JP2021525305A - 二官能性修飾バイオポリマー系ポリマー及びかかる二官能性修飾バイオポリマー系ポリマーから得られるヒドロゲル - Google Patents
二官能性修飾バイオポリマー系ポリマー及びかかる二官能性修飾バイオポリマー系ポリマーから得られるヒドロゲル Download PDFInfo
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Abstract
Description
a)少なくとも1つのポリマー鎖を含むバイオポリマー系ポリマーを準備する工程であって、該ポリマー鎖が、一級官能基を含む、工程と、
b)該一級官能基の第1の部分を官能化してn個の第1の官能基を導入する工程であって、nはゼロではなく、該第1の官能基が、フリーラジカル連鎖重合に続いてラジカル架橋され得る、工程と、
c)該一級官能基の第2の部分を官能化してm個の第2の官能基を導入する工程であって、mはゼロではなく、該第2の官能基が、チオール−エン架橋性基を含む、工程と、
を含み、
工程b)及び工程c)を同時に行うことができるか、又は工程b)を工程c)の前若しくは後に行うことができる。好ましい方法では、工程b)は、工程c)の前に行われる。代替の方法では、工程c)は、工程b)の前に行われる。工程b)の前に工程c)を行う方法には、第1の官能基との反応の前に官能基を導入する利点がある。これは、架橋前の材料の疎水性に影響を与えるか、又は架橋後に切断することができる光可逆基をチオール−エン化学を介して導入して、より低い機械的特性のゾーンを時空間制御によって導入するために重要となる可能性がある。
a)少なくとも1つのポリマー鎖を含むゼラチンを準備する工程であって、該ポリマー鎖が、例えばアミン官能基及び/又はカルボン酸(carboxylic acid)官能基のような一級官能基を含む、工程と、
b)該一級官能基の第1の部分を官能化してn個の第1の官能基を導入する工程であって、nはゼロではなく、該第1の官能基が、フリーラジカル連鎖重合に続いてラジカル架橋され得る、工程と、
c)該一級官能基の第2の部分を官能化してm個の第2の官能基を導入する工程であって、mはゼロではなく、該第2の官能基が、チオール−エン架橋性基を含む、工程と、
を含み、
工程b)及び工程c)を同時に行うことができるか、又は工程b)を工程c)の前若しくは後に行うことができる。好ましい方法では、工程b)は、工程c)の前に行われる。代替の方法では、工程c)は、工程b)の前に行われる。
a)上記した二官能性修飾バイオポリマー系ポリマー、例えば二官能性修飾ゼラチン又は二官能性修飾コラーゲンを準備する工程と、
b)上記n個の第1の官能基の少なくとも一部のフリーラジカル連鎖重合によって上記二官能性修飾バイオポリマー系ポリマーを架橋する工程と、
c)上記m個の第2の官能基の少なくとも一部を架橋及び/又は官能化する工程と、
を含む。
材料
以下の化学物質を使用した:
Rousselot(ベルギー国ヘント)により提供された、牛皮からアルカリ処理で単離されたゼラチンBタイプ。
Sigma-Aldrich(ベルギー国ディーゲム)製の無水メタクリル酸、5-ノルボルネン-2-カルボン酸、1-エチル-3-(3-ジメチルアミノ)プロピル)-カルボジイミド塩酸塩(EDC)、D,L-ジチオスレイトール(dithiothreitol)(DTT)。
Acros(ベルギー国ギール)から購入したジメチルスルホキシド(DMSO)(99.85%)及びN-ヒドロキシスクシンイミド(98%)(NHS)。
BASF製のIrgacure 2959(1-[4-(2-ヒドロキシエトキシ)-フェニル]-2-ヒドロキシ-2-メチル-1-プロパン-1-オン)。
polylab(ベルギー国アントワープ)から透析膜Spectra/por(MWCO 12 kDa〜14 kDa)を受け取った。
DS(置換度)72%のgel-MODを、A. I. Van Den Bulcke, B. Bogdanov, N. De Rooze, E. H. Schacht, M. Cornelissen, and H. Berghmans, "Structural and Rheological Properties of Methacrylamide Modified Gelatin Hydrogels," Biomacromolecules, vol. 1, no. 1, pp. 31-38, Mar. 2000に記載されるプロトコルに従い、以下の反応により合成した。
