JPH02287145A - Method for fixing small-diameter pipe where receptor is fixed and receptor - Google Patents
Method for fixing small-diameter pipe where receptor is fixed and receptorInfo
- Publication number
- JPH02287145A JPH02287145A JP1109997A JP10999789A JPH02287145A JP H02287145 A JPH02287145 A JP H02287145A JP 1109997 A JP1109997 A JP 1109997A JP 10999789 A JP10999789 A JP 10999789A JP H02287145 A JPH02287145 A JP H02287145A
- Authority
- JP
- Japan
- Prior art keywords
- small
- receptor
- diameter
- tube
- analyte
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000012491 analyte Substances 0.000 claims abstract description 30
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- 239000000463 material Substances 0.000 abstract description 2
- 238000003780 insertion Methods 0.000 abstract 1
- 230000037431 insertion Effects 0.000 abstract 1
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- 239000000427 antigen Substances 0.000 description 12
- 102000036639 antigens Human genes 0.000 description 12
- 108091007433 antigens Proteins 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 9
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- 238000005259 measurement Methods 0.000 description 8
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- 238000000691 measurement method Methods 0.000 description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は微量アナライト物質の測定、特に免疫反応（抗
原−抗体反応）を利用して生体試料のような多成分系に
＠置台まれる特定の物質を定量的に測定するために用い
られる、レセプタが固定された細径管およびレセプタの
固定方法に関するものである。Detailed Description of the Invention (Industrial Field of Application) The present invention is applicable to the measurement of trace amounts of analyte substances, particularly in multicomponent systems such as biological samples, using immune reactions (antigen-antibody reactions). The present invention relates to a small diameter tube on which a receptor is fixed and a method for fixing the receptor, which is used for quantitatively measuring a specific substance.
（従来の技術）
生体の生理活性に関与する物質は概して１＃量であり、
しかも生体に対して非常に重要な役割を演じるものが少
なくない。したがって、このような微量の生理活性物質
を定量的に測定することは医学、生化学等の生物関連分
野にとって重要であり、そのための種々の方法が考案さ
れ、実用化されている。そのうち酵素、放射性同位元素
、化学発光物質、螢光物質などを標識として用いるアナ
ライト−レセプタ方式の測定が従来より広く普及してい
る。アナライト−レセプタ方式の測定においてはまずｉ
１１定対象物質たるアナライトと特異的に結合し得る第
１のレセプタを固定化した固相を試料溶液と標識第２レ
セプタ、もしくは標識アナライト（以下これらの標識体
をコンジュゲートという）と同時、または逐次的に接触
させてアナライト−レセプタ反応を行なわせた後、洗浄
し、しかる後に該固相上に残存している標識物質の量を
測定することによって試料溶液中のアナライトの量を測
定するのである。ここで標識としてはラジオアイソトー
プや酵素等の増感作用の大きい物質が用いられる。また
レセプタとしてはアナライト、抗原やハプテンのときは
それに対する特異抗体、あるいはアナライトが抗体であ
る時はその抗体に対する抗原性物質、アナライトがＤＮ
ＡやＲＮＡである時にはそれらに相捕的なりＮＡやＲＮ
Ａ、アナライトがリガンドである時にはそれに対するレ
セプタがそれぞれ用いられる。かかる測定方法の代表例
として不均一法Ｅ Ｉ Ａ、いわゆるＥｎｚｙｍｅＬｉ
ｎｋｅｄ ｌｉｍｕｎｏ ５ｏｒｂｅｎｔ Ａｓ５ａｙ
（Ｅ Ｌ Ｉ Ｓ Ａ ）が知られている。(Prior art) Substances involved in the physiological activity of living organisms are generally in an amount of 1#,
Moreover, many of them play extremely important roles in living organisms. Therefore, quantitatively measuring such minute amounts of physiologically active substances is important in biology-related fields such as medicine and biochemistry, and various methods for this purpose have been devised and put into practical use. Among them, analyte-receptor measurements using enzymes, radioactive isotopes, chemiluminescent substances, fluorescent substances, etc. as labels have become more widespread than before. In the analyte-receptor method measurement, first
11 A solid phase on which a first receptor capable of specifically binding to an analyte, which is a target substance, is immobilized is simultaneously mixed with a sample solution and a labeled second receptor, or a labeled analyte (hereinafter, these labeled substances are referred to as conjugates). Alternatively, the amount of analyte in the sample solution can be determined by sequentially contacting the solid phase to cause an analyte-receptor reaction, washing, and then measuring the amount of labeling substance remaining on the solid phase. is measured. Here, as a label, a substance with a large sensitizing effect such as a radioisotope or an enzyme is used. In addition, the receptor is the analyte, and when it is an antigen or hapten, it is a specific antibody against it, or when the analyte is an antibody, it is an antigenic substance against that antibody, and the analyte is DN.
