JP3610504B2 - Biodegradable absorbable cell structure - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は、医療用途に適した生体内分解吸収性セル構造体に関する。
【０００２】
【従来の技術】
医療用途を目的とする生体内分解吸収性のセル構造体（多孔体）としては、特公昭６３−６４９８８号に開示された生体内分解吸収性スポンジや、特開平２−６３４６５号に開示された歯周組織再建用素材などが知られている。
【０００３】
前者の生体内分解吸収性スポンジは、手術時の止血や生体の軟組織（例えば肝臓等の臓器）の縫合時の補綴材料として使用されるもので、分子量（重量平均分子量）が２千〜６０万のポリ乳酸等から形成された連続気泡構造を有する柔軟なスポンジである。このスポンジは、上記のポリ乳酸等をベンゼン又はジオキサンに溶解させ、そのポリマー溶液を凍結乾燥する方法によって製造される。
【０００４】
また、後者の歯周組織再建用素材は、重量平均分子量が４万〜５０万の乳酸−カプロラクトン共重合体等から形成された多孔質の柔軟なフィルム状もしくはシート状の肉薄の素材であり、この素材も上記と同様の溶剤を用いて凍結乾燥法により製造されるものである。
【０００５】
両者の方法の主な目的の一つは、フロロカーボン系の溶剤（フレオン）やヘキサフルオロイソプロパノール、ヘキサフルオロアセトンセスキヒドラートのようなフッ素系の特殊であり、生体に対して毒性があり、地球のオゾン層を破壊するような公害の恐れのある溶剤を使わないことにある。しかし、上記のベンゼンやジオキサンなどの溶剤もまた完全に気泡体から除去することは容易でなく、残留溶剤の毒性の危惧は否定できない。
【０００６】
【発明が解決しようとする課題】
前記のスポンジ状の補綴材や組織の再建用素材のように重量平均分子量が６０万以下のポリ乳酸や乳酸−カプロラクトン共重合体から形成された多孔体は、柔軟で硬度や強度（引張強度、曲げ強度等）が低く、脆いこと、および加水分解により低分子量に早くなるため、生体内で数ケ月に亘って保形性と相当の硬度及び強度が要求される医療用途には使用できないという問題がある。
【０００７】
加うるに生体内に埋入して使う医療材料は、使用以前に必ず滅菌しなければならない。代表的な滅菌方法は放射線（電子線）、エチレンオキサイドガス（ＥＯＧ）および加圧蒸気による滅菌である。然るにセル構造体の如き表面積の極めて大きな多孔体は、ガス滅菌時にガスが完全に微孔内に拡散されているかどうか、セル壁のポリマー内部まで滅菌できているかどうかが不明であり、そのために分解過程で感染の恐れを常に危惧しなければならない。ガス滅菌した多孔体では、まれに感染が報告されることがある。そのために有効であり安心できる方法は、材料の内部まで完全に滅菌できる放射線あるいは加熱蒸気による滅菌である。しかるにポリ乳酸などの生体内分解吸収性のα−ポリエステル系のポリマーは放射線により劣化し、加熱蒸気によっては加熱分解、加水分解する。従って初期分子量の低いポリマーでは、これらの滅菌により更に低い分子量のセル構造体に変化するので、生体内での分解・吸収が早いものしか得られない。実際の臨床の場では生体内での分解・吸収の早さが種々異なるセル構造体が要望されているので、初期重量平均分子量が６０万程度までの低いものはそのニーズに応えるものではない。
【０００８】
また、前記のスポンジや再建用素材のように凍結乾燥法によって製造される多孔体は、せいぜい１ｍｍ以下、普通には数１００μｍ以下の薄いフィルム状ないしシート状の多孔体であり、これより厚いものを得ようと試みても、凝固点以下の低温にて結晶化したベンゼン、ジオキサン等の溶剤の昇華に時間がかかり、長時間昇華させてもなお溶剤が一部残留するので、生体内での安全性を損なう恐れがあるために、１ｍｍ以上の厚い毒性のない多孔体を得ることは困難である。このような薄いフィルム又はシート状の多孔体は、例えば生体内の損傷部位の複雑な三次元空間に形状的にあてはめて、一時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再建を図るような場合には使用に値しないという問題がある。
【０００９】
この問題をより詳しく述べる。組織再生 （ｒｅｇｅｎｅｒａｔｅ ｏｒｇａｎｓ）や細胞移植（ｃｅｌｌ ｔｒａｎｓｐｌａｎｔａｔｉｏｎ）のための足場（ｓｃａｆｆｏｌｄ）が現在種々検討されている。それには細胞の植付け（ｃｅｌｌ ｓｅｅｄｉｎｇ）と細胞の付着（ｃｅｌｌ ａｔｔａｃｈｍｅｎｔ） に効率の良い、高い多孔度と大きな表面積をもつセル構造体が有用であるとみなされている。基材が生体内分解吸収生ポリマーである場合は自らが徐々に消滅するので、新しい細胞が完全に再生し、組織機能を復帰する可能性が大きいので、現在、この種のポリマーのセル構造体の開発が真に要望されるわけである。失われた器官の機能を復元できるような生体の組織をつくり出すことを目的とする組織工学（Ｔｉｓｓｕｅ Ｅｎｇｉｎｅｅｒｉｎｇ）においては、例えば皮膚（Ｓｋｉｎ）、神経（Ｎｅｒｖｅ）、食道（Ｅｓｏｐｈａｇｕｓ）、前十字靱帯（Ａｎｔｅｒｉｏｒ Ｃｒｕｃｉａｔｅ Ｌｉｇａｍｅｎｔ）、骨（Ｂｏｎｅ）、あるいは血管新生などへの組織誘導（Ｔｉｓｓｕｅ Ｉｎｄｕｃｔｉｏｎ）と軟骨（Ｃａｒｔｉｌａｇｅ）、骨、尿道（Ｕｒｏｔｈｅｌｉｕｍ）、腸（Ｉｎｔｅｓｔｉｎｅ）、神経、肝臓（Ｌｉｖｅｒ）などの再生のために足場への細胞の植付けが検討されている。そして、多孔質の生体内分解吸収性ポリマーの足場をつくる方法には、▲１▼繊維不織布あるいは複数本の繊維の交差点で繊維を結合させた（Ｆｉｂｅｒ Ｂｏｎｄｉｎｇ）メッシュ状の繊維、▲２▼ポリマー溶液をキャスティング（ｃａｓｔｉｎｇ） して蒸散した溶剤の空隙孔をつくり、多孔質とする溶液キャスティング（Ｓｏｌｖｅｎｔ−Ｃａｓｔｉｎｇ）法、あるいは溶解性の粒径を選んだ微粒状の充填材（食塩、クエン酸ソーダなど）をポリマーに混合分散してキャスティングによりフィルム、シートをつくり、この微粒子を浸出−溶出（Ｐａｒｔｉｃｕｌａｔｅ−Ｌｅａｃｈｉｎｇ）する方法、およびこれら両者の併用法がある。しかし▲１▼の方法の欠点は空隙率と孔のサイズを自由にコントロールすることが技術的に容易ではないこと、▲２▼の方法は、孔の大きさが充填粒子の大きさに依存するので比較的制御できるが、せいぜい２ｍｍ厚さの薄いウエファース（Ｗａｆｅｒｓ）や膜（Ｍｅｎｂｒａｎｅｓ） しかつくれないこと、である。また、完全に微粒子を浸出−溶出することは容易でないので、充填粒子の毒性に配慮が必要である。そこで▲３▼の方法として、▲２▼でつくった膜の表面を少量のクロロホルムに溶かして貼り合わせして厚い多孔体を得る膜ラミネート（Ｍｅｍｂｒａｎｅ Ｌａｍｉｎａｔｉｏｎ） 法により三次元の形状物を得る方法が考案されているが、この方法は煩雑であり、ラミネート面で孔が不連続になるという欠点がある。
【００１０】
また、先記の凍結乾燥法によって製造されるポリ乳酸等の多孔体は、発泡倍率を高くする目的で大量溶剤を含ませると、乾燥時に多孔体が歪曲する。特に、重量平均分子量が６０万以下で厚さが１ｍｍ以上の肉厚の場合は歪曲が顕著となるので、実際には高い発泡倍率のものを得ることができない。また発泡倍率の低い多孔体は、高倍率の多孔体に比べて材料の比率が高いので、生体内での加水分解の進行に伴って一時期に２０〜３０μｍ程度の分解細片を局所に多量に発生する機会が高発泡倍率と比較して多いため、その異物反応によって一過性の炎症を起こしやすいという問題がある。
【００１１】
【課題を解決するための手段】
本発明は上記の問題を全て解決している。本発明の生体内分解吸収性セル構造体は、重量平均分子量が６０万〜２００万であるポリ乳酸、又は乳酸とグリコール酸との共重合体、又は乳酸とカプロラクトンとの共重合体を用いて、下記のＳＰＴ法により形成された連続気孔を有するセル構造体であって、その厚さが１ｍｍ以上であり、その発泡倍率が５〜３０倍であり、その連続気孔の平均孔径が５〜３００μｍ程度であることを特徴とするものである。ここにセル構造体とは、気孔を取り囲む一つの構造単位であるセルの壁が相互につながったネットワークからなる固体のことであり、多孔体や発泡体と表現しても本質的な差異がないものである。
【００１２】
即ち、本発明のセル構造体は、上記のポリマーを、ポリマーを溶解する溶剤と該溶剤より高沸点のポリマーを溶解しない非溶剤との混合溶媒に溶解し、このポリマー溶液から混合溶媒を溶剤の沸点より低温で気散させることによってポリマーを沈殿させる方法（Ｓｏｌｕｔｉｏｎ Ｐｒｅｃｉｐｉｔａｔｉｎｇ Ｔｅｃｈｎｉｑｕｅ：ＳＰＴ）により得られるものであって、後述するように溶剤として塩化メチレンを用い、非溶剤として６０〜１１０℃（１気圧下）の範囲内で沸点を有する一価アルコールを用いるものである。そのセル構造形成の原理は以下のように考察される。
【００１３】
