JP7239402B2 - Drip detection device and drip detection program for surface acoustic wave sensor - Google Patents

Drip detection device and drip detection program for surface acoustic wave sensor Download PDF

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JP7239402B2
JP7239402B2 JP2019120399A JP2019120399A JP7239402B2 JP 7239402 B2 JP7239402 B2 JP 7239402B2 JP 2019120399 A JP2019120399 A JP 2019120399A JP 2019120399 A JP2019120399 A JP 2019120399A JP 7239402 B2 JP7239402 B2 JP 7239402B2
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賢吾 戸枝
直之 吉村
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Japan Radio Co Ltd
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本開示は、血液等の検体中の抗原濃度を検出する技術に関する。 The present disclosure relates to technology for detecting antigen concentration in a specimen such as blood.

血液等の検体中の抗原濃度を検出するために、弾性表面波センサを利用している（例えば、特許文献１等を参照。）。つまり、検体の滴下の前後における、弾性表面波の伝搬位相の変化に基づいて、検体中の抗原濃度を検出する。弾性表面波センサは、櫛形電極及び検出領域を備える。櫛形電極は、圧電基板上に形成され、弾性表面波を送信、受信又は反射する。検出領域は、圧電基板上に形成され、検体を滴下される。 A surface acoustic wave sensor is used to detect the antigen concentration in a sample such as blood (see, for example, Patent Document 1). That is, the antigen concentration in the specimen is detected based on the change in the propagation phase of the surface acoustic wave before and after the specimen is dropped. A surface acoustic wave sensor comprises interdigitated electrodes and a detection area. Comb electrodes are formed on the piezoelectric substrate to transmit, receive or reflect surface acoustic waves. A detection region is formed on the piezoelectric substrate and onto which the sample is dropped.

特開２０１７－００９４９２号公報JP 2017-009492 A

従来技術の抗原濃度の検出方法を図１に示す。まず、抗原を包含する検体を、酵素免疫測定法の抗体が固定化された検出領域に滴下する。次に、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化に基づいて、検体中の抗原濃度を検出する。なお、抗体固定チャネルの出力信号の位相Ｐ（ｔ）のサンプリング周波数は、任意であり例えば数Ｈｚである。また、期間ｔ０～ｔ１、期間ｔ１～ｔ２、期間ｔ２～ｔ３及び期間ｔ３～ｔ４は、抗体固定チャネルの出力信号の位相Ｐ（ｔ）のサンプリング間隔と異なってもよく等しくてもよい。 A prior art method for detecting antigen concentration is shown in FIG. First, a specimen containing an antigen is dropped onto a detection region on which an antibody for enzyme immunoassay is immobilized. Next, the antigen concentration in the specimen is detected based on the time change of the phase P(t) of the output signal of the antibody-fixed channel. The sampling frequency of the phase P(t) of the output signal of the antibody-fixed channel is arbitrary and is several Hz, for example. Also, the periods t 0 to t 1 , t 1 to t 2 , t 2 to t 3 and t 3 to t 4 may be different from the sampling interval of the phase P(t) of the output signal of the antibody-fixed channel. may well be equal.

ここで、抗体固定チャネルの出力信号の位相Ｐ（ｔ）は、検体の滴下の前後における、弾性表面波の伝搬位相の変化である。そして、抗原濃度検出に先立って、検体中の既知の様々な抗原濃度に対して、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２と、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４と、での抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きを測定したうえで、位相傾き／抗原濃度換算曲線を記憶している。 Here, the phase P(t) of the output signal of the antibody-immobilized channel is the change in the propagation phase of the surface acoustic wave before and after the specimen is dropped. Then, prior to antigen concentration detection, for various known antigen concentrations in the specimen, a period t 1 to t 2 after a short time from the dropping time t 0 and a period t after a long time from the dropping time t 0 3 to t4 , the gradient of the phase P(t) of the output signal of the antibody-immobilized channel over time is measured, and the phase gradient/antigen concentration conversion curve is stored.

検体中の抗原濃度が高濃度であるときには、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きは、滴下時刻ｔ０以降は負であり、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２では急勾配であり、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４では飽和状態でほぼ０である。そこで、検体中の抗原濃度の検出精度を向上させるために、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２での、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きと、位相傾き／抗原濃度換算曲線と、に基づいて、検体中の抗原濃度を検出する。 When the antigen concentration in the specimen is high, the slope of the time change of the phase P(t) of the output signal of the antibody-immobilized channel is negative after dropping time t0 , and becomes negative after a short time after dropping time t0 . The gradient is steep during the period t 1 to t 2 , and is almost 0 in a saturated state during the period t 3 to t 4 after a long time from the dropping time t 0 . Therefore, in order to improve the detection accuracy of the antigen concentration in the sample, the time change of the phase P(t) of the output signal of the antibody-fixed channel during the period t 1 to t 2 a short time after the dropping time t 0 The antigen concentration in the specimen is detected based on the slope and the phase slope/antigen concentration conversion curve.

