JP2019521708A - 組織再生のための細胞組成物 - Google Patents
組織再生のための細胞組成物 Download PDFInfo
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Abstract
Description
本出願は、2016年7月11日出願の米国特許仮出願第62/360,500号の優先権の利益を主張するものである。上記文書の内容は、本明細書に全て示されたのと同様に、全体として参照により本明細書に組み入れられる。
組織エンジニアリングおよび再生医療は、損傷を受けた臓器および組織の治癒を支援するための興味深い新規処置を提供する。組織エンジニアリングの1つの重要な側面は、ヒトの自身の細胞を使用してそのヒトを処置する能力である。自家細胞を使用することにより、組織拒絶または移植片拒絶のリスクが、排除される。
第一の態様によれば、本発明は、対照発現レベルに比較した複数の遺伝子の発現レベルの差を特徴とする細胞集団を含む組成物であって、前記複数の遺伝子が、表1〜11から選択される少なくとも2つの表から選択される、組成物を提供する。
本発明は、幾つかの実施形態において、表1〜11に示された遺伝子発現プロファイルを特徴とする細胞集団を含む組成物を提供する。幾つかの実施形態において、該細胞集団は、必要とする患者における移植、埋め込み、投与、および/または注射のためのものである。幾つかの実施形態において、該細胞集団は、エクスビボで生育された細胞に由来する。
一態様によれば、該組成物が表1〜11のいずれか1つに示される遺伝子発現プロファイルを特徴とする、細胞集団を含む組成物が提供される。幾つかの実施形態において、該細胞集団は、表1〜10から選択される複数の遺伝子の発現レベルの差を特徴とする。幾つかの実施形態において、該細胞集団は、表1〜11から選択される複数の遺伝子の発現レベルの差を特徴とする。幾つかの実施形態において、該細胞集団は、表11から選択される複数の遺伝子の発現レベルの差を特徴とする。
MSCマーカーの下方制御
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、ANPEP(CD13)、NT5E(CD73)、THY1(CD90)、およびKLF4(表1bに示される)から選択される幹細胞関連遺伝子の減少を特徴とする。
以下の実施例の節に例示される通り、3D培養で育成された細胞に由来する細胞集団は、表2bに示された遺伝子発現レベルの差を特徴とする。さらに、3D培養で育成された細胞に由来する細胞集団は、AURKA、FOS、FGF2、BCL2L1、DDX21、RRAS2、STAT1、およびANXA2から選択される増殖調節遺伝子の発現減少を特徴とする。さらに、3D培養で育成された細胞に由来する細胞集団は、SFRP2、MRAS、NOX4、NOTCH3、およびRGCCから選択される分化調節遺伝子の発現レベルの誘導を特徴とする。実施例の節にさらに例示される通り、骨形成誘導に供された2Dまたは3D培養で生育されたHATDCは両者とも、ID1、ID2、およびID3からなる群から選択される増殖調節遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表3bに示される)に比較したMHCI遺伝子の発現レベルの誘導を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表4bに示される)に比較した複数の脂肪細胞マーカー遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表5bに示される)に比較した複数の骨芽細胞マーカー遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表6bに示される)に比較した複数の骨軟骨前駆体および/または肥大軟骨細胞遺伝子マーカーの発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、本発明の細胞集団は、2D培養で培養された対照集団(表7bに示される)に比較した複数の細胞外マトリックス(ECM)マーカー遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表8bに示される)に比較した1つまたは複数の構造タンパク質遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表9bに示される)に比較した1つまたは複数の血管関連マーカー遺伝子の発現レベルの差を特徴とする。
