JP2006263144A - Soft biotissue substitute grafting material and its production method - Google Patents
Soft biotissue substitute grafting material and its production method Download PDFInfo
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本発明は生体軟組織代替移植材料に関する。さらに詳しく言えば、病変血管の代用として生体の血管とつなぎ合わせて移植され、手術時の操作性および長期開存成績に優れた人工血管や心臓の血液接触面の一部を修復するためのシート等として使用される、組織適合性に優れた生体軟組織代替移植材料とその製造方法に関する。 The present invention relates to a living soft tissue replacement graft material. More specifically, a sheet for repairing a part of a blood vessel contact surface of an artificial blood vessel or a heart that is transplanted by joining with a blood vessel of a living body as a substitute for a diseased blood vessel and has excellent operability during surgery and long-term patency. The present invention relates to a living soft tissue replacement graft material excellent in tissue compatibility and a method for producing the same.
1950年代後半以降、病変血管の機能を人工材料の管で置き換える「人工血管」が臨床で用いられている。すなわち、病変血管を置換し、もしくは病変部位を迂回して人の自己血管と縫い合わせて、その内部に血液を流すことにより、病変部位の末梢組織への血液循環を確保することが可能となった。今日、日本では年間約40,000人以上の患者が人工血管移植技術により、大血管の破裂や末梢動脈の動脈硬化性の閉塞などの治療時にその恩恵に浴している。 Since the late 1950s, “artificial blood vessels” that replace the function of diseased blood vessels with tubes of artificial materials have been used clinically. In other words, it is possible to secure blood circulation to the peripheral tissue at the lesion site by replacing the lesioned blood vessel or bypassing the lesion site and stitching it with human autologous blood vessels to allow blood to flow inside. . Today, more than 40,000 patients annually in Japan benefit from artificial blood vessel transplantation techniques during the treatment of ruptured large vessels and arteriosclerotic obstruction of peripheral arteries.
この人工血管は体内に埋め込まれて、直接血液と接触して使用されるため、血液や周辺組織との生体適合性が良いことは勿論のこと、内側から常時１００〜２００ｍｍＨｇの血圧のもとで、１日１０万回もの心臓の拍動による脈圧に晒されるため、これに耐えうる強度が必要なことに加えて、生体内で劣化の少ない材料であることが絶対必須の条件である。さらに、この材料と接触する軟組織に対する刺激が少なく異物反応が少ないことも必要条件である。 Since this artificial blood vessel is implanted in the body and is used in direct contact with blood, it has good biocompatibility with blood and surrounding tissues, and is always under a blood pressure of 100 to 200 mmHg from the inside. Since it is exposed to the pulse pressure due to the heartbeat of 100,000 times a day, it must be strong enough to withstand this, and in addition, it must be a material that has little deterioration in vivo. Furthermore, it is a necessary condition that there is little irritation | stimulation with respect to the soft tissue which contacts this material, and there are few foreign body reactions.
これらの条件を満たす素材としては、1950年代後半に人工血管が実用化された際に採用された、ポリエチレンテレフタレート（ＰＥＴ）を代表とするポリエステル繊維のメリヤス編または平織の布、およびポリテトラフルオロエチレン（以下、ＰＴＦＥと略記することがある。）を引き伸ばして得られる微繊維構造からなる連通孔を壁面全体に有する延伸ポリテトラフルオロエチレンの２種類が今日でも専ら使用されている。そのほかの材料では、生体内劣化が速く進み、要求される十年以上にわたる強度維持を満たすことが出来ないので人工血管などの永久使用を前提とした移植材料には適用されていない。 Materials that satisfy these conditions include knitted or plain woven fabrics of polyester fibers, such as polyethylene terephthalate (PET), and polytetrafluoroethylene, which were used when artificial blood vessels were put to practical use in the late 1950s. (Hereinafter, it may be abbreviated as PTFE.) Two types of expanded polytetrafluoroethylene having a communication hole having a fine fiber structure on the entire wall surface obtained by stretching are still used today. Other materials are not applied to transplanted materials based on the premise of permanent use, such as artificial blood vessels, because the deterioration in vivo progresses rapidly and the required strength maintenance over ten years cannot be satisfied.
特に内径が５〜６ｍｍ以下の細い動脈用としては、ポリエステル繊維製よりも後者の延伸ポリテトラフルオロエチレン製の人工血管が多用されている。内径が細くなると、内腔でのわずかな血液凝固が流路の狭窄を招き、ひいては内腔の閉塞を引き起こす原因になり易いので、抗血栓が重要な品質特性である。ＰＴＦＥのフィルムをストレッチすることによって形成される多孔構造を有するシートでは、小繊維で相互に接続された微細な繊維構造のＰＴＦＥと空気とで形成される微細な不均質構造が優れた抗血栓性を発現する。特に４〜６ｍｍの比較的細い末梢動脈や、慢性腎不全の患者が人工透析を受けるめの血液の出入り口として使用するブラッドアクセスとして皮下に移植される。 Especially for fine arteries having an inner diameter of 5 to 6 mm or less, the latter artificial blood vessel made of expanded polytetrafluoroethylene is more frequently used than polyester fiber. Anti-thrombosis is an important quality characteristic because as the inner diameter becomes smaller, slight blood coagulation in the lumen tends to cause a narrowing of the flow path, which in turn causes the lumen to become occluded. In a sheet having a porous structure formed by stretching a PTFE film, a fine heterogeneous structure formed by PTFE having fine fiber structure connected to each other by fibrils and air has excellent antithrombogenicity. Is expressed. In particular, it is transplanted subcutaneously as a 4-6 mm relatively thin peripheral artery or as a blood access used by a patient with chronic renal failure as a blood entrance for receiving artificial dialysis.
細い動脈として、内腔が閉塞しないで血液の流路として長期間機能する性能、すなわち人工血管の開存成績の向上には２つの課題がある。 There are two problems in improving the ability to function as a blood flow path for a long time as a thin artery without blocking the lumen, that is, the patency of the artificial blood vessel.
