JP2019527551A - マルチウェルデバイスを用いたマルチz撮像及び分注 - Google Patents
マルチウェルデバイスを用いたマルチz撮像及び分注 Download PDFInfo
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Abstract
Description
以下のワークフローステップは、一体化された分注・撮像組立体(例えばマルチZ性能を有する分注・撮像組立体)を使用するときに例示的な実施形態で用いられる。最初に、蛍光染色した細胞を384 ウェルプレートに予めロードする。この例示的な実施形態では、8つのサンプルをマルチウェルデバイス(例えば、WAFERGEN(WaferGen Bio-systems, Inc.)によって販売されている5184ウェルを有するSMARTCHIP (商標)マルチウェルデバイス)に分注することができる。図2は、マルチウェルデバイスの上側で一体化されたシステムを自動的に移動させるための移動要素と共に細胞を分注して撮像することができる例示的な一体化されたシステムを示す。図2に示されているシステムは、2つの移動要素(「レール」)及び一体化された撮像・分注システム(挿入図)を備えており、分注システムは複数の分注先端を有している。撮像要素と分注要素との一体化によって、撮像システムを使用して行われるような候補細胞含有ウェルの検出と、分注システムを使用して行われるようなウェルへの細胞の分注、及び該当する場合にはその後の処理試薬の添加との調整を可能にする。
dtot=(λn/NA2)+{(n/M NA)e}
ここで、dtot:被写界深度、
λ0:波長
n:屈折率
NA:開口数
M:対物レンズの倍率
e:撮像分解能
本明細書に記載されている方法、デバイス、組立体及びシステムの態様がマルチZ面撮像を利用してもよい。「マルチZ面撮像」とは、撮像される一又は複数の対象からの複数の撮像距離で行われる1つの視野の撮像を意味する。このような複数の撮像距離はZ距離と称されてもよく、各Z距離はZ面を定めてもよい。最も微視的な対物レンズの浅い被写界深度を考慮すると、異なるZ面で撮られた画像は一般に、画像内に対象に関して異なる質の焦点を含む。例えば、対物レンズから異なる距離にある2つの対象の第1の画像は、2つの対象の第1の焦点を合わせて、2つの対象の第2の焦点をずらす場合がある。第2の画像を異なるZ距離で撮ると、第1の対象は焦点から移動し、第2の対象が焦点に移動する場合がある。
生成されたマルチZ面画像は、様々な画像処理ステップ及び/又は画像処理アルゴリズムを通して処理されてもよい。場合によっては、生成されたマルチZ面画像を処理して、マルチウェルデバイスの候補ウェルを識別してもよい。場合によっては、マルチZ面画像の画像処理は合成画像の生成を含んでもよく、合成画像から、候補ウェルの識別を行ってもよい。場合によっては、マルチウェルプレートの候補ウェルを識別する際に、合成画像を生成することなく、生成されたマルチZ面画像を使用してもよく、例えば、合成画像を生成することなく、例えば一又は複数の画像処理ステップを通して、生成されたマルチZ面画像から候補ウェルを直接識別してもよい。様々な画像処理ステップを、一組のマルチZ面画像の個々の画像、一組のマルチZ面画像から生成された合成画像、又はこれら両方に行ってもよい。
本開示の方法、デバイス、組立体及びシステムは、一又は複数の細胞計数ステップ及び/又はウェル識別ステップを有してもよい。このようなステップは、様々な顕微鏡検査で利用可能な細胞計数ソフトウェア又は細胞計数コンピュータアプリケーション、及び/又は画像処理の市販されている自由に入手可能なソフトウェアパッケージによって行われてもよい。本明細書で使用されている「細胞計数」は一般に、マルチウェルデバイスのウェル又は複数のウェルに存在する細胞の数を識別する処理を指す。本明細書で使用されている「ウェル識別」は一般に、マルチウェルデバイスのウェルが予め定められた所望の数の細胞を含んでいるか否かを識別することを指す。ウェルが識別され得る細胞の所望の数は異なってもよく、例えば、一又は複数の細胞の存在又は欠如、1つの細胞の存在、2以上の細胞の存在(つまりマルチピレット)、特定のマルチピレットの存在(例えば2つの細胞の存在、3つの細胞の存在、4つの細胞の存在など)、細胞の欠如(つまり、「空」のウェル)などを含んでもよい。従って、ウェル識別は、場合によっては二進法であってもよく、つまり、ウェルが所望の数の細胞を含んでいるか否かであってもよい。
