JP3811652B2

JP3811652B2 - Dispensing device and automatic analyzer using the same

Info

Publication number: JP3811652B2
Application number: JP2002058143A
Authority: JP
Inventors: 雅人石沢; 紀和有馬; 和美草野
Original assignee: Hitachi High Technologies Corp
Current assignee: Hitachi High Tech Corp
Priority date: 2002-03-05
Filing date: 2002-03-05
Publication date: 2006-08-23
Anticipated expiration: 2022-03-05
Also published as: JP2003254982A

Description

【０００１】
【発明の属する技術分野】
本発明は一方の容器から他方の容器へ分注プローブにより液体を分注する機能を備えた分注装置に係り、特に吸引動作の正常終了を判断すべく、分注プローブと同流路に接続された圧力センサの信号出力を監視する機能を有した分注装置及びそれを備えた自動分析装置に関する。
【０００２】
【従来の技術】
従来の自動分析装置は、血液や尿などの生体試料からなるサンプルを、サンプル容器から反応ライン上の反応容器へ分注し、サンプルと試薬の混合液を光度計の如き測定手段によって測定する。
【０００３】
分注動作の際には分注対象の液体内へ分注プローブの先端を侵入させるが、その侵入深さが大きいほどプローブ外壁への液体付着量が増しコンタミネーションが大きくなる。そこで、分注プローブの侵入深さを極力低減する為に、容器内の液体の液面を検出しプローブの先端が液面より僅かに下に達した位置でプローブの下降動作を停止させ、次いでプローブ内へ所定量の液体を吸入するように動作制御する。
【０００４】
更に液体の吸入動作時は期待量通りの吸引が行われたことを確認すべく、吸引前後、或いは吸引中の流路内圧力値を確認し、分注プローブ先端の詰まり等の要因による所定量以下の吸引、つまり吸引異常が発生したことを検知する手法が一般的である。
【０００５】
しかし、一般的に圧力センサは分注プローブと同じ流路に接続され、圧力センサの信号出力を監視する構成となるが、長期間装置を使用しなかった場合、流路水内に溶存酸素が発生する等の要因により当該流路内に気泡が混入する可能性がある。特に圧力センサの検出部周辺に気泡が溜まった場合は気泡が圧力伝導の緩衝材として機能し正常な圧力が検出できなくなり、吸引動作中に異常であっても正常と誤った判断をする可能性を有していた。つまり、定量吸引できなくとも正常と認識し、最終的に分析結果異常となる危険性があった。
【０００６】
このため、特開平１０−２２７７９９号公報には、圧力センサの出力波形の立ち上がり時刻の遅れや、変化率の低下，ピーク値の減少から気泡の存在を検出する手法が開示されている。
【０００７】
【発明が解決しようとする課題】
特開平１０−２２７７９９号公報記載の技術はノズル近傍と、分注ポンプ近傍にそれぞれ圧力センサを設けそれら圧力センサの圧力変動に基づいて、気泡の存在を認識しているが、ノイズ除去のため、明細書の図４に表されているように、圧力測定の時定数を大きくして測定し、平均的な圧力値を用いて判断している。
【０００８】
このような方法では、分注量が十μｌのオーダーのような微少量の場合、気泡の存在を感度良く検出できない可能性があった。また分注精度も一桁％を確保するのは困難の可能性があった。
【０００９】
本発明の目的は、微少量の分注量に対しても、高い分注精度を確保できる分注装置及びそれを用いた自動分析装置を提供することにある。
【００１０】
【課題を解決するための手段】
上記目的を達成するための本発明の構成は、分注ノズルと分注ポンプを接続する圧力伝達管内の圧力を時定数が少なく、高感度の測定装置で検出し、吸引速度に比例した発振波形が観測し吸引中の振動周期幅、或いは振幅高さを監視することにより気泡の存在を検出する機能を備えた分注装置である。
【００１１】
検出波形を高感度にすることにより、装置の異常状態、例えば圧力センサの動作不良，流路漏れ（Leak）等の検出も可能となる。
【００１２】
また、検出波形を高感度にすることにより、圧力センサ１個でも装置の異常状態、例えば圧力センサの動作不良，流路漏れ（Leak）等の検出が可能となる。
【００１４】
時定数が少なく、高感度にしたために正常時は吸引直後はオーバーシュート、吸引停止直後はアンダーシュート、吸引中も吸引速度に比例した発振波形が観測される。この吸引停止直後のアンダーシュートの波形を分析することにより、圧力センサの動作不良，流路漏れ（Leak）等の検出が可能となる。
【００１５】
この構成により分注量が１０〜５０ｕｌ、分注精度は１％程度を達成することができるが、従来の技術では分注量が数百ｕｌ〜数ｍｌ、分注精度も数十％程度しか達成できない。
【００１６】
更に検知可能な気泡も本発明では直径φ１mm程度でも検出可能であるが、従来の技術ではφ１mm程度の検知は困難であった。
【００１７】
（実施例）
以下に本発明の実施例を図１から順を追って説明する。
【００１８】
図１は一般的な自動分析装置の分注機構周辺部概略図を示す。各部の機能は公知のものである為、詳細についての記述は省略する。サンプリング機構１のサンプリングアーム２は上下すると共に回転し、サンプリングアーム２に取り付けられたプローブ１０５を用いて、左右に回転するサンプルディスク１０２に配置されたサンプル容器１０１内の試料７を吸引し、反応容器１０６へ吐出するように構成されている。本図からもわかるようにサンプル容器１０１のサンプルディスク１０２への配置はサンプルディスク１０２上へ直接配置する場合や試験管（図示は無い）上にサンプル容器１０１を載せる事も可能なユニバーサルな配置に対応可能な構造のものが一般的である。