その第１は、内表面における抗血栓性である。元来、血液は異物に触れると凝固する性質を持っている。異物である人工血管の表面に厚い血栓が形成されると内腔が狭くなり、血流に対する抵抗となって流速が低下して、血液凝固反応が加速されてしまう。したがって、人工血管の内面の抗血栓性が高いことが開存率向上のために重要である。 The first is antithrombogenicity on the inner surface. Originally, blood has the property of coagulating when it comes into contact with a foreign object. When a thick thrombus is formed on the surface of an artificial blood vessel that is a foreign body, the lumen becomes narrow, resistance to the blood flow, the flow rate decreases, and the blood coagulation reaction is accelerated. Therefore, high antithrombogenicity of the inner surface of the artificial blood vessel is important for improving the patency rate.
第２の因子は、人工血管と生体血管とを縫い合わせた部分、すなわち吻合部での狭塞を起こりにくくすることである。吻合部閉塞は４ｍｍ以下の動脈と結合された人工血管が閉塞する最大の原因となっている。人工血管の他の部分に血栓が生じない場合であっても、徐々に吻合部で新しく形成される組織が盛り上がってきて血液の流れを阻害することが解決困難な問題として今日まで残っていた。この新しく形成される組織は、新生内膜（ネオインティマ）、肉芽（パヌス）の過剰形成などと呼ばれて、生体軟組織と人工材料の境界で発生する不可避の現象とされてきた。内径２０ｍｍの人工血管を移植する場合には、吻合部の肉芽の１ｍｍ程度までの成長は血流への影響が少ない。しかしながら、内径が３〜４ｍｍの人工血管の場合には，わずか１ｍｍ程度の吻合部狭窄が血流路の状態に致命的な影響を及ぼし、短期間で全体が血栓で閉塞してしまう。 The second factor is to make it difficult to cause stenosis at the portion where the artificial blood vessel and the biological blood vessel are stitched together, that is, at the anastomosis portion. Anastomosis occlusion is the largest cause of occlusion of an artificial blood vessel combined with an artery of 4 mm or less. Even when a thrombus does not occur in other parts of the artificial blood vessel, it has remained as a difficult problem to solve until the tissue formed newly in the anastomosis gradually rises and obstructs the blood flow. This newly formed tissue has been called an inevitable phenomenon that occurs at the boundary between living soft tissue and artificial materials, and is called neointima, excessive formation of granulation (panus), or the like. When an artificial blood vessel having an inner diameter of 20 mm is transplanted, the growth of granulation at the anastomosis part to about 1 mm has little influence on the blood flow. However, in the case of an artificial blood vessel having an inner diameter of 3 to 4 mm, anastomotic stenosis of only about 1 mm has a fatal effect on the state of the blood flow path, and the whole is blocked with a thrombus in a short period of time.
このような吻合部狭窄を招く肉芽の過剰形成の過程は当該技術分野の研究者にはよく知られているところであるが、以下にその機序を説明する。
切断された生体血管が人工材料と接続されると組織の断端を治癒しようとして、人工血管の血液流路である内腔表面に接触しながら新しく組織が成長してくる。このわずか１〜２ｍｍの長さに伸びた組織が人工血管の表面から剥離すると、この剥離した組織と人工血管表面との間に隙間が出来て血液の滞溜場所となり、滞溜した血液は凝固する。
The process of excessive formation of granulation leading to such anastomotic stenosis is well known to researchers in the technical field, and the mechanism will be described below.
When the cut biological blood vessel is connected to the artificial material, a new tissue grows while contacting the surface of the lumen, which is the blood flow path of the artificial blood vessel, in an attempt to heal the stump of the tissue. When the tissue having a length of only 1 to 2 mm is peeled off from the surface of the artificial blood vessel, a gap is formed between the peeled tissue and the surface of the artificial blood vessel, and the blood stays there. To do.
凝固した血塊中では、徐々に紡錘形の繊維芽細胞が増植してくる。この細胞は２０〜３０μｍ（ミクロン）の長さがあるので少なくとも２０ミクロン以上の孔径（ポアサイズ）を持つ開放孔構造がなければその中に侵入して行くことは難しい。また単に孔の大きさのみならずこの細胞の進入には材料の性質が影響することも経験的にわかっている。ポリテトラフルオロエチレン（ＰＴＦＥ）のように疎水性の著しい表面よりも親水性表面の方が侵入しやすい傾向がある。この繊維芽細胞はやがてコラーゲンを産生して、徐々に消失してゆく。 Spindle-shaped fibroblasts gradually grow in the coagulated blood clot. Since these cells have a length of 20 to 30 μm (microns), it is difficult to enter the cells without an open pore structure having a pore size (pore size) of at least 20 microns or more. It has also been empirically found that the nature of the material affects not only the pore size but also the cell entry. There is a tendency that a hydrophilic surface is more likely to enter than a highly hydrophobic surface such as polytetrafluoroethylene (PTFE). These fibroblasts eventually produce collagen and gradually disappear.
このようにして形成される新しい組織は、血管の内膜が新たに再生されたという意味で新生内膜と呼ばれる。この内膜は吻合部から徐々に伸長して理想的には人工血管の内面の全面を被覆する。このような人工血管の内面全体が新生内膜で覆われるという状態は内径の大きな人工血管でポリエステル繊維製の布で隙間の多い編布の場合に得られやすいことが知られている。しかし、細い人工血管として使用されている延伸されたポリテトラフルオロエチレン（ＰＴＦＥ）多孔質体の場合には、人工血管の内表面での血液凝固は起こりにくいという反面、吻合部から伸長した新生内膜はしばしば経時的に人工血管の表面から剥離する。 The new tissue thus formed is called the neointima in the sense that the vascular intima has been newly regenerated. The intima gradually extends from the anastomosis and ideally covers the entire inner surface of the artificial blood vessel. It is known that such a state that the entire inner surface of the artificial blood vessel is covered with the neointima is easily obtained in the case of an artificial blood vessel having a large inner diameter and a knitted fabric made of polyester fiber and having many gaps. However, in the case of a stretched polytetrafluoroethylene (PTFE) porous body used as a thin artificial blood vessel, blood coagulation on the inner surface of the artificial blood vessel is unlikely to occur, but on the other hand, it is a newly formed intranasal region that extends from the anastomosis. The membrane often delaminates from the surface of the artificial blood vessel over time.
