JP7053503B2 - 3dバイオプリンティングバイオインクとしての細胞外マトリックス成分で修飾されたセルロースナノ原繊維の調製 - Google Patents
3dバイオプリンティングバイオインクとしての細胞外マトリックス成分で修飾されたセルロースナノ原繊維の調製 Download PDFInfo
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Description
[0017] RGDペプチドとのバイオ接合、及び皮膚様モデルの3Dバイオプリンティング
[0018] カルボキシメチル化されたセルロースナノ原繊維を、EDS-NHS接合方法を使用してRGDペプチドで修飾した。その後、24個の反応CNFを、カットオフ10kDの透析チューブの中に2週間置いた。精製した接合されたCNFを、バイオインクの調製に使う未修飾のCNFと混合した。2つの異なるバイオインクを調製した。第1のバイオインクは、RGD-CNFと、塩化カルシウムの添加後に架橋を可能にするアルギン酸塩とから構成された。第2のバイオインクは、チラミンで修飾されたヒアルロン酸の添加によって調製され、ホースラディッシュペルオキシダーゼ及び過酸化水素を用いて架橋された。いずれのバイオインクとも良好な印刷適性を有した。600万個の初代ヒト線維芽細胞継代#3を解凍し、2個の150cm2のT-フラスコへ播種した。培養物が約90%コンフルエントに達したとき、TrypLEを使用して細胞を収集し、フラスコを静かに軽くたたいて細胞を表面から剥離させた。トリパンブルー染色を用いて細胞を数え(1.9M細胞/mL)、細胞生存率を算出して細胞が生きていることを保証した。次いで、細胞を遠心分離し、培地中に再懸濁した後、T150フラスコへ2,500細胞/cm2で播種した。培地(フェノールレッド含有、10%FBS、1%ペニシリン/ストレプトマイシン、1%GlutaMAXのDMEM)は、1週間当たり3回交換した。細胞をバイオインクと混合して最終濃度を520万細胞/mlとし、次いで、プリンターのカートリッジへ注意深く移動した。CELLINK AB、Sweden、からの3DバイオプリンターINKREDIBLEを使用して、構築物を6mm×6mm×1mmのサイズの3層の格子パターンでプリントした(圧力:24kPa、供給速度:10mm/s)(図2を参照されたい)。プリンティング後、構築物を架橋した。
[0021] ナノセルロース原繊維とラミニン521との間のバイオ接合反応、及びiPSCを用いた3Dバイオプリンティング
[0022] カルボジイミドカップリング方法を使用して、セルロース-ECM接合を調製した。カルボキシメチル化CNF、MFC8(3重量%)(Stora Enso、Finland)をMiliQ水で希釈し(0.2重量%)、ウルトラタラックスで10分間、10,000rpmで混合した。反応は、セルロースナノ原繊維上のすべてのカルボキシル基を活性化するのに過剰量の1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、EDC(Sigma Aldrich)、及びN-ヒドロキシスルホスクシンイミド、NHS(Sigma Aldrich)を用いて行った。pHは、HClで所望の5.3に調整した。次いで、ラミニン521(Biolamina、Sweden)などのECMを、ラミニンに対する乾燥セルロース質量の様々な重量比で添加した後、pHをpH7.2に調節し、反応物を氷上に置き、24時間、反応を行った。
[0026] TGFベータ1とのバイオ接合、及び幹細胞を伴う軟骨組織の3Dバイオプリンティング
[0027] セルロース-TGFベータ1(TGFB1)接合を、カルボジイミドカップリング方法を使用して調製した。カルボキシメチル化CNFであるMFC8(3重量%)(Stora Enso、Finland)をMiliQ水で希釈し(0.2重量%)、ウルトラタラックスで10分間、10,000rpmで混合した。セルロースナノ原繊維上のすべてのカルボキシル基を活性化するのに過剰量の1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、EDC(Sigma Aldrich)及びN-ヒドロキシスルホスクシンイミド、NHS(Sigma Aldrich)を用いて、反応を行った。pHは、HClで所望の5.3に調整した。TGFベータ1(Termofisher、Sweden)などのECMを、TGFベータ1に対する乾燥セルロース質量の様々な重量比で添加した後、pHをpH7.2に調節し、反応物を氷上に置き、24時間、反応を行った。
[0031] 神経組織の3Dバイオプリンティング
[0032] ラミニンで修飾されたCNFを使用して、カーボンナノチューブを添加したバイオインクを調製した。かかる導電性バイオインクは、細胞接着、及び神経ネットワークの形成を示した。
本発明は、例えばEDS-NHS接合方法を使用する、細胞外マトリックス成分、例えばコラーゲン、エラスチン、フィブロネクチンもしくはRGD配列、又は成長因子、例えばTGFベータでのセルロースナノ原繊維(CNF)の修飾と、ヒトの皮膚又は神経組織などの組織モデルの3Dバイオプリンティングのためのバイオインクの調製とに関する。セルロースナノ原繊維は、3Dバイオプリントされた構築物への酸素の拡散及び栄養素の拡散にきわめて重要である、優れたプリンティングフィディリティーを提供する。表面に接合された細胞外マトリックス成分は、接着部位を提供すること又は分化プロセスを誘導することによって生物学的活性を誘導する。3DバイオプリントされたCNFバイオインクをベースとしたバイオインクは、ヒト線維芽細胞の接着を誘導する能力、及びI型コラーゲン産生を刺激する能力が非常に大きかった。したがって、このようなバイオインクは、組織モデルの3Dバイオプリンティングに好適である。
