JP2004329423A - Implant made from titanium and method for surface treating implant made from titanium - Google Patents
Implant made from titanium and method for surface treating implant made from titanium Download PDFInfo
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- JP2004329423A JP2004329423A JP2003127138A JP2003127138A JP2004329423A JP 2004329423 A JP2004329423 A JP 2004329423A JP 2003127138 A JP2003127138 A JP 2003127138A JP 2003127138 A JP2003127138 A JP 2003127138A JP 2004329423 A JP2004329423 A JP 2004329423A
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- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims abstract description 5
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 claims abstract description 5
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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Images
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、骨結合を得るためのチタン製インプラント及びその表面処理方法に関するものであり、更に詳しくはリン酸化アミノ酸及び／又はリン酸化ペプチドでその表面をコーティング処理されたチタン製インプラント及びその表面処理方法に関するものである。
【０００２】
【従来の技術】
インプラント治療は歯科補綴治療の一選択肢として広く普及している。この歯科補綴治療法における成否の主要因として「骨結合」の獲得の良否があり、骨結合によりインプラントのフィクスチャーは顎骨と一体化され、その後フィクスチャー上部に歯科補綴物が固定されて歯科補綴機能を果たす。しかしながら、骨結合を得るには下顎で３〜４ヶ月、上顎で６ヶ月の長期間に亘りフィクスチャーを歯肉下で安静状態に置くことが必要とされている。現在、患者を中心に考えるインプラント治療への気運が高まる中で骨結合を得るために要するこの３〜６ヶ月の期間を短縮することが課題となっている。
【０００３】
そのためには骨結合を早期に達成させることが極めて重要であり、この達成のためにインプラント材料表面の改質が技術的中心となっている。現在、インプラント材料として臨床で最も広く応用されているチタンの生体適合性は、表面に生成された緻密で強固な不動態膜と呼ばれる酸化膜（ＴｉＯ２）に起因すると考えられており、化学的侵襲に対して耐腐蝕性が高いだけでなく生体組織との強固な結合を得るのに充分な誘電率も有している。このチタンの性質を維持したまま早期に骨結合を得るための表面性状の改良、即ち「表面改質」は現在までに金属イオン処理（例えば、特許文献１〜４参照。），プラズマコーティング（例えば、非特許文献１参照。），リン酸カルシウムコーティング（例えば、非特許文献２参照。），サンドブラストと酸処理の併用（例えば、非特許文献３参照。），水熱アルカリ処理（例えば、非特許文献４参照。）などがある。しかしながら、これらの従来の表面改質ではコーティング材料とチタンとの界面が破壊してしまったり、コーティング材料自体が破壊を起こしてしまうなどの問題があり、必ずしも充分な骨結合が早期に達成されているとは言えなかった。
【０００４】
そこで最近では、細胞接着性タンパク質や構造タンパク質などの組織再生を誘導する生体機能性タンパク質によるチタン表面改質が注目を集めている。例えば、骨芽細胞を表面にコーティングしたり（例えば、特許文献５参照。）、カルシウム又はリンと酵素でコーティングしたり（例えば、特許文献６参照。）、チタン表面にシラン処理を行った上でペプチドを結合させたり（例えば、非特許文献５参照。）、シラン処理を行った上で生体吸収性高分子材料を結合させたり（例えば、非特許文献６参照。）、チタン表面に金蒸着を行った上でペプチドを結合させたり（例えば、非特許文献７参照。）、チタン表面に生体吸収性高分子材料をコーティングした上でペプチドを結合させる方法（例えば、非特許文献８参照。）が行われた。しかしながら、これらの試みはいずれも処理過程が複雑な上に表面をコーティングしただけで化学的に結合していないため不安定であるなどの問題があり、接着因子をチタン表面に確実に結合させるには至っていない。
