JP4871356B2 - 無細胞移植片 - Google Patents
無細胞移植片 Download PDFInfo
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- JP4871356B2 JP4871356B2 JP2008514034A JP2008514034A JP4871356B2 JP 4871356 B2 JP4871356 B2 JP 4871356B2 JP 2008514034 A JP2008514034 A JP 2008514034A JP 2008514034 A JP2008514034 A JP 2008514034A JP 4871356 B2 JP4871356 B2 JP 4871356B2
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Description
インビトロでの成長因子および分化因子、ケモカインおよびヒト血清によるヒト間葉系幹細胞の動員
A ヒト間葉系幹細胞の単離および培養
ヒト間葉系幹細胞(MSC)を骨髄から単離する方法は、既に記載されている[独国特許出願公開第10333901号明細書]。最大3mlの骨髄穿刺液を10mlのPBSと混合し、310g、室温にて10分間遠心分離する。細胞ペレットを再懸濁し、再びPBSで洗浄する。細胞を20mlのDME培地(10〜20% FBS、2% HEPES、4mMのL−グルタミン、100U/mlのペニシリン、100μg/mlのストレプトマイシンを含む)に入れる。この細胞懸濁液を5mlずつ、1.073g/mlの密度を有するパーコール密度勾配(Percoll density gradient)20ml上に導入する。細胞を900gにて32分間遠心分離する。上相を新しい遠心チューブに移す。2.5倍量のPBSを添加した後、310gにて6分間遠心分離する。細胞ペレットをDME培地に入れる。細胞培養フラスコにて培養するために1.5×105〜3.5×105個細胞/cm2を移し、37℃、5% CO2にてインキュベートする。培地を72時間後に初めて交換し、次に、3〜4日毎に交換する。この方法で単離すると、細胞は2〜3週間後にコンフルエントに成長し、次に、それをトリプシン処理により6,000個細胞/cm2培養表面の細胞密度で新たな培養容器に移す(継代1)。約1週間後、再び細胞をトリプシン処理する(継代2)。ヒト間葉系幹細胞のこの培養物の均一性を、FACS分析により確かめる。FACS分析では表面抗原のエンドグリンとALCAMが同定されるが、表面抗原のCD34、CD45およびCD14は同定されない。
間葉系幹細胞および前駆細胞に対する、軟骨由来形態形成タンパク質−1(CDNP1または成長因子および分化因子−5、GDF5)および軟骨由来形態形成タンパク質−2(SDNP2または成長因子および分化因子−6、GDF6)などの成長因子および分化因子の走化効果は、既に記載されている[前記特許文献6:独国特許出願公開第19957388号明細書]。間葉系幹細胞および前駆細胞を動員するためのストローマ由来因子−1α(SDF1−α)またはインターロイキン−8(IL8)などのケモカインの走化効果または使用も記載されている[独国特許出願公開第10333901号明細書]。
驚くべきことに、Bにおいて記載した試験方法によるヒト血清の試験は、ヒト血清が、成長因子および分化因子およびケモカインと比べて、インビトロでヒト間葉系幹細胞および前駆細胞に対して有意により強い走化効果を有することを示した。異なる処方(ダイエット培地中またはヒアルロン酸中)のヒト血清により動員されたヒト間葉系幹細胞および前駆細胞の細胞カウントの平均を、対応する標準偏差と一緒に図2に示す。処方に依存して、最小2,135個(PGA−HA lyo.+HS)および最大10,332個(5% HS−HA−培地)のヒト間葉系幹細胞および前駆細胞がヒト血清により動員された。走化因子としてダイエット培地中にヒト血清を含まないヒアルロン酸における試験は、平均24個(HA培地)および平均48個(PGA−HA lyo.+NaCl)のヒト間葉系幹細胞および前駆細胞が動員されたことを示した。
アルファ・リサーチ・スイス GmbH(Alpha Research Switzerland GmbH)により(登録商標)PDA−ソフト フェルト(PDA−Soft Felt(登録商標))で市販されているポリグリコール酸フリースを、20mm×15mm×1.1mmの寸法に切断した。この材料に、実施例1記載の10% 血清含有ヒアルロン酸混合物を染み込ませ、次に、乾燥させた。乾燥をまず−20℃で、次に、凍結乾燥機にて16時間行った。1〜2mlの生理食塩水溶液に10分間浸すことにより、フリースをもどした。
Claims (19)
- (i)フリースまたはフェルト構造物、スポンジ、詰め物、ウール、ヒモ、規則的に配列された繊維束およびランダムな繊維束、ならびにこれらの組合せからなる群より選択される、生物学的かつ医薬的に許容される材料で作られた結合力のある開放多孔性構造形成マトリックスおよび(ii)血清を含む無細胞移植片であって、マトリックスの少なくとも片側に適用されるか、および/または少なくとも部分的にそれを貫通するゲルをさらに含有する、無細胞移植片。
- マトリックス材料が吸収性または非吸収性である、請求項1に記載の無細胞移植片。
