JP4610885B2 - Cell growth suppression film and medical device - Google Patents
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本発明は、細胞増殖抑制フィルム、細胞増殖抑制フィルムを用いる細胞増殖抑制法および医療用具に関する。 The present invention relates to a cell growth suppression film, a cell growth suppression method using the cell growth suppression film, and a medical device.
細胞と材料との相互作用において、細胞は材料表面の化学的な性質のみならず微細な形状によっても影響を受けることが知られている。例えば、特許文献１には、生体分解性かつ両親媒性を有する単独のポリマーまたは生体分解性ポリマーと両親媒性ポリマーとからなるポリマー混合物の疎水性有機溶媒溶液を基板上にキャストし、該有機溶媒を蒸散させると同時にキャストした有機溶媒溶液（キャスト液）表面で結露させ、該結露により生じた微小水滴を蒸発させることにより得られるハニカム構造体フィルムまたはその延伸フィルムが記載されている。そして、このポリマーフィルム上でラット胎児心臓由来心筋細胞を培養すると、細胞がよく伸展したことから、このポリマーフィルムは、細胞培養用基材として有用であるとされている。 In the interaction between cells and materials, it is known that cells are influenced not only by the chemical properties of the material surface but also by the fine shape. For example, in Patent Document 1, a hydrophobic organic solvent solution of a biodegradable and amphiphilic polymer or a polymer mixture composed of a biodegradable polymer and an amphiphilic polymer is cast on a substrate, and the organic A honeycomb structure film or a stretched film obtained by condensing on the surface of a cast organic solvent solution (cast liquid) at the same time as evaporating the solvent and evaporating fine water droplets generated by the condensation is described. Then, when rat fetal heart-derived cardiomyocytes are cultured on this polymer film, the cells are well stretched. Therefore, this polymer film is considered to be useful as a cell culture substrate.
また特許文献２には、前記特許文献１に記載されているフィルムと同様の方法により形成される、特定の孔径と孔径バラツキをもつハニカム様構造を有する血液濾過膜が記載されている。この濾過膜は、輸血用の全血から白血球を除去するためのものである。 Patent Document 2 describes a blood filtration membrane having a honeycomb-like structure having a specific pore diameter and pore diameter variation, which is formed by the same method as the film described in Patent Document 1. This filtration membrane is for removing white blood cells from whole blood for transfusion.
ところで、近年、種々の病症を治療するためにステントなどの医療用具を体内に留置することが行われている。例えば、がんなどで狭窄・閉鎖した胆管や尿管を拡張するための医療用具として胆管ステントや尿管ステントが知られている。 By the way, in recent years, in order to treat various diseases, medical devices such as stents are placed in the body. For example, bile duct stents and ureteral stents are known as medical devices for dilating bile ducts and ureters that have been narrowed or closed due to cancer or the like.
これらのステントを用いる場合には、がんの進行により、一旦拡張した胆管や尿管が再狭窄・閉鎖してしまう場合がある。そこで、これを防ぐために、特許文献３には、ステントなどの医療器具の表面に被覆層を設け、この被覆層から、経時的に制がん剤などのがん細胞の増殖を抑制できる生理活性物質を放出するようにした医療器具が提案されている。
しかしながら、この医療器具においては、生理活性物質が人体に与える副作用が大きく、患者に与える負担も大きいという問題があった。
When these stents are used, the bile ducts and ureters that have been once expanded may be restenotic or closed as the cancer progresses. Therefore, in order to prevent this, Patent Document 3 discloses that a coating layer is provided on the surface of a medical device such as a stent, and from this coating layer, a physiological activity capable of suppressing the growth of cancer cells such as anticancer agents over time. Medical devices that release substances have been proposed.
However, this medical device has a problem that the physiologically active substance has a large side effect on the human body and a large burden on the patient.
本発明は、このような従来技術の実情に鑑みてなされたものであり、制がん剤等の生理活性物質を使用することなくとも細胞増殖抑制作用を示し、医療用具を構成するために好適な材料を提供することを課題とする。 The present invention has been made in view of such a state of the art, and exhibits a cell growth inhibitory effect without using a physiologically active substance such as an anticancer agent, and is suitable for constituting a medical device. It is an object to provide a new material.
本発明者らは、特許文献１および２に記載された方法と同様な方法により、１，２−ポリブタジエンなどの樹脂の有機溶媒溶液を基板上にキャストして、ハニカム様構造の多孔構造を有するフィルムを得た。そして、このフィルムを培地中に設置して、該フィルム上で悪性胆嚢がん細胞の培養を試みたところ、意外にも、特許文献１の心筋細胞に対する例とは反対に該がん細胞の増殖が著しく抑制されることを見出した。また、このフィルムを医療用具基材に被覆することにより、生理活性物質の副作用による患者への負担が無く、がんの進行を抑制することができる医療用具を得ることができることを見出し，本発明を完成するに至った。 The present inventors have a porous structure having a honeycomb-like structure by casting an organic solvent solution of a resin such as 1,2-polybutadiene on a substrate by a method similar to the method described in Patent Documents 1 and 2. A film was obtained. Then, when this film was placed in a medium and culturing of malignant gallbladder cancer cells was attempted on the film, surprisingly, the growth of the cancer cells was contrary to the example of cardiomyocytes of Patent Document 1. Has been found to be significantly suppressed. Further, the present inventors have found that by coating this film on a medical device substrate, a medical device that can suppress the progression of cancer without causing a burden on the patient due to side effects of physiologically active substances can be obtained. It came to complete.
かくして本発明の第１によれば、少なくとも表面部に多孔構造が形成されている樹脂からなる細胞増殖抑制フィルムが提供される。
本発明の細胞増殖抑制フィルムは、多孔構造が、ハニカム様構造であることが好ましい。
また、本発明の細胞増殖抑制フィルムは、多孔構造を構成する孔の平均孔径が０．１〜１００μｍであることが好ましく、多孔構造を構成する孔の孔径の変動係数が３０％以下であることが好ましい。
Thus, according to the first aspect of the present invention, there is provided a cell growth inhibition film made of a resin having a porous structure formed at least on the surface thereof.
In the cell growth inhibiting film of the present invention, the porous structure is preferably a honeycomb-like structure.
In the cell growth-suppressing film of the present invention, the average pore diameter of the pores constituting the porous structure is preferably 0.1 to 100 μm, and the variation coefficient of the pore diameter of the pores constituting the porous structure is 30% or less. Is preferred.
本発明の細胞増殖抑制フィルムは、樹脂の有機溶媒溶液を基板上にキャストし、該有機溶媒を蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させることにより得られるフィルムまたはその延伸フィルムであることが好ましい。 The cell growth-suppressing film of the present invention is obtained by casting an organic solvent solution of a resin on a substrate, evaporating the organic solvent, causing condensation on the surface of the casting solution, and evaporating minute water droplets generated by the condensation. It is preferable that it is a film obtained or its stretched film.
本発明の第２によれば、少なくとも表面部に多孔構造が形成されている樹脂からなるフィルムの表面部を接触させることにより、該接触部における細胞の増殖を抑制することを特徴とする細胞増殖抑制法が提供される。
本発明の細胞増殖抑制法においては、用いるフィルムの多孔構造がハニカム様構造であることが好ましい。
本発明の細胞増殖抑制法においては、用いるフィルムの多孔構造を構成する孔の平均孔径が０．１〜１００μｍであることが好ましく、多孔構造を構成する孔の孔径の変動係数が３０％以下であることが好ましい。
According to a second aspect of the present invention, cell growth is characterized in that at least the surface portion of a film made of a resin having a porous structure formed on the surface portion is brought into contact with each other, thereby suppressing cell growth in the contact portion. Inhibition methods are provided.
