JP6549556B2 - ポリマーベースのヒドロゲル - Google Patents
ポリマーベースのヒドロゲル Download PDFInfo
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Description
ゲルの調製
担体として活性分子に用いられるゲルは、1%カルボポールを用いることにより調製する。そのゲルの調製において、1%カルボポールを加えた蒸留水は、室温での水和のために残る。水和プロセスにおいて、カルボポールは、完全に水飽和した1リットル溶液に1.6グラムの18%NaOHを加えることによりゲル化される。3%ホウ素化合物および4%ポロキサマーをゲル混合物に加え、水和の完了後に混合により均質化した。その混合物を4℃にて16〜24時間貯蔵し、使用に備えた。
ディスク拡散法
開発したヒドロゲル組成物の抗微生物特性は、文献(LalithaおよびVellore、2005年)に従前に記載されたディスク拡散法によってテストした。108cfu/mlの細菌、106cfu/mlの酵母および104胞子/mlの真菌を含有する100μl溶液を新しい培養液で調製し、各々、栄養寒天培地(NA)、サブローデキストロース寒天培地(SDA)およびポテトデキストロース寒天培地(PDA)上の拡散方法で接種した。20μlのヒドロゲル組合せを空ディスク上に導入し、次いで、接種媒体上に置いた。その有効成分を含有しないヒドロゲルを陰性対照として用いた。陽性対照については、オフロキサシン(10μg/ディスク)およびナイスタチン(30μg/ディスク)を各々、細菌および真菌に用いた。接種後のペトリ皿を36±1℃にて、細菌について24時間、酵母について48時間、および25±1℃にて真菌について72時間培養した。ディスク拡散法においてテストした微生物に対する抗微生物活性を阻止帯の測定により評価した。
調製したゲル組合せの毒作用は、文献(Yalvacら、2009年)に与えられたMTS(3−(4,5−ジメチル−チアゾール−2−イル)−5−(3−カルボキシ−メトキシフェニル)−2−(4−スルホフェニル)−2H−テトラゾリウム)法を用いることにより決定した。ゲルに用いた分子は、培地中で単独または組合せて調製し、計数することにより、96ウェルプレート(5000細胞/ウェル)に蒔いたL929(マウス繊維芽細胞)、HF(ヒト線維芽細胞)およびヒト角化細胞の細胞系に適用した。分子の毒性に対する細胞の応答は、3日間細胞生存率を測定することによって決定した。細胞生存率は、細胞のミトコンドリア脱水素酵素活性を測定するMTSと呼ばれる方法を用いて決定した。培地と一緒に細胞に加えたMTS物質の結果、細胞生存率の指標として有色のホルマザン結晶形成を生じる。得られた色彩変化は、ELISAプレートリーダーを用いることにより、吸収度測定に基づいて評価した(図1、2、3、4、5)。得られた結果を分析した。
創傷治癒に対するゲルの効果、細胞遊走についてのその能力および創傷閉鎖を決定するために、文献(Walterら、2010)に記載されたスクラッチアッセイを用いることにより分析した。in vitroでの創傷治癒モデルにおいて、L929(マウス繊維芽細胞)、HF(ヒト線維芽細胞)およびヒト角化細胞の細胞系ならびにL929−HUVEC共培養物を用いた。細胞は100,000細胞/ウェルの濃度にて12ウェルプレート上に接種し、次いで、付着し、十分な密度に達することができるように、二酸化炭素インキュベーターにそれらを貯蔵した。スクラッチは、アセテートペンにより、ウェルの中心からウェル外側に描いた水平線に垂直になるように、200μlピペットチップを用いて形成した。ゲル組合せを細胞に適用し、スクラッチ閉鎖を観察した。スクラッチ閉鎖(図6〜7)は、スクラッチ領域の撮影に際して、NIH画像プログラムを用いることにより分析し、スクラッチ領域はアセテートペンにより描かれた線に対応し、0、12および24時間での顕微鏡視野内にある。
