JP2017518503A - 流体チップにおいてビーズを分離する方法 - Google Patents
流体チップにおいてビーズを分離する方法 Download PDFInfo
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- JP2017518503A JP2017518503A JP2016572749A JP2016572749A JP2017518503A JP 2017518503 A JP2017518503 A JP 2017518503A JP 2016572749 A JP2016572749 A JP 2016572749A JP 2016572749 A JP2016572749 A JP 2016572749A JP 2017518503 A JP2017518503 A JP 2017518503A
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Abstract
Description
− 粒子は、非常に大きな表面対体積比を有する。
− 粒子は、バッチにおいて効率的に官能化され、ゆえに均一な懸濁液を形成するように混合することができる。
− 粒子の懸濁液は、直接液体形態で用いることができるようにアリコートに分配することができ、又は錠剤若しくは凍結乾燥した球等、乾燥したアリコートとして配合することができる。
− 粒子は、粒子に明確な特徴を付与する材料が投入されていても、又は明確な特徴を付与する材料から作られていてもよい。これには、光吸収、光散乱、光放射(発光)等の明確な光学的特徴、並びに磁性、放射能、触媒/酵素、電気化学的、及びその他の測定可能な特徴が含まれる。
− 粒子は、懸濁液中にある場合、マイクロ流体系内に運搬され得る。
− 粒子は、溶液中の試料と効率的に混合することができる。
− 懸濁液中の粒子は、重力、遠心分離、ろ過、磁力(磁性粒子)、若しくは電気力、又はこれらの組合せによって溶液から分離することができる。
− 粒子は、粒子を分散させた媒体に対する密度に応じて、沈降し、懸濁液中に留まり、又は浮遊し得る。
− 粒子は、単分散にすることができ、多孔性、又は孔のない滑らかな固体表面を有する両方の完全な球体にすることができる。
− 粒子は、カラムを含めた様々な容器中に充填しても、又は積層させてもよい。
− 粒子は、不透明(着色)でも、又は実質的に透明で様々な光学ベースの測定系における互換性及び使用を許容してもよい。
− 緻密な単分散粒子をカラム等におけるフィルタ上に積層する場合、これらは規則的で規定された間隔を有する多孔性の格子構造体を形成し得る。液体は、このようなカラムを介して、制御され、再現性のよい様式で流れることができる。
a)少なくとも、密度m1を有する第1のセットのビーズ及び密度m2を有する第2のセットのビーズを、流体回路のセクションにおいて提供する工程であって、セクションは少なくとも第1の出口を含む工程と、
b)第1の液体媒体をセクションにおいて提供する工程であって、液体媒体は、m1<d3<m2であるように密度d3を有する工程と、
c)第1のセットのビーズ及び第2のセットのビーズがセクション内で反対方向に遊走するように、第1の遠心力を加える工程と
を含む、方法を提供する。
d)第2の液体媒体をセクションにおいて提供する工程であって、第2の液体媒体は、密度d4<m1、m2を有する工程と、
e)第1のセットのビーズが第2のセットのビーズに向かって遊走し、第1のセットのビーズ及び第2のセットのビーズの隣接層における積層をもたらすように遠心力を加える工程と
を含む。
f)第3の液体媒体をセクションにおいて提供する工程であって、第3の液体媒体は、密度d5<m1、m2、m3を有する工程と、
g)第3のセットのビーズが第1のセットのビーズに向かって遊走し、第1のセットのビーズ及び第3のセットのビーズの隣接層における積層をもたらすように遠心力を加える工程と
を含む。
セクションにおいて提供する液体媒体が、粒子保持エレメントを介して流れて、第1のセットのビーズ及び第2のセットのビーズ又は第1のセットのビーズ及び第3のセットのビーズの隣接層における積層を得るように遠心力を加える工程
を含む。
好ましくは第1のセットのビーズが第1の出口を介してデカントされるように、第1のセットのビーズを、遠心力の方向を変えることによってセクションの外へ移送し、第2のセットのビーズは前記セクションに留まる工程
を含む。
第1のセットのビーズが第1の出口を介して移送され、第2のセットのビーズが第2の出口を介して移送されるように、遠心力の方向を変える工程
を含む。