以下の実施例の節で例示される通り、3D培養で育成された細胞に由来する細胞集団は、2D培養で培養された対照集団(表10bに示される)に比較した1つまたは複数の上流調節因子遺伝子の発現レベルの差を特徴とする。
以下の実施例の節(表12)に例示される通り、骨形成誘導に供されたHATDCは、遺伝子ATOH8、CGB1、CMTM4、FOXO、ID1、ID2、ID3、NEBL、OSR1、PRRX2、SAMD11、SLC16A3、およびSMAD9の発現レベルにおいて変調を呈することが見出された。
一態様によれば、移植のための細胞組成物の適切性を計測するための方法であって、前記組成物の、複数の遺伝子またはその産物の発現レベルを計測することを含み、対照に比較した、前記複数の遺伝子の発現レベルの有意差が、移植に適した組成物の指標となる、方法が提供される。
遺伝子発現は、RNAポリメラーゼによるメッセンジャーRNAへのDNAの転写である。本明細書で用いられる用語「発現」は、前記遺伝子産物の転写および/または翻訳をはじめとする遺伝子産物の生合成を指す。したがって核酸分子の発現は、核酸断片の転写(例えば、mRNAまたは他の機能的RNAをもたらす転写)および/または前駆体もしくは成熟タンパク質(ポリペプチド)へのRNAの翻訳を指すことができる。
幾つかの態様によれば、該キット、パネル、またはマイクロアレイは、細胞集団を含む組成物が必要とする対象への移植に適するか否かを決定するためのものである。幾つかの実施形態において、複数のリガンドを含むキット、パネル、またはマイクロアレイが提供され、各リガンドは、表1〜11に列挙された遺伝子から選択される単一遺伝子と特異的に複合体形成すること、結合すること、ハイブリダイズすること、または該単一遺伝子を定量的に検出もしくは同定することが可能である。幾つかの実施形態において、該複数のリガンドは、独立して、表1〜11に列挙された遺伝子から選択される複数の遺伝子を検出または同定することが可能である。幾つかの実施形態において、該複数のリガンドは、独立して、表1〜11から選択される表に列挙された遺伝子から選択される複数の遺伝子を検出または同定することが可能である。本明細書に記載された複数の遺伝子は、少なくとも1つの他のマーカー、例えば他の公知の遺伝子を特色とする任意の部分的組み合わせおよび/または組み合わせを場合により包含する。幾つかの実施形態において、該複数の遺伝子は、表1から選択される1つもしくは複数の遺伝子、表2から選択される1つもしくは複数の遺伝子、表3から選択される1つもしくは複数の遺伝子、表4から選択される1つもしくは複数の遺伝子、表5から選択される1つもしくは複数の遺伝子、表6から選択される1つもしくは複数の遺伝子、表7から選択される1つもしくは複数の遺伝子、表8から選択される1つもしくは複数の遺伝子、表9から選択される1つもしくは複数の遺伝子、表10から選択される1つもしくは複数の遺伝子、および/または表11から選択される1つもしくは複数の遺伝子、あるいはそれらの組み合わせから選択される。
幾つかの実施形態によれば、本発明の細胞集団は、異種細胞集団である。
幾つかの実施形態において、多層細胞培養物は、少なくとも2種の細胞型で構成された異種細胞培養物である。別の実施形態において、多層細胞培養物は、少なくとも3種の細胞型で構成された異種細胞培養物である。別の実施形態において、多層細胞培養物は、少なくとも4種の細胞型で構成された異種細胞培養物である。別の実施形態において、多層細胞培養物は、骨形成プライミング期間に続く48時間のヒト脂肪組織由来細胞(HATDC)を含む。
別の実施形態において、該組成物は、骨伝導性粒子をさらに含む。本明細書で用いられる「骨伝導性」は、適当な鋳型として働く物質、または骨を生育させ得る物質の能力を指す。非限定的例として、該骨伝導性粒子の1つまたは複数の型は、炭酸カルシウム、ヒドロキシアパタイト(HA)、脱灰骨材料、粉砕骨移植片、皮質海綿状同種移植片、皮質海綿状自家移植片、皮質海綿状異種移植片、リン酸三カルシウム、ウミヒバ鉱物および硫酸カルシウムからなる群から選択される骨伝導性セラミック粒子である。
骨組織に由来する。別の実施形態において、骨組織は、骨組織の長さに沿って、またはきめの方向に沿って切断されて、骨線維を形成する。
組織から遊走した細胞の播種
幾つかの実施形態において、細胞の播種は、鉱物粒子への細胞の遊走および付着を可能にする所定の期間に、鉱物粒子に対する組織の特異的比率で脂肪組織と鉱物粒子との接触を維持することにより実行される。幾つかの実施形態において、該脂肪組織は、無傷のままであるか、あるいは機械的に解離される(例えば、小さな組織断片に細断される)。
