JP6220894B2 - 関節軟骨の変性部位の可視化用組成物 - Google Patents
関節軟骨の変性部位の可視化用組成物 Download PDFInfo
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- JP6220894B2 JP6220894B2 JP2015552445A JP2015552445A JP6220894B2 JP 6220894 B2 JP6220894 B2 JP 6220894B2 JP 2015552445 A JP2015552445 A JP 2015552445A JP 2015552445 A JP2015552445 A JP 2015552445A JP 6220894 B2 JP6220894 B2 JP 6220894B2
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Description
(1)関節軟骨の正常部位と正常でない変性部位とを明瞭に区別して可視化することができる。
(2)軟骨変性の早期発見や変性度合の精密な識別を容易に行うことができる。
(3)関節鏡による診断又は手術の際に、関節軟骨イメージング組成物を使用することにより、生体内において、関節軟骨の変性部位を可視化させて診断または治療することができる。
(4)関節腔に関節軟骨イメージング組成物を注入することなどにより、in vivoイメージング技術を利用して非侵襲的又は低侵襲的に軟骨の変性状態を診断することができる。
(5)安全性の高い物質から構成されているため、取り扱いも容易である。また、分解産物についても同様に安全性が高い。
(6)検査や手術が終了した後には、代謝、加水分解又は組織液による希釈によって効率よく排除される。
1.陽性荷電化アルブミンの調整
ウシ血清アルブミン5g(シグマ−アルドリッチ合同会社製品)を純水25mLに溶解させた。他方、無水エチレンジアミン67mL(シグマ−アルドリッチ合同会社製品)を純水500mLに添加し、氷水中で6Nの塩酸約350mLを徐々に加えてpHを4.75に調製した。さらに、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1.8g(シグマ−アルドリッチ合同会社製品)を上記エチレンジアミン溶液に添加し、先に調製したウシ血清アルブミン水溶液を加えた。氷水で調整容器を冷却して温度とpHを保ちながら2時間撹拌した後、4Mの酢酸緩衝液を5mL加えて反応を停止させた。得られた溶液を4°Cにて純水で72時間透析した後、凍結乾燥を行った。凍結乾燥により得られた結晶は白色で光沢があり、薄膜状の外観を呈した。
2.陽性荷電化アルブミンとインドシアニングリーンの至適濃度の検討
蛍光色素であるインドシアニングリーン(ICG)は、ICGのみからなる水溶液の状態では蛍光は認められないが、タンパク質と結合すると近赤外光領域の蛍光を発する。実施例1で作成した陽性荷電化アルブミンにICGを結合させ、ICGから発せられる蛍光強度を以下のようにして測定した。なお、対照試験として、陽性荷電化されていないアルブミンとICGの結合による蛍光強度も測定した。
3.関節軟骨イメージング組成物によるウシ正常関節軟骨を用いた損傷軟骨モデルのイメージング(1)
生後2〜3週間の精肉用ウシの前肢肩部の関節軟骨を約1.5cm×約2cmの大きさで切り出し、下骨は取り除いた。次に、図3の損傷軟骨モデル図に示すように、切り出した関節軟骨片の表面をカミソリで0.1〜0.2mm程度の深さで一部切除し、軟骨表面に欠損部を生じさせた。実際の臨床での利用を想定して、各関節軟骨片に約5mLの生理食塩水を注射筒で噴射して洗浄した。次に、純水に陽性荷電化アルブミンとICGを溶解させて調製した関節軟骨イメージング組成物(陽性荷電化アルブミン濃度:2.5mg/mL、ICG濃度:0.125mg/mL)200μLを疎水性プラスチック面に滴下し、関節軟骨片の表面を下にして疎水性プラスチック面に置き、関節軟骨イメージング組成物に浸漬させた。約10〜15分後に生理食塩水で余分な関節軟骨イメージング組成物を洗い流し、赤外線カメラ(浜松ホトニクス株式会社製品)を用いて、各関節軟骨切片の表面の画像を記録した。