すなわち、上記のポリマー溶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、遂には、溶剤と非溶剤がある比率に達すると、溶媒はポリマーを溶解できなくなる。そして、ある時期、ある高い濃度に達するとポリマーが急激に沈殿し、濃度の高くなった非溶剤のために沈殿したポリマーが収縮、固化して固定化され、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。その後は残りの溶剤がセル壁の一部分を破壊しながら細孔をつくって気散し、沸点の高い非溶剤もまた徐々に気散して、遂には非溶剤も完全に気散する。その結果、セル壁に包まれていた溶媒の溜め跡が気孔として残り、基本的に気孔が連続した連続気孔のセル構造体が得られる。但し、これらの現象は条件により逐次、あるいは同時に併行すると考えられる。
【００１４】
本発明のように重量平均分子量が６０万より高いポリ乳酸又は上記の共重合体から形成された連続気孔を有するセル構造体は、三次元的に連続するセル壁が高分子量のポリマーからなるため、後述の実施例に示すように低分子量のものより比較的強度（引張強度や曲げ強度）があり、しかも、分子量が高いものほど生体内での加水分解による低分子化が遅くなるので、生体内での強度持続の期間を長くすることができる。
【００１５】
また、本発明のように材料ポリマー（ポリ乳酸又は上記の共重合体）が６０万より高い重量平均分子量を有するものであれば、ＳＰＴの方法によればポリマー溶液の濃度を調整することにより、発泡倍率が２〜３０倍と広範囲に、しかも歪みのないセル構造体を容易に得ることができる。その場合、ポリマー溶液を型内に充填して混合溶媒を気散させる速さをコントロールすると、厚さが１ｍｍ以上である所望の立体的な異形状のセル構造体を容易に成形することができる。上記のような高発泡倍率のセル構造体は、材料が量的に稀薄であるから、生体内で加水分解して強度と形状を失って吸収される過程で、一時的に急激に多くの量の細片を生成することがないため、細片が惹起する異物反応による一過性の炎症を起こす心配が殆どない。更に、上記のように成形された肉厚のセル構造体は、生体内の損傷部位の複雑な三次元空間に形状的にあてはめて埋入することにより、一時的な補綴材（Ｐｒｏｓｔｈｅｓｉｓ）や足場（Ｓｃａｆｆｏｌｄ）としての機能を発揮させることができる。
【００１６】
斯かる重量平均分子量が６０万よりも遥かに大きい高分子量のセル構造体は、放射線（γ線）や電子線あるいは蒸気滅菌のような、ポリマー材料の内部までも完全に滅菌できるような方法で滅菌したときに、その分子量が低下してもなお、重量平均分子量が６０万以上を維持することができる。これは、滅菌後でさえも高い強度と分解して吸収されるまでのかなりの長い時間を維持できるものである。
【００１７】
ただし、初期の重量平均分子量Ｍｗが６０万以上の高分子量であっても、Ｍｗ：６０万以下の任意の低分子量のセル構造体をつくる場合は滅菌時間を長くしたり、滅菌回数を増せばよい。特に低分子量のポリマー（Ｍｖ≒１０万以下、Ｍｗ≒３０万以下）を使って約１０倍以上の高倍率のセル構造体をつくることは、本発明法に限らず、他の方法においても実際は困難であるから、高分子量で高倍率のセル構造体をつくって後に滅菌を長時間行ったり、繰り返すことにより厚物、低分子量、高倍率のセル構造体に変化させることは新規にして且つ有効である。
【００１８】
凍結乾燥法によって得たＭｗ：６０万のスポンジは、上記の過酷な滅菌法では分子量の低下により６０万よりもかなり低い、低分子量（例えばＭｗ：６０万はＭｗ：３０万程度に低下する）の低倍率スポンジに変化するので、３０万から６０万の間は空白となり、この間の分子量を欲する用途に対応できない。
【００１９】
【発明の実施の形態】
本発明のセル構造体に用いる材料のポリ乳酸としては、Ｌ−乳酸のホモポリマーや、Ｌ−乳酸とＤ−乳酸のランダムコポリマーが使用され、また、共重合体としては、乳酸とグリコール酸、あるいは乳酸とカプロラクトンのモル比が９９：１〜７５：２５の範囲にあるものが使用される。グリコール酸やカプロラクトンの比率が上記範囲より高くなると、得られるセル構造体の耐加水分解性が低下し、早期に強度劣化を招く恐れがあるので好ましくない。また高倍率体を得ることが難しい。また、これらの共重合体以外にも、ポリ乳酸とポリエチレングリコールの共重合体や、ポリ乳酸とポリプロピレングリコールとの共重合体も使用できる。
【００２０】
これらのポリ乳酸や共重合体は、重量平均分子量が６０万より高いものを使用することが必要であり、このような高分子量のポリ乳酸や共重合体を用いると、強度（引張強度や曲げ強度）があり、且つ、生体内での強度維持期間が数ケ月以上と長い高発泡倍率のセル構造体を得ることができる。ポリ乳酸や共重合体の重量平均分子量が高くなればなるほど、セル構造体の硬度や強度、強度保持期間等は向上するが、分子量があまり高すぎるとポリマーが溶剤に溶け難くなるので、高発泡倍率のセル構造体を得ることが難くなるから、重量平均分子量が３００万以下のポリ乳酸や共重合体を使用することが望ましい。ポリ乳酸等の更に望ましい重量平均分子量は６０万〜２００万の範囲である。また、場合によっては、これらのポリ乳酸や共重合体に、重量平均分子量が６０万以下とならない範囲内で、低分子量のものを適量配合してもよい。このように低分子量のものを配合すると、セル構造体の初期の加水分解速度を適度に速めることが可能となる。
【００２１】
ここで、分子量及び分子量分布について記述する。一般に、高分子の分子量は重量平均分子量Ｍｗ、数平均分子量Ｍｎおよび粘度平均分子量Ｍｖのいずれかを用いて表される。Ｍｎを求めるには末端基定量、電子顕微鏡、浸透圧、蒸気圧、氷点降下および沸点上昇などの方法があり、Ｍｗを求めるには光散乱、Ｘ線小角散乱、沈降平衡、融液粘度による方法がある。しかし、現在、最も簡便であり、一般に行われているのはＧＰＣ（Ｇｅｌ Ｐｅｒｍｅａｔｉｏｎ Ｃｈｒｏｍａｔｏｇｒａｐｈｙ） による方法である。そして、分子量分布を求めるには濁り度滴定法、超遠心法、拡散法、あるいはＧＰＣによる方法等がある。現在、最も簡便な方法であるＧＰＣ法によって測定したＭｗ／Ｍｎ＝αを分子量分布として用いることが多い。ＧＰＣ法で得られる平均分子量、分子量分布、αは使用する分子篩いとしてのカラム内のゲルの種類によってその値にかなりの幅がある。従って、ポリマーを実際に溶液に溶かした粘度から測定した粘度平均分子量Ｍｖと対比することにより、分子量の実際の大きさと分布を把握することが肝要である。
【００２２】
本発明のポリ乳酸あるいはその共重合体の場合は、実際に使用するＧＰＣのカラムの種類、その連結の数により異なるが、この種のポリマーの一般的な合成法によって得たポリマーは経験的にはαはおよそ２〜４の範囲であり、また、ＭｗとＭｖの比率Ｍｗ／Ｍｖはおよそ３〜４である。従って、Ｍｗが６０万以下の該ポリマーは、実際のＭｖは経験的に１５〜２０万以下に相当する。この程度のＭｖのポリマーは、高い強度を要求され、その強度を骨癒合に必要な３〜４ケ月間維持することが必要な骨折固定材の原料ポリマーに使うには低きに過ぎるので、高い強度が得られないことは周知である。従って、本発明のセル構造体にあっても、高い強度と適切な長期間の強度の維持は得られるものでない。また、この程度までの分子量は低→中程度の分子量域であるから、分解・吸収の早さを調節するためにはあまり余裕のあるものではない。
【００２３】
本発明のセル構造体は、上記のような高分子量のポリ乳酸又は共重合体を、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し、このポリマー溶液から混合溶媒を溶剤の沸点より低温で気散させることによって、ポリ乳酸又は共重合体を沈殿させる溶液沈殿法（Ｓｏｌｕｔｉｏｎ Ｐｒｅｃｉｐｉｔａｔｉｎｇ Ｔｅｃｈｎｉｑｕｅ：ＳＰＴ）により得られるものであり、溶剤や非溶剤として以下のものが使用される。
【００２４】
即ち、溶剤としては、ポリ乳酸や共重合体を溶解でき、常温よりやや高い温度で気散しやすい低沸点の溶剤、例えば塩化メチレン（ＣＨ２Ｃｌ２）、クロロホルム（ＣＨＣｌ３）、１，１−ジクロルエタン（ＣＨ３ＣＨＣｌ２）などが使用される。この中では最も低い沸点と最も高い蒸気圧を示す低毒性の塩化メチレンが最適であり、クロロホルムも好適である。
【００２５】