次に、この剥離した吻合部から伸びた新生組織の陰に血栓が出来て剥離するという過程を反復して吻合に肥厚した組織（肉芽（パヌス））ができ、このパヌスは最終的には内腔での血流を妨げるに到る。
このパヌス形成の原因は、新生内膜が人工材料表面に安定的に接合せずに剥れることによる。したがって、この新生組織の剥離の抑制と内孔表面での抗血液凝固性を兼ね備えた開存性の良い人工血管が求められているが未だ成功していない。
Next, by repeating the process of forming a thrombus in the shadow of the new tissue extending from the exfoliated anastomosis and exfoliating, a thickened tissue (granulation (panus)) is formed. This leads to obstruction of blood flow in the cavity.
The cause of this panus formation is that the neointima is peeled off without being stably bonded to the artificial material surface. Therefore, there is a need for an artificial blood vessel with good patency that has both the suppression of the detachment of the new tissue and the anticoagulant property on the inner pore surface, but it has not been successful.
このポリテトラフルオロエチレン（ＰＴＦＥ）の人工血管の弱点を解決するために、従来試みられている一つの手段は多孔質の孔径を大きくして繊維芽細胞や新生組織の侵入を促し機械的に接合強度を高めることであった。ポリテトラフルオロエチレン（ＰＴＦＥ）多孔質体の平均孔径を５〜５０ミクロンの間で変化させると、孔径が小さい程、内表面の抗血栓性が高い反面、吻合部での新生組織の結合力は低いために剥離が起こり易く、数ヶ月以上の長期間経過した後に、狭塞する傾向が高い。 In order to solve this weakness of the artificial blood vessel of polytetrafluoroethylene (PTFE), one means that has been tried conventionally is to increase the pore size of the porous material to promote the invasion of fibroblasts and new tissue and mechanically join them. It was to increase the strength. When the average pore size of the polytetrafluoroethylene (PTFE) porous material is changed between 5 and 50 microns, the smaller the pore size, the higher the antithrombogenicity of the inner surface, but the binding force of the new tissue at the anastomosis is Since it is low, peeling is likely to occur, and after a long period of time of several months or more, the tendency to close is high.
近年は、閉塞の主な原因が吻合部に在るとの仮説に基づき、最大孔径を２０〜５０ミクロン、さらには１００ミクロン以上として繊維芽細胞などを人工血管の表面や生体血管と接した横断面から容易に侵入させることを意図した研究が多くおこなわれている。しかし、この場合においても吻合部狭塞は完全に克服は出来ていない。また内表面の大きな凹凸による血液の停滞が原因となって血栓が形成されるという望ましくない傾向が助長される。
上記の如く、ポリテトラフルオロエチレン（ＰＴＦＥ）単独で、かつ延伸という方法によって多孔質構造の孔径を変化させるという手段のみによっては、内径４ｍｍ以下の細い人工血管での開存率を向上することはこれまで成功していない。
In recent years, based on the hypothesis that the main cause of occlusion is in the anastomosis, the maximum pore size is 20-50 microns, more than 100 microns, and the fibroblasts are in contact with the surface of the artificial blood vessel or the living blood vessel. Many studies have been conducted with the aim of allowing easy entry from the surface. However, even in this case, the anastomotic stenosis cannot be completely overcome. It also promotes the undesirable tendency of thrombus formation due to blood stagnation due to large irregularities on the inner surface.
As described above, it is possible to improve the patency rate in a thin artificial blood vessel having an inner diameter of 4 mm or less only by means of polytetrafluoroethylene (PTFE) alone and changing the pore diameter of the porous structure by a method of stretching. It has not been successful so far.
そこで、近年、前記延伸ポリテトラフルオロエチレン（ＰＴＦＥ）の多孔質材料と他の材料とを組み合わせて、長期開存成績を向上させるいくつかの試みが行なわれてきた。
その典型的な方法は、新生する生体組織の結合を促進するために延伸ポリテトラフルオロエチレンの多孔質の繊維長を６０ミクロン以上にすると共に、生体組織誘導性物質（コラーゲンなど）、抗血栓性物質（ヘパリン）および細胞接着性物質（フィブロネクチンなど）を含ませた材料でチューブの内外壁面を含む全ての表面に被覆するものである（特許第３０１４３２４号公報；特許文献１）。この発明は初期血栓による閉塞をヘパリンで防ぎ、細胞が侵入するに十分な孔径を有する延伸ポリテトラフルオロエチレンの壁の内部に含ませた新生組織となじみのよいコラーゲン等の生体組織誘導性物質が徐々に溶解し、それに伴って新生組織が入り込み、その組織がフィブロネクチンの細胞接着作用で剥離しないように構成されているところに特徴がある。しかしこの小口径の人工血管の開存率向上に必要な機能が全て組み込まれたかのように工夫されたこの発明によっても製品化には成功していないのが実情である。
In recent years, therefore, several attempts have been made to improve long-term patency results by combining the porous material of expanded polytetrafluoroethylene (PTFE) with other materials.
