JP2021137597A - ナノヒドロキシアパタイトを含む多孔質多糖足場、及び骨形成のための使用 - Google Patents
ナノヒドロキシアパタイトを含む多孔質多糖足場、及び骨形成のための使用 Download PDFInfo
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- JP2021137597A JP2021137597A JP2021083699A JP2021083699A JP2021137597A JP 2021137597 A JP2021137597 A JP 2021137597A JP 2021083699 A JP2021083699 A JP 2021083699A JP 2021083699 A JP2021083699 A JP 2021083699A JP 2021137597 A JP2021137597 A JP 2021137597A
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- polysaccharide
- bone
- scaffold
- matrix
- porous
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Abstract
【解決手段】i)少なくとも1つの多糖の量、架橋剤の量、及びポロゲン剤の量を含むアルカリ性水溶液を調製すること、ii)前記溶液を、約4℃〜約80℃の温度で、前記多糖の量を架橋させるのに十分な時間置くことによって、当該溶液をヒドロゲルにトランスフォーメーションすること、iii)前記ヒドロゲルを溶媒、好ましくは水溶液に浸すこと、及びiv)工程iii)で得られた多孔質多糖足場を洗浄することを含み、工程i)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含む、方法である。
【選択図】なし
Description
骨関連障害の話題は、過去数年にわたってかなりの注目を集めている。自己骨及び同種骨を使用することは、骨欠損などの骨関連障害を克服するために、病院で広く行われている。しかしながら、自己骨を使用することは、二次的なトラウマをもたらすことが公知であり、同種骨は、免疫反発を引き起こす。加えて、自己骨及び同種骨の使用は、欠損部のサイズ及び局在に依存するので、自己骨及び同種骨には深刻な限界がある。例えば、大きな欠損部における移植片は、骨形成の完了前に体に再吸収されたので、この治療の成功について疑問が残ることが報告された(Hoexter DL. Bone regeneration graft materials J Oral Implantol. 2002;28(6); Delloye C, Cornu O, Druez V, Barbier O. Bone allografts: What they can offer and what they cannot. J Bone Joint Surg Br. 2007 May;89(5):574-9)。
i)少なくとも1つの多糖の量、架橋剤の量、及びポロゲン剤の量を含むアルカリ性水溶液を調製すること、
ii)前記溶液を、約4℃〜約80℃の温度で、前記多糖の量を架橋させるのに十分な時間置くことによって、当該溶液をヒドロゲルにトランスフォーメーションすること、
iii)前記ヒドロゲルを溶媒、好ましくは水溶液に浸すこと、及び
iv)工程iii)で得られた多孔質多糖足場を洗浄すること
を含み、
工程i)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含む、方法に関する。
a)少なくとも1つの多糖、及び1つの架橋剤の量を含むアルカリ性水溶液を調製すること、
b)工程a)の水溶液を凍結すること、
c)工程b)の凍結溶液を昇華させること
を含み、
工程a)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含み、
工程a)の溶液中で多糖の架橋が起こる前に工程b)が実施される、方法に関する。
定義
本明細書において使用される「多糖」という用語は、2つ以上の単糖単位を含む分子を指す。
第1の目的では、本発明は、多孔質多糖足場を調製するための方法であって、以下の工程:
i)少なくとも1つの多糖の量、架橋剤の量、及びポロゲン剤の量を含むアルカリ性水溶液を調製すること、
ii)前記溶液を、約4℃〜約80℃の温度で、前記多糖の量を架橋させるのに十分な時間置くことによって、当該溶液をヒドロゲルにトランスフォーメーションすること、
iii)前記ヒドロゲルを溶媒、好ましくは水溶液に浸すこと、及び