ある実施形態では、本明細書で提供されている方法、システム及び組立体は、マルチウェルデバイスでの単細胞の分析に使用される。細胞不均一性は、一般に生体組織及び細胞の一般的な特徴である。遺伝学者は癌、自己免疫疾患及び神経障害を含む複雑な病気を特徴付ける努力をしている。しかしながら、これらの病気を進める基本的なメカニズムの決定は達成困難なままである。細胞が新たな突然変異体を蓄積するにつれて、正常細胞と共存する多クローン性細胞集団を形成する場合がある。その結果、大量の細胞集団の配列決定は、これらの特有の珍しい細胞型の基本的な不均一性をマスクし得るため、「干し草の山に針を見つける」ほど困難になる。集団内/細胞間の差異を明らかにするための代替の手法は、集団から選択された個々の細胞の核酸配列を評価することである。単細胞の分析を使用して、別個のDNA 発現プロファイル及びRNA 発現プロファイルを有するサブ集団を定めている。要約すると、単細胞の分析は複雑な病気の既に「隠された」メカニズムを明らかにし得ると広く信じられている。
上記に要約されているように、本方法で用いられる本システムの構成要素、例えば分注要素及びその部品、撮像要素及びその部品などはコンピュータ制御されてもよい(つまりロボットであってもよい)。従って、本方法及び本システムは、構成要素の一又は複数の動作を制御するためにシステムの一又は複数の電気部品と接続されているか、又は別の方法で通信するプロセッサを使用してもよい。
実施例1:候補ウェルを識別する際の遠心分離、Z面サンプリング及び細胞分注量の影響
識別される候補ウェルの数に対する遠心分離の影響を調査した。具体的には、細胞懸濁液を1mm(150 nl)及び1.6 mm(250 nl)マルチウェルチップにポアソン分注し、候補ウェル識別(つまり、所望の数(この場合「1つ」)の細胞を含むウェルの識別)を、マルチウェルチップの遠心分離の前後に行った。遠心分離の前後の3つのZ焦点面(Z1〜Z3)での撮像を使用して、候補ウェルの数を定量化した。表2及び表3は、1mm及び1.6 mmのチップに関してこの定量化の結果を夫々示し、Olympus 顕微鏡を使用して生成された対照候補ウェルの定量化の結果を含んでいる。
単細胞を含むと識別された候補ウェルのマルチピレット(つまり、2以上の細胞を含むウェル)の発生に対する遠心分離の影響を、混合種配列決定実験を使用して評価した。具体的には、等しい比率(50nl当たり1つの細胞)で混合したヒトK-562 細胞及びマウス3T3 細胞をマルチウェルチップに分注し、単細胞を含む候補ウェルを、事前の遠心分離有り及び無しで識別し、候補ウェルをRT-PCRのために処理し、続いて配列決定した。配列決定リードをマウスゲノム及びヒトゲノムに整列させて、個々のウェルを、マウスのみ、ヒトのみ又は両方に整列したリードを含むと遡及的に識別した。マウス及びヒトの両方に整列したリードを含むウェルを、マルチピレットを含むと判断した。遠心分離前サンプル(図10)及び遠心分離後サンプル(図11)に関する配列決定リードアライメントデータを与える。遠心分離前の場合のマルチピレット率は5.8 %である一方、遠心分離後のマルチピレット率はより低く、3.5 %であった。これらのデータは、場合によっては、識別された単細胞候候補ウェルでのマルチピレットの発生を減少させるために遠心分離が使用され得ることを実証している。
a) ある量の細胞懸濁液を前記マルチウェルチップのウェルに分注し、
b) 前記マルチウェルチップを撮像して複数のZ面で前記ウェルの複数の画像を得て、
c) 得た複数の画像に基づき、前記マルチウェルチップの空のウェル及び細胞含有ウェルを識別する、前記マルチウェルチップのマップを生成し、
d) 前記マルチウェルチップの識別された細胞含有ウェルのみを処理することを特徴とする方法。
b) 前記分注・撮像システム組立体と通信するプロセッサと、前記プロセッサによって実行されると、前記分注・撮像システム組立体に、
i) ある量の細胞懸濁液をマルチウェルチップのウェルに分注するステップ、
ii) 前記マルチウェルチップを撮像して複数のZ面で前記ウェルの複数の画像を得るステップ、及び
