WO2009084902A2 - Stent and manufacturing method thereof - Google Patents

Stent and manufacturing method thereof Download PDF

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Publication number
WO2009084902A2
WO2009084902A2 PCT/KR2008/007785 KR2008007785W WO2009084902A2 WO 2009084902 A2 WO2009084902 A2 WO 2009084902A2 KR 2008007785 W KR2008007785 W KR 2008007785W WO 2009084902 A2 WO2009084902 A2 WO 2009084902A2
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WO
WIPO (PCT)
Prior art keywords
stent
drug
pores
metal layer
oxide layer
Prior art date
Application number
PCT/KR2008/007785
Other languages
French (fr)
Other versions
WO2009084902A3 (en
Inventor
Yang-Soo Jang
Dong-Hoon Choi
Deug-Joong Kim
Ji-Beom Yoo
Original Assignee
Dio Corporation
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Publication date
Application filed by Dio Corporation filed Critical Dio Corporation
Publication of WO2009084902A2 publication Critical patent/WO2009084902A2/en
Publication of WO2009084902A3 publication Critical patent/WO2009084902A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30107—Properties of materials and coating materials using materials or accessories for preventing galvanic or electrolytic corrosion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0009—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using materials or accessories for preventing galvanic or electrolytic corrosion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/0054—V-shaped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir

Definitions

  • the present invention relates to a stent and a method for manufacturing the same. More particularly, the present invention relates to a stent on which a protective metal layer is formed to ensure the mechanical stability that the outermost biocompatible metal oxide layer containing pores therein does not fall off even after expansion and contraction and which releases a drug loaded into the pores in a delayed pattern for a prolonged period of time, and a method for the manufacture thereof.
  • a protective metal layer is formed to ensure the mechanical stability that the outermost biocompatible metal oxide layer containing pores therein does not fall off even after expansion and contraction and which releases a drug loaded into the pores in a delayed pattern for a prolonged period of time
  • a stent generally is used when a vessel is narrowed by various factors or disorders and flow constriction results. That is, a stent is a medical instrument or support which is designed for insertion into a narrowed region of, for example, a vessel and to expand thereat in order to counteract the constriction of blood flow.
  • stent implantation There are various surgical operations for stent implantation, with highest preference given for the balloon dilatation method wherein a stent is inserted together with a balloon catheter into a vessel such as a heart blood vessel, the aorta, a brain blood vessel, etc., followed by inflation of the balloon to expand the coronary passage.
  • a vessel such as a heart blood vessel, the aorta, a brain blood vessel, etc.
  • stents Flexibility and ductility are required in order for stents to expand a narrowed region of a vessel outwards so it regains its original passage size as the balloon inflates.
  • Stents must be highly ductile so as to pass through complex and bent ducts when, for example, a balloon catheter is inserted into and fixed at a desired region and is then inflated to expand the narrowed region.
  • the stents must be flexible enough so that their structures are prevented from becoming deformed by the contraction of the vessel tissues (heart blood vessels, aorta, brain blood vessels, etc.) after completion of the operation.
  • conventional stents are made of strong corrosion resistant stainless steel.
  • stents have reduced acute occlusion and restenosis after balloon angioplasty.
  • excess neointima formation occurs, incurring restenosis at the stented vessels.
  • a stent is coated with a polymer associated with a drug so that the drug is released into the vessels to inhibit neointima formation.
  • the polymer employed for drug release causes thrombosis.
  • biocompatible materials are required for use in the surface of stents.
  • stents have evolved to have a structure that contains the drug therein.
  • a stent with a ceramic introduced into the surface thereof is disclosed in Korean Patent Application Laid-Open No. 2004-0011463.
  • an aluminum thin film is applied to the stainless steel surface and anodized to form porous nano-structures into which a drug for preventing the restenosis of vessels is then injected.
  • the material constituting the surface of the conventional stent that is, stainless steel or cobalt-chrome, is also partially corroded to reduce the bonding between the resulting oxide layer and the stent, so that the oxide layer readily falls off following even weak impact.
  • the conventional stent has the shortcoming that the drug can be released only in a very small amount for a short period of time because it is not introduced into the pores formed on the stent due to capillary phenomenon, surface tension or drug particle size, and is present only on the surface of the pores.
  • the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a stent in which the material such as stainless steel or cobalt-chrome alloy for the stent frame can be protected from attacks which may occur when a metal oxide layer is formed thereon.
  • the present invention provides a method for manufacturing a stent, comprising: forming on the surface of a stent frame a protective metal layer for prevention of corrosion; layering aluminum or titanium on the protective metal layer, followed by anodizing the aluminum or titanium layer to form a metal oxide layer having pores; and introducing a drug into the pores.
  • the method may further comprise hydrophilizing a surface of the metal oxide layer before introducing the drug into the pores.
  • the hydrophilizing step is conducted by plasma treatment, and preferably by O 2 plasma treatment.
  • the drug is an inhibitor of cell proliferation or thrombosis formation.
