JP2005147990A - Method for measuring substrate concentration - Google Patents
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Abstract
Description
本発明は、血液中に含まれる基質を定量するために、バイオセンサ及びこのバイオセンサが装着される測定装置を用いる測定方法に関するものであり、特に血液中のヘマトクリットによる測定誤差を減少させる為の新規な定量方法を提供するものである。 The present invention relates to a measurement method using a biosensor and a measurement device to which the biosensor is mounted in order to quantify a substrate contained in blood, and particularly for reducing measurement errors due to hematocrit in blood. A new quantitative method is provided.
バイオセンサとは、微生物、酵素、抗体、ＤＮＡ、ＲＮＡ等の生物材料の分子認識能を利用し、生物材料を分子識別素子として応用した、試料液中の基質含有量を定量するセンサである。即ち、生物材料が目的の基質を認識したときに起こる反応、例えば微生物の呼吸による酸素の消費、酵素反応、発光等、を利用して試料液中に含まれる基質を定量するのである。そして各種バイオセンサの中でも酵素センサの実用化は進んでおり、例えば、グルコース、乳酸、コレステロール、アミノ酸用のバイオセンサである酵素センサは医療計測や食品工業に利用されている。この酵素センサは、例えば検体である試料液に含まれる基質と酵素などとの反応により生成する電子によって電子伝達体を還元し、測定装置がその電子伝達体の還元量を電気化学的に計測することにより、検体の定量分析を行うようになっている。 A biosensor is a sensor that uses the molecular recognition ability of biological materials such as microorganisms, enzymes, antibodies, DNA, RNA, etc., and applies the biological material as a molecular identification element to quantify the substrate content in a sample solution. That is, the substrate contained in the sample solution is quantified using a reaction that occurs when the biological material recognizes the target substrate, for example, oxygen consumption due to respiration of microorganisms, enzyme reaction, luminescence, and the like. Among various biosensors, enzyme sensors have been put to practical use. For example, enzyme sensors that are biosensors for glucose, lactic acid, cholesterol, and amino acids are used in the medical measurement and food industries. This enzyme sensor, for example, reduces an electron carrier by electrons generated by a reaction between a substrate contained in a sample solution that is a specimen and an enzyme, and the measuring device electrochemically measures the reduction amount of the electron carrier. Thus, the quantitative analysis of the specimen is performed.
このようなバイオセンサを用いた測定方法について様々な形態のものが提案されている。そこで従来の測定方法について説明する。（例えば特許文献１参照。）試料液中の基質含有量を定量するには、バイオセンサを測定装置に挿入後、後述するバイオセンサの電極に測定装置によって一定電圧が印加された状態で、試料液を試料点着部に供給する。点着された試料液がバイオセンサの内部に吸引されて試薬層の溶解が始まる。測定装置はバイオセンサの電極間に生じる電気的変化を検知して定量動作を開始するようになっている。 Various types of measurement methods using such biosensors have been proposed. Therefore, a conventional measurement method will be described. (For example, refer to Patent Document 1.) In order to quantify the substrate content in the sample solution, after inserting the biosensor into the measurement device, the sample is applied in a state where a constant voltage is applied to the electrode of the biosensor described later by the measurement device. The liquid is supplied to the sample spotting part. The spotted sample solution is sucked into the biosensor and the reagent layer starts to dissolve. The measuring device detects the electrical change that occurs between the electrodes of the biosensor and starts the quantitative operation.
試料液供給検知後のプロファイルを図５に示す。本プロファイルには三つの連続期間からなり、例えば時刻ｔ０からｔ１の第１印加期間、時刻ｔ１からｔ２の待機時間、時刻ｔ２からｔ３の第２印加期間からなる。この第１印加期間を設けることでヘマトクリットによる測定誤差を抑制することができる。 The profile after detecting the sample liquid supply is shown in FIG. This profile includes three continuous periods, for example, a first application period from time t0 to t1, a standby time from time t1 to t2, and a second application period from time t2 to t3. By providing this first application period, measurement errors due to hematocrit can be suppressed.