他の実施形態において、細胞の播種が、鉱物粒子への細胞の付着を可能にする所定の期間、鉱物粒子に対する細胞の特異的比率で鉱物粒子の存在下、細胞の特異的濃度を維持することにより実行される。
別の実施形態において、本発明は、該組成物がアルブミンをさらに含むことを提供する。別の実施形態において、本発明は、該組成物が細胞外マトリックス(ECM)タンパク質をさらに含むことを提供する。別の実施形態において、本発明は、該組成物がフィブリンをさらに含むことを提供する。別の実施形態において、本発明は、該組成物がフィブロネクチンをさらに含むことを提供する。別の実施形態において、本発明は、該組成物がコラーゲンI型をさらに含むことを提供する。別の実施形態において、本発明は、該組成物がラミニンをさらに含むことを提供する。別の実施形態において、本発明は、該組成物がビトロネクチンをさらに含むことを提供する。
本発明の組成物は、複数の代替的工程により製造されてもよい。幾つかの実施形態において、該工程は、該細胞を3D培養で培養することを含む。幾つかの実施形態において、該工程は、該細胞を3D培養で培養する前に、2D培養で培養することを含む。
一般に、本明細書で用いられる専門語および本発明で利用される検査手順は、分子、生化学、微生物および組換えDNAの技術を包含する。そのような技術は、文献に完全に説明されている。例えば“Molecular Cloning:A laboratory Manual”Sambrook et al.,(1989);“Current Protocols in Molecular Biology”Volumes I−III Ausubel,R.M.,ed.(1994);Ausubel et al.,“Current Protocols in Molecular Biology”,John Wiley and Sons,Baltimore,Maryland(1989);Perbal,“A Practical Guide to Molecular Cloning”,John Wiley & Sons,New York(1988);Watson et al.,“Recombinant DNA”,Scientific American Books,New York;Birren et al.(eds)“Genome Analysis:A Laboratory Manual Series”,Vols.1−4,Cold Spring Harbor Laboratory Press,New York(1998);米国特許第4,666,828号、同第4,683,202号、同第4,801,531号、同第5,192,659号および同第5,272,057号に示された方法論;“Cell Biology:A Laboratory Handbook”,Volumes I―III Cellis,J.E.,ed.(1994);“Culture of Animal Cells − A Manual of Basic Technique”by Freshney,Wiley−Liss,N.Y.(1994),Third Edition;“Current Protocols in Immunology”Volumes I―III Coligan J.E.,ed.(1994);Stites et al.(eds),“Basic and Clinical Immunology”(8th Edition),Appleton & Lange,Norwalk,CT(1994);Mishell and Shiigi(eds),“Selected Methods in Cellular Immunology”,W.H.Freeman and Co.,New York(1980)を参照されたい;利用可能な免疫アッセイは、特許および科学文献に詳細に記載されており、例えば米国特許第3,791,932号、同第3,839,153号、同第3,850,752号、同第3,850,578号、同第3,853,987号、同第3,867,517号、同第3,879,262号、同第3,901,654号、同第3,935,074号、同第3,984,533号、同第3,996,345号、同第4,034,074号、同第4,098,876号、同第4,879,219号、同第5,011,771号および同第5,281,521号、“Oligonucleotide Synthesis”Gait,M.J.,ed.(1984);“Nucleic Acid Hybridization”Hames,B.D.,and Higgins S.J.,eds.