JP6984053B2 - マイクロ流体デバイスにおける細胞の凍結及び保管 - Google Patents
マイクロ流体デバイスにおける細胞の凍結及び保管 Download PDFInfo
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Description
部分−(L)n−LG 式2
部分−(L’)m−Rpx 式5
[00181] 本出願の発明者らは、標準的な培養プレートで成長させた生体細胞を36℃でマイクロ流体デバイスに導入した。次いで、細胞を操作し、マイクロ流体デバイス内の各単離領域に隔離した(引き続き36℃)。マイクロ流体デバイス内に15%DMSO溶液(媒体中)を流入させ、その後デバイスを36℃で30分間、追加のかん流なしでインキュベートした。次いで、マイクロ流体デバイスを1.8℃/分の制御速度で0℃まで冷却した。隔離された細胞は凍結プロセス中に移動し続けたが、温度が低下するにつれて減速したことが観察された。デバイスを発泡スチロールの箱に入れ、次いでこれを−80℃冷凍庫内に一晩置いた。翌日、マイクロ流体デバイスを冷凍庫から(及び発泡スチロールの箱から)取り出し、高い室温(top room temperature)まで温めた(比較的小さいデバイスサイズのため、デバイス温度は1分内に室温まで上昇したと仮定する)。次いで、デバイスを試験器械の上に置き、ペルチェ(Peltier)を約24℃に設定し、媒体のかん流を開始した。その後、デバイスの温度を約3℃/分で36℃まで上昇させた。いくつかの細胞がデバイスの解凍中に移動し始めたこと、いくつかの生存(生きている)細胞が1日中移動し続けたこと、更に、1日の終わりにはごく一部が生存し、生体細胞の標準的な凍結解凍手順と一致していたことが観察された。マイクロ流体デバイスを凍結し、次いで解凍させた後、マイクロ流体デバイス(及びその中で隔離した細胞)に対してOETプロセスは引き続き機能した。
[00182] 組織生検を単一細胞に解離し、マイクロ流体デバイスに導入した。細胞懸濁液12mLを、1×106細胞/mLの濃度でデバイス内に取り込んだ。デバイスは約1.0mLの全チャネル体積を有し、どの時点においても目に見える名目上の細胞量は約1000の細胞であった。自動ペニングアルゴリズム(automated penning algorithm)を用いて、細胞を個々に単離チャンバに配置した。細胞の挿入及び単離プロセスの間、デバイス温度は12℃に設定した。次いでマイクロ流体デバイスを、凍結に充分な時間にわたって冷凍庫に入れた。次いで、デバイスを冷凍庫から取り出すことで解凍させ、器械の上に置いた(T=12℃で)。単離チャンバ内の生存細胞はOETを用いて可動性であり、隔離のような別の分析のため外に出せることが観察された。
Claims (28)
- 生体細胞を処理及び貯蔵する方法であって、
マイクロ流体デバイス内に流動性媒体を導入することであって、前記マイクロ流体デバイスは、電極活性化基板を内面上に備えるベースと、その上に配置されたマイクロ流体回路構造と、カバーとを有し、前記マイクロ流体回路構造は、流れ領域と、1つ以上の単離チャンバとを有し、各単離チャンバは、単離領域と、前記流れ領域内への近位開口及び1つ以上の前記単離領域内への遠位開口を含む接続領域とを有し、前記単離領域は、前記接続領域への単一の開口を有し、前記単離領域は、一掃されない領域であり、
前記マイクロ流体デバイスの前記1つ以上の単離領域に前記流動性媒体からの1つ以上の生体細胞を隔離することと、
内部で隔離された前記1つ以上の生体細胞を含む前記マイクロ流体デバイスを一定期間凍結することと、
前記マイクロ流体デバイスを解凍することと、
前記マイクロ流体デバイスから、少なくとも1つの隔離された細胞及び/又はそこから生成した細胞を検索することと、
を備える、方法。 - 単一の生体細胞が複数の単離領域の各々において隔離されている、請求項1に記載の方法。
- 各単離領域は1.5×105立方ミクロン〜1.5×106立方ミクロンの範囲内の体積を有する、請求項1又は2に記載の方法。
- 前記マイクロ流体デバイスを凍結する前に、前記1つ以上の隔離された生体細胞の各々について少なくともアイデンティティ及び単離領域位置を含む在庫目録を生成することと、前記マイクロ流体デバイスに関連付けられたメモリに前記在庫目録を記憶することと、
を更に含む、請求項1〜3のいずれか1項に記載の方法。 - 前記在庫目録は、(i)前記流動性媒体中の前記生体細胞がどのように取得されたか、(ii)前記マイクロ流体デバイス内に導入される前又は後に前記生体細胞に実行された処理が存在する場合はこの処理、(iii)前記マイクロ流体デバイス内で隔離された後に前記1つ以上の隔離された生体細胞に実行された処理が存在する場合はこの処理、及び(iv)そのような隔離前又は隔離後の処理の過程において得られたデータ、のうち1つ以上を識別する情報を更に含む、請求項4に記載の方法。
- 前記マイクロ流体デバイスを凍結することは、0℃の温度までの前記マイクロ流体デバイスの最初の制御冷却、及び、その後の氷点下の温度までの前記マイクロ流体デバイスの冷却を含む、請求項1〜5のいずれか1項に記載の方法。
