JP6317309B2 - ナノリアクターの形成および制御において使用するマイクロ流体デバイスおよび方法 - Google Patents
ナノリアクターの形成および制御において使用するマイクロ流体デバイスおよび方法 Download PDFInfo
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
- C12N15/1075—Isolating an individual clone by screening libraries by coupling phenotype to genotype, not provided for in other groups of this subclass
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Description
本発明は、一般に、流体種の形成および/または制御のためのシステムおよび方法、そのようなシステムおよび方法によって生産された製品に関する。さらに詳しくは、本発明は、正確な流体取扱のための高スループットマイクロ流体デバイスの開発、および種々の生物学的、化学的、または診断アッセイにおけるそのようなシステムの使用に関する。
高スループット分子スクリーニング(HTS)は、生物学的メカニズムまたは病気の細胞モデルにおける、または生化学または薬理学アッセイにおける、数千の区別される小さな分子またはプローブの自動迅速テストである。HTSを介して同定された活性な化合物は、化学的遺伝子アプローチを通じて生物学的プロセスを解明するための強力なリサーチツールを提供することができ、あるいは治療剤またはイメージング剤開発プログラムの基礎を形成できる。HTSは、分子生物学およびコンビナトリアル化学、および近代の情報管理システムの取込以来、技術の革新的変化を経験してきた。現在のHTSインストルメンテーションは、10年前に可能であったよりも桁違いに速い速度で、1日における数十万の化合物のスクリーニングを可能とする。しかしながら、(a)化合物収集維持、追跡、および分配、および(b)アッセイインストルメンテーションの迅速性、正確性および内容のような、HTS能力を現在制限する障害が依然として存在する。
K=(ε* p−ε* m)/(ε* p+2ε* m)
の実数部分であって、ε* pおよびε* mは小滴および担体流体の複素誘電率である)。
本発明は、細胞、核酸、酵素、コードされたマイクロビーズ、および他の生体物質とのまれな相互作用について分子ライブラリーを通じてサーチするのに必須である、単離された化合物の多−工程処理を行うように、流体処理システムに組み合わせることができる個々の流体取扱モジュールを有するデバイスを提供する。直径が20〜100ミクロンの荷電した、および中性の小滴の静電および誘電泳動操作に基づく原理を用い、本明細書中に記載されるマイクロ流体デバイスは試薬を安価にカプセル化し、それを組み合せ、分析し、および日当たり1×109小滴の範囲で分類できる。本発明は、微細加工基材を含むマイクロ流体デバイスを提供する。該基材は、流体連絡するように相互に対して一体的に配置された複数の電気的にアドレス可能なチャネル担持マイクロ流体モジュールを含むことができる。微細加工基材は、例えば、(i)分散した相流体を運ぶのに適合させた少なくとも1つの入口チャネルを有する1以上の入口モジュール、(ii)連続的相流体を運ぶのに適合させた少なくとも1つの主要チャネル、ここで、該入口チャネルは、該分散した相流体が連続相流体と非混和性であって、連続相流体中で複数の小滴を形成するように、主要チャネルと流体連絡しており、および(iii)主要チャネルを介して入口モジュールから下流の、かつ該モジュールと流体連絡した凝集モジュール、ここで、そこを通る2以上の小滴は凝集してナノリアクターを形成する。本発明のマイクロ流体デバイスは、さらに、ソーティングモジュール、混合モジュール、遅延モジュール、UV−放出モジュール、検出モジュール、収集モジュール、廃棄モジュール、および/または音響アクチュエーター、および/またはその組合せをいずれかの順序で含むことができる。これらのモジュールは主要チャネルと流体連絡している。分散相および連続相の流動は、例えば、圧力で駆動することができる。
本明細書中に記載されたマイクロ流体デバイスおよび使用方法は、不活性フルオロカーボン油ストリームによって完全にカプセル化された水性相小滴の作成および電気的操作に基づく。この組合せは、電気的にアドレス可能な小滴の創製、高度に有効な小滴の凝集、正確な小滴破壊および再荷電、および制御可能な単一小滴ソーティングを可能とする。さらなる受動的モジュールは多−ストリーム小滴処方、混合モジュール、および精度破壊モジュールを含む。これらのモジュールの一体化は、小滴ベースの高スループットマイクロ流体リアクターシステムのための必須の実施化技術である。本発明のマイクロ流体デバイスは、流動−フォーカシング幾何学を用いて、小滴を形成することができる。例えば、水ストリームは狭い収縮を通じて1つのチャネルから注入することができ;反対増殖油ストリーム(好ましくは、フッ素化油)は水力学的に水ストリームに焦点を当て、それが収縮を通るに連れてミクロンサイズ小滴への破壊を安定化させる。小滴を形成するために、油によって水ストリームに適用された粘性力は水の表面張力に打ち勝たなければならない。生成速度、水小滴のスペーシングおよびサイズは、油および水ストリームの相対的流速、およびノズルの幾何学によって制御される。この乳化技術は極端に頑強であるが、小滴のサイズおよび速度は流体流動速度およびチャネル寸法に密接にカップリングされる。さらに、小滴生産のタイミングおよび相は制御することができない。