【０００５】
【特許文献１】
特開平５−２８５２１２号公報
【特許文献２】
特開平５−２８５２１３号公報
【特許文献３】
特開平８−２９９４２９号公報
【特許文献４】
特開平１０−１０８９０５号公報
【特許文献５】
特開２００１−３３３９７４号公報
【特許文献６】
特開平５−２３３６１号公報
【非特許文献１】
Ｆｉｌｉａｇｇｉ， Ｍ．Ｊ．， Ｃｏｏｍｂｓ， Ｎ．Ａ． ａｎｄ Ｐｉｌｌｉａｒ， Ｒ．Ｍ．： Ｃｈａｒａｃｔｅｒｉｚａｔｉｏｎ ｏｆ ｔｈｅ ｉｎｔｅｒｆａｃｅ ｉｎ ｔｈｅ ｐｌａｓｍａ−ｓｐｒａｙｅｄ ＨＡ ｃｏａｔｉｎｇ／Ｔｉ−６Ａｌ−４Ｖ ｉｍｐｌａｎｔ ｓｙｓｔｅｍ． Ｊ． Ｂｉｏｍｅｄ． Ｍａｔｅｒ Ｒｅｓ． ２５， １２１１−１２２９， １９９１．
【非特許文献２】
Ｈｕｌｓｈｏｆｆ， Ｊ．Ｅ．Ｇ．， ｖａｎ Ｄｉｊｋ， Ｋ．， ｄｅ Ｒｕｉｊｔｅｒ， Ｊ．Ｅ．， Ｒｉｅｔｖｅｌｄ， Ｆ．Ｊ．Ｒ．， Ｇｉｎｓｅｌ， Ｌ．Ａ． ａｎｄ Ｊａｎｓｅｎ， Ｊ．Ａ． Ｉｎｔｅｒｆａｃｉａｌ ｐｈｅｎｏｍｅｎａ： Ａｎ ｉｎ ｖｉｔｒｏ ｓｔｕｄｙ ｏｆ ｔｈｅ ｅｆｆｅｃｔ ｏｆ ｃａｌｃｉｕｍ ｐｈｏｓｐｈａｔｅ （Ｃａ−Ｐ） ｃｅｒａｍｉｃ ｏｎ ｂｏｎｅ ｆｏｒｍａｔｉｏｎ． Ｊ． Ｂｉｏｍｅｄ． Ｍａｔｅｒ Ｒｅｓ． ４０， ４６４−４７４， １９９８
【非特許文献３】
Ｃａｒｌｓｓｏｎ， Ｌ．， Ｒｏｅｓｔｌｕｎｄ， Ｔ．， Ａｌｂｒｅｋｔｓｓｏｎ， Ｂ． ａｎｄ Ａｌｂｒｅｋｔｓｓｏｎ， Ｔ．： Ｒｅｍｏｖａｌ ｔｏｒｑｕｅｓ ｆｏｒ ｐｏｌｉｓｈｅｄ ａｎｄ ｒｏｕｇｈ ｔｉｔａｎｉｕｍ ｉｍｐｌａｎｔｓ． Ｉｎｔ． Ｊ． Ｏｒａｌ Ｍａｘｉｌｌｏｆａｃ． Ｉｍｐｌａｎｔｓ ３， ２１−２４， １９８８．
【非特許文献４】
Ｙａｎ， Ｗ．Ｑ．， Ｎａｋａｍｕｒａ， Ｔ．， Ｋｏｂａｙａｓｈｉ， Ｍ．， Ｋｉｍ， Ｈ−Ｍ．， Ｍｉｙａｊｉ， Ｆ． ａｎｄ Ｋｏｋｕｂｏ， Ｔ．： Ｂｏｎｄｉｎｇ ｏｆ ｃｈｅｍｉｃａｌｌｙ ｔｒｅａｔｅｄ ｔｉｔａｎｉｕｍ ｉｍｐｌａｎｔｓ ｔｏ ｂｏｎｅ． Ｊ． Ｂｉｏｍｅｄ． Ｍａｔｅｒ Ｒｅｓ． ３７， ２６７−２７５， １９９７．
【非特許文献５】
Ｘｉａｎｏ， Ｓ．Ｊ．， Ｔｅｘｔｏｒ， Ｍ．， Ｓｐｅｎｃｅｒ， Ｎ．Ｄ．， Ｗｉｅｌａｎｄ， Ｍ．， Ｋｅｌｌｅｒ， Ｂ． ａｎｄ Ｓｉｇｒｉｓｔ， Ｈ．： Ｉｍｍｏｂｉｌｉｚａｔｉｏｎ ｏｆ ｔｈｅ ｃｅｌｌ−ａｄｈｅｓｉｖｅ ｐｅｐｔｉｄｅ Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｃｙｓ （ＲＧＤＣ） ｏｎ ｔｉｔａｎｉｕｍ ｓｕｒｆａｃｅｓ ｂｙ ｃｏｖａｌｅｎｔ ｃｈｅｍｉｃａｌ ａｔｔａｃｈｍｅｎｔ． Ｊ． Ｍａｔｅｒ Ｓｃｉ： Ｍａｔｅｒ Ｍｅｄ． ８， ８６７−８７２， １９９７．
【非特許文献６】
Ｂｅａｒｉｎｇｅｒ， Ｊ．Ｐ．， Ｃａｓｔｎｅｒ， Ｄ．Ｇ．， Ｇｏｌｌｅｄｇｅ， Ｓ．Ｌ．， Ｒｅｚａｎｉａ， Ａ．， Ｈｕｂｃｈａｋ， Ｓ． ａｎｄ Ｈｅａｌｙ， Ｋ．Ｅ．： Ｐ（ＡＡｍ−ｃｏ−ＥＧ） ｉｎｔｅｒｐｅｎｅｔｒａｔｉｎｇ ｎｅｔｗｏｒｋｓ ｇｒａｆｔｅｄ ｔｏ ｏｘｉｄｅ ｓｕｒｆａｃｅｓ： Ｓｕｒｆａｃｅ ｃｈａｒａｃｔｅｒｉｚａｔｉｏｎ， ｐｒｏｔｅｉｎ ａｄｓｏｒｐｔｉｏｎ， ａｎｄ ｃｅｌｌ ｄｅｔａｃｈｍｅｎｔ ｓｔｕｄｉｅｓ． Ｌａｎｇｍｕｉｒ １３， ５１７５−５１８３， １９９７．
【非特許文献７】
Ｆｅｒｒｉｓ， Ｄ．Ｍ．， Ｍｏｏｄｉｅ， Ｇ．Ｄ．， Ｄｉｍｏｎｄ， Ｐ．Ｍ．， Ｇｉｏｒａｎｎｉ， Ｃ．Ｗ．， Ｅｈｒｌｉｃｈ， Ｍ．Ｇ， ａｎｄ Ｖａｌｅｎｔｉｎｉ， Ｒ．Ｆ．： ＲＧＤ−ｃｏａｔｅｄ ｔｉｔａｎｉｕｍ ｉｍｐｌａｎｔｓ ｓｔｉｍｕｌａｔｅ ｉｎｃｒｅａｓｅｄ ｂｏｎｅ ｆｏｒｍａｔｉｏｎ ｉｎ ｖｉｖｏ． Ｂｉｏｍａｔｅｒｉａｌｓ ２０， ２３２３−２３３１， １９９９．
【非特許文献８】