When it is A or RNA, it is complementary to them, NA or RN.
A. When the analyte is a ligand, a receptor for it is used. A representative example of such a measurement method is the heterogeneous method EIA, so-called EnzymeLi.
nked limuno 5orbent As5ay
(ELISA) is known.
ＥＬ Ｉ ＳＡにおいては、試料溶液中の測定対象物質
を捕捉するために、測定対象アナライトと特異的に結合
し得るレセプタを試験管、マイクロプレート等に固定化
した固相が用いられ、増感用の標識として酵素が用いら
れる。例えば測定対象アナライトが抗原の場合、サンド
イツチ法ＥＬＩＳＡにおいては該抗原に結合し得る第２
抗体く第２レセプタ）に酵素を標識する。また競合法Ｅ
ＬＩＳＡにおいては測定対象抗原と同一の抗原に酵素を
標識する。−力測定対象アナライトが抗体であり、これ
を抗原サンドイツチ法で測定する場合には、レセプタと
して抗原が用いられ、さらに酵素標識した抗原が第２レ
セプタとして用いられる。In ELISA, in order to capture the substance to be measured in the sample solution, a solid phase is used in which a receptor that can specifically bind to the analyte to be measured is immobilized on a test tube, microplate, etc. Enzymes are used as labels for For example, when the analyte to be measured is an antigen, in Sand-Germany ELISA, a second analyte that can bind to the antigen is used.
The antibody (second receptor) is labeled with the enzyme. Also, competition law E
In LISA, the same antigen as the antigen to be measured is labeled with an enzyme. - When the analyte to be measured is an antibody and this is measured by the antigen-Sand-Deutsch method, the antigen is used as the receptor, and an enzyme-labeled antigen is used as the second receptor.
また競合法によって抗体（アナライト）を測定する場合
には、レセプタとして抗原を用い、該抗原に対して測定
対象抗体と競合し得る抗体を選択しこれに酵素が標識さ
れる。上記標識として用いられた酵素に対する基質溶液
と、そしてさらに必要ならば発色試薬を固相と接触させ
る。すると基質溶液の分解反応に伴う基質溶液の光学的
性質が変化するので、その変化を観察するのである。Furthermore, when measuring an antibody (analyte) by a competitive method, an antigen is used as a receptor, an antibody that can compete with the antibody to be measured for the antigen is selected and labeled with an enzyme. A substrate solution for the enzyme used as the label and, if necessary, a coloring reagent are brought into contact with the solid phase. Then, the optical properties of the substrate solution change due to the decomposition reaction of the substrate solution, and this change is observed.
基質溶液の光学的性質の変化を観察するには、従来から
いくつかの方法が用いられている。そのうち機器を用い
る方法としては、吸光光度計、蛍光光度計、化学発光光
度計などで基質溶液の光学的性質の変化を光学的に測定
するものがある（例えば、石川、回合、宮井、酵素免疫
測定法、医学書院（１９８２）参照）。Several methods have been used to observe changes in the optical properties of substrate solutions. Among these, instrumental methods include those that optically measure changes in the optical properties of substrate solutions using spectrophotometers, fluorometers, chemiluminescence photometers, etc. (See Measurement Method, Igaku Shoin (1982)).
また、別の方法として基質溶液と対照基質溶液を対比さ
せ基質溶液の色の違いを肉眼で観察して微量アナライト
物質の存在を判定するものがある。Another method involves comparing a substrate solution with a control substrate solution and visually observing the difference in color between the substrate solutions to determine the presence of a trace amount of the analyte substance.
しかしながら機器を用いたこれらの光学的測定系は通常
安定な光源、高感度の光度計、精密な光学系増幅回路等
を要するために、高価で、大がかりで摸雑な装置になら
ざるを得なかった。また測定するに当り、特殊な技術を
必要とするため取扱いのための専門の技術者を配置しな
ければならなかった。However, these optical measurement systems using instruments usually require a stable light source, a highly sensitive photometer, a precise optical amplifier circuit, etc., so they have to be expensive, large-scale, and complicated equipment. Ta. Furthermore, since measurement requires special techniques, a specialist engineer must be assigned to handle the measurement.
一方肉眼で直接観察する方法は、定性的な測定方法であ
り、色の変化のバラツキや観察者の主観が入るので判定
に個人差が生じやすい。さらに、極く微量の物質の測定
の場合には色の変化が少なく判定が困難であった。On the other hand, the method of direct observation with the naked eye is a qualitative measurement method, and because it involves variations in color change and the subjectivity of the observer, individual differences in judgment are likely to occur. Furthermore, when measuring a very small amount of a substance, there is little change in color, making it difficult to judge.
