JP4184652B2

JP4184652B2 - Organic-inorganic composite porous body and method for producing the same

Info

Publication number: JP4184652B2
Application number: JP2001360766A
Authority: JP
Inventors: 保夫敷波
Original assignee: Takiron Co Ltd
Current assignee: Takiron Co Ltd
Priority date: 2001-11-27
Filing date: 2001-11-27
Publication date: 2008-11-19
Anticipated expiration: 2021-11-27
Also published as: JP2003159321A; CN1981879A

Description

【０００１】
【発明の属する技術分野】
本発明は有機−無機複合多孔体に関し、殊に、生体骨組織再生用の足場(Scaffold)、補綴材、ボーンフィラー、インプラントと生体骨組織との間の介在物、海綿骨の代替物、ＤＤＳ(Drug Deliverly System) の薬物徐放用キャリアなどの用途に適した有機−無機複合多孔体に関する。
【０００２】
【従来の技術】
医療用途を目的とする無機の多孔体として、例えば、セラミックスを仮焼または焼結(Calcined，Sintered)して得られる多孔性セラミックスが知られている。しかしながら、かかる多孔性セラミックスは、生体骨組織再建用の足場や補綴材などの用途に使用するには硬いが、脆いという欠点があるので、術後のわずかな衝撃による破損が常に危惧される。また、手術現場で多孔性セラミックスの形状を生体骨組織の欠損部の形状に合うように加工、変形することも難しい。
【０００３】
一方、医療用途を目的とする有機の多孔体として、例えば、特公昭６３−６４９８８号に開示されたスポンジ等が知られている。このスポンジは、普通には手術時の止血や生体の軟組織（例えば臓器など）の縫合時の補綴材料として使用されるもので、生体内分解吸収性のポリ乳酸からなる連続気孔を有するスポンジである。かかるスポンジは、ポリ乳酸をベンゼン又はジオキサンに溶解し、そのポリマー溶液を凍結乾燥して溶剤を昇華させる方法によって製造される。
【０００４】
しかしながら、上記のスポンジのように凍結乾燥法によって製造される多孔体は、昇華に長時間を要して、完全には溶剤を除くことが困難であり、その厚さが１ｍｍ以下（通常、数百μｍ程度）と薄く、数ｍｍ以上の厚い多孔体を製造することは現実的に困難である。連続気孔を有する多孔体を造る他の方法としては、上記の凍結乾燥法の他にも種々の方法が検討されているが、いずれも数ｍｍの厚い多孔体を得ることは困難である。このような薄い多孔体を例えば生体組織損傷部位の複雑で比較的大きい三次元空間に形状的にあてはめて、一次的な補綴材としての機能を発揮させながら立体的な損傷部位の組織再建を図る材料とするには困難がある。そこで、厚みが大きく、自由な形状の三次元立方体に術前あるいは術後に細工できるものが求められる。
【０００５】
また、連続多孔体をつくるもう一つの有力な方法として、ポリマーに水溶性である所定の大きさのＮａＣｌなどの可溶性の粉粒を多量に混合し、シート状などの肉薄の成形物をつくった後、水（溶剤）に浸漬して該粉粒を溶出することにより、該粉粒と同じ径の連続孔を形成する溶出法が知られているが、該粉粒を完全に溶出するのは困難であるため、肉薄の連続多孔体に限定される。また、水溶性の粉粒の比率が高くなれば、連続気泡とはなり難い。しかも、この多孔体を生体内埋入材料とするときは、残留する該粉粒の毒性に煩わされるという問題がある。
【０００６】
上記のスポンジのように、生体活性なバイオセラミックス等の無機粉粒を含まない多孔体は、硬骨や軟骨などの生体骨組織との直接の結合性（direct bonding ability to bone）、伝導性（osteoconductivity）、置換性（bone replacement）等が欠乏しているために骨芽細胞ではない軟組織が侵入、介在するので、生体の骨組織が完全に置換して再生されるまでにかなりの長期間を要するか、置換されないままに終わる。
【０００７】
そこで、本出願人は、骨芽細胞を播種されて三次元立方体の足場となり、大きな骨の欠損部に橋わたしのために植付けることのできるところの、内部にバイオセラミックス粉粒が含有された生体内分解吸収性ポリマーからなる連続気孔を有する厚みの大きい多孔体を既に出願した（特願平８−２２９２８０号）。
【０００８】
この多孔体は、溶液沈殿法と称される多孔体の製造方法によるものである。即ち、生体内分解吸収性ポリマーをその溶剤とその溶剤より高沸点の非溶剤との混合溶媒に溶解させると共に、バイオセラミックス粉粒を分散させて懸濁液を調製し、この懸濁液から混合溶媒を溶剤の沸点より低温で気散させて、バイオセラミックス粉粒を内包する生体内分解吸収性ポリマーを沈殿させる方法によるものである。
【０００９】
この溶液沈殿法による多孔体の形成原理は、次の通りである。即ち、上記の懸濁液から混合溶媒を溶剤の沸点より低温で気散させると、沸点の低い溶剤が優先的に気散して沸点の高い非溶剤の比率が次第に上昇し、溶剤と非溶剤がある比率に達すると溶剤はポリマーを溶解できなくなる。そのため、ポリマーが析出・沈殿を開始し、当初から沈降を開始しているバイオセラミックス粉粒を内包し、析出・沈殿したポリマーが高比率の非溶剤により収縮、固化してバイオセラミックス粉粒を含有したまま固定化され、連結したポリマーの薄いセル壁に混合溶媒が内包された状態のセル構造が形成される。そして、残りの溶剤がセル壁の一部を破壊しながら細孔をつくって気散・消失し、沸点の高い非溶剤も該細孔を通じて徐々に気散して、遂には完全に気散・消失する。その結果、ポリマーのセル壁に包まれていた混合溶媒の溜め跡が連続気孔として繋がったバイオセラミックス粉粒含有多孔体が形成されるのである。
【００１０】
【発明が解決しようとする課題】
上記の溶液沈殿法は、低発泡倍率から高発泡倍率の厚みの大きい多孔体を形成する画期的な方法であり、数ｍｍないし数十ｍｍの厚さを有するブロック状の三次元多孔体を得ることが可能である。それゆえ、立体形状（三次元立体構造）の骨再生の足場などには頗る有用である。
【００１１】
しかしながら、この方法の欠点は、大量にバイオセラミックス粉粒を含んだ懸濁液では、平均粒径のうちで比較的大きな粒径分布に属するバイオセラミックス粉粒が、溶剤揮散をはじめる当初から沈降を開始し、ポリマーが析出・沈殿を開始したときには、既にかなりのバイオセラミックス粉粒が底部に向けて濃度勾配をもって沈降しているため、得られる多孔体はバイオセラミックス粉粒の含有量が部分的に均一でなく、多孔体の上面側から底面側に近づくにつれて含有量が多くなる。このように含有量が濃度勾配をもっている不均一な多孔体は、骨組織再建用の足場、補綴材あるいはボーンフィラー等の用途には有効に使用し難い。かかる問題は、バイオセラミックス粉粒の沈降速度等をコントロールすることにより、ある程度改善することは可能であるが、完全に解決することはできない。特に、３０重量％以上ものバイオセラミックス粉粒を含有する均質、かつ均等な濃度をもつ三次元の骨再建用の多孔体とするのは困難である。
【００１２】
上記の方法で製造されるバイオセラミックス粉粒の含有量が少ない多孔体は、バイオセラミックス粉粒の大半がポリマーのセル壁に内包されて連続気孔の内面に露出しにくいため、生体内に埋め込んだとき、埋め込み当初からバイオセラミックス粉粒による生体骨組織の伝導作用が発揮され難く、連続気孔内面のスキン層を形成するポリマーの分解に併行して露出したバイオセラミックス粉粒と共に生体活性が発現されるという問題がある。
【００１３】
更に、上記の方法で製造される多孔体は、極細粒を選んだとしてもバイオセラミックス粉粒の含有率をせいぜい３０重量％程度までとする必要があり、これより多量に含有させると、バイオセラミックス粉粒が一層沈降しやすくなるため、得られる多孔体の底面側が多量のバイオセラミックス粉粒を含んで極めて脆くなるという限界がある。
【００１４】
また、上記の方法で製造される多孔体は、通常、連続気孔の占める割合（気孔率）が８０％以上と大きいけれども、一般的に言って、孔径が数μｍないし数十μｍと比較的小さい連続気孔しか得られないので、多孔体内部への骨芽細胞の侵入と成長にとって理想的な孔径、孔の形態を形成しているとは言えない。
【００１５】
本発明は、これらの問題を解決し得る有機−無機複合多孔体と、その製造方法を提供することを目的としている。
【００１６】
【課題を解決するための手段】
本発明に係る有機−無機複合多孔体は、有機ポリマーの多孔質マトリックス中に無機粉粒が均一に分散し、内部に連続気孔を有する多孔体であって、その表面と気孔内面に無機粉粒の一部が露出したものであり、有機ポリマーとして、ポリ−Ｄ，Ｌ−乳酸、Ｌ−乳酸とＤ，Ｌ−乳酸のブロック共重合体、乳酸とグリコール酸の共重合体、乳酸とｐ−ジオキサノンの共重合体、乳酸とカプロラクトンの共重合体、乳酸とエチレングリコールの共重合体、これらの混合体、のいずれかの生体内分解吸収性ポリマーを使用し、無機粉粒として未仮焼、未焼成のハイドロキシアパタイト、ジカルシウムホスフェート、トリカルシウムホスフェート、テトラカルシウムホスフェート、オクタカルシウムホスフェート、カルサイト、セラバイタル、ジオプサイト、天然珊瑚のいずれかの生体活性な全吸収性のバイオセラミックス粉粒を使用したものである。そして、連続気孔は、骨芽細胞が侵入して増殖、安定化するのに好適な１００〜４００μｍ程度の孔径に調節され、無機粉粒は６０〜９０重量％と多量に含有されている。また、多孔体の厚みは１〜５０ｍｍと大きく、三次元立体形状を有している。
【００１７】
このような有機−無機複合多孔体は、本発明の製造方法、即ち、揮発性溶媒に有機ポリマーとして前記の生体内分解吸収性ポリマーを溶解し、無機粉粒として前記の生体活性な全吸収性のバイオセラミックス粉粒を分散させて調製した懸濁液から不織布状の繊維集合体をつくり、これを加熱下に加圧成形して多孔質の繊維集合成形体となし、次いで、揮発性溶媒に繊維集合成形体を浸漬したのち該溶媒を除去する方法によって、製造することができる。懸濁液から不織布状の繊維集合体をつくる手段としては、懸濁液を繊維化しつつスプレーする手段が好ましく採用され、また、揮発性溶媒に繊維集合成形体を浸漬する際には、繊維集合成形体の形状を保持するような外力を加えておくことが望ましく、これにより、機械的強度のある多孔体が得られる。
【００１８】
上記のように、繊維集合体をつくる手段として、調整された懸濁液を繊維化しつつスプレーする手段を採用すると、無機粉粒を含んだ有機ポリマーの繊維が互いに絡み合って相互の接点で溶着し、揮発性溶媒の揮散により繊維が集合固化して、任意の形状の厚肉の不織布状の繊維集合体が形成される。この繊維集合体は、繊維間空隙は細胞状の孔（round cell space）ではないが、溶着固化した繊維相互の間隔が数百μｍ程度の連続した空間をもつものであり、無機粉粒は繊維に包含されて繊維集合体の全体に亘って均一に分散している。この繊維集合体を加熱下に加圧成形して多孔質の繊維集合成形体をつくり、外力を加えながらその形状を保持しつつ揮発性溶媒に浸漬すると、繊維が収縮、融合する。そして実質的に繊維状の形態が消失し、繊維間空隙が丸みを有するセル構造をもった連続気孔体に形態変化した多孔質マトリックスになる。そして、この変態に伴って、多量に含有されている無機粉粒はその一部が気孔内面に露出すると共に、表面にも無機粉粒が容易に脱落しない程度に填まり込んで露出し、目的とする有機−無機複合多孔体、即ち無機粉粒が高含有率で実質的に均一に分散し、その一部が表面や連続気孔の内面に露出した有機−無機複合多孔体が得られる。勿論、条件によって表面にスキン層が形成されたときには、サンディングすることで無機粉粒を露出させてもよい。この複合多孔体は、繊維集合成形体を揮発性溶媒に浸漬する際に、その形状を保持するための外圧を調節することによって、連続気孔の平均孔径を骨芽細胞の侵入と安定化に都合のよい１００〜４００μｍ程度にコントロールできると共に、気孔率を５０〜９０％程度の望ましい条件をもつ気孔形態にすることが望ましい。
【００１９】
本発明の製造方法では、繊維化が可能な範囲内で６０〜９０重量％（平均粒径が３μｍのとき４１〜８１容積％に相当）の無機粉粒を気孔体中に均一に含有させることが可能である。多量に含有させても無機粉粒が沈降する以前に該繊維が溶着するので、前述した溶液沈殿法で得られる多孔体よりも無機粉粒が均一に分散していて含有率が遥かに高い複合多孔体を最終的に得ることができる。但し、あまりに高含有率であれば、バインダーとしてのポリマー量が少なくなり、多孔体は脆くなって形状を維持することが困難になる。
【００２０】
生体骨組織再生用の足場など医療用途を目的とする本有機−無機複合多孔体は、有機ポリマーとして溶剤特性が本製造方法に見合っており、既に実用されて安全性が確認されており、分解が比較的速く、多孔体となっても脆くないポリマーが選択される。即ち、非晶質あるいは結晶と非晶の混在したポリ−Ｄ，Ｌ−乳酸、Ｌ−乳酸とＤ，Ｌ乳酸のブロック共重合体、乳酸とグリコール酸の共重合体、乳酸とｐ−ジオキサノンの共重合体、乳酸とカプロラクトンの共重合体、乳酸とエチレングリコールの共重合体、或は、これらの混合体などの生体内分解吸収性ポリマーが使用される。その粘度平均分子量は、不織布状の繊維集合体を形成しやすいことや、生体内での分解吸収の期間を考慮して、５万〜１００万のものが好ましく使用される。
【００２１】
特に、モノマー比率に起因して非晶性を示すポリ−Ｄ，Ｌ−乳酸、Ｌ−乳酸とＤ，Ｌ乳酸のブロック共重合体、乳酸とグリコール酸の共重合体、乳酸とｐ−ジオキサノンの共重合体などの生体内分解全吸収性ポリマーは、不織布状の繊維集合体を形成するとき、及び、これを加熱下に加圧成形した繊維集合成形体を揮発性溶媒で処理するときの溶媒特性からみて好適であり、これらのポリマーを使用すると、多量の無機粉粒を含んでいても脆くなく、海綿骨なみの圧縮強度（１〜５ＭＰａ程度の圧縮強度）を持ち、セラミックス単体の多孔体とは異なって比較的低温（７０℃程度）で熱変形させることができ、生体内ですみやかに加水分解して６〜１２ケ月で全吸収される、有機−無機複合多孔体を得ることができる。このような特性を有する複合多孔体は、生体骨の欠損部に充填する生体材料として極めて好ましいものである。複合体であるが故に、セラミックスのみの材料と異なり手術中に熱変形させて欠損部に合致するように形を整えることができる熱可塑性ポリマー特有の利点も残している。
【００２２】
生体内分解全吸収性ポリマーの分子量は、加水分解して全吸収されるまでの時間や繊維化の可否に影響を及ぼすので、上記のように５万〜１００万の粘度平均分子量を有するポリマーが使用される。５万より小さい粘度平均分子量を有するポリマーは、オリゴマーないしモノマー単位の低分子までに加水分解される時間は短いけれども、曳糸性が不足するので繊維化しながらスプレーして複合繊維集合体を形成することが困難である。また、１００万より大きい粘度平均分子量を有するポリマーは、完全加水分解するまでに長期間を要するので、生体組織との早期置換を目的とする場合には複合多孔体のポリマーとしては不適当である。ポリマーによって異なるが、その好ましい粘度平均分子量は大略１０万〜３０万であり、この範囲の分子量を有するポリマーを用いると、繊維集合体の形成が容易となり、且つ、適度な加水分解完了時間を有する本発明の複合多孔体を得ることができる。
【００２３】
前述の医療用途を目的とする有機−無機複合多孔体では、無機粉粒として、生体活性があり、良好な骨伝導能（時として骨誘導能を示すとされる）と良好な生体親和性を有するバイオセラミックス粉粒が使用される。そのようなバイオセラミックス粉粒としては、例えば、表面生体活性な焼成、仮焼成ハイドロキシアパタイト、アパタイトウォラストナイトガラスセラミックス、生体活性かつ生体内全吸収性の未仮焼、未焼成ハイドロキシアパタイト、ジカルシウムホスフェート、トリカルシウムホスフェート、テトラカルシウムホスフェート、オクタカルシウムホスフェート、カルサイト、セラバイタル、ジオプサイト、天然珊瑚等の粉粒が挙げられる。また、これらの粉粒の表面にアルカリ性の無機化合物や塩基性の有機物等を付着させたものも使用可能である。自らの生体組織により全置換が為されて組織再生が行われることは理想的であるとの理由により、これらの中でも、生体内で全吸収され骨組織と完全に置換される生体内全吸収性のバイオセラミックス粉体が好ましく、特に未仮焼、未焼成のハイドロキシアパタイト、トリカルシウムホスフェート、オクタカルシウムホスフェートは、活性が最も大きく、骨伝導能に優れ、生体親和性に優れて為害性が低く、短期間で生体に吸収されるので、最適である。
【００２４】
上記のバイオセラミックス粉粒は、粒径が１０μｍ以下のものを使用することが好ましく、これより大きい粒径のバイオセラミックス粉粒を使用すると、該粉粒を混合した懸濁液を繊維化しながらスプレーする際に繊維が短く切断されて、繊維集合体を形成することが困難となり、たとえ繊維集合体を形成できたとしても、繊維が固化するまでにバイオセラミックス粉粒が多少沈降して不均一に分散する恐れがある。２０〜３０μｍを越える大きさのものは、それが全吸収性であっても完全吸収に長時間を要し、その間の組織反応が時として発現するので好ましくない。
【００２５】
バイオセラミックス粉粒の更に好ましい粒径は０．２〜５μｍであり、このようなバイオセラミックス粉粒を使用すると、本発明のように高濃度に該粉粒を混合した懸濁液を１〜３μｍ程度と細く繊維化して繊維集合体を形成する場合でも、繊維が切断され難く、本発明のように高濃度であるときには該粉粒が繊維から露出した状態で繊維に包含されるようになり、繊維集合体を揮発性溶媒で浸漬処理した後に、該粉粒が表面や連続気孔の内面から露出した複合多孔体となる。
【００２６】
バイオセラミックス粉粒の含有率は、再生医工学における足場やＤＤＳのためのキャリアあるいはボーンフィラー、異形状海綿骨（Allograft：同種異植片）の代替物等の医療用途を目的とする有機−無機複合多孔体の場合、６０〜９０重量％とすることはバイオセラミックスの生体活性効果からすると好ましい。本発明のように無機粉粒を含んだ繊維の集合体を形成し、これを加熱下に加圧成形した繊維集合成形体を揮発性溶媒に浸漬して複合多孔体を得る場合は、繊維化が可能な範囲内で多量の無機粉粒を含有させることができるため、上記のようにバイオセラミックス粉粒の含有率を６０〜９０重量％（平均粒径３μｍのときの体積比率は４１〜８１％の高比率に相当する）と高めることができる。バイオセラミックス粉粒の含有率が９０重量％を越えると、繊維化するときに短く切れて満足な繊維にならないため繊維集合体の形成が困難となり、一方、６０重量％を下回ると、バイオセラミックス粉粒が不足し、表面に露出するものが少ないので、生体に埋入した初期からバイオセラミックス粉体に由来する生体活性が発現され難い。
【００２７】
ハイドロキシアパタイト等のセラミックスを焼結して得られる多孔性セラミックスは、硬いけれども脆いため、薄物は外力により容易に割れたり欠けたりするので、インプラントとしては不満足なものである。これに対し、バイオセラミックス粉体を殊に非晶性である生体内分解吸収性ポリマーに含有させた複合多孔体は、バイオセラミックス粉体の含有率が６０〜９０重量％と高い場合でも、そのポリマーの結合（binding）効果により、可撓性を保持した脆くない海綿骨なみの圧縮強度、具体的には１ＭＰａ〜５ＭＰａ程度の圧縮強度を有するため、海綿骨の代替（同種骨移植用：Allograft boneの代替）、ボーンフィラーや補綴材、再生用の足場やＤＤＳのキャリアとして好適に使用される。
【００２８】
また、別の有力な用途として、生体骨（硬骨、軟骨）用の人工インプラントとの間の介在物が挙げられる。例えば、生体活性かつ生体吸収性の骨接合材であるバイオセラミックス粉入りのポリ乳酸系ポリマーから造られた高濃度を有する人工物を埋入するとき、生体との間に隙間が生ずることは避け難いので、この間に本複合多孔体を介在して直接骨組織と接触させると、骨伝導性が顕著に発現される。これは生体骨の種々の部位で有効に働くが、例えば胸骨正中切開の場合に本多孔体を貫通させた胸骨固定ピンを正中骨に埋入することで、骨粗鬆症（osteoporosis）のはげしい中空化した骨中に骨誘導（サイトカインとの併用）や骨伝導をもたらすことができる。あるいはこの種のプレートの下敷きとして使い、骨との密着を図ることもできる。人工椎間板と椎体終板（endplate）への直接の結合を図るなど、生体と人工物の介在物としての用途は多い。
【００２９】
この有機−無機複合多孔体は、気孔率（全気孔率）が５０％以上であり、技術的には約９０％まで可能であるが、この複合多孔体の物理的強度と骨芽細胞の侵入および安定化の双方を勘案すれば、大略６０〜８０％が良く、また、複合多孔体の中心部までの骨芽細胞の侵入の効率を考えれば、連続気孔が気孔全体の５０〜９０％、なかんずく７０〜９０％を占めることが好ましい。
【００３０】
この有機−無機複合多孔体の連続気孔は、その孔径が大略１００〜４００μｍに調整されている。ポーラスセラミックスの孔径と骨芽細胞の侵入および安定化の研究は既に幾度も為されており、その結果からすると３００〜４００μｍの孔径が最も石灰化に効果的であって、それより離れるに従い効果が薄れることが判っている。それ故、本発明の複合多孔体の孔径は上記のように大略１００〜４００μｍに調節されているが、５０〜５００μｍの範囲の孔径のものを含み、分布中心が２００〜４００μｍであってもよい。
