JP2008502027A - 微小流体素子のための光学レンズシステムおよび方法 - Google Patents
微小流体素子のための光学レンズシステムおよび方法 Download PDFInfo
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Abstract
Description
本出願は、2004年6月7日に出願された米国仮出願番号60/578,106号(これは、本明細書中において、全ての目的のために、参考として援用される)に対する優先権を主張する。
本発明は、大まかには微小流体技術に関する。特に、本発明は、微小流体素子のチャンバ内で1つ以上のエンティティ(例えば、多量の流体内に浮遊している)を撮像する方法とシステムを提供する。より詳細には、本撮像方法と撮像システムは、微小流体素子内の1つ以上のエンティティに関連付けられた蛍光信号からの指標を用いる。微小流体素子に連結された蛍光体、化学発光、および生体発光リーダーを用いた微小流体方法およびシステムの技術は単なる例として適用されており、本発明がより広い範囲の適用可能性を有することは言うまでもない。
・身元確認処理(例えば、実父確定および法医学的用途)
・特定の疾病または遺伝性疾患に関連付けられた固有の核酸の発見と特徴付け
・特定の薬物行動に関連付けられた遺伝子発現プロファイル/配列の発見(例えば、薬理遺伝学上の目的、すなわち、固有の遺伝プロファイルに適合的/特に効果的な、あるいは危険ではない薬物を選択するため)
・遺伝子型解析および遺伝子発現解析の実施(例えば、識別的遺伝子発現研究)。
本発明によれば、微小流体システム技術が提供される。とりわけ、本発明は、微小流体素子のチャンバ内のある量の流体内に浮かんでいる1つ以上のエンティティを撮像する方法およびシステムを提供する。より詳細には、本撮像方法および撮像システムでは、微小流体素子内の1つ以上のエンティティに関連付けられた蛍光信号からの指標が用いられる。単なる例として、微小流体方法およびシステムの技術は、微小流体素子に連結された蛍光リーダー、化学発光リーダー、および生体発光リーダーを用いて適用されるが、本発明がより広い範囲の適用可能性を有することは言うまでもない。
本発明によれば、微小流体システム用の技術が提供される。特に、本発明は微小流体素子のチャンバ内である量の流体内に浮かんでいる1つ以上のエンティティを撮像する方法とシステムを提供する。より詳細には、本撮像方法と撮像システムは、微小流体素子内の1つ以上のエンティティに関連付けられた蛍光信号からの指標を用いる。微小流体素子に連結された蛍光体リーダー、化学発光リーダー、および生体発光リーダーを用いた微小流体方法およびシステムの技術は単なる例として適用されており、本発明がより広い範囲の適用可能性を有することは言うまでもない。
フィルタ1:中心波長485nm、スペクトルバンド幅20nmのフィルタ
フィルタ2:中心波長530nm、スペクトルバンド幅20nmのフィルタ、および
フィルタ3:中心波長580nm、スペクトルバンド幅20nmのフィルタ。
Claims (80)
- 微小流体素子からの選択された1つ以上の蛍光指標を撮像する装置であって、
少なくとも1つの微小流体素子内の少なくとも1つのチャンバに連結された撮像パスであって、該撮像パスは、該少なくとも1つの微小流体素子内の該少なくとも1つのチャンバ内の1つ以上のサンプルからの1つ以上の蛍光発光信号の送信を行い、該チャンバは、該撮像パスの法線の実空間寸法によって特徴付けられるチャンバサイズを有する撮像パスと、
該撮像パスに連結され、該チャンバに関連付けられた該1つ以上の蛍光信号を送信するよう構成された光学レンズシステムとを備える、装置。 - 前記光学レンズシステムは、前記実空間寸法のサイズを定まったレベルまで縮小させるよう構成され、該定まったレベルで縮小されたサイズの前記チャンバに関連付けられた前記1つ以上の蛍光発光信号を送信するよう構成された、請求項1に記載の装置。