また、誤差影響を補正して分析対象物の濃度を求めるバイオセンサの測定方法について説明する。（例えば特許文献２参照。）バイオセンサに定められた電圧を２回印加して電気化学反応を促進させ、その結果得られる電流値から下記パラメータＰ１及びＰ２を算出し、これらのパラメータから統計的手法により誤差を補正して分析対象物濃度を算出する。Ｐ１：１回目励起における電流の最大値または最大値以降の電流値（Ｉｆ）と２回目励起の任意の時点における電流値（Ｉｂ）の比（Ｉｆ／Ｉｂ）。Ｐ２：２回目励起の任意の時点における電流値（Ｉｂ）。
しかしながら従来の測定方法には、血液のヘマトクリットが測定感度に影響を及ぼすという問題があった。ヘマトクリットとは血液中に占める有形成分の体積比（％）である。一般的に貧血のない人では赤血球が４０〜５０％を占める。慢性腎不全になり腎性貧血になるとヘマトクリットは下がり１５％を下回る状態になる場合もあり、個人差、男女差も大きい。 However, the conventional measurement method has a problem that blood hematocrit affects measurement sensitivity. Hematocrit is the volume ratio (%) of the formed component in the blood. In general, red blood cells account for 40 to 50% in people without anemia. In chronic renal failure and renal anemia, the hematocrit may fall below 15%, and there are large individual and gender differences.
一方、近年のバイオセンサに要求されるスペックとして測定時間の短縮化が望まれている。バイオセンサを用いて迅速に基質の測定を行う場合、試料の粘性がその測定精度に大きな影響を与える。特に、人体の血液を試料液とする場合、粘性の高い（Ｈｃｔが高い：以下、高Ｈｃｔ）血液の場合は応答レベルが相対的に低下し、粘性の低い（Ｈｃｔが低い：以下、低Ｈｃｔ）血液の場合は応答レベルが相対的に高くなり、この傾向は測定時間の短縮化が進むにつれ顕著になる場合がある。この現象は、試薬層の血液への溶解性、および溶存種の拡散速度がＨｃｔの影響を受けていることを示唆する。 On the other hand, shortening of measurement time is desired as a specification required for recent biosensors. When a substrate is measured quickly using a biosensor, the viscosity of the sample greatly affects the measurement accuracy. In particular, when human blood is used as a sample solution, the response level is relatively low and the viscosity is low (Hct is low: hereinafter, low Hct) in the case of blood having high viscosity (high Hct: hereinafter, high Hct). ) In the case of blood, the response level is relatively high, and this tendency may become more prominent as the measurement time is shortened. This phenomenon suggests that the solubility of the reagent layer in blood and the diffusion rate of dissolved species are affected by Hct.
図６は測定時間とヘマトクリットの関係を示す図である。これは、図５で示した特許文献１の測定手法に準じて測定を行った結果である。測定時間とは図５で示したｔ３であり、低Ｈｃｔおよび高Ｈｃｔの血液を用いて測定した時のｔ３における電流値をそれぞれプロットしたものである。図６から明らかなように、測定時間が短くなるとヘマトクリットの差異による電流値の差が大きくなることが分かる。とりわけ、測定時間が５秒程度の場合にはヘマトクリットの影響を大きく受ける。その為、特許文献１の測定法で時間短縮を行うことはヘマトクリットによる測定誤差が顕著となり、非常に困難であった。 FIG. 6 is a diagram showing the relationship between measurement time and hematocrit. This is a result of measurement according to the measurement method of Patent Document 1 shown in FIG. The measurement time is t3 shown in FIG. 5, and is a plot of current values at t3 when measured using low and high Hct blood. As is apparent from FIG. 6, it can be seen that the difference in current value due to the difference in hematocrit increases as the measurement time becomes shorter. In particular, when the measurement time is about 5 seconds, it is greatly affected by hematocrit. For this reason, it is very difficult to reduce the time by the measurement method of Patent Document 1 because the measurement error due to hematocrit becomes remarkable.
