JP6622725B2 - 分析方法 - Google Patents
分析方法 Download PDFInfo
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- JP6622725B2 JP6622725B2 JP2016572803A JP2016572803A JP6622725B2 JP 6622725 B2 JP6622725 B2 JP 6622725B2 JP 2016572803 A JP2016572803 A JP 2016572803A JP 2016572803 A JP2016572803 A JP 2016572803A JP 6622725 B2 JP6622725 B2 JP 6622725B2
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Description
− 粒子は、非常に大きな表面対体積比を有する。
− 粒子は、バッチにおいて効率的に官能化され、ゆえに均一な懸濁液を形成するように混合することができる。
− 粒子の懸濁液は、直接液体形態で用いることができるようにアリコートに分配することができ、又は錠剤若しくは凍結乾燥した球等、乾燥したアリコートとして配合することができる。
− 粒子は、粒子に明確な特徴を付与する材料が投入されていても、又は明確な特徴を付与する材料から作られていてもよい。これには、光吸収、光散乱、光放射(発光)等の明確な光学的特徴、並びに磁性、放射能、触媒/酵素、電気化学的、及びその他の測定可能な特徴が含まれる。
− 粒子は、懸濁液中にある場合、マイクロ流体系内に運搬され得る。
− 粒子は、溶液中の試料と効率的に混合することができる。
− 懸濁液中の粒子は、重力、遠心分離、ろ過、磁力(磁性粒子)、若しくは電気力、又はこれらの組合せによって溶液から分離することができる。
− 粒子は、粒子を分散させた媒体に対する密度に応じて、沈降し、懸濁液中に留まり、又は浮遊し得る。
− 粒子は、単分散にすることができ、多孔性、又は孔のない滑らかな固体表面を有する両方の完全な球体にすることができる。
− 粒子は、カラムを含めた様々な容器中に充填しても、又は積層させてもよい。
− 粒子は、不透明(着色)でも、又は実質的に透明で様々な光学ベースの測定系における互換性及び使用を許容してもよい。
− 緻密な単分散粒子をカラム等におけるフィルタ上に積層する場合、これらは規則的で規定された間隔を有する多孔性の格子構造体を形成し得る。液体は、このようなカラムを介して、制御され、再現性のよい様式で流れることができる。
a)分析物を、密度m1を有するビーズと相互作用させる工程と、
b)密度m2を有する定量化可能なビーズ複合体を含む充填ビーズの構造体を得る工程と
を含み、洗浄工程は、
c)密度d>m2及びm1を有する液体媒体中に充填ビーズを分散させる工程と、
d)液体媒体と、定量化可能なビーズ複合体を含むビーズとを分離する工程と
を含む、方法を提供する。
本発明の文脈における「分析物」の語は、本発明による方法において定量的又は定性的に決定することができるあらゆる化合物を網羅するものと理解されたい。特に、「分析物」の語は、生物体、好ましくはヒトの身体の特定の疾患状態又はいくつかの他の生理学的状態の指標として用いることができるあらゆる化合物(即ち、バイオマーカー)を包含するものとされる。バイオマーカーは、例えば、貧血に対するバイオマーカー、例えば、エリスロポエチン(EPO)、フェリチン、可溶性トランスフェリン受容体(sTrR)、葉酸(フォレート)、トランスフェリン、ヘモグロビン、ビタミンB12、骨疾患に対するバイオマーカー、例えば、アルカリホスファターゼ(ALP)、オステオカルシン、副甲状腺ホルモン(PTH)、骨特異的アルカリホスファターゼ(BSAP)、ビタミンD、1,25ジヒドロキシ、I型コラーゲンC−末端テロペプチド(CTx)、ビタミンD、25ヒドロキシ、I型コラーゲンN−末端テロペプチド(NTx)、心疾患に対するバイオマーカー、例えば、アポリポタンパク質E(Apo E)、脳性ナトリウム利尿ペプチド(BNP)、LDH、CK、CKMB、プロB型ナトリウム利尿ペプチド(Pro−BNP)、C反応性タンパク質(CRP)、トロポニンI、トロポニンT、CRPh(超高感度)、糖尿病に対するバイオマーカー、例えば、C−ペプチド、HbA1c、IA−2抗体、インスリン、フルクトサミン、インスリン成長因子(IGF−1)、グルカゴン、ミクロアルブミン、グルコース、プロインスリン、抗体、内分泌科に関するバイオマーカー、例えば、アルファ−フェトプロテイン、成長ホルモン、副腎皮質刺激ホルモン(ACTH)、成長ホルモン放出因子(GRF)、コルチコステロン、プロラクチン、コルチゾール、テストステロン、卵胞刺激ホルモン(FSH)、胃腸科に関するバイオマーカー、例えば、ガストリン、リパーゼ、感染症に関するバイオマーカー、例えば、抗ボレリア、抗風疹、抗HBs、抗HBc、抗HBe、抗HCV、抗HIV