JP5462382B2 - 修飾された生体高分子の製造方法及び生体高分子の架橋方法 - Google Patents
修飾された生体高分子の製造方法及び生体高分子の架橋方法 Download PDFInfo
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Description
好ましくは、架橋剤は、縮合剤又は酵素である。
好ましくは、架橋剤は、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド、又はトランスグルタミナーゼである。
好ましくは、生体高分子は、コラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フィブロイン、フィブリン、キトサン、フィブロネクチン、及びビトロネクチンからなる群より選ばれる少なくとも一種のタンパク質を含む。
好ましくは、タンパク質の由来はヒト、牛、豚、魚、又は遺伝子組み換えである。
好ましくは、生体高分子により作製した構造物に、添加剤が含まれている。
好ましくは、反応前の混合温度は0℃〜25℃である。
好ましくは、生体高分子は、タンパク質、多糖、及びそれらの誘導体からなる群から選ばれる少なくとも一種を含む。
好ましくは、生体高分子はタンパク質である。
好ましくは、タンパク質の由来はヒト、牛、豚、魚、植物又は遺伝子組み換えである。
好ましくは、架橋剤はアルデヒド、縮合剤、又は酵素である。
好ましくは、架橋剤はアルデヒドである。
好ましくは、架橋剤はグルタルアルデヒドである。
好ましくは、有機フッ素化合物は、アルコール、ケトンまたはカルボン酸である。
好ましくは、有機フッ素化合物は1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール、2,2,2-トリフルオロエタノール、ヘキサフルオロアセトン、トリフルオロ酢酸、またはペンタフルオロプロピオン酸である。
好ましくは、有機フッ素化合物は1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール、又は2,2,2−トリフルオロエタノールである、
本発明の別の側面によれば、ヤング率が200 KPa以上である架橋ゼラチンが提供される。
好ましくは、ヤング率が300 KPa以上である架橋ゼラチンが提供される。
好ましくは、該架橋ゼラチンの架橋剤はグルタルアルデヒドである。
好ましくは、該ゼラチンは酸処理ゼラチンである。
また本発明を実施することにより、(1)水系に比べて効率の良い反応、(2)水溶液中では低温でゲル形成するゼラチンのような基質でかつ反応性の高い試薬を用いる場合にハンドリングが容易になる。それらの結果、高強度の架橋生体高分子を作製することができる。
(1)修飾された生体高分子の製造方法
本発明で用いる生体高分子は、生体由来の高分子であれば特に限定されないが、好ましくは、タンパク質、糖、又はその誘導体である。生体高分子は、より好ましくは、コラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フィブロイン、フィブリン、キトサン、フィブロネクチン、ビトロネクチン、又はヒアルロン酸エステルである。生体高分子は、さらに好ましくは、コラーゲン、ゼラチン、アルブミン、カゼイン、又はフィブロインであり、最も好ましくはコラーゲンまたはゼラチンである。生体高分子がタンパク質である、タンパク質の由来は特に限定せず、ヒト、牛、豚、魚、および遺伝子組み換え体のいずれを用いてもよい。また、遺伝子組み換えゼラチンとしては、例えばEU1014176A2、US6992172に記載のものを用いることができるがこれらに限定されるものではない。
本発明による生体高分子の架橋方法は、生体高分子を架橋剤で処理することを含み、反応混合物中の架橋剤の濃度が1.0〜10重量%であり、かつ架橋を有機フッ素化合物の存在下で行うことを特徴とする方法である。
本発明において生体高分子を架橋剤で処理する際の混合温度は、溶液を均一に攪拌できる限り特に限定されないが、好ましくは0℃〜40℃であり、より好ましくは0℃〜30℃であり、より好ましくは3℃〜25℃であり、より好ましくは3℃〜15℃であり、さらに好ましくは3℃〜10℃であり、特に好ましくは3℃〜7℃である。
生体高分子と架橋剤を攪拌した後は温度を上昇させることができる。反応温度としては架橋が進行する限りは特に限定はないが、生体高分子の変性や分解を考慮すると実質的には0℃〜60℃であり、より好ましくは0℃〜40℃であり、より好ましくは3℃〜25℃であり、より好ましくは3℃から15℃であり、さらに好ましくは3℃〜10℃であり、特に好ましくは3℃〜7℃である。
架橋した生体高分子に封入する細胞の種類は特に限定されないが、例えば、骨髄細胞、胚性幹細胞、成体幹細胞、軟骨細胞、骨芽細胞、繊維芽細胞、血管内皮細胞、血管平滑筋細胞、心筋細胞、上皮細胞が挙げられる。
生体組織中への埋め込み部位として特に強度が求められる部位としては、例えば、骨、軟骨、心臓、血管などが挙げられる。
酸処理ゼラチン(5%または20%、PSPゼラチン、ニッピ社製)およびパクリタキセル(1 mg/mL)を含むHFIP溶液をポリプロピレン製の基板上に塗布した(サイズ:20 cm x 20 cm、塗布厚:1 mm)。該パクリタキセル封入ゼラチンフィルムを3日間自然乾燥し、パクリタキセル封入ゼラチンフィルムを得た。
(1)温度50℃、湿度95%
(2)温度50℃、湿度10%
