JP4374410B2 - Bone regeneration induction material - Google Patents
Bone regeneration induction material Download PDFInfo
- Publication number
- JP4374410B2 JP4374410B2 JP2000185878A JP2000185878A JP4374410B2 JP 4374410 B2 JP4374410 B2 JP 4374410B2 JP 2000185878 A JP2000185878 A JP 2000185878A JP 2000185878 A JP2000185878 A JP 2000185878A JP 4374410 B2 JP4374410 B2 JP 4374410B2
- Authority
- JP
- Japan
- Prior art keywords
- bone
- bone regeneration
- inducing material
- copolymer
- periosteum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Materials For Medical Uses (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、リン酸カルシウムと乳酸／グリコール酸／ε-カプロラクトン共重合体とを含有してなる生体材料に骨膜を縫合や接着により装着した骨再生誘導材料に関し、特に巨大な骨欠損の迅速な治療に適用され、漸次分解吸収される骨再生誘導材料に関する。
【０００２】
【従来の技術及び発明が解決しようとする課題】
骨組織、軟骨組織のような硬組織及び上皮組織、結合組織、神経組織のような軟組織の外傷、炎症、腫瘍摘出あるいは整形美容術などにより生じた生体内の欠損部は、従来より種々の方法により補綴され機能回復が行われており、それらに用いられる材料も数多く研究されてきた。
生体内の骨欠損部を補綴する場合、従来より同種骨移植、異種骨移植よりも移植床への生着性がよくウイルス、プリオン等の感染あるいは免疫上の問題の少ない自家骨移植が行われてきた。しかし、自家骨移植では採取可能な量に限界があり、しかも移植骨獲得のための新たな手術創形成による感染への危険性、患者の苦病の長期化などの問題があった。
自家骨移植に代わる方法として、ステンレス、チタン合金等の金属材料を人工生体材料として用いる方法があり、生体材料の目覚ましい発展と材料入手の容易さからこれらが使用されてきた。
しかし、これらの人工材料は、生体組織より物理的、機械的強度が大きくなりすぎることと、腐食による含有金属の生体に対する毒性があり、また、生体親和性も劣っていた。
そこで生体親和性を改良する方法として、金属材料表面にヒドロキシアパタイト等の生体親和性材料による表面処理を施し、周囲組織との親和性を改良する方法も行われているが未だ十分なものではない。
【０００３】
一方、生体親和性材料として、生体内分解性脂肪族ポリエステルである乳酸、グリコール酸、トリメチレンカーボネートあるいはε-カプロラクトン等のラクトン類のポリマー及びその共重合体も修復材料として検討され、また、特開平９−１３２６３８号記載のようなポリ乳酸とポリε−カプロラクトンとポリグリコール酸とのブロック共重合体も検討されている。しかし、これら材料は、生体内に於ける分解時に機械的強度が低下して疲労劣化を生じたり、骨伝導は阻害しないものの骨誘導性に関しての作用は殆ど示さない。
一方、アルミナ、バイオグラス、Ａ−Ｗ結晶化ガラス、ヒドロキシアパタイト等のバイオセラミックスは生体親和性が高く、人工骨、歯科用インプラント等の材料として利用され、生体内に於いて表面に新生骨の形成が認められ、補填機能と骨組織との接着性に優れている。
しかし、これらの材料は生体内において非吸収性の材料であるため、形成された骨組織内に残存し新生骨の成長に影響を与え、骨の強度が低下するという問題がある。リン酸三カルシウムは生体内吸収性材料であり、骨欠損部に使用すると材料表面から吸収、また崩壊して新生骨に置換するが、顆粒状であるため骨移植材の形態付与性及びその維持安定性に乏しく、複雑で広範囲な欠損に対しては充填操作が困難となったり、顆粒流出に伴う治療の遅延等の問題が残る。
これらの問題を解決する方法として、バイオセラミックスとポリマーとを複合化した材料も数多く研究されている。米国特許第４３４７２３４号には、バイオセラミックスとコラーゲンとの複合体が提案されている。しかし、このようなコラーゲンを用いると、コラーゲンが天然由来であるため、その分子量、アミノ酸組成、量、保水量等が一定せず、また、抗原性を有するテロペプタイド部分の完全な除去が困難であることから、生体内に於いて異物反応を起こし、異物巨細胞や他の食細胞等が活性化されるため骨誘導能は発現されない。
【０００４】
コラーゲンに代えて、免疫学的に問題のないポリ乳酸等の脂肪族ポリエステルとヒドロキシアパタイト等とを複合化した材料も数多く提案されている。特開平１０−３２４６４１号公報には重合触媒を失活処理したジオールとジカルボン酸を構成単位に有する乳酸系ポリエステルとリン酸カルシウムからなる吸収性遮断膜が開示されている。また、米国特許第４５９５７１３号にはε−カプロラクトンが主要量を占める乳酸ε−カプロラクトン共重合体とβ−リン酸カルシウム、ヒドロキシアパタイト等の骨形成物質からなる複合体が開示されている。前者は、生体内吸収性であり骨誘導性を有するが、乳酸セグメントとその他の成分がブロック化しているため、リン酸カルシウムの性状が現れ形態の付与と維持安定性が小さい。後者に関しては、適用する組織に対する機械強度は低く、材料分解速度が遅いため骨形成が抑制される。何れの材料もβ−リン酸カルシウムの有する生体内での骨形成量が少ないという問題が解決されていない。このことから骨欠損部の治療箇所の大きさも限界があった。
【０００５】
材料単独では治療効果に限界があることから、骨形成量を補う目的として、骨髄を充填することを利用した補充療法の研究も数多くされている。骨髄には造骨性細胞が多く存在することから骨誘導性は高い。しかし、骨髄の使用は採取量に限界がある。その適用に於いても複雑で広範囲な欠損に対しては充填操作が困難となったり、流出を防ぐための形態付与性及び維持安定性を有する材料は未だ十分なものはない。