これらの制限を克服するために、本発明のマイクロ流体デバイスは一体化された電場を取り込むことができ、それにより、電気的にアドレス可能な乳化系を作り出すことができる。1つの実施形態態様において、これは、高い電圧を水性ストリームに適用することによって達成することができ、油水界面を荷電することができる。水ストリームは導体として挙動し、他方、油は絶縁体であり;電気化学的反応はキャパシターのように流体界面を荷電する。スナップ−オフにおいて、界面の電荷は小滴に残る。小滴のサイズは場の強さを増大させるにつれて減少する。低い印加電圧において、電場は無視できる効果を有し、小滴形成は、前記したように、表面張力および粘性流油の間の競合によって専ら駆動される。本発明のマイクロ流体小滴−ベースの反応−封じ込め系は、さらに、2以上の試薬を組合せて、化学反応を開始させるミキサーを含むことができる。多−成分小滴は、小滴が作製される地点において材料のストリームを一緒に運ぶことによって容易に生成させることができる。しかしながら、最も単純な反応を除いた全ては、新しい試薬が各工程の間に加えられる多数の工程を必要とする。小滴−ベースのマイクロ流体デバイスにおいては、これは、各々が個々の反応体を含有する異なる小滴を合わせる(すなわち、凝集させる)ことによって最良に達成することができる。しかしながら、これはマイクロ流体デバイスにおいて達成するのが特に困難である。なぜならば、表面張力、界面活性剤安定化、および排出力は全てが小滴凝集を妨げるからであり;さらに、小滴は、その各流動を規定するストリームラインを横切らなくてはならず、かつ凝集のための正確な地点に到達するには完全に同調されなければならない。本発明のマイクロ流体デバイスは、静電化を用い、反対の符号の電荷を各小滴上に置き、次いで、電場を印加して、それらを凝集させることによってこれらの困難を克服する。非限定的例として、本発明によるデバイスは、異なる組成および反対電荷を持つ小滴を生じさせる2つの別々のノズルを含むことができる。小滴は2つのストリームの密集において一緒にされる。形成に際して小滴を荷電させるのに用いる電極もまた電場を供して、小滴を蒸気ラインを横切らせ、凝集に導く。電場の不存在下では、2つの蒸気中の小滴は、一般には、正確に同時に密集の地点に到達しない。それらが同調して到達する場合には、小滴を分離する油層は、凝集を容易とするのに十分に早く排出できず、その結果、小滴は凝集しない。対照的に、電場の印加に際して、小滴形成は正確に同調されるようになり、小滴は各々同時に密集の地点に到達することが確実とされる(すなわち、対合小滴)。
また、本発明は、マイクロ流体デバイスを製造する方法も提供する。マイクロ流体デバイスを製造する方法はいずれかの組合せにて以下の工程の1以上を含む:1)ハードリソグラフィー、2)ソフトリソグラフィー、3)抽出および/またはパンチスルー、4)ボンディング、5)チャネルコーティング、6)相互結合アセンブリ、7)電極注入、および8)導波管注入およびファイバー取付。前記工程を本明細書中にてより詳細に記載する。
本発明は、流体に対する境界を形成するチャネルを有するマイクロ流体デバイスを提供する。デバイスのチャネルは、油−水混合物のような非適合性または非混和性流体の混合物を運ぶ。生物学的/化学的物質を含有する水溶液の小滴は、油または他の非適合性溶媒内に分散される。この多−相混合物の各小滴は1以上の分子、粒子または細胞をカプセル化することができる。小滴は捕獲され、それらの境界はチャネルの壁によって規定され、従って、それらは拡散および/または混合されない。個々の粒子または分子は、個々の小滴内部に別々に区画化することができる。これらの小滴を分析し、(例えば、小滴内容物を反応させるための)他の小滴と組み合わせ、分析し、次いで、ソートすることができる。かくして、本発明は、生物学的/化学的物質を分析し、組合せ、検出しおよび/または分類する方法も提供する。
(Berkeley, Calif.)から入手可能なもの、例えば、PurSil(登録商標)およびCarboSil(登録商標)のようなシリコン−ウレタン複合体からの、シリコンエラストマー(例えば、RTV)、ウレタン組成物から形成することができる。チャネルは界面活性剤、TEFLON、あるいはその各々がフルオロ界面活性剤を含有するように修飾することができる、オクタデカフルオロオクタン(98%,Aldrich)、またはFluorinert(FC−3283;3M)、またはフルオロノナンのようなフッ素化油のような添加剤または剤で被覆することもできる。フッ素化油は、マイクロ流体適用において望ましい、化学的不活性性、高いガス浸透性、および生体適合性を含めた好都合な特性を有する。TEFLONは、疎水性であって、有利には水を吸収しないシリコンエラストマー(RPV)チャネルに特に適しているが、それらは油相に暴露した場合に膨潤する傾向があり得る。膨潤はチャネルの寸法および形状を変化させることができ、チャネルを閉じることさえでき、あるいは例えば、エラストマーおよびカバースリップの間のシールに応力を与えることによってチップの一体性に影響することができる。ウレタン基材は油中で膨潤する傾向はないが、親水性であり、それらは望ましくなく水を吸収でき、より高い操作圧力を用いる傾向がある。疎水性コーティングを用いて、水吸収を低下させ、または排除することができる。吸収または膨潤の論点もまた、圧力または小滴頻度を改変または最適化する(例えば、周期性を増加させて吸収を低下させる)ことによって取り組むこともできる。RTV−ウレタンハイブリッドを用いて、ウレタンの親水性特性とシリコンの疎水性特性とを組み合わせることができる。