第2の液体媒体をセクションに提供する工程であって、液体媒体は密度d4>m2を有する工程と、
第2のセットのビーズが、遠心力の方向と反対の方向に遊走するように、遠心力を加える工程と
を含む。
好ましくは第2のセットのビーズが第1の出口を介してデカントされるように、第2のセットのビーズを、遠心力の方向を変えることによって、セクションの外へ移送する工程
を含む。
本出願において、「流体チップ」の語は、内部流体回路を含む、あらゆるタイプのチップ又はカートリッジであって、内部流体回路を介して、ビーズ、及び少なくとも1つの分析物を含有する試料を含む様々な反応物が、遠心力を使って移動することができる、チップ又はカートリッジを包含するものとされる。流体回路において様々な反応物が、液体媒体と一緒に、及び/又は液体媒体内を移動することができる。
本発明は、流体又はマイクロ流体チップ又はカートリッジにおいて、異なる密度のビーズ又は固相粒子を分離するための単純な方法に関する。分離方法は、以下に記載するもの等の分析アッセイと組み合わせるのが有利であり得る。開示する分析方法では、第1の溶液中の反応物と、固相粒子の表面に付着している反応物との間の非常に効率的な相互作用を、第2の溶液を用いて固相粒子を懸濁液にすることにより、非常に効率的な固相粒子の洗浄と組み合わせる。
分析方法の模式図を図1a〜図1kに示す。方法は、1つ又は複数の対象の分析物に関して、試料を分析しようとするものである。方法は、液体中に溶解され得るあらゆるタイプの試料に適し、このような分析を行うためのアッセイに提供することができる前記試料中のあらゆるタイプの化合物又は物質を検出/定量するのにも適する。
図1a〜図1kに記載する分析方法では、方法を、一度に1つの分析物を分析するものとして示す。しかし、本発明による分離方法を用いることにより、分析方法は、一度にたった1つの分析物を分析することに制限されない。
ビーズの運搬に関して、本開示は、本発明による方法に依存せず、本発明による方法の本質的な部分でもない、本発明の概念を表すものである。概念の一実施形態を図1l〜図1pに開示する。概念は、マイクロ流体チップ等のラボチップ装置に関して本質的に関係がある問題を解決するものであり、この場合、ビーズは、遠心力を使って流体回路を介して運搬されなければならない。従来技術では、ビーズの運搬は常に、遠心力と同じ方向で行われ、流体回路のデザインに利用できる選択肢は、よって限られる。本発明の概念により、密度d2を有する液体媒体を、m1に等しく、又はm1より低い密度を有するビーズに添加することにより、加える遠心力と反対の方向にビーズを運搬することができ、この場合d2>m1である。
内部流体回路を含む流体チップであって、内部流体回路を介して、ビーズ、及び少なくとも1つの分析物を含有する試料を含む様々な反応物が遠心力を使って移動することができる、流体チップにおいてビーズを移送する方法であって、
− m1に等しく、又はm1より低い密度を有するビーズを、流体回路の空洞において提供する工程であって、空洞は少なくとも第1の出口を含む工程、
− 第1の液体媒体を空洞に提供する工程であって、液体媒体は、d2>m1であるように、密度d2を有する工程、及び
− ビーズが遠心力の反対方向に遊走するように、遠心力を加える工程
を含む方法。
− 好ましくはビーズが第1の出口を介してデカントされるように、遠心力の方向を変えることによってビーズを空洞の外に移送する工程
を含む。
2 第1の出口
3 第2の出口
4 入口
5 第1のフィルタエレメント
6 第2のフィルタエレメント
7 カラム構造体、カラム形状の空洞
8 ビーズ
8a 第1のセットのビーズ
8b 第2のセットのビーズ
8c 第3のセットのビーズ
9 トレーサー物質
10 第2のカラム形状の空洞
11 液体媒体
12 入口
13 第1の出口
14 第2の出口
15 空洞
16 第1の出口
17 第1の出口
19 フィルタエレメント
20 分離セクション
21 積層セクション
22 第1の終端
23 第2の終端
24 第1の液体媒体
25 高密度の液体媒体
26 第2の液体媒体
Claims (20)
- 内部流体回路を含む流体チップであって、その内部流体回路を介して、反応物の少なくとも1つがビーズである様々な反応物が、遠心力を使って移動され得る、流体チップにおいてビーズを分離する方法であって、
a)少なくとも、密度m1を有する第1のセットのビーズ(8a)及び密度m2を有する第2のセットのビーズ(8b)を、前記流体回路のセクション(7、15、18)において提供する工程であって、前記セクションは少なくとも第1の出口(16、13、17)を含む工程と、