The typical method is to increase the porous fiber length of stretched polytetrafluoroethylene to 60 microns or more in order to promote the binding of nascent biological tissue, and to induce biological tissue-inducing substances (such as collagen), antithrombotic properties. All the surfaces including the inner and outer wall surfaces of the tube are coated with a material containing a substance (heparin) and a cell adhesion substance (fibronectin or the like) (Patent No. 3014324; Patent Document 1). This invention prevents hematopoietic occlusion due to initial thrombus, and a biological tissue-inducing substance such as collagen that is compatible with the new tissue contained inside the wall of expanded polytetrafluoroethylene having a pore size sufficient for cells to enter. It is characterized in that it is constructed so that it dissolves gradually, and a new tissue enters with it, and the tissue is not detached by the cell adhesion action of fibronectin. However, the present invention, which is devised as if all the functions necessary for improving the patency rate of this small-diameter artificial blood vessel have been incorporated, has not been successfully commercialized.
本発明者等の動物実験の結果によると、生体組織誘導性物質の消失後に新生内膜が剥離することを完全には防止できないことが判明している。細胞接着性物質には延伸ポリテトラフルオロエチレンの多孔質の表面に新生組織を長期間に亘り、接着させておく効力はない。また、移植前の乾燥や滅菌工程を経てコラーゲンが収縮するので、疎水性表面であるポリテトラフルオロエチレン（ＰＴＦＥ）からコラーゲンやゼラチンなどの親水性のゲルが剥離する傾向があることが知られている。すなわち、本来疎水性の組織結合性が良くない素材に、親水性の蛋白質を含むゲルを担持させる手段を講じても、その溶解や分解速度と新生組織の成長速度を適切に制御することは至難である。新生組織が最終的に接するのはポリテトラフルオロエチレン（ＰＴＦＥ）の表面であって、前記特許の方法ではその本質的な問題を十分に解決するには至っていない。 According to the results of animal experiments by the present inventors, it has been found that the neointimal cannot be completely prevented from peeling off after the disappearance of the biological tissue-inducing substance. The cell adhesive substance does not have the effect of adhering the new tissue to the porous surface of expanded polytetrafluoroethylene for a long period of time. In addition, since collagen shrinks after drying and sterilization steps before transplantation, it is known that hydrophilic gels such as collagen and gelatin tend to peel from polytetrafluoroethylene (PTFE) which is a hydrophobic surface. Yes. In other words, it is difficult to appropriately control the dissolution and degradation rate and the growth rate of new tissue even if a material that is inherently hydrophobic and does not have good tissue binding is equipped with a gel containing a hydrophilic protein. It is. The neotissue finally comes into contact with the surface of polytetrafluoroethylene (PTFE), and the method of the above-mentioned patent has not sufficiently solved the essential problem.
児玉らは、ポリテトラフルオロエチレン（ＰＴＦＥ）の表面をポリアミノ酸・ウレタン共重合体をコーティングして親水化することによって組織の多孔質材料への結合性を高めることができると報告している（J.of Biomedical Materials Research, Vol.62-3,315-322 (2002)；非特許文献１）。しかし、この方法も実用化には成功していない。 Kodama et al. Have reported that the surface of polytetrafluoroethylene (PTFE) can be made hydrophilic by coating it with a polyamino acid / urethane copolymer to enhance the tissue binding to a porous material ( J. of Biomedical Materials Research, Vol.62-3,315-322 (2002); However, this method has not been successfully put into practical use.
新生内膜の剥離を繰り返すことによる内膜肥厚のプロセスは１ヶ月以上を経てから顕著に進行する。従って、被覆された材料は人工血管移植後の短期間のみ保持されるのではなく、数ヶ月以上さらに半永久的に安定でなければ結果的に皮膜の分解、劣化に伴って新生内膜も剥離する原因になってしまう。すなわち、被覆した材料が、長期間にわたって安定で、劣化して剥離したり亀裂が入ったりしないこと、かつ生体組織に対して刺激性が少ないことが求められるのである。 The process of thickening the intima by repeatedly exfoliating the neointima proceeds significantly after a month or more. Therefore, the coated material is not held only for a short period after the grafting of the artificial blood vessel, and if it is not semi-permanently stable for several months or longer, the neointimal also peels off as the film is decomposed or deteriorated. It becomes a cause. That is, the coated material is required to be stable for a long period of time, not to deteriorate and peel off or crack, and to be less irritating to living tissue.
延伸ポリテトラフルオロエチレンの表面を他の生体組織となじみの良い材料で被覆する手段としてプラズマを用いる方法は従来から試みられている。プラズマ処理して表面を親水性にしたり、他のビニルモノマーを共存させてプラズマによって発生した活性点からグラフト重合したりすることも可能である。しかしながら、真空条件下で行なわなければならないので、装置が巨大になり、連続処理が困難であり工業生産には適しない。児玉、小駒（こごま）らはキャリアガスに不活性ガスを用いるなどの工夫によって大気圧ブロー放電処理装置を開発して延伸ポリテトラフルオロエチレンの表面にポリエチレングリコールをグラフトすることに成功している（J.of Biomedical Materials Research, Vol.60-3, 502-509 (2002)；非特許文献２）。これらの手段は表面処理方として優れてはいるが、壁の内部まで均一に処理することは困難である。しかるに新生組織の安定化には、表面のみならず多孔質体の深部まで十分に組織が侵入することが必要不可欠であることから目的を十分に達成するには至っていない。 Attempts have heretofore been made to use plasma as means for coating the surface of expanded polytetrafluoroethylene with a material that is compatible with other living tissues. It is also possible to make the surface hydrophilic by plasma treatment or graft polymerization from active sites generated by plasma in the presence of other vinyl monomers. However, since it must be performed under vacuum conditions, the apparatus becomes huge and continuous processing is difficult, which is not suitable for industrial production. Kodama, Kogoma and others have succeeded in grafting polyethylene glycol onto the surface of expanded polytetrafluoroethylene by developing an atmospheric pressure blow discharge treatment device by using an inert gas as a carrier gas. (J. of Biomedical Materials Research, Vol. 60-3, 502-509 (2002); Non-Patent Document 2). Although these means are excellent as a surface treatment method, it is difficult to uniformly treat the inside of the wall. However, in order to stabilize the new tissue, it is indispensable that the tissue sufficiently penetrates not only to the surface but also to the deep part of the porous body, so that the object has not been sufficiently achieved.