【００３１】
因みに、連続気孔の孔径が４００μｍより大きく、気孔率(全気孔率)が９０％よりも高い場合は、複合多孔体の強度が低下するので生体内埋入中に容易に破壊する恐れが大きい。一方、孔径が１００μｍよりも小さく、気孔率が５０％よりも低い場合は、複合多孔体の強度は向上するが、骨芽細胞の侵入が困難であり、加水分解して完全吸収するまでの時間が長くなる。しかし、このような孔径の小さい低気孔率の複合多孔体は、ＤＤＳのキャリアとしてポリマーの分解と併行する比較的長い時間の徐放性を維持することを望む材料としては場合によって利用可能である。連続気孔のより好ましい孔径は１５０〜３５０μｍであり、より好ましい気孔率（全気孔率）は７０〜８０％である。尚、連続気孔の孔径や、気孔全体に占める連続気孔の比率は、前述したように、繊維集合体を加圧成形して繊維集合成形体となすときの圧縮率の調節や、繊維集合成形体をその形状を保持して揮発性溶媒に浸漬するときの形状保持のための外圧の調節によって、コントロールできる。
【００３２】
以上のような有機−無機複合多孔体は、例えば種々の形状のインプラントとして生体骨の欠損部位に埋め込んで使用できる。その際、有機ポリマーの熱可塑性を利用して複合多孔体を７０℃程度に加熱して欠損部分の形状に合致するように変形させることにより、欠損部分に隙間なく埋め込むことができるので、埋め込み作業を簡単且つ正確に行うことが可能となる。また、有機ポリマーのもつ靱性とセラミックス粉粒の硬さのために、手術中にメスで任意の形状に形崩れなく切断して使うこともできる。
【００３３】
複合多孔体を例えば上記のように生体の骨組織内に埋め込むと、体液が複合多孔体の表面から連続気孔内を通って複合多孔体の内部に速やかに浸透するため、複合多孔体の表面と連続気孔の内部の双方から生体内分解吸収性ポリマーの加水分解が殆ど同時に進行するので、多孔体全体に亘って均一に分解が進行する（但し、生体液との濡れ特性は多量に含有し、表面に露出したバイオセラミックス粉粒の濡れ特性により、ポリマーのみの場合より著しく向上しているか、ポリマーの濡れ特性も改善して増殖すべき細胞の侵入、成長をより効果的にする目的で、多孔体にコロナ放電、プラズマ処理、過酸化水素水処理などの酸化処理を行ってもよい）。そして、骨細胞が存在するか、骨細胞と接触する部位に埋入された複合多孔体は、その表面に露出するバイオセラミックス粉粒の骨伝導能により、複合多孔体の表層部に骨組織がすみやかに伝導形成されて骨の小柱（trabecular bone）となって成長し、短期間のうちに複合多孔体が生体骨の欠損部位と結合すると共に、気孔内面に露出するバイオセラミックス粉粒の骨伝導能により、骨組織が複合多孔体の内部にも侵入して骨芽細胞が伝導されて成長するので、周囲骨と直接結合する。この現象は、生体内分解吸収性ポリマーの分解の進行に伴って顕著となり、徐々に周囲骨と置換される。そして、最終的にはポリマーが完全に分解吸収され、また、バイオセラミックス粉粒が生体内吸収性である場合はバイオセラミックス粉粒も完全に吸収されて、成長した骨組織によって完全に置換され、骨欠損部の再生が完了する。
【００３４】
また、上記のような全置換を要求される生体再建用の足場として分解吸収される速度に見合って、気孔内に予め充填されるか、ポリマー中に予め溶解して担持させたサイトカイン等の種々の成長因子や、種々の治療のための薬剤、抗菌剤などを徐放させることで、生体再生や病気の治癒を促進したり効果的にしたりすることができる。尚、上記の複合多孔体が当然、先述したように単独又は同種骨（Allograft bone）との組合わせによって欠損組織の充填材や補綴材になることは明らかである。
【００３５】
上記の有機−無機複合多孔体は、全置換又は一部置換型の生体組織再生用の足場、薬剤のキャリア、補綴材、ボーンフィラー、インプラントと生体組織との間の介在物、海綿骨の代替物等の医療用途を目的とするものであるが、他の用途を目的とする有機−無機複合多孔体の場合は、有機ポリマーとしてポリメチルメタクリレート、ポリ酢酸ビニル、ポリ塩化ビニル、ポリウレタン、ポリアルキレンオキサイド、その他の揮発性溶媒に可溶な各種の汎用樹脂が用途に応じて適宜選択使用される。そして、無機粉粒も、用途に応じて各種の工業用フィラー、機能性フィラー、セラミックス粉粒、カーボン粉、カーボンナノチューブ等が適宜選択使用される。
【００３６】
次に、本発明の製造方法について説明する。
【００３７】
本発明の製造方法によれば、まず、揮発性溶媒に前述の有機ポリマーを溶解させると共に前述の無機粉粒を均一に分散させて懸濁液を調製する。揮発性溶媒としては、常温よりやや高い温度で揮散しやすい低沸点のジクロロメタン、ジクロロエタン、塩化メチレン、クロロホルム等の溶剤が使用される。また、これらの溶剤に、これらの溶剤よりも沸点が高い非溶剤、例えば、沸点が６０〜１１０℃の範囲にあるメタノール、エタノール、１−プロパノール、２−プロパノール、２−ブタノール、ｔｅｒ−ブタノール、ｔｅｒ−ペンタノール等のアルコールのいずれか単独又は二種以上を混合した揮発性の混合溶媒も使用される。
【００３８】
次いで、懸濁液をスプレー器に填装し、窒素ガス等の不活性な高圧噴射ガスでスプレー器の噴射孔から懸濁液を被噴射体に繊維化しながらスプレーする。このようにスプレーすると、揮発性溶媒が揮散しつつ懸濁液が繊維化されて互いに絡み合い、繊維が相互の接点で溶着しながら固化して、不織布状の繊維集合体が形成される。医療用途の生体材料として時として必要な５〜５０ｍｍの厚肉の複合多孔体を得るには、この繊維集合体をスプレーにより形成した後、溶媒が揮散して乾燥するのを待って、再び、その上にスプレーして厚肉化する操作を繰り返して所定の肉厚となるようにすればよい。
【００３９】
被噴射体としては、剥離性の良好なポリエチレンその他のオレフィン系樹脂、フッ素樹脂、シリコン系樹脂等からなる網体や板体が使用される。特に、網体のような通気自在な被噴射体を用いると、スプレーにより懸濁液が繊維化されて網体に当った後、揮発性溶媒が網目を通じて揮散するため、網体側の表面の繊維が融合してスキン層を生じることがなく、溶剤の浸透処理がしやすい繊維集合体を形成できる利点がある。網体としては５０〜３００メッシュのものが好ましく、５０メッシュよりも大きい網目を有する網体は、繊維が網目を通して裏側まで回り込むため、形成された繊維集合体を網体から剥離することが難くなり、３００メッシュよりも小さい網目を有する網体は、揮発性溶媒がスムーズに揮散しにくいため、網体側の繊維が融合してスキン層が形成され易くなる。なお、被噴射体は平坦な網体や板体に限らず、凸曲及び／又は凹曲した立体的な網体や板体を使用してもよい。このような立体的な被噴射体を使用すると、その立体的な形状通りの厚肉の繊維集合体を形成できる利点がある。
【００４０】
上記のように懸濁液を繊維化しながらスプレーして形成される繊維集合体は、繊維間空隙の大きさが数百μｍと大きく、繊維間空隙の占める割合（空隙率）は６０〜９０％程度である。そして、無機粉粒が繊維に包含されて、沈降することなく、繊維集合体の全体に亘って均一に分散している。
【００４１】
この繊維集合体の繊維長は３〜１００ｍｍ程度であることが好ましく、繊維径は０．５〜５０μｍ程度であることが好ましい。この程度の繊維長及び繊維径を有する繊維集合体は、後の溶剤の浸透処理によって繊維が容易に融合し、実質的に繊維が消失した複合多孔体となる。
【００４２】
繊維長は主として有機ポリマーの分子量、懸濁液のポリマー濃度、無機粉粒の含有率や粒径などに依存し、分子量が大きくなるほど、ポリマー濃度が高くなるほど、無機粉粒の含有率が少なくなるほど、無機粉粒の粒径が小さくなるほど、長くなる傾向にある。一方、繊維径は主として懸濁液のポリマー濃度、無機粉粒の含有率、スプレー器の噴射孔の大きさなどに依存し、ポリマー濃度が高くなるほど、無機粉粒の含有率が多くなるほど、噴射孔が大きくなるほど、太くなる傾向にある。また、繊維径は噴射ガスの圧力によっても変化する。従って、上記の繊維長及び繊維径となるように、ポリマーの分子量、ポリマー濃度、無機粉粒の含有率と粒径、噴射孔の大きさ、ガス圧などを調製することが必要である。
【００４３】
上記の繊維集合体は、次いで、加熱下に加圧成形して多孔質の繊維集合成形体とする。その際、まず繊維集合体を加熱、加圧下に固めて連続した空隙を持つ予備成形物をつくり、更に、より高圧下に予備成形物を加圧成形して、連続空隙孔が調整された強度のある多孔質の繊維集合成形体とすることが望ましい。このように加圧成形して多孔質の繊維集合成形体をつくると、最終的に得られる複合多孔体の連続気孔の孔径や気孔率を調節することができ、複合多孔体の強度を向上させることもできる。尚、加圧成形時の加熱は、繊維集合体が少し軟化する程度で充分であり、また、加圧は、最終的に得られる複合多孔体の気孔率が５０〜９０％となるように、且つ、連続気孔の孔径が大略１００〜４００μｍとなるように圧縮できる圧力で行えばよい。
【００４４】
次いで、この繊維集合成形体を揮発性溶媒に浸漬して成形体内部に該溶媒を浸透させた後、この浸透させた溶媒を除去する。繊維集合成形体を揮発性溶媒に浸漬する際には、多数の細孔を有する所定の型に繊維集合成形体を充填し、外側から繊維集合成形体に圧力を加えた状態で形状を保持しながら浸漬することが好ましい。尚、繊維集合成形体の上面に溶媒を流して浸透させるようにしてもよい。また、溶媒を除去する方法としては、繊維集合成形体内部の溶媒を真空吸引する方法などが採用される。
【００４５】
揮発性溶媒としては、前述したジクロロメタン、ジクロロエタン、塩化メチレン、クロロホルム等の溶剤や、これらの溶剤に前述のメタノール、エタノール、１−プロパノール、２−プロパノール、２−ブタノール、ｔｅｒ−ブタノール、ｔｅｒ−ペンタノール等のアルコールのいずれか単独又は二種以上を混合したものが好ましく使用される。
【００４６】
上記のように繊維集合成形体を揮発性溶媒に浸漬して成形体内部に溶媒を浸透させると、繊維が表面から溶媒に溶けるため、繊維同士が融合して実質的に繊維が消失し、繊維間空隙が１００〜４００μｍ程度の孔径を有する丸みを持った連続気孔を残した状態で気泡壁を形成する。そして、繊維に含まれた無機粉粒の一部は、繊維の融合に伴って沈降することなく気孔内面（気泡壁面）に露出し、多孔体表面にも露出する。但し、スキン層が表面に形成された場合は、これをサンディングすることで取り除き、表層に存在する無機粉粒を露出させる処置を施せばよい。以上により、孔径が１００〜４００μｍと大きい連続気孔を有し、多量の無機粉粒が均一に分散すると共に、表面と気孔内面に無機粉粒が露出した、目的とする有機−無機複合多孔体が得られる。その場合、５０〜６０℃の加熱下に繊維集合成形体の揮発性溶媒への浸漬処理を行うと、繊維集合成形体を５〜１０分間放置するだけで、繊維同士が充分に融合し、目的とする複合多孔体を効率良く得ることができる。
【００４７】
以上の製造方法によって得られる有機−無機複合多孔体は、既述したように、生体骨組織再建用の足場、補綴材、ボーンフィラー、インプラントと生体骨組織との間の介在物、バルク形状の海綿骨の代替物、薬物徐放用キャリア等として有効に使用されるものであり、従って、この有機−無機複合多孔体よりなる生体骨組織再建用の足場、補綴材、ボーンフィラー、インプラントと生体骨組織との間の介在物、バルク形状の海綿骨の代替物、薬物徐放用キャリアは、いずれも本発明に含まれる。
【００４８】
【発明の実施の形態】
次に、本発明の具体的な実施例を説明する。
【００４９】
［実施例１］
粘度平均分子量が２０万のポリ−Ｄ，Ｌ−乳酸（ＰＤＬＬＡ）（Ｄ−乳酸とＬ−乳酸のモル比５０／５０）をジクロロメタンに溶解したポリマー溶液（濃度：ＰＤＬＬＡ４ｇ／ジクロロメタン１００ｍｌ）と、平均粒径３μｍの未焼成のハイドロキシアパタイト粉粒（ｕ−ＨＡ）をエタノールに混和した混和液とを均一にホモジナイズすることによって、ｕ−ＨＡをＰＤＬＬＡ１００重量部に対して２３０重量部の割合となるように混合した懸濁液を調製した。
【００５０】
スプレー器としてＨＰ−Ｅエアーブラシ（アネスト岩田(株)製）を使用し、これに上記の懸濁液を填装して、１．６ｋｇ／ｃｍ² の窒素ガスにより、約１２０ｃｍ離れたポリエチレン製の網体（１５０メッシュ）にスプレーして、繊維集合体を形成し、網体から繊維集合体を剥離した。この繊維集合体の繊維径は１．０μｍ程度、繊維長は１０〜２０ｍｍ程度、見掛け比重は０．２であった。
【００５１】
この繊維集合体を適当な大きさに切断して、直径３０ｍｍ、深さ３０ｍｍの円筒雌型に充填し、繊維集合体の見掛け比重が０．５になるように雄型で圧縮することにより、直径３０ｍｍ、厚さ５ｍｍの円板状の繊維集合成形体を得た。
【００５２】
次いで、エタノールを混合したジクロロメタンからなる溶媒に上記の繊維集合成形体を浸漬して該溶媒を成形体内部に浸透させ、６０℃で１０分放置した後、成形体内部の溶媒を真空吸引により除去して、直径３０ｍｍ、厚さ５ｍｍ、ｕ−ＨＡの含有率７０重量％の有機−無機複合多孔体を得た。
【００５３】
この複合多孔体の部分切断面を電子顕微鏡で観察したところ、繊維が融合して消失し、１００〜４００μｍ程度の大きい孔径を有する連続気孔が形成され、ｕ−ＨＡが均一に分散し、気孔内面と表面にｕ−ＨＡが露出していた。この複合多孔体の見掛け比重は０．５、連続気孔の気孔全体に占める率（連続気孔率）は７５％、圧縮強度は１．１ＭＰａであった。
【００５４】
［実施例２］
実施例１と同様にして、直径３０ｍｍ、厚さ５ｍｍの円板状の繊維集合成形体を予備成形物として造り、これをギヤオーブン中で８０℃に加熱した後、直径の大きさが異なる縮径部を有するチャンバーに入れ、下部の直径が１０．６ｍｍの円筒に圧入した。このようにして加熱下に加圧成形された円柱ロッド状の繊維集合成形体の圧縮強度は、約２．５ＭＰａであった。
【００５５】
次いで、この円柱ロッド状の繊維集合成形体を、周囲に孔の開いた同径のシリンジに充填し、その上面と下面から圧力を加えて円柱ロッド状の繊維集合成形体の高さが変わらない程度に圧迫しながら、１５重量％のメタノールを混合したジクロロメタンよりなる溶媒（６０℃）に１０分間浸漬した後、該溶媒を除去して複合多孔体を得た。
【００５６】
この複合多孔体の部分切断面とサンディングした表面の電子顕微鏡写真は、繊維が消失した多孔質の形態をとり、孔径は１５０〜３００μｍ程の混合孔から成っており、ｕ−ＨＡ粒は多孔体表面や気孔内面から露出していた。この複合多孔体の見掛け比重は約０．５５であり、連続気孔率は７０％、圧縮強度は約３．５ＭＰａに上昇していた。本複合多孔体は、ＰＤＬＬＡの粘度平均分子量と、占める量の比率、平均粒径３μｍのｕ−ＨＡのｉｎｖｉｖｏでの生体内分解吸収特性からすると、埋入部位やサイズに依存するが、約６ケ月で完全吸収すると考えられる。
【００５７】
［実施例３］
粘度平均分子量が１０万のＰＤＬＬＡ（Ｄ−乳酸とＬ−乳酸のモル比３０／７０）を合成し、実施例１と同様の方法で平均粒径３μｍ程度のβ−トリカルシウムホスフェート（β−ＴＣＰ）を８０重量％均一に混合して懸濁液を調製した。このβ−ＴＣＰは生体活性かつ生体内吸収性であることが確認されており、機構はｕ−ＨＡとは異なるが、生体内でＨＡ生成による骨伝導性を示すことが知られている。
【００５８】
この懸濁液を用いて、実施例２と同様にスプレー法で作製した繊維集合体を加熱下に圧縮成形して繊維集合成形体となし、これを溶剤浸漬処理することで、見掛け比重が約０．６、連続気孔率が７５％、圧縮強度が４．２ＭＰａの複合多孔体を得た。この複合多孔体のβ−ＴＣＰ粒の体積比率は約６５容量％であり、ｕ−ＨＡが７０重量％（約５５容量％）の実施例１，２の複合多孔体よりもかなり無機粉粒の体積が大きいので、多孔体の表面や気孔内面へのβ−ＴＣＰの露出により、生体活性が顕著に発現される。
【００５９】
この複合多孔体は、不織布状の繊維集合体のときの繊維が消失してバルク状のセル壁にβ−ＴＣＰ粒が埋没した形態に変化しているので、生体内の体液に浸漬しているときも崩壊してこの粉粒が周囲に分散されることは容易に起きず、３〜５ケ月程度で良好な生体活性を示しながら完全に分解吸収されることが確認された。従って、この複合多孔体は良好な硬組織（硬骨、軟骨）用の足場となる。
【００６０】
［実施例４］
Ｄ，Ｌ−乳酸（Ｄ／Ｌのモル比１）とグリコール酸（ＧＡ）を、そのモル比が８：２となるように配合し、既知の方法により粘度平均分子量が１３万の共重合体Ｐ（ＤＬＬＡ−ＧＡ）を合成した。実施例１と同様の方法で、このポリマーにオクタカルシウムホスフェート（ＯＣＰ）を６０重量％均一に混合した懸濁液を調製し、実施例２と同様にスプレー法で作製した繊維集合体を加熱下に圧縮成形して繊維集合成形体となし、これを溶剤浸漬処理することで、最終的に見掛け比重が０．５０の複合多孔体を得た。この複合多孔体は、ＯＣＰの活性度が高く、共重合体の分解吸収がＧＡに起因して速いので、良好な骨伝導（新生骨に変わり易い）を示しながら、３〜４ケ月後にはその大半が吸収されて骨に置換されていた。
【００６１】
［実施例５］
Ｄ，Ｌ−ラクチド（lactide）とパラ−ジオキサノン（ｐ−ＤＯＸ）をそのモル比が８：２となるように配合し、既知の方法で共重合して粘度平均分子量が約１０万の共重合体を得た。ｐ−ＤＯＸのポリマーは揮発性の汎用な良溶媒は見当たらないが、上記の比率ではクロロホルム、ジクロロメタンなどに可溶となるので、前述した実施例と同様の方法で目的とする複合多孔体を得ることができた。また、上記の共重合体は、実施例４のＤ，Ｌ−乳酸とグリコール酸との共重合体Ｐ（ＤＬＬＡ−ＧＡ）よりは可塑性のあるゴム様の性状を示すので、無機粉粒の粒径が３μｍのときに無機粉粒の体積比率が７０容量％（８５重量％）と高くできるため、この複合多孔体は、共重合体の分解生成物による生体反応が極力回避され、生体活性な無機粉粒の活性度が極めて有効に発現される。特に、ｐ−ＤＯＸの特性から、親水性がＰＤＬＬＡよりも高いので、この複合多孔体はEx vivo（体外シャーレ）で細胞を増殖させるための軟骨の再生の足場などに有効と考えられる。
【００６２】
【発明の効果】
以上の説明から明らかなように、本発明の有機−無機複合多孔体は、多量の無機粉粒を有機ポリマー中に均一な分散状態で含有しており、内部に形成された孔径の大きい連続気孔を通じて体液等がすみやかに浸入して、表面や連続気孔の内面に露出したバイオセラミックス等の無機粉粒によって、早期に生体骨との結合や生体(骨)組織の再生を行うことができる場を提供し、医療用途に必要な実用強度も備えるといった効果を奏する。従って、生体骨組織再建用の足場、補綴材、ボーンフィラー、インプラントと生体骨組織との間の介在物、海綿骨の代替物、薬物徐放用キャリアとして実用される。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an organic-inorganic composite porous body, and more particularly to a scaffold for regenerating a living bone tissue, a prosthetic material, a bone filler, an inclusion between an implant and a living bone tissue, a cancellous bone substitute, (Drug Deliverly System) An organic-inorganic composite porous material suitable for uses such as a drug sustained-release carrier.
[0002]
[Prior art]
As an inorganic porous material for medical purposes, for example, porous ceramics obtained by calcining or sintering (Calcined, Sintered) ceramics are known. However, such porous ceramics are hard to use in applications such as scaffolds for reconstruction of living bone tissue and prosthetic materials, but have the disadvantage of being brittle, and therefore there is always a fear of damage due to slight impact after surgery. It is also difficult to process and deform the porous ceramic shape so as to match the shape of the defect of the living bone tissue at the surgical site.
[0003]
On the other hand, as an organic porous material for medical purposes, for example, a sponge disclosed in Japanese Examined Patent Publication No. 63-64988 is known. This sponge is normally used as a prosthetic material for hemostasis at the time of surgery and for suturing soft tissues (for example, organs) of a living body, and is a sponge having continuous pores made of biodegradable polylactic acid. . Such a sponge is produced by a method in which polylactic acid is dissolved in benzene or dioxane, the polymer solution is lyophilized, and the solvent is sublimated.