In the cell growth suppression method of the present invention, the porous structure of the film used is preferably a honeycomb-like structure.
In the cell growth inhibition method of the present invention, the average pore diameter of the pores constituting the porous structure of the film to be used is preferably 0.1 to 100 μm, and the variation coefficient of the pore diameter of the pores constituting the porous structure is 30% or less. Preferably there is.
本発明の細胞増殖抑制法においては、用いるフィルムが、樹脂の有機溶媒溶液を基板上にキャストし、該有機溶媒を蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させることにより得られるフィルムまたはその延伸フィルムであることが好ましい。 In the method for inhibiting cell growth of the present invention, the film used is a cast of an organic solvent solution of a resin on a substrate to evaporate the organic solvent and cause dew condensation on the surface of the cast solution. A film obtained by evaporating or a stretched film thereof is preferred.
本発明の第３によれば、医療用具基材の表面の全部または一部を、少なくとも表面部に多孔構造が形成されている樹脂からなるフィルムで被覆してなる医療用具が提供される。
本発明の医療用具において、医療用具基材を被覆するフィルムの多孔構造は、ハニカム様構造であることが好ましい。
また、本発明の医療用具において、医療用具基材を被覆するフィルムの多孔構造を構成する孔の平均孔径が０．１〜１００μｍであることが好ましく、多孔構造を構成する孔の孔径の変動係数が３０％以下であることが好ましい。
According to 3rd aspect of this invention, the medical device formed by coat | covering the whole or one part of the surface of a medical device base material with the film which consists of resin in which the porous structure is formed in the surface part at least is provided.
In the medical device of the present invention, the porous structure of the film covering the medical device substrate is preferably a honeycomb-like structure.
In the medical device of the present invention, the average pore diameter of the pores constituting the porous structure of the film covering the medical device substrate is preferably 0.1 to 100 μm, and the variation coefficient of the pore diameter of the pores constituting the porous structure Is preferably 30% or less.
本発明の医療用具において、医療用具基材を被覆するフィルムは、樹脂の有機溶媒溶液を基板上にキャストし、該有機溶媒を蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させることにより得られるフィルムまたはその延伸フィルムであることが好ましい。 In the medical device of the present invention, the film covering the medical device base material is produced by casting an organic solvent solution of a resin on a substrate, causing the organic solvent to evaporate and causing condensation on the surface of the cast solution. A film obtained by evaporating fine water droplets or a stretched film thereof is preferred.
本発明によれば、生理活性物質を使用しなくとも優れた細胞増殖抑制作用を示し、医療用具を構成するために好適な細胞増殖抑制フィルムが提供される。また、このフィルムを用いた細胞増殖抑制法と、医療用具基材にこのフィルムが被覆されてなる医療用具が提供される。 ADVANTAGE OF THE INVENTION According to this invention, even if it does not use a bioactive substance, the cell growth inhibitory effect which showed the outstanding cell growth action, and suitable for comprising a medical device is provided. Moreover, the cell growth suppression method using this film and the medical device by which this film is coat | covered with a medical device base material are provided.
本発明の細胞増殖抑制フィルム、細胞増殖抑制法および医療用具によれば、生理活性物質を使用しなくとも、細胞増殖抑制作用を発揮できるので、生理活性物質による副作用を回避することができる。 According to the cell growth-suppressing film, the cell growth-suppressing method and the medical device of the present invention, the cell growth-suppressing action can be exerted without using a physiologically active substance, so that side effects due to the physiologically active substance can be avoided.
以下、本発明について詳細に説明する。
１）細胞増殖抑制フィルム
本発明の細胞増殖抑制フィルムは、少なくとも表面部に多孔構造が形成されていて、樹脂からなることを特徴とし、細胞増殖抑制作用を発揮するものである。
Hereinafter, the present invention will be described in detail.
1) Cell Growth Inhibition Film The cell growth inhibition film of the present invention is characterized in that a porous structure is formed at least on the surface portion and is made of a resin, and exhibits a cell proliferation inhibition action.
ここで、細胞増殖抑制作用とは、がん細胞または腫瘍細胞が増殖するのを抑制する作用および／または細胞を死滅させる作用をいう。
具体的には、培地中に本発明の細胞増殖抑制フィルムを配置して、このフィルム上にがん細胞または腫瘍細胞の細胞株を播種して細胞の培養を行ったときに、多孔構造をもたない通常の平膜構造の樹脂フィルム上では細胞が正常に増殖するのに対し、本発明の細胞増殖抑制フィルムを用いる場合には、細胞の増殖が著しく抑制され、あるいは細胞が死滅する。
従って、本発明の細胞増殖抑制フィルムは、医療用具を構成する材料などとして有用である。
Here, the cell growth inhibitory action refers to the action of suppressing the growth of cancer cells or tumor cells and / or the action of killing cells.
Specifically, when the cell growth inhibitory film of the present invention is placed in a medium, and a cell line of cancer cells or tumor cells is seeded on the film and the cells are cultured, the porous structure is maintained. On the other hand, cells normally grow on a resin film having a normal flat membrane structure, whereas when the cell growth inhibitory film of the present invention is used, cell growth is remarkably suppressed or cells are killed.
Therefore, the cell growth inhibiting film of the present invention is useful as a material constituting a medical device.
本発明の細胞増殖抑制フィルムは、少なくとも表面部に多孔構造を有するものであればよい。また、多孔構造を構成する孔は、貫通孔、非貫通孔のいずれであってもよい。 The cell growth-suppressing film of the present invention only needs to have a porous structure on at least the surface portion. Further, the holes constituting the porous structure may be either through holes or non-through holes.
本発明の細胞増殖抑制フィルムにおいて、前記多孔構造はハニカム様構造であるのが特に好ましい。ここで、ハニカム様構造とは、孔径がほぼ一定の複数の孔が規則正しく配列してなる多孔構造をいう。一例として、ハニカム様構造を有するフィルムの光学顕微鏡写真のスケッチ図を図１に示す。 In the cell growth inhibiting film of the present invention, the porous structure is particularly preferably a honeycomb-like structure. Here, the honeycomb-like structure refers to a porous structure in which a plurality of holes having a substantially constant hole diameter are regularly arranged. As an example, FIG. 1 shows a sketch of an optical micrograph of a film having a honeycomb-like structure.
また本発明の細胞増殖抑制フィルムにおいては、前記多孔構造の各孔同士がフィルム内部において連通している連続性多孔構造を有するものであるのがより好ましい。 Moreover, in the cell growth suppression film of this invention, it is more preferable to have a continuous porous structure in which the pores of the porous structure communicate with each other inside the film.
本発明の細胞増殖抑制フィルムにおいて、前記多孔構造を構成する孔の平均孔径は、０．１〜１００μｍであることが好ましく、０．１〜２０μｍであることがより好ましく、０．５〜１０μｍであることがさらに好ましい。 In the cell growth inhibition film of the present invention, the average pore diameter of the pores constituting the porous structure is preferably 0.1 to 100 μm, more preferably 0.1 to 20 μm, and 0.5 to 10 μm. More preferably it is.