10 gのgel-MOD-NBを調製するため、最初に5-ノルボルネン-2-カルボン酸をそのスクシンイミジルエステルへと活性化した。この目的のため、最初に、添加されるEDCに対して1.6倍過剰(638 mg、4.62 mmol)の5-ノルボルネン-2カルボン酸を乾燥DMSO(乾燥剤としてCaH2を用いた真空蒸留によって得られる)50 mlに溶解した。完全に溶解した後、0.75当量のEDC(555 mg、2.9 mmol)(ゼラチン10 g中に存在する元の一級アミンに対して、すなわち0.38 mmol/gゼラチン)及び1.5当量のNHS(EDCに対して)添加し、続いて3回脱気した。反応を少なくとも25時間にわたって行い、次の反応工程の間にゼラチン架橋をもたらす可能性がある、あらゆる未反応EDC官能基を排除した。
5時間 15 時間
図1は、異なるゼラチン誘導体の貯蔵弾性率G'(上)及び質量膨潤率(下)を示す。貯蔵弾性率G'は、それぞれ、gel-MOD DS 72の場合、gel-NB DS 90 + DTT(チオール/エン:1)の場合、5 mMのDTTの存在下での追加の30分間の架橋に続く平衡膨潤の前後の、gel-MOD-NB DS 72の場合、及びgel-MOD DS 95の場合の、30分間の架橋(光開始剤として2モル%(架橋性官能基の量に対して)のLi-TPO-Lを用いる)及びmilliQ中で24時間のインキュベーションの後の平衡膨潤状態の10重量/体積%の架橋ゼラチンの貯蔵弾性率と一致する。
col-MODの調製
A. I. Van Den Bulcke, B. Bogdanov, N. De Rooze, E. H. Schacht, M. Cornelissen, and H. Berghmans, "Structural and Rheological Properties of Methacrylamide Modified Gelatin Hydrogels," Biomacromolecules, vol. 1, no. 1, pp. 31-38, Mar. 2000に記載されるプロトコルを適合させ、以下の反応に従ってcol-MODを合成した。
10 gのcol-MOD-NBを調製するため、最初に5-ノルボルネン-2-カルボン酸をそのスクシンイミジルエステル(succinimidyl ester)へと活性化した。この目的のため、最初に、添加されるEDCに対して1.6倍過剰の5-ノルボルネン-2カルボン酸を乾燥DMSO(乾燥剤としてCaH2を用いた真空蒸留によって得られる)50 mlに溶解した。完全に溶解した後、0.75当量のEDC(コラーゲン10 g中に存在する元の一級アミンに対して)及び1.5当量のNHS(EDCに対して)を添加し、続いて3回脱気した。反応を少なくとも25時間にわたって行い、次の反応工程の間にコラーゲン架橋をもたらす可能性がある、あらゆる未反応EDC官能基を排除した。
図1
Storage modulus 貯蔵弾性率
Mass swelling ratio 質量膨潤率
図3
Cell viability (%) 細胞生存率(%)
Gelatin concentration (w/v%) ゼラチン濃度(重量/体積%)
gel-MOD 2h gel-MOD 2時間
gel-MOD 24h gel-MOD 24時間
gel-MOD-NB 2h gel-MOD-NB 2時間
gel-MOD-NB 24h gel-MOD-NB 24時間
gel-NB 2h gel-NB 2時間
gel-NB DS90 24h gel-NB DS90 24時間
Claims (15)
- 二官能性修飾バイオポリマー系ポリマーであって、少なくとも1つのポリマー鎖を含み、前記少なくとも1つのポリマー鎖が、n個の第1の官能基及びm個の第2の官能基を含み、n及びmはゼロではなく、前記第1の官能基が、フリーラジカル連鎖重合に続いてラジカル架橋され得る基を含み、前記第2の官能基が、チオール−エン架橋が可能な基を含み、前記第2の官能基が、前記第1の官能基のフリーラジカル連鎖重合中に未反応のまま残る、二官能性修飾バイオポリマー系ポリマー。