Ｋｅｎａｕｓｉｓ， Ｇ．Ｌ．， Ｖｏｅｒｏｅｓ， Ｊ．， Ｅｌｂｅｒｔ， Ｄ．Ｌ．， Ｈｕａｎｇ， Ｎ．， Ｈｏｆｅｒ， Ｒ．， Ｒｕｉｚ−Ｔａｙｌｏｒ， Ｌ．， Ｔｅｘｔｏｒ， Ｍ．， Ｈｕｂｂｅｌｌ， Ｊ．Ａ． ａｎｄ Ｓｐｅｎｃｅｒ， Ｎ．Ｄ．： Ｐｏｌｙ（Ｌ−１ｙｓｉｎｅ）−ｇ−ｐｏｌｙ （ｅｔｈｙｌｅｎｅ ｇｌｙｃｏｌ） Ｉａｙｅｒｓ ｏｎ ｍｅｔａｌ ｓｕｒｆａｃｅｓ： ａｔｔａｃｈｍｅｎｔ ｍｅｃｈａｎｉｓｍ ａｎｄ ｅｆｆｅｃｔｓ ｏｆ ｐｏｌｙｍｅｒ ａｒｃｈｉｔｅｃｔｕｒｅ ｏｎ ｒｅｓｉｓｔａｎｃｅ ｔｏ ｐｒｏｔｅｉｎ ａｄｓｏｒｐｔｉｏｎ． Ｊ． Ｐｈｙ Ｃｈｅｍ． Ｂ １０４， ３２９８−３３０９， ２０００．
【０００６】
【発明が解決しようとする課題】
そこで本研究は、処理が複雑で不安定であったチタン製インプラントの従来の表面改質に代えて、早期に且つ簡単確実に骨結合を得ることが可能な表面改質を行ったチタン製インプラント及びその表面処理方法を提供することを課題とする。
【０００７】
【課題を解決するための手段】
本発明者等は前記課題を解決すべく鋭意検討した結果、生体機能性タンパク質やペプチドなどを細胞接着因子として用いてチタン表面の改質を行った場合には、細胞接着因子が生体内でチタン表面から剥がれてしまい標的となる細胞に先に結合し、その結果細胞が材料表面へ接着することを妨げられるか、又はこれらの細胞接着因子と細胞とが共に材料表面から剥がれしまい生体内でインプラントの表面改質の効果が十分に発揮されない可能性が高いと考えた。そこで、従来の生体機能性タンパク質やペプチドなどの細胞接着因子に比べて分子量の小さいアミノ酸や分子量の小さい（又は三次元構造を有さない、又は結合しているアミノ酸の数が大凡３０以下の）ペプチドであればその合成純度が高く三次元構造にも依存しないこと及びリン酸基がチタンに対して結合性が高いことに着目し、接着性タンパク質の構成分子であるアミノ酸をリン酸化するか又はペプチドをリン酸化してチタン表面に化学的に結合させることで課題は解決可能であることを究明して本発明を完成したのである。
【０００８】
即ち本発明は、リン酸化したアミノ酸及び／又はリン酸化したペプチドで表面がコーティングされていることを特徴とするチタン製インプラントと、リン酸化したアミノ酸及び／又はリン酸化したペプチドでチタン製インプラントの表面をコーティング処理することを特徴とするチタン製インプラントの表面処理方法とに関するものである。
【０００９】
そして、リン酸化したアミノ酸としては、リン酸化チロシン，リン酸化セリン又はリン酸化スレオニンが、リン酸化したペプチドとしては、アルギニン−グリシン−アスパラギン酸の順に配列したペプチドの末端基がリン酸化されたものが好ましいことも究明したのである。
【００１０】
またこのようなチタン製インプラントの表面処理方法においては、チタン製インプラントの表面のコーティング処理を、濃度が０．０５〜５重量％であるペルオキソ二硫酸ナトリウム（Ｎａ２Ｓ２Ｏ８）の水溶液，０．０１Ｎ以上の硫酸（Ｈ２ＳＯ４）水溶液，０．０１Ｎ以上の塩酸（ＨＣｌ）水溶液の中から選ばれた少なくとも１種の水溶液により表面を洗浄した後に行うことが好ましいことも究明したのである。
【００１１】
【発明の実施の形態】
本発明で言うチタン製インプラントとは、チタン又はチタン合金により構成された生体内で使用するための成形体を意味する。チタン製インプラントは生体内で使用するために必要な物性と安全性とを有するものであれば、形状、使用形態などを特に問わない。例えば、人工骨金属材料としては柱状，板状，ブロック状，シート状，繊維状，ペレット状など任意の形状のものが使用できる。また、人工股関節用ステム材，骨補填材，人工椎体，人工歯根，人工椎間板，骨プレート，骨スクリューなどの製品形態をしていてもよい。
【００１２】
本発明に係るチタン製インプラントの表面処理は、リン酸化したアミノ酸及び／又はリン酸化したペプチドで表面処理を行うのに先立って、チタン製インプラントの表面を洗浄することが好ましい。洗浄は酸処理が好ましく、中でも濃度が０．０５〜５重量％であるペルオキソ二硫酸ナトリウム（Ｎａ２Ｓ２Ｏ８）の水溶液，０．０１Ｎ以上の硫酸（Ｈ２ＳＯ４）水溶液，０．０１Ｎ以上の塩酸（ＨＣｌ）水溶液の中から選ばれた少なくとも１種の水溶液で行うのが好ましい。特に、塩酸で処理した場合にはリン酸化したアミノ酸及やリン酸化したペプチドのチタン表面への結合が著しく向上するので最も好ましい。
【００１３】
前記したように必要により酸処理による表面洗浄を行った後、リン酸化したアミノ酸、好ましくはリン酸化チロシン，リン酸化セリン，リン酸化スレオニンと、リン酸化したペプチド、好ましくはアルギニン−グリシン−アスパラギン酸の順に配列したペプチドの末端基がリン酸化されたものの中から選ばれた少なくとも１種で表面にコーティング処理を行う。各リン酸化したアミノ酸及びリン酸化したペプチドは水溶液の状態でチタン製インプラントの表面にコーティング処理することが好ましく、その濃度は５ｍＭ以上であることが好ましい。５ｍＭ未満であると表面処理に時間が必要となるのは勿論、リン酸化したアミノ酸及びリン酸化したペプチドのコーティング層の安定性が低下する虞がある。表面処理は０〜１２０℃の範囲で行うことができるが、アミノ酸及びペプチドの熱変性を考慮すると４２℃以下であることが好ましく、表面処理の効率から考えて２０℃未満での処理は現実的ではない。特に好ましくは２５〜３７℃である。