ここで、孔径とは、孔の開口形状に対する最大内接円の直径を指し、例えば、孔の開口形状が実質的に円形状である場合はその円の直径を指し、実質的に楕円形状である場合はその楕円の短径を指し、実質的に正方形状である場合はその正方形の辺の長さを指し、実質的に長方形状である場合はその長方形の短辺の長さを指すものである。
このような平均孔径を有する孔から多孔構造が構成されてなることにより、より優れた細胞増殖抑制作用を有するフィルムを得ることができる。
また、前記多孔構造の各孔の開口形状に特に限定はなく、円形状、楕円形状、正方形状、長方形状、六角形状などのいかなる形状であってもよい。
Here, the hole diameter refers to the diameter of the maximum inscribed circle with respect to the opening shape of the hole. For example, when the opening shape of the hole is substantially circular, it refers to the diameter of the circle, and is substantially elliptical. In some cases, it indicates the minor axis of the ellipse, in the case of being substantially square, it indicates the length of the side of the square, and in the case of being substantially rectangular, it indicates the length of the short side of the rectangle. It is.
By forming a porous structure from pores having such an average pore diameter, a film having a more excellent cell growth inhibitory effect can be obtained.
The opening shape of each hole of the porous structure is not particularly limited, and may be any shape such as a circular shape, an elliptical shape, a square shape, a rectangular shape, or a hexagonal shape.
本発明の細胞増殖抑制フィルムにおいて、前記多孔構造を構成する孔の孔径の変動係数〔＝標準偏差÷平均値×１００（％）〕が３０％以下であることが好ましく、孔径の変動係数が２０％以下であることがより好ましい。
このような孔径の均一性が高い孔から多孔構造が構成されてなることにより、より優れた細胞増殖抑制作用を有するフィルムを得ることができる。
In the cell growth suppression film of the present invention, the pore diameter variation coefficient [= standard deviation ÷ average value × 100 (%)] constituting the porous structure is preferably 30% or less, and the pore diameter variation coefficient is 20%. % Or less is more preferable.
By forming a porous structure from such highly uniform pore diameters, it is possible to obtain a film having a better cell growth inhibitory effect.
本発明の細胞増殖抑制フィルムの厚さは特に限定されないが、通常、０．１〜１００μｍであり、好ましくは０．５〜２０μｍである。
本発明の細胞増殖抑制フィルムを構成する樹脂は特に限定されないが、有機溶媒に溶解する高分子化合物であって、毒性の少ないものが好ましい。
Although the thickness of the cell growth suppression film of this invention is not specifically limited, Usually, it is 0.1-100 micrometers, Preferably it is 0.5-20 micrometers.
The resin constituting the cell growth-suppressing film of the present invention is not particularly limited, but is preferably a polymer compound that dissolves in an organic solvent and has low toxicity.
このような樹脂としては、ポリブタジエン、ポリイソプレン、スチレン−ブタジエン共重合体、アクリロニトリル−ブタジエン−スチレン共重合体などの共役ジエン系高分子；ポリε−カプロラクトン；ポリウレタン；酢酸セルロース、セルロイド、硝酸セルロース、アセチルセルロース、セロファンなどのセルロース系高分子；ポリアミド６、ポリアミド６６、ポリアミド６１０、ポリアミド６１２、ポリアミド１２、ポリアミド４６などのポリアミド系高分子；ポリテトラフルオロエチレン、ポリトリフルオロエチレン、パーフルオロエチレン−プロピレン共重合体などのフッ素系高分子；ポリスチレン、スチレン−エチレン−プロピレン共重合体、スチレン−エチレン−ブチレン共重合体、スチレン−イソプレン共重合体、塩素化ポリエチレン−アクリロニトリル−スチレン共重合体、メタクリル酸エステル−スチレン共重合体、スチレン−アクリロニトリル共重合体、スチレン−無水マレイン酸共重合体、アクリル酸エステル−アクリロニトリル−スチレン共重合体などのスチレン系高分子；ポリエチレン、塩素化ポリエチレン、エチレン−α−オレフィン共重合体、エチレン−酢酸ビニル共重合体、エチレン−塩化ビニル共重合体、エチレン−酢酸ビニル共重合体、ポリプロピレン、オレフィン−ビニルアルコール共重合体、ポリメチルペンテンなどのオレフィン系高分子；フェノール樹脂、アミノ樹脂、尿素樹脂、メラミン樹脂、ベンゾグアナミン樹脂などのホルムアルデヒド系高分子；ポリブチレンテレフタレート、ポリエチレンテレフタレート、ポリエチレンナフタレートなどのポリエステル系高分子；エポキシ樹脂；ポリ（メタ）アクリル酸エステル、ポリ−２−ヒドロキシエチルアクリレート、メタクリル酸エステル−酢酸ビニル共重合体などの（メタ）アクリル系高分子；ノルボルネン系樹脂；シリコン樹脂；ポリ乳酸、ポリヒドロキシ酪酸、ポリグリコール酸などのヒドロキシカルボン酸の重合体；などが挙げられる。これらは１種単独で、あるいは２種以上を組み合わせて用いることができる。 Examples of such resins include conjugated diene polymers such as polybutadiene, polyisoprene, styrene-butadiene copolymer, acrylonitrile-butadiene-styrene copolymer; polyε-caprolactone; polyurethane; cellulose acetate, celluloid, cellulose nitrate, Cellulosic polymers such as acetyl cellulose and cellophane; polyamide polymers such as polyamide 6, polyamide 66, polyamide 610, polyamide 612, polyamide 12, polyamide 46; polytetrafluoroethylene, polytrifluoroethylene, perfluoroethylene-propylene Fluoropolymers such as copolymers; polystyrene, styrene-ethylene-propylene copolymer, styrene-ethylene-butylene copolymer, styrene-isoprene copolymer, chlorinated poly Styrene polymers such as tylene-acrylonitrile-styrene copolymer, methacrylate ester-styrene copolymer, styrene-acrylonitrile copolymer, styrene-maleic anhydride copolymer, acrylate ester-acrylonitrile-styrene copolymer Polyethylene, chlorinated polyethylene, ethylene-α-olefin copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, polypropylene, olefin-vinyl alcohol copolymer, Olefin polymers such as polymethylpentene; formaldehyde polymers such as phenol resin, amino resin, urea resin, melamine resin, and benzoguanamine resin; polybutylene terephthalate, polyethylene terephthalate, polyethylene naphtha Polyester polymers such as carbonates; epoxy resins; (meth) acrylic polymers such as poly (meth) acrylic acid esters, poly-2-hydroxyethyl acrylate, methacrylic acid ester-vinyl acetate copolymers; norbornene resins A silicon resin; a polymer of hydroxycarboxylic acid such as polylactic acid, polyhydroxybutyric acid, polyglycolic acid; and the like. These can be used alone or in combination of two or more.
