WO2004089433A1 - Anti-adhesive membrane and method for production thereof - Google Patents

Anti-adhesive membrane and method for production thereof Download PDF

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Publication number
WO2004089433A1
WO2004089433A1 PCT/JP2004/004947 JP2004004947W WO2004089433A1 WO 2004089433 A1 WO2004089433 A1 WO 2004089433A1 JP 2004004947 W JP2004004947 W JP 2004004947W WO 2004089433 A1 WO2004089433 A1 WO 2004089433A1
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Prior art keywords
fiber
adhesion
producing
fibrous
solution
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PCT/JP2004/004947
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French (fr)
Japanese (ja)
Inventor
Takanori Miyoshi
Shinya Komura
Hiroyoshi Minematsu
Yoshihiko Sumi
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Teijin Limited
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Priority to JP2005505287A priority Critical patent/JP4384116B2/en
Publication of WO2004089433A1 publication Critical patent/WO2004089433A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable

Definitions

  • the present invention relates to an adhesion preventing film and a method for producing the same. More particularly, the present invention relates to an anti-adhesion film having excellent handling properties and an extremely high cell adhesion suppressing effect, and a method for producing the same. Background art
  • a nonwoven fabric made of a biodegradable and absorbable polymer has been proposed as an adhesion-preventing film having good handleability.
  • an anti-adhesion film consisting of a film mainly composed of collagen has been proposed.
  • Patent Document 3 See, for example, Patent Document 3.
  • Aldehydes and isocyanates are used as a crosslinking agent for controlling the degradability of the anti-adhesion film.
  • the use of these is undesirable because the decomposition products have an adverse effect in vivo.
  • an anti-adhesion membrane composed of a biodegradable and absorbable polymer made of a lactic acid-glycolic acid copolymer and a lactate monoprolactone copolymer, which has no immunological problems, has been proposed (for example, Patent Reference 4). Further, an adhesion preventing film made of a nonwoven fabric of polylactic acid or a lactic acid-glycolic acid copolymer prepared by an electrospinning method has been proposed (for example, see Patent Document 5).
  • the nonwoven fabric produced by the electrospinning method has an advantage that the fiber diameter is extremely small, so that the nonwoven fabric has excellent flexibility and good handleability.
  • the anti-adhesion membranes that have been proposed up to now have an insufficient effect of preventing adhesion because cells and tissues easily adhere to and penetrate the membrane, and have an effect of inhibiting adhesion of cells and tissues. Therefore, an anti-adhesion film having a high adhesion is desired.
  • Patent Document 1 JP-A-10-99422
  • Patent Document 2 Japanese Patent Application Laid-Open No. 2003- "19194
  • Patent Document 3 JP-A-3-295561
  • Patent Document 4 Japanese Patent Application Laid-Open No. 60-14861
  • Patent Document 5 US2002Z0173213 Patent Disclosure of the Invention
  • the present invention is as follows. 1.
  • an adhesion preventing film comprising a fibrous structure of a biodegradable and absorbable polymer
  • the average diameter of the fibers forming the fibrous structure is 0.05 to 50 im
  • the fiber surface structure of the fibrous structure is An anti-adhesion film having a depression having a diameter of 0.01 to 1 m, wherein the depression occupies 10 to 95% of the fiber surface.
  • the fibrous structure is a non-woven fabric.
  • the adhesion preventing film according to 1 or 2 wherein the fibrous structure mainly comprises an aliphatic polyester.
  • a step of producing a solution in which the fiber-forming polymer is dissolved in a volatile solvent a step of spinning the solution by an electrostatic spinning method, and a step of obtaining a fiber structure accumulated on a collecting substrate.
  • a method for producing a fibrous structure comprising a fiber-forming polymer and producing an adhesion preventing film from the fibrous structure, wherein the average diameter of the fibers forming the fibrous structure is 0.05 to 50 m.
  • the fiber surface structure of the fibrous structure has a concave portion having a diameter of 0.01 to 1 ⁇ m, and the concave portion occupies 10 to 95% of the fiber surface.
  • a method for manufacturing a protective film a method for manufacturing a protective film.
  • the volatile solvent is at least one selected from the group consisting of methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, tetrahydrofuran, and 1,4-dioxane.
  • FIG. 1 shows an example of an apparatus used in an electrostatic spinning method of discharging a spinning solution into an electrostatic field in the production method of the present invention.
  • FIG. 2 shows a method of introducing fine droplets of a spinning solution into an electrostatic field in the production method of the present invention. It is an example of an apparatus used in the electrospinning method.
  • FIG. 3 shows the surface (2000 times) of the fibrous structure obtained in Example 1.
  • FIG. 4 shows the surface (20,000 times) of the fibrous structure obtained in Example 1.
  • FIG. 5 shows the results of evaluation of cell adhesion to the fibrous structure obtained in Example 1 ( ⁇ 1,000).
  • FIG. 6 shows the surface (8000 times) of the fiber structure obtained in Comparative Example 1.
  • FIG. 7 shows the surface (20,000 times) of the fiber structure obtained in Comparative Example 1.
  • FIG. 8 shows the results of evaluating cell adhesion to the fibrous structure obtained in Comparative Example 1 ( ⁇ 1,000).
  • the fibrous structure used in the present invention refers to a three-dimensional structure formed by laminating one or more fibers, weaving, knitting or other methods.
  • the form of the fiber structure preferably include, for example, a nonwoven fabric, a woven fabric, a knitted fabric, a tube, and a mesh.
  • a more preferred form is a nonwoven fabric.
  • the fiber surface structure of the fiber structure used in the present invention has a recess having a diameter of 0.01 to 1 m. If the diameter of the concave portion is out of the above range, the effect of suppressing tissue adhesion is small, which is not preferable. More preferred is 0.02-0. 5 ⁇ m.
  • the depression is on the fiber surface 1
  • the recessed portion occupies 10 to 95% of the fiber surface. If the proportion of the dents occupying the fiber surface is out of the above range, the effect of suppressing tissue adhesion is undesirably small.
  • the proportion of the recess occupying the fiber surface is preferably between 40 and 95. / o, more preferably 60 to 95%, even more preferably 60 to 80%.
  • the adhesion preventing film of the present invention is required to have the fibrous structure. That is, the adhesion preventing film of the present invention is combined with another member which may be formed only of the fibrous structure. May be combined.
  • the members to be combined include, for example, a tissue adhesive component for fixing the anti-adhesion film to the affected part of the operation, and a high-strength material for enhancing resistance to suturing.
  • the tissue adhesive component is combined, for example, the tissue adhesive component is fixed on one surface of the fibrous structure, and the surface on which the tissue adhesive component is fixed is stuck to the affected part of the operation to fix the adhesion preventing film.
  • a structure can be formed by preventing other tissue from adhering to the other surface.
  • the average fiber diameter of the fibers forming the fiber structure used in the present invention is preferably 0.05 to 50 im. If the average fiber diameter is smaller than 0.05 jUm, the strength of the fiber structure cannot be maintained, which is not preferable. On the other hand, if the average fiber diameter is larger than 50 m, the flexibility becomes poor, which is not preferable. A more preferred average fiber diameter is from 0.07 to 30 ⁇ m.
  • the fibrous structure used in the present invention is mainly composed of a biodegradable and absorbable polymer, since there is no fear that the fibrous structure remains on the biological tissue surface and delays the repair of the tissue.