【００１９】
図１における自動分析装置の構成をさらに説明する。回転自在な試薬ディスク１２５上には分析対象となる複数の分析項目に対応する試薬のボトル１１２が配置されている。可動アームに取り付けられた試薬分注プローブ１１０は、試薬ボトル１１２から反応容器１０６へ所定量の試薬を分注する。
【００２０】
サンプル分注プローブ１０５は、サンプル用シリンジポンプ１０７の動作に伴ってサンプルの吸入動作、及び吐出動作を実行する。試薬分注プローブ１１０は、試薬用シリンジポンプ１１１の動作に伴って試薬の吸入動作、及び吐出動作を実行する。各サンプルのために分析すべき分析項目は、キーボード１２１、又はＣＲＴ１１８の画面のような入力装置から入力される。この自動分析装置における各ユニットの動作は、コンピュータ１０３により制御される。
【００２１】
サンプルディスク１０２の間欠回転に伴ってサンプル容器１０１はサンプル吸入位置へ移送され、停止中のサンプル容器内にサンプル分注プローブ１０５が降下される。その下降動作に伴って分注プローブ１０５の先端がサンプルの液面に接触すると液面検出回路１５１から検出信号が出力され、それに基づいてコンピュータ１０３がサンプリングアーム２の駆動部の下降動作を停止するよう制御する。次に分注プローブ１０５内に所定量のサンプルを吸入した後、分注プローブ１０５は上死点まで上昇する。分注プローブ１０５がサンプルを所定量吸入している間は、分注プローブ１０５とサンプル用ポンプ１０７流路間の吸引動作中の流路内圧力変動を圧力センサ１５２からの信号を用い圧力検出回路１５３で監視し、吸引中の圧力変動に異常を発見した場合は所定量吸引されていない可能性が高い為、当該分析データに対しアラームを付加する。
【００２２】
次にサンプリングアーム２が水平方向に旋回し反応ディスク１０９上の反応容器１０６の位置でサンプル分注プローブ１０５を下降し反応容器１０６内へ保持していたサンプルを吐出する。サンプルが入った反応容器１０６が試薬添加位置まで移動された時に、該当する分析項目に対応した試薬が試薬分注プローブ110から添加される。サンプル、及び試薬の分注に伴ってサンプル容器１０１内のサンプル、及び試薬ボトル１１２内の試薬の液面が検出される。サンプル、及び試薬が加えられた反応容器内の混合物は、攪拌器１１３により攪拌される。反応容器列の移送中に複数の反応容器が光源１１４からの光束を横切り、各混合物の吸光度、あるいは発光値が測定手段としての光度計１１５により測定される。吸光度信号は、Ａ／Ｄ変換器１１６を経由しインターフェース１０４を介してコンピュータ１０３に入り、分析項目の濃度が計算される。分析結果は、インターフェース１０４を介してプリンタ１１７に印字出力するか、又はＣＲＴ１１８に画面出力すると共に、メモリとしてのハードディスク１２２に格納される。測光が終了した反応容器１０６は、洗浄機構１１９の位置にて洗浄される。洗浄用ポンプ１２０は、反応容器へ洗浄水を供給すると共に、反応容器から廃棄を排出する。図１の例では、サンプルディスク１０２に同心円状に３列のサンプル容器１０１がセットできるように３列の容器保持部が形成されており、サンプル分注プローブ１０５によるサンプル吸入位置が各々の列に１個ずつ設定されている。
【００２３】
次に〔従来の技術〕にて記したが、異常吸引を検知する一具体例について図２を用い以下に説明する。図２に示す吸引動作前（停止）の圧力値を基準とし、吸引動作後（停止）の圧力値との相対変化量を算出し、図２の上側に示す波形の様に変化量がしきい値以下の場合は正常吸引が行われたと判断する。相反し図２の下側に示す波形の様に変化量がしきい値以上の場合はサンプルの粘性が非常に高い、或いはサンプル中のゴミなどの固形物により吸引動作中にサンプル分注プローブ１０５の先端が詰まる現象が発生し定量吸引されなかったと判断し、分析結果にアラームを付加する手法が一般的である。
【００２４】
次に〔発明が解決しようとする課題〕にて記したが、本発明が解決すべき内容の具体例について図３を用い以下に説明する。図３内の上側の波形は流路内に気泡が無い場合、つまり正常時の圧力波形を示す。一方、図３内の下側は流路内に気泡が存在した異常時の圧力波形をそれぞれ示す。次に前述の一般的な手法を用い吸引前後の圧力値を比較した場合、下側の波形、つまり流路内に気泡が存在した場合は気泡が緩衝材となり圧力の伝達を妨げ、吸引動作直後の立ち上がり波形が非常に緩やかに上昇する。或いは吸引停止後の圧力変動値が不安定となり図３に示す様にしきい値以上となる場合も想定され、結果的に吸引動作中にサンプル分注プローブ１０５の先端が詰まっていないにも拘わらず、詰まりが発生したと誤認識し当該検体に対しアラームが付加される可能性を有していた。よって本発明では前述詰まり検知機能の不安定要素となり得る流路内の気泡を検出する機能を提唱することにある。
【００２５】
以下に図面を用いて本発明の実施例を説明する。なお、図４〜図７は吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象とした気泡検出方法について説明するための図であるが、これは出願後の請求項の補正に伴い本発明の実施例ではなくなった。図８に示す吸引動作停止直後の圧力波形を監視範囲対象とした気泡検出方法が本発明の実施例である。
図４は吸引直後の一定差分検知圧力値を用いた気泡検出機能、図５は吸引直後の検知圧力値の固定時間単位での平均値を用いた気泡検出機能、図６は吸引直後の検知圧力値の移動平均値を用いた気泡検出機能、図７は吸引直後の検知圧力値の微分値を用いた気泡検出機能、図８は吸引停止直後の検知圧力値の変動周期幅を用いた気泡検出機能をそれぞれ示す。
【００２６】