本発明の細胞増殖抑制フィルムを構成する樹脂としては、非生体分解性樹脂と生体分解性樹脂のいずれも使用できるが、生体内において細胞増殖抑制作用を長期間持続させる観点からは、生体内で容易に分解されない非生体分解性樹脂から形成されてなるものが好ましい。なかでも、優れた細胞増殖抑制作用を有する細胞増殖抑制フィルムを得ることができることから、共役ジエン系高分子、スチレン系高分子またはポリウレタンの使用が特に好ましい。 As the resin constituting the cell growth inhibitory film of the present invention, either a non-biodegradable resin or a biodegradable resin can be used. From the viewpoint of maintaining the cell growth inhibitory action in vivo for a long time, Those formed from non-biodegradable resins that are not easily decomposed are preferred. Among them, the use of a conjugated diene polymer, a styrene polymer, or polyurethane is particularly preferable because a cell growth suppression film having an excellent cell growth suppression action can be obtained.
また、本発明の細胞増殖抑制フィルムを構成する樹脂には、両親媒性物質を添加してもよい。
添加する両親媒性物質としては、ポリエチレングリコール／ポリプロピレングリコールブロック共重合体；アクリルアミドポリマーを主鎖骨格とし疎水性側鎖としてドデシル基と親水性側鎖としてラクトース基またはカルボキシル基を併せ持つ両親媒性樹脂；ヘパリンやデキストラン硫酸、核酸（ＤＮＡやＲＮＡ）などのアニオン性高分子と長鎖アルキルアンモニウム塩とのイオンコンプレックス；ゼラチン、コラーゲン、アルブミンなどの水溶性タンパク質を親水性基とした両親媒性樹脂；ポリ乳酸−ポリエチレングリコールブロック共重合体、ポリε−カプロラクトン−ポリエチレングリコールブロック共重合体、ポリリンゴ酸−ポリリンゴ酸アルキルエステルブロック共重合体などの両親媒性樹脂；などが挙げられる。
Moreover, you may add an amphiphilic substance to resin which comprises the cell growth suppression film of this invention.
The amphiphilic substance to be added is a polyethylene glycol / polypropylene glycol block copolymer; an amphiphilic resin having an acrylamide polymer as a main chain skeleton, a dodecyl group as a hydrophobic side chain, and a lactose group or a carboxyl group as a hydrophilic side chain. An ion complex of an anionic polymer such as heparin, dextran sulfate, and nucleic acid (DNA or RNA) and a long-chain alkylammonium salt; an amphiphilic resin having a water-soluble protein such as gelatin, collagen or albumin as a hydrophilic group; And amphiphilic resins such as a polylactic acid-polyethylene glycol block copolymer, a polyε-caprolactone-polyethylene glycol block copolymer, and a polymalic acid-polymalic acid alkyl ester block copolymer.
本発明の細胞増殖抑制フィルムは、生理活性物質を添加しなくとも細胞増殖抑制作用を示すので、副作用を回避する観点から、細胞増殖抑制作用を有する生理活性物質を添加しないことが好ましい。ただし、より強い細胞増殖抑制作用を得る目的で、細胞増殖抑制作用を有する生理活性物質を添加しても良い。この場合でも、従来に比し少ない添加量で、十分な細胞増殖抑制作用を得ることができるので、生理活性物質による副作用は低減される。 Since the cell growth inhibitory film of the present invention exhibits a cell growth inhibitory action without adding a physiologically active substance, it is preferable not to add a physiologically active substance having a cell growth inhibitory action from the viewpoint of avoiding side effects. However, for the purpose of obtaining a stronger cell growth inhibitory action, a physiologically active substance having a cell growth inhibitory action may be added. Even in this case, since a sufficient cell growth inhibitory action can be obtained with a smaller amount of addition than in the past, side effects due to the physiologically active substance are reduced.
本発明の細胞増殖抑制フィルムを作製する方法は特に限定されないが、例えば、樹脂の有機溶媒溶液を基板上にキャストし、該有機溶媒を蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させる方法が挙げられる。 The method for producing the cell growth inhibiting film of the present invention is not particularly limited. For example, an organic solvent solution of a resin is cast on a substrate to evaporate the organic solvent and cause condensation on the surface of the cast solution. There is a method of evaporating the fine water droplets generated by the above.
より具体的には、（１）樹脂の有機溶媒溶液を基板上にキャストし、高湿度空気を吹き付けることで該有機溶媒を徐々に蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させる方法、または、（２）樹脂の有機溶媒溶液を、相対湿度５０〜９５％の大気下で基板上にキャストし、該有機溶媒を蒸散させるとともに該キャスト液表面で結露を起こさせ、該結露により生じた微小水滴を蒸発させる方法である。これらの方法によれば、比較的容易に、所望の孔径を有し、しかも孔径の均一性が高い孔からなり、ハニカム様構造である多孔構造を有する細胞増殖抑制フィルムを得ることができる。 More specifically, (1) the organic solvent solution of the resin is cast on the substrate, and the organic solvent is gradually evaporated by blowing high-humidity air, and condensation is caused on the surface of the cast liquid. A method of evaporating the generated fine water droplets, or (2) an organic solvent solution of a resin is cast on a substrate in an atmosphere with a relative humidity of 50 to 95% to evaporate the organic solvent, and at the surface of the cast liquid, condensation occurs. This is a method of evaporating minute water droplets generated by the condensation. According to these methods, it is possible to obtain a cell growth-inhibiting film having a porous structure having a desired pore diameter and having a highly uniform pore diameter and having a porous structure having a honeycomb-like structure.
これらの方法により本発明の細胞増殖抑制フィルムを作製するにあたっては、キャスト液表面上に微小な水滴粒子を形成させる必要があることから、使用する有機溶媒は非水溶性であることが好ましい。 In producing the cell growth-inhibiting film of the present invention by these methods, it is necessary to form fine water droplet particles on the surface of the casting solution, so that the organic solvent to be used is preferably water-insoluble.
用いる有機溶媒としては、クロロホルム、塩化メチレンなどのハロゲン化炭化水素系溶媒；ｎ−ペンタン、ｎ−ヘキサン、ｎ−ヘプタンなどの飽和炭化水素系溶媒；シクロペンタン、シクロヘキサンなどの脂環式炭化水素系溶媒；ベンゼン、トルエン、キシレンなどの芳香族炭化水素系溶媒；酢酸エチル、酢酸ブチルなどのエステル系溶媒；ジエチルケトン、メチルイソブチルケトンなどのケトン系溶媒；二硫化炭素；などが挙げられる。これらの有機溶媒は１種単独で、あるいはこれらの溶媒を組み合わせた混合溶媒として使用することができる。 Examples of the organic solvent used include halogenated hydrocarbon solvents such as chloroform and methylene chloride; saturated hydrocarbon solvents such as n-pentane, n-hexane, and n-heptane; alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane Solvents; aromatic hydrocarbon solvents such as benzene, toluene and xylene; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as diethyl ketone and methyl isobutyl ketone; carbon disulfide; These organic solvents can be used alone or as a mixed solvent in which these solvents are combined.
有機溶媒に溶解する樹脂の濃度は、好ましくは０．０１〜１０重量％であり、より好ましくは０．０５〜５重量％である。樹脂濃度が０．０１重量％より低いと得られるフィルムの力学的強度が不足し望ましくない。また、樹脂濃度が１０重量％以上では、所望の多孔構造が得られなくなるおそれがある。 The concentration of the resin dissolved in the organic solvent is preferably 0.01 to 10% by weight, more preferably 0.05 to 5% by weight. If the resin concentration is lower than 0.01% by weight, the resulting film has insufficient mechanical strength, which is not desirable. Further, if the resin concentration is 10% by weight or more, a desired porous structure may not be obtained.