一方、骨髄と同様に造骨能を有するものに骨芽細胞が豊富に存在する骨膜がある。骨髄と比較して手術創形成なく容易に膜状として多量に採取可能であり、採取しても再生されるため採取部の骨には侵襲はない。また、骨膜は丈夫な膜であるため骨髄での流出等の問題もない。
このようなことから、骨膜及び骨誘導性を有する材料を適用して、大きな骨欠損部の治療を行うことが期待されているが、膜状の骨膜を維持安定させる十分な性能を有する骨誘導性材料は得られていないのが現状である。
【０００６】
本発明者らは前述の課題を解決すべく、生体内分解性を有し、生体内に於いて異物反応を起こさず、適正な強度と分解性を有し骨組織再生を促進させ、さらに、骨膜の維持安定性に適切な柔軟性を有する生体材料とこれに骨膜を装着した骨再生誘導材料について鋭意研究を重ねた。その結果以下に詳述する本発明を完成したものである。
【０００７】
【課題を解決するための手段】
即ち本発明は、リン酸カルシウムと、乳酸：グリコール酸：ε−カプロラクトンの組成モル比が５〜９０：３〜７５：５〜４０モル％の範囲である乳酸／グリコール酸／ε−カプロラクトン共重合体とを含有してなる生体材料に縫合や接着等の手段により骨膜を装着した骨再生誘導材料に関する。
【０００８】
【発明の実施形態】
以下、本発明をさらに詳細に説明する。
本発明に使用する骨膜は、自家骨膜が好ましく、自家骨膜であれば採取に関しては、骨膜採取可能な生体部分の全ての生体部位から採取して使用することができる。例えば骨欠損部位の治療に於ける本来外科手術により摘出される骨膜を使用すれば簡単に多量に入手できる。また術前に採取して保存した骨膜も使用できる。以上の骨膜は生体由来の骨膜であるが、将来人工的に前記生体由来の骨膜と実質的に同等の機能を有する人工骨膜が開発されればこれらの人工骨膜も使用することができる。
骨膜の生体材料への装着は、吸収性縫合糸による縫合、フィブリン接着剤による接着等、要するに骨膜が固定できれば、どのような手段でも良い。骨膜の生体材料への装着形態は、生体材料の形態（繊維、フィルム、ブロック、チューブ等）に応じて自由に設定することができる。例えば骨膜は治療目的に応じて生体材料表面（片面、両面、内周、外周）全域または一部に部分的に装着しても良い。
本発明の好ましい骨再生誘導材料の形態は、フィルム状の生体材料の表面に骨膜を前記手段により装着し、これらをチューブ状に丸めて骨欠損部位に骨膜が接するように固定できるようにした膜状の形態が好ましい。
また本発明の骨再生誘導材料の剛性率は４〜４０℃において２００〜２００００ＭＰａに設定するのが好ましい。２００ＭＰａ未満では剛性が低いため膜状の形態に適用するには柔らかすぎ、２００００ＭＰａを超えると剛性が高くなり膜状の形態には硬すぎるため骨膜を欠損部へ装着することが不可能となるためである。
【０００９】
本発明に使用する乳酸／グリコール酸／ε−カプロラクトン共重合体は、一般的な方法により製造するものであればいずれの方法によるものであってもよい。その一例を挙げれば、ラクチド、グリコリド、ε−カプロラクトンをオクタン酸スズ、塩化スズ、ジラウリン酸ジブチルスズ、アルミニウムイソプロポキシド、チタニウムテトライソプロポキシド、トリエチル亜鉛等の触媒存在下で加熱して、１００〜２５０℃で開環重合を行うことによって製造することができる。
重合に使用する乳酸およびラクチドのモノマーは、Ｄ体、Ｌ体、ＤＬ体のいずれであっても良いし、これらを混合して使用しても良い。しかしながら、得られた共重合体にモノマー、オリゴマーが存在すると、組織反応及び分解が異常に促進され、マクロファージの吸収分解以上に分解切片が生成するため、組織傷害性を生ずる原因となる。したがって、再沈殿化法等の方法で精製して使用するのが好ましい。
【００１０】
本発明に使用する共重合体としては、乳酸：グリコール酸：ε−カプロラクトンの組成モル比が５〜９０：３〜７５：５〜４０モル％の範囲である乳酸／グリコール酸／ε−カプロラクトン共重合体であることが必要である。
この場合に、ε−カプロラクトン含量が５モル％未満では剛性が高く脆いため、骨膜の装着が困難であり、ポリマー切片により生体組織を損傷する可能性があり適当でない。一方、４０モル％を越えると必要な強度が得られず、また、生体分解吸収性が遅くなるため好ましくない。
また、共重合体中の乳酸含量及びグリコール酸含量は任意に変更することができるが、グリコール酸含量が３モル％未満の場合、必要な分解速度が達成されず組織修復を阻害する問題が生じ、７５％を越えると前述した分解切片による組織損傷を生ずることもあるので好ましくない。
さらに、共重合体中の乳酸含量は５〜９０モル％の範囲であるが、この場合に乳酸含量が５モル％未満では、必要な分解速度が達成されず骨組織の修復を阻害する。
また、９０モル％を越えると剛性が高くなりポリマー切片により生体組織を損傷する可能性がある。
【００１１】
このようにして得られる乳酸／グリコール酸／ε-カプロラクトン共重合体の数平均分子量は３００００〜２０００００であることが好ましい。共重合体の分子量がこの範囲を逸脱し、３００００を下回ると乳酸、グリコール酸等のオリゴマーを多含するため、生体組織への刺激性が強くなり問題となるばかりでなく、加水分解を促進し強度低下を生じ、必要な期間の物性が得られない。また逆に、分子量が２００００００を越えると、加水分解速度が低下して骨組織修復を阻害することに加えて、かつリン酸カルシウムとの混合操作が困難となり、共重合体中におけるリン酸カルシウムの分散が不均一となる。
なお、本発明の目的を損なわない範囲であれば、少量の他の共重合体成分を含有してもよい。かかる共重合成分としては、β−ヒドロキシ酪酸、γ−ブチロラクトン、δ−バレロラクトン等ヒドロキシカルボン酸を構成する環状モノマーが例として挙げられる。
【００１２】