特許文献２に示される従来の測定方法は、１回目励起における電流の最大値または最大値以降の電流値と、２回目励起の任意の時点における電流値の比を試料物性による影響をより大きく受けるパラメータとして使用している。１回目励起は溶解初期の段階であることから、試薬層の血液への溶解性および溶存種の拡散速度が律速になり、ヘマトクリットに依存した電流値が得られやすいが、血液の供給速度、手技の差によって電流値がばらつきやすい。さらに血液中に含まれる易酸化性物質が１回目励起の際に電流値として検出されやすく、血中易酸化性物質の個人差により１回目励起の電流値は誤差が生じやすい。また、１回目励起の電流の最大値または最大値以降の電流を補正に用いるためには、ある程度の印加時間が必要である。しかし初期段階（１回目励起）で長時間電位をかけると、還元性電子伝達体が過剰量酸化されるため、待機時間を長くして還元性電子伝達体を再び蓄積しなければ２回目励起期間で検知される応答値の基質依存性が悪くなる可能性がある。その為特許文献２の測定方法では、ばらつきを抑えた測定を行うこと、測定時間の短縮を行うことが非常に困難であった。 In the conventional measurement method disclosed in Patent Document 2, the ratio of the maximum current value in the first excitation or the current value after the maximum value to the current value at an arbitrary time point in the second excitation is more greatly affected by the physical properties of the sample. Used as a parameter. Since the first excitation is in the early stage of dissolution, the solubility of the reagent layer in blood and the diffusion rate of dissolved species become rate limiting, and it is easy to obtain a current value depending on hematocrit. The current value tends to vary due to the difference between the two. Furthermore, an easily oxidizable substance contained in blood is easily detected as a current value at the time of the first excitation, and the current value of the first excitation is likely to cause an error due to individual differences in blood oxidizable substances. Further, in order to use the maximum value of the first excitation current or a current after the maximum value for correction, a certain amount of application time is required. However, if an electric potential is applied for a long time in the initial stage (first excitation), the reducing electron carrier is oxidized excessively. Therefore, if the waiting time is lengthened and the reducing electron carrier is not accumulated again, the second excitation period There is a possibility that the substrate dependence of the response value detected by the method will deteriorate. Therefore, in the measurement method of Patent Document 2, it is very difficult to perform measurement with reduced variation and to shorten the measurement time.
前記従来の課題を解決するために、本発明の基質濃度の測定方法は、絶縁基板上の少なくとも一部に形成された対電極、測定電極を含む電極部、当該電極部上または周辺に少なくとも酵素、電子伝達体を含む試薬層を有するバイオセンサと、当該電極部の各電極に電位を印加する為の接続端子及び駆動電源を有する測定装置を用い、当該駆動電源によって前記電極部に電位を印加させて出力される電流を検知し、血液中に含まれる基質を定量する測定方法であって、断続的な３回以上の電圧印加工程を包含する。 In order to solve the above conventional problems, the substrate concentration measuring method of the present invention includes a counter electrode formed on at least a part of an insulating substrate, an electrode part including a measuring electrode, and at least an enzyme on or around the electrode part. A biosensor having a reagent layer containing an electron carrier and a measuring device having a connection terminal and a driving power source for applying a potential to each electrode of the electrode unit, and applying a potential to the electrode unit by the driving power source This is a measurement method for detecting a current output and quantifying a substrate contained in blood, and includes three or more intermittent voltage application steps.
また、前記断続的な電圧印加工程が、少なくとも血液前処理のための電圧印加工程、データ補正のための電圧印加工程、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程を包含してもよい。 The intermittent voltage application step includes at least a voltage application step for blood pretreatment, a voltage application step for data correction, and a voltage application step for oxidizing a reduced electron carrier generated after a certain period of time. May be included.
また、前記電圧印加工程において、血液前処理のための電圧印加工程の後に、データ補正のための電圧印加工程が実施され、当該データ補正のための電圧印加工程の後に、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程が実施されてもよい。 Further, in the voltage application process, a voltage application process for data correction is performed after the voltage application process for blood pretreatment, and the voltage application process for the data correction is generated after a certain time has elapsed. A voltage application step for oxidizing the reduced electron carrier may be performed.
また、前記データ補正のための電圧印加工程より得られたピーク電流値と、前記一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程より得られたピーク電流値との比に基づいてヘマトクリットに依存したパラメータを算出し、前記パラメータにより基質量を補正してもよい。 Further, the ratio between the peak current value obtained from the voltage application step for data correction and the peak current value obtained from the voltage application step for oxidizing the reduced electron carrier generated after the lapse of the predetermined time. The parameter depending on the hematocrit may be calculated based on the above, and the base mass may be corrected by the parameter.
また前記パラメータを判別係数とする判別関数を用いてヘマトクリットを補正してもよい。 Further, the hematocrit may be corrected using a discriminant function using the parameter as a discriminant coefficient.
また、前記血液前処理のための電圧印加工程およびデータ補正のための電圧印加工程における印加電圧が、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程における印加電圧よりも大きいことを特徴とする測定方法としてもよい。 Further, the applied voltage in the voltage application step for blood pretreatment and the voltage application step for data correction is more than the applied voltage in the voltage application step for oxidizing the reduced electron carrier generated after a lapse of a certain time. It may be a measuring method characterized by being large.
また、前記血液前処理のための電圧印加工程における電圧印加時間が０．２秒〜２秒であることを特徴とする測定方法としてもよい。 The voltage application time in the voltage application step for blood pretreatment may be 0.2 second to 2 seconds.
