JP3570434B2 - Stent and method for manufacturing the same - Google Patents
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Description
【０００１】
【産業上の利用分野】
本発明は、生体適合性に優れたステント及びステントの製造方法に関する。
【０００２】
【従来の技術】
ステントは、収縮した管腔部分を拡張したり、管腔内に解放通路を設けるための装置であり、疾病等によって狭窄した血管、尿管、消化管、気管等の管腔状器官・組織の流路再開、例えば動脈硬化性閉塞症における血流再開を目的として、臨床的に使用されている。
【０００３】
従来、ステントとして、弾性線材で構成された管状構造のもの（管状ステントまたはワイヤステント）が知られている。ステントの材質としては、ステンレス鋼ワイヤ等の金属線が好適に用いられ、これをコイル状またはジグザグ状等に屈９曲及び接続して管状構造を形成している。このような構造の管状ステントは、圧縮して細長い形状にすることが可能である。
【０００４】
このようなステントとしては、例えば、多数の直線部分が互いに屈曲部により接続されてジグザグ構造の閉ループに形成されたワイヤからなるステント（特公平４−３２６６２号公報）、一連の直線部分及び複数の屈曲部を含む円筒形状のヘビ状形態に形成されたワイヤからなるステント（特開昭６３−２３０１５８号公報）、複数個のワイヤの各端部を互いに溶接してなる管状ステント２個以上を柔軟なヒンジ部で接合した間接接合型ステント（特開平３−１５１９８３号公報）、ウズ巻バネからなるステント（米国特許第４，５５３，５４５号明細書）、コイル状に形成した熱記憶合金からなるステントなどが提案されている。
【０００５】
ステントの適用方法としては、例えば、ステントを圧縮した状態でカテーテル先端に取り付け、経皮的に血管などの管腔内に挿入して患部付近に運搬し、次いで、カテーテル先端から管腔内の狭窄部位に遊離させ、ステント自身の弾性的復元力によって形状を復元し、それによって狭窄部位の内径を拡張して、流路再開を行う方法、あるいは、カテーテル先端にステントと共に取り付けたバルーンを膨張させ、それによって圧縮されたステントを拡張させる方法がある。
【０００６】
ステントによる治療法は、同様の症例で施行される代替管の移植外科手術のような外科的切開手術が不要で、簡易な非侵襲的治療法である。また、ステントによる治療法は、バルーン、ナイフまたはカッター等をカテーテル先端に取り付けて行う経皮的管形成術に比して、効果が確実で、しかも安全性に問題がない。そこで、近年、特に血管系において、ステントの使用例が多く報告されている。
【０００７】
ところで、従来のステントは、弾性的復元力または拡張後の形状維持力が必要なことから、ステンレス鋼ワイヤ等の金属線をコイル状またはジグザグ状に屈曲加工したもの、あるいはこれらの金属線と接続用プラスチック糸で構成されたものであるため、生体適合性に乏しいという問題がある。このような構造のステントを、例えば、血管系で使用する際には、折角確保した血流路が金属の高い血栓性によって血栓閉塞を引き起こし、ごく初期の開存しか得られないか、あるいは血栓性の低い部位での使用に適用範囲が限られるなどの問題があった。また、元々治療対象となる管腔状器官は、ガンや動脈硬化などの原因でその管腔組織が異常に内腔側に増殖・膨張する症状を持っている。したがって、ステントにより管腔を拡張しても、ステントを構成する金属線の隙間から管腔組織が増殖・膨張して再び閉塞してしまうという問題があった。
【０００８】
【発明が解決しようとする課題】
本発明の目的は、生体適合性、特に抗血栓性に優れ、再狭窄の危険の少ないステントを提供することにある。
本発明者は、前記従来技術の問題点を克服するために鋭意研究した結果、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜を配置し、内面側及び外面側の管状膜相互間を部分的に熱融着させることにより、抗血栓性に優れ、しかも管腔組織の増殖・膨張による管腔の再閉塞が抑制されるなど、優れた特性を有するステントの得られることを見出した。
【０００９】
四弗化エチレン樹脂多孔質体は、その優れた生体適合性から、人工血管等の医療材料として使用されている。本発明では、これを金属線等の弾性線材で構成された管状構造物の内外面に配置することにより、弾性線材を生体より遮断し、従来得られなかった抗血栓性等の生体適合性をステントに付与し、しかも再狭窄の危険を少なくすることに成功した。
【００１０】
また、内面側及び外面側の四弗化エチレン樹脂多孔質体膜の相互間を部分的に熱融着させることにより、弾性線材で構成された管状構造物の圧縮折り畳みの自由度を保持することができる。多孔質体膜相互間を、四弗化エチレン樹脂よりも低融点の熱可塑性樹脂を用いて接着してもよい。
本発明は、これらの知見に基づいて完成するに至ったものである。
【００１１】
【課題を解決するための手段】
かくして、本発明によれば、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜が配置され、内面側及び外面側の管状膜相互間が部分的に熱融着されていることを特徴とするステント、並びに、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜が配置されていると共に、これら管状膜間に四弗化エチレン樹脂よりも低融点の熱可塑性樹脂が配置されており、該熱可塑性樹脂により、内面側及び外面側の管状膜相互間が部分的に加圧接着されていることを特徴とするステントが提供される。
【００１２】
また、本発明によれば、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜を配置し、内面側及び外面側の管状膜相互間を部分的に熱融着させることを特徴とするステントの製造方法が提供される。さらに、本発明によれば、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜を配置すると共に、これら管状膜間に四弗化エチレン樹脂よりも低融点の熱可塑性樹脂を配置し、四弗化エチレン樹脂の融点未満で熱可塑性樹脂の融点以上に加温した状態で、内面側及び外面側の管状膜相互間を部分的に加圧接着させることを特徴とするステントの製造方法が提供される。
【００１３】
以下、本発明について詳述する。
本発明で使用する弾性線材で構成された管状構造物としては、特に限定されず、例えば、従来から知られている金属線を主とした管状ステントを使用することができる。弾性線材で構成された管状構造物は、弾性線材を屈曲及び接続して構成されたものであって、弾性的に圧縮した時、当初の内径より細径の通路に挿入可能で、かつ、弾性的復元力を解放した時、当初形状に復元可能なものであることが好ましい。
【００１４】
このような管状構造物は、弾性線材をコイル状またはジグザグ状等に屈曲及び接続して、管状構造を形成することにより作成することができる。その具体例としては、図２に示すような構造のものを挙げることができる。即ち、ステンレス線（９）をジグザグに折り曲げて円筒状にし、円筒状の両端の各折り曲げ部分に輪（１０）を形成して、その輪の中にステンレスコイル管（８）を円状に配置して管状構造物を作成する。図１は、図２の管状構造物（３）を四弗化エチレン樹脂多孔質体膜（１）及び（２）で被覆した構造のステントの模式図である。図５に示すように、ステンレス線（４）をコイル状に巻いて管状構造を形成してもよい。このような構造の管状構造物は、変形させ、当初内径よりも細径の通路に挿入することができる。
【００１５】
弾性線材の材質としては、本発明品の製造工程において、四弗化エチレン樹脂多孔質体をその融点以上に加熱融着させることから、四弗化エチレン樹脂の融点付近の温度において溶融切断等の起こらない材質のものが好ましい。また、ステントには、弾性的復元力及び形状維持力が必要である。したがって、弾性線材としては、ステンレス鋼、タングステン、プラチナ等の金属線、炭素繊維複合線を主として、これらを管状に構成する目的で使用されうる接続線も、金属線及び四弗化エチレン樹脂糸を使用することが望ましい。
【００１６】
本発明で使用される四弗化エチレン樹脂多孔質体膜は、例えば、特公昭４２−１３５６０号公報に記載の方法により製造することができる。即ち、先ず、四弗化エチレンの未燒結粉末に液状潤滑剤を混和し、押出・圧延によりチューブ状またはシート状に予備成形する。この成形体から液状潤滑剤を除去し、または除去することなく、少なくとも一軸方向に延伸すると未燒結の多孔質体が膜状で得られる。この多孔質体を収縮しないように固定した状態で、四弗化エチレン樹脂の融点である３２７℃以上に加熱して、延伸した構造を燒結・固定すると、強度の向上した燒結品が得られる。
【００１７】
四弗化エチレン樹脂多孔質体膜は、その材質に由来する無毒性、生体内非分解性、抗血栓性等の生体適合性に加え、微小な結節とそれを連結する細い繊維からなる微細な多孔質体構造によって、十分な強度と可撓性を有している。したがって、四弗化エチレン樹脂多孔質体膜は、ステントによる治療において、カテーテル内腔へのステント圧縮挿入の際に、弾性線材からなる管状構造物の形状変化に追随し、しかも、その弾性的復元力を妨げない。
【００１８】