用語「流動」は、デバイスを通っての、または本発明の方法における液体または固体のいずれの移動も意味し、制限なくしていずれの流体のストリームも、および物質がストリームによって運ばれるか否かを問わず、ストリームと共に、ストリームの中で、またはストリームに対して移動するいずれの物質も含む。例えば、デバイスを通っての、または本発明の方法における、例えば、本発明のマイクロ流体チップのチャネルを通っての分子、ビーズ、細胞またはビリオンの移動は流動を含む。これは、本発明によると、分子、ビーズ、細胞またはビリオンが流動をやはり含む流体のストリームによって運ばれるか否かを問わず、あるいは分子、細胞またはビリオンがいくつかの他の直接的または間接的力またはモチベーションによって移動されるか否かを問わず、およびいずれの原動力の性質が知られているかまたは理解されているか否かに関わらず、そうである。いずれの力の適用を用いても、限定されるものではないが、分子、細部またはビリオンが本発明による検出、測定またはソーティングのために向けられる限り、いずれかの特定の理論または作用メカニズムに関することもなく、圧力、毛管作用、電気−浸透圧、電気詠動、誘電泳動、光学ピンセット、およびその組合せを含めた流動を供することができる。
70, 1909−1915(1998))。これらの値は、ストリーム中の球によって経験される水力学力よりもかなり大きい(3.4ミクロン球について約0.3pN、および15ミクロン球について1.5pN)。従って、個々の細胞または粒子の操作は誘電泳動を用い、細胞ソーターデバイスにおけるようにストリーミング流体で達成することができる。慣用的な半導体技術を用い、電極を基材上に微細加工して、本発明の微細加工ソーティングデバイスにおける力の場を制御することができる。誘電泳動は、導電体である動く物体に特に適している。AC電流の使用は、イオンの永久的整列を妨げるのに好ましい。メガヘルツの周波数は、比較的長い距離に渡っての正味の整列、引力、および移動を供するのに適している。米国特許第5,454,472号参照。
P≦2=1−{1+[細胞]×V}×e−[細胞]×V
として表すことができ、ここで、「[細胞]」は立法ミクロン(μm3)当たりの分子、細胞または粒子の数のユニットにおける分子、細胞または粒子の濃度であり、Vはμm3のユニットにおける小適の容量である。
「入口モジュール」は、凝集、検出および/またはソーティングのために分子、細胞、小分子または粒子を受け取る微細加工されたデバイスの領域である。入口モジュールは1以上の入口チャネル、ウェルまたは貯蔵庫、開口、および分子、細胞、小分子または粒子のデバイスへの進入を容易とする他の特徴を含有することができる。チップは、所望であれば、1を超える入口モジュールを含有することができる。入口モジュールは主要チャネルと流体連絡している。入口モジュールは、本発明のデバイスの入口チャネルおよび主要チャネルの間の接合を含むことができる。該接合は、圧縮された流体の主要チャネルへの導入を可能とすることができる。入口チャネルは、主要チャネルにおける流体の流動に対して垂直な角度とすることができる。入口モジュールを通って主要チャネルに導入される流体は、入口モジュールを通って導入される流体の小滴が主要チャネルにおける連続流体の流れ中に形成されるように、主要チャネルにおける流体と「非適合性」(すなわち、非混和性)である。
本発明のデバイスは1以上の凝集モジュールも含む。「凝集モジュール」は、小滴内に含まれる分子、細胞、小分子または粒子が、分子、細胞、小分子または粒子を含む他の小滴と近接される場合に、および近接する小滴が凝集し、またはそれらの内容物を合わせる場合に、入口モジュールにおいて、またはその下流の主要チャネルの少なくとも一部内にあり、またはそれと一致する。凝集モジュールは装置、好ましくは、誘電泳動力を生じさせるための1以上の電極、またはパターン化された導電性層を含むこともできる。1以上の電極またはパターン化された導電性層によって生じた誘電泳動力は、主要チャネル内の小滴を遅らせ、または停止させることができ、それにより、それらの近接、および結果としての凝集または合体を容易とする。
本明細書中に記載されたマイクロ流体デバイスの特別な設計の実施形態は、特定の液体の小滴のものより再現性があり、かつ制御可能な鉗合、続いての、これらの小滴の対−様式凝集を可能とする。小滴対は異なる組成および/または容量の液体を含有することができ、これは、次いで、組み合わされて、特定の反応が調べられることを可能とする。小滴の対は以下の:(i)2つの連続水性ストリームおよび油ストリーム;(ii)連続水性ストリーム、エマルジョンストリーム、および油ストリーム、または(iii)2つのエマルジョンストリームおよび油ストリームのいずれかから由来することができる。図17A〜D。
「検出モジュール」は、典型的には、少なくとも1つの所定の特徴に基づいて分子、細胞、小分子または粒子がそこで検出され、同定され、測定され、または問い合わせされるべき主要チャネル内であるデバイス内の位置である。分子、細胞、小分子または粒子は一度に調べることができ、特徴は、例えば、所望により、レポーターの存在または量についてテストすることによって光学的に検出され、または測定される。例えば、検出モジュールは1以上の検出装置と連絡している。検出装置は光学または電気的検出器またはその組合せとすることができる。適当な検出装置の例は光学導波管、顕微鏡、ダイオード、光刺激デバイス(例えば、レーザー)、光電子増倍管、およびプロセッサー(例えば、コンピュータおよびソフトウェア)、およびその組合せを含み、それらは、協働して、特徴、マーカー、またはレポーターに代表的なシグナルを検出し、および測定、またはソーティングモジュールにおけるソーティング作用を決定し、および指令する。