I/II、並びに感染物質に対する他の抗体、及び感染物質の一部である特異的抗原、例えば、HIV−p24、HBsAg等、炎症/免疫に関するバイオマーカー、例えば、免疫グロブリン(IgA、IgG、IgM、IgE、IgD、及びこれらのサブクラス)、クラステリン(アポリポタンパク質J)、C反応性タンパク質(CRP)、CRPh(超高感度)、プロカルシトニン(PCT)、ヘパリン結合タンパク質(HPB)、カルプロテクチン、ヒト好中球リポカリン/好中球ゼラチナーゼ関連リポカリン(HNL/NGAL)、エンドセリン−1、フィブリノゲン、グルコース−6−ホスフェートデヒドロゲナーゼ(G−6−PDH)、IFNγによって誘発されるモノカイン(MIG/CXCL9)、IFN−アルファ、ネオプテリン、IFNγ(IL−2、IL−4、IL−10)−4−plex、IL−10、IL−10(IL−2、IL−4、IFNγ)−4−plex、IL−1β、Rantes/CCL5、IL−2(IL−4、IL−10、IFNγ)−4−plex、IL−4(IL−2、IL−10、IFNγ)−4−plex、腫瘍成長因子(TGF−β1)、IL−6、腫瘍壊死因子(TNFα)、IL−8、脂質代謝に関するバイオマーカー、例えば、アポリポタンパク質AI(Apo AI)、コレステロール、アポリポタンパク質AII(Apo AII)、HDL−コレステロール、アポリポタンパク質B−100(Apo B)、LDL−コレステロール、アポリポタンパク質B48(Apo B48)、レシチンコレステロールアシルトランスフェラーゼ(LCAT)、アポリポタンパク質CII(Apo CII)、パラキソナーゼ(PON1)、アポリポタンパク質CIII(Apo CIII)、ホスファチジルイノシトールグリカンF(PIGF)、アポリポタンパク質E(Apo E)、トリグリセリド、腎臓学に関するバイオマーカー、例えば、アルファ−GST、ベータ−2−ミクログロブリン(血清)、ミクロアルブミン、ベータ−2−ミクログロブリン(尿)システインC、クレアチニン、腫瘍学に関するバイオマーカー、例えば、炭水化物抗原19−9(CA19−9)、前立腺特異抗原(PSA)、癌胎児抗原(CEA)、血管内皮増殖因子(VEGF)、線維芽細胞成長因子(FGFb)、並びに甲状腺の状態に関するバイオマーカー、例えば、抗甲状腺ペルオキシダーゼAb(TPO)、甲状腺刺激ホルモン(TSH)、抗サイログロブリンAb、総チロキシン(T4)、遊離チロキシン(FT4)、総トリヨードチロニン(T3)、遊離トリヨードチロニン(FT3)、TSH受容体Ab、及びサイログロブリンであってよい。
本発明は、第1の溶液中の反応物と、固相粒子の表面に付着している反応物との間の非常に効率的な相互作用を、第2の溶液を用いて固相粒子を懸濁液にすることによる、固相粒子の非常に効率的な洗浄と組み合わせた分析方法を記載するものである。
本発明による方法の図による説明を図1a〜図1kに示す。方法は、1つ又は複数の対象の分析物に関して、試料を分析しようとするものである。方法は、液体中に溶解され得るあらゆるタイプの試料に適し、このような分析を行うためのアッセイに提供することができる前記試料中のあらゆるタイプの化合物又は物質を検出/定量するのにも適する。
図1a〜図1kによって記載する実施形態において、本発明の方法を、一度に1つの分析物を分析するものとして示す。しかし、方法は、一度にたった1つの分析物を分析することに制限されない。
内部流体回路を含む流体チップであって、内部流体回路を介して、ビーズ、及び少なくとも1つの分析物を含有する試料を含む様々な反応物が遠心力を使って移動することができる、流体チップにおいてビーズを分離する方法であって、
− 密度m1を有する少なくとも第1のセットのビーズ、及び密度m2を有する第2のセットのビーズを、流体回路の空洞において提供する工程であって、空洞は少なくとも第1の出口を含む工程、
− 第1の液体媒体を空洞に提供する工程であって、液体媒体は、m1<d3<m2であるような密度d3を有する工程、並びに
− 第1のセットのビーズ及び第2のセットのビーズが空洞内の反対の方向に遊走するように、遠心力を加える工程
を含む方法。
− 好ましくは第1のセットのビーズが第1の出口を介してデカントされるように、第1のセットのビーズを遠心力の方向を変えることにより空洞の外へ移送し、第2のセットのビーズは前記空洞に留まる工程
を含む。
− 第1のセットのビーズが第1の出口を介して移送され、第2のセットのビーズが第2の出口を介して移送されるように、遠心力の方向を変える工程
を含む。
