JP7303952B2 - 個別化された血管を作製する方法 - Google Patents
個別化された血管を作製する方法 Download PDFInfo
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- JP7303952B2 JP7303952B2 JP2023000388A JP2023000388A JP7303952B2 JP 7303952 B2 JP7303952 B2 JP 7303952B2 JP 2023000388 A JP2023000388 A JP 2023000388A JP 2023000388 A JP2023000388 A JP 2023000388A JP 7303952 B2 JP7303952 B2 JP 7303952B2
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Description
本出願は、2018年8月3日に出願されたアメリカ合衆国仮出願第62/714,200号の恩恵を主張する。
本明細書に開示されている個別化された血管を作製する方法は、無細胞性管状足場を使用する。本明細書では、「無細胞性管状足場」という用語は、実質的に無細胞である管状足場を意味する。無細胞性管状足場は、ドナーからの天然の血管を脱細胞化することによって作製できる。ドナーとして、ヒト、または適切な種からの動物が可能である。無細胞性足場は、生体適合性材料をインビトロで組み立てること(例えばバイオプリンティングまたはポリマー自己組織化)によっても取得できる。
いくつかの実施態様では、全血サンプルの中に存在する細胞の集団は足場に定着する。患者の全血は、希釈せずに用いること、または実施例4~5に記載されているような生理学的灌流溶液または他の臓器保存溶液(例えばPerfadex(商標)、STEEN(商標)、Euro Collins溶液、ウィスコンシン大学冷蔵溶液、Celsior(登録商標)溶液など)で希釈して用いることができる。
本開示の1つの側面は個別化された血管を作製する方法に関係しており、この方法は、無細胞性管状足場の表面を、その個別化された血管を必要とする対象からの希釈されていない全血サンプルと接触させることを含み、この接触操作は2日間超にわたって実施する。
別の1つの側面では、本発明は、無細胞性管状足場を、希釈された患者全血と接触させることに関する。
全血サンプルまたは希釈されていない全血サンプルにさらに添加される薬剤
いくつかの実施態様では、全血サンプルは1つ以上の非細胞性因子を含んでおり、全血の1つ以上の非細胞性因子は足場に定着し、血管がグラフトされると無細胞性管状足場の細胞化と血管の宿主適合性を促進する。本明細書では、「非細胞性因子」という用語は、全血懸濁液の中にあって完全な真核細胞を含んでいない化合物を意味する。非細胞性因子として任意のタイプの分子が可能であり、その非限定的な例に含まれるのは、タンパク質、核酸、糖、脂質、小分子、金属イオン、またはこれらの複合体または組み合わせである。
本開示により、個別化された血管を作製する方法として、無細胞性管状足場(例えば脱細胞化された血管、またはバイオプリントされた管状足場)の表面(例えば内面)を、全血を含む懸濁液に48時間超にわたって接触させることにより、血液の中に存在する細胞が足場に定着できるようにすることを含む方法が提供される。いくつかの実施態様では、無細胞性管状足場の表面は、この無細胞性管状足場の内面である。
別の1つの側面では、本開示により、個別化された血管を作製する方法として、無細胞性管状足場(例えば脱細胞化された血管、またはバイオプリントされた管状足場)の表面を、全血を含む懸濁液に接触させ、複数の環境パラメータ(例えば温度、および/またはpH、および/または酸素含量、および/またはCO2含量)を連続的または定期的にモニタして調節することを含む方法が提供される。
いくつかの実施態様では、本開示により、個別化された血管を作製する方法として、全血の1つ以上の成分を富化して選択した後、無細胞性管状足場の表面に添加してこの足場の内面と接触させる方法が提供される。例えば血小板、有核細胞、タンパク質、増殖因子、シグナル伝達因子、免疫グロブリンと、これらの任意の組み合わせから選択された成分を無細胞性管状足場の内面に添加することができる。成分は、例えば遠心分離、勾配遠心分離、選択的接着による分離、濾過、ソーティング(例えばFACS、MACS)のいずれかによって富化または選択することができる。
