JP6134793B2 - 神経組織を修復するためのキトサンハイドロゲル - Google Patents
神経組織を修復するためのキトサンハイドロゲル Download PDFInfo
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- JP6134793B2 JP6134793B2 JP2015522153A JP2015522153A JP6134793B2 JP 6134793 B2 JP6134793 B2 JP 6134793B2 JP 2015522153 A JP2015522153 A JP 2015522153A JP 2015522153 A JP2015522153 A JP 2015522153A JP 6134793 B2 JP6134793 B2 JP 6134793B2
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Description
・ニューロン、Nogo−Aにおいて同じ受容体を共有するミエリンの特定の成分(Nogo、MAG、及びOmgp)の抑制作用に拮抗させるためのIN1抗体の注射
・軸索成長の阻害因子でもあるプロテオグリカンCSPGの、細胞外マトリックスでの特定の酵素(ChABC、ABC型のコンドロイチナーゼ)による分解
・軸索の成長にとって好ましい接着分子の作用を模倣するペプチドの注射。これは脳内で接着分子のNCAM(神経細胞接着分子)と関係があるオリゴ糖のPSA(ポリシアル酸)の機能を模倣するペプチドの場合である。成長時のNCAMはPSAに富み、繊維束の成長及び結束のために原始的な役割を果たす。
・グリア反応、特にアストロサイトのグリア反応を減少させるための遺伝子工学
・生存率を高め、さらに軸索再生を助長するための神経栄養因子(BDNF(脳由来の神経栄養因子)、NT3(Neutrophin 3))、又はニューロン上で栄養作用を有する細胞の供給
・胚ニューロン、幹細胞、シュワン細胞(末梢神経系の髄鞘形成細胞)の移植による損傷した組織の置換、又はさらに軸索を誘導し、必要であれば軸索の髄鞘形成を行うための嗅神経鞘細胞の移植による損傷した組織の置換
(i)効率的な軸索再生のための時間窓を制御する必要があること。人は損傷を受けた後できる限り早く行動する必要がある。
(ii)許容環境だけでなく軸索再生の誘導に寄与する空間的構成をもたらすよう、損傷部位の空間的構成を考慮する必要があること。
・精製し、凍結乾燥したキトサンと酢酸の水溶液を混合することにより、濃度が、溶液の総重量を基準として0.25重量%〜5重量%のキトサンの溶液を調製し、
・得られた溶液をアンモニアの蒸気と接触させてゲル化させ、
・得られたハイドロゲルを洗浄することにより、アンモニアと、ゲル化の間に形成された塩を除去する。水系経路の長所は、得られたハイドロゲルが人体内で迅速に生分解される点である。
Mahtani Chitosan社から市販されている、イカのキチン由来の、アセチル化度が3%のキトサンを、酢酸の水溶液(アミン性官能基に対して化学量論的量を加えた)に溶解させることにより、0.5重量%のキトサンを含有する溶液を得る。
3μm、1μm、及び0.45μmのフィルター上で濾過する。
ソーダ又はアンモニアを用いて、pHが14になるまで沈殿させる。
遠心分離によって沈殿物を回収する。
塩が除去されるように、洗浄液のpHが中性になるまで脱イオン水で洗浄する。
洗浄した沈殿物を凍結乾燥して乾燥品を得る。
上記沈殿物と純水(Versol(R))とから、モル質量が450,000g/molのキトサンを、溶液の総重量を基準として2.5%の濃度で含有する溶液を調製する。
直径数cmのペトリ皿の中で、アンモニアの蒸気の存在下、溶液を接触させる(72時間)ことによりゲル化させる。
ハイドロゲルを脱イオン水で洗浄してアンモニアを除去する。
その操作を繰り返して合計で7回洗浄する。
pHが中性の値を示しているか確認する。
IKAブランドのULTRATURAX装置を用いてハイドロゲルを粉砕する(回転速度11,000rpmで3×10秒間操作し、一連の操作の間に30秒間停止する)。
ハイドロゲルの微粒子を、オートクレーブ(121℃で20分間)を用いて滅菌する。
遠心分離(Bioblock ScientificブランドのSigma 3K30型装置を用いて13,000rpmで3分間行う)により、メジアン径d50が約20μmの滅菌された微粒子を回収する。
最初のキトサンとしてアセチル化度が35%のものを用いた以外は実施例1で用いられた方法と同じ方法を用いる(得られた微粒子は実施例1のものとメジアン径d50が同じであり、キトサン含有量も実施例1のものと同じであり、得られた懸濁液の粘度も同じである)。そのようなアセチル化度のキトサンを得るために、文献(Biomacromolecules. 2001 2(3):765−72. Relation between the degree of acetylation and the electrostatic properties of chitin and chitosan. Sorlier P, Denuziere A, Viton C, Domard A)に記載されている方法に従って、Mahtani Chitosan社から購入した低アセチル化度(3%)のキトサンを再アセチル化し、水−アルコール媒体中で実施例1に示されている方法と同様の方法で乾燥させた。
