JP2017104863A - 圧力駆動プラグによる輸送と反応のための装置および方法 - Google Patents
圧力駆動プラグによる輸送と反応のための装置および方法 Download PDFInfo
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Abstract
【解決手段】基板の第1流路へ搬送流体を導入する手段(ステップ)と、搬送流体に対して非混和性を持つ少なくとも2つの異なるプラグ流体を1つ以上のプラグ形成領域の第1流路へ導入する手段と、プラグ流体混合物を含む少なくとも1つのプラグを形成するために基板で流体の流れを誘発することを目的として第1流路に圧力を適用(加圧)する手段を備え、プラグ断面積がプラグ形成領域の第1流路断面積と本質的に同一であることを特徴とする、基板内部の少なくとも1つのプラグの内部における反応を誘導する方法。
【選択図】なし
Description
非線形力学は、マイクロフルイディック(微細流体)とともに、本発明による装置の設計および方法において中心的な役割を果たす。マイクロフルイディックは、通常、ミクロレベルの寸法である流路網(チャンネル・ネットワーク)を通り流体の輸送処理を行う。(「チップ上の実験室(LOC)」とも称される)マイクロフルイディック・システムは、マイクロスケール化学または生物学的分析(マイクロ総合分析システム)の手段となりうる。マイクロフルイディック・システムの主な利点は、その高速試剤と低消費量にある。したがって、医療診断および高度な処理能力を伴うスクリーニングの分野において非常に有望である。マイクロフルイディック・システムの高度な平列構造は、巨視的な量におよぶ化学的および生物学的な化合物合成(例:化学兵器破壊・調合薬合成)の手段となりうる。その利点はより高度に物質および熱輸送を制御しうるということである。
発明による基板内部反応の伝導方法とは、基板第1流路に搬送流体を導入すること、第1流路に少なくとも2本のプラグ流体を導入すること、そして、プラグ流体の混合物を含む実質上同一のプラグを形成すべく基板内流体の流れを誘導するために第一流路に圧力を加えることが可能であるものとする。プラグ流体は搬送流体に対し不混和性を持つ。プラグ形成中に、プラグ断面は第1流路断面に実質的似ているため、プラグが第1流路の壁全体に著しく接することになる。プラグ形成後、プラグ断面は流路断面より縮小する可能性がある。搬送流体の薄い層が消える場合もあるが、通常、この層は流路の壁とプラグの間に存在する。一般的に、流路における初期形成時と各プラグサイズが著しく類似する。さらに、流路内プラグのキャピラリー数は、一般的に1未満、というよりも ≦約0.2が好ましく、さらに ≦約0.1がより理想である。
(項目1)
基板の第1流路へ搬送流体を導入する手段(ステップ)と、搬送流体に対して非混和性を持つ少なくとも2つの異なるプラグ流体を1つ以上のプラグ形成領域の第1流路へ導入する手段と、プラグ流体混合物を含む少なくとも1つのプラグを形成するために基板で流体の流れを誘発することを目的として第1流路に圧力を適用(加圧)する手段を備え、プラグ断面積がプラグ形成領域の第1流路断面積と本質的に同一であることを特徴とする、基板内部の少なくとも1つのプラグの内部における反応を誘導する方法。
(項目2)
搬送流体が油を含むことを特徴とする、請求項1に記載の方法。
(項目3)
搬送流体にフッ素化物を含むことを特徴とする、請求項1に記載の方法。
(項目4)
フッ素添加油がパーフルオロデカリンまたはパーフルオパーハイドロフェナントレンであることを特徴とする、請求項3に記載の方法。
(項目5)
搬送流体が少なくとも1つの界面活性剤を含むことを特徴とする、請求項1に記載の方法。
(項目6)プラグ流体の少なくとも1つが試剤と溶媒を含むことを特徴とする、請求項1に記載の方法。
(項目7)
プラグ流体の少なくとも1つが溶媒と界面活性剤を含むことを特徴とする、請求項1に記載の方法。
(項目8)
プラグ流体が少なくとも1つの入口を通って導入されることを特徴とする、請求項1に記載の方法。
(項目9)
プラグ流体の体積流量調節によりプラグに含まれるプラグ流体の濃度を調節する手段をさらに備えた、請求項1に記載の方法。
(項目10)
プラグがキャピラリー数<約0.2で形成されることを特徴とする、請求項1に記載の方法。
(項目11)
プラグ流体の反応により少なくとも1つのプラグ内部に不溶性反応生成物が形成されることを特徴とする、請求項1に記載の方法。
(項目12)
プラグ流体の反応により少なくとも1つのプラグ内部に溶性反応生成物が形成されることを特徴とする、請求項1に記載の方法。
(項目13)
プラグ流体が単一の入口を通って第1流路へ導入されることを特徴とする、請求項1に記載の方法。
(項目14)
入口における又は入口前のプラグ流体が特異的な(はっきりと識別できる)層流であることを特徴とする、請求項13に記載の方法。
(項目15)
プラグ流体が2つ以上の入口を通って第1流路へ導入されることを特徴とする、請求項1に記載の方法。
(項目16)
プラグ内におけるプラグ流体の混合を加速する手段をさらに備えた請求項1に記載の方法。
(項目17)
流路に沿った幾何学様式(形状)の変化により混合が加速されることを特徴とする、請求項16に記載の方法。