カテーテル内腔へのステント圧縮挿入を考慮すると、本発明品を構成する四弗化エチレン樹脂多孔質体膜は、力学的特性を満足する範囲内で、十分に薄くする必要がある。あまり厚い多孔質体膜を被覆すると、ステントをカテーテル内腔へ圧縮挿入することが困難になる。本発明者の検討では、弾性線材による管状構造物の形状・径によっても異なるが、内外面ともに膜厚５０μｍ以下とすることが好ましく、さらに膜厚３０μｍ以下とすることがより好ましい。しかし、一般に膜厚２０μｍ以下となると製造上困難な上、力学的強度が低く圧縮拡張に耐えられなくなるため、実質上、膜厚は２５〜５０μｍの範囲が最適となる。
【００１９】
四弗化エチレン樹脂多孔質体の多孔質構造は、前述のように可撓性の点で重要である。延伸倍率が小さく、気孔率の低過ぎる多孔質体は、固くて使用し難い。しかし、逆に、延伸倍率が大きく、気孔率の高過ぎる多孔質体は、強度が十分ではなく、弾性線材を生体から遮断することが困難となる。本発明者の検討では、孔径が０．２μｍ〜１μｍの範囲で、バブルポイントが０．０３〜３．０ｋｇ／ｃｍ２の範囲の四弗化エチレン樹脂多孔質体が好ましい。
【００２０】
従来の金属線で構成された管状ステントを用いて、例えば、狭窄した血管内面を押し広げると、強度の低下した患部や柔軟な血栓では、金属線が血管壁に食い込んで破ったり、血栓中に潜り込んでしまい、血流路を回復できない場合があった。これに対して、本発明のステントでは、外面の四弗化エチレン樹脂多孔質体膜によって、面状に狭窄部位を押し広げるため、このような問題が生じない。また、金属線のみのステントでは、患部に存在した血栓が回復した流路の内面に必ず残るが、本発明のステントでは、外面の四弗化エチレン樹脂多孔質体膜によって、血栓が周辺に押し付けられて流路から完全になくなってしまう。
【００２１】
弾性線材からなる管状構造の内外面を多孔質体膜で遮断した本発明のステントは、生体内において血流や細胞の浸潤を防止することも可能である。例えば、悪性新生物、癌の治療において、患部に対する血管分岐部に本発明品を挿入することで血流を遮断し、癌の壊死・発育の抑制を図ったり、癌細胞の流出を阻害して転移を防止する等の治療に使用することが可能である。
【００２２】
本発明で使用する四弗化エチレン樹脂多孔質体膜の多孔質構造は、生体細胞の通過を遮断する孔径とすることが好ましい。本発明者の検討では、繊維長で平均１５μｍ以下、バブルポイントで０．３ｋｇ／ｃｍ２以上の多孔質体膜を使用することにより、細胞浸潤を遮断することが可能であり、このような遮断を目的とするステント治療においては、このような物性を有する四弗化エチレン樹脂多孔質体膜を使用することが好ましい。
【００２３】
四弗化エチレン樹脂の抗血栓性をより有効に発揮させるために、ステントの内面は、血流の乱れを生じる皺や弛みのない滑らかな面にすることが望ましい。このため、四弗化エチレン樹脂多孔質体膜は、管状構造物と一体化する際に、形状に応じて伸びてフィットし易い二軸延伸された未燒結品あるいは半燒結品を使用することが望ましい。二軸延伸された半燒結品は、例えば、配管等のシール材として利用されているグレードのものである。四弗化エチレン樹脂ファインパウダーは、３４７℃に融点ピークを持ち、これを燒結体とすると３２７℃に融点ピークをもつ。したがって、半燒結品は、特性として原料である四弗化エチレン樹脂ファインパウダーの３４７℃の融点ピークを部分的に持つ点で、完全燒結体と区別される。
【００２４】
本発明のステントを製造するには、弾性線材で構成された管状構造物の内面及び外面に、チューブ状に成形した四弗化エチレン樹脂多孔質体膜（管状膜）を配置する。次に、四弗化エチレン樹脂の融点より高い温度に加熱した金属体にて、内外面の四弗化エチエン樹脂多孔質体膜を挟み込み、熱融着させる。この場合、ステントの内径によっては、加熱した金属体を内腔に挿入することが困難な場合があるが、そのような場合には、管状構造物の内径と同径の金属棒を挿入し、外側から加熱した金属体を押しつけることで、内面の金属棒と外面の加熱金属体の間で内外面の四弗化エチレン樹脂多孔質体膜を挟み込み、熱融着させることが可能である。
【００２５】
この熱融着による一体化は、内外両面の四弗化エチレン樹脂多孔質体膜の全面に行うと、熱融着により多孔質構造が無孔化し、四弗化エチレン樹脂多孔質体膜の可撓性が減少する。また、全面融着は、管状構造物の圧縮折り畳みの自由度を減少させ、ステントのカテーテルへの圧縮挿入性を低下させる。
【００２６】
このため、内外面の四弗化エチレン樹脂多孔質体膜の熱融着は、部分的に行うことが望ましい。具体的には、例えば、水玉模様状あるいは何本かの線状に熱融着部分を設けると、上記のような問題を回避することができる。また、管状構造物の変形に対する自由度を保持するためには、管状構造物が四弗化エチレン樹脂多孔質体膜間にない部分で、これらの部分接着を行う方がより有効である。
熱融着では、完全に燒結された多孔質体膜よりも、未燒結品を用いた方が、高い接着力を得ることができる。この点でも、本発明に使用される四弗化エチレン樹脂多孔質体膜は、半燒結品または未燒結品が好ましい。
【００２７】
本発明のステントを製造する他の方法としては、内外面の四弗化エチレン樹脂多孔質体膜を、接着剤として熱可塑性樹脂を用い、加熱・加圧して接着させる方法がある。具体的には、弾性線材で構成された管状構造物の内面及び外面に、四弗化エチレン樹脂多孔質体の管状膜を配置すると共に、これら２つの管状膜間に四弗化エチレン樹脂よりも低融点の熱可塑性樹脂を配置し、四弗化エチレン樹脂の融点未満で熱可塑性樹脂の融点以上に加温した状態で、内面側及び外面側の管状膜相互間を部分的に加圧接着させる。
【００２８】
熱可塑性樹脂としては、ポリプロピレン、ポリエチレン、エチレン−酢酸ビニル共重合体、アイオノマーなどのヒートシール型の接着剤（シーラント）等があり、通常、フィルムや不織布などの層状のものを弾性線材で構成された管状構造物の所要箇所に巻き付けて、２つの管状膜の間に配置することが好ましい。例えば、金属線管状構造物の所要箇所にポリプロピレン不織布を帯状に巻き付け、その内外面に四弗化エチレン樹脂多孔質体の管状膜を配置する。
【００２９】
この熱可塑性樹脂を用いた接着法によれば、四弗化エチレン樹脂の融点よりも低い温度で管状膜相互間を接着させることができるため、内外面の四弗化エチレン樹脂多孔質体膜相互間を部分的に熱融着させる方法と比較して、四弗化エチレン樹脂多孔質体膜の変形やピンホール発生などのおそれがない。また、四弗化エチレン樹脂多孔質体は、完全焼成物よりも半焼成物の方が細胞等に対するバリヤ性に優れているが、この接着法によれば、接着部分の四弗化エチレン樹脂多孔質体膜が焼成されることがない。さらに、架橋型の接着剤は、生体適合性に難があるが、ポリオレフィン等の熱可塑性樹脂を用いると、そのような問題はない。
【００３０】
本発明のステントは、次のような特徴を有している。
（１）無毒性、生体内非分解性、抗血栓性等の生体適合性に優れる。
（２）管腔内面を四弗化エチレン樹脂多孔質体膜により面状で押し広げるため、血栓が、再開通した血流路内に残らない。
（３）癌治療など、血流・細胞の遮断目的に使用できる。
（４）四弗化エチレン樹脂多孔質体の低摩擦性により、カテーテルへの挿入が容易である。
これらの特徴により、本発明品は、生体適合性、適用範囲、作業性が著しく改善されたものであり、ステントによる治療の有効性をさらに高めることができ、血管などの狭窄内腔の良好な再開通を実現することができる。
【００３１】
【実施例】
以下、本発明について、実施例及び比較例を挙げて具体的に説明するが、本発明は、これらの実施例のみに限定されるものではない。
【００３２】
なお、物性の測定方法は以下の通りである。
〈バブルポイント〉
四弗化エチレン樹脂多孔質体膜をイソプロピルアルコールに含浸し、膜の孔内をイソプロピルアルコールで充満した後、膜の一方の面より徐々に空気圧を負荷したときに、初めて反対面から気泡が出てくるときの圧力。
〈開存率〉
ステントを動物の血管内に配置し、ある一定期間生かした後の、その時点で血流が認められたステントの本数の、配置したステント全数に対する比率。
〈形成血栓厚み〉
ステントを動物に移植し、ある一定期間生かした後に取り出したステントをホルマリン固定後、臨界点乾燥を施し、走査型電子顕微鏡で、長軸方向に切断した断面の内面に付着した血栓層を測定した平均値。
〈焼成度〉
四弗化エチレン樹脂多孔質体膜を示差走査熱量計にて１０℃／分の昇温速度にて融点解析し、３４７℃の時点で吸熱ピークのないものを完全焼成、あるものを半焼成、半焼成のうち、融点ピークが３４５℃以下のものを未焼成とした。
【００３３】
［実施例１］
０．３５ｍｍφのステンレス線（９）の両端をつないで円状にし、その接続部に内外径０．３５ｍｍ、０．４ｍｍφのステンレス管で被覆し補強したものを、２．５ｃｍ間隔でジグザグに１６回折り曲げて、両端に各８ケの折り曲げ部分が並ぶ図２に示すような円筒状にした。折り曲げ部は、図２のように０．２ｍｍφほどの円（１０）を形成するように曲げ、この円内を通って、両端それぞれの折り曲げ部先端をつなぐ円状にステンレスコイル管（８）を配置した。ステンレスコイル管としては、８０μｍ線を隙間なくコイル状に巻き、０．４ｍｍφの円筒状にしたものを用い、全体として、長さ１ｃｍ、内径１０ｍｍφの金属線からなる管状構造物（３）を作製した。
【００３４】
