JP2011516867A - 細胞、小胞、ナノ粒子およびバイオマーカーを分離および単離するためのエキソビボの多次元システム - Google Patents
細胞、小胞、ナノ粒子およびバイオマーカーを分離および単離するためのエキソビボの多次元システム Download PDFInfo
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Abstract
Description
本出願は、2008年4月3日に出願された、「細胞、小胞、ナノ粒子およびバイオマーカーを分離および単離するためのエキソビボの多次元システム(Ex−Vivo Multi−Dimensional System for the Separation and Isolation of Cells,Vesicles,Nanoparticles and Biomarkers)」を発明の名称とする米国仮特許出願第61/042,228号明細書の利益を主張するものであり、その開示内容全体を参照によって本明細書に援用する。
本研究は、NIH Grant/Contract CA119335の支援を受けて実施した。米国政府はこの発明に一定の権利を有する場合がある。
5倍濃縮トリス・ホウ酸・EDTA(TBE)緩衝溶液をUSB Corporation(USB、Cleveland、Ohio、USA)から入手し、脱イオンミリQ超純水(55nS/cm)を用いて0.01×TBE、0.1×TBEおよび1×TBEの濃度に希釈した。ダルベッコリン酸緩衝生理食塩水(1×PBS)溶液をInvitrogen(Invitrogen、Carlsbad、CA、USA)から入手し、ミリQ水を用いて0.1×PBSに希釈した。適切な伝導率標準液(conductivity standards)で調整した2セル(範囲:10〜2000μS)および4セル(範囲:1〜200mS)電極を用いてAccumet Research AR−50 Conductivityメーター(Fisher Scientific、Fair Lawn、NJ、USA)で伝導度の測定を行った。以下の緩衝液伝導度を測定した:0.01×TBE−18.1μS/cm;0.1×TBE−125μS/cm;1×TBE−1.09mS/cm;0.1×PBS−1.77mS/cm;および1×PBS−16.8mS/cm。
NeutrAvidinを表面被覆した蛍光ポリスチレンナノ粒子(FluoSpheres)をInvitrogen(Invitrogen、San Diego、CA、USA)から購入した。ナノ粒子の直径は0.04μm(40nm)および0.2μm(200nm)であった。40nmのポリスチレンナノ粒子は赤色蛍光(ex:585/em:605)であり、200nmのポリスチレンナノ粒子は黄色−緑色蛍光(ex:505/em:515)であった。より大きな10.14μmのカルボキシル化ポリスチレン粒子をBangs Labs(Bangs Labs、Fishers、IN、USA)から入手した。ビオチン化DNAオリゴヌクレオチド配列をTrilink Bio Technologies(Trilink、San Diego、CA、USA)から入手した。40nmのナノ粒子の誘導体化に使用した51merの一本鎖DNAオリゴヌクレオチドは配列が[5]’−ビオチン−TCA GGG CCT CAC CAC CTA CTT CAT CCA CGT TCA CTC AGG GCC TCA CCA CCT[3]’であった。使用した23merの第2の一本鎖DNAオリゴヌクレオチドは配列が[5]’−ビオチン−GTA CGG CTG TCA TCA CTT AGA CC[3]’であった。まず40nmのNeutrAvidinナノ粒子を様々な濃度のトリス・ホウ酸・EDTA(0.01×、0.1×、1×TBE)またはリン酸塩緩衝生理食塩水(0.1×、1×PBS)緩衝液に懸濁して、ビオチン化DNAオリゴヌクレオチドでこのナノ粒子の誘導体化を行った。この混合物に、51merのss−DNA配列に対して400:1(DNA:40nmのナノ粒子)の割合の量で、23merのss−DNA配列に対して6500:1(DNA:40nmのナノ粒子)の割合の量でss−DNAオリゴヌクレオチドを加えた。DNAを加えたら、この溶液を高速度で20秒間ボルテックスし、次いで約20分間反応させた。40nmのDNA誘導体化ナノ粒子の実験では、0.5μLの原液を299μLの適当な緩衝液に加えてDNAナノ粒子混合物を作製した。200nmのナノ粒子の実験では、0.5μLの原液を299μLの適当な緩衝液に加えた。最後に、このサンプルに10.14μmのポリスチレン粒子原液1μLを加え、次いでサンプルを約10秒間ゆっくりと混合した。これでサンプルをマイクロアレイカートリッジ装置に充填する準備が整った。
