JP4777659B2 - 集積化固相親水性マトリクス回路およびマイクロ・アレイ - Google Patents
集積化固相親水性マトリクス回路およびマイクロ・アレイ Download PDFInfo
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- JP4777659B2 JP4777659B2 JP2004555907A JP2004555907A JP4777659B2 JP 4777659 B2 JP4777659 B2 JP 4777659B2 JP 2004555907 A JP2004555907 A JP 2004555907A JP 2004555907 A JP2004555907 A JP 2004555907A JP 4777659 B2 JP4777659 B2 JP 4777659B2
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Description
本発明による集積化流体i/o態様は、好ましくは、囲まれた親水性マトリクス回路を用いて実施される。それぞれの囲まれた親水性マトリクス回路は、好ましくは、本質的に乾燥した固相実体として製造される成形された親水性マトリクス構造を含む。一つの実施形態において、この親水性マトリクスの領域は、好ましくは、乾燥化学物質を含有する。
本発明は、また、マイクロ反応器および流体i/oの種々の構成を提供する。以下に記載されるこれらの構成において、囲まれた親水性マトリクス回路は、一般に、1以上のマイクロ反応部位に集積化流体i/oを提供する。すなわち、囲まれた親水性マトリクス回路は、i)マイクロ反応部位に化学物質を供給し、および/またはii)マイクロ反応部位から化学物質を引き出すことができる。化学物質は、マイクロ反応部位から引き出すことができると共に、囲まれた回路内に含有される排水領域に移動するか、または囲まれた回路を通して別のマイクロ反応部位での次のさらなる反応のため別の位置に移動することができる。化学物質は、マイクロ反応部位から回路内の位置にまたは成分分離および分析用のデバイスの別の隣接回路に引き出すことができる。
本発明によるデバイスの一つの用途において、囲まれた親水性マトリクス流体i/o回路は、化学物質を隣接マイクロ反応器中に流体的にポンプ注入するために用いられる。こうした用途において、囲まれた親水性マトリクス回路は、マイクロ反応器に供給しようとする化学物質を含有する親水性マトリクスのリザーバ領域に接続する通路を含み、通路は、回路のとり囲む絶縁体中のオリフィスを通してマイクロ反応器に流体的に接続される流出領域を有する。少なくとも一つの動電学的ポンピング手段は、化学物質を、囲まれた通路に沿って囲まれたリザーバ領域からマイクロ反応器に輸送するために提供される。この実施形態の一つの変形において、通路は、通路に沿っての拡散のせいでマイクロ反応器に入る化学物質の量がマイクロ反応器への化学物質の有効ポンピング前の時間帯の間最小であるように、十分に長くあるように寸法化される。別の変形において、空隙は、マイクロ反応器への化学物質の拡散的輸送を防止するために、マイクロ反応器に接続するリザーバと流出領域間の通路中に提供される。従って、材料は、通路に沿っての流体の対流流れにより流体的に輸送されねばならないし、流体はそれが有効にポンプ注入される場合空隙を横切る。集積化動電学的ポンピング電極は、空隙上流の囲まれた親水性マトリクス回路中に位置する。例えば、一つの電極はリザーバ領域中に、別のものは空隙のすぐ上流の通路中に位置付けられる。別の変形において、リザーバは、囲まれた親水性マトリクス回路の組立ての間化学物質のプリント積層を可能とするために円形に寸法化される。なお別の変形において、流体を通路に沿って輸送するための動力を供給するために、ポンプリザーバおよび間をとった集積化電極を有する輸送通路がある。通路は、さらに、ポンプ注入しようとする化学物質を含有する第2試薬リザーバに流体的に接続される。試薬リザーバは、ポンプリザーバおよび通路およびその集積化電極の下流にある。試薬リザーバは、囲む絶縁体中の流出オリフィスを通してマイクロ反応器に、流体的に接続される。
