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WO2006118248A1 - Element d’inhibition de croissance cellulaire, element d’inhibition de metastases cellulaires, procede d’inhibition de croissance cellulaire, procede d’inhibition de metastases cellulaires, film en plusieurs couches et instrument medical - Google Patents

Element d’inhibition de croissance cellulaire, element d’inhibition de metastases cellulaires, procede d’inhibition de croissance cellulaire, procede d’inhibition de metastases cellulaires, film en plusieurs couches et instrument medical Download PDF

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Publication number
WO2006118248A1
WO2006118248A1 PCT/JP2006/308980 JP2006308980W WO2006118248A1 WO 2006118248 A1 WO2006118248 A1 WO 2006118248A1 JP 2006308980 W JP2006308980 W JP 2006308980W WO 2006118248 A1 WO2006118248 A1 WO 2006118248A1
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WO
WIPO (PCT)
Prior art keywords
cell
film
suppressing member
porous structure
member according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2006/308980
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English (en)
Japanese (ja)
Inventor
Masaru Tanaka
Junichi Hamada
Yoshihide Toyokawa
Sada-Aki Yamamoto
Masatsugu Shimomura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hokkaido University NUC
Japan Science and Technology Agency
Zeon Medical Inc
Original Assignee
Hokkaido University NUC
Japan Science and Technology Agency
Zeon Medical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hokkaido University NUC, Japan Science and Technology Agency, Zeon Medical Inc filed Critical Hokkaido University NUC
Priority to JP2007514835A priority Critical patent/JPWO2006118248A1/ja
Publication of WO2006118248A1 publication Critical patent/WO2006118248A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS 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
    • A61L31/00—Materials 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials

Definitions

  • Cell proliferation inhibiting member cell metastasis inhibiting member, cell proliferation inhibiting method, cell metastasis inhibiting method, laminated film and medical device
  • the present invention relates to a cell growth suppressing member, a cell metastasis suppressing member, a cell proliferation suppressing method, a cell migration suppressing method, a laminated film and a medical device.
  • cancer treatment mainly consists of surgical treatment for resecting a tumor by surgery or the like, and acupuncture using an anti-cancer drug (anti-cancer drug) that selectively inhibits the growth of cancer (tumor) cells. It is
  • Surgical treatment is effective for treatment of solid tumors, but can not cope well with leukemia, lymphoma and metastatic cancer cells.
  • Chemotherapy with anticancer drugs is effective against leukemia and lymphoma.
  • tumor cells and normal cells show similar properties, so there are few anticancer drugs that show excellent selective toxicity.
  • anticancer drugs have different therapeutic effects for each patient, and it is difficult to predict their effects before the administration of anticancer drugs.
  • the anticancer drug which often causes side effects due to the administration of the anticancer drug, causes the patient to suffer undue pain.
  • Patent Document 1 a hydrophobic organic solvent solution of a biodegradable and amphiphilic single polymer or a polymer mixture consisting of a biodegradable polymer and an amphiphilic polymer is cast on a substrate, A HA-CAM structure film obtained by evaporating on a surface of an organic solvent solution (cast liquid) cast simultaneously with evaporating the solvent and evaporating fine water droplets generated by the condensation is described or a stretched film thereof. . And, when rat fetal heart-derived cardiomyocytes are cultured on this polymer film, since the cells were well expanded, this polymer film is considered to be useful as a substrate for cell culture.
  • Patent Document 2 describes the method described in Patent Document 1 in the same manner as the film described above.
  • a hemofilter membrane having a cam-like structure with a specific pore size and pore size variation that is formed is described. This filtration membrane is for removing white blood cells from whole blood for blood transfusion.
  • a medical device such as a stent has been kept in the body.
  • biliary stents and ureteral stents are known as medical tools for dilation of ureteral ducts and strictures due to stenosis or obstruction due to cancer.
  • Patent Document 3 a coating layer is provided on the surface of a medical device such as stent, and from this coating layer, a physiologically active substance capable of suppressing the growth of cancer cells such as a cancer drug is released over time. Medical devices that have been designed to
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2002-335949
  • Patent Document 2 Japanese Unexamined Patent Application Publication No. 2003-149096
  • Patent Document 3 JP 2001-512354 (W098 Z36784)
  • the present invention has been made in view of the circumstances of the prior art as described above, and exhibits a cytostatic action or a cytostatic action even without using a physiologically active substance such as an anticancer drug, and a medical device It is an object of the present invention to provide a material suitable for constructing the
  • the present inventors by a method similar to the method described in Patent Documents 1 and 2, select a resin such as 1, 2-polybutadiene (note that, in the present specification, a resin is generally used). A solution of an organic solvent (including rubber) is also cast on the substrate to obtain a film having a porous structure. Then, when this film was placed in a culture medium and culture of various tumor cells was tried on the film, the growth of tumor cells was remarkably remarkable contrary to the example for cardiomyocytes of Patent Document 1. I found it to be suppressed.
  • an organic solvent solution containing a resin composition obtained by adding a predetermined amount of an anti-oxidation agent to a resin such as 1,2-polybutadiene is applied onto a substrate by the same method as described above.
  • a film having a porous structure was obtained, this film was placed in a culture medium, and culture of various tumor cells was attempted on the film.
  • this film significantly suppresses the growth of tumor cells, and is resistant to deterioration in the body which is difficult to oxidatively deteriorate even when stored for a long period of time, and is suitable for constructing a medical device. I found that.
  • the inventors of the present invention have the mechanical strength of the film so that the film is less likely to be damaged. As a result of examining the improvement of the degree (film strength), it was found that the method of laminating with another film to make a laminated film is preferable.
  • a cell proliferation suppressing member characterized by having a porous structure.
  • the cell growth suppressing member according to any one of (1) to (3), which is a film obtained by releasing the film, or a stretched film thereof.
  • a cell metastasis suppressing member characterized by having a porous structure.
  • An organic solvent solution containing a resin composition is cast on a substrate to evaporate the organic solvent and cause condensation on the surface of the organic solvent solution, thereby evaporating water droplets generated by the condensation.
  • (12) to (14) which is a film obtained by releasing the film, or a stretched film thereof.
  • the average pore diameter of the pores constituting the porous structure is 0.1 to 1: LOO / zm.
  • the following medical grade (23) is provided.
  • the cell proliferation suppressing member according to any one of (1) to (9), or all or part of the surface of a medical device substrate according to any one of (1) to (9), or any one of (12) to (20) A medical device characterized in that it is covered with a cell metastasis suppressing member.
  • a cell growth suppressing member and a cell growth suppressing member suitable for constituting a medical device which exhibit an excellent cell growth suppressing action without using a physiologically active substance, are hard to be damaged and hardly deteriorate.
  • a laminated film is provided.
  • a method for cell growth suppression using the cell growth suppression member of the present invention and a medical device in which this member is coated on a medical device substrate.
  • a cell metastasis suppressing member and a laminated film suitable for constituting a medical device which exhibit excellent cell metastasis suppressing action without using a physiologically active substance, are hard to break and hardly deteriorate, are provided.
  • a method for cell metastasis suppression using the cell metastasis suppressor of the present invention and a medical device in which the medical device substrate is coated with this member.
  • the cell proliferation suppressing member, the cell metastasis inhibiting member, the cell proliferation inhibiting method, the cell proliferation inhibiting method, the laminated film and the medical device of the present invention the cell proliferation inhibiting action and the Z without using a physiologically active substance Alternatively, since it can exert a cell metastasis suppressive action, it is possible to avoid the side effect of a physiologically active substance.