上述した方法により多孔構造を有するフィルムを作製する場合は、前述の両親媒性物質を樹脂に添加することが好ましい。なかでも、水に対して溶解性が低く、有機溶媒に可溶である、下記に示す両親媒性樹脂（以下「Ｃａｐ樹脂」という。）を添加することが好ましい。 When producing a film having a porous structure by the method described above, it is preferable to add the above-mentioned amphiphile to the resin. Among them, it is preferable to add an amphiphilic resin (hereinafter referred to as “Cap resin”) shown below, which has low solubility in water and is soluble in an organic solvent.
（上記式中、ｍ、ｎはそれぞれ任意の自然数を表す。）
このような両親媒性物質を添加することで、水滴の融合が抑えられ安定化するので、孔径の均一性がさらに向上した多孔構造を有するフィルムを得ることができる。両親媒性物質を添加する量は、樹脂：両親媒性物質の重量比で９９：１〜５０：５０であることが好ましい。
(In the above formula, m and n each represents an arbitrary natural number.)
By adding such an amphiphilic substance, fusion of water droplets is suppressed and stabilized, so that a film having a porous structure with further improved pore diameter uniformity can be obtained. The amount of the amphiphilic substance added is preferably 99: 1 to 50:50 by weight ratio of resin: amphiphile.
前記樹脂の有機溶媒溶液をキャストする基板としては、ガラス基板、金属基板、シリコン基板などの無機基板；ポリプロピレン、ポリエチレン、ポリエーテルケトンなどの高分子からなる有機基板；水、流動パラフィン、液状ポリエーテルなどの液状物からなる液状基板；などが挙げられる。 As a substrate for casting the organic solvent solution of the resin, an inorganic substrate such as a glass substrate, a metal substrate, or a silicon substrate; an organic substrate made of a polymer such as polypropylene, polyethylene, or polyetherketone; water, liquid paraffin, or liquid polyether And a liquid substrate made of a liquid material such as
孔の孔径は、キャストする液の樹脂濃度および液量を調節してシャーレなどの支持層に供給し、雰囲気あるいは吹き付ける空気の温度および／または湿度と吹き付ける空気の流量を制御することにより、或いは溶媒の蒸発スピードおよび／または結露スピードを制御することによって、制御することができる。 The hole diameter is adjusted by adjusting the resin concentration and the liquid amount of the liquid to be cast and supplying it to a support layer such as a petri dish, and controlling the atmosphere or the temperature and / or humidity of the sprayed air and the flow rate of the sprayed air, or the solvent Can be controlled by controlling the evaporation speed and / or the condensation speed.
キャスト液に吹き付ける高湿度空気は、キャスト液表面に空気中の水分を結露させることができる湿度であればよいが、相対湿度が２０〜１００％のものが好ましく、３０〜８０％のものがより好ましい。また、空気に限らず窒素、アルゴンなどの不活性なガスを用いてもよい。 The high-humidity air blown onto the casting liquid may be any humidity that can condense moisture in the air onto the casting liquid surface, but preferably has a relative humidity of 20 to 100%, more preferably 30 to 80%. preferable. Moreover, you may use not only air but inert gas, such as nitrogen and argon.
キャスト液に吹き付ける高湿度空気の流量は、キャスト液面に空気中の水分を結露させることができ、キャストに用いた溶媒を蒸発させることができる流量であればよく、例えば、直径１０ｃｍのガラスシャーレ上でフィルムを作製する場合は、１〜５Ｌ／ｍｉｎであることが好ましい。 The flow rate of the high-humidity air blown to the casting liquid may be any flow rate that can cause moisture in the air to condense on the casting liquid surface and evaporate the solvent used for casting. For example, a glass petri dish having a diameter of 10 cm. When producing a film above, it is preferable that it is 1-5 L / min.
高湿度空気を吹き付ける時間は、キャストに用いた溶媒が蒸発し、フィルムが成膜されるまでであり、通常、１〜６０分である。
高湿度空気を吹き付けるときの雰囲気の温度は、キャストに用いた溶媒が蒸発することができる温度であればよいが、５〜８０℃の温度であることが望ましい。
High humidity air is blown until the solvent used for casting evaporates and a film is formed, and is usually 1 to 60 minutes.
The temperature of the atmosphere when high-humidity air is blown may be a temperature at which the solvent used for casting can evaporate, but is preferably 5 to 80 ° C.
本発明においては、上記のようにして作製した多孔構造を有するフィルムをそのまま用いるほか、このフィルムを延伸することにより得られる延伸フィルムを用いることもできる。 In the present invention, a film having a porous structure produced as described above can be used as it is, and a stretched film obtained by stretching this film can also be used.
フィルムの延伸の方法は特に限定されず、例えば、多孔構造を有するフィルムの２以上の端を把持して、伸長方向に引っ張ることにより行うことができる。また延伸は、一軸延伸、二軸延伸または三軸延伸であってもよい。本発明において、延伸方向の伸長率は特に限定されないが、好ましくは１．１〜１０倍の範囲内である。 The method for stretching the film is not particularly limited. For example, the film can be stretched by gripping two or more ends of the film having a porous structure and pulling in the stretching direction. The stretching may be uniaxial stretching, biaxial stretching, or triaxial stretching. In the present invention, the elongation ratio in the stretching direction is not particularly limited, but is preferably in the range of 1.1 to 10 times.
また本発明において、延伸は、後述するように、本発明の細胞増殖抑制フィルムを医療用具基材に被覆し、該医療用具基材を拡張させることによっても行うことができる。すなわち、本発明の細胞増殖抑制フィルムで被覆した医療用具基材を拡張させることにより、延伸された細胞増殖抑制フィルムが得られる。 In the present invention, the stretching can also be performed by covering the medical device base material with the cell growth suppressing film of the present invention and expanding the medical device base material, as will be described later. That is, the stretched cell growth suppression film is obtained by expanding the medical device base material coated with the cell growth suppression film of the present invention.
２）細胞増殖抑制法
本発明の細胞増殖抑制法は、少なくとも表面部に多孔構造が形成されている樹脂からなるフィルムの表面部を接触させることにより、該接触部における細胞の増殖を抑制することを特徴とするものである。接触させるフィルムとしては、前述の細胞増殖抑制フィルムとして好ましいフィルムを用いることが好ましい。
2) Cell growth inhibition method The cell growth inhibition method of the present invention suppresses cell proliferation at the contact portion by contacting the surface portion of a film made of a resin having a porous structure at least on the surface portion. It is characterized by. As the film to be contacted, it is preferable to use a film that is preferable as the above-described cell growth inhibiting film.
３）医療用具
本発明の医療用具は、医療用具基材の表面の全部または一部を、少なくとも表面部に多孔構造が形成されている樹脂からなるフィルムで被覆してなることを特徴とする。
3) Medical device The medical device of the present invention is characterized in that all or part of the surface of the medical device substrate is covered with a film made of a resin having a porous structure formed at least on the surface portion.
ここで、医療用具基材とは、フィルムを被覆することで医療用具として用いることができる基材であるが、単体であっても医療用具として用いることができるものであってもよい。 Here, the medical device base material is a base material that can be used as a medical device by coating a film, but may be a single device or a medical device that can be used as a medical device.
