JP2021517121A - 注射可能な既製の軟骨、腱および靭帯修復組成物およびその使用方法 - Google Patents
注射可能な既製の軟骨、腱および靭帯修復組成物およびその使用方法 Download PDFInfo
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Abstract
Description
本明細書で使用する場合、単数形「a」、「an」、および「the」には、文脈が明らかにそうでないことを指示しない限り、複数への言及が含まれることに留意されたい。例えば、構成要素への言及は、複数の構成要素の組成物を含むことも意図されている。構成要素を含む組成物への言及は、指定されたものに加えて他の構成要素を含むことが意図されている。言い換えると、「a」、「an」、および「the」という用語は、数量の制限を示すものではなく、言及される項目の「少なくとも1つ」の存在を示すものである。各用語は、当業者によって理解されるその最も広い意味を企図しており、同様の目的を達成するために同様に動作するすべての技術的同等物を含むことが意図されている。
初期継代の拡大された脂肪由来幹細胞(ADSC)をLaCell LLCから得て、抗原性について徹底的に試験する。GMPグレードの成分を使用して細胞を拡大および継代する。4回目の継代後、ADSCを軟骨形成培地に導入し、そこでCMBが形成される。
in vitro軟骨欠損モデルを充填するCMB/ヒドロゲルの実現可能性および有効性を、凍結保存されたCMBおよび作りたてのCMBを使用して試験する。生存不能なウシ軟骨外植片(直径5mmおよび高さ5mm)において、直径3mmの全層軟骨欠損を作成する。CMBを、様々なヒドロゲルビヒクルを用いて欠損に挿入する。各ビヒクルは、I型コラーゲン、ヒアルロン酸、およびフィブリンの1つまたは複数を含み、ビヒクルの比較分析を行って最適なヒドロゲル組成を決定する。次に、ヒドロゲルビヒクルを欠損に押し込む(図4)。構築物を、上記のように、TGF−β3およびBMP−6を含む軟骨形成培地で最大5週間培養し、分析する。組織学的、生化学的および機械的分析を行う[19]。DNA、GAG、およびヒドロキシプロリン(コラーゲン)の含有量も測定する。
骨軟骨移植片からの成長因子の長期放出を持続させるために、制御放出技術を組み込んで試験する。試験サンプルでは、マイクロスフェアを使用して、軟骨形成を誘導および増強する成長因子を送達する。対照サンプルでは、マイクロスフェアを使用しない。
実施例1〜3のプロトコルを最適化し、適切な条件および成分を選択すると、CMB、ヒドロゲル、およびGF注入微粒子から作成した選択材料をin vitro軟骨欠損モデルで試験する。実施例1および2に記載のように、選択材料を外植片軟骨欠損モデルに注入し、機械的負荷の下で培養する。外植片は、外因性GFの捕足なしの軟骨形成培地で最大5週間育てる。実施例1および2に概説するように、得られた組織を機能性について評価する。さらに、培地へのGF放出を培地交換ごとに評価して、PTOAの長期処置に対するこれらプラットフォームの有効性をさらに判断する。組織学的、生化学的および機械的分析も実施して、コンポジット構築物の生物学的および機械的特性を評価する。成功基準は、欠損部における軟骨組織の形成、ならびに隣接する軟骨および軟骨下骨への組織の癒合によって決定する。
ADSCを介した軟骨形成に対する凍結保存の影響を、図1に概説するように試験した。図1では、CMB培養の2次元(2−D)または3次元(3−D)の段階で細胞を凍結保存した。2次元条件の場合、細胞を、(i)凍結保存なしでP4まで継代する(フレッシュ)、(ii)間質血管画分(SVF)を採取した直後に凍結保存し、解凍し、P4まで継代する(SVFクライオ)、または(iii)P1まで継代し、凍結保存し、解凍し、P4まで継代する(P1クライオ)のいずれかであった。3−D条件に関しては、CMBを、形成後維持して凍結保存しない(対照)、または培養3日後に凍結保存して凍結保存の1〜5週間後に解凍した。