【００１４】
【実施例】
以下、実施例により本発明を具体的に説明するが、本発明はこの実施例に限定されるものではない。
【００１５】
実施例１
チタン製インプラントの材料としてＪＩＳＨ４６５０（チタン棒）の２種であって、直径５．８ｍｍ，厚さ２ｍｍのチタンディスクを用いた。このチタンディスクを１０Ｎ塩酸（片山化学工業社製）水溶液中で３０分間超音波洗浄処理後、超純水中にて３０分間超音波洗浄処理した。結合させるアミノ酸としてリン酸化したＬ−スレオニン（Ｏ−Ｐｈｏｓｐｈｏ−Ｌ−ｔｈｒｅｏｎｉｎｅ：シグマ社製）（以下、Ｐ−Ｔｈｒと表記する）を用いた。チタンディスクを５０ｍＭに調整したＰ−Ｔｈｒ溶液中に３７℃，１２時間浸漬して表面にコーティング処理を行った。
【００１６】
Ｐ−Ｔｈｒとチタンディスク表面との結合の度合いを評価するためにＸ線光電子分光法（ＸＰＳ）装置（ＡＸＩＳ−ＨＳ，Ｋｒａｔｏｓ社製）を用いてチタンディスク表面のＰ−ＴｈｒのＰ２ｐのナロースペクトルにおける結合エネルギーを測定し、Ｐ−Ｔｈｒのみの値との間の有意差について一元配置分散分析法及び多重比較Ｔｕｋｅｙ法を用いて有意水準１％及び５％統計学的分析を行った。
【００１７】
＜Ｐ２ｐスペクトルの結合エネルギーの評価＞
Ｐ−Ｔｈｒ粉末単体及び表面処理したチタンディスク表面上のＰ−ＴｈｒのＰ２ｐのナロースペクトルを図１に示した。表面処理したチタンディスク表面上のＰ−ＴｈｒのＰ２ｐの結合エネルギーは１３３．７ｅＶを示し、粉末単体の１３４．ＯｅＶと比較して有意に０．３ｅＶ低エネルギー側にシフトしていることが確認でき（Ｐ＜０．０５）、Ｐ−Ｔｈｒがチタン表面に化学的に結合していることが確認された。また、この結合は蒸留水，生理食塩水などの水や、エタノール，アセトン中で解離することが無く極めて安定であることを別途確認した。
【００１８】
実施例２
実施例１と同様なチタンディスクを実施例１と同じ方法で洗浄処理後、結合させるアミノ酸としてリン酸化したＬ−セリン（Ｏ−Ｐｈｏｓｐｈｏ−Ｌ−Ｓｅｒｉｎｅ：シグマ社製）を用いた。チタンディスクを５０ｍＭに調整したＬ−セリン溶液中に３０℃，１２時間浸漬して表面にコーティング処理を行った。
【００１９】
実施例３
実施例１と同様なチタンディスクを１０Ｎ硫酸（片山化学工業社製）水溶液中で３０分間超音波洗浄処理後、超純水中にて３０分間超音波洗浄処理した。結合させるアミノ酸として実施例１と同じリン酸化したＬ−スレオニンを用いて、実施例１と同様にして表面にコーティング処理を行った。
【００２０】
実施例２及び実施例３において、リン酸化したアミノ酸がチタンディスク表面に結合している割合を実施例１と同様に評価した。その結果、結合エネルギーが有意に低エネルギー側にシフトしていることが確認され、チタン表面に化学的に結合していることが確認できた。
【００２１】
【発明の効果】
以上から明らかなように本発明に係るチタン製インプラントの表面処理方法で表面処理されたチタン製インプラントは、細胞接着因子である特定のアミノ酸やペプチドをリン酸化することでチタン製インプラント表面に簡単且つ確実に結合させコーティングされたものであり、その結果、簡単にインプラントの早期の骨結合を得ることができるのでチタン製インプラントを用いる医療分野に貢献する価値の非常に大なるものである。
【図面の簡単な説明】
【図１】Ｐ−Ｔｈｒ粉末単体及び表面処理したチタンディスク表面上のＰ−ＴｈｒのＰ２ｐのナロースペクトル図である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a titanium implant for obtaining osteointegration and a surface treatment method thereof, and more particularly, to a titanium implant whose surface is coated with a phosphorylated amino acid and / or a phosphorylated peptide and a surface treatment thereof It is about the method.
[0002]
[Prior art]
