JP2010529177A - 接着分子のグラフト鎖を共有結合させて変性したコラーゲンスキャフォールドと、その収縮細胞の組織工学および胸部及び心臓血管治療への応用 - Google Patents
接着分子のグラフト鎖を共有結合させて変性したコラーゲンスキャフォールドと、その収縮細胞の組織工学および胸部及び心臓血管治療への応用 Download PDFInfo
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Abstract
Description
本発明は特に、被覆コラーゲン支持体、特に組織回復および再生医学用の被覆したコラーゲン支持体に関するものである。
(1) 接着分子または生物学的薬剤分子(例えばプロテオグリカン、成育因子またはサイトカイン)の支持体(コラーゲンの場合、アクセス可能基チオール、アミンまたはカルボキシルを有する)に対する接着、定着を改善する、
(2) 系中(インサイチュウ、in situ)での細胞発育に悪影響を及ぼす毒性物質を生じない、化学反応による架橋によってコラーゲン スキャフォールドの生体親和性を改善する。
本発明は、支持体またはスキャフォールド(フランス語ではechafaudage)または三次元スキャフォールド(これらの用語は互いに同様な意味で使用する)を製造することにある。
本発明の三次元スキャフォールドは液相で形成でき、この液相は頒布後に、賦活後または賦活なしで、固相(例えば溶液、ペースト、ゲル、懸濁コロイド、プラズマ)に変換できる。
本発明の三次元スキャフォールドは顕微鏡構造的に自発的に集合可能な疎水性および親水性のアミノ酸から成るヒドロゲルから成ることができる。
本発明の三次元スキャフォールドはゲルまたは界面活性剤にすることができる。
スキャフォールドが界面活性剤または「インテリジェントエージェント」である三次元スキャフォールドは、分子レベルで局所的相互作用による大規模な自発的集合構造から成る生物学的材料である。
種類の異なる複数の3Dスキャフォールドをシーケンシャル、その他の方法で積み重ねることができる。
本発明の三次元スキャフォールドはコラーゲン(I、II、Ill、IV、V、VI、VII、Xlおよびその他のコラーゲン)から成り、また、種々の種類を組合せることができる。「コラーゲン」という用語には不溶性コラーゲン、可溶性コラーゲン、コラーゲン分子の末端をコラゲナーゼ以外のプロテアーゼを用いてテロペプタイト除去して得られるアテロ(atelo)コラーゲンが含まれる。三次元コラーゲンスキャフォールドは自己、同種または異種由来の正常組織でもよい。この組織は脱細胞化(de細胞化)されていてもよく、また、物理的および/または酵素処理(例えばコラゲナーゼ)および/または化学的に、セこれらを組合せて変性されていてもよい。コラーゲンは尿管、心膜、例えばブタ腸粘膜下の「SIS」(参照文献83、84)、血筋、腱、筋膜、脱細胞化腱膜、アミノ型メンブレン、硬膜、心臓弁、その他のような自己、同種または異種由来のコラーゲン含有組織から精製できる。また、コラーゲンの合成コピー、例えばポリマー繊維またはフィブリル形成ペプチドでもよい。
接着性分子は化学的にフィブリノーゲンまたはフィブリンに結合できおよび/または、例えばコラーゲンゲルとフィブリンの場合、調整物中に組み込まれるコラーゲン成分中に含まれる。
RGD/RGEペプチドのような接着分子のコラーゲンスキャフォールドへの共有結合カップリング、または、スキャフォールドがコラーゲンから作られている、および/または、チオール、アミンまたはカルボキシルのアクセス可能な基を含む場合にはプロテオグリカン、成育因子またはサイトカインのような生物学的薬剤への共有結合カップリング
接着分子で官能化したコラーゲンスキャフォールドの収縮性組織の製造での使用
収縮性細胞