本発明者らは従来の測定方法の欠点を解消し、観察者の
主観による判定基準の曖昧さを除去して、基質溶液の分
解反応を客観的に、しかも高い検出精度で測定する操作
の簡単な微量アナライト物質の測定装置を特願昭６３−
３８２７４号に提案した。The present inventors have solved the shortcomings of conventional measurement methods, removed the ambiguity of judgment criteria caused by observer's subjectivity, and made it possible to measure the decomposition reaction of a substrate solution objectively and with high detection accuracy. A patent application was filed in 1983 for a device for measuring trace amounts of analyte substances.
It was proposed in No. 38274.
かかる装置は第４図に示すように、基質溶液の入口１２
と出口１３を有するセル１１と、該セル１１内に収容さ
れたｐＨ電極１４（通常ｐＨ感応電界効果トランジスタ
が用いられる）及び比較電極１５と、セル内に基質溶液
を供給するポンプ２０と、内表面にレセプタを固定した
細径管ｌをセル１１内に収納する手段９で構成されてい
る。Such a device has a substrate solution inlet 12 as shown in FIG.
a cell 11 having an outlet 13 and a pH electrode 14 (usually a pH sensitive field effect transistor) and a reference electrode 15 housed within the cell 11; a pump 20 supplying a substrate solution into the cell; It consists of a means 9 for storing in a cell 11 a small diameter tube l having a receptor fixed on its surface.
上記装置の基本的な操作は、まず内壁にレセプタを固定
化した細径管１を準備する。次に該細径管をアナライト
溶液およびコンジュゲート溶液と反応させ、内壁にアナ
ライト−レセプタ複合体（フンシュゲートを含む）を形
成させる。その後細径管を洗浄して遊離のアナライトや
遊離のコンシュゲートを除去する。次に細径管をセル内
に収容する手段９により、第５図に示すように細径管ｌ
がｐ）ｌ電極１４のｐＨ感応面１６を包囲するようにセ
ル内に収容する。そのとき細径管１の内壁とｐＨ電極１
４のｐＨ感応面１６の間隙が１ｍｍ以下に設定すること
が重要である。この前もしくは後に少くともこの間隙に
基質溶液を導入して、細径管の内壁に吸着したコンジュ
ゲートによって基質溶液を分解し、この時の基質溶液の
ｐＨ変化をｐＨ電極１４で測定する。The basic operation of the above device is to first prepare a small diameter tube 1 with a receptor immobilized on its inner wall. The narrow diameter tube is then reacted with an analyte solution and a conjugate solution to form an analyte-receptor complex (including Funshugate) on the inner wall. The small diameter tube is then washed to remove free analyte and free consulate. Next, by the means 9 for accommodating the small diameter tube in the cell, the small diameter tube l
is housed in the cell so as to surround the pH sensitive surface 16 of the p)l electrode 14. At that time, the inner wall of the small diameter tube 1 and the pH electrode 1
It is important that the gap between the pH sensitive surfaces 16 of No. 4 is set to 1 mm or less. Before or after this, a substrate solution is introduced into at least this gap, and the substrate solution is decomposed by the conjugate adsorbed on the inner wall of the small diameter tube, and the pH change of the substrate solution at this time is measured with the pH electrode 14.
かかる装置は従来の光学的検出器を用いて微量なアナラ
イト物質を検出する方法に比べて、装置が簡易で、また
細径管の先端部内壁を固相とするために、洗浄が容易で
、かつ免疫反応時間および酵素反応時間が短くても測定
が可能であるという優れた利点を有している。Compared to the conventional method of detecting trace amounts of analyte substances using optical detectors, such a device is simpler and easier to clean because the inner wall of the tip of the small diameter tube is a solid phase. , and has the excellent advantage that measurement can be performed even if the immune reaction time and enzyme reaction time are short.
（発明が解決しようとする課題）
上記測定法において、一定の品質を有する面相用の細径
管を量産することは、再現性の良好な測定結果を得るた
めに極めて重要である。また細径管の先端部内壁に固定
されるレセプタは高価であるので、そのロスを少なくす
ることら重要である。(Problems to be Solved by the Invention) In the above measurement method, it is extremely important to mass-produce small-diameter tubes for surface phase having a certain quality in order to obtain measurement results with good reproducibility. Furthermore, since the receptor fixed to the inner wall of the tip of the small diameter tube is expensive, it is important to reduce its loss.
したがって、本発明の目的は上記装置に適用可能な、レ
セプタが固定された細径管を提供することである。さら
に本発明の目的は上記二つの条件を満たしなから細径管
の先端部内壁に抗原や抗体などのレセプタを固定する方
法を提供することである。Therefore, an object of the present invention is to provide a small-diameter tube to which a receptor is fixed, which can be applied to the above-mentioned device. A further object of the present invention is to provide a method for immobilizing receptors such as antigens and antibodies on the inner wall of the tip of a small diameter tube while satisfying the above two conditions.