四弗化エチレン樹脂多孔質体膜として、バブルポイント１．３ｋｇ／ｃｍ２、厚み３０μｍの未燒結品シート（住友電工社製ポアフロン・メンブレンフィルターＵＰ−０２０−４０）を使用し、折り返した端部を熱融着させた後、熱融着による接着代が内面になるように内外面を反転させて、９ｍｍφのチューブ状にした。
【００３５】
次に、金属線管状構造物を、内径５ｍｍφ、外径７ｍｍφの管の内腔に圧縮挿入しておき、この管の外に、用意した四弗化エチレン樹脂多孔質体チューブを配置し、ここから金属線管状構造物を挿入した管のみを抜き去ることで、金属線管状構造物の外面に四弗化エチレン樹脂多孔質体膜を被覆した。四弗化エチレン樹脂多孔質体チューブは、金属線管状構造物より十分長くしておいて、図３に示すように、この余分な部分を金属線管状構造物の内腔に折り込んで反対の端部より出し（７）、その端部（６）で金属線管状構造物の内外面の四弗化エチレン樹脂多孔質体を熱融着した。
【００３６】
このようにして得られた四弗化エチレン樹脂多孔質体膜（１、２）で内外面を被覆した金属線管状構造物（３）の内腔に、外径１０ｍｍφのステンレス丸棒を挿入し、図４のように金属線管状構造物の２本の支柱（４）とステンレスコイル管で成す１６個の三角形の各重心付近に、５００℃に加熱した１ｍｍφの円柱の端部を押し付け、内外の四弗化エチレン樹脂多孔質体膜を点接着（５）して、長さ２ｃｍ、内径１０ｍφのステントを作製した。
【００３７】
［実施例２］
実施例１と同じステンレス線を、１．５ｍｍピッチで内径２ｍｍ、長さ１ｃｍのコイル状に巻いたものを金属線管状構造物とし、実施例１と同じ四弗化エチレン樹脂多孔質体未燒結品シートを内径１．８ｍｍφのチューブ状に成形したものを四弗化エチレン樹脂多孔質体管状膜として、実施例１同様にして金属線管状構造物に被覆した。次いで、２ｍｍφのステンレス丸棒を挿入して、金属線管状構造物のコイルと同じピッチで、金属線と重ならないように０．３５ｍｍφのステンレス線を外周に巻き付けた後に、３５０℃に加熱した３５ｍｍφガラス管円筒加熱炉に炉内滞在時間２分間の条件で加熱した。外周に巻いたステンレス線及び内腔のステンレス丸棒を除去し、図５に示すような長さ１ｃｍ、内径２ｍφのステントを作製した。
【００３８】
［実施例３］
四弗化エチレン樹脂多孔質体膜として、バブルポイント１．３ｋｇ／ｃｍ２、厚み８０μｍの四弗化エチレン樹脂多孔質体未燒結品シート（住友電工社製ポアフロンメンブレンフィルタ−ＵＰ−０２０−８０）を使用したこと以外は、実施例１と同様にしてステントを作成した。
【００３９】
［実施例４］
四弗化エチレン樹脂多孔質体膜として、バブルポイント０．３３ｋｇ／ｃｍ２、厚み５０μｍの四弗化エチレン樹脂多孔質体完全燒結品シート（住友電工社製ポアフロンメンブレンフィルタ−ＷＰ−１００−５０）を使用したこと以外は、実施例１と同様にしてステントを作成した。
【００４０】
［実施例５］
四弗化エチレン樹脂多孔質体膜として、バブルポイント０．１８ｋｇ／ｃｍ２、厚み５０μｍの四弗化エチレン樹脂多孔質体完全燒結品シート（住友電工社製ポアフロンメンブレンフィルタ−ＷＰ−３００−５０）を使用したこと以外は、実施例２と同様にしてステントを作成した。
【００４１】
［実施例６］
実施例１と同様に金属線管状構造物の周囲に、図４の内外の四弗化エチレン樹脂多孔質体膜の接着部分を含む円筒帯状にポリプロピレン不織布（三井石油化学工業社製シンテックスＰＳ−１０８）を巻き付け、その内外面に四弗化エチレン樹脂多孔質体膜を配置して、１ｍｍφの円柱の端部を２００℃に加熱したこと以外は、実施例１と同様にして、ポリプロピレン不織布を介して内外面の四弗化エチレン樹脂多孔質体膜を接着した構造のステントを作成した。
【００４２】
［比較例１］
実施例１で使用した金属線管状構造物を管状ステントとした。
［比較例２］
実施例２で使用した金属線管状構造物を管状ステントとした。
【００４３】
［比較例３］
実施例１で作製した四弗化エチレン樹脂多孔質体膜で内外面を被覆した金属線管状構造物の内腔に、外径１０ｍｍφのステンレス丸棒を挿入し、３５０℃恒温槽に１０分間入れることで、四弗化エチレン樹脂多孔質体膜を完全燒結したものを比較例３とした。
【００４４】
［比較例４］
実施例１で金属線管状構造物の外側に四弗化エチレン樹脂多孔質体膜を被覆した状態で両端の長さをそろえ、金属線管状構造物の外面にのみ四弗化エチレン樹脂多孔質体を被覆したものを比較例４とした。
【００４５】
［比較例５］
実施例２で金属線管状構造物の外側に四弗化エチレン樹脂多孔質体膜を被覆した状態で両端の長さを切りそろえ、金属線管状構造物の外面にのみ四弗化エチレン樹脂多孔質体を被覆したものを比較例５とした。
【００４６】
〈圧縮挿入性評価〉
各実施例及び比較例で得られたステントについて、圧縮挿入性を比較した。具体的には、ステントを径の違うＦＥＰチューブ内腔に挿入して行き、挿入可能な最小内径を求めた。
【００４７】
同じ金属線管状構造物を用いた実施例１、３、４及び６と比較例１、３及び４のステントうち、実施例１及び６と比較例１及び４のものは、内径２ｍｍφと同じで、四弗化エチレン樹脂多孔質体層による圧縮性の低下はなかった。実施例３のステントは、４ｍｍφ、実施例４は、３ｍｍφと若干圧縮挿入性が低下したが、ステントとしての使用において問題はないと考えられる。比較例３のステントは、内外面の四弗化エチレン樹脂多孔質体膜と金属線管状構造物が強固に固定されており、５ｍｍφが限度で多少圧縮挿入性に難があった。
【００４８】
また、元の内径が２ｍｍφの実施例２と比較例２及び５のステントは、内径１．２ｍｍφまでと差はなかったが、実施例５のものについては、１．５ｍｍφと若干圧縮挿入性が低下した。
【００４９】
挿入可能な最小径の管に対する挿入・離脱後の形状復帰性（形状回復性）については、実施例１、２及び６と比較例１及び２のステントについては、２０回挿入・離脱を繰り返しても全く元と変化はなかったが、実施例３及び４のものでは、挿入１０回を越えるくらいから、四弗化エチレン樹脂多孔質体膜と金属線管状構造物の位置関係が微妙にずれだして、部分的に微小な皺が発生したが、構造が破壊することはなかった。
【００５０】
これらに対して、比較例３のステントは、１回の挿入で形状がいびつになり、また、一部の四弗化エチレン樹脂多孔質体膜が破れた部分、金属線が四弗化エチレン樹脂多孔質体より露出した部分ができた。比較例４及び５のステントは、３〜５回の挿入で両端部の四弗化エチレン樹脂多孔質体膜が皺になり、金属端が露出して被覆しない部分ができた。
【００５１】
〈移植評価〉
実施例２及び５と比較例２及び５のステントをそれぞれ、体重１３〜１５ｋｇのウサギの頚動脈内に挿入移植を行った。先端にステントを予め内腔に挿入した外径１．５ｍｍφ、内径１．２ｍｍφのＦＥＰチューブを、頚動脈の移植部位の１ｃｍ下流より血管内に挿入し、ＦＥＰチューブ内腔の他端より棒を挿入してステントを血管内に放出した。移植後５分、１時間、２４時間、及び２週間後、生育後屠殺して、該ステントを取り出し、開存率を調査した後に、ホルマリン固定し、次いで臨界点乾燥を行い、走査型電子顕微鏡で、ステント内面の血栓形成状態、形成血栓厚みを観察・測定した。また、２週後のサンプルについては、病理組織標本を作製し、治癒状態について観察した。
【００５２】
移植評価の結果、比較例２及び５のステントは、移植後５分後にすでに金属線周辺に活性化し偽足を伸ばす血小板の集積が見られ、１時間後には、形成血栓層の厚みが不均一で赤血球を含む赤色血栓が形成されたところも多数散見された。移植後１日でも血小板を含む安定しない血栓が部分的に観察され、開存率が示すように、閉塞するものもあった。移植２週後でもまだ赤色血栓は残存し、開存率は低下していた。病理組織標本の観察では、形成された血栓層も３０〜５０μｍと厚く、器質化していない血栓層が多く見られた。特に、比較例２のものでは、ステンレス線のすぐ外側の血管内膜及び中膜に圧迫による壊死変性部が認められた。
【００５３】
それに対して、実施例２及び５のステントは、開存率は良好で、全般的に形成血栓厚みは薄く均一であった。移植後５分では少量の血小板の付着が見られる程度で、１時間後には、血栓層の増加および活性状態が見られたが、１日後には既に血小板の少ないフィブリン様物質に覆われた安定な血栓層となっていた。２週後には、血栓層はほぼ器質化され、ステント両端部で血管内皮細胞の伸展が見られ、良好な治癒が行われていた。また、実施例５のものでは、四弗化エチレン樹脂多孔質体の多孔質内にステント外壁からの組織細胞の侵入が見られた。
【００５４】
〈埋植評価〉
四弗化エチレン樹脂多孔質体膜膜で被覆しない比較例１及び２を除く各実施例及び比較例のステントの両端に栓をした状態で、ウサギの背皮下に埋植試験を行った。埋植後３週間で各ステントを取り出し、病理組織標本として組織の侵入性を観察した。
【００５５】
四弗化エチレン樹脂多孔質体膜のバブルポイントが１．３ｋｇ／ｃｍ２の実施例１〜３、６及び比較例３〜５、及び被覆した四弗化エチレン樹脂多孔質体膜のバブルポイントが０．３３ｋｇ／ｃｍ２の実施例４のステントでは、ステント内腔への組織侵入は全く認められなかったが、比較例４及び５のものについては、四弗化エチレン樹脂多孔質体が若干収縮して、一部に膜が被覆しない部分が生じ、その隙間より内腔への組織侵入が起こっているサンプルもあった。
【００５６】