図３に示す波形から容易に判断できるように気泡混入時の波形は気泡が圧力伝導の緩衝材として機能する為に正常時と比較し明らかに立ち上がりが遅い。流路内の気泡を検出する検知圧力値のデータ対象範囲としてプローブの吸引直後の圧力データが持つ本挙動を気泡検知の判定論理に活用することもできる。図４を用い本波形上の特異性を顕著に検出する一手法とし、吸引直後の検知圧力値の差分値を用いた気泡検出機能を説明する。
【００２７】
図４に示す正常吸引時、及び気泡混入時の各波形は図３に示したそれぞれの波形を２０ｍｓ前の値と比較しその差分を算出し示したものである。又、算出式としては下式を得る。
【００２８】
【数１】
Ｎ番目の差分圧力値：Ｐ_dif _N＝Ｐ_20*+N −Ｐ_N …（１）
（但し、１＜Ｎ＜２０＊の場合はＰ_dif _N＝Ｐ_N）
図４に示す波形から正常吸引時の波形は気泡混入時と比較し、明らかに最大変動時の波形高さが異なりピーク高は“正常吸引時”≫“気泡混入時”となる。つまり監視範囲内の差分圧力値を算出し、当該圧力のピーク値監視を監視範囲内で行い特定値（しきい値）を超過した場合は正常吸引、相反し一定値を超過しなかった場合は気泡混入と判断でき気泡混入と判断した時は当該分析検体に対しアラームを付加し、異常データ発生の可能性を防止する。
【００２９】
尚、図４に示す事例では現実的な装置上での適用例とし、検知圧力の取り込み周期は１ｍｓ周期サンプリング、更に２０ｍｓ間隔の差分幅で差分圧力値を算出した場合の一事例を示す。しかし、これらサンプリング周期、及び算出差分幅は装置として当該機能に要求される検出精度や装置での流路構成に伴い変化する圧力検出波形形状に依存し、当然固定値として扱われるものではなく、本発明を適用する装置により適宜最適化することが望ましい。
【００３０】
次に図５を用い吸引開始直後時の検知圧力の固定時間単位での平均値を用い、流路内の気泡を検出する機能を説明する。前述図４の説明と同様に図５に示す正常吸引時、及び気泡混入時の各波形は図３に示したそれぞれの波形を１０ｍｓ単位で収集した平均値を表したものである。図５に示す波形から正常吸引時の波形は気泡混入時と比較し、明確に最大変動時の波形が異なりピーク値は“正常吸引時”≪“気泡混入時”となる挙動を示し、前述図４で説明した場合とは逆の特性を示す。従い監視範囲内の固定時間単位での平均値を算出し、当該圧力のピーク値監視を監視範囲内で行い特定値（しきい値）を超過した場合は気泡混入、相反し一定値を超過しなかった場合は正常吸引と判断でき、本判定時は当該分析検体に対しアラームを付加し異常データ発生の可能性を防止する。算出式としては下式を得る。
【００３１】
【数２】

【００３２】
又、前述と同様に本説明で平均値を算出する為に用いた１０ｍｓの平均値幅は当然固定値として扱われるものではなく、本発明を適用する装置により適宜最適化することが望ましい。
【００３３】
次に図６を用い吸引開始直後時の検知圧力の移動平均値を用い、流路内の気泡を検出する機能を説明する。前述図４の説明と同様に図６に示す正常吸引時、及び気泡混入時の各波形は図３に示したそれぞれの波形を１０ｍｓ幅で算出した移動平均値を表したものである。図６に示す波形から正常吸引時の波形は気泡混入時と比較し最大変動時の波形が異なり、ピーク値は“正常吸引時”≪“気泡混入時”となる挙動を示し、前述図５で説明した場合と同様の特性を示す。従い監視範囲内の固定時間間隔での移動平均値を算出し、当該圧力のピーク値監視を監視範囲内で行いある特定値（しきい値）を超過した場合は気泡混入、相反し一定値を超過しなかった場合は正常吸引と判断でき、本判定時は当該分析検体に対しアラームを付加し異常データ発生の可能性を防止する。算出式としては下式を得る。
【００３４】
【数３】
ｎ番目の移動平均圧力値：Ｐ_move ＝Ｐ(ｎ＋１０)−Ｐｎ …（３）
又、前述同様本説明にて移動平均値算出する為に用いた１０ｍｓのパラメータは当然固定値として扱われるものではなく、本発明を適用する装置により適宜最適化することが望ましい。
【００３５】
次に図７を用い吸引開始直後時の検知圧力の微分値を用い、流路内の気泡を検出する機能を説明する。前述図４の説明と同様に図７に示す正常吸引時、及び気泡混入時の各波形は図３に示したそれぞれの波形を単位時間１ｍｓで算出した微分値を表したものである。図７に示す波形から正常吸引時の波形は気泡混入時と比較し吸引動作中の変動幅が異なり、ピーク値は“正常吸引時”≫“気泡混入時”となる挙動を示す。流路内の気泡がエアーダンパー、つまり緩衝材として機能する為に検知圧力波形そのものが高周波を遮断するフィルターを通過したような効果を受け、見かけ上リップル分が減少した波形となる。当該事例では本特徴を抽出すべく、当該圧力値の正負ピーク値監視を監視範囲内で行い、ある特定範囲（しきい値範囲）を超過した場合は正常吸引、相反し一定値を超過しなかった場合は気泡混入と判断し、気泡混入と判定時は当該分析検体に対しアラームを付加することにより、異常データ発生の可能性を防止する。算出式としては下式を得る。
【００３６】
【数４】
ｎ番目の微分圧力値：Ｐ_move ＝Ｐ(ｎ＋１)−Ｐｎ …（４）
又、前述同様本説明にて微分値を算出する為に用いた１ｍｓの単位時間は当然固定値として扱われるものではなく、本発明を適用する装置により適宜最適化することが望ましい。
【００３７】
次に図８を用い吸引停止直後時の検知圧力値を用い、流路内の気泡を検出する機能の一実施例を説明する。図８に示す正常吸引時、及び気泡混入時の各波形は図３に示した波形と同一波形を示す。図４〜図７までの事例は吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象としているが、図８を用いた事例では吸引動作停止直後の圧力波形を監視範囲対象と定義する。本範囲内での圧力波形の特異的な挙動は図８からわかるように正常吸引時の場合、吸引停止によるリバウンドとして数百ｍｓの間オーバーシュートが複数回発生する。
