JP7448491B2 - 外科的移植のための生体組織を調製する方法 - Google Patents
外科的移植のための生体組織を調製する方法 Download PDFInfo
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- JP7448491B2 JP7448491B2 JP2020573519A JP2020573519A JP7448491B2 JP 7448491 B2 JP7448491 B2 JP 7448491B2 JP 2020573519 A JP2020573519 A JP 2020573519A JP 2020573519 A JP2020573519 A JP 2020573519A JP 7448491 B2 JP7448491 B2 JP 7448491B2
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Description
(1)架橋剤で処理された生体組織に生理食塩溶液を含浸させる工程と、
(2)含浸された生体組織を、過酸化水素を含む水溶液と接触させる工程と、
(3)生体組織をPBS及びEDTAを含む水溶液と接触させる工程と、
(4)生体組織をグリセロール、エタノール及びEDTAを含む溶液と接触させる工程と、
(5)生体組織をグリセロール溶液と接触させる工程と、
を含む、方法が提供される。
ウシ心膜「sample 180702-1」(P+F Brasil社、EDQM認定)から選択された1×1cmの生体組織を含む40枚のメンブレンを、最初に0.625%のグルタルアルデヒド溶液(P+F GmbH社/Biocollagen)から取り出し、その後に冷えた0.9%の生理食塩溶液(JP Pharma社)中で3分間含浸させた。次いで、含浸された組織を0.5容量%の過酸化水素(Sigma-Aldrich社)中に18℃で60分間浸漬させた。次の工程として、該組織を、冷えた(10℃)PBS(pH7.4)及び0.5重量%のEDTAと3分間接触させた(Sigma-Aldrich社)。その後に、該組織を、激しく撹拌しながら22℃の温度で60秒間、99容量%のエタノール(Sigma-Aldrich社)中に浸漬させた後に、ゆっくりと撹拌しながら22℃の温度で60分間、グリセロール/エタノール(50/50)及び0.5重量%のEDTA(Sigma-Aldrich社)の混合物中に浸漬させた。さらに、該組織を、ゆっくりと撹拌しながら22℃の温度で120分間、99%のグリセロール(Sigma-Aldrich社)中に浸漬させた。次に、該組織を、激しく撹拌しながら22℃の温度で60秒間、99容量%の無水エタノール(Sigma-Aldrich社)及び0.5重量%のEDTAで含浸させた。最後に、該組織に、HEPAフィルターを通した空気を通気しながら18℃の温度で18時間、溶剤蒸発の処置を行う。次に、該組織を二重のタイベック製パウチに包み、Sterium社(Sterium Company)でETO滅菌(55℃、4時間のETO曝露)した。
ウシ心膜「sample 180702-2」から選択された1×1cmの生体組織を含む40枚のメンブレンを、実施例1-1に記載される手順に従って調製した。
ウシ心膜「sample 180803-1」から選択された1×1cmの生体組織を含む40枚のメンブレンを、0.625%のグルタルアルデヒド溶液(P+F GmbH社/Biocollagen)から取り出し、更に処理をせずに比較試料として使用した。
実施例1-1~実施例1-3からのウシ心膜メンブレン(試料の番号:180702-2及び180702-1は本発明によるものであり、180803-1は比較例である)を生理食塩溶液中で2分間含浸させた後に、表3に示されるようにヒト血漿と同様のイオン濃度を有する溶液である擬似体液(SBF)中に浸漬させ、同じ生理的条件のpH及び温度(pH7.4及び温度36.5℃)で維持した。浸漬時間は1日から30日の間で変化させた。
ウシ心膜(P+F Brasil社)から選択され、グルタルアルデヒド(Sigma-Aldrich社、0.625容量%)の存在下で固定された75単位の生体組織を、冷えた0.9%の生理食塩溶液(JP Farma社)中に置き、その後にpH7.4のPBS(Sigma-Aldrich社)及びEDTA(Sigma-Aldrich社、0.2重量%)を含む水溶液中に3分間置き、引き続きエタノール(Sigma-Aldrich社、70容量%)ですすいだ。次いで、含浸された組織を周囲温度で約1分間エタノール中に浸漬させた。次の工程として、該組織をグリセロール(Sigma-Aldrich社、99%)、エタノール及びEDTA溶液の混合物(70%のグリセロール、29.8%のエタノール及び0.2%のEDTA溶液)と周囲温度で少なくとも90分間接触させた。その後に、該組織を撹拌しながら少なくとも90分間グリセロール中に浸漬させ、引き続きエタノールですすいだ。次いで、該組織を溶液から慎重に取り出し、空気で乾燥させた。16時間の乾燥後に、該組織を再水和及び機械的安定性に関して調べた。
