JP2004502926A - 濃度勾配をもたらすマイクロ流体用装置 - Google Patents

濃度勾配をもたらすマイクロ流体用装置 Download PDF

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JP2004502926A
JP2004502926A JP2001585928A JP2001585928A JP2004502926A JP 2004502926 A JP2004502926 A JP 2004502926A JP 2001585928 A JP2001585928 A JP 2001585928A JP 2001585928 A JP2001585928 A JP 2001585928A JP 2004502926 A JP2004502926 A JP 2004502926A
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fluid
channel
microfluidic device
inlet
concentration gradient
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．バットレル、シー．、フレデリック
バーデル、ロナルド、エル．
クライン、ジェラード、エル．
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マイクロニックス、インコーポレーテッド
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Abstract

マイクロ流体が流れるチャネル中に安定した濃度勾配を作り出す装置を提供する。可溶性化合物の所定濃度の溶液と希釈液とをチャネル中に投入する。これら２種の溶液の流速を変えることによって可溶性化合物の濃度をチャネル長さの関数として変化させることができる。
【選択図】図７

Description

【０００１】
【発明の属する技術分野】本発明は２０００年５月２４日に出願の米国特許出願第６０／２０１，８７８号に基づき優先権を主張する出願に係る。
【０００２】
本発明は分析試験を行うときに使うマイクロ流体用の装置に関する。より具体的にはチャネル中を流れる溶液の流速を変化させることによってチャネル中のマイクロ流体の濃度勾配を安定させる装置ならびに方法に関する。
【０００３】
マイクロ流体の装置は最近、分析試験を行うとき利用されるようになっている。電子部品を微小化するために半導体工業で開発されてきた種々の道具を使うことで、比較的廉価で複雑な流体システムを製造することもできるようになっている。こうしたシステムは医療分野における情報収集を目的とした種々の分析技術の必要性に押されて開発されてきた。
【０００４】
【従来の技術】米国特許第５，７１６，８５２号は、拡散原理を利用して流れる細胞中に微粒子が存在するか否かを分析し、存在するときはその濃度まで分析する方法に関する。この特許に言及したことでその内容を本明細書に取り込むものとするが、この特許はサンプルのストリーム中の被分析体である粒子の存否を検出するチャネルシステムに関し、指示薬のストリームとサンプルのストリームとを供給する少なくとも２個の取入口を備えた薄層フローのチャネルであって、これらストリームが薄層の流れとなるに十分な浅さと、検出域を形成するように指示薬のストリーム中に被分析体の粒子が十分拡散できる長さと、を備え、１本の混合した流れとなるように１個の出口を備えている。Ｔ形センサーと呼ばれるこの装置は指示薬ストリーム中の変化を検出する外的手段も備えている。こうした検出手段としては、例えば蛍光の光学分光学とか吸光分光学など光学手段の従来技術を使う。
【０００５】
米国特許第５，９３２，１００号は、この特許に言及したことでその内容を本明細書に取り込むものとするが、拡散原理を利用してマイクロ流体用のチャネル中の粒子を分析する別の方法を開示する。サンプルのストリーム中に懸濁している粒子の混合体が、装置の上方のアームからＨ形の微細なチャネルに構成された抽出チャネル中に入れられる。一方、抽出ストリーム（希釈ストリーム）が抽出チャネルの同じ側にある下方のアームから入れられるが、マイクロ流体用の抽出チャネルの細さのため流れは薄層となって、それらのストリームは混合しない。サンプルのストリームは抽出チャネルの端部の上方アームに副産物ストリームとして存在するが、抽出ストリームは下方アームに産物ストリームとして存在する。これらストリームが並行の薄層であるうちは流れは抽出チャネル中にあって、相対的に大きい拡散係数の粒子（アルブミン、糖、小イオンなど相対的に小さい粒子）が抽出ストリーム中に拡散する時間があるが、大きい粒子（血液細胞）はサンプルストリーム中に残る。出て行く抽出ストリーム（ここでは産物ストリームと呼ぶ）中の粒子は大きい粒子から干渉を受けることなしに分析することができる。このマイクロ流体用装置は一般にＨ形フィルタと呼ばれるが、所望の粒子を、それら粒子を含有するサンプルストリームから抽出するのに使うことができる。