  • FIG. 1 is a sketch diagram of an optical micrograph of a cell proliferation suppressing member in which pores constituting a porous structure are arranged in a honeycomb manner.
  • FIG. 2 is a cross-sectional view of a tumor cell culture plate used in Example 1.
  • Example 1 the gallbladder cancer-derived cell line of the cell growth suppressing member according to the example
  • Example 2 the gallbladder cancer-derived cell line of the cell growth suppressing member according to the example
  • FIG. 5 is a histogram showing the results of examining the growth inhibitory action of a cell growth suppressing member on a common cholangiocarcinoma-derived cell line (TFK-1) in Example 1.
  • FIG. 6 is a histogram showing the results of examining the growth inhibitory action of a cell growth suppressing member on a common cholangiocarcinoma-derived cell line (TFK-1) in Example 2.
  • FIG. 7 is a histogram showing the results of examining the growth inhibitory action of a cell growth suppressing member on a malignant melanoma-derived cell line (MeWo) in Example 1.
  • FIG. 8 is a histogram showing the results of examining the growth inhibitory action of the cell growth suppressing member on a malignant melanoma-derived cell line (MeWo) in Example 2.
  • Example 1 the breast cancer-derived cell line of the cell growth inhibitory member (MDA-MB- 4
  • Example 2 a breast cancer-derived cell line (MDA-MB- 4) of the cell growth suppressing member
  • FIG. 11 A diagram summarizing the results of Example 1, and showing the growth inhibitory action of various cell growth suppressing members on various tumor cells (56 strains).
  • FIG. 12 is a diagram summarizing the results of Example 2, and showing the growth inhibitory action of various cell growth suppressing members on various tumor cells (56 strains).
  • FIG. 13 A diagram showing the results of examining the infiltration suppressing effect of PCL flat membranes on tumor cells (SAS) in Example 3, (a) is a microscope image at 100 times magnification, (b) is a microscopic image. It is a microscope image with a magnification of 200 times.
  • FIG. 14 A diagram showing the results of examining the infiltration inhibitory effect of the cell metastasis inhibiting member according to the present invention on tumor cells (SAS) in Example 3, and (a) is a microscopic image at 100 times magnification. (B) is a microscope image of 200 ⁇ magnification, and (c) is a microscope image of 400 ⁇ magnification.
  • SAS tumor cells
  • the cell growth suppressing member of the present invention is characterized by having a porous structure, and exerts a cell growth suppressing action.
  • the cytostatic activity refers to the activity of inhibiting the growth of tumor cells (including cancer cells) and the activity of killing Z or tumor cells.
  • the cell growth suppressing member of the present invention when the cell growth suppressing member of the present invention is disposed in a medium, and a cell line of tumor cells is seeded on this member to culture the cells, it has a porous structure, While cells proliferate normally on flat membrane structural members, when using the cell growth suppressing member of the present invention, cell proliferation is significantly suppressed or cells are killed. Therefore, the cell proliferation suppressing member of the present invention is useful as a material or the like constituting a medical device.
  • the porous structure is formed at least on the surface portion.
  • the respective pores of the porous structure have a continuous porous structure in which the pores of the porous structure communicate with each other in the interior of the member.
  • the holes constituting the porous structure may be through holes, non-through holes!
  • the opening shape of each hole of the porous structure may be any shape such as a circular shape, an elliptical shape, a square shape, a rectangular shape, or a hexagonal shape which is not particularly limited.
  • the average pore diameter of the pores constituting the porous structure is usually 0.50 to: LOO / zm, 0.1 to 1: LOO / zm. It is more preferable that the force S be S preferably 0.1 to 20 / ⁇ ⁇ 0 0.5 to L 0 m. Such an average By forming the porous structure from pores having a pore size, it is possible to obtain a member having a more excellent cell proliferation inhibitory action.
  • the hole diameter refers to the diameter of the largest inscribed circle with respect to the opening shape of the hole, and for example, when the hole opening shape is a substantially circular shape, it refers to the diameter of the circle. In the case of an oval shape, it refers to the minor axis of the ellipse, in the case of a substantially square shape it refers to the length of the side of the square, and in the case of a substantially rectangular shape, the length of the short side of the rectangle Point to the The measurement of the pore size can be performed using a scanning electron microscope (SEM) or the like.
  • SEM scanning electron microscope
  • the width between the pores constituting the porous structure is preferably 0.01 to 50 m. It is more preferable that it is -10 m.
  • the stem width is a hole constituting the porous structure in the cell proliferation suppressing member, and means the average value of the shortest distance between adjacent holes.
  • the stem width can be measured using a scanning electron microscope (SEM) or the like.
  • the porosity of the cell growth suppressing member of the present invention is not particularly limited !, but is preferably 10 to 90%, and more preferably 20 to 80%. More preferably, it is 70%.
  • the porosity means the ratio of the area occupied by the openings of the pores constituting the porous structure on the surface of the portion where the porous structure of the cell proliferation suppressing member of the present invention is present.
  • the porosity can be calculated, for example, using a photograph such as a scanning electron microscope (SEM) using a known image analysis software Scion Image (Scion Corporation). More specifically, it is as follows. When using SEM pictures, the holes appear black and round, and the stems appear white.
  • the porosity can be determined by [(total surface area of pores: total surface area of black portion) ⁇ (surface area of cell proliferation suppressing member: total surface area of total white and black portions) x 100].
  • the pores constituting the porous structure are regularly arranged and preferably arranged in a honeycomb manner.
  • the holes constituting the porous structure are arranged in the form of a hard cam, and the like, and the holes are the same as the arrangement in the case where the circle having the diameter is close-packed flatly. It indicates that the cells are arranged in the cell growth suppressing member, and the size and shape of each hole and the distance between the holes are not intended to be limited at all.
  • a sketch of an optical micrograph of a cell proliferation suppressing member in which the pores constituting the porous structure are arranged in a honeycomb-like manner is shown in FIG.
  • the material for the cell proliferation suppressing member of the present invention is not particularly limited as long as it can form a porous structure, but from the viewpoint of ease of coating on a medical device, it is preferable to be a resin. In addition, glass, ceramic or the like may be contained to improve the durability.
  • the resin that constitutes the cell growth suppressing member of the present invention No particular limitation is imposed on the resin that constitutes the cell growth suppressing member of the present invention, and the deviation of non-biodegradable resin and biodegradable resin can also be used.
  • a non-biodegradable resin which is not easily degraded in vivo.
  • the resin be soluble in an organic solvent.
  • the resin constituting the cell growth suppressing member of the present invention include polybutadiene (1,2 polybutadiene, 1,4 polybutadiene), polyisoprene, styrene butadiene copolymer, styrene-isoprene copolymer, Conjugated gen-type polymers such as acrylonitrile-butadiene-styrene copolymer; poly ⁇ -force prorataton; polyurethane; cellulose acetate, cenoreloid, cenolerose pate, casserole cenorerose such as acetinole cenorelose, cellophane cenorelase type r3 ⁇ 4 6, polyamides such as positamide 66, positamide 610, positamide 612, positamide 12, polyamide 46, and the like; polyamide based polymers such as polytetrafluoroethylene; polytetrafluoroethylene, polytrifluoroethylene
  • phenol resin amino resin Formaldehyde polymers such as urea resin, melamine resin and benzoguanamine resin
  • polyester polymers such as polybutylene terephthalate, polyethylene terephthalate and polyethylene naphthalate
  • epoxy resin poly (meth) acrylate (Meth) acrylic polymers such as sters, poly (2-hydroxy-) atalylate, methacrylate ester / cobalt acetate copolymer
  • norbornene resin silicone resin
  • polylactic acid, polyhydroxybutyric acid, polyglycolic acid And polymers of hydroxycarboxylic acids such as These can be used singly or in combination of two or more.
