JP7430885B2 - 細胞播種基材の低温保存及び関連する方法 - Google Patents
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Description
本出願は、全ての目的のために参照によりその全体を本明細書に組み込む、2018年9月7日出願の米国仮出願第62/728,646号の利益を主張する。
該当なし
本出願は一般に、超薄基材を標的組織に移植するための器具及び方法に関し、超薄基材は、他の治療的処置の中でも、幹細胞療法のための幹細胞、マイクロバブル、及び薬物送達のための注入されたゲルの播種に適している。超薄基材は更に、細胞の再生可能な培養及び細胞を播種した後の低温保存に使用することができる。
細胞の損失又は損傷に関与するヒト疾患の範囲は、非常に広く、それだけには限らないが、眼疾患、神経変性疾患、内分泌疾患、心臓血管疾患、及び癌を含む。細胞療法は、患部組織又は損傷組織を治療するために細胞の使用を伴う。それは、多くの疾患、特に従来の薬理学的治療に反応しない個人に影響を与える疾患を治療する用意ができている技術の最先端に急速に台頭してきている。これらの疾患の多くは、長期の集中した標的領域治療の恩恵を受け、それは全身性副作用を減らすであろう。しかしながら、タンパク質治療薬等の特定の薬物は、高価であり、1バイアル当たり数千ドルかかり、終わりのない反復治療を必要とする。
説明された技術の実装形態は、ハードウェア、方法若しくはプロセス、又はコンピューターアクセス可能媒体上のコンピューターソフトウェアを含み得る。
いくつかの実施形態では、基材は、播種表面として機能する生体適合性ポリマーを含む。いくつかの実施形態では、基材は、他の材料と併せてパリレンを含み、他の材料は、生分解性又は非生分解性のいずれかである。いくつかの実施形態では、播種された細胞の生存度を向上させる1つ又は複数の特性を有するように、基材を処理する。例えば、いくつかの実施形態では、基材は、基材への細胞の付着を向上させるためのコーティングを更に含む。ある実施形態では、コーティングは、1つ又は複数のマトリゲル、ビトロネクチン、フィブロネクチン、及びレトロネクチン、又は誘導体化パリレンの層を含む。当業者に既知の他の細胞培養液及びその種々の組合せは、代用可能である。他の実施形態では、他のコーティング又は表面改質を用いて、基材への改善された細胞付着を達成及び/又は低温保存プロセス中及びその後における細胞及び基材の耐久性及び/又は生存度を改善する。例えば、いくつかの実施形態では、コーティングは、低温保存中、低温保存後、又は両方における細胞の生存度を向上させる。別の実施例では、基材の細胞増殖表面を酸素で処理して、親水性細胞増殖表面を作成する。他の表面処理は、酸素プラズマ処理、化学エッチング、及び追加のポリマー堆積を含む。追加のポリマー堆積は、その弾性(例えば200の破断点伸び(%))に関してパリレン-C、その高い酸素ガス透過性(cc.mm/m2日)に関してパリレン-N等、それらの機能的要求に応じて、異なるパリレン型を使用する場合に特に有用である。(Specialty Coating Systems社、KISCO株式会社)。更に、官能化パリレンは、表面に堆積させて、それだけには限らないが、(1)抗凝固特性を有し、それによって移植の血液適合性を高めるタンパク質であるR-ヒルジン、(2)骨芽細胞の付着を改善するためにフィブロネクチンを表面に共有結合させるアミン官能基、及び(3)組織の付着を促進する疎水性表面を形成するpNIPAM鎖(Tanら2010)を含む、活性な化学官能基を付与することができる。