【０００６】
こうしたマイクロ流体用装置は微細なチャネル中でさまざまな分析を行うのに拡散原理を利用している。しかし場合によっては検出域におけるある化合物の反応を決定する懸濁流れ中の物質をリアルタイムで分析することも有益である。この種の装置例が２０００年８月１日に発行の米国特許第６，０９６，５０９号に記載されている。そこでは流れる細胞の懸濁液に１個の試験化合物または一連の試験化合物の細胞反応をリアルタイムで測定する装置および方法が記載される。均質な懸濁液にされたさまざまな型の一連の細胞各々を試験化合物の集合体に混入して、その試験化合物の集合体中の細胞が検出域中を流れるときの細胞の反応をリアルタイムで測定するため検出域中を通過させている。
【０００７】
【発明が解決しようとする課題】本発明の目的は一つには、マイクロ流体の通るチャネル中に安定した濃度勾配を創出できる装置を提供することである。
【０００８】
また、溶液化合物の濃度がチャネル長さの関数として変化することができるように流速を変化させるマイクロ流体用の装置を提供することも目的とする。
【０００９】
さらに、薬物探索系に有用な濃度勾配の並行プロセスができる微細なチャネルシステムを提供することも目的とする。
【００１０】
これらの目的ならびにその他の目的も以下の詳細な説明から明らかになろう。
【００１１】
【課題を解決するための手段】上記の課題を解決するため本発明に係る濃度勾配をもたらすマイクロ流体用装置は、請求項１で、第１取入口及び第２取入口と第１出口とを有するマイクロ流体のためのチャネルと、前記第１取入口から前記チャネルに流し込む拡散性の組成物を含む第１流体と、該第１流体がチャネルの少なくとも一部分でチャネルと並行に流れるように前記チャネルに前記第２取入口から流し込む第２流体であって、前記第１流体と第２流体間に拡散境域を提供し、前記拡散性の組成物が前記第１流体から前記第２流体へ拡散性の種の濃度が前記拡散境域の軸方向に変化するようにしたものと、を有する。
【００１２】
また、請求項５で、第１取入口と第１溶液と、第２取入口と第１の可溶性化合物からなる第２溶液と、前記第１取入口および第２取入口に接続した第１チャネルと、拡散によって混合して前記第１チャネルの軸方向に濃度勾配を示すストリームを形成する前記第１チャネル中を互いに並行に流れる前記第１溶液と第２溶液と、前記第１取入口と第２取入口の下流に設けられる第３取入口であって、該第３取入口に微粒子物質含有の第３溶液を流し、該第３溶液と前記ストリームとが前記第３取入口の下流のチャネル部分で並行に流れるようにし、それによって前記微粒子物質を濃度勾配させるものと、を有する。
【００１３】
【発明の実施の形態】以下、本発明の実施の形態について図面を参照しながら説明する。
【００１４】
図１はＴ形センサ１０を示す。Ｔ形センサ１０の原理は米国特許第５７１６８５２号に詳述されている。センサー１０はサンプル取入口１２と、サンプルチャネル１４と、指示薬取入口１６と、指示薬チャネル１８とを有する。サンプルチャネル１４はフローチャネル２２の入り口にあるＴ形ジョイント部２０で指示薬チャネル１８と合流する。液体サンプルがサンプル取入口１２と指示薬取入口１６からそれぞれ入れられると、各スツリーム２４、２６は、サンプルチャネル１４および指示薬チャネル１８を経由してフローチャネル２２へ入る。各スツリーム２４、２６は、フローチャネル２２中のレイノルズ数のため並行に層流をなしてフローチャネル２２内を流れ、乱流は起こさない。フローチャネル２２は出口２８まで続く。サンプル取入口１２からの流速および指示薬取入口１６からの流速は一定で、したがって各スツリーム２４、２６もチャネル中を流速変化することなく同一速度で流れる。フローチャネル２２中で乱流が起こる唯一の原因はサンプルスツリーム２４から出る相対的に小さい粒子によってスツリーム２４、２６間の層境界を越える拡散が起こる場合である。センサー１０内の拡散が平衡に至り、サンプル取入口１２からの流速が一定で、かつ、指示薬取入口１６からの流速が一定であれば、フローチャネル２２は均一の溶液をもつことになり、フローチャネル２２中全域を通して濃度に過疎は存在しない。
【００１５】
マイクロ流体が流れるチャネル全域にわたる濃度勾配の形成状態を図２、図３、図４に示す。図２において、所定濃度の可溶性化合物の第１溶液５０を層５２ａ〜ｄを備えるマイクロ流体のチャネル５２に投入する。本実施例において第１溶液５０は層５２ｂと層５２ｃ間からチャネル５２に注入される。一方、溶液５４が層５２ａと層５２ｂ間から、及び層５２ｃと層５２ｄ間からの２カ所から投入される。溶液５４は両側から第１溶液５０に接触するが、第１溶液５０は可溶性化合物を含むから薄いリボン６０状になって、チャネル５２の幅全域に均一に分布する。
【００１６】