(項目18)
流路が1つ以上の曲がり角、屈曲、および直線部またはそれらの組み合わせを備えることを特徴とする、請求項17に記載の方法。
(項目19)
「ベーカーによる変態の(補助)定理」の実装を目的として設計された流路形状を通してプラグを流すことにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目20)
プラグ流体または搬送流体の少なくとも1つの構成を変化することにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目21)
プラグ流体または搬送流体の少なくとも1つの粘度を変化することにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目22)
流路壁のパターンを変化することにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目23)
第1流路または分岐流路の少なくとも一部分の親水特性を変化することにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目24)
第1流路または分岐流路の少なくとも一部分の電荷を変化することにより混合が加速されることを特徴とする、請求項16に記載の方法。
(項目25)
少なくとも1つのプラグが第1流路のプラグ形成領域下流にある別のプラグと融合する手段をさらに備える、請求項1に記載の方法。
(項目26)
第1流路および基板上の第2流路へ搬送流体を導入する手段を備えた第1および第2流路が流体交流(伝達)することを特徴とする、および、搬送流体に対して非混和性を持つ第1プラグ流体を第1プラグ形成領域の第1流路へ導入する手段と、搬送流体に対して非混和性を持つ第2プラグ流体を第2プラグ形成領域の第2流路へ導入する手段と、第1プラグ流体を含む第1プラグ集合体そして第2プラグ流体を含む第2プラグ集合体の形成を目的として基板で流体の流れを誘導するために圧力を適用(加圧)する手段を備えた、プラグ断面積がプラグ形成領域の流路断面積と本質的に同一であることを特徴とする、そして、第1プラグ集合体からの少なくとも1つのプラグが第2プラグ集合体からの少なくとも1つのプラグと融合することを特徴とする、基板内部における反応を誘導する方法。
(項目27)
プラグの第1および第2集合体の各断面が本質的に類似していることを特徴とする、請求項26に記載の方法。
(項目28)
プラグの第1および第2集合体が異なる相対速度であることを特徴とする、請求項26に記載の方法。
(項目29)
第1流路においてプラグ形成領域下流の2箇所以上へとプラグを分裂させる手段をさらに備えた請求項1に記載の方法。
(項目30)
少なくとも1つのプラグを2箇所以上に分裂させ、従って、プラグ形成箇所の下流に第2流路が存在すことを特徴とする空間(流路)を通過して第1プラグ集合体が第2流路へと送られる手段をさらに備えた請求項1に記載の方法。
(項目31)
第1流路の断面寸法が第2流路の断面寸法と異なることを特徴とする、請求項30に記載の方法。
(項目32)
第1流路の断面寸法が第2流路の断面寸法とほぼ等しいことを特徴とする、請求項30に記載の方法。
(項目33)
第1流路内の圧力が第2流路の圧力と異なることを特徴とする、請求項30に記載の方法。
(項目34)
第1および第2流路の合流地点またはその付近に収縮(圧縮)作用が存在することを特徴とする、請求項30に記載の方法。
(項目35)
搬送流体からの少なくとも1つのプラグを分離する手段をさらに備えた請求項1に記載の方法。
(項目36)
第1流路のプラグ形成領域下流において少なくとも1つのプラグの存在を検出する手段をさらに備えた請求項1に記載の方法。
(項目37)
反応生成物の検出をさらに備えた請求項1に記載の方法。
(項目38)
反応監視能力をさらに備えた請求項1に記載の方法。
(項目39)
反応速度の監視能力をさらに備えた請求項1に記載の方法。
(項目40)
プラグの少なくとも1つの光学特性を測定する能力が監視機能に含まれることを特徴とする、請求項38に記載の方法。
(項目41)
搬送流体およびプラグ流体の屈折率が本質的に類似していることを特徴とする、請求項1に記載の方法。
(項目42)
基板流路沿いの一箇所以上で監視が行われることを特徴とする、請求項38に記載の方法。
(項目43)
多大なる数の基板を並行して消耗する機能をさらに備えた請求項1に記載の方法。
(項目44)
流体を一定期間停止する機能をさらに備えた請求項1に記載の方法。
(項目45)
重合反応を特徴とする、請求項1に記載の方法。
(項目46)
搬送流体を基板の第1流路へ導入する手段と、少なくとも1つのプラグ形成領域における少なくとも第1および第2プラグ流体を第1流路へ導入する手段と、少なくとも第1および第2プラグ流体を備えるプラグ形成を目的として基板における流体の流れを誘発するために第1流路に圧力を適用(加圧)する手段を備えた、少なくともプラグのいくつかにおいて結晶が形成されることを特徴とする、物質の結晶化方法。
(項目47)
物質がナノ粒子であるところの、請求項46に記載の方法。
(項目48)