（課題を解決するための手段）
すなわち、本発明の細径管は先端に設けられたｐＨ電極
挿入用の細管部から後端に向って拡径するピペットチッ
プ形状の細径管の少くとも細管部内壁に、測定対象物質
たるアナライトと特異的に結合する第！のレセプタが固
定された細径管である。(Means for Solving the Problems) That is, the small diameter tube of the present invention is at least a small diameter tube in the shape of a pipette tip whose diameter increases from the thin tube part for inserting a pH electrode provided at the tip toward the rear end. The first part that specifically binds to the analyte, which is the substance to be measured, on the inner wall of the part! It is a small diameter tube with a fixed receptor.
さらに本発明の製造方法は複数の上記細径管を直列に連
結して、最後部の細径管の後端開口に吸引手段を接続す
るとともに、該吸引手段によって先端部の細径管の細管
部先端から測定対象物質たるアナライトと特異的に結合
する第１のレセプタを溶解させた緩衡溶液を吸引するこ
とにより、各細径管の少くとも細管部内壁に第１のレセ
プタを固定する方法である。Furthermore, the manufacturing method of the present invention connects a plurality of the above-mentioned small-diameter tubes in series, connects a suction means to the rear end opening of the rearmost small-diameter tube, and uses the suction means to The first receptor is fixed to at least the inner wall of each narrow tube by suctioning a buffer solution in which the first receptor that specifically binds to the analyte, which is the substance to be measured, is dissolved from the tip of the tube. It's a method.
第１図は本発明の細径管ｌの断面図であり、該細径管は
先端にｐＩ（電極を挿入する細管部２と、拡径部３及び
後端に設けられたヘッド４で構成されている。拡径部３
はさらにセルに設けられたテーパに沿って細径管の先端
細径部２をｐＨｉ極に確実に包囲させるためのガイドと
しての第！の拡冬部ａと、後述する複数の細径管を直列
に連結するための第２の拡径部す及び吸引手段（図示せ
ず）の先端に設けられたテーパが嵌設される第３の拡径
部Ｃを有している。細径管ｌの先端細管部２はその中に
挿入されるｐＨ１１極の外径らしくは幅より若干太めに
設計されろ。例えばｐＨ電瓶の幅が４５０μｍであれば
通常内径５００〜６００μｍか適当である。また細管部
の長さは、通常挿入されるｐ）！電極の長さの２〜ｌＯ
倍が適当である。例えばｐｔ＋電極としてＩ）Ｈ感応電
界効果トランノスタを使用すると、その長さが通常１．
５＋ｎｍであるので細管部２の長さは３〜１５ｍｍ程度
が好ましい。細径管ｌの有効内容積は細管部２、第１の
拡径部λ及び第２の拡径部すの内容積の和に等しい。し
たがって所望する容積に応じて第１の拡径部λ及び第２
の拡径部すの内径と長さが設計される。第３の拡径部Ｃ
の内径およびテーパは吸引手段（通常ピペッタ、シリン
ジなどが使用される）の外径とテーパに対応して設計さ
れる。第２の拡径部すの内壁テーパと外壁テーパは複数
の細径管を直列に連結したときに液密に接合するように
その勾配を部分的もしくは全体的に一致させる必要であ
るが、例えば第３のｔｒｉ： ｉＭ部Ｃの内壁と第２の
拡径部すの外壁の一部、あるいは細管部２の内壁もしく
は第１の拡径部１の外壁を接合さけても２つの細径管を
液密に連結できる。FIG. 1 is a cross-sectional view of a small-diameter tube l of the present invention. Expanded diameter part 3
Further, the second part is used as a guide to ensure that the thin end portion 2 of the small diameter tube is surrounded by the pHi electrode along the taper provided in the cell. , a second expanded diameter section for connecting a plurality of small diameter tubes in series, which will be described later, and a third expanded section into which a taper provided at the tip of a suction means (not shown) is fitted. It has an enlarged diameter portion C. The tip thin tube part 2 of the small diameter tube 1 should be designed to be slightly thicker than the width, considering the outer diameter of the pH 11 pole to be inserted therein. For example, if the width of the pH bottle is 450 μm, the inner diameter is usually 500 to 600 μm. Also, the length of the thin tube section is usually inserted p)! 2~1O of the length of the electrode
Double is appropriate. For example, when an I)H-sensitive field-effect trannostar is used as the pt+ electrode, its length is usually 1.