一方、非溶剤は、その沸点が上記の溶剤より高く、且つ、上記の溶剤と相溶性があるものを使用する必要があり、相溶性に劣る非溶剤を用いると、発泡倍率が高く均一で微細な気孔を有するセル構造体を得ることが困難になる。この非溶剤の沸点は上限が１１０℃付近（１気圧）までであり、溶剤と非溶剤との組合わせを決める場合、溶剤の沸点よりもかなり高い沸点の非溶剤を選ぶことが望ましい。非溶剤が１１０℃より高い沸点を有するものであると、常温での蒸気圧が低く常温での気散が遅すぎるために、セル構造体の製造に時間がかかり、非溶剤がセル内に残留しやすくなる。また、非溶剤と溶剤の沸点差が約１５℃より小さい場合は、溶剤が非溶剤と共に気散し易くなるので、非溶剤の沈殿剤としての働きが低下する。好ましい非溶剤としては、前記の塩化メチレン等の溶剤と相溶性があり、沸点が６０℃〜１１０℃（１気圧下）の範囲内にある一価アルコール、例えばメタノール、エタノール、１−プロパノール、２−プロパノール（イソプロピルアルコール）、２−ブタノール、ｔｅｒ−ブタノール、ｔｅｒ−ペンタノールなどが挙げられるが、毒性、臭などを考慮すると、エタノール、１−プロパノール、２−プロパノールが特に好適に使用される。また、これらの一価アルコールに少量の水を加えた非溶剤も好適に使用される。水はアルコールよりもより強い沈殿剤としての働きを有し、ポリ乳酸や共重合体の沈殿を促進するからである。
【００２６】
表１に、好ましい溶剤と非溶剤を列挙し、それぞれの沸点と２０℃における蒸気圧を示す。また、表２に、塩化メチレン、クロロホルムと各非溶剤との沸点差及び蒸気圧差を示す。溶剤と非溶剤の組合わせは、この表１の沸点と蒸気圧を勘案して適宜選択すればよく、溶剤に塩化メチレンやクロロホルムを選んだときは、表２に示す沸点差と蒸気圧差を勘案して非溶剤を選択すればよい。
【表１】
ポリ乳酸や共重合体を溶解する混合溶媒は、前記の溶剤と非溶剤の体積比率が一般に１０：１〜１０：１０であればセル構造体を得ることができる。これよりも溶剤の比率が大きいと、溶媒の気散終了時までポリマーの溶解が続き、セル壁の沈殿が生ぜず、溶媒の気散後に気泡を介在しない透明なポリマー塊ができるのみである。一方、溶剤の比率が上記よりも小さい場合は、僅かの溶剤が気散しただけでポリ乳酸等が一挙に沈殿するため、セル間の溶着が不完全となり、セル間の物理的つながりのない脆いセル構造体が出来上がったり、型の形状とは全く異なる収縮、変形したセル構造体ができるので良くない。三次元空間的にセルが連結してしっかりした形状の安定なセル構造体が形成されるにふさわしい比率の範囲は、溶媒組成によって異なるが、１０：１〜１０：７である。
【００２８】
上記の混合溶媒にポリ乳酸や共重合体を溶解して調製したポリマー溶液は、型内に充填した後、溶剤の沸点より低い温度、好ましくは２０℃以下の温度で常圧又は減圧下に溶媒を気散させることが重要である。溶剤の沸点以上の温度で溶媒を気散させると、溶剤が沸騰してセル壁を破壊し、溶着するので、良質のセル構造体を得ることはできない。この気散の工程を、気散した溶媒を回収することのできる密閉された装置の中で行うと、回収された溶媒を何度も繰り返して使用することができ、操作中に吸入することもないので安全かつ省資源的である。また、ポリマー溶液の粘度を上げてセル壁の固定化を図る目的で、溶媒を気散させる前に約１０℃以下の低温に冷却して増粘し、減圧下に気散させる操作を採用することも望ましい。この操作は肉厚のシート状や異形状のセル構造体をつくる場合に有効である。
【００２９】
このようにポリマー溶液から混合溶媒を気散させると、数１００μｍ以下の薄いフィルム状やシート状のセル構造体であれば、見ている間の短時間に製造することができる。そして、１ｍｍ以上の厚肉のプレート状又は異形状のセル構造体の場合も、型の深さや形状を変えてポリマー溶液の充填量を増加させるだけで、少し長い時間を要するが、同様に簡単に製造することができる。このとき溶剤が型の全面から均等に気散できるように、型として、ポリ乳酸や共重合体を通過させないが溶媒を通過させる微細な通気孔を無数に有する多孔質の型、例えば素焼きの陶器製の型などを使用することも一つの方法である。また、溶媒の気散を速めることと、構造体内部のポリマー溶液の未沈殿部分への陥没と変形を避けて形状を保つことを目的として、ポリマー溶液を約１０℃以下の低温にて増粘し、減圧下に溶媒を強制的に気散させる操作を採ることも望ましい一つの方法である。ただし、溶媒の気散速度はポリマーの分子量、種類、濃度、求めるセル構造体の厚さ、形状、倍率によって微妙に調節する必要がある。このようにすれば、５ｃｍ以上の厚さをもつブロック状あるいは異形状に成形されたセル構造体を容易に製造することができる。
【００３０】
セル構造体の発泡倍率は２〜３０倍の発泡倍率、好ましくは５〜３０倍の高発泡倍率であることが望ましく、このような発泡倍率のセル構造体は、生体内での加水分解による細片の生成量が少ないため、異物反応による一過性の炎症を起こす心配が殆どないという利点を有する。
【００３１】
セル構造体の発泡倍率を決定する要因には、ポリマー溶液の粘度、ポリマー濃度、ポリマーの分子量、混合溶媒の組成比、溶媒の気散速度等が挙げられるが、ポリマー溶液が沈殿してセル構造体を形成する原理からすれば、ポリマー濃度が最も重要な要因の一つである。ポリマー濃度と発泡倍率は反比例の関係にあり、ポリマー濃度が高くなるほど発泡倍率は低くなる。そして、ポリマー濃度が１０重量％より高くなると、５倍以上の発泡倍率を有するセル構造体を得ることが難しくなる。従って、高発泡倍率のセル構造体を得るためには、ポリマー濃度を下げる必要があり、ポリマー濃度を２重量％程度まで下げると、混合溶媒の組成比によって差異はあるが、３０倍前後の発泡倍率を有するセル構造体を得ることができる。しかし、ポリマー濃度を更に下げて１重量％以下にすると、満足なセル構造体を得ることが困難となる。
【００３２】
また、ポリマーの分子量と発泡倍率の関係は、ある分子量領域で発泡倍率が最も高くなり、分子量がその領域より大きくなっても小さくなっても発泡倍率は低下する傾向がある。後述の実施例のデーターから分かるように、発泡倍率が最も高くなるポリマー（ポリ乳酸又は共重合体）の重量平均分子量の領域は、Ｍｗ／Ｍｖを３〜４とすると、７５〜１４０万ないし１０５〜１４０万程度（粘度平均分子量では２５万〜３５万程度）であり、ポリマーの重量平均分子量が６０万（粘度平均分子量１５〜２０万）以下であり、特に４５万以下のときは発泡倍率の高いものを得難くなる。
【００３３】
また、混合溶媒の組成比と発泡倍率の関係については、後述の実施例のデーターから分かるように、適当な溶媒の混合比の範囲内で非溶剤の比率が高くなるほど、発泡倍率が高くなる関係にある。
【００３４】
従って、ポリマー濃度、ポリマーの分子量、混合溶媒の組成比等を種々変化させれば、セル構造体の発泡倍率を自由にコントロールすることができ、２〜３０倍の発泡倍率を有するセル構造体を容易に製造することができる。このような発泡倍率のセル構造体は、連続気孔の平均孔径が３〜３００μｍ程度であり、この範囲の中で１５０〜３００μｍ程度の孔径を選択すれば、生体内の損傷部位に埋入したとき、体液や周囲の組織細胞の侵入が容易であるので、組織再生や細胞移植のための生体内分解吸収性の基材として有用である。
【００３５】
【実施例】
以下、本発明の実施例を説明する。
【００３６】
［実施例１］
溶剤に塩化メチレン（ＣＨ２Ｃｌ２）、非溶剤（沈殿剤）にエタノール（Ｃ２Ｈ５ＯＨ）を使用し、溶剤と非溶剤の体積比（溶剤／非溶剤）を１０／０、１０／１、１０／３、１０／５、１０／７、１０／９に変化させた６種類の混合溶媒に、重量平均分子量が約１０５万（粘度平均分子量は約３０万、分子量分布；分散度Ｍｗ／Ｍｎ＝２．５）のポリ−Ｌ−乳酸を４ｇ／ｄｌの濃度に溶解してポリマー溶液を調製した。
【００３７】
これらのポリマー溶液を、直径が１０ｃｍのシャーレに液面が１３ｍｍの高さとなるように注入し、そのまま蓋をして室温（１０〜２０℃）で大気圧下に静置してセル構造体をつくった。２４時間後にはポリマー溶液の溶媒は蒸散しており、溶媒の組成比（溶剤／非溶剤）が１０／７と１０／９のもののみが僅かにエタノール臭を残しているに過ぎなかった。その後、減圧乾燥すると、ガスクロマトグラフで溶媒を検知できなくなった。得られたセル構造体の性状等を下記の表３にまとめて示す。
【００３８】
また、得られたセル構造体の硬度、曲げ強度、引張強度を測定したところ、表３に示す結果が得られた。なお、硬度はデュロメータ硬さの試験方法（ＪＩＳ Ｋ ７２１５）により、曲げ強度は３点曲げ試験方法（ＪＩＳ Ｋ ７２２１）により、引張強度は万能試験機により測定した（ＪＩＳ Ｋ ７１１３）ものである。
【表３】
さらに、１０／０及び１０／５の溶媒組成比のものから得たセル構造体の３７℃のリン酸緩衝液中における加水分解実験を行った結果は図１のようになった。
【００４０】
以上の結果からすれば、塩化メチレンとエタノールの混合溶媒の場合は、溶媒の組成比（塩化メチレン／エタノール）が１０／１〜１０／６で比較的良好なセル構造体が得られる。溶媒組成比が１０／５で発泡倍率１０．０倍という高い値のセル構造体が得られ、発泡倍率とともにセル構造体が厚くなった。これは溶液の外気と接触している表面からポリマーが溶剤の気散により直ちに沈殿、固化し、セル壁を形成して固定化したために厚みが維持されたためと考えられる。この事実は、ある発泡倍率のある厚みのセル構造体を要求するときは、溶媒の組成比とポリマー溶液の濃度を調節すればよいことを示唆している。
