JP2021534908A - 生体活性ガラスを含むマトリックス - Google Patents
生体活性ガラスを含むマトリックス Download PDFInfo
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Abstract
Description
本出願は、2018年8月31日に出願された米国仮特許出願第62/725,865号の利益を主張するものであり、その開示全体は、参照により本明細書に組み込まれる。
本開示の一態様は、組織容積損失を示す組織の欠損を治療するためのマトリックス組成物を含む。組成物は、第1の表面および第2の表面を含むポリマー膜と、ポリマー膜の表面と会合した生体活性ガラスと、を含む。生体活性ガラスは、組織治癒を促進することができる無機元素を含む。
本明細書で使用される場合、「生体活性ガラス」および「バイオガラス」は、互換的に使用され、生体組織と接触すると、生体組織内の生物活性を誘導するガラス組成物を指す。例えば、本開示の生体活性ガラスが骨組織と接触するとき、生体活性ガラスは、損傷された組織の治癒および復元をもたらす生物活性を誘導する。生体活性ガラスはまた、組織と接触するときの反応を最小限に抑えるために生体適合性であることが認識されるであろう。さらに、本開示の生体活性ガラスは、生分解性であり得る。
組成物のポリマー膜は、一般に、生体適合性ポリマーを含む。生体適合性ポリマーは、再吸収性であり得る。本開示の膜に好適な吸収性生体適合性ポリマーは、当該技術分野において既知である。例えば、その開示はその全体が本明細書に組み込まれる、Shimp,N.G.(2018)“Biodegradable and Biocompatible Polymer Composites;Processing,Properties and Applications,”Elsevier Scienceを参照されたい。組成物のポリマー膜は、可撓性であり得る。可撓性吸収性膜材料は、その全体が本明細書に組み込まれる米国特許出願第14/510917号に開示される通りであり得る。
上述されたように、本開示のマトリックス組成物は、ポリマー膜と、ポリマー膜と会合する生体活性ガラスと、を含む。本開示の組成物は、吸収性かつ可撓性であり得る。
本開示の別の態様は、組織容積損失を示す組織の欠損を治療する方法を含む。この方法は、本開示のマトリックス組成物を得ることと、組織損失に隣接する健康な組織をマトリックスと接触させることと、欠損をマトリックスで取り囲み、それによって欠損の容積損失の周囲に囲いを形成することと、を含む。容積損失の周囲の囲いは、組織内の欠損の修復を誘導するための損失組織の形態であり得る。マトリックス組成物は、セクションIで上述された通りであり得る。
本開示の別の態様は、組織容積損失を示す組織の欠損を治療するためのマトリックス組成物の製造方法を含む。マトリックス組成物は、本明細書のセクションIに記載される通りであり得る。方法は、生体活性ガラスおよびポリマー膜を得ることと、生体活性ガラスをポリマー膜の層と会合させ、それによってマトリックスを形成することと、を含む。
本明細書で使用される場合、「生体適合性」という用語は、特定の用途において適切な宿主応答を伴い実行するか、または少なくとも、宿主の生体系に対して、局所的または全身的に毒性または別様に有害な影響を有することなく実行する能力(例えば、組成物または材料の)を指す。
血管発生(vasculogenesis)および血管新生(angiogenesis):組織の発生および修復への重要な工程。
血管発生は、間葉細胞によって新たな血管を形成するために行われる分化の生物学的プロセスを特定し、3つの異なる段階を伴う:1)血管芽細胞(angioblast)または血球血管前駆細胞(hemangioblast)の中胚葉細胞の分化;2)血管芽細胞または血球血管前駆細胞の内皮細胞への分化;3)一次毛細管への新たな内皮の組織化。対照的に、血管新生は、新たな毛細血管の形成が既存の血管の発芽を介して生じる生物学的プロセスを指す。血管発生は典型的には、胚組織の発生に限定されるが、血管新生は、既存の血管または内皮前駆細胞から発生することができ、成人の生活における胚発生ならびに正常および病理的血管形成に関与する。