iii) 得た複数の画像に基づき、前記マルチウェルチップの空のウェル及び細胞含有ウェルを識別する、前記マルチウェルチップのマップを生成するステップ
を実行させる指示を記憶するコンピュータメモリと
を備えていることを特徴とするシステム。
a) i) 第1の量の水溶液を含む複数のウェルを有する第1のマルチウェルデバイスであって、前記複数のウェルの少なくとも1%が1つの細胞のみ又は2つの細胞を含んでいる前記第1のマルチウェルデバイスと、
ii) 異なるZ面で焦点を合わせて画像を生成することができる画像取得システムと、
iii) 任意には、前記第1の量の水溶液を含む複数のウェルを有する第2のマルチウェルデバイスであって、前記複数のウェルの少なくとも1%が1つの細胞のみ又は2つの細胞のみを含んでいる前記第2のマルチウェルデバイスと
を準備し、
b) 第1組の撮像パラメータを有するように構成された前記画像取得システムを使用して、前記複数のウェルの第1の部分の前記マルチウェルデバイスの上側の異なるZ面から複数の画像を取り込み、
c) 前記異なるZ面からZmax面及びZmin面を決定し、前記Zmax面は、少なくとも1つの焦点が合っている細胞を含む前記マルチウェルデバイスから最も遠い面であり、前記Zmin面は、少なくとも1つの焦点が合っている細胞を含む前記マルチウェルデバイスに最も近い面であり、
d) 前記複数のウェルの前記第1の部分に存在する細胞の全ての焦点画像を与える合成画像を生成するために画像の撮像に必要な前記異なるZ面の最小数を決定し、前記最小数の前記異なるZ面は、少なくとも前記Zmax面及び前記Zmin面を含み、
e) i) 前記画像取得システムを使用して、前記最小数の異なるZ面のみを用いて前記マルチウェルデバイスの前記複数のウェルの第2の部分を撮像する、及び/又は、
ii) 前記第1組の撮像パラメータを有するように構成された画像取得システムを使用して前記第2のマルチウェルデバイスの少なくとも一部を、前記最小数の異なるZ面のみを用いて撮像する
の少なくとも1つを行うことを特徴とする方法。
a) 複数のウェルを有するマルチウェルデバイスを定位置に固定するように構成されたマルチウェルデバイス固定要素と、
b) i) マルチウェルデバイスのウェルに液体を分注するように構成された液体分注要素、及び
ii) 前記マルチウェルデバイスの上側の異なるZ面で焦点を合わせて画像を生成することができる画像取得要素であって、前記液体分注要素に取り付けられるか、又は前記液体分注要素に隣り合う前記画像取得要素
を有する分注・撮像システム組立体と、
c) 前記マルチウェルデバイスが前記定位置にあるとき、前記マルチウェルデバイスの前記複数のウェルの大部分又は全てが、
i) 前記液体分注要素から液体を受けることができ、
ii) 前記画像取得要素によって撮像されることができる
ように、前記分注・撮像組立体を前記マルチウェルデバイスに対して移動させるように構成された移動要素と
を備えていることを特徴とするシステム。
ii) 複数のウェルを有するマルチウェルデバイスを定位置に固定するように構成されたマルチウェルデバイス固定要素と、
iii) A) I) マルチウェルデバイスのウェルに液体を分注するように構成された液体分注要素、及びII) 前記マルチウェルデバイスの上側の異なるZ面で焦点を合わせて画像を生成することができる画像取得要素であって、前記液体分注要素に取り付けられるか、又は前記液体分注要素に隣り合う前記画像取得要素を有する分注・撮像組立体と、
B) 前記マルチウェルデバイスに対して前記分注・撮像組立体を移動させるように構成された移動要素と
を有する多目的のシステムと
を準備し、
b) 前記マルチウェルデバイスが前記定位置に配置されるように前記マルチウェルデバイスを前記固定要素に置き、
c) 前記マルチウェルデバイスの前記複数のウェルの大部分又は全てが、
i) 前記複数のウェルの少なくとも1%が1つの細胞のみ又は2つの細胞を含むように前記液体分注要素から細胞含有液体を受け、
ii) 前記マルチウェルデバイスの上側の複数のZ面で前記画像取得要素によって撮像されることにより、異なるZ面から複数の画像を生成する
ように、前記分注・撮像組立体を作動することを特徴とする方法。
Claims (15)
- マルチウェルチップの細胞含有ウェルを処理する方法であって、
a) ある量の細胞懸濁液を前記マルチウェルチップのウェルに分注し、