しかし、気泡混入時は図７の事例と同様に流路内の気泡がエアーダンパー、つまり緩衝材として機能し吸引停止によるリバウンドも同様に減衰され数百ｍｓ間のオーバーシュートは１回以下、すなわち半波（半周期）のみ発生する。当該事例では本特徴を抽出する手法として吸引停止直後数百ｍｓ間の圧力波形を監視し監視範囲内でのピーク値の回数、つまり変動周期長さを検出しピーク値が複数回以上存在し変動周期長が５０ｍｓ程度の場合は正常吸引、一方ピーク値が単数のみで変動周期長が１００ｍｓ以上の場合は気泡混入と判断できる。監視手法としては前述図４〜図７を用いた事例で示したように特定差分幅での差分圧力値，平均値，微分値等の換算値を用いることにより前述の実施例からわかるようにピーク値検出が容易であることは自明であり、変動周期長のしきい値も含め、圧力波形の加工手段を本実施例で限定すべきものではない。
【００３８】
次に前述の実施例において流路内の気泡を検出した場合は当該分析検体に対しアラームを付加し、オペレータに対し異常データ発生の可能性を伝えることを主な目的としていたが、流路内に気泡が存在し続けた場合は、当該分析検体のみならず引き続き分析される検体も同様に異常データ発生の可能性を有すことになり、結果的に装置の分析動作を中断し流路内の気泡を排出するメインテナンス動作の実行が必要となるケースが容易に推定できる。本実施例は気泡検出を認識した当該状態で装置としてリカバリー動作、つまり実行中である分析動作を中断させることなく、流路内の気泡を排出すべく流路水の置換動作を分析動作内のタイムチャートに自動的に組み込み、置換完了後にセルフチェックを行い正常と認識した場合に、自動的に分析動作に復帰するよう考慮されたタイムチャートを備える自動分析装置を提供することができる。
【００３９】
【発明の効果】
以上説明したように本発明によれば、流路内に気泡が混入した場合、気泡が緩衝材として機能する為に吸引動作中に詰まり検知機能が異常動作し、定量吸引できなくとも正常吸引完了と判定され結果的に分析結果異常となる可能性を有していたが、本発明を実施することにより、当該分析結果に対しアラームを付加し異常な分析結果の発生を大幅に抑制することが可能となる。
【００４０】
更に流路内の気泡混入を認識した場合に自動的に流路内の気泡排出動作を実行することにより、当該分析結果、及び引き続く分析検体に対し異常な分析結果の発生を自動的、且つ効率的に抑制することを可能とする。
【図面の簡単な説明】
【図１】本発明が適用される自動分析装置の全体構成を示す概略図。
【図２】検体プローブ吸引動作時の圧力波形。
【図３】気泡混入時の従来の検体プローブ吸引動作時の圧力波形。
【図４】吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象とした気泡検出方法について説明するための図（比較例）。
【図５】吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象とした気泡検出方法について説明するための図（比較例）。
【図６】吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象とした気泡検出方法について説明するための図（比較例）。
【図７】吸引動作前〜吸引動作開始直後の圧力波形を監視範囲対象とした気泡検出方法について説明するための図（比較例）。
【図８】本発明による一実施例（吸引停止後の波形監視）。
【符号の説明】
１…サンプリング機構、２…サンプリングアーム、１０１…試料容器、１０２…サンプルディスク、１０３…コンピュータ、１０４…インターフェース、１０５…サンプル分注プローブ、１０６…反応容器、１０７…サンプル用シリンジポンプ、１０９…反応ディスク、１１０…試薬分注プローブ、１１１…試薬用シリンジポンプ、１１２…試薬ボトル、１１３…攪拌器、１１４…光源、１１５…光度計、１１６…Ａ／Ｄ変換器、１１７…プリンタ、１１８…ＣＲＴ、１１９…洗浄機構、１２０…洗浄用ポンプ、１２１…キーボード、１２２…ハードディスク、１２５…試薬ディスク、１５１…液面検出回路、１５２…圧力センサ、１５３…圧力検出回路。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a dispensing apparatus having a function of dispensing a liquid from one container to another container using a dispensing probe, and is particularly connected to the same flow path as the dispensing probe in order to determine the normal end of the suction operation. The present invention relates to a dispensing device having a function of monitoring a signal output of a pressure sensor and an automatic analyzer having the same.
[0002]
[Prior art]
A conventional automatic analyzer dispenses a sample made of a biological sample such as blood or urine from a sample container to a reaction container on a reaction line, and measures a mixed solution of the sample and the reagent by a measuring means such as a photometer.