  • the drug is selected from the group consisting of: nitro donors; soluble guanylate cyclase (sGC) activators; Ca 2+ channel blockers; angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; cisplatin; corticosteroid; 17-beta-estradiol; cyclosporine; mycophenolic acid; VEGF or VEGF receptor activators; tranilasts; COX-2 antagonists; COX-1 inhibitors; plasminogen activator inhibitor-1 ; serpin, thrombin inhibitors, hirudin, hirulog, agratroban, PPACK or interleukin-10; rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl- taxol;
  • the drug is paclitaxel.
  • the stent frame is made of stainless steel or cobalt-chrome alloy.
  • the protective metal layer is formed of a metal selected from the group consisting of Au, Ag, R and a combination thereof.
  • the present invention provides a stent, comprising: a stent frame; an protective metal layer for prevention of corrosion which is formed on a surface of the stent frame; a metal oxide layer comprising pores therein which is formed on the protective metal layer; and a drug for inhibition of cell proliferation or thrombosis formation which is loaded into the pores.
  • the stent may be manufactured using the method of the present invention.
  • the stainless steel or cobalt-chrome alloy of the stent frame is protected from the attack which may occur upon the formation of the outermost metal oxide layer, to increase the adhesion of the metal oxide layer to the stent and thus ensure the mechanical stability even after the expansion and contraction of the stent.
  • the stent of the present invention can release a large amount of drug, for example, a cell growth inhibitor, loaded within the pores of the metal oxide layer, in a delayed pattern, thus preventing neointima formation for a prolonged period of time.
  • FIG. 1 is a schematic view showing the manufacturing processes of the stent according to the present invention.
  • FIG. 2 is of scanning electron microphotographs showing the surfaces of titanium oxides layers anodized at various voltages.
  • FlG. 3 is a scanning electron microphotograph showing a uniformly coated titanium oxide layer which remains intact after the expansion of the stent manufactured according to an embodiment of the present invention.
  • FIG. 4 is a scanning electron microphotograph showing a cross-sectional view of the stent of FIG. 3 which has a titanium oxide layer uniformly formed thereon.
  • FIG. 5 is a graph showing the drug release of the stent of the present invention in a delayed pattern (- ⁇ -: just washed with D.I. water, - A- : treated with O 2 plasma),
  • FIG. 6 shows an application example of the stent of the present invention.
  • FIG. 7 is a cross-sectional view showing the release of a drug through the pores of the metal oxide layer (e.g., titanium oxide layer) formed on the surface of the stent of the present invention.
  • the metal oxide layer e.g., titanium oxide layer
  • Stent 130 Titanium oxide layer
  • Pores 150 Drug
  • the present invention provides a method for manufacturing a stent, comprising: forming on the surface of a stent frame a protective metal layer for prevention of corrosion; layering aluminum or titanium on the protective metal layer, followed by anodizing the aluminum or titanium layer to form a metal oxide layer having pores, and introducing a drug into the pores.
  • the stent frame useful in the present invention is not coated with a polymer and may be made of stainless steel or cobalt-chrome alloy.
  • the protective metal layer on the stent frame such as stainless steel or cobalt- chrome alloy and the subsequent metal layer for anodization may be formed by conventional deposition technique.
  • the deposition technique may include, for example, physical vapor deposition, electron beam evaporation or thermal evaporation.
  • the thickness of the protective metal layer may range from 10 nm to 200 nm, but is not limited thereto. Further, the thickness of the metal layer for anodization may range from 100 nm to 2 ⁇ m, but is not limited thereto.
  • the protective metal layer may be formed of metal(s) selected from the group comprising anti-corrosive metals and precious metals. Preferably, it may be at least one selected from the group consisting of Au, Ag, R and a combination thereof.
  • the aluminum or titanium layer is oxidized by anodization to an oxide thereof, that is aluminum oxide or titanium oxide.
  • a metal oxide layer with a porous structure is formed. Injecting a drug inhibitory of thrombosis and neointima formation into the pores leads to the stent of the present invention.
  • Anodization is a process used to form an oxide layer on the surface of a metal in various shape patterns, roughnesses and crystal thicknesses depending on voltage, current, reaction time, composition and concentration of the electrolyte, and temperature.
  • anodization refers to Ishizawa H et al. (J Biomed Mater Res. 1995; 29(1): 65-72) and Zhu X et al. (2001. Biomaterials. 2001; 22: 2199-2206; J Biomed Mater Res. 2002; 60(2): 333-338).
  • potentiostatic anodization or galvanostatic anodization may be used.
  • a constant voltage of 0.1 ⁇ 100V and preferably of 0.3-40V is applied between a stent coated with metal (e.g., aluminum or titanium) as an anode and a carbon electrode as a cathode in a suitable electrolyte for 10 min ⁇ 5 hrs and preferably for 30 min ⁇ 2 hrs.
  • metal e.g., aluminum or titanium
  • the surface of the stent and/or the metal oxide layer of the porous structure may be subjected to plasma treatment to enhance wettability of inside of the pores, thereby allowing the pores to hold a large amount of the drug for as long a period of time as possible.
  • the plasma useful in the present invention may be O 2 plasma.
  • O 2 plasma treatment may be carried out by flowing oxygen at a vacuum of 10 ⁇ 100 millitorrs for 10 sec - 10 min in a radiofrequency (R.F.) plasma reactor.