5+nm, the length of the thin tube portion 2 is preferably about 3 to 15 mm. The effective internal volume of the small diameter tube l is equal to the sum of the internal volumes of the thin tube section 2, the first enlarged diameter section λ, and the second enlarged diameter section I. Therefore, depending on the desired volume, the first enlarged diameter part λ and the second enlarged diameter part λ
The inner diameter and length of the enlarged diameter section are designed. Third enlarged diameter part C
The inner diameter and taper of the tube are designed to correspond to the outer diameter and taper of the suction means (usually a pipettor, syringe, etc.). The slopes of the inner wall taper and outer wall taper of the second enlarged diameter portion need to match partially or completely so that when a plurality of small diameter pipes are connected in series, they are joined in a liquid-tight manner. Third tri: Even if the inner wall of the iM section C and a part of the outer wall of the second enlarged diameter section, or the inner wall of the narrow tube section 2 or the outer wall of the first enlarged diameter section 1 are avoided, two small diameter tubes are formed. can be connected liquid-tightly.
細径管の材質としては、例えばポリスチレン、ポリエチ
レン、ポリプロピレン、ポリテトロフロロエチレン、ポ
リ塩化ビニル、ポリメチルメタクリレート、ポリビニル
アルコール、エチレン−ビニルアルコール共重合体等の
ポリオレフィン系ポリマー ポリエチレンテレフタレー
トやポリブチレンテレフタレート等のポリエステル系ポ
リマーポリジメチルシロキサン等のポリンロキサン系ボ
リマー、６ナイロン、６．６−ナイロン等のポリアミド
系ポリマー、ポリカーボネート、酢酸セルロースやニト
ロセルロースのようなセルロース系ポリマー さらには
各種無機ガラスを用いることができる。Materials for the small diameter tube include, for example, polyolefin polymers such as polystyrene, polyethylene, polypropylene, polytetrofluoroethylene, polyvinyl chloride, polymethyl methacrylate, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyethylene terephthalate, polybutylene terephthalate, etc. Polyester polymers Polylinoxane polymers such as polydimethylsiloxane, polyamide polymers such as 6-nylon and 6.6-nylon, polycarbonate, cellulose polymers such as cellulose acetate and nitrocellulose, and various inorganic glasses can be used. .
上記細径管１の少くとも先端細管部２の内壁に測定対象
物質たるアナライトと特異的に結合する第１のレセプタ
５が固定されている。細管部２の内壁は第２図に示すよ
うに多数の凹凸を設けて表面積を大きくすると検出感文
を向上させたり、インキュベーション時間を短縮するこ
とができて好ましい。A first receptor 5 that specifically binds to an analyte, which is a substance to be measured, is fixed to the inner wall of at least the tip capillary portion 2 of the small diameter tube 1. As shown in FIG. 2, the inner wall of the thin tube section 2 is preferably provided with a large number of irregularities to increase the surface area, since this can improve the detection sensitivity and shorten the incubation time.
なお、この上うな細径管にレセプタを固定化し、微蛍物
質の検出に利用することかできると思われる物質と、そ
れらにより測定できると考えられる項目の一例を表−【
に示す。In addition, the following table lists examples of substances that can be used to detect faintly fluorescent substances by immobilizing receptors on small-diameter tubes, and items that can be measured using them.
Shown below.
表
次に細径管ｌの少くとも先端細管部２の内壁にレセプタ
を固定する方法について説明する。まず複数、例えば４
ケの細径管１（ａ）、１ （ｂ）、１（ｃ）、１（ｄ）
を用意して、細径管１ （ａ）の後端開口から順次細径
管１（ｂ）、１（ｃ）、ｌ （ｄ）の先端を挿入して第
３図に示すように直列に連結する。この場合細径管に設
けられた第２の拡径部の外壁と、隣接する細径管に設け
られた第２の拡径部の内壁が液密に接合されるように細
径管を隣接する細径管の内腔へ嵌挿する。Next, a method for fixing the receptor to the inner wall of at least the tip capillary portion 2 of the small diameter tube 1 will be described. First, multiple, e.g. 4
Small diameter tubes 1(a), 1(b), 1(c), 1(d)
Prepare the small diameter tubes 1(a) and insert the tips of the small diameter tubes 1(b), 1(c), and l(d) in series from the rear end opening of the tube 1(a) as shown in Figure 3. Link. In this case, the small-diameter tubes are placed adjacently so that the outer wall of the second enlarged-diameter portion provided on the small-diameter tube and the inner wall of the second enlarged-diameter portion provided on the adjacent small-diameter tube are fluid-tightly joined. Insert into the lumen of a small diameter tube.
