JP4529005B2 - Biomaterial - Google Patents
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- JP4529005B2 JP4529005B2 JP23034899A JP23034899A JP4529005B2 JP 4529005 B2 JP4529005 B2 JP 4529005B2 JP 23034899 A JP23034899 A JP 23034899A JP 23034899 A JP23034899 A JP 23034899A JP 4529005 B2 JP4529005 B2 JP 4529005B2
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- tissue
- biomaterial
- copolymer
- lactic acid
- caprolactone
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- 239000012620 biological material Substances 0.000 title claims description 29
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 60
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 54
- 229920001577 copolymer Polymers 0.000 claims description 39
- 239000001506 calcium phosphate Substances 0.000 claims description 38
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 38
- 239000004310 lactic acid Substances 0.000 claims description 30
- 235000014655 lactic acid Nutrition 0.000 claims description 30
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 23
- 235000011010 calcium phosphates Nutrition 0.000 claims description 21
- 210000000988 bone and bone Anatomy 0.000 claims description 18
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 14
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 14
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 14
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
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- 229910052588 hydroxylapatite Inorganic materials 0.000 description 5
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 5
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- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
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- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- JVZACCIXIYPYEA-UHFFFAOYSA-N CC[Zn](CC)CC Chemical compound CC[Zn](CC)CC JVZACCIXIYPYEA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
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- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
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- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 239000012975 dibutyltin dilaurate Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
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- 150000002596 lactones Chemical class 0.000 description 1
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- -1 molecular weight Substances 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
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- VUQCHHHVRHCENT-UHFFFAOYSA-N oxan-2-one;oxolan-2-one Chemical compound O=C1CCCO1.O=C1CCCCO1 VUQCHHHVRHCENT-UHFFFAOYSA-N 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
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- 229920001610 polycaprolactone Polymers 0.000 description 1
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- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
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- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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- Materials For Medical Uses (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、りん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関し、特に生体内に於いて硬組織及び軟組織の再建に適用され、しかも組織形成に伴って、漸次分解吸収される優れた生体用材料に関する。
【０００２】
【従来の技術】
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、摘出あるいは再建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。
【０００３】
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良くウイルス、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等の問題があった。
【０００４】
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、これらの人工生体材料は、生体組織より物理的、機械的強度が大きくなり過ぎることと、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充分なものではない。
【０００５】
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、これらの材料は、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。
【０００６】
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など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。りん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、骨と比較して機械的強度が小さく、体重等の負荷のかかる部位への使用は制限される。
また、りん酸三カルシウムは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、顆粒の流出に伴う治癒の遅延等の問題が残る。
【０００７】
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の材料であるため、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は発現されない。
