JP2018522586A - バリア機能の測定 - Google Patents
バリア機能の測定 Download PDFInfo
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- JP2018522586A JP2018522586A JP2018521170A JP2018521170A JP2018522586A JP 2018522586 A JP2018522586 A JP 2018522586A JP 2018521170 A JP2018521170 A JP 2018521170A JP 2018521170 A JP2018521170 A JP 2018521170A JP 2018522586 A JP2018522586 A JP 2018522586A
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Abstract
Description
上皮組織は、4種類の基本的な組織(上皮組織、結合組織、筋肉組織、及び神経組織)の中の1つを含む。上皮細胞は、動物(脊椎動物及び無脊椎動物の両方)並びに植物において認められ、そして生物の生理機能において中心的な役割を果たす。
定義
本発明の方法、組成物、使用、及び他の態様に関する様々な用語が、明細書及び特許請求の範囲の全体を通して使用されている。このような用語には、特記されない限り、本発明が属する技術分野のその通常の意味が与えられる。他の具体的に定義された用語は、本明細書に提供された定義と一致した意味で解釈される。本明細書に記載のものと類似した又は等価なあらゆる方法及び材料を、本発明を試験するための実践に使用することができるが、好ましい材料及び方法は本明細書に記載されている。
上皮バリア機能に対する試験化合物の調節効果をインビトロにおいて決定するための方法を開示する。上皮バリアは、固定された静的な構造ではない。それらは、様々な異なる刺激に応答してより漏出するようになったり又はあまり漏出しなくなったりし得る。疾患プロセス及び薬剤は、バリア壁をより漏出性とする場合がり、そしてこのような漏出部位は例えば密着結合部であることが多い(Mullin et al. (2005) Drug Discov. Today, 10:395-408)。
a)複数の中空マイクロ流体チャネルを含むマイクロ流体システムを準備する工程(ここで、該チャネルは少なくとも部分的にゲルで充填されている);
b)上皮細胞をマイクロ流体チャネルに導入し、そして上皮細胞がゲルと接触することを可能とする工程;
c)マイクロ流体チャネルに導入された上皮細胞を培養し、これによりマイクロ流体チャネル内で細胞がゲル上で頂端側及び基底外側を有する細胞層を形成することを可能とし、好ましくはこれにより細胞が頂端側及び基底外側を有する細管構造を形成することを可能とする工程;
d)マイクロ流体チャネル内の上皮細胞に、プローブ及び試験化合物を与える工程(ここで、該プローブ及び該試験化合物は、独立して、頂端側、基底外側、又は頂端側と基底外側の両方に与えられる);
e)様々な時点において、マイクロ流体チャネル内若しくはゲル内のプローブ、又はマイクロ流体チャネル内とゲル内の両方のプローブによって与えられるか又は作られるシグナルを決定する工程。
であり、ここで、tは時間であり、Aは、プローブが横断することのできる細胞層の面積であり、Vreceiverはプローブが向かって拡散又はドリフトするデバイスの部分の容積であり、Creceiverは、プローブが向かって拡散又はドリフトするデバイスの部分におけるプローブ濃度であり、及びCdonor,initialは、区画(これからプローブが拡散して出て行く)内のプローブの初期濃度である。
を使用することができる。
へと再編成することができる。
f)工程e)で得られたシグナルから、試験化合物及び/又はプローブを上皮細胞に与えた時点から、マイクロ流体チャネル内及び/又はゲル内の予め決定された蛍光の数値又は予め決定された蛍光の数値の変化が達成された時点までに、あるいはマイクロ流体チャネル(頂端側)及びゲル(基底外側)内の予め決定された蛍光の比率の数値又は予め決定された蛍光の比率の数値の変化が達成された時点までに経過した時間を決定する工程
を含む。
1)チャネル内、すなわち、プローブが与えられた側(ドナー側)に定常流が適用され得る。このような実施態様では、これは、例えば基底外側又は頂端側における定常的なプローブ発生源を引き起こす。このような実施態様における測定は、好ましくは、他方の側で得られたシグナルに基づいて行なわれる。
Claims (24)
- 上皮バリア機能に対する試験化合物の調節効果をインビトロにおいて決定するための方法であって、該方法は、
a)複数の中空マイクロ流体チャネルを含むマイクロ流体システムを準備する工程(ここで、該チャネルは少なくとも部分的にゲルで充填されている);
b)上皮細胞をマイクロ流体チャネルに導入し、そして上皮細胞がゲルと接触することを可能とする工程;
c)マイクロ流体チャネルに導入された上皮細胞を培養し、これによりマイクロ流体チャネル内で細胞がゲル上で頂端側及び基底外側を有する細胞層を形成することを可能とし、好ましくはこれにより細胞が頂端側及び基底外側を有する細管構造を形成することを可能とする工程;
d)マイクロ流体チャネル内の上皮細胞に、プローブ及び試験化合物を与える工程(ここで、該プローブ及び該試験化合物は、独立して、頂端側、基底外側、又は頂端側と基底外側の両方に与えられる);
e)様々な時点において、マイクロ流体チャネル内若しくはゲル内のプローブ、又はマイクロ流体チャネル内とゲル内の両方におけるプローブによって与えられるシグナルを決定する工程
を含む、該方法。 - 前記方法がさらに、