異なる結合組織の血管形成および修復、およびより具体的には骨再生を増強するための戦略としてのWNT3aシグナル伝達のLPR5非依存的活性化は、組換えヒトWNTタンパク質の外因性投与によって実証されている。このアプローチは、ヒト臨床試験を通じて時間的に安全で効果的であることが証明され得るが、時間およびコストに関して規制経路は負担となる。あるいは、標準的なWNTシグナル伝達経路の薬理学的操作は、グリコーゲンシンターゼキナーゼ3β(GSK3)の阻害剤であるイオン性リチウムによる外部処理によって可能になる。GSK3の阻害は、β−カテニン核内移行および下流WNTシグナル伝達を増強することが報告されている。ドープ飲料水または動物の強制摂食について報告されているように、全身に送達されたリチウムは、骨強度を増強し、骨折修復を加速し、高齢マウスにおける骨壊死性骨病変を復元することが示された。これらのモデルにおける組織修復は、脂肪形成を犠牲にして、間葉系前駆細胞の骨形成系統の細胞への関与の強化を介して生じることが報告された。したがって、リチウムを含む無機元素の局所溶解によるβ−カテニンの安定化は、タンパク質同化組織再生を増強し、胚組織発生を誘導することが知られているプロセスを効果的に再現するように見える。提案される作用機序は、→VEGF−A、BMP−2、−4、−6、→Runx2→WNTシグナル伝達を含み得る。
生体活性ガラスを、所望の生分解性を付与するために、特許第8,337,875号に記載のガラス形成剤を使用するガラス溶融手順を使用して調製した(52.95重量%、0重量%、4.0重量%のホウ酸塩、ケイ酸塩、およびリン酸塩)。米国特許第8,337,875号に従って、この材料を、血管発生を増強するために、CuおよびZnでさらにドープした。しかしながら、新たに形成された基底マトリックス内のプロテオグリカン沈着を最適化するために、亜鉛および銅の硫酸塩を利用した。血管発生を増強するための代替アプローチとして、酸化コバルトを使用してドーピングを達成することができる。リチウムは、WNTシグナル伝達、復元胚組織形成を促進するためにさらに添加される。
タバコ使用歴のある62歳の農業従事者は、8cmの中央骨欠損として提示されたフォークリフトによる損傷を経験している右脛骨の開放骨折で、ERに空輸された。組織の壊死組織除去術および抗生物質で骨と周囲の軟組織を大量に洗浄した後、損傷した骨膜を切除し、外因性骨移植片を保持する実用的な方法がないまま骨欠損を残した。生体活性ガラスを含有するマトリックスを、欠損全体にわたるように、幅14cm(長さ24cm)に切断した。マトリックス中で脛骨を包む前に、欠損部を、CellPoint Concentrated Bone Marrow Aspirate System(Isto Biologics,Hopkinton,MA)を使用して、腸骨稜から採取した患者由来の濃縮骨髄穿刺液(総吸引量220cc;移植片で送達される総量16cc)を混合することによって、最初に水和した合成骨移植片で埋めた。その後、記載される無細胞マトリックスを使用して、適用された骨移植片を3回巻き、剛体プレート固定を達成した。損傷した筋肉を縫合糸で修復し、マトリックスと直接接触して直接置いた。外科医は、生体活性ガラスを含有するマトリックスの抗菌性が、損傷を引き起こす農機具によって伝達された可能性のある好気性および嫌気性細菌を効果的に死滅させると確信していた。患者は術後6週目に顕著な骨の圧密化示し、6ヶ月目の来診時にリモデリングを進め、痛みのない歩行をもたらした。二段階のマスクレット手順を排除することで、驚くべきことに、高齢患者は8ヶ月未満で限られた農作業に復帰し、11ヶ月目には合併症なしに完全な作業に復帰した。
28歳の男性サーファーが北カリフォルニアの海岸でサメに襲われ、右前下肢に大きな裂傷を負った。大腿直筋のおよそ30%、および内側広筋の25%が、神経および血管支持組織と共に攻撃で失われた。大腿骨は、それ以外は無傷のままであった。患者を、入院後24時間以内に安定化させ、その際、それ以外は健常な若い男性において肢体を温存し、限られた機能を復元させようと試みた。生存可能な筋肉組織を壊死組織除去術後に採取し、持続放出されるリチウムおよびコバルトを含有する二重表面生体活性ガラスマトリックスに充填して、損傷した組織の血行再建を促進した。2つの個々のマトリックスを作成して、各筋肉群の一般的な形状の鋳型を提供した。