【００４１】
溶剤のみの場合は、溶剤が気散完了するまでポリマーを溶解しながら気散するので、溶剤の抜けがらの孔は溶着して孔として残らない。そのために、ポリマー本来の透明なシートが形成された。
【００４２】
溶剤の比率が高い場合は、溶剤の気散により体積が減少し、その分だけ厚みが低下したところで沈殿、固化してセル壁の固定化がなされるために、セル構造体の厚みと発泡倍率が低下したと考えられる。逆に初期の非溶剤（沈殿剤）の比率が高い場合は、溶剤のわずかな気散によって直ちに非溶剤の沈殿剤としての効果が発現され、沈殿が一気に生成する。このとき、ポリマーを溶解して連続したセル壁を形成するだけの量の溶剤が残っていないので、孔が生成するときに大きく収縮したり、沈殿したポリマーの粒子が単に溶着して連結体を形成し、それが気孔を介在したような一種の焼結体のごときセル構造体を形成すると考えられる。実際に、溶媒組成比が１０／７では沈殿、固化するときの収縮が厳しく、表面に多くの皺のある変形したセル構造体が得られ、溶媒組成比が１０／９では脆くて粒子が容易に脱落するセル構造体が得られた。しかし、セル構造体を形成する比率の上限は１０／１０と考えられる。この事実は本発明のセル構造の生成機構を良く裏付けている。
【００４３】
また、溶媒の組成比が１０／１、１０／３、１０／５となるに従って発泡倍率は大きくなる。それにともなって硬度、強度ともに小さくなっている。これは、発泡倍率が大きくなると、気孔の数あるいはその大きさが大きくなるために、セルの壁の厚さが薄くなって強度が低下したと考えられる。
【００４４】
更に、３７℃リン酸緩衝液中における加水分解実験では、溶媒の組成比が１０／０のものから得た非セル構造の均質な固体と比較して、溶媒の組成比が１０／５のものから得た発泡倍率の高いセル構造体は、水が表面の細孔から内部に容易に浸透し水との接触面積が拡がるために、分解が速くなったと考えられる。
【００４５】
［実施例２］
溶媒の組成比（ＣＨ２Ｃｌ２／Ｃ２Ｈ５ＯＨ）を１０／５に固定し、実施例１のポリ−Ｌ−乳酸の濃度を１．０、２．０、３．０、４．０、５．０、７．０ｇ／ｄｌに変えてポリマー溶液を調製した。そして、これらのポリマー溶液を実施例１と同形のシャーレに充填し、同様にしてセル構造体を得た。得られたセル構造体の性状と、硬度、曲げ強度、引張強度を下記表４にまとめて示す。
【表４】
この結果から、発泡倍率が濃度に逆比例的に依存することが明らかである。実施例１と同様にポリマー濃度が小さくなると、セル構造体の発泡倍率は大きくなるが、それに伴って硬度、曲げ強度、引張強度は小さくなった。これはセル構造体の気孔の数と大きさがポリマー濃度の減少に伴って増加し、セル壁の強度が脆くなったためと考えられる。
【００４７】
［実施例３］
実施例１で用いたポリ−Ｌ−乳酸を、塩化メチレンとエタノールと水の混合溶媒（ＣＨ２Ｃｌ２／Ｃ２Ｈ５ＯＨ／Ｈ２Ｏ＝１０／５／０．３）に４ｇ／ｄｌの濃度で溶解してポリマー溶液を調製した。
【００４８】
このポリマー溶液を、型内に液面が８ｃｍの高さとなるまで充填し、５日間、室温、常圧下に静置した。その結果、厚さが３．１ｍｍ、発泡倍率が約１０倍のセル構造体が得られた。このセル構造体は実施例１の溶媒組成比が１０／１の場合のそれよりも硬かった。これは水の影響によりポリマーの沈殿、固化が急激であり、結晶化度がやや高くなったこと、およびセル壁の固定が強固になったためと考えられる。
【００４９】
［実施例４］
溶媒の組成比（ＣＨ２Ｃｌ２／Ｃ２Ｈ５ＯＨ）を１０／５、ポリマー濃度を２ｇ／ｄｌに固定し、Ｍｗが約１４０万（Ｍｖ：約４０万）、Ｍｗが約１０５万（Ｍｖ：約３０万）、Ｍｗが約６５万（Ｍｖ：約１８．５万）のポリ−Ｌ−乳酸をそれぞれ用いて、実施例１と同様の方法でセル構造体を得た。得られたセル構造体の硬度、曲げ強度、引張強度を表５に示す。
【表５】
その結果、重量平均分子量が大きくなると、セル構造体の硬度、強度とも大きくなった。また、Ｍｗが約１０５万のものとＭｗが約６５万のものを比較すれば、Ｍｗが約６５万のセル構造体の方が発泡倍率が小さいにもかかわらず、硬度、強度とも小さな値を示した。これは、平均分子量の違いがセル構造体の形成の難易と関係し、Ｍｗが６０万より高いときのポリマー粘度が本法によってセル構造体を容易に形成しやすいことの裏付けである。そして良質のセル構造体の物性がセルの均質さ、気孔の大きさ、数、セル壁の硬さにより影響を受けたためと考えられる。
【００５１】
［比較例１］
Ｍｗが約６０万（Ｍｖ：約１５万）、Ｍｗが約４０万（Ｍｖ：約１１．５万）のポリ−Ｌ−乳酸をそれぞれ使用し、実施例４と同様にして溶液沈殿法によりセル構造体を得た。このものは、実施例４のセル構造体とは異なり、多孔質粒子が集合したようなセル構造体であった。この構造体の硬度、曲げ強度、引張強度は表６に示すように、Ｍｗが６０万より高い表５のセル構造体の値と比較すると小さく、脆弱な物質であった。
【表６】
この事実により、Ｍｗが６０万より高いもは、溶液沈殿法によって高倍率、肉厚、均一な気泡を有して機械的強度にも優れたセル構造体を形成することが明らかである。
【００５３】
［比較例２］
Ｍｗが約１４０万（Ｍｖ：約４０万）、Ｍｗが約１０５万（Ｍｖ：約３０万）、Ｍｗが約６５万（Ｍｖ：約１８．５万）、Ｍｗが約６０万（Ｍｖ：約１５万）、Ｍｗが約４０万（Ｍｖ：約１１．５万）のポリ−Ｌ−乳酸をそれぞれ用いて溶液沈殿法によりセル構造体を得た。そして、これらのセル構造体を加圧蒸気で滅菌した後の重量平均分子量を測定した。その結果を表７に示す。
【表７】
この表７から判るように、Ｍｗが６０万（Ｍｖ：１５万）より大きい分子量のポリ−Ｌ−乳酸を用いたセル構造体は、蒸気滅菌により分子量が低下しても尚かなりの大きさの重量平均分子量を残しており、生体内でかなりの時間、分解せずに残存する可能性があるのに比べ、Ｍｗが６０万（Ｍｖ：１５万）以下のポリ−Ｌ−乳酸を用いたセル構造体は、１回の滅菌後にＭｗが４０万以下の低分子量となる。従って、生体内の補綴材や足場として利用するには、前者は分解して低分子量になるまでに要する時間が適度であるから実用的であるが、後者は本来その強度が不足しているが、加えて分解してより低分子になり吸収されるのが早すぎるので実用的でないと言える。
【００５５】
［実施例５］
重量平均分子量Ｍｗが１０５万（粘度平均分子量Ｍｖ：３０万）のポリ−Ｌ−乳酸を用いて、溶媒の組成比（ＣＨ２Ｃｌ２／Ｃ２Ｈ５ＯＨ）を１０／１〜１０／６、濃度を１〜４ｇ／ｄｌの範囲となるようにポリマー溶液を調製し、実施例１と同様の方法でセル構造体を得た。
【００５６】
このセル構造体の断面を走査電子顕微鏡（ＳＥＭ）を用いて観察し、セル構造体の気孔の大きさを測定した。その結果を表８に示す。
【表８】
［実施例６］
グリコール酸（ＧＡ）とＬ−乳酸（ＬＡ）の共重合体（ＧＡ／ＬＡのモル比：１０／９０、重量平均分子量Ｍｗ：７３万）を、溶媒の組成比（ＣＨ２Ｃｌ２／Ｃ２Ｈ５ＯＨ）が１０／３、１０／５である混合溶媒に、４ｇ／ｄｌのポリマー濃度となるように溶解し、実施例１と同様の方法によりセル構造体を得た。このセル構造体の性状、硬度、強度等を表９に示す。
【表９】
この結果、グリコール酸が１０％モル比結合することにより、Ｌ−乳酸単体のセル構造体よりも発泡倍率、強度は小さくなるが、硬度はほとんど同等であった。しかし、ＰＬＬＡのセル構造体と比較すると、やや軟らかいセル構造体であった。
【００５９】
なお、乳酸−カプロラクトン共重合体も同様にしてセル構造体をつくることができる。
【００６０】
【発明の効果】
以上の説明から理解できるように、本発明のセル構造体は、硬度や強度（曲げ強度、引張強度）があり、加水分解により強度を失う期間が早くないので、生体内で数ケ月のあいだ強度を維持することができ、しかも、製造が簡単で有害なベンゼン等の溶剤が全く含有、残存しないため安全であり、生体材料として極めて有用である。そして、１ｍｍ以上の厚肉のセル構造体は、生体内の損傷部位の複雑な三次元空間に形状的にあてはめて埋入することにより、一時的な補綴材や足場として、或は移植細胞の増殖用基材として機能を発揮させることができる。また、この５〜３０倍の発泡倍率のセル構造体は、生体内での加水分解によって生ずる細片の量が少ないため、異物反応による一過性の炎症を起こす心配が殆となく、更に、５〜３００μｍの平均孔径を任意に有するセル構造体は、体液、周囲組織細胞の侵入やフィブリン糊、ゼラチン糊等の生体接着剤の含浸もまた容易である。
【図面の簡単な説明】
【図１】本発明の実施例のセル構造体についての加水分解期間と粘度平均分子量との関係を示すグラフである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a biodegradable absorbent cell structure suitable for medical use.
