JP6169111B2 - マイクロ流体工学を利用した複数の単一細胞の捕捉及び処理の方法、システム、並びにデバイス - Google Patents
マイクロ流体工学を利用した複数の単一細胞の捕捉及び処理の方法、システム、並びにデバイス Download PDFInfo
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Description
その方法は、1つ以上の溶液をマイクロ流体デバイス内に収容するステップ、1つ以上の溶液を利用するマイクロ流体デバイスを準備するステップ、複数細胞をマイクロ流体デバイス内に収容するステップ、複数細胞のうちの個別の細胞がマイクロ流体デバイスの個別の捕捉部位で捕捉されるように、複数細胞をマイクロ流体デバイス内に流すステップ、マイクロ流体デバイス上の捕捉された個別の細胞の1つ以上を画像化するステップ、少なくとも、1つ以上の溶解試薬、1つ以上の逆転写試薬、又は1つ以上のPCR試薬をマイクロ流体デバイス内に収容するステップ、マイクロ流体デバイスの個別の捕捉部位で捕捉された複数の個別の細胞を溶解させるステップ、マイクロ流体デバイス内で、複数の個別の溶解した細胞に逆転写を実行し、各個別の細胞に関連する逆転写産物を生成するステップ、マイクロ流体デバイス内で、各個別の溶解した細胞に関連する個別の逆転写産物にPCRを実行し、各個別の捕捉された細胞に関連するPCR産物を生成するステップ、各個別の捕捉された細胞に関連するPCR産物を、マイクロ流体デバイスの複数の収穫入口のうちの個別の収穫入口に運ぶステップ、1つ以上の収穫入口の1つ以上の保護層を除去するステップ、及び/又は、マイクロ流体デバイスの複数の収穫入口のうちの各個別の収穫入口から、PCR産物を収穫するステップ、を含みうる。
粒子、例えば細胞、の操作及び分析が、マイクロ流体システムで実施される。マイクロ流体システムは、一般的に、非常に小量の流体が貯蔵され操作される任意のシステムを備え、一般的に約500μL未満、典型的には約100μL未満、更に典型的には約10μL未満である。マイクロ流体システムは、1つ以上のマイクロ流体流路を介して規定の経路で流体を運ぶ。マイクロ流体流路は、最小の寸法を持ってもよく、一般的に、高さ又は幅が、約200、約100、又は約50μm未満でもよい。流路については、下記セクションIIでより詳細に説明する。
マイクロ流体システムは、粒子アッセイ用の、少量の流体の統合された操作(流体及び流体に結合した粒子の移動及び/又は保存を含む)のための任意の好適な構造を含みうる。当該構造は、とりわけ、流路、貯蔵器、及び/又は調整器を含みうる。
マイクロ流体システムは、粒子を操作する、及び/又は分析するために使用してもよい。粒子は、一般的に、流体に関連するマイクロ流体ネットワーク内に入力されて操作されるのに十分小さく、流体から識別するのに十分大きい任意のオブジェクトを備える。ここで使用される粒子は、典型的には微小又はほぼ微小であり、直径が約0.005〜100μm、約0.1〜50μm、又は約0.5〜30μmであってもよい。あるいは、又は更に、粒子は、質量が約10−20〜10−5g、約10−16〜10−7g、又は約10−14〜10−8gであってもよい。例示的な粒子としては、細胞、ウイルス、細胞小器官、ビーズ、及び/又は小胞、並びに、例えば二量体、三量体などの会合体を含みうる。
マイクロ流体システムは、マイクロ流体ネットワークと連結する1つ以上の入力機構を含みうる。入力機構は、一般的に、物質(例えば、粒子、流体、及び/又は試薬)をマイクロ流体チップのマイクロ流体ネットワークに入力するのに好適な任意の機構を含み、選択的(すなわち、一成分ずつ)及び/又は大量の機構を備える。
マイクロ流体システムは、1つ以上の配置機構を含みうる。配置機構は、例えば、とりわけ、保持、成長、処理、及び/又は測定のために、一般的に、入力後の粒子をチップ上の予め選択された位置に配置するための任意の機構を備える。配置機構は、様々な方法で制限なく分類分けしてもよく、例えば、直接及び/又は間接、流体媒体及び/又は非流体媒体、外部及び/又は内部などを含む、粒子の起源及び/又は動作原理を反映する方法がある。これら分類は、相互排他的ではない。よって、所定の配置機構は、2以上の方法で粒子を配置してもよい。例えば、電場は粒子を直接的に(例えば電気泳動を介して)及び間接的に(例えば電気浸透を介して)配置してもよい。