検体中の抗原濃度が低濃度であるときには、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きは、滴下時刻ｔ０以降は負であり、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２では緩勾配であり、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４でも依然として緩勾配である。そこで、検体中の抗原濃度の検出精度を向上させるために、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４での、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きと、位相傾き／抗原濃度換算曲線と、に基づいて、検体中の抗原濃度を検出する。 When the antigen concentration in the specimen is low, the slope of the time change of the phase P(t) of the output signal of the antibody-immobilized channel is negative after the dropping time t0 , and after a short time after the dropping time t0 . The slope is gentle during the period t 1 to t 2 , and is still gentle during the period t 3 to t 4 after a long time from the dropping time t 0 . Therefore, in order to improve the detection accuracy of the antigen concentration in the sample, the time change of the phase P(t) of the output signal of the antibody-fixed channel during the period t 3 to t 4 after a long time from the dropping time t 0 The antigen concentration in the specimen is detected based on the slope and the phase slope/antigen concentration conversion curve.

ここで、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きは、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４では、滴下時刻ｔ０の検出精度にあまり影響されないが、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２では、滴下時刻ｔ０の検出精度に大きく影響される。つまり、検体中の抗原濃度の検出精度は、低濃度では滴下時刻ｔ０の検出精度にあまり影響されないが、高濃度では滴下時刻ｔ０の検出精度に大きく影響される。 Here, the slope of the time change of the phase P(t) of the output signal of the antibody-immobilized channel is not significantly affected by the detection accuracy at the dropping time t 0 in the period t 3 to t 4 long after the dropping time t 0 . However, in the period t 1 to t 2 after a short time from the dropping time t 0 , the detection accuracy of the dropping time t 0 is greatly affected. That is, the detection accuracy of the antigen concentration in the sample is not so much affected by the detection accuracy at the dropping time t0 at low concentrations, but is greatly affected by the detection accuracy at the dropping time t0 at high concentrations.

そこで、前記課題を解決するために、本開示は、血液等の検体中の抗原濃度を検出するために、弾性表面波センサ及び酵素免疫測定法を利用するにあたり、検体の滴下時刻の検出精度を向上させることにより、検体中の抗原濃度の検出精度を抗原濃度によらず向上させることを目的とする。 Therefore, in order to solve the above problems, the present disclosure uses a surface acoustic wave sensor and an enzyme immunoassay method to detect the antigen concentration in a specimen such as blood, and improves the detection accuracy of the dropping time of the specimen. It is an object of the present invention to improve the detection accuracy of the antigen concentration in the sample regardless of the antigen concentration.

実験によれば、抗体固定チャネルの出力信号の位相は、酵素免疫測定法の抗体の固定方法及び保存方法によっては、検体の滴下前後間で単調減少することもあれば、検体の滴下前後間で一旦増加した後に減少することもある。その一方では、抗体固定チャネルの出力信号の振幅は、酵素免疫測定法の抗体の固定方法及び保存方法によらずに、検体の滴下前後間で単調減少するのみである。そこで、前記課題を解決するために、そして、検体の滴下時刻を容易に検出するために、抗体固定チャネルの出力信号の振幅が、検体の滴下前後間で減少した期間内の時刻を、検体の滴下時刻として検出することとした。 According to experiments, the phase of the output signal of the antibody-fixed channel may monotonically decrease between before and after the dropping of the sample, depending on the method of fixing and storing the antibody in the enzyme immunoassay method. It may increase and then decrease. On the other hand, the amplitude of the output signal of the antibody-immobilized channel only monotonously decreases between before and after the dropping of the specimen, regardless of the antibody immobilization method and storage method of the enzyme immunoassay. Therefore, in order to solve the above problems and to easily detect the time of dropping the sample, the time in the period when the amplitude of the output signal of the antibody-fixing channel decreased before and after the dropping of the sample is We decided to detect it as the dropping time.

具体的には、本開示は、酵素免疫測定法の抗体が固定化された検出領域と、弾性表面波を送信及び受信又は送信及び反射する櫛形電極と、を備えるチャネルの出力信号を取得する信号取得部と、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出する滴下検出部と、を備えることを特徴とする弾性表面波センサの滴下検出装置である。 Specifically, the present disclosure provides a detection region on which an enzyme immunoassay antibody is immobilized, and a comb-shaped electrode that transmits and receives or transmits and reflects surface acoustic waves. an acquisition unit, and a dropping detection unit that detects a time within a period in which the amplitude of the output signal of the channel decreased between before and after dropping the sample onto the detection region, as the sample dropping time onto the detection region. A drip detection device for a surface acoustic wave sensor, comprising:

また、本開示は、酵素免疫測定法の抗体が固定化された検出領域と、弾性表面波を送信及び受信又は送信及び反射する櫛形電極と、を備えるチャネルの出力信号を取得する信号取得ステップと、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出する滴下検出ステップと、を順にコンピュータに実行させるための弾性表面波センサの滴下検出プログラムである。 In addition, the present disclosure includes a detection region on which an enzyme-linked immunosorbent assay antibody is immobilized, and a signal acquisition step of acquiring an output signal of a channel provided with interdigitated electrodes that transmit and receive or transmit and reflect surface acoustic waves. , a dropping detection step of detecting the time within the period in which the amplitude of the output signal of the channel decreased before and after dropping the sample onto the detection region as the sample dropping time onto the detection region, and It is a dropping detection program for the surface acoustic wave sensor to be executed.

これらの構成によれば、検体の滴下時刻の検出精度を向上させることにより、検体中の抗原濃度の検出精度を抗原濃度によらず向上させることができる。 According to these configurations, it is possible to improve the detection accuracy of the antigen concentration in the sample regardless of the antigen concentration by improving the detection accuracy of the dropping time of the sample.

また、本開示は、前記滴下検出部は、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間の所定時間幅で、前記チャネルの出力信号の振幅のノイズレベルより大きい所定閾値より大きく減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出することを特徴とする弾性表面波センサの滴下検出装置である。 Further, according to the present disclosure, the drop detection unit is configured such that the amplitude of the output signal of the channel is greater than the noise level of the amplitude of the output signal of the channel within a predetermined time interval between before and after dropping of the sample onto the detection region. The drop detection device for a surface acoustic wave sensor is characterized in that the time within a period when the sample has decreased significantly below the threshold value is detected as the drop time of the specimen onto the detection region.

この構成によれば、抗体固定チャネルの出力信号の振幅が、ノイズレベル又は不十分な滴下濡れにより減少したとしても、そのような減少の期間内の時刻を、検体の滴下時刻として検出しないため、検体の滴下時刻の検出精度を向上させることができる。 According to this configuration, even if the amplitude of the output signal of the antibody-immobilized channel decreases due to the noise level or insufficient drip wetting, the time within the period of such decrease is not detected as the sample drip time. It is possible to improve the detection accuracy of the dropping time of the sample.

また、本開示は、前記滴下検出部は、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で変曲点を示す時刻の近傍を、前記検出領域への検体の滴下時刻として検出することを特徴とする弾性表面波センサの滴下検出装置である。 Further, in the present disclosure, the drop detection unit detects the vicinity of the time at which the amplitude of the output signal of the channel indicates an inflection point between before and after dropping the sample onto the detection region. A drop detection device for a surface acoustic wave sensor characterized by detecting as time.

この構成によれば、抗体固定チャネルの出力信号の振幅が、検体の滴下前及び滴下後ではほぼ時間変化せず、検体の滴下前後間では単調減少することを利用して、検体の滴下時刻を検出するため、検体の滴下時刻の検出精度を向上させることができる。 According to this configuration, the amplitude of the output signal of the antibody-immobilized channel does not change with time before and after the dropping of the sample, and monotonously decreases before and after the dropping of the sample. Since the detection is performed, it is possible to improve the detection accuracy of the dropping time of the sample.

このように、本開示は、血液等の検体中の抗原濃度を検出するために、弾性表面波センサ及び酵素免疫測定法を利用するにあたり、検体の滴下時刻の検出精度を向上させることにより、検体中の抗原濃度の検出精度を抗原濃度によらず向上させることができる。 In this way, the present disclosure uses a surface acoustic wave sensor and an enzyme immunoassay method to detect the antigen concentration in a specimen such as blood, and by improving the detection accuracy of the dropping time of the specimen, the specimen It is possible to improve the detection accuracy of the antigen concentration in the medium regardless of the antigen concentration.

従来技術及び本開示の抗原濃度の検出方法を示す図である。FIG. 1 shows a method of detecting antigen concentration according to the prior art and the present disclosure. 本開示の弾性表面波センサの構成を示す図である。It is a figure which shows the structure of the surface acoustic wave sensor of this indication. 本開示の弾性表面波センサの滴下検出手順を示す図である。It is a figure which shows the dropping detection procedure of the surface acoustic wave sensor of this disclosure. 本開示の弾性表面波センサの滴下検出方法を示す図である。FIG. 4 is a diagram showing a dropping detection method of the surface acoustic wave sensor of the present disclosure; 本開示の弾性表面波センサの滴下検出方法を示す図である。FIG. 4 is a diagram showing a dropping detection method of the surface acoustic wave sensor of the present disclosure;

添付の図面を参照して本開示の実施形態を説明する。以下に説明する実施形態は本開示の実施の例であり、本開示は以下の実施形態に制限されるものではない。 Embodiments of the present disclosure will be described with reference to the accompanying drawings. The embodiments described below are examples of implementing the present disclosure, and the present disclosure is not limited to the following embodiments.