本発明で使用されるリン酸カルシウムとしては、リン酸三カルシウム、ヒドロキシアパタイト、第二リン酸カルシウム等が例示される。本発明共重合体との関係に於いて、最も望ましいリン酸カルシウムは、共重合体との親和性がよく、生体内で吸収崩壊して新組織と置換され骨組織修復を促進するリン酸三カルシウムである。平均粒径としては、０．１〜２００μｍのリン酸カルシウムを用いる。平均粒径０．１μｍ未満では溶解速度が速いため、材料の崩壊が促進され十分な骨組織修復を示さない。また、平均粒径２００μｍを越えると、材料表面に存在するリン酸カルシウムにより組織修復が遅延する。さらに、本発明の好ましいリン酸三カルシウムは６５０〜１５００℃で焼結されたリン酸三カルシウムである。リン酸三カルシウムは焼結することにより構造が安定化し高密度化するが、焼結温度が６５０℃未満では、リン酸三カルシウム中に水和水が存在する不安定な構造となるため、複合化に際しポリマーの分解を促進する。また、１５００℃を越えるとリン酸三カルシウムの分解により骨組織修復を阻害する成分が生成する。
【００１３】
本発明において、適切な強度及び分解性を有し骨組織修復に有効な骨再生誘導材料を得るためには、リン酸カルシウムと乳酸／グリコール酸／ε−カプロラクトン共重合体との生体材料を製造する必要がある。生体材料は、例えば以下の方法により製造される。
リン酸カルシウムと乳酸／グリコール酸／ε−カプロラクトン共重合体を共重合体の軟化点以上で加熱混練することにより製造される。加熱混練の条件は使用する乳酸／グリコール酸／ε−カプロラクトン共重合体の組成、分子量およびリン酸カルシウムの種類、物性などによって異なるため特定できないが、好ましくは、５０〜２５０℃で、真空中、空気中あるいは窒素雰囲気下で行う。混練時間は５〜６０分程度要する。加熱混練法以外の生体材料の製造方法としては、例えば乳酸／グリコール酸／ε−カプロラクトン共重合体とリン酸カルシウムを溶媒中で混練した後に溶媒を除去する方法、固体混合後加圧プレスあるいは加温プレスする方法等がある。
【００１４】
リン酸カルシウムと乳酸／グリコール酸／ε−カプロラクトン共重合体はいかなる割合でも混合可能であり、得られる複合体は混合割合により引張り強度、分解速度等の物性が異なるが、一般的には、リン酸カルシウムと乳酸／グリコール酸／ε−カプロラクトン共重合体の混合割合が重量比で１：０．１〜２．０であることが好ましい。乳酸／グリコール酸／ε−カプロラクトン共重合体含有量が０．１未満では複合体は脆くなり形態付与性及び維持安定性が低下する。また、乳酸／グリコール酸／ε−カプロラクトン共重合体含有量が２．０を越えると必要な剛性が得られず、骨再生誘導材料としての機能が減少する。
【００１５】
また、本発明で得られる骨再生誘導材料の特徴を損なわない範囲であれば、抗腫瘍剤、抗癌剤、抗炎症剤あるいは活性型ビタミンＤ等のビタミン類、甲状腺刺激ホルモン等のポリペプタイドのような生理活性物質等の薬剤を複合体に添加し、徐放化機能をもたせ骨組織修復を促進させることもできる。更にまた、本発明の骨再生誘導材料は、人工血管、神経修復誘導管としても使用することができる。
このようにして製造された生体材料は、キャスト、射出成形、押出成形、ホットプレス法等公知の方法により成形加工することができ、繊維、フィルム、ブロック、チューブ等任意の形態で使用することができる。また、溶媒からの凍結乾燥等により多孔質体とすることもできる。
また、本発明による骨再生誘導材料は、温水に浸漬する等の方法により加熱することで簡単に変形することができ、複雑な患部への充填を容易に行うことができるという特徴を有する。生体への埋入、充填後、組織が修復するまでの期間、生体材料は体温付近でもその形態、強度を保持しており、体重などの負荷がかかる部位への利用にも極めて有効である。
【００１６】
【実施例】
以下実施例を挙げてさらに本発明を詳細に説明するが、本発明はこれに限定されるものではない。なお、特に断らない限り％は全て重量％を示す。
実施例１
骨組織誘導能評価
Ｌ−ラクチド２２０ｇとグリコリド３５ｇとε−カプロラクトン１９６ｇとをオクタン酸スズ０．０１ｇの存在下で１０-3ｍｍＨｇの減圧下１５０℃で２４時間重合反応を行った。反応後、クロロホルムに溶解しメタノール中で析出させることにより精製処理を行い、２７３ｇの乳酸／グリコール酸／ε−カプロラクトン共重合体を得た。
このようにして得られた共重合体の数平均分子量はＧＰＣにより１０００００であり、その組成（モル比）はＨ−ＮＭＲからモル比で乳酸／グリコール酸／ε−カプロラクトン＝６５／８／２７であった。
この乳酸／グリコール酸／ε−カプロラクトン共重合体と８００℃で焼成した平均粒径１０μｍのβ−リン酸三カルシウムとを表１に示す割合により１８０℃で１０分間加熱混練して複合化した。
このようにして得られた生体材料をホットプレス法により成形加工し、２００μｍの厚さを有するフィルムを製造し、エチレンオキサイド滅菌を行った。物性試験の結果を表１に示す。
【００１７】
【表１】
細胞培養実験の結果、前記フィルム状の生体材料に使用したリン酸三カルシウム、乳酸／グリコール酸／ε−カプロラクトン共重合体の双方とも複合化前の生体に対する特性を保持していた。
犬の２０ｍｍの脛骨骨欠損の人工欠損動物モデルを用いて評価を行った。欠損部より採取した骨膜を前記フィルム状の生体材料の表面に縫着して膜状の骨再生誘導材料を作製し、この骨再生誘導材料を骨膜が骨欠損部位に接するようにチューブ状に丸めながら、吸収性縫合糸により欠損部を覆うように移植を行い、創外固定器により固定して骨再生経過をＸ線等により観察した。
その結果、Ｘ線写真観察により移植後４週間で骨再生誘導材料が消失し、欠損部分の骨が早期に再生誘導されることが観察された。移植後８週に創外固定器のワイヤーを一部カットしても歩行可能となった。1２週後、切開して目視により骨再生誘導材料の消失、骨欠損部の再生が確認された。２４週経過後、創外固定器を撤去した状態で完全歩行可能となった。
【００１９】
比較例１
実施例１と同様の方法で、乳酸：グリコール酸＝８０：２０の数平均分子量１０００００の二元共重合体を合成した。これを８００℃で焼結した平均粒径１μｍのα−リン酸三カルシウムと７０／３０の重量比で２００℃、１０分間加熱混練して複合体を合成した。
得られた複合体は剛性が高く脆いため、成形が困難であり、吸収性縫合糸により骨膜を装着することも不可能であった。
比較例２