Implant treatment is widely used as an option for dental prosthetic treatment. The main factor in the success or failure of this dental prosthesis treatment is the success or failure of obtaining the “osseointegration”. The osseointegration integrates the fixture of the implant with the jawbone, and then the dental prosthesis is fixed on the upper part of the dental prosthesis. Perform the function. However, obtaining the osteointegration requires the fixture to rest subgingivally for a prolonged period of 3-4 months in the lower jaw and 6 months in the upper jaw. At present, it is an issue to shorten the period of 3 to 6 months required for obtaining osteointegration in a situation where patient treatment is focused on implant treatment.
[0003]
For that purpose, it is extremely important to achieve osteointegration early, and for this purpose, the modification of the surface of the implant material has become a technical center. At present, the biocompatibility of titanium, which is most widely applied clinically as an implant material, is considered to be due to an oxide film (TiO 2 ) called a dense and strong passivation film formed on the surface. It is not only highly corrosion resistant to invasion, but also has a sufficient dielectric constant to obtain a strong bond with living tissue. Improvement of surface properties to obtain osteointegration as early as possible while maintaining the properties of titanium, that is, "surface modification" has been performed by metal ion treatment (for example, see Patent Documents 1 to 4), plasma coating (for example, see Patent Documents 1 to 4). , Non-patent document 1), calcium phosphate coating (for example, see non-patent document 2), combined use of sandblasting and acid treatment (for example, see non-patent document 3), and hydrothermal alkali treatment (for example, non-patent document 4) Reference). However, with these conventional surface modifications, there is a problem that the interface between the coating material and titanium is destroyed or the coating material itself is destroyed, and sufficient osteointegration is not necessarily achieved early. I couldn't say.