これに対して、四弗化エチレン樹脂多孔質体膜のバブルポイントが０．１８ｋｇ／ｃｍ２の実施例５のステントでは、好中球を主とする細胞がステントの内腔及び四弗化エチレン樹脂多孔質体膜の多孔質内に散見され、一部に繊維芽細胞を中心とする組織の侵入が認められ、細胞の遮断性においては、実施例１〜３、４及び６が優れている。
以上の実施例及び比較例のステントの構造、圧縮挿入性評価、及び移植評価の結果を表１及び表２に一括して示す。
【００５７】
【表１】
【表２】
なお、表１〜２中で示した構造・特性についての略語は、以下のことを示す。
・内径：ステントの内径。
・内層ＰＴＦＥ厚：ステントの金属線管状構造物内面に被覆した四弗化エチレン樹脂多孔質体膜の厚み。
・外層ＰＴＦＥ厚：ステントの金属線管状構造物外面に被覆した四弗化エチレン樹脂多孔質体膜の厚み。
・ＢＰ：使用した四弗化エチレン樹脂多孔質体膜のバブルポイント。
・接着量：内外面に被覆した四弗化エチレン樹脂多孔質体膜の全接触面積に対する、これらを接着した部分の面積の割合（百分率）。
・焼成度：ステントの四弗化エチレン樹脂多孔質体膜の焼成度。
・形状復帰挿入回数：元の状態に復帰可能な平均挿入回数。
・挿入による変形：挿入可能最小径に対する２０回以内の挿入で発生するステントの形状及び形態の変化。
【００６０】
【発明の効果】
本発明のステントは、ステントのもつ手術の簡易性、確実な開存性に加え、四弗化エチレン樹脂多孔質体の材質がもつ抗血栓性を合わせ持つ。したがって、本発明のステントは、血管系における閉鎖性血管疾患や動脈瘤などにおける血管の再建に特に有効である。また、本発明のステントは、バブルポイント０．３ｋｇ／ｃｍ２以上の四弗化エチレン樹脂多孔質体膜を使用することにより、生体細胞の遮断が可能となり、癌による圧迫閉塞などの各種生体管に対する再建にも有効である。
【図面の簡単な説明】
【図１】本発明のステントの一例を示す模式図で、外面の四弗化エチレン樹脂多孔質体膜層の一部を切りとった形状を示す。
【図２】本発明で使用する弾性線材からなる管状構造物の１例を示す模式図である。
【図３】本発明の製造方法の１例を示す模式図で、金属線管状構造物に四弗化エチレン樹脂多孔質体膜を被覆する工程を断面図で示す。
【図４】本発明の製造方法の１例を示す模式図で、最終段階を示す。
【図５】本発明のステントの１例を示す模式図で、その一部を切り取った形状を示す。
【符号の説明】
１：管状構造物内面の四弗化エチレン樹脂多孔質体膜層
２：管状構造物外面の四弗化エチレン樹脂多孔質体膜層
３：弾性線材からなる管状構造物
４：金属線管状構造物が膜に内包された部分（破線）
５：内外の四弗化エチレン樹脂多孔質体層の接着部分（斜線部）
６：加熱接着する部位（円内）
７：四弗化エチレン樹脂多孔質体チューブの反転して内側に折り込まれた部分
８：金属線の折り曲げ部に設けた輪をつなぐコイル状金属線（点線）
９：金属線
１０：金属線の折り曲げ部に設けた輪[0001]
[Industrial applications]
The present invention relates to a stent excellent in biocompatibility and a method for manufacturing a stent.
[0002]
[Prior art]
A stent is a device for expanding a contracted lumen portion or providing a release passage in the lumen, and is a device for luminal organs / tissues such as blood vessels, ureters, digestive tracts, and trachea which are narrowed due to a disease or the like. It is used clinically for the purpose of reopening a flow channel, for example, resuming blood flow in atherosclerotic obstruction.
[0003]
BACKGROUND ART Conventionally, a stent having a tubular structure (tubular stent or wire stent) made of an elastic wire has been known. As the material of the stent, a metal wire such as a stainless steel wire is suitably used, and this is bent and connected in a coil shape or a zigzag shape to form a tubular structure. The tubular stent having such a structure can be compressed into an elongated shape.
[0004]
As such a stent, for example, a stent (Japanese Patent Publication No. 4-32662) composed of a wire in which a large number of linear portions are connected to each other by a bent portion and formed in a closed loop having a zigzag structure, a series of linear portions and a plurality of linear portions A stent made of a wire formed into a cylindrical snake-like shape including a bent portion (Japanese Patent Application Laid-Open No. 63-230158), and two or more tubular stents formed by welding each end of a plurality of wires to each other are made flexible. Indirectly bonded stents (Japanese Patent Laid-Open No. 3-151983), stents composed of quail-wound springs (U.S. Pat. No. 4,553,545), and thermal memory alloy formed in a coil shape Stents and the like have been proposed.
[0005]
As a method of applying the stent, for example, the stent is attached to the distal end of the catheter in a compressed state, inserted into a lumen such as a blood vessel percutaneously, and transported to the affected area, and then, stenosis in the lumen from the distal end of the catheter. Release to the site, restore the shape by the elastic restoring force of the stent itself, thereby expanding the inner diameter of the stenosis site, a method of resuming the flow path, or inflating the balloon attached with the stent to the catheter tip, There are ways to expand the compressed stent thereby.
[0006]
Stent treatment is a simple, non-invasive treatment that does not require surgical incision surgery such as replacement-tube transplant surgery performed in similar cases. Moreover, the treatment method using a stent is more effective than the percutaneous angioplasty performed by attaching a balloon, a knife, a cutter, or the like to the catheter tip, and has no problem in safety. Therefore, in recent years, many examples of the use of stents, particularly in the vascular system, have been reported.