[0004]
However, a porous body produced by freeze-drying such as the above-mentioned sponge requires a long time for sublimation, and it is difficult to completely remove the solvent, and its thickness is 1 mm or less (usually several It is practically difficult to produce a thin porous body as thin as about 100 μm and thicker than several mm. As other methods for producing a porous body having continuous pores, various methods other than the above-described freeze-drying method have been studied, but it is difficult to obtain a porous body having a thickness of several millimeters. Such a thin porous body is geometrically applied to, for example, a complicated and relatively large three-dimensional space of a damaged portion of a living tissue, and a three-dimensional damaged portion is reconstructed while exhibiting a function as a primary prosthetic material. There are difficulties in using it as a material. Therefore, there is a demand for a three-dimensional cube having a large thickness that can be crafted before or after surgery.
[0005]
As another effective method for producing a continuous porous body, a large amount of soluble powder such as NaCl having a predetermined size which is water-soluble is mixed with a polymer to produce a thin molded article such as a sheet. Then, an elution method is known in which continuous pores with the same diameter as the powder particles are formed by immersing them in water (solvent) to elute the powder particles. Since it is difficult, it is limited to a thin continuous porous body. Moreover, if the ratio of water-soluble powder becomes high, it will be difficult to become open cells. In addition, when this porous body is used as an in-vivo embedding material, there is a problem that it is bothered by the toxicity of the remaining powder particles.
[0006]
Like the above sponges, porous bodies that do not contain bioactive ceramics and other inorganic particles are directly bonding ability to bone and osteoconductivity. ), Because soft tissue that is not osteoblasts invades and intervenes due to lack of bone replacement, etc., it takes a considerable amount of time for bone tissue in the body to be completely replaced and regenerated Or it ends up not being replaced.
[0007]
Therefore, the present applicant was seeded with osteoblasts to become a scaffold for a three-dimensional cube and contained bioceramic powder particles inside that could be planted for a bridge in a large bone defect. An application has already been filed for a porous body having a large thickness having continuous pores made of a biodegradable polymer (Japanese Patent Application No. 8-229280).
[0008]
This porous body is based on a method for producing a porous body called a solution precipitation method. That is, the biodegradable absorbable polymer is dissolved in a mixed solvent of the solvent and a non-solvent having a higher boiling point than the solvent, and a suspension is prepared by dispersing bioceramic powder particles. This is due to the method of precipitating the biodegradable absorbent polymer enclosing the bioceramic powder particles by aerating the solvent at a temperature lower than the boiling point of the solvent.
[0009]
The principle of forming a porous body by this solution precipitation method is as follows. That is, when the mixed solvent is diffused from the suspension at a temperature lower than the boiling point of the solvent, the solvent having a low boiling point is preferentially diffused, and the ratio of the non-solvent having a high boiling point gradually increases. When a certain ratio is reached, the solvent cannot dissolve the polymer. For this reason, the polymer starts to precipitate and precipitate, and encloses the bioceramics particles that have started to settle from the beginning, and the precipitated and precipitated polymer is shrunk and solidified by a high proportion of non-solvent and contains bioceramics particles. The cell structure is formed in such a state that the mixed solvent is encapsulated in the thin cell walls of the linked polymer that is fixed as it is. The remaining solvent creates pores while destroying part of the cell wall and diffuses and disappears, and the non-solvent with a high boiling point gradually diffuses through the pores. Disappear. As a result, a bioceramics particle-containing porous body is formed in which the accumulated traces of the mixed solvent wrapped in the polymer cell walls are connected as continuous pores.
[0010]
[Problems to be solved by the invention]
The solution precipitation method is an epoch-making method for forming a porous body having a large thickness from a low foaming ratio to a high foaming ratio, and a block-shaped three-dimensional porous body having a thickness of several mm to several tens of mm. It is possible to obtain. Therefore, it is useful for scaffolds for bone regeneration having a three-dimensional shape (three-dimensional structure).
[0011]
However, the disadvantage of this method is that in a suspension containing a large amount of bioceramics particles, the bioceramics particles belonging to a relatively large particle size distribution out of the average particle size are settled from the beginning of solvent evaporation. When the polymer starts to precipitate and settle, since a considerable amount of bioceramics particles have already settled toward the bottom with a concentration gradient, the resulting porous body has a partial content of bioceramics particles. It is not uniform, and the content increases as it approaches the bottom surface side from the upper surface side of the porous body. Such a non-uniform porous material having a concentration gradient is difficult to use effectively for applications such as scaffolds for bone tissue reconstruction, prosthetic materials, or bone fillers. Such a problem can be improved to some extent by controlling the sedimentation rate of bioceramic powder particles, but cannot be completely solved. In particular, it is difficult to obtain a porous body for three-dimensional bone reconstruction having a homogeneous and uniform concentration containing 30% by weight or more of bioceramic powder particles.
[0012]
The porous body with a small content of bioceramic powder particles produced by the above method is embedded in the living body because most of the bioceramic powder particles are embedded in the polymer cell walls and are not easily exposed to the inner surface of the continuous pores. At the time of implantation, it is difficult for the bioceramics particles to conduct the biological bone tissue from the beginning of the implantation, and the bioactivity is expressed with the exposed bioceramics particles along with the decomposition of the polymer that forms the skin layer on the inner surface of the continuous pores. There is a problem.
[0013]
Furthermore, the porous body manufactured by the above method needs to have a content of bioceramics particles of up to about 30% by weight even if ultrafine particles are selected. Since the powder particles are more likely to settle, there is a limit that the bottom surface side of the obtained porous body contains a large amount of bioceramic powder particles and becomes extremely brittle.
[0014]
In addition, the porous body produced by the above method usually has a large proportion of continuous pores (porosity) of 80% or more, but generally speaking, the pore diameter is relatively small such as several μm to several tens of μm. Since only continuous pores can be obtained, it cannot be said that an ideal pore diameter and pore shape are formed for the invasion and growth of osteoblasts into the porous body.
[0015]
An object of this invention is to provide the organic-inorganic composite porous body which can solve these problems, and its manufacturing method.
[0016]
[Means for Solving the Problems]
The organic-inorganic composite porous body according to the present invention is a porous body in which inorganic powder particles are uniformly dispersed in a porous matrix of an organic polymer and have continuous pores therein, and the inorganic powder particles on the surface and the inner surface of the pores. Is a part of As an organic polymer, poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L-lactic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and p-dioxanone, Caprolactone copolymer, lactic acid and ethylene glycol copolymer, and mixtures of these biodegradable absorbable polymers are used as inorganic particles, uncalcined, uncalcined hydroxyapatite, dicalcium Uses bio-active, fully-absorbable bioceramics granules of phosphate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcite, serabital, diopsite, or smallpox. The The continuous pores are adjusted to have a pore diameter of about 100 to 400 μm, which is suitable for osteoblasts to enter and proliferate and stabilize, and the inorganic particles are contained in a large amount of 60 to 90% by weight. Moreover, the thickness of a porous body is as large as 1-50 mm, and has a three-dimensional solid shape.
[0017]