- 前記少なくとも1つの微小流体素子は、微小流体寸法により特徴付けられ、前記光学レンズシステムは、前記微小流体寸法とほぼ同じサイズである前記少なくとも1つの微小流体素子のイメージを提供するよう構成され、かつ前記ほぼ同じサイズの前記チャンバに関連付けられた前記1つ以上の蛍光発光信号を送信するよう構成された、請求項1に記載の装置。
- 前記実空間寸法の前記縮小サイズと前記実空間寸法の比率が1未満であることを特徴とする、請求項2に記載の装置。
- 前記比率が0.9未満である、請求項4に記載の装置。
- 前記比率が0.5未満である、請求項5に記載の装置。
- 前記微小流体素子はエラストマー微小流体素子であり、前記少なくとも1つのチャンバは閉鎖反応チャンバである、請求項1に記載の装置。
- 微小流体素子の少なくとも1つのチャンバから選択された1つ以上の蛍光指標を撮像する方法であって、
少なくとも1つの微小流体素子の該少なくとも1つのチャンバ内の1つ以上のサンプル由来の1つ以上の蛍光発光信号を、該少なくとも1つのチャンバに連結された撮像パスに沿って送信する工程であって、ここで該少なくとも1つのチャンバは、該撮像パスの法線の実空間寸法によって特徴付けられるチャンバサイズを有する、工程、
該撮像パスに連結された光学レンズシステムを介して該チャンバに関連付けられた該1つ以上の蛍光発光信号を送信し、ここで該光学レンズシステムは該実空間寸法のサイズを定まったレベルまで縮小させるよう構成されている工程、
を包含する、方法。 - 前記実空間寸法の前記縮小サイズと前記実空間寸法の比率が1未満であることを特徴とする、請求項8に記載の方法。
- 前記比率が0.9未満である、請求項9に記載の方法。
- 前記比率が0.5未満である、請求項10に記載の方法。
- 前記微小流体素子はエラストマー微小流体素子であり、前記少なくとも1つのチャンバは閉鎖反応チャンバである、請求項8に記載の方法。
- 微小流体素子の1つ以上のチャンバから1つ以上の指標を撮像するシステムであって、
微小流体素子の空間領域の一部分の1つ以上のイメージを該微小流体素子の該空間領域の該部分から送信できる光学経路であって、該微小流体素子の該空間領域の該一部分は第1の寸法に特徴付けられる、光学経路と、
該光学経路の第1の部分に連結され、第1光学特性によって特徴付けられる第1レンズシステムと、
該光学経路の第2の部分に連結され、第2光学特性によって特徴付けられる第2レンズシステムと、
該光学経路の第3の部分に連結された検出器素子であって、該検出器素子は該空間領域の該部分の該1つ以上のイメージをキャプチャし、該検出器は該1つ以上のイメージをキャプチャするように構成され、該1つ以上のイメージは該検出器素子においてほぼ第1の寸法またはそれ以下の定まったサイズを有する検出器素子と
を備えるシステム。 - 前記定まったサイズは前記第1の寸法の約0.99またはそれ未満である、請求項13に記載のシステム。
- 前記第1レンズシステムおよび前記第2レンズシステムは、タンデムレンズシステムとして特徴付けられる、請求項13に記載のシステム。
- 前記微小流体素子は微小流体寸法により特徴付けられ、前記検出器素子は活性領域における空間寸法により特徴付けられる、請求項13に記載のシステム。
- 前記微小流体寸法は前記空間寸法とほぼ同じサイズである、請求項16に記載のシステム。
- 前記微小流体寸法は前記空間寸法より小さい、請求項16に記載のシステム。
- 前記微小流体素子は、少なくとも48個の閉鎖反応チャンバを備えるエラストマー微小流体素子である、請求項13に記載のシステム。
- 前記少なくとも48個の閉鎖反応チャンバは、ほかの反応チャンバのいずれからも流体的に分離されている、請求項19に記載のシステム。
- 微小流体素子の1つ以上のチャンバから1つ以上の指標を撮像する方法であって、
微小流体素子の空間領域の一部分の1つ以上のイメージを該微小流体素子の該空間領域の該部分から光学経路に沿って送信する工程であって、該微小流体素子の該空間領域の該部分は第1の寸法に特徴付けられる工程、