  • Biodegradable and absorbable polymers include synthetic polymers such as polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, trimethylene carbonate, polybutylene succinate, and copolymers thereof, collagen, chitin, chitosan, and the like. Examples include natural polymers such as alginic acid, hyaluronic acid, starch II, and derivatives thereof. From the viewpoint of antigenicity and quality control, synthetic polymers are preferred.
  • aliphatic polyesters are more preferable from the viewpoint of mechanical properties and degradability in vivo, and polylactic acid is particularly preferable. It is more preferable that the weight average molecular weight of the polylactic acid is 100,000 or more from the viewpoint of mechanical strength and biodegradability.
  • biodegradable and absorbable polymers may be used alone or in combination.
  • the method for producing the fiber structure used in the present invention is not particularly limited as long as it is a method capable of obtaining the fiber having the above-mentioned surface structure, but the electrostatic spinning method is preferable.
  • the method of producing by the electrospinning method will be described in detail.
  • a solution in which a fiber-forming polymer is dissolved in a volatile solvent is discharged into an electrostatic field formed between the electrodes, and the solution is drawn toward the electrodes by spinning.
  • the fibrous structure can be obtained by accumulating the fibrous substance on the collecting substrate.
  • the fibrous material means not only a state in which the solvent of the solution has been completely distilled off to form a fibrous structure, but also a state in which the solvent of the solution is still contained.
  • the electrode used in the present invention may be any metal, inorganic substance, or organic substance as long as it shows conductivity. Further, a thin film of a metal, an inorganic substance, or an organic substance having conductivity may be provided over an insulator.
  • the electrostatic field in the present invention is formed between a pair or a plurality of electrodes, and a high voltage may be applied to any of the electrodes. This includes, for example, two high voltage electrodes with different voltage values (for example, 15 kV and 1 OkV) and a total of three electrodes connected to earth, or more than three electrodes. It includes the case of using.
  • the concentration of the fiber-forming polymer in the solution in the production method of the present invention is preferably 1 to 50% by weight. If the concentration of the fiber-forming polymer is less than 1% by weight, the concentration is too low and it is difficult to form a fiber structure, which is not preferable. On the other hand, if it is more than 50% by weight, the viscosity of the solution increases, so that it is necessary to apply a higher voltage between the electrodes, which is not preferable. A more preferred concentration of the fiber-forming polymer is 2 to 30% by weight.
  • the volatile solvent that forms a solution in the present invention is a substance that dissolves the aliphatic polyester, has a boiling point at normal pressure of 200 ° C or lower, and is liquid at normal temperature (for example, 27 ° C).
  • Specific volatile solvents include, for example, methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, acetone, methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, 1 , 1,1,3,3,3-hexafluoroisopropanol, 1,4-dioxane, carbon tetrachloride, cyclohexane, cyclohexanone, acetonidyl and the like.
  • methylene chloride chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, tetrahydrochloride, because fibers having the above surface structure can be easily formed. Mouth furan and 1,4-dioxane are preferred, and methylene chloride is particularly preferred.
  • volatile solvents may be used alone or a plurality of volatile solvents may be combined. Further, in the present invention, other nonvolatile solvents may be used in combination as long as the object is not impaired.
  • any method can be used to discharge the solution into an electrostatic field.
  • the solution is placed at an appropriate position in the electrostatic field, and the solution is drawn from the nozzle by an electric field to form fibers.
  • an appropriate device can be used.
  • an injection needle-shaped solution ejected by applying a voltage to the tip of the cylindrical solution holding tank 3 of the syringe by an appropriate means, for example, the high voltage generator 6. Install nozzle 1 and guide the solution to its tip.
  • the tip of the jet nozzle 1 is arranged at an appropriate distance from the grounded fibrous substance collecting electrode 5, and when the solution 2 exits the tip of the jet nozzle 1, the tip of the jet nozzle 1 and the fibrous substance collecting electrode 5 are separated. To form a fibrous substance.
  • the production rate of the fibrous substance can be increased by using several nozzles.
  • the distance between the electrodes depends on the charge amount, the nozzle size, the spinning solution flow rate, the spinning solution concentration, etc., but when it is about 10 kV, a distance of 5 to 20 cm was appropriate.
  • the applied electrostatic potential is generally 3 to 100 kV, preferably 5 to 50 kV, and more preferably 5 to 30 kV.
  • the desired potential may be created by any appropriate method.
  • the above description is for the case where the electrode also serves as the collecting substrate.However, by installing a potential collecting substrate between the electrodes, a collecting substrate is provided separately from the electrode, and the fiber structure is collected there. You can do this. In this case, for example, a belt-like substance is placed between the electrodes, and this is used as a collecting substrate. By doing so, continuous production is also possible.
  • the fiber having the above surface structure can be easily obtained, which is preferable. More preferable relative humidity is 25 to 95% or more.
  • the solvent evaporates according to the conditions to form a fibrous substance.
  • the solvent evaporates completely before being collected on the collecting substrate, but if the solvent evaporation is insufficient, the spinning may be performed under ⁇ J pressure conditions.
  • the spinning temperature depends on the evaporation behavior of the solvent and the viscosity of the spinning solution, but is usually 0 to 50 ° C.
  • the anti-adhesion film of the present invention can be used as long as its characteristics are not impaired, as long as it does not impair its characteristics. Combination of agents such as substances can promote tissue repair.
  • the fibrous structure is made of a biodegradable and absorbable polymer, the above-mentioned drug can be contained in the fiber to provide a sustained release function.
  • the obtained fiber structure was cut into a circular shape having a diameter of 24 mm, immersed in a 70% ethanol aqueous solution for sterilization, air-dried, and then set on a cell culture insert (BD Biosciences).
  • the film was seeded with mouse embryonic fibroblasts at 2 x 105 cells / ml / well without immersion in the medium, and 3 ml of the medium was placed in a well plate for 2 days at 5% C02 and 37 ° C in an incubator (H eraeus).
  • FIG. 5 shows a scanning electron micrograph after cell adhesion.
  • Fig. 8 shows a scanning electron micrograph after cell adhesion.
  • the present invention can provide an anti-adhesion film having an extremely high anti-adhesion effect, and a method for producing the same, by having a fiber structure made of fibers having a unique surface structure.

Abstract

An anti-adhesive membrane which is comprised of a fiber structure of a bio-degradable and -absorbable polymer, characterized in that a fiber forming said fiber structure has an average diameter of 0.05 to 50 μm, and the fiber surface structure of said fiber structure comprises concave portions having a diameter of 0.01 to 1 μm and accounting for 10 to 95 % of the fiber surface.