本試験に使用した微小電極アレイ装置は、Nanogen(San Diego、CA、USA、NanoChip(登録商標)100Cartridge)から入手した。アレイの円形微小電極は直径が80μmで、白金製であった。このマイクロアレイは10μm厚の多孔性ポリアクリルアミドヒドロゲル層で被覆されている。マイクロアレイは、アレイ上にガラス窓で覆われた20μLのサンプルチャンバーを形成するマイクロ流体カートリッジに封入される。個々の微小電極の電気的接続部は、カートリッジの底部にピンで留められている(pinned out to)。9枚の微小電極の3×3サブセットだけを使用してDEPを行った。チェッカーボードアドレッシングパターン(checkerboard addressing pattern)内の9枚の微小電極に交流(AC)電界を印加した。このチェッカーボードアドレッシングパターンにおいて、各微小電極は最近接電極と反対のバイアスを持つ。このパターンによる形成される非対称な電界分布に対応するコンピューターモデルは、既に考察されている[27]。このモデルでは、正のDEP電界の最大値(高電場領域)が微小電極(上)に存在し、負のDEP電界の最小値(低電場領域)が電極間の領域に存在することが示される。一般に、低い導電率溶液におけるDEPの場合、60nmのDNAおよび200nmのナノ粒子は微小電極の正または高電場領域に濃縮されると予想され[28]、10ミクロン粒子は微小電極間の負または低電界DEP領域に濃縮される[29]。この以前のモデルの計算は、5×5微小電極セットを対象に行われた[27]。各実験の前に、マイクロアレイカートリッジを、200μLの適当な緩衝液で5分にわたり10回フラッシュする。カートリッジを5分間静置し、次いで200μLの緩衝液でさらに2回洗浄する。次いでナノ粒子混合物を含むサンプル溶液を合計150μLゆっくりとカートリッジに注入し、最終的に約20μLのサンプル量がカートリッジに残る。
本マイクロアレイ装置は、100枚の各微小電極に印加される電圧を個々に制御できる特注の切り換えシステム(我々の実験室において設計および構成された)を用いて制御した。微小電極を、Agilent 33120A Arbitrary Function Generator(Agilent、Santa Clara、CA、USA)を用いて適切なAC周波数および電圧に設定した。AC周波数は、10ボルト 最大振幅で1000Hz〜10,000Hzの範囲であった。実験に使用した波形はすべて正弦波であった。実験は、適切な励起および発光フィルター(緑色蛍光Ex505nm、Em515nm;赤色蛍光Ex585nm、Em605nmを使用してJenaLumar落射蛍光顕微鏡(Zeiss、Jena、Germany)の10×PL Fluotar対物レンズで可視化した。バックライト画像および蛍光画像はどちらもOptronics 24−bit RGB CCDカメラ(Optronics、Goleta、CA、USA)を用いて撮像した。画像データは、Adobe Premiere Pro(Adobe Systems Inc、San Jose、CA、USA)あるいはWindows Movie Makerを用いてラップトップコンピューターに接続されたCanopus ADVC−55ビデオキャプチャカード(Canopus、San Jose、CA、USA)により処理した。最終の蛍光データは、0分時点、30秒時点、1分時点、2分時点、4分時点、8分時点、16分時点および20分時点にビデオの個々の蛍光画像フレームをMATLAB(Mathworks、Natick、MA、USA)に入力して解析した。グラフは、微小電極全体の蛍光強度値に関するMATLAB解析により得られたデータからExcelを用いて作成した。MATLABを用いて作成した。グラフの作成には以下のデータを使用した:σp(200nm)=18mS、σp(40nm+DNA)=50mS Ks=0.9nS、εp=2.55ε0。r=30nmおよびr=100nm。f=3kHz。DEP実験の終了後、FCOSマイクロアレイの表面からすべての流体を除去し、Phillips XL30走査型電子顕微鏡(SEM)で視覚化した。SEMを用いてマイクロアレイの表面上の最終的なナノ粒子層を画像化した。
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Claims (18)
- サンプル流体中の生物材料を分離するためのサンプル処理装置であって、
前記サンプル流体を供給し、前記サンプル流体を電極アレイに導く少なくとも1つの入口と、
前記電極アレイから前記サンプル流体を受け取る少なくとも1つの出口
とを含み、
前記電極アレイは、電極の少なくとも1つの小区画部が、電極の残りの小区画部と異なるように帯電することができることにより、異なるように帯電した前記電極によって、前記電極においての異なるように帯電した誘電泳動(DEP)力領域(force region)を構成し、前記異なるように帯電したDEP力領域によって、前記生物材料の分離を開始できるように形成された複数の電極を含む、サンプル処理装置。 - 前記電極アレイは、
前記装置の前記入口と前記出口との間の平面領域に配列される複数の交流(AC)電極と、
前記AC電極に隣接して配列される複数の直流(DC)電極
とを含む、請求項1に記載のサンプル処理装置。 - 前記DC電極は、前記AC電極の前記平面領域の外側に延在する、請求項2に記載のサンプル処理装置。
- 前記AC電極の少なくとも1つの小区画部は、前記残りのAC電極の小区画部と、電流の周波数が異なるAC電流が流される、請求項2に記載のサンプル処理装置。
- 前記電極は、電解作用による腐食に対して抵抗性がある強固な材料で構成される、請求項1に記載のサンプル処理装置。
- 多孔性材料が電解作用による腐食に対して抵抗性を示すように、前記多孔性材料の積層が前記電極に形成されている、請求項1に記載のサンプル処理装置。
- 前記装置から分析物の流れを排出する少なくとも1つの分析物の出口をさらに含む、請求項1に記載のサンプル処理装置。
- 生物材料を分離するためのシステムであって、
請求項1に記載のサンプル処理装置と、