細胞(フラスコ内の2D)に対する凍結保存の影響のさらなるアッセイを行った。対照「フレッシュ」、「SVFクライオ」、および「p1クライオ」CMBを上記の方法で図3に示すように調製した。培養28日後、「フレッシュ」、「SVFクライオ」、「p1クライオ」の各サンプルのCMBの直径を測定し、図4Aに示した。フレッシュCMBの直径は約1.9mmであり、SVFクライオCMBの直径は約1.7mmであり、PlクライオCMBの直径は約1.6mmである。
CMBペレット(ウェル内の3D)に対する凍結保存の影響のさらなるアッセイを行った。
軟骨形成CMBの細胞表面マーカーの分析をフローサイトメトリーによって行った。ISOに対する抗体を陰性対照として使用し、CD59およびCD90に対する抗体を陽性対照として使用した。HLAクラスII、CD40、CD80またはCD86の発現を試験した。また、CD34、CD45、CD73、CD90およびCD105の発現も試験した。図7Aにおいて、フローサイトメトリーの結果は、HLAクラスII、CD40、CD80、およびCD86の発現の陰性により、軟骨形成CMBの抗原性を示す。発現の陰性は、陰性対照として使用されるISO抗体でも見られ、一方、陽性対照として使用されるCD59およびCD90では発現の陽性が見られた。
I型コラーゲン、ヒアルロン酸、およびI型コラーゲン:ヒアルロン酸塩(4:1、1:1、1:4の比率)を、CMBおよび成長因子微粒子のための送達ビヒクルとして検討する。我々のヒドロゲル送達ビヒクルならびにCMBおよび微粒子のパラメーターの最適化のために、図8に示すように、外植片欠損モデルを模倣するシリコーンゴムリング法(内径5mm、厚さ2mm)を使用する。ヒドロゲルとCMBをシリコーン欠損に添加する。湿重量、DNA質量比、GAG質量比、およびコラーゲン質量比のパラメーターを図8の表に示しており、すべてのゲル製剤が、CMBを送達するのに適した選択肢である。各ヒドロゲルの濃度およびゲル化時間の最適化をシリコーン欠損モデルで行う。(i)コラーゲンおよび(ii)コラーゲン:ヒアルロン酸塩(1:1、4:1、1:4)を用いて送達されるCMBを充填したシリコーン欠損モデルおよび軟骨欠損モデルの両方で追加の最適化を行い、どの条件が軟骨の表現型および周囲軟骨との癒合の最良の組合せを与えるかを決定する。
薬物をCMB−ヒドロゲルの組合せに組み込んで、hADSC軟骨形成を誘導できるかどうかを試験した。薬物放出製剤は、薬物が軟骨分化培地に直接添加されるhADSC軟骨形成を誘導するために以前に使用された薬物補充法と同等であるように設計された。平均1〜10μmのサイズを有する粒子に、0.02%(w/w%)の薬物を装填した。80mgの薬物を含む微粒子を作製し、長期の薬物放出(最大35日)を試験して、hADSC軟骨形成をうまく誘導するのに必要な最適な微粒子濃度を決定した。経時的な薬物放出を、図10Aに記載の実験プロトコルを使用してアッセイした。
2つの薬物、TGF−β3とBMP−6を、CMB−ヒドロゲルの組合せに添加し、それらがex vivoモデルで軟骨欠損を充填するかどうか、および動的変形荷重(dynamic deformational loading)がGAGおよびコラーゲンの含有量に影響を及ぼすかどうかを試験した。動的変形荷重(1%の風袋荷重、それに続く1Hzでの1日3時間、週5〜7日の10%の表面間変形[Ng et al., Cell Mol. Bioeng., Sep. 1, 2009, 2(3):386-394])を用いてADSCを刺激して、軟骨細胞に分化させ、またグリコサミノグリカン、軟骨オリゴマータンパク質(COMP)、リンクタンパク質、ヒアルロン酸、およびコラーゲン(特に、II型コラーゲン、IX型コラーゲン、XI型コラーゲン)などの、軟骨分化誘導因子の産生を増加させた。動的変形荷重を負荷された軟骨充填材および対照軟骨充填材のGAG含有量およびコラーゲン含有量をアッセイした。結果を図11Aおよび11Bに示す。