また、前記データ補正のための電圧印加工程直前の開回路時間が０．２秒〜１秒であることを特徴とする測定方法としてもよい。 The open circuit time immediately before the voltage application process for data correction may be 0.2 seconds to 1 second.
また、前記データ補正のための電圧印加工程における電圧印加時間が０．２秒〜２秒であることを特徴とする測定方法としてもよい。 The voltage application time in the voltage application process for data correction may be 0.2 second to 2 seconds.
また、前記一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程直前の開回路時間が１秒〜６秒であることを特徴とする測定方法としてもよい。 Further, the measurement method may be characterized in that the open circuit time immediately before the voltage application step for oxidizing the reduced electron carrier generated after the lapse of the predetermined time is 1 second to 6 seconds.
本発明の基質濃度の測定方法によれば、絶縁基板上の少なくとも一部に形成された対電極、測定電極を含む電極部、当該電極部上または周辺に少なくとも酵素、電子伝達体を含む試薬層を有するバイオセンサと、当該電極部の各電極に電位を印加する為の接続端子及び駆動電源を有する測定装置を用い、当該駆動電源によって前記電極部に電位を印加させて出力される電流を検知し、血液中に含まれる基質を定量する測定方法であって、血液前処理のための電圧印加工程、データ補正のための電圧印加工程、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程を包含し、前記補正のための電圧印加工程より得られたピーク電流値と、前記一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程より得られたピーク電流値との比に基づいてヘマトクリットに依存したパラメータを算出し、前記パラメータにより基質量を補正することで、測定精度の良好な測定方法を提供することができる。 According to the substrate concentration measuring method of the present invention, the counter electrode formed on at least a part of the insulating substrate, the electrode part including the measurement electrode, the reagent layer including at least the enzyme and the electron carrier on or around the electrode part A measuring device having a connection terminal for applying a potential to each electrode of the electrode unit and a drive power supply, and detecting a current output by applying the potential to the electrode unit by the drive power source A method for measuring a substrate contained in blood, wherein a voltage application step for blood pretreatment, a voltage application step for data correction, and a reduced electron carrier generated after a certain period of time are oxidized. Including a voltage application step for the peak current value obtained from the voltage application step for the correction, and a voltage application step for oxidizing the reduced electron carrier generated after the lapse of the predetermined time. Calculating a parameter that depends on the hematocrit based on the ratio of the peak current value that is, by correcting the amount of substrate by the parameter, it is possible to provide a good method for measuring the measurement accuracy.
以下に、本発明の基質濃度の測定方法の実施の形態を図面とともに詳細に説明する。 Embodiments of the substrate concentration measuring method of the present invention will be described below in detail with reference to the drawings.
（実施の形態１）
図１は、本発明の第１の実施例における基質濃度の測定方法のプロファイル図を示す。
(Embodiment 1)
FIG. 1 shows a profile diagram of a substrate concentration measurement method in the first embodiment of the present invention.
図１におけるプロファイルにおいて、血液が供給されたことを検知した時刻をT０とする。図１のプロファイルにおいては、５つの工程からなり、Ｔ０からＴ１を第１工程（血液前処理の為の電圧印加工程）、Ｔ１からＴ２を第２工程（開回路）、Ｔ２からＴ３を第３工程（データ補正のための電圧印加工程）、Ｔ３からＴ４を第４工程（開回路）、Ｔ４からＴ５を第５工程（一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程）とする。 In the profile in FIG. 1, the time when it is detected that blood is supplied is T0. The profile of FIG. 1 includes five steps, T0 to T1 being the first step (voltage application step for blood pretreatment), T1 to T2 being the second step (open circuit), and T2 to T3 being the third step. Step (voltage application step for data correction), T3 to T4 for the fourth step (open circuit), T4 to T5 for the fifth step (voltage application for oxidizing the reduced electron carrier generated after a certain period of time Process).
血液前処理のための第１工程では、溶解初期の段階で酵素反応の結果生成した還元型電子伝達体が酸化されると同時に、血液中に含まれる易酸化性物質が最初の電圧印加工程である第１工程で酸化される。 In the first step for blood pretreatment, the reduced electron carrier generated as a result of the enzyme reaction in the initial stage of dissolution is oxidized, and at the same time, an oxidizable substance contained in the blood is added in the first voltage application step. It is oxidized in a certain first step.
次に第２工程を開回路にすることで、酵素反応により生成した還元型電子伝達体が蓄積されていく。 Next, by making the second step an open circuit, the reduced electron mediator generated by the enzyme reaction is accumulated.
