JP2009544043A - マイクロチャネル装置を用いた標的分子の検出または単離 - Google Patents
マイクロチャネル装置を用いた標的分子の検出または単離 Download PDFInfo
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Abstract
Description
本発明は概して、標的分子の検出または単離、および特に所望の標的細胞または生体分子を検出または単離するのに有用な装置または方法に関する。
異種混交的な細胞集団からの希少な細胞の有効な単離および収集は、疾患の診断および治療、例えば遺伝子治療に用いるため、ならびに基礎科学研究のための、単離された細胞集団に対する需要の高まりを理由として、未だに大きな関心を集めている。例えば、癌細胞のように病的に変化した細胞を、より多数の正常細胞集団から分離することができ、続いて、浄化された細胞集団を患者に移植して戻すこともできる。
ランダム化流路、特にランダム化流体マルチチャネルパターンによって提供されたランダム化流路を、標的分子または実体を単離または検出するために使用可能であることが、本発明の知見である。したがって、本発明は、標的分子、特に標的細胞または生体分子を単離または検出するのに有用な装置および方法を提供する。
生体分子を分離するためのマイクロフロー装置は、実施例1に記載のプロトタイプ基板を用いて構築される。基板はPDMSから形成され、フローチャネルを閉鎖するために平坦ガラスプレートと結合される。収集領域の全体にわたる内面は、Dow Corning Z-6020の容積百分率10パーセント溶液とともに室温で30分間インキュベートすることによって誘導体化される。エタノールで洗浄した後、それらを脱脂乳により室温で約1時間処理し、薄いカゼインコーティングを生じさせる。水中10%エタノールでの洗浄に続き、イソシアネートでキャップした平均MWが6000のPEGトリオールをベースとするヒドロゲルを用いて処置を行う。用いる製剤は、約3%のポリマーから構成される。ヒドロゲルプレポリマーは、6部の有機溶媒に対して重量で1部のポリマーを用いて作製する。すなわち、アセトニトリルおよびDMFを、BSAを含む100 mMのホウ酸ナトリウム(pH 8.0)中1 mg/mlの抗体溶液と混合した。特定の製剤は、Acn/DMF中100 mgのプレポリマー、ホウ酸緩衝液中0.25 mg/ml抗体混合物を350μL、およびホウ酸緩衝液中1 mg/ml BSAを350μL含み、約2重量%のポリマーを含有する。
生体分子を分離するためのマイクロフロー装置を、実施例1に記載のプロトタイプ基板を用いて構築する。基板はPDMSから形成され、フローチャネルに近接した平坦なガラスプレートに結合される。収集領域全体にわたる内部表面は、10容量%のDow Corning Z-6020溶液と共に室温で30分間インキュベートすることによって誘導体化される。エタノールで洗浄後、室温で約1時間それらを脱脂乳で処理し、薄いカゼインコーティングを生成させる。水中10%エタノールでの洗浄に続き、イソシアネートでキャップした平均MWが6000のPEGトリオールをベースとするヒドロゲルを用いて処置を行う。用いる製剤は、約3%のポリマーから構成される。ヒドロゲルプレポリマーは、6部の有機溶媒、すなわち、アセトニトリルおよびDMFに対して重量で1部のポリマーを用いて作製し、BSAを含む100 mMのホウ酸ナトリウム(pH 8.0)中1 mg/mlの抗体溶液と混合する。得られた特定の製剤は、Acn/DMF中100 mgのプレポリマー、ホウ酸緩衝液中0.25 mg/ml抗体混合物を350μL、およびホウ酸緩衝液中1 mg/ml BSAを350μL含み、約2重量%のポリマーを含有する。栄養芽細胞の外表面に担持されているリガンドに特異的である抗体Trop-1およびTrop-2を再度用いる。
生体分子を分離するための別のマイクロフロー装置を、実施例1に記載のプロトタイプ基板を用いて構築する。基板はPDMSから形成され、フローチャネルに近接した平坦なガラスプレートに結合される。収集領域全体にわたる内部表面は、10容量%のDow Corning Z-6020溶液と共に室温で30分間インキュベートすることによって誘導体化される。エタノールで洗浄後、室温で約1時間それらを脱脂乳で処理し、薄いカゼインコーティングを生成させる。
基本的な実験アプローチ:
・ドナー1人当たり6×10 mlの血液を採取する
・フィコール細胞ペレットを各10 mlから調製する(主に血液の有核白血球成分を含む)
・約50 JEG細胞を各細胞ペレットにスパイクする
・MACSで3回、CEEで3回実行する、すなわち同じドナーから3つ組で実行する
・MACSとCEEは両方とも、通常MACSで血液中の上皮細胞を捕捉するために用いられるEpCAM抗体で、コーティングされている
・MACSとCEEからのJEG細胞の回収率をカウントする
・MACSとCEE上のバックグラウンドDAPIポジティブ細胞をカウントする
・6つの異なるドナーで繰り返す(合計18試料/デバイス)
・累計CEE捕捉はMACSより約2倍高かった(p<0.0001)
・全体のMACS非特異的捕捉はCEEより約13倍高かった(p<0.0001)
・フィコールからの特異的および非特異的な捕捉変動率は、両方の手法で高く、試料操作に起因するところが大きく、試料の変動率ではないようである