様々な組成および濃度のヒドロゲルを、全層軟骨外植片欠損モデルにおいて保持時間およびゲル化時間について試験した。試験したゲル成分には、フィブリンのみ、およびコラーゲン/ヒアルロン酸の様々な組合せが含まれていた。様々なヒドロゲル組成物を外植片の欠損部に送達し、硬化させ、その後にPBS中において37℃で最大5日間攪拌することにより、ゲル保持能力を試験した。
軟骨構築物の質に対するCMBのサイズの影響を評価した。50K、100K、および250Kの細胞からCMBを作成した。次に、各CMBのサイズで構築物を作成し、4週間培養し、目視検査、組織学的検査、および定量評価のために採取した。目視検査は、すべての実験条件のサンプルが十分に融合したCMBを示すことを明らかにした。データを図15Aに示す。さらに、構築物は不透明であり、それは軟骨様品質の指標である。図15Bに示すように、H&Eの組織学的染色が目視観察を追認し、すべての群で融合したCMBを示した。軟骨形成マーカー、GAGおよびコラーゲンの組織学的染色は、実験条件間で同等の分化を示した。CMBのサイズが構築物の品質にどのように影響するかを特定するために、サンプルの湿重量、DNA、GAG、およびコラーゲンの定量も群間で比較した。データを図15Cに示す。すべてのパラメーターについて、値は群間で比較的一貫していた。これらの結果は、50K、100K、および250KのCMBのサイズが、すべて同等の軟骨品質をもたらし、軟骨充填材製品の製造の対象になり得ることを示す。
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Claims (32)
- a)間葉系細胞凝集体(CMB);および
b)ヒドロゲル;
を含む組成物。 - c)1つまたは複数の薬物または成長因子をさらに含む、請求項1に記載の組成物。
- ポリマーマイクロスフェアをさらに含み、1つまたは複数の薬物または成長因子がポリマーマイクロスフェアに封入されている、請求項1または請求項2に記載の組成物。
- 前記ポリマーマイクロスフェアが、乳酸・グリコール酸共重合体(PLGA)、ポリ(乳酸)(PLA)、またはPLGAとPLAの組合せを含む、請求項3に記載の組成物。
- 前記CMBが、結合組織細胞と軟骨細胞、腱細胞、靱帯細胞または半月板細胞を形成することができる前駆細胞とから選択される細胞を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記CMBが、軟骨、腱、靭帯または半月板から分離された細胞を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記細胞が、軟骨細胞、腱細胞、腱芽細胞、線維細胞または線維芽細胞である、請求項6に記載の組成物。
- 前記CMBが、間葉系幹細胞(MSC)、脂肪由来幹細胞(ADSC)、骨髄由来幹細胞(BMSC)、臍帯血幹細胞(UB−MSC)、神経堤幹細胞、人工多能性幹細胞、胚性幹細胞、および初代軟骨細胞から選択される幹細胞を含む、請求項5に記載の組成物。
- 前記細胞が、同種供給源または自家供給源に由来する、請求項5に記載の組成物。
- 前記細胞が、抗免疫原性および/または免疫抑制性である、請求項5に記載の組成物。
- 前記CMBが、約−1℃未満の温度で少なくとも1日凍結保存される、請求項5に記載の組成物。
- 前記CMBが、0℃〜30℃の間の温度で少なくとも1日低温保存される、請求項5に記載の組成物。
- 前記CMB中の細胞が、その細胞表面上に実質的または検出可能な量のヒト白血球抗原(HLA)クラスII、CD40、CD80、またはCD86を発現しない、請求項1〜12のいずれか一項に記載の組成物。