図３と図４はチャネル５２にわたる本実施例の拡散特性を示す。図３はある時間Ｘにおけるチャネル５２全域にわたる拡散をしめすチャネル５２の平面図であるが、矢印Ａ方向にチャネル５２中を混合した溶液が流れる。第１溶液５０から出た微粒子がチャネル５２の壁６２、６４に向けて拡散し始め溶液５０の両側に第１域６６、６６を形成、さらに第２域６８、６８を壁６２、６４との間に形成する。図４は時間Ｘｉ＋１におけるチャネル５２の状態を示すが、チャネル５２全域にわたって均一になった溶液７０が同じく矢印Ａ方向に流れていて、拡散がチャネルの幅方向にわずか数秒という短時間のうちに急速に行われたことを示している。
【００１７】
流体の濃度勾配はマイクロ流体を流す装置の主チャネルの長さ方向に安定していることがしばしば求められる。こうした濃度は生物材料や化学材料の濃度に関する効果を上手に測定するときに利用することができる。安定した濃度勾配を作り出すのは可溶性化合物を含む溶液とか希釈液を含む溶液、あるいはこれら双方を含む溶液中の流速を変化させることで行う。これら溶液の流速比を変えることで、チャネル中の可溶性化合物の濃度をチャネル長さの関数として変えることができる。
【００１８】
チャネル中の濃度勾配例を図９に示す。図９は図２のチャネル５２の下流の状態を示すが、溶液５０と溶液５４との流速比は一定ではない。チャネル５２中の箇所８０で濃度勾配が作り出されていることが分かる。このようにチャネル５２中の幅方向での拡散は数秒のうちに起こるが、チャネルの軸方向での拡散は非常に長時間をかけて起こる。
【００１９】
図５は、１００ｍｍのチャネル長さにわたる材料５００ＭＷの拡散状態を示すグラフである。濃度は１時間かけて実質的に安定したこと、濃度勾配はチャネル５２の軸方向において非常に安定していることが分かる。次に図６は同じ１００ｍｍのチャネル長さにわたる１箇月間（７２０時間）の濃度を示すグラフである。これほど長い期間になるとほとんど何も変化がない。つまり本発明の濃度勾配は非常に安定していることが分かる。
【００２０】
図１０は図９のチャネル中の複数溶液間の流速比を示す。図１０は図２のチャネル５２の下流の状態を示すが、２種類の溶液の流速比が定期的に、例えばシヌソイド的に（正弦波的に）変化している。濃度勾配は箇所９０に見られるようにシヌソイド的に変化する。
【００２１】
安定した濃度勾配を用いる分析サンプルのマイクロ流体の一体型回路を図７に示す。図７は本発明の原理に係る回路１００である。可溶性化合物を含む溶液１０２が図２に示したような希釈液１０６の層中に主チャネル１０４から注入される。希釈液１０６及び／又は可溶性化合物溶液１０２のいずれの流速も、チャネル１０４中の箇所１１０に見られるような濃度勾配を確立するために変化させられる。生物材料１１２が、チャネル１０４から注入されてこの濃度勾配中に入る。生物材料１１２はチャネル１０４中を流れてその濃度勾配と相互に反応することができ、第１の測定域１１４または、好ましくはこの第１測定域１１４における測定値との差を検出できるようにされている第２の測定域１１６、で検出される。
【００２２】
図７に示す回路１００の原理は、薬物探索系として使用し得る濃度勾配マイクロ流体の並行プロセスシステムに適用することができる。図８は可溶性組成物を複数本の希薄化溶液ストリーム［ｄｉｌｕｔｉｎｇ ｓｏｌｕｔｉｏｎ ｓｔｒｅａｍｓ］１３４中に並行に注入する複数本の並行なチャネル１３２を備える系１３０を示す。チャネル１３２の下流には濃度勾配が成立するが、各チャネル１３２に生物材料１３６または化学材料１３６を注入し、２本のセンサー１４０が相互作用域１４２内における結合または結合阻害の状態をモニターして、チャネル１３２中に含まれる特定の細胞もしくはタンパク質に対する効果を決定するようにしている。この実施例は、マイクロリットルフォーマット（８×１０）を使う薬物探索系に簡単に適用でき、１個のチップの上に作ることができる。
【００２３】
以上のように本発明の好ましい実施例をいくつか説明してきたが、本発明はそれら実施例の範囲に限定されるものではなく、本発明の精神に則り特許請求の範囲に記載の事項にまで広く及ぶものであることを理解されたい。
【図面の簡単な説明】
【図１】Ｔ形センサのマイクロ流体フローチャネル中の流体の流れを示す概念図。
【図２】本発明におけるチャネルの断面図。
【図３】チャネル全体にわたる拡散を示す本発明のチャネルの平面図。
【図４】図３のチャネルの一定時間経過後の平面図。
【図５】チャネルの軸方向に物質が拡散した１時間の状態を示す斜視図。
【図６】チャネルの軸方向に物質が拡散した１カ月間の状態を示す斜視図。
【図７】本発明の原理を利用したマイクロ流体の集積回路の概念図。
【図８】本発明の原理を利用したマイクロ流体の並列チャネルプロセス装置の概念図。
【図９】チャネルへ入る溶液の流速変化が作り出す濃度勾配を示すチャネルの部分図。
【図１０】チャネルへ入る溶液の流速の定期的変化が作り出す濃度勾配を示すチャネルの部分図。