[0003]
During the dispensing operation, the tip of the dispensing probe is inserted into the liquid to be dispensed. As the penetration depth increases, the amount of liquid attached to the outer wall of the probe increases and contamination increases. Therefore, in order to reduce the penetration depth of the dispensing probe as much as possible, the liquid level of the liquid in the container is detected, and the descending operation of the probe is stopped at the position where the tip of the probe has reached slightly below the liquid level. Operation control is performed so as to suck a predetermined amount of liquid into the probe.
[0004]
Furthermore, during the liquid suction operation, in order to confirm that the expected amount of suction has been performed, check the pressure value in the flow path before and after suction, or during suction, to determine the predetermined amount due to factors such as clogging at the tip of the dispensing probe. A general technique is to detect the following suction, that is, the occurrence of suction abnormality.
[0005]
However, in general, the pressure sensor is connected to the same flow path as the dispensing probe and monitors the signal output of the pressure sensor. However, if the device is not used for a long period of time, dissolved oxygen will be present in the flow path water. There is a possibility that bubbles may be mixed in the flow path due to factors such as generation. In particular, if air bubbles accumulate around the detection part of the pressure sensor, the air bubbles function as a buffer for pressure conduction and normal pressure cannot be detected. Had. In other words, even if the quantitative suction could not be performed, it was recognized as normal and there was a risk that the analysis result would eventually become abnormal.
[0006]
For this reason, Japanese Patent Laid-Open No. 10-227799 discloses a method for detecting the presence of bubbles from a delay in the rise time of the output waveform of the pressure sensor, a decrease in change rate, and a decrease in peak value.
[0007]
[Problems to be solved by the invention]
In the technique described in Japanese Patent Laid-Open No. 10-227799, pressure sensors are provided in the vicinity of the nozzle and in the vicinity of the dispensing pump, respectively, and the presence of bubbles is recognized based on the pressure fluctuations of these pressure sensors. As shown in FIG. 4 of the specification, the pressure measurement time constant is increased and measured, and an average pressure value is used for determination.
[0008]
In such a method, there is a possibility that the presence of bubbles cannot be detected with high sensitivity when the dispensing amount is as small as the order of 10 μl. In addition, it may be difficult to secure a single digit% in dispensing accuracy.
[0009]
The objective of this invention is providing the dispensing apparatus which can ensure high dispensing precision with respect to a very small dispensing quantity, and an automatic analyzer using the dispensing apparatus.
[0010]
[Means for Solving the Problems]
The configuration of the present invention for achieving the above object is that the pressure in the pressure transmission pipe connecting the dispensing nozzle and the dispensing pump is detected by a highly sensitive measuring device with a small time constant, and an oscillation waveform proportional to the suction speed Is a dispensing device having a function of detecting the presence of bubbles by monitoring and monitoring the vibration period width or amplitude height during suction.
[0011]
By making the detection waveform highly sensitive, it is possible to detect an abnormal state of the apparatus, for example, a malfunction of the pressure sensor, a leak of the flow path (Leak), and the like.
[0012]
Further, by making the detection waveform highly sensitive, even a single pressure sensor can detect an abnormal state of the apparatus, for example, a malfunction of the pressure sensor, a leak (leak), or the like.
[0014]
Since the time constant is small and the sensitivity is high, overshoot is observed immediately after suction, undershoot immediately after suction stops, and an oscillation waveform proportional to the suction speed is observed even during suction. By analyzing the undershoot waveform immediately after Aspirate stop this, malfunction of the pressure sensor, it is possible to detect such flow path leakage (Leak).
[0015]
With this configuration, a dispensing amount of 10 to 50 ul and a dispensing accuracy of about 1% can be achieved, but with conventional techniques, a dispensing amount of several hundred ul to several ml and a dispensing accuracy of only about several tens of percent. Cannot be achieved.
[0016]
Further, in the present invention, a detectable bubble can be detected even with a diameter of about φ1 mm, but it has been difficult to detect about φ1 mm with the conventional technique.
[0017]
(Example)
Embodiments of the present invention will be described below in order from FIG.
[0018]
FIG. 1 is a schematic view of the periphery of a dispensing mechanism of a general automatic analyzer. Since the function of each part is well-known, detailed description is omitted. The sampling arm 2 of the sampling mechanism 1 moves up and down and rotates. Using the probe 105 attached to the sampling arm 2, the sample 7 in the sample container 101 arranged on the sample disk 102 rotating left and right is sucked and reacted. It is comprised so that it may discharge to the container 106. FIG. As can be seen from this figure, the sample container 101 is arranged on the sample disk 102 in a universal arrangement in which the sample container 101 can be placed directly on the sample disk 102 or the sample container 101 can be placed on a test tube (not shown). The thing of the structure which can respond is common.
[0019]
The configuration of the automatic analyzer in FIG. 1 will be further described. On the rotatable reagent disk 125, reagent bottles 112 corresponding to a plurality of analysis items to be analyzed are arranged. The reagent dispensing probe 110 attached to the movable arm dispenses a predetermined amount of reagent from the reagent bottle 112 to the reaction container 106.
[0020]
The sample dispensing probe 105 performs a sample suction operation and a discharge operation in accordance with the operation of the sample syringe pump 107. The reagent dispensing probe 110 performs a reagent inhaling operation and a discharging operation in accordance with the operation of the reagent syringe pump 111. The analysis items to be analyzed for each sample are input from an input device such as a keyboard 121 or a CRT 118 screen. The operation of each unit in this automatic analyzer is controlled by the computer 103.