前記サンプル処理装置の前記電極に選択的に電圧を加え、前記生物材料の分離を開始させるように形成されるコントローラ
とを含む、システム。 - 前記生物材料から分離される生物学的成分の前記分離工程および解析のモニタリングに関連する検出システムをさらに含む、請求項8に記載のシステム。
- 生物材料を分離する方法であって、
前記生物材料を、電極の少なくとも1つの小区画部が、電極の残りの小区画部と異なるように帯電できることにより、異なるように帯電した前記電極によって、前記電極において異なるように帯電した誘電泳動(DEP)力領域を構成できるように形成された、複数の前記電極を有する電極アレイを備えたサンプル処理装置に供給すること、
前記電極を選択的に電圧を加え、前記異なるように帯電した電極によって、前記電極において異なるように帯電したDEP力領域を構成すること、
前記異なるように帯電したDEP力領域によって、前記生物材料を、前記サンプル処理装置の分析物の出口に供給される少なくとも1種の分離された分析物成分と前記生物材料の残りの成分とに分離すること
を含む、方法。 - 分離される生物学的成分の分離工程および解析のモニタリングをさらに含む、請求項10に記載の方法。
- 前記分離することは、前記電極の小区画部の1つに少なくとも1種の生物材料が保持されることを含む、請求項10に記載の方法であって、
前記サンプル処理装置に試薬を導入すること、
前記サンプル処理装置において前記導入した試薬を前記保持された生物材料種と反応させること
を含む、方法。 - 前記試薬は蛍光色素を含む、請求項12に記載の方法。
- 前記試薬は抗体を含む、請求項12に記載の方法。
- 前記反応させることは、前記保持された生物材料種についてPCR操作を行うことを含む、請求項12に記載の方法。
- 生物材料を分離するためのシステムであって、
電界が外側の電極チャンバーから通過できる孔(ポータル、穴)を持つ内側のチャンバー構造体により区切られ、かつ各々が電極を有する2つ以上の異なる電極チャンバー構造体と、前記生物材料を供給する前記内側のチャンバーへの入口と、前記生物材料の分離された成分を前記内側のチャンバーから受け取る少なくとも1つの分析物の出口と、前記生物材料の残りの成分を受け取る別の出口と、
前記電極に選択的に電圧を加え、前記生物材料の分離を開始させるように形成されたコントローラと、
分離された生物学的成分の分離工程および解析のモニタリングに関連する検出システムと
を含む、システム。 - 生物材料を分離する方法であって、
前記生物材料を、外側の電極チャンバー構造体を有する内側のチャンバー構造体、前記生物材料を供給する入口、前記生物材料の分離された成分を前記内側のチャンバーから受け取る少なくとも1つの分析物の出口、前記生物材料の残りの成分を受け取る出口、および分離された生物学的成分の分離工程および解析のモニタリングに関連する検出システムに、前記電極を選択的に電圧を加えることにより供給すること、
前記生物材料を、前記内側のチャンバー構造体の分析物の出口に供給される少なくとも1種の分離された分析物成分と、前記生物材料の残りの成分とに分離すること
を含む、方法。 - 請求項11〜15のいずれかに記載のシステムが、分子、ポリマー、DNAおよびタンパク質誘導体化ナノ粒子、量子ドット、ナノチューブおよび同種のものなどのナノ要素、ならびにメソスケールの成分の三次元高次構造体、材料および装置へのアシスト型自己組織化(assisted self−assembly)を行うのに使用される、方法。
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US8932447B2 (en) | 2015-01-13 |
IL208429A0 (en) | 2010-12-30 |
EP2260297A4 (en) | 2012-07-18 |
GB201007402D0 (en) | 2010-06-16 |
CN103353476B (zh) | 2016-05-25 |
JP6190629B2 (ja) | 2017-08-30 |
CN103353476A (zh) | 2013-10-16 |
BRPI0910898B1 (pt) | 2021-09-14 |
WO2009146143A3 (en) | 2010-03-04 |
US20140048417A1 (en) | 2014-02-20 |
GB2468226B (en) | 2011-06-01 |
JP2016026297A (ja) | 2016-02-12 |
CN102037351A (zh) | 2011-04-27 |
EP2260297A2 (en) | 2010-12-15 |
GB2468226A (en) | 2010-09-01 |
US20110108422A1 (en) | 2011-05-12 |
ES2699679T3 (es) | 2019-02-12 |
CA2720324C (en) | 2016-08-23 |
BRPI0910898A2 (pt) | 2020-08-04 |
CA2720324A1 (en) | 2009-12-03 |
EP2260297B1 (en) | 2018-08-01 |
IL208429A (en) | 2016-08-31 |
WO2009146143A2 (en) | 2009-12-03 |
JP2013224947A (ja) | 2013-10-31 |
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