【０００８】
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りん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−りん酸カルシウム、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、りん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的強度は低く、材料の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−りん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。
【０００９】
また、特開平６−２９８６３９号には乳酸−グリコール酸共重合体と抗生物質との複合体にβ−りん酸三カルシウムが分散する徐放性材料が開示されている。同様に、血管、末梢神経等の軟組織の再建に関する多くの研究はあるものの、十分な材料は得られておらず、従って生体適合性に優れ、組織が再生するまでの期間、強度を維持し、移植後から分解吸収される、組織の代謝に近い材料が求められている。
【００１０】
【発明が解決しようとする課題】
本発明者らは前記問題点を解決すべく、生体内分解性を有し、生体内に於いて異物反応を生じない、適正な強度及び分解性を有する組織再生に有効な生体材料について鋭意研究を重ねた。その結果以下に詳記する本発明を完成したものである。
【００１１】
【課題を解決するための手段】
即ち本発明は、りん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関する。
【００１２】
【発明の実施の形態】
以下、本発明を更に詳細に説明する。
本発明の生体材料は、りん酸カルシウムが乳酸／グリコール酸／ε−カプロラクトン共重合体のカルボニル基により配位した構造となっているため、りん酸カルシウムの生体内分解性と生体組織誘導能とが調節され、その生体組織誘導能は著しく促進される。一般的に、再建される生体組織の形状は複雑であるが、乳酸／グリコール酸／ε−カプロラクトン共重合体の組成および分子量を調節することにより、可撓性から高強度にいたる各種の材料が成形されるため、本発明生体材料は、組織の圧迫により変形することなく組織に密着した固定が可能となる。また、適用部位の損傷に適合した分解速度に調節できるため生体組織の再生を阻害することなく、速やかな組織修復を可能とする。
【００１３】
即ち、本発明生体材料を生体内で硬組織および軟組織の再建材料として使用した場合、速やかに組織と直接結合し、組織が再生するまでの期間、強度を維持し、新たな生体組織の形成に伴って徐々に生体内に吸収されるため、広範囲に適用可能な生体適合性材料となる。
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何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よいし、これらを混合して使用してもよい。また、得られた共重合体中にモノマー、オリゴマーが存在すると、組織反応及び分解速度が異常に促進され、マクロファージの吸収分解能以上に分解切片が生成するため、組織為害性を生ずる原因となる。従って、再沈殿化法等の方法で精製して使用するのが好ましい。
【００１４】
乳酸／グリコール酸／ε−カプロラクトン共重合体は組成および分子量により機械的強度、柔軟性、加水分解速度が異るため、本発明に使用する共重合体としては、ε−カプロラクトン含量が１〜４５モル％であることが好ましい。ε−カプロラクトン含量が１モル％未満では剛性が高く脆いため、生体組織との密着性が低下することと分解速度が遅くなることで適用できない。
一方、４５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。
【００１５】
共重合体中の乳酸含量およ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５モル％未満の場合、必要な分解速度が達成されず、組織再生を阻害するという問題が生じ、７０モル％を超えると前述した分解切片による組織為害性を生ずることもあるので好ましくない。
【００１６】
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３０，０００〜２００，０００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、３０，０００を下廻ると乳酸、グリコール酸等のモノマー、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の原因となるため適当でない。また逆に、分子量が２００，０００を越えると、加水分解速度が低下して組織再生を阻害する可能性があることに加えて、後述のりん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りん酸カルシウムの分散性が不均一となる。
【００１７】
なお、本発明の目的を損なわない範囲であれば、少量の他の共重合成分を含有していても良い。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好例として挙げられる。
【００１８】
本発明で使用されるりん酸カルシウムとしては、りん酸三カルシウム、ヒドロキシアパタイト、第二りん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、最も望ましいりん酸カルシウムは、共重合体との親和性が良く、生体内で吸収崩壊して新組織と置換され組織再生を促進するりん酸三カルシウムである。
平均粒径としては、０．１〜２００μｍのりん酸三カルシウムを用いる。
平均粒径０．１μｍ未満では、溶解速度が速く十分な組織再建能を示さない。
また、平均粒径２００μｍを越えると、溶解速度が遅くなり組織再建を阻害する。
さらに、本発明の好ましいりん酸三カルシウムは６５０℃〜１５００℃で焼結されたりん酸三カルシウムである。りん酸三カルシウムは焼成することにより構造が安定化し高密度化する。
焼結温度が、６５０℃未満では、りん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。
１５００℃を越えると、りん酸三カルシウムが分解し始め生体組織再建を阻害する成分が生成する。
【００１９】
本発明において、適正な強度および分解性を有し組織再生に有効な生体材料を得るためには、りん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複合体を製造する必要がある。
複合体は例えば、以下の方法により製造される。りん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、分子量およびりん酸カルシウムの種類、物性等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。混合時間は５〜６０分程度必要である。
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りん酸カルシウムを溶媒中で混合した後溶媒を除去する方法、固体混合後加圧プレスあるいは加熱プレスする方法等が挙げられる。
【００２０】
りん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っ張り強度、分解速度等の物性が異なるが、一般的には、りん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およ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を越えると必要な強度が得られず、組織の誘導再生能が減少する。
また、本発明で得られる成形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組織再生を促進させることもできる。更にまた、本発明生体材料は癒着防止膜、人工血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複合体は、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、スクリュー等任意の形態で使用に供することができる。また、溶液からの凍結乾燥等により多孔質化することもできる。
【００２１】
本発明による生体材料は、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させることができ、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、組織が再生するまでの期間、複合体は体温付近でその形態、強度を保持しており、体重等の負荷がかかる部位への利用にも極めて有効である。
【００２２】
【実施例】
以下実施例を挙げて更に本発明を詳細に説明するが、本発明はこれらに限定されるものではない。尚、特に断らない限り％は全て重量％を示す。
【００２３】
（実施例１）
Ｌ−ラクチド２２０ｇとグリコリド３５ｇとε−カプロラクトン４５ｇ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、１８５ｇ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１２０，０００であり、その組成はＨ−ＮＭＲからモル比で乳酸：グリコール酸：ε−カプロラクトン＝８０：１５：５であった。
【００２４】