従って、本発明の課題は、従来の延伸されたポリテトラフルオロエチレン（ＰＴＦＥ）の多孔質構造を有する移植材料であって、軟組織と接して使用される管状もしくはシート状の人工器官、とりわけ、人工血管と生体組織の境界での新生組織の長期に亘る安定化を促進することによって、開存率を高めた材料を提供することにある。 Accordingly, an object of the present invention is to provide a conventional graft material having a porous structure of stretched polytetrafluoroethylene (PTFE), which is a tubular or sheet-like prosthesis used in contact with soft tissue, in particular, an artificial material. The object is to provide a material with an increased patency rate by promoting long-term stabilization of new tissue at the boundary between blood vessels and living tissue.
本発明者らは、上記課題に鑑みて延伸ポリテトラフルオロエチレン（ＰＴＦＥ）多孔質体からなる優れた人工血管を開発すべく鋭意研究を重ねた結果、生分解性が実質的になく生体適合性の良い組織刺激性の低い特定のポリエステル樹脂の特定溶媒の溶液に浸漬することにより、そのポリエステル樹脂が多孔質体材料の内外表面および内孔表面に、多孔質体の孔を閉塞せずに強固に被覆することを見出し本発明を完成するに至った。
すなわち、本発明は下記の生体軟組織代替移植材料およびその製造方法を提供するものである。
In view of the above problems, the present inventors have conducted extensive research to develop an excellent artificial blood vessel composed of a porous polytetrafluoroethylene (PTFE) porous material. As a result, the present inventors have substantially no biodegradability and are biocompatible. By soaking in a specific solvent solution of a specific polyester resin with good tissue irritation, the polyester resin is strong on the inner and outer surfaces and inner surface of the porous material without blocking the pores of the porous material. The present invention has been completed.
That is, the present invention provides the following biological soft tissue replacement transplant material and a method for producing the same.
１．延伸されたポリテトラフルオロエチレンの多孔質体からなる生体軟組織代替移植材料において、前記多孔質材料の表面および内孔表面を熱可塑性ポリエステル樹脂またはポリエステルを主成分とする熱可塑性樹脂組成物の薄膜で被覆してなることを特徴とする生体軟組織代替移植材料。
２．上記熱可塑性ポリエステル樹脂または樹脂組成物の主成分がポリエチレンテレフタレートである前項１記載の生体軟組織代替移植材料。
３．多孔質体が管状である前項１または２記載の生体軟組織代替移植材料。
４．人工血管である前項３記載の生体軟組織代替移植材料。
５．多孔質体がシート状である前項１または２記載の生体軟組織代替移植材料。
６．心臓血管修復用パッチである前項５記載の生体軟組織代替移植材料。
７．熱可塑性ポリエステル樹脂を溶解する溶媒を用い、添加剤を含まない熱可塑性ポリエステル樹脂を0.2〜１０質量％溶解した前記溶媒の溶液中に延伸されたポリテトラフルオロエチレンの多孔質体からなる材料を浸漬した後、付着した過剰な溶液および溶媒を除去、乾燥し、揮発性・水溶性の溶剤によって洗浄後乾燥することを特徴とする生体軟組織代替移植材料の製造方法。
８．熱可塑性ポリエステル樹脂が、ポリエチレンテレフタレート、またはポリエチレンテレフタレートを主成分とし他のポリエステルを配合した樹脂組成物である前項７に記載の生体軟組織代替移植材料の製造方法。
９．溶媒が、ヘキサフルオロイソプロパノール、またはヘキサフルオロイソプロパノールを主成分とし乾燥速度制御用の他の溶剤を含有する混合溶剤である前項７に記載の生体軟組織代替移植材料の製造方法。
1. In a living soft tissue replacement graft material composed of a stretched polytetrafluoroethylene porous body, the surface of the porous material and the inner surface of the porous material are made of a thermoplastic polyester resin or a thin film of a thermoplastic resin composition mainly composed of polyester. A living soft tissue replacement graft material characterized by being coated.
2. 2. The living soft tissue substitute graft material according to item 1, wherein the thermoplastic polyester resin or resin composition is composed of polyethylene terephthalate.
3. 3. The living soft tissue replacement graft material according to item 1 or 2, wherein the porous body is tubular.
4). 4. The living soft tissue replacement graft material according to 3 above, which is an artificial blood vessel.
5. 3. The living soft tissue replacement graft material according to item 1 or 2, wherein the porous body is in the form of a sheet.
6). 6. The living soft tissue replacement graft material according to item 5, which is a patch for cardiovascular repair.
7). A solvent consisting of a thermoplastic polyester resin is used, and a material made of a polytetrafluoroethylene porous body is immersed in a solution of the solvent in which 0.2 to 10% by mass of a thermoplastic polyester resin not containing an additive is dissolved. Then, the attached excessive solution and solvent are removed, dried, washed with a volatile / water-soluble solvent, and then dried.
8). 8. The method for producing a living soft tissue replacement graft material according to item 7, wherein the thermoplastic polyester resin is a polyethylene terephthalate or a resin composition containing polyethylene terephthalate as a main component and other polyesters.
9. 8. The method for producing a living soft tissue replacement graft material according to item 7, wherein the solvent is hexafluoroisopropanol or a mixed solvent containing hexafluoroisopropanol as a main component and containing another solvent for controlling the drying rate.
