JP6662899B2 - 人工デスメ膜 - Google Patents
人工デスメ膜 Download PDFInfo
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- JP6662899B2 JP6662899B2 JP2017549655A JP2017549655A JP6662899B2 JP 6662899 B2 JP6662899 B2 JP 6662899B2 JP 2017549655 A JP2017549655 A JP 2017549655A JP 2017549655 A JP2017549655 A JP 2017549655A JP 6662899 B2 JP6662899 B2 JP 6662899B2
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- descemet
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Description
人工デスメ構築物の製造
1. リソグラフィーによる型の製造
1.1 2光子リソグラフィー
2光子リソグラフィー(2PL)は、2光子吸収(2PA)の物理的作用を基本とし、横分解能150nm及び軸分解能400nmで三次元構造を製造することを可能にする。波長780nmを有する拡大されたフェムト秒ファイバレーザのビームは、倒立顕微鏡の対物レンズに結合され、これによって液体の感光性ポリマーに集光される。レーザが集光され、パルス状であるので、焦点での強度は、焦点内で2光子吸収が可能になるほど十分高い。対応する範囲において、赤外線ではなく波長390nmの紫外線が放射される。液状の光ポリマーは、高エネルギーUV線により露光された場合にのみ架橋し、その結果2光子吸収が起こる範囲では、液状ポリマーが硬化する。
a) 従来法の場合、レーザビームがガラス板を通して感光性ポリマーに集光される。加えて、できるだけ多くのレーザ光をポリマー内に結合させ、それにより最大の解像度を可能にするために、顕微鏡対物レンズとガラス板の間に液浸油がある。本方法のこの変形形態の場合、対物レンズの作動距離は、最大の構造高さを限定する。構造体は、基板の上側から上方に向かって構築される。
b) ディップインレーザリソグラフィー(DiLL)は、金属又はシリコンのような不透明基板の使用も可能にする。この場合、レーザビームは基板の下面に集光され、感光性ポリマーは、顕微鏡対物レンズと基板の間にあり、同時に液浸媒として役立つ。構造体は基板の下面から下向きに構築される。最大の構造高さは、ピエゾ駆動に基づき300μmであるが、顕微鏡対物レンズのzドライブの使用によりずっと高い構造体も実現することができる。
c) 第3の変形は、空気対物レンズの使用にその本質がある。原理は、従来の方法の原理に該当するが、しかしながら液浸油を使用しない。
d) ガルバノスキャナに基づくアドオンを通じて、多焦点を用いたマーキングにより同時にマーキング速度が最高200倍に高められる。
- 接着剤(Fixogum)で基板を試料ホルダーに固定する
- 基板の上面(従来法及び空気対物レンズについて)又は下面(DiLL法について)に適切なフォトポリマーを滴下する
- 従来法について、さらに基板の下面に液浸油を適用する
- 試料を備える試料ホルダーを2PL機器に固定する
- 構造の適切なプログラミングによりマーキングプロセスを開始する。プログラムされた構造に応じてレーザの焦点に対して試料を移動させる。
干渉リソグラフィーの場合、適切な干渉パターンを感光面に結像させ、記録するために2ビーム又はマルチビーム干渉法が利用される。そのために、レーザビーム(アルゴンイオンレーザ)が拡大され、(例えばキューブ型ビームスプリッタにより)2つの部分ビームに分割される。鏡(平面鏡又は凹面鏡)を用いてこれらを特定の角度で交差させる(重ね合わせる)ことにより、この角度及び使用する波長に依存して一定の格子定数を有する縞模様が生じる。