Claims (28)
- 流入口手段、流出口手段、および流入口手段と流出口手段の間に伸びるマイクロチャネル配列を含むランダム化流路を有する主要部分を備えるマイクロフロー装置であって、該マイクロチャネル配列が、マイクロチャネルの基部表面と一体化しかつそこから突出している複数の横断するセパレータポストを含み、該ポストが該ランダム化流路を提供できるパターンで配置される、マイクロフロー装置。
- ポストが、基部表面に対して実質的に垂直に整列化される、請求項1記載の装置。
- ポストが、数学的アルゴリズムによって生成されるランダム化パターンで配置される、請求項1記載の装置。
- ポストが、該ポストの総数と該ポストのうちの2つの間の最小距離を用いた数学的アルゴリズムによって生成されるランダム化パターンで配置される、請求項1記載の装置。
- ポストが、少なくとも2つの異なる横断面サイズを有する、請求項1記載の装置。
- ポストの平均横断面サイズが、マイクロチャネルを流れる標的分子のサイズに関連する、請求項1記載の装置。
- ポストの横断面が、マイクロチャネルの基部表面の横断面の約20%〜約75%を占める、請求項1記載の装置。
- ポストの総容量が、マイクロチャネルの総容量の約15%〜約25%である、請求項1記載の装置。
- 2つのポスト間の最小距離が、ポストの最小横断面サイズに関連する、請求項1記載の装置。
- マイクロチャネルの表面が親水性の層でコーティングされる、請求項1記載の装置。
- マイクロチャネルの表面が、PEG、PPG、またはそのコポリマーのイソシアネート官能性ポリマーを含む少なくとも約1ミクロンの厚さの親水性の層でコーティングされる、請求項1記載の装置。
- マイクロチャネルの表面が隔離剤(sequestering agent)でコーティングされている、請求項1記載の装置。
- マイクロチャネルの表面が、抗体、抗原、受容体、リガンド、オリゴヌクレオチド、およびペプチドからなる群より選択される隔離剤でコーティングされる、請求項1記載の装置。
- 隔離剤が、リンカーによってマイクロチャネルの表面に結合される、請求項1記載の装置。
- 隔離剤が、親水性リンカーまたはヒドロゲル層によってマイクロチャネルの表面に結合される、請求項1記載の装置。
- 流入口手段が、液体試料を保持することが可能なウェルを含む、請求項1記載の装置。
- マイクロチャネルが、ポストの自由端に取り付けられたプレートで密封される、請求項1記載の装置。
- マイクロチャネルが、光学的に透過性である基部表面を含み、かつ光学的検出手段によって見ることができる、請求項1記載の装置。
- マイクロチャネルが、ポストの自由端に取り付けられたプレートで密封され、該マイクロチャネルの基部表面および該プレートが、光学的に透過性である、請求項1記載の装置。
- 請求項1記載の装置と、マイクロチャネルの表面を隔離剤でコーティングするための説明書とを含む、キット。
- マイクロチャネルの表面が隔離剤でコーティングされている、請求項1記載の装置を含むキット。
- 以下の段階を含む、試料中の標的分子を捕捉する方法:
該試料を含む液体本体を、請求項1記載の装置のマイクロチャネル中を流れさせる段階であって、該マイクロチャネルの表面が標的分子に結合可能な隔離剤でコーティングされている、段階。 - 以下の段階を含む、試料中の標的分子を検出する方法:
該試料を含む液体本体を、請求項1記載の装置のマイクロチャネル中を流れさせる段階であって、該マイクロチャネルの表面が標的分子に結合可能な隔離剤でコーティングされている、段階、および
標的分子を検出する段階。 - 標的分子が状態に関連する細胞である、請求項23記載の方法。
- 標的分子が癌または腫瘍細胞である、請求項23記載の方法。
- 標的分子が胎児細胞である、請求項23記載の方法。
- 標的分子が標的細胞であり、試料中の標的細胞数と総細胞数の比が、少なくとも1:107、1:108、または1:109である、請求項23記載の方法。
- 試料を含む液体本体が、約0.5 mm〜約5 mm/秒の速度でマイクロチャネルを通って流れる、請求項23記載の方法。
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IL196553A0 (en) | 2009-11-18 |
EP2052074A2 (en) | 2009-04-29 |
US20060252087A1 (en) | 2006-11-09 |
WO2008011486A2 (en) | 2008-01-24 |
HK1135725A1 (en) | 2010-06-11 |
EP2052074A4 (en) | 2016-02-24 |
US20120258475A1 (en) | 2012-10-11 |
KR20090033899A (ko) | 2009-04-06 |
KR101472599B1 (ko) | 2014-12-15 |
CA2658336C (en) | 2018-02-27 |
WO2008011486A3 (en) | 2008-10-23 |
CN101535466B (zh) | 2014-07-09 |
CN101535466A (zh) | 2009-09-16 |
CA2658336A1 (en) | 2008-01-24 |
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