第1光学特性によって特徴付けられる第1レンズシステムを該光学経路の第1の部分に連結する工程、
第2光学特性によって特徴付けられる第2レンズシステムを該光学経路の第2の部分に連結する工程、
該光学経路の第3の部分に連結された検出器素子を用いて該空間領域の該部分の該1つ以上のイメージをキャプチャする工程であって、該1つ以上のイメージは該検出器素子においてほぼ第1の寸法またはそれ未満の定まったサイズを有する工程、
を包含する、方法 - 前記定まったサイズは前記第1の寸法の約0.99またはそれ未満である、請求項21に記載の方法。
- 前記第1レンズシステムおよび前記第2レンズシステムは、タンデムレンズシステムとして特徴付けられる、請求項21に記載の方法。
- 前記微小流体素子は微小流体寸法により特徴付けられ、前記検出器素子は活性領域における空間寸法により特徴付けられ、前記微小流体寸法は該空間寸法とほぼ同じサイズである、請求項21に記載の方法。
- 微小流体素子の撮像方法であって、
微小流体素子の96を超える数のチャンバに関連付けられた空間領域のイメージを送信する工程、
イメージ検出器素子に関連付けられて該微小流体素子の該空間領域のサイズとほぼ等しいサイズであるイメージ検出空間領域を用いて、該空間領域の該イメージをキャプチャする工程、
を包含する、方法。 - 前記イメージ検出空間領域により分割される前記空間領域はほぼ1である、請求項25に記載の方法。
- 前記イメージ検出空間領域により分割される前記空間領域はほぼ0.99以下である、請求項25に記載の方法。
- 前記イメージ検出空間領域により分割される前記空間領域はほぼ0.88以下である、請求項27に記載の方法。
- 前記イメージ検出空間領域はほぼ30.7mm×30.7mm以上である、請求項25に記載の方法。
- 前記イメージ検出空間領域はほぼ27.6mm×27.6mm以上である、請求項25に記載の方法。
- 前記イメージ検出空間領域はほぼ2048×2048画素領域である、請求項25に記載の方法。
- 前記イメージ検出空間領域はほぼ2048×2048画素領域を含み、該画素領域のそれぞれはほぼ15μm×15μm以上の空間寸法を有する、請求項25に記載の方法。
- 少なくとも2つの画素領域は前記チャンバの少なくとも1つに関連付けられている、請求項32に記載の方法。
- 少なくとも9つの画素領域は前記チャンバの少なくとも1つに関連付けられている、請求項33に記載の方法。
- 20個より多くの画素領域は前記チャンバの少なくとも1つに関連付けられている、請求項34に記載の方法。
- 微小流体素子の撮像方法であって、
微小流体素子の少なくとも定まった数のチャンバに関連付けられた空間領域のイメージを、1分未満のタイムフレームでイメージ検出空間領域を用いてキャプチャする工程であって、ここで該空間領域の該イメージの該キャプチャには実質的にスティッチングプロセスおよび/またはスキャニングプロセスがない工程を包含する、方法。 - さらに、前記微小流体素子の少なくとも前記定まった数のチャンバに関連付けられた前記空間領域の前記イメージを、10ミリ秒を超えるタイムフレームで前記イメージ検出空間領域を用いてキャプチャする工程を包含する、請求項36に記載の方法。
- 前記空間領域の前記イメージのキャプチャは30秒未満のタイムフレームで行われる、請求項36に記載の方法。
- 前記空間領域の前記イメージのキャプチャは15秒未満のタイムフレームで行われる、請求項36に記載の方法。
- 前記キャプチャは、前記定まった数のチャンバについて1分未満のタイムフレームで同時に行われる、請求項36に記載の方法。
- 前記キャプチャは、前記定まった数のチャンバを定まった温度範囲に維持しつつ行われる、請求項36に記載の方法。
- 前記定まった温度範囲は±2℃である、請求項41に記載の方法。
- 前記定まった温度は、PCRプロセスに関連付けられた周期的温度環境の一部分である、請求項41に記載の方法。