本発明の生体軟組織代替移植用材料は、従来のものに比べて、血管などの軟組織と縫い合わせた接合部に於ける組織とのなじみがよく、肉芽の剥離による過剰な成長を抑制する優れた性質がある。従って、特に血流に接触する管状もしくはシート状の人工器官の吻合部における肉芽の過剰形成が抑制されるので、管状体内腔の開存を長期間に亘り保持することができる。 Compared to conventional materials, the material for living body soft tissue substitute transplant of the present invention has better compatibility with the tissue at the joint part stitched with soft tissue such as blood vessels, and has excellent properties to suppress excessive growth due to granulation detachment There is. Therefore, the excessive formation of granulation in the anastomosis portion of the tubular or sheet-like prosthesis that is in contact with the blood flow is suppressed, so that the patency of the tubular body lumen can be maintained for a long period of time.
本発明の生体軟組織代替移植用材料は、例えばシート状であればそのまま人工心膜、人工硬膜として用いることもできるが、改質された表面および内孔表面特性を利用して、多孔質部分にさらに生体適合性の材料を埋め込む２次加工して利用することもできる。 The biological soft tissue replacement transplant material of the present invention can be used as an artificial pericardium or artificial dura mater as long as it is in a sheet form, for example. Furthermore, it is also possible to use it after secondary processing in which a biocompatible material is embedded.
以下、本発明を詳細に説明する。
本発明に用いられるポリエステル樹脂は生体適合性に優れ、長期間体内に移植されても、生分解せず、溶媒に溶解する熱可塑性ポリエステル樹脂が適している。具体例としては、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリシクロヘキサンテレフタレート、ポリエチレン２，６−ナフタレート、ポリブチレン２，６−ナフタレートなどが挙げられ、これらが単独もしくは混合物として用いられる。これらの中でも好ましいのはポリエチレンテレフタレート単独、あるいはポリエチレンテレフタレートを主成分とし他のポリエステルを配合した樹脂組成物が好ましい。
Hereinafter, the present invention will be described in detail.
The polyester resin used in the present invention is excellent in biocompatibility, and a thermoplastic polyester resin that does not biodegrade and dissolves in a solvent even when transplanted into the body for a long period of time is suitable. Specific examples include polyethylene terephthalate, polybutylene terephthalate, polycyclohexane terephthalate, polyethylene 2,6-naphthalate, polybutylene 2,6-naphthalate and the like, and these are used alone or as a mixture. Among these, polyethylene terephthalate alone or a resin composition containing polyethylene terephthalate as a main component and other polyesters is preferable.
コーティングに使用するポリエステル樹脂は、分子量（重量平均分子量、以下同様）5000〜２０万、好ましくは２万〜５万のものである。分子量が5000未満だとコーティング層の物性が脆弱となり、手術操作に伴う変形や外力によって破壊されやすい。一方２０万を超えると多孔質チューブが固くなり、延伸ポリテトラフルオロエチレンの柔軟な物性を損なう。 The polyester resin used for coating has a molecular weight (weight average molecular weight, the same applies hereinafter) of 5,000 to 200,000, preferably 20,000 to 50,000. When the molecular weight is less than 5,000, the physical properties of the coating layer are fragile, and are easily destroyed by deformation and external force associated with surgical operation. On the other hand, if it exceeds 200,000, the porous tube becomes hard and the flexible physical properties of the expanded polytetrafluoroethylene are impaired.
以下にコーティング方法について詳述する。
コーティング溶液の調製には、ポリエステル樹脂を溶解し、かつ延伸ポリテトラフルオロエチレンと親和性のある、すなわち多孔質の深部まで濡らすことのできる溶剤を使用する。多孔質構造を形成する繊維状のポリテトラフルオロエチレンの表面を完全に濡らして被覆し、かつ微細な空隙を閉塞しないように処理するためには、粘性が低く、かつポリエステルに対する溶解性が高いことが必須である。
The coating method will be described in detail below.
For the preparation of the coating solution, a solvent that dissolves the polyester resin and has an affinity for expanded polytetrafluoroethylene, that is, can be wetted to the depth of the porous layer, is used. In order to cover the surface of the fibrous polytetrafluoroethylene forming the porous structure by completely wetting it and not to close the fine voids, it must have low viscosity and high solubility in polyester. Is essential.
このような溶媒としては、例えば、ヘキサフルオロイソプロパノール、ピリジン、フェノール、ジクロロ酢酸、トリフルオロ酢酸の単独もしくはこれらの混合物が挙げられる。これらの中でも、ポリエステル樹脂が優れた溶解性を示すヘキサフルオロイソプロパノール（ＨＦＩＰＡ）が特に好ましい。但し、ヘキサフルオロイソプロパノール（ＨＦＩＰＡ）は揮発性が高いので他の溶剤やアルコール類（メタノール、エチルアルコール、イソプロパノール等）などの貧溶剤を少量混合して乾燥速度を制御することが、多孔質体の内部の繊維構造の表面まで薄い均質なポリエステル樹脂の皮膜で被覆する目的のために有効である。もちろん、溶剤濃度の高い雰囲気中でコーティング工程を実施すことによって蒸発速度を抑制することもできる。 Examples of such a solvent include hexafluoroisopropanol, pyridine, phenol, dichloroacetic acid, trifluoroacetic acid alone or a mixture thereof. Among these, hexafluoroisopropanol (HFIPA) in which the polyester resin exhibits excellent solubility is particularly preferable. However, since hexafluoroisopropanol (HFIPA) is highly volatile, it is possible to control the drying speed by mixing a small amount of other solvents and poor solvents such as alcohols (methanol, ethyl alcohol, isopropanol, etc.). Useful for the purpose of coating with a thin homogeneous polyester resin coating down to the surface of the internal fiber structure. Of course, the evaporation rate can be suppressed by carrying out the coating process in an atmosphere having a high solvent concentration.