[0021]
As the sample disk 102 rotates intermittently, the sample container 101 is transferred to the sample suction position, and the sample dispensing probe 105 is lowered into the stopped sample container. When the tip of the dispensing probe 105 comes into contact with the liquid level of the sample in accordance with the lowering operation, a detection signal is output from the liquid level detection circuit 151, and based on this, the computer 103 stops the lowering operation of the driving unit of the sampling arm 2. Control as follows. Next, after a predetermined amount of sample is inhaled into the dispensing probe 105, the dispensing probe 105 rises to the top dead center. While the dispensing probe 105 is sucking a predetermined amount of sample, the pressure detection circuit uses the signal from the pressure sensor 152 to detect the pressure fluctuation in the flow channel during the suction operation between the dispensing probe 105 and the sample pump 107 flow channel. When monitoring is performed at 153 and an abnormality is found in the pressure fluctuation during suction, an alarm is added to the analysis data because there is a high possibility that a predetermined amount has not been sucked.
[0022]
Next, the sampling arm 2 rotates in the horizontal direction, the sample dispensing probe 105 is lowered at the position of the reaction vessel 106 on the reaction disk 109, and the sample held in the reaction vessel 106 is discharged. When the reaction container 106 containing the sample is moved to the reagent addition position, a reagent corresponding to the corresponding analysis item is added from the reagent dispensing probe 110. As the sample and reagent are dispensed, the liquid level of the sample in the sample container 101 and the reagent in the reagent bottle 112 is detected. The sample and the mixture in the reaction vessel to which the reagent has been added are stirred by the stirrer 113. During the transfer of the reaction container row, a plurality of reaction containers cross the light beam from the light source 114, and the absorbance or luminescence value of each mixture is measured by a photometer 115 as a measuring means. The absorbance signal enters the computer 103 via the interface 104 via the A / D converter 116, and the concentration of the analysis item is calculated. The analysis result is printed out to the printer 117 via the interface 104 or output to the CRT 118 and stored in the hard disk 122 as a memory. After completion of photometry, the reaction vessel 106 is cleaned at the position of the cleaning mechanism 119. The cleaning pump 120 supplies cleaning water to the reaction container and discharges waste from the reaction container. In the example of FIG. 1, three rows of container holders are formed so that three rows of sample vessels 101 can be set concentrically on the sample disk 102, and the sample suction position by the sample dispensing probe 105 is in each row. One by one is set.
[0023]
Next, as described in [Prior Art], a specific example of detecting abnormal suction will be described below with reference to FIG. Based on the pressure value before (stop) the suction operation shown in FIG. 2, the relative change amount with the pressure value after (stop) the suction operation is calculated, and the change amount is the threshold as shown in the waveform shown in the upper side of FIG. If it is less than the value, it is determined that normal suction has been performed. In contrast, when the amount of change is equal to or greater than the threshold value as shown in the waveform shown in the lower part of FIG. Generally, there is a method in which a phenomenon that the tip of the tube is clogged occurs and it is determined that the quantitative suction is not performed, and an alarm is added to the analysis result.
[0024]
Next, although described in [Problems to be Solved by the Invention], a specific example of the contents to be solved by the present invention will be described below with reference to FIG. The upper waveform in FIG. 3 shows the pressure waveform when there is no bubble in the flow path, that is, when it is normal. On the other hand, the lower side in FIG. 3 shows a pressure waveform at the time of abnormality when bubbles exist in the flow path. Next, when the pressure values before and after suction are compared using the general method described above, if there is a bubble in the lower waveform, that is, in the flow path, the bubble acts as a cushioning material and prevents pressure transmission. The rising waveform rises very slowly. Alternatively, it may be assumed that the pressure fluctuation value after the suction stop becomes unstable and exceeds the threshold value as shown in FIG. 3, and as a result, the tip of the sample dispensing probe 105 is not clogged during the suction operation. Therefore, there is a possibility that an alarm may be added to the sample by erroneously recognizing that clogging has occurred. Therefore, the present invention proposes a function of detecting bubbles in the flow path that can be an unstable element of the clogging detection function.
[0025]
Embodiments of the present invention will be described below with reference to the drawings. 4 to 7 are diagrams for explaining the bubble detection method in which the pressure waveform before the suction operation and immediately after the start of the suction operation is the target of the monitoring range, this is accompanied by the correction of the claims after the application. It is no longer an embodiment of the invention. The bubble detection method in which the pressure waveform immediately after stopping the suction operation shown in FIG.
Figure 4 is a bubble detection function using a constant difference detection pressure value after absorption 引直, 5 bubble detection function using the average value of a fixed time unit for detecting the pressure value after absorption 引直, 6 intake bubble detection function using a moving average value of the sensed pressure value after 引直, 7 bubble detection function using a differential value of the detected pressure value after absorption 引直, 8 Aspirate stopped immediately after the detection pressure value shows the bubble detection function with fluctuation cycle width, respectively.
[0026]
As can be easily determined from the waveform shown in FIG. 3, the waveform at the time of bubble mixing is clearly slower than that at normal time because the bubble functions as a buffer for pressure conduction . This behavior of the pressure data immediately after suction of the probe as the data target range of the detected pressure value for detecting bubbles in the flow path can also be used for the determination logic of bubble detection . And one approach to significantly detect the specificity of the present waveform will be described using FIG bubble detection function using a difference value between the sensed pressure value after absorption引直.
[0027]
The waveforms at the time of normal suction and at the time of bubble mixing shown in FIG. 4 are obtained by comparing the respective waveforms shown in FIG. 3 with values before 20 ms and calculating the difference. Further, the following formula is obtained as a calculation formula.