Claims (17)

  1. 第１取入口及び第２取入口と第１出口とを有するマイクロ流体のためのチャネルと、
    前記第１取入口から前記チャネルに流し込む拡散性の組成物を含む第１流体と、
    該第１流体がチャネルの少なくとも一部分でチャネルと並行に流れるように前記チャネルに前記第２取入口から流し込む第２流体であって、前記第１流体と第２流体間に拡散境域を提供し、前記拡散性の組成物が前記第１流体から前記第２流体へ拡散性の種の濃度が前記拡散境域の軸方向に変化するようにしたものと、
    を有することを特徴とする濃度勾配をもたらすマイクロ流体用装置。
  2. 相互反応が拡散性の種の異なる濃度によって異なる測定結果を示すように、前記第２流体が前記第１流体の拡散性の組成物と相互反応する粒子を含むことを特徴とする請求項１に記載の濃度勾配をもたらすマイクロ流体用装置。
  3. 前記チャネルへの第３流体取入口と、前記第１流体および第３流体が前記第２流体を両側で囲み拡散性の組成物が該第２流体中に拡散するように第３流体取入口からチャネルへ入る拡散性の組成物を有する第３の流体と、このようにして前記第２流体の濃度が前記第１流体および第２流体が互いに接触する前記チャネルの箇所から離れるにつれて徐々に減少していくようにしたことを特徴とする請求項１に記載の濃度勾配をもたらすマイクロ流体用装置。
  4. 前記第１流体と第３流体とが、同一の取入口から前記第１流体取入口と第３流体取入口へ導入されるようにしたことを特徴とする請求項４に記載の濃度勾配をもたらすマイクロ流体用装置。
  5. 第１取入口と第１溶液と、
    第２取入口と第１の可溶性化合物からなる第２溶液と、
    前記第１取入口および第２取入口に接続した第１チャネルと、
    拡散によって混合して前記第１チャネルの軸方向に濃度勾配を示すストリームを形成する前記第１チャネル中を互いに並行に流れる前記第１溶液と第２溶液と、
    前記第１取入口と第２取入口の下流に設けられる第３取入口であって、該第３取入口に微粒子物質含有の第３溶液を流し、該第３溶液と前記ストリームとが前記第３取入口の下流のチャネル部分で並行に流れるようにし、それによって前記微粒子物質を濃度勾配させるものと、
    を有することを特徴とする粒子を濃度勾配させるマイクロ流体用装置。
  6. １個のチップ上に前記マイクロ流体装置の複数を設けたことを特徴とする請求項５に記載の粒子を濃度勾配させるマイクロ流体用装置。
  7. 前記チップ上に設けたマイクロ流体装置内に差異を測定する測定域を設けたことを特徴とする請求項６に記載の粒子を濃度勾配させるマイクロ流体用装置。
  8. 前記第１流体と前記第２流体の流速が一定に維持されることを特徴とする請求項１に記載の濃度勾配をもたらすマイクロ流体用装置。
  9. 前記第１流体の流速が前記第２流体の流速に対して変化するようにしたことを特徴とする請求項１に記載の濃度勾配をもたらすマイクロ流体用装置。
  10. 前記拡散性の組成物が可溶性化合物からなることを特徴とする請求項１に記載の濃度勾配をもたらすマイクロ流体用装置。
  11. 前記微粒子物質が生物材料を含むことを特徴とする請求項５に記載の粒子を濃度勾配させるマイクロ流体用装置。
  12. 前記生物材料が細胞を含むことを特徴とする請求項１１に記載の粒子を濃度勾配させるマイクロ流体用装置。
  13. 前記生物材料がタンパク質を含むことを特徴とする請求項１１に記載の粒子を濃度勾配させるマイクロ流体用装置。
  14. 前記ストリームと前記第３溶液中の微粒子物質との反応を測定する感知手段を備えたことを特徴とする請求項５に記載の粒子を濃度勾配させるマイクロ流体用装置。
  15. 前記粒子がタンパク質の分子を含むことを特徴とする請求項２に記載の濃度勾配をもたらすマイクロ流体用装置。
  16. 前記粒子が不可溶性の大きな粒子を含むことを特徴とする請求項２に記載の濃度勾配をもたらすマイクロ流体用装置。
  17. 前記不可溶性の大きな粒子がマイクロビーズを含むことを特徴とする請求項１６に記載の濃度勾配をもたらすマイクロ流体用装置。
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