物質が、タンパク質、DNA、RNA、病原体、薬剤、薬剤同質異像または小型分子であるところの、請求項46に記載の方法。
(項目49)
物質が、タンパク質、DNA、RNA、病原体、薬剤、薬剤同質異像または小型分子2つ以上の錯体であるところの、請求項46に記載の方法。
(項目50)
第1プラグ流体がタンパク質を含み、第2プラグ流体が沈殿剤を含むことを特徴とする、請求項46に記載の方法。
(項目51)
第1および第2プラグ流体間の界面を作り出す手段をさらに備えた請求項50に記載の方法。
(項目52)
第1流路長さ分(流体が第1流路を通過する間)界面が十分に維持されることを特徴とする、請求項50に記載の方法。
(項目53)
プラグの蒸発をさらに備えた請求項46に記載の方法。
(項目54)
一定の期間にわたり流体の流れを停止する機能をさらに備えた請求項46に記載の方法。
(項目55)
反応により不安定中間体が生じることを特徴とする、請求項1に記載の方法。
(項目56)
非直線部を少なくとも1つ備えた少なくとも1つの流路と、前述流路と流体が交流している少なくとも1つのプラグ流体入口と、前述流路と流体が交流している少なくとも1つの搬送流体入口と、前述流路内部に流体の流れを生成する手段を備えた、少なくとも1つの基板を備える装置。
(項目57)
流体の流れが減速するところの、流路沿い膨張範囲1つ以上をさらに備えた請求項56に記載の装置。
「分析」という用語は典型的に、分類・試験・測定・最適化・識別・総合・追加・ろ過・分解または混合を含む、物理学・化学・生化学・生物学的分析に関係する工程または手段に関係する。
発明の一態様として、出口とは別の入口を備える第1流路を備える1つ以上の基板をともなう装備が装置にはなされている。状況に応じて、第1流路と流体が伝達する1本以上の第2流路(又は分岐流路)、第1流路と流体が伝達する少なくとも1つの搬送流体貯水溝、第1流路と流体が伝達する少なくとも2つのプラグ流体貯水溝、そして基板内部の流体に連続的な圧力を加えるための手段も装備可能である。
ソフトリソグラフィを例とする従来のフォトリソグラフィ(写真平版)技術またはマイクロ加工技術を用いてシリコン基板・チップまたは装置をエッチングすることにより、発明による基板と装置が製作される。ポリジメチルシロキサン を用いるマイクロフルイディック装置の製作は前ですでに述べられている。これらの製作およびその他の方法は、低コストの小型化された装置を提供する手段となりえ、ソフトリソグラフィの場合には、改善された柔軟性、安定性および機械的耐久性のような有利な特性を持つ強固な装置を提供する手段となりえる。好ましくは、光学的検出が用いられる場合、プラグ・搬送流体・および基板材質などから発する光拡散性が発明により最小限に保たれる。発明による装置は、比較的低コストでセットアップが簡単である。
発明による様々な流路、基板および装置は、主としてプラグ形成・操作のために使われる。
C.n. = Uμ/γ Eqn.(1)
から算出されるキャピラリー数C.nが低数値の時に、選択的プラグ形成が生じる。 等
式 (1) において、Uは流速、μはプラグ流体または搬送流体の粘度、そしてγは水と界面活性剤の界面における表面張力である。
図7(a)-(b)は、同値の総流速にて屈曲流路を通るプラグ内急速混合(a)と層流内のごくわずかな混合作用(b)を図示するマイクロ写真(10p.s露光)を示す。水性流は、図7(a)-(b)に示される吸入口700番〜705番に導入された。図7(c)と7(e)において、Fluo-4は吸入口706番と709番に導入され、緩衝液は吸入口707番と710番に導入され、CaCkは吸入口708番と711番に導入された。図7(c)は緩衝ナトリウム・モルホリノプロパンスルホン酸水溶液(aqueous sodium morpholinepropanesulfonate buffer) (20μM、pH 7.2)内のFluo-4溶液(54μM)とCaCl2溶液(70μM)から成るプラグ内部の急速混合により生じる時間平均された蛍光性を示す偽色彩法マイクロ写真(2s露光、個々のプラグは見えない)を示す。この緩衝液は中間水性流としても用いられた。図7(d)は、プラグを通り移動した距離の関数(左)と所定流量でその距離を移動するのに要した時間の関数(右)に基づき、画像から得た相関的且つ正規化補正後の蛍光強度(I)の線グラフを示す。全流路幅にわたる強度が測定された。「PFD:水」の総体積流(μL min-1の流量)は、0.6 : 0.3、 1.0 : 0.6、12.3 : 3.7、10: 6、20: 6であった。図7(e)は、(c)で使用された溶液の層流における小規模な混合から生じる弱い蛍光性の偽色彩法マイクロ写真(2s露光)を示す。全流路の深さは45μm。吸入口流路の幅は50μmで、屈曲流路の幅は28μm:Re(レイノルズ数) -(約)5.3 (水)、 -(約)2. 0 (PFD)。
ST(tn)=ST(t0)× 2-n Eqn.(2)
により得られる指数関数の減少が光条厚にもたらされる。等式(2)において、ST(tn)はtn時の光条厚さ、ST(t0)はt0時の初期光条厚さとして示され、nはフォールディング‐アンフォールディング・方向転換作用の数を示す。
n×22n ≒ dU/D Eqn. (3)