b) 前記マルチウェルチップを撮像して複数のZ面で前記ウェルの複数の画像を得て、
c) 得た複数の画像に基づき、前記マルチウェルチップの空のウェル及び細胞含有ウェルを識別する、前記マルチウェルチップのマップを生成し、
d) 前記マルチウェルチップの識別された細胞含有ウェルのみを処理することを特徴とする方法。 - 前記マップを生成する際に、得た複数の画像を組み合わせて、拡張焦点深度を有する合成画像を生成することを特徴とする請求項1に記載の方法。
- 前記複数の画像は少なくとも3つのZ面を有することを特徴とする請求項1又は2に記載の方法。
- 前記マルチウェルチップのウェルの一部をパイロット撮像して、撮像で使用された複数のZ面を推定することを特徴とする請求項1〜3のいずれか一項に記載の方法。
- 撮像する際に、複数のウェルを同時的に撮像することを特徴とする請求項1〜4のいずれか一項に記載の方法。
- 前記マルチウェルチップのマップは、前記細胞含有ウェルが単細胞を含んでいるか又はマルチピレットを含んでいるかを更に識別し、単細胞を含んでいると識別された細胞含有ウェルのみを処理することを特徴とする請求項1〜5のいずれか一項に記載の方法。
- 細胞懸濁液の量は、30nl〜50nlであることを特徴とする請求項1〜6のいずれか一項に記載の方法。
- 前記マルチウェルチップの前記ウェルの数は100 以上であることを特徴とする請求項1〜7のいずれか一項に記載の方法。
- 処理する際に、識別された細胞含有ウェルに少なくとも1つの試薬を分注することを特徴とする請求項1〜8のいずれか一項に記載の方法。
- 処理する際に、識別された細胞含有ウェルの少なくとも一部で核酸増幅反応を行うことを特徴とする請求項1〜9のいずれか一項に記載の方法。
- a) 液体分注要素及び画像取得要素を有する分注・撮像システム組立体と、
b) 前記分注・撮像システム組立体と通信するプロセッサと、前記プロセッサによって実行されると、前記分注・撮像システム組立体に、
i) ある量の細胞懸濁液をマルチウェルチップのウェルに分注するステップ、
ii) 前記マルチウェルチップを撮像して複数のZ面で前記ウェルの複数の画像を得るステップ、及び
iii) 得た複数の画像に基づき、前記マルチウェルチップの空のウェル及び細胞含有ウェルを識別する、前記マルチウェルチップのマップを生成するステップ
を実行させる指示を記憶するコンピュータメモリと
を備えていることを特徴とするシステム。 - 前記コンピュータメモリは、得た複数の画像を組み合わせて、拡張焦点深度を有する合成画像を生成することにより、前記マップを生成するための指示を更に有することを特徴とする請求項11に記載のシステム。
- 前記コンピュータメモリは、前記マルチウェルチップのウェルの一部をパイロット撮像して、撮像で使用された複数のZ面を推定するための指示を更に有することを特徴とする請求項11又は12に記載のシステム。
- 前記コンピュータメモリは、前記プロセッサによって実行されると、前記システムに前記マルチウェルチップの識別された細胞含有ウェルのみを更に処理させる指示を更に有することを特徴とする請求項11〜13のいずれか一項に記載のシステム。
- 前記マルチウェルチップの識別された細胞含有ウェルのみを更に処理させる指示は、前記液体分注要素を使用して、識別された細胞含有ウェルのみに少なくとも1つの試薬を分注させる指示を含むことを特徴とする請求項14に記載のシステム。
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EP3487616A4 (en) | 2020-02-26 |
WO2018017892A1 (en) | 2018-01-25 |
EP3487616B1 (en) | 2023-08-09 |
CN109070044B (zh) | 2021-07-30 |
JP7075394B2 (ja) | 2022-05-25 |
CN109070044A (zh) | 2018-12-21 |
US20190113457A1 (en) | 2019-04-18 |
EP3487616A1 (en) | 2019-05-29 |
US11460405B2 (en) | 2022-10-04 |
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