データ補正のための第３工程では、第２工程の開回路時間を十分に持たせずに印加を開始するので、特に高Ｈｃｔの血液になるほど、還元型電子伝達体を十分に蓄積できず、ピーク電流ｉ２はヘマトクリットの影響を大きく受けた値となる。 In the third step for data correction, the application is started without sufficiently having the open circuit time of the second step, so that the reduced electron mediator cannot be sufficiently accumulated especially as the blood becomes high Hct, The peak current i2 is a value greatly affected by hematocrit.
本発明においては、データ補正に使用する第３工程以外に血液前処理として第１工程を設けることで、血液の供給速度、手技の差によるばらつきや血中の還元性物質の影響を除去することができ、ヘマトクリットの影響のみを受けたパラメータが第３工程で得られる。更にこの第１工程の存在により、血中の易酸化性物質の影響を軽減させた最終応答値を得ることが同時に可能となる。 In the present invention, in addition to the third step used for data correction, the first step is provided as a blood pretreatment, thereby eliminating the variation due to the difference in blood supply speed and procedure and the influence of reducing substances in the blood. In the third step, parameters that are only affected by hematocrit can be obtained. Furthermore, the presence of the first step makes it possible to simultaneously obtain a final response value in which the influence of easily oxidizable substances in blood is reduced.
次に第４工程で再び開回路にし、再度、還元型電子伝達体を蓄積する。このとき、一定時間以上時間をとることで、高Ｈｃｔの血液においても十分量の還元型電子伝達体が蓄積される。 Next, in the fourth step, the circuit is opened again, and the reduced electron carrier is accumulated again. At this time, a sufficient amount of reduced electron carrier is accumulated even in high-Hct blood by taking a certain time or more.
第５工程で電位Ｖ３を印加した際に得られるピーク電流ｉ４は、見かけ上ヘマトクリットの影響が小さい値となる。その後基質濃度との最も依存性が高い電流値を示すｉ５の電流値を測定する。このｉ５を最終応答値とする。そして、ヘマトクリットの最終応答値に与える影響を低減させるため、データ補正のための第３工程で求めたｉ２を利用して、ｉ４／ｉ２のパラメータを算出し、応答値ｉ５にこのパラメータを基に予め決めておいた補正を加える。 The peak current i4 obtained when the potential V3 is applied in the fifth step is a value that is apparently less influenced by hematocrit. Thereafter, the current value of i5 indicating the current value having the highest dependence on the substrate concentration is measured. Let i5 be the final response value. Then, in order to reduce the influence of the hematocrit on the final response value, the i4 / i2 parameter is calculated using i2 obtained in the third step for data correction, and the response value i5 is based on this parameter. Add a predetermined correction.
本測定方法では、データ補正のための電圧印加工程の前の開回路時間Ｔ１〜Ｔ２は使用する酵素の能力によって異なるが、０．２秒から１秒が好ましい。また、血液前処理のための電圧印加工程の時間Ｔ０〜Ｔ１及びデータ補正のための電圧印加工程の時間Ｔ２〜Ｔ３は使用する酵素の能力によって異なるが、０．２秒から２秒が好ましい。また、前記血液前処理のための電圧印加工程およびデータ補正のための電圧印加工程における印加電圧が、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程における印加電圧よりも大きいことが好ましい。さらに、電圧Ｖ２は０．１Ｖ〜０．８Ｖが好ましい。また一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程直前の開回路時間は１秒〜６秒であることが好ましい。 In this measurement method, the open circuit time T1 to T2 before the voltage application step for data correction varies depending on the ability of the enzyme used, but is preferably 0.2 seconds to 1 second. Further, the time T0 to T1 of the voltage application process for blood pretreatment and the time T2 to T3 of the voltage application process for data correction vary depending on the ability of the enzyme to be used, but are preferably 0.2 seconds to 2 seconds. Further, the applied voltage in the voltage application step for blood pretreatment and the voltage application step for data correction is more than the applied voltage in the voltage application step for oxidizing the reduced electron carrier generated after a lapse of a certain time. Larger is preferred. Furthermore, the voltage V2 is preferably 0.1V to 0.8V. Moreover, it is preferable that the open circuit time just before the voltage application process for oxidizing the reduced electron carrier produced | generated after progress for a fixed time is 1 second-6 seconds.