グレイスケールリソグラフィーは、マスクの露光に基づき、マスクのパターンは、露光により感光性ポリマー中に記録される。その際、異なるグレイスケールにより異なる構造深さがマスク上に実現される。マスクの裏側にマスク上のグレイスケール分布に対応する強度分布が形成する。ポジ型レジストを使用した場合、強度が最高の位置の構造が最も深い。ネガ型レジスト材料について、この関係は逆になる。
細胞分化のために材料特性が極めて重要であるので、そのようにリソグラフィーにより製造された構造体は、シリコーンゴム又は動物若しくはヒトのコラーゲンのような、より柔らかな材料で成形されることにより、その材料の模擬デスメ構造体が形成する。生体適合性材料から移植可能なデスメ構築物を製造するために、注型可能なコラーゲン組成物が使用され、まず第一にプラスチックから構造化された型が製造される。
インビトロ角膜内皮組織の製造
予め脂肪組織から採取及び分離された間葉系幹細胞を、実施例1により製造された人工デスメ構築物上に少なくとも5×105細胞/cm2の細胞密度で播種する。均等な分布及び接着のために構築物を軌道振盪する。
Claims (14)
- 生体細胞を新生角膜内皮組織に機械的シグナル伝達により分化させるための人工デスメ構築物であって、ドーム型基材(10)の凹面(12)に形成したハニカム構造を有する基材(10)から形成されている人工デスメ構築物。
- ハニカム構造が、中央の凹み(22)及び側方の張出し(24)を有する繰り返し基本要素(20)から形成されており、張出し高さが0.3〜1μmであり、張出し幅が1〜8μmであり、張出しで囲まれた中央の凹みの幅がそれぞれ10〜20μmである、請求項1に記載の構築物。
- ハニカム構造が、本質的に同じサイズの繰り返し基本要素(20)から形成されている、請求項2に記載の構築物。
- ハニカム構造が、異なるサイズの繰り返し基本要素(20)から形成されている、請求項2に記載の構築物。
- 基本要素(20)が、それぞれ6角形の基本形を有する、請求項2から4のいずれか1項に記載の構築物。
- 生体ポリマー又は生体適合性ポリマーからなる、請求項1から5のいずれか1項に記載の構築物。
- 請求項1から6のいずれか1項に記載のデスメ構築物、及び分離された細胞から新たに形成された角膜内皮組織を含む、インビトロ移植片。
- 請求項1から6のいずれか1項に記載の人工デスメ構築物を製造するための方法であって、
- ポリマー基材を用意するステップ、
- フォトリソグラフィーによる構造化、光分解アブレーション、マイクロメカニカルアブレーション、注型成形及びプレス成形から選択される微細構造化法を用いて、基材の表面に立体的ハニカム構造を形成させるステップ
を含む方法。 - 立体的ハニカム構造を形成させるステップが、
- 微細構造化法の1つを用いてハニカム構造のネガ型を作るステップ、及び続いて
- 作られたネガ型を用いて注型又はプレスにより生体適合性ポリマー又は生体ポリマーのハニカム構造を形成させるステップ
を含む、請求項8に記載の方法。 - 間葉系幹細胞を角膜内皮組織に機械的シグナル伝達により分化させるための、請求項1から6のいずれか1項に記載の人工デスメ構築物の使用。
- 分離された生体細胞から新生インビトロ角膜内皮移植片を製造するための方法であって、
- 分離された生体細胞を、請求項1から6のいずれか1項に記載の人工デスメ構築物と接触させるステップ、
- デスメ構築物上で細胞を培養するステップであって、角膜内皮の内皮細胞への細胞分化が行われるステップ、及び
- 新生角膜内皮に分化した組織をデスメ構築物と共にインビトロ角膜内皮移植片として得るステップ
を含む、方法。 - - 新生角膜内皮に分化した組織をデスメ構築物から剥離し、分離された角膜内皮をインビトロ角膜内皮移植片として得る
さらなるステップを有する、請求項11に記載の方法。 - 分離された生体細胞が間葉系幹細胞である、請求項11又は12に記載の方法。
- 請求項11から13のいずれか1項に記載の方法により製造された、インビトロ角膜内皮移植片。
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