本発明のデバイスは、さらに、1以上のソーティングモジュールを含むことができる。「ソーティングモジュール」は、検出モジュールにおける調査と関連して受け取られたシグナルに依存し、分子、細胞、小分子または粒子の流れが1以上の他のチャネル、例えば、出口モジュール(すなわち、収集または廃棄モジュール)への送達用のブランチチャネルに入る方向を変化させることができるチャンネルの接合である。典型的には、ソーティングモジュールをモニターし、および/または検出モジュールの制御下では、従って、ソーティングモジュールはそのような検出モジュールに「対応」するであろう。ソーティング領域は1以上のソーティング装置と連絡し、影響される。ソーティング装置は技術または制御システム、例えば、誘電、電気、電気−浸透圧、(マイクロ−)バルブ等を含む。制御システムは種々のソーティング技術を使用して、分子、細胞、小分子または粒子の所定のブランチチャネルへの流動を変化させ、または向けることができる。「ブランチチャネル」は、ソーティング領域および主要チャネルと連絡しているチャネルである。典型的には、ブランチチャネルは、検出モジュールによって検出され、およびソーティングモジュールにおいてソートされる注目する分子、細胞、小分子または粒子の特徴に依存して、分子、細胞、小分子または粒子を受ける。ブランチチャネルは出口モジュールを有することができ、および/またはウェルまたは貯蔵庫で終わって、分子、細胞、小分子または粒子の収集または廃棄(各々、収集モジュールまたは廃棄モジュール)を可能とすることができる。別法として、ブランチチャネルは他のチャネルと連絡して、さらなるソーティングを可能とすることができる。
1以上の凝集モジュール中での1以上の小滴の凝集は(例えば、小滴内に存在する回転渦を通って)凝集した小滴の内容物を混合するのに十分であり得るが、本発明のデバイスは、さらに、1以上の混合モジュールを含むことができる。「混合モジュール」は、その内容物を混合するように小滴を振盪し、またはそうでなければ操作するための特徴を含むことができる。混合モジュールは、好ましくは、凝集モジュールは下流にあり、かつ検出モジュールから上流にある。混合モジュールは限定されるものではないが、小滴の内容物を混合し、およびマイクロ流体デバイス中の単一小滴に合体された流体についての混合回数を低下させるための、金属合金成分電極または導電性パターン化電極の使用を含むことができる。
本発明のデバイスは、さらに、1以上の遅延モジュールを含むことができる。「遅延モジュール」は遅延ラインであり得る。小滴内の反応が取るに足らない長さの時間の間起こるマイクロ流体デバイスの操作は、デバイス内の滞留時間を増加させるために遅延ラインを必要とする。かなりの滞留時間を要求する反応では、より長い、より大きな遅延ラインが要求される。従って、本発明は、マイクロ流体デバイス内での滞留時間を増加させる方法を提供する。
本発明のデバイスは、さらに、1以上のUV−放出モジュールを含むことができる。「UV−放出モジュール」は主要チャネルと流体連絡している。UV−放出モジュールは入口モジュールの下流であって、凝集モジュールの上流に位置する。UV−モジュールはビーズアッセイで用いることができる。カプセル化ビーズからの化合物は、UV光を用いてUV−放出モジュールにおいて切断することができる。光不安定リンカーは、単一ビーズがカプセル化された後に要求に応じて破壊することができ、かくして、単一化合物の多数のコピーが溶液に放出される。本明細書中に開示された細胞ベースのアッセイにおいて、アッセイされた化学化合物は、溶液中にあって、細胞膜に浸透することが望まれる。さらに、単一化合物の細胞での区画化を確保するために、固体支持体からの化合物の切断は、ビーズがカプセル化された後においてのみなすことができる。光切断性リンカーを利用して、UV−放出モジュールを通じて滴を通過させることによって滴形成後にビーズの化合物を切断することができる。(すなわち、適当な波長のレーザー)。
便宜のために、本明細書中に記載され、かつ本発明で使用される試薬、化合物ライブラリーおよび/またはエマルジョンの所定量は、所望により、本明細書中に記載された種々のアッセイおよび方法の適用を容易とするためにパッケージされた組合せでのキットで提供することができる。そのようなキットが、典型的には、主題のアッセイを行うための使用説明書を含み、所望により、その中で反応を行うべき流体容器、例えば、キュベット、マルチウェルプレート、マイクロ流体デバイスなどを含む。
本明細書中で用いられる用語は、一般には、本発明の文脈内で、かつ各用語が用いられる特定の関係において、当該分野におけるその通常の意味を有する。ある用語は後に、あるいは明細書中の他の箇所で議論して、本発明のデバイスおよび方法、およびそれらをどのようにして製造し使用するかを記載するにおいて実行者に対してさらなるガイドを供する。同一のことが典型的には1を超える方法で記載することができることは認識されるであろう。その結果、代替言語および同義語を本明細書中で議論される用語のいずれかの1以上で用いることができる。ある用語の同義語を供する。しかしながら、1以上の同義語の引用は他の同義語の使用を排除せず、また、用語が本明細書中において工夫されているか、議論されているか否かについていずれの特別な重要性もない。本明細書中で言及される全ての刊行物、特許出願、特許および他の文献は、ここに引用して援用される。コンフリクトする場合には、定義を含めて本明細書が優先される。くわえて、材料、方法および実施例は説明的なものに過ぎず、限定的なことを意図しない。