  • R.F. radiofrequency
  • the stent manufactured as described above allows the drug contained in the pores to be slowly released along the passage.
  • the pores are nano structures of the metal oxides (AI 2 O 3 , TiO 2 ), porous organization, naturally formed during the anodization of aluminum or titanium. These pores may be formed in an amorphous, crumpled structure according to the condition such as the electric field applied upon anodization. Crumpled pores form can delay the release rate of drug compared to pores in a straight tube form and thus can be applied to where it is required to release a drug in a delayed pattern.
  • Non-limiting examples of the injection of a drug into the pores of the nano structure include the coating of the stent with the drug and the immersion of the stent in a drug solution, with preference for immersion in the drug solution.
  • the drug solution may be a solution of the drug in a suitable solvent such as ethanol.
  • any drug can be used in the present invention.
  • the drug useful in the present invention may be selected from the following groups and mixtures thereof: Group 1 : nitro donors; soluble guanylate cyclase (sGC) activators; Ca 2+ channel blockers; angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; cisplatin,
  • Group 2 corticosteroid; 17-beta-estradiol; cyclosporin; mycophenolic acid; VEGF or VEGF receptor activators; tranilasts; COX-2 antagonists; COX-1 inhibitors; plasminogen activator inhibitor-1 ; serpin, thrombin inhibitors, hirudin, hirulog, agratrobanm, PPACK or interieukin-10,
  • Group 3 rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl- taxol; cisplatin; binblastin; mitozantrone; combretastatin A4; topotecan; metotrexate; flavopiridol; actinomycin D; ReoPro/Abciximab or probucol; cordycepin; topoisomerase inhibitor.
  • nitro donors examples include molsidomine, linsidomine, sodium nitroprusside, and nitroglycerin, but are not limited thereto.
  • soluble guanylate cyclase (sGC) activator BAY 41-2272(5-(cyclopropyl-2[1-fluorobenzyl)-1 H- pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamin) may be used.
  • illustrative, non-limiting examples of the Ca 2+ channel blockers include hydralazine, verapamil, diltiazem, nifedipine, and nimodipine.
  • angiotensin converting enzyme inhibitors examples include captopril, enalapril, licinopril, and quinapril, but are not limited thereto.
  • Illustrative, non-limiting examples of the antiotensin receptor antagonists include rosartan, candesartan, irbesartan, and valsartan.
  • corticosteroids include dexamethasone, betamethasone, and prednisone.
  • the COX-2 antagonists may be non-limitedly exemplified by meloxicam, celebrex and vioxx. Indomethacin, diclofenac, ibuprofen, or naphroxen may be used as a COX-1 inhibitor.
  • rapamycin derivatives include sirolimus, rapamycin, and SDZ RAD (40-O-(2-hydroxyethyl)rapamycin. More preferably, the drug useful in the present invention is selected from the following groups and mixtures thereof:
  • Group 1 molsidomine, linsidomine, sodium nitroprusside, nitroglycerin; BAY 41 -2272(5-(cyclopropyl-2[1 -fluorobenzyl)-1 H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4- ylamin); captopril, enalapril, licinopril, quinapril; rasartan, candesartan, irbesartan, valsartan; cisplatin,
  • Group 2 dexamethasone, betamethasone, prednisone; VEGF or VEGF receptor activators; plasminogen activator inhibitor-1 orserpin,
  • Group 3 sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin, or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol; mitozantrone; combretastatin A4; flavopiridol; cordycepin; topoisomerase inhibitor.
  • two or more drugs may be used without limitation.
  • the stent with a structure in accordance with the present invention is operated as follows.
  • a stent 100 has a cylindrical shape and is reduced enough in volume by compression so as to be insertable into a vessel 300.
  • the stent 100 is expanded by the inflation of the balloon to forcibly widen the narrowed region.
  • the balloon catheter 200 accommodated within the stent 100 reaches the narrowed region, it is inflated to expand the stent 100 outwards.
  • its outer surface is brought into direct contact with the narrowed region of the vessel 300 to widen the narrow passage to the original diameter.
  • the balloon catheter 200 is withdrawn out of the stent 100 which can support itself, supporting the widened vessel thanks to its elasticity.
  • the drug 150 contained within the pores 135 formed in the titanium oxide layer 130 of the stent 100 of the present invention is slowly released along the passages of the pores 135 to the vessel 300.
  • the pores 135 can release the drug
  • the stent 100 of the present invention can restrain restenosis and thus allow blood to flow well after insertion into the vessel 300.
  • a stent frame made of stainless steel was washed by ultrasonication and dried.
  • a protective metal layer and a metal layer for anodization were sequentially formed over the stent frame.
  • the stent frame was coated first with gold (Au) to a thickness of 30 nm and then with titanium to a thickness of 800 nm by E-beam evaporation while being rotated at a speed of 10 rpm.
  • a potentiostatic process was used for anodization.
  • a constant voltage of 1 V was applied for 2 hrs between the titanium-coated stent frame as an anode and a carbon electrode as a cathode in an electrolyte (maintaining to 20 " C) containing NH 4 F (0.3%), H 2 O (2%) and ethylene glycol to conduct anodization.