[0004]
Therefore, recently, titanium surface modification by a biofunctional protein that induces tissue regeneration such as a cell adhesive protein or a structural protein has attracted attention. For example, after osteoblasts are coated on the surface (for example, see Patent Literature 5), or coated with calcium or phosphorus and an enzyme (for example, see Patent Literature 6), or after silane treatment is performed on the titanium surface, A peptide is bonded (for example, see Non-Patent Document 5), or a bioabsorbable polymer material is bonded after silane treatment (for example, see Non-Patent Document 6), or gold deposition is performed on a titanium surface. A method of binding a peptide after performing the method (for example, see Non-Patent Document 7) or a method of binding a peptide after coating a bioabsorbable polymer material on a titanium surface (for example, see Non-Patent Document 8). It was conducted. However, each of these attempts has a problem that the treatment process is complicated and is unstable because it is not chemically bonded only by coating the surface, and it is difficult to surely bond the adhesion factor to the titanium surface. Has not been reached.
[0005]
[Patent Document 1]
JP-A-5-285212 [Patent Document 2]
JP-A-5-285213 [Patent Document 3]
JP-A-8-299429 [Patent Document 4]
JP-A-10-108905 [Patent Document 5]
JP 2001-333974 A [Patent Document 6]
JP-A-5-23361 [Non-Patent Document 1]
Filiagi, M.A. J. Coombs, N .; A. and Pillar, R.A. M. : Characterization of the interface in the plasma-sprayed HA coating / Ti-6Al-4V implant system. J. Biomed. Mater Res. 25, 1211-1229, 1991.
[Non-patent document 2]
Hulshoff, J .; E. FIG. G. FIG. , Van Dijk, K .; , De Ruijter, J. et al. E. FIG. , Rietveld, F.A. J. R. Ginsel, L .; A. and Jansen, J.M. A. Interfacial phenomena: An in vitro study of the effect of calcium phosphate (Ca-P) ceramic on bone formation. J. Biomed. Mater Res. 40, 464-474, 1998
[Non-Patent Document 3]
Carlsson, L.A. Roestlund, T .; Albrktsson, B .; and Albrektsson, T.W. : Removal toques for Polished and rooted titanium implants. Int. J. Oral Maxillofac. Implants 3, 21-24, 1988.
[Non-patent document 4]
Yan, W.C. Q. Nakamura, T .; Kobayashi, M .; , Kim, HM. , Miyaji, F .; and Kokubo, T.W. : Bonding of chemically treated titanium implants to bone. J. Biomed. Mater Res. 37, 267-275, 1997.
[Non-Patent Document 5]
Xiano, S.M. J. , Textor, M.A. , Spencer, N .; D. Wieland, M .; Keller, B .; and Sigrist, H.C. : Immobilization of the cell-adhesive peptide Arg-Gly-Asp-Cys (RGDC) on titanium surfactants by covalent chemical attachment. J. Mater Sci: Mater Med. 8, 867-872, 1997.
[Non-Patent Document 6]
Bearinger, J. et al. P. , Castner, D.A. G. FIG. Golledge, S .; L. , Rezania, A .; , Hubchak, S .; and Heally, K.C. E. FIG. : P (AAm-co-EG) interpenetrating networks grafted to oxide surfaces: Surface characterisation, protein adoption, and cell detachment studies. Langmuir 13, 5175-5183, 1997.
[Non-Patent Document 7]
Ferris, D.M. M. Moody, G .; D. , Dimond, P .; M. Giorani, C .; W. Ehrlich, M .; G. and Valentini, R .; F. : RGD-coated titanium implants stimulant increased bone formation in vivo. Biomaterials 20, 2323-2331, 1999.
[Non-Patent Document 8]
Kenausis, G .; L. , Voeroes, J .; , Elbert, D.A. L. Huang, N .; Hofer, R .; , Ruiz-Taylor, L .; , Textor, M.A. , Hubbell, J .; A. and Spencer, N.W. D. Poly (L-1 ysine) -g-poly (ethylene glycol) Layers on metal surfaces: attachment mechanism and effects of polymer proofing in trophy. J. Phys Chem. B 104, 3298-3309, 2000.
[0006]
[Problems to be solved by the invention]
In this study, instead of the conventional surface modification of a titanium implant, which had been complicated and unstable, the present study conducted a surface modification that could quickly and easily obtain osteointegration. And to provide a surface treatment method therefor.
