WO2017047912A1

WO2017047912A1 - Bioimplantation metal having nano-patterning groove surface, method for preparing metal, implant, method for manufacturing implant, stent, and method for manufacturing stent

Info

Publication number: WO2017047912A1
Application number: PCT/KR2016/006518
Authority: WO
Inventors: 김두헌
Original assignee: 한국전기연구원
Priority date: 2015-09-16
Filing date: 2016-06-20
Publication date: 2017-03-23

Abstract

The present invention relates to a bioimplantation metal having a nano-patterning groove surface, a method for preparing the metal, an implant, a method for manufacturing the implant, a stent, and a method for manufacturing the stent. The subject matter of the present invention comprises the steps of: forming a titanium oxide nanotube by anodizing a metal base comprising titanium metal or a titanium alloy; and forming a groove on a surface of the metal base by removing the titanium oxide nanotube. Therefore, a groove is formed on the surface by removing the anodized surface after anodizing the surface of a metal base, and an anodized titanium oxide film is stripped off such that a leak thereof from the inside of a living body is prevented and impurities remaining on the surface are effectively removed. In addition, when titanium or a titanium alloy for bioimplantation, is used as a metal base material and is bioimplanted by the groove formed through surface anodizing, such that the surface area is maximized, thereby having excellent bioaffinity, chemical compatibility and mechanical compatibility during bioimplantation, and various sizes of grooves comprising nano-patterning can be formed by carrying out anodizing in combination with sandblasting or sandblasted, large-grit, acid-etched (SLA) method.

Description

Biograft metal with nanopatterned groove surface, metal manufacturing method, implant, implant manufacturing method, stent and stent manufacturing method

The present invention relates to a metal for biotransplantation, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method having a nanopatterning groove surface, and more particularly, after anodizing the surface of the metal base material. A groove is formed on the surface to remove the anodized titanium oxide film and prevents the nanopatterning groove surface from leaking out of the living body, a method for manufacturing a metal, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method It is about.

Biotransplantation metals have superior strength, fatigue resistance, and molding processability compared to other materials such as ceramics, polymers, etc. and are still used for dental, orthopedic, It is the most widely used biomaterial in plastic surgery. Such biograft metals are magnesium (Mg), calcium (Ca, phosphorus (P), zinc (Zn), iron (Fe), chromium (Cr), nickel (Ni), stainless steel (Stainless steel), cobalt alloy (Co) alloy), titanium (Ti), titanium alloy (Ti alloy), zirconium (Zr), niobium (Nb), tantalum (Ta), gold (Au), silver (Ag), and the like. In comparison, titanium, titanium alloys, and gold, which are excellent in corrosion resistance and stable in human tissues, are most widely used in the human body.

Representative products manufactured using such a biograft metal include implants and stents. Implants are used to support or attach tissue during treatment, such as molded parts such as membranes, fixed sheets, three-dimensional or spatial parts that can be implanted into organ organs, or fixed means such as screws, pins, rivets, tacks, or tissues It is used for the purpose of separating the from other tissues. In the case of a stent, when a diameter of a blood vessel is narrowed due to various diseases occurring in a living body and blood circulation does not occur smoothly, the stent is a medical apparatus used to expand the diameter of the blood vessel by performing the treatment inside the blood vessel.

As such, the implant and stent inserted into the living body should satisfy the following two conditions for the biograft metal forming the same. First, biocompatibility should be excellent. In other words, the use of metal as a biosupport substitute should not cause foreign body reactions and toxicity to surrounding tissues. Second, the bone forming cells that differentiate at various stages and the new bone must have a surface that can fuse well with the implanted metal surface. Since the 1990s, various surface modification methods have been developed to improve fusion and bone tissue around implant metals and to improve soft tissue and biocompatibility. Surface treatment method of pure titanium metal and titanium alloy is blasting, acid treatment, anodization, mechanical grinding, laser processing, sintering, hydroxyapatite coating, Ti plasma spray There are various attempts, such as ion implantation, and the method widely used to date is SLA (sandblasted, large grit, acid etched) method.