各タイプの細胞は平滑筋細胞、骨格筋細胞または心筋細胞として完全分化前後に収縮活動を有する。予備分化したまたは未分化の胎生期幹細胞(分化試薬は例えば成育因子または成育因子の組合せにすることができる。FGF、TGFβ、BMP-2、SDF 1タイプ、その他の成育因子の培地からのいくらかのファクタの除去または阻害、酸素圧低下、電気刺激、凝固、機械応力のような物理条件)も収縮性細胞への分化を促進する能力を示す。髄骨細胞(造血性細胞または間葉系細胞)、循環血液から分離した細胞(さい帯血から分離した細胞を含む)。また、収縮潜在細胞は、分化した組織(胎児または成体組織)、筋組織(筋芽細胞または心筋生成細胞)、胎仔または大人の分化組織(肝臓、膵臓、心筋、肺臓、その他)、羊水、遺伝子改質細胞等から単離する。
この実施例では従来から使われている分化した収縮性細胞の新生ラット心筋ミオサイト(生後二日目のラット心室の消化で得た)を接着ペプチドで官能化した(またはしていない)コラーゲンマトリックスに配置した。コラーゲンマトリックスはDHTで得た。以下の実施例はUltrafoam(登録商標)(Bard)タイプの商用マトリックスであるが、他のタイプのコラーゲン成分から成るマトリックスを使用することもできる。すなわち、1×107細胞/cm3の多数の細胞をコラーゲンマトリックスのマトリックス中に置いた。比較として、心筋組織中の心臓のミオサイトは組織容積が0.5〜l×108心筋ミオサイト/cm3である(M. Radisic et al 2003参照)(参照文献102)。接着ペプチドで改質したコラーゲンスキャフォールド(寸法:直径8mm×厚さ×5mm)に1.5×107細胞/cm3濃度で2×106の心臓ミオサイトを種付けした。細胞を付けた直後にマトリックスを1000回転/分で6分間、遠心分離して、交換効率と細胞の分布を均一化にした。固定しないでペレット中に残った細胞は再びマトリックス上に堆積させた。
次に、細胞化したマトリックスを12-ウエルプレートに移し、10%馬漿液を使用しないウシ胎仔血清リッチな従来の培地DMEM 2m1(Eagle培地をダルベッコで修正)を用い、バイオリアクタなしに静的に培養した。24時間後、5%のウシ胎仔血清のみを含み、トランスフェリン(10mg/mI)、インシュリン(1mg/mI)およびセレニウムを含むDMEM培地に変えた。培地は1日に2回変え、8日間培養した。Matrigel(登録商標)タイプの細胞間マトリックスは全く必要無かったことを強調しておなければならない。また、電気的刺激または機械応力のような物理的刺激や、バイオリアクタや、高濃度の馬漿液等の異種漿液を使用せずに、下記の結果が得られた。
細胞化されたマトリックスを10%ホルマリン中で8日間固定し、パラフィンに埋め込み、従来の組織学的分析を実行した。構造解析のために5μmの横断面をHES(haematoxylin-eosin-saffron)で染色し、細胞数および分布を求めた。細胞化したマトリックスの一部を液体窒素で凍結し、免疫ラベル化を行なった。解凍後、3%ウシ血清アルブミンを含むPBSで飽和したトリトンX-100で断片を透析した(permeabilized)。次に、蛍光標識剤(Alexa)に共有結合した主抗体および第2抗体と一緒に上記断片を培養した。すなわち、RGD修正されたマトリックスをalex-546(分子プローブ)と共役結合したハツカネズミ抗α‐アクチニン抗体(希釈度1:500を使用(シグマ))とハツカネズミ第二抗体(1:300希釈)と一緒に培養した。細胞核はDAPI特異的ラベル化された。
接着分子で官能化したマトリックスに血管内皮細胞を組合せたインビトロ脈管形成誘導
他のタイプの製造方法では、対象細胞、例えば血管内皮細胞(成熟細胞または原体細胞)を接着分子(好ましくはROD単位)で官能化した3D-コラーゲンマトリックスに収縮性細胞や繊維芽細胞、ケラチン合成細胞、収縮性細胞、遺伝子改質細胞等の他タイプの細胞(これらは独立して使用できる)の存在下または非存在下で移植する。この支持体は血管内皮細胞と同様に組合せた細胞群の生残および分化を促進する。上記細胞群は収縮性細胞と組合せてまたは独立して使用できる。この支持体は初めに細胞群と組合せずに使用し、後で細胞が支持体にコロニーを作るようにすることもできる。血管内皮細胞は3D-支持体に移植した収縮性細胞の生残と分化を促進し(DA Narmoneva、et. al 2004)(参照文献32)、筋−骨格(musculo-skeletal)組織のインビトロ予備血管化(pre-vascularization)によって移植後の生残率が改良されることが証明されている(S. Levenberg andaL 2005)(参照文献101)。