[0007]
By the way, since a conventional stent requires an elastic restoring force or a shape maintaining force after expansion, a metal wire such as a stainless steel wire is bent into a coil shape or a zigzag shape, or is connected to these metal wires. There is a problem that it is poor in biocompatibility because it is composed of plastic threads for use. When a stent having such a structure is used in, for example, a vascular system, a blood flow path secured at an angle causes thrombotic occlusion due to a high thrombotic property of metal, and only a very early patency can be obtained, or There is a problem that the range of application is limited for use in low-potency parts. In addition, a luminal organ to be treated originally has a symptom that its luminal tissue abnormally proliferates and expands to the luminal side due to cancer or arteriosclerosis. Therefore, even if the lumen is expanded by the stent, there is a problem that the lumen tissue proliferates and expands from the gap between the metal wires constituting the stent and is closed again.
[0008]
[Problems to be solved by the invention]
An object of the present invention is to provide a stent that is excellent in biocompatibility, particularly, antithrombotic properties, and that has a low risk of restenosis.
The inventor of the present invention has conducted intensive studies to overcome the above-mentioned problems of the prior art. As a result, the inner and outer surfaces of a tubular structure made of an elastic wire material have porous tetrafluoroethylene resin bodies. Is disposed, and the inner and outer tubular membranes are partially heat-sealed to each other. As a result, it has been found that a stent having excellent properties, such as excellent antithrombotic properties and suppression of reocclusion of the lumen due to proliferation and expansion of the lumen tissue, can be obtained.
[0009]
BACKGROUND ART Porous tetrafluoroethylene resin bodies have been used as medical materials such as artificial blood vessels because of their excellent biocompatibility. In the present invention, by arranging this on the inner and outer surfaces of a tubular structure formed of an elastic wire such as a metal wire, the elastic wire is shielded from the living body, and biocompatibility such as antithrombotic properties, which was not obtained conventionally, is obtained. It has been successfully applied to stents and has reduced the risk of restenosis.
[0010]
In addition, the degree of freedom of compression folding of the tubular structure composed of the elastic wire is maintained by partially heat-sealing the inner and outer surfaces of the porous ethylene tetrafluoride resin membrane. Can be. The porous membranes may be bonded to each other using a thermoplastic resin having a lower melting point than the ethylene tetrafluoride resin.
The present invention has been completed based on these findings.
[0011]
[Means for Solving the Problems]
Thus, according to the present invention, on the inner surface and the outer surface of the tubular structure formed of the elastic wire, the porous body made of ethylene tetrafluoride resin is provided. The tubular membranes are disposed, and the inner and outer tubular membranes are partially heat-sealed to each other. Stent characterized by the fact that And a tubular film of a porous tetrafluoroethylene resin is disposed on the inner surface and the outer surface of the tubular structure formed of the elastic wire, and a melting point lower than that of the tetrafluoroethylene resin is provided between these tubular films. Wherein the tubular membranes on the inner surface side and the outer surface side are partially pressure-bonded to each other by the thermoplastic resin. Is provided.
[0012]
Further, according to the present invention, a tubular film of a porous material of tetrafluoroethylene resin is disposed on the inner surface and the outer surface of the tubular structure composed of the elastic wire, and a portion between the inner and outer tubular films is partially formed. The present invention provides a method for producing a stent, which is characterized in that the stent is thermally fused. Further, according to the present invention, a tubular membrane of a porous tetrafluoroethylene resin is disposed on the inner surface and the outer surface of the tubular structure formed of the elastic wire, and the ethylene tetrafluoride resin is disposed between the tubular membranes. In addition, a low-melting thermoplastic resin is placed, and the inner and outer tubular membranes are partially press-bonded while being heated to a temperature lower than the melting point of the tetrafluoroethylene resin and higher than the melting point of the thermoplastic resin. A method for manufacturing a stent is provided.
[0013]
Hereinafter, the present invention will be described in detail.
The tubular structure formed of the elastic wire used in the present invention is not particularly limited, and for example, a conventionally known tubular stent mainly composed of a metal wire can be used. The tubular structure made of an elastic wire is formed by bending and connecting an elastic wire, and when elastically compressed, can be inserted into a passage having a diameter smaller than the initial inner diameter, and When the target restoring force is released, it is preferable that the original shape can be restored.
[0014]
Such a tubular structure can be produced by bending and connecting an elastic wire into a coil shape or a zigzag shape to form a tubular structure. Specific examples thereof include those having a structure as shown in FIG. That is, the stainless wire (9) is bent in a zigzag manner to form a cylinder, and a loop (10) is formed at each bent portion at both ends of the cylindrical shape, and the stainless coil tube (8) is arranged in a circle in the loop. To form a tubular structure. FIG. 1 is a schematic view of a stent having a structure in which the tubular structure (3) of FIG. 2 is covered with a porous film of a tetrafluoroethylene resin (1) and (2). As shown in FIG. 5, a stainless steel wire (4) may be wound into a coil to form a tubular structure. A tubular structure having such a structure can be deformed and inserted into a passage whose diameter is smaller than the initial inner diameter.
[0015]
As the material of the elastic wire, in the production process of the product of the present invention, the porous body of ethylene tetrafluoride resin is heated and fused to a temperature higher than its melting point. A material that does not occur is preferable. In addition, the stent requires an elastic restoring force and a shape maintaining force. Therefore, as the elastic wire, metal wires such as stainless steel, tungsten, and platinum, and carbon fiber composite wires are mainly used, and connection wires that can be used for the purpose of forming these into a tubular shape also include metal wires and ethylene tetrafluoride resin yarn. It is desirable to use.
[0016]
The porous film of a tetrafluoroethylene resin used in the present invention can be produced, for example, by the method described in JP-B-42-13560. That is, first, a liquid lubricant is mixed with the unsintered powder of ethylene tetrafluoride, and is preformed into a tube or sheet by extrusion and rolling. When the liquid lubricant is removed from the molded body or at least uniaxially stretched without removing the lubricant, an unsintered porous body is obtained in the form of a film. When this porous body is fixed so as not to shrink and heated to 327 ° C. or more, which is the melting point of the ethylene tetrafluoride resin, and the stretched structure is sintered and fixed, a sintered product having improved strength can be obtained.
[0017]
In addition to biocompatibility, such as non-toxicity, non-degradability in vivo, and antithrombotic properties, the porous material of the tetrafluoroethylene resin porous body is made of fine nodules and fine fibers that connect them. The porous structure has sufficient strength and flexibility. Therefore, in the treatment with the stent, the porous tetrafluoroethylene resin membrane follows the shape change of the tubular structure made of the elastic wire when the stent is compressed and inserted into the lumen of the catheter, and furthermore, its elastic recovery. Do not hinder power.
[0018]
In consideration of compressive insertion of the stent into the lumen of the catheter, the porous film of the polytetrafluoroethylene resin constituting the product of the present invention needs to be sufficiently thin as far as the mechanical properties are satisfied. Coating a too thick porous membrane makes it difficult to compress the stent into the lumen of the catheter. According to the study by the present inventor, the thickness is preferably 50 μm or less, and more preferably 30 μm or less, on both the inner and outer surfaces, although it depends on the shape and diameter of the tubular structure made of the elastic wire. However, in general, when the film thickness is less than 20 μm, it is difficult to manufacture, and the mechanical strength is so low that it cannot withstand compression expansion. Therefore, the film thickness is practically optimal in the range of 25 to 50 μm.
[0019]
The porous structure of the porous tetrafluoroethylene resin is important in terms of flexibility as described above. A porous body having a small stretching ratio and too low porosity is hard and difficult to use. However, conversely, a porous body having a large stretching ratio and an excessively high porosity does not have sufficient strength, and it is difficult to shield the elastic wire from a living body. According to the study of the present inventor, when the pore diameter is in the range of 0.2 μm to 1 μm, the bubble point is 0.03 to 3.0 kg / cm. 2 Is preferred.
[0020]
Using a tubular stent composed of a conventional metal wire, for example, when the inner surface of a stenotic blood vessel is expanded, in a diseased part or a soft thrombus with reduced strength, the metal wire cuts into the blood vessel wall and breaks, In some cases, they could not recover the blood flow channel. On the other hand, in the stent of the present invention, such a problem does not occur because the stenosis site is spread in a planar manner by the porous tetrafluoroethylene resin membrane on the outer surface. Further, in the stent using only the metal wire, the thrombus existing in the affected area always remains on the inner surface of the recovered flow path. However, in the stent of the present invention, the thrombus is pressed against the periphery by the porous tetrafluoroethylene resin membrane on the outer surface. And completely disappear from the channel.
[0021]
The stent of the present invention in which the inner and outer surfaces of the tubular structure made of an elastic wire are blocked with a porous membrane can also prevent blood flow and infiltration of cells in a living body. For example, in the treatment of malignant neoplasms and cancer, the blood flow is blocked by inserting the product of the present invention into the vascular bifurcation to the affected area, thereby suppressing the necrosis / growth of the cancer or inhibiting the outflow of cancer cells. It can be used for treatment such as prevention of metastasis.