iv)工程iii)で得られた多孔質多糖足場を洗浄すること
を含み、
工程i)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含む、方法に関する。
a)少なくとも1つの多糖、及び1つの架橋剤の量を含むアルカリ性水溶液を調製すること、
b)工程a)の水溶液を凍結すること、
c)工程b)の凍結溶液を昇華させること
を含み、
工程a)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含み、
工程a)の溶液中で多糖の架橋が起こる前に工程b)が実施される、方法に関する。
本発明者らは、本発明の多孔質多糖足場の移植が、高密度コラーゲンネットワーク及び血管形成、並びに骨芽細胞様細胞のリクルートの刺激につながることを示した。皮下部位における本発明の足場の前記移植は、高密度石化組織の形成、そしてそれ故骨形成につながる。
実施例1:無胸腺マウスの頭蓋冠部位における本発明の足場の移植。
材料と方法
ナノヒドロキシアパタイトの調製
0.6Mリン酸溶液(H3PO4Rectapur, Prolabo(登録商標), France)及び1M水酸化カルシウム溶液(CaOH2 Alfa Aesar, Germany)を使用する湿式化学沈殿によって、ナノヒドロキシアパタイト(n−HA)を調製した。100mlのH3PO4溶液を100mlのCaOH2溶液に、室温で激しく撹拌しながら30分間かけて一滴ずつ加えた。反応終了時に、0.4.10−3molの0.6M水酸化ナトリウム溶液を使用して、pHを9に調整し、次いで、12時間撹拌し続けた。
9gのプルラン及び3gのデキストランを、14gのNaClを含む27mLの蒸留水及び13mLのナノヒドロキシアパタイト懸濁液(n−HA、6.36%w/v)に溶解させることによって調製したプルラン/デキストラン75:25の混合物(プルラン, MW 200,000, Hayashibara Inc, デキストランMW 500,000, Pharmacia)を使用して、マクロ多孔質複合足場(MATRI+)を調製した。アルカリ性条件下、トリメタリン酸三ナトリウムSTMP(Sigma)を使用して、化学的架橋を行った。つまり、1mLの10M酸化ナトリウムを10gの多糖混合物に加え、続いて、300mgのSTMPを含む1mLの水を加えた。50℃で15分間インキュベーションした後、得られた足場を直径6mmの円板に切断し、PBS10X(pH7.4)中で中和し、次いで、0.025%NaCl溶液で広範囲に洗浄した。凍結乾燥工程後、多孔質複合多糖足場を、使用するまで室温で保管した。架橋前に、1%のフルオレセインイソチオシアネート(FITC)デキストラン(Sigma, St. Louis MO, USA)をこの混合物に加えることによって、蛍光足場を調製した。
Gimble et al, 2007によって以前に記載されているように、0.1%(w/v)コラゲナーゼI型で分解した後のヒト脂肪組織から、脂肪由来間質細胞(ADSC)を単離し、培養した。基礎培地(10%(v/v)ウシ胎仔血清(FBS)を補充したDMEM F12培地(Invitrogen))、又はADSCの骨芽細胞分化を誘導するための骨形成培地(10%(v/v)FBS(Lonza)、10−8Mデキサメタゾン(Sigma)、50mg/mlアスコルビン酸(Sigma)及び10mMβ−グリセロリン酸塩(Sigma)を補充したIMDM培地(Invitrogen))中で、残りの間質血管画分(SVF)を培養した。
無胸腺マウスの頭蓋冠部位において、同所性新骨形成を評価した。12週齢ヌードマウスをイソフルレン/N2O混合物で麻酔し、外科手術に供して、冠状の歯科用バーを使用して、左側及び右側頭頂骨に直径4mmの全層を作製した。n−HAを含まない円板状のマトリックス(グループ1)及びn−HAを含む複合多糖足場MATRI+(グループ2)を、頭頂骨の骨膜先端に移植した。グループ3は、移植前1週間に分化したADSCに結合した複合多糖足場を移植したマウスに対応する。
in vivo Explore Locus SP X-Rayマイクロコンピューター化断層撮影(マイクロCT)装置(General Electric)において、等方性分解能45μmで、マウスをスキャンした。回転中心の修正及びミネラル密度の校正をした後に、頭頂及び皮下領域の再構築を実施した。「Advanced Bone Analysis」(商標)ソフトウェア(GE)を使用して、骨の分析を実施した。バックグラウンドから石化要素を分離するために、ヒストグラムツールを使用して、濃淡値の閾値化を実施した。関心対象の領域(ROI)において、石化組織の密度(TMD)を決定した。