から得られる。等式(3)において、nはサイクル数、Uは流速、Dは拡散定数を示し、一サイクルは6dに等しいと想定され、さらに、対流と拡散の時間尺度が一致するときに混合が生じるとする。混合時間は、主としてサイクル数によって定められる。当結果は、混合が、単に流路直径に正比例して加速されるのではないだろうことを示す。例として、dが因数10の数により減少するとき、混合時間はd×Log(d)=10×Log(10)の因数により減少する。設計が適切になされている流路の場合、1μm流路の混合時間は約20μsに制限されるかもしれない。しかしながら、(タンパク質結晶化等に関係する)低流量又は長い流路の場合でさえもなお、著しい混合が生じえる。さらに、理論に関わらず、因数10の数による流量Uの増加は、因数Log (U)/U=(Log (10))/10の数による混合時間の減少につながると推測される。
本発明は、さらに基板内におけるプラグの融合方法を提供する(図12の上を参照)。プラグは前述で説明されたのように形成される。異なるプラグ流体を個別に流路へ導入することにより異なる試剤を含むプラグを形成することが可能である。異なる試剤を含む複数のプラグは、本質的に類似する又は異なる粘度を有するかもしれない。異なる試剤を含む複数のプラグは各々、本質的に類似する又は異なるサイズを有するかもしれない。異なる試剤を含む複数のプラグの相対速度が異なるという条件の下に、これらのプラグが流路において融合する。様々な方法で融合地点を制御することが可能である。その方法例として、プラグ流体入口の位置変化によるもの、(流体を形成するプラグの1つを第2流路へ導入する場合)流路合流地点の位置変化によるもの、プラグのサイズ変化によるもの、本質的に同サイズのプラグの粘度または表面張力変化によるもの、異なるプラグ集合体の輸送速度調節によるもの、などが挙げられる。
本発明はさらに、基板内プラグ分裂方法を提供する。第2流路がプラグ形成箇所下流にある開口(経路)を通して、プラグの始部を第2流路へ送ることによりプラグを分裂することが可能である、あるいは、流路の「Y字型」交差点でプラグを分裂しうる。両実施形態において、元のプラグは始部と別の部分に分かれて分裂する。そしてその後、各片は個別の流路(あるいは出口)へと送られる。一旦形成されたプラグが分割、あるいは、融合されたプラグが分裂しうるかのどちらかである。図6は、複数の入口(試剤A・B・C・D用入口601番・603番・605番・607番;水性流用入口602番・604番・606番)によりプラグ分割および融合の両機能を備えるマイクロフルイディック・ネットワークの一部を図示する概要図を示す。この概要図は、同時に誘導される2反応を示す。(最初の2反応による混合の中間である)第3反応は精密な時間的遅れを利用して誘導される。プラグは反応前と反応後のどちらでも分裂しうる。図6はさらに、初期混合物60(A+B)と初期混合物61(C+D)から、混合溶液62(A+B)と63(C+D)およびこれら四成分の混合物64(A+B+C+D)にいたる、様々な混合過程におけるプラグを示す。
本発明のシステムは、標準顕微鏡のような機器を用いての光測定に非常に適している。例として、PDMSは可視部において透明である。基板構築にPDMSを使う場合、PDMSネットワークを覆うか密閉するのにガラスまたは石英ガラスのカバースリップを手段としうる。それによって、可視光線、紫外線、または赤外線で特性化されうる一式の流路を構築しうる。蛍光測定は吸収測定より高感度が強いので、好ましくは、後者の代わりに前者を実行する。光学測定によりプラグを監視する場合、搬送流体およびプラグ流体の屈折率は、本質的に類似していることが好ましいが、場合によっては異なりうる。
発明による様々な装置および方法は、プラグ組成と特性の制御および操作を可能にする。例として、プラグ内部の試剤濃度の変形形態を可能にする。発明による一様態において、プラグ内の試剤濃度は、プラグ流体の相対流量を変えることにより変化される。これは従来のシステムにおいて可能であるが、混合速度が遅くおよび分散の問題によって作業が複雑になる。発明による方法は、単一設定(Setup)で濃度を変更することができるため、多数の実験的条件(「スクリーニング」)を同時にテストするのに都合がよい。したがって、例として、シリンジを取り外したり再度接続したりする必要がなく、また、上記の技術を用いてプラグ中の試剤濃度を変化するために発明によるシステムの入口を補充する必要もない。
発明による一様態において、圧力駆動による流れの分散はプラグ流体の連続的な流れに勾配を生成する手段となる。プラグを形成することによって、勾配が「固定」される(つまり、勾配形成の原因である分散がプラグによって止められる)。流れが水性でなければならないとは限らないが、水性流は様々な用途を備えている。例として、これらに限定されないが、その使用例を下記する。
