JP2012502012A - 軟組織工学のための方法及び手段 - Google Patents
軟組織工学のための方法及び手段 Download PDFInfo
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- JP2012502012A JP2012502012A JP2011525584A JP2011525584A JP2012502012A JP 2012502012 A JP2012502012 A JP 2012502012A JP 2011525584 A JP2011525584 A JP 2011525584A JP 2011525584 A JP2011525584 A JP 2011525584A JP 2012502012 A JP2012502012 A JP 2012502012A
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Abstract
Description
細胞培養及び動物試験のための脂肪組織抽出物の調製
脂肪吸引術より得られた、及び外科手術から皮下組織として得られたヒト脂肪組織試料、並びに犠牲ラットから得られたラット脂肪組織試料を、必要に応じて小片に細分化した。組織片又は脂肪吸引術試料を50mlの試験管(Nunc)に移した。補給剤を一切含まない滅菌塩溶液(動物試験用)、又はDMEM/F12培地(細胞培養試験用)を試験管に添加し、少なくとも45分間インキュベーションした。インキュベーション中に、試験管を数回、穏やかに振とうした。脂肪組織抽出物(ATE)のサンプルを様々な時刻に収集し(各収集時には、培地又は塩溶液を完全に除去し、新鮮な液に交換した)、12000rpmで5分間遠心分離し、及び細胞培養又は動物実験で使用する前に滅菌ろ過した。ATEを作製してから24時間後に細胞を単離し、更に細胞を培養することにより、細胞の生存率を分析した。間質血管細胞群の細胞は形態学的に正常であり、生物学的活性を保持し、また正常に増殖した。
脂肪組織抽出物の脂肪形成能力
ヒト脂肪由来幹細胞(hASC)は、Zuk PAら(Mol Biol Cell.2002年12月;第13巻(12):4279〜95頁)から修正したプロトコールに基づき単離した。簡潔には、外科手術又は脂肪吸引術から得られたヒト脂肪組織試料を、必要に応じて小断片に切断し、0.05%コラゲナーゼIを補充したDMEM/F12培地内で、37℃、60〜90分間、シェーカー内において酵素的に消化した。消化を容易にするために、インキュベーション中に組織を時々吸引した。間質血管細胞群及び幹細胞集団を分離するために、消化組織を600×gで、10分間、室温にて遠心分離した。消化済みの組織を、最初孔径100μmを有するフィルターでろ過し、次いで孔径40μmを有するフィルターでろ過した。得られたヒト幹細胞集団を、15%ヒト血清(HS、Cambrex)、1mM L−グルタミン、及び1%抗生物質−抗真菌薬混合物(Gibco)を補充したDMEM/F12内で培養した。一定湿度に保たれた5%CO2を含む空気雰囲気の下で、細胞を37℃に維持した。細胞を付着させたまま1晩放置した。翌日、細胞を数回洗浄し、培地を交換してデブリを除去した。
脂肪組織抽出物の血管形成能力
BJ線維芽細胞(CRL−2522;American Type Culture Collection、Manassas、バージニア州、米国)を、10%ウシ胎仔血清、1%L−グルタミン、1%非必須アミノ酸(Gibco)、及び1%抗生物質−抗真菌薬混合物(Gibco)を補充したMEM(Gibco)中で培養した。一定湿度に保たれた5%CO2を含む空気雰囲気の下で、細胞を37℃に維持した。培地を2〜3日毎に交換し、密集状態の細胞を1:4に分割した。
注射可能なインプラントの作製