非常に多数の収縮性細胞すなわち約0.5〜10×107細胞/cm3の収縮性組織を必要とする収縮性組織に対して、血管内皮細胞に必要な数は約106細胞/cm3とはるかに少ない。成熟したハツカネズミの分化した血管内皮細胞(Arbiser et al 1997に記載)をMile Svenl(MS1)コラーゲンマトリックス(ATCC #CRL-2279)に移植した。接着分子、好ましくはROD単位で官能化したコラーゲンマトリックスタイプのスキャフォールドとしないもの(RGD+(TR)またはRGD-(T))に、異なる濃度のMS1細胞を付け、さらに4mM L−グルタミン、1.5のg/I重炭酸ナトリウム、4.5g/lのグルコース、1mMのソジウムピルベート、ペニシリン、ストレプトマイシンおよび5%ウシ胎仔血清(FCS)を含むDMEM(Hyclone、Logan, Utah)中で12-ウエルプレート中で37℃で3〜6週間の期間、5%のCO2気圧下で培養したRGEのようなアゴニスト/アンタゴニストペプチドも加えた。電子顕微鏡でインビトロでの脈管形成の成長を観察した。普通の顕微鏡の低倍率では脈管発生は見られず、脈管構造の存在は高倍率の電子顕微鏡(EM)でしか見られない。
官能化コラーゲンスキャフォールド中で薬剤を分泌可能な遺伝子で改質した移植細胞の可能性
以下の実施例では、マトリックスに移植した細胞を遺伝子的に改質して生物学的製剤、例えば脈管の形成、移動、生残、増殖、アポプトーシス、分化、劣化および細胞間マトリックス発生制御、免疫、炎症腫瘍反応制御、その他に関係する製剤を放出できるようにした。収縮性細胞、例えば筋芽細胞を血管新生に関与する遺伝子、例えばVEGF、アンギオテンシン等で遺伝子操作して移植後の組織の品質をより良くすることは可能である(D.E. Coppi and al. 2005)(参照文献109)。本実施例では、内皮タイプの細胞(MS1)を活性遺伝子Ras+を含むウイルスのトランスフェクショで改質した。Ras/Map Kinase経路は血管新生を制御する制御するための重要な賦活経路でることは報告されている(Ilan et al 1998)(参照文献36)。MS1 Ras+細胞はSEVN1 ras (SVR)(ATCC #CRL-2280)として公知である(Arbiser,1997)(参照文献110)。SVR細胞([図5])を移植し、上記の種々のマトリックスで6週間培養した。本実施例が示すように、細胞の生物学的活性度は遺伝子操作で修正でき、しかも、その挙動および分化度はマトリックスを接着分子で官能化することによって影響される。血管内皮細胞をRasで修飾することで血管由来ポテンシャルが増加する。すなわち、脈管構造および基礎メンブレンの存在が観測され、基礎的コラーゲン・マトリックス(T)中でも単位mm2当たり約7つの脈管構造が見られる([図5a])。このタイプの細胞でも、これらの細胞を接着分子(TR)で官能化されたマトリックス中に置いた場合、脈管形成がより進む([図5b])。接着分子の存在によって量的(mm2当たりの脈管構造の数(40対7)、RGD+対RGD−)(p有意)([図5a])および質的(分岐導管の%、(75対10)、RGD+対RGD−)(p有意)([図5a])の両方でより発達した脈管形成が得られ、脈管の複雑さでは、特に核と細胞質の相互作用が少なく、各脈管内腔に関係する細胞の数が多い(4.5対3)RGD+対RGD−)(ns)([図5b])。
コラーゲン支持体に接着分子を共有結合で結合する効果の評価
支持体への固定の重要性を観測された効果から研究するために、収縮性細胞または血管内皮細胞の存在下でのコラーゲンスキャフォールドの可溶性RGD単位または単なるRGD単位吸着性を試験した。1〜1000μg/mlの高濃度のRGDを培地と組合せるか、各