  • a cell growth suppressing member having an excellent cell growth suppressing action since a cell growth suppressing member having an excellent cell growth suppressing action can be obtained, the use of a conjugated gen polymer, a styrenic polymer or a polyurethane is preferred. 1, 2-polybutadiene The use of is particularly preferred.
  • an amphipathic substance may be added to the resin constituting the cell growth suppressing member of the present invention.
  • the amphiphilic substance to be added polyethylene glycol-polypropylene daly block copolymer; an acrylamide polymer as a main chain skeleton, a parent having both a dodecyl group as a hydrophobic side chain and a ratatose group or a carboxyl group as a hydrophilic side chain.
  • Hyperlipidates Ion complexes of hyperphilic polymers such as heparin and dextran sulfate, nucleic acids (DNA and RNA) and long-chain alkyl ammonium salts; Water-soluble proteins such as gelatin, collagen and albumin Amphiphilic resins with a hydrophilic group; polylactic acid-polyethylene glycol block copolymers, poly ⁇ monoprolatatone polyethylene glycol block copolymers, polymalic acid-polymalic acid alkyl ester block copolymers, etc. amphiphilic Resin; and the like.
  • the cell growth suppressing member of the present invention exhibits a cell growth suppressing action without the addition of a physiologically active substance, so from the viewpoint of avoiding a side effect, a physiologically active substance having a cell growth suppressing action It is preferred not to add quality. However, in order to obtain a stronger cell growth inhibitory action, a physiologically active substance having a cell proliferation inhibitory action may be added. Even in this case, since a sufficient cell growth inhibitory action can be obtained with a smaller addition amount as compared with the conventional case, the side effects due to the physiologically active substance can be significantly reduced.
  • the cell growth suppressing member of the present invention is preferably composed of a resin composition containing an anti-acid agent in addition to the above-mentioned resin.
  • a member having a porous structure is easily deteriorated due to its large specific surface area, but the addition of an anti-acid agent prevents the acid deterioration and enables long-term storage, and also in the body. Deterioration can also occur.
  • the antioxidative agent there are no particular limitations on the antioxidative agent to be used, and for example, it is preferable to use a phenolic antioxidant, a phosphorous antioxidant, an amine antioxidant, an aqueous antioxidant, etc. Can. Among these, it is preferable to use a phenol-based acid inhibitor and a phosphorus-based acid inhibitor together with a phenol-based acid inhibitor and a Z- or phosphorus-based acid inhibitor. Especially preferred.
  • One of the antioxidants may be used alone, or two or more thereof may be used in combination.
  • phenol-based anti-acid agents include: 2 tert-butyl 6- (3 tert-butyl-2 hydroxy- 1 5-methyl benzyl) 4- methylphenyl atalylate, 2, 4 di-tert-amylou 6-[1-(3, 5 di-tertiary amylu 2 hydroxyphenyl) ethyl] phenyl atarylated phenolic compounds such as atarilate; 2,6 di-tert-butyl-4-methylphenol, 2, 6 Tertiary butyl-4 hydroxyethyl phenol, octadecyl 3-(3, 5 di tertiary butyl 4 hydroxy phenyl) propionate, 2, 2, 1 methylene one bis (4 methyl 6-tertiary butyl phenol), 4, 4, -Butylidene-bis (6-tert-butyl-m-taresol), 4-, 4-thiobis (3-methyl-6-tert-butylphenol), bis (3-cycloxane-
  • phosphorus-based antioxidants include triphenyl phosphite, diphenylisodecyl phosphite, ferridiisodecyl phosphite, tris (no-phenyl) phosphite, and tris (zino-phenyl) phosphite, Tris (2,4 di-tert-butylphenyl) phosphite, tris (2 tert-butyl 4-methylphenyl) phosphite, tris (cyclohexylene) phosphite, 2, 2-methylenebis (4, 6 di-tert-butylphenyl) octyl phosphite, 9, 10 dihydro-9 oxa 10, phosphaphenanthrene 10-oxide, 10- (3, 5-di-tert-butyl 4-hydroxybenzyl) 9, 10 dihydro-l 9- oxa 10 Phosphaphenanthrene 10 Oxide, 10
  • di-type antioxidants examples include dilauryl 3,3'-thiodipropionate, dimyristyl 3,3,1-thiodipropionate, distearyl 3,3,1-thiodipropionate, lauryl stearyl 3 , 3, 1-thiodipropionate, pentaerythritol-tetrakis-( ⁇ lauryl thiopropionate), 3, 9 bis (2 dodecyl thioethyl) 2, 4, 8, 10-tetraoxaspiro [5, 5 ] Undecane etc. can be mentioned.
  • the amount of the anti-acid agent (total amount when two or more types are used) is not particularly limited, but preferably 0.1 to 5 parts by weight with respect to 100 parts by weight of the resin used. More preferably 0.5 to 2 parts by weight.
  • the shape of the cell growth suppressing member of the present invention is not particularly limited, but is preferably in the form of a film.
  • the cell growth suppressing member of the present invention is a film-like material, it may be a film consisting of a single layer or a laminated film consisting of a plurality of layers.
  • a film may be formed on a substrate (for example, plastic, glass, etc.) It may be a laminated material.
  • the film thickness is not particularly limited. 0.50 to 50: preferred from the force of LOO / zm, 0.5 to 20 m The power of certain ⁇ ⁇ more preferred.
  • the cell growth suppressing member of the present invention is a laminated film of a resin film (second resin film) having a porous structure and another resin film (first resin film).
  • first resin film a resin film having a porous structure
  • second resin film another resin film
  • first resin film a resin film having a porous structure
  • second resin film another resin film
  • the mechanical strength (film strength) of the film is enhanced and the film is less likely to be damaged. Therefore, even when the cell growth suppressing member of the present invention, which is the laminated film of the present invention, is covered on the surface of a medical device substrate such as a stent substrate, the member can be installed and used in the body. It becomes possible to maintain the cell proliferation suppressing action which is difficult to damage the film for a long time.
  • the first resin film is a resin film laminated to a second resin film having a porous structure, and has a role of reinforcing the second resin film.
  • the first resin film has a role of reinforcing the second resin film, It is not particularly limited.
  • the first resin film may be, for example, a non-porous film (flat membrane) or a film having a porous structure.
  • a film having a porous structure is used as the first resin film, in the first resin film, the holes constituting the porous structure to be described later are arranged in a honeycomb pattern. You may use a film of the same form as the film used as the second resin film.
  • the first resin film may be a film having a single layer strength or a film having a plurality of layer strengths.
  • these layers may be composed of layers of the same form, or may be composed of layers of different forms.
  • the pore diameter of the pores forming the porous structure in the case of using a film having a porous structure as the first resin film is not particularly limited, but may be in the range of 0.1 to 500 m. It is more preferable that it is in the preferred range of 0. 1 to 1: LOO / zm.
  • polystyrene 1,2 polybutadiene, 1,4 polybutadiene
  • polyisoprene 1,2 polybutadiene, 1,4 polybutadiene
  • polyisoprene 1,4 polybutadiene
  • styrene butadiene copolymer 1,4 polybutadiene
  • styrene isoprene copolymer acrylico-tolyl butadiene-styrene copolymer, etc.