コーティング溶液の濃度は0.2〜１０質量％、好ましくは0.5〜５質量％の範囲である。0.2質量％未満では、乾燥後に形成される皮膜が薄すぎるために、屈曲した際に皮膜に亀裂が入り易く、部分的にポリエステルで被覆されていない表面が残ることがある。したがって、長期間移植後の新生内膜の剥離を起こし易い。１０質量％を超えると溶剤系の選択に関らず溶液の粘度が高過ぎて、多孔質体の深部までポリエステルを浸みこませることが困難である。 The concentration of the coating solution is in the range of 0.2 to 10% by mass, preferably 0.5 to 5% by mass. If it is less than 0.2% by mass, the film formed after drying is too thin, so that when the film is bent, the film tends to crack, and a surface that is not partially covered with polyester may remain. Therefore, the neointima is easily detached after transplantation for a long time. If it exceeds 10% by mass, the viscosity of the solution is too high regardless of the choice of the solvent system, and it is difficult to soak polyester into the deep part of the porous body.
0.5〜５質量％の濃度範囲であれば、ポリエステルの被覆層が厚すぎず、十分な強度があり、かつ多孔質体の深部までポリエステルで被覆される。また、処理前の延伸ポリテトラフルオロエチレン多孔体には、孔径の分布が存在するが、５質量％以下では５ミクロン程度の小さな孔もポリエステル樹脂で閉塞されずに開孔状態に保たれる。 When the concentration is in the range of 0.5 to 5% by mass, the polyester coating layer is not too thick, has sufficient strength, and is coated with the polyester up to the depth of the porous body. In addition, the expanded polytetrafluoroethylene porous body before treatment has a pore size distribution, but if it is 5% by mass or less, small pores of about 5 microns are not blocked by the polyester resin and are kept open.
基材となる延伸ポリテトラフルオロエチレンの管状体は既に半世紀にわたって工業生産・販売されており、基本的製造方法は既によく知られている。近年はこれらの汎用技術に様々な工夫を加えて管状体の内外面で孔径分布が異なるなどの特徴を有するものも多く提案されている（特許第２８１４４１５号公報等） The expanded polytetrafluoroethylene tubular body used as a base has already been industrially produced and sold for half a century, and the basic production method is already well known. In recent years, various devices have been proposed in addition to these general-purpose technologies, and many of them have characteristics such as different pore diameter distributions on the inner and outer surfaces of the tubular body (Japanese Patent No. 2814415).
本発明によれば、厚みが0.1〜２ｍｍの延伸ポリテトラフルオロエチレンの多孔質材料の数ミクロン〜２００ミクロン以上に及ぶ広範な孔径分布をもつ多孔質体の微細な繊維状組織の内孔表面を含む全表面を厚みの全体にわたり均一に被覆することができる。 According to the present invention, an inner surface of a fine fibrous structure of a porous body having a wide pore size distribution ranging from several microns to 200 microns or more of an expanded polytetrafluoroethylene porous material having a thickness of 0.1 to 2 mm. The entire surface can be uniformly coated over the entire thickness.
ポリエステル樹脂としては、添加剤を含まないものを使用することが重要である。ポリエステルを溶解した前記溶媒の溶液に延伸ポリテトラフルオロエチレンの多孔質材料（人工血管等）を浸漬すると、溶液は滲みこんでゆく。浸漬時間は溶液が多孔質材料の内部に十分に滲み込む時間の範囲で任意であるが、通常は数分間の静置で充分であるが、確実に被覆するにはさらに短時間減圧／加圧を繰り返して脱気することも有効である。 It is important to use a polyester resin that does not contain additives. When a stretched polytetrafluoroethylene porous material (artificial blood vessel or the like) is immersed in a solution of the solvent in which polyester is dissolved, the solution penetrates. The immersion time is arbitrary as long as the solution sufficiently penetrates into the porous material, but it is usually sufficient to let it stand for several minutes. It is also effective to deaerate repeatedly.
次に溶液に浸した多孔質材料をとり出し、付着した過剰な溶液を除去して、清浄な低湿度の雰囲気中で乾燥する。次にエタノールおよびアセトンなどの揮発性水溶性の溶剤によって十分洗浄した後乾燥するすることにより多孔質材料の表面および内孔表面をポリエステル樹脂またはポリエステルを主成分とする樹脂組成物の薄膜で被覆した本発明の生体軟組織代替移植材料が得られる。 Next, the porous material soaked in the solution is taken out, the excessive solution attached thereto is removed, and the porous material is dried in a clean low-humidity atmosphere. Next, after thoroughly washing with a volatile water-soluble solvent such as ethanol and acetone, and drying, the surface of the porous material and the inner pore surface were coated with a polyester resin or a thin film of a resin composition mainly composed of polyester. The living soft tissue replacement graft material of the present invention is obtained.
以下、実施例を挙げて本発明の生体軟組織代替移植材料を具体的に説明するが、本発明は下記の例のみに限定されるものではない。 The living soft tissue replacement graft material of the present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples.