比較例１と同様にして乳酸：ε−カプロラクトン＝７０：３０の数平均分子量１１００００の二元共重合体を合成し、比較例１と同様の方法で複合体を合成した。この複合体をホットプレスにより厚さ約２００μｍのフィルムに形成し、エチレンオキサイド滅菌後、骨膜を吸収性縫合糸により装着して犬の脛骨骨欠損部に移植した。1２週後、切開して目視により複合体の分解速度が遅く残留物が観測され、骨欠損部の再生が阻害されていた。
【００２０】
【発明の効果】
本発明で得られるリン酸カルシウムと乳酸／グリコール酸／ε−カプロラクトン共重合体を含有してなる複合体に骨膜を装着させた骨再生誘導材料は、生体適合性に優れ、適切な剛性及び分解速度を有し、治療部位の形状に応じて任意に調整でき、生体内で該複合体が徐々に分解しリン酸カルシウムを放出し、しかも骨再生時においては治療部位と外部との隔壁になり、周囲軟組織からの繊維芽細胞の侵入を阻止し骨再生に有利な環境を形成すると同時に、骨膜より造血性細胞と該複合体よりリン酸カルシウムを供給して骨再生を促し、骨再生後は生体内で代謝もしくは骨の一部となるので、従来法では完全な治療が不可能とされた大きな骨欠損部の治療にも使用可能であり、骨組織の再生治療に有効に使用することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a bone regeneration-inducing material in which a periosteum is attached to a biomaterial containing calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer by stitching or bonding, and particularly for rapid treatment of a huge bone defect. The present invention relates to a bone regeneration-inducing material that is applied and gradually decomposed and absorbed.
[0002]
[Prior art and problems to be solved by the invention]
Hard tissue such as bone tissue and cartilage tissue and epithelial tissue, connective tissue, soft tissue trauma such as nerve tissue, in vivo defects caused by inflammation, tumor extraction or orthopedic cosmetics, etc., have been various methods The restoration of the function has been carried out and the materials used for them have been studied extensively.
When prosthetic bone replacement in vivo, autologous bone transplantation is better than conventional allograft and xenogeneic bone transplantation, with better engraftment on the transplantation bed and less virus or prion infection or immune problems. I came. However, autologous bone transplantation has a limit in the amount that can be collected, and there are also problems such as the risk of infection due to the formation of a new surgical wound to acquire the transplanted bone, and prolonged patient illness.
As an alternative to autologous bone transplantation, there is a method using a metal material such as stainless steel or titanium alloy as an artificial biomaterial, and these have been used because of remarkable development of biomaterials and easy availability of materials.
However, these artificial materials have physical and mechanical strengths that are excessively greater than that of living tissue, and the toxicity of the contained metal due to corrosion to the living body, and also have poor biocompatibility.
Therefore, as a method for improving biocompatibility, a method for improving the affinity with surrounding tissues has been carried out by applying a surface treatment with a biocompatible material such as hydroxyapatite to the surface of the metal material, but this is not sufficient. .