本開示の弾性表面波センサの構成を図２に示す。弾性表面波センサＳは、抗体固定チャネル１、リファレンスチャネル２及び滴下検出装置３から構成される。抗体固定チャネル１は、検出領域１１及び櫛形電極１２、１２から構成される。リファレンスチャネル２は、検出領域２１及び櫛形電極２２、２２から構成される。滴下検出装置３は、信号取得部３１、滴下検出部３２及び濃度検出部３３から構成され、図３に示した滴下検出プログラムをコンピュータにインストールすることにより実現される。 FIG. 2 shows the configuration of the surface acoustic wave sensor of the present disclosure. A surface acoustic wave sensor S is composed of an antibody-immobilized channel 1 , a reference channel 2 and a drip detector 3 . The antibody-immobilized channel 1 is composed of a detection region 11 and interdigitated electrodes 12,12. The reference channel 2 consists of a detection region 21 and comb electrodes 22 , 22 . The drop detection device 3 is composed of a signal acquisition section 31, a drop detection section 32, and a concentration detection section 33, and is realized by installing the drop detection program shown in FIG. 3 into a computer.

検出領域１１は、酵素免疫測定法の抗体が固定化される。櫛形電極１２、１２は、弾性表面波を送信及び受信又は送信及び反射する。検出領域２１は、リファレンス用に、検体中の抗原と反応しないブロッキング膜が固定化される。櫛形電極２２、２２は、リファレンス用に、弾性表面波を送信及び受信又は送信及び反射する。信号取得部３１、滴下検出部３２及び濃度検出部３３については、図３～５を用いて説明する。 The detection region 11 is immobilized with an enzyme-linked immunosorbent assay antibody. The comb electrodes 12, 12 transmit and receive or transmit and reflect surface acoustic waves. A blocking membrane that does not react with antigens in the specimen is immobilized on the detection region 21 for reference. The comb electrodes 22, 22 transmit and receive or transmit and reflect surface acoustic waves for reference. The signal acquisition unit 31, drop detection unit 32, and concentration detection unit 33 will be described with reference to FIGS.

本開示の弾性表面波センサの滴下検出手順を図３に示す。本開示の弾性表面波センサの滴下検出方法を図４、５に示す。なお、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のサンプリング周波数は、任意であり例えば数Ｈｚである。また、図５に示した隣接する黒丸印の時間間隔は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のサンプリング間隔と等しい。まず、抗原を包含する検体を、検出領域１１、２１に滴下する。ここで、不十分な滴下濡れつまり気泡の混入を防止することが望ましい。 FIG. 3 shows a dropping detection procedure of the surface acoustic wave sensor of the present disclosure. 4 and 5 show a dropping detection method of the surface acoustic wave sensor of the present disclosure. Note that the sampling frequency of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is arbitrary and is, for example, several Hz. Also, the time interval between adjacent black circles shown in FIG. First, a specimen containing an antigen is dropped onto the detection regions 11 and 21 . Here, it is desirable to prevent insufficient drip wetting, ie, entrapment of air bubbles.

最初に、信号取得部３１は、抗体固定チャネル１の出力信号を取得する（ステップＳ１）。ここで、抗体固定チャネル１の出力信号は、検体の滴下の前後における、弾性表面波の伝搬振幅又は伝搬位相の変化である。そして、リファレンスチャネル２の出力信号をリファレンスとすることで、検体の粘弾性の影響を除去したうえで、検出領域１１上の抗体の影響及びこれと結合した検体中の抗原の影響のみを抽出する。 First, the signal acquisition unit 31 acquires the output signal of the antibody-fixed channel 1 (step S1). Here, the output signal of the antibody-immobilized channel 1 is the change in propagation amplitude or propagation phase of the surface acoustic wave before and after dropping the sample. By using the output signal of the reference channel 2 as a reference, the effect of the viscoelasticity of the sample is removed, and only the effect of the antibody on the detection area 11 and the antigen in the sample bound thereto is extracted. .

次に、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）が、検体の滴下前後間で減少した期間ｔＤ－ΔＴ～ｔＤ内の時刻を、滴下時刻ｔ０として検出する（ステップＳ２～Ｓ４）。最後に、濃度検出部３３は、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の時間変化に基づいて、検体中の抗原濃度を検出する（ステップＳ５）。 Next, the dropping detection unit 32 sets the time within the period t D −ΔT to t D in which the amplitude A(t) of the output signal of the antibody-fixed channel 1 decreased before and after the dropping of the sample as the dropping time t 0 . Detect (steps S2 to S4). Finally, the concentration detection unit 33 detects the antigen concentration in the specimen based on the time change of the phase P(t) of the output signal of the antibody-fixed channel 1 (step S5).