マイクロ流体システムは、1つ以上の保持機構を含みうる。保持機構は、一般的に、マイクロ流体ネットワークの予め選択された位置又は領域の粒子を保持する(又は支持し、捕捉し、若しくは捕獲する)任意の好適な機構を備え、当該機構は単一の又は複数の機構を含み、直列及び/又は並列に動作する。保持機構は、流体流動により働く配置の力に打ち勝つように働くことができる。更に、保持機構は、捕捉機構又は捕獲機構とも称されるが、単一粒子又は粒子のグループ/個体群を含む、任意の好適な数の粒子を保持することができる。好適な保持機構は、とりわけ、流動、化学相互作用、真空力、ループ内の流体流動、重力、遠心力、磁力、電気力、及び/又は光学的に生成された力で接続した物理的障壁に基づくことができる。
処理機構は、流体介在の機構及び流体非介在の機構を含む、一般的に、粒子を試薬及び/又は物理的状況に晒すのに好適な任意の機構を備える。
マイクロ流体システムにより操作された粒子は、1つ以上の測定部位で1つ以上の測定機構により分析することができる。測定機構は、一般的に、予め選択された粒子又は粒子の特性(例えば、とりわけ、粒子、粒子成分、及び/又はアッセイ生成物により与えられる)を検出する任意の好適な装置又は方法を備える。測定部位は、一般的に、任意の好適な粒子位置若しくは測定が行われた位置、システムの内部及び/又は外部を含む。
マイクロ流体システムは、任意の好適な数の粒子放出機構を含みうる。放出機構は、一般的に、保持された粒子が予め選択された部位/エリア(粒子が保持されている)から離れることを許容する任意の機構を備え、粒子を保持する保持機構を取り除き、克服し、及び/又は無効化することを含む。好適な放出機構は、少なくとも部分的に、保持力に基づいて選択することができる。放出後、粒子(又は粒子成分)は、任意の目的地を持ちうる。
マイクロ流体システムは、マイクロ流体ネットワークと連通する1つ以上の出力機構を含みうる。出力機構は、一般的に、物質(例えば、流体、粒子、及び/又は試薬)を、マイクロ流体システム又は当該システムの一部から出力する任意の好適な機構を備え、選択的及び/又はバルク機構を含む。出力機構により、出力された物質は任意の好適な位置、例えばシンクの内部及び/又は外部、に向かわせられうる。シンクは、一般的に、任意のレセプタクル、又は出力された物質を受け入れるための他の部位、処分するための他の部位(例えば廃棄部位)若しくは更なる研究若しくは操作のための他の部位(例えば収集部位)を備える。マイクロ流体システムからの物質の出力は、任意の好適な促進機構、例えば内圧及び/又は外部の真空の発生源を用いて促進及び/又は調整されうる。出力機構は、選択機構、例えばある基準(例えば物質が粒子か流体のいずれであるか)に基づいて出力された物質を選択するフィルター、を含みうる。
細胞はマイクロ流体システム内の細胞培養機構を用いて培養されうる。細胞培養機構は、一般的に、細胞の維持及び/又は増殖を含む、細胞を成長させるための任意の好適な機構を備える。好適な細胞については、上記セクションIIIで説明する。
マイクロ流体システムは、粒子の操作のために使用される。粒子の操作は、一般的に、所望の機能又はアッセイを実行するための、任意の好適な順序の一体の操作を含む。一体の操作は、とりわけ、セクションIV〜Xで上述した各機構により実行されうる。
以下の実施例を用いて、選択された態様及び実施形態(複数の単一粒子(例えば単一細胞)に対する、マイクロ流体工学を利用した処理の方法、システム、及びデバイス)を説明する。これらの実施例は、説明のために含められるものであり、発明の全体の範囲を制限し、又は定義する意図はない。
画像化モジュール1760は、マイクロ流体デバイスの1つ以上の面を画像化するように構成されうる。画像化モジュール1760は、マイクロデバイス内の1つ以上の捕捉された細胞を画像化するように構成された、少なくとも顕微鏡又はカメラを含みうる。画像化モジュール1760は、マイクロ流体デバイス内の1つ以上の反応産物を画像化するように構成された、少なくとも顕微鏡又はカメラを含みうる。
Claims (16)