[0003]
On the other hand, as biocompatible materials, biodegradable aliphatic polyesters such as lactic acid polymers such as lactic acid, glycolic acid, trimethylene carbonate or ε-caprolactone, and copolymers thereof have been studied as restoration materials. A block copolymer of polylactic acid, polyε-caprolactone and polyglycolic acid as described in Kaihei 9-132638 has also been studied. However, these materials exhibit a deterioration in mechanical strength due to degradation in the living body to cause fatigue deterioration, or exhibit little effect on osteoinductivity although they do not inhibit bone conduction.
On the other hand, bioceramics such as alumina, bioglass, AW crystallized glass, and hydroxyapatite have high biocompatibility, and are used as materials for artificial bones, dental implants, etc. Formation is recognized and has excellent filling function and adhesion to bone tissue.
However, since these materials are non-absorbable materials in vivo, there is a problem that they remain in the formed bone tissue and affect the growth of new bone, and the strength of the bone is reduced. Tricalcium phosphate is a bioresorbable material that, when used in bone defects, absorbs from the surface of the material and disintegrates and replaces it with new bone. Poor stability, complicated and wide-ranging defects remain difficult to fill, and problems such as delayed treatment associated with granule outflow remain.
As a method for solving these problems, many materials obtained by combining bioceramics and polymers have been studied. U.S. Pat. No. 4,347,234 proposes a composite of bioceramics and collagen. However, when such collagen is used, since the collagen is naturally derived, its molecular weight, amino acid composition, amount, water retention amount, etc. are not constant, and it is difficult to completely remove the antigenic telopeptide portion. For this reason, a foreign body reaction occurs in the living body, and foreign body giant cells and other phagocytic cells are activated, so that the osteoinductive ability is not expressed.
[0004]
In place of collagen, many materials have been proposed in which an aliphatic polyester such as polylactic acid and hydroxyapatite, which have no immunological problems, are combined. Japanese Patent Laid-Open No. 10-324641 discloses an absorptive barrier film composed of a lactic acid-based polyester having a diol and a dicarboxylic acid as constituent units and a calcium phosphate, in which a polymerization catalyst is deactivated. U.S. Pat. No. 4,595,713 discloses a complex composed of a lactic acid ε-caprolactone copolymer in which ε-caprolactone is a major amount and a bone-forming substance such as β-calcium phosphate and hydroxyapatite. The former is bioresorbable and has osteoinductivity, but since the lactic acid segment and other components are blocked, the properties of calcium phosphate appear and the form imparting and maintenance stability is small. Regarding the latter, the mechanical strength against the tissue to be applied is low, and bone formation is suppressed because the material degradation rate is slow. None of these materials has solved the problem that β-calcium phosphate has a small amount of bone formation in vivo. For this reason, there was a limit to the size of the treatment site of the bone defect.
[0005]
Since the material alone has a limited therapeutic effect, many studies of replacement therapy using filling of bone marrow have been conducted for the purpose of supplementing the amount of bone formation. Bone marrow is highly osteoinductive because there are many osteogenic cells. However, the use of bone marrow has a limited collection volume. Even in this application, there are not enough materials having a form-providing property and a maintenance stability to prevent a filling operation from being complicated and a wide range of defects and to prevent outflow.
On the other hand, there is periosteum in which osteoblasts are abundant in those having osteogenic ability like bone marrow. Compared to bone marrow, it can be easily collected in large quantities as a film without forming a surgical wound, and since it is regenerated even after being collected, there is no invasion in the bone of the collection part. Further, since the periosteum is a strong membrane, there is no problem such as outflow in the bone marrow.
For this reason, it is expected to apply a periosteum and osteoinductive material to treat a large bone defect, but it has sufficient performance to maintain and stabilize the membranous periosteum. The present condition is that the property material is not obtained.
[0006]
In order to solve the above-mentioned problems, the present inventors have biodegradability, do not cause a foreign body reaction in the living body, have appropriate strength and degradability, promote bone tissue regeneration, Intensive research has been conducted on biomaterials that have flexibility appropriate to the periosteal maintenance stability and bone regeneration-inducing materials with periosteum attached thereto. As a result, the present invention described in detail below is completed.
[0007]
[Means for Solving the Problems]
That is, the present invention relates to a calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer having a composition molar ratio of lactic acid: glycolic acid: ε-caprolactone in the range of 5 to 90: 3-75: 5 to 40 mol%. The present invention relates to a bone regeneration-inducing material in which a periosteum is attached to a biomaterial containing ligation by means such as suturing or bonding.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
The periosteum used in the present invention is preferably autologous periosteum. If it is autologous periosteum, the periosteum can be collected and used from all living body parts of the living body part where periosteum can be collected. For example, if periosteum that is originally removed by surgery in the treatment of a bone defect site is used, it can be easily obtained in large quantities. Periosteum collected and stored before surgery can also be used. The above periosteum is a living body-derived periosteum, but if an artificial periosteum having a function substantially equivalent to that of the living body-derived periosteum is developed in the future, these artificial periosteum can also be used.
The periosteum can be attached to the biomaterial by any means as long as the periosteum can be fixed, such as suturing with an absorbable suture or adhesion with a fibrin adhesive. The mounting form of the periosteum to the biomaterial can be freely set according to the form of the biomaterial (fiber, film, block, tube, etc.). For example, the periosteum may be partially attached to the whole or a part of the surface of the biomaterial (one side, both sides, inner circumference, outer circumference) depending on the purpose of treatment.