本発明に基づく、2つの異なる注射可能なインプラントを、動物試験用に処方した:1)ラットATEを54.5%(総タンパク質濃度が1.3mg/ml)、及びヒアルロン酸を45.5%含むインプラント;及び2)ヒトATEを54.5%(総タンパク質濃度が2.5mg/ml)、及びヒアルロン酸を45.5%含むインプラント。かかる処方では、使用したヒアルロン酸は、20mg/mlの非動物由来の安定化ヒアルロン酸(NASHA)、すなわちRestylane(Q−Med、Uppsala、スウェーデン)であった。欠損の種類に応じて異なる形態の架橋化ヒアルロン製品(例えば、Restylane Perlane、又はRestylane Touch、又はMacrolane)も利用可能である。
in vivoでのインプラントの脂肪形成活性及び血管形成活性(動物試験)
すべての動物実験はフィンランド動物保護法に基づき、また西部フィンランド、州地方事務所、社会福祉及び保健サービス部門から承認を得た。
臨床前試験
滅菌シリンジ内への直接吸引による脂肪吸引サンプルから、ヒト脂肪組織抽出物を調製した。タンパク抽出を最大化するために、脂肪吸引により得られた脂肪2.5mlを滅菌等張塩溶液1.5mlと、滅菌シリンジ内で混合し、室温で45分間インキュベーションした。インキュベーション中、シリンジを数回振とうした。得られた抽出物の総タンパク質濃度は2.5mg/mlであり、また増殖因子濃度は、VEGFが17pg/ml、またFGF−2が177pg/mlであった。
Claims (17)
- 事前決定された量のVEGF、FGF−2、及びIGF−1を含む、細胞不含脂肪組織抽出物。
- 総タンパク質1mg当たりの前記増殖因子含量が、少なくとも1pgのVEGF、少なくとも70pgのFGF−2、及び少なくとも50pgのIGF−1である、請求項1に記載の抽出物。
- 総タンパク質1mg当たりの前記VEGF含量が、少なくとも7pgである請求項2に記載の抽出物。
- アンジオジェニン、アディポネクチン、TIMP−1及びTIMP−2、MIF、IGFBP−6、NAP−2、レプチン、PDGF−BB、並びにGROを更に含む、請求項2に記載の抽出物。
- アンジオジェニン、IL−5、IL−6、IL−8、CCL5、NAP−2、MCP−1、アディポネクチン、GRO、TIMP−1、TIMP−2を更に含む、請求項2又は3に記載の抽出物。
- 軟組織の修復又は工学的操作で、創傷治癒で、火傷治療で又は虚血状態の治療で用いられる、請求項1から5までのいずれか一項に記載の抽出物。
- 請求項1から5までのいずれか一項に記載の細胞不含脂肪組織抽出物、及び生体適合性マトリクスを含むインプラント。
- 前記生体適合性マトリクスがヒドロゲルである、請求項7に記載のインプラント。
- 前記ヒドロゲルがヒアルロン酸、キトサン、フィブリン、コラーゲン、アルギン酸塩、ポリ乳酸ベースのポリエステル、ポリ乳酸グリコール酸、ポリカプロラクトン、及びこれらの混合物からなる群から選択される、請求項8に記載のインプラント。
- 注射可能である、請求項7から9までのいずれか一項に記載のインプラント。
- 前記抽出物が同系異種である、請求項7から10までのいずれか一項に記載のインプラント。
- 軟組織の修復又は工学的操作で、創傷治癒で、火傷治療で又は虚血状態の治療で用いられる、請求項7から11までのいずれか一項に記載のインプラント。
- 事前に決定された量のVEGF、FGF−2、及びIGF−1を含む、細胞不含脂肪組織抽出物を調製する方法であって、
a)生存細胞を含むホモジナイズされていない脂肪組織サンプルを提供するステップ、
b)前記サンプルを事前に決定された時間インキュベートするステップ、及び
c)前記抽出物を収集するステップ
を含む前記方法。 - 請求項13に記載の方法によって取得可能な細胞不脂肪組織抽出物。
- 前記脂肪組織抽出物を前記生体適合材料と混合する、又は前記脂肪組織抽出物を前記生体適合材料に吸収させるステップを含む、請求項7から11までのいずれか一項に記載のインプラントを調製する方法。
- 脂肪形成を誘発する方法であって、請求項7から11までのいずれか一項に記載のインプラントを、これを必要とする対象に移植するステップを含む、前記方法。
- 血管形成を誘発する方法であって、請求項7から11までのいずれか一項に記載のインプラントを、これを必要とする対象に移植するステップを含む、前記方法。
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