode, and the size can be reduced. Further, it is also possible to form an electrode system by forming a platinum layer on a substrate by a snow vine method or a vapor deposition method.
酸化型色素及び酵素よりなる反応層は、試料液をすみや
かに吸収し酵素反応をおこなわせることかできるように
、親水性の多孔体膜であることが望ましい。たとえば、
ろ紙やパルプの不織布、セラミックやカラスの多孔体な
どを用いると、試料液が均一にすばやく浸透し再現性も
良好であった。The reaction layer consisting of the oxidized dye and the enzyme is preferably a hydrophilic porous membrane so that the sample liquid can be quickly absorbed and the enzyme reaction can be carried out. for example,
When filter paper, pulp nonwoven fabric, ceramic or glass porous materials were used, the sample liquid penetrated uniformly and quickly, and the reproducibility was also good.
さらに、ナイロン不織布において、前記の界面活性剤で
処理したものは、処理しなかったものより試料液の浸透
がすみやかであり、測定の迅速化に効果かあった。Furthermore, in the nylon nonwoven fabrics treated with the above-mentioned surfactant, the sample solution permeated more quickly than in the untreated fabrics, which was effective in speeding up the measurement.
酵素と酸化型色素を細かく粉砕混合後、加圧した成形体
を反応層とすると、血液の液体成分によりすみやかに溶
は均一に混合するため、反応の迅速化に大きく貢献した
。！、た、酸化型色素と酵素を加圧成形する際、結着剤
として、８１０２ などを少量混合すると、成形体の強
度か増すので取り扱いが簡易となる。結着剤としては、
酵素反応及び電極反応に無関係で親水性のものが適して
いる。By using a molded product made by finely pulverizing and mixing enzymes and oxidized pigments and pressurizing them as the reaction layer, the liquid components of blood quickly and uniformly mixed the solution, which greatly contributed to speeding up the reaction. ! Additionally, when press molding the oxidized dye and enzyme, mixing a small amount of 8102 or the like as a binder increases the strength of the molded product, making it easier to handle. As a binder,
Hydrophilic materials that are unrelated to enzyme reactions and electrode reactions are suitable.
酸化型色素および酵素は、なるべく血液の液体成分に速
く溶ける状態におくことが望捷しい。そこで、酸化型色
素の溶液をナイロン不織布に含浸後、熱風乾燥すると、
真空乾燥したものより非常に細かい結晶となり、液体に
とけやすくな−だ。It is desirable that the oxidized pigment and enzyme be in a state where they dissolve as quickly as possible in the liquid components of blood. Therefore, by impregnating a nylon nonwoven fabric with a solution of oxidized dye and drying it with hot air,
The crystals are much finer than those dried in vacuum, and they dissolve more easily in liquids.
又、酸化型色素の溶液を浸漬したナイロン不織布を、エ
タノールのような水に対する溶解度の大きい有機溶媒中
に浸漬後真空乾燥すると、さらに細かい結晶を担持する
ことができた。酵素は熱などに弱いため、含浸後真空乾
燥を行なった。Furthermore, when a nylon nonwoven fabric soaked in a solution of an oxidized dye was immersed in an organic solvent with high solubility in water, such as ethanol, and then vacuum-dried, even finer crystals could be supported. Since enzymes are sensitive to heat, vacuum drying was performed after impregnation.
そこで、第６図の構成からなるセンサを試みだ。Therefore, we tried a sensor with the configuration shown in Figure 6.
電極系は第４図と同様で、その土にポリカーボネート多
孔体膜からなる濾過層１６、次にグルコースオキシダー
ゼ１４を担持したナイロン不織布１８、その上部にフェ
リンアン化カリウム１５を含浸後江タノールに浸漬し乾
燥して担持したナイロン不織布１９を設置する。なお−
ポリカーボネート多孔体膜およびナイロン不織布は、あ
らかじめ前記の界面活性剤で処理し、抗凝血剤であるフ
ッ化ナトリウノ、を含浸後乾燥して相持した。The electrode system was the same as that shown in Fig. 4, and the soil was impregnated with a filtration layer 16 made of a porous polycarbonate membrane, then a nylon nonwoven fabric 18 carrying glucose oxidase 14, and potassium ferrinanide 15 on top of the nylon nonwoven fabric 18, which was then immersed in ethanol. A dried and supported nylon nonwoven fabric 19 is installed. Note-
The polycarbonate porous membrane and the nylon nonwoven fabric were treated in advance with the above-mentioned surfactant, impregnated with sodium fluoride, which is an anticoagulant, and then dried and bonded together.
このセンサに血液を添加すると、抗凝血剤により凝血す
ることなく、すみやかにナイロン不織布の層に浸透し、
フェリシアン化カリウム１５とグルコースオキシダーゼ
１４が溶解して反応が進みながら、血液の液体成分のみ
１濾過層１６を通過し電極系に至る。フェリシアン化カ
リウムを細かい結晶状態で４１１持しであるので、すみ
やかに溶解し酵素と共役して反応でき、反応時間か約１
分間以内と短縮できた。濾過層は、第５図のように電極
上においても１反応層の上部においてもよい。又、色素
担持層１９と酵素担持層１８ではさんでもよい。液の浸
透は、濾過層が反応層の下に設置した時が一番早く反応
時間が短かかった。When blood is added to this sensor, it quickly penetrates the nylon nonwoven layer without clotting due to the anticoagulant.