高処理能力分子生物学および候補薬物化合物の高処理能力試験において特別の興味がある不均一レセプター/リガンド結合反応は、核酸を含むものおよびタンパク質を含むものである。
本発明のデバイスを用いて行われる均一系反応の代表的な例は、薬物試験用の酵素アッセイである。候補薬物化合物は、それらが特定の酵素反応の反応速度の変化を引き起こす場合、潜在的に興味あるものである。こうしたアッセイはフォーマット化されて発色性、蛍光発生または発光性基質:酵素反応の際に蛍光性または発光性となる酵素用の合成基質の使用により光学的に検出可能な反応速度を与えることができる。その速度が光学的手段により測定される酵素反応をフォーマット化するためのこのおよび多くの他の体系は、技術上公知である。この均一アッセイを遂行するために必要とされる本発明のデバイスの微細位置および親水性マトリクス回路の特定の構築および設定は、本発明のデバイスの各種実施形態の上記検討から明らかである。
本発明によりアレイ上で行うことができる複雑な反応フォーマットの代表的な例は、ピロシーケンシング反応フォーマットである。この方法において、4個のヌクレオチド塩基が、DNAテンプレート上の伸長DNA鎖を含有する反応器に順序どおりに添加される。技術上公知(米国特許第6,210,891号)のように、塩基を組み込むと無機ピロリン酸塩の放出がある。この技術は、技術上公知であり、以下の反応シーケンスに基づく酵素発光性無機ピロリン酸塩(PPi)検出アッセイ(Nyren and Lundin,Anal.Chem.151,504〜509,1985)を用いる。
本発明によるデバイスの別の好ましい実施形態において、各微細位置は、集積化ナノ流体i/oを提供する隣接の囲まれた親水性マトリクス回路を有するマイクロ反応器を含む。この実施形態において、集積化ナノ流体i/oは位置特定反応条件を達成するために用いることができる。マイクロ反応部位中に導入される1以上の化学物質の濃度は、アッセイ手順の間計器により制御することができる。これは、今、用量反応滴定、および濃度段階変更後の迅速な過渡測定、ならびに他の化学物質の部位特定制御を可能とする。多ポンプアレイの制御は、電動学的ポンプ電極アレイのパッシブ・マトリクスアドレス指定を通しての、公知技術の平面ディスプレイデバイスのマトリクスアドレス指定に類似するやり方にある。各微細位置での反応条件の制御の一つの好ましい方法は、フィードバック制御を用いる。こうした体系において、各微細位置でのマイクロ反応器は、試薬または試料溶液を囲まれたリザーバから反応器へ供給する1以上の独立にポンプ注入される流体入力を提供する囲まれた親水性マトリクス回路に接続される。各独立にポンプ注入されるリザーバは、制御されたやり方および標識化分子においてマイクロ反応器に供給するために必要な化学物質を含有する。マイクロ反応器中の特定標識化分子の濃度は、標識を含む隣接リザーバからマイクロ反応器中にポンプ注入される材料の量を示す。測定プローブは、マイクロ反応器中の反応化学物質および標識の濃度を探知する。標識の濃度は、標識を含有するリザーバからのポンプを制御するためにフィードバックされる。好ましい実施形態において、マイクロ反応器アレイは、アッセイ反応が蛍光または発光シグナルを生成する場合がそうであろうように、光学的に走査される。この場合において、ポンプ制御性標識化分子は、また、それがアッセイ用に用いられるのと同じ光学的走査システムにより測定することができるように発光性である。各試薬リザーバは、各標識がアッセイ反応に含まれる発光分子により出される波長とはまた異なるそれ自身の異なる波長で発光するそれ自身の発光標識を含有する。
本発明によるデバイスの一つの好ましい実施形態において、各微細位置は、マイクロ反応器が1または少数の細胞または細胞溶解物を含有する隣接の集積化流体i/oを有するマイクロ反応器を含む。集積化流体i/oは、反応微小体積への、(細胞から押し出される細胞成分または化学物質の単一細胞反応または高感度アッセイ研究用の反応微小体積への)原位置での制御された試薬の添加を可能とする。
我々は、種々の成分材料およびそれらの輸送特性の試験で用いる、薄膜技術での図1に示すデバイスを組み立てた。これらの薄膜の囲まれた親水性マトリクスデバイスは、標準4インチ径の研磨シリコン・ウエハー上に組み立てられた。