Such an organic-inorganic composite porous material is produced by the production method of the present invention, that is, an organic polymer in a volatile solvent. As said biodegradable absorbable polymer Dissolve the inorganic powder As said bioactive total absorbable bioceramics granules A non-woven fiber assembly is prepared from the suspension prepared by dispersing the resin, and this is pressure-formed under heating to form a porous fiber assembly, and then the fiber assembly is formed in a volatile solvent. It can be produced by a method of removing the solvent after immersion. As a means for producing a non-woven fiber assembly from the suspension, a means for spraying the suspension while forming a fiber is preferably employed. When the fiber assembly molded body is immersed in a volatile solvent, the fiber assembly It is desirable to apply an external force that maintains the shape of the molded body, whereby a porous body having mechanical strength can be obtained.
[0018]
As described above, if a means for spraying the prepared suspension while making it into a fiber is used as a means for producing a fiber assembly, the organic polymer fibers containing inorganic particles are entangled with each other and welded at mutual contacts. The fibers are aggregated and solidified by volatilization of the volatile solvent, and a thick nonwoven fabric-like fiber aggregate having an arbitrary shape is formed. In this fiber assembly, the inter-fiber voids are not round cell spaces, but have a continuous space where the distance between the welded and solidified fibers is about several hundred μm. And uniformly dispersed throughout the fiber assembly. When this fiber aggregate is pressure-formed under heating to form a porous fiber aggregate molded article and immersed in a volatile solvent while maintaining its shape while applying an external force, the fibers shrink and fuse. And a fibrous form lose | disappears substantially and it becomes the porous matrix which the shape changed to the continuous pore body with the cell structure in which the space | gap between fibers is round. Along with this transformation, a part of the inorganic powder contained in a large amount is exposed on the inner surface of the pores, and also exposed to the surface so that the inorganic powder is not easily dropped off. The organic-inorganic composite porous body, ie, the organic-inorganic composite porous body in which the inorganic powder particles are dispersed substantially uniformly at a high content and a part thereof is exposed on the surface or the inner surface of the continuous pores. Of course, when the skin layer is formed on the surface depending on the conditions, the inorganic powder particles may be exposed by sanding. This composite porous body is suitable for osteoblast invasion and stabilization by adjusting the external pressure to maintain the shape of the fiber aggregate molded body when immersed in a volatile solvent. Therefore, it is desirable to control the pore size so that the porosity can be controlled to about 100 to 400 μm and the porosity is preferably about 50 to 90%.
[0019]
In the production method of the present invention, 60 to 90% by weight (corresponding to 41 to 81% by volume when the average particle size is 3 μm) is uniformly contained in the pores within the range in which fiberization is possible. Is possible. Even if it is contained in a large amount, the fibers are welded before the inorganic particles settle, so that the inorganic particles are evenly dispersed and the content is much higher than the porous body obtained by the solution precipitation method described above. A porous body can finally be obtained. However, if the content is too high, the amount of the polymer as the binder decreases, and the porous body becomes brittle and it is difficult to maintain its shape.
[0020]
This organic-inorganic composite porous material for medical applications such as scaffolds for regenerating living bone tissue is compatible with this production method as an organic polymer, has already been practically used and has been confirmed to be safe. A polymer is selected that is relatively fast and that is not brittle even if it becomes porous. That is, amorphous or mixed poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L lactic acid, copolymer of lactic acid and glycolic acid, lactic acid and p-dioxanone. A biodegradable polymer such as a copolymer, a copolymer of lactic acid and caprolactone, a copolymer of lactic acid and ethylene glycol, or a mixture thereof is used. A viscosity average molecular weight of 50,000 to 1,000,000 is preferably used in consideration of easy formation of a non-woven fiber aggregate and a period of decomposition and absorption in vivo.
[0021]
In particular, poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L lactic acid, copolymer of lactic acid and glycolic acid, lactic acid and p-dioxanone, which are amorphous due to the monomer ratio Biodegradable total absorbable polymer such as copolymer is a solvent for forming non-woven fiber aggregates and treating fiber aggregate compacts that have been pressure-molded with heating with a volatile solvent. It is suitable from the viewpoint of characteristics. When these polymers are used, even if they contain a large amount of inorganic particles, they are not brittle, have a compressive strength similar to that of cancellous bone (compressive strength of about 1 to 5 MPa), and a porous ceramic body Unlike organic materials, an organic-inorganic composite porous body that can be thermally deformed at a relatively low temperature (about 70 ° C.) and that can be quickly hydrolyzed in vivo and totally absorbed in 6 to 12 months can be obtained. . A composite porous body having such characteristics is extremely preferable as a biomaterial to be filled in a defect of a living bone. Because it is a composite, unlike the ceramic-only material, it still retains the advantages inherent in thermoplastic polymers that can be thermally deformed during surgery to conform to the defect.
[0022]
Since the molecular weight of the biodegradable total absorbable polymer affects the time until hydrolysis and total absorption and the possibility of fiberization, a polymer having a viscosity average molecular weight of 50,000 to 1,000,000 as described above. used. A polymer having a viscosity average molecular weight of less than 50,000 has a short time to be hydrolyzed to a low molecular weight of an oligomer or a monomer unit. However, since the spinnability is insufficient, it is sprayed while fiberizing to form a composite fiber aggregate. Is difficult. In addition, a polymer having a viscosity average molecular weight greater than 1,000,000 takes a long time until complete hydrolysis, and therefore is not suitable as a polymer for a composite porous body when intended for early replacement with a living tissue. . Although the viscosity average molecular weight is preferably about 100,000 to 300,000 depending on the polymer, the use of a polymer having a molecular weight within this range facilitates the formation of a fiber assembly and has a suitable hydrolysis completion time. The composite porous body of the present invention can be obtained.
[0023]
In the organic-inorganic composite porous body for the purpose of medical use described above, as an inorganic powder particle, there is bioactivity, good bone conduction ability (sometimes said to show osteoinductive ability) and good biocompatibility. The bioceramic powder that has is used. Examples of such bioceramic powder particles include surface bioactive firing, calcined hydroxyapatite, apatite wollastonite glass ceramics, bioactive and bioabsorbable non-calcined, unfired hydroxyapatite, dicalcium Examples thereof include powders such as phosphate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcite, serabital, diopsite, and smallpox. In addition, it is also possible to use those obtained by adhering an alkaline inorganic compound or a basic organic substance to the surface of these powder particles. Because it is ideal that all tissue replacement is performed by its own biological tissue, among these, total in vivo absorbability that is totally absorbed in vivo and completely replaced with bone tissue Bioceramics powders are preferred, especially uncalcined and uncalcined hydroxyapatite, tricalcium phosphate, octacalcium phosphate have the highest activity, excellent osteoconductivity, excellent biocompatibility and low harm, It is optimal because it is absorbed into the body in a short period of time.
[0024]
It is preferable to use a bioceramic particle having a particle size of 10 μm or less. When a bioceramic particle having a particle size larger than this is used, spraying while making a suspension of the mixed powder into fibers. When the fiber is cut, it becomes difficult to form a fiber aggregate, and even if the fiber aggregate can be formed, the bioceramics powder settles slightly and becomes uneven before the fiber solidifies. There is a risk of dispersal. Those having a size exceeding 20 to 30 μm are not preferable because even if they are totally absorptive, it takes a long time for complete absorption, and a tissue reaction during that time sometimes develops.
[0025]
The more preferable particle diameter of the bioceramic powder is 0.2 to 5 μm. When such a bioceramic powder is used, a suspension in which the powder is mixed at a high concentration as in the present invention is 1 to 3 μm. Even in the case of forming a fiber aggregate by forming a fiber as thin as the degree, the fiber is difficult to cut, and when the concentration is high as in the present invention, the powder particles are included in the fiber exposed from the fiber, After the fiber assembly is dipped in a volatile solvent, the powder becomes a composite porous body exposed from the surface or the inner surface of the continuous pores.