また、データ補正のための電圧印加を数回行い、数回のデータ補正のための電圧印加で得られた複数の電流値を補正に用いることでさらに精度が向上する。その際の電圧は違う電圧を印加してもよい。 Further, accuracy is further improved by performing voltage application for data correction several times and using a plurality of current values obtained by voltage application for data correction several times for correction. In this case, a different voltage may be applied.
また、前記データ補正の為の電圧印加工程、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程で得られた電流値を、上記特許文献２に示されたような方法で、判別係数とする判別関数を用いてヘマトクリットを補正してもよい。 Further, the current value obtained in the voltage application step for the data correction and the voltage application step for oxidizing the reduced electron carrier generated after a predetermined time has passed can be obtained by the method as described in Patent Document 2 above. Thus, the hematocrit may be corrected using a discriminant function as a discriminant coefficient.
データ補正のための電圧印加工程ではヘマトクリットの影響を大きく受けた値が得られればどのポイントの電流値を用いても可能であるが、誤差の少ない補正を行う為にはその影響が顕著に出やすいピーク電流を用いることが、好ましい。 In the voltage application process for data correction, the current value at any point can be used as long as a value that is greatly affected by hematocrit is obtained, but the effect is significant in order to perform correction with less error. It is preferable to use an easy peak current.
本発明のより具体的な実施の形態について図面とともに詳細に説明する。以下の構成からなるバイオセンサをセンサの一例として用いた。 More specific embodiments of the present invention will be described in detail with reference to the drawings. A biosensor having the following configuration was used as an example of the sensor.
図２（ａ）はバイオセンサの分解斜視図であり、図２（ｂ）はバイオセンサの上面から見た電極部の構成を示す図である。１９はポリエチレンテレフタレート等からなる絶縁性の基板（以下、「基板」とする。）であって、基板１９の表面にはパラジウムからなる導体層がスパッタリングによって形成されている。２６は中央部に空気孔２７が設けられた絶縁性の基板であって、切欠部２５を有するスペーサ２４を基板１９との間に挟みこんで基板１９と一体に配置される。
FIG. 2A is an exploded perspective view of the biosensor, and FIG. 2B is a diagram illustrating the configuration of the electrode portion viewed from the top surface of the biosensor.
基板１９上には、複数のスリットによって導体層が分割されて対電極２１、測定電極２０および検知極２２が形成されている。
On the
スペーサ２４は基板１９上の対電極２１、測定電極２０および検知電極２２を覆うように配置され、検体供給路２５ａが形成される。スペーサ２４の切欠部２５から露出している対電極２１、測定電極２０および検知電極２２上に、酵素としてグルコースデヒドロゲナーゼ、電子伝達体としてフェリシアン化カリウム等を含有する試薬を塗布し試薬層２３を形成させる。
The
この酵素と電子伝達体が含まれる試薬層が検体供給路に吸引された血液に溶解し、血液中の基質であるグルコースとの間で酵素反応が進行し電子伝達体が還元されて還元型電子伝達体が生成される。この還元型電子伝達体を電気化学的に酸化し、このとき得られる電流値から血液中のグルコース濃度が測定される。このような一連の反応は、対電極２１、測定電極２０及び検知電極２２によって電気化学的変化に伴う電流値を読み取る。
The reagent layer containing the enzyme and the electron carrier is dissolved in the blood sucked into the specimen supply channel, and an enzyme reaction proceeds with glucose, which is a substrate in the blood, to reduce the electron carrier and reduce the reduced electron. A transmitter is generated. The reduced electron carrier is electrochemically oxidized, and the glucose concentration in the blood is measured from the current value obtained at this time. In such a series of reactions, the
図３はＨｃｔが２５％（低Ｈｃｔ）、４５％、６５％（高Ｈｃｔ）の血液を用いて、本測定方法において算出したパラメータである。第１工程（血液前処理のための電圧印加）が０．５Ｖ印加で０．５秒、第２工程（開回路）が０．５秒、第３工程（データ補正のための印加）が０．５Ｖ印加で０．５秒、第４工程（開回路）が１．５秒、第５工程（一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加）が０．２Ｖ印加で２秒となっている。そして第３工程での電圧印加開始より０．１秒後の電流値ｉ２と第５工程での電圧印加開始より０．１秒後の電流値ｉ４を測定して算出したｉ４／ｉ２が図３のパラメータとなる。横軸が第５工程での電圧印加開始より２秒後の最終応答値ｉ５、縦軸がｉ４／ｉ２である。ヘマトクリット値を判別することの困難な点は、低Ｈｃｔの低基質濃度の血液と、高Ｈｃｔの高基質濃度の血液とｉ５において、同じ電流値が得られる場合があることである。図５のパラメータを用いることによって、ｉ５が同じ電流値を示す場合でもヘマトクリットごとに分別することができることが明らかである。 FIG. 3 shows parameters calculated in this measurement method using blood with Hct of 25% (low Hct), 45%, and 65% (high Hct). The first step (voltage application for blood pretreatment) is 0.5 seconds when 0.5 V is applied, the second step (open circuit) is 0.5 seconds, and the third step (application for data correction) is 0. .5V applied for 0.5 seconds, 4th step (open circuit) for 1.5 seconds, 5th step (voltage applied to oxidize reduced electron carrier generated after a certain period of time) applied 0.2V It is 2 seconds. Then, i4 / i2 calculated by measuring the current value i2 0.1 seconds after the voltage application start in the third step and the current value i4 0.1 seconds after the voltage application start in the fifth step is shown in FIG. Parameter. The horizontal axis represents the final response value i5 after 2 seconds from the start of voltage application in the fifth step, and the vertical axis represents i4 / i2. The difficulty in discriminating the hematocrit value is that the same current value may be obtained for blood with a low substrate concentration of low Hct and blood with a high substrate concentration of high Hct and i5. By using the parameters of FIG. 5, it is clear that even if i5 shows the same current value, it can be classified for each hematocrit.