ここで、滴下検出部３２が、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化に基づいて、滴下時刻ｔ０を検出するのは、以下の理由からである。 Here, the dropping detection unit 32 detects the dropping time t0 based on the time change of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 for the following reasons.

図４の上段に示したように、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）は、酵素免疫測定法の抗体の固定方法及び保存方法によらずに、滴下前後間（ｔＢ～ｔＡ）でＡＢからＡＡへと単調減少するのみである。一方で、図４の下段に示したように、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）は、酵素免疫測定法の抗体の固定方法及び保存方法によっては、滴下前後間（ｔＢ～ｔＡ）でＰＢからＰＡへと単調減少することもあれば、滴下前後間（ｔＢ～ｔＡ）でＰＢからＰＰへと一旦増加した後にＰＰからＰＦへと減少することもある。そこで、滴下検出部３２は、滴下時刻ｔ０を高精度にかつ容易に検出するために、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化を利用するのである。 As shown in the upper part of FIG. 4, the amplitude A(t) of the output signal of the antibody-immobilized channel 1 varies between before and after dropping (t B to t A ) only monotonously decreases from A B to A A. On the other hand, as shown in the lower part of FIG. 4, the phase P(t) of the output signal of antibody immobilization channel 1 varies between before and after dropping (t B ~ It may monotonically decrease from P B to P A at t A ), or once increase from P B to PP before and after dropping (t B to t A ), and then decrease from P P to P F. Sometimes. Therefore, the dropping detection unit 32 uses the time change of the amplitude A(t) of the output signal of the antibody-fixed channel 1 in order to detect the dropping time t0 with high accuracy and easily.

一方で、濃度検出部３３が、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の時間変化に基づいて、検体中の抗原濃度を検出するのは、以下の理由からである。 On the other hand, the reason why the concentration detection unit 33 detects the antigen concentration in the specimen based on the time change of the phase P(t) of the output signal of the antibody-fixed channel 1 is as follows.

図４の上段に示したように、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）は、滴下後（ｔＡ～）でほぼ時間変化しない。一方で、図４の下段に示したように、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）は、滴下後（ｔＡ～）で大きく時間変化する。そこで、濃度検出部３３は、検体中の抗原濃度を高精度にかつ容易に検出するために、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の時間変化を利用するのである。 As shown in the upper part of FIG. 4, the amplitude A(t) of the output signal of the antibody-immobilized channel 1 does not substantially change with time after dropping (t A ∼). On the other hand, as shown in the lower part of FIG. 4, the phase P(t) of the output signal of the antibody-immobilized channel 1 greatly changes with time after dropping (t A ∼). Therefore, the concentration detector 33 utilizes the time change of the phase P(t) of the output signal of the antibody-fixing channel 1 in order to detect the antigen concentration in the specimen with high accuracy and easily.

なお、検体の滴下前（～ｔＢ）では、空気が検出領域１１、２１に負荷されるのみであるため、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）及び位相Ｐ（ｔ）は、ほぼ時間変化しない。一方で、検体の滴下後（ｔＡ～）では、抗原抗体反応が平衡状態へ進行するため、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）は、大きく時間変化する。 Since air is only applied to the detection areas 11 and 21 before the dropping of the specimen (˜t B ), the amplitude A(t) and phase P(t) of the output signal of the antibody-fixing channel 1 are almost unchanged over time. On the other hand, after the sample is dropped (t A ∼), the antigen-antibody reaction progresses to an equilibrium state, so the phase P(t) of the output signal of the antibody-fixing channel 1 changes greatly over time.

次に、ステップＳ２～Ｓ４について説明する。まず、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）が、検体の滴下前後間の所定時間幅ΔＴで、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮより大きい所定閾値ＡＴＨより大きく減少した期間ｔＤ－ΔＴ～ｔＤを検出する（ステップＳ２）。 Next, steps S2 to S4 will be described. First, the drop detection unit 32 detects noise in the amplitude A(t) of the output signal of the antibody-fixed channel 1 with a predetermined time width ΔT between before and after dropping the sample, and the amplitude A(t) of the output signal of the antibody-fixed channel 1 . A period t D −ΔT˜t D in which the level has decreased significantly from a predetermined threshold value A TH which is higher than the level A N is detected (step S2).