リアルタイムPCR(ポリメラーゼ連鎖反応)分析をSYBRグリーン法を用いることによる文献(Yalvac、2010年ら)に従い行った。コラーゲン、フィブロネクチン、ラミニン、Akt、BaxおよびP53遺伝子に属するプライマーは、プライマーBLASTソフトウェア(米国国立バイオテクノロジーセンター=NCBI)を用いて設計した。合計RNAは、ゲル組合せが適用され、cDNAが合成された細胞から単離した。合成されたcDNAは、最終体積が20μlになるように、SYBRグリーンミックス溶液中でプライマーと混合し、遺伝子(図8)の発現レベルをBIO−RADデバイスを用いて分析した。
抗酸化パラメーターは、グルタチオンペルオキシダーゼおよびスーパーオキシドジスムターゼ酵素活性アッセイ、およびMDA(マロンジアルデヒド)のレベルの分析によって決定した。6ウェルプレート中でゲル組合せ、活性剤、および対照目的用培地だけに付した細胞を収集し、タンパク質単離をRIPA緩衝液を用いることにより細胞ペレットから行った。単離タンパク質の濃度は、吸収度を測定し、ウシアルブミンタンパク質標準(0.125、0.25、0.5、0.75、1.0、1.5、2.0mg/ml)を用いることにより、96ウェルELISAプレート中のブラッドフォード溶液で595nmの波長にて標準曲線を描くことにより決定した。酵素活性アッセイおよびMDAレベルは、市販キットに与えられたプロトコールに従って決定した(図9)。
ゲル組合せが染色体異常を引き起こすかどうかは、文献(Yalvacら、2011年)に従って細胞遺伝学的分析を用いることにより決定した。細胞は、有効成分群および対照群が存在するようなT−75細胞培養プレート中で50%濃度まで増殖させた。細胞は、最初に2.45時間染色体溶解溶液中に、次いで、75分間分裂中期停止溶液中に貯蔵した。細胞をトリプシンで収集した後、それらをカルノワ固定剤で固定し、スライドガラス上に広げ、65℃にて一晩培養し、ギムザで染色し、その分裂中期の出現を光学顕微鏡によって分析した(図10)。
in vitroでの細胞生存率分析は、五ホウ酸ナトリウム五水和物およびポロキサマーポリマーの組合せからなるゲル混合物中で、単独または組み合わせて、分子の毒作用を決定する目的でL929細胞(マウス繊維芽細胞)に対して行った。ゲルの調製に用いた15μg/mlの五ホウ酸ナトリウム五水和物およびポロキサマー混合物が、創傷治癒実験におけるモデル細胞として用いたマウス繊維芽細胞に対して毒作用を有しないことを観察した。3日間行ったMTS分析の後、ゲル組合せおよびその組成物に用いた物質が、毒作用を有しなかったと決定した(図1)。
Al-Bayaty, Fouad, and Mahmood Ameen Abdulla. "A Comparison of Wound Healing Rate Following Treatment with Aftamed and Chlorine Dioxide Gels in Streptozotocin-Induced Diabetic Rats." Evidence-Based Complementary and Alternative Medicine 2012 (2012).
auf dem Keller, Ulrichら, "Reactive oxygen species and their detoxification in healing skin wounds." Journal of Investigative Dermatology Symposium Proceedings. Vol. 11. No. 1. Nature Publishing Group, 2006.
Bartosz, Grzegorz. "Reactive oxygen species: destroyers or messengers?."Biochemical pharmacology 77.8 (2009): 1303-1315.
Batrakova, Elena V., and Alexander V. Kabanov. "Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers." Journal of Controlled Release 130.2 (2008): 98-106.