SLA sprays micro-sized ceramic particles (usually using alumina) with a strong pressure on the titanium alloy surface to form tens of micrometers of micro-roughness on the titanium-based metal surface, followed by acid etching. It is a method of increasing the surface area by further forming a roughness of several micrometer scale through. Roughness of various micrometer sizes formed through SLA surface treatment has the advantage of improving the anchoring force of the new bone on the surface of the biograft metal at the beginning of the implantation, and also improves the degree of adhesion after the initial stage. However, residual chemicals generated in the process of treating the ceramic particles with the strong acid on the surface of the biograft metal may act as contaminants, and the interface of the metal particles may show fracture. In addition, the process of treating with strong acid itself is a way of causing environmental pollution, and after the surface treatment process, dozens of washing processes are required to remove chemicals remaining on the titanium surface, which makes the process complicated and wastes energy. There is a disadvantage that the manufacturing cost of the metal for biotransplantation increases.

The quality of dental biograft metals is determined by the chemical, physical, mechanical and topographical properties of the surface. Surface chemistry affects protein adsorption and cellular activity, surface roughness affects cell migration and proliferation, and surface topography is responsible for cell growth and osteoblast cell growth. It is known to affect changes and bone tissue formation. When appropriately formed macro-roughness (roughness of tens of micrometers to several millimeters) formed on the surface of the biotransplant metal, the initial fixation force of the biograft metal and the physical and mechanical properties of the surface of the biograft metal and surrounding bone and soft tissue It can improve stability. Micrometer-level roughness (roughness of hundreds of nanometers to tens of micrometers) formed on the surface of the biograft metal may maximize the bond between the surface and the mineralized bone tissue. In addition, nano-roughness (a few nanometers to tens of nanometers of roughness) affects the protein adsorption, osteoclast adhesion and osteointegration rate of the surface of the metal for transplantation. In addition, nanometer-level roughness increases surface energy to improve the hydrophilicity of the surface of the biograft metal and facilitates cell adhesion and protein substrate and fibrin binding to control osteoblast differentiation. Can be.

However, conventional surface treatment methods such as SLA cannot give nanometer roughness. Recently, as a nanometer surface treatment method, the implant materials and manufacturing method of the prior art 'Korean Patent Office Publication No. 10-2009-0060833 anodizing method', 'Korean Patent Office Publication No. 10-2011-0082658 Titanium implant Surface treatment method and the implant prepared by the method ',' the surface treatment method using the same and the surface treatment method using the same and the implant prepared by the method ' It is known to form nanotubes on the surface by anodizing, thereby promoting bone adhesion of metals. However, the metal oxide film on the metal base material obtained through anodization, as in the prior art, is weak in mechanical strength and may be peeled off from the metal surface while being inserted into the living body and leaked into the living body. 1 is a SEM photograph showing that the metal surface is anodized by a conventional method, it can be seen that the metal oxide film formed by anodizing the metal surface is separated. 2 is a SEM photograph showing that the metal oxide film is easily peeled off and the metal inside is exposed.

It can be seen that the anodized metal oxide film is easily peeled off from the metal surface by applying a physical force such as bending. In this case, the anodized metal oxide film which has fallen off is leaked into the living body and has a serious effect on the living body. In addition, the problem of the anodization method has a problem of surface contamination due to the residual of the electrolyte or chemical components used during anodization. The smaller the porosity of the anodized surface is at the nanoscale level, the more difficult it is to remove residual impurities.

The present invention relates to a method of imparting nanometer-level roughness to the surface of a biograft metal while simultaneously anodizing and removing the anodized surface to remove residual contaminants present on the surface. This is a surface treatment method that can form a micro / nanometer roughness when used in combination with the surface treatment method existing micro-level roughness exists.

Therefore, an object of the present invention is to remove the anodized surface after anodizing the surface of the metal base material, a groove is formed on the surface, and the anodized titanium oxide film is peeled off to prevent leakage from the inside of the body and at the same time when peeling By removing impurities remaining on the surface of the present invention to provide a metal for implantation, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method having a nanopatterning groove surface.

In addition, a biograft metal having a nanopatterning groove surface having excellent biocompatibility, chemical compatibility, and mechanical compatibility when implanted into a living body by using a biograft titanium or a titanium alloy as a material of a metal base material by a groove formed through surface anodization. To provide a metal manufacturing method, implant, implant manufacturing method, stent and stent manufacturing method.

In addition, the production of biotransplant metals and metals with nanopatterned groove surfaces that can be formed with sandblasting or anodized with SLA (Sand blasted, Large-grit, Acid etched) processes to form grooves of various sizes, including nanopatterning It is to provide a method, an implant, an implant manufacturing method, a stent, and a stent manufacturing method.