- 前記最初の制御冷却は、毎分0.1℃〜毎分2℃の範囲内の速度で前記マイクロ流体デバイスを冷却することを含む、請求項6に記載の方法。
- 前記氷点下の温度は、−20℃以下、−80℃以下、及び−150℃以下のうちの1つである、請求項6又は7に記載の方法。
- 前記マイクロ流体デバイスを凍結する前に、前記マイクロ流体デバイス内に細胞保存試薬を導入することを更に含む、請求項1〜8のいずれか1項に記載の方法。
- 前記細胞保存試薬はジメチルスルホキシド(DMSO)を含む、請求項9に記載の方法。
- 前記DMSOは、前記マイクロ流体デバイスの凍結時に前記1つ以上の隔離された生体細胞が10%DMSOを含有する溶液によって実質的に取り囲まれるように選択された濃度及び持続時間で、前記マイクロ流体デバイスに導入されるか、又は、前記DMSOは、体積で15%から25%の濃度で前記マイクロ流体デバイスに導入され、隔離された生体細胞を含む前記1つ以上の単離領域に拡散されるか、又は
前記DMSOは、前記1つ以上の単離領域の各々において10%のDMSO濃度を達成するのに充分な時間量、前記マイクロ流体デバイスをかん流させる、請求項10に記載の方法。 - 前記マイクロ流体デバイスを解凍した後、前記マイクロ流体デバイス内で1つ以上の生存細胞を培養し、これによって追加の細胞を生成することを更に含む、請求項1に記載の方法。
- 前記マイクロ流体デバイスを解凍した後、前記1つ以上の隔離された細胞及び/又はそこから生成した細胞のうちどれが生存しているか識別することを更に含む、請求項12に記載の方法。
- 前記マイクロ流体デバイスを解凍することは、(i)前記マイクロ流体デバイスの制御加熱、及び(ii)前記マイクロ流体デバイスを室温まで自己加熱させること、の一方又は双方を含む、請求項12又は13に記載の方法。
- 前記1つ以上の隔離された生体細胞は、第1の単離領域において隔離された少なくとも1つ以上の開始細胞を含み、前記方法は、前記マイクロ流体デバイスを凍結する前に、前記1つ以上の開始細胞を培養して前記第1の単離領域において複数の新しい細胞を生成することであって、前記複数の新しい細胞は、前記マイクロ流体デバイスを解凍した後に前記第1の単離領域に少なくとも1つの生存細胞が位置するように適切な数である、ことを更に含む、請求項1〜14のいずれか1項に記載の方法。
- 前記1つ以上の隔離された生体細胞のアッセイを実行することを更に含む、請求項1〜15のいずれか1項に記載の方法。
- 前記アッセイを用いて、細胞分泌物又は細胞表面マーカ、及び免疫学的分子を含む細胞分泌物のうちの1つを検出する、請求項16に記載の方法。
- 前記流れ領域及び1つ以上の単離領域はブロッキング溶液で処理されて細胞接着を防止又は軽減する、請求項1〜17のいずれか1項に記載の方法。
- 前記マイクロ流体デバイスは、コーティング材料を含む内側基板表面を含む、請求項1〜18のいずれか1項に記載の方法。
- 前記コーティング材料は、連結基及びアルキル部分を有する分子を含み、前記連結基は前記内側基板表面に共有結合している、請求項19に記載の方法。
- 前記連結基はシロキシ連結基であり、且つ/又は、前記アルキル部分は少なくとも10の炭素原子を含む炭素の直鎖を含み、且つ/又は、前記コーティング材料の前記分子は、前記内側基板表面に共有結合している高密度充填単層構造を形成する、請求項20に記載の方法。
- 前記コーティング材料は、連結基及びカチオン性部分及び/又はアニオン性部分を有する分子を含み、前記連結基は前記内側基板表面に共有結合している、請求項19に記載の方法。
- 前記コーティング材料は、アルキレンエーテル部分、サッカライド部分、又はアミノ酸部分を含むポリマーを含む、請求項19に記載の方法。
- 前記コーティング材料はポリエチレングリコールを含む、請求項23に記載の方法。
- 前記流れ領域は、マイクロ流体チャネルを含み、前記接続領域は、前記マイクロ流体チャネル内への、20ミクロンから100ミクロンの範囲の幅Wconを有する近位開口、及び前記単離領域内への遠位開口を含み、前記接続領域の前記近位開口から前記遠位開口までの長さLconは、前記接続領域の前記近位開口の幅Wconの少なくとも1.0倍である、請求項1に記載の方法。
- 前記接続領域の前記近位開口から前記遠位開口までの前記Lconは、前記接続領域の前記近位開口の前記幅Wconの少なくとも2.0倍である、請求項25に記載の方法。
- 前記接続領域の前記近位開口における前記マイクロ流体チャネルの高さは、20ミクロンから100ミクロンの間である、請求項25又は26に記載の方法。
- 前記カバー及び前記ベースは、微小物体に対する誘電泳動(DEP)力を選択的に誘発するためのDEP機構の一部であり、前記DEP力は、前記1つ以上の単離領域内に前記1つ以上の生体細胞を選択的に隔離するように用いられ、且つ/又は前記1つ以上の単離領域から前記1つ以上の生体細胞を選択的に外に出すように用いられる、請求項1に記載の方法。
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