図３で得られたパラメータの各数値に対する補正値を下記のテーブル１に示す。 Table 1 below shows correction values for the numerical values of the parameters obtained in FIG.
このテーブルに従い、補正値を最終応答値ｉ５に掛ける。 According to this table, the correction value is multiplied by the final response value i5.
図４は本発明の測定手法、従来の手法を用いて測定した際のヘマトクリットの影響を示す図である。従来の測定方法は、第１印加として０．５Ｖを６秒、待機時間を６秒、第２印加として０．２Ｖを３秒のトータル測定時間が１５秒の場合と、第１印加として０．５Ｖを２秒、待機時間を２秒、第２印加として０．２Ｖを１秒のトータル測定時間を５秒に短縮した場合を示す。従来の測定方法は１５秒から５秒に時間短縮を行うことによって、Ｈｃｔ２５％の低Ｈｃｔ血液は測定結果が基準のＨｃｔ４５％比べて相対的に高く、Ｈｃｔ６５％の高Ｈｃｔ血液は相対的に低くなる。 FIG. 4 is a diagram showing the influence of hematocrit when measurement is performed using the measurement method of the present invention and the conventional method. In the conventional measurement method, 0.5 V is applied as the first application for 6 seconds, the standby time is 6 seconds, 0.2 V is applied as the second application for 3 seconds, and the total measurement time is 15 seconds. The case is shown where the total measurement time of 5 V for 2 seconds, the standby time of 2 seconds, and the second application of 0.2 V for 1 second is shortened to 5 seconds. The conventional measurement method shortens the time from 15 seconds to 5 seconds, so that the Hct25% low Hct blood has a relatively high measurement result compared to the reference Hct45%, and the Hct65% high Hct blood has a relatively low value. Become.
本測定方法を用いることによって、トータルの測定時間は等しいにも関わらず、ヘマトクリットのバラツキを低減することが可能になる。 By using this measurement method, it is possible to reduce the variation in hematocrit even though the total measurement time is equal.
本発明にかかるバイオセンサの測定方法は、絶縁基板上の少なくとも一部に形成された対電極、測定電極を含む電極部、当該電極部上または周辺に少なくとも酵素、電子伝達体を含む試薬層を有するバイオセンサと、当該電極部の各電極に電位を印加する為の接続端子及び駆動電源を有する測定装置を用い、当該駆動電源によって前記電極部に電位を印加させて出力される電流を検知し、血液中に含まれる基質を定量する測定方法であって、血液前処理のための電圧印加工程、データ補正のための電圧印加工程、一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程を包含し、前記補正のための電圧印加工程より得られたピーク電流値と、前記一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程より得られたピーク電流値との比に基づいてヘマトクリットに依存したパラメータを算出し、前記パラメータにより基質量を補正することで、血液中に含まれる基質濃度を定量するバイオセンサの測定精度の良好な測定方法等として有用である。 The biosensor measurement method according to the present invention includes a counter electrode formed on at least a part of an insulating substrate, an electrode part including the measurement electrode, and a reagent layer including at least an enzyme and an electron carrier on or around the electrode part. And a measuring device having a connection terminal and a driving power source for applying a potential to each electrode of the electrode unit, and detecting a current output by applying a potential to the electrode unit by the driving power source. A measurement method for quantifying a substrate contained in blood, in which a voltage application step for blood pretreatment, a voltage application step for data correction, and a reduced electron carrier generated after a certain period of time are oxidized A voltage application step for oxidizing the reduced electron mediator generated after elapse of the predetermined time, and a peak current value obtained from the voltage application step for the correction Based on the ratio to the peak current value obtained, the hematocrit-dependent parameter is calculated, and the base mass is corrected by the parameter, thereby improving the measurement accuracy of the biosensor that quantifies the substrate concentration contained in the blood. It is useful as a simple measuring method.