The above object is to anodize a metal base material consisting of titanium metal or titanium alloy to form titanium oxide nanotubes; Removing the titanium oxide nanotubes is achieved by a method for producing a bio-grafted metal having a nano-patterned groove surface comprising the step of forming a groove (groove) on the surface of the metal base material.

Here, the step of forming the titanium nanotubes oxidized by oxidizing the anode are, fluoride (F ^-) ions by immersing the base metal in the electrolytic solution, and oxidizing the anode containing the electrolyte solution containing fluoride ions, fluoride Salts containing ions; It is preferable to include; at least one solvent of an inorganic acid, an organic acid, and a polymer alcohol.

The salt includes at least one of hydrogen fluoride (HF), sodium fluoride (NaF) and ammonium fluoride (NH ₄ F), and the solvent is phosphoric acid (H ₃ PO ₄ ), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ), glycerol (glycerol), it is preferable to include one or more of ethylene glycol (ethylene glycol).

The method may further include forming an oxide film having a thickness of 10 nm to 1,000 nm on the surface of the metal base material by heat-treating the metal base material after forming the grooves on the surface of the metal base material. It is preferable to make at 1200 degreeC.

Here, the groove has a hemispherical shape, the diameter has a size of 10nm to 1,000nm, the hemispherical groove preferably further comprises a micropore (pore) of several nanometers on the surface.

The titanium oxide nanotubes are removed by ultrasonic cleaning by immersing the metal base material in hydrogen peroxide (H ₂ O ₂ ), and the titanium oxide nanotubes are preferably removed by immersing in an organic acid or an aqueous base solution.

Prior to forming the titanium oxide nanotubes, the method may further include sandblasting the surface of the metal base material, and the sandblasting may include sand blasting the metal blast surface on the surface of the metal base material. It is preferable to further include the step of forming a micro groove in the micrometer to 500㎛, or surface treatment of the metal base material through a sand blasted, large-grit, acid etched (SLA) method.

Before forming the titanium oxide nanotubes, forming a polymer protective layer to prevent anodization on a portion of the surface of the metal base material, and after forming the titanium oxide nanotubes, Preferably, the method further comprises removing the polymer protective layer.

After forming the grooves on the surface of the metal base material, further comprising coating a biocompatible material on the surface of the metal base material, or heat-treating the metal base material to form an oxide film on the surface of the metal base material; The method may further include coating a biocompatible material on the surface of the oxide film, and the coating of the biocompatible material may preferably use an electron beam deposition method or an electrolytic coating method.

The electrolytic coating method, after the step of immersing the metal base material in an aqueous solution containing the biocompatible material and then applying electricity to the aqueous solution to coat the biocompatible material, after forming a groove on the surface of the metal base material, Changing the surface of the metal base material to a hydrophilic state; It is preferred to further include the step of injecting a drug into the groove of the metal base material is hydrophilic, the drug is preferably a hydrophilic polymer drug.

The above object is, the surface of the nano-patterned grooves, characterized in that the anodized metal base material consisting of titanium metal or titanium alloy to form titanium oxide nanotubes, the titanium oxide nanotubes are removed to form grooves on the surface of the metal base material It is also achieved by a biograft metal having a.

The above object is also achieved by a biotransplantable metal having a nanopatterned groove surface characterized in that it comprises a metal matrix having hemispherical grooves formed on the surface thereof.

The above object is to anodize an implant body made of titanium metal or titanium alloy to form titanium oxide nanotubes; Removing the titanium oxide nanotubes is achieved by an implant manufacturing method having a nano-patterned groove surface comprising the step of forming a groove (groove) on the surface of the implant body.

The above object is, the surface of the nano-patterned grooves, characterized in that the implant body made of titanium metal or titanium alloy anodized to form titanium oxide nanotubes, the titanium oxide nanotubes are removed to form grooves on the surface of the implant body It is also achieved by implants with.

The above object is also achieved by an implant having a nanopatterning groove surface, characterized in that it comprises an implant body with hemispherical grooves formed on the surface.

The above object is to anodize a stent body made of titanium metal or titanium alloy to form titanium oxide nanotubes; Removing the titanium oxide nanotubes is achieved by a method for manufacturing a stent having a nano-patterned groove surface comprising the step of forming a groove (groove) on the surface of the stent body.