- 前記定まった数のチャンバは少なくとも96個以上である、請求項36に記載の方法。
- さらに、前記微小流体素子の少なくとも前記定まった数のチャンバに関連付けられた前記空間領域の少なくとも第2イメージを、前記1分未満のタイムフレームで前記イメージ検出空間領域を用いてキャプチャする工程を包含し、ここで前記空間領域の前記第2イメージの前記キャプチャは蛍光発光を表す、請求項36に記載の方法。
- 微小流体素子から選択された1つ以上の蛍光指標を撮像する装置であって、
少なくとも1つの微小流体素子内の少なくとも1つのチャンバに連結された撮像パスであって、該撮像パスは、該少なくとも1つの微小流体素子内の該少なくとも1つのチャンバ内の1つ以上のサンプルからの1つ以上の蛍光発光信号の送信を行う撮像パスと、
該撮像パスの第1の空間部分に連結され、該1つ以上の発光信号の送信用に備えられた光フィルタ素子であって、該1つ以上の蛍光発光信号から選択されたスペクトルバンド幅を送信するよう構成され、該1つ以上の蛍光発光信号に関連付けられた1つ以上の色収差を定まったレベルに処理するよう構成された光フィルタ素子とを備える、装置。 - さらに、前記撮像パスの第2の空間部分に連結されて、前記1つ以上の蛍光発光信号の一部分を読む検出器と、
前記撮像パスの第3の空間部分に連結された第1レンズシステムであって、前記少なくとも1つの微小流体素子内の前記少なくとも1つのチャンバからの1つ以上の蛍光発光信号をキャプチャするよう構成された、第1レンズシステムと、
1つ以上のスペクトルバンド幅によって特徴付けられる電磁放射を発する光源と、
該光源に連結された光学素子であって、該光学素子が、前記少なくとも1つの微小流体素子の少なくとも96個のチャンバを照射するよう構成されており、ここで48個より多いチャンバ群は、前記48個より多いチャンバ群のほかのチャンバのいずれからも流体的に分離されている、光学素子、
を備える、請求項46に記載の装置。 - さらに、
前記撮像パスの第4の空間部分に連結された第2レンズシステムと、
前記少なくとも1つの微小流体素子に熱制御を行うよう構成された熱制御モジュールとを備え、
前記光フィルタ素子は複数の分光フィルタおよび複数のゼロ出力ダブレットを備える、請求項47に記載の装置。 - 前記複数のゼロ出力ダブレットは、第1の所定波長で色収差を低減するよう構成された第1ゼロ出力ダブレットと、第2の所定波長で色収差を低減するよう構成された第2ゼロ出力ダブレットとを備える、請求項46に記載の装置。
- 前記光フィルタ素子は、前記撮像パスの一部分に関連付けられたバックグラウンド信号を所定のレベルまで縮小させる、請求項46に記載の装置。
- 前記1つ以上の色収差の処理は前記1つ以上の色収差の補正を含む、請求項46に記載の装置。
- 前記1つ以上の色収差の補正は前記1つ以上の色収差を所定のレベルまで縮小させることを含み、該所定のレベルは、第1の色によって特徴付けられた第1の光線および第2の色によって特徴付けられた第2の光線に関連付けられた焦点における所定のシフトによって特徴付けられる、請求項51に記載の装置。
- エラストマー微小流体素子における処理の解析方法であって、
1分未満の時間の間に少なくとも96個のチャンバのイメージをキャプチャする工程であって、ここで該少なくとも96個のチャンバのそれぞれは、該少なくとも96個のチャンバのほかのチャンバのいずれからも流体的に分離されている工程、
該イメージを処理する工程、
を包含する、方法。 - さらに、1分未満の時間の間に前記少なくとも96個のチャンバの第2イメージをキャプチャする工程、および前記第2イメージを処理する工程を包含する、請求項53に記載の方法。
- イメージのキャプチャは、開口数が0.23以上で倍率が2以下である光システムを用いて行われる、請求項53に記載の方法。
- 前記光システムは開口数が0.23以上である、請求項55に記載の方法。
