JP7386999B2 - 生体細胞によってコロニー形成される生体適合性ポリマーからなる3dスキャフォールド、及びその製造 - Google Patents
生体細胞によってコロニー形成される生体適合性ポリマーからなる3dスキャフォールド、及びその製造 Download PDFInfo
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Description
(a)リソグラフィ3D印刷法によって生体適合性ポリマーから3Dスキャフォールドが構築されること;及び、
(b)生体細胞による3Dスキャフォールドでのコロニー形成のために、少なくとも部分的に上方が覆われた中空スペースに生体細胞を含む懸濁液が充填されること。
(i)光重合可能又は光架橋可能な物質が存在する焦点面に電磁放射が焦点合わせされることによって光重合可能又は光架橋可能な物質が硬化されること。
(I)光重合可能又は光架橋可能な液体が反応容器に入れられること、
(II)液体で充填された反応容器の領域の内部に位置する焦点面に合わせて電磁放射が焦点合わせされること、
(III)電磁放射によって反応容器の中で焦点面の層に重合又は架橋した構造が生成されること、
(IV)別の光重合可能又は光架橋可能な液体が反応容器に入れられ、それにより以前に生成された重合又は架橋した構造が少なくとも部分的に別の光重合可能又は光架橋可能な液体で覆われること、
(V)別の液体で充填された反応容器の領域の内部に位置する別の焦点面に合わせて別の電磁放射が焦点合わせされること、
(VI)別の電磁放射によって反応容器の中で別の層で別の重合又は架橋した構造が生成され、別の重合又は架橋した構造は以前に作成された重合又は架橋した構造の上に直接的に配置されて、これと結合されること、
(VII)3Dスキャフォールドが作成されるまで、そのつど別の光重合可能又は光架橋可能な液体によってステップ(IV)から(VI)が反復されること。
1.)CADファイルが作成され、印刷原画が計算されること;
2.)使用されるべき光重合可能又は光架橋可能な液体がプリンタに装備されること;
3.)プリンタ、軸、及び印刷ヘッドがキャリブレーションされること;
4.)印刷が実行され、第1の光重合可能又は光架橋可能な液体のために印刷プラットフォームが第1の印刷面まで降下すること;
5.)印刷されるべき構造体の第1の層高さについてポリマー1からなるアーキテクチャのために第1の光重合可能又は光架橋可能な液体から第1のポリマーが印刷されること;このとき構造体の第1の層高さについて第1のポリマーの計算された設計図が、印刷ヘッドのある印刷平面に投影される;このとき利用者の希望と計画に応じて、1つ又は複数の構造体を同時に製作することができる;このとき制限因子は、印刷プラットフォームないし設計スペースのサイズである;
6.)必要な場合、第1のポリマーから第2の光重合可能又は光架橋可能な液体への、及びこの逆への、移行を防止するためのプリンタの洗浄ステップ-任意選択(第2のポリマーが必要となる場合に限る);
7.)必要な場合、第1の層について第2のポリマーからなるアーキテクチャのために第2のポリマーが印刷されること-任意選択(第2のポリマーが使用される場合に限る);
8.)第3のポリマーが使用される場合、ステップ6及び7が反復されること;
9.)第2の層高さを印刷できるようにするために印刷平面が変更されること;
10.)印刷されるべき構造体の第2の層高さについて第1のポリマーからなるアーキテクチャのために第1のポリマーが印刷されること;
11.)必要な場合、第1のポリマーから第2の光重合可能又は光架橋可能な液体への、及びこの逆への、移行を防止するためのプリンタの洗浄ステップ-任意選択(第2のポリマーが必要となる場合に限る);
12.)必要な場合、第2の層について第2のポリマーからなるアーキテクチャのために第2の光重合可能又は光架橋可能な液体から第2のポリマーが印刷されること-任意選択(第2のポリマーが使用される場合に限る);
13.)第3のポリマーが使用される場合、ステップ11及び12が反復されること;
14.)第3の層高さを印刷できるようにするために印刷平面が変更されること;
15.)完全なアーキテクチャが印刷されるまで、ステップ5から8が反復されること;
16.)印刷の完了後、印刷プラットフォームを初期平面をへと移動させて、含まれている3Dスキャフォールドを取り外す;
17.)引き続き、3Dスキャフォールドを乾燥させることができ、又は即座に使用することができる。
18.)3Dスキャフォールドが乾燥される場合、このことは滅菌雰囲気の中で行われる;このとき3Dスキャフォールドからすべての水が取り除かれ、それにより乾燥したポリマースキャフォールドが生じる;
19.)乾燥の後、3Dスキャフォールドを滅菌条件のもとで保管することができる。
3Dスキャフォールドの外側直径:6mm
3Dスキャフォールドの高さ :2mm
中空スペースの容積 :9.9mm3
充填開口部の内径 :1.6mm
側方のチャネル(方形)及び
排出開口部の断面 :0.4mm×0.4mm
溶剤:RPMI 1640+25mM HEPES(Biochrom FG 1383)、リン酸緩衝生理食塩水
光架橋可能な物質:ゼラチン-メタクリレート、50g/kg;ポチエチレングリコール-ジアクリレート、50g/L
その他の添加物:リチウムフェニル-2,4,6-トリメチルベンゾイルホスフィン酸、5g/kg;タートラジン、2mM