  • conjugated diene polymers poly epsilon - ⁇ Pu ⁇ easier Bokun; Pojikuretan; polyamide, 6, Pojiamido, 66, Pojiamido, 610, Pojiamido, 612, polyamide 12, polyamide-based polymers such as polyamide 46; polybutylene terephthalate, Polyester-based polymers such as poly (ethylene terephthalate) and polyethylene naphthalate; cenolose-based polymers such as cenolerose acetate, cenoreloid, cenolerose with correct acid, acetinolecenorelose and cellophane; polytetrafluoroethylene, polytrifluoroethylene , Perfull Fluoropolymers such as ethylene-propylene copolymer; polystyrene, styrene-ethylene-propylene copolymer, styrene-ethylene-butylene copolymer, chlorinated polyethylene-acrylonit
  • Olefin polymers such as phenol resin, amino resin, urea resin, melamine resin, benzoguanamine resin; epoxy resin; poly (meth) acrylic acid ester, poly 2-hydroxy ethyl (Meth) acrylic polymers such as atalylate, methacrylate ester / co-acetate copolymer; norbornene resin; silicone resin; polymer of hydroxycarboxylic acid such as polylactic acid, polyhydroxybutyric acid, polyglycolic acid; etc. Are listed. These can be used alone or in combination of two or more.
  • a polyurethane which is preferably used, such as a conjugated gen polymer, a polyurethane, a polyamide polymer, and a polyester polymer.
  • the method for producing the first resin film is not particularly limited, and a conventionally known molding method can be employed. For example, a heat melt molding method, a solution casting method, etc. may be mentioned. Also, the first resin film may be stretched.
  • the first resin film When a film having a porous structure is used as the first resin film, a method similar to the method for producing the cell proliferation suppressing member of the present invention, which is a film-like material described later, is used. It can also be used to produce the first resin film.
  • the thickness of the first resin film obtained as described above is not particularly limited, but usually 1 to 500 m, preferably 1
  • the present invention is not limited to the one comprising only the first resin film and the second resin film, for example, another film And the like may be included.
  • the method for producing the cell growth suppressing member of the present invention is not particularly limited.
  • an organic solvent solution containing the above-mentioned resin and a resin composition containing an antioxidant if desired is cast on a substrate.
  • an organic solvent solution containing (1) a resin composition and, optionally, a resin composition containing an acid inhibitor is cast on a substrate and sprayed with a high humidity gas.
  • a method of gradually evaporating the organic solvent and condensing moisture in the high-humidity gas on the surface of the cast liquid to evaporate water droplets generated by the condensation, or Solvent solution containing the resin composition containing the agent is cast on a substrate under gas with a relative humidity of 50 to 95% to evaporate the organic solvent and to condense moisture in the gas on the surface of the cast liquid
  • a method of evaporating water droplets generated by the condensation is cast on a substrate under gas with a relative humidity of 50 to 95%.
  • the organic solvent used be non-water soluble because it is necessary to form water droplet particles on the surface of the cast liquid. ,.
  • organic solvent to be used examples include halogenated hydrocarbon solvents such as chloroform and methylene chloride; saturated hydrocarbon solvents such as n-pentane, n-hexane and n-heptane; cyclopentane and cyclohexane Alicyclic hydrocarbon solvents such as benzene; aromatic hydrocarbon solvents such as benzene, toluene and xylene; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as jetyl ketone and methyl isopyl ketone; Carbon and the like. These organic solvents can be used alone or as a mixed solvent of two or more of them.
  • halogenated hydrocarbon solvents such as chloroform and methylene chloride
  • saturated hydrocarbon solvents such as n-pentane, n-hexane and n-heptane
  • cyclopentane and cyclohexane Alicyclic
  • the concentration of fat dissolved in an organic solvent is preferably 0.01 to 10% by weight, more preferably 0.05 to 5% by weight.
  • the resin concentration is lower than 0.01% by weight, the mechanical strength of the resulting film is insufficient and it is not desirable.
  • the concentration of fat is 10% by weight or more, the desired porous structure may not be obtained.
  • Cap resin amphipathic resin
  • the amount to which the amphiphilic substance is added is preferably 99: 1 to 50:50 in weight ratio of resin: amphipathic substance.
  • an inorganic substrate such as a glass substrate, a metal substrate, a silicon substrate, etc .; an organic material such as polypropylene, polyethylene, polyether ketone etc.
  • Substrates include liquid substrates that can also be liquid such as water, liquid paraffin, liquid polyethers, and the like.
  • the pore diameter of the hole is adjusted to the resin concentration and amount of the solution to be cast and supplied to the support layer such as petri dish, and there is an atmosphere !, the temperature of the blowing gas and Z or the humidity and the flow rate of the blowing gas It can be controlled by control or by controlling the evaporation speed and Z or condensation speed of the solvent.
  • the high-humidity gas sprayed onto the cast liquid may be any humidity capable of causing moisture in the gas to condense on the surface of the cast liquid, but one having a relative humidity of 20 to 100% is preferred 30 to 80 % Is more preferable.
  • the gas air; inert gas such as nitrogen, argon or the like can be used.
  • the flow rate of the high-humidity gas sprayed on the cast liquid can be such that the water content of the gas can be condensed on the cast liquid surface and the solvent used in the cast can be evaporated.
  • the time for spraying the high-humidity gas is 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 spraying a high humidity gas may be a temperature at which the solvent used for casting can evaporate, but a temperature of 5 to 80 ° C. is desirable.
  • the method for producing the laminated film is not particularly limited.
  • An organic solvent solution hereinafter sometimes referred to as “resin solution”
  • resin solution An organic solvent solution containing resin used to form a fat film is cast, and the organic solvent is evaporated and the cast organic solvent solution is formed on the surface.
  • a method of causing condensation and evaporating a water droplet generated by the condensation may be mentioned, and the method (a) is preferable from the viewpoint of simplicity.
  • a film having a porous structure at least on its surface prepared as described above can be used as it is as a cell proliferation member. Force obtained by stretching this film A film can also be used as a cell proliferation inhibiting member.
  • the method for stretching the film is not particularly limited, and for example, it can be performed 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 or biaxial stretching.
  • the elongation rate in the stretching direction is not particularly limited.
  • the force is preferably in the range of 1. 1 to 10 times.
  • the stretching can also be performed by covering the cell growth inhibitory film of the present invention on a medical device base and expanding the medical device base. That is, by expanding the medical device substrate coated with the cell growth suppression film of the present invention, a stretched cell growth suppression film can be obtained.
  • the resin composition may be molded into a desired shape and size using a printing method such as an inkjet method or a screen method.
  • the surface may be further formed using a photolithography method or the like.
  • the method for suppressing cell growth of the present invention is characterized by suppressing the growth of cells in the contact portion by bringing the portion in which the porous structure of the cell growth suppressing member of the present invention is formed into contact with cells. .
  • the contact portion is obtained by bringing the surface portion of the cell growth suppressing member of the present invention into contact with cells.
  • the application target of the cell growth suppression method of the present invention is not particularly limited as long as it is a cell, but a tumor cell is preferable.
  • the tumor cells may be benign tumor cells or malignant tumor cells (cancer cells).
  • the above tumor may be an epithelial tumor that is a squamous epithelial 'glandular epithelial tumor, or a non-epithelial tumor that is a connective tissue' blood vessel ⁇ hematopoietic tissue ⁇ muscle tissue ⁇ nerve tissue tumor.