- 複数の単一細胞の捕捉及び処理のためのマイクロ流体デバイスであって、
直列に接続した複数の捕捉構造と、
複数のマルチチャンバ反応構造と、を備え、
前記複数の捕捉構造は、各個別の捕捉構造が、
入力チャネルと、
捕捉ネストと、
1つ以上のバイパスチャネルと、
出力チャネルと、を有し、
前記捕捉ネストは、複数細胞のうちの単一細胞を捕捉し、残りの複数細胞が前記1つ以上のバイパスチャネルを通過して前記直列に接続した次の捕捉構造へ至るように構成され、
前記複数のマルチチャンバ反応構造は、各個別のマルチチャンバ反応構造が、前記複数の捕捉構造のうちの個別の捕捉構造と接続し、かつ、単一細胞の処理のために構成される、
マイクロ流体デバイス。 - 前記複数のマルチチャンバ反応構造は、それぞれ、
前記捕捉構造に接続された第1の反応チャンバと、
2つのオーバーラップしない流体流路を介して前記第1の反応チャンバに接続された第2の反応チャンバと、
前記第1の反応チャンバと前記第2の反応チャンバとを互いに流体的に隔離させるように配置された複数のバルブと、
前記捕捉構造を前記マルチチャンバ反応構造から流体的に隔離させるように配置されたバルブと、
を備える、請求項1に記載のマイクロ流体デバイス。 - 前記捕捉ネストは、単一細胞のみを支持するようなサイズに形成された1つ以上の物理的障壁を備える、請求項1又は2に記載のマイクロ流体デバイス。
- 前記捕捉構造は、凹面を形成するように構成されて単一細胞のみを捕捉するようなサイズ形成され、ドレインチャネルと接続する、1つ以上の物理的障壁を有する捕捉ネストを備え、
前記捕捉ネストに入る細胞は、前記ドレインチャネルを通る流動のみを停止させ、一方、前記複数細胞のうちの他の細胞が前記1つ以上のバイパスチャネルを通って出力チャネルに流れて下流の捕捉構造に入ることを許容する、
請求項1に記載のマイクロ流体デバイス。 - 前記各個別の捕捉構造は、
入力チャネルと出力チャネルとに接続する1つ以上のバイパスチャネルと、
前記入力チャネルと前記出力チャネルとに接続するドレインと、
前記入力チャネルと前記1つ以上のバイパスチャネルとの接合部に近接し、かつ、前記ドレインに接続する捕捉ネストと、を備え、
前記捕捉ネストが複数細胞のうちの単一細胞を捕捉するように構成されており、前記単一細胞が前記捕捉ネスト内に捕捉されると、前記複数細胞の残部が前記1つ以上のバイパスチャネルの少なくとも1つに流入させられ、
前記ドレインチャネルは、前記入力チャネル及び前記出力チャネルと流体的に連通するので、前記ドレインを通って前記入力チャネルから前記出力チャネルに流れる溶液が、前記バイパスチャネルを流れることなく前記出力チャネルを通って前記捕捉構造を出る、
請求項1から4の何れか一項に記載のマイクロ流体デバイス。 - 前記1つ以上のバイパスチャネルは、対称的に構成された一対のバイパスチャネルである、請求項1から5の何れか一項に記載のマイクロ流体デバイス。
- 少なくとも前記入力チャネル又は前記出力チャネルは、更に収束チャネルとして構成される、請求項1から6の何れか一項に記載のマイクロ流体デバイス。
- 複数の収穫ウェルを更に備え、各個別の収穫ウェルは、前記個別のマルチチャンバ反応構造と接続し、かつ、反応産物を更なる分析のために送るように構成される、請求項1から7の何れか一項に記載のマイクロ流体デバイス。
- 前記第2の反応チャンバは、前記第1の反応チャンバに隣接する、請求項2に記載のマイクロ流体デバイス。
- 前記マルチチャンバ反応構造は、それぞれ、
2つのオーバーラップしない流体流路を介して前記第2の反応チャンバと接続する第3の反応チャンバと、
前記第2の反応チャンバと前記第3の反応チャンバとを互いに流体的に隔離させる複数バルブと、
を備える、請求項2又は9に記載のマイクロ流体デバイス。 - 前記複数のマルチチャンバ反応構造は、それぞれのマルチチャンバ反応構造の1つ以上のバルブが作動する間、熱循環するように更に構成される、請求項2に記載のマイクロ流体デバイス。
- 複数単一細胞処理のために構成されたマイクロ流体システムであって、
マイクロ流体デバイスと、
前記マイクロ流体デバイスと接続するマイクロ流体コントローラと、を備え、
前記マイクロ流体デバイスは、
直列に接続した複数の捕捉構造と、
複数のマルチチャンバ反応構造と、を備え、