Description

明 細 書 癒着防止膜およびその製造方法 技術分野  Description Anti-adhesion film and method for producing the same
本発明は癒着防止膜、およびその製造方法に関する。更に詳しくは、取扱性が良ぐ 細胞接着抑制効果が極めて高い癒着防止膜、およびその製造方法に関する。 背景技術  The present invention relates to an adhesion preventing film and a method for producing the same. More particularly, the present invention relates to an anti-adhesion film having excellent handling properties and an extremely high cell adhesion suppressing effect, and a method for producing the same. Background art
心臓外科、整形外科、脳神経外科、腹部外科、産婦人科等の臨床分野において、 様々な外科手術後に、あるいは外傷によって、患部の生体組織が癒着することが、 重大な問題となっている。組織の癒着が発生すると、例えば、痛みや機能障害を引 き起こし、ひどい場合には前記癒着を剥離するための手術が別途必要になることも ある。また、癒着により、原疾患に対する再手術が困難になるという問題も生じてい る。そこで、従来、生体組織の癒着を防止するために、癒着が発生するおそれがあ る組織を覆い、保護する癒着防止膜が開発されており、実際に、再生酸化セルロー ス布ゃヒアルロン酸'カルボキシルメチルセルロース混合膜等が、癒着防止膜として 実用化されている。  In clinical fields such as cardiac surgery, orthopedic surgery, neurosurgery, abdominal surgery, obstetrics and gynecology, the adhesion of living tissue in affected areas after various surgical operations or due to trauma has become a serious problem. When tissue adhesion occurs, for example, it causes pain and dysfunction, and in severe cases, an additional operation to remove the adhesion may be required. Another problem is that adhesions make it difficult to perform reoperation for the underlying disease. Therefore, in order to prevent adhesion of living tissue, an adhesion prevention film has been developed to cover and protect a tissue where adhesions may occur. In practice, regenerated oxidized cellulose cloth / hyaluronic acid / carboxylate has been developed. Methylcellulose mixed films and the like have been put to practical use as adhesion preventing films.
例えば、酸化セルロースの多層フィルムを癒着防止膜として用いることが提案され ている(例えば、特許文献 1参照。)。また、ヒアルロン酸とカルボキシメチルセルロー スを凍結処理したゲル組成物を癒着防止膜として用いることが提案されている (例え ば、特許文献 2参照。)。  For example, it has been proposed to use a multilayer film of oxidized cellulose as an adhesion preventing film (for example, see Patent Document 1). Further, it has been proposed to use a gel composition obtained by freeze-treating hyaluronic acid and carboxymethyl cellulose as an anti-adhesion film (for example, see Patent Document 2).
しかしながら、これら癒着防止膜は水分を吸収することによって接着性が生じるた め、手術中外科医の手袋に付着するなど、取扱性に難がある。  However, these anti-adhesion films are difficult to handle, for example, they adhere to surgeon's gloves during surgery, because they absorb water and become adhesive.
取扱性が良い癒着防止膜として、生体内分解吸収性ポリマ一からなる不織布など が提案されている。例えば、コラーゲンを主とする膜よりなる癒着防止膜が提案され ている(例えば、特許文献 3参照。 )。しかし、このようなコラーゲンを用いると、コラー ゲンが天然由来の材料であるため、抗原性を有するテロぺプタイド部分の完全な除 去が困難であることとプリオン等混入の危険性を生じる。ます 癒着防止膜の分解 性を制御するための架橋剤としてアルデヒド類、イソシァネート類を使用しているが、 これらの使用は生体内に於いては分解生成物が悪影響を及ぼし好ましくない。 一方、コラーゲンに代えて、免疫学的に問題のない乳酸ーグリコール酸共重合体、 乳酸一力プロラクトン共重合体による生体内分解吸収性ポリマーからなる癒着防止 膜が提案されている (例えば、特許文献 4参照。)。また、静電紡糸法によって作成し たポリ乳酸や乳酸ーグリコール酸共重合体の不織布からなる癒着防止膜も提案さ れている (例えば、特許文献 5参照。)。 A nonwoven fabric made of a biodegradable and absorbable polymer has been proposed as an adhesion-preventing film having good handleability. For example, an anti-adhesion film consisting of a film mainly composed of collagen has been proposed. (See, for example, Patent Document 3). However, when such collagen is used, since collagen is a naturally-derived material, it is difficult to completely remove the antigenic telopeptide portion, and there is a risk of contamination with prions and the like. Aldehydes and isocyanates are used as a crosslinking agent for controlling the degradability of the anti-adhesion film. However, the use of these is undesirable because the decomposition products have an adverse effect in vivo. On the other hand, instead of collagen, an anti-adhesion membrane composed of a biodegradable and absorbable polymer made of a lactic acid-glycolic acid copolymer and a lactate monoprolactone copolymer, which has no immunological problems, has been proposed (for example, Patent Reference 4). Further, an adhesion preventing film made of a nonwoven fabric of polylactic acid or a lactic acid-glycolic acid copolymer prepared by an electrospinning method has been proposed (for example, see Patent Document 5).
特に、静電紡糸法によって作成した不織布は繊維径が極めて小さいため、柔軟性 に優れ、かつ取扱性が良いという利点を有している。  In particular, the nonwoven fabric produced by the electrospinning method has an advantage that the fiber diameter is extremely small, so that the nonwoven fabric has excellent flexibility and good handleability.
しかしながら、これまで提案されてきた癒着防止膜は、その膜に対して細胞や組織 が容易に接着、浸透するため癒着を防止する効果は不十分なままであり、細胞や組 織の接着抑制効果の高い癒着防止膜が望まれている。  However, the anti-adhesion membranes that have been proposed up to now have an insufficient effect of preventing adhesion because cells and tissues easily adhere to and penetrate the membrane, and have an effect of inhibiting adhesion of cells and tissues. Therefore, an anti-adhesion film having a high adhesion is desired.
(特許文献 1 ) 特開平 10— 99422号公報  (Patent Document 1) JP-A-10-99422
(特許文献 2) 特開 2003— " 19194号公報  (Patent Document 2) Japanese Patent Application Laid-Open No. 2003- "19194
(特許文献 3) 特開平 3— 295561号公報  (Patent Document 3) JP-A-3-295561
(特許文献 4) 特開昭 60— 14861号公報  (Patent Document 4) Japanese Patent Application Laid-Open No. 60-14861
(特許文献 5) US2002Z0173213号公報 発明の開示  (Patent Document 5) US2002Z0173213 Patent Disclosure of the Invention
本発明の課題は、高い癒着防止効果を有し、かつ取扱性に優れる癒着防止膜を 提供することにある。また同時に本発明の他の課題は、簡便な操作で、高い癒着防 止効果を有する癒着防止膜の製造方法を提供することにある。  An object of the present invention is to provide an adhesion preventing film having a high adhesion preventing effect and having excellent handleability. Another object of the present invention is to provide a method for producing an adhesion preventing film having a high adhesion preventing effect by a simple operation.
本発明は、以下のとおりである。 1 .生体内分解吸収性ポリマーの繊維構造体からなる癒着防止膜において、該繊維 構造体を形成する繊維の平均直径が 0. 05〜50 i mであ 、かつ該繊維檐造体の 繊維表面構造が、 0. 01〜1 mの直径を有する凹み部を有し、その凹み部が繊維 表面の 1 0〜95%を占有することを特徴とする癒着防止膜。 The present invention is as follows. 1. In an adhesion preventing film comprising a fibrous structure of a biodegradable and absorbable polymer, the average diameter of the fibers forming the fibrous structure is 0.05 to 50 im, and the fiber surface structure of the fibrous structure is An anti-adhesion film having a depression having a diameter of 0.01 to 1 m, wherein the depression occupies 10 to 95% of the fiber surface.
2.繊維構造体が不織布である、 1.記載の癒着防止膜。 2. The fibrous structure is a non-woven fabric.