小さな基材/膜(100mm2未満)、又は薄い基材/膜(50ミクロン未満)が、後の移植による要件である実施形態において、最小の質量では所定量の培養液内で浮かびやすくなるので、基材を標準的な培養ウェル内で維持することが困難であり、それによって基材が動き回り、播種された細胞が取り外される可能性がある。基材のそのような動きを防ぐ一方法は、蒸発乾燥によって膜を組織培養プレートに可逆的に付着させることである。多くの細胞培養プレートには蒸発を最小限にする追加の特徴があるので、これは直感に反するように見えるかもしれない(例えばThermoFisher Scientific社製 Nunc Edge 2.0 96-ウェル細胞培養プレートにおける滅菌水又は培養液で満たされる蒸発モート)。一実施形態では、膜を最初に、組織培養プレートのウェルに蒸発させる溶液(例えばDulbecco社のリン酸緩衝食塩水(DPBS))と一緒に配置する。膜がウェルの底で平らになり、膜の底とウェルの底の表面の間に液体の残留量が残るまで、DPBSをウェルからゆっくり取り出す。他の全ての該当するウェルで繰り返した後、組織培養プレートを乾燥させる。乾燥の種々の方法は、デシケーター、温度/湿度制御チャンバー、乾燥器でのベーク、又はクリーンルーム等の制御された部屋での放置の使用を含む。この乾燥フェーズ中、残留DPBSが蒸発し、それによって膜がウェルの底に付着し、それによって細胞増殖コーティング(例えばビトロネクチン)並びに細胞播種の適用がより容易になる。ウェル内の動きを制限することによって、既知のX、Y、及びZ軸を必要とし、通常2次元機能に限定される均一な播種に自動細胞播種機を使用することができる。細胞播種後、DPBSをウェルに導入することによって膜を可逆的に付着させ、膜をウェル底面から取り外し、培養のために別のウェルに移動できるようにする。他の実施形態では、pH、塩分、又は他の細胞増殖因子を否定的に変えない種々の他の溶液をDPBSの代わりに使用することができる。
基材に播種された細胞を低温保存する実施形態では、最適な低温保存生存度特性は、各製造段階で異なる。
種々の実施形態では、細胞の培養は、パラクリン、自己分泌、内分泌、及び細胞間の電気シグナル伝達で使用されるものを含む多くの細胞化学製品を生成することを示している。これらの化学製品は、細胞培養で見つけることができ、抽出及び分類された後、細胞培養添加剤としての潜在的な価値がある。細胞分泌物は、タンパク質、ホルモン、酵素、副産物、廃棄物、又はその組合せを含んでいてもよい。得られた因子の生の組合せ、それらの選択された組合せ、又は精製された形態は、以後、総称的に「標的上清」と呼ばれる。
低温休止(Cryo-hibernation)プロトコール
ある実施形態では、標準的な低温保存プロトコールの代替の低温休止プロトコールは、基材に播種された解凍細胞の生存度の増加を示している。低温保存プロトコールは、以下のとおりである。初期の制御された温度ランプダウンフェーズに続いて、播種された細胞の潜熱放出よりも低い第1の温度に達すると(0℃~20℃)、細胞は第1の期間、第1の温度に保たれる。第1の温度は、潜熱放出温度より低い任意の温度であり、-20、-30、-40、-50、-60、-70、-80、-90、又は-100℃であってもよい。第1の期間は、12時間、1日、7日、28日であり、温度を急激に変化させることなく細胞を低温保存状態に順応させるのに役立つ。この順応は更に、温度低下(-1℃/分以上)によって引き起こされる可能性がある微小引裂が基材に形成されるのを防ぐ。第1の期間後、低温保存した細胞を移し、第2の期間、保存温度で維持する。ほとんどの場合、保存温度は、便宜上-196℃(例えば液体窒素の温度)であるが、休止温度と同じ温度でもよい。ある実施形態では、第2の温度が得られるまで、毎分約-1℃~毎分約-30℃の制御された温度ランプダウンフェーズの温度低下速度、又はこの範囲内の任意の速度で、細胞が播種された基材を第2の温度に移すことも実施される。この特定の温度ランプダウンは、種々の要素(すなわち基材、少なくとも1つの細胞型、凍結保護溶液、及び低温保存容器)の均一な温度低下に役立つ。
hESC-RPE細胞の特定の実施形態では、種々の組合せの低温保存プロトコールをテストし、特定の細胞株を最適化した。特定の細胞株をテストしたが、上記の細胞株及び基材特性の主要因子を考慮したので、他のRPE細胞株についても同様の結果が予想される。
Claims (19)
- 基材上の細胞を低温保存する方法であって、
未成熟網膜色素上皮(RPE)細胞の単層が播種された生体適合性ポリマー基材を準備する工程であって、ポリマー基材が細胞播種表面を提供する、工程と;
i)未成熟RPE細胞の単層が基材上で90%~99%集密に達する場合、及びii)未成熟RPE細胞のほとんどが完全に色素沈着していない場合を識別する工程と;