の細胞を移植する前に24時間以上マトリックス上に吸着させた。全てのケースで分化でのROD単位の有利な効果と、血管内皮細胞または心臓ミオサイトの生残が見られた。さらに、細胞を接着ペプチドで変性したコラーゲンスキャフォールドで培養した場合でも、媒体に可溶な形のRGD単位が存在するとこの効果は抑制される([図5a])。
生物学的薬剤の存在下での接着分子で官能化したマトリックスの使用
成育因子のような上記薬剤のいくつかをコラーゲン支持体に吸着された培地とインビトロで単に組合せるか、我々が提案する手段を使用して(または使用しないで)共有結合で結合した(EJ Suuronen wt al 2003)(参照文献54)。マトリックスは成育因子を保持可能なプロテオグリカン等で官能化できる。上記薬剤の例は成育因子、成育因子安定化剤(「オリゴマー状再生剤」(RGTAs))、ケモキン、収縮促進剤、脈管形成促進剤、炎症反応制御剤、劣化制御剤または重合促進剤である。この薬剤は支持体上に置かれるか、その末端または心室リモデリングの制御または異常心筋を処理する付随デバイスに投与される。また、支持体は所定面積にこれらの薬剤を送達、濃縮または維持するために用いることができる。また、薬剤は天然または改質後の支持体と組合せた細胞によって作ることもできる。一般に、成育因子は1fg/ml〜1mg/ml(1-10nM)の濃度で使用される(EJ Suuronen and al. (2003))(文献番号54)が、他の濃度を使用することもできる。
VEGF(VEOF 164(RocD、Minneapolis, MN)が4ng/mlの濃度で存在すると、接着分子による官能化がなくても、MS1細胞の分化が誘発され、基礎的コラーゲンマトリックス(T)で脈管構造が形成される([図6a])。しかし、この構造の絶対数およびその複雑度レベルは低い(単位mm2当り平均3つ)ままである:単位管腔当り単に2.5+/−0.5([図6b])、厚壁導管(実質的に細胞質の延長なし)、構造の10%のみが分岐し([図6a])、分岐では単に2つの隣接細胞(n12)だけ。VEGFで得られる導管は完全には形成されず、脈管の血管外遊出を発達させる傾向があることは知られている。これに対してRGD単位(TR)が存在すると脈管構造密度が増加8.7+-0.7/mm2([図6a])し、その複雑度も同様に増加する:脈管内腔当りの細胞数 4+/-1.1、25%分枝、3.5の隣接内腔、常に分岐([図6a]-[図6b])。
RGDペプチドのような接着分子で官能化したコラーゲンスキャフォールドはそれと組合せた細胞に対して反アポプトーシス(apoptotic)効果を有する
インテグリンレセプタは生育環境への細胞接着に貢献する他に、アポプトーシスによる細胞死を制限して、生残する遺伝子の数を増加させるという重要な役割を有している(Meredith and al. 1997)(文献番号18)。すなわち、心臓ミオサイトのような付着性細胞の多くは周囲マトリックスとの接触が無くなると、細胞死する(D. Kuppuswamy et al 2002) (文献番号17)。この細胞死の一部は上記の相互作用の阻害にあると思われ、それが組織中に細胞を単独で注入してもほとんど効果がなく、約95%の高死亡率を誘発する理由であり、注入時に3D-マトリックスを使用することで生育環境が再形成されることの理由であろう。しかし、3D-支持体適切な機械特性も有していなければならなず、3D-系内で相互作用するためには特異的なリガンドが必要である。
グルタールアルデヒドでの固定とヘパリンのようなプロテオグリカンの使用またはゲニピンの使用とを組合せた非細胞毒処理−細胞療法によっるコラーゲンスキャフォールドの制御
コラーゲンを固定するための最も効率的な方法はグルタールアルデヒドによる化学的架橋である。しかし、グルタールアルデヒドは重合し、ゆっくり解重合し、細胞に毒性のあるグルタールアルデヒドを放出する。
本発明ではコラーゲンに対する炎症反応を2つの方法で減少できる。最初のアプローチでは組織をグルタールアルデヒドで固定し、遊離アルデヒド基をグリコサミノグリカンル(glycosaminonoglycan)(GAG)例えばヘパリン/ヘパランスルフェート、コンドロイチン硫酸、デルマタン硫酸を使用して不可逆的に中和する。GAGはマトリックスの水和度を制御することは知られているが、多くの成育因子のリガンドとしても働く。