3.繊維構造体が主として脂肪族ポリエステルよりなる、 1 .または 2.に記載の癒着 防止膜。  3. The adhesion preventing film according to 1 or 2, wherein the fibrous structure mainly comprises an aliphatic polyester.
4.繊維構造体が主としてポリ乳酸よりなる、 1 .または 2.に記載の癒着防止膜。 4. The adhesion preventing film according to 1. or 2., wherein the fibrous structure mainly comprises polylactic acid.
5.繊維形成性ポリマーを揮発性溶媒に溶解した溶液を製造する段階と、前記溶液 を静電紡糸法にて紡糸する段階、および捕集基板に累積される繊維構造体を得る 段階を経て、繊維形成性ポリマーよりなる繊維構造体を製造し、該繊維構造体から 癒着防止膜を製造する方法であって、該繊維構造体を形成する繊維の平均直径が 0. 05〜50〃 mであり、かつ該繊維構造体の繊維表面構造が、 0. 01〜1 ^ mの 直径を有する凹み部を有し、その凹み部が繊維表面の 1 0〜95%を占有する繊維 構造体からなる癒着防止膜の製造方法。 5. a step of producing a solution in which the fiber-forming polymer is dissolved in a volatile solvent, a step of spinning the solution by an electrostatic spinning method, and a step of obtaining a fiber structure accumulated on a collecting substrate. A method for producing a fibrous structure comprising a fiber-forming polymer and producing an adhesion preventing film from the fibrous structure, wherein the average diameter of the fibers forming the fibrous structure is 0.05 to 50 m. And the fiber surface structure of the fibrous structure has a concave portion having a diameter of 0.01 to 1 ^ m, and the concave portion occupies 10 to 95% of the fiber surface. A method for manufacturing a protective film.
6.揮発性溶媒が、塩化メチレン、クロ口ホルム、ジクロロエタン、テトラクロロェタン、 トリクロロェタン、ジブロモメタン、ブロモホルム、テトラヒドロフラン、 1 , 4—ジォキサ ンよりなる群から少なくとも 1種選ばれる、 5.に記載の癒着防止膜の製造方法。 6. The volatile solvent is at least one selected from the group consisting of methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, tetrahydrofuran, and 1,4-dioxane. 3. The method for producing an adhesion preventing film according to item 1.
7.静電紡糸法で紡糸する段階において、繊維状物質が形成されるノズルと捕集基 板の間の相対湿度を 20%以上とする 5.または 6.に記載の癒着防止膜の製造方 法。 図面の簡単な説明 7. The method for producing an anti-adhesion film according to 5. or 6., wherein the relative humidity between the nozzle on which the fibrous substance is formed and the collecting substrate is 20% or more in the step of spinning by the electrostatic spinning method. BRIEF DESCRIPTION OF THE FIGURES
図 1は、本発明の製造方法のなかで、紡糸液を静電場中に吐出する静電紡糸法で 用いる装置の一例である。  FIG. 1 shows an example of an apparatus used in an electrostatic spinning method of discharging a spinning solution into an electrostatic field in the production method of the present invention.
図 2は、本発明の製造方法のなかで、紡糸液の微細滴を静電場中に導入する静 電紡糸法で用いる装置の一例である。 FIG. 2 shows a method of introducing fine droplets of a spinning solution into an electrostatic field in the production method of the present invention. It is an example of an apparatus used in the electrospinning method.
図 3は、実施例 1で得られた繊維構造体の表面(2000倍)。  FIG. 3 shows the surface (2000 times) of the fibrous structure obtained in Example 1.
図 4は 実施例 1で得られた繊維構造体の表面(20000倍)。  FIG. 4 shows the surface (20,000 times) of the fibrous structure obtained in Example 1.
図 5は、実施例 1で得られた繊維構造体への細胞接着性評価結果(1 000倍)。 図 6は、比較例 1で得られた繊維構造体の表面(8000倍)。  FIG. 5 shows the results of evaluation of cell adhesion to the fibrous structure obtained in Example 1 (× 1,000). FIG. 6 shows the surface (8000 times) of the fiber structure obtained in Comparative Example 1.
図 7は、比較例 1で得られた繊維構造体の表面(20000倍)。  FIG. 7 shows the surface (20,000 times) of the fiber structure obtained in Comparative Example 1.
図 8は、比較例 1で得られた繊維構造体への細胞接着性評価結果(1 000倍)。 発明を実施するための最良の形態  FIG. 8 shows the results of evaluating cell adhesion to the fibrous structure obtained in Comparative Example 1 (× 1,000). BEST MODE FOR CARRYING OUT THE INVENTION
以下、本発明について詳述する。本発明に用いる繊維構造体とは、単数または複 数の繊維が積層され、織り、編まれ若しくはその他の手法により形成された 3次元の 構造体を指す。単繊維であるフィラメントおよびフィラメントを複数集めたヤーンで形 成された 3次元の構造体もまた包含されるものとする。  Hereinafter, the present invention will be described in detail. The fibrous structure used in the present invention refers to a three-dimensional structure formed by laminating one or more fibers, weaving, knitting or other methods. A three-dimensional structure formed by filaments, which are monofilaments, and yarns having a plurality of filaments, is also included.
具体的な繊維構造体の形態としては、例えば不織布、織布、編布、チューブ、メッ シュ、などが好ましく挙げられる。より好ましい形態は、不織布である。  Specific examples of the form of the fiber structure preferably include, for example, a nonwoven fabric, a woven fabric, a knitted fabric, a tube, and a mesh. A more preferred form is a nonwoven fabric.
本発明に用いる繊維構造体の繊維表面構造は、 0. 01〜1 mの直径を有する 凹み部を有する。凹み部の直径が上記範囲外では組織の接着抑制効果が小さく、 好ましくない。より好まし ま、 0. 02-0. 5〃 mである。その凹み部が繊維表面の 1 The fiber surface structure of the fiber structure used in the present invention has a recess having a diameter of 0.01 to 1 m. If the diameter of the concave portion is out of the above range, the effect of suppressing tissue adhesion is small, which is not preferable. More preferred is 0.02-0. 5〃 m. The depression is on the fiber surface 1
〜95%を占有する。 Occupies ~ 95%.
本発明に用いる繊維構造体の繊維表面構造は、該凹み部が繊維表面の 1 0〜9 5%を占有することが望ましい。凹み部が繊維表面を占有する割合が上記範囲外で は組織の接着抑制効果が小さぐ好ましくない。凹み部が繊維表面を占有する割合 は好ましくは 40〜95。/oであり、より好ましくは 60〜95%、さらに好ましくは 60〜8 0%である。  In the fiber surface structure of the fiber structure used in the present invention, it is desirable that the recessed portion occupies 10 to 95% of the fiber surface. If the proportion of the dents occupying the fiber surface is out of the above range, the effect of suppressing tissue adhesion is undesirably small. The proportion of the recess occupying the fiber surface is preferably between 40 and 95. / o, more preferably 60 to 95%, even more preferably 60 to 80%.