- マトリックスが、コラーゲン、ヒアルロン酸、キトサン、キチン、多糖、セルロースおよびそれらの誘導体などの天然および合成ポリマー、タンパク質、ポリペプチド、ポリグリコール酸、ポリ乳酸、ポリ(グリコリド、乳酸塩)、カプロラクタム、および金属の酸化物、炭化物、窒化物および炭窒化物などのセラミック材料;金属の、ハロゲン化物、水酸化物、リン酸塩、硫酸塩などの鉱物、リン酸カルシウム、アパタイト、ヒドロキシルアパタイト;チタン、アルミニウム、金、銀、ステンレス鋼などの金属およびそれらの混合物からなる群より選択される材料である、請求項1または2に記載の無細胞移植片。
- ゲルが天然または合成ヒドロゲルである、請求項1に記載の無細胞移植片。
- ゲルがマトリックスより低い剛性のものである、請求項1または4に記載の無細胞移植片。
- ゲルが、多糖、ポリペプチド、ヒアルロン酸、フィブリン、コラーゲン、アルギン酸塩、アガロースおよびキトサン、ならびにそれらの混合物からなる群から選択される、請求項1、4または5のいずれか一項に記載の無細胞移植片。
- ゲルが、ヒアルロン酸である、請求項6に記載の無細胞移植片。
- 血清が、自系、同種または異種性である、請求項1〜7のいずれか一項に記載の無細胞移植片。
- 血清が、さらに少なくとも1種類の要素を添加すること、および/または少なくとも1種類の血清成分を除去することにより任意に修飾される、請求項8に記載の無細胞移植片。
- 成長因子、分化因子、ホルモン、ケモカイン、サイトカイン、細胞接着分子、走化因子、酵素、酵素インヒビター、補酵素、鉱物、脂肪、脂質、糖類、医薬物質、緩衝物質、安定剤およびビタミンからなる群から選択される1種類以上の要素をさらに含有する、請求項1〜9のいずれか一項に記載の無細胞移植片。
- ホルモン、成長因子および分化因子が、インスリン、PDGF、IGF、GMCSF、GDF5、GDF6、FGF、BMP2、BMP4、BMP7、IL8、SDF1−α、EGFまたはそれらの組合せである、請求項10に記載の無細胞移植片。
- マトリックスおよびゲルが血清と接触されることによる、請求項1〜11のいずれか一項に記載の無細胞移植片の製造方法。
- 接触が、滴下、軟化、含浸または浸漬により達成される、請求項12に記載の方法。
- ゲルが、まずマトリックスに取り込まれ、および/またはそれに適用され、次に、血清と接触される、請求項12または13に記載の方法。
- ゲルとマトリックスとの組合せならびに他の任意の構成物質が、接触前または後に乾燥される、請求項12〜14のいずれか一項に記載の方法。
- 移植片が乾燥状態から元に戻される、請求項15に記載の方法。
- 有効成分として請求項1〜11のいずれか一項に記載の無細胞移植片を含む、組織再生用組成物。
- 組織が、間葉組織である、請求項17に記載の組成物。
- 間葉組織が、軟骨および/または骨である、請求項18に記載の組成物。
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DE102005030614.4 | 2005-06-30 | ||
PCT/EP2006/006281 WO2007003324A2 (de) | 2005-06-30 | 2006-06-29 | Zellfreies transplantat aus matrix und serum |
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EP1933767B1 (de) | 2013-04-03 |
DE102005030614B4 (de) | 2014-05-08 |
ES2419160T3 (es) | 2013-08-19 |
HK1117028A1 (en) | 2009-01-09 |
AU2006265361A1 (en) | 2007-01-11 |
IL188305A (en) | 2012-01-31 |
US9125871B2 (en) | 2015-09-08 |
US20080206302A1 (en) | 2008-08-28 |
WO2007003324A2 (de) | 2007-01-11 |
CN101184450B (zh) | 2013-03-13 |
CA2606622A1 (en) | 2007-01-11 |
CN101184450A (zh) | 2008-05-21 |
BRPI0613123A2 (pt) | 2010-12-21 |
EP1933767A2 (de) | 2008-06-25 |
CA2606622C (en) | 2011-05-17 |
AU2006265361B2 (en) | 2009-10-22 |
BRPI0613123B8 (pt) | 2021-06-22 |
RU2404820C2 (ru) | 2010-11-27 |
BRPI0613123B1 (pt) | 2018-10-30 |
JP2008541905A (ja) | 2008-11-27 |
DE102005030614A1 (de) | 2007-01-11 |
IL188305A0 (en) | 2008-04-13 |
RU2008103337A (ru) | 2009-08-10 |
WO2007003324A3 (de) | 2007-08-16 |
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