また、被覆に用いるフィルムとしては、前述の細胞増殖抑制フィルムとして好ましいフィルムを用いることが好ましい。 Moreover, as a film used for coating, it is preferable to use a film preferable as the above-mentioned cell growth suppression film.
本発明の医療用具は、がん細胞又は腫瘍細胞に対し、細胞増殖抑制作用を示すフィルムが被覆されてなるので、該フィルムの接触部においてがんの進行を抑制することができる。また、この細胞増殖抑制作用は、制がん剤などの生理活性物質を必要とすることなく発揮されるので、生理活性物質による副作用を回避することができる。 Since the medical device of the present invention is formed by coating a cancer cell or tumor cell with a film exhibiting a cell growth-inhibiting action, cancer progression can be suppressed at the contact portion of the film. Moreover, since this cell growth inhibitory effect is exhibited without the need for a physiologically active substance such as an anticancer agent, side effects due to the physiologically active substance can be avoided.
本発明の医療用具としては、例えば、ステント、カテーテル、医療用チューブなどが挙げられるが、ステントであるのが好ましく、特にがん細胞または腫瘍細胞により狭窄または閉塞した体内管腔に留置されるステントであるのが好ましい。そのようなステントとしては、尿管ステント、胆管ステント、気道ステント、食道ステント、大腸ステントなどが挙げられる。 The medical device of the present invention includes, for example, a stent, a catheter, a medical tube, and the like, and is preferably a stent, and in particular, a stent placed in a body lumen narrowed or occluded by cancer cells or tumor cells. Is preferred. Such stents include ureteral stents, bile duct stents, airway stents, esophageal stents, colonic stents and the like.
また、本発明の医療器具が、胆管、食道、十二指腸、大腸などの消化器系体内管腔に留置される消化器系ステントである場合には、被覆に用いるフィルムには、多孔構造が貫通孔からなり、その平均孔径が０．１〜２０μｍであるものを用いることが好ましい。このようなフィルムを被覆することで、細胞増殖抑制作用のみならず、消化液およびそれに含まれる消化酵素を透過させ、がん細胞（腫瘍細胞）は透過させない機能をも備えた消化器系ステントが得られる。 Further, when the medical device of the present invention is a digestive system stent placed in a digestive system body lumen such as a bile duct, esophagus, duodenum, large intestine, etc., a porous structure has a through-hole in the film used for coating It is preferable to use those having an average pore diameter of 0.1 to 20 μm. By coating such a film, a digestive system stent that has not only a cell growth-inhibiting action but also a function of permeating the digestive fluid and digestive enzymes contained therein and not allowing cancer cells (tumor cells) to permeate. can get.
前記医療用具基材にフィルムを被覆する方法は特に限定されないが、本発明の細胞増殖抑制フィルムを作製する方法と同様に、フィルムを作製した後に、医療用具基材に被覆させることが好ましい。この場合は、作製したフィルムを医療用具基材の表面に接触させるのみで接着力が得られるが、必要に応じて、接着剤、溶媒による融着、熱による融着などの手段を用いても良い。 Although the method for coating the medical device substrate with the film is not particularly limited, it is preferable that the medical device substrate is coated after the film is prepared in the same manner as the method for producing the cell growth inhibitory film of the present invention. In this case, adhesive force can be obtained simply by bringing the produced film into contact with the surface of the medical device substrate, but if necessary, means such as fusion with an adhesive, a solvent, or fusion with heat may be used. good.
医療用具基材にフィルムを被覆する他の方法としては、医療用具基材を基板として前述の方法を適用し、医療用具基材上でフィルムを成膜する方法が挙げられる。 As another method of coating a film on a medical device substrate, there is a method in which the above-described method is applied using the medical device substrate as a substrate, and a film is formed on the medical device substrate.
次に、実施例および比較例により本発明をさらに具体的に説明するが、本発明は以下の実施例に限定されるものではない。 Next, although an example and a comparative example explain the present invention still more concretely, the present invention is not limited to the following examples.
（実施例１）細胞増殖抑制フィルムの作製
ポリε−カプロラクトン（粘度平均分子量：７０，０００、和光純薬社製）とＣａｐ樹脂（重量平均分子量：６２，０００、数平均分子量：２１，０００）を、１０：１の重量比でクロロホルムに溶解した溶液（樹脂濃度：０．２７重量％）６ｍｌを、直径１０ｃｍのガラスシャーレ上に一様に展開した。
次いで、２３．０℃、相対湿度４０％の雰囲気下、相対湿度７０％の高湿度空気を２Ｌ／ｍｉｎの流量で、１分間ガラスシャーレ上の液面に吹き付けることにより、膜厚１〜２μｍフィルムＡを得た。フィルムＡを光学顕微鏡（ＢＨ２、オリンパス社製）を用いて、１００倍の倍率で観察した結果、ハニカム様構造の多孔構造が形成されていることが確認された。その多孔構造を構成する孔の平均孔径は３．５μｍ、孔径の変動係数は９％であった。なお、平均孔径および孔径の変動係数は、顕微鏡視野中（１００μｍ×１００μｍ）の全ての孔の孔径を測定することにより求めたものである。
Example 1 Production of Cell Growth Inhibitory Film Polyε-caprolactone (viscosity average molecular weight: 70,000, manufactured by Wako Pure Chemical Industries) and Cap resin (weight average molecular weight: 62,000, number average molecular weight: 21,000) 6 ml of a solution (resin concentration: 0.27 wt%) dissolved in chloroform at a weight ratio of 10: 1 was uniformly spread on a glass petri dish having a diameter of 10 cm.
Next, in an atmosphere of 23.0 ° C. and a relative humidity of 40%, high-humidity air with a relative humidity of 70% is blown onto the liquid surface on the glass petri dish at a flow rate of 2 L / min for 1 minute to a film thickness of 1 to 2 μm. A was obtained. As a result of observing the film A with an optical microscope (BH2, manufactured by Olympus Corporation) at a magnification of 100, it was confirmed that a porous structure having a honeycomb-like structure was formed. The average pore size of the pores constituting the porous structure was 3.5 μm, and the variation coefficient of the pore size was 9%. The average pore size and the variation coefficient of the pore size are determined by measuring the pore sizes of all the pores in the microscope field (100 μm × 100 μm).
（実施例２、３）細胞増殖抑制フィルムの作製
実施例２では２４．０℃、実施例３では２５．０℃の雰囲気下で行ったこと以外は、実施例１と同様にしてハニカム様構造の多孔構造を有するフィルムＢおよびＣを得た。
得られたフィルムＢ、Ｃの膜厚および多孔構造を構成する孔の平均孔径、孔径の変動係数を第１表に示す。
(Examples 2 and 3) Production of Cell Growth Inhibitory Film A honeycomb-like structure was performed in the same manner as in Example 1 except that it was performed in an atmosphere of 24.0 ° C. in Example 2 and 25.0 ° C. in Example 3. Films B and C having the following porous structure were obtained.
Table 1 shows the film thicknesses of the obtained films B and C, the average pore diameter of pores constituting the porous structure, and the variation coefficient of the pore diameter.