本発明による装置と方法はまた、不安定中間体の合成および分離の手段となりうる。発明による装置を手段として形成された不安定中間体は、さらなる反応且つ又は分析に適した作りを伴っていること、又は、さらなる反応且つ又は分析に適しうるところの他の装置部に導かれることが好ましい。一様態において、不安定中間体形成のために相互反応をもたらす少なくとも2つの異なるプラグ流体を使用する。基板の動力伝達路沿いに不安定中間体が形成されるときに、例として反応速度に関する情報を得ることができる。このような不安定中間体は、不安定中間体を含むプラグを別のプラグ流体と融合することにより、別の試剤とさらなる反応を示しうる。不安定中間体の例としてはこれらに限定されないが、遊離基、有機イオン、リビングイオン重合鎖、リビング有機金属の重合体鎖、リビング遊離基重合鎖、局部てにフォールドされたタンパク質または他の高分子、引き伸ばされた(Strained)分子、結晶化核、合成ナノ粒子核などが挙げられる。
マイクロフルイディック装置において、システムの寸法が縮小するとともに表面積対体積率が増加するため、表面化学の制御は特に重要である。特に、タンパク質と細胞の吸着に概して不活性な表面は、マイクロフルイディックにおいて非常に貴重な存在となる。ポリエチレングリコール(PEG)およびオリゴエチレングリコール(OEG)は表面上タンパク質の非特異性吸着を減少すると認められている。金上のOEGを末端にもつアルカンチオール自己組織化単層膜は、モデル基板として使われており、タンパク質吸着抵抗を実証および綿密に特性化する手段として利用されてきた。溶液が露出される表面化学は、シリコーン表面上の自己組織化単層膜、またはPDMS上のグラフトPEG含有重合体およびマイクロフルイディック装置製作に用いられる他の物質を生成することにより制御することができる。しかしながら、このような表面は大量生産するのが困難かもしれず、また、製作後(例:貯蔵または使用中)に不安定になりうる。
発明による装置および方法はまた、典型的にわずかな試剤を様々な濃度で混合して監視または分析するマイクロタイター・プレートなどにおいて行われる実験の手段となりえる。これは、例として、必要な場合は流れを止め、可変組成を伴うプラグを形成した後にプラグを監視することにより実施されうる。評価分析(Assays)を位置的に暗号化(コード化)しうる。すなわち、プラグ組成は流路内プラグ位置から推定されうるということである。発明による装置および方法は、高性能なスクリーニングの使用することもでき、その評価分析法は例として診断および新薬発見に有用である。特に、発明による装置および方法は、比較的高速の反応速度測定を行なう手段とすることができる。
ΔP=28.42 U μl/a b Eqn.(9)
等式(9)において、U(m/s)は流速(キログラム/メーター-秒)、kg m-1s-1)は流体の粘度、l (m)は毛管長さ、a(m)は毛管高さ、そしてb(m)は毛管幅を指す。通常、マイクロフルイディック装置がどれだけの圧力に耐えられるかには物理的限界がある(例: PDMSは約3気圧、ガラスおよびSiは約5気圧)。当限界は小規模な流路において非常に重要であり、流路の全長に限界を及ぼし、したがって測定の(最大圧力÷混合距離の流量が維持されうる)ダイナミック・レンジを制限することになる。
確率的挙動は、多くの化学反応(例:無機化学薬品反応といった自己触媒反応、燃焼、爆発)および鎌状赤血球貧血の重合作用において認められる。結晶化も自触媒作用工程の一つであると言えうる。これらの反応に対する理論的対応(処理)方法のいくつかが開発されてきている。これらの反応は、混合に対して高度に敏感である傾向がある。広範囲にわたり研究されてきたNaClO2とNa2S2O3間に生じる確率的な自触媒作用の化学反応(亜塩素酸塩―チオ硫酸塩反応)を考えてみる。当反応メカニズムを、反応(1)と(2)により説明することができる。
S2O3 2-+2 ClO2 -+H2O 2SO4 2-+2H++2Cl- rate (v) α[H+]2[Cl] (2)
[H+]はH+の濃度を表わす。低速反応(1)は、反応混合物に対して若干のアルカリ性pH=7.5で優性となり、反応混合物のアルカリ性pHを維持する(当反応速度vが[H+]に正比例するため、その反応作用によりH+が消費され、自抑制性をもたらす)。反応(2)は、酸性pHで優性となる(当反応速度は[H+] 2[C1-]に比例して変動するため、その反応作用により両H+とC1+が生成され、超自触媒作用をもたらす)。図21は、曲線211・212番に関連する2反応の反応線図を示す。特定のpH価で、当2反応(ここで反応211番および反応212番とする)の速度は、不安定限界点において等しくなる。当限界点におけるNaC102およびNaS203反応混合物の寿命はその攪拌工程に極めて依存する。攪拌の非存在下で、溶液の確率的変動は[H+]の局部的増加をもたらす。このような[H+]増加による反応212番の加速現象はわずかなものだが、反応211番は[H+]に高次依存性を持つため及ぼされる加速効果がはるかに大きい。
Co (III)- [5-Br-PAPS] (還元)+HSO5 -→
Co2++[5-Br-PAPS](酸化)+ HSO4-
(Co (III)-5-Br-PAPS)とペルオキソ1硫酸のバイオレット(すみれ色の)混合物へCo2+を少量追加することにより、急速な色素減少が生じて無色溶液が生成される。当変質現象前に生じる時間的遅延は、溶液に追加されるCo2+の量に依存する。当反応は1×l0-1mole/Lといった低いCo2+濃度を検出する手段とされてきた。他のイオン(V (V)、 Cr (III)、 Cr (VI)、 Mn (II)、 Fe (II)、 Ni (II)、 Cu (II)、およびZn (II))の存在下において、反応は優れた選択性を示す。