本発明の癒着防止膜は、該繊維構造体を有することを必須とする。すなわち、本 発明の癒着防止膜は該繊維構造体のみで形成されていても良ぐ他の部材と組み 合わせても良い。組み合わせる部材としては、例えば癒着防止膜を手術した患部に 固定するための組織接着性成分や、縫合に対する耐性を強化するための辅強材な どが挙げられる。組織接着性成分を組み合わせる場合は、例えば該繊維構造体の 一方の面に組織接着性成分を固定し、該組織接着性成分を固定した面を手術した 患部に貼ることで癒着防止膜を固定し、他方の面へ他の組織が癒着することを防止 するといつた構造を形成出来る。 The adhesion preventing film of the present invention is required to have the fibrous structure. That is, the adhesion preventing film of the present invention is combined with another member which may be formed only of the fibrous structure. May be combined. The members to be combined include, for example, a tissue adhesive component for fixing the anti-adhesion film to the affected part of the operation, and a high-strength material for enhancing resistance to suturing. When the tissue adhesive component is combined, for example, the tissue adhesive component is fixed on one surface of the fibrous structure, and the surface on which the tissue adhesive component is fixed is stuck to the affected part of the operation to fix the adhesion preventing film. In other words, a structure can be formed by preventing other tissue from adhering to the other surface.
本発明に用いる繊維構造体を形成する繊維の平均繊維径は 0. 05〜50 i mであ ることが好ましい。平均繊維径が 0. 05 jU mより小さいと、該繊維構造体の強度が 保てないため好ましくない。また、平均繊維径が 50 mより大きいと柔軟性が乏しく なり好ましくなし、。より好ましい平均繊維径は 0. 07〜30 ^ mである。  The average fiber diameter of the fibers forming the fiber structure used in the present invention is preferably 0.05 to 50 im. If the average fiber diameter is smaller than 0.05 jUm, the strength of the fiber structure cannot be maintained, which is not preferable. On the other hand, if the average fiber diameter is larger than 50 m, the flexibility becomes poor, which is not preferable. A more preferred average fiber diameter is from 0.07 to 30 ^ m.
本発明に用いる繊維構造体が主として生体内分解吸収性ポリマ一よりなると、生 体組織面に残存し組織の修復を遅らせる恐れがなく、好ましい。生体内分解吸収性 ポリマーとしては、ポリ乳酸、ポリグリコール酸、ポリジォキサノン、ポリ力プロラクトン、 卜リメチレンカーボネート、ポリブチレンサクシネート、あるいはこれらの共重合体など の合成ポリマーやコラーゲン、キチン、キトサン、アルギン酸、ヒアルロン酸、デンプ ンゃ、これらの誘導体など天然ポリマーが挙げられるが、抗原性や品質制御の観点 から、合成ポリマーが好ましい。このうち、脂肪族ポリエステルが力学物性と生体内 での分解性からより好ましく、特にポリ乳酸が好ましい。ポリ乳酸の重量平均分子量 が 1 0万以上であると更に力学強度や生体内分解性の観点からより好ましい。  It is preferable that the fibrous structure used in the present invention is mainly composed of a biodegradable and absorbable polymer, since there is no fear that the fibrous structure remains on the biological tissue surface and delays the repair of the tissue. Biodegradable and absorbable polymers include synthetic polymers such as polylactic acid, polyglycolic acid, polydioxanone, polycaprolactone, trimethylene carbonate, polybutylene succinate, and copolymers thereof, collagen, chitin, chitosan, and the like. Examples include natural polymers such as alginic acid, hyaluronic acid, starch II, and derivatives thereof. From the viewpoint of antigenicity and quality control, synthetic polymers are preferred. Of these, aliphatic polyesters are more preferable from the viewpoint of mechanical properties and degradability in vivo, and polylactic acid is particularly preferable. It is more preferable that the weight average molecular weight of the polylactic acid is 100,000 or more from the viewpoint of mechanical strength and biodegradability.
これらの生体内分解吸収性ポリマーは単独で用いても良ぐまた複数種を用いても 良い。  These biodegradable and absorbable polymers may be used alone or in combination.
本発明に用いる繊維構造体を製造する方法としては、先述の表面構造を有する繊 維等が得られる手法であれば特に限定されないが、静電紡糸法が好ましい。以下静 電紡糸法により製造する方法について詳細に説明する。  The method for producing the fiber structure used in the present invention is not particularly limited as long as it is a method capable of obtaining the fiber having the above-mentioned surface structure, but the electrostatic spinning method is preferable. Hereinafter, the method of producing by the electrospinning method will be described in detail.
本発明で用いる静電紡糸法では繊維形成性ポリマーを揮発性溶媒に溶解した溶 液を電極間で形成された静電場中に吐出し、溶液を電極に向けて曳糸し、形成され る繊維状物質を捕集基板に累積することによって繊維構造体を得ることができる。 繊維状 ¾質とは既に溶液の溶媒が完全に留去されて繊維構造体となっている状態 のみならず、いまだ溶液の溶媒を含んでいる状態も示している。 In the electrospinning method used in the present invention, a solution in which a fiber-forming polymer is dissolved in a volatile solvent is discharged into an electrostatic field formed between the electrodes, and the solution is drawn toward the electrodes by spinning. The fibrous structure can be obtained by accumulating the fibrous substance on the collecting substrate. The fibrous material means not only a state in which the solvent of the solution has been completely distilled off to form a fibrous structure, but also a state in which the solvent of the solution is still contained.
まず静電紡糸法で用いる装置について説明する。本発明で用いられる電極は、金 属、無機物、または有機物のいかなるものでも導電性を示しさえすれば良い。また、 絶縁物上に導電性を示す金属、無機物、または有機物の薄膜を持つものであっても 良い。本発明における静電場は一対又は複数の電極間で形成されており、いずれ の電極に高電圧を印加しても良し、。これは例えば電圧値が異なる高電圧の電極が 2 つ(例えば 1 5kVと 1 OkV)と、アースにつながった電極の合計 3つの電極を用いる場 合も含み、または 3本を越える数の電極を使う場合も含むものとする。  First, an apparatus used in the electrostatic spinning method will be described. The electrode used in the present invention may be any metal, inorganic substance, or organic substance as long as it shows conductivity. Further, a thin film of a metal, an inorganic substance, or an organic substance having conductivity may be provided over an insulator. The electrostatic field in the present invention is formed between a pair or a plurality of electrodes, and a high voltage may be applied to any of the electrodes. This includes, for example, two high voltage electrodes with different voltage values (for example, 15 kV and 1 OkV) and a total of three electrodes connected to earth, or more than three electrodes. It includes the case of using.
次に静電紡糸法による本発明の製造手法について詳細に説明する。まず繊維形 成性ポリマーを揮発性溶媒に溶解した溶液を製造する段階がある。本発明の製造 方法における溶液中の繊維形成性ポリマーの濃度は 1 ~50重量%であることが好 ましい。繊維形成性ポリマーの濃度が 1重量%より小さいと、濃度が低すぎるため繊 維構造体を形成することが困難となり好ましくない。また、 50重量%より大きいと溶 液の粘度力《増大するために、電極間により高電圧をかける必要が生じるため好まし くなし、。より好ましい繊維形成性ポリマーの濃度は 2〜30重量%である。  Next, the production method of the present invention by the electrospinning method will be described in detail. First, there is a step of producing a solution in which the fiber-forming polymer is dissolved in a volatile solvent. The concentration of the fiber-forming polymer in the solution in the production method of the present invention is preferably 1 to 50% by weight. If the concentration of the fiber-forming polymer is less than 1% by weight, the concentration is too low and it is difficult to form a fiber structure, which is not preferable. On the other hand, if it is more than 50% by weight, the viscosity of the solution increases, so that it is necessary to apply a higher voltage between the electrodes, which is not preferable. A more preferred concentration of the fiber-forming polymer is 2 to 30% by weight.