本明細書に開示されている方法により、細胞および/または前駆細胞を無細胞性管状足場(例えば脱細胞化された血管、またはバイオプリントされた管状足場)の表面(例えば内面)に定着させることが可能になり、そのことによって個別化された血管が生成する。いくつかの実施態様では、細胞は内皮細胞を含んでいる。いくつかの実施態様では、細胞は平滑筋細胞を含んでいる。いくつかの実施態様では、前駆細胞は内皮前駆細胞を含んでいる。いくつかの実施態様では、前駆細胞は平滑筋前駆細胞を含んでいる。当業者であればわかるように、細胞および/または前駆細胞は1つ以上のやり方で足場に定着させることができる。足場への定着は、インビトロで移植の前に、または生体内で移植の後に起こることができる。いくつかの実施態様では、細胞は足場に付着する。いくつかの実施態様では、前駆細胞は増殖および/または分化して前駆細胞を生成させ、これら前駆細胞が足場に付着する。
別の1つの側面では、本開示により、治療に用いるための、本明細書に開示されている個別化された血管が提供される。いくつかの実施態様では、対象に移植するのに用いるための個別化された血管が提供される。いくつかの実施態様では、本開示により、血管疾患または血管障害の治療を必要とする対象のその疾患または障害を治療するのに用いるための個別化された血管が提供される。
別の1つの側面では、本開示により、個別化された血管を作製するためのバイオリアクターが提供され、このバイオリアクターは、ポンプ(例えば蠕動ポンプ、重力ポンプ、プランジャポンプや、それ以外の適切なポンプ)、容器、第1のコネクタ、第2のコネクタを含んでいて、第1と第2のコネクタは容器に直接的または間接的に接続され、各コネクタは、本明細書に開示されている個別化された血管を作製するための方法の任意の1つによって個別化された血管を作製するため管状足場の一端に接続され、第1と第2のコネクタが管状足場の2つの端部に接続されているとき、ポンプが、懸濁液、または全血、または溶液の閉回路での循環を媒介する。多くの実施態様において、本明細書で用いられているポンプ(例えば蠕動ポンプ、重力ポンプ、プランジャポンプや、それ以外の適切なポンプ)は、十分に静かで、血液細胞に対する損傷が最少であることが有利である。
方法が、記載されている具体的な実施態様に限定されることはないため、変化してもよいことを理解すべきである。本明細書で用いられている用語は具体的な実施態様を記述することだけを目的としており、制限する意図はないことも理解すべきである。本発明の技術の範囲は、添付の請求項によってだけ制限される。
ブタP-TEVグラフトを用意し、安全性と実現可能性を生体内で調べた。具体的には、ヒト大腿静脈の血管壁のサイズと厚みを模倣した置換モデル系として、ブタ大静脈を選択した。
大静脈をブタの死体から回収し、脱細胞化してこのドナーの細胞とDNAを取り出した。簡単に述べると、静脈セグメントにDC溶液1、DC溶液2、DC溶液3をこの順番で灌流させ、減菌水を用いた洗浄工程を異なるDC溶液の間に挟んだ。この実施例では、Triton Xを24時間、TNBPを8時間、DNアーゼを16時間使用した。次いでこれら静脈セグメントをDC基礎溶液とPBSで1時間にわたって徹底的に洗浄した後、最終洗浄を48時間にわたって実施した。次に、静脈セグメントを減菌溶液の中で減菌し、PBSの中で徹底的に洗浄した(1時間の減菌洗浄と、48時間の最終洗浄)。次いでそれぞれの減菌DC静脈セグメントを、剥がれないラベル付きの容器に移し、PBSの中で-80℃で凍結させた。脱細胞化と減菌に使用した溶液の組成を表1に示す。
再調整/再細胞化されたP-TEVをレシピエントのブタに手術によって埋め込んだ。具体的には、白線に切れ込みを入れた。最初の2匹のブタでは大静脈を特定する従来の技術を利用した。すなわち、生理食塩水の中で湿らせたガーゼと、手術用フックを用いて腸を脇に保持し、大静脈のうちで大腿静脈への分岐部と腎静脈に挟まれた部分を切除して周囲の組織から自由な状態にした。2匹のブタの一方で腸癒着が形成されたため、別の6匹のブタ(4匹にはP-TEVが埋め込まれ、2匹は偽手術を受けた)では改良された後腹膜技術を利用して大静脈を特定した。すなわち、腹膜と腹壁を分離して右側の大静脈まで下げることにより、腸に触れていない状態にした。P-TEVを移植されたブタに関しては、大静脈を切断し、約4 cmのP-TEVを端々吻合によって付着させた。偽手術したブタでは、静脈の圧力のためにP-TEV移植片のように2箇所で切断して縫合することはできなかった。その代わりに大静脈を切断して1つの吻合によって縫合した。