  • Malignant epithelial tumors include carcinoma, and malignant non-epithelial tumors include sarcoma, leukemia and the like. More specifically, oral squamous cell carcinoma (e.g. gingiva, tongue), squamous cell carcinoma (e.g. esophageal cancer, lung cancer, cervical cancer, skin cancer), adenocarcinoma (e.g.
  • the cell metastasis suppressing member of the present invention is characterized in that a porous structure is formed, and exerts a cell metastasis suppressing action. At this time, it is preferable that the cell metastasis suppressing member has a porous structure formed on at least a surface portion thereof.
  • cell metastasis refers to a phenomenon in which cells, in particular tumor cells, are transported to a place away from the primary site, and established and proliferated there. Metastasis may occur through processes such as migration of tumor cells from the main tumor, invasion and transport into the vessel, colonization and extravasation of the vessel wall, and growth at that site. Known! /.
  • the cell metastasis suppressing member according to the present invention is a member capable of suppressing the invasion of the tumor cells into peripheral yarns and weaves such as vessels, among the above-mentioned steps. It can suppress the metastasis of sexual tumors.
  • Cell metastasis suppression is also intended to suppress or arrest metastasis 100%.
  • the cell metastasis-suppressing member of the present invention has a function to inhibit tumor cell metastasis
  • tumor cells are layered on collagen gel containing human fetal fibroblasts
  • culture is carried out by bringing the cell metastasis-inhibiting member into contact with the tumor cells and in the case where the culture is carried out without bringing the cell metastasis-inhibition member into contact with the tumor cells V.
  • This evaluation method is a method uniquely devised by the present inventors after intensive studies.
  • the culture medium liquid
  • the cell metastasis suppressing member the test substance
  • the two can not be brought into close contact with each other. It was not possible to evaluate the infiltration suppressing ability of the substance.
  • the surface of the tumor cell layer is in contact with air (strictly, 5% (v / v) CO, 95% (v / v) air), and
  • Methods of evaluating tumor cell infiltration in vitro include conventionally known methods other than the above-mentioned methods (eg, Albini A, Iwamoto Y, Kleinman, Martin GR, Aaronson SA, Kozlowski JM, A cancer in vitro assay f or quantitating the invasive potential of tumor cells.
  • 'Cancer Res. 1987 Jun 15; 47 (12): 3239-45. Miyazaki YJ, Hamada J, Tada M, F uruuchi K, Takahashi Y, Kondo S, Katoh H, Moriuchi T. "HOX D3 enhances motility and invasiveness through the TGF- beta depend ent and-independent pathways in A549 cells.” Oncogene.
  • tumor cells contacted with a cell metastasis-inhibiting member and tumor cells not contacted are transplanted into the body (subcutaneous, abdominal cavity or thoracic cavity) of experimental animals such as mice and rats, respectively, and after a certain period of time, transplantation is carried out. Isolated the surrounding tissue and evaluate the presence or absence of tumor cell infiltration around the tumor and metastasis to the lymph node and other organs by staining, etc.
  • a cell metastasis suppressor is introduced into the affected area where the tumor arose,
  • a method is available in which peripheral tissues after a lapse of time are compared with peripheral tissues of the affected area by introducing a cell migration-suppressing member.
  • the same materials as those of the cell proliferation suppressing member described above can be suitably exemplified, and the material can be manufactured by the same manufacturing method.
  • the application target of the cell metastasis suppression method is not particularly limited as long as it is a cell, but a tumor cell is preferable.
  • the tumor cells may be benign tumor cells or malignant tumor cells (cancer cells).
  • the above tumor may be an epithelial tumor which is a squamous epithelial 'glandular epithelial tumor or a non-epithelial tumor which is a tumor of a connective tissue' blood vessel ', hematopoietic tissue, muscle tissue, nerve tissue.
  • Malignant epithelial tumors include carcinoma, and malignant non-epithelial tumors include sarcoma, leukemia and the like. More specifically, oral squamous cell carcinoma (e.g. gingiva, tongue), squamous cell carcinoma (e.g. esophageal cancer, lung cancer, cervical cancer, skin cancer), adenocarcinoma (e.g.
  • intrahepatic cholangiocarcinoma intrahepatic cholangiocarcinoma, common cholangiocarcinoma, Gallbladder cancer, breast cancer, renal cancer, stomach cancer, splenic cancer, thyroid cancer, prostate cancer, colon cancer, lung cancer), hepatocellular carcinoma, bladder cancer (transitional cell carcinoma), ovarian cancer, glioblastoma, malignant black Tumors, osteosarcoma, fibrosarcoma, neuroblastoma, choriocarcinoma and the like. 5) Medical Tools
  • the medical device of the present invention is characterized in that the whole or a part of the surface of the medical device substrate is coated with the cell proliferation suppressing member or the cell metastasis suppressing member of the present invention.
  • the medical device substrate is a substrate that can be used as a medical device by covering the cell proliferation suppressing member or the cell metastasis suppressing member of the present invention, but even if it is used alone, it can be used as a medical treatment. It may be used as a tool.
  • the medical device of the present invention is coated with a member that exhibits cytostatic and Z or cell migration inhibitory effects on tumor cells, so that the cancer can be progressed at the contact portion of the member. It can be suppressed.
  • cytostatic action and for inhibiting Z or cell metastasis are exhibited without the need for a physiologically active substance such as an anticancer drug, it is possible to avoid the side effects due to the physiologically active substance.
  • the medical device of the present invention is preferably a stent such as a stent, a catheter, a medical tube or the like, preferably a stent placed in a body lumen narrowed or occluded by tumor cells. Preferably there.
  • stents examples include ureteral stents, biliary stents, airway stents, esophageal stents, colon stents and the like.
  • the medical device of the present invention is a catheter based stent placed in a digestive system internal lumen such as bile duct, esophagus, duodenum, large intestine, etc. It is preferable to use one having a porous structure consisting of through holes, an average pore diameter of 0.1 to 20 / ⁇ , and a variation coefficient of the pore diameter of 30% or less. By coating such a member, it is possible to obtain a digestive system stent having functions not only for cell growth suppression but also for permeating digestive fluid and digestive enzymes contained therein and not permeating tumor cells. .
  • the method of coating the cell proliferation suppressing member or the cell metastasis suppressing member (hereinafter sometimes referred to as “the member of the present invention”) of the present invention on the medical device substrate For example, (.alpha.)
  • the method of coating the medical device substrate after producing the member of the present invention may be mentioned.
  • the first resin film and the second resin film are separately produced and A second resin film on the medical device substrate, and A method of coating a first resin film on the second resin film, ( ⁇ ) coating a second resin film on a medical device substrate, and forming a second resin film on the second resin film; And a method of forming a resin film of In these cases, adhesion can be obtained simply by bringing the manufactured member of the present invention into contact with the surface of the medical device base, but if necessary, means such as fusion with an adhesive or solvent, fusion with heat, etc. May be used.
  • the shape of the stent base is not particularly limited as long as it is a tubular body, but in general, it is a tubular body in which linear bodies or strip bodies are connected in a network to form a peripheral wall.
  • the wire diameter in the case where the stent base material is formed of a linear body is preferably 0.50 to: L mm.
  • the thickness is preferably in the range of 0.1 to 5 mm, preferably in the range of 0.1 to LO mm.