（実施例４〜６）
樹脂として、ポリε−カプロラクトンに代えて、１，２−ポリブタジエン（商品名：ＲＢ８２０、ＪＳＲ社製）を使用する以外は、それぞれ実施例１、２、３と同様にして、フィルムＤ、Ｅ、Ｆを得た。
得られたフィルムＤ〜Ｆを光学顕微鏡で観察した結果、ハニカム様構造の多孔構造が形成されていることが確認された。フィルムＤ〜Ｆの膜厚および多孔構造を構成する孔の平均孔径、孔径の変動係数を第１表に示す。
(Examples 4 to 6)
As the resin, instead of polyε-caprolactone, films D, E, and D were used in the same manner as in Examples 1, 2, and 3, except that 1,2-polybutadiene (trade name: RB820, manufactured by JSR) was used. F was obtained.
As a result of observing the obtained films D to F with an optical microscope, it was confirmed that a porous structure having a honeycomb-like structure was formed. Table 1 shows the film thicknesses of the films D to F, the average pore diameter of the pores constituting the porous structure, and the variation coefficient of the pore diameter.
（実施例７、８）
樹脂として、ポリε−カプロラクトンに代えて、ポリウレタン（商品名：ミラクトランＥ３８５、日本ミラクトラン社製）を使用する以外は、それぞれ実施例１、２と同様にして、フィルムＧ、Ｈを得た。
得られたフィルムＧ、Ｈを光学顕微鏡で観察した結果、ハニカム様構造の多孔構造が形成されていることが確認された。フィルムＧ、Ｈの膜厚および多孔構造を構成する孔の平均孔径、孔径の変動係数を第１表に示す。
(Examples 7 and 8)
Films G and H were obtained in the same manner as in Examples 1 and 2, respectively, except that polyurethane (trade name: Milactolan E385, manufactured by Nihon Milactolan) was used as the resin instead of poly-ε-caprolactone.
As a result of observing the obtained films G and H with an optical microscope, it was confirmed that a porous structure having a honeycomb-like structure was formed. Table 1 shows the film thicknesses of the films G and H, the average pore diameter of the pores constituting the porous structure, and the variation coefficient of the pore diameter.
（比較例１〜３）
実施例１で使用したポリε−カプロラクトン／Ｃａｐ樹脂のクロロホルム溶液、実施例４〜６で使用した１，２−ポリブタジエン／Ｃａｐ樹脂のクロロホルム溶液、および実施例７、８で使用したポリウレタン／Ｃａｐ樹脂のクロロホルム溶液を、それぞれ直径１０ｃｍのガラスシャーレ上に６ｍｌずつ展開し、２３．０℃、相対湿度４０％の雰囲気下で、高湿度空気を吹き付けることなく放置して、クロロホルムを蒸発させることにより、比較例１〜３のフィルムＩ〜Ｋをそれぞれ得た。比較例１〜３のフィルムＩ〜Ｋを光学顕微鏡で観察すると、平膜構造（多孔構造ではない）を有していた。比較例１〜３のフィルムＩ〜Ｋの厚みを第１表に示す。
(Comparative Examples 1-3)
Chloroform solution of poly ε-caprolactone / Cap resin used in Example 1, chloroform solution of 1,2-polybutadiene / Cap resin used in Examples 4 to 6, and polyurethane / Cap resin used in Examples 7 and 8 6 ml of each chloroform solution was developed on a glass petri dish having a diameter of 10 cm, left in an atmosphere of 23.0 ° C. and a relative humidity of 40% without blowing high-humidity air, and the chloroform was evaporated, Films I to K of Comparative Examples 1 to 3 were obtained. When the films I to K of Comparative Examples 1 to 3 were observed with an optical microscope, they had a flat film structure (not a porous structure). Table 1 shows the thicknesses of the films I to K of Comparative Examples 1 to 3.
（細胞増殖抑制作用評価試験）
実施例１〜８および比較例１〜３のフィルムＡ〜Ｋのそれぞれを下記の培地中に置き、それぞれのフィルム上に下記の細胞株ＡおよびＢを播種して、下記に示す培養条件で培養を行った。
(Cell growth inhibitory action evaluation test)
Each of the films A to K of Examples 1 to 8 and Comparative Examples 1 to 3 is placed in the following medium, and the following cell lines A and B are seeded on each film, and cultured under the culture conditions shown below. Went.
１）使用培地
（１）培地Ａ：Ｄｕｌｂｅｃｃｏ’ｓ ｍｏｄｉｆｉｅｄ Ｅａｇｌｅ’ｓ培地 インビトロゲン社（Ｉｎｖｉｔｒｏｇｅｎ Ｃｏｒｐｏｒａｔｉｏｎ）から購入したものを用いた。
（２）培地Ｂ：Ｗｉｌｌｉａｍ’ｓ Ｅ培地
アイシーエヌ社（ＩＣＮ Ｂｉｏｍｅｄｉｃａｌｓ Ｉｎｃ．）から購入したものを用いた。また、Ｌ−グルタミン酸ナトリウムおよびピルビン酸も、アイシーエヌ社（ＩＣＮ Ｂｉｏｍｅｄｉｃａｌｓ Ｉｎｃ．）から購入したものを用いた。
1) Medium used (1) Medium A: Dulbecco's modified Eagle's medium Purchased from Invitrogen Corporation.
(2) Medium B: William's E medium The one purchased from ICN Biomedicals Inc. was used. Further, sodium L-glutamate and pyruvic acid were also purchased from ICN Biomedicals Inc.
２）ウシ胎仔血清（ＦＢＳ）は、ジェイアールエイチ社（ＪＲＨ Ｂｉｏｓｃｉｅｎｃｅ）から購入したものを用いた。 2) The fetal bovine serum (FBS) used was purchased from JR H Bioscience.
３）細胞株
細胞株として、細胞株Ａ：ヒト胆嚢がん細胞株ＮＯＺ（Ｃｅｌｌ ｎｕｍｂｅｒ：ＪＣＲＢ１０３３）、および、細胞株Ｂ：ヒト悪性胆嚢がん細胞株ＯＣＵＧ−１（Ｃｅｌｌ ｎｕｍｂｅｒ：ＪＣＲ Ｂ０１９１）は、それぞれヒューマンサイエンス振興財団研究資源バンクより購入したものを用いた。
3) Cell line As cell lines, cell line A: human gallbladder cancer cell line NOZ (Cell number: JCRB1033) and cell line B: human malignant gallbladder cancer cell line OCUG-1 (Cell number: JCR B0191) are These were purchased from the Research Resource Bank of the Human Science Foundation.
４）培養条件
細胞株Ａ（ＮＯＺ）は、１０％ＦＢＳおよび２ｍＭＬ−グルタミン酸ナトリウムを含むＷｉｌｌｉａｍ’ｓ Ｅ培地中で３７℃、５％ＣＯ２で培養した。
細胞株Ｂ（ＯＣＵＧ−１）は、１０％ＦＢＳおよび０．５ｍＭピルビン酸を含むＤｕｌｂｅｃｃｏ’ｓ ｍｏｄｉｆｉｅｄ Ｅａｇｌｅ’ｓ培地中で、３７℃、５％ＣＯ２で培養した。
１ウェルにつき約１×１０４の細胞が２４ウェルプレート（ファルコン ３０４７）で平板培養され（一晩インキュベーション）、結果として次の日に約８０％のコンフルエンシーが得られた。
4) Culture conditions Cell line A (NOZ) was cultured at 37 ° C. and 5% CO 2 in William's E medium containing 10% FBS and 2 mM L-glutamate sodium.