(1985);“Transcription and Translation”Hames,B.D.,and Higgins S.J.,eds.(1984);“Animal Cell Culture”Freshney,R.I.,ed.(1986);“Immobilized Cells and Enzymes”IRL Press,(1986);“A Practical Guide to Molecular Cloning”Perbal,B.,(1984)and“Methods in Enzymology”Vol.1−317,Academic Press;“PCR Protocols:A Guide To Methods And Applications”,Academic Press,San Diego,CA(1990);Marshak et al.,“Strategies for Protein Purification and Characterization − A Laboratory Course Manual”CSHL Press(1996)を参照されたい(それらの全てが、参照により組み入れられる)。他の一般的参照は、本文書全体で提供されている。
実験計画
細胞を4つの異なる条件下(処置群BL、A、B、およびCで表す)で育成させており、これらの異なる条件を表13に要約する。各実験を3回繰り返した。
QiacubeロボットをRNeasy miniキット(Qiagen)と共に用いて、RNAを抽出した。総RNA試料の全ての品質を、TapeStation(Agilent)を用いて評価した。全試料のRNA値が、>9.5であった。Illumina BeadChips(Epicentre)のためのTargetAmp Nano標識キットを用いたインビトロ転写により、RNAをビオチン化cRNAに増幅した。ビオチン化cRNAを、Direct Hybridizationアッセイ(Illumina Inc.)に従ってIllumina HumanHT−12 v4 Expression BeadChipにハイブリダイズした。ハイブリダイズされたチップを、ストレプトアビジン−Cy3(GE Healthcare Amersham)を用いてストレプトアビジンで染色し、Illumina HiScanでスキャンし、品質管理(QC)のために画像をGenomeStudio(Illumina)にインポートした。その後、データを、統計解析のためにJMP Genomics(SAS)に、そしてネットワークエンリッチメント解析のためにIPAにインポートした。
マイクロアレイ解析のために、47,000より多くのプローブを標的とするHumanHT−12 v4 Expression BeadChip Kit(illumina)を用いた。得られた生データは、47,000より多くのプローブを含んだ。log2変換、低発現のふるい分け、試料間の低分散のふるい分けに続いて、約9,000のプローブが統計解析に残った。
遺伝子発現の生データを、GenomeStudioからエクスポートし、JMP Genomics v7ソフトウエア(SAS Institute Inc、ノースカロライナ州ケーリー所在)にインポートした。試料での非発現遺伝子(検出p値<0.01)および低分散の転写産物(分散<5%)についてのふるい分けの後、JMP Genomicsでの品質管理および解析を、log2変換データで実施した。データ分布は類似の発現を示し、それゆえデータを正規化しなかった。一元配置分散分析を用いてデータを解析した。発現変動遺伝子(DEG)を、少なくとも2倍の変動差を有する偽陽性率(FDR)を利用して、補正p値≦0.05で統計学的に有意であった転写産物と定義した。以下のソフトウエアを用いて、データ解析を実施した:(1)GeneAnalytics,LifeMap sciences、(2)Ingenuity Pathway analysis(IPA 8.0)、Ingenuity,Qiagen。
qRT−PCRにより分析された内在性BMP−2、SP7、ALPの発現
3D系(群CおよびD)および2D系(群A)の骨形成能を評価するために、早期骨形成マーカー(内在性骨形成タンパク質(BMP2)、Ostrix(SP7)、およびアルカリホスファターゼ(ALP))の発現レベルを検査した。最初に、群A、BおよびCの骨形成系細胞分化を、150ng/ml BMP2を補充したゼノフリー培地により2日間、誘導した。次に、系A、B、およびCから得られたRNA試料を、qRT−PCRにより分析した。発現レベルを、対照群(群BL)のレベルに対比して分析した。実験は、異なる生物学的供給源からの3種のリプリケート(AD153、AD154、およびAD160で表す)を利用して実施し、結果をそれぞれ図1、2、および3に表す。