  • the size of the stent base as a tubular body varies depending on the size of the indwelling body lumen, but generally, the outer diameter is 2 to 30 mm, the inner diameter is 1 to 29 mm, and the length is 5 to 5 mm. It is 200 mm. In particular, when used to construct a biliary stent, it is preferable that the outer diameter is 5 to 20 mm, the inner diameter is 4 to 19 mm, and the length is 10 to 100 mm!
  • a synthetic resin or a metal is used as a material of the stent base.
  • the synthetic resin is used to some extent with hardness and elasticity, and a biocompatible resin is preferred.
  • a biocompatible resin is preferred.
  • polyolefin, polyester, fluorine resin and the like examples include polyethylene and polypropylene, and examples of the polyester include polyethylene terephthalate and polybutylene terephthalate.
  • the fluorine resin include polytetrafluoroethylene (PTFE) and ethylene.tetrafluoroethylene copolymer. And coalescence (ETFE).
  • a superelastic alloy such as a nickel titanium (Ti-Ni) alloy, a stainless steel, tantalum, titanium, a cobalt-chromium alloy and the like can be used.
  • a superelastic alloy is preferable.
  • the mechanical properties of the superalloy can be changed as appropriate by selecting the cooling processing rate and the condition of Z or final heat treatment.
  • stent base material for example, laser processing (for example, YAG laser), electrical discharge processing
  • the stent base material can be confirmed by fluoroscopy when deployed in a body lumen.
  • x-ray markers are provided.
  • the X-ray marker is formed of an X-ray contrast material (X-ray opaque material). This makes it possible to grasp the position of the stent base under radiography.
  • the radiopaque material for example, radiopaque metals such as gold, platinum, platinum-iridium alloy, platinum, silver, stainless steel, or alloys thereof are preferable.
  • the X-ray marker may be a resin molding containing an X-ray contrast material powder.
  • the X-ray contrast material powder barium sulfate, bismuth subcarbonate, tungsten powder, the above-mentioned metal powder and the like can be used.
  • the method for coating the inventive member on a stent substrate is not particularly limited, and a method for sticking the inventive member on a stent substrate can be mentioned.
  • the member of the present invention which also has a first resin film and a second resin film force
  • the stent substrate surface is coated with a second resin film, and then the second resin film is used.
  • a method of coating the first resin film on a fat film, and the like can be mentioned.
  • means such as adhesion with an adhesive or a solvent, or fusion with a heat may be used.
  • a method similar to a conventional stent may be used.
  • the stent base material is made of a highly elastic material such as a superelastic alloy
  • the stent peripheral wall is contracted, and the stent is inserted into a delivery catheter and carried to the place to be placed, and then the stent is removed.
  • the peripheral wall of the stent is expanded and deployed by taking it out of the delivery catheter.
  • it is made of a material with poor elasticity such as stent base material S stainless steel, it is necessary to externally fit the stent on the balloon catheter lane and carry it to the place where it is to be placed, and then the balloon.
  • stents are used as insulators When indwelling in the inner lumen, usually the force with which the stent base material is expanded The expansion of the stent base material may be used to stretch the coated member (film).
  • a stent which is an example of the medical device of the present invention, has a stent base coated with a member of the present invention
  • the stent can be placed in a body lumen narrowed or occluded by tumor cells to obtain tumor cells. Can prevent the narrowing of the body lumen caused by growth beyond the peripheral wall of the stent.
  • the cell growth suppressing member to be used in the present invention was produced as follows.
  • PCL resin weight average molecular weight: 70, 000 to 100, 000, hereinafter referred to as "PCL resin”
  • Cap resin (weight) Average molecular weight: 620,000, number average molecular weight: 21,000) were mixed at a weight ratio of 10: 1, and then dissolved in chloroform to prepare a fat solution (1) at a concentration of 5.
  • the prepared resin solution (1) is cast into a glass petri dish (diameter 9 cm), and then high humidity air with an relative humidity of 80% under an atmosphere of 23 ° C and a relative humidity of 35% 2.
  • OLZmin The cell growth suppression member (films A to G) having a porous structure was produced by spraying the liquid surface on a glass petri dish at a flow rate of
  • Films A to G were produced by changing the amount of the resin solution (1) cast in the above in the range of 4 to 20 mL.
  • the pore diameter, stem width and porosity of (the pores constituting) the porous structure of each of the produced films were measured and determined using a scanning electron microscope (SEM) (HITACHI, S-3500).
  • the stem width was determined by measuring the shortest distance between the holes at five arbitrary points per image and a total of 25 points using a total of five images, and calculating the average value.
  • the porosity was calculated using a SEM photograph and calculated using Scion Image software (manufactured by Scion Corporation) for image analysis.
  • PCL flat membrane (1) A film made of fat (hereinafter referred to as "PCL flat membrane (1)") was produced.
  • the cell growth suppressing member to be used in the present invention was produced as follows.
  • Films H to N were produced by changing the amount of the resin solution (2) cast in the above in the range of 4 to 20 mL.
  • the pore diameter, stem width and porosity of the pores constituting the porous structure of each of the produced films were measured and determined using a scanning electron microscope (SEM) (HITACHI, S-3500).
  • the hole diameter was determined by selecting an arbitrary 5 holes per image using a total of 5 images, and calculating the average value of the diameter of a total of 25 holes.
  • the stem width was determined by measuring the shortest distance between the holes at five arbitrary points per image and a total of 25 points using a total of five images, and calculating the average value.
  • the porosity is determined by using an SEM image and using Scion Image (Scion) software for image analysis. It calculated and calculated
  • the pore diameter, stem width, porosity and coefficient of variation of the pores constituting the porous structure of the cell proliferation suppressing member obtained by the above operation were as shown in Table 1 below, respectively.
  • PCL flat membrane (2) A film made of fat (hereinafter referred to as "PCL flat membrane (2)") was produced.
  • the cell proliferation suppressing member (films A to N) or the PCL flat membranes (1) and (2) prepared above were cut out and closely adhered to a circular cover glass (manufactured by MATSUNAMI) having a diameter of about 14 mm. Thereafter, it was placed in a well of a 24-well tissue culture plate (manufactured by Falcon). In order to fix the cover glass, a glass cylinder with an outer diameter of about 14 mm was set inside the well. In the case of control, only the above glass cylinder was set without laying the above cover glass.
  • a cross-sectional view of the tumor cell culture plate prepared above is shown in FIG.
  • DMEZF12 medium Dulbecco's modified MEM medium (available from: Nissui Pharmaceutical Co., Ltd.) and Ham's F12 medium (available from: Sigma company) in a volume of 1: 1) The culture medium was removed using an aspirator.
  • DMEZF12 medium was again injected at 1 mL per volume, and the medium was removed using an aspirator. Thereafter, DMEZF12 medium (hereinafter referred to as "DMEZF12-10% FBS") containing 10% fetal bovine serum (fetal bovine serum (FBS): manufactured by Ken Brecks Co., Ltd.) was injected at 0.95 mL per volume.
  • DMEZF12-10% FBS 10% fetal bovine serum
  • FBS fetal bovine serum
  • a suspension of various tumor cells prepared with DMEZF12-10% FBS was added at 0.05 mL / well at 1 X 10 7 ZmL, and cultured at 37 ° C for 2 to 4 days.
  • CO concentration 0.05 mL / well at 1 X 10 7 ZmL
  • the following cell lines were used as tumor cells.