[0026]
Bioceramics powder content is organic-inorganic for medical use such as scaffolds in regenerative medical engineering, carriers for DDS or bone fillers, substitutes for allograft (allograft) In the case of a composite porous body, it is preferable to set it as 60 to 90 weight% from the bioactivity effect of bioceramics. In the case of forming a fiber aggregate containing inorganic particles as in the present invention and immersing the fiber aggregate molded body pressure-formed under heating in a volatile solvent to obtain a composite porous body, Therefore, the content of bioceramics particles is 60 to 90% by weight (the volume ratio when the average particle size is 3 μm is 41 to 81). % Corresponding to a high ratio). If the content of the bioceramic powder exceeds 90% by weight, it will be short when fiberized and will not be a satisfactory fiber, so that it will be difficult to form a fiber assembly. Since there are few grains and few are exposed on the surface, it is difficult for the biological activity derived from the bioceramic powder to be expressed from the initial stage of implantation in the living body.
[0027]
Porous ceramics obtained by sintering ceramics such as hydroxyapatite are hard but brittle, and thin materials are easily cracked or chipped by external force, which is unsatisfactory as an implant. On the other hand, the composite porous body in which the bioceramic powder is contained in the biodegradable absorbent polymer that is amorphous in particular, even when the content of the bioceramic powder is as high as 60 to 90% by weight, Due to the binding effect of the polymer, it has a compressive strength similar to that of a non-brittle cancellous bone that retains flexibility, specifically, a compressive strength of about 1 MPa to 5 MPa. bone substitute), bone filler, prosthetic material, scaffold for regeneration, and carrier for DDS.
[0028]
Another potential use is inclusions between artificial bone implants (bones and cartilage). For example, when embedding a high-concentration artificial product made from a polylactic acid-based polymer containing bioceramic powder, which is a bioactive and bioresorbable bone bonding material, avoid creating a gap between the living body and the living body. Since it is difficult, if this composite porous body is interposed between them and directly brought into contact with bone tissue, osteoconductivity is remarkably exhibited. This works effectively in various parts of living bones. For example, in the case of a median sternotomy, a sternum fixation pin that penetrates this porous body is embedded in the median bone, resulting in a severe hollowing out of osteoporosis. Bone induction (in combination with cytokines) and bone conduction can be brought into the bone. Alternatively, it can be used as an underlay for this type of plate to achieve close contact with the bone. There are many uses as an intervening body between a living body and an artificial object, such as a direct connection between an artificial intervertebral disc and a vertebral body endplate.
[0029]
This organic-inorganic composite porous body has a porosity (total porosity) of 50% or more and can be technically up to about 90%. However, the physical strength of this composite porous body and the invasion of osteoblasts are possible. In consideration of both stabilization and stabilization, approximately 60 to 80% is good, and considering the efficiency of osteoblast invasion to the center of the composite porous body, continuous pores are 50 to 90% of the total pores, Above all, it is preferable to occupy 70 to 90%.
[0030]
The continuous pores of the organic-inorganic composite porous body are adjusted to have a pore diameter of about 100 to 400 μm. There have already been many studies on the pore size and osteoblast invasion and stabilization of porous ceramics. As a result, the pore size of 300-400 μm is the most effective for calcification, and the effect increases as the distance increases. It turns out to fade. Therefore, the pore diameter of the composite porous body of the present invention is adjusted to approximately 100 to 400 μm as described above, but may include those having a pore diameter in the range of 50 to 500 μm, and the distribution center may be 200 to 400 μm. .
[0031]
Incidentally, when the pore diameter of continuous pores is larger than 400 μm and the porosity (total porosity) is higher than 90%, the strength of the composite porous body is lowered, so that there is a high possibility that it is easily broken during implantation in the living body. On the other hand, when the pore diameter is smaller than 100 μm and the porosity is lower than 50%, the strength of the composite porous body is improved, but the invasion of osteoblasts is difficult, and the time until hydrolysis and complete absorption is achieved. Becomes longer. However, such a low-porosity composite porous body having a small pore diameter can be used as a material for a DDS carrier that desires to maintain a sustained release property for a relatively long time in parallel with the decomposition of the polymer. . The more preferable pore diameter of the continuous pores is 150 to 350 μm, and the more preferable porosity (total porosity) is 70 to 80%. As described above, the pore diameter of the continuous pores and the ratio of the continuous pores to the whole pores are the adjustment of the compression ratio when the fiber assembly is pressure-molded into a fiber assembly molded product, or the fiber assembly molded product. Can be controlled by adjusting the external pressure for maintaining the shape when the substrate is immersed in a volatile solvent while maintaining its shape.
[0032]
The organic-inorganic composite porous body as described above can be used, for example, by being embedded in a defect site of a living bone as an implant having various shapes. At that time, the composite porous body is heated to about 70 ° C. by using the thermoplasticity of the organic polymer and deformed so as to match the shape of the defect part, so that the defect part can be embedded without a gap. Can be performed easily and accurately. In addition, due to the toughness of the organic polymer and the hardness of the ceramic particles, it can be cut into any shape with a scalpel during surgery without being deformed.
[0033]
When the composite porous body is embedded in the bone tissue of a living body as described above, for example, body fluid quickly penetrates into the composite porous body through the continuous pores from the surface of the composite porous body. Since the hydrolysis of the biodegradable absorbent polymer proceeds almost simultaneously from both inside the continuous pores, the degradation proceeds uniformly over the entire porous body (however, wetting characteristics with the biological fluid are contained in a large amount, Porous for the purpose of making the invasion and growth of cells to be propagated more effective due to the wettability characteristics of the bioceramics particles exposed on the surface, which is significantly improved compared to the case of the polymer alone or by improving the wettability characteristics of the polymer. The body may be subjected to oxidation treatment such as corona discharge, plasma treatment, or hydrogen peroxide treatment). The composite porous body in which bone cells are present or embedded in a site in contact with the bone cells has a bone tissue on the surface layer portion of the composite porous body due to the osteoconductivity of the bioceramic powder particles exposed on the surface. Bone of bio-ceramics particles that are rapidly formed into a conductive bone and grow into a trabecular bone, and in a short period of time, the composite porous body binds to the defect site of the living bone and is exposed to the inner surface of the pore Due to the conducting ability, bone tissue also penetrates into the inside of the composite porous body, and osteoblasts are conducted and grow, so that they directly bond with surrounding bone. This phenomenon becomes prominent with the progress of the degradation of the biodegradable absorbable polymer, and is gradually replaced with surrounding bone. Finally, the polymer is completely decomposed and absorbed, and if the bioceramic powder is bioabsorbable, the bioceramic powder is also completely absorbed and completely replaced by the grown bone tissue, Regeneration of the bone defect is completed.
[0034]
In addition, in accordance with the rate of decomposition and absorption as a scaffold for biological reconstruction that requires total substitution as described above, various kinds of cytokines or the like that are prefilled in the pores or dissolved and supported in the polymer in advance By gradually releasing the growth factors, various therapeutic agents, antibacterial agents, and the like, it is possible to promote or effectively regenerate the living body and cure the disease. It is obvious that the above composite porous body naturally becomes a filling material or a prosthetic material for a defective tissue by itself or in combination with allograft bone as described above.
[0035]