  • the sizes of pores are dependent on the voltage applied upon anodization.
  • Experimental results accounting for the voltage dependence are shown in FIG. 2.
  • the pore size was increased from 30 nm through 40 nm to 55 nm following an increase of the voltage from 10 V through 15 V to 20 V, respectively. From this data, it can be inferred that larger pore sizes may be formed at a voltage larger than 20 V.
  • the anodized stent was ultrasonicated for 20 min, followed by drying at 8O 0 C for 23 hrs.
  • the titanium oxide layer (metal oxide layer) of the anodized stent was treated at a vacuum of 30 millitorrs with a flow of oxygen for 1 min in a radiofrequency (R. F.) reactor.
  • paclitaxel (v/v) was ultrasonicated for 20 min to provide good dissolution of paclitaxel in ethanol.
  • the anodized stent was immersed in the solution of paclitaxel in ethanol, followed by ultrasonication for 2 hrs to load the solution into the pores.
  • the drug-loaded stent thus obtained was naturally dried for 24 hrs.
  • PREPARATION EXAMPLE 2 Manufacture of Stent 2 The same procedure as in Preparation Example 1 was repeated, with the exception that an aluminum oxide layer, instead of the titanium oxide layer, was formed as follows.
  • an aluminum (Al) layer was deposited at a thickness of 1 ,000 nm by thermal evaporation. Subsequently, a constant voltage of 40 V was applied for 40 min between the aluminum-coated stent frame acting as an anode and a carbon electrode acting as a cathode in a 0.3 M oxalic acid electrolyte to conduct anodization. The anodized stent was washed for 20 min by ultrasonication and then dried at 8O 0 C for 23 hrs.
  • PREPARATION EXAMPLE 5 Manufacture of Stents The same procedure as in Preparation Example 1 was repeated with the exception that silver (Ag), instead of gold (Au), was used for the protective metal layer.
  • TEST EXAMPLE 1 Mechanical Stability
  • a balloon catheter was inserted into the stent of Preparation Example 1 and inflated to outstretch the stent which was then analyzed via scanning electron microphotographs.
  • the outermost layer of the stent that is, the titanium oxide layer remained uniformly deposited without being destroyed. Therefore, the stent of the present invention maintained excellent mechanical stability after expansion, indicating superior adhesion between the stent frame and the ceramic layer.
  • the O 2 plasma-treated stent of Preparation Example 1 was immersed in 10 cc of PBS and analyzed for drug release during incubation at 36.5 0 C for 21 days.
  • a stent in which the metal oxide layer containing pores therein was washed only with deionized (Dl) water was used. The results are given in FIG. 5.
  • the stent which was improved in wettability by treatment with O 2 plasma allowed paclitaxel to be sufficiently loaded therein and to be released in a total amount of 70 ⁇ g for 21 days, showing a suspended release pattern.
  • the stent with the metal oxide layer washed only with Dl water released the drug only for 3 ⁇ 4 days because the drug was difficult to load into the pores of the metal oxide layer and existed on the surface of the metal oxide layer. Consequently, the stent of the present invention can release a drug in a highly delayed pattern.

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Abstract

Provided are a stent and a method for manufacturing the same. On the stent is formed a protective metal layer which ensures the mechanical stability that the outermost biocompatible metal oxide layer containing pores therein does not fall off the stent frame even after expansion and contraction. Treated with plasma, the stent can release a drug loaded into the pores in a delayed pattern for a prolonged period of time.

Description

[DESCRIPTION] [Invention Title]
STENTAND MANUFACTURING METHOD THEREOF [Technical Field] The present invention relates to a stent and a method for manufacturing the same. More particularly, the present invention relates to a stent on which a protective metal layer is formed to ensure the mechanical stability that the outermost biocompatible metal oxide layer containing pores therein does not fall off even after expansion and contraction and which releases a drug loaded into the pores in a delayed pattern for a prolonged period of time, and a method for the manufacture thereof. [Background Art]
A stent generally is used when a vessel is narrowed by various factors or disorders and flow constriction results. That is, a stent is a medical instrument or support which is designed for insertion into a narrowed region of, for example, a vessel and to expand thereat in order to counteract the constriction of blood flow.
There are various surgical operations for stent implantation, with highest preference given for the balloon dilatation method wherein a stent is inserted together with a balloon catheter into a vessel such as a heart blood vessel, the aorta, a brain blood vessel, etc., followed by inflation of the balloon to expand the coronary passage.
Flexibility and ductility are required in order for stents to expand a narrowed region of a vessel outwards so it regains its original passage size as the balloon inflates. Stents must be highly ductile so as to pass through complex and bent ducts when, for example, a balloon catheter is inserted into and fixed at a desired region and is then inflated to expand the narrowed region. Also, the stents must be flexible enough so that their structures are prevented from becoming deformed by the contraction of the vessel tissues (heart blood vessels, aorta, brain blood vessels, etc.) after completion of the operation. To meet such requirements, conventional stents are made of strong corrosion resistant stainless steel.