粉砕、遠心分離、及びガラスプレート上での部分的乾燥を行わない点を除き、実施例1と同様の方法を用いる。得られた物理ハイドロゲルは目的の大きさに切り出される前に直接滅菌される。
この粒子を得る方法は、最初のハイドロゲル中のキトサンの濃度が、総重量を基準として3.5重量%であり、ゲルの粉砕時間が3×10秒の代わりに10秒のみである点を除き、実施例1の方法と同じである。
これらのテストでは、成体ラットの脊髄の、横方向への胸の半側切断 Th8/Th9を行った後、暴露されたセグメントから、横方向へ背部分のサンプリング(2〜3mm)を行う。このタイプの損傷は、最後の胸のセグメントと最初の腰のセグメントの間に見られた。半側切断の場合、これによって損傷と同じ側の後部足に麻痺が生じる。対照ラットには、同じタイプの損傷を与えるが、移植組織は用いずに自然治癒させる。
・約2〜3mm3の本発明の微粒子(実施例1によって得られたもの)の水性溶液、
・約2〜3mm3の、高アセチル化度を有するキトサン(比較例1によって得られたもの)の、ハイドロゲル微粒子の水性溶液
・又は比較例2に従って得られたキトサン物理ハイドロゲルの、切り出された約2〜3mm3のブロック
Claims (11)
- 数分布から得られるメジアン径d50が1〜500μmのキトサンのハイドロゲル微粒子であって、
前記キトサンはアセチル化度が20%以下であり、かつそのハイドロゲル中での濃度が、ハイドロゲルの総重量を基準として0.25〜5重量%であり、
前記ハイドロゲル微粒子は、ニューロンの再生及び/又は神経系、有利には中枢神経系、の修復のため、及び/又はニューロン又は神経細胞の前駆体の分枝化のため、及び/又は神経変性疾患の治療、及び/又は虚血性結合、及び/又は麻痺の治療のために使用される
キトサンのハイドロゲル微粒子。 - 修復、再生、又は麻痺の治療を神経系の外傷性損傷、特に脊髄の外傷性損傷の後に行うことを特徴とする、
請求項1に記載の微粒子。 - 数分布から得られるメジアン径d50は5〜300μmであることを特徴とする、
請求項1又は2に記載の微粒子。 - キトサンのアセチル化度は5%未満であることを特徴とする、
請求項1〜3のいずれか1項に記載の微粒子。 - 前記ハイドロゲル中の前記キトサンの濃度は、ハイドルゲルの総重量を基準として4重量%未満であることを特徴とする、
請求項1〜4のいずれか1項に記載の微粒子。 - 前記ハイドロゲルはキトサンの物理ハイドロゲルであることを特徴とする、
請求項1〜5のいずれか1項に記載の微粒子。 - 水性懸濁液として存在し、有利には、22℃において、せん断速度0.001s−1に対して連続モードで測定した粘度が1000Pa・s超の水性懸濁液として存在することを特徴とする、
請求項1〜6のいずれか1項に記載の微粒子。 - 前記懸濁液は、注射可能、又は外科手術により移植可能であることを特徴とする、
請求項7に記載の微粒子。 - シュワン細胞及び/又は幹細胞及び/又は栄養因子と共に混合されていることを特徴とする、
請求項7又は8に記載の微粒子。 - アルツハイマー病、パーキンソン病、又は多発性硬化症の治療用であることを特徴とする、
請求項1〜9のいずれか1項に記載の微粒子。 - 請求項9に記載の微粒子の水性懸濁液を含有する移植組織。
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FR1257006A FR2993566B1 (fr) | 2012-07-19 | 2012-07-19 | Hydrogel de chitosane pour la reparation du tissu nerveux |
FR1257006 | 2012-07-19 | ||
PCT/FR2013/051710 WO2014013188A1 (fr) | 2012-07-19 | 2013-07-16 | Hydrogel de chitosane pour la reparation du tissu nerveux |
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FR3016882A1 (fr) | 2014-01-30 | 2015-07-31 | Sofradim Production | Procede de preparation de chitosane a haut degre d’acetylation |
EP3034612A1 (en) * | 2014-12-16 | 2016-06-22 | Greenaltech, S.L. | Chitin and chitosan producing methods |
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US20220257662A1 (en) * | 2018-10-26 | 2022-08-18 | Tessara Therapeutics Pty Ltd | Nervous system cell therapy |
FR3108260B1 (fr) | 2020-03-17 | 2024-01-05 | Neurobiomat | Hydrogel hétérogène hybride, procédé de fabrication et utilisation comme implant de comblement non-dégradable in-situ |
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