The above-mentioned organic-inorganic composite porous body is a completely or partially substituted living tissue regeneration scaffold, a drug carrier, a prosthetic material, a bone filler, an inclusion between an implant and a living tissue, and a substitute for cancellous bone. In the case of organic-inorganic composite porous materials for other medical purposes, the organic polymer is polymethyl methacrylate, polyvinyl acetate, polyvinyl chloride, polyurethane, polyalkylene. Various general-purpose resins that are soluble in oxide and other volatile solvents are appropriately selected and used depending on the application. As the inorganic powder, various industrial fillers, functional fillers, ceramic powder, carbon powder, carbon nanotubes, and the like are appropriately selected and used depending on applications.
[0036]
Next, the manufacturing method of this invention is demonstrated.
[0037]
According to the production method of the present invention, first, the above-mentioned organic polymer is dissolved in a volatile solvent and the above-mentioned inorganic particles are uniformly dispersed to prepare a suspension. As the volatile solvent, solvents such as dichloromethane, dichloroethane, methylene chloride, chloroform and the like having a low boiling point that easily evaporate at a temperature slightly higher than normal temperature are used. In addition, these solvents include non-solvents having boiling points higher than these solvents, such as methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, ter-butanol having a boiling point in the range of 60 to 110 ° C. A volatile mixed solvent in which any one of alcohols such as ter-pentanol or a mixture of two or more thereof is also used.
[0038]
Next, the suspension is filled in a sprayer, and sprayed while the suspension is made into a fiber to be ejected from an injection hole of the sprayer with an inert high-pressure injection gas such as nitrogen gas. When sprayed in this way, the suspension is fiberized while the volatile solvent is volatilized and entangled with each other, and the fibers are solidified while being welded at the respective contact points to form a nonwoven fabric-like fiber aggregate. In order to obtain a thick composite porous body of 5 to 50 mm, which is sometimes necessary as a biomaterial for medical use, after forming this fiber assembly by spraying, wait for the solvent to evaporate and dry, What is necessary is just to repeat the operation which sprays on it and thickens so that it may become predetermined | prescribed thickness.
[0039]
As the object to be ejected, a net or plate made of polyethylene or other olefin-based resin, fluorine resin, silicon-based resin or the like having good peelability is used. In particular, when an air-permeable target such as a mesh body is used, the suspension is made into a fiber by spraying and hits the mesh body, and then the volatile solvent evaporates through the mesh. Is advantageous in that a fiber assembly can be formed without causing a skin layer by fusing with each other and allowing easy solvent permeation treatment. The mesh is preferably 50 to 300 mesh, and the mesh having a mesh larger than 50 mesh is difficult to peel off the formed fiber assembly from the mesh because the fibers wrap around to the back side through the mesh. In the mesh body having a mesh size smaller than 300 mesh, the volatile solvent is not easily volatilized smoothly, so that the fibers on the mesh body side are fused to form a skin layer. The ejected body is not limited to a flat net or plate, but may be a convex and / or concave three-dimensional net or plate. Use of such a three-dimensional object to be ejected is advantageous in that a thick fiber assembly according to the three-dimensional shape can be formed.
[0040]
The fiber assembly formed by spraying while pulverizing the suspension as described above has a large interfiber gap size of several hundred μm, and the proportion of the interfiber gap (porosity) is 60 to 90%. Degree. And the inorganic particle is included in the fiber and is uniformly dispersed throughout the fiber assembly without settling.
[0041]
The fiber length of this fiber assembly is preferably about 3 to 100 mm, and the fiber diameter is preferably about 0.5 to 50 μm. The fiber assembly having such a fiber length and fiber diameter becomes a composite porous body in which the fibers are easily fused by the subsequent solvent infiltration treatment, and the fibers are substantially lost.
[0042]
The fiber length mainly depends on the molecular weight of the organic polymer, the polymer concentration of the suspension, the content and particle size of the inorganic powder, and the higher the molecular weight, the higher the polymer concentration, and the lower the content of the inorganic powder. The smaller the particle size of the inorganic powder particles, the longer it tends to be. On the other hand, the fiber diameter mainly depends on the polymer concentration of the suspension, the content of the inorganic powder, the size of the spray hole of the sprayer, etc., and the higher the polymer concentration, the higher the content of the inorganic powder, The larger the hole, the thicker it tends to be. The fiber diameter also changes depending on the pressure of the injection gas. Therefore, it is necessary to adjust the molecular weight of the polymer, the polymer concentration, the content and particle size of the inorganic powder, the size of the injection hole, the gas pressure, etc. so that the above fiber length and fiber diameter are obtained.
[0043]
Next, the above-mentioned fiber aggregate is pressure-formed under heating to form a porous fiber aggregate compact. At that time, the fiber assembly is first heated and solidified under pressure to form a preform having continuous voids, and further, the preform is pressure-molded under higher pressure to adjust the strength of the continuous void holes. It is desirable to have a porous fiber assembly molded body with a certain thickness. When a porous fiber assembly molded body is produced by pressure molding in this way, the pore size and porosity of the continuous pores of the finally obtained composite porous body can be adjusted, and the strength of the composite porous body is improved. You can also. In addition, the heating at the time of pressure molding is sufficient that the fiber aggregate is slightly softened, and the pressing is performed so that the porosity of the composite porous body finally obtained is 50 to 90%. Further, the pressure may be compressed so that the pore diameter of the continuous pores is approximately 100 to 400 μm.
[0044]
Next, the fiber assembly molded body is immersed in a volatile solvent so that the solvent penetrates into the molded body, and then the permeated solvent is removed. When immersing the fiber assembly molded body in a volatile solvent, the fiber assembly molded body is filled into a predetermined mold having a large number of pores, and the shape is maintained with pressure applied to the fiber assembly molded body from the outside. It is preferable to immerse while. In addition, you may make it make a solvent flow and infiltrate the upper surface of a fiber assembly molded object. Further, as a method for removing the solvent, a method of vacuum suction of the solvent inside the fiber assembly molded body is adopted.
[0045]
Examples of the volatile solvent include the above-described solvents such as dichloromethane, dichloroethane, methylene chloride, and chloroform, and the above-described solvents such as methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, ter-butanol, and ter-pen. Any one of alcohols such as butanol or a mixture of two or more of them is preferably used.
[0046]
When the fiber assembly molded body is immersed in a volatile solvent as described above and the solvent is infiltrated into the molded body, the fibers are dissolved from the surface into the solvent. A bubble wall is formed in a state in which a continuous pore having a roundness having a pore diameter of about 100 to 400 μm is left. And a part of inorganic particle contained in the fiber is exposed to the pore inner surface (bubble wall surface) without being settled with the fusion of the fiber, and is also exposed to the porous body surface. However, when the skin layer is formed on the surface, it may be removed by sanding, and a treatment for exposing the inorganic powder particles existing on the surface layer may be performed. As described above, the target organic-inorganic composite porous body having continuous pores having a large pore size of 100 to 400 μm, a large amount of inorganic powder particles uniformly dispersed, and inorganic powder particles exposed on the surface and the inner surface of the pores. can get. In that case, when the fiber assembly molded body is immersed in a volatile solvent under heating at 50 to 60 ° C., the fibers are sufficiently fused by simply leaving the fiber assembly molded body for 5 to 10 minutes. The composite porous body can be obtained efficiently.
[0047]
As described above, the organic-inorganic composite porous body obtained by the above production method is a scaffold for bone tissue reconstruction, a prosthetic material, a bone filler, an inclusion between the implant and the bone tissue, and a bulk shape. It can be used effectively as a substitute for cancellous bone, a carrier for sustained release of drugs, etc. Therefore, a scaffold, a prosthetic material, a bone filler, an implant and a living body made of this organic-inorganic composite porous body Interventions between bone tissues, bulky cancellous bone substitutes, and sustained drug carriers are all included in the present invention.