我々は、薄膜または薄および厚膜組合せ技術において図2に示されるデバイスを組み立てた。図2は集積化トップ・サイド電極を有する囲まれた親水性マトリクスデバイスの一つの変形である。このデバイスにおいて、4個の離れた金電極215、216、217および218を有する平面絶縁性シリコン基板200がある。我々は金を有する酸化ケイ素基板(図1のデバイス用の手法のとおりに成膜され光処理された)を用いた。末端204および205を有する親水性マトリクス輸送通路202を、末端204を電極217上にしてそれと接触させ、末端205を電極218上にしてそれと接触させて、4個の離れた電極に接触するように位置付けた。
図1構成の薄膜デバイスおよび図2構成の薄/厚膜組合せデバイスの両方を組み立ててきて、それらの水吸収特性を調査した。我々は、図1の配置図により薄膜親水性マトリクスデバイスを組み立てた。それらは酸化物被覆シリコン基板上にポリ−イソプレン絶縁化金電極を含んだ。我々は、2種類の親水性マトリクスを有するデバイスを組み立てた。一つは、前述のように組み立てたドライエッチング化、7マイクロメートル厚さのマイクロ多孔質セルロース・アセテート層を含むマイクロ多孔質マトリクスであった。他は、ナノ多孔質ポリビニルアルコールであった。通路次元は、W=60マイクロメートルおよびL=500マイクロメートルであった。リザーバは、X=1.2mm掛けるY=2.4mmであった。リザーバパッド上に溶解試薬を微細分配することにより、試薬をリザーバ中に導入した。10マイクロメートル厚さのPI−PDMS膜であるガス透過性絶縁体を、親水性マトリクス上にトリクロロエチレン10%溶液からのスピンコーティングにより塗布した。
我々は、濡れ後の親水性マトリクス材料の輸送特性を研究するために図2の構成を用いた。候補の親水性マトリクス材料を、平面基板上の輸送通路中に組み立て、表4中に並べられる方策により処理し、次に、さらに加工して図2に示されるような平面基板上に囲まれる親水性マトリクスデバイスを形成した。
我々は、表4のデバイス番号1を評価した。2mMリン酸緩衝液の水溶液を室208中に、水を中央室209に導入し、流出室210は最初空であった。大きな電極217(これは供給源室208に近接して親水性マトリクス通路に接触した)と500マイクロメートルx500マイクロメートル寸法の接点を有する輸送路において親水性マトリクスに接触する電極216間に、電圧をかけた。かけた電圧は、通路に沿っての電解質の電動学的流動を駆動するための動力を提供した。電極215および218は電位計に接続されて通路に沿っての各位置での電圧を探知した。給与電圧が216で0Vに対して217上で+10Vである(輸送通路にわたる電圧降下は6Vであった)場合、電極316の分極は1.5V、電極317の分極は0.5V、電流は2マイクロ−アンペアであった。満杯の供給源室208から当初空であった流出室210への通路に沿って流体流れがあった。空の流出室210に集められる流体量対時間を、形成水滴の径対時間を監視することにより容量分析で推定した。我々は、このポンプに対して6Vで秒当り0.1マイクロリットルと推定した。これは、正の供給源電極から離れて流出室に至る約1x10-4cm2/Vsの推定電気浸透移動度をもたらした。
我々は、多孔質材料のゼータ電位を調整するために、界面活性剤の使用を調査した。表4のデバイス2に関する輸送実験において、我々は、未処理のマイクロ多孔質のセルロース・アセテート/セルロース・ナイトレートマトリクスが、孔表面上の固定化負電荷のせいで低ゼータ電位を有し、一部の電気浸透ポンピングが起こることを見出した。我々は、溶液成形されたマイクロ多孔質セルロース・アセテートを含む表のデバイス7を用いて行われる輸送実験に関する類似の結果を得た。
集積化トップ・サイド電極を有する囲まれた親水性マトリクスデバイスの別の実施形態を図3に示す。この実施例の注入器−ポンプデバイスは、本発明の集積化流体i/oを有するマイクロ反応器アレイの基本的な構築物である。
Claims (15)
- 電気絶縁基板、
マトリクス通路が親水性マトリクス通路に沿って電位生成用動力供給源とのそれぞれの電気接触用の一対の離れた接触位置を有する、溶質の動電学的輸送用の基板上の親水性マトリクス通路、