[0002]
[Prior art]
Examples of the biodegradable and absorbable cell structure (porous body) for medical use include the biodegradable and absorbable sponge disclosed in Japanese Patent Publication No. 63-64888, and Japanese Patent Laid-Open No. 2-63465. Materials for periodontal tissue reconstruction are known.
[0003]
The former biodegradable absorbable sponge is used as a prosthetic material for hemostasis at the time of surgery and for suturing soft tissues of the living body (for example, organs such as the liver), and has a molecular weight (weight average molecular weight) of 2,000 to 600,000. It is a flexible sponge having an open-cell structure formed from polylactic acid or the like. This sponge is produced by a method in which the above polylactic acid or the like is dissolved in benzene or dioxane, and the polymer solution is lyophilized.
[0004]
The latter periodontal tissue reconstruction material is a porous flexible film-like or sheet-like thin material formed from a lactic acid-caprolactone copolymer having a weight average molecular weight of 40,000 to 500,000, etc. This material is also produced by freeze-drying using the same solvent as described above.
[0005]
One of the main objectives of both methods is fluorine-based specialties such as fluorocarbon solvents (freons), hexafluoroisopropanol and hexafluoroacetone sesquihydrate, which are toxic to living organisms, The use of solvents that could cause pollution that would destroy the ozone layer. However, it is not easy to completely remove the above-mentioned solvents such as benzene and dioxane from the foams, and the risk of toxicity of the residual solvent cannot be denied.
[0006]
[Problems to be solved by the invention]
The porous body formed from polylactic acid or lactic acid-caprolactone copolymer having a weight average molecular weight of 600,000 or less, such as the sponge-like prosthetic material or the tissue reconstruction material, is flexible and has hardness and strength (tensile strength, Bending strength, etc.) is low, brittle, and has a low molecular weight due to hydrolysis, so it cannot be used for medical applications requiring shape retention and considerable hardness and strength in vivo for several months. There is.
[0007]
In addition, medical materials that are implanted in the body must be sterilized before use. A typical sterilization method is sterilization by radiation (electron beam), ethylene oxide gas (EOG) and pressurized steam. However, it is unclear whether a porous body with a very large surface area such as a cell structure is completely diffused into the micropores during gas sterilization or whether it can be sterilized to the inside of the polymer on the cell wall. You must always be afraid of infection during the process. In rare cases, infection is reported in gas-sterilized porous materials. For this purpose, an effective and reliable method is sterilization by radiation or heated steam that can completely sterilize the inside of the material. However, biodegradable and absorbable α-polyester polymers such as polylactic acid are deteriorated by radiation, and are thermally decomposed and hydrolyzed by heated steam. Therefore, a polymer having a low initial molecular weight can be converted into a cell structure having a lower molecular weight by sterilization, and therefore, only a polymer that is rapidly decomposed and absorbed in vivo can be obtained. In an actual clinical field, cell structures having different rates of degradation and absorption in vivo are desired, and those having an initial weight average molecular weight as low as about 600,000 do not meet the needs.
[0008]
Further, the porous body manufactured by freeze-drying method such as the sponge or the reconstruction material is a thin film or sheet-like porous body of 1 mm or less, usually several 100 μm or less, and thicker than this. Even if an attempt is made to obtain a solvent, it takes time to sublimate a solvent such as benzene or dioxane that is crystallized at a low temperature below the freezing point. Therefore, it is difficult to obtain a porous body having a thickness of 1 mm or more and having no toxicity. Such a thin film or sheet-like porous body is applied, for example, in a complicated three-dimensional space of a damaged part in a living body, and exhibits a function of a temporary prosthetic material while exhibiting a three-dimensional damaged part. When rebuilding, there is a problem that it is not worth using.
[0009]
This problem will be described in more detail. Various scaffolds for regenerative organs and cell transplantation are currently under investigation. To that end, cell structures with high porosity and large surface area that are efficient for cell seeding and cell attachment are considered useful. If the base material is a biodegradable biopolymer, it will gradually disappear, so there is a high possibility that new cells will completely regenerate and restore tissue function. There is a real need for the development of In tissue engineering for the purpose of creating a tissue of a living body that can restore the function of a lost organ, for example, skin, nerve, esophagus, anterior cruciate ligament ( Tissue induction and bone cartilage (Cartilage), bone, urethra (Urothelium), intestine (Intestine), nerve, liver (Liver), etc. Therefore, planting of cells on the scaffold is being studied. And, there are (1) fiber non-woven fabric or fiber-bonded fiber at the intersection of multiple fibers, and (2) polymer to create a porous biodegradable polymer scaffold. Solvent-casting method that creates pores of solvent evaporated by casting the solution and makes it porous, or fine filler (sodium chloride, sodium citrate) with a selected particle size of solubility Etc.) are mixed and dispersed in a polymer to form a film or sheet by casting, and the fine particles are leached-eluted (Particulate-Leaching), or a combination of both. However, the disadvantage of the method (1) is that it is not technically easy to freely control the porosity and pore size, and the method (2) depends on the size of the packed particles. Therefore, it can be controlled relatively, but at most, only thin wafers or membranes having a thickness of 2 mm can be produced. Moreover, since it is not easy to completely leach and elute the fine particles, it is necessary to consider the toxicity of the packed particles. Therefore, as a method of (3), there is a method of obtaining a three-dimensional shape by a membrane lamination method in which the surface of the membrane prepared in (2) is dissolved in a small amount of chloroform and bonded together to obtain a thick porous body. Although devised, this method is complicated and has the disadvantage that the holes are discontinuous on the laminate surface.
[0010]
Further, when a porous material such as polylactic acid produced by the above-described freeze-drying method is added with a large amount of solvent for the purpose of increasing the expansion ratio, the porous material is distorted during drying. In particular, when the weight average molecular weight is 600,000 or less and the thickness is 1 mm or more, the distortion becomes remarkable, so that a product having a high expansion ratio cannot be obtained in practice. In addition, since the porous body with a low expansion ratio has a higher material ratio than the porous body with a high magnification, a large amount of decomposed debris of about 20 to 30 μm at a time as the hydrolysis progresses in vivo. Since there are many opportunities to generate | occur | produce compared with high foaming ratio, there exists a problem that it is easy to raise | generate a temporary inflammation by the foreign material reaction.
[0011]
[Means for Solving the Problems]
The present invention solves all the above problems. The biodegradable absorbable cell structure of the present invention comprises: The weight average molecular weight is 600,000-2 million Polylactic acid, or a copolymer of lactic acid and glycolic acid, or a copolymer of lactic acid and caprolactone Using the following SPT method A cell structure having continuous pores formed, the thickness is 1 mm or more, the expansion ratio is 5 to 30 times, and the average pore diameter of the continuous pores is about 5 to 300 μm Ru It is characterized by this. Here, the cell structure is a solid consisting of a network in which cell walls, which are one structural unit surrounding pores, are connected to each other, and there is no essential difference even if expressed as a porous body or foam. Is.