A preferred form of the bone regeneration-inducing material of the present invention is a membrane in which periosteum is attached to the surface of a film-like biomaterial by the above-described means, and these are rolled into a tube shape and fixed so that the periosteum contacts with a bone defect site. The shape is preferred.
The rigidity of the bone regeneration-inducing material of the present invention is preferably set to 200 to 20000 MPa at 4 to 40 ° C. If the pressure is less than 200 MPa, the rigidity is low, so that it is too soft to be applied to a film-like form, and if it exceeds 20000 MPa, the rigidity becomes high and the film-like form is too hard, so that it becomes impossible to attach the periosteum to the defect. It is.
[0009]
The lactic acid / glycolic acid / ε-caprolactone copolymer used in the present invention may be produced by any method as long as it is produced by a general method. For example, lactide, glycolide, and ε-caprolactone are heated in the presence of a catalyst such as tin octoate, tin chloride, dibutyltin dilaurate, aluminum isopropoxide, titanium tetraisopropoxide, triethylzinc, and the like, It can be produced by ring-opening polymerization at 250 ° C.
The monomers of lactic acid and lactide used for the polymerization may be any of D-form, L-form and DL-form, or may be used by mixing them. However, when monomers and oligomers are present in the obtained copolymer, the tissue reaction and degradation are abnormally accelerated, and a degraded section is generated more than the macrophage absorption degradation, which causes tissue damage. Therefore, it is preferable to use it after purification by a method such as reprecipitation.
[0010]
The copolymer used in the present invention includes a lactic acid / glycolic acid / ε-caprolactone copolymer having a composition molar ratio of lactic acid: glycolic acid: ε-caprolactone in the range of 5 to 90: 3 to 75: 5 to 40 mol%. It must be a polymer.
In this case, if the ε-caprolactone content is less than 5 mol%, the rigidity is high and the brittleness makes it difficult to attach the periosteum, and the polymer section may damage the living tissue, which is not appropriate. On the other hand, if it exceeds 40 mol%, the required strength cannot be obtained, and the biodegradability is slow.
In addition, the lactic acid content and glycolic acid content in the copolymer can be arbitrarily changed. However, when the glycolic acid content is less than 3 mol%, the necessary degradation rate is not achieved and there is a problem of inhibiting tissue repair. If it exceeds 75%, tissue damage due to the above-described decomposition section may occur, which is not preferable.
Furthermore, the lactic acid content in the copolymer is in the range of 5 to 90 mol%. In this case, if the lactic acid content is less than 5 mol%, the necessary degradation rate is not achieved, and bone tissue repair is inhibited.
Moreover, when it exceeds 90 mol%, rigidity becomes high and there is a possibility of damaging a living tissue by a polymer slice.
[0011]
The number average molecular weight of the lactic acid / glycolic acid / ε-caprolactone copolymer thus obtained is preferably 30,000 to 200,000. When the molecular weight of the copolymer deviates from this range and falls below 30000, it contains oligomers such as lactic acid and glycolic acid. The strength is lowered, and physical properties for a necessary period cannot be obtained. On the other hand, if the molecular weight exceeds 2000000, in addition to inhibiting the bone tissue repair by reducing the hydrolysis rate, the mixing operation with calcium phosphate becomes difficult, and the dispersion of calcium phosphate in the copolymer is uneven. It becomes.
In addition, as long as the objective of this invention is not impaired, you may contain a small amount of other copolymer components. Examples of such copolymer components include cyclic monomers constituting hydroxycarboxylic acids such as β-hydroxybutyric acid, γ-butyrolactone, and δ-valerolactone.
[0012]
Examples of calcium phosphate used in the present invention include tricalcium phosphate, hydroxyapatite, dicalcium phosphate and the like. In the relationship with the copolymer of the present invention, the most desirable calcium phosphate is tricalcium phosphate, which has good affinity with the copolymer and absorbs and disintegrates in vivo to replace new tissue and promote bone tissue repair. is there. As an average particle diameter, 0.1-200 micrometers calcium phosphate is used. When the average particle size is less than 0.1 μm, the dissolution rate is high, so that the material collapse is promoted and sufficient bone tissue repair is not exhibited. On the other hand, when the average particle size exceeds 200 μm, tissue repair is delayed by calcium phosphate existing on the material surface. Furthermore, the preferred tricalcium phosphate of the present invention is tricalcium phosphate sintered at 650-1500 ° C. When tricalcium phosphate is sintered, the structure is stabilized and densified. However, if the sintering temperature is less than 650 ° C., it becomes an unstable structure in which hydrated water is present in tricalcium phosphate. Promotes polymer degradation during conversion. When the temperature exceeds 1500 ° C., a component that inhibits bone tissue repair is generated due to decomposition of tricalcium phosphate.
[0013]
In the present invention, it is necessary to manufacture a biomaterial of calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer in order to obtain a bone regeneration-inducing material having appropriate strength and degradability and effective for bone tissue repair. There is. The biomaterial is manufactured, for example, by the following method.
It is produced by heating and kneading a calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer at or above the softening point of the copolymer. The conditions of the heat-kneading cannot be specified because they vary depending on the composition, molecular weight, calcium phosphate type, physical properties, etc. of the lactic acid / glycolic acid / ε-caprolactone copolymer to be used, but are preferably 50 to 250 ° C. in vacuum or in the air Alternatively, it is performed in a nitrogen atmosphere. The kneading time takes about 5 to 60 minutes. Examples of methods for producing biomaterials other than the heat kneading method include, for example, a method of kneading a lactic acid / glycolic acid / ε-caprolactone copolymer and calcium phosphate in a solvent and then removing the solvent, a solid mixing pressure press or heating press There are ways to do this.
