JP2022526302A - 間葉系幹細胞-ヒドロゲルを含有する注射用組成物、並びにその製造、凍結及び解凍方法 - Google Patents
間葉系幹細胞-ヒドロゲルを含有する注射用組成物、並びにその製造、凍結及び解凍方法 Download PDFInfo
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Abstract
Description
脂肪組織は、通常の脂肪吸引術で得ることができるが、これに限定されるものではない。
1)細胞-フィブリングルーヒドロゲルビーズの製造
実施例1で得られた脂肪由来間葉系幹細胞1~3×105個/mLにトロンビン溶液を添加した。1.8~90mg/mLのフィブリノゲンを準備した。ディスペンサを用いて培養容器にそれぞれ1~10uLの容量のフィブリノゲンと細胞-トロンビン溶液を点滴し、細胞を含むフィブリングルーヒドロゲルビーズ(以下、細胞-ヒドロゲルビーズ)を製造した。
細胞-ヒドロゲルビーズが培養容器上で完全に固まったら、そこに細胞培養培地を添加し、その後37℃の5%CO2インキュベータで4~8日間培養した。半球形の形態を示すことが確認された。
また、2)の培養容器付着培養方法に代えて浮遊培養方法を用いてもよい。細胞-ヒドロゲルビーズが完全に固まったら、培養容器の底からビーズを取り出し、培養容器に移した。細胞培養培地を添加してビーズを浮遊させ、その後37℃の5%CO2インキュベータで4~8日間培養した。なお、浮遊培養は、大容量の培養が容易であるという利点を有する。
培養液を除去し、培養容器から細胞-ヒドロゲルビーズを回収した。回収したビーズは、10%~20%DMSOを含むヒト血清アルブミンと1:1の比率で混合し、その後-80℃で凍結保存した。
実施例2で培養、洗浄、凍結、解凍した細胞-ヒドロゲルビーズを顕微鏡で観察した結果、ビーズ内に細胞が均質に分布することが確認された(図1)。次に、実施例2で培養、洗浄、凍結、解凍した細胞-ヒドロゲルビーズに酵素を添加してフィブリングルーを溶解し、その後細胞を取得した。トリパンブルーで染色して細胞数及び細胞生存率を分析した結果、1ビーズ当たり約15,000個の細胞が含まれており、細胞生存率は95%以上であった。
間葉系幹細胞は、培養中に様々な活性因子を分泌することが知られている。よって、細胞-ヒドロゲルビーズ製造工程で細胞から分泌される活性因子がビーズ内にキャプチャされているか活性因子を確認するために、実施例2で培養、洗浄、凍結、解凍した細胞-ヒドロゲルビーズに酵素を添加してフィブリングルーを溶解した溶出液を採取し、細胞-ヒドロゲルビーズ内の活性因子を分析した。
間葉系幹細胞は、分泌作用(paracrine action)により抗炎症効能、抗細胞死効能、細胞増殖促進効能を有することが知られている。
実施例2で培養、洗浄、凍結、解凍した細胞-ヒドロゲルビーズ30個をマウスの左側、右側の2カ所に皮下注射し、その後の体積変化を7日間測定した。
代表的な筋骨格系疾患である骨関節炎は、軟骨細胞死によりさらに悪化することが知られている。よって、実施例2で製造した細胞-ヒドロゲルビーズの軟骨細胞死抑制能を確認した。
ヒト単核球細胞をホルボール12-ミリスタート13-アセタート(phorbol 12-myristate 13-acetate;PMA)で24時間処理してマクロファージへの分化を誘導し、その後実施例2で製造した細胞-ヒドロゲルビーズを添加し、次いで48時間追加培養した。その後、上清を回収して前炎症(pro-inflammatory)の特性を有する活性化されたM1マクロファージから分泌されるTNF-α、及び抗炎症(anti-inflammatory)の特性を有する活性化されたM2マクロファージから分泌されるIL-10の量を酵素結合免疫吸着法(enzyme-linked immunosorbent assay;ELISA)で測定した。
Claims (19)
- 細胞及びヒドロゲルを含み、
ビーズ(bead)の形態であり、
前記細胞及びヒドロゲルは、直径が0.1mm以上5mm以下である
細胞-ヒドロゲル組成物。 - 細胞及びヒドロゲルは、直径が1mm以上4mm以下である、請求項1に記載の組成物。
- 細胞は、幹細胞、体細胞及び生殖細胞からなる群から選択されるいずれかである、請求項1に記載の組成物。
- ヒドロゲルは、フィブリングルー、ヒアルロン酸、ゼラチン、コラーゲン、アルギン酸、キトサン、セルロース、ペクチン、2-ヒドロキシエチルメタクリレート誘導体及びその共重合体、ポリエチレンオキシド並びにポリビニルアルコールからなる群から選択される1種または2種以上の複合体である、請求項1に記載の組成物。
- 請求項1~4のいずれかに記載の組成物を有効成分として含む、筋骨格系疾患、瘻孔性疾患または炎症性疾患の予防または治療用薬学的組成物。