The introduction of such metallic stents has reduced acute occlusion and restenosis after balloon angioplasty. In the course of regenerating the vessels injured by stent expansion upon balloon angioplasty, however, excess neointima formation occurs, incurring restenosis at the stented vessels. In an effort for restenosis prevention, a stent is coated with a polymer associated with a drug so that the drug is released into the vessels to inhibit neointima formation. However, a new problem arises because the polymer employed for drug release causes thrombosis. Thus, biocompatible materials are required for use in the surface of stents. In addition, stents have evolved to have a structure that contains the drug therein.
For example, a stent with a ceramic introduced into the surface thereof is disclosed in Korean Patent Application Laid-Open No. 2004-0011463. In this stent, an aluminum thin film is applied to the stainless steel surface and anodized to form porous nano-structures into which a drug for preventing the restenosis of vessels is then injected.
When the aluminum thin film deposited over the surface of the stent is anodized, the material constituting the surface of the conventional stent, that is, stainless steel or cobalt-chrome, is also partially corroded to reduce the bonding between the resulting oxide layer and the stent, so that the oxide layer readily falls off following even weak impact.
Further, the conventional stent has the shortcoming that the drug can be released only in a very small amount for a short period of time because it is not introduced into the pores formed on the stent due to capillary phenomenon, surface tension or drug particle size, and is present only on the surface of the pores.
Hence, the conventional technique is difficult to commercialize and there is a need for a novel stent that can overcome the problems encountered in the prior art.
[Disclosure] [Technical Problem]
Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a stent in which the material such as stainless steel or cobalt-chrome alloy for the stent frame can be protected from attacks which may occur when a metal oxide layer is formed thereon.
It is another object of the present invention to provide a stent in which the mechanical stability is ensured even after the expansion and contraction of the stent because of increased adhesion of the metal oxide layer to the stent frame.
It is a further object of the present invention to provide a stent which can release a drug loaded into the pores for a prolonged period of time.
It is still a further object of the present invention to provide a method for manufacturing the stent.
[Technical Solution]
In order to accomplish the above objects, the present invention provides a method for manufacturing a stent, comprising: forming on the surface of a stent frame a protective metal layer for prevention of corrosion; layering aluminum or titanium on the protective metal layer, followed by anodizing the aluminum or titanium layer to form a metal oxide layer having pores; and introducing a drug into the pores.
In an embodiment of the present invention, the method may further comprise hydrophilizing a surface of the metal oxide layer before introducing the drug into the pores.
In another embodiment of the method, the hydrophilizing step is conducted by plasma treatment, and preferably by O2 plasma treatment. In a further embodiment of the method, the drug is an inhibitor of cell proliferation or thrombosis formation. The drug is selected from the group consisting of: nitro donors; soluble guanylate cyclase (sGC) activators; Ca2+ channel blockers; angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; cisplatin; corticosteroid; 17-beta-estradiol; cyclosporine; mycophenolic acid; VEGF or VEGF receptor activators; tranilasts; COX-2 antagonists; COX-1 inhibitors; plasminogen activator inhibitor-1 ; serpin, thrombin inhibitors, hirudin, hirulog, agratroban, PPACK or interleukin-10; rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl- taxol; cisplatin; binblastin; mitozantrone; combretastatin A4; topotecan; metotrexate; flavopiridol; actinomycin D; ReoPro/Abciximab or probucol; cordycepin; topoisomerase inhibitor; and combinations thereof.
In still a further embodiment of the method, the drug is paclitaxel. In still another embodiment of the method, the stent frame is made of stainless steel or cobalt-chrome alloy.
In yet another embodiment of the method, the protective metal layer is formed of a metal selected from the group consisting of Au, Ag, R and a combination thereof.
Also, the present invention provides a stent, comprising: a stent frame; an protective metal layer for prevention of corrosion which is formed on a surface of the stent frame; a metal oxide layer comprising pores therein which is formed on the protective metal layer; and a drug for inhibition of cell proliferation or thrombosis formation which is loaded into the pores.
The stent may be manufactured using the method of the present invention. [Advantageous Effects]
When the stent is manufactured using the method of the present invention, the stainless steel or cobalt-chrome alloy of the stent frame is protected from the attack which may occur upon the formation of the outermost metal oxide layer, to increase the adhesion of the metal oxide layer to the stent and thus ensure the mechanical stability even after the expansion and contraction of the stent. Also, the stent of the present invention can release a large amount of drug, for example, a cell growth inhibitor, loaded within the pores of the metal oxide layer, in a delayed pattern, thus preventing neointima formation for a prolonged period of time. [Description of Drawings]
FIG. 1 is a schematic view showing the manufacturing processes of the stent according to the present invention.
FIG. 2 is of scanning electron microphotographs showing the surfaces of titanium oxides layers anodized at various voltages. FlG. 3 is a scanning electron microphotograph showing a uniformly coated titanium oxide layer which remains intact after the expansion of the stent manufactured according to an embodiment of the present invention.