本発明で溶液を形成する揮発性溶媒は、脂肪族ポリエステルを溶解し、常圧での 沸点が 200°C以下であり、常温 (例えば 27°C)で液体である物質である。具体的な 揮発性溶媒としては、例えば塩化メチレン、クロ口ホルム、ジクロロェタン、テトラクロ ロェタン、卜リクロロエタン、ジブロモメタン、ブロモホルム、アセトン、メタノール、エタ ノール、プロパノール、イソプロパノール、トルエン、亍トラヒドロフラン、 1 , 1 , 1 , 3, 3, 3—へキサフルォロイソプロパノール、 1 , 4·一ジォキサン、四塩化炭素、シクロへキ サン、シクロへキサノン、ァセトニドリルなどが挙げられる。これらのうち、上記表面構 造を有する繊維を容易に形成できることから、塩化メチレン、クロ口ホルム、ジクロロ ェタン、テトラクロロェタン、トリクロロェタン、ジブロモメタン、ブロモホルム、テトラヒド 口フラン、 1, 4一ジォキサンが好ましく、特に塩化メチレンが好ましい。 The volatile solvent that forms a solution in the present invention is a substance that dissolves the aliphatic polyester, has a boiling point at normal pressure of 200 ° C or lower, and is liquid at normal temperature (for example, 27 ° C). Specific volatile solvents include, for example, methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, acetone, methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, 1 , 1,1,3,3,3-hexafluoroisopropanol, 1,4-dioxane, carbon tetrachloride, cyclohexane, cyclohexanone, acetonidyl and the like. Of these, methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, tetrahydrochloride, because fibers having the above surface structure can be easily formed. Mouth furan and 1,4-dioxane are preferred, and methylene chloride is particularly preferred.
これらの揮発性溶媒は単独で用いても良く、複数の揮発性溶媒を組み合わせても 良い。また、本発明においては 本目的を損なわない範囲で、他の不揮発性溶媒を 併用しても良い。  These volatile solvents may be used alone or a plurality of volatile solvents may be combined. Further, in the present invention, other nonvolatile solvents may be used in combination as long as the object is not impaired.
次に前記溶液を静電紡糸法にて紡糸する段階について説明する。該溶液を静電 場中に吐出するには、任意の方法を用いることが出来る。例えば、一例として図 1を 用いて以下説明する。溶液 2をノズルに供給することによって、溶液を静電場中の適 切な位置に置き、そのノズルから溶液を電界によって曳糸して繊維化させる。このた めには適宜な装置を用いることができ、例えば注射器の筒状の溶液保持槽 3の先端 部に適宜の手段、例えば高電圧発生器 6にて電圧をかけた注射針状の溶液噴出ノ ズル 1を設置して、溶液をその先端まで導く。接地した繊維状物質捕集電極 5から適 切な距離に該噴出ノズル 1の先端を配置し、溶液 2が該噴出ノズル 1の先端を出ると きにこの先端と繊維状物質捕集電極 5の間にて繊維状物質を形成させる。  Next, the step of spinning the solution by the electrostatic spinning method will be described. Any method can be used to discharge the solution into an electrostatic field. For example, an example will be described below with reference to FIG. By supplying the solution 2 to the nozzle, the solution is placed at an appropriate position in the electrostatic field, and the solution is drawn from the nozzle by an electric field to form fibers. For this purpose, an appropriate device can be used.For example, an injection needle-shaped solution ejected by applying a voltage to the tip of the cylindrical solution holding tank 3 of the syringe by an appropriate means, for example, the high voltage generator 6. Install nozzle 1 and guide the solution to its tip. The tip of the jet nozzle 1 is arranged at an appropriate distance from the grounded fibrous substance collecting electrode 5, and when the solution 2 exits the tip of the jet nozzle 1, the tip of the jet nozzle 1 and the fibrous substance collecting electrode 5 are separated. To form a fibrous substance.
また当業者には自明の方法で該溶液の微細滴を静電場中に導入することもできる。 一例として図 2を用いて以下に説明する。その際の唯一の要件は液滴を静電場中に 置いて、繊維化が起こりうるような距離に繊維状物質捕集電極 5から離して保持する ことである。例えば、ノズル 1を有する溶液保持槽 3中の溶液 2に直接、直接繊維状 物質捕集電極に対抗する電極 4を揷入しても良い。  It is also possible to introduce fine droplets of the solution into an electrostatic field in a manner obvious to a person skilled in the art. This will be described below with reference to FIG. 2 as an example. The only requirement at that time is to place the droplet in an electrostatic field and keep it away from the fibrous substance collecting electrode 5 at a distance where fibrillation can occur. For example, the electrode 4 that opposes the fibrous substance collecting electrode may be directly inserted into the solution 2 in the solution holding tank 3 having the nozzle 1.
該溶液をノズルから静電場中に供給する場合、数個のノズルを用いて繊維状物質 の生産速度を上げることもできる。電極間の距離は、帯電量、ノズル寸法、紡糸液流 量、紡糸液濃度等に依存するが、 1 0kV程度のときには 5~20cmの距離が適当で あった。また、印加される静電気電位は、一般に 3〜1 00kV、好ましくは 5〜50kV、 一層好ましくは 5〜30kVである。所望の電位は任意の適切な方法で作れば良い。 上記説明は、電極が捕集基板を兼ねる場合であるが、電極間に捕集基板となりう る物を設置することで、電極と別に捕集基板を設け、そこに繊維構造体を捕集するこ とが出来る。この場合、例えばベルト状物質を電極間に設置して、これを捕集基板と することで、連続的な生産も可能となる。 When the solution is supplied from a nozzle into an electrostatic field, the production rate of the fibrous substance can be increased by using several nozzles. The distance between the electrodes depends on the charge amount, the nozzle size, the spinning solution flow rate, the spinning solution concentration, etc., but when it is about 10 kV, a distance of 5 to 20 cm was appropriate. The applied electrostatic potential is generally 3 to 100 kV, preferably 5 to 50 kV, and more preferably 5 to 30 kV. The desired potential may be created by any appropriate method. The above description is for the case where the electrode also serves as the collecting substrate.However, by installing a potential collecting substrate between the electrodes, a collecting substrate is provided separately from the electrode, and the fiber structure is collected there. You can do this. In this case, for example, a belt-like substance is placed between the electrodes, and this is used as a collecting substrate. By doing so, continuous production is also possible.
本発明において、ノズルと捕集基板の間の相対湿度を 20%以上に維持すると、上 記表面構造を有する繊維を簡便に得ることができ、好ましい。より好ましい相対湿度 は 25 ~ 95%以上である。  In the present invention, when the relative humidity between the nozzle and the collecting substrate is maintained at 20% or more, the fiber having the above surface structure can be easily obtained, which is preferable. More preferable relative humidity is 25 to 95% or more.