[0022]
It is preferable that the porous structure of the porous film of the tetrafluoroethylene resin used in the present invention has a pore size that blocks passage of living cells. According to the study by the present inventors, the average fiber length is 15 μm or less, and the bubble point is 0.3 kg / cm. 2 By using the above-mentioned porous membrane, it is possible to block cell invasion, and in a stent treatment aiming at such a block, a porous tetrafluoroethylene resin having such properties is used. Preferably, a membrane is used.
[0023]
In order to more effectively exhibit the antithrombotic properties of the tetrafluoroethylene resin, it is preferable that the inner surface of the stent has a smooth surface without wrinkles or slack that causes disturbance of blood flow. For this reason, when the tetrafluoroethylene resin porous material membrane is integrated with the tubular structure, a biaxially stretched unsintered product or a semi-sintered product that easily stretches and fits according to the shape may be used. desirable. The biaxially stretched semi-sintered product is, for example, a grade used as a sealing material for piping and the like. The ethylene tetrafluoride resin fine powder has a melting point peak at 347 ° C., and when it is used as a sintered body, has a melting point peak at 327 ° C. Accordingly, the semi-sintered product is distinguished from the completely sintered product in that it partially has a melting point peak at 347 ° C. of the raw material of the tetrafluoroethylene resin fine powder as a characteristic.
[0024]
In order to manufacture the stent of the present invention, a tubular porous tetrafluoroethylene resin membrane (tubular membrane) is arranged on the inner surface and the outer surface of a tubular structure composed of an elastic wire. Next, the porous body of the tetrafluoroethylene resin on the inner and outer surfaces is sandwiched by a metal body heated to a temperature higher than the melting point of the ethylene tetrafluoride resin, and thermally fused. In this case, depending on the inner diameter of the stent, it may be difficult to insert the heated metal body into the lumen, in such a case, insert a metal rod having the same diameter as the inner diameter of the tubular structure, By pressing the metal body heated from the outside, it is possible to sandwich the inner and outer surfaces of the porous tetrafluoroethylene resin film between the metal rod on the inner surface and the heated metal body on the outer surface and to perform heat fusion.
[0025]
The integration by heat fusion is performed on the entire surface of the porous film of tetrafluoroethylene resin on both the inside and outside. When you do In addition, the porous structure is made nonporous by heat fusion, and the flexibility of the porous film of the tetrafluoroethylene resin is reduced. Also, full-surface fusion reduces the degree of freedom in compressing and folding the tubular structure, and reduces the compressibility of the stent into the catheter.
[0026]
For this reason, it is desirable that the thermal fusion of the porous film of tetrafluoroethylene resin on the inner and outer surfaces be partially performed. Specifically, for example, when the heat-sealed portion is provided in a polka-dot pattern or in some lines, the above-described problem can be avoided. In addition, in order to maintain the degree of freedom of the tubular structure from being deformed, it is more effective to partially bond the tubular structure at a portion where the tubular structure is not between the porous tetrafluoroethylene resin membranes.
In the case of heat fusion, higher adhesive strength can be obtained by using an unsintered product than by using a completely sintered porous film. In this respect, the semi-sintered product or the unsintered product is preferable as the porous tetrafluoroethylene resin film used in the present invention.
[0027]
As another method for producing the stent of the present invention, there is a method in which the porous film of the tetrafluoroethylene resin on the inner and outer surfaces is bonded by heating and pressing using a thermoplastic resin as an adhesive. Specifically, on the inner surface and the outer surface of the tubular structure composed of the elastic wire, a tubular membrane of a porous body of ethylene tetrafluoride resin is arranged, and between these two tubular membranes, a resin material of less than ethylene tetrafluoride resin is used. A thermoplastic resin having a low melting point is arranged, and while being heated to a temperature lower than the melting point of the tetrafluoroethylene resin and higher than the melting point of the thermoplastic resin, the inner and outer tubular films are partially pressure-bonded to each other. .
[0028]
Examples of the thermoplastic resin include a heat-sealable adhesive (sealant) such as polypropylene, polyethylene, ethylene-vinyl acetate copolymer, and ionomer. Usually, a layered material such as a film or a nonwoven fabric is formed of an elastic wire. It is preferable to wind around the required portion of the tubular structure and arrange it between the two tubular membranes. For example, a polypropylene nonwoven fabric is wound around a required portion of a metal wire tubular structure in a belt shape, and a tubular film of a porous body of a tetrafluoroethylene resin is disposed on the inner and outer surfaces thereof.
[0029]
According to this bonding method using a thermoplastic resin, the tubular membranes can be bonded to each other at a temperature lower than the melting point of the ethylene tetrafluoride resin. Compared to the method of partially heat-sealing the gap, there is no risk of deformation of the porous tetrafluoroethylene resin film or generation of pinholes. In addition, although the semi-baked product has a better barrier property against cells and the like than the completely-baked product, the porous tetrafluoroethylene resin material according to this bonding method, The solid body film is not fired. Further, the cross-linking type adhesive has poor biocompatibility. However, such a problem does not occur when a thermoplastic resin such as polyolefin is used.
[0030]
The stent of the present invention has the following features.
(1) It is excellent in biocompatibility such as non-toxicity, non-degradability in vivo, and antithrombotic property.
(2) Since the inner surface of the lumen is spread in a planar manner by the porous film of the tetrafluoroethylene resin, the thrombus does not remain in the blood flow path that has resumed.
(3) It can be used for the purpose of blocking blood flow and cells such as cancer treatment.
(4) Insertion into a catheter is easy due to the low friction property of the porous tetrafluoroethylene resin material.
Due to these features, the product of the present invention has significantly improved biocompatibility, application range and workability, can further enhance the effectiveness of treatment with a stent, and can improve the stenosis lumen such as blood vessels. Resumption communication can be realized.
[0031]
【Example】
Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to only these Examples.
[0032]
In addition, the measuring method of a physical property is as follows.
<Bubble Point>
After impregnating the porous tetrafluoroethylene resin membrane with isopropyl alcohol and filling the pores of the membrane with isopropyl alcohol, when air pressure is gradually applied from one side of the membrane, bubbles are generated from the opposite side for the first time. Pressure when coming.
<Patency rate>
The ratio of the number of stents that showed blood flow at that point in time after the stents were placed in the blood vessel of the animal for a certain period of time to the total number of stents placed.
<Thickness of formed thrombus>
The stent was implanted in an animal, and after taking out the stent for a certain period of time, the removed stent was fixed in formalin, dried at the critical point, and the thrombus layer attached to the inner surface of the cross section cut in the longitudinal direction was measured with a scanning electron microscope. Average value.
<Baking degree>
Melting point analysis of the ethylene tetrafluoride resin porous film at a heating rate of 10 ° C./min with a differential scanning calorimeter, complete calcination of a material having no endothermic peak at 347 ° C. Among the semi-baked, those having a melting point peak of 345 ° C. or lower were unfired.
[0033]
[Example 1]
Both ends of a 0.35 mmφ stainless steel wire (9) are connected to form a circular shape, and the connection is coated and reinforced with a 0.35 mm, 0.4 mmφ stainless steel tube with an inner and outer diameter of 16 mm. It was folded into a cylindrical shape as shown in FIG. 2 in which eight bent portions were arranged at both ends. The bent portion is bent so as to form a circle (10) having a diameter of about 0.2 mm as shown in FIG. 2, and the stainless steel coil tube (8) is formed into a circle connecting the ends of the bent portions at both ends through this circle. Placed. As the stainless steel coil tube, an 80 μm wire is wound into a coil shape with no gap and made into a cylindrical shape of 0.4 mmφ, and as a whole, a tubular structure (3) made of a metal wire having a length of 1 cm and an inner diameter of 10 mmφ is produced. did.
[0034]
Bubble point 1.3 kg / cm 2 Using a 30 μm thick unsintered product sheet (Pouflon membrane filter UP-020-40 manufactured by Sumitomo Electric Co., Ltd.), the folded end is heat-sealed, and the bonding margin by heat-sealing is on the inner surface. The inner and outer surfaces were inverted to form a 9 mmφ tube.
[0035]
Next, the metal wire tubular structure is compressed and inserted into the lumen of a tube having an inner diameter of 5 mmφ and an outer diameter of 7 mmφ, and the prepared porous tetrafluoroethylene resin tube is placed outside this tube. By removing only the tube into which the metal wire tubular structure was inserted from, the outer surface of the metal wire tubular structure was covered with a porous film of a tetrafluoroethylene resin. The tetrafluoroethylene resin porous body tube is made sufficiently longer than the metal wire tubular structure, and as shown in FIG. 3, this extra portion is folded into the lumen of the metal wire tubular structure so that the opposite end is formed. (7), and at its end (6), the porous tetrafluoroethylene resin on the inner and outer surfaces of the metal wire tubular structure was heat-sealed.