基板上に支持されると共に、動力供給源に接続するための接触端および接触位置の一つでの親水性マトリクスとの電気接触用のマトリクス端を有する電極、
初期に乾燥しており、マトリクスの水吸収率を増大させるための湿潤剤を含む、マイクロ多孔質であるマトリクス、
絶縁体が水蒸気透過性である、絶縁体と基板間のマトリクスを密閉するための親水性マトリクスを囲む絶縁体、および
絶縁体を通しての水性溶質通過用のマトリクス上の絶縁体中のオリフィス、
を含む、親水性マトリクス通路がそこを通しての水性溶質の電気浸透輸送用の固定化電荷を有する水性溶質輸送用の囲まれた親水性マトリクスデバイス。 - 基板上に支持される一対の電極を含み、それぞれの電極は動力供給源に接続するための接触端、および接触位置の一つでのマトリクスに対する電気接続用のマトリクス端を有する、請求項1に記載のデバイス。
- 親水性マトリクスが、初期、それが実質的に非導電性である乾燥および不活性状態にあり、囲む絶縁体を水性環境にさらすと、絶縁体を通しての水蒸気の輸送により湿った状態に移行する、請求項1に記載のデバイス。
- 絶縁体がオリフィスを通しての毛細管作用によりマトリクス中への水の組込みを可能とするためにガス透過性である、請求項3に記載のデバイス。
- 湿潤剤が、水中に溶解する場合、溶液の粘度が純水よりも有意により高くない濃度で純水よりも有意により少ない水蒸気圧を有する水溶液を形成する低分子量中性分子である、請求項1に記載のデバイス。
- 湿潤剤が、尿素、アラニン、オルシニン、プラリーヌ、リジン、グリシン、ポリオールおよび砂糖、蔗糖、グルコース、キシリトール、ソルビトール、マンニトール、乳糖、マルトース、ラクツロース、グリセロール、プロピレン・グリコール、クエン酸、酒石酸、リンゴ酸およびそれらの組合せの群から選択される、請求項5に記載のデバイス。
- 電極およびマトリクス通路が接触位置で離れており、電気接触が、接触位置でマトリクス中に含まれ、マトリクスが乾燥状態にある場合初期に乾燥および非導電性状態にありマトリクスが濡れると導電性が与えられる親水性物質により達成されると共に、濡れの後接触位置で電極とマトリクス間の空間を電気的に橋渡しする、請求項2に記載のデバイス。
- 親水性マトリクス通路がそこを通しての水性溶質の電気浸透輸送用の固定化電荷を有する、請求項1に記載のデバイス。
- 親水性マトリクスがさらに酸化還元添加剤を含有する、請求項1に記載のデバイス。
- 電極対の一つが酸素還元反応を支持するためのカソード電極として構築され、囲む絶縁体が絶縁体を通しての酸素の側方拡散を可能とするためガス透過性である、請求項1に記載のデバイス。
- 電極対の一つが水酸化反応を支持するためのアノード電極として構築され、囲む絶縁体がガス透過性絶縁体を通しての側方透過による電極領域からの酸素除去を可能とするためガス透過性である、請求項1に記載のデバイス。
- 親水性マトリクス通路がさらに電動学的輸送によりマトリクス通路に沿って輸送しようとする試薬を含有するためのリザーバを含む、請求項1に記載のデバイス。
- 輸送通路がマトリクスリザーバと絶縁体中のオリフィス間に位置する空隙を含む、請求項12に記載のデバイス。
- マトリクスがさらに他の電極とオリフィス間に置かれる第2親水性マトリクスリザーバを含む、請求項12に記載のデバイス。
- 第2リザーバがオリフィスを通して電動学的にポンプ注入されようとする試薬を含有する、請求項14に記載のデバイス。
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US10/307,468 US7201833B2 (en) | 2001-06-04 | 2002-12-02 | Integrated solid-phase hydrophilic matrix circuits and micro-arrays |
PCT/CA2003/001843 WO2004050243A1 (en) | 2002-12-02 | 2003-11-27 | Integrated solid-phase hydrophilic matrix circuits and micro-arrays |
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