The above object is, the surface of the nano-patterned grooves, characterized in that anodizing the stent body made of titanium metal or titanium alloy to form titanium oxide nanotubes, the titanium oxide nanotubes are removed to form grooves on the surface of the stent body Achieved by a stent with

The above object is also achieved by a stent having a nanopatterned groove surface, characterized in that it comprises a stent body with hemispherical grooves formed on the surface.

The above object is also achieved by a stent having a nanopatterned groove surface, wherein the surface of the stent body on which the groove is formed is hydrophilic and a hydrophilic polymer drug is injected into the groove of the stent body which is hydrophilic.

According to the above-described configuration of the present invention, after anodizing the surface of the metal base material, an anodized surface is removed to form grooves on the surface, and anodized titanium oxide film can be peeled off to prevent leakage from the inside of the living body. Impurities remaining in the can be effectively removed.

In addition, by using a biograft titanium or titanium alloy as a material of the metal base material to maximize the surface area when implanted in the living body by the groove formed through the surface anodization, it has excellent biocompatibility, chemical compatibility and mechanical compatibility, sandblasting or SLA (Sand blasted, Large-grit, Acid etched) and anodization can be performed to form grooves of various sizes including nanopatterning.

1 and 2 are SEM images of the anodized metal oxide film according to the embodiment of the prior art,

3 is a flow chart of a method for manufacturing a bio-transplant metal having a nano-patterned groove surface according to the first embodiment of the present invention,

Figure 4 is a schematic diagram showing a method for producing a metal for transplantation,

Figure 5 is a flow chart of a method for producing a metal for transplantation according to the second embodiment,

6 is a flow chart of a method for manufacturing a metal for transplantation according to a third embodiment,

7 is a flow chart of a method for manufacturing a bio-transplant metal according to a fourth embodiment,

8 is a flow chart of a method for manufacturing a bio-transplant metal according to a fifth embodiment,

9 is a flowchart of a method of manufacturing a metal for transplantation according to a sixth embodiment;

10 is an SEM photograph showing the surface of the metal base material before anodization;

11 is a schematic diagram showing a state of anodizing a metal base material,

12 is a SEM photograph showing that a titanium oxide film is formed on the metal base material according to the first embodiment;

FIG. 13 is an SEM photograph showing that grooves are formed on the surface of the metal base material from which the titanium oxide film is removed according to the first embodiment;

14 and 15 are SEM photographs showing grooves and micropores formed on the surface of the metal base material from which the titanium oxide film was removed according to the first embodiment;

16 is a graph showing the XPS surface component analysis results of the metal base material before and after the nanopatterning process according to the first embodiment;

17 is an AFM photograph of a surface of a metal base material having a titanium oxide film removed according to the first embodiment,

18 is a SEM photograph of the surface of the sandblasted metal base material according to the second embodiment,

19 is a SEM photograph showing that a groove is formed on the surface of the metal base material from which the titanium oxide film is removed according to the second embodiment;

20 is an AFM photograph of a surface of a metal base material having a titanium oxide film removed according to a second embodiment;

21 is a SEM photograph showing the surface change of the titanium metal base material according to the step of the second embodiment,

FIG. 22 is a SEM photograph of the surface of the metal base material removed after the SLA surface treatment and the titanium oxide film formed thereon according to the step of the third embodiment.

Hereinafter, with reference to the drawings will be described in detail a metal for transplantation, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method having a nanopatterning groove surface (groove) according to an embodiment of the present invention. Here, the biograft metal, implant, and stent of the present invention are manufactured using a metal base material, and have an implant body made of an implant shape, a stent body made of a stent shape, or a metal base material for a biograft metal, having a shape suitable for use. In the present invention will be described through a metal base material representatively.

In the manufacturing method according to the first embodiment, as shown in FIG. 3, first, anodizing a metal base material forms titanium oxide nanotubes on a surface (S1a).

As shown in FIG. 4, a metal base material 100 made of titanium (Ti) or a titanium alloy is prepared, and the metal base material 100 is anodized to form a titanium nanotube structure having a titanium nanotube structure on its surface. To form 200. Since titanium or titanium alloy is a suitable metal as a living implant material, the metal base material 100 of the present invention uses only titanium or titanium alloy as a material.