本発明にのっとって、基板内反応を処理する方法が提供される。本発明の基板内に反応原系を含む2つ以上のプラグ流体を導入することにより、反応が導かれる。
移動中のプラグ内部の流れは、重合体と微粒子を分離する手段となりうる。まず最初に移動中プラグ内の流れを使ってプラグ内部の重合体または微粒子(例:プラグの前後左右どれかに存在する余分な重合体)の分布を確立し、そしてその次に、分裂を利用して高濃度の重合体または微粒子を含むプラグの一部を分離および隔離するといった方法で、プラグを分離工程に利用することができる。二個の重合体または微粒子がプラグの内部に存在して異なる分布を確立している場合、重合体または微粒子の分離に分裂を利用しえる。当アプローチは、例としてこれらに限定されないが次のものいずれかをマイクロフルイディック・チップ上で達成する際に有用となりうる:分離、精製、濃縮、非膜透析および濾過。
発明による装置および方法は、既存の結晶化法および例として新型タンパク質のスクリーニングおよび結晶化技術に適応できる他の方法の高速且つ低価格な小型化を可能にする。発明による結晶化法は様々な薬剤、物質、小型分子、高分子、コロイドまたはナノ粒子、あるいはこれらのあらゆる組み合わせに適用しうる。用途に適した多くのタンパク質構造が結晶化に対する抵抗性を有するために未定義のままである。さらに、関心をそそる多くのタンパク質はマイクログラムレベルの量においてのみ利用可能である。したがって、スクリーニング工程での分析を少量のタンパク質だけで実施せざるをえない。現在の結晶化スクリーニング技術は、通常、ミリグラム単位で、タンパク質結晶化の理想条件を定義する。
移動中プラグ内部の流れは、重合体と微粒子の分離に使用することができる。まず最初に移動中プラグ内の流れを使ってプラグ内部の重合体または微粒子(例:プラグ前後左右の側面内部のいずれかに存在する余分な重合体)の分布を確立し、そしてその次に、分裂を利用して高濃度の重合体または微粒子を含むプラグの一部を分離および隔離するといった方法で、分離工程にプラグを使用できる。2種の重合体または微粒子がプラグ内部に存在する時にそれらが異なる分布を確立している場合、重合体または微粒子を分離するために分裂を手段とすることができる。
親水性流路面を備えるマイクロフルイディック装置は、ポリジメチルシロキサンにおける急速プロトタイピングにより製作された。流路面は、シラン処理または熱処理のいずれかを経て疎水性とされた。流路面をシラン処理するために、(トリデカフルオロ-1,1, 2,2-テトラハイドロオクチル)-1-トリクロロシラン(United Chemical Technologies, Inc.社 )の蒸気を搬送ガスとして、約1気圧より約40〜60mm Hg高圧で乾燥窒素を有する装置入口に適用した。それと同時に真空作用を、大気圧より約650mm Hg低圧で装置出口に適用した。約1〜3時間シラン蒸気があてられた。流路を熱処理するために、装置を約3時間およそ120 ℃の炉(オーブン)の中に放置した。ちなみに、代替として、パナソニック製1300ワット電子レンジ「The Genius」の出力(温度調整)を10に設定てし約10分間、装置を加熱することもできる。
図25A〜Cそれぞれの左側に、マイクロフルイディック・ネットワークおよび実験条件の概要図が示されている。図25A〜Cそれぞれの右側に、異なる濃度の水性流によるプラグの形成を図示するマイクロ写真が示されている。食用染料水溶液(赤/濃・緑/淡)および水により3本の流れが構成された。溶液3種の体積流量(μL/分単位の流量)が示される。濃い色の流れは薄い色の流れより粘着性が強い。したがって、濃い色の (粘着性強の)流れは、さらにゆっくりと移動し(mm/s単位の測定値)、所定の体積流量でより大きな流路の一画を占める。
長方形断面を持つマイクロチャンネル・ネットワークはPDMSにおける急速なプロトタイピングにより製作された。ここで、PDMSとしてDow Corning社シルガード・ブランド製品184シリコーン・エラストマー(Sylgard Brand 184 Silicone Elastomer)が使用され、そしてプラズマプレプII(Plasma PrepII、SPI Supplies社)で装置を密閉した。2〜4時間120℃で装置を焼成することにより装置表面に疎水性をもたらした。
異なる(T字型またはY字型の)流路合流地点、横断面および流量におけるプラグの融合を調査する実験が行なわれた(図33a-dを参照)。
図35b-cで示されるような収縮作用が存在しない流路網を使ってプラグの分裂を調査した。当実験の場合はプラグが分裂しお互いに90度の角度を成す2本の流路それぞれへと合流地点を通過した後に流れ込んでいったということを除いては、図34aに示されるものに類似した流路網が使用された(ここでいうプラグ流れは矢印によって指されている)。油および水性流(4:1の油:水性流比)は、入口3500と3501番へそれぞれ導入された。油のみの流れは流路3502番を流れた。全流路の断面積は50×50μm2であった。ここで適用された流量は4.3mm/秒だった。流路網の平面図を表わす図35a-cは、流路収縮(図35b-cに見られる収縮)の非存在下における合流地点を通過するときに当実施例のプラグは実施例3のプラグと比べると異なった動きをするということを示す。図35cが示すように、P1<P2の時に、プラグは合流地点を通り抜けた後にも原型を保っていた。さらに、プラグはより低圧(図35cにおけるP1)の流路に沿って流れ、その一方で間に入る油流れが合流地点で分裂した。合流地点における油流れの分裂は、分岐点または合流地点上流の流路内プラグ間の分離と比較して、圧力Pを伴う流路を流れるプラグ間の分離時間の短縮をもたらす。