[0036]
A stainless steel round bar having an outer diameter of 10 mmφ is inserted into the inner cavity of the metal wire tubular structure (3) whose inner and outer surfaces are covered with the porous film of the tetrafluoroethylene resin thus obtained (1, 2). As shown in FIG. 4, the end of a 1 mmφ cylinder heated to 500 ° C. is pressed against the vicinity of each of the sixteen triangular centers of gravity formed by two pillars (4) of a metal wire tubular structure and a stainless steel coil tube. (5), a stent having a length of 2 cm and an inner diameter of 10 mφ was prepared.
[0037]
[Example 2]
The same stainless steel wire as in Example 1 was wound into a coil shape with a pitch of 1.5 mm, an inner diameter of 2 mm, and a length of 1 cm to form a metal wire tubular structure, and the same porous sintered body of ethylene tetrafluoride resin as in Example 1 was obtained. The product sheet was formed into a tubular shape having an inner diameter of 1.8 mmφ as a porous film of a porous tetrafluoroethylene resin, and was coated on a metal wire tubular structure in the same manner as in Example 1. Next, a stainless steel round bar of 2 mmφ was inserted, and at the same pitch as the coil of the metal wire tubular structure, a stainless wire of 0.35 mmφ was wound around the outer periphery so as not to overlap with the metal wire, and then heated to 350 ° C. at 35 mmφ. The glass tube was heated in a cylindrical heating furnace under the conditions of a residence time of 2 minutes in the furnace. The stainless steel wire wound around the outer circumference and the stainless steel round bar in the lumen were removed to prepare a stent having a length of 1 cm and an inner diameter of 2 mφ as shown in FIG.
[0038]
[Example 3]
Bubble point 1.3 kg / cm 2 A stent was prepared in the same manner as in Example 1 except that an unsintered product sheet of a porous material of tetrafluoroethylene resin having a thickness of 80 μm (Poreflon membrane filter-UP-020-80 manufactured by Sumitomo Electric Industries, Ltd.) was used. .
[0039]
[Example 4]
Bubble point 0.33 kg / cm 2 A stent was prepared in the same manner as in Example 1 except that a 50 μm-thick porous sheet of a tetrafluoroethylene resin porous body was completely sintered (Poreflon Membrane Filter-WP-100-50 manufactured by Sumitomo Electric Industries, Ltd.). .
[0040]
[Example 5]
Bubble point 0.18 kg / cm 2 A stent was prepared in the same manner as in Example 2, except that a sheet of a completely sintered product of a porous body of a tetrafluoroethylene resin having a thickness of 50 μm (Poreflon membrane filter-WP-300-50 manufactured by Sumitomo Electric Industries, Ltd.) was used. .
[0041]
[Example 6]
As in Example 1, a polypropylene nonwoven fabric (Shintex PS- manufactured by Mitsui Petrochemical Industry Co., Ltd.) is formed around the metal wire tubular structure in a cylindrical band shape including an adhesive portion of the inner and outer porous polytetrafluoroethylene resin films shown in FIG. 108) was wound, and a polytetrafluoroethylene resin porous membrane was disposed on the inner and outer surfaces thereof, and the end of a 1 mmφ cylinder was heated to 200 ° C. in the same manner as in Example 1, except that a polypropylene nonwoven fabric was used. Thus, a stent having a structure in which the porous film of the tetrafluoroethylene resin on the inner and outer surfaces was bonded to the inner surface of the stent was prepared.
[0042]
[Comparative Example 1]
The metal wire tubular structure used in Example 1 was used as a tubular stent.
[Comparative Example 2]
The metal wire tubular structure used in Example 2 was used as a tubular stent.
[0043]
[Comparative Example 3]
A stainless steel round bar having an outer diameter of 10 mm is inserted into the lumen of the metal wire tubular structure whose inner and outer surfaces are covered with the porous film of the tetrafluoroethylene resin produced in Example 1, and is placed in a 350 ° C constant temperature bath for 10 minutes. Thus, Comparative Example 3 was obtained by completely sintering the porous polyethylene tetrafluoride resin membrane.
[0044]
[Comparative Example 4]
In Example 1, both ends of the metal wire tubular structure were covered with the porous tetrafluoroethylene resin film on the outside of the metal wire tubular structure, and only the outer surface of the metal wire tubular structure was coated on the outer surface of the metal wire tubular structure. Was coated as Comparative Example 4.
[0045]
[Comparative Example 5]
In Example 2, the length of both ends was trimmed in a state where the outer surface of the metal wire tubular structure was covered with the porous film of the tetrafluoroethylene resin, and only the outer surface of the tubular structure was covered with the ethylene tetrafluoroethylene resin. Was coated as Comparative Example 5.
[0046]
<Compression insertion evaluation>
The stents obtained in each of the examples and comparative examples were compared in terms of their compressibility and insertability. Specifically, the stent was inserted into the lumens of the FEP tubes having different diameters, and the minimum insertable inner diameter was determined.
[0047]
Of the stents of Examples 1, 3, 4 and 6 and Comparative Examples 1, 3 and 4 using the same metal wire tubular structure, those of Examples 1 and 6 and Comparative Examples 1 and 4 had the same inner diameter of 2 mmφ. There was no decrease in compressibility due to the porous layer of ethylene tetrafluoride resin. Although the compressibility of the stent of Example 3 was 4 mmφ and that of Example 4 was 3 mmφ, the compressibility was slightly reduced, but it is considered that there is no problem in use as a stent. In the stent of Comparative Example 3, the inner and outer surfaces of the porous tetrafluoroethylene resin membrane and the metal wire tubular structure were firmly fixed, and the compression insertability was somewhat difficult with a limit of 5 mmφ.
[0048]
The stents of Example 2 having an original inner diameter of 2 mmφ and Comparative Examples 2 and 5 did not differ from the stents having an inner diameter of up to 1.2 mmφ. Dropped.
[0049]
Regarding the shape resilience (shape resilience) after insertion / removal of the tube having the smallest diameter that can be inserted, the stents of Examples 1, 2 and 6 and Comparative Examples 1 and 2 were repeatedly inserted / removed 20 times. Although there was no change from the original, the positional relationship between the porous tetrafluoroethylene resin membrane and the metal wire tubular structure slightly shifted from about 10 insertions in Examples 3 and 4. Although fine wrinkles were partially generated, the structure was not destroyed.
[0050]
On the other hand, in the stent of Comparative Example 3, the shape was distorted by one insertion, and a part of the porous film of the tetrafluoroethylene resin was broken, and the metal wire was changed to the tetrafluoroethylene resin. An exposed portion was formed from the porous body. In the stents of Comparative Examples 4 and 5, after 3 to 5 insertions, the porous tetrafluoroethylene resin membranes at both ends became wrinkled, and the metal ends were exposed and uncovered portions were formed.
[0051]
<Transplant evaluation>
The stents of Examples 2 and 5 and Comparative Examples 2 and 5 were respectively implanted and implanted into the carotid artery of a rabbit weighing 13 to 15 kg. A FEP tube with an outer diameter of 1.5 mmφ and an inner diameter of 1.2 mmφ with a stent previously inserted into the lumen at the tip is inserted into the blood vessel from 1 cm downstream of the carotid artery implantation site, and a rod is inserted from the other end of the lumen of the FEP tube. The stent was released into the blood vessel. 5 minutes, 1 hour, 24 hours, and 2 weeks after transplantation, the rats were sacrificed after growth, the stents were removed, the patency was examined, formalin fixation was performed, and then critical point drying was performed. Then, the state of thrombus formation on the inner surface of the stent and the thickness of the formed thrombus were observed and measured. In addition, for the sample after 2 weeks, a pathological tissue specimen was prepared and the healing state was observed.
[0052]
As a result of the transplantation evaluation, in the stents of Comparative Examples 2 and 5, accumulation of platelets activated and stretched around the metal wire was already observed 5 minutes after transplantation, and the formed thrombus layer was uneven in thickness after 1 hour. A large number of red thrombi including red blood cells were formed in the sample. One day after transplantation, an unstable thrombus containing platelets was partially observed, and some were blocked as indicated by the patency rate. Two weeks after transplantation, the red thrombus still remained, and the patency rate had decreased. In the observation of the histopathological specimen, the formed thrombus layer was as thick as 30 to 50 μm, and many unorganized thrombus layers were observed. In particular, in the case of Comparative Example 2, necrotic degeneration due to compression was observed in the intima and media of the blood vessel just outside the stainless wire.
[0053]
In contrast, the stents of Examples 2 and 5 had a good patency rate, and the formed thrombus thickness was thin and uniform overall. At 5 minutes after transplantation, a small amount of platelets adhered. One hour later, an increase in the thrombus layer and an active state were observed. Had a thrombotic layer. Two weeks later, the thrombus layer had become almost organic, vascular endothelial cells had spread at both ends of the stent, and good healing had been performed. In the case of Example 5, invasion of tissue cells from the outer wall of the stent was observed in the porous material of the porous tetrafluoroethylene resin.