本発明のデバイスは生きた/死滅した細胞ベースのアッセイで用いることができる。1つの例において、アッセイは2つのフルオロフォアを用い;1つは細胞膜を横切って透過でき、第二の染料はDNAに結合し、もし膜が危うくなった場合のみ細胞に進入することができる。同様な生きた/死滅アッセイが細菌および酵母について存在する。タグされた化学ライブラリーおよび光切断可能リンカーをそのようなアッセイで用いることができる。分裂−ビーズ合成を通じて得られたコンビナトリアル1−ビーズ−1−化合物ライブラリーは、化合物を信頼性良く同定するためにそれらの合成履歴を記載するタグを必要とする。ビーズ、ロッドおよびクラウンのようなマイクロ担体についてのいくつかのコーディング技術が過去10年間にわたって開発され、この要求に取り組んできた。単純かつ効果的な方法は、注目する利用される直交化学の化学的存在と並行して生じる分光学的化学タグに依拠する。代替物はDNAのような核酸の使用、続いての、コードされたビーズを解読するポリメラーゼ連鎖反応(PCR)の使用を含む。
本発明は、記載された本発明のナノリアクターにおいてポリメラーゼ連鎖反応を行うための方法を提供する。PCRは、本発明によるマイクロ流体デバイスにおいて滴×滴ベースで行うことができる。モノリシックチップを設けることができ、ここで、加熱および冷却ラインがチップに形成され、ソーティング手段が提供される。そのようなチップ上の小滴においてPCRを行う利点は、チップが使い捨て可能であって、反応の間にデバイスを清浄化することなく反復できることである。さらに、チップは、正しい濃度において小滴にてPCRを行うための全ての成分を得る便宜な方法を提供する。加えて、PCRはより有効である。なぜならば、熱移動は小さな容量のためより有効である。これはより短いインキュベーション−滞留時間を提供する。核酸、すべてのPCRプライマーおよび、もし存在すれば、ビーズを含有する小滴は秒当たり100および20,000小滴の間の率にて一度に1つ生成される。次いで、小滴を、加熱および冷却ラインの間のセルペンチン経路を通って送って、小滴内部の遺伝物質を増幅することができる。デバイスから出るに際して、小滴をさらなるオン−チップまたはオフ−チップ処理のために送り、もう1つのチップに向けることができ、あるいはエマルジョンを分解して、PCR産物を放出させることができる。もし存在すれば、ビーズは、濾過デバイス、沈積、または遠心にエマルジョンを通すことによって収穫することができる。
本発明のデバイスを用いて、樹立された細胞系に対する少なくとも106分子からなる化学ライブラリーをスクリーニングすることができる。このようにして、陽性および陰性ナノリアクターを追跡し、核酸ベースの、または多色ビーズ−ベースのコーディングスキームいずれかを用いてソートすることができる。例えば、公知のヒットを持つ対照ライブラリーはヒト癌細胞系に対してスクリーニングすることができる。
本発明は、蛍光偏光(FP)を用いてナノリアクター中で生物学的アッセイを行う方法も提供する。蛍光偏光技術は何十年の間、基本的な研究および商業的診断アッセイで用いられてきたが、薬物発見に広く用いられ始めたのは、過去6年の間だけである。元来、薬物発見のためのFPアッセイは単一−チューブ分析機器のために開発されたが、同等な感度を持つ商業的プレートリーダーが利用可能となると、高スループットスクリーニングアッセイに迅速に変換された。これらのアッセイはキナーゼ、ホスファターゼ、プロテアーゼ、G−プロテイン結合受容体、および核受容体のようなよく知られた医薬標的を含む。
using fluorescence polarization: nuclear receptor−ligand−binding and kinase/phosphatase assays)。FP−ベースのエストロゲン受容体(ER)アッセイは、ERへの結合についてのフルオレセイン−標識エストラジオールおよびエストロゲン−様化合物の競合に基づく。転写活性化スクリーニングからの50のリード化合物のスクリーニングにおいて、21の化合物は10マイクロM未満のIC50値を有し、1つはERalphaよりもERbetaに対する大まか100倍高い親和性を呈する。FP−ベースの競合結合アッセイを用いて、ERに対する広い範囲の結合親和性を持つ多様な化合物をスクリーニングすることができる。
Kinases.Analytical Biochemistry,November 1997,vol.253,no.2,pp.210−218(9))。このアッセイは、蛍光化ペプチド基質とキナーゼ、ATP、および抗−ホスホチロシン抗体とのインキュベーションを含む。リン酸化ペプチド産物は抗−ホスホチロシン抗体で免疫複合体化され、その結果、蛍光偏光アナライザーで測定して偏光シグナルが増加する。これらの結果は、蛍光偏光アッセイが阻害剤を検出でき、32PO4で導入アッセイと匹敵することを示す。蛍光偏光方法は32PO4導入アッセイあるいはELISAまたはDELFIAと比較して有利である。なぜならば、それはいくつかの洗浄、液体導入、および試料調製工程を含まない1−工程アッセイだからである。それは非同位体基質を用いる追加の利点を有する。かくして、蛍光偏光アッセイは環境に安全であり、取り扱いの問題を最小化する。
Fluorescence Polarization−Based Diagnostic Assay for Equine Infectious Anemia Virus.Journal of Clinical Microbiology,May 2000,P.1854−1859,Vol.38,No.5)。FPアッセイを最適化して、フルオレセイン−標識免疫反応性ペプチド診断抗原のFPの変換によってEIAV−特異的抗体の存在を検出した。最も感受性かつ特異的なペプチドプローブは、EIAV膜貫通タンパク質gp45の免疫優勢領域に対応するペプチドであった。このプローブを、151のAGID−陽性ウマ血清および106のAGID−陰性血清試料での最適化されたFPアッセイにおけるその反応性についてテストした。これらの研究の結果は、FPアッセイ反応性が、106の陰性血清試料のうち106(100%特異性)、および151の陽性血清試料のうち135(89.4%感度)における報告されたAGID結果と相関したことを示す。FPアッセイは、非常に低いバックグラウンド反応性を有し、感染において早く(<3週間後感染)生じた抗体を容易に検出することも判明した。