実験期間の終了時に、マウスを安楽死させ、サンプルをばらばらにし、PBS 0.1M pH7.4に溶解させた3.7%(v/v)パラホルムアルデヒド中で固定した。サンプルの一部分を脱石灰化し、パラフィンに包埋した。7ミクロンの永久切片を、ヘマトキシリン及びエオシン及びマッソントリクローム色素で染色した。Schenk et al, 1984によって記載されているように、サンプルの他の部分をメチルメタクリレートに包埋した。Leicaミクロトーム及びタングステンカーバイドブレードを使用して、縦切片(15μmの厚さ)を調製した。切片をGoldnerトリクロム, Von Kossaで染色し、Nikon Eclipse 80i顕微鏡を使用して観察した。DXM 1200 C (Nikon)CCDカメラを使用して、写真を作製した。
出発製剤にn−HAを含め、PCT patent applications WO2009/047346及びWO2009/047347に開示されている方法に従って、3D多孔質マトリックス(図1)を得た。懸濁液中のn−HA(6.36%(w/v))により、得られた3DマトリックスにおけるHAナノ粒子の均一分散が可能になった。n−HAマトリックスは、乾燥状態で、2.8+/−0.1%(w/w)のHAを含んでいた。n−HA懸濁液の代わりに乾燥形態のn−HAを使用することにより、マトリックス内部に大きな凝集を誘導した。n−HAの存在下における3Dマトリックスは、特許取得済みのプロセスによってコントロールされる孔のサイズを有する多孔質(図2)である。
材料と方法
実施例1に記載されるように、本発明のナノヒドロキシアパタイト及び足場を調製した。本発明者らは、前記足場の移植を動物において評価した。手順及び動物処置は両方とも、National Society for Medical Researchによって策定されたPrinciples of Laboratory Animal Careに従った。認可(No: 3300048 of the Ministere de l’Agriculture, France)の下、University of Bordeaux Segalenの公認動物施設において研究を行い、Animal Research Committee of Bordeaux Universityによって承認された。
2つの異なる足場製剤:n−HAを含まない円板状マトリックス(グループ1)及びn−HAを含む複合足場(MATRI+)(グループ2)(直径4mm及び深さ6mmの円柱状)を、体重25〜30gの12週齢Balb/cマウス(Charles River Laboratories, France)の背部に作製した皮下ポケットに挿入した。移植の15、30及び60日後にサンプルを取り出し、マイクロCT及び組織学的分析のために処理した。各グループにおいて、8個のサンプルを組織学的観察及びマイクロCTに使用した。
冠状の歯科用バーを使用して、体重150〜200gのWistarラット(Charles River Laboratories, France)の左側及び右側大腿顆の両方に内部穴(直径5mm及び深さ6mm)を作製した。骨欠損部から骨片を除去し、足場を欠損部内に導入する前に、この穴を生理溶液(NaCl0.9%(w/v))で洗浄した。2つの異なる足場製剤(n−HAを含まないマトリックス、及びn−HAを含む複合足場)を、各骨欠損部に移植した。足場を用いないコントロール実験も行った。手術後15、30、60及び90日にインプラントを取り出し、マイクロCT及び組織学的分析のために処理した。各グループにおいて、6個のサンプルをマイクロCT及び組織学的観察に使用した。
各移植期間の終了時に、過剰量のペントバルビタールナトリウム(Nembutal(登録商標))を注射することによって、動物を安楽死させた。その後すぐに、インプラント及び周囲組織を取り出し、0.1Mリン酸緩衝液に溶解させた4%(w/v)パラホルムアルデヒドで固定し、組織学の前にマイクロCTでスキャンした。次いで、組織学的分析のために、サンプルを調製した。一部分を脱石灰化し、脱水し、パラフィンに包埋した。薄片(厚さ7μm)を調製し、ヘマトキシリン及びエオシン、並びに類骨染色用のGoldnerトリクロムで染色した。他の部分を段階的な一連のエタノール中で脱水し、次いで、メチルメタクリレートで包埋し、続いて、これを重合させた。各インプラントから得られた4つの切片を用いて、改変したダイヤモンドブレードミクロトーム(Leica Microsystems SP1600, Rijswijk, The Netherlands)を使用して、10〜15μmの横切片を作製した。切片をGoldnerトリクロム、Von Kossaで染色し、Nikon Eclipse 80i顕微鏡を使用して観察した。DXM 1200 C (Nikon)CCDカメラを使用して、写真を作製した。