図37は、確率的自己触媒反応の調査に関係している発明によるマイクロフルイディック装置における化学物質増幅に関係する実験設計を図示する。当事例は、酸に鋭敏なNaC1 O2・NaS2O3間の自己触媒反応を研究するにあたり本発明の装置をどのように利用しうるかを例証する。マイクロフルイディック・ネットワークの左側において、3本の流路から成る入口は、流路3702番経由で水性流を、流路3701番経由でエステルを、および流路3703番経由でエステラーゼを導入する。油は流路3713と3714番を通って流れた。エステルとエステラーゼ間の反応は、少量の酸を含むプラグ3704番をもたらす。マイクロフルイディック・ネットワークの右側において、5本の流路からなる入口は、入口3705番からNaC1O2を、入口3706番から水性流を、入口3707番からpH指示薬を、入口3708番から第2水性流を、および流路3709番経由でNaS203を導入する。搬送流体は流路3713と3714番を通って流れる。
発明による一様態において、制御されている自触媒システムによる順次的増幅は、自触媒単一分子を含むサンプルを、十分な高濃度の自触媒を含むサンプル内へと増幅する手段となる。これにより、増幅された自触媒が肉眼でも検出できうる。確率的挙動を示すシステムが高感度性および増幅を示すと推測されるが、様々な自触媒システムが発明にのっとって使用されうる。発明によるマイクロフルイディック装置による順次的増幅は分析的に標識付けられた反応を用いて例証することができる。無色Co2+イオンを生成するカリウム・ペルオキソ1硫酸を伴う酸化における、バイオレットbis[2- (5-ブロモ-ピリジルアゾ)-5- (N-プロピル基-N-スルホプロピル-アミノ酸-フェノラート]コバルト酸、(Co(III)-5-Br-PAPS)、の自触媒分解。ここで、Co2+イオンは、自触媒として役立つ(当反応に対する自触媒現象(m)のオーダーは未だ確立されていない。)。
Co2+ +[5-Br-PAPS](酸化) +HS04 -(3)
(Co (III)-5-Br-PAPS)とペルオキソ1硫酸のバイオレット混合物へCo2+を少量追加することにより、無色溶液を提供すべく急速な色素減少を生じる。当分解発生前に生じる時間的遅延は、溶液に追加されるCo2+の量に依存する。
図38は、発明によるマイクロフルイディック装置による、単一分子検出用の多段化学物質増幅用の方法を例証する。当事例は、Co2+イオンによって自触媒されたpH=7緩衝液(入口3802番から導入)内のCo(III)-5-Br-PAPS(入口3803番から導入)とKHSO4(入口3801番から導入)間自己触媒反応の使用を例証する。流路3804と3805番を通って油流れが流れることを可能とする。当反応混合物(プラグ3811番に含まれる)は不安定で、少量のCo2+3810番が追加されただけで急速に分解する(赤で表示)。したがって、当反応混合物は好ましくは敏速に混合され、直ちに使用される。反応混合物は、サイズが(1μm)3、(10 μm)3、 (100 μm)3のプラグ内ネットワークを介して好ましくは輸送される。マイクロフルイディック・ネットワークの左側において、分析用サンプルのおよそ1μm3のプラグが流路2本の合流地点(緑で表示)で形成される。そのCo2+イオンを含むプラグ、および反応混合物を含むプラグの融合は、急速な自己触媒反応に帰着する。さらなる大規模な反応混合物のプラグが増幅に用いられるところの増幅階段流によって、プラグ内のCo2+イオン各々を、一プラグ当たり約10l0個のCo2+イオンに増幅することができる。増幅の結果は視覚検知できる。(10μm)3のプラグは、およそ4x10-8mole/LのCo2+イオン溶液を供給するために第3流路のより大きな(100μm)3のプラグと好ましくは融合する。およそ10−9Lのプラグにおける自己触媒分解により約2.4×1010のCo2+イオン(4x10-5 mole/L)を伴うプラグ3809番が生成される。各分岐でプラグが費やす時間を制御するために、好ましくは当システムに対する慎重な制御がほどこされる。
いき通った研究がなされている酵素リボヌクレアーゼA(RNase A; EC 3.1. 27.5)のミリ秒単位のシングルターンオーバーの動力学(single-turnover kinetics)を測定するために、発明によるマイクロフルイディック・チップが使用される。従来、これらの測定にはおびただしい量の酵素消費量にともない高濃度な酵素と基板の両方が必要とされたたため、このような測定を行なう際にサンプル消費量が単にマイクロリットル以下にすぎないという事実は、マイクロフルイディック・チップを格別魅力的なものとする。