FIG. 4 is a scanning electron microphotograph showing a cross-sectional view of the stent of FIG. 3 which has a titanium oxide layer uniformly formed thereon. FIG. 5 is a graph showing the drug release of the stent of the present invention in a delayed pattern (-■-: just washed with D.I. water, - A- : treated with O2 plasma), FIG. 6 shows an application example of the stent of the present invention. FIG. 7 is a cross-sectional view showing the release of a drug through the pores of the metal oxide layer (e.g., titanium oxide layer) formed on the surface of the stent of the present invention.
* Description for Main Numerals of the Drawings * 100: Stent 130: Titanium oxide layer
135: Pores 150: Drug
200: Balloon catheter 300: Vessel [Best Mode] Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings.
In accordance with an aspect thereof, the present invention provides a method for manufacturing a stent, comprising: forming on the surface of a stent frame a protective metal layer for prevention of corrosion; layering aluminum or titanium on the protective metal layer, followed by anodizing the aluminum or titanium layer to form a metal oxide layer having pores, and introducing a drug into the pores.
The stent frame useful in the present invention is not coated with a polymer and may be made of stainless steel or cobalt-chrome alloy.
The protective metal layer on the stent frame such as stainless steel or cobalt- chrome alloy and the subsequent metal layer for anodization may be formed by conventional deposition technique. The deposition technique may include, for example, physical vapor deposition, electron beam evaporation or thermal evaporation. The thickness of the protective metal layer may range from 10 nm to 200 nm, but is not limited thereto. Further, the thickness of the metal layer for anodization may range from 100 nm to 2 μm, but is not limited thereto.
For use in preventing the corrosion of the stainless steel or cobalt-chrome alloy, the protective metal layer may be formed of metal(s) selected from the group comprising anti-corrosive metals and precious metals. Preferably, it may be at least one selected from the group consisting of Au, Ag, R and a combination thereof. After being uniformly deposited on the protective metal layer, the aluminum or titanium layer is oxidized by anodization to an oxide thereof, that is aluminum oxide or titanium oxide.
Thus formed is a metal oxide layer with a porous structure. Injecting a drug inhibitory of thrombosis and neointima formation into the pores leads to the stent of the present invention.
Anodization is a process used to form an oxide layer on the surface of a metal in various shape patterns, roughnesses and crystal thicknesses depending on voltage, current, reaction time, composition and concentration of the electrolyte, and temperature. For details of anodization refer to Ishizawa H et al. (J Biomed Mater Res. 1995; 29(1): 65-72) and Zhu X et al. (2001. Biomaterials. 2001; 22: 2199-2206; J Biomed Mater Res. 2002; 60(2): 333-338). For example, potentiostatic anodization or galvanostatic anodization may be used. For anodization under galvanostatic conditions, a constant voltage of 0.1~100V and preferably of 0.3-40V is applied between a stent coated with metal (e.g., aluminum or titanium) as an anode and a carbon electrode as a cathode in a suitable electrolyte for 10 min ~ 5 hrs and preferably for 30 min ~ 2 hrs.
In an embodiment of the present invention, the surface of the stent and/or the metal oxide layer of the porous structure may be subjected to plasma treatment to enhance wettability of inside of the pores, thereby allowing the pores to hold a large amount of the drug for as long a period of time as possible.
The plasma useful in the present invention may be O2 plasma. O2 plasma treatment may be carried out by flowing oxygen at a vacuum of 10 ~ 100 millitorrs for 10 sec - 10 min in a radiofrequency (R.F.) plasma reactor. After insertion into vessels, the stent manufactured as described above allows the drug contained in the pores to be slowly released along the passage. Meanwhile, the pores are nano structures of the metal oxides (AI2O3, TiO2), porous organization, naturally formed during the anodization of aluminum or titanium. These pores may be formed in an amorphous, crumpled structure according to the condition such as the electric field applied upon anodization. Crumpled pores form can delay the release rate of drug compared to pores in a straight tube form and thus can be applied to where it is required to release a drug in a delayed pattern.
Non-limiting examples of the injection of a drug into the pores of the nano structure include the coating of the stent with the drug and the immersion of the stent in a drug solution, with preference for immersion in the drug solution. The drug solution may be a solution of the drug in a suitable solvent such as ethanol.
As long as it acts to inhibit cell proliferation or to prevent thrombosis or neointima formation, any drug can be used in the present invention. Preferably, the drug useful in the present invention may be selected from the following groups and mixtures thereof: Group 1 : nitro donors; soluble guanylate cyclase (sGC) activators; Ca2+ channel blockers; angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; cisplatin,
Group 2: corticosteroid; 17-beta-estradiol; cyclosporin; mycophenolic acid; VEGF or VEGF receptor activators; tranilasts; COX-2 antagonists; COX-1 inhibitors; plasminogen activator inhibitor-1 ; serpin, thrombin inhibitors, hirudin, hirulog, agratrobanm, PPACK or interieukin-10,
Group 3: rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl- taxol; cisplatin; binblastin; mitozantrone; combretastatin A4; topotecan; metotrexate; flavopiridol; actinomycin D; ReoPro/Abciximab or probucol; cordycepin; topoisomerase inhibitor.