[0014]
Calcium phosphate and lactic acid / glycolic acid / ε-caprolactone copolymer can be mixed in any proportion, and the resulting composite has different physical properties such as tensile strength and degradation rate depending on the mixing proportion. The mixing ratio of / glycolic acid / ε-caprolactone copolymer is preferably 1: 0.1 to 2.0 by weight. If the content of lactic acid / glycolic acid / ε-caprolactone copolymer is less than 0.1, the composite becomes brittle and the form-providing property and the maintenance stability are lowered. On the other hand, if the lactic acid / glycolic acid / ε-caprolactone copolymer content exceeds 2.0, the required rigidity cannot be obtained, and the function as a bone regeneration-inducing material is reduced.
[0015]
In addition, as long as the characteristics of the bone regeneration-inducing material obtained in the present invention are not impaired, vitamins such as antitumor agents, anticancer agents, anti-inflammatory agents or active vitamin D, and polypeptides such as thyroid stimulating hormone are used. A drug such as a physiologically active substance can be added to the complex to provide a sustained release function and promote bone tissue repair. Furthermore, the bone regeneration-inducing material of the present invention can be used as an artificial blood vessel or a nerve repair induction tube.
The biomaterial produced in this way can be molded by known methods such as casting, injection molding, extrusion molding, hot pressing, etc., and can be used in any form such as fibers, films, blocks, tubes, etc. it can. It can also be made porous by freeze-drying from a solvent or the like.
In addition, the bone regeneration-inducing material according to the present invention is characterized in that it can be easily deformed by being heated by a method such as being immersed in warm water, and a complicated affected part can be easily filled. The biomaterial retains its shape and strength even near body temperature during the period from implantation and filling into the living body until the tissue is repaired, and it is extremely effective for use in a site where a load such as weight is applied.
[0016]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to this. Unless otherwise specified, all percentages are by weight.
Example 1
Evaluation of bone tissue induction ability 220 g of L-lactide, 35 g of glycolide, and 196 g of ε-caprolactone were subjected to a polymerization reaction at 150 ° C. under reduced pressure of 10 −3 mmHg in the presence of 0.01 g of tin octoate. After the reaction, purification treatment was performed by dissolving in chloroform and precipitating in methanol to obtain 273 g of lactic acid / glycolic acid / ε-caprolactone copolymer.
The number average molecular weight of the copolymer thus obtained is 100,000 by GPC, and the composition (molar ratio) is lactic acid / glycolic acid / ε-caprolactone = 65/8/27 by molar ratio from H-NMR. there were.
This lactic acid / glycolic acid / ε-caprolactone copolymer and β-tricalcium phosphate having an average particle diameter of 10 μm calcined at 800 ° C. were heated and kneaded at 180 ° C. for 10 minutes at a ratio shown in Table 1 to form a composite.
The biomaterial thus obtained was molded by a hot press method to produce a film having a thickness of 200 μm and sterilized with ethylene oxide. Table 1 shows the results of the physical property test.
[0017]
[Table 1]
As a result of the cell culture experiment, both the tricalcium phosphate and the lactic acid / glycolic acid / ε-caprolactone copolymer used for the film-like biomaterial retained the properties of the living body before complexing.
The evaluation was carried out using an artificial defect animal model of a dog's 20 mm tibial bone defect. The periosteum collected from the defect is sewn to the surface of the film-like biomaterial to produce a membrane-like bone regeneration-inducing material, and this bone regeneration-inducing material is rolled into a tube shape so that the periosteum contacts the bone defect site. However, transplantation was performed so as to cover the defect with an absorbable suture, and the bone regeneration process was observed by X-ray or the like after fixation with an external fixator.
As a result, it was observed by X-ray photography that the bone regeneration-inducing material disappeared 4 weeks after transplantation, and the bone in the defective part was regenerated and induced early. It was possible to walk even if a part of the wire of the external fixator was cut 8 weeks after transplantation. After 12 weeks, an incision was made and the disappearance of the bone regeneration-inducing material and the regeneration of the bone defect were confirmed by visual inspection. After 24 weeks, the patient was able to walk completely with the external fixator removed.
[0019]
Comparative Example 1
In the same manner as in Example 1, a binary copolymer of lactic acid: glycolic acid = 80: 20 and a number average molecular weight of 100,000 was synthesized. This was heated and kneaded at a weight ratio of 70/30 to α-tricalcium phosphate having an average particle diameter of 1 μm sintered at 800 ° C. for 10 minutes to synthesize a composite.
Since the obtained composite had high rigidity and was brittle, it was difficult to mold, and it was impossible to attach the periosteum with an absorbable suture.
Comparative Example 2
In the same manner as in Comparative Example 1, a binary copolymer of lactic acid: ε-caprolactone = 70: 30 and a number average molecular weight of 110000 was synthesized, and a composite was synthesized in the same manner as in Comparative Example 1. This composite was formed into a film having a thickness of about 200 μm by hot pressing, and after sterilization with ethylene oxide, the periosteum was attached with a resorbable suture and transplanted to a dog tibia bone defect. After 12 weeks, an incision was made, and the degradation rate of the complex was visually observed, and a residue was observed. The regeneration of the bone defect was inhibited.