G.Receptor & Enzyme Screening Technologies, Glaxo Wellcome Medicines Research Centre,Stevenage,Herts,UK)。もし蛍光または消光化合物が排除されたならば(全ての化合物の3%)、0.4%未満の化合物はFP測定に干渉することが見出された。化合物は先験的にアッセイされ、これらの望ましくない特徴を有するものは排除される。
本発明は、前記した本発明のナノリアクター中で縮合化学を行って、高度に収束した方法で薬物−様分子のライブラリーを合成する方法を提供する。
本発明は、自己−抗原を単離する方法を提供する。次いで、各々、第一の小滴組内に別々にまたは多数で含有される単細胞を作り出すように処理された、多細胞生物から得られた腫瘍よりなる該第一の試料小滴組を、生物から単離された1以上のt−細胞よりなる小滴の第二の組と組合せ、得られた組み合わされた小滴を、検出手段を用いて組み合わされた小滴内に含有された腫瘍細胞のt−細胞殺傷について分析する。検出手段は、細胞の溶解に際して小滴環境に放出されるであろう細胞質酵素についての分析を含むことができる。小滴はソートすることができるか、またはソートすることができず、次いで、さらに、t−細胞によって認識される腫瘍細胞エピトープの同定のために分析される。
本発明は、相化的アプローチまたはその誘導体を用いるマトリックススクリーニングの方法を提供する。試料ウェル内に各々別々に含有された多数の試料から構成されるデバイスは、各試料が流体−流動内の小滴内にカプセル化でき、かつ別々の、順次の小滴の組合せの相を変化させることによって、他の試料の各々と順次にかつ別々に組み合わせることができるように操作できるように、1以上の入口チャネルに結合した。
本発明は、本発明によるマイクロ流体デバイスでの使用のための公知のアッセイの適合も提供する。例えば、蛍光偏光、分子ビーコン、およびタックマン(taqman)アッセイをSNP、DGE、および核酸同定での使用のために適合させることができる。高スループット様式において、個々の小滴を有機または無機染料のいずれか、または着色ビーズで標識することができる。区別される利点は、ビーズは必要とされず、全アッセイは溶液中で実行できることである。いくつかの例示的アッセイを記載する。
フルオロ界面活性剤は、揮発性フッ素化溶媒中にてKrytox 157 FSL、FSM、またはFSHを水酸化アンモニウム水溶液と反応させることによって合成される。溶媒および残存する水およびアンモニアはロータリーエバポレーターで除去する。次いで、界面活性剤をフッ素化油(例えば、3MからのFC−3283)に溶解させることができ、これは、次いで、エマルジョンの連続相として用いることができる。典型的な濃度は油に溶解させた界面活性剤の2.5wt%である。
乳化された化合物のライブラリーの質を制御して、小滴間を交差する化合物をライブラリーから排除することもできる。q−ドットでコードされた緩衝液−のみの小滴を乳化し、それを1〜1000の別々に乳化された化合物と共にインキュベートすることによって、ライブラリーの質制御を達成することができる。インキュベーションの後、ユニークにコードされたq−ドット小滴は化合物−含有小滴からソートされ、小滴の他の1〜1000タイプに乳化された化合物のいずれかの存在について(例えば、質量分析によって)分析される。小滴の間を交差する化合物を同定し、ライブラリーから排除する。
本発明により、ユーザーは、シグナル増幅用の手段に付着されたアフィニティ−試薬の結合に基づいて細胞をソートすることを可能とする。非限定的例として、酵素(例えば、alk/phos、β−gal、ホースラディッシュペルオキシダーゼ等)に融合した抗体を細胞のミックスに加え、インキュベートする。抗体は、例えば、癌マーカーのような特定の細胞表面マーカーに対するものとすることができる。細胞懸濁液を洗浄することができ、または洗浄しなくても良い(もし抗体が低濃度であれば、すなわち、小滴当たり1抗体未満であれば、抗体は良好な結合特性を有する)。
本発明のデバイスを用いて、個々の染色体または腫瘍細胞から個々のエクソンを配列決定することもできる。この方法を実行するための模式的ダイアグラムを図19に掲げる。プライマー−結合ビーズ(例えば、Dynalストレプアビジンビーズ)と共に異なるエクソンに対する個々の特異的プライマー−対(例えば、表皮成長因子受容体(EGFR)エクソン−特異的プライマー対)を、各々、乳化し、次いで、プールして、ライブラリーエマルジョンを作成する(図19においては、96エクソンプライマー対の組を説明目的で示す)。別途、染色体DNA溶液を、本明細書中に記載されたマイクロ流体デバイスでの乳化に際して、30〜50ミクロン小滴が、平均して、DNAのわずかに半分未満のゲノム濃度を含有するように水性緩衝液に希釈する。エクソン−特異的プライマーのプールされたエマルジョンライブラリーからの小滴を、本明細書中に記載されたマイクロ流体デバイスにて染色体DNAの希釈された溶液を含有する小滴と凝集させ、ビーズ−ベースのDNA増幅反応(例えば、PCR)で用いる。本明細書中に記載されたマイクロ流体デバイスは24時間以内に1×109のこれらの小滴を収集し、その結果、小滴のエマルジョンが得られ、そのいくつかは増幅されたエクソン−DNAが付着されたビーズを含有する。