実施例１：
厚さ0.3ｍｍ最大孔径５０ミクロンの延伸ポリテトラフルオロエチレンの多孔質管状体（商品名：フルオロテックス，Bridger Biomed社製）をエタノールに浸漬して洗浄後、清浄な雰囲気中で乾燥した。添加剤を含まない分子量３万のポリエチレンテレフタレートをヘキサフルオロイソプロパノール（試薬特級）に溶解して、１、３、および５質量％の溶液を調製した。それらの３種類の溶液にメチレンブルーを少量加えて溶解して着色した後、前記管状体を浸漬した。この容器ごと真空デシケータに入れて３０秒間減圧して脱泡して常圧に戻した。次に換気の良い、清浄な空気が流通する雰囲気中で、室温で２４時間乾燥した。さらに、真空乾燥してからエタノールおよびアセトンにそれぞれ４時間浸漬した。最後に、注射用水で洗浄してからクリンベンチ内で乾燥して、エチレンオキサイドガスによって滅菌した。前記３種類の管状体のそれぞれの一部を横断して長さ３ｍｍのリング状にした後、２０倍の解剖顕微鏡で内外表面と断面を観察した。１、３および５質量％のいずれで処理した試料も、全てメチレンブルーの青色で内外面および断面の全面が均一に着色されていることが目視で観察された。
前記１、３および５質量％の溶液を用いた３種類の処理条件で加工した管状体ではポリエステルの濃度が高い程、硬くなる傾向が顕著であった。
しかしながら、曲げたり、はさみで切断したり、外科用の縫合針による操作の上で何ら支障はなかった。
走査型電子顕微鏡観察の結果、内外表面および断面にはポリエステル樹脂の塊状の凝固物は何等観察されず、数ミクロンの孔も閉塞されずに連通孔の凝固物が存在せず、数ミクロンの孔も閉塞されずに、連通孔が保持されていることが確認された。
内径３ｍｍの滅菌済み管状体の長さ３ｃｍをとり、体重７〜８ｋｇの犬３頭の大腿動脈の一部を端々吻合によって、片側の大腿動脈には比較のために未処理のもので置換した。本品２例を３ヶ月後に摘出して内腔を観察したところ、吻合部狭塞は全く起こっていなかった。対照の未処理品は全て閉塞していた。
さらに、６ヶ月後に１例を摘出したが、吻合部に肉芽の過剰な形成は見られず、血管の内腔全体に薄い白色透明な組織がしっかりと結合していた。
Example 1:
A porous tubular body of expanded polytetrafluoroethylene having a thickness of 0.3 mm and a maximum pore diameter of 50 microns (trade name: Fluorotex, manufactured by Bridger Biomed) was immersed in ethanol, washed, and then dried in a clean atmosphere. Polyethylene terephthalate having a molecular weight of 30,000 and containing no additive was dissolved in hexafluoroisopropanol (special grade reagent) to prepare solutions of 1, 3 and 5% by mass. A small amount of methylene blue was added to these three kinds of solutions to dissolve and color them, and then the tubular body was immersed. The whole container was put in a vacuum desiccator, depressurized for 30 seconds, defoamed and returned to normal pressure. Next, it was dried at room temperature for 24 hours in a well-ventilated atmosphere in which clean air circulated. Further, after vacuum drying, each was immersed in ethanol and acetone for 4 hours. Finally, it was washed with water for injection, dried in a clean bench, and sterilized with ethylene oxide gas. After crossing a part of each of the three types of tubular bodies into a ring shape having a length of 3 mm, the inner and outer surfaces and the cross section were observed with a 20-fold dissecting microscope. It was visually observed that the samples treated with 1, 3, and 5% by mass were all methylene blue and the inner and outer surfaces and the entire cross section were uniformly colored.
In the tubular body processed under the three kinds of processing conditions using the 1, 3 and 5 mass% solutions, the higher the polyester concentration, the more prominent the tendency to become harder.
However, there was no problem in bending, cutting with scissors, or operation with a surgical suture needle.
As a result of observation with a scanning electron microscope, no solidified aggregates of polyester resin are observed on the inner and outer surfaces and cross-sections, the pores of several microns are not blocked, there are no solidified pores of communication holes, and pores of several microns It was confirmed that the communication hole was retained without being blocked.
A 3 mm long sterilized tubular body with an inner diameter of 3 mm was taken. A portion of the femoral artery of three dogs weighing 7-8 kg was replaced by anastomosis, and one femoral artery was replaced with an untreated one for comparison. . Two cases of this product were removed 3 months later and the lumen was observed, and no anastomotic stenosis occurred. All control untreated products were occluded.
Furthermore, one case was removed 6 months later, but no excessive formation of granulation was observed at the anastomosis, and a thin white transparent tissue was firmly bonded to the entire lumen of the blood vessel.
Claims (9)
The method for producing a living soft tissue replacement graft material according to claim 7, wherein the solvent is hexafluoroisopropanol or a mixed solvent containing hexafluoroisopropanol as a main component and containing another solvent for controlling the drying rate.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008072378A1 (en) * | 2006-12-13 | 2008-06-19 | Fujifilm Corporation | Method for coating the surface of synthetic polymer with biopolymer |
| CN117364291A (en) * | 2023-11-09 | 2024-01-09 | 江苏江南高纤股份有限公司 | Ultra-smooth composite short fiber and preparation method and application thereof |
| US11969334B2 (en) | 2018-09-05 | 2024-04-30 | Kake Educational Institution | Artificial blood vessel |
| CN117364291B (en) * | 2023-11-09 | 2024-06-07 | 江苏江南高纤股份有限公司 | Ultra-smooth composite short fiber and preparation method and application thereof |
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| JPH07163653A (en) * | 1993-12-14 | 1995-06-27 | Ube Ind Ltd | Artificial blood vessel |
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| JP2004089361A (en) * | 2002-08-30 | 2004-03-25 | Inst Of Physical & Chemical Res | Biological repair material having affinity with biological tissue adhesive |
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| JPS55152728A (en) * | 1979-05-16 | 1980-11-28 | Sumitomo Electric Ind Ltd | Porous polytetrafluoroethylene material having composite-structure and preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008072378A1 (en) * | 2006-12-13 | 2008-06-19 | Fujifilm Corporation | Method for coating the surface of synthetic polymer with biopolymer |
| US9585985B2 (en) | 2006-12-13 | 2017-03-07 | Fujifilm Corporation | Method for coating synthetic polymer surface with biopolymer |
| US11969334B2 (en) | 2018-09-05 | 2024-04-30 | Kake Educational Institution | Artificial blood vessel |
| CN117364291A (en) * | 2023-11-09 | 2024-01-09 | 江苏江南高纤股份有限公司 | Ultra-smooth composite short fiber and preparation method and application thereof |
| CN117364291B (en) * | 2023-11-09 | 2024-06-07 | 江苏江南高纤股份有限公司 | Ultra-smooth composite short fiber and preparation method and application thereof |
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