- 前記筋骨格系疾患は、関節の外傷、骨の疾患、筋肉の弱化、関節の神経損傷による関節の外傷、骨の疾患、筋肉の弱化、関節の神経損傷による筋炎、筋筋膜性疼痛症候群、腱炎、腱鞘炎、滑液包炎、結節腫、手根管症候群、ギヨン管症候群、手首の腱炎、手腕振動症候群、ばね指、ガングリオン、白蝋病、レイノー症候群、外側上顆炎、内側上顆炎、橈骨管症候群、尺骨管症候群、肘頭部滑液包炎、正中神経絞扼障害、肩インピンジメント症候群、癒着性肩関節包炎、変性性関節炎、頭部前方位姿勢、頸部神経根症、腰仙部挫傷、椎間板ヘルニア、脊椎分離症、脊椎すべり症、変形性腰椎症、変性疾患、尿失禁症、靭帯及び腱損傷からなる群から選択されるいずれかであることを特徴とする、請求項5に記載の筋骨格系疾患、瘻孔性疾患または炎症性疾患の予防または治療用薬学的組成物。
- 前記炎症性疾患は、アトピー性皮膚炎、全身性エリテマトーデス、ループス、凍瘡性狼瘡、結核性狼瘡、ループス腎炎、栄養障害型表皮水疱症、乾癬、リウマチ熱、関節リウマチ、腰痛症、線維筋痛症、筋膜疾患、未分化脊椎関節症、未分化関節症、関節炎、炎症性骨溶解、反応性関節炎、骨関節炎、強皮症、骨粗鬆症、ウイルスまたはバクテリア感染による慢性炎症疾患、大腸炎、潰瘍性大腸炎、炎症性腸疾患、真菌症、熱傷、外科または歯科手術による傷、糖尿病性足部潰瘍、1型糖尿病、2型糖尿病、潰瘍性皮膚疾患、副鼻腔炎、鼻炎、結膜炎、喘息、皮膚炎、炎症性膠原血管病、糸球体腎炎、脳炎、炎症性腸疾患、慢性閉塞性肺疾患、敗血症、敗血症性ショック、肺線維症、アテローム性動脈硬化、心筋炎、心内膜炎、心膜炎、嚢胞性線維症、橋本病、バセドウ病、ハンセン病、梅毒、ライム病(Lyme disease)、ボレリア症(Borreliosis)、神経ボレリア症、結核、サルコイドーシス(Sarcoidosis)、黄斑変性、ぶどう膜炎、過敏性腸症候群、クローン病、シェーグレン症候群、慢性疲労症候群、慢性疲労免疫不全症候群、筋痛性脳脊髄炎、筋萎縮性側索硬化症、パーキンソン病、多発性硬化症からなる群から選択されるいずれかであることを特徴とする、請求項5に記載の筋骨格系疾患、瘻孔性疾患または炎症性疾患の予防または治療用薬学的組成物。
- 請求項1~4のいずれかに記載の組成物を含む注射剤。
- 前記注射剤は、経皮注射、皮下注射、筋肉内注射、粘膜下注射及び腹腔注射からなる群から選択されるいずれかにより投与されることを特徴とする、請求項8に記載の注射剤。
- (a)細胞を培養するステップと、
(b)前記培養した細胞とヒドロゲル溶液を混合して0.1mm以上5mm以下の細胞ヒドロゲルビーズを形成するステップと、
(c)前記細胞ヒドロゲルビーズを培養するステップとを含む、細胞-ヒドロゲル組成物の製造方法。 - ヒドロゲルは、フィブリングルー、ヒアルロン酸、ゼラチン、コラーゲン、アルギン酸、キトサン、セルロース、ペクチン、2-ヒドロキシエチルメタクリレート誘導体及びその共重合体、ポリエチレンオキシド並びにポリビニルアルコールからなる群から選択される1種または2種以上の複合体であることを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- ヒドロゲルはフィブリングルーであることを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- フィブリングルーは、1.8~90mg/mLの濃度のフィブリノゲンを含むことを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- 細胞ヒドロゲルビーズは、1mm以上~4mm以下であることを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- ステップ(c)の細胞ヒドロゲルビーズを培養した後に、凍結及び解凍するステップをさらに含むことを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- ステップ(c)の後に、細胞-ヒドロゲル組成物を注射器に充填するステップ(d)をさらに含むことを特徴とする、請求項10に記載の細胞-ヒドロゲル組成物の製造方法。
- 薬学的に有効量の
細胞及びヒドロゲルを含み、
ビーズ(bead)の形態であり、
前記細胞及びヒドロゲルは、直径が0.1mm以上5mm以下である細胞-ヒドロゲル組成物を個体に投与するステップを含む、筋骨格系疾患、瘻孔性疾患または炎症性疾患の予防または改善方法。 - 薬学的に有効量の
細胞及びヒドロゲルを含み、
ビーズ(bead)の形態であり、
前記細胞及びヒドロゲルは、直径が0.1mm以上5mm以下である細胞-ヒドロゲル組成物を個体に投与するステップを含む、筋骨格系疾患、瘻孔性疾患または炎症性疾患の治療方法。 - 筋骨格系疾患、瘻孔性疾患または炎症性疾患の予防または治療用薬学的組成物として用いる、
細胞及びヒドロゲルを含み、
ビーズ(bead)の形態であり、
前記細胞及びヒドロゲルは、直径が0.1mm以上5mm以下である細胞-ヒドロゲル組成物の用途。
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