次いで細径管１（ｄ）の端部開口からピペッタのヘッド
６を液密に嵌挿する。そして細径管１（ａ）の先端細管
部２を測定対象物質たるアナライトと特異的に結合する
第１のレセプタを溶解させた緩衡溶液７中に入れ、ピペ
ッタで所望容積の緩衡溶液を各細径管内に吸引する。こ
の時吸引する溶液の容積Ｖは、第１図に示す細管部２と
第１の拡径部＆の内部の容積をＶ、直列に連結された細
径管の数をｎとすると、Ｖ＝ｎｖであられされる。この
状態で所定時間静置後、細径管内の緩衡溶液を排出する
ことによりアナライトと特異的に結合する第１のレセプ
タ（例えば抗原、抗体など）が細径管１の先端細管部２
及び第１の拡径部ａ内壁に物理吸着らしくは化学結合に
より固定される。化学結合により固定する場合には細径
管のすくなくとも先端細管部２及び第１の拡径部１の内
壁に官能基を導入しておく必要がある。Next, the head 6 of the pipettor is inserted into the end opening of the small diameter tube 1(d) in a fluid-tight manner. Then, the tip tube portion 2 of the thin tube 1(a) is placed in a buffer solution 7 in which the first receptor that specifically binds to the analyte, which is the substance to be measured, is dissolved, and the buffer solution has a desired volume using a pipettor. into each small diameter tube. The volume V of the solution to be sucked at this time is V= It is raining on nv. After standing still in this state for a predetermined period of time, the buffer solution in the small diameter tube is discharged, and the first receptor (e.g., antigen, antibody, etc.) that specifically binds to the analyte is transferred to the tip capillary portion 2 of the small diameter tube 1.
And it is fixed to the inner wall of the first enlarged diameter part a by physical adsorption or chemical bonding. When fixing by chemical bonding, it is necessary to introduce functional groups into the inner walls of at least the tip capillary tube part 2 and the first enlarged diameter part 1 of the small diameter tube.
通常細径管の少くとも先端細管部の内壁へ第１のレセプ
タを固定した後、酵素標識体等の非特異的吸着を抑制す
るためブロッキングが行われる。Usually, after the first receptor is immobilized on the inner wall of at least the distal end capillary portion of the small diameter tube, blocking is performed to suppress nonspecific adsorption of enzyme labels and the like.
そのために例えば、牛の血清アルブミン等のアッセイ中
の免疫反応に関与しない蛋白質の水溶液を細径管内に導
入して所定時間静置する。その後ブロッキング溶液を排
出し、細径管を乾燥することにより少くとも細管部に第
１のレセプタが固定された細径管が製造される。細径管
の乾燥は複数の細径管を連結した状態のままでピペッタ
ヘッドをはずし、連結された細径管の内部に乾燥空気を
流通させることにより行うことができる。また複数の細
径管の連結をほどき、各細径管をバラバラにした状態で
所定温度・所定湿度下に静置することによっても行うこ
とができる。細径管の良好な保存安定性を確保するため
に、ブロッキング溶液に糖類などを共存させておいても
よい。For this purpose, for example, an aqueous solution of a protein that is not involved in the immune reaction during the assay, such as bovine serum albumin, is introduced into a small diameter tube and allowed to stand for a predetermined period of time. Thereafter, the blocking solution is discharged and the thin tube is dried, thereby producing a thin tube in which at least the first receptor is fixed to the thin tube portion. Drying of the small diameter tubes can be carried out by removing the pipettor head while the plurality of small diameter tubes are still connected, and flowing dry air into the inside of the connected small diameter tubes. It can also be carried out by uncoupling a plurality of small-diameter tubes and leaving each small-diameter tube in pieces at a predetermined temperature and a predetermined humidity. In order to ensure good storage stability of the small diameter tube, sugars and the like may be present in the blocking solution.
（実施例）
第１図に示したような細径管をポリプロピレン樹脂を用
いて成型した。細径管の先端細管部の内壁は５６０μ■
、その部分の長さは８ｍｍである。また細管部と第１の
拡径部の内容積の和は６．５μｇである。(Example) A small diameter tube as shown in FIG. 1 was molded using polypropylene resin. The inner wall of the tip thin tube part of the small diameter tube is 560μ■
, the length of that part is 8 mm. Further, the sum of the internal volumes of the thin tube portion and the first enlarged diameter portion is 6.5 μg.