最後に捕集基板に累積される繊維積層体を得る段階について説明する。本発明 においては、該溶液を捕集基板に向けて曳糸する間に、条件に応じて溶媒が蒸発し て繊維状物質が形成される。通常の室温であれば捕集基板上に捕集されるまでの 間に溶媒は完全に蒸発するが、もし溶媒蒸発が不十分な場合は^ J圧条件下で曳糸 しても良い。また、曳糸する温度は溶媒の蒸発挙動や紡糸液の粘度に依存するが、 通常は、 0〜50°Cである。  Finally, the step of obtaining the fiber laminate accumulated on the collecting substrate will be described. In the present invention, during the spinning of the solution toward the collecting substrate, the solvent evaporates according to the conditions to form a fibrous substance. At normal room temperature, the solvent evaporates completely before being collected on the collecting substrate, but if the solvent evaporation is insufficient, the spinning may be performed under ^ J pressure conditions. The spinning temperature depends on the evaporation behavior of the solvent and the viscosity of the spinning solution, but is usually 0 to 50 ° C.
本発明の癒着防止膜は、その特徴を損なわない範囲であれば、抗腫瘍剤、抗癌剤、 抗炎症剤あるいは活性型ビタミン D等のビタミン類、甲状腺刺激ホルモン等のポリべ プタイドのような生理活性物質等の薬剤を組み合わせ、組織修復 促進さ ることも できる。また、該繊維構造体が生体内分解吸収性ポリマーよりなるときは、その繊維 中に上記薬剤を含有させることで、徐放化機能をもたせることも出来る。  The anti-adhesion film of the present invention can be used as long as its characteristics are not impaired, as long as it does not impair its characteristics. Combination of agents such as substances can promote tissue repair. When the fibrous structure is made of a biodegradable and absorbable polymer, the above-mentioned drug can be contained in the fiber to provide a sustained release function.
以下に、図 1〜2に用いられている符号の簡単な説明を記載する。  The following is a brief description of the reference numerals used in FIGS.
1 . ノズル  1. Nozzle
2. 紡糸液  2. Spinning solution
3. 紡糸液保持槽  3. Spinning solution holding tank
4. 電極 4. Electrode
5. 繊維状物質捕集電極  5. Fibrous substance collecting electrode
6. 高電圧発生器  6. High voltage generator
【実施例】  【Example】
以下本発明を実施例により説明するが、本発明は、これらの実施例に限定される ものではない。また以下の各実施例、比較例における評価項目は以下のとおりの手 法にて実施した。 [繊維表面構造の凹み部] Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples. The evaluation items in each of the following Examples and Comparative Examples were implemented by the following methods. [Dent of fiber surface structure]
得られた繊維構造体の表面の走査型電子顕微鏡写真(倍率 20000倍)を撮影し、 その写真から π = 20にて、凹み部の直径を測定した平均値を算出した。  A scanning electron micrograph (magnification: 20000 times) of the surface of the obtained fiber structure was taken, and from π = 20, the average value of the diameter of the recess was measured at π = 20.
また、 η = 5にて、繊維表面に対する凹み部の占有割合を測定した平均値を算出し た。  Further, at η = 5, the average value of the occupation ratio of the concave portion to the fiber surface was calculated.
[平均繊維径]  [Average fiber diameter]
得られた繊維構造体の表面の走査型電子顕微鏡写真 (倍率 2000倍および 800 0倍)を撮影し、その写真から η = 20にて繊維径を測定した平均値を算出した。  Scanning electron micrographs (2000 × and 8000 ×) of the surface of the obtained fiber structure were taken, and the average value of the fiber diameter measured at η = 20 was calculated from the photographs.
[細胞接着性 価]  [Cell adhesion value]
得られた繊維構造体を直径 24mmの円形に切り出し、滅菌のために 70%ェタノ —ル水溶液に浸漬し風乾させた後、セルカルチャーインサート(BD Biosciences) にセットした。フイルムは培地に浸すことなく 2x1 05Cells/ml/wellでマウス胎児 線維芽細胞を播種し、 wellプレート内に 3mlの培地を入れて 2日間、 5%C02、 3 7 °Cの条件でインキュベーター( H eraeus )内で培養を行った。  The obtained fiber structure was cut into a circular shape having a diameter of 24 mm, immersed in a 70% ethanol aqueous solution for sterilization, air-dried, and then set on a cell culture insert (BD Biosciences). The film was seeded with mouse embryonic fibroblasts at 2 x 105 cells / ml / well without immersion in the medium, and 3 ml of the medium was placed in a well plate for 2 days at 5% C02 and 37 ° C in an incubator (H eraeus).
培養後培地を取り除き、 2. 5%グルタルアルデヒド Zリン酸緩衝液(0. 2Mリン酸 1ナトリウム 1 9ml、0. 2Mリン酸 2ナトリウム 8 Ί mしィ才ン交換水 Ί 00ml) = 1 9(体積比)を 1 ml加え、 4°Cで 2時間放置した。 2時間後リン酸緩衝液で洗浄した 後、 50、 70、 90、 95、 99. 5%エタノールの順で月兑水を行った。  After cultivation, remove the medium and add 2.5% glutaraldehyde Z phosphate buffer (0.2 M monosodium phosphate 19 ml, 0.2 M disodium phosphate 8 μm exchange water 00 ml) = 1 9 (Volume ratio) (1 ml) was added and left at 4 ° C for 2 hours. Two hours later, after washing with a phosphate buffer, monthly water was applied in the order of 50, 70, 90, 95, and 99.5% ethanol.
走査型電子顕微鏡写真を撮影した。(倍率 : 1 ,000倍)繊維構造体面積に占める、 細胞および細胞外マドリクスの付着面積の割合を、 n = 3にて測定した平均値を算出 した。  Scanning electron micrographs were taken. (Magnification: 1,000 times) The ratio of the area of attachment of cells and extracellular madrids to the area of the fibrous structure was calculated as an average value measured at n = 3.
[実施例 1 ]  [Example 1]
ポリ乳酸(島津製作所:商品名「し acty 9031」、重量平均分子量 1 68, 000) 1重 量部を塩化メチレン (和光純薬工業、特級) 9重量部に室温 (22°C)にて溶解し、溶 液を作成した。図 2にしめす装置を用いて、該溶液を繊維状物質捕集電極 5に 5分 間吐出した。噴出ノズル 1の内径は 0. 8mm.電圧は 1 2kV、噴出ノズル 1から繊維 状物質捕集電極 5までの距離は 1 2cm,相対湿度 35%であった。得られた繊維構 造体を走査型電子顕微鏡(日立製作所 S— 2400)で測定したところ、平均繊維径は 3 H mであり、繊維表面の凹み部の平均直径は 0. 1 5 i m 凹み部の面積が繊維 表面に占める割合は 68%であった。繊維構造体の走査型電子顕微鏡写真を図 3, 4に示す。 1 part by weight of polylactic acid (Shimadzu Corp .: trade name “Shi acty 9031”, weight average molecular weight: 168,000) dissolved in 9 parts by weight of methylene chloride (Wako Pure Chemical Industries, special grade) at room temperature (22 ° C) Then, a solution was prepared. The solution was discharged to the fibrous substance collecting electrode 5 for 5 minutes using the apparatus shown in FIG. The inner diameter of the ejection nozzle 1 is 0.8 mm, the voltage is 12 kV, and the fiber The distance to the particulate matter collecting electrode 5 was 12 cm and the relative humidity was 35%. When the obtained fiber structure was measured with a scanning electron microscope (Hitachi S-2400), the average fiber diameter was 3 Hm, and the average diameter of the concave portion on the fiber surface was 0.15 im concave portion. The area occupied by the surface of the fiber was 68%. Scanning electron micrographs of the fiber structure are shown in FIGS.