識別されたら、細胞が播種された基材を、-20℃未満の第1の温度に達するまで、-1℃/分~-30℃/分の制御された温度低下速度に曝露する工程と
を含む、方法。 - 細胞が播種された基材が、播種された細胞の潜熱放出を表す温度よりも低い温度に達する、請求項1に記載の方法。
- 表面が、播種された細胞の潜熱放出に反応して核形成及び効率的な温度補償を誘導するのに十分である程度に、基材上に播種された未成熟RPE細胞の単層と実質的に平行である、請求項2に記載の方法。
- 細胞が播種された基材を第1の温度で維持する工程であって、温度の均一性を得るために第1の期間の制御された温度低下速度後に第1の温度が-20℃~-100℃である、工程と;
細胞を第1の温度より50℃以内の第1の温度よりも低い保存温度で第2の期間維持し、それによって低温保存された細胞を得る工程と
を更に含む、請求項1に記載の方法。 - 細胞が播種された基材を第1の温度で維持する工程であって、第1の期間の制御された温度低下速度後に第1の温度が-20℃~-100℃である、工程と;
第2の制御された温度低下速度を実施して最終的に細胞を-196℃未満の保存温度で第2の期間維持し、それによって低温保存された細胞を得る工程と
を更に含む、請求項1に記載の方法。 - 第2の期間が24時間~60か月である、請求項5に記載の方法。
- 第2の制御された温度低下速度が-1℃/分~-30℃/分である、請求項5に記載の方法。
- 細胞の単層が、細胞懸濁液1ミリリットル当たり細胞200,000~700,000個、又は基材表面1平方センチメートル当たり細胞100,000~350,000個の細胞播種密度を有する、請求項1に記載の方法。
- RPE細胞の50%超が丸石状の形態を有する、請求項1に記載の方法。
- RPE細胞が色素沈着していない、又は部分的に色素沈着している、請求項1に記載の方法。
- 細胞が、(i)色素沈着していない又は部分的に色素沈着したRPE細胞、(ii)付着しているが非分極、部分分極、又は完全分極のRPE細胞、(iii)成熟した丸石状の形態を有する又は有しないRPE細胞、(iv)遺伝子発現レベルが成熟細胞のレベルよりも低い又は特定の遺伝子発現が欠如しているRPE細胞、及び(v)集密又は90%を超える準集密単層構成のRPE細胞から選択される低温保存生存度特性を示すRPE細胞である、請求項1に記載の方法。
- 基材が、表面改質を有する、請求項1に記載の方法。
- 生体適合性ポリマーがパリレンを含む、請求項1に記載の方法。
- 識別する工程が、未成熟RPE細胞の少なくとも1つ又は複数の頂端分泌物、基底分泌物、又は非極性特異的分泌物が成熟RPE細胞のレベルよりも低いレベルである場合を決定することを含む、請求項1に記載の方法。
- 頂端分泌物が、αBクリスタリン、ヒアルロナン、マトリックスメタロペプチダーゼ(MMP)-9、色素上皮由来因子(PEDF)、形質転換成長因子(TGF)-β、メタロプロテイナーゼ(TIMP)-Iの組織阻害剤、又はメカノ成長因子(MGF)-E8を含む、請求項14に記載の方法。
- 基底分泌物が、シスタチンC、エンドセリンI、繊維芽細胞成長因子(FGF)5、又は血管内皮増殖因子(VEGF)を含む、請求項14に記載の方法。
- 非極性特異的分泌物が、脳由来神経栄養因子(BDNF)、補体因子H(CFH)、毛様体神経栄養因子(CNTF)、フィブリン3/5、繊維芽細胞成長因子(FGF)2、ヘパリン結合性上皮成長因子(HB-EGF)、肝細胞成長因子(HGF)、インスリン様成長因子(IGF)-I、白血病抑制因子(LIF)、マトリックスメタロプロテイナーゼ(MMP)-9、神経成長因子(NGF)、又はトロポエラスチンを含む、請求項14に記載の方法。
- 識別する工程が、少なくとも1つ又は複数のRPE65、REX1、EIF2B2、SERF2、UBE2R2の未成熟RPE細胞の遺伝子発現が、成熟RPE細胞の発現よりも低いことを決定することを含む、請求項1に記載の方法。
- 基材が、細胞がそれを通して栄養素を拡散できるように構成された薄い領域を含む、請求項1に記載の方法。
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