Claims (20)
- セルロースナノ原繊維(CNF)を、コラーゲン、エラスチン、フィブロネクチン、RGD配列、ラミニン、成長因子、TGFベータ、又は骨形成タンパク質から選択される細胞外マトリックス成分で修飾し、バイオプリント可能な修飾されたセルロースナノ原繊維(CNF)を形成する方法であって、
修飾することが、カルボジイミドカップリング反応を含む、
方法。 - 前記カルボジイミドカップリング反応が、N-ヒドロキシスルホスクシンイミド、及び/又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドを使用して実施される、請求項1に記載の方法。
- 前記修飾されたCNFを備える3Dプリント可能なバイオインクを調製することをさらに含む、請求項1又は2に記載の方法。
- セルロースナノ原繊維(CNF)と、一又は複数の細胞外マトリックス成分と、のカルボジイミドカップリング接合物を備えるバイオインク。
- 細胞と共に又は細胞なしで、セルロースナノ原繊維(CNF)と、一又は複数の細胞外マトリックス成分と、のカルボジイミドカップリング接合物を備えるバイオインクを用いて、3D構築物をバイオプリントし、3D構築物を形成することを含む、in vitroの3Dバイオプリンティング方法。
- 前記3D構築物が、組織様構築物である、請求項5に記載の方法。
- 前記組織様構築物を、創薬、及び/又は化粧品の試験のために、及び/又は疾患モデルとして使用することをさらに含む、請求項6に記載の方法。
- 前記バイオインクがアルギン酸塩をさらに備える、請求項5から7のいずれか1項に記載の方法。
- 前記バイオインクがヒアルロン酸をさらに備える、請求項5から7のいずれか1項に記載の方法。
- セルロースナノ原繊維(CNF)と、一又は複数の細胞外マトリックス成分と、のカルボジイミドカップリング接合物中に生きている線維芽細胞を含有する、組織。
- 前記組織内の空間が、栄養素、酸素、タンパク質、及び/又は成長因子の拡散を可能にする、請求項10に記載の組織。
- 前記細胞外マトリックス成分が、コラーゲン、エラスチン、フィブロネクチン、RGD配列、ラミニン、成長因子、TGFベータ、又は骨形成タンパク質から選択される、請求項10又は11に記載の組織。
- 当該組織が、その上で培養された角化細胞から形成された表皮を備える、皮膚様組織である、請求項10から12のいずれか1項に記載の組織。
- セルロースナノ原繊維(CNF)と、一又は複数の細胞外マトリックス成分と、のカルボジイミドカップリング接合物を備える、神経組織。
- 細胞と共に又は細胞なしで、前記修飾されたCNFを備えるバイオインクから、3D構築物をバイオプリントすることをさらに含み、
前記3D構築物が、創薬、及び/又は化粧品の試験、及び/又は疾患モデルのために使用される組織様構築物である、請求項1に記載の方法。 - in vitroで神経組織をバイオプリントすることをさらに含む、請求項1から3、及び5から9のいずれか1項に記載の方法。
- 修飾された前記CNFが、UV架橋可能な基で修飾されたゼラチン又はコラーゲンと共に使用され、架橋がUV光によって生じる、請求項1から3、及び5から9のいずれか1項に記載の方法。
- バイオプリント可能な修飾されたセルロースナノ原繊維(CNF)を調製する方法であって、
希釈液にセルロースナノ原繊維(CNF)を加えることと、
一又は複数の試薬で、前記CNFのカルボキシル基を活性化することと、
前記活性化されたCNFと、コラーゲン、エラスチン、フィブロネクチン、RGD配列、ラミニン、成長因子、TGFベータ、又は骨形成タンパク質から選択される細胞外マトリックス成分と、の分散物を調製することと、
前記活性化されたCNFと前記細胞外マトリックス成分の分散物から、バイオプリント可能な修飾されたセルロースナノ原繊維(CNF)を形成させることと、
により、カルボジイミドカップリング反応を実施すること、
を含む、方法。 - 前記カルボジイミドカップリング反応が、前記一又は複数の試薬として、N-ヒドロキシスルホスクシンイミド、及び/又は1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドを使用して実施される、請求項18に記載の方法。
- 前記バイオプリント可能な修飾されたCNFを備える3Dプリント可能なバイオインクを調製することをさらに含む、請求項18又は19に記載の方法。
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EP3469004A4 (en) | 2020-05-06 |
WO2017214592A1 (en) | 2017-12-14 |
US20190209738A1 (en) | 2019-07-11 |
EP3469004A1 (en) | 2019-04-17 |
JP2019517355A (ja) | 2019-06-24 |
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