[0012]
That is, In the cell structure of the present invention, the above polymer is dissolved in a mixed solvent of a solvent that dissolves the polymer and a non-solvent that does not dissolve a polymer having a higher boiling point than the solvent, and the mixed solvent is dissolved from the boiling point of the solvent. Obtained by a method of precipitating a polymer by aeration at a low temperature (Solution Precipitating Technique: SPT), As described later, methylene chloride is used as a solvent, and a monohydric alcohol having a boiling point within a range of 60 to 110 ° C. (under 1 atm) is used as a non-solvent. The principle of the cell structure formation is considered as follows.
[0013]
That is, when the mixed solvent is diffused from the polymer solution 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 the non-solvent reaches a certain ratio, the solvent cannot dissolve the polymer. When a certain high concentration is reached at a certain time, the polymer rapidly precipitates, and the precipitated polymer shrinks due to the high concentration of the non-solvent, solidifies and immobilizes, and mixes with the thin cell walls of the connected polymer. A cell structure in which the solvent is encapsulated is formed. After that, the remaining solvent breaks a part of the cell wall and creates pores and diffuses, and the non-solvent having a high boiling point gradually diffuses and finally the non-solvent is also completely diffused. As a result, the solvent traces encased in the cell walls remain as pores, and a continuous pore cell structure in which the pores are basically continuous is obtained. However, these phenomena are considered to be performed sequentially or simultaneously depending on conditions.
[0014]
A cell structure having continuous pores formed from polylactic acid having a weight average molecular weight higher than 600,000 or the above copolymer as in the present invention has a three-dimensional continuous cell wall made of a high molecular weight polymer. As shown in the examples below, there are relatively higher strengths (tensile strength and bending strength) than those with low molecular weight, and the higher the molecular weight, the slower the lowering of the molecule due to hydrolysis in vivo. The duration of strength maintenance in the body can be lengthened.
[0015]
Further, if the material polymer (polylactic acid or the above copolymer) has a weight average molecular weight higher than 600,000 as in the present invention, by adjusting the concentration of the polymer solution according to the SPT method, A cell structure having a wide expansion ratio of 2 to 30 times and no distortion can be easily obtained. In that case, by controlling the speed at which the mixed solvent is diffused by filling the polymer solution into the mold, a desired three-dimensional irregularly shaped cell structure having a thickness of 1 mm or more can be easily formed. . In the cell structure with a high expansion ratio as described above, since the material is dilute in quantity, a large amount is temporarily and rapidly absorbed in the process of being hydrolyzed in the living body and losing strength and shape. Therefore, there is almost no fear of causing transient inflammation due to a foreign body reaction caused by the strip. Furthermore, the thick cell structure formed as described above is inserted into a complicated three-dimensional space of a damaged part in a living body in a shape to be embedded, whereby a temporary prosthesis or scaffold The function as (Scaffold) can be exhibited.
[0016]
Such a high molecular weight cell structure having a weight average molecular weight far greater than 600,000 can be completely sterilized even inside the polymer material, such as radiation (γ-rays), electron beam or steam sterilization. When sterilized, the weight average molecular weight can be maintained at 600,000 or more even if the molecular weight decreases. This is capable of maintaining high strength and a fairly long time to break down and be absorbed even after sterilization.
[0017]
However, even if the initial weight average molecular weight Mw is a high molecular weight of 600,000 or more, in the case of producing an arbitrary low molecular weight cell structure of Mw: 600,000 or less, if the sterilization time is increased or the number of sterilization is increased. Good. In particular, using a low molecular weight polymer (Mv≈100,000 or less, Mw≈300,000 or less) to produce a cell structure with a magnification of about 10 times or more is not limited to the method of the present invention, and is actually used in other methods. Because it is difficult, it is new and effective to create a cell structure with high molecular weight and high magnification, and then change to a thick, low molecular weight, high magnification cell structure by sterilization for a long time or by repeating. It is.
[0018]
Sponge with Mw: 600,000 obtained by freeze-drying method is considerably lower than 600,000 due to the decrease in molecular weight in the above-mentioned severe sterilization method (for example, Mw: 600,000 decreases to about 300,000) Since it changes to a low-magnification sponge, it is blank between 300,000 to 600,000, and cannot be used for applications that require a molecular weight during this period.
[0019]
DETAILED DESCRIPTION OF THE INVENTION
As the polylactic acid of the material used for the cell structure of the present invention, a homopolymer of L-lactic acid or a random copolymer of L-lactic acid and D-lactic acid is used, and as a copolymer, lactic acid and glycolic acid, Alternatively, those having a molar ratio of lactic acid to caprolactone in the range of 99: 1 to 75:25 are used. If the ratio of glycolic acid or caprolactone is higher than the above range, the hydrolysis resistance of the resulting cell structure is lowered, and there is a risk of causing strength deterioration at an early stage. It is also difficult to obtain a high magnification body. In addition to these copolymers, a copolymer of polylactic acid and polyethylene glycol, or a copolymer of polylactic acid and polypropylene glycol can also be used.
[0020]
These polylactic acids and copolymers need to have a weight average molecular weight higher than 600,000. When such a high molecular weight polylactic acid or copolymer is used, strength (tensile strength or bending strength) is required. It is possible to obtain a cell structure having a high expansion ratio and having a strength maintaining period in vivo of several months or more. The higher the weight average molecular weight of polylactic acid or copolymer, the better the cell structure's hardness, strength, strength retention period, etc., but if the molecular weight is too high, the polymer will be difficult to dissolve in the solvent. Since it becomes difficult to obtain a cell structure with a magnification, it is desirable to use polylactic acid or a copolymer having a weight average molecular weight of 3 million or less. A more desirable weight average molecular weight such as polylactic acid is in the range of 600,000 to 2,000,000. Moreover, depending on the case, you may mix | blend an appropriate quantity with a low molecular weight in these polylactic acid and a copolymer within the range in which a weight average molecular weight does not become 600,000 or less. When a low molecular weight compound is blended in this way, the initial hydrolysis rate of the cell structure can be appropriately increased.
[0021]
Here, the molecular weight and molecular weight distribution will be described. In general, the molecular weight of a polymer is expressed using one of a weight average molecular weight Mw, a number average molecular weight Mn, and a viscosity average molecular weight Mv. To determine Mn, there are methods such as end group determination, electron microscope, osmotic pressure, vapor pressure, freezing point drop and boiling point rise, and to determine Mw, light scattering, X-ray small angle scattering, sedimentation equilibrium, melt viscosity method There is. However, at present, the method that is the simplest and generally used is a method by GPC (Gel Permeation Chromatography). The molecular weight distribution can be obtained by a turbidity titration method, an ultracentrifugation method, a diffusion method, a method by GPC, or the like. Currently, Mw / Mn = α measured by the GPC method, which is the simplest method, is often used as the molecular weight distribution. The average molecular weight, molecular weight distribution, and α obtained by the GPC method vary considerably depending on the type of gel in the column as the molecular sieve to be used. Therefore, it is important to grasp the actual size and distribution of the molecular weight by comparing with the viscosity average molecular weight Mv measured from the viscosity of the polymer actually dissolved in the solution.
[0022]
In the case of the polylactic acid of the present invention or a copolymer thereof, the polymer obtained by a general synthesis method of this kind of polymer is empirically different depending on the type of GPC column actually used and the number of linkages. Α is in the range of approximately 2-4, and the ratio Mw / Mv of Mw to Mv is approximately 3-4. Accordingly, the polymer having an Mw of 600,000 or less corresponds to an actual Mv of 150 to 200,000 or less empirically. This level of Mv polymer is required to have high strength and is too low to be used as a raw material polymer for bone fracture fixing materials that need to maintain the strength for 3-4 months necessary for bone fusion. It is well known that no strength can be obtained. Therefore, even in the cell structure of the present invention, it is not possible to obtain high strength and appropriate long-term strength maintenance. Further, since the molecular weight up to this level is in the low to medium molecular weight range, there is not much room for adjusting the speed of decomposition and absorption.
[0023]
In the cell structure of the present invention, the above-described high molecular weight polylactic acid or copolymer is dissolved in a mixed solvent of the solvent and a non-solvent having a higher boiling point than the solvent, and the mixed solvent is dissolved in the solvent from the polymer solution. The solution is obtained by a solution precipitation method (SPT) in which polylactic acid or a copolymer is precipitated by being diffused at a temperature lower than the boiling point, and the following solvents and non-solvents are used.
[0024]
That is, as the solvent, polylactic acid or a copolymer can be dissolved, and a low boiling point solvent that is easily diffused at a temperature slightly higher than normal temperature, such as methylene chloride (CH 2 Cl 2 ), Chloroform (CHCl 3 ), 1,1-dichloroethane (CH 3 CHCl 2 ) Etc. are used. Of these, low-toxic methylene chloride having the lowest boiling point and the highest vapor pressure is most suitable, and chloroform is also preferred.