[0028]
[Expression 1]
Nth differential pressure value: P _dif _N = P _{20 * + N} −P _N (1)
(However, when 1 < N < 20 *, P _dif _N = P _N )
From the waveform shown in FIG. 4, the waveform during normal suction is obviously different from the waveform height during maximum fluctuation, and the peak height is “normal suction” >> “when air bubbles are mixed”. In other words, if the differential pressure value within the monitoring range is calculated, the peak value of the pressure is monitored within the monitoring range, and if a specific value (threshold value) is exceeded, normal suction is performed. When it is determined that air bubbles are mixed, an alarm is added to the analysis sample to prevent the occurrence of abnormal data.
[0029]
The example shown in FIG. 4 is an example of application on a realistic apparatus, and shows an example in which a differential pressure value is calculated with a differential sampling interval of 1 ms as the sensed pressure capture period and a 20 ms interval. However, these sampling periods and calculated difference widths depend on the detection accuracy required for the function as a device and the pressure detection waveform shape that changes with the flow path configuration in the device, and are not treated as fixed values. It is desirable to optimize appropriately by the apparatus to which the present invention is applied.
[0030]
Then using the average value at fixed time units of sensed pressure at immediately after use I吸 pull start to FIG. 5, a function of detecting air bubbles in the flow path. Similar to the description of FIG. 4 described above, the waveforms at the time of normal suction and mixing of bubbles shown in FIG. 5 represent average values obtained by collecting the respective waveforms shown in FIG. 3 in units of 10 ms. From the waveform shown in FIG. 5, the waveform at normal suction is clearly different from that at the time of bubble mixing, and the waveform at the time of the maximum fluctuation is clearly different, and the peak value shows the behavior of “at normal suction” << “at the time of bubble mixing”. The characteristics opposite to those described in FIG. Therefore, the average value in the fixed time unit within the monitoring range is calculated, the peak value of the pressure is monitored within the monitoring range, and if a specific value (threshold value) is exceeded, air bubbles are mixed in, and contradictory, the constant value is exceeded. If not, it can be determined as normal aspiration, and at the time of this determination, an alarm is added to the analysis sample to prevent the possibility of abnormal data. The following formula is obtained as a calculation formula.
[0031]
[Expression 2]

[0032]
Further, as described above, the average value width of 10 ms used for calculating the average value in this description is not treated as a fixed value, and is preferably optimized as appropriate by the apparatus to which the present invention is applied.
[0033]
Then using the moving average of the sensed pressure at the time right after use I吸 pull start to FIG. 6, a function of detecting air bubbles in the flow path. Similar to the description of FIG. 4, the waveforms at the time of normal suction and at the time of bubble mixing shown in FIG. 6 represent moving average values obtained by calculating the respective waveforms shown in FIG. From the waveform shown in FIG. 6, the waveform during normal suction is different from that during bubble mixing, and the peak value shows a behavior of “normal suction” << “bubble mixing”. It exhibits the same characteristics as described. Therefore, the moving average value is calculated at fixed time intervals within the monitoring range, and the peak value of the pressure is monitored within the monitoring range. If it does not exceed, it can be determined that the suction is normal, and at the time of this determination, an alarm is added to the analysis sample to prevent the possibility of occurrence of abnormal data. The following formula is obtained as a calculation formula.
[0034]
[Equation 3]
n-th moving average pressure value: P _move = P (n + 10) −Pn (3)
Further, as described above, the 10 ms parameter used for calculating the moving average value in the present description is not treated as a fixed value, and it is desirable to optimize it appropriately by the apparatus to which the present invention is applied.
[0035]
Then using a differential value of the detected pressure during immediately after use I吸 pull start to FIG. 7, the functions of detecting the bubbles in the flow path. Similarly to the description of FIG. 4 described above, the waveforms at the time of normal suction and at the time of bubble mixing shown in FIG. 7 represent differential values calculated from the respective waveforms shown in FIG. 3 per unit time of 1 ms. From the waveform shown in FIG. 7, the waveform during normal suction shows a behavior in which the fluctuation range during the suction operation is different from that during bubble mixing, and the peak value is “normal suction” >> “bubble mixed”. Since the air bubbles in the flow path function as an air damper, that is, a buffer material, the detected pressure waveform itself has an effect that it has passed through a filter that cuts off high frequencies, so that the ripple is apparently reduced. In this case, in order to extract this feature, the positive / negative peak value of the pressure value is monitored within the monitoring range, and when it exceeds a certain range (threshold range), normal suction, contradictory and does not exceed a certain value If it is determined that air bubbles are mixed, an alarm is added to the analysis sample when it is determined that air bubbles are mixed, thereby preventing the occurrence of abnormal data. The following formula is obtained as a calculation formula.
[0036]
[Expression 4]
nth differential pressure value: P _move = P (n + 1) −Pn (4)
Further, as described above, the unit time of 1 ms used for calculating the differential value in the present description is not treated as a fixed value, and it is desirable to optimize appropriately by the apparatus to which the present invention is applied.
[0037]
Then using the sensed pressure value when immediately after use I吸 pull stop 8, a description will be given of an embodiment of a function of detecting the air bubbles in the flow path. Each waveform at the time of normal suction and mixing of bubbles shown in FIG. 8 shows the same waveform as that shown in FIG. 4 to 7, the pressure waveform before the suction operation to immediately after the start of the suction operation is the monitoring range target, but in the case using FIG. 8, the pressure waveform immediately after the suction operation is stopped is defined as the monitoring range target. As can be seen from FIG. 8, the specific behavior of the pressure waveform within this range causes overshoot multiple times for several hundreds of milliseconds as rebound due to the suction stop in the case of normal suction.