マイクロアレイ分析
最初に、異なる処置群(系)の間、および異なるバイオロジカルリプリケート(AD153、AD154、およびAD160)の間の差を分析することにより、分散成分を確定した。
マイクロアレイ分析の結果
マイクロアレイの結果を分析して、DEGを異なるクラスターにグループ分けした。結果から、14のDEGのみが、ベースラインレベル(BL)に比較して1種または複数の骨形成誘導因子での骨形成誘導を受けた処置群(群A、B、およびC)で共通することが実証された(表12)。
CD13、CD73、CD90、およびKLF4をはじめとする多能性(pluripotent)/複能性(multipotent)幹細胞マーカーの発現レベルは、対照(BL)に比較して3D系(群BおよびC)で生育されたHATDCで低下している(表1および1b)。これらの結果から、3D系で生育されたHATDCが分化の増進を受けたことが示される。
3D系で生育されたHATDCは、増殖の減少および分化の増進を呈している。マイクロアレイの結果から、3D系で生育されたHATDCが細胞マーカー:AURKA、FOS、FGF2(bFGF)、BCL2L1、DDX21、RRAS2、STAT1、およびANXA2の発現増加を呈することが実証される。加えて、3D系で生育されたHATDCは、SFRP2、ID1、ID2、ID3、MRAS、NOX4、NOTCH3、およびRGCCをはじめとする細胞マーカーの発現増加を呈する(表2および2b)。
主要組織適合性複合体(MHC)抗原は、ほとんど全ての分化細胞で発現される。これらのタンパク質は、免疫系への外来抗原の提示に関与する。MSCは、低レベルのMHCクラスI分子を発現することが知られている。
成熟した脂肪細胞は、骨の分化が既にコミットされているため、該細胞の遺伝子マーカー(例えば、PPARG)は減少した(表4、4b)。しかし、早期脂肪細胞マーカーは、3Dで誘導される(例えば、DLK1、SOX9)(表4、4b)。これらの結果は、適切な生育条件下では、3D系で生育された細胞が脂肪細胞に加え骨にも分化する能力を有することを示唆する可能性がある。
これらのクラスターの遺伝子マーカーは、2D条件に対比して3D条件で増進する骨芽細胞分化(例えば、内在性BMP2、SP7、およびALP)にとって不可欠である。
破骨細胞マーカーは、軟骨発達、軟骨細胞、骨軟骨前駆体および肥大軟骨細胞に特異性がある。これらの遺伝子マーカーから、骨分化メカニズムが軟骨内骨化に関与することが示される(表6、6b)。特異的マーカーは、COL10A1、MMP13およびCOMPである。
ECM(表7、7b)および構造タンパク質(表8、8b)の遺伝子マーカーは、3Dにおける細胞の分化増進を示す。その上、複数のECMタンパク質は、軟骨内骨化工程で肥大軟骨細胞から作製される。主なECMマーカーは、TNCおよびDPT遺伝子である。
血管新生および脈管形成(vasclorogenic)遺伝子マーカーは、血管新生および脈管形成工程に寄与する。一部は、PGFおよびIL8などの成長因子またはサイトカインである。その他は、ANG、ANGPT2およびANGPTL2などの血管形成の特異的メディエータである。典型的には、大規模な骨形成の際に、主に軟骨内骨化工程を介して、血管新生が増進される。
表11bから、DEGが少なくとも3倍の変動を有することが実証される(図11参照)。
Claims (30)
- 対照発現レベルに比較した複数の遺伝子の発現レベルの差を特徴とする細胞集団を含む組成物であって、前記複数の遺伝子が、表1〜11から選択される少なくとも2つの表から選択される、組成物。
- 前記複数の遺伝子が、表1〜11の各1つの1つまたは複数の遺伝子から選択される、請求項1に記載の組成物。
- 前記複数の遺伝子が、表1〜11に列挙された前記遺伝子の少なくとも50%を含む、請求項1に記載の組成物。
- 前記複数の遺伝子が、表1〜11から選択される表に列挙された遺伝子から選択される、請求項1に記載の組成物。
- 前記細胞集団が、エクスビボで生育された細胞に由来する、請求項1に記載の組成物。
- 前記細胞集団が、三次元培養で生育された細胞に由来する、請求項1に記載の組成物。
- 鉱物粒子をさらに含み、前記細胞集団の少なくとも一部が前記鉱物粒子と接触(例えば、付着)している、請求項1に記載の組成物。
- 前記鉱物粒子が、サンゴの鉱物粒子、海綿骨および皮質骨からなる群から選択される、請求項7に記載の組成物。
- 前記細胞集団が、ヒト脂肪組織由来細胞(HATDC)に由来する、請求項1に記載の組成物。