[0054]
<Embedding evaluation>
An implantation test was performed subcutaneously on the back of rabbits with both ends of the stent of each of Examples and Comparative Examples except Comparative Examples 1 and 2 not covered with the porous film of the tetrafluoroethylene resin covered. Three weeks after implantation, each stent was taken out, and the invasiveness of the tissue was observed as a pathological tissue specimen.
[0055]
The bubble point of the porous film of the tetrafluoroethylene resin is 1.3 kg / cm. 2 Examples 1 to 3 and 6 and Comparative Examples 3 to 5 and the bubble point of the coated porous polyethylene tetrafluoride resin film was 0.33 kg / cm. 2 In the stent of Example 4, no invasion of tissue into the lumen of the stent was observed at all, but in Comparative Examples 4 and 5, the porous tetrafluoroethylene resin material slightly contracted, and In some samples, a part of the membrane was not covered, and the tissue penetrated into the lumen through the gap.
[0056]
In contrast, the bubble point of the ethylene tetrafluoride porous resin membrane is 0.18 kg / cm. 2 In the stent of Example 5, cells mainly composed of neutrophils are scattered in the lumen of the stent and the porous material of the porous film of the tetrafluoroethylene resin, and a part of the tissue is mainly composed of fibroblasts. Examples 1 to 3, 4 and 6 are excellent in cell blocking properties.
Tables 1 and 2 collectively show the structures of the stents of the above Examples and Comparative Examples, the results of the evaluation of compression insertion properties, and the results of the evaluation of transplantation.
[0057]
[Table 1]
[Table 2]
The abbreviations for structures and characteristics shown in Tables 1 and 2 indicate the following.
Inner diameter: the inner diameter of the stent.
-Inner layer PTFE thickness: The thickness of the porous polyethylene tetrafluoride resin film coated on the inner surface of the metal wire tubular structure of the stent.
-Outer layer PTFE thickness: The thickness of the porous tetrafluoroethylene resin membrane coated on the outer surface of the metal wire tubular structure of the stent.
BP: Bubble point of the used tetrafluoroethylene resin porous membrane.
Adhesion amount: The ratio (percentage) of the area of the portion where these are adhered to the total contact area of the porous tetrafluoroethylene resin membrane coated on the inner and outer surfaces.
Firing degree: Firing degree of the porous tetrafluoroethylene resin membrane of the stent.
-Shape return insertion times: Average number of insertions that can return to the original state.
Deformation due to insertion: Changes in the shape and form of the stent caused by insertion within 20 times the minimum insertable diameter.
[0060]
【The invention's effect】
INDUSTRIAL APPLICABILITY The stent of the present invention has the antithrombotic property of the material of the porous material of the tetrafluoroethylene resin in addition to the simplicity of operation and the reliable patency of the stent. Therefore, the stent of the present invention is particularly effective for reconstructing a blood vessel in a closed vascular disease in a vascular system or an aneurysm. Further, the stent of the present invention has a bubble point of 0.3 kg / cm. 2 The use of the above porous membrane of ethylene tetrafluoride resin makes it possible to block living cells, and is also effective in reconstructing various living tubes such as compression obstruction caused by cancer.
[Brief description of the drawings]
FIG. 1 is a schematic view showing an example of a stent according to the present invention, which shows a shape in which a part of an outer surface of a porous film of a tetrafluoroethylene resin is cut off.
FIG. 2 is a schematic view showing an example of a tubular structure made of an elastic wire used in the present invention.
FIG. 3 is a schematic view showing one example of the production method of the present invention, and is a sectional view showing a step of coating a metal wire tubular structure with a porous film of a tetrafluoroethylene resin.
FIG. 4 is a schematic view showing one example of the production method of the present invention, showing a final stage.
FIG. 5 is a schematic view showing one example of the stent of the present invention, and shows a shape in which a part thereof is cut away.
[Explanation of symbols]
1: Porous ethylene tetrafluoride resin membrane layer on inner surface of tubular structure
2: Porous ethylene tetrafluoride resin membrane layer on outer surface of tubular structure
3: Tubular structure made of elastic wire
4: Part where the metal wire tubular structure is included in the membrane (dashed line)
5: Adhesion portion of inner and outer porous layers of ethylene tetrafluoride resin (hatched portion)
6: Heat bonding area (circle)
7: Inverted and folded inside portion of the porous tube made of ethylene tetrafluoride resin
8: Coiled metal wire connecting the loops provided at the bent part of the metal wire (dotted line)
9: metal wire
10: Loop provided at the bent part of the metal wire
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28574993A JP3570434B2 (en) | 1993-05-10 | 1993-10-20 | Stent and method for manufacturing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13269793 | 1993-05-10 | ||
| JP5-132697 | 1993-05-10 | ||
| JP28574993A JP3570434B2 (en) | 1993-05-10 | 1993-10-20 | Stent and method for manufacturing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0724072A JPH0724072A (en) | 1995-01-27 |
| JP3570434B2 true JP3570434B2 (en) | 2004-09-29 |
Family
ID=26467215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28574993A Expired - Fee Related JP3570434B2 (en) | 1993-05-10 | 1993-10-20 | Stent and method for manufacturing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3570434B2 (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2660318B2 (en) * | 1994-04-15 | 1997-10-08 | 株式会社エヌアンドエム | Internal fistula assembly for biliary stricture |
| US5575816A (en) | 1994-08-12 | 1996-11-19 | Meadox Medicals, Inc. | High strength and high density intraluminal wire stent |
| WO1996036297A1 (en) * | 1995-05-19 | 1996-11-21 | Kanji Inoue | Transplantation instrument, method of bending same and method of transplanting same |
| US6270520B1 (en) | 1995-05-19 | 2001-08-07 | Kanji Inoue | Appliance to be implanted, method of collapsing the appliance to be implanted and method of using the appliance to be implanted |
| US6364901B1 (en) | 1996-12-20 | 2002-04-02 | Kanji Inoue | Appliance collapsible for insertion into a human organ and capable of resilient restoration |
| JP3645399B2 (en) | 1997-06-09 | 2005-05-11 | 住友金属工業株式会社 | Endovascular stent |
| JPH1142284A (en) * | 1997-07-25 | 1999-02-16 | Ube Ind Ltd | Artificial blood vessel with stent |
| US6273917B1 (en) | 1998-03-27 | 2001-08-14 | Kanji Inoue | Transplantation device |
| AU749930B2 (en) | 1998-07-10 | 2002-07-04 | Shin Ishimaru | Stent (or stent graft) indwelling device |
| US6755856B2 (en) * | 1998-09-05 | 2004-06-29 | Abbott Laboratories Vascular Enterprises Limited | Methods and apparatus for stenting comprising enhanced embolic protection, coupled with improved protection against restenosis and thrombus formation |
| US6537284B1 (en) | 1998-10-29 | 2003-03-25 | Kanji Inoue | Device for guiding an appliance |
| WO2000067674A1 (en) | 1999-05-06 | 2000-11-16 | Kanji Inoue | Apparatus for folding instrument and use of the same apparatus |
| EP1136044A1 (en) | 1999-10-04 | 2001-09-26 | Kanji Inoue | Method of folding transplanting instrument and transplanting instrument |
| US6245100B1 (en) | 2000-02-01 | 2001-06-12 | Cordis Corporation | Method for making a self-expanding stent-graft |
| US6296661B1 (en) | 2000-02-01 | 2001-10-02 | Luis A. Davila | Self-expanding stent-graft |
| WO2002078573A2 (en) | 2001-03-30 | 2002-10-10 | Terumo Kabushiki Kaisha | Stent cover and stent |
| EP1550477B1 (en) * | 2002-08-23 | 2015-11-04 | National Cerebral and Cardiovascular Center | Stent and process for producing the same |
| GB0309616D0 (en) * | 2003-04-28 | 2003-06-04 | Angiomed Gmbh & Co | Loading and delivery of self-expanding stents |
| AU2004316360B2 (en) | 2004-02-27 | 2010-06-17 | Sumitomo Electric Industries, Ltd. | Composite structure and process for producing the same |
| US20080124795A1 (en) * | 2004-03-10 | 2008-05-29 | Hideyuki Miyake | Vascular Cell Culture Patterning Substrate |
| US8377110B2 (en) * | 2004-04-08 | 2013-02-19 | Endologix, Inc. | Endolumenal vascular prosthesis with neointima inhibiting polymeric sleeve |
| US20090326640A1 (en) * | 2007-02-01 | 2009-12-31 | Shinichi Yoshimura | Medical device for body cavity and method of producing the same |
| DE102008052406A1 (en) * | 2008-08-08 | 2010-02-11 | Epionics Medical Gmbh | Method and device for detecting parameters for characterizing movements on the human or animal body |
-
1993
- 1993-10-20 JP JP28574993A patent/JP3570434B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0724072A (en) | 1995-01-27 |
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