ここで、検体の滴下前後間の所定時間幅ΔＴは、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の単調減少期間と同程度である。そして、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮは、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の不十分な滴下濡れつまり気泡の混入による減少量レベルを含む概念である。 Here, the predetermined time width ΔT between before and after the dropping of the sample is about the same as the monotonically decreasing period of the amplitude A(t) of the output signal of the antibody-fixing channel 1 . The noise level A N of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 is the level of the amount of decrease in the amplitude A(t) of the output signal of the antibody-immobilized channel 1 due to insufficient dripping wetting, ie, inclusion of air bubbles. It is a concept that includes

図５の第１段に示したように、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）は、検体の滴下前後間の所定時間幅ΔＴの期間ｔＤ－ΔＴ～ｔＤ内で、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮより大きい所定閾値ＡＴＨより大きく減少している。 As shown in the first stage of FIG. 5, the amplitude A(t) of the output signal of the antibody-immobilized channel 1 is such that the antibody The amplitude A(t) of the output signal of the fixed channel 1 has decreased more than a predetermined threshold A TH which is greater than the noise level AN .

次に、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）が、検体の滴下前後間で変曲点を示す時刻ｔＩを検出する（ステップＳ３）。ここで、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点は、以下のように検出される。 Next, the dropping detection unit 32 detects the time t I at which the amplitude A(t) of the output signal of the antibody-fixed channel 1 reaches an inflection point between before and after the dropping of the sample (step S3). Here, the inflection point of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 is detected as follows.

図５の第２段に示したように、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間２階微分Ａ”（ｔ）が、正負間を遷移する時刻ｔＩを検出してもよい。抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮが小さいならば、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化が検出環境に大きく影響されるとしても、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点を高精度で検出可能である。 As shown in the second stage of FIG. 5, the drop detector 32 detects the time t when the time second derivative A″(t) of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 transitions between positive and negative. It is also possible to detect I. If the noise level AN of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is small, the time change of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is detected by the detection environment. , the inflection point of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 can be detected with high accuracy.

図５の第３段に示したように、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間２階微分Ａ”（ｔ）に対する、隣接サンプリング時刻ｔ、ｔ－Δｔ間の積Ａ”（ｔ）Ａ”（ｔ－Δｔ）が、ほぼ０又は負となるとともに、所定閾値Ａ”ＴＨより小さい又は時間変化のうちの最小値となる時刻ｔＩを検出してもよい。 As shown in the third stage of FIG. 5, the drop detection unit 32 detects adjacent sampling times t, t− A time tI at which the product A″(t)A″(t−Δt) between Δt becomes approximately 0 or negative and is smaller than the predetermined threshold A″ TH or becomes the minimum value among time variations is detected. good too.

所定閾値Ａ”ＴＨを用いるときには、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮが小さいとともに、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化が検出環境に大きく影響されないならば、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点を高精度で検出可能である。最小値を用いるときには、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮが大きいとともに、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化が検出環境に大きく影響されるとしても、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点を高精度で検出可能である。 When the predetermined threshold value A″ TH is used, the noise level A N of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is small, and the time change of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is controlled by the detection environment. , it is possible to detect the inflection point of the amplitude A(t) of the output signal of the antibody-fixed channel 1 with high accuracy if it is not greatly affected by . Even if the noise level A( t ) of the output signal of the antibody-fixed channel 1 is large and the time change of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is greatly affected by the detection environment, the amplitude A(t) of the output signal of the antibody-fixed channel 1 is ) can be detected with high accuracy.

図５の第４段に示したように、滴下検出部３２は、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間１階微分Ａ’（ｔ）が、負となるとともに、所定閾値Ａ’ＴＨより小さい又は時間変化のうちの最小値となる時刻ｔＩを検出してもよい。 As shown in the fourth stage of FIG. 5, the dropping detection unit 32 detects that the first-order time differential A'(t) of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 becomes negative, and the predetermined threshold value A time t I that is smaller than A' TH or that is the minimum value of time variations may be detected.

所定閾値Ａ’ＴＨを用いるときには、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮが小さいとともに、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化が検出環境に大きく影響されないならば、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点を高精度で検出可能である。最小値を用いるときには、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）のノイズレベルＡＮが大きいとともに、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の時間変化が検出環境に大きく影響されるとしても、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）の変曲点を高精度で検出可能である。 When the predetermined threshold value A' TH is used, the noise level A N of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is small, and the time change of the amplitude A(t) of the output signal of the antibody-fixed channel 1 is controlled by the detection environment. , the inflection point of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 can be detected with high accuracy. When the minimum value is used, the noise level A N of the amplitude A(t) of the output signal of antibody-fixed channel 1 is large, and the time change of the amplitude A(t) of the output signal of antibody-fixed channel 1 greatly affects the detection environment. Even so, the inflection point of the amplitude A(t) of the output signal of the antibody-immobilized channel 1 can be detected with high accuracy.

次に、滴下検出部３２は、ステップＳ２で検出した期間ｔＤ－ΔＴ～ｔＤ内の時刻かつステップＳ３で検出した時刻ｔＩの近傍を、滴下時刻ｔ０として検出する（ステップＳ４）。 Next, the dropping detection unit 32 detects the time within the period t D −ΔT to t D detected in step S2 and the vicinity of the time t I detected in step S3 as the dropping time t 0 (step S4).