Cell line B (OCUG-1) was cultured in Dulbecco's modified Eagle's medium containing 10% FBS and 0.5 mM pyruvate at 37 ° C., 5% CO 2 .
Approximately 1 × 10 4 cells per well were plated in 24-well plates (Falcon 3047) (overnight incubation), resulting in approximately 80% confluency the next day.
５）細胞増殖抑制活性の評価
培養後、所定の日数が経過した細胞は、マグネシウムを含まないＤｕｌｂｅｃｃｏ’ｓリン酸バッファー（大日本製薬）で二回洗浄した後、ライト液（血液染色用 和光純薬）で１０分間染色した。
染色した各細胞を位相差顕微鏡（視野：１００μｍ×１００μｍ）で観察した。観察した結果、細胞接着面積が視野面積の３０％未満の場合を◎、細胞接着面積が視野面積の３０％以上５０％未満の場合を○、細胞接着面積が視野面積の５０％以上の場合を×で評価した。評価結果を第２表に示す。
5) Evaluation of cell growth inhibitory activity Cells that have passed a predetermined number of days after culturing were washed twice with Dulbecco's phosphate buffer (Dainippon Pharmaceutical Co., Ltd.) that does not contain magnesium, and then light solution (Wako Pure for blood staining) Stained for 10 minutes.
Each stained cell was observed with a phase contrast microscope (field of view: 100 μm × 100 μm). As a result of the observation, ◎ when the cell adhesion area is less than 30% of the visual field area, ○ when the cell adhesion area is 30% or more and less than 50% of the visual field area, and when the cell adhesion area is 50% or more of the visual field area It evaluated by x. The evaluation results are shown in Table 2.
第２表より、本発明の細胞増殖抑制フィルムは、細胞株Ａ：ヒト胆嚢がん細胞株（ＮＯＺ）、および細胞株Ｂ：ヒト悪性胆嚢がん細胞株（ＯＣＵＧ−１）に対して、優れた細胞増殖抑制活性を有していることがわかる。また、実施例１〜３、実施例４〜６をそれぞれ比較すると、平均孔径が小さいものほど細胞増殖抑制活性が高いことも分かる。
一方、多孔構造を有していない比較例１〜３のフィルムを用いた場合には、細胞増殖抑制活性はまったく認められなかった。
From Table 2, the cell growth suppression film of the present invention is superior to cell line A: human gallbladder cancer cell line (NOZ) and cell line B: human malignant gallbladder cancer cell line (OCUG-1). It can be seen that it has cell growth inhibitory activity. In addition, when Examples 1 to 3 and Examples 4 to 6 are compared, it can be seen that the smaller the average pore size, the higher the cell growth inhibitory activity.
On the other hand, when the films of Comparative Examples 1 to 3 having no porous structure were used, no cell growth inhibitory activity was observed.
Claims (6)
前記表面部をがん細胞又は腫瘍細胞と接触させることにより、該接触部におけるこれらの細胞の増殖を抑制するのに用いる、胆管ステント用細胞増殖抑制フィルム。 It consists of a resin having a honeycomb-like porous structure formed at least on its surface, and the resin is composed of a composition containing a non-biodegradable resin and an amphiphilic substance,
A cell growth inhibitory film for a biliary stent , which is used to suppress the growth of these cells in the contact portion by bringing the surface portion into contact with cancer cells or tumor cells.
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| JP2003399195A JP4610885B2 (en) | 2003-11-28 | 2003-11-28 | Cell growth suppression film and medical device |
| US10/580,648 US20070275156A1 (en) | 2003-11-28 | 2004-11-26 | Cell Growth Inhibiting Film, Medical Instrument and Digestive System Stent |
| EP04819437A EP1688155A4 (en) | 2003-11-28 | 2004-11-26 | Cell growth-inhibiting film, medical instrument and stent for digestive organs |
| CNB2004800410903A CN100542617C (en) | 2003-11-28 | 2004-11-26 | Cell growth-inhibiting film, medical instruments and stent for digestive |
| PCT/JP2004/017572 WO2005051450A1 (en) | 2003-11-28 | 2004-11-26 | Cell growth-inhibiting film, medical instrument and stent for digestive organs |
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| JP2003399195A JP4610885B2 (en) | 2003-11-28 | 2003-11-28 | Cell growth suppression film and medical device |
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| JP2011156083A (en) * | 2010-01-29 | 2011-08-18 | Nippon Zeon Co Ltd | Stent for digestive system |
| JP5405374B2 (en) * | 2010-03-26 | 2014-02-05 | 富士フイルム株式会社 | Manufacturing method of honeycomb structure film |
| JP6343492B2 (en) | 2013-07-09 | 2018-06-13 | 豊田合成株式会社 | Method for producing polyurethane porous membrane for use in at least one of cell culture and cancer cell growth suppression |
| JP6480285B2 (en) * | 2015-08-04 | 2019-03-06 | 豊田合成株式会社 | Cell culture device and method for producing the same |
| JP7014714B2 (en) * | 2016-06-17 | 2022-02-01 | 旭化成株式会社 | Porous membrane and method for producing porous membrane |
| WO2017222090A1 (en) * | 2016-06-23 | 2017-12-28 | 주식회사 엠아이텍 | Multi-hole stent for digestive organs |
| CN109730802B (en) * | 2018-12-27 | 2021-12-21 | 北京理工大学 | Titanium alloy implantation instrument with antithrombotic, anti-infection and honeycomb-shaped porous structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001149061A (en) * | 1999-10-20 | 2001-06-05 | Creavis G Fuer Technol & Innov Mbh | Structurized surface having property for inhibiting cell proliferation, method for producing the same and use thereof |
| JP2001157574A (en) * | 1999-11-30 | 2001-06-12 | Terumo Corp | Honeycomb structure, method for preparing the structure, film and cell culture bade using the structure |
| JP2002347107A (en) * | 2001-05-22 | 2002-12-04 | Inst Of Physical & Chemical Res | Stretched film and cell culture base material using the same |
| JP2003102849A (en) * | 2001-09-28 | 2003-04-08 | Terumo Corp | Stent indwelling in living body |
| WO2004089434A1 (en) * | 2003-04-10 | 2004-10-21 | Teijin Limited | Biodegradable film having honeycomb structure |
-
2003
- 2003-11-28 JP JP2003399195A patent/JP4610885B2/en not_active Expired - Fee Related
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001149061A (en) * | 1999-10-20 | 2001-06-05 | Creavis G Fuer Technol & Innov Mbh | Structurized surface having property for inhibiting cell proliferation, method for producing the same and use thereof |
| JP2001157574A (en) * | 1999-11-30 | 2001-06-12 | Terumo Corp | Honeycomb structure, method for preparing the structure, film and cell culture bade using the structure |
| JP2002347107A (en) * | 2001-05-22 | 2002-12-04 | Inst Of Physical & Chemical Res | Stretched film and cell culture base material using the same |
| JP2003102849A (en) * | 2001-09-28 | 2003-04-08 | Terumo Corp | Stent indwelling in living body |
| WO2004089434A1 (en) * | 2003-04-10 | 2004-10-21 | Teijin Limited | Biodegradable film having honeycomb structure |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100542617C (en) | 2009-09-23 |
| CN1905912A (en) | 2007-01-31 |
| JP2005152526A (en) | 2005-06-16 |
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