2匹のブタが手術後に腸癒着を起こしたため、腸閉塞の症状を理由として計画したエンドポイントよりも前に安楽死させねばならなかった。1匹はP-TEVのブタであり、大静脈を従来の技術を利用して特定した。手術から16日後に安楽死させねばならず、腸は解剖時に大量の癒着を示していた。もう1匹は偽手術のブタであり、手術から7日後に安楽死させた。このブタの腹膜は手術中に破裂したため、腸を従来の技術の場合のように湿ったガーゼとフックで取り扱わねばならなかった。
血管造影法を麻酔下で実施した後、手術から4~5週間生きていた1匹の偽手術のブタとP-TEVの3匹のブタを安楽死させた。造影剤を大腿静脈に注入し、C-bow X線を用いて大静脈を生きたままモニタした。図1A~図1Bに示されているように、P-TEV(図1B)の静脈と偽手術(図1A)の静脈は両方とも開いていて自由に血液が流れた。
カルシウムとマグネシウムを含む900 mlのダルベッコのリン酸塩緩衝化生理食塩水(DPBS)を室温にて60 rpmで連続的に撹拌した。(凝集を避けるため)74 gのヒト血清アルブミンの粉末をこの液体の表面に層状にしてゆっくりと添加し、完全に溶けるまで撹拌した。rpmを一時的に小さくすることによって泡の形成を回避した。その後、6.7 gのデキストラン-40を溶液に添加し、完全に溶けるまで撹拌した。NaOHを用いてpHを7.4にし、DPBSをカルシウムおよびマグネシウムとともに用いて最終体積を1000 mlに調節した。次いで低タンパク質結合減菌フィルタを用いてこの生理学的灌流溶液を減菌濾過した後、50 mlの試験管の中の25 mlのアリコートに分割し、2~8℃で12ヶ月間まで保管した。
患者からの25 mlの減菌血漿を、減菌した50 mlの試験管に移した。次に1.5 mlの100 g/Lの減菌濾過デキストラン-40貯蔵溶液を血漿に添加し、この溶液を、完全に混合されるまで注意深く撹拌した。減菌生理学的灌流溶液を2~8℃で7日間まで保管した。
カルシウムおよびマグネシウムと、70 g/LのHSAと、5 g/Lのデキストラン-40と、11ミリモル/Lのグルコースを含有するDPBS
実施例1は、脱細胞化された管状足場を用いて個別化された血管を作製する方法を記述している。あるいは個別化された血管は、バイオプリントされた管状無細胞性足場から作製する。簡単に述べると、バイオプリントされた血管足場を、ゲル、スポンジ、泡、パッチ、半液体/流体いずれかの形態の(天然または合成)ポリマーの表面に作製する。この方法では、ポリマー製足場に全血、または溶液の中で希釈した全血(例えば全血を含む懸濁液)を灌流させ、個別化された血管を作製する。
移植される血管を必要とする対象を選択し、本開示の実施例1または実施例2に示されている方法で作製した個別化された血管を対象に埋め込む/移植する。移植後の対象の予後と回復をモニタする。
個別化された血管を作製するための無細胞性足場の再細胞化/再調整プロセスには、患者からの全血の小さなサンプルが関係する。この実施例では、再細胞化/再調整のプロセスに関係する全血の細胞成分と非細胞成分(例えば血小板、有核細胞、タンパク質、増殖因子、シグナル伝達因子、免疫グロブリン)を選択または富化してこのプロセスで用いる。一例では、全血の細胞成分と非細胞成分を全血と組み合わせる。あるいは再細胞化/再調整プロセスで全血の細胞成分と非細胞成分を全血の代わりに用いる。後者のプロセスは、プロセスに関係する理由で、および/または血管の個別化を最適化するため、実施される。富化または選択は、例えば遠心分離、勾配遠心分離、選択的接着による分離、濾過、ソーティング(例えばFACS、MACS)のいずれかを利用して実施される。
本発明をその詳細な記述と組み合わせて記述してきたが、上記の記述は本開示を説明することを目的としており、その範囲を制限する意図はなく、本開示の範囲は添付の請求項の範囲によって規定される。他の側面、利点、改変は、以下の請求項の範囲に含まれる。本明細書に提示されているあらゆる定義は、本発明の主題を理解することと、添付の請求項を構成することを目的として含まれている。本明細書で用いられている略号は、化学と生物学の分野における従来からの意味を持つ。
Claims (23)