上記細径管の１００本を直列に連結し、その開口部末端
の細径管にピペッタを挿入した。一方５０μｇ／ａＱの
抗アルファフェトプロティン抗体を含むリン酸緩衡溶液
を調製し、この溶液中に上記直列に連結された細径管の
先端を挿入し、７００μＱの該溶液を吸引し、２５℃で
２４時間静置することにより、細管部２及び第１の拡径
部ａの内壁に抗アルファフェトプロティン抗体を吸着さ
せた。次に該抗体溶液をピペッタで排出し、リン酸緩衡
溶液（ｐＨ７゜Ｏ） ７００μＱの吸引、排出を５回繰
りかえすことにより、細径管内を洗浄した。次いで１％
の牛血清アルブミンを含むリン酸緩衡溶液７００μＱを
吸引して２５℃で３時間静置することによりブロッキン
グ処理を行った。この溶液を排出した後、ピペッタを取
りはずし、乾燥した窒素ガスを直列に連結された細径管
内にゆるやかに流通させて細径管を乾燥さ仕た。One hundred of the above-mentioned small-diameter tubes were connected in series, and a pipettor was inserted into the small-diameter tube at the end of the opening. On the other hand, prepare a phosphate buffer solution containing 50 μg/aQ of anti-alphafetoprotein antibody, insert the tips of the thin tubes connected in series into this solution, aspirate 700 μQ of the solution, and hold the solution at 25°C. By allowing the tube to stand for 24 hours, the anti-alphafetoprotein antibody was adsorbed onto the inner walls of the thin tube section 2 and the first enlarged diameter section a. Next, the antibody solution was discharged with a pipetter, and the inside of the small diameter tube was washed by repeating suction and discharge of 700 μQ of phosphate buffer solution (pH 7°O) five times. Then 1%
Blocking treatment was carried out by aspirating 700 μQ of a phosphate buffer solution containing bovine serum albumin and allowing it to stand at 25° C. for 3 hours. After discharging this solution, the pipettor was removed, and dry nitrogen gas was gently passed through the serially connected small diameter tubes to dry the small diameter tubes.
このようにして作成された１００本の細径管を用いて、
以下のようにしてアルファフェトプロティンのサンドイ
ッチアッセイを行い、１００本の細径管の性能のバラつ
きを測定した。すなわちｓｏｎｇ／１１１２のアルファ
フェトプロティンと５μｇ／ ｍＱのウレアーゼｍ識抗
アルファフェトプロティン抗体および１０％ヒト血清を
含むリン酸緩衡溶液を調製し、該溶液２０μＱを上記各
細径管中に吸引し、３７℃で１０分間インキュベーショ
ンした。その後細径管を、１００１１Ｍの塩化アンモニ
ウムと１５０ｍＭの塩化ナトリウムを含む水溶液で、５
回の吸引・排出処理することにより洗浄した。Using 100 small diameter tubes created in this way,
A sandwich assay for alpha-fetoprotein was performed as follows, and variations in the performance of 100 small-diameter tubes were measured. Specifically, a phosphate buffer solution containing alpha-fetoprotein of song/1112, 5 μg/mQ of urease m-recognizing alpha-fetoprotein antibody, and 10% human serum was prepared, and 20 μQ of the solution was aspirated into each of the above-mentioned small diameter tubes. , and incubated for 10 minutes at 37°C. The small diameter tube was then treated with an aqueous solution containing 10011M ammonium chloride and 150mM sodium chloride for 5 hours.
It was cleaned by suctioning and discharging twice.
この処理の後、細径管の先端細管部内壁に残存するウレ
アーゼの活性を、第４図に示す装置を用いて測定した。After this treatment, the activity of urease remaining on the inner wall of the distal end of the thin tube was measured using the apparatus shown in FIG.
基質溶液としては、ｌｏＯｍＭの尿素と１００ｍＭの塩
化アンモニウムおよび１５０１１Ｍの塩化ナトリウムを
含む水溶液を用いた。As the substrate solution, an aqueous solution containing loOmM urea, 100mM ammonium chloride, and 15011M sodium chloride was used.
ウレアーゼ活性の指標としては、ｐＨ感応電界効果トラ
ンジスタのソース電位の変化速度の最大値（ピークレー
ト）を用いた。As an index of urease activity, the maximum value (peak rate) of the rate of change of the source potential of the pH-sensitive field effect transistor was used.
１００本の細径管についてその値の最大・最小値、平均
値はそれぞれ１．８３＋ａＶ／ ｓｅａ、 １．８５ｍ
Ｖ／ ｓｅａ。The maximum, minimum, and average values for 100 small diameter pipes are 1.83+aV/sea and 1.85m, respectively.
V/sea.
１．７４ｍＪ／ ｓｅｃでその中心変動値（ＣＶ値）は
わずか１．８８％であった。At 1.74 mJ/sec, its center variation value (CV value) was only 1.88%.
（発明の効果）
以上に述べた本発明のレセプタが固定された細径管およ
びその製造方法は次のような優れた効果を有する。(Effects of the Invention) The small-diameter tube to which the receptor is fixed and the manufacturing method thereof of the present invention described above have the following excellent effects.