[0025]
On the other hand, it is necessary to use a non-solvent having a boiling point higher than that of the above solvent and compatible with the above solvent. If a non-solvent having poor compatibility is used, the foaming ratio is high, uniform and fine. It becomes difficult to obtain a cell structure having a pore. The upper limit of the boiling point of this non-solvent is up to around 110 ° C. (1 atm). When determining the combination of the solvent and the non-solvent, it is desirable to select a non-solvent having a boiling point considerably higher than that of the solvent. If the non-solvent has a boiling point higher than 110 ° C., the vapor pressure at room temperature is low and the air diffusion at room temperature is too slow, so it takes time to produce the cell structure, and the non-solvent remains in the cell. It becomes easy to do. Further, when the difference in boiling point between the non-solvent and the solvent is smaller than about 15 ° C., the solvent is easily diffused together with the non-solvent, so that the function of the non-solvent as a precipitant is lowered. Preferred non-solvents are monohydric alcohols that are compatible with the above-mentioned solvents such as methylene chloride and have a boiling point in the range of 60 ° C. to 110 ° C. (under 1 atm), such as methanol, ethanol, 1-propanol, 2 -Propanol (isopropyl alcohol), 2-butanol, ter-butanol, ter-pentanol and the like can be mentioned, but ethanol, 1-propanol and 2-propanol are particularly preferably used in consideration of toxicity, odor and the like. A non-solvent obtained by adding a small amount of water to these monohydric alcohols is also preferably used. This is because water acts as a stronger precipitant than alcohol and promotes precipitation of polylactic acid and a copolymer.
[0026]
Table 1 lists preferred solvents and non-solvents, and shows their boiling points and vapor pressures at 20 ° C. Table 2 shows the boiling point difference and vapor pressure difference between methylene chloride and chloroform and each non-solvent. The combination of solvent and non-solvent may be selected as appropriate in consideration of the boiling point and vapor pressure in Table 1. When methylene chloride or chloroform is selected as the solvent, the difference in boiling point and vapor pressure shown in Table 2 is taken into consideration. Thus, a non-solvent may be selected.
[Table 1]
When the mixed solvent for dissolving polylactic acid and the copolymer has a volume ratio of the solvent to the non-solvent of generally 10: 1 to 10:10, a cell structure can be obtained. When the ratio of the solvent is larger than this, the dissolution of the polymer continues until the end of the evaporation of the solvent, the cell wall does not precipitate, and only a transparent polymer mass without bubbles is formed after the evaporation of the solvent. On the other hand, when the ratio of the solvent is smaller than the above, polylactic acid or the like is precipitated all at once when only a small amount of solvent is diffused, so that the welding between the cells becomes incomplete, and there is no physical connection between the cells. It is not good because a cell structure is completed or a contracted and deformed cell structure completely different from the shape of the mold is formed. The range of the ratio suitable for forming a stable cell structure having a solid shape by connecting cells in three dimensions is 10: 1 to 10: 7, depending on the solvent composition.
[0028]
A polymer solution prepared by dissolving polylactic acid or a copolymer in the above mixed solvent is filled in the mold, and then the solvent is at a temperature lower than the boiling point of the solvent, preferably at a temperature of 20 ° C. or lower, at normal pressure or reduced pressure. It is important to distract. If the solvent is diffused at a temperature equal to or higher than the boiling point of the solvent, the solvent boils, breaks the cell walls, and is welded. Therefore, a high-quality cell structure cannot be obtained. If this air diffusing step is performed in a sealed device that can recover the evacuated solvent, the recovered solvent can be used over and over again and can be inhaled during operation. It is safe and resource-saving. In addition, for the purpose of increasing the viscosity of the polymer solution and fixing the cell wall, the operation of cooling to a low temperature of about 10 ° C. or lower to increase the viscosity before the solvent is diffused and then venting under reduced pressure is adopted. It is also desirable. This operation is effective for producing a thick sheet-like or irregularly shaped cell structure.
[0029]
When the mixed solvent is diffused from the polymer solution as described above, a thin film-like or sheet-like cell structure having a thickness of several hundred μm or less can be manufactured in a short time while viewing. And in the case of a thick plate-like or irregularly shaped cell structure of 1 mm or more, it takes a little longer time just by changing the depth and shape of the mold and increasing the filling amount of the polymer solution. Can be manufactured. At this time, so that the solvent can be uniformly diffused from the entire surface of the mold, the mold is a porous mold that has innumerable fine ventilation holes that do not allow polylactic acid or a copolymer to pass therethrough but allows the solvent to pass through, for example, unglazed pottery One method is to use a mold made of metal. In addition, the viscosity of the polymer solution is increased at a low temperature of about 10 ° C. or lower for the purpose of accelerating the solvent diffusion and maintaining the shape by avoiding the depression and deformation of the polymer solution inside the structure. It is also desirable to take an operation of forcibly evaporating the solvent under reduced pressure. However, the evaporation rate of the solvent needs to be finely adjusted depending on the molecular weight, type and concentration of the polymer, the thickness, shape and magnification of the desired cell structure. In this way, it is possible to easily manufacture a cell structure molded into a block shape or a different shape having a thickness of 5 cm or more.
[0030]
The cell structure has an expansion ratio of 2 to 30 times, preferably a high expansion ratio of 5 to 30 times, and the cell structure having such an expansion ratio is finely divided by hydrolysis in vivo. Since the amount of pieces produced is small, there is an advantage that there is almost no fear of causing transient inflammation due to a foreign body reaction.
[0031]
Factors that determine the expansion ratio of the cell structure include the viscosity of the polymer solution, the polymer concentration, the molecular weight of the polymer, the composition ratio of the mixed solvent, and the air diffusivity of the solvent. From the principle of forming the body, polymer concentration is one of the most important factors. The polymer concentration and the expansion ratio are in an inversely proportional relationship, and the higher the polymer concentration, the lower the expansion ratio. When the polymer concentration is higher than 10% by weight, it becomes difficult to obtain a cell structure having an expansion ratio of 5 times or more. Therefore, in order to obtain a cell structure having a high expansion ratio, it is necessary to lower the polymer concentration. When the polymer concentration is decreased to about 2% by weight, there is a difference depending on the composition ratio of the mixed solvent, but the expansion is about 30 times. A cell structure having a magnification can be obtained. However, if the polymer concentration is further reduced to 1% by weight or less, it becomes difficult to obtain a satisfactory cell structure.
[0032]
The relationship between the molecular weight of the polymer and the expansion ratio is that the expansion ratio is the highest in a certain molecular weight region, and the expansion ratio tends to decrease even if the molecular weight is larger or smaller than that region. As can be seen from the data of Examples described later, the region of the weight average molecular weight of the polymer (polylactic acid or copolymer) having the highest foaming ratio is 75 to 1.4 million to 105 when Mw / Mv is 3 to 4. ˜1.4 million (viscosity average molecular weight is about 250,000 to 350,000), and the weight average molecular weight of the polymer is 600,000 (viscosity average molecular weight 15 to 200,000) or less. It becomes difficult to get expensive things.
[0033]
In addition, regarding the relationship between the composition ratio of the mixed solvent and the expansion ratio, as can be seen from the data of the examples described later, the higher the ratio of the non-solvent within the range of the appropriate solvent mixing ratio, the higher the expansion ratio. It is in.
[0034]
Therefore, if the polymer concentration, the molecular weight of the polymer, the composition ratio of the mixed solvent, etc. are changed variously, the expansion ratio of the cell structure can be freely controlled, and the cell structure having an expansion ratio of 2 to 30 times can be obtained. It can be manufactured easily. The cell structure having such an expansion ratio has an average pore size of about 3 to 300 μm of continuous pores, and when a pore size of about 150 to 300 μm is selected within this range, Since the invasion of body fluid and surrounding tissue cells is easy, it is useful as a biodegradable and absorbable base material for tissue regeneration and cell transplantation.
[0035]
【Example】
Examples of the present invention will be described below.
[0036]
[Example 1]
Methylene chloride (CH 2 Cl 2 ), Non-solvent (precipitant) and ethanol (C 2 H 5 OH), and the volume ratio of solvent to non-solvent (solvent / non-solvent) was changed to 10/0, 10/1, 10/3, 10/5, 10/7, 10/9. A polymer obtained by dissolving poly-L-lactic acid having a weight average molecular weight of about 1,050,000 (viscosity average molecular weight of about 300,000, molecular weight distribution; dispersity Mw / Mn = 2.5) at a concentration of 4 g / dl in a mixed solvent. A solution was prepared.
[0037]
These polymer solutions are poured into a petri dish having a diameter of 10 cm so that the liquid surface has a height of 13 mm, and the lid is left as it is, and the cell structure is left at room temperature (10 to 20 ° C.) under atmospheric pressure. I made it. After 24 hours, the solvent of the polymer solution had evaporated, and only those having a solvent composition ratio (solvent / non-solvent) of 10/7 and 10/9 left a slight ethanol odor. After that, when dried under reduced pressure, the solvent could not be detected by gas chromatography. Properties and the like of the obtained cell structure are summarized in Table 3 below.
[0038]
Moreover, when the hardness, bending strength, and tensile strength of the obtained cell structure were measured, the results shown in Table 3 were obtained. The hardness was measured by a durometer hardness test method (JIS K 7215), the bending strength was measured by a three-point bending test method (JIS K 7221), and the tensile strength was measured by a universal testing machine (JIS K 7113).
[Table 3]
Further, FIG. 1 shows the result of the hydrolysis experiment of the cell structure obtained from the solvent composition ratios of 10/0 and 10/5 in the phosphate buffer at 37 ° C.
[0040]
From the above results, in the case of a mixed solvent of methylene chloride and ethanol, a relatively good cell structure can be obtained with a solvent composition ratio (methylene chloride / ethanol) of 10/1 to 10/6. A cell structure having a high solvent composition ratio of 10/5 and an expansion ratio of 10.0 times was obtained, and the cell structure became thicker together with the expansion ratio. This is presumably because the polymer was immediately precipitated and solidified from the surface of the solution in contact with the outside air by the evaporation of the solvent, and the cell wall was formed and fixed, so that the thickness was maintained. This fact suggests that when a cell structure having a certain expansion ratio and a certain thickness is required, the composition ratio of the solvent and the concentration of the polymer solution may be adjusted.