20.)細胞懸濁液が、利用者により事前に調整された濃度でフィラーネックを通じて、1.)から19.)に従って製作された3Dスキャフォールドの中にピペットで移される;このとき最大で、3Dスキャフォールドの中空スペースの容積に相当する細胞懸濁液容積が利用される;3Dスキャフォールドがステップ18.)で乾燥される場合には、あらためて使用するために利用者によって事前に再び水和されなければならない;そのために水、PBS、細胞培養媒体などの滅菌媒体が適している;
21.)ピペットで移すことで3Dスキャフォールド内部で懸濁液が分散され、細胞を3Dスキャフォールド内部で培養することができる;
神経芽細胞腫(SK-N-BE(2))による中空スペースでのコロニー形成のために、細胞懸濁液(溶剤:DMEM高グルコース+10%FCS+1%ペニシリン/ストレプトマイシン;細胞濃度:150×106細胞/L)を製作する。この懸濁液6μL mmをフィラーネックを通じて3Dスキャフォールドの中空スペースにピペットで移す。引き続き、構造体を37℃と5%CO2のもとで培養する。
2 中空スペース
3 充填開口部
4 排出開口部
5 カラム
6 コロニー形成領域
Claims (12)
- 生体細胞によってコロニー形成される生体適合性ポリマーからなる3Dスキャフォールド(1)を製造する方法において、前記3Dスキャフォールド(1)は少なくとも部分的に上方が覆われた中空スペース(2)を有し、次の各ステップ、
(a)リソグラフィ3D印刷法によって生体適合性ポリマーから3Dスキャフォールド(1)が構築されること、及び、
(b)生体細胞による前記3Dスキャフォールド(1)でのコロニー形成のために、少なくとも部分的に上方が覆われた前記中空スペース(2)に生体細胞を含む懸濁液が充填されること、を有し、
前記生体適合性ポリマーは、バイオポリマーを、光反応性基を導入することで光重合可能又は光架橋可能な出発物質とすることによって得られ、前記バイオポリマーは、プロテイン、DNA、RNA、炭水化物及び炭水化物誘導体、コラーゲン、フィブリン、アルギン酸、ゼラチン、ヒアルロン酸からなる群から選択される方法。 - 前記3Dスキャフォールド(1)の構築がステレオリソグラフィ3D印刷法によって行われる、請求項1に記載の方法。
- 前記ステップ(a)での前記3Dスキャフォールド(1)の構築は、次のステップ、
(i)光重合可能又は光架橋可能な物質が存在する焦点面に電磁放射が焦点合わせされることによって光重合可能又は光架橋可能な物質が硬化されること、
によって行われる、請求項1又は2に記載の方法。 - 別の焦点面に別の電磁放射が焦点合せされることによって前記ステップ(i)が反復される、請求項3に記載の方法。
- 前記ステップ(i)が反復されるときに別の光重合可能又は光架橋可能な物質が使用される、請求項4に記載の方法。
- 生体細胞を含む懸濁液の充填は前記3Dスキャフォールド(1)にある充填開口部(3)を通して行われる、請求項1から5のいずれか1項に記載の方法。
- 前記ステップ(a)と前記ステップ(b)の間で前記3Dスキャフォールド(1)が乾燥される、請求項1から6のいずれか1項に記載の方法。
- 前記ステップ(b)の後に生体細胞が3D細胞培養構造体をなすように培養される、請求項1から7のいずれか1項に記載の方法。
- 前記3D細胞培養構造体が別の細胞、ウィルス、バクテリア、酵素、又は作用物質によって浸透される、請求項8に記載の方法。
- 請求項1から9のいずれか1項に記載の方法に基づいて得られる、生体細胞によってコロニー形成される3Dスキャフォールド(1)。
- 1つ又は複数の排出開口部(4)を有する、請求項10に記載の生体細胞によってコロニー形成される3Dスキャフォールド(1)。
- 上方が覆われた前記中空スペースにカラム(5)、グリッド、又は横支柱を有する、請求項10又は11に記載の生体細胞によってコロニー形成される3Dスキャフォールド(1)。
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DE102007020302B4 (de) * | 2007-04-20 | 2012-03-22 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Verbesserte dreidimensionale biokompatible Gerüststruktur, die Nanopartikel beinhaltet |
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CN108699520A (zh) * | 2016-01-29 | 2018-10-23 | 国立研究开发法人国立循环器病研究中心 | 细胞块、细胞结构体以及立体组织体 |
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2019
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EP4065371A1 (de) | 2022-10-05 |
US20230133963A1 (en) | 2023-05-04 |
WO2021104571A1 (de) | 2021-06-03 |
CN115943076A (zh) | 2023-04-07 |
DE102019132214B3 (de) | 2021-04-29 |
IL293339A (en) | 2022-07-01 |
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