ウシ心膜(P+F Brasil社)から選択され、グルタルアルデヒド(Sigma-Aldrich社、0.625容量%)の存在下で固定された04(130mmの直径を有する円形の4つのパッチ)単位の生体組織を、冷えた0.9%の生理食塩溶液(JP Farma社)中に置き、その後にpH7.4のPBS(Sigma-Aldrich社)及びEDTA(Sigma-Aldrich社、0.2重量%)を含む水溶液中に3分間置き、引き続きエタノール(Sigma-Aldrich社、70容量%)ですすいだ。次いで、含浸された組織を周囲温度で約1分間エタノール中に浸漬させた。次の工程として、該組織をグリセロール(Sigma-Aldrich社、99%)、エタノール及びEDTA溶液の混合物(70%のグリセロール、29.8%のエタノール及び0.2%のEDTA溶液)と周囲温度で少なくとも90分間接触させた。その後に、該組織を撹拌しながら少なくとも90分間グリセロール中に浸漬させ、引き続きエタノールですすいだ。これらの試料を、原子吸光分析ContrAA 300(Analytik Jena社、ドイツ、イエナ)にかけた。表2は、標準的なグルタルアルデヒド保存されたウシ心膜に対するこれらの試料のカルシウム含有量を示している。
染剤を使用した組織学的評価によってコラーゲン線維の完全性を調査して、ウシ心膜試料における乾燥過程後のコラーゲン線維の保存を調べた。Eclipse E-200(株式会社ニコン)と一緒にフルデジタルビデオHD Lite 1080p(Tucsen社)を使用して画像を取得した。結果を標準的なグルタルアルデヒド保存された材料試料と比較した。図4(乾燥させたウシ心膜)及び図5(標準的なウシ心膜)に示される種々の染剤を使用して検査を行った。ここで、HEはヘマトキシリンを意味し、REはレゾルシン-オルセインを意味し、TMはマッソントリクロームを意味し、TGはゴモリトリクロームを意味する(全ての染剤はMerck社により供給された)。
標準的なウシ心膜及び乾燥したウシ心膜(両方)のコラーゲン構造及び乾燥過程の抗石灰化効果を、種々の分解能を使用して走査型電子顕微鏡法(SEM、FESEM、JEOL社、モデル7500F)によって評価した:
(a)乾燥させたウシ心膜:図6:倍率200倍、図7:倍率3000倍、図8:倍率50000倍、図9:倍率100000倍;
(b)標準的なウシ心膜:図10:倍率200倍、図11:倍率3000倍、図12:倍率50000倍、図13:倍率100000倍。
Claims (15)
- 生体組織を処理する方法であって、
(1)架橋剤で処理された生体組織に生理食塩溶液を含浸させる工程と、
(2)前記含浸された生体組織を、過酸化水素を含む水溶液と接触させる工程と、
(3)前記生体組織をPBS及びEDTAを含む水溶液と接触させる工程と、
(4)前記生体組織をグリセロール、エタノール及びEDTAを含む溶液と接触させる工程と、
(5)前記生体組織をグリセロール溶液と接触させる工程と、
を含む、方法。 - 前記生体組織を少なくとも70容量%の濃度内のエタノールと接触させる工程(3a)及び/又は工程(5a)を更に含む、請求項1に記載の方法。
- 前記架橋剤はグルタルアルデヒドである、請求項1又は2に記載の方法。
- 前記生体組織は、ウシ又はブタの心膜又は心臓弁である、請求項1~3のいずれか一項に記載の方法。
- 前記生理食塩溶液は、0.9%の塩化ナトリウムを含む水溶液である、請求項1~4のいずれか一項に記載の方法。
- 工程(4)におけるグリセロール:エタノールの容量比は、1:5~5:1である、請求項1~5のいずれか一項に記載の方法。
- 工程(3)及び工程(4)におけるEDTAは、0.01重量%~10.0重量%の濃度を有する、又は工程(2)における過酸化水素は、0.05容量%~5.0容量%の濃度を有する、請求項1~6のいずれか一項に記載の方法。
- 前記生体組織を乾燥させる工程(6)と、前記生体組織をパッケージ中に入れる工程(7)と、前記パッケージを密封する工程(8)と、前記パッケージを滅菌する工程(9)とを更に含む、請求項1~7のいずれか一項に記載の方法。
- 前記生体組織を含むパッケージの滅菌は、前記パッケージをエチレンオキシドガスに曝露することによって実施される、請求項8に記載の方法。
- 前記工程(1)~前記工程(5)は10℃~25℃の温度で実施され、特に前記工程(6)及び前記工程(7)は、10℃~25℃の温度で実施される、請求項1~9のいずれか一項に記載の、特に請求項8に記載の方法。
- 前記工程(4)及び前記工程(5)は、撹拌しながら少なくとも60分間実施される、請求項1~10のいずれか一項に記載の方法。
- 請求項1~11のいずれか一項に記載の方法に従って調製された生体組織を含む生体組織。
- 外科的移植用の、請求項12に記載の生体組織。
- 生体補綴物用の、請求項12に記載の生体組織。
- 請求項12に記載の生体組織を含む経カテーテル心臓弁。
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