前記複数の捕捉構造は、各個別の捕捉構造が、
入力チャネルと出力チャネルとに接続する複数のバイパスチャネルと、
前記入力チャネルと前記出力チャネルとに接続するドレインと、
前記入力チャネルと前記複数のバイパスチャネルとの接合部の近傍に位置し、かつ、前記ドレインに接続する捕捉ネストと、を備え、
前記捕捉ネストが複数細胞のうちの個別の細胞を捕捉するように構成されることで、前記個別の細胞が前記捕捉ネスト内に捕捉されると、残存複数細胞が前記複数のバイパスチャネルの少なくとも1つに流入させられ、
前記複数のマルチチャンバ反応構造は、各個別のマルチチャンバ反応構造が前記複数の捕捉構造のうちの個別の捕捉構造と接続し、かつ、単一細胞処理のために構成され、前記マイクロ流体コントローラは、
筐体と、
前記マイクロ流体デバイスを前記筐体内に収容及び排出するように構成されたマイクロ流体デバイス入力出力モジュールと、
前記マイクロ流体デバイスに制御圧を与えるために前記マイクロ流体デバイスと接続するように構成された圧力モジュールと、
1つ以上の圧力シールを前記マイクロ流体デバイスに提供するように構成された封止モジュールと、
前記マイクロ流体デバイスの熱を循環させるように構成された熱循環モジュールと、を備える、
マイクロ流体システム。 - マイクロ流体工学を用いた複数単一細胞の捕捉及び処理のための方法であって、
請求項1から12の何れか一項に記載のマイクロ流体デバイス内に、複数の細胞を収容し、少なくとも単一細胞の複数段階の処理を実行するステップ、
を含む方法。 - マイクロ流体工学を用いた複数単一細胞の捕捉及び処理のための方法であって、
a)複数細胞をマイクロ流体デバイスに収容するステップと、
b)前記複数細胞を前記マイクロ流体デバイスの第1捕捉構造に流し込み、前記第1捕捉構造は、単一細胞を捕捉するようにサイズ形成された1つ以上の物理的障壁を有する細胞捕捉ネストを備えるステップと、
c)前記第1捕捉構造内で前記複数細胞のうちの第1単一細胞を捕捉するステップと、
d)前記複数細胞のうちの第1残存複数細胞を、1つ以上の第1バイパスチャネルを経由して、前記マイクロ流体デバイスの第2捕捉構造に流し込むステップと、
e)前記第2捕捉構造内で前記第1残存複数細胞のうちの第2単一細胞を捕捉し、前記第2捕捉構造は、単一細胞を捕捉するようにサイズ形成された1つ以上の物理的障壁を有する細胞捕捉ネストを備えるステップと、
f)前記複数細胞のうちの第2残存複数細胞を、1つ以上の第2バイパスチャネルを経由して、前記マイクロ流体デバイスの第3捕捉構造へ流し込むステップと、
g)前記マイクロ流体デバイスで、少なくとも前記捕捉された第1単一細胞及び前記捕捉された第2単一細胞に対して複数段階の処理を実行し、少なくとも前記捕捉された第1単一細胞及び前記捕捉された第2単一細胞に関する個別の収穫生成物を生成するステップと、
を含む請求項13に記載の方法。 - a)前記第1捕捉構造内で前記複数細胞のうちの第1単一細胞を捕捉するステップは、単一細胞のみを支持するようにサイズ形成された1つ以上の物理的障壁を利用し、
前記第1捕捉構造は、
第1入力チャネル及び第1出力チャネルと接続する1つ以上のバイパスチャネルと、
前記第1入力チャネルと前記第1出力チャネルとに接続する第1ドレインと、
前記第1ドレインと接続し、かつ、前記複数細胞のうちの個別細胞を捕捉するように構成された第1捕捉ネストと、を備え、
前記捕捉ネストが捕捉された細胞で満たされると、ドレインチャネルを通り抜ける流動が妨げられるので、捕捉されていない細胞が一対の前記バイパスチャネルに逸れて、単一の前記出力チャネルに流れ込み、
b)前記第2捕捉構造は、
第2入力チャネルと第2出力チャネルとに接続する複数のバイパスチャネルと、
第2ドレインと接続し、前記第1残存複数細胞のうちの個別細胞を捕捉するように構成された第2捕捉ネストと、を備え、
前記第2入力チャネルは、前記第1捕捉構造の前記第1出力チャネルと、前記第2入力チャネルに接続される第2ドレインと、前記第2出力チャネルとに接続され、
c)前記第2捕捉構造内の前記第1残存複数細胞のうちの第2単一細胞を捕捉するステップは、単一細胞のみを支持するようにサイズ成形された1つ以上の物理的障壁を利用し、