- 個別化された血管を作製する方法であって、無細胞性管状足場の表面を、前記個別化された血管を必要とする対象からの希釈されていない全血サンプルと接触させることを含み、この接触操作を3~14日間にわたって実施する方法。
- 前記全血サンプル内の細胞の集団が前記無細胞性管状足場に定着する、請求項1に記載の方法。
- 前記全血サンプルが1つ以上の非細胞性因子を含み、前記全血の1つ以上の非血管性因子が前記足場に定着し、これら非血管性因子が、無細胞性管状足場の細胞化と、移植時の血管の宿主適合性を促進する、請求項1に記載の方法。
- 前記希釈されていない全血サンプルが抗血栓因子をさらに含む、請求項1に記載の方法。
- 前記抗血栓因子が抗凝固剤を含む、請求項4に記載の方法。
- 前記抗凝固剤がヘパリンまたはデキストランを含む、請求項5に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記ヘパリンが、前記希釈されていない全血サンプルの中に約0.5 IU/ml~約150 IU/mlの濃度で存在する、請求項6に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記ヘパリンが、前記希釈されていない全血サンプルの中に約6.7 IU/mlの濃度で存在する、請求項7に記載の方法。
- 前記デキストランがデキストラン-40である、請求項6に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記デキストランが、前記希釈されていない全血サンプルの中に約1 g/L~約55 g/Lの濃度で存在する、請求項6に記載の方法。
- 前記抗血栓因子がアスコルビン酸を含む、請求項4に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記アスコルビン酸が、前記希釈されていない全血サンプルの中に約0.2μg/ml~約200μg /mlの濃度で存在する、請求項11に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記アスコルビン酸が、前記希釈されていない全血サンプルの中に約5μg/mlの濃度で存在する、請求項11に記載の方法。
- 前記抗血栓因子がアセチルサリチル酸を含む、請求項4に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記アセチルサリチル酸が、前記希釈されていない全血サンプルの中に約0.2μg/ml~約200μg /mlの濃度で存在する、請求項14に記載の方法。
- 前記無細胞性管状足場の接触操作を開始するとき、前記アセチルサリチル酸が、前記希釈されていない全血サンプルの中に約5μg/mlの濃度で存在する、請求項14に記載の方法。
- 前記全血サンプルが、集団平均生理学的レベルと等しいかそれよりも高いレベルの増殖因子をさらに含み、この増殖因子の選択が、顆粒球マクロファージ-コロニー刺激因子(GM-CSF)、インターロイキン(IL)-3、IL-4、ニュートロフィン(NT)-6、プレイオトロフィン(HB-GAM)、ミッドカイン(MK)、インターフェロン誘導タンパク質-10(IP-10)、血小板因子(PF)-4、単球走化性タンパク質-1(MCP-1)、RANTES(CCL-5、ケモカイン(C-Cモチーフ)リガンド5)、IL-8、IGF、線維芽細胞増殖因子(FGF)-l、FGF-2、FGF-3、FGF-4、FGF-5、FGF-6、FGF-7、FGF-8、FGF-9、トランスフォーミング増殖因子(TGF)-β、VEGF、血小板由来増殖因子(PDGF)-A、PDGF-B、HB-EGF、肝細胞増殖因子(HGF)、腫瘍壊死因子(TNF)-α、インスリン様増殖因子(IGF)-1と、これらの任意の組み合わせからなされる、請求項1に記載の方法。
- 前記増殖因子が線維芽細胞増殖因子(FGF)-2である、請求項17に記載の方法。
- 前記接触操作を4~14日間にわたって実施する、請求項1に記載の方法。
- 前記接触操作を5~14日間にわたって実施する、請求項1に記載の方法。
- 前記接触操作を6~14日間にわたって実施する、請求項1に記載の方法。
- 前記接触操作を7~14日間にわたって実施する、請求項1に記載の方法。
- 前記接触操作を7~9日間にわたって実施する、請求項1に記載の方法。
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