ビーズの運搬に関して、本開示は、本発明による方法に依存せず、本発明による方法の本質的な部分でもない、本発明の更なる概念も表すものである。概念の一実施形態を図1l〜図1pに開示する。概念は、流体又はマイクロ流体チップ等のラボチップ装置に関して本質的に関係がある問題を解決するものであり、この場合、ビーズは、遠心力を使って流体回路を介して運搬されなければならない。従来技術では、ビーズの運搬は常に、遠心力と同じ方向で行われ、流体回路のデザインに利用できる選択肢は、よって限られる。本発明の更なる概念により、密度d2を有する液体媒体を、m1に等しく、又はm1より低い密度を有するビーズに添加することにより、加える遠心力と反対の方向にビーズを運搬することができ、この場合d2>m1である。
内部流体回路を含む流体チップであって、内部流体回路を介して、ビーズ、及び少なくとも1つの分析物を含有する試料を含む様々な反応物が遠心力を使って移動することができる、流体チップにおいてビーズを移送する方法であって、
− m1に等しく、又はm1より低い密度を有するビーズを、流体回路の空洞において提供する工程であって、空洞は少なくとも第1の出口を含む工程、
− 第1の液体媒体を空洞に提供する工程であって、液体媒体は、d2>m1であるように、密度d2を有する工程、及び
− ビーズが遠心力の反対方向に遊走するように、遠心力を加える工程
を含む方法。
− 好ましくはビーズが第1の出口を介してデカントされるように、遠心力の方向を変えることによってビーズを空洞の外に移送する工程
を含む。
2 第1の出口
3 第2の出口
4 入口
5 第1のフィルタエレメント
6 第2のフィルタエレメント
7 カラム構造体、カラム形状の空洞
8 ビーズ
9 トレーサー物質
10 第2のカラム形状の空洞
11 液体媒体
12 入口
13 第1の出口
14 第2の出口
15 水平チャネル
16 水平チャネル
17 水平チャネル
Claims (12)
- 定性的及び/又は定量的に決定しようとする分析物を含有する試料を分析する方法であって、結合工程及び洗浄工程を含み、前記結合工程は、
a)前記分析物を、密度m1を有するビーズと相互作用させる工程と、
b)密度m2を有する定量化可能なビーズ複合体を含む充填ビーズの構造体を得る工程であって、前記充填ビーズの構造体は、前記ビーズを流体回路のセクションに配置し、前記セクションに対して第1の方向の遠心力を加えることにより前記ビーズを充填することによって得られ、前記セクションが、第1及び第2の開口、並びに前記ビーズを前記セクション中に保持することができる粒子保持エレメントを含む、工程と
を含み、前記洗浄工程は、
c)実質的に前記第1の方向の遠心力を加えながら、密度d>m2及びm1を有する液体媒体中に充填ビーズを分散させる工程と、
d)液体媒体と、前記定量化可能なビーズ複合体を含む前記ビーズとを分離する工程と
を含む、方法。 - 工程a)のビーズが前記分析物に結合することができ、競合的アッセイの場合には規定量の分析物−トレーサー物質単位を含み、
前記分析物−トレーサー物質単位とは、トレーサー物質に結合している分析物からなる単位を意味し、
前記規定量では、前記ビーズが既知の分析結果又はシグナルを提供するように標準化されている、請求項1に記載の方法。 - 前記分析物が、工程a)の前、間、又は後にトレーサー物質と相互作用する、請求項1又は2に記載の方法。
- 前記分析物の、密度m1を有する前記ビーズとの前記相互作用が、前記定量化可能なビーズ複合体を提供する、請求項1から3のいずれか一項に記載の方法。
- 前記粒子保持エレメントが、前記第1又は第2の開口に配置されるフィルタエレメント又はベンドである、請求項1に記載の方法。
- 前記セクションが流体チップの内部流体回路の一部であり、その内部流体回路を介して、ビーズ、及び少なくとも1つの分析物を含有する試料を含む様々な反応物が、遠心力を使って移動され得る、請求項1又は5に記載の方法。
- 工程a)が、密度d1<m1を有する第1の液体媒体中で行われる、請求項1から6のいずれか一項に記載の方法。
- 前記結合工程が、前記第1の液体媒体と前記ビーズとを分離する工程を更に含む、請求項7に記載の方法。
- 工程c)に、密度d2>m2及びm1を有する第2の液体媒体を前記充填ビーズに添加する工程が先行する、請求項1から8のいずれか一項に記載の方法。
- 前記定量化可能なビーズ複合体を含む前記ビーズが、前記第1の方向と異なる第2の方向を有する遠心力を加えることにより前記セクションから移送される、請求項1に記載の方法。
- 前記試料の前記分析物が定性的及び/又は定量的に決定されるように、前記定量化可能なビーズ複合体を分析する工程を更に含む、請求項1から10のいずれか一項に記載の方法。
- マイクロ流体チップの配向を、加えられた遠心力に対して変動させることができる、遠心機器用のマイクロ流体チップにおける請求項1から11のいずれか一項に記載の方法の使用であって、前記マイクロ流体チップは内部流体回路を含み、その内部流体回路を介して、前記ビーズ、及び少なくとも1つの分析物を含有する試料を含む、前記方法の様々な反応物が、遠心力を使って移動され得る、使用。
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