4.関節軟骨イメージング組成物によるウシ正常関節軟骨を用いた損傷軟骨モデルのイメージング(2)
生後2〜3週間の精肉用ウシの前肢肩部の関節軟骨を無菌的に約1cm×約1.5cmの大きさで切り出し、下骨は可及的に取り除いた。切り出した軟骨は生理的リン酸緩衝液に浸漬させた。次に、切り出した関節軟骨片の表面の略半面(平面視、右側半面)を、手術用メス(No.11)で約0.1〜0.2mm程度の深さで切除し、軟骨表面に欠損部を作成した。この処理により、関節軟骨片の平面視左側半面は無傷の対照区となり、平面視右側半面は、軟骨の表層損傷モデルとなる。また、測定及び観察の際の位置確認のため、損傷させた面の一端の角を斜めに削除した。蛍光観察に先立ち、各関節軟骨片に約2〜3mLの生理的リン酸緩衝液を注射筒で吹き付けて洗浄した。余剰の緩衝液はキムワイプ(登録商標)で除去した。次に、後述する試料液1〜4を50μLずつ夫々疎水性シャーレに垂らし、各関節軟骨片の表面を下にしてシャーレの上に垂らした試料液の上に置き、関節軟骨片の表面に試料液を浸漬させた。約10分後に余分な試料液を2〜3mLの生理的リン酸緩衝液で洗い流し、余剰の緩衝液はキムワイプで除去した。各関節軟骨片を黒色の紙片の上に置き、近赤外光下及び可視光下で写真撮影を行った。
5.関節軟骨イメージング組成物によるヒト損傷軟骨のイメージング
本発明の関節軟骨イメージング組成物を用いたヒトの関節軟骨の損傷部分のイメージングを試みた。試験材料として、人工膝関節手術のために切除され、医療廃棄されたヒトの関節の変性軟骨を用いた。無菌的に約1cm×約1.5cmの大きさで関節軟骨片を切り出した。切り出した軟骨は生理的リン酸緩衝液に浸漬させた。蛍光観察に先立ち、関節軟骨片に約2〜3mLの生理的リン酸緩衝液を注射筒で吹き付けて洗浄し、可視光下でカラー写真撮影を行った。余剰の緩衝液はキムワイプ(登録商標)で除去した。次に、純水に陽性荷電化アルブミンとICGを溶解させて調製した関節軟骨イメージング組成物(陽性荷電化アルブミン濃度:2.5mg/mL、ICG濃度:0.125mg/mL)100μLを疎水性シャーレにのせ、関節軟骨片の表面を下にしてシャーレの上に置き、関節軟骨片の表面に関節軟骨イメージング組成物を浸漬させた。約10分後に余分なイメージング組成物を2〜3mLの生理的リン酸緩衝液で洗い流し、余剰の緩衝液はキムワイプで除去した。関節軟骨片を黒色の紙片の上に置き、近赤外光下で表面及び側面の写真撮影を行った。近赤外光下での撮影は、近赤外発光ダイオード16本を円形に配列させた光源(励起波長:770nm、各30mA)で各関節軟骨片の試料液を励起させ、ICG用832nmのフィルター(Semrock社製品、BrightLine ICG−B)を介して、高感度CCDカメラ(浜松ホトニクス株式会社製品、ORCA−ER)にて、全て同一条件(100ms、low light及び8×binning mode、Auto−contrast mode)で行った。
Claims (2)
- インドシアニングリーンで標識されている陽性荷電化アルブミンを含有することを特徴とする関節軟骨の変性部位の可視化用組成物。
- 前記可視化用組成物は、変性部位を有する関節軟骨の表面に噴霧、滴下、塗布又は浸漬させて、前記陽性荷電化アルブミンが前記関節軟骨の変性部位に吸着されるように用いられることを特徴とする請求項1に記載の関節軟骨の変性部位の可視化用組成物。
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