グルタールアルデヒドを用いた固定はUltrafoam(登録商標)コラーゲンスキャフォールドを0.625%のグルタールアルデヒドを含むNaCl(50mM)緩衝液中で37℃で1月間培養して行なう。洗浄後、コラーゲンスキャフォールドを0.2%キトサン溶液(Sigma Aldrich)中に入れた後、1%グリシン(Sigma Aldrich)と0.02%ゲンタミシン硫酸(Sigma Aldrich)中に20℃で2週間置く。塩酸(1M、pH 2.0)の存在下で4℃で3時間、亜硝酸ナトリウムをヘパリン硫酸とを反応させて部分的に劣化したヘパリン溶液を作った。この溶液をNソーダでpH 7.4にし、この溶液とコラーゲン支持体とを12時間接触させる。得られたコラーゲン調整物をNaCl緩衝液(50mM)で洗浄した後、20℃で前日製造したNaCl緩衝液(50mM)中の1%ナトリウムシアノボロハイドライド溶液(Sigma Aldrich)と6時間接触させる。その後、コラーゲン調整物を再び洗浄し、1%グリシンと0.02%ゲンタミシン硫酸とを含む溶液中で最終使用時まで保存する。
新鮮または細胞化した組織をゲニピン(genipin)を使用して固着することは既に提案されている(Hsing-Wen、et. al.2003は米国特許で細胞質生物物質をゲニピンで化学処理している)。我々はこの著者が提案した手順に従った。PBS中0.625%のゲニピン(Biopproducts CO.、台湾)を使用した(pH 7.4、37℃、3日間)。
各種タイプのマトリックスを麻酔したラットの脊骨筋に注入した。10日後の組織学解析では基礎コラーゲンマトリックスが炎症細胞で大きく浸潤され、コラーゲン格子が健著且つ未熟に劣化し、マトリックスが貧弱な血管線維に置換しているのが示された。コラーゲン/ゲニピンマトリックスおよびコラーゲン-glut/GAGマトリックスでは浸潤はマトリックス末梢に限られていた。面白いことに、マトリックス内部への導管の挿入は制限されるが、これらのマトリックスはマトリックス近傍での脈管形成を発達を強く促進する。成育因子の吸着と提示を促進することが知られているプロテオグリカンがマトリックス中に存在することで脈管形成の局所的な強い誘起の理由の一部が説明できる。1ヵ月後、初期の直径が最も大きい(8mm)であった全ての16/16コラーゲンマトリックスが消えた。反対に、全てのコラーゲン-glut/GAGマトリックス、n=16またはコラーゲン/ゲニピンマトリックス、n=16は寸法が不変(p有意)で、細胞浸潤は末梢に限られる。それに加えて、この浸潤中では炎症細胞は多くはない。
コラーゲン-グルタールアルデヒド/GAG支持体またはコラーゲン/ゲニピン支持体へ接着分子を固定して官能化
この組合せで炎症および組織への免疫応答を制御し、対象細胞のコロニー化を選択することができる。
10日後の組織学解析で基礎コラーゲン・マトリックスが炎症細胞で大きく浸潤し、コラーゲン格子が大きく且つ未熟に劣化し、貧弱に血管化した線維でマトリックスが置換されていた。glut/GAG処理でマトリックスの初期細胞炎症が制限され、マトリックスの細胞浸潤および劣化が遅れ、脈管形成は末梢に限られる。極めて面白いことに、RGD単位のような接着単位(glut/PGAコラーゲンマトリックス)の存在下では、導管および周囲組織の細胞はマトリックス内部に、極めて迅速に、深く入り込み、移植から10日後には、マトリックス外部の2/3は既にコロニー化され、血管化している。螢光標識ISL-B4(分子プローブ)を血管内に注射する脈管形成動力学解析法を用いてマトリックスでの脈管形成を数量化した。その結果、マトリックスは血管化しており、この脈管形成は第2週から開始し、3週間後には約6%のプラトーができたことが確認された。より長い時間での他の実験では、この脈管形成はゆっくり進むことを確認したが、Matrigel(登録商標)マトリックスのような他のタイプの支持体で起ることとは逆に、この脈管形成は数ヶ月後に減少する傾向がない。マトリックスの脈管形成レベルは脊骨筋のような筋を囲んで観測し、比較しなければならない点に留意する必要がある。この脈管形成は約3%+/-1%を占める。