[0020]
【The invention's effect】
The bone regeneration-inducing material in which the periosteum is attached to the composite containing calcium phosphate and lactic acid / glycolic acid / ε-caprolactone copolymer obtained in the present invention is excellent in biocompatibility and has an appropriate rigidity and degradation rate. It can be arbitrarily adjusted according to the shape of the treatment site, the complex is gradually decomposed in vivo to release calcium phosphate, and at the time of bone regeneration, it becomes a partition wall between the treatment site and the outside, and from the surrounding soft tissue Prevents the invasion of fibroblasts and forms a favorable environment for bone regeneration. At the same time, it supplies hematopoietic cells from the periosteum and calcium phosphate from the complex to promote bone regeneration. Therefore, it can be used for the treatment of a large bone defect that cannot be completely treated by the conventional method, and can be used effectively for the regeneration treatment of bone tissue.
Claims (11)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000185878A JP4374410B2 (en) | 2000-06-21 | 2000-06-21 | Bone regeneration induction material |
| DE60035403T DE60035403T2 (en) | 1999-08-17 | 2000-08-10 | BIOLOGICAL MATERIALS |
| PCT/JP2000/005353 WO2001012240A1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| US09/807,707 US6441073B1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| EP00950053A EP1121943B1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| CA002347256A CA2347256C (en) | 1999-08-17 | 2000-08-10 | Biological materials |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000185878A JP4374410B2 (en) | 2000-06-21 | 2000-06-21 | Bone regeneration induction material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002000717A JP2002000717A (en) | 2002-01-08 |
| JP4374410B2 true JP4374410B2 (en) | 2009-12-02 |
Family
ID=18686132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000185878A Expired - Lifetime JP4374410B2 (en) | 1999-08-17 | 2000-06-21 | Bone regeneration induction material |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4374410B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004073849A (en) * | 2002-06-18 | 2004-03-11 | National Institute Of Advanced Industrial & Technology | Globular calcium phosphate coated with biodegradable plastic and its application |
| EP1433489A1 (en) * | 2002-12-23 | 2004-06-30 | Degradable Solutions AG | Biodegradable porous bone implant with a barrier membrane sealed thereto |
| JP4717336B2 (en) * | 2003-08-06 | 2011-07-06 | グンゼ株式会社 | Bone regeneration base material and method for producing the same |
| JP4674315B2 (en) * | 2004-02-19 | 2011-04-20 | 川澄化学工業株式会社 | Osteoinductive regenerative membrane material |
| KR100946268B1 (en) * | 2007-10-26 | 2010-03-09 | 주식회사 메가젠임플란트 | Bone regeneration membrane and method for manufacturing bone regeneration membrane |
-
2000
- 2000-06-21 JP JP2000185878A patent/JP4374410B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002000717A (en) | 2002-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1121943B1 (en) | Biological materials | |
| Tan et al. | Biodegradable materials for bone repairs: a review | |
| CA2475110C (en) | Bioresorbable osteoconductive compositions for bone regeneration | |
| Rokkanen | Absorbable materials in orthopaedic surgery | |
| US20100131064A1 (en) | Bioresorbable polymer reconstituted bone and methods of formation thereof | |
| Hokugo et al. | Prefabrication of vascularized bone graft using guided bone regeneration | |
| Chen et al. | Reconstruction of calvarial defect using a tricalcium phosphate-oligomeric proanthocyanidins cross-linked gelatin composite | |
| Athanasiou et al. | Applications of biodegradable lactides and glycolides in podiatry | |
| Miki et al. | Osteoinductive potential of freeze-dried, biodegradable, poly (glycolic acid-co-lactic acid) disks incorporated with bone morphogenetic protein in skull defects of rats | |
| JP4378442B2 (en) | Anti-adhesion material | |
| JP4374410B2 (en) | Bone regeneration induction material | |
| Kinoshita et al. | Study on the efficacy of biodegradable polyf (l-lactide) mesh for supporting transplanted particulate cancellous bone and marrow: experiment involving subcutaneous implantation in dogs | |
| JP4529005B2 (en) | Biomaterial | |
| Wiśniewska et al. | Bioresorbable polymeric materials–current state of knowledge | |
| Wolter | Der Plattenfixateur interne für lange Röhrenknochen | |
| JP6129861B2 (en) | Polymer composite artificial bone implants or bone grafts with osteogenic properties | |
| Kaur | A review on bioresorbable materials: Application in oral and maxillofacial surgery | |
| Hossain | Biomaterials for Orbital Reconstruction | |
| Suuronen et al. | Developments in craniomaxillofacial surgery: Use of self-reinforced bioabsorbable osteofixation devices | |
| Zeng | Application of poly (trimethylene carbonate) and calcium phosphate composite biomaterials in oral and maxillofacial surgery | |
| Suuronen et al. | Bioresorbable materials for bone fixation: Review of biological concepts and mechanical aspects | |
| Kuo et al. | The use of poly (l-lactic-co-glycolic acid)/tricalcium phosphate as a bone substitute in rabbit femur defects model | |
| Gkioni et al. | Biodegradable polymeric/ceramic composite scaffolds to regenerate bone tissue | |
| Kargozar et al. | Scaffolds for the repair of orbital wall defects | |
| Siracusa et al. | State-of-Art of Standard and Innovative Materials Used in Cranioplasty. Polymers 2021, 13, 1452 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20051115 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20060525 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20060525 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080303 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20080303 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080303 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080507 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20080507 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080507 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090630 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090717 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4374410 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120918 Year of fee payment: 3 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120918 Year of fee payment: 3 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120918 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130918 Year of fee payment: 4 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313117 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| EXPY | Cancellation because of completion of term |