筋肉は、衛星細胞の成長を促進するために細かく切断され、脂肪吸引によって収集された自家脂肪移植片とその場で組み合わされた。吸引脂肪組織を限定されたコラーゲナーゼ消化を通してさらに処理して、混合され、各マトリックス中に装填される50ccの微小血管断片を得た。混合された構築物は、既存の筋肉に従って固定されたマトリックスの各々を充填し、それ以外は健常な筋肉とマトリックスとの有意な重なりを確保した。皮膚移植は、筋肉の再灌流の証拠が得られるまで延期された。術後7日間の再灌流は、最初に、レーザー補助インドシアニン緑色染料イメージング(Novodaq SPY Elite、Stryker)を介して観察された。皮膚移植は、合併症なく21日目に完了した。組織生存率および組織化のMRI評価は、筋肉修復の3ヶ月後に顕著な開存性および血管構造を示した。患者は8週目に理学療法を開始し、初回手術から6ヶ月後に損傷した肢部を利用して筋力および筋緊張の継続的な改善を示す。
Claims (20)
- 組織容積損失を示す組織の欠損を治療するためのマトリックス組成物であって、前記マトリックスが、
a.第1の表面および第2の表面を含むポリマー膜と、
b.前記ポリマー膜の表面と会合した生体活性ガラスであって、前記生体活性ガラスが、組織治癒を促進することができる無機元素を含む、生体活性ガラスと、を含む、マトリックス組成物。 - 前記マトリックスが、生体適合性、可撓性、吸収性、またはこれらの組み合わせである、請求項1に記載の組成物。
- 前記生体活性ガラスが、繊維または球体の形態である、請求項1に記載の組成物。
- 前記生体活性ガラスが、多孔質である、請求項1に記載の組成物。
- 前記生体活性ガラスが、約50〜55重量%のホウ酸塩、約0%のケイ酸塩、および約3.0〜5.0重量%のリン酸塩を含むホウ酸塩ガラスである、請求項1に記載の組成物。
- 前記無機元素が、Cu、Se、Co、Zn、Li、およびこれらの組み合わせから選択される、請求項1に記載の組成物。
- 前記無機元素が、Cu、Zn、およびLi、CuおよびLi、またはCoおよびLiである、請求項1に記載の組成物。
- 前記生体活性ガラスが、前記ポリマー膜の前記第1の表面と会合している、請求項1に記載の組成物。
- 前記ポリマー膜が、前記ポリマー膜内に埋め込まれた、治療濃度の前記無機元素をさらに含む、請求項1に記載の組成物。
- 前記ポリマー膜内に埋め込まれた前記無機元素が、アルギン酸塩、コラーゲンもしくはデキストラン、ガラス、またはケイ酸塩から作製されるビーズの形態で配合される、請求項9に記載の組成物。
- 前記ポリマー膜が、内部ポリマー層と、前記内部ポリマー層の各表面と接触する少なくとも1つのポリマー層と、を含み、前記内部ポリマー層が、前記内部ポリマー層内に埋め込まれた、治療濃度の前記無機元素をさらに含み、前記生体活性ガラスが、前記ポリマー膜の少なくとも1つの表面と会合している、請求項1に記載の組成物。
- 組織容積損失を示す組織における欠損の治療方法であって、前記方法が、
a.請求項1に記載のマトリックスを得ることと、
b.前記組織損失に隣接する健康な組織を、前記マトリックスと接触させることと、
c.前記欠損を前記マトリックスで取り囲むことにより、前記組織損失の周囲に囲いを形成することと、を含む、方法。 - 前記組織損失が、分節性骨損失である、請求項12に記載の方法。
- 前記方法が、前記囲い内に骨移植片材料を含有することをさらに含む、請求項13に記載の方法。
- 前記骨移植片材料が、患者由来の骨髄穿刺液濃縮物を含む、請求項14に記載の方法。
- 前記組織容積損失が、筋組織損失である、請求項12に記載の方法。
- 前記方法が、前記囲い内に筋移植片材料を含有することをさらに含む、請求項16に記載の方法。
- 前記筋移植片材料が、生存筋組織、脂肪吸引組織(lipoaspirate)、および微小血管断片を含む、請求項17に記載の方法。
- 前記欠損が、結合組織損失である、請求項12に記載の方法。
- 請求項1に記載のマトリックスの製造方法であって、
a.前記生体活性ガラスを得ることと、
b.ポリマー膜を得ることと、
c.前記生体活性ガラスをポリマー膜の層と会合させ、それによって前記マトリックスを形成することと、を含む、方法。
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