(3)温度40℃、湿度80%
なお、上記トランスグルタミナーゼの融点は50℃以上であり、40℃又は50℃では固体である。
実施例1に用いたパクリタキセル封入ゼラチンフィルム(3 cm x 3 cm、厚さ:100μm)を1%トランスグルタミナーゼ水溶液(10mL)に浸漬させ、25℃あるいは50℃で15時間静置した。25℃の水溶液に浸漬させたパクリタキセル封入ゼラチンフィルムは架橋したが、面積が2倍程度に膨潤した。一方、50℃のトランスグルタミナーゼ水溶液に浸漬させたパクリタキセル封入ゼラチンフィルムは架橋前に、水に溶解し、架橋体を作製できなかった。
所定濃度の酸処理ゼラチン(PSPゼラチン、ニッピ社製)を含むHFIP又はPBS水溶液を4℃、25℃又は40℃とし、それぞれの温度の25%グルタルアルデヒド(GA)水溶液を表1に記載の濃度になるように加え、ピペッティングした(表1参照)。該溶液(3.6mL)を角型ディッシュ(3 cm x 3 cm x 1 cm)に流し込み(液厚:4 mm)、それぞれの温度で17時間静置した。得られたゲルを5Mグリシン水溶液中に一晩浸漬した。該ゲルをミリQ水にて洗浄し、強度測定用のサンプルとした。
Claims (13)
- 生体高分子を架橋剤で処理することを含む生体高分子の架橋方法において、反応混合物中の架橋剤の濃度が1.0〜10重量%であり、かつ架橋を有機フッ素化合物の存在下で行うことを特徴とする生体高分子の架橋方法。
- 反応前の混合温度が0℃〜30℃である、請求項1に記載の方法。
- 反応前の混合温度が0℃〜25℃である、請求項1に記載の方法。
- 生体高分子が、タンパク質、多糖、及びそれらの誘導体からなる群から選ばれる少なくとも一種を含む、請求項1又は2に記載の方法。
- 生体高分子がタンパク質である、請求項1から4の何れか1項に記載の方法。
- タンパク質がコラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フィブロイン、フィブリン、フィブロネクチン、ビトロネクチン、ウロキナーゼ、トロンボモジュリン、及びアンチトロンビンIIIからなる群から選ばれる少なくとも一種を含む、請求項1から5の何れか1項に記載の方法。
- タンパク質の由来がヒト、牛、豚、魚、植物又は遺伝子組み換えである、請求項5又は6に記載の方法。
- 架橋剤がアルデヒド、縮合剤、又は酵素である、請求項1から7の何れか1項に記載の方法。
- 有機フッ素化合物の炭素数が1から8である、請求項1から8の何れか1項に記載の方法。
- 有機フッ素化合物が、アルコール、ケトンまたはカルボン酸である、請求項1から9の何れか1項に記載の方法。
- 有機フッ素化合物が1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール、2,2,2−トリフルオロエタノール、ヘキサフルオロアセトン、トリフルオロ酢酸、またはペンタフルオロプロピオン酸である、請求項1から10の何れか1項に記載の方法。
- 有機フッ素化合物が1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール、又は2,2,2−トリフルオロエタノールである、請求項1から11の何れか1項に記載の方法。
- 請求項1から12の何れか1項に記載の方法を含む、架橋した生体高分子の製造方法。
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IT1391734B1 (it) * | 2008-07-29 | 2012-01-27 | Anika Therapeutics Srl | Nuovi biomateriali, loro preparazione per elettrospinning e loro uso in campo biomedico e chirurgico. |
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WO2010064403A1 (ja) * | 2008-12-02 | 2010-06-10 | 富士フイルム株式会社 | 生体高分子と生体分解性合成高分子を含む組成物の製造方法 |
JP5351183B2 (ja) * | 2009-02-05 | 2013-11-27 | ニチバン株式会社 | 照射架橋水溶性高分子粒子及び照射架橋ゼラチン粒子の製造方法 |
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WO2017131003A1 (ja) | 2016-01-25 | 2017-08-03 | サントリーホールディングス株式会社 | 機能性物質を含有するカプセル及びその製造方法 |
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CN112898591B (zh) * | 2021-02-19 | 2022-06-21 | 杭州楠大环保科技有限公司 | 一种复合微生物制剂用载体及其制备方法 |
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US6992172B1 (en) | 1999-11-12 | 2006-01-31 | Fibrogen, Inc. | Recombinant gelatins |
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