f)工程e)で得られたシグナルから、試験化合物及び/又はプローブを上皮細胞に与えた時点から、マイクロ流体チャネル内及び/又はゲル内の予め決定された蛍光の数値又は予め決定された蛍光の数値の変化が達成された時点までに、あるいはマイクロ流体チャネル及びゲル内の予め決定された蛍光の比率の数値又は予め決定された蛍光の比率の数値の変化が達成された時点までに経過した時間を決定する工程
を含む、請求項1記載の方法。 - 前記方法が、1つを超える濃度の試験化合物について実施され、好ましくは工程f)が1つを超える濃度の試験化合物について決定される、請求項1又は2記載の方法。
- 上皮バリア機能に対する試験化合物の効果が、培養上皮細胞を含む1つを超えるマイクロ流体チャネルにおいて同時に決定され、好ましくは上皮バリア機能に対する1つを超える濃度の試験化合物の効果が同時に決定される、請求項1〜3のいずれか一項に記載の方法。
- 独立して、上皮バリア機能に対する1つを超える試験化合物の効果が、培養上皮細胞を含む複数のマイクロ流体チャネルの少なくとも一部において同時に決定される、請求項1〜4のいずれか一項に記載の方法。
- 工程d)より前に又は工程d)と同時に、バリア機能が破壊される、請求項1〜5のいずれか一項に記載の方法。
- 試験化合物が、プローブより前に、後に、又は同時にのいずれかで細胞に与えられる、請求項1〜6のいずれか一項に記載の方法。
- 工程c)で培養された細胞は単層を形成し、好ましくは該単層は実質的にプローブが頂端側から基底外側へと、及び/又は頂端側から基底外側へと拡散することを可能としない、請求項1〜7のいずれか一項に記載の方法。
- 工程e)における2つの連続した時点が互いに1秒間から24時間以内である、請求項1〜8のいずれか一項に記載の方法。
- 工程e)における様々な時点が10分間から4週間の間隔内(境界値を含む)である、請求項1〜9のいずれか一項に記載の方法。
- ゲルの隣に、ゲルと接触しているさらなるチャネルが存在し、該チャネルは、培養上皮細胞を含むマイクロ流体チャネルと直接接触していない、請求項1〜10のいずれか一項に記載の方法。
- 前記のさらなるチャネル内にゲルからプローブを除去する流動が存在し、そして好ましくは工程e)のゲル内のプローブによって与えられたシグナルの決定は、前記のさらなるチャネル内に存在する流動中のシグナルの測定を含む、請求項11記載の方法。
- 工程b)において様々な種類の上皮細胞が同じマイクロ流体チャネル内に導入され、及び/又は、工程b)において様々なマイクロ流体チャネルに、様々な種類の上皮細胞が与えられる、請求項1〜12のいずれか一項に記載の方法。
- ゲルが基底膜抽出物、細胞外マトリックス成分、コラーゲン、コラーゲンI型、コラーゲンIV型、フィブロネクチン、ラミニン、ビトロネクチン、D−リジン、エンタクチン、ヘパラン硫酸プロテオグリカン、又はその組合せであり、そして好ましくはゲルは人工膜又は拡散バリアを含まず、及び/又は、ゲルは細胞層と直接接触し、この2つを隔てる物理膜を全く有さない、請求項1〜13のいずれか一項に記載の方法。
- 上皮細胞が動物上皮細胞、動物上皮細胞株の細胞、動物上皮初代細胞、哺乳動物上皮細胞、哺乳動物上皮細胞株の細胞、哺乳動物の上皮初代細胞、ヒト上皮細胞、ヒト上皮細胞株の細胞、又はヒト上皮初代細胞である、請求項1〜14のいずれか一項に記載の方法。
- 工程e)のプローブによって与えられるシグナルの決定が、画像撮影装置、顕微鏡、自動顕微鏡、ハイコンテント画像撮影装置、プレートリーダー、又はマルチモードリーダーを使用した測定を含む、請求項1〜15のいずれか一項に記載の方法。
- マイクロ流体デバイスが、マイクロ流体チャネルへの及び/又はゲルへの及び/又はさらなるチャネルへの連続的な光路を提供する、請求項1〜16のいずれか一項に記載の方法。
- 調節効果が、上皮バリア機能を破壊又は修復することである、請求項1〜17のいずれか一項に記載の方法。
- 工程d)において試験化合物が与えられる前にプローブが上皮細胞に与えられ、そして好ましくはプローブが与えられた後に、マイクロ流体チャネル内若しくはゲル内に、又はマイクロ流体チャネル内とゲル内の両方に与えられたシグナルが、様々な時点において及び試験化合物が与えられる前に決定される、請求項1〜18のいずれか一項に記載の方法。
- マイクロ流体システムが少なくとも3個、好ましくは10個超、さらにより好ましくは約40個、96個、256個、384個のマイクロ流体チャネルを含み、好ましくは上皮細胞を含む少なくとも3個、好ましくは10個超、さらにより好ましくは約40個、96個、256個、384個のマイクロ流体チャネルが同時に、順次、又は平行して測定される、請求項1〜19のいずれか一項に記載の方法。
- 様々なサイズのプローブが工程d)において与えられ、好ましくは各々の異なるサイズのプローブは異なる蛍光標識で標識されている、請求項1〜20のいずれか一項に記載の方法。
- プローブが与えられた側(基底外側又は頂端側)に超過圧力が加えられ、好ましくは超過圧力は、他方の側における又は他方の側に相当するレザバーにおける流体の量と比較して、プローブが与えられた側への又はプローブが与えられた側に相当するレザバーへのより多量の流体の添加によって実現される、請求項1〜21のいずれか一項に記載の方法。
- ゲルが、主としてより親水性の高いチャネル内のピラー、リッジ、溝、疎水性パッチ又はより親水性の低いパッチなどの毛管圧技術を用いてマイクロ流体チャネル内に構造化される、請求項1〜22のいずれか一項に記載の方法。
- 1つ以上のプローブが、上皮細胞に、試験化合物の添加と一緒に又は添加後の時点で与えられ、そして1つ以上のプローブは好ましくは光学的手段によって第一のプローブから識別可能である、請求項19記載の方法。
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