b)第1の液体媒体を前記セクションにおいて提供する工程であって、前記液体媒体は、m1<d3<m2であるように密度d3を有する工程と、
c)前記第1のセットのビーズ(8a)及び前記第2のセットのビーズ(8b)が前記セクション内で反対方向に遊走するように、第1の遠心力(G)を加える工程と
を含む方法。 - 前記第2のセットのビーズ(8b)が、任意選択により、前記セクションに対する方向が前記第1の遠心力と異なる第2の遠心力を加えた後、前記セクションに配置される粒子保持エレメントに向かって遊走し、前記粒子保持エレメント上に前記第2のセットのビーズの層を形成する、請求項1に記載の方法。
- d)第2の液体媒体を前記セクションにおいて提供する工程であって、前記第2の液体媒体は、密度d4<m1、m2を有する工程と、
e)前記第1のセットのビーズ(8a)が前記第2のセットのビーズ(8b)に向かって遊走し、前記第1のセットのビーズ及び前記第2のセットのビーズの隣接層における積層をもたらすように遠心力(G)を加える工程と
を含む、請求項1又は2に記載の方法。 - 工程a)において、密度m3<d3、d4を有する第3のセットのビーズ(8c)を提供する、請求項1から3のいずれか一項に記載の方法。
- f)第3の液体媒体を前記セクションにおいて提供する工程であって、前記第3の液体媒体は、密度d5<m1、m2、m3を有する工程と、
g)前記第3のセットのビーズ(8c)が前記第1のセットのビーズ(8a)に向かって遊走し、前記第1のセットのビーズ及び前記第3のセットのビーズの隣接層における積層をもたらすように遠心力(G)を加える工程と
を含む、請求項4に記載の方法。 - 前記セクションにおいて提供される前記液体媒体が、粒子保持エレメントを介して流れて、前記第1のセットのビーズ及び前記第2のセットのビーズ又は前記第1のセットのビーズ及び第3のセットのビーズの隣接層における積層を得るように遠心力(G)を加える工程
を含む、請求項2又は4に記載の方法。 - 前記第1のセットのビーズ(8a)が前記第1の出口(16、13)に向かって遊走する、請求項1に記載の方法。
- 好ましくは前記第1のセットのビーズ(8a)が前記第1の出口(16、13)を介してデカントされるように、前記第1のセットのビーズ(8a)を、前記遠心力(G)の方向を変えることによって前記セクション(7、15)の外へ移送し、前記第2のセットのビーズ(8b)は前記セクションに留まる工程
を含む、請求項7に記載の方法。 - 前記セクション(15)が第2の出口(14)を含み、
前記方法が、前記第1のセットのビーズ(8a)が前記第1の出口(13)を介して移送され、前記第2のセットのビーズ(8b)が前記第2の出口(14)を介して移送されるように、前記遠心力(G)の方向を変える工程を含む、
請求項7に記載の方法。 - 第2の液体媒体を前記セクションに提供する工程であって、前記液体媒体は密度d4>m2を有する工程と、
前記第2のセットのビーズ(8b)が、前記遠心力の方向と反対の方向に遊走するように、遠心力(G)を加える工程と
を含む、請求項8に記載の方法。 - 好ましくは前記第2のセットのビーズ(8b)が前記第1の出口(16)を介してデカントされるように、前記第2のセットのビーズを、前記遠心力(G)の方向を変えることによって前記セクションの外へ移送する工程
を含む、請求項10に記載の方法。 - 前記セクションが、分離セクション及び積層セクションを含む、請求項1から6のいずれか一項に記載の方法。
- 前記積層セクションが、第1の終端で前記分離セクションに接続され、第2の終端で粒子保持エレメントを含む、請求項12に記載の方法。
- 工程c)が前記分離セクションにおいて行われる、請求項12又は13に記載の方法。
- 前記セクションに対する第2の遠心力の方向が、前記第1の遠心力の方向と異なる、請求項14に記載の方法。
- 前記流体チップがマイクロ流体チップである、請求項1から15のいずれか一項に記載の方法。
- 前記流体チップが、前記セクションに対して可変の方向を有する遠心力を提供することができる遠心機に配置されている、請求項1から16のいずれか一項に記載の方法。
- 前記第2のセットのビーズ(8b)における前記ビーズが、シリカビーズ、好ましくは不活性なシリカビーズである、請求項1から17のいずれか一項に記載の方法。
- 粒子保持エレメントがフィルタである、請求項1から18のいずれか一項に記載の方法。
- 前記反応物が、1つ又は複数の分析物を含有する試料を含む、請求項1から19のいずれか一項に記載の方法。
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