[0007]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, when the surface of titanium is modified using a biofunctional protein or peptide as a cell adhesion factor, the cell adhesion Either they are detached from the surface and bind to target cells first, which prevents the cells from adhering to the material surface, or these cell adhesion factors and cells are both detached from the material surface and implanted in vivo It was considered that there was a high possibility that the effect of surface modification of the compound was not sufficiently exhibited. Therefore, compared to conventional cell adhesion factors such as biofunctional proteins and peptides, amino acids having a small molecular weight or small molecular weight (or having no three-dimensional structure or having about 30 or less bound amino acids) Focusing on the fact that the peptide has a high synthetic purity and does not depend on the three-dimensional structure and that the phosphate group has a high binding property to titanium, the peptide phosphorylates the amino acid that is a constituent molecule of the adhesive protein or The present inventors have determined that the problem can be solved by phosphorylating the peptide and chemically bonding the peptide to the titanium surface, thereby completing the present invention.
[0008]
That is, the present invention provides a titanium implant characterized in that the surface is coated with a phosphorylated amino acid and / or a phosphorylated peptide, and a surface of the titanium implant with a phosphorylated amino acid and / or a phosphorylated peptide. A surface treatment method for a titanium implant, which is characterized by performing a coating treatment on a titanium implant.
[0009]
The phosphorylated amino acids are phosphorylated tyrosine, phosphorylated serine or phosphorylated threonine, and the phosphorylated peptides are those in which the terminal group of the peptide arranged in the order of arginine-glycine-aspartic acid is phosphorylated. We have also found good things.
[0010]
In such a method for treating the surface of a titanium implant, the surface of the titanium implant is coated with an aqueous solution of sodium peroxodisulfate (Na 2 S 2 O 8 ) having a concentration of 0.05 to 5% by weight. Since it was also determined that it is preferable to perform the cleaning after cleaning the surface with at least one aqueous solution selected from a 0.01 N or more aqueous sulfuric acid (H 2 SO 4 ) solution and a 0.01 N or more aqueous hydrochloric acid (HCl) solution. is there.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
The titanium implant referred to in the present invention means a molded body made of titanium or a titanium alloy for use in a living body. The shape and use form of the titanium implant are not particularly limited as long as it has physical properties and safety necessary for use in a living body. For example, as the artificial bone metal material, any shape such as a column, a plate, a block, a sheet, a fiber, and a pellet can be used. Further, it may be in the form of a product such as an artificial hip joint stem material, a bone replacement material, an artificial vertebral body, an artificial tooth root, an artificial intervertebral disc, a bone plate, and a bone screw.
[0012]
In the surface treatment of the titanium implant according to the present invention, it is preferable to clean the surface of the titanium implant before performing the surface treatment with the phosphorylated amino acid and / or the phosphorylated peptide. The washing is preferably carried out by an acid treatment, and among them, an aqueous solution of sodium peroxodisulfate (Na 2 S 2 O 8 ) having a concentration of 0.05 to 5% by weight, an aqueous solution of sulfuric acid (H 2 SO 4 ) of 0.01 N or more, and an aqueous solution of 0. It is preferable to use at least one aqueous solution selected from aqueous solutions of hydrochloric acid (HCl) of 01N or more. In particular, treatment with hydrochloric acid is most preferable because the binding of phosphorylated amino acids and phosphorylated peptides to the titanium surface is significantly improved.
[0013]
As described above, after washing the surface by acid treatment as necessary, a phosphorylated amino acid, preferably phosphorylated tyrosine, phosphorylated serine, phosphorylated threonine, and a phosphorylated peptide, preferably arginine-glycine-aspartic acid, The coating treatment is performed on the surface with at least one selected from phosphorylated terminal groups of the peptides arranged in order. Each phosphorylated amino acid and phosphorylated peptide is preferably coated on the surface of a titanium implant in an aqueous solution, and the concentration thereof is preferably 5 mM or more. When the concentration is less than 5 mM, not only does the surface treatment require time, but also the stability of the coating layer of phosphorylated amino acids and phosphorylated peptides may be reduced. The surface treatment can be performed in the range of 0 to 120 ° C, but is preferably 42 ° C or less in consideration of the thermal denaturation of amino acids and peptides, and the treatment at less than 20 ° C is practical in view of the efficiency of the surface treatment. is not. Particularly preferably, it is 25 to 37 ° C.
[0014]
【Example】
Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
[0015]
Example 1
Two types of JIS H4650 (titanium rod) were used as titanium implant materials, and titanium disks having a diameter of 5.8 mm and a thickness of 2 mm were used. This titanium disk was subjected to ultrasonic cleaning in an aqueous solution of 10N hydrochloric acid (manufactured by Katayama Chemical Industry) for 30 minutes, and then ultrasonically cleaned in ultrapure water for 30 minutes. Phosphorylated L-threonine (O-Phospho-L-threonine: manufactured by Sigma) (hereinafter referred to as P-Thr) was used as the amino acid to be bound. A titanium disk was immersed in a P-Thr solution adjusted to 50 mM at 37 ° C. for 12 hours to perform a coating treatment on the surface.