該繊維構造体の細胞接着性評価結果は約 1 0%であり、細胞接着が抑制されてい ることが分かった。細胞接着後の走査型電子顕微鏡写真を図 5に示す。  The result of evaluating the cell adhesion of the fibrous structure was about 10%, indicating that the cell adhesion was suppressed. FIG. 5 shows a scanning electron micrograph after cell adhesion.
[比較例 1 ]  [Comparative Example 1]
ポリ乳酸 (島津製作所:商品名「LaCty 9031」、重量平均分子量 1 68, 000) 1重 量部を塩化メチレン (和光純薬工業、特級) 4. 5重量部、 N, N—ジメチルホルムアミ ド 4. 5重量部 (和光純薬工業、特級)に室温 (22°C)にて溶解し、溶液を作成した。 図 2にしめす装置を用いて、該溶液を繊維状物質捕集電極 5に 5分間吐出した。噴 出ノズル 1の内径は 0. 8mm、電圧は 1 2kV、噴出ノズル 1から繊維状物質捕集電 極 5までの距離は 1 0cm,相対湿度 32%であった。得られた繊維構造体を走査型 電子顕微鏡(日立製作所 S— 2400)で測定したところ、平均繊維径は 0. 5〃mであ リ、繊維表面には凹み部が観察されなかった。繊維構造体の走査型電子顕微鏡写 真を図 6, 7に示す。 Polylactic acid (Shimadzu: trade name "La C ty 9031", weight average molecular weight of 68, 000) 1 by weight part of methylene chloride (Wako Pure Chemical Industries, special grade) 4.5 parts by weight, N, N-dimethylformamide The amide was dissolved in 4.5 parts by weight (Wako Pure Chemical Industries, special grade) at room temperature (22 ° C) to prepare a solution. The solution was discharged to the fibrous substance collecting electrode 5 for 5 minutes using the apparatus shown in FIG. The inside diameter of the ejection nozzle 1 was 0.8 mm, the voltage was 12 kV, the distance from the ejection nozzle 1 to the fibrous material collecting electrode 5 was 10 cm, and the relative humidity was 32%. When the obtained fiber structure was measured with a scanning electron microscope (S-2400, Hitachi, Ltd.), the average fiber diameter was 0.5 μm, and no dents were observed on the fiber surface. Figures 6 and 7 show scanning electron micrographs of the fiber structure.
該繊維構造体の細胞接着性評価結果は約 70%であり、細胞および細胞外マトリ クスが繊維構造体をほぼ多い尽くしていることが分かった。細胞接着後の走查型電 子顕微鏡写真を図 8に示す。 産業上の利用可能性  The result of evaluating the cell adhesion of the fiber structure was about 70%, and it was found that the cell and extracellular matrix almost completely consumed the fiber structure. Fig. 8 shows a scanning electron micrograph after cell adhesion. Industrial applicability
本発明は特異な表面構造を有する繊維からなる繊維構造体を有することで、極め て高い癒着防止効果を有する癒着防止膜、およびその製造方法を提供できる。  The present invention can provide an anti-adhesion film having an extremely high anti-adhesion effect, and a method for producing the same, by having a fiber structure made of fibers having a unique surface structure.

Claims

請 求 の 範 囲 The scope of the claims
1 .生体内分解吸収性ポリマーの繊維構造体からなる癒着防止膜において、該繊維 構造体を形成する繊維の平均直径が 0. 05〜50 mであり、かつ該繊雜構造体の 繊維表面構造が、 0. 01 - 1 mの直径を有する凹み部を有し、その凹み部が繊維 表面の 1 0〜95%を占有することを特徵とする癒着防止膜。 1. In the adhesion preventing film composed of a fiber structure of a biodegradable and absorbable polymer, the average diameter of the fibers forming the fiber structure is 0.05 to 50 m, and the fiber surface structure of the complex structure However, an anti-adhesion film characterized in that it has a recess having a diameter of 0.01-1 m, and the recess occupies 10 to 95% of the fiber surface.
2.繊維構造体が不織布である、請求項 1記載の癒着防止膜。  2. The adhesion preventing film according to claim 1, wherein the fibrous structure is a nonwoven fabric.
3.該繊維構造体が主として脂肪族ポリエステルよりなる、請求項 1または 2に記載 の癒着防止膜。  3. The adhesion preventing film according to claim 1, wherein the fibrous structure mainly comprises an aliphatic polyester.
4.該繊維構造体が主としてポリ乳酸よりなる、請求項 1または 2に記載の癒着防止 膜。 4. The adhesion preventing membrane according to claim 1, wherein the fiber structure is mainly composed of polylactic acid.
5.繊維形成性ポリマーを揮発性溶媒に溶解した溶液を製造する段階と、前記溶液 を静電紡糸法にて紡糸する段階、および捕集基板に累積される繊維構造体を得る 段階を経て、繊維形成性ポリマーよりなる繊維構造体を製造し、該繊維構造体から 癒着紡糸膜を製造する方法であって、該繊維構造体を形成する繊維の平均直径が 0. 05〜50 mであり、かつ該繊維構造体の繊維表面構造が、 0. 01 - 1 μ mの 直径を有する凹み部を有し、その凹み部が繊維表面の 1 0~95%を占有する繊維 構造体からなる癒着防止膜の製造方法。  5. a step of producing a solution in which the fiber-forming polymer is dissolved in a volatile solvent, a step of spinning the solution by an electrostatic spinning method, and a step of obtaining a fiber structure accumulated on a collecting substrate. A method for producing a fibrous structure comprising a fiber-forming polymer and producing an adhesion-spun membrane from the fibrous structure, wherein the fibers forming the fibrous structure have an average diameter of 0.05 to 50 m, In addition, the fiber surface structure of the fiber structure has a depression having a diameter of 0.01 to 1 μm, and the adhesion prevention is formed by the fiber structure in which the depression occupies 10 to 95% of the fiber surface. Manufacturing method of membrane.
6.該揮発性溶媒が、塩化メチレン、クロ口ホルム、ジクロロエタン、テトラクロ口エタ ン、トリクロロェタン、ジブロモメタン、ブロモホルム、テトラヒドロフラン、 1 , 4—ジォキ サンよりなる群から少なくとも 1種選ばれる、請求項 5に記載の癒着防止膜の製造方 法。  6. The method according to claim 1, wherein the volatile solvent is at least one selected from the group consisting of methylene chloride, chloroform, dichloroethane, tetrachloroethane, trichloroethane, dibromomethane, bromoform, tetrahydrofuran, and 1,4-dioxane. Item 6. The method for producing an adhesion preventing film according to Item 5.
7.該静電紡糸法で紡糸する段階において、繊維状物質が形成されるノズルと捕集 基板の間の相対湿度を 20%以上とする請求項 5または 6に記載の癒着防止膜の製 造方法。  7. The method for producing an adhesion preventing film according to claim 5, wherein in the step of spinning by the electrostatic spinning method, the relative humidity between the nozzle on which the fibrous substance is formed and the collecting substrate is 20% or more. Method.
PCT/JP2004/004947 2003-04-07 2004-04-06 Anti-adhesive membrane and method for production thereof WO2004089433A1 (en)

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