上記乳酸／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１μｍのβ−りん酸三カルシウムとを３０／７０重量比で、２００℃で１０分間加熱混練した。強度試験の結果、組成は均一で骨強度に近く、曲げ強度は７０ＭＰａ、ヤング率は２５ＧＰａを持つ複合体が得られた。細胞培養実験の結果、複合体に使用したりん酸三カルシウム、乳酸／グリコール酸／ε−カプロラクトン共重合体とも複合化前の生体に対する特性を保持していた。
【００２５】
（実施例２〜９）
表１〜２に示す組成の異なる乳酸／グリコール酸／ε−カプロラクトン共重合体を合成し、それを表１〜２に示す割合で異なる物性のりん酸カルシウムと混合して複合化し、生体材料を製造した。その結果を表１〜２に示す。なお、数平均分子量は略９０，０００〜１２０，０００である。
【００２６】
【表１】
【表２】
＜生体組織誘導能評価＞
実施例２〜９で製造した生体材料をホットプレスにより厚さ約２００μｍのフィルムに成形し、エチレンオキサイド滅菌後、犬の下顎骨の人工欠損に移植した。その結果、約４週間で複合体フィルムが消失し、約１２週間で欠損部分が再建された。
【００２９】
（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１００，０００の二元共重合体を合成した。これを８００℃で焼成した平均粒径１μｍのα−りん酸三カルシウムと７０／３０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、即ち、形態が維持できなかった。
【００３０】
（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１１０，０００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、犬の下顎骨の人工欠損に移植した。約１２週間後観察した結果、複合体の分解速度が遅く組織再生が阻害されていた。
【００３１】
【発明の効果】
本発明で得られるりん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生体材料は、生体適合性に優れ、適正な強度および分解速度を有する組織再生に有効な材料である。この生体材料を硬組織または軟組織の再建材料として使用すると、組織が再生するまでの期間、強度を維持し、組織の再生にともなって生体内に吸収されるため組織再生を阻害することがない。また残留物による異物反応を示すこともない。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a biomaterial containing calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer, and is particularly applicable to the reconstruction of hard and soft tissues in vivo, and with tissue formation. The present invention relates to an excellent biomaterial that is gradually decomposed and absorbed.
[0002]
[Prior art]
Hard tissue such as bone tissue and cartilage tissue and epithelial tissue, connective tissue, soft tissue trauma such as nerve tissue, inflammation, tumor, in vivo defect caused by cosmetic surgery, etc. A prosthetic method is used to restore the function, and many materials have been studied.
[0003]
When prosthetic bone defects in vivo, autologous bone transplantation is better than conventional allograft or xenogeneic bone transplantation, with better engraftment on the transplantation bed and fewer virus or prion infections or immune problems. I have been. However, autologous bone transplantation has a limit in the amount that can be collected, and there are problems such as risk of infection due to formation of a new surgical wound for obtaining bone graft, and prolonged suffering of patients.
[0004]
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 biomaterials have physical and mechanical strengths that are excessively greater than those 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 of improving the affinity with surrounding tissues by applying surface treatment with a biocompatible material such as hydroxyapatite on the surface of the metal material has been performed, but it is not sufficient. .
[0005]
On the other hand, as biocompatible materials, polymers of lactones such as lactic acid, glycolic acid, trimethylene carbonate or ε-caprolactone, which are biodegradable aliphatic polyesters, 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 vivo and cause fatigue deterioration, or show no effect on osteoinductivity although they do not inhibit bone conduction.
[0006]
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 and dental implants. 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 is absorbed from the surface of the material when it is used in a bone defect, and disintegrates and replaces it with new bone. Use on such sites is limited.
In addition, since tricalcium phosphate is granular, it lacks the formability and maintenance stability of the bone graft material, making it difficult to perform filling operations for complex and wide-ranging defects, and healing accompanying granule outflow Problems such as delays remain.
[0007]
As a method for solving these problems, many researches have been made on composite materials of bioceramics and polymers. U.S. Pat. No. 4,347,234 proposes a composite of bioceramics and collagen. However, when such collagen is used, since collagen is a naturally derived material, its molecular weight, amino acid composition, amount, water retention amount, etc. are not constant, and complete removal of antigenic telopeptide parts is not possible. Since it is difficult, a foreign body reaction occurs in the living body, and foreign body giant cells and other phagocytic cells are activated, so that bone induction is not expressed.