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Claims (9)
- 担体として調製したゲルに、ホウ素化合物およびポロキサマーを加えてなることにより得られる、3%ホウ素化合物、4%ポロキサマーおよびゲルを含む抗老化性、抗微生物性かつ創傷治癒性のポリマーベースのヒドロゲルであって、
ホウ素化合物が、五ホウ酸ナトリウム五水和物、ホウ酸、アルカリ金属ホウ酸塩、アルカリ土類金属ホウ酸塩、およびこれらのホウ酸塩のすべての水和物、ならびにアンモニウムホウ酸塩およびホウ酸エステルよりなる群から選択される該ヒドロゲル。 - 1%カルボポールが、調製したゲルに用いられてなる請求項1記載のヒドロゲル。
- 五ホウ酸ナトリウム五水和物がホウ素化合物として用いられてなる請求項1または2記載のヒドロゲル。
- 五ホウ酸ナトリウム五水和物が、ホウ素化合物として用いられてなる請求項1〜3のいずれか1記載のヒドロゲル。
- ゲル、ホウ素化合物およびポロキサマーの混合物が4℃にて16〜24時間貯蔵されてなる請求項1〜4のいずれか1記載のヒドロゲル。
- ホウ酸がホウ素化合物として用いられてなる請求項1または2記載のヒドロゲル。
- アルカリ金属ホウ酸塩がホウ素化合物として用いられてなる請求項1または2記載のヒドロゲル。
- アルカリ土類金属ホウ酸塩がホウ素化合物として用いられてなる請求項1または2記載のヒドロゲル。
- ローション、クリーム、エマルジョン、スプレー、フォーム、ゼラチン、ペースト、パウダー、プラスター、スキンプレートまたは創傷包帯織物品になる請求項1〜8いずれか1記載のヒドロゲル。
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GB0808376D0 (en) | 2008-05-08 | 2008-06-18 | Bristol Myers Squibb Co | Wound dressing |
GB0817796D0 (en) | 2008-09-29 | 2008-11-05 | Convatec Inc | wound dressing |
GB201020236D0 (en) | 2010-11-30 | 2011-01-12 | Convatec Technologies Inc | A composition for detecting biofilms on viable tissues |
ES2748519T3 (es) | 2010-12-08 | 2020-03-17 | Convatec Technologies Inc | Accesorio de sistema de exudado de heridas |
US10207031B2 (en) | 2010-12-08 | 2019-02-19 | Convatec Technologies Inc. | Integrated system for assessing wound exudates |
GB201115182D0 (en) | 2011-09-02 | 2011-10-19 | Trio Healthcare Ltd | Skin contact material |
GB2497406A (en) | 2011-11-29 | 2013-06-12 | Webtec Converting Llc | Dressing with a perforated binder layer |
GB201120693D0 (en) | 2011-12-01 | 2012-01-11 | Convatec Technologies Inc | Wound dressing for use in vacuum therapy |
KR20150099776A (ko) | 2012-12-20 | 2015-09-01 | 컨바텍 테크놀러지스 인크 | 화학적 개질된 셀룰로스 섬유의 처리 |
JP2019513238A (ja) | 2016-03-30 | 2019-05-23 | クオリザイム・ダイアグノスティクス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング・ウント・コムパニー・コマンディットゲゼルシャフトQualizyme Diagnostics Gmbh And Co. Kg | 創傷における微生物感染の検出 |
EP3936095B1 (en) | 2016-03-30 | 2024-06-19 | ConvaTec Technologies Inc. | Detecting microbial infections in wounds |
CA3030151A1 (en) | 2016-07-08 | 2018-01-11 | Convatec Technologies Inc. | Fluid collection apparatus |
AU2017292028B2 (en) | 2016-07-08 | 2023-03-02 | Convatec Technologies Inc. | Fluid flow sensing |
TW201805034A (zh) | 2016-07-08 | 2018-02-16 | 美商康瓦鐵克科技股份有限公司 | 彈性的負壓系統 |
TR201610999A2 (tr) * | 2016-08-05 | 2018-02-21 | Univ Yeditepe | Jelati̇n veya pekti̇n bazli anti̇mi̇krobi̇yal yüzey kaplama malzemesi̇ |
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TR201908285A2 (tr) * | 2019-05-30 | 2020-12-21 | Univ Yeditepe | Ameli̇yat sonrasi yapişikliklari önleyen gli̇serol ve sodyum pentaborat temelli̇ bi̇r formülasyon |
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