[0048]
DETAILED DESCRIPTION OF THE INVENTION
Next, specific examples of the present invention will be described.
[0049]
[Example 1]
A polymer solution (concentration: PDLLA 4 g / dichloromethane 100 ml) in which poly-D, L-lactic acid (PDLLA) (molar ratio of D-lactic acid and L-lactic acid 50/50) having a viscosity average molecular weight of 200,000 was dissolved in dichloromethane, By uniformly homogenizing a mixture of unfired hydroxyapatite particles (u-HA) having a particle size of 3 μm and mixed with ethanol, the ratio of u-HA becomes 230 parts by weight with respect to 100 parts by weight of PDLLA. A suspension was prepared.
[0050]
Use a HP-E airbrush (manufactured by Anest Iwata Co., Ltd.) as a sprayer and fill the above suspension with 1.6 kg / cm ² Was sprayed onto a polyethylene mesh body (150 mesh) separated by about 120 cm to form a fiber assembly, and the fiber assembly was peeled from the mesh body. The fiber aggregate had a fiber diameter of about 1.0 μm, a fiber length of about 10 to 20 mm, and an apparent specific gravity of 0.2.
[0051]
By cutting this fiber assembly into an appropriate size, filling it into a cylindrical female mold having a diameter of 30 mm and a depth of 30 mm, and compressing with a male mold so that the apparent specific gravity of the fiber assembly is 0.5, A disk-shaped fiber assembly molded body having a diameter of 30 mm and a thickness of 5 mm was obtained.
[0052]
Next, the above fiber aggregate molded body is immersed in a solvent composed of dichloromethane mixed with ethanol so that the solvent penetrates into the molded body and left at 60 ° C. for 10 minutes, and then the solvent inside the molded body is removed by vacuum suction. Thus, an organic-inorganic composite porous body having a diameter of 30 mm, a thickness of 5 mm, and a u-HA content of 70% by weight was obtained.
[0053]
When the partially cut surface of this composite porous body was observed with an electron microscope, the fibers fused and disappeared, continuous pores having a large pore size of about 100 to 400 μm were formed, u-HA was uniformly dispersed, and the pore inner surface U-HA was exposed on the surface. The apparent specific gravity of this composite porous body was 0.5, the ratio of continuous pores to the whole pores (continuous porosity) was 75%, and the compressive strength was 1.1 MPa.
[0054]
[Example 2]
In the same manner as in Example 1, a disk-shaped fiber assembly molded body having a diameter of 30 mm and a thickness of 5 mm was prepared as a preform, and this was heated to 80 ° C. in a gear oven, and then contracted with different diameters. It put into the chamber which has a diameter part, and press-fitted into the cylinder whose diameter of the lower part is 10.6 mm. The compressive strength of the cylindrical rod-shaped fiber assembly molded in this way under pressure was about 2.5 MPa.
[0055]
Next, the cylindrical rod-shaped fiber assembly molded body is filled in a syringe having the same diameter with a hole in the periphery, and pressure is applied from the upper surface and the lower surface thereof so that the height of the cylindrical rod-shaped fiber assembly molded body does not change. After immersing in a solvent (60 ° C.) made of dichloromethane mixed with 15% by weight of methanol for 10 minutes while pressing to the extent, the solvent was removed to obtain a composite porous body.
[0056]
The electron micrograph of the partially cut surface and the sanded surface of this composite porous body has a porous form in which fibers have disappeared, and the pore diameter is composed of mixed pores of about 150 to 300 μm. The u-HA grains are porous bodies. It was exposed from the surface and the inner surface of the pores. This composite porous body had an apparent specific gravity of about 0.55, a continuous porosity of 70%, and a compressive strength of about 3.5 MPa. This composite porous material depends on the in vivo biodegradability and absorption characteristics of u-HA having an average particle diameter of 3 μm, depending on the implantation site and size, although the viscosity average molecular weight of PDLLA and the ratio of the amount occupied, It is thought that it will be completely absorbed in 6 months.
[0057]
[Example 3]
PDLLA (molar ratio of D-lactic acid and L-lactic acid: 30/70) having a viscosity average molecular weight of 100,000 was synthesized, and β-tricalcium phosphate (β-TCP) having an average particle diameter of about 3 μm by the same method as in Example 1. ) Was uniformly mixed to prepare a suspension. This β-TCP has been confirmed to be bioactive and bioresorbable, and although the mechanism is different from u-HA, it is known to exhibit osteoconductivity due to HA generation in vivo.
[0058]
Using this suspension, the fiber assembly produced by the spray method in the same manner as in Example 2 was compression-molded under heating to form a fiber assembly molded body, and this was subjected to solvent immersion treatment, whereby the apparent specific gravity was about A composite porous body having 0.6, a continuous porosity of 75%, and a compressive strength of 4.2 MPa was obtained. The volume ratio of β-TCP particles of this composite porous material is about 65% by volume, and the inorganic porous particles are considerably more than the composite porous material of Examples 1 and 2 in which u-HA is 70% by weight (about 55% by volume). Since the volume is large, the biological activity is remarkably expressed by the exposure of β-TCP to the surface of the porous body and the inner surface of the pores.
[0059]
This composite porous body is immersed in a body fluid in a living body because the fibers in the case of a non-woven fiber assembly have disappeared and β-TCP particles have been buried in the bulk cell wall. It was confirmed that the powder was not easily disintegrated and dispersed in the surroundings, and was completely decomposed and absorbed while showing good bioactivity in about 3 to 5 months. Therefore, this composite porous body is a good scaffold for hard tissues (bone, cartilage).
[0060]
[Example 4]
D, L-lactic acid (D / L molar ratio 1) and glycolic acid (GA) are blended so that the molar ratio is 8: 2, and a copolymer having a viscosity average molecular weight of 130,000 by a known method P (DLLA-GA) was synthesized. A suspension in which 60% by weight of octacalcium phosphate (OCP) was uniformly mixed with this polymer was prepared in the same manner as in Example 1, and the fiber assembly produced by the spray method as in Example 2 was heated. The composite porous body having an apparent specific gravity of 0.50 was finally obtained by compression molding to form a fiber aggregate molded body and subjecting this to a solvent immersion treatment. This composite porous body has a high OCP activity, and the degradation and absorption of the copolymer is fast due to GA, so that it shows good bone conduction (easy to change to new bone), but after 3 to 4 months Most were absorbed and replaced by bone.
[0061]
[Example 5]
D, L-lactide (lactide) and para-dioxanone (p-DOX) were blended so as to have a molar ratio of 8: 2, and copolymerized by a known method to give a copolymer having a viscosity average molecular weight of about 100,000. Coalescence was obtained. The p-DOX polymer is not a volatile general-purpose good solvent, but is soluble in chloroform, dichloromethane, etc. at the above ratio, so that the target composite porous material is obtained in the same manner as in the above-described Examples. I was able to. In addition, since the above copolymer exhibits a rubber-like property that is more plastic than the copolymer P (DLLA-GA) of D, L-lactic acid and glycolic acid of Example 4, the particles of inorganic powder Since the volume ratio of the inorganic particles can be as high as 70% by volume (85% by weight) when the diameter is 3 μm, this composite porous body avoids the biological reaction due to the decomposition product of the copolymer as much as possible, and is bioactive. The activity of inorganic powder is expressed very effectively. In particular, because of the characteristics of p-DOX, since the hydrophilicity is higher than that of PDLLA, this composite porous body is considered to be effective as a scaffold for regeneration of cartilage for proliferating cells in ex vivo.
[0062]
【The invention's effect】
As is clear from the above description, the organic-inorganic composite porous body of the present invention contains a large amount of inorganic particles in a uniform dispersed state in the organic polymer, and is a continuous pore having a large pore diameter formed inside. A place where body fluids can quickly infiltrate through the surface and inorganic powder particles such as bioceramics exposed on the surface and the inner surface of the continuous pores can be used for early bonding with living bones and regeneration of living (bone) tissue. It provides the effect of providing practical strength necessary for medical use. Therefore, it is put to practical use as a scaffold for reconstruction of living bone tissue, a prosthetic material, a bone filler, an inclusion between an implant and living bone tissue, a substitute for cancellous bone, and a carrier for sustained drug release.