Examples of the nitro donors include molsidomine, linsidomine, sodium nitroprusside, and nitroglycerin, but are not limited thereto. As the soluble guanylate cyclase (sGC) activator, BAY 41-2272(5-(cyclopropyl-2[1-fluorobenzyl)-1 H- pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamin) may be used. In addition, illustrative, non-limiting examples of the Ca2+ channel blockers include hydralazine, verapamil, diltiazem, nifedipine, and nimodipine. Examples of the angiotensin converting enzyme inhibitors include captopril, enalapril, licinopril, and quinapril, but are not limited thereto. Illustrative, non-limiting examples of the antiotensin receptor antagonists include rosartan, candesartan, irbesartan, and valsartan.
Further, non-limiting examples of the corticosteroids include dexamethasone, betamethasone, and prednisone. The COX-2 antagonists may be non-limitedly exemplified by meloxicam, celebrex and vioxx. Indomethacin, diclofenac, ibuprofen, or naphroxen may be used as a COX-1 inhibitor.
Illustrative, non-limiting examples of the rapamycin derivatives include sirolimus, rapamycin, and SDZ RAD (40-O-(2-hydroxyethyl)rapamycin. More preferably, the drug useful in the present invention is selected from the following groups and mixtures thereof:
Group 1 : molsidomine, linsidomine, sodium nitroprusside, nitroglycerin; BAY 41 -2272(5-(cyclopropyl-2[1 -fluorobenzyl)-1 H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4- ylamin); captopril, enalapril, licinopril, quinapril; rasartan, candesartan, irbesartan, valsartan; cisplatin,
Group 2: dexamethasone, betamethasone, prednisone; VEGF or VEGF receptor activators; plasminogen activator inhibitor-1 orserpin,
Group 3: sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin, or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol; mitozantrone; combretastatin A4; flavopiridol; cordycepin; topoisomerase inhibitor.
As long as they are known to be mixed together in the art, two or more drugs may be used without limitation.
The stent with a structure in accordance with the present invention is operated as follows.
As seen in FIG. 6, a stent 100 according to the present invention has a cylindrical shape and is reduced enough in volume by compression so as to be insertable into a vessel 300. After insertion together with a balloon catheter 200 into a narrowed region of the vessel 300, the stent 100 is expanded by the inflation of the balloon to forcibly widen the narrowed region. When the balloon catheter 200 accommodated within the stent 100 reaches the narrowed region, it is inflated to expand the stent 100 outwards. Hence, its outer surface is brought into direct contact with the narrowed region of the vessel 300 to widen the narrow passage to the original diameter. Then, the balloon catheter 200 is withdrawn out of the stent 100 which can support itself, supporting the widened vessel thanks to its elasticity.
Thereafter, the drug 150 contained within the pores 135 formed in the titanium oxide layer 130 of the stent 100 of the present invention, as shown in FIG. 7, is slowly released along the passages of the pores 135 to the vessel 300. Formed in an amorphous, crumpled, interconnected structure, the pores 135 can release the drug
150 to the vessel 300 in a very delayed pattern to prevent restenosis of vessel 300 for a highly prolonged period of time as compared to the pores formed in a straight structure.
Consequently, the stent 100 of the present invention can restrain restenosis and thus allow blood to flow well after insertion into the vessel 300. [Mode for Invention]
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention. PREPARATION EXAMPLE 1: Manufacture of Stent 1
A stent frame made of stainless steel was washed by ultrasonication and dried. A protective metal layer and a metal layer for anodization were sequentially formed over the stent frame. In this regard, after being fixed on a rotatable jig installed within an evaporation chamber, the stent frame was coated first with gold (Au) to a thickness of 30 nm and then with titanium to a thickness of 800 nm by E-beam evaporation while being rotated at a speed of 10 rpm.
For anodization, a potentiostatic process was used. A constant voltage of 1 V was applied for 2 hrs between the titanium-coated stent frame as an anode and a carbon electrode as a cathode in an electrolyte (maintaining to 20 "C) containing NH4F (0.3%), H2O (2%) and ethylene glycol to conduct anodization.
At this time, the sizes of pores are dependent on the voltage applied upon anodization. Experimental results accounting for the voltage dependence are shown in FIG. 2. As seen in FIG. 2, the pore size was increased from 30 nm through 40 nm to 55 nm following an increase of the voltage from 10 V through 15 V to 20 V, respectively. From this data, it can be inferred that larger pore sizes may be formed at a voltage larger than 20 V.
The anodized stent was ultrasonicated for 20 min, followed by drying at 8O0C for 23 hrs.
In order to make its surface hydrophilic, the titanium oxide layer (metal oxide layer) of the anodized stent was treated at a vacuum of 30 millitorrs with a flow of oxygen for 1 min in a radiofrequency (R. F.) reactor.
A mixture of 10:1 pure ethanol (99.999%) : paclitaxel (v/v) was ultrasonicated for 20 min to provide good dissolution of paclitaxel in ethanol. The anodized stent was immersed in the solution of paclitaxel in ethanol, followed by ultrasonication for 2 hrs to load the solution into the pores. The drug-loaded stent thus obtained was naturally dried for 24 hrs.
PREPARATION EXAMPLE 2: Manufacture of Stent 2 The same procedure as in Preparation Example 1 was repeated, with the exception that an aluminum oxide layer, instead of the titanium oxide layer, was formed as follows.