マイクロCTを使用して、インプラント及び周囲組織の三次元画像を現像した;これらのモデルを使用して、各移植部位における骨形成を定量化した。電源電圧80kV、電流60μA、及び分解能15μmのex vivo General Electric (GE)マイクロCT(Explore LP Locus, General Electric)を使用して、X線写真を得た。電源電圧150mV、電流450μA、及び分解能45μmで、in vivoマイクロCT(General Electric)を実施した。スキャン後、断面の切片を再構築し、Microviewソフトウェアを使用して3D分析を実施した。同じ閾値を使用して、各スキャン結果を再構築し、骨と空気とを区別した。各グループの骨ミネラル量(BMC)及び骨ミネラル密度(BMD)容量を測定し、スチューデントt検定を使用して統計的に分析した。
プロテアーゼ阻害剤(10μg/mlアプロチニン(Sigma)、10μg/mlロイペプチン(Sigma)及び1mM(4−(2−アミノエチル)ベンゼンスルホニルフルオリド塩酸塩(AEBSF)(Fluka)のカクテルを含むPBS中、電動破砕機を用いて、移植の2、15、30及び60日後に取り出した皮下インプラントを氷上で破砕した。次いで、溶解物を16000rpm、4℃で20分間遠心分離した。上清を回収し、次いで、ELISA分析のために−80℃で凍結した。Smith PK et al. (1985)によって記載されているビシンコニン酸(BCA)タンパク質アッセイキット (Thermoscientific)を使用して、タンパク質の定量化を実施した。550nmで吸光度を読み込んだ。毎回の移植に関してそれぞれ、n−HAを含まないマトリックス(グループ1)及びn−HAサンプルを含む複合足場MATRI+(グループ2)が8個あった。マウスVEGF免疫アッセイキット(MMV00, Quantikine(登録商標), R&D sytems)、及びBMP−2免疫アッセイキット(DBP200, Quantikine(登録商標), R&D sytems)をそれぞれ用いて、2つの異なるインプラント製剤内に保持されたVEGF165及びBMP2の量を定量化した。
移植の15、30及び60日後に、n−HAを含まないマトリックス及びn−HAを含む複合足場MATRI+の皮下インプラントを取り出した。いかなる有機組織も含まない微粉を得るために、それらを漂白剤により室温で2時間処理し、次いで、遠心分離してペレットのみの状態を維持した。二次モノクロメーターを備えるPANalytical X’pert MPD回折計(Bragg Brentano t-t geometry)及び銅放射線(平均λ=1,5418A°)を使用して、X線回折(XRD)によって、構造特性を調査したところ、作用張力及び強度は、それぞれ40kV及び40mAであった。
すべてのデータを平均±標準偏差(SD)として表し、スチューデントt検定の標準分析を使用して分析した。p<0.05(a)又はp<0.01(b)の場合、差が有意であると考えた。
2つの異なる足場(n−HAを含まないマトリックス(グループ1)及びn−HAを含む複合足場MATRI+(グループ2))を、Balb/cマウスに15、30及び60日間移植した。両グループに関して、マイクロCT、石化の定量化(BMC及びBMD分析)、及び組織学的研究を実施した。マイクロCT(図5A)並びにBMC及びBMDの定量化(図5B)によって示されるように、n−HAを含まないマトリックスの移植により、15日目〜60日目に、いかなる石化組織も形成されなかった。対照的に、各時点(図1B)で測定したBMC(骨ミネラル量)及びBMD(骨ミネラル密度)によって定量化すると、n−HAを含むマトリックス(いかなる細胞及び成長因子も含まない)の皮下部位における移植は、高密度石化組織の形成をもたらす(図5A)。石化プロセスは、15日目に足場周辺から始まり(図1A)、移植の60日後に高密度石化組織をもたらす。
Claims (15)
- 多孔質多糖足場を調製するための方法であって、以下の工程:
i)少なくとも1つの多糖の量、架橋剤の量、及びポロゲン剤の量を含むアルカリ性水溶液を調製すること、
ii)前記溶液を、約4℃〜約80℃の温度で、前記多糖の量を架橋させるのに十分な時間置くことによって、当該溶液をヒドロゲルにトランスフォーメーションすること、
iii)前記ヒドロゲルを溶媒、好ましくは水溶液に浸すこと、及び
iv)工程iii)で得られた多孔質多糖足場を洗浄すること
を含み、