１ ｔ０ 従来の測定方法における血液が供給された時間
２ ｔ１ 従来の測定方法における第１印加期間が終了し開回路が開始される時間
３ ｔ２ 従来の測定方法における第２印加期間が開始される時間
４ ｔ３ 従来の測定方法における最終応答値として電流値を読み取る時間
５ ｖ１ 従来の測定方法における第１印加期間の電圧
６ ｖ２ 従来の測定方法における第２印加期間の電圧
７ Ｔ０ 本発明の測定方法における血液が供給された時間
８ Ｔ１ 本発明の測定方法における血液前処理のための電圧印加工程が終了する
時間
９ Ｔ２ 本発明の測定方法におけるデータ補正のための電圧印加工程が開始する
時間
１０ Ｔ３ 本発明の測定方法におけるデータ補正のための電圧印加工程が終了する
時間
１１ Ｔ４ 本発明の測定方法における一定時間経過後に生成した還元型電子伝達体を酸化するための電圧印加工程が開始する時間
１２ Ｔ５ 本発明の測定方法における最終応答値として電流値を読み取る時間
１３ Ｖ１ 本発明の測定方法における血液前処理のための印加電圧
１４ Ｖ２ 本発明の測定方法におけるデータ補正のための印加電圧
１５ Ｖ３ 本発明の測定方法における一定時間経過後に生成した還元型電子伝達体
を酸化するための印加電圧
１６ ｉ２ 本発明の測定方法における血液前処理のための電圧印加工程で得られる
ピーク電流
１７ ｉ４ 本発明の測定方法における一定時間経過後に生成した還元型電子伝達体
を酸化するための電圧印加工程で得られるピーク電流
１８ ｉ５ 本発明の測定方法における最終応答値
１９ 絶縁性の基板
２０ 測定電極
２１ 対極
２２ 検知電極
２３ 試薬層
２４ スペーサ
２５ 切欠部
２５ａ 検体供給路
２６ 絶縁性の基板
２７ 空気孔
1 t0 Time when blood is supplied in the conventional measurement method 2 t1 Time when the first application period ends in the conventional measurement method and the open circuit starts 3 t2 Time when the second application period starts in the conventional measurement method 4 t3 Time to read the current value as the final response value in the
Time 9 T2 The voltage application process for data correction in the measurement method of the present invention starts.
Time 11 T4 Time when the voltage application step for oxidizing the reduced electron carrier generated after a lapse of a certain time in the measurement method of the present invention starts 12 T5 Time for reading the current value as the final response value in the measurement method of the present invention 13 V1 Applied voltage for blood pretreatment in the measurement method of the present invention 14 V2 Applied voltage for data correction in the measurement method of the present invention 15 V3 Reduced electron carrier generated after a certain period of time in the measurement method of the present invention
Applied voltage for oxidizing 16 i2 obtained in the voltage application step for blood pretreatment in the measurement method of the present invention
Peak current 17 i4 Reduced electron carrier generated after a certain period of time in the measurement method of the present invention
Peak current obtained in the voltage application process for oxidizing 18 i5 Final response value in the measurement method of the
Claims (10)
10. The method for measuring a substrate concentration according to claim 1, wherein the open circuit time immediately before the voltage application step for oxidizing the reduced electron carrier generated after the lapse of the predetermined time is 1 second to 6 seconds. .
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| JPWO2005054839A1 (en) * | 2003-12-04 | 2007-06-28 | 松下電器産業株式会社 | Method for measuring hematocrit (Hct), sensor used therefor, and measuring apparatus |
| JPWO2005054840A1 (en) * | 2003-12-04 | 2007-06-28 | 松下電器産業株式会社 | Blood component measuring method, sensor and measuring apparatus used therefor |
| JP2007271623A (en) * | 2006-03-31 | 2007-10-18 | Lifescan Inc | System and method for discriminating control solution from physiological sample |
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