While potassium ferricyanide 15 and glucose oxidase 14 are dissolved and the reaction progresses, only the liquid component of the blood passes through one filtration layer 16 and reaches the electrode system. Potassium ferricyanide is in a fine crystalline state and has a 411 concentration, so it can be dissolved quickly and conjugated with enzymes for reaction, and the reaction time is about 1.
I was able to shorten it to less than a minute. The filtration layer may be placed on the electrode or on top of one reaction layer as shown in FIG. Alternatively, it may be sandwiched between the dye-supporting layer 19 and the enzyme-supporting layer 18. The liquid permeation was fastest and the reaction time was shortest when the filtration layer was placed below the reaction layer.
しかし、反応層の上部Ｋ濾過層を設置すると、先に血液
中の固体成分が濾過できるので、反応層において血球な
どによる妨害がないため、スムーズに反応が進むという
利点があり、高精度であった。However, if a K filtration layer is installed above the reaction layer, the solid components in the blood can be filtered out first, so there is no interference from blood cells in the reaction layer, and the reaction proceeds smoothly, resulting in high precision. Ta.
濾過層としては、不織布、化学繊維１紙（濾紙）カラス
の多孔体なとか考えられる。血球をｆｉ過するだめには
孔径が２〜３μｍ以下であることが必要である。血球ｌ
濾過か可能な均一な孔径のメンブランフィルタ−やカラ
スの多孔体が適している。Possible filter layers include non-woven fabric, chemical fiber paper (filter paper), and glass porous materials. In order to pass through blood cells, the pore size must be 2 to 3 μm or less. blood cells l
Membrane filters or glass porous bodies with uniform pore diameters that allow filtration are suitable.
色素としては、上記に用いだフェリシアン化カリウムか
安定に反応するので適しているが、Ｐ −ベンゾキノン
を使えば、反応速度が早いので高速化に適している。又
、２．６−／クロロフェノールＩイントフユノール、メ
チレンブルー、フェナ／ンメトザルフェ−１・、β−ナ
フトキ／ン４−スルホン酸カリウムなとも使用できる。Potassium ferricyanide used above is suitable as the dye because it reacts stably, but P-benzoquinone is suitable for increasing the reaction rate because it has a fast reaction rate. In addition, 2,6-/chlorophenol I intofunol, methylene blue, phenanemethosulfe-1, β-naphthoquinone 4-potassium sulfonate can also be used.
抗凝血剤としてｄ、フッ化すトリウムが安定で取扱いも
簡易なため適しているか、ヘパリンやクエン酸ナトリウ
ム、エチレン／アミン四酢酸も血液濾過を迅速におこな
わせるのに有用であった。As an anticoagulant, thorium fluoride is suitable because it is stable and easy to handle, and heparin, sodium citrate, and ethylene/aminetetraacetic acid are also useful for rapidly performing blood filtration.
なお、上記実施例におけるセンサはグルコース、ｆ、＜
限う−ｒ−アルコールセンザやコレステロールセンサ
など、酸化童元酵素の開力する系に用いることができる
。又、酵素は固定化した状態で担持することにより長期
保存においても安定に活性を維持することができる。Note that the sensor in the above embodiment has glucose, f, <
It can be used in systems that activate oxidized enzymes, such as r-alcohol sensors and cholesterol sensors. Furthermore, by supporting the enzyme in an immobilized state, the activity can be stably maintained even during long-term storage.
発明の効果本発明のセンサによれは、直接血液を含浸させて微量の
特定成分を簡易に、しかも迅速に精度よく測定すること
ができる。また、１濾過層により、電極を長期間安定に
保持できる。さらに、抗凝血剤を担持することにより、
血液を凝血させることなくすみやかに濾過させ、反応時
間を短縮することができる。ADVANTAGEOUS EFFECTS OF THE INVENTION The sensor of the present invention allows direct impregnation with blood to easily, quickly, and accurately measure minute amounts of specific components. Furthermore, the single filtration layer allows the electrode to be stably maintained for a long period of time. Furthermore, by carrying an anticoagulant,
Blood can be quickly filtered without clotting, and reaction time can be shortened.
第１図及び第２図は従来のグルコースセンサの構成を示
す図、第３図、第４図及び第５図は本発明の実施例であ
るグルコースセンサの模式図である。１０ ・基板、１１・・・・・・測定極、１２・・・対
極、１３・ ・・多孔体（反応層）、１４ ・・・・酵
素、１５・・・・・・色素、１６・・・・・・濾過層、
１７・・・・・参照極。1 and 2 are diagrams showing the configuration of a conventional glucose sensor, and FIGS. 3, 4, and 5 are schematic diagrams of a glucose sensor that is an embodiment of the present invention. 10...Substrate, 11...Measurement electrode, 12...Counter electrode, 13...Porous body (reaction layer), 14...Enzyme, 15...Dye, 16... ...filtration layer,
17...Reference pole.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59030542AJPS60173457A (en) | 1984-02-20 | 1984-02-20 | Biosensor |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59030542AJPS60173457A (en) | 1984-02-20 | 1984-02-20 | Biosensor |
| Publication Number | Publication Date |
|---|---|
| JPS60173457Atrue JPS60173457A (en) | 1985-09-06 |
| JPH0430543B2 JPH0430543B2 (en) | 1992-05-22 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59030542AGrantedJPS60173457A (en) | 1984-02-20 | 1984-02-20 | Biosensor |
| Country | Link |
|---|---|
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| Date | Code | Title | Description |
|---|---|---|---|
| EXPY | Cancellation because of completion of term |