工程i)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含む、方法。 - ポロゲン剤が、塩化ナトリウム、塩化カルシウム、炭酸アンモニウム、重炭酸アンモニウム、炭酸カルシウム、炭酸ナトリウム、及び重炭酸ナトリウム、及びそれらの混合物からなる群において選択される、請求項1記載の方法。
- 多糖とポロゲン剤の重量比が、1:50〜50:1、好ましくは1:30〜30:1、好ましくは1:12〜12:1、の範囲であり、好ましくは12:14である、請求項1又は2記載の方法。
- 多孔質多糖足場を調製するための方法であって、以下の工程:
a)少なくとも1つの多糖、及び1つの架橋剤の量を含むアルカリ性水溶液を調製すること、
b)工程a)の水溶液を凍結すること、
c)工程b)の凍結溶液を昇華させること
を含み、
工程a)のアルカリ性水溶液が、ヒドロキシアパタイト、好ましくはナノヒドロキシアパタイトをさらに含み、
工程a)の溶液中で多糖の架橋が起こる前に工程b)が実施される、方法。 - 前記多糖が、デキストラン、プルラン、寒天、アルギン酸、デンプン、ヒアルロン酸、イヌリン、ヘパリン、フコイダン、キトサン、及びそれらの混合物からなる群より選択される、請求項1〜4のいずれか一項に記載の方法。
- 前記多糖が、95:5〜5:95の範囲の比、好ましくは75:25(w/w)の比のプルラン/デキストラン混合物である、請求項1〜5のいずれか一項に記載の方法。
- 前記多糖が、約70:20:10〜約50:20:30、好ましくは約70:20:10〜約50:30:20の範囲の比、最も好ましくは約73:22:5(w/w)の比のプルラン/デキストラン/フコイダン混合物である、請求項1〜5のいずれか一項に記載の方法。
- 前記架橋剤が、トリメタリン酸三ナトリウム(STMP)、オキシ塩化リン(POCl3)、エピクロロヒドリン、ホルムアルデヒド、カルボジイミド、グルタルアルデヒド、及びそれらの混合物からなる群より選択される、請求項1〜7のいずれか一項に記載の方法。
- 前記ナノヒドロキシアパタイトが、0.3〜1Mに含まれる濃度、好ましくは0.6Mのリン酸溶液と、0.5〜1.5Mに含まれる濃度、好ましくは1Mの水酸化カルシウム溶液から、選択的に室温で化学沈殿することによって得られる、請求項1〜8のいずれか一項に記載の方法。
- アルカリ性多糖溶液中のナノヒドロキシアパタイトの濃度(w/v)が、0.01〜10%(w/v)、好ましくは0.1〜0.5%(w/v)、より好ましくは0.1〜0.3%(w/v)に含まれる、請求項9記載の方法。
- 請求項1〜10のいずれか一項に記載の方法によって得られる、多孔質多糖足場。
- 孔のサイズが、約1μm〜約500μm、好ましくは約10μm〜約200μmに含まれ、孔隙率が、約4%〜約75%、好ましくは約4%〜約50%である、請求項11記載の多孔質多糖足場。
- 骨の生成、好ましくは骨の修復及び/又は骨の発達に使用するための、請求項1〜10記載の方法によって得られる、多孔質多糖足場。
- 異所性石化組織形成を刺激するのに使用するための、請求項1〜10記載の方法によって得られる、多孔質多糖足場。
- 骨関連障害の処置において使用するための、請求項1〜10記載の方法によって得られる、多孔質多糖足場。
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Also Published As
Publication number | Publication date |
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WO2012028620A1 (en) | 2012-03-08 |
JP6049619B2 (ja) | 2016-12-21 |
US9757494B2 (en) | 2017-09-12 |
US20130224277A1 (en) | 2013-08-29 |
EP2611470B1 (en) | 2017-08-23 |
JP2019069231A (ja) | 2019-05-09 |
JP2017221738A (ja) | 2017-12-21 |
US20170319741A1 (en) | 2017-11-09 |
JP2013540465A (ja) | 2013-11-07 |
JP2016187585A (ja) | 2016-11-04 |
EP2611470A1 (en) | 2013-07-10 |
US10143774B2 (en) | 2018-12-04 |
US20150328365A1 (en) | 2015-11-19 |
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