[0008]
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 Application 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 a constituent unit and calcium phosphate, in which a polymerization catalyst is deactivated. U.S. Pat. No. 4,595,713 discloses a complex composed of a lactic acid- [epsilon] -caprolactone copolymer in which [epsilon] -caprolactone is a major amount and a bone-forming substance such as [beta] -calcium phosphate and hydroxyapatite. The former is bioabsorbable 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 since the decomposition rate of the material is slow, bone formation is suppressed. None of the materials has solved the problem that β-calcium phosphate has a small amount of bone formation in vivo.
[0009]
JP-A-6-298639 discloses a sustained-release material in which β-tricalcium phosphate is dispersed in a complex of a lactic acid-glycolic acid copolymer and an antibiotic. Similarly, although there are many studies on the reconstruction of soft tissues such as blood vessels and peripheral nerves, sufficient materials have not been obtained, so it is excellent in biocompatibility and maintains strength until the tissue is regenerated, There is a need for a material that is decomposed and absorbed after transplantation and is close to tissue metabolism.
[0010]
[Problems to be solved by the invention]
In order to solve the above problems, the present inventors have conducted intensive research on biomaterials that are biodegradable, do not cause foreign body reactions in the living body, and have an appropriate strength and degradability and are effective for tissue regeneration. Repeated. As a result, the present invention described in detail below is completed.
[0011]
[Means for Solving the Problems]
That is, the present invention relates to a biomaterial comprising calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
Since the biomaterial of the present invention has a structure in which calcium phosphate is coordinated by a carbonyl group of a lactic acid / glycolic acid / ε-caprolactone copolymer, the biodegradability and biological tissue inducing ability of calcium phosphate Is regulated, and its ability to induce biological tissue is remarkably promoted. In general, the shape of the reconstructed living tissue is complicated, but various materials ranging from flexibility to high strength can be obtained by adjusting the composition and molecular weight of the lactic acid / glycolic acid / ε-caprolactone copolymer. Since it is molded, the biomaterial of the present invention can be fixed in close contact with the tissue without being deformed by compression of the tissue. In addition, since the degradation rate can be adjusted to suit the damage to the application site, rapid tissue repair is possible without inhibiting the regeneration of living tissue.
[0013]
That is, when the biomaterial of the present invention is used as a reconstruction material for hard tissue and soft tissue in vivo, it quickly bonds directly with the tissue, maintains the strength until the tissue is regenerated, and forms a new biological tissue. Accordingly, it is gradually absorbed into the living body, so that it becomes a biocompatible material applicable to a wide range.
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. In addition, when monomers and oligomers are present in the obtained copolymer, the tissue reaction and the degradation rate are abnormally accelerated, and the degradation section is generated more than the absorption resolution of macrophages, which causes tissue damage. Therefore, it is preferable to use it after purification by a method such as reprecipitation.
[0014]
Since the lactic acid / glycolic acid / ε-caprolactone copolymer has different mechanical strength, flexibility and hydrolysis rate depending on the composition and molecular weight, the copolymer used in the present invention has an ε-caprolactone content of 1 to 45. It is preferable that it is mol%. If the ε-caprolactone content is less than 1 mol%, the rigidity is high and brittle, so that it cannot be applied because the adhesion to living tissue is lowered and the decomposition rate is slow.
On the other hand, if it exceeds 45 mol%, the required strength cannot be obtained and the biodegradability is slow, which is not preferable.
[0015]
The lactic acid content and glycolic acid content in the copolymer can be arbitrarily changed. However, when the glycolic acid content is less than 5 mol%, the necessary degradation rate is not achieved, which causes a problem of inhibiting tissue regeneration. If it exceeds 70 mol%, the above-mentioned decomposition section may cause tissue damage, which is not preferable.
[0016]
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 is less than 30,000, it contains many monomers and oligomers such as lactic acid and glycolic acid. It is not suitable because it promotes hydrolysis and causes a decrease in strength. On the other hand, if the molecular weight exceeds 200,000, the hydrolysis rate decreases and the tissue regeneration may be inhibited. In addition, the mixing operation with calcium phosphate described later becomes difficult, and the copolymer Dispersibility of calcium phosphate in the inside becomes uneven.