PCRの後、エマルジョンを遠心によって破壊し、ビーズを単離し、洗浄し、次いで、本明細書中に記載されたマイクロ流体デバイスにてDNA−含有ビーズを豊富化する。エクソン−および染色体−特異的DNA−含有ビーズをランダムにピコタイタープレート(454 Corp.)に入れ、(454 Corp.によって供され、およびその各々をここに引用してその全体を援用する、2001年3月21日に出願された米国出願第09/814,338号;2002年3月21日に出願された米国出願第10/104,280号;2004年1月28日に出願された米国出願第10/767,899号;2005年1月28日に出願された米国出願第11/045,678号;または2005年8月1日に出願された米国出願第11/195,254号のいずれかに記載された)Life Sciences DNA配列決定機器を用いて配列決定される。このプロセスのまとめは図20によって供される。エマルジョンPCR増幅反応は、鋳型としての対照染色体DNA、およびエクソン−特異的プライマーの単一組を用いてオフ−チップにて、あるいはオン−チップにて(すなわち、本明細書中に記載された本発明のマイクロ流体デバイスにて)行うことができる。
例えば、本発明は、以下の項目を提供する:
(項目1)
ナノリアクターの作成方法であって、
a)相互に流体連絡するように基材上に一体的に配置されたマイクロ流体モジュールを担持する複数の電気的にアドレス可能なチャネルを含む微細加工基材を供し、それにより、少なくとも1つの連続相流体を運ぶように適合された少なくとも1つの主要チャネルを形成し;
b)該主要チャネル内を流動する該連続相流体中に1以上の小滴が形成されるように、第一の分散相流体を第一の入口チャネルを通って該主要チャネルに流動させ;
c)該主要チャネル内を流動する該連続相流体中に1以上の小滴が形成されるように、第二の分散相流体を第二の入口チャネルを通って該主要チャネルに流動させ;次いで、
d)該小滴が該微細加工基材の凝集モジュールを通過するときに、工程(b)で形成された少なくとも1つの小滴を、工程(c)で形成された少なくとも1つの小滴と凝集させ、それにより、ナノリアクターを得る;
ことを含む、方法。
(項目2)
上記凝集工程が電場によって達成される、項目1に記載の方法。
(項目3)
上記凝集工程が受動的である、項目1に記載の方法。
(項目4)
上記第一および第二の分散相流体が生物学的物質または化学的物質を含む、項目1に記載の方法。
(項目5)
上記生物学的物質または化学的物質が、組織、細胞、粒子、タンパク質、抗体、アミノ酸、ヌクレオチド、小分子、および医薬よりなる群から選択されるメンバーである、項目4に記載の方法。
(項目6)
さらに、e)遅延モジュール内でナノリアクターをインキュベートし、次いで、f)検出モジュール内で所定の特徴について上記ナノリアクターに問い合わせることを含む、項目4に記載の方法。
(項目7)
上記生物学的物質または化学的物質が標識される、項目4に記載の方法。
(項目8)
上記標識がタンパク質、DNAタグ、染料、または量子ドットである、項目7に記載の方法。
(項目9)
上記第一および第二の分散相流体が2つの水性ストリーム、1つの水性ストリームと1つのエマルジョンストリーム、および2つのエマルジョンストリームよりなる群から選択されるメンバーである、項目1に記載の方法。
(項目10)
2以上の反応性サブ構造から化合物を合成する方法であって、
a)反応性サブ構造を、該サブ構造に対してユニークな標識で標識し;
b)マイクロ流体デバイス上で該標識された反応性サブ構造の水性溶液を乳化して、小滴を形成し;次いで、
c)該マイクロ流体デバイス上で該小滴をランダムに合わせて、化合物を形成する;
ことを含む、方法。
(項目11)
工程(a)および(b)が、予め形成された標識エマルジョンを導入することによって交互に行われる、項目10に記載の方法。
(項目12)
さらに:
d)該化合物によって呈される望ましい化学的特性または生物学的特性に基づいて工程(c)で形成された化合物をスクリーニングし;次いで、
e)標識を解読することによって該化合物の構造を同定する;
ことを含む、項目10に記載の方法。
(項目13)
マイクロ流体デバイス上でライブラリーからの単一化合物を同定する方法であって、
a)化合物の水性溶液およびユニークな液体標識の水性溶液を乳化することによって化合物のライブラリーを標識し、それにより、各化合物はユニークな液体標識で標識され;
b)工程(a)から得られた標識されたエマルジョンをプールし;
c)特定の細胞または酵素を含有するエマルジョンと、該標識されたエマルジョンを凝集させ、それにより、ナノリアクターを形成し;
d)該ナノリアクターの内容物の間の望ましい反応について該ナノリアクターをスクリーニングし;次いで、
e)該液体標識を解読し、それにより、化合物のライブラリーから単一の化合物を同定する;
ことを含む、方法。
(項目14)
さらに、上記スクリーニング工程を行うに先立って、上記ナノリアクターの内容物をインキュベートすることを含む、項目13に記載の方法。
(項目15)
上記液体標識が量子ドットまたは染料である、項目13に記載の方法。
(項目16)
上記液体標識が有機物または無機物である、項目13に記載の方法。
(項目17)
上記ライブラリーが組織、細胞、粒子、タンパク質、抗体、アミノ酸、ヌクレオチド、小分子、および医薬よりなる群のメンバーから選択された生物学的物質または化学的物質を含む、項目13に記載の方法。
(項目18)
工程(d)が蛍光偏光によって行われる、項目13に記載の方法。
(項目19)
乳化された化合物のライブラリーの質を制御する方法であって、
a)乳化された化合物のライブラリーを供し;