- 前記少なくとも96個のチャンバはそれぞれ、約100ナノリットル以下の容積を有する、請求項53に記載の方法。
- 前記少なくとも96個のチャンバはそれぞれ、約10ナノリットル以下の容積を有する、請求項57に記載の方法。
- 前記少なくとも96個のチャンバはそれぞれ、約100ピコリットル以下の容積を有する、請求項58に記載の方法。
- 前記少なくとも96個のチャンバそれぞれの密度は約100チャンバ/cm2以上である、請求項53に記載の方法。
- 前記少なくとも96個のチャンバそれぞれの密度は約250チャンバ/cm2以上である、請求項60に記載の方法。
- 前記少なくとも96個のチャンバそれぞれの密度は約1,000チャンバ/cm2以上である、請求項61に記載の方法。
- M個のサンプルから選択された少なくとも1つのサンプルとN個の試薬から選択された少なくとも1つの試薬とを含む複数の処理部位を備える微小流体素子の撮像装置であって、該装置は、
該微小流体素子に連結され、該微小流体素子を電磁放射で照射するよう構成された照明システムと、
該微小流体素子に連結され、該複数の処理部位から発せられた電磁放射を受光するよう構成された撮像システムと、
該撮像システムと連結された検出器、
を備える、装置。 - 前記微小流体素子はエラストマー微小流体素子である、請求項63に記載の装置。
- 前記処理部位は閉鎖反応チャンバである、請求項63に記載の装置。
- 前記複数の閉鎖反応チャンバは反応密度が、平方cmの面積あたりの流体的に分離された反応が約250以上である、請求項65に記載の装置。
- 前記複数の処理部位から発せられる前記電磁放射は蛍光信号である、請求項63に記載の装置。
- さらに、前記微小流体素子に連結された熱制御部を備える、請求項67に記載の装置。
- 前記複数の処理部位は約100ナノリットル以下の容積により特徴づけられる、請求項68に記載の装置。
- 前記複数の処理部位は約10ナノリットル以下の容積により特徴づけられる、請求項69に記載の装置。
- 前記複数の処理部位は250部位/cm2以上のアレー密度により特徴づけられる、請求項69に記載の装置。
- 前記複数の処理部位は1,000部位/cm2以上のアレー密度により特徴づけられる、請求項69に記載の装置。
- 前記複数の処理部位はタンパク質結晶化処理に対応するよう構成されている、請求項63に記載の装置。
- 前記電磁放射は光学的放射である、請求項63に記載の装置。
- 光撮像システムであって、
コンピュータと、
流体的に分離された少なくとも1,536個の反応チャンバを有するエラストマー微小流体アレー素子を照射するために適合された光学照射システムであって、該エラストマー微小流体アレー素子は複数の層から形成される弾性ブロックを備え、少なくとも1つの層は少なくとも1つのくぼみがその内部に形成されており、該くぼみは該くぼみを有する該層に一体形成された少なくとも1つの偏向膜を有する、光学照射システムと、
光検出システムとを備える、システム。 - 前記少なくとも1,536個の反応チャンバは100ナノリットル未満の容積により特徴づけられる、請求項75に記載の光撮像システム。
- 前記少なくとも1,536個の反応チャンバは、250チャンバ/平方センチメータ以上のアレー密度で空間的に配置されている、請求項75に記載の光撮像システム。
- M個のサンプルおよびN個の試薬は、前記少なくとも1,536個の反応チャンバに分散している、請求項75に記載の光撮像システム。
- 前記光照明システムは、前記少なくとも1,536個の反応チャンバのサブセットからの1つ以上の蛍光信号の発光を誘導する、請求項75に記載の光撮像システム。
- 前記光検出システムは、前記少なくとも1,536個の反応チャンバのサブセットに関連付けられたタンパク質結晶化処理の1つ以上のイメージを提供するよう構成されている、請求項75に記載の光撮像システム。
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