- 前記ヒドロゲルが、フィブリン糊、多血小板血漿(PRP)、I型コラーゲン、キトサン、ゼラチン、ポリエチレングリコールジアクリレート、ヒアルロン酸、ならびにフィブリン糊、PRP、I型コラーゲン、キトサン、ゼラチン、ポリエチレングリコールジアクリレート、およびヒアルロン酸の任意の組合せから選択される、請求項1に記載の組成物。
- 前記成長因子がTGF−βスーパーファミリーのメンバーである、請求項2に記載の組成物。
- 前記成長因子が、OP−1、OP−2、OP−3、TGF−β1、TGF−β2、TGF−β3、TGF−β4、BMP−1、BMP−2、BMP−3、BMP−4、BMP−5、BMP−6、BMP−8、BMP−9、BMP−10、BMP−11、BMP−12、BMP−13、BMP−15、BMP−16、BMP−17、BMP−18、DPP、Vg1、Vgr−1、60Aタンパク質、GDF−1、GDF−2、GDF−3、GDF−5、GDF−6、GDF−7、GDF−8、GDF−9、GDF−10、GDF−11、GDF−12、CDMP−1、CDMP−2、CDMP−3、NODAL、UNIVIN、SCREW、ADMP、NEURALからなる群より選択される形態形成タンパク質である、請求項2に記載の組成物。
- インスリン、トランスフェリン、ヒト血清アルブミン、プロリン、ウシ血清アルブミン、セレン酸、リノール酸、デキサメタゾン、およびアスコルビン酸のうちの1つまたは複数をさらに含む、請求項1〜16のいずれか一項に記載の組成物。
- 前記CMBが、単細胞を含む懸濁液中にある、請求項1に記載の組成物。
- 前記CMBはサイズが均一または不均一である、請求項1に記載の組成物。
- 前記組成物が注射可能である、請求項1に記載の組成物。
- 請求項1〜20のいずれか一項に記載の組成物を結合組織または結合組織の周囲の領域に投与することを含む、患者における結合組織欠損を治療する方法。
- 請求項1〜20のいずれか一項に記載の組成物を軟骨または軟骨の周囲の領域に投与することを含む、患者における軟骨劣化を予防する、または軟骨損傷、軟骨変性疾患もしくは軟骨障害を処置する方法。
- 前記軟骨が関節軟骨である、請求項22に記載の方法。
- 前記軟骨が非関節軟骨である、請求項22に記載の方法。
- 前記軟骨が、鼻軟骨、耳介軟骨、気管気管支軟骨、肋軟骨、半月板および椎間板からなる群より選択される、請求項24に記載の方法。
- 軟骨欠損、軟骨劣化、軟骨損傷、軟骨変性疾患または軟骨障害の部位に1〜20%(w/w)のグリコサミノグリカン(GAG)を含む組織を形成するのに有効である、請求項21〜25のいずれか一項に記載の方法。
- 軟骨欠損、軟骨劣化、軟骨損傷、軟骨変性疾患または軟骨障害の部位に少なくとも0.5%(w/w)のコラーゲンを含む組織を形成するのに有効である、請求項21〜25のいずれか一項に記載の方法。
- 軟骨欠損、軟骨劣化、軟骨損傷、軟骨変性疾患または軟骨障害の部位に少なくとも100kPaのヤング率および最大0.8の摩擦係数を有する軟骨を形成するのに有効である、請求項21〜27のいずれか一項に記載の方法。
- 軟骨欠損、軟骨劣化、軟骨損傷、軟骨変性疾患または軟骨障害の部位に軟骨を形成するのに有効であり、その軟骨は、前記部位またはその周囲の任意の隣接する軟骨および軟骨下骨組織と癒合する、請求項21〜28のいずれか一項に記載の方法。
- 請求項1〜20のいずれか一項に記載の組成物を使用して、in vitroまたはin vivoで軟骨組織を形成する方法。
- 請求項1〜20のいずれか一項に記載の組成物を、断裂もしくは破裂した結合組織に、または断裂もしくは破裂した結合組織の周囲の領域に投与することを含む、患者における断裂または破裂した結合組織を処置する方法。
- 前記結合組織が、靭帯、腱または半月板である、請求項31に記載の方法。
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