Claims

Poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L-lactic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and p-dioxanone, copolymer of lactic acid and caprolactone, Copolymers of lactic acid and ethylene glycol, and mixtures thereof, in a porous matrix of biodegradable absorbent polymer, uncalcined, uncalcined hydroxyapatite, dicalcium phosphate, tricalcium phosphate, tetra Any of bioactive, all-absorbable bioceramics particles of calcium phosphate, octacalcium phosphate, calcite, serabital, diopsite, and smallpox are uniformly dispersed, and have continuous pores inside, surface and pore inner surface An organic-inorganic composite porous body in which a part of the bioceramic powder particles is exposed.

As a volatile solvent, poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L-lactic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and p-dioxanone, lactic acid and caprolactone A biodegradable absorbent polymer of any one of a copolymer, a copolymer of lactic acid and ethylene glycol, and a mixture thereof is dissolved , uncalcined, unfired hydroxyapatite, dicalcium phosphate, tricalcium phosphate, A non-woven fiber assembly from a suspension prepared by dispersing bioactive, all-absorbable bioceramics particles of tetracalcium phosphate, octacalcium phosphate, calcite, serabital, diopsite, or natural cocoon Made into a porous fiber aggregate molded body by pressure molding under heating, and a fiber aggregate molded body in a volatile solvent A porous body obtained by immersing and removing the solvent, wherein the bioceramic powder particles are uniformly dispersed in the porous matrix of the biodegradable absorbent polymer, have continuous pores inside, and have a surface And an organic-inorganic composite porous body in which part of the bioceramic powder particles is exposed on the inner surface of the pores.

The organic-inorganic composite porous body according to claim 1 or 2, wherein the porosity is 50 to 90%, and continuous pores occupy 50 to 90% of the entire pores.

The organic-inorganic composite porous body according to any one of claims 1 to 3, wherein the pore size of the continuous pores is 100 to 400 µm.

The organic-inorganic composite porous body according to any one of claims 1 to 4, wherein a content of the bioceramic powder particles is 60 to 90% by weight.

The organic-inorganic composite porous body according to any one of claims 1 to 5, having a thickness of 1 to 50 mm and a thick three-dimensional solid shape.

The organic-inorganic composite porous body according to any one of claims 1 to 6, which has a compressive strength of 1 to 5 MPa.

The organic-inorganic composite porous body according to any one of claims 1 to 7, which has been subjected to an oxidation treatment.

As a volatile solvent, poly-D, L-lactic acid, block copolymer of L-lactic acid and D, L-lactic acid, copolymer of lactic acid and glycolic acid, copolymer of lactic acid and p-dioxanone, lactic acid and caprolactone A biodegradable absorbent polymer of any one of a copolymer, a copolymer of lactic acid and ethylene glycol, and a mixture thereof is dissolved , uncalcined, unfired hydroxyapatite, dicalcium phosphate, tricalcium phosphate, A non-woven fiber assembly from a suspension prepared by dispersing bioactive, all-absorbable bioceramics particles of tetracalcium phosphate, octacalcium phosphate, calcite, serabital, diopsite, or natural cocoon Made into a porous fiber aggregate molded body by pressure molding under heating, and a fiber aggregate molded body in a volatile solvent Organic and removing the solvent after dipping and - method of producing an inorganic composite porous body.

When a fiber assembly is pressure-formed under heating to form a porous fiber assembly-molded body, the fiber assembly is first heated and pressed to form a preform with continuous voids, and then preformed. The preform is pressure-molded at a pressure higher than the pressure at which the article is made, thereby forming a strong porous fiber assembly molded body with adjusted continuous pores. The manufacturing method as described.

The porous fiber aggregate molded body is immersed in a volatile solvent, and the fiber aggregate molded body is filled into a predetermined mold having a large number of pores and immersed while maintaining the shape. The manufacturing method as described.

A scaffold for regeneration of living bone or cartilage tissue comprising the organic-inorganic composite porous body according to any one of claims 1 to 8.