  • Ca92 22 oral squamous cell carcinoma (gum), source: human science research resource bank), HSC 3 (oral squamous cell carcinoma (tongue), source: human science research resource bank), KYSE- 110 (esophageal cancer) (Squamous cell carcinoma), source: human science research resource bank), Li 7 (hepatocellular carcinoma, source: Tohoku University Institute of Aging Medicine, Medical Cell Resource Center), HuH-28 (intrahepatic cholangiocarcinoma (Adenal cancer), source: Tohoku University Institute of Aging Medicine, Medical Cell Resource Center, TFK-1 (Bobiliary ductal cancer (adenoma cancer), source: Tohoku University Institute of Aging Medicine, Medical Cell Resource Center) , GB-dl (gland cancer cancer (adrenal cancer), obtained from: Fukuoka University medical department Hideo Shimura), A549 (lung cancer (adrenal cancer), obtained from: Human Science research resource bank), Lu 99 (lung cancer (squamous epithelium)
  • SF 539 glioblastoma, source: National Cancer Institute, USA
  • SNB 75 glioblastoma, source: National Cancer Institute, USA
  • SNB-78 glioblastoma, available Destination: National Cancer Institute, USA
  • T98G glioblastoma, source: Human Science Research Resources Bank
  • AKI malignant melanoma, available from: RIKEN cell bank
  • A375M malignant melanoma, available from: Toyama Medical and Pharmaceutical University, Japanese medicine research institute Ikaki Michio
  • SaOS-2 osteosarcoma, available from: American Type Culture Collection
  • HT- 1080 fibrosarcoma, source: Human Science Research Resource Bank
  • HSC 2 oral squamous cell carcinoma, source: Human Science research resource bank
  • HSC-4 oral squamous cell carcinoma
  • Tongue Obtained from: Human Science Research Resources Bank
  • KATO III gastric cancer (adrenal cancer), Obtained from: Human science research resource bank), MKN-1 (stomach cancer (adrenal cancer), Obtained from: Human Science research resource bank), AZ- 521 (stomach cancer (adrenal cancer), source: Human science research resource bank), OCUG-1 (biliary gall bladder cancer (adrenal cancer) source: human science research resource bank), MIA PaCa
  • IMR- 32 (neuroblastoma, source: Human Science Research Resources Bank), GOTO
  • the number of cultured tumor cells was measured using Cell Counting Kit-8 (Dojindo).
  • the Cell Counting Kit- 8 produces a water-soluble formazan 4 ⁇ 3- (2- methoxy-4-nitrophenyl)-2- (4-nitrophenyl) -2H- 5-tetrazolio ⁇ -1, 3 -Benzene disulphonate sodium salt (hereinafter referred to as "WST-8".
  • WST-8 water-soluble formazan 4 ⁇ 3- (2- methoxy-4-nitrophenyl)-2- (4-nitrophenyl) -2H- 5-tetrazolio ⁇ -1, 3 -Benzene disulphonate sodium salt
  • WST-8 Dojindo Co., Ltd.
  • WST-8 is used as a chromophore
  • WST-8 is reduced by intracellular dehydrogenases to form water-soluble formazan. Since there is a linear proportional relationship between the number of cells and the water-soluble formazan, it is possible to easily determine the number of cells by measuring the absorbance value of formazan.
  • FIGs 3 and 4 show the results of gallbladder cancer-derived cell lines (GB-dl).
  • the results for the strain (TFK-1) are shown in Figure 5 and Figure 6, the results for the malignant melanoma cell line (MeWo) are shown in Figures 7 and 8, and the results for the breast cancer cell line (MDA-MB-435S) are shown. 9 and 10 show respectively.
  • the vertical axis shows the absorbance (450 nm), and the higher the absorbance, the larger the number of cells.
  • the horizontal axis shows the results for each well, and from left is control (indicated by C in the figure), and culture on a PCL flat membrane (in the figure, “FL1” when using the PCL flat membrane (1), The case of using PCL flat membrane (2) is shown as "FL 2".
  • Culture on films A to N film A in the figure is simply referred to as "A”.
  • films B to N And the same).
  • the growth of the malignant melanoma-derived cell line (MeWo) when cultured on the cell growth suppressing member is about 40% as compared to the culture on the PCL flat membrane. It was suppressed.
  • the above “about 40%” is an average value of the growth inhibitory rate (growth inhibitory action) of the tumor cells on the PCL flat membranes for the films B, D and F, and I, K and M, respectively.
  • the growth of the breast cancer cell line (MDA-MB-435S) when cultured on the cell growth-suppressing member is about compared to when grown on a PCL flat membrane. 50% was suppressed.
  • the above “about 50%” refers to the growth inhibitory rate of tumor cells on PCL flat membranes for films B, D and F, and I, K and M respectively Average value of
  • FIG. 11 shows the case where films A to G are used
  • FIG. 12 shows the case where films H to N are used.
  • evaluation of the growth inhibitory effect in FIG. 11, FIG. 12 was performed using the average value of the growth inhibitory rate (growth inhibitory effect) of the tumor cell with respect to PCL flat membrane about each of film AN.
  • The] in the column of the growth inhibitory action in FIG. 11 and FIG. 12 represents 60% or more of the cell proliferation of the culture on the PCL flat membrane when the cell proliferation is cultured on the cell proliferation suppression member.
  • the results of cells in which the cell growth inhibitory action was observed are shown, and ⁇ indicates that the cell growth when cultured on the cell growth inhibitory member is 30% or more and less than 60% of the cell growth in culture on PCL flat sheet
  • the results for cells with growth inhibitory activity were shown, and ⁇ represents cell proliferation when cultured on a cell proliferation inhibitory member, 10% or more but less than 30% of cell proliferation on culture on PCL flat membranes.
  • the results for cells with growth inhibitory activity are shown, and ⁇ indicates cell proliferation when cultured on a cell proliferation inhibitory member. Less than 10% of proliferation inhibitory activity on cell proliferation in culture on PCL flat membranes. The results of the seen cells are shown.
  • FIG. 11 from 12, Te 49 strain, i.e. 87.5 0/0 strain [trick! ⁇ of 56 Itoda ⁇ discussed, growth inhibition of 10% or more was observed.
  • the cell growth suppressing member of the present invention is a material that can be particularly used to suppress the growth of tumor cells.
  • Example 1 and Example 2 are different from Example 1 in that the acid anti-oxidant is not used, while Example 2 is the antioxidant (cyclic neopentanetetrayl bis (2, 6). -Di-Peptyl 4-methylphenyl phosphite))) but different from Example 1 and Example The cell growth inhibitory effect almost equivalent to 2 was obtained.
  • Example 2 since an antioxidant is added to the fat, oxidation degradation is prevented, long-term storage is possible, and degradation in the body also occurs. It is expected to do.
  • the pore diameter (of the pores constituting the film), the stem width, the porosity and the coefficient of variation of the porous structure of film (O) by the same method as in Example 2, the pore diameter is 12.5 / ⁇ .
  • the stem width was 5.3 ⁇ m, the porosity was 49.2%, and the coefficient of variation was 7%.
  • the purified Eagle's medium (DEM medium, manufactured by Invitrogen) and the suspension of human fetal fibroblasts are mixed at a ratio of 8: 1: 1: 0.5, and a 6-well tissue culture plate (Falcon) was injected in 3 mL Z-well.
  • the collagen gel is also peeled off by the swelling force, the collagen gel is suspended on a DEM liquid medium, and further cultured at 37 ° C for 2 days in a CO incubator (CO 5% vZv).
  • FIG. Fig. 13 (a) The microscope image when the PCL flat membrane (1) was placed on the side of the tumor cell (SAS) is shown in FIG. Fig. 13 (a) is observed at a magnification of 100 times, and Fig. 13 (b) is observed at a magnification of 200 times.