[0016]
In order to evaluate the degree of bonding between P-Thr and the surface of the titanium disk, a narrow spectrum of P2Th of P-Thr on the surface of the titanium disk using an X-ray photoelectron spectroscopy (XPS) apparatus (AXIS-HS, manufactured by Kratos). Was measured, and significance levels of 1% and 5% were analyzed using a one-way analysis of variance method and a multiple comparison Tukey method for a significant difference from the value of P-Thr alone.
[0017]
<Evaluation of binding energy of P2p spectrum>
FIG. 1 shows the narrow spectrum of P2Th powder alone and P2P of P-Thr on the surface-treated titanium disk surface. The binding energy of P2Th P2p on the surface-treated titanium disk surface was 133.7 eV, and that of the powder alone was 134.eV. It was confirmed that the energy was significantly shifted to 0.3 eV lower energy side as compared with OeV (P <0.05), and it was confirmed that P-Thr was chemically bonded to the titanium surface. In addition, it was separately confirmed that this bond was extremely stable without dissociation in water such as distilled water or physiological saline, ethanol, or acetone.
[0018]
Example 2
After washing the same titanium disk as in Example 1 in the same manner as in Example 1, phosphorylated L-serine (O-Phospho-L-Serine: manufactured by Sigma) was used as the amino acid to be bound. A titanium disk was immersed in an L-serine solution adjusted to 50 mM at 30 ° C. for 12 hours to coat the surface.
[0019]
Example 3
The same titanium disk as in Example 1 was subjected to ultrasonic cleaning in an aqueous solution of 10N sulfuric acid (manufactured by Katayama Chemical Industry Co., Ltd.) for 30 minutes, and then subjected to ultrasonic cleaning in ultrapure water for 30 minutes. Using the same phosphorylated L-threonine as in Example 1 as the amino acid to be bound, the surface was coated in the same manner as in Example 1.
[0020]
In Examples 2 and 3, the ratio of phosphorylated amino acids binding to the titanium disk surface was evaluated in the same manner as in Example 1. As a result, it was confirmed that the binding energy was significantly shifted to the lower energy side, and it was confirmed that the binding energy was chemically bonded to the titanium surface.
[0021]
【The invention's effect】
As is clear from the above, the titanium implant surface-treated by the method for treating the surface of the titanium implant according to the present invention can be easily and easily applied to the surface of the titanium implant by phosphorylating a specific amino acid or peptide that is a cell adhesion factor. It is of great value to the medical field using titanium implants because it is a secure bond and coated, so that an early osteointegration of the implant can easily be obtained.
[Brief description of the drawings]
FIG. 1 is a narrow spectrum diagram of P2Th powder alone and P2P of P-Thr on a surface-treated titanium disk surface.
Claims (5)
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| CN114917414A (en) * | 2022-04-26 | 2022-08-19 | 东南大学 | Multifunctional composite coating for preparing magnesium alloy cardiac stent material and preparation method thereof |
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| WO2001056628A1 (en) * | 2000-02-04 | 2001-08-09 | Isotis N.V. | Proteinaceous coating |
| JP2002035107A (en) * | 2000-06-21 | 2002-02-05 | Merck Patent Gmbh | Coating for metallic implantation |
| WO2003035123A1 (en) * | 2001-10-24 | 2003-05-01 | Howmedica Osteonics Corp. | Antibiotic calcium phosphate coating |
| JP2003225087A (en) * | 2002-02-04 | 2003-08-12 | Univ Hiroshima | Substrate board for adhering cell and method for treating surface of the substrate board |
| JP2005525152A (en) * | 2002-02-15 | 2005-08-25 | ドット ゲーエムベーハー | Titanium implant with one or more foundations to replace body joints |
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| JPH10113130A (en) * | 1996-10-09 | 1998-05-06 | Ajinomoto Co Inc | Feed additive composition for ruminant |
| WO2001056628A1 (en) * | 2000-02-04 | 2001-08-09 | Isotis N.V. | Proteinaceous coating |
| JP2002035107A (en) * | 2000-06-21 | 2002-02-05 | Merck Patent Gmbh | Coating for metallic implantation |
| WO2003035123A1 (en) * | 2001-10-24 | 2003-05-01 | Howmedica Osteonics Corp. | Antibiotic calcium phosphate coating |
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| CN114917414A (en) * | 2022-04-26 | 2022-08-19 | 东南大学 | Multifunctional composite coating for preparing magnesium alloy cardiac stent material and preparation method thereof |
| CN114917414B (en) * | 2022-04-26 | 2023-09-29 | 东南大学 | Multifunctional composite coating for preparing magnesium alloy heart stent material and preparation method thereof |
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