d)前記マイクロ流体デバイスで、少なくとも前記捕捉された第1単一細胞及び前記捕捉された第2単一細胞に対して前記複数段階の処理を実行して、少なくとも前記捕捉された第1単一細胞及び前記捕捉された第2単一細胞に関する個別の収穫生成物を生成するステップは、
前記マイクロ流体デバイスで、各個別の捕捉された細胞を溶解させ、当該各個別の細胞の1つ以上の成分を放出するステップと、
各個別に捕捉された細胞の前記1つ以上の成分を、更なる処理のために前記マイクロ流体デバイスの個別のマルチチャンバ反応構造に流すステップと、
を更に含む、請求項14に記載の方法。 - 前記マイクロ流体デバイス内の個別の捕捉された細胞を画像化するステップを更に含む、請求項13から15の何れか一項に記載の方法。
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US9429500B2 (en) | 2012-02-29 | 2016-08-30 | Fluidigm Corporation | Methods, systems and devices for multiple single-cell capturing and processing using microfluidics |
CN104471077B (zh) | 2012-05-21 | 2017-05-24 | 富鲁达公司 | 颗粒群的单颗粒分析 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11213824B2 (en) | 2017-03-29 | 2022-01-04 | The Research Foundation For The State University Of New York | Microfluidic device and methods |
US11911763B2 (en) | 2017-03-29 | 2024-02-27 | The Research Foundation For The State University Of New York | Microfluidic device and methods |
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CN104350374B (zh) | 2018-04-27 |
US20130302884A1 (en) | 2013-11-14 |
EP3285062B1 (en) | 2019-08-07 |
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EP3285062A1 (en) | 2018-02-21 |
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CA2878787A1 (en) | 2013-09-06 |
JP2015515263A (ja) | 2015-05-28 |
US20130295602A1 (en) | 2013-11-07 |
CN104350374A (zh) | 2015-02-11 |
US20130296196A1 (en) | 2013-11-07 |
EP2820394A4 (en) | 2015-07-08 |
SG11201405235VA (en) | 2014-11-27 |
SG10201608159XA (en) | 2016-11-29 |
EP2820394A1 (en) | 2015-01-07 |
US20130302883A1 (en) | 2013-11-14 |
WO2013130714A1 (en) | 2013-09-06 |
US9304065B2 (en) | 2016-04-05 |
US20130302807A1 (en) | 2013-11-14 |
EP2820394B1 (en) | 2017-07-12 |
EP3627140A1 (en) | 2020-03-25 |
US20180306683A1 (en) | 2018-10-25 |
US9429500B2 (en) | 2016-08-30 |
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