図５の第１段に示したように、滴下時刻ｔ０として、期間ｔＤ－ΔＴ～ｔＤ内の時刻のうちの、時刻ｔＤ、時刻ｔＩ又は時刻ｔＤ－ΔＴ等を検出してもよい。特に、滴下時刻ｔ０として、期間ｔＤ－ΔＴ～ｔＤ内の時刻のうちの、時刻ｔＤを検出してもよい。すると、滴下過渡状態による抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の時間変化期間（図４の下段の「滴下中」を参照。）を除去したうえで、抗原抗体反応による抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の単調減少期間（図４の下段の「滴下後」を参照。）を抽出することにより、検体中の抗原濃度の検出精度を抗原濃度によらず向上させることができる。 As shown in the first stage of FIG. 5, the time tD, the time tI , or the time tD- ΔT among the times within the period tD - ΔT to tD is detected as the dropping time t0 . may In particular, the time t D among the times within the period t D -ΔT to t D may be detected as the dropping time t 0 . Then, after removing the time change period of the phase P(t) of the output signal of the antibody-fixed channel 1 due to the dropping transient state (see “during dropping” in the lower part of FIG. 4), the antibody-fixed channel due to the antigen-antibody reaction is removed. By extracting the monotonically decreasing period of the phase P(t) of the output signal of 1 (see "after dropping" in the lower part of FIG. 4), the detection accuracy of the antigen concentration in the sample is improved regardless of the antigen concentration. be able to.

次に、ステップＳ５について説明する。濃度検出部３３は、抗体固定チャネル１の出力信号の位相Ｐ（ｔ）の時間変化に基づいて、検体中の抗原濃度を検出する（ステップＳ５）。本開示の抗原濃度の検出方法（従来技術とほぼ同様。）を図１に示す。 Next, step S5 will be described. The concentration detection unit 33 detects the antigen concentration in the sample based on the time change of the phase P(t) of the output signal of the antibody-fixed channel 1 (step S5). FIG. 1 shows the antigen concentration detection method of the present disclosure (substantially similar to the conventional technique).

抗原濃度検出に先立って、検体中の既知の様々な抗原濃度に対して、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２と、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４と、での抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きを測定したうえで、位相傾き／抗原濃度換算曲線を記憶している。検体中の抗原濃度が高濃度であるときには、検体中の抗原濃度の検出精度を向上させるために、滴下時刻ｔ０から短時間後の期間ｔ１～ｔ２での、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きと、位相傾き／抗原濃度換算曲線と、に基づいて、検体中の抗原濃度を検出する。検体中の抗原濃度が低濃度であるときには、検体中の抗原濃度の検出精度を向上させるために、滴下時刻ｔ０から長時間後の期間ｔ３～ｔ４での、抗体固定チャネルの出力信号の位相Ｐ（ｔ）の時間変化の傾きと、位相傾き／抗原濃度換算曲線と、に基づいて、検体中の抗原濃度を検出する。 Prior to antigen concentration detection, for various known antigen concentrations in the sample, a period of t 1 to t 2 after a short time from the dropping time t 0 and a period of t 3 to t 3 after a long time from the dropping time t 0 After measuring the slope of the time change of the phase P(t) of the output signal of the antibody-immobilized channel at t4 and t4 , the phase slope/antigen concentration conversion curve is stored. When the antigen concentration in the specimen is high, in order to improve the detection accuracy of the antigen concentration in the specimen, the output signal of the antibody-fixed channel during the period t 1 to t 2 a short time after the dropping time t 0 The antigen concentration in the sample is detected based on the slope of time change of the phase P(t) and the phase slope/antigen concentration conversion curve. When the antigen concentration in the specimen is low, in order to improve the detection accuracy of the antigen concentration in the specimen, the output signal of the antibody-fixed channel during the period t 3 to t 4 after a long time from the dropping time t 0 The antigen concentration in the sample is detected based on the slope of time change of the phase P(t) and the phase slope/antigen concentration conversion curve.