After the stent frame was coated with gold (Au) at a thickness of 30 nm, an aluminum (Al) layer was deposited at a thickness of 1 ,000 nm by thermal evaporation. Subsequently, a constant voltage of 40 V was applied for 40 min between the aluminum-coated stent frame acting as an anode and a carbon electrode acting as a cathode in a 0.3 M oxalic acid electrolyte to conduct anodization. The anodized stent was washed for 20 min by ultrasonication and then dried at 8O0C for 23 hrs.
PREPARATION EXAMPLE 3: Manufacture of Stent 3
The same procedure as in Preparation Example 1 was repeated with the exception that platinum (R), instead of gold (Au), was used for the protective metal layer.
PREPARATION EXAM PLE 4: Manufacture of Stent 4
The same procedure as in Preparation Example 2 was repeated with the exception that platinum (R), instead of gold (Au), was used for the protective metal layer.
PREPARATION EXAMPLE 5: Manufacture of Stents The same procedure as in Preparation Example 1 was repeated with the exception that silver (Ag), instead of gold (Au), was used for the protective metal layer. TEST EXAMPLE 1: Mechanical Stability
A balloon catheter was inserted into the stent of Preparation Example 1 and inflated to outstretch the stent which was then analyzed via scanning electron microphotographs. As seen in the S.E.M. of FIGS. 3 and 4, the outermost layer of the stent, that is, the titanium oxide layer remained uniformly deposited without being destroyed. Therefore, the stent of the present invention maintained excellent mechanical stability after expansion, indicating superior adhesion between the stent frame and the ceramic layer.
TEST EXAMPLE 2: Drug Reusability
The O2 plasma-treated stent of Preparation Example 1 was immersed in 10 cc of PBS and analyzed for drug release during incubation at 36.50C for 21 days. For comparison, a stent in which the metal oxide layer containing pores therein was washed only with deionized (Dl) water was used. The results are given in FIG. 5.
As depicted in FIG. 5, the stent which was improved in wettability by treatment with O2 plasma allowed paclitaxel to be sufficiently loaded therein and to be released in a total amount of 70 μg for 21 days, showing a suspended release pattern. In contrast, the stent with the metal oxide layer washed only with Dl water released the drug only for 3 ~ 4 days because the drug was difficult to load into the pores of the metal oxide layer and existed on the surface of the metal oxide layer. Consequently, the stent of the present invention can release a drug in a highly delayed pattern.

Claims

[CLAIMS]
[Claim 1 ]
A method for manufacturing a stent, comprising: forming on a surface of a stent frame a protective metal layer for prevention of corrosion; layering aluminum or titanium on the protective metal layer, followed by anodizing the aluminum or titanium layer to form a metal oxide layer having pores; and introducing a drug into the pores.
[Claim 2] The method according to claim 1, further comprising hydrophilizing a surface of the metal oxide layer before introducing the drug into the pores.
[Claim 3]
The method according to claim 2, wherein the hydrophilizing step is conducted by plasma treatment.
[Claim 4]
The method according to claim 3, wherein the plasma treatment is O2 plasma treatment.
[Claim 5]
The method according to claim 1, wherein the drug is an inhibitor of cell proliferation or thrombosis formation.
[Claim 6]
The method according to claim 1 , wherein the drug is selected from the group consisting of: nitro donors; soluble guanylate cyclase (sGC) activators; Ca2+ channel blockers; angiotensin converting enzyme inhibitors; angiotensin receptor antagonists; cisplatin; corticosteroid; 17-beta-estradiol; cyclosporine; mycophenolic acid; VEGF or VEGF receptor activators; tranilasts; COX-2 antagonists; COX-1 inhibitors; plasminogen activator inhibitor-1 ; seφin, thrombin inhibitors, hirudin, hirulog, agratroban, PPACK or interleukin-10; rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol; cisplatin; binblastin; mitozantrone; combretastatin A4; topotecan; metotrexate; flavopiridol; actinomycin D; ReoPro/Abciximab or probucol; cordycepin; topoisomerase inhibitor; and combinations thereof.
[Claim 7]
The method according to claim 1, wherein the drug is paclitaxel.
[Claim 8] The method according to claim 1 , wherein the stent frame is made of stainless steel or cobalt-chrome alloy.
[Claim 9]
The method according to claim 1 , wherein the protective metal layer is formed of a metal selected from the group consisting of Au, Ag, R and a combination thereof.
[Claim 10]
A stent, comprising: a stent frame; an protective metal layer for prevention of corrosion which is formed on a surface of the stent frame; a metal oxide layer comprising pores therein which is formed on the protective metal layer; and a drug for inhibition of cell proliferation or thrombosis formation which is loaded into the pores.
[Claim 11 ] The stent according to claim 10, wherein the stent is manufactured using the method of claim 1. [Claim 12]
The stent according to claim 10, wherein the protective metal layer is formed a metal selected from the group consisting of Au, Ag1 R and a combination thereof.
PCT/KR2008/007785 2008-01-02 2008-12-30 Stent and manufacturing method thereof WO2009084902A2 (en)

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