- 前記細胞集団が、骨形成系細胞分化に供されたHATDCに由来する、請求項9に記載の組成物。
- 前記対照発現レベルが、二次元培養物中で生育された細胞に由来する第二の細胞集団に対応する、請求項1に記載の組成物。
- 前記第二の細胞集団が、骨形成誘導に供された細胞集団である、請求項7に記載の組成物。
- 前記骨形成系細胞分化が、骨形成タンパク質(BMP)−2、BMP−3、BMP−4、BMP−5、BMP−6およびBMP−7からなる群から選択される骨形成誘導因子により誘導される、請求項10または12のいずれか1項に記載の組成物。
- 必要とする対象への移植における使用のための、請求項1に記載の組成物。
- 細胞集団において複数の遺伝子の発現レベルを計測することを含む、必要とする対象への移植に適した細胞集団を同定するための方法であって、対照発現レベルに比較した、表1〜11から選択される少なくとも2つの表から選択される前記遺伝子から選択される複数の遺伝子の発現レベルの差が、前記細胞集団が移植に適することを示す、方法。
- 発現レベルの前記差が、各遺伝子で独立して、上方制御および下方制御から選択される、請求項1に記載の組成物、または請求項15に記載の方法。
- 前記複数の遺伝子が、表1〜11の各1つの1つまたは複数の遺伝子から選択される、請求項15に記載の方法。
- 前記複数の遺伝子が、表1〜11から選択される表に列挙された前記遺伝子から選択される、請求項15に記載の方法。
- 前記複数の遺伝子が、表1〜11に列挙された前記遺伝子の少なくとも50%を含む、請求項15に記載の方法。
- 前記計測ステップが、前記細胞集団から核酸分子を得るステップを含む、請求項15に記載の方法。
- 前記核酸分子が、mRNA分子、DNA分子およびcDNA分子から選択される、請求項20に記載の方法。
- 前記cDNA分子が、前記mRNA分子を逆転写することにより得られる、請求項21に記載の方法。
- 前記計測が、前記核酸分子を複数のリガンドとハイブリダイズするステップをさらに含み、各リガンドが、表1〜11に列挙された前記遺伝子から選択される単一遺伝子と特異的に複合体形成すること、結合すること、ハイブリダイズすること、または前記単一遺伝子を定量的に検出もしくは同定することが可能である、請求項15に記載の方法。
- 複数のリガンドを含むキットであって、各リガンドが、表1〜11から選択される少なくとも2つの表から選択される複数から選択される単一遺伝子と特異的に複合体形成すること、結合すること、ハイブリダイズすること、または前記単一遺伝子を定量的に検出もしくは同定することが可能である、キット。
- 対象への移植に適した細胞集団を同定するための、請求項24に記載のキット。
- 前記差が、上方制御、下方制御、またはそれらの組み合わせから選択される、請求項24に記載のキット。
- 前記複数の遺伝子が、表1〜11の各1つの1つまたは複数の遺伝子から選択される、請求項24に記載のキット。
- 前記複数の遺伝子が、表1〜11から選択される表に列挙された前記遺伝子から選択される、請求項24に記載のキット。
- 前記複数の遺伝子が、表1〜11の各1つの1つまたは複数の遺伝子から選択される、請求項24に記載のキット。
- 前記複数の遺伝子が、表1〜11に列挙された前記遺伝子の少なくとも50%を含む、請求項24に記載のキット。
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IL264205B2 (en) | 2023-12-01 |
EP3481967A4 (en) | 2020-04-22 |
AU2017296175B2 (en) | 2023-11-02 |
CN109689893A (zh) | 2019-04-26 |
US20190224244A1 (en) | 2019-07-25 |
IL264205B1 (en) | 2023-08-01 |
EP3481967A1 (en) | 2019-05-15 |
IL264205A (en) | 2019-02-28 |
AU2017296175A1 (en) | 2019-02-28 |
RU2019103657A (ru) | 2020-08-11 |
KR20190038833A (ko) | 2019-04-09 |
RU2019103657A3 (ja) | 2021-04-12 |
WO2018011804A1 (en) | 2018-01-18 |
JP7268943B2 (ja) | 2023-05-08 |
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