[0017]
In addition, as long as the objective of this invention is not impaired, you may contain a small amount of other copolymerization components. Examples of such copolymer components include cyclic monomers constituting hydroxycarboxylic acids such as β-hydroxybutyric acid and γ-butyrolactone-δ-valerolactone.
[0018]
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 decays in vivo to replace the new tissue and promote tissue regeneration. It is.
As an average particle diameter, 0.1-200 micrometers tricalcium phosphate is used.
When the average particle size is less than 0.1 μm, the dissolution rate is high and sufficient tissue reconstruction ability is not exhibited.
On the other hand, when the average particle size exceeds 200 μm, the dissolution rate becomes slow and the tissue reconstruction is inhibited.
Further, the preferred tricalcium phosphate of the present invention is tricalcium phosphate sintered at 650 ° C to 1500 ° C. The structure of tricalcium phosphate is stabilized and densified by firing.
When the sintering temperature is less than 650 ° C., the structure becomes unstable in which hydrated water is present in tricalcium phosphate.
When the temperature exceeds 1500 ° C., tricalcium phosphate begins to decompose, and a component that inhibits the reconstruction of living tissue is generated.
[0019]
In the present invention, it is necessary to produce a complex of calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer in order to obtain a biomaterial having an appropriate strength and degradability and effective for tissue regeneration. is there.
The composite is produced, 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 above the softening point. The conditions for heating and kneading cannot be specified because they differ 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 , In air or in a nitrogen atmosphere. The mixing time is about 5 to 60 minutes.
Examples of methods for producing biomaterials other than the heat-kneading method include, for example, a method in which lactic acid / glycolic acid / ε-caprolactone copolymer and calcium phosphate are mixed in a solvent and then the solvent is removed. Examples include a pressing method.
[0020]
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 calcium acid and lactic acid / 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 strength cannot be obtained, and the induced regeneration ability of the tissue decreases.
In addition, as long as the characteristics of the molding material obtained in the present invention are not impaired, physiological activities such as antitumor agents, anticancer agents, anti-inflammatory agents, vitamins such as active vitamin D, and polypeptides such as thyroid stimulating hormone A drug such as a substance can be added to the complex to provide a sustained release function and promote tissue regeneration. Furthermore, the biomaterial of the present invention can be used as an adhesion prevention film or an artificial blood vessel.
The composite 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, screws, etc. Can be provided. It can also be made porous by freeze-drying from a solution or the like.
[0021]
The biomaterial according to the present invention is characterized in that it can be easily deformed by being heated by a method such as immersing in warm water, and a complicated affected part can be easily filled.
The complex retains its form and strength near body temperature during the period from implantation / filling into a living body until tissue regeneration, and it is extremely effective for use in a site where a load such as weight is applied.
[0022]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these. Unless otherwise specified, all percentages are by weight.
[0023]
Example 1
L-lactide 220 g, glycolide 35 g, and ε-caprolactone 45 g were subjected to a polymerization reaction for 24 hours at 150 ° C. under reduced pressure of 10-3 mmHg in the presence of 0.01 g of tin octoate. After the reaction, purification was performed by dissolving in chloroform and precipitating in methanol to obtain 185 g of lactic acid / glycolic acid / ε-caprolactone copolymer.
The number average molecular weight of the copolymer thus obtained was 120,000 by GPC, and its composition was lactic acid: glycolic acid: ε-caprolactone = 80: 15: 5 in molar ratio from H-NMR. .
[0024]
The lactic acid / glycolic acid / ε-caprolactone copolymer and β-tricalcium phosphate having an average particle size of 1 μm calcined at 800 ° C. were heated and kneaded at 200 / ° C. for 10 minutes at a 30/70 weight ratio. As a result of the strength test, a composite having a uniform composition close to bone strength, a bending strength of 70 MPa, and a Young's modulus of 25 GPa was obtained. As a result of the cell culture experiment, the tricalcium phosphate and the lactic acid / glycolic acid / ε-caprolactone copolymer used for the complex retained the properties of the living body before the complexing.
[0025]
(Examples 2-9)
Lactic acid / glycolic acid / ε-caprolactone copolymers having different compositions shown in Tables 1 and 2 were synthesized, mixed with calcium phosphate having different physical properties at the ratios shown in Tables 1 and 2, and composited. Manufactured. The results are shown in Tables 1-2. The number average molecular weight is approximately 90,000 to 120,000.