In this case, when the metal base material 100 is an implant base material, grooves are formed on the surface of the artificial tooth by anodizing the artificial tooth area. Metal base material 100 is divided into a crown (crown), abutment and artificial tooth root, the metal base material (100) is formed by forming a groove in the artificial root to be placed in the root of the tooth to induce bone adhesion It can be used for a long time without departing from the roots.

Titanium oxide nanotubes 200 made of titanium oxide (TiO ₂ ) are formed in a region in which the electrolyte is in contact with the metal base material 100 as an anode and then immersed in the electrolyte. The titanium oxide nanotubes 200 are formed in the form of a tube on the surface of the metal base material 100, and the interface contacting the metal base material 100 is in the form of a hemisphere like the lower shape of the tube. The size of the area recessed by the tubular shape has a diameter of several tens to hundreds of nanometers, which can be adjusted by controlling the anodization conditions.

The electrolyte solution is an electrolyte solution containing fluoride (F ⁻ ) ions, and is oxidized by immersing the metal base material 100 in the electrolyte solution. The electrolyte solution containing fluoride ions is preferably formed by mixing a salt containing fluoride ions, a solvent selected from at least one of a group consisting of an inorganic acid, an organic acid, a polymer alcohol and a mixture thereof, and water. Salts containing fluoride ions are salts consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium fluoride (NH ₄ F) and mixtures thereof, phosphoric acid (H ₃ PO ₄ ), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ), glycerol (glycerol), ethylene glycol (ethylene glycol) and a solvent selected from the group consisting of a mixture thereof, it is preferable to use a mixture of water.

The halide ions can effectively elute the metal to create pitting corrosion on the metal. However, in the case of other halides such as chloride (Cl ⁻ ) and bromide (Br ⁻ ) among halide ions, it is difficult to form a straight and uniform nanotube structure. However, when anodizing is performed in an electrolyte solution containing fluoride ions, since the titanium oxide nanotubes 200 having a uniform size and spacing are formed, the present invention uses an electrolyte solution containing fluoride ions.

Removing the titanium oxide nanotubes 200 to form a hemispherical groove 110 on the surface of the metal base material 100 (S2a).

Titanium oxide nanotubes 200 formed by anodization have a physical force applied to the metal base material 100 in vivo when or after the metal base material 100 formed of titanium or titanium alloy is inserted into a living body. The surface is easily peeled off as shown in FIGS. 1 and 2. 1 and 2 are anodized the metal surface by a general anodization method as in the prior art, it can be seen that the metal oxide film immediately falls off even if a little external force is applied. Therefore, when the biograft metal prepared by the prior art is inserted into the living body, the metal oxide film is peeled off, and the peeled metal oxide film causes problems such as necrosis of somatic cells and a decrease in the degree of bone fusion of the biograft metal. In addition, it is difficult to effectively remove impurities remaining in the oxide film when nano-sized micropores are formed through anodization. In order to solve this problem, the present invention removes the titanium oxide nanotubes 200 formed on the metal base material 100.

The hemispherical groove 300 is formed on the surface of the metal base material 100 by removing the titanium oxide nanotubes 200 formed on the surface of the metal base material 100 using a physical method or a chemical method. Even if the titanium oxide nanotubes 200 are removed, the hemispherical grooves 300 formed by the titanium oxide nanotubes 200 remain on the surface of the metal base material 100. The physical method is preferably a method of ultrasonic cleaning by immersing the titanium oxide nanotubes 200 in hydrogen peroxide (H ₂ O ₂ ), chemical method is titanium oxide nano immersed by immersing the metal base material 100 in an organic acid or aqueous base solution A method of causing the tube 200 to fall apart is preferred, but not limited to these methods.

As such, when the titanium oxide nanotubes 200 formed on the surface of the metal base material 100 are removed, nanosized grooves 300 having a substantially hemispherical shape are formed on the surface of the metal base material 100, and the hemispherical grooves 110 are formed. A metal base material 100 having micropores 111 and pores having a size smaller than that of a hemispherical groove 110 may be obtained. The hemispherical groove 110 may be formed to a diameter (d) of 10 to 1,000nm. This is possible by controlling electrochemical conditions such as applied voltage, an electrolyte solution, and temperature during anodization.

When the diameter (d) and the height (h) ratio of the groove 110 is determined, the diameter (d): height (h) = 1: 0.01 to 0.5 so that the groove 110 can be formed in a hemispherical shape. If the height h of the groove 