炎症細胞からではないマトリックス内の細胞コロニー化がある。このアプローチは3D-支持体細胞のコロニー化を阻止し、血管内皮細胞のような重要細胞を選ばれた選択した接着分子によって選択するための最初の処理を提案するので非常に重要である。接着ペプチドで変性したコラーゲン-glut/GAGマトリックス内での強いネオ-脈管形成の存在はこのタイプのインプラントの非常に優れた生体親和性を示し、低い毒性を示し、細胞治療での使用に適している。
RGDペプチドのような接着分子で官能化した(またはしない)架橋したコラーゲンスキャフォールドの細胞治療での使用
このタイプの支持体の生残と分化に対する移植細胞の能力を分析した。分化度合いの異なるヒトおよびヒト以外の細胞(幹細胞、始原細胞、成熟細胞、遺伝子操作した(またはしない)細胞)を異なるタイプのRGDペプチドで官能化した(またはしない)支持体に注入した。この支持体の細胞の脈管形成への貢献度を筋組織(骨格筋タイプ)用移植モデルでアセスし、この支持体に対する脈管形成の定量化分析法を開発した。
(1)ハツカネズミの成熟した血管内皮細胞MS1
(2)遺伝子操作で変性したマウスの成熟血管内皮細胞SVR
(3)分化した組織から単離したハツカネズミ幹細胞
我々は各種組織でハツカネズミの発達中の血管内皮細胞原体を単離し、特徴付け方法を最近報告した(S. Cherqui、SM.Kurian O. Schussler et al 2006)(文献番号111)。これらの前駆細胞(原体)はコラゲナーゼで酵素処理して消化した新生児ハツカネズミの肝臓エキスからの接着能力の低い細胞分画からを単離した。細胞はインビトロ培養の8日目に集めた。
(1)「HUVEC」として知られる臍帯静脈壁から単離したヒトの成熟血管内皮細胞
(2)さい帯血から単離したヒト起源の血管内皮細胞原体
これらの細胞は上記(Crisa et al 1999)およびHildbrand et al (2004)に記載の方法で製造した(参照文献112、113)。
異なるタイプの血管内皮細胞をグルタールアルデヒド/GAGで処理し且つRODペプチドのような接着ペプチドで改質した(またはしていない)マトリックス中に置いた。免疫欠陥ハツカネズミをペントバルビタールで麻酔し、上記マトリックスを脊骨筋に6週間までの期間で注入して8つのマトリックスを各ハツカネズミに植え付けた。同じ動物で異なる組合せでテストした。種々の時間でマトリックスを取出し、マトリックス中の脈管形成の定量化を行なった。
我々はインビボで脈管形成を定量化できる信頼のある再現性に優れた方法を開発した。導管をインビボで抗マウス血管内皮細胞蛍光ラベルル化剤MECA32(University of Iowa, USA)またはISL-B4(Vector Laboratories, Burlingame, CA)で標識化した。振動ブレート「Automatic Oscillating Tissue Slicer」(OTS-4000)(Electron Microscopy Sciences)を用いて厚い切片(200μm)を切断後、マトリックスの厚さ全体の所定組織容積の脈管形成をアセスするために透過光を使用し、通常の蛍光顕微鏡を使用して蛍光を調べ、蛍光強度をデジタル化した。蛍光強度に従って導管を識別できた。所定検査材料でイントラー−およびインター・オブザーババリアブリティーは10%以下であった。統計的な比較はANOVAタイプのテストまたはStudentテストを使用して行なった。
本発明のアプローチ方法は二重の効果を有している。第1の効果はプロ脈管形成(proangiogenic)特性を有する細胞を用いた初期脈管形成を促進、加速することであり、第2の効果は組織自体を分化可能な血管内皮細胞の細胞群へ集合して最適に変性された3D環境の導管を形成することである。これは全て初期ポスト移植虚血現象を制限し、虚血または壊死面積での脈管形成を改善するパラメータである。
Claims (15)
- 細胞治療、組織工学および胸部及び心臓血管の医学および外科分野の医学/外科デバイスで使用さる三次元スキャフォールドにおいて、