[0026]
[Table 1]
[Table 2]
<Evaluation of biological tissue induction ability>
The biomaterial produced in Examples 2 to 9 was formed into a film having a thickness of about 200 μm by hot pressing, and after being sterilized with ethylene oxide, it was transplanted to an artificial defect of the mandible of the dog. As a result, the composite film disappeared in about 4 weeks, and the defect portion was reconstructed in about 12 weeks.
[0029]
(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 calcined at 200 ° C. for 10 minutes at a 70/30 weight ratio with α-tricalcium phosphate having an average particle diameter of 1 μm calcined at 800 ° C. to synthesize a composite.
Since the obtained composite had high rigidity and was brittle, it was difficult to mold, that is, the form could not be maintained.
[0030]
(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 110,000 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 being sterilized with ethylene oxide, it was transplanted into an artificial defect of the mandible of the dog. As a result of observation after about 12 weeks, the degradation rate of the complex was slow and tissue regeneration was inhibited.
[0031]
【The invention's effect】
A biomaterial containing calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer obtained in the present invention is a material that is excellent in biocompatibility and has an appropriate strength and decomposition rate and is effective for tissue regeneration. is there. When this biomaterial is used as a reconstruction material for hard tissue or soft tissue, the strength is maintained for a period until the tissue is regenerated, and it is absorbed into the living body as the tissue is regenerated, so that tissue regeneration is not hindered. Also, no foreign matter reaction due to the residue is shown.
Claims (7)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
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| JP23034899A JP4529005B2 (en) | 1999-08-17 | 1999-08-17 | Biomaterial |
| EP00950053A EP1121943B1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| CA002347256A CA2347256C (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| DE60035403T DE60035403T2 (en) | 1999-08-17 | 2000-08-10 | BIOLOGICAL MATERIALS |
| US09/807,707 US6441073B1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
| PCT/JP2000/005353 WO2001012240A1 (en) | 1999-08-17 | 2000-08-10 | Biological materials |
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| JP23034899A JP4529005B2 (en) | 1999-08-17 | 1999-08-17 | Biomaterial |
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| JP2001054564A JP2001054564A (en) | 2001-02-27 |
| JP4529005B2 true JP4529005B2 (en) | 2010-08-25 |
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| US8029755B2 (en) | 2003-08-06 | 2011-10-04 | Angstrom Medica | Tricalcium phosphates, their composites, implants incorporating them, and method for their production |
| JP5214129B2 (en) * | 2006-10-10 | 2013-06-19 | 川澄化学工業株式会社 | Absorbable porous membrane material for soft tissue reconstruction |
| JP5188857B2 (en) * | 2008-03-28 | 2013-04-24 | グンゼ株式会社 | Method for producing osteosynthesis material |
| JP7220852B2 (en) * | 2017-06-23 | 2023-02-13 | 帝人メディカルテクノロジー株式会社 | Membrane for GBR |
| US11147682B2 (en) | 2017-09-08 | 2021-10-19 | Pioneer Surgical Technology, Inc. | Intervertebral implants, instruments, and methods |
| USD907771S1 (en) | 2017-10-09 | 2021-01-12 | Pioneer Surgical Technology, Inc. | Intervertebral implant |
| CN116966337B (en) * | 2023-07-19 | 2024-12-13 | 河北医科大学第四医院 | A degradable polymer repair material and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08215299A (en) * | 1994-11-30 | 1996-08-27 | Ethicon Inc | Hard tissue bone cement and substitution |
| WO1997038676A1 (en) * | 1996-04-16 | 1997-10-23 | Depuy Orthopaedics, Inc. | Bioerodable polymeric adhesives for tissue repair |
| JPH11192299A (en) * | 1997-12-29 | 1999-07-21 | Takiron Co Ltd | Plastic adhesive material which is degradable and absorbed in vivo |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08215299A (en) * | 1994-11-30 | 1996-08-27 | Ethicon Inc | Hard tissue bone cement and substitution |
| WO1997038676A1 (en) * | 1996-04-16 | 1997-10-23 | Depuy Orthopaedics, Inc. | Bioerodable polymeric adhesives for tissue repair |
| JPH11192299A (en) * | 1997-12-29 | 1999-07-21 | Takiron Co Ltd | Plastic adhesive material which is degradable and absorbed in vivo |
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