  • the area to the left of the arrow is the area covered by the PCL flat membrane (1) and the right side is the area not covered by the PCL flat membrane (1) (ie, the control area). Is shown.
  • FIG. 14 shows a microscopic image when the film (O) is placed on the side of the tumor cell (SAS).
  • Fig. 14 (a) is observed at a magnification of 100
  • Fig. 14 (b) is observed at a magnification of 200
  • Fig. 14 (c) is observed at a magnification of 400.
  • the area to the right of the arrow is covered by the porous film (O)
  • the left side is covered by the porous film (O). Show me! /.
  • film thickness 3-5 by spraying high humidity air with a relative humidity of 70% at a flow rate of 2L Zmin for 1 minute on a liquid surface on a glass petri dish under an atmosphere of 23.0 ° C and a relative humidity of 40%.
  • a zm film (P) was obtained.
  • Table 2 shows the film thickness of the film ( ⁇ ), the average pore diameter of the pores constituting the porous structure, and the variation coefficient of the pore diameter.
  • the film thickness of the obtained film (Q) and the average pore diameter of the pores constituting the porous structure and the variation coefficient of the pore diameter were measured in the same manner as described above. The measurement results are shown in Table 2.
  • film T What obtained the obtained film (P) and film (R) on each other (this is referred to as “film T”), and obtained on the film (Q) and film (S) on each other (this is called “film U”.
  • film T the film
  • film U the film
  • Each of the film (P) and the film (Q) was cut into a circle of 10 cm in diameter.
  • Each of the films (T), (U), (P) and (Q) was set in a tensile tester by being sandwiched from both sides by a chuck having a width of 10 cm and a distance between chucks of 1 cm. At this time, a 1 mm-thick silicone rubber sheet was sandwiched between the chuck and the film so that the center of the film was positioned between the chucks. Then, the film was pulled from both sides at a tensile speed of 30 mm Zmin, and the load when the film was broken (when one of the films was broken) was recorded.
  • Table 3 The test results are shown in Table 3.
  • the laminated film (T) was a film which was hard to be broken because the load at break was significantly larger than that of the single-layer resin film (P).
  • the laminated film (U) also had a load that was significantly greater than that of the single-layer resin film (Q) and was not easily broken.
  • the laminated films (T) and (U) are used by being placed in the body, they are unlikely to be damaged, and it is expected that the action to suppress cell proliferation and Z or cell metastasis is maintained for a long time.

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Abstract

La présente invention concerne (1) un élément d’inhibition de croissance cellulaire caractérisé en ce qu’il présente une structure poreuse ; (2) un procédé d’inhibition de croissance cellulaire caractérisé en ce qu’il comprend la mise en contact d’une partie présentant la structure poreuse formée dans celle-ci de l’élément d’inhibition de croissance cellulaire mentionné ci-dessus avec des cellules et inhibe ainsi la croissance des cellules dans la partie de contact ; (3) un film en plusieurs couches composé d’un premier film de résine et d’un deuxième film de résine, qui est l’élément d’inhibition de croissance cellulaire mentionné ci-dessus, appliqué en couche sur celui-ci ; (4) un élément d’inhibition de métastases cellulaires caractérisé en ce qu’il a une structure poreuse ; (5) un procédé d’inhibition des métastases cellulaires caractérisé en ce qu’il comprend la mise en contact d’une partie présentant la structure poreuse formée dans celle-ci de l’élément d’inhibition de métastases cellulaires mentionné ci-dessus avec des cellules et inhibe ainsi les métastases des cellules dans la partie de contact ; (6) un film en plusieurs couches composé d’un premier film de résine et d’un deuxième film de résine, qui est l’élément d’inhibition de métastases cellulaires mentionné ci-dessus, appliqué en couche sur celui-ci ; et (7) un instrument médical caractérisé en ce que la surface de l’instrument médical est entièrement ou partiellement recouverte avec l’élément d’inhibition de croissance cellulaire mentionné ci-dessus ou l’élément d’inhibition de métastases cellulaires mentionné ci-dessus. Ainsi, on peut obtenir un excellent effet d’inhibition de croissance cellulaire ou un excellent effet d’inhibition de métastases cellulaires sans avoir recours à une substance physiologiquement active telle qu’un agent carcinostatique.
PCT/JP2006/308980 2005-04-28 2006-04-28 Element d’inhibition de croissance cellulaire, element d’inhibition de metastases cellulaires, procede d’inhibition de croissance cellulaire, procede d’inhibition de metastases cellulaires, film en plusieurs couches et instrument medical Ceased WO2006118248A1 (fr)

Priority Applications (1)

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JP2007514835A JPWO2006118248A1 (ja) 2005-04-28 2006-04-28 細胞増殖抑制部材、細胞転移抑制部材、細胞増殖抑制方法、細胞転移抑制方法、積層フィルムおよび医療用具

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JP2009242492A (ja) * 2008-03-28 2009-10-22 Fujifilm Corp 多孔フィルムの製造方法
JP2011156083A (ja) * 2010-01-29 2011-08-18 Nippon Zeon Co Ltd 消化器系ステント
JP2012080836A (ja) * 2010-10-13 2012-04-26 Toyo Seikan Kaisha Ltd 接着細胞用培養容器、及び接着細胞用培養容器の製造方法
WO2015190541A1 (fr) * 2014-06-12 2015-12-17 国立研究開発法人国立循環器病研究センター Endoprothèse
CN105496475A (zh) * 2015-11-23 2016-04-20 安徽养和医疗器械设备有限公司 一种抗菌型介入医疗器械
KR101730482B1 (ko) 2015-07-23 2017-04-27 재단법인 한국화학융합시험연구원 신체 조직 보호용 인조포의 제조방법 및 그 인조포
US9637722B2 (en) 2013-07-09 2017-05-02 Toyoda Gosei Co., Ltd. Production method of polyurethane porous membrane to be used for at least one of applications of cell culture and cancer cell growth inhibition
CN113144297A (zh) * 2021-04-30 2021-07-23 中山大学孙逸仙纪念医院 一种用于阻断卵巢生殖细胞肿瘤扩散的薄膜材料及其制备方法

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009242492A (ja) * 2008-03-28 2009-10-22 Fujifilm Corp 多孔フィルムの製造方法
JP2011156083A (ja) * 2010-01-29 2011-08-18 Nippon Zeon Co Ltd 消化器系ステント
JP2012080836A (ja) * 2010-10-13 2012-04-26 Toyo Seikan Kaisha Ltd 接着細胞用培養容器、及び接着細胞用培養容器の製造方法
US9637722B2 (en) 2013-07-09 2017-05-02 Toyoda Gosei Co., Ltd. Production method of polyurethane porous membrane to be used for at least one of applications of cell culture and cancer cell growth inhibition
WO2015190541A1 (fr) * 2014-06-12 2015-12-17 国立研究開発法人国立循環器病研究センター Endoprothèse
KR101730482B1 (ko) 2015-07-23 2017-04-27 재단법인 한국화학융합시험연구원 신체 조직 보호용 인조포의 제조방법 및 그 인조포
CN105496475A (zh) * 2015-11-23 2016-04-20 安徽养和医疗器械设备有限公司 一种抗菌型介入医疗器械
CN113144297A (zh) * 2021-04-30 2021-07-23 中山大学孙逸仙纪念医院 一种用于阻断卵巢生殖细胞肿瘤扩散的薄膜材料及其制备方法

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