(a) 上記スキャフォールドの内容物(continu)の全部または一部がコラーゲンで形成され、
(b) 上記スキャフォールドのコラーゲンの内容物が接着分子の共有結合によって部分的または完全に変性(modifie)されている、
ことを特徴とする三次元スキャフォールド。 - 一種または複数の生物学的活性分子または薬剤を含むか、それと組合された請求項1に記載の三次元スキャフォールド。
- 細胞コンティンジェント(contingent cellulaire)を含む請求項1または2に記載のスキャフォールド。
- スキャフォールド特性を機械的応力、電磁場または電気刺激のような物理的処理で変性する請求項1〜3のいずれか一項に記載のスキャフォールド。
- 共有結合で結合される接着分子が化学処理、酵素処理、機械処理、熱処理またはこれらの組合せによって切断できる請求項1〜4のいずれか一項に記載のスキャフォールド。
- 接着分子/または生物学的活性剤を結合するスペーサ基の親水性、柔軟性および長さが、利用可能な空間を最適化し、提示(presentation)および対象細胞との相互作用を容易にするように選択される請求項1〜5のいずれか一項に記載のスキャフォールド。
- 生物学的活性な分子の第一アミン基を三次元スキャフォールド中に存在する第一アミン基に共有結合で一方向に結合するスルホ-LCSPDPのようなヘテロ二官能性カップリング反応剤を用いて接着分子の共有結合が実施された請求項1〜6のいずれか一項に記載のスキャフォールド。
- グルタールアルデヒドによる架橋、プロテオグリカンベースの処理およびシッフ塩基の還元反応処理のような種々の架橋方法で架橋できる請求項1〜7のいずれか一項に記載のスキャフォールド。
- プロテオグリカンと組合せて、または組合せずに、架橋がジェニピン(genipin)作用か、それと他の架橋方法とを組合せて得られる請求項1〜8のいずれか一項に記載のコラーゲン スキャフォールド。
- スルホ-LCSPDPのようなヘテロ二官能性のカップリング反応剤を用いて、接着分子を含む生物学的活性分子の第一アミン基を三次元スキャフォールド中またはそれと組合せた生物学的活性剤中に存在する第一アミンに共有結合で一方向に結合させるスキャフォールドの製造方法。
- (a)スキャフォールドの内容物(continu)の全部または一部をコラーゲンで形成し、
(b)スキャフォールドの内容物を部分的または完全に接着分子の共有結合によっ変性し、
(c)スキャフォールドをグルタールアルデヒドとシッフ塩基の還元剤とで架橋し、
(d)スキャフォールドをプロテオグリカンで処理するか、処理しない、
ことを特徴とするスキャフォールドの製造方法。 - (a)スキャフォールドの内容物(continu)の全部または一部をコラーゲンで形成し、
(b)スキャフォールドの内容物を部分的または完全に接着分子の共有結合によって変性し、
(c)得られたスキャフォールドをゲニピン(genipin)で架橋し、
(d)スキャフォールドをプロテオグリカンで処理するか、処理しない、
ことを特徴とするスキャフォールドの製造方法。 - 請求項1〜12のいずれか一項に記載の三次元スキャフォールドの、胸部および心臓血管外科および/または医学分野の各種デバイス、例えばバイオペースメーカー、局所的に脈管形成を改善し、生物学的バイパスを作るための細胞化冠状ステント、順応性および収縮性のバイオ弁、小寸法の冠状のグラフト、生育可能な弁、組織パッチ、弁部品、外科用固定具、液体または空気を密封装置、梗塞後支柱ネクローシス処理用小突起筋、人工血管、生物学的内部補助具を作るための電気刺激可能な収縮性人工血管、a) リモデリングを制御するか心室の拡張を制限する装置およびb) 心筋収縮を改善する装置と組合せた心筋条件処理装置、活性薬剤放出具、バイオ糊、三次元スキャフォールドと細胞とを組合せた異常肺の実質を再コロニー化し、再構成するための肺気腫処理装置、コラーゲン気管支のコイルおよびバイパスの透過性を改善するための装置、活性剤、特に腫瘍病理学的活性剤を気管支に放出し、他の呼吸器機能不全を治療する装置、胸部および心臓血管の分野での細胞治療および組織工学技術用スキャフォールドでの使用。