本発明のシステムおよび方法は例として数十マイクロ秒から数百秒にわたる時間を要するフォールディングの反応速度測定を実施するために好ましくは使われる。発明によるシステムと方法は、少量のサンプルのみでの反応速度測定を可能にするため、何百もの異なるRNA突然変異体のフォールディングを測定することができ、そしてフォールディングに対する突然変異の影響を確証することができる。発明による一様態において、RNAフォールディングの反応速度は、異なる位置で対となったFRETにより標識付けされあらかじめ合成されたアンフォールド(引き伸ばし)状態のRNA溶液にMg2+を入れることにより好ましくは測定される。
図15は、CdSナノ粒子155番の合成技術を図示する。一実験において、ナノ粒子がマイクロフルイディック・ネットワークにおいて形成された。マイクロフルイディック装置の流路横断面積は50μm×50μm。フッ化搬送流体(パーフルオロヘキサンとlH, lH, 2H, 2H-パーフルオオクタノールの10:1 v/v混合物)は、15μL/分で主要(メイン)流路を通って流れた。0.80mMのCdCl2水溶液と0.80mMの3-メルカプトプロピオン酸水溶液(pH=11.4)は8μL min-1で左端の吸込路151番を通って流れた。0.80mMポリリン酸塩Na(PO3)n水溶液(水様液)は8μL/分で中央の吸込路152番を通って流れ、そして、0.96mMのNa2S水溶液(水様液)は8μL min-1で右端の吸込路153番を通って流れた。
マイクロ流路網はポリジメチルシロキサン(PDMS)における急速なプロトタイピングを手段として製作された。
その後、インク流れは入口411、412、413番へと導入された。
実験中に、1.0μL/分の搬送流体の流れが確立され、次に、水溶液の流れが2.1μL/分の流量で確立された。プラグ形成がマイクロチャンネル内部に認められた。その後、出口からの圧力を加えてシリンジポンプを同時に止めることによりおよそ5〜10分間流れを停止した。
実験中に、1.0μL/分で油の流れが確立された。その後、水の流れが0.1μL/分で確立された。最後に、リゾチームと沈殿剤の流れが0.2 μL/分で確立された。プラグ形成がマイクロチャンネル内部に認められた。流路内部の流れが安定した後、水の流れを0まで減速した。その後、出口からの圧力を加えてシリンジポンプを同時に止めることによりおよそ5〜10分間流れを停止した。
発明にのっとって、全フッ素置換された位相に対して溶性である中性界面活性剤が、好ましくは正および負の電荷を持つ界面を作り出す手段とされる。水との相互作用によって(例:アミンまたはグアニジン基のプロトン化〔図24B〕又はカルボン酸基の脱プロトン化〔図24C〕によって)電荷を持ちえる中性界面活性剤が、好ましくは電荷を伴う表面を作り出す手段となる。
油/水の界面は、キャピラリー数(C.n.)を低数値に保つのに十分な(十分高い)表面引張力を伴わなければならない。不水溶性フッ素界面活性剤のフッ素界面活性剤/水の界面は特性化されていないが、これらの界面活性剤はヘキサン/水の界面上のスパンに関係するシステムで認められたもの(約20 mN/m)同様のものに、表面引張力を下げると推測される。水様液/フルオラス(fluorous)の界面の表面引張力は、ハンギングドロップ法によりフッ素界面活性剤の存在下で好ましくは測定される。これらのような測定用に特別に構築されたビデオ顕微鏡検査機器は界面の特性化に使用され成功結果を生み出している。図24は、パーフルオアルキル鎖およびオリゴエチレン・グリコール基を含むフッ化界面活性剤の合成を図示する。
図42は、流量変化による勾配形成に関係する実験を示す。当実験において、マイクロチャンネル・ネットワークはポリジメチルシロキサン(PDMS)における急速なプロトタイピングを手段として製作された。流路の幅および高さは両方とも50μm。パーフルオパーハイドロフェナントレンに含まれる10%のlH, lH, 2H, 2H-パーフルオデカノールが油として用いられた。0.5MのNaCl溶液におけるウォーターマン赤インク50%溶液からなる赤色水溶液は入口421番へ導入された。油は0.5μl/分で流路424番を通って流れた。水性流は入口422と423番へ導入された。流路にインク勾配を生じさせるために、水の総流量を0.01/分丁度の勾配率(Ramp Rate)で20秒間に0.03 μL/分から0.23μl/分へと徐々に上げた。同時に、インク流量を勾配率0.01μl/分で20秒間かけて0.25pl/分から0.05μl/分へと徐々に下げた。
図43は、勾配によるリソゾーム結晶の形成に関係する実験を図示する。流路領域436番が最適値域にある沈殿剤濃度に関連する一方、流路領域435と437番は沈殿剤濃度が非常に低い流路領域に関連する。当実験において、マイクロチャンネルのネットワークはポリジメチルシロキサン(PDMS)における急速なプロトタイピングを手段として製作された。流路の幅は150μm、高さは100μm。パーフルオパーハイドロフェナントレンの10%の1H, 1H, 2H, 2H-パーフルオデカノールが油として使用された。
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