However, when air bubbles are mixed, the air bubbles in the flow path function as an air damper, that is, a buffer material as in the case of FIG. 7, and the rebound due to the suction stop is similarly attenuated, and the overshoot for several hundred ms is less than one time. Only half wave (half cycle) is generated. In this case, as a method to extract this feature, the pressure waveform for several hundreds of milliseconds is monitored immediately after stopping the suction, and the number of peak values within the monitoring range, that is, the fluctuation cycle length is detected. When the cycle length is about 50 ms, it can be determined that normal suction is performed. On the other hand, when the peak value is only one and the variation cycle length is 100 ms or more, it can be determined that air bubbles are mixed. As shown in the examples using FIGS. 4 to 7 as the monitoring method, the peak value as shown in the above-described embodiment can be obtained by using the converted values such as the differential pressure value, the average value, and the differential value in the specific difference width. It is obvious that the value can be easily detected, and the processing means for the pressure waveform including the threshold value of the fluctuation cycle length should not be limited in this embodiment.
[0038]
When detecting bubbles in the flow path in the above embodiments in the following by adding the alarm to the analysis sample, it was intended primarily to convey the possibility of abnormal data generated to the operator, the channel If air bubbles continue to exist, not only the sample to be analyzed but also the sample to be continuously analyzed has the possibility of abnormal data being generated. It is possible to easily estimate the case where the maintenance operation for discharging the bubbles is required. This embodiment recognizes the detection of bubbles, and the recovery operation as a device, that is, the operation of replacing the flow path water in order to discharge the bubbles in the flow path without interrupting the analysis operation being performed is included in the analysis operation. It is possible to provide an automatic analyzer that includes a time chart that is automatically incorporated into a time chart and that is considered to automatically return to the analysis operation when self-checking is performed after completion of replacement and it is recognized as normal.
[0039]
【The invention's effect】
As described above, according to the present invention, when bubbles are mixed in the flow path, the bubbles function as a cushioning material, so the clogging detection function operates abnormally during the suction operation, and normal suction is completed even if quantitative suction cannot be performed. However, by implementing the present invention, it is possible to add an alarm to the analysis result and greatly suppress the occurrence of the abnormal analysis result. It becomes possible.
[0040]
Furthermore, by automatically performing bubble discharge operation in the flow channel when it recognizes the inclusion of bubbles in the flow channel, the generation of abnormal analysis results for the analysis results and subsequent analysis samples automatically and efficiently Can be suppressed.
[Brief description of the drawings]
FIG. 1 is a schematic diagram showing the overall configuration of an automatic analyzer to which the present invention is applied.
FIG. 2 shows a pressure waveform during a sample probe aspirating operation.
FIG. 3 shows a pressure waveform during a conventional specimen probe suction operation when bubbles are mixed.
FIG. 4 is a diagram (comparative example) for explaining a bubble detection method in which a pressure waveform before a suction operation and immediately after the start of a suction operation is used as a monitoring range target ;
FIG. 5 is a diagram (comparative example) for explaining a bubble detection method in which a pressure waveform before a suction operation and immediately after the start of the suction operation is used as a monitoring range object ;
FIG. 6 is a diagram (comparative example) for explaining a bubble detection method in which a pressure waveform from before the suction operation to immediately after the start of the suction operation is used as a monitoring range object ;
FIG. 7 is a diagram (comparative example) for explaining a bubble detection method in which a pressure waveform from before the suction operation to immediately after the start of the suction operation is monitored .
FIG. 8 shows an embodiment according to the present invention (waveform monitoring after stopping suction).
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Sampling mechanism, 2 ... Sampling arm, 101 ... Sample container, 102 ... Sample disk, 103 ... Computer, 104 ... Interface, 105 ... Sample dispensing probe, 106 ... Reaction container, 107 ... Sample syringe pump, 109 ... Reaction Disc 110, reagent dispensing probe, 111 ... reagent syringe pump, 112 ... reagent bottle, 113 ... stirrer, 114 ... light source, 115 ... photometer, 116 ... A / D converter, 117 ... printer, 118 ... CRT DESCRIPTION OF SYMBOLS 119 ... Cleaning mechanism, 120 ... Cleaning pump, 121 ... Keyboard, 122 ... Hard disk, 125 ... Reagent disk, 151 ... Liquid level detection circuit, 152 ... Pressure sensor, 153 ... Pressure detection circuit

Claims

A nozzle immersed in the liquid to be sucked;
A dispensing pump for generating pressure for sucking the liquid sucked from the nozzle;
In a dispensing device comprising a pressure transmission pipe connecting the nozzle and the dispensing pump,
Measuring means for detecting the suction pressure inside the pressure transmission pipe,
Immediately after stopping the operation of sucking the liquid from the nozzle, the pressure waveform for several hundred ms is monitored, the number of peak values within the monitoring range is detected, and when the peak value exists more than once, normal suction, the peak value is A dispensing apparatus comprising a judging means for judging that air bubbles are mixed in the case of a single unit.

The dispensing device according to claim 1,
The dispensing apparatus according to claim 1, wherein the determination means determines that normal suction is performed when the fluctuation cycle length of the pressure waveform is about 50 ms, and that air bubbles are mixed when the fluctuation cycle length is 100 ms or more.

A dispensing device for dispensing the sample into the reaction vessel;
An analyzer for reacting a sample and a reagent in the reaction vessel and measuring the reaction;
In an automatic analyzer equipped with
The dispensing device is according to claim 1 or 2,
Furthermore, when the dispensing device detects the presence of bubbles, the automatic analyzer has a function of notifying the state that the sample cannot be quantitatively sucked into the dispensing probe as an alarm.

A dispensing device for dispensing the sample into the reaction vessel;
An analyzer for reacting a sample and a reagent in the reaction vessel and measuring the reaction;
In an automatic analyzer equipped with
The dispensing device is according to claim 1 or 2,
Furthermore, an automatic analyzer having a function of automatically performing an avoidance operation when it is recognized that the sample cannot be quantitatively sucked into the dispensing probe.