- (a)接着分子の共有結合によって部分的または完全に変性され、(b)一種または複数の生物学的活性分子を含むか、それと組合され、(c)筋の細胞治療で細胞と組合せが可能なことを特徴とするコラーゲンスキャフォールドの、平滑筋または骨格または収縮性組織の製造での使用。
- 請求項10または11または12に記載の方法で製造されたスキャフォールドの、細胞治療および組織工学での使用。
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JP2011087928A (ja) * | 2009-10-26 | 2011-05-06 | Tyco Healthcare Group Lp | 反応性外科用インプラント |
JP2015047076A (ja) * | 2013-08-29 | 2015-03-16 | 独立行政法人産業技術総合研究所 | 細胞培養基材、並びにそれを用いた骨芽細胞分化誘導方法及び骨芽細胞製造方法 |
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JP2019180420A (ja) * | 2017-01-31 | 2019-10-24 | 凸版印刷株式会社 | 三次元組織体及びその製造方法、並びに、三次元組織体の形成剤 |
JPWO2018143286A1 (ja) * | 2017-01-31 | 2019-11-07 | 凸版印刷株式会社 | 三次元組織体及びその製造方法、並びに、三次元組織体の形成剤 |
US20190351098A1 (en) * | 2017-01-31 | 2019-11-21 | Toppan Printing Co., Ltd | Three-dimensional tissue body, method for producing same, and formation agent for three-dimensional tissue body |
US11179495B2 (en) | 2017-01-31 | 2021-11-23 | Toppan Printing Co., Ltd. | Three-dimensional tissue body, method for producing same, and formation agent for three-dimensional tissue body |
JP7402152B2 (ja) | 2017-07-27 | 2023-12-20 | ユニバーシティー ヘルス ネットワーク | イン・ビトロおよびイン・ビボにおける組織伝導の増強のための導電性安息香酸系ポリマー含有生体材料 |
Also Published As
Publication number | Publication date |
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CA2692005C (fr) | 2017-04-18 |
US20100184183A1 (en) | 2010-07-22 |
US20160199538A1 (en) | 2016-07-14 |
US9289533B2 (en) | 2016-03-22 |
CA2692005A1 (fr) | 2009-01-15 |
FR2917293B1 (fr) | 2010-11-26 |
ES2665282T3 (es) | 2018-04-25 |
WO2009007531A3 (fr) | 2009-04-16 |
WO2009007531A2 (fr) | 2009-01-15 |
WO2009007531A4 (fr) | 2009-06-25 |
EP2157983A2 (fr) | 2010-03-03 |
EP2157983B1 (fr) | 2018-01-10 |
FR2917293A1 (fr) | 2008-12-19 |
JP5722033B2 (ja) | 2015-05-20 |
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