（１）大量の均質な細径管を一度に製造することができ
る。（２）使用する測定対象物質たるアナライトと特異
的に結合する第１のレセプタが極めて少量ですむ。通常
細径管の先端細管部２と第１の拡径部λの８稜すなわち
１つの細径管あたりの第１のレセプタの使用量は敗μＱ
であり、これは従来よく用いられているマイクロプレー
トのｌウェルあたりの使用量（通常１００μに前後）の
十分の１以下である。（３）第１のレセプタ（抗原や抗
体など）は高価であり、その使用量は細径管のコストを
決める重要な因子であるのが、本発明の細径管は第１の
レセプタの使用量が極めて少ないため安価である。(1) A large quantity of homogeneous small-diameter tubes can be manufactured at once. (2) An extremely small amount of the first receptor that specifically binds to the analyte, which is the substance to be measured, is required. Normally, the amount of the first receptor used per small diameter tube is 8 ridges of the tip capillary section 2 and the first enlarged diameter section λ, that is, the amount of the first receptor used per small diameter tube is
This is less than one-tenth of the amount used per 1 well of conventional microplates (usually around 100μ). (3) The first receptor (antigen, antibody, etc.) is expensive, and the amount used is an important factor that determines the cost of the thin tube, but the thin tube of the present invention uses the first receptor. It is inexpensive because the quantity is extremely small.
第１図及び第２図は本発明の第１のレセプタが固定され
た細径管の断面図であり、第３図は複数の細径管を直列
に連結した状態を示す断面図であり、第４図は本発明の
細径管を使用した微量アナライト物質の測定装置の模式
図であり、第５図は細径管をセル内に挿入した状態を示
す断面図である。
！・・・細径管 ２・・・細管部３・・・拡径
部 ４・・・ヘッド５・・・第１のレセプタ
６・・・ピペッタヘッド＆ ・・・第１の拡径部 ｂ
・・・第２の拡径部Ｃ・・・第３の拡径部
特許出願人 株式会社 り ラ し1 and 2 are cross-sectional views of a small-diameter tube to which the first receptor of the present invention is fixed, and FIG. 3 is a cross-sectional view showing a state in which a plurality of small-diameter tubes are connected in series, FIG. 4 is a schematic diagram of a device for measuring trace amounts of analyte substances using the small diameter tube of the present invention, and FIG. 5 is a sectional view showing the state in which the small diameter tube is inserted into a cell. ! ...Thin diameter tube 2...Thin tube part 3...Enlarged diameter part 4...Head 5...First receptor
6... Pipettor head &... First enlarged diameter part b
...Second enlarged diameter section C...Third enlarged diameter section Patent applicant RiRa Shi Co., Ltd.
Claims (1)
に向つて拡径するピペットチップ形状の細径管の少くと
も細管部内壁に、測定対象物質たるアナライトと特異的
に結合する第１のレセプタが固定されてなることを特徴
とするレセプタが固定された細径管。 ２、請求項１記載の複数の細径管を直列に連結して、最
後部の細径管の後端開口に吸引手段を接続するとともに
、該吸引手段によつて先端部の細径管の細管部先端から
測定対象物質たるアナライトと特異的に結合する第１の
レセプタを溶解させた緩衡溶液を吸引することにより、
各細径管の少くとも細管部内壁に第１のレセプタを固定
することを特徴とするレセプタの固定方法。[Scope of Claims] 1. An analyte, which is a substance to be measured, is placed on at least the inner wall of a pipette tip-shaped narrow tube whose diameter expands toward the rear end from a thin tube section for inserting a pH electrode provided at the tip. 1. A narrow diameter tube to which a receptor is fixed, characterized in that a first receptor that specifically binds to is fixed to the first receptor. 2. A plurality of small diameter tubes according to claim 1 are connected in series, and a suction means is connected to the rear end opening of the rearmost small diameter tube, and the suction means is used to suck the small diameter tube at the tip end. By suctioning a buffer solution in which the first receptor that specifically binds to the analyte, which is the substance to be measured, is dissolved from the tip of the thin tube,
A method for fixing a receptor, comprising fixing a first receptor to at least an inner wall of a thin tube portion of each small diameter tube.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109997A JP2752429B2 (en) | 1989-04-27 | 1989-04-27 | Small-diameter tube to which receptor is fixed and method of fixing receptor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109997A JP2752429B2 (en) | 1989-04-27 | 1989-04-27 | Small-diameter tube to which receptor is fixed and method of fixing receptor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02287145A true JPH02287145A (en) | 1990-11-27 |
| JP2752429B2 JP2752429B2 (en) | 1998-05-18 |
Family
ID=14524479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1109997A Expired - Fee Related JP2752429B2 (en) | 1989-04-27 | 1989-04-27 | Small-diameter tube to which receptor is fixed and method of fixing receptor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2752429B2 (en) |
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| US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US9011332B2 (en) | 2001-01-02 | 2015-04-21 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US9017259B2 (en) | 2000-06-27 | 2015-04-28 | Abbott Diabetes Care Inc. | Integrated sample acquisition and analyte measurement device |
| US9039975B2 (en) | 2006-03-31 | 2015-05-26 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
| US9066695B2 (en) | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US9078607B2 (en) | 2005-11-01 | 2015-07-14 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
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-
1989
- 1989-04-27 JP JP1109997A patent/JP2752429B2/en not_active Expired - Fee Related
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