[0041]
In the case of using only the solvent, since the polymer is diffused until the solvent is completely diffused, the holes from which the solvent is removed do not remain as holes. Therefore, the original transparent sheet of the polymer was formed.
[0042]
When the ratio of the solvent is high, the volume decreases due to the evaporation of the solvent, and when the thickness is reduced by that amount, the cell wall is fixed and the cell wall is fixed by precipitation and solidification. Is thought to have declined. On the other hand, when the ratio of the initial non-solvent (precipitating agent) is high, the effect of the non-solvent as a precipitating agent is immediately manifested by slight evaporation of the solvent, and precipitates are generated at once. At this time, since there is not enough solvent left to dissolve the polymer to form a continuous cell wall, the polymer shrinks greatly when pores are formed, or the precipitated polymer particles are simply welded to form a connected body. It is considered that a cell structure such as a kind of sintered body is formed, which has pores interposed therebetween. Actually, when the solvent composition ratio is 10/7, the shrinkage during precipitation and solidification is severe, and a deformed cell structure with many wrinkles on the surface is obtained, and when the solvent composition ratio is 10/9, the particles are brittle and easy A cell structure that dropped out was obtained. However, the upper limit of the ratio for forming the cell structure is considered to be 10/10. This fact well supports the cell structure generation mechanism of the present invention.
[0043]
Further, the foaming ratio increases as the composition ratio of the solvent becomes 10/1, 10/3, or 10/5. Along with this, both hardness and strength have decreased. This is considered to be because when the expansion ratio is increased, the number of pores or the size of the pores is increased, so that the thickness of the cell wall is reduced and the strength is lowered.
[0044]
Furthermore, in the hydrolysis experiment in a 37 ° C. phosphate buffer, the solvent composition ratio is 10/5 compared to the non-cell structure homogeneous solid obtained from the
[0045]
[Example 2]
Solvent composition ratio (CH 2 Cl 2 / C 2 H 5 OH) was fixed at 10/5, and the poly-L-lactic acid concentration of Example 1 was changed to 1.0, 2.0, 3.0, 4.0, 5.0, 7.0 g / dl. A polymer solution was prepared. And these polymer solutions were filled in the petri dish of the same shape as Example 1, and the cell structure was obtained similarly. The properties, hardness, bending strength, and tensile strength of the obtained cell structure are summarized in Table 4 below.
[Table 4]
From this result, it is clear that the expansion ratio depends inversely on the concentration. As in Example 1, when the polymer concentration was decreased, the expansion ratio of the cell structure was increased, but the hardness, bending strength, and tensile strength were decreased accordingly. This is probably because the number and size of the pores of the cell structure increased as the polymer concentration decreased, and the strength of the cell wall became brittle.
[0047]
[Example 3]
The poly-L-lactic acid used in Example 1 was mixed with methylene chloride, ethanol and water mixed solvent (CH 2 Cl 2 / C 2 H 5 OH / H 2 O = 10/5 / 0.3) was dissolved at a concentration of 4 g / dl to prepare a polymer solution.
[0048]
This polymer solution was filled in the mold until the liquid level reached 8 cm, and allowed to stand at room temperature and normal pressure for 5 days. As a result, a cell structure having a thickness of 3.1 mm and an expansion ratio of about 10 times was obtained. This cell structure was harder than that in Example 1 where the solvent composition ratio was 10/1. This is presumably because the precipitation and solidification of the polymer was rapid due to the influence of water, the crystallinity was slightly increased, and the cell walls were firmly fixed.
[0049]
[Example 4]
The solvent composition ratio (CH2Cl2 / C2H5OH) is fixed to 10/5, the polymer concentration is fixed to 2 g / dl, Mw is about 1.4 million (Mv: about 400,000), Mw is about 1.05 million (Mv: about 300,000), A cell structure was obtained in the same manner as in Example 1 using each of poly-L-lactic acid having an Mw of about 650,000 (Mv: about 185,000). Table 5 shows the hardness, bending strength, and tensile strength of the obtained cell structure.
[Table 5]
As a result, as the weight average molecular weight increased, the hardness and strength of the cell structure increased. In addition, if the Mw is about 1.05 million and the Mw is about 650,000, the cell structure having an Mw of about 650,000 has a lower hardness and strength, although the expansion ratio is smaller. Indicated. This is related to the fact that the difference in average molecular weight is related to the difficulty of forming the cell structure, and the polymer viscosity when the Mw is higher than 600,000 is easy to form the cell structure by this method. It is considered that the physical properties of the high-quality cell structure were influenced by the homogeneity of the cells, the size and number of pores, and the hardness of the cell walls.
[0051]
[Comparative Example 1]
Using poly-L-lactic acid having a Mw of about 600,000 (Mv: about 150,000) and a Mw of about 400,000 (Mv: about 115,000), respectively, the cell was prepared by the solution precipitation method in the same manner as in Example 4. A structure was obtained. Unlike the cell structure of Example 4, this was a cell structure in which porous particles were aggregated. As shown in Table 6, the hardness, bending strength, and tensile strength of this structure were small and fragile compared to the values of the cell structure in Table 5 where Mw was higher than 600,000.
[Table 6]
From this fact, it is clear that when the Mw is higher than 600,000, a cell structure having high magnification, wall thickness, uniform bubbles and excellent mechanical strength is formed by the solution precipitation method.
[0053]
[Comparative Example 2]
Mw is about 1.4 million (Mv: about 400,000), Mw is about 1.05 million (Mv: about 300,000), Mw is about 650,000 (Mv: about 150,000), Mw is about 600,000 (Mv: about 150,000) and poly-L-lactic acid having Mw of about 400,000 (Mv: about 115,000), respectively, to obtain a cell structure by a solution precipitation method. And the weight average molecular weight after sterilizing these cell structures with pressurized steam was measured. The results are shown in Table 7.
[Table 7]
As can be seen from Table 7, the cell structure using poly-L-lactic acid having a molecular weight of more than 600,000 (Mv: 150,000) is still considerably large even when the molecular weight is reduced by steam sterilization. A cell using poly-L-lactic acid having an Mw of 600,000 (Mv: 150,000) or less compared with the case where the weight average molecular weight remains and it may remain without being decomposed in a living body for a considerable time. The structure has a low molecular weight of Mw of 400,000 or less after one sterilization. Therefore, in order to use it as a prosthetic material or scaffold in a living body, the former is practical because the time required to decompose and become low molecular weight is appropriate, but the latter originally lacks strength. In addition, it can be said to be impractical because it decomposes to become a lower molecule and is absorbed too soon.
[0055]
[Example 5]
Using poly-L-lactic acid having a weight average molecular weight Mw of 1,050,000 (viscosity average molecular weight Mv: 300,000), the composition ratio of the solvent (CH 2 Cl 2 / C 2 H 5 A polymer solution was prepared so that OH) was in the range of 10/1 to 10/6 and the concentration was in the range of 1 to 4 g / dl, and a cell structure was obtained in the same manner as in Example 1.
[0056]
The cross section of the cell structure was observed using a scanning electron microscope (SEM), and the pore size of the cell structure was measured. The results are shown in Table 8.
[Table 8]
[Example 6]
A copolymer of glycolic acid (GA) and L-lactic acid (LA) (GA / LA molar ratio: 10/90, weight average molecular weight Mw: 730,000) is mixed with the solvent composition ratio (CH 2 Cl 2 / C 2 H 5 OH) was dissolved in a mixed solvent of 10/3 and 10/5 to a polymer concentration of 4 g / dl, and a cell structure was obtained in the same manner as in Example 1. Table 9 shows the properties, hardness, strength and the like of this cell structure.
[Table 9]
As a result, when the glycolic acid was bonded at a molar ratio of 10%, the expansion ratio and strength were smaller than those of the cell structure of L-lactic acid alone, but the hardness was almost the same. However, the cell structure was slightly softer than the PLLA cell structure.
[0059]
A cell structure can also be produced in the same manner with a lactic acid-caprolactone copolymer.
[0060]
【The invention's effect】
As can be understood from the above description, the cell structure of the present invention has hardness and strength (bending strength, tensile strength), and since the period of losing strength by hydrolysis is not early, the strength for several months in vivo. In addition, since it is easy to manufacture and contains no harmful solvent such as benzene, it is safe and extremely useful as a biomaterial. A thick cell structure having a thickness of 1 mm or more is embedded in a complicated three-dimensional space of a damaged site in a living body so as to be used as a temporary prosthetic material or scaffold, or as a transplanted cell. The function can be exhibited as a base material for propagation. In addition, since the cell structure having an expansion ratio of 5 to 30 times is small in the amount of fine pieces generated by hydrolysis in vivo, there is almost no fear of causing transient inflammation due to a foreign body reaction. Cell structures having an average pore size of 5 to 300 μm are also easy to infiltrate body fluids and surrounding tissue cells and impregnate bioadhesives such as fibrin glue and gelatin glue.
[Brief description of the drawings]
FIG. 1 is a graph showing a relationship between a hydrolysis period and a viscosity average molecular weight of a cell structure of an example of the present invention.
Claims (2)
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| JP26076995A JP3610504B2 (en) | 1995-09-12 | 1995-09-12 | Biodegradable absorbable cell structure |
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