- 前記バイオポリマー系ポリマーが、ポリペプチド、タンパク質、多糖、核酸、ゼラチン、コラーゲン、アルギン酸塩、デキストラン、アガロース、グリコサミノグリカン、キトサン及びカラギーナン、それらに由来する誘導体、組み換え類縁体及び合成類縁体からなる群から選択される、請求項1に記載の二官能性修飾バイオポリマー系ポリマー。
- 前記第1の官能基が、メタクリルアミド官能基、アクリルアミド官能基、メタクリレート官能基及び/又はアクリレート官能基を含む、請求項1又は2に記載の二官能性修飾バイオポリマー系バイオポリマー。
- 前記第2の官能基が、ノルボルネン官能基、ビニルエーテル官能基、ビニルエステル官能基、アリルエーテル官能基、プロペニルエーテル官能基、アルケン官能基及び/又はN-ビニルアミド官能基を含む、請求項1〜3のいずれか一項に記載の二官能性修飾バイオポリマー系バイオポリマー。
- 前記バイオポリマー系ポリマーが、1つのポリマー鎖を含む、請求項1〜4のいずれか一項に記載の二官能性修飾バイオポリマー系ポリマー。
- 請求項1〜5のいずれか一項に記載の二官能性修飾バイオポリマー系ポリマーを製造する方法であって、
a)一級官能基を含む少なくとも1つのポリマー鎖を含むバイオポリマー系バイオポリマーを準備する工程と、
b)前記一級官能基の第1の部分を官能化してn個の第1の官能基を導入する工程であって、nはゼロではなく、前記第1の官能基が、フリーラジカル連鎖重合に続いてラジカル架橋され得る、工程と、
c)前記一級官能基の第2の部分を官能化してm個の第2の官能基を導入する工程であって、mはゼロではなく、前記第2の官能基が、チオール−エン架橋性基を含み、前記第2の官能基が、前記一級官能基のフリー連鎖重合中に未反応のまま残る、工程と、
を含み、
工程b)及び工程c)を同時に行うことができるか、又は工程b)を工程c)の前若しくは後に行うことができる、方法。 - 前記一級官能基が、アミン官能基及び/又はカルボン酸官能基及び/又はヒドロキシル官能基を含み、工程b)が、前記アミン官能基の反応及び/又は前記カルボン酸官能基の反応及び/又は前記ヒドロキシル官能基の反応を含む、請求項6に記載の方法。
- 前記一級官能基が、アミン官能基及び/又はカルボン酸官能基及び/又はヒドロキシル官能基を含み、工程c)が、前記アミン官能基の反応及び/又は前記カルボン酸官能基の反応及び/又は前記ヒドロキシル官能基の反応を含む、請求項6又は7に記載の方法。
- 前記アミン官能基の前記反応及び/又は前記カルボン酸官能基との前記反応及び/又は前記ヒドロキシル官能基との前記反応が、カルボジイミドカップリング化学を使用する、請求項8に記載の方法。
- ヒドロゲルを製造する方法であって、
a)請求項1〜5のいずれか一項に記載の二官能性修飾バイオポリマー系ポリマーを準備する工程と、
b)前記n個の第1の官能基の少なくとも一部のフリーラジカル連鎖重合によって前記二官能性修飾バイオポリマー系バイオポリマーを架橋する工程と、
c)前記m個の第2の官能基の少なくとも一部を架橋及び/又は官能化する工程と、
を含む、方法。 - 工程c)が、前記m個の第2の官能基の少なくとも一部を架橋することを含む、請求項10に記載の方法。
- 工程c)が、前記m個の官能基の少なくとも一部を官能化することを含む、請求項10に記載の方法。
- 工程c)が、前記m個の官能基の第1の部分を架橋すること、及び前記m個の官能基の第2の部分を官能化することを含む、請求項10に記載の方法。
- 請求項10〜13のいずれか一項に記載の方法によって得られるヒドロゲル。
- 組織工学及びバイオファブリケーションのための請求項14に記載のヒドロゲルの使用。
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CA3101402C (en) | 2023-09-12 |
AU2019276160B2 (en) | 2022-08-18 |
BR112020024128A2 (pt) | 2021-02-17 |
KR102592759B1 (ko) | 2023-10-20 |
KR20210030903A (ko) | 2021-03-18 |
AU2022211848A1 (en) | 2022-08-25 |
KR20230013155A (ko) | 2023-01-26 |
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