検体中の抗原濃度の検出精度は、低濃度では滴下時刻ｔ０の検出精度にあまり影響されないが、高濃度では滴下時刻ｔ０の検出精度に大きく影響される。しかし、滴下時刻ｔ０の検出精度を向上させることにより、検体中の抗原濃度の検出精度を抗原濃度によらず向上させることができる。そして、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）が、ノイズレベルＡＮ又は不十分な滴下濡れにより減少したとしても、そのような減少の期間内の時刻を、滴下時刻ｔ０として検出しないため、滴下時刻ｔ０の検出精度を向上させることができる。さらに、抗体固定チャネル１の出力信号の振幅Ａ（ｔ）が、検体の滴下前及び滴下後ではほぼ時間変化せず、検体の滴下前後間では単調減少することを利用して、滴下時刻ｔ０を検出するため、滴下時刻ｔ０の検出精度を向上させることができる。 The detection accuracy of the antigen concentration in the specimen is not much affected by the detection accuracy at the dropping time t0 at low concentrations, but is greatly affected by the detection accuracy at the dropping time t0 at high concentrations. However, by improving the detection accuracy at the dropping time t0 , the detection accuracy of the antigen concentration in the sample can be improved regardless of the antigen concentration. Then, even if the amplitude A(t) of the output signal of the antibody-immobilized channel 1 decreases due to the noise level AN or insufficient drip wetting, the time within the period of such decrease is detected as the drip time t0. Therefore, it is possible to improve the detection accuracy of the dropping time t0 . Furthermore, by utilizing the fact that the amplitude A(t) of the output signal of the antibody-immobilized channel 1 does not change with time before and after the dropping of the specimen and monotonically decreases before and after the dropping of the specimen, the dropping time t0 is detected, it is possible to improve the detection accuracy of the dropping time t0 .

本開示の弾性表面波センサの滴下検出装置及び滴下検出プログラムは、酵素免疫測定法を利用して、血液等の検体中の抗原濃度を検出する用途に、適用することができる。 The drip detection device and drip detection program of the surface acoustic wave sensor of the present disclosure can be applied to the use of detecting the antigen concentration in a sample such as blood using the enzyme immunoassay method.

Ｓ：弾性表面波センサ
１：抗体固定チャネル
２：リファレンスチャネル
３：滴下検出装置
１１、２１：検出領域
１２、２２：櫛形電極
３１：信号取得部
３２：滴下検出部
３３：濃度検出部 S: Surface Acoustic Wave Sensor 1: Antibody Immobilization Channel 2: Reference Channel 3: Drop Detection Devices 11, 21: Detection Areas 12, 22: Comb Electrode 31: Signal Acquisition Section 32: Drop Detection Section 33: Concentration Detection Section

Claims (4)

酵素免疫測定法の抗体が固定化された検出領域と、弾性表面波を送信及び受信又は送信及び反射する櫛形電極と、を備えるチャネルの出力信号を取得する信号取得部と、
前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出する滴下検出部と、
を備えることを特徴とする弾性表面波センサの滴下検出装置。 a signal acquisition unit for acquiring an output signal of a channel comprising a detection region on which an enzyme immunoassay antibody is immobilized, and a comb-like electrode for transmitting and receiving or transmitting and reflecting a surface acoustic wave;
a dropping detection unit that detects a time within a period in which the amplitude of the output signal of the channel decreases before and after dropping the sample onto the detection region as the sample dropping time onto the detection region;
A dropping detection device for a surface acoustic wave sensor, comprising: 前記滴下検出部は、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間の所定時間幅で、前記チャネルの出力信号の振幅のノイズレベルより大きい所定閾値より大きく減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出する
ことを特徴とする、請求項１に記載の弾性表面波センサの滴下検出装置。 The drop detection unit detects a period during which the amplitude of the output signal of the channel decreases more than a predetermined threshold value, which is larger than the noise level of the amplitude of the output signal of the channel, within a predetermined time width between before and after dropping of the sample onto the detection area. 2. The dropping detection device for a surface acoustic wave sensor according to claim 1, wherein the time within is detected as the time when the sample is dropped onto the detection area. 前記滴下検出部は、前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で変曲点を示す時刻の近傍を、前記検出領域への検体の滴下時刻として検出する
ことを特徴とする、請求項１又は２に記載の弾性表面波センサの滴下検出装置。 The dropping detection unit detects the vicinity of the time at which the amplitude of the output signal of the channel shows an inflection point between before and after dropping the sample onto the detection region, as the dropping time of the sample onto the detection region. 3. The dropping detection device for a surface acoustic wave sensor according to claim 1 or 2. 酵素免疫測定法の抗体が固定化された検出領域と、弾性表面波を送信及び受信又は送信及び反射する櫛形電極と、を備えるチャネルの出力信号を取得する信号取得ステップと、
前記チャネルの出力信号の振幅が、前記検出領域への検体の滴下前後間で減少した期間内の時刻を、前記検出領域への検体の滴下時刻として検出する滴下検出ステップと、
を順にコンピュータに実行させるための弾性表面波センサの滴下検出プログラム。 A signal acquisition step of acquiring an output signal of a channel comprising a detection region on which an enzyme immunoassay antibody is immobilized and a comb-shaped electrode that transmits and receives or transmits and reflects a surface acoustic wave;
a drop detection step of detecting a time within a period in which the amplitude of the output signal of the channel decreased before and after dropping the sample onto the detection region as the drop time of the sample onto the detection region;
A dropping detection program for a surface acoustic wave sensor for causing a computer to execute in order.
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