b)不活性なフルオロカーボン媒体中にq−ドットでコードされた水性緩衝液を乳化させ、それにより小滴を形成し;
c)該乳化された化合物のライブラリーと共に該q−ドットでコードされた小滴をインキュベートし;
d)該ライブラリーから該q−ドットでコードされた小滴をソートし;
e)該ライブラリーで乳化された化合物のいずれかの存在について該q−ドットでコードされた小滴を分析し;次いで、
f)該乳化された化合物のライブラリーから工程(e)で同定された化合物を排除することを含み、
ここで、工程(a)〜(f)の1以上がマイクロ流体デバイス上で行われる、方法。
(項目20)
上記分析工程が質量分析によって行われる、項目19に記載の方法。
(項目21)
細胞をソートする方法であって、
a)アフィニティ−試薬を酵素に融合させ;
b)工程(a)の融合産物を細胞集団と混合し;
c)該融合産物に付着した細胞を単離し;
d)工程(c)の細胞を不活性なフルオロカーボン媒体中に乳化し;
e)工程(a)の酵素に対応する基質を含むエマルジョンと工程(d)の細胞エマルジョンを凝集させ、それにより、ナノリアクターを形成し;次いで、
f)該ナノリアクターの内容物の間で望ましい反応につき該ナノリアクターをスクリーニングすることを含み、
ここで、(a)〜(f)の1以上の工程がマイクロ流体デバイス上で行われる、方法。(項目22)
上記アフィニティ−試薬はタンパク質、核酸、抗体、または酵素が結合することができる他の分子である、項目21に記載の方法。
(項目23)
上記抗体が細胞表面のマーカーへの結合に対して特異的である、項目22に記載の方法。(項目24)
上記細胞表面マーカーが癌マーカーである、項目23に記載の方法。
(項目25)
上記酵素がalk/phos、β−ガラクトシダーゼ、またはホースラディッシュペルオキシダーゼである、項目21に記載の方法。
(項目26)
上記抗体が多数の酵素に融合される、項目21に記載の方法。
(項目27)
複数の基質が乳化され、工程(d)で形成された細胞エマルジョンと凝集される、項目21に記載の方法。
(項目28)
個々の染色体から個々のエクソンを配列決定する方法であって、
a)エクソンに対する特異的プライマー−対を、該プライマー−対に結合することができるビーズで乳化させ;
b)工程(a)のエマルジョンをプールして、ライブラリーエマルジョンを作成し;
c)別の染色体DNAエマルジョンを供し;
d)工程(b)のライブラリーエマルジョンを、工程(c)の染色体エマルジョンと凝集させ、それにより、ナノリアクターを形成し;
e)該ナノリアクター中でDNAを増幅し;
f)該ビーズを単離し;
g)DNAを含有するビーズについてスクリーニングし;次いで、
h)DNAを含有するビーズを配列決定することを含み、
ここで、(a)〜(h)の1以上の工程がマイクロ流体デバイス上で行われる、方法。(項目29)
項目28に記載の方法を行うためのキットであって、
a)エクソンに対して特異的なプライマー−対、および該プライマー−対に結合することができるビーズのエマルジョンライブラリー;ならびに
b)染色体DNAエマルジョン;
を含む、キット。
Claims (20)
- 少なくとも1種の界面活性剤を含む非混和性油内に複数のプールされた水性小滴を含む、単一のオフ−ライン容器中のエマルジョンライブラリーであって、各小滴は、同じ水性流体と、異なるプライマー対とを含み、そして、各個々のプライマー対が、異なる標的核酸配列に結合するように構成され、それによって、各異なる標的核酸配列が、異なるプライマー対に特異的に結合するように構成される、エマルジョンライブラリー。
- 各小滴が、複数コピーで存在する1以下のプライマー対を含む、請求項1に記載のエマルジョンライブラリー。
- 各小滴が、直径100μm未満である、請求項1に記載のエマルジョンライブラリー。
- 各小滴が、標識をさらに含む、請求項1に記載のエマルジョンライブラリー。
- 前記標識が、蛍光偏光、蛍光強度、蛍光寿命、蛍光エネルギー移動、pH、イオン性内容物、温度、または、これらの組み合わせによって検出され得る、請求項4に記載のエマルジョンライブラリー。
- 前記異なる標的が、1つの核酸上の異なる遺伝子座である、請求項1に記載のエマルジョンライブラリー。
- 前記小滴が均一なサイズである、請求項1に記載のエマルジョンライブラリー。
- 前記油がフルオロカーボン油である、請求項1に記載のエマルジョンライブラリー。
- 前記界面活性剤がフルオロ界面活性剤である、請求項1に記載のエマルジョンライブラリー。
- 各小滴が、プローブをさらに含む、請求項1に記載のエマルジョンライブラリー。
- 前記プローブがクエンチャー−染料を含む、請求項10に記載のエマルジョンライブラリー。
- 前記単一の容器がバイアルである、請求項1に記載のエマルジョンライブラリー。
- 前記プライマー対が、ビーズに付着している、請求項1に記載のエマルジョンライブラリー。
- 各プライマー対が、エクソンに特異的である、請求項10に記載のエマルジョンライブラリー。
- 前記標識が、有機染料である、請求項4に記載のエマルジョンライブラリー。
- 各小滴が、約1〜500のプライマー対を含む、請求項1に記載のエマルジョンライブラリー。
- 各小滴が、1種類のプローブを含む、請求項1に記載のエマルジョンライブラリー。
- 各小滴が、2種類のプローブを含む、請求項10に記載のエマルジョンライブラリー。
- 各小滴が、ビーズに付着した1種類のプローブを含む、請求項17に記載のエマルジョンライブラリー。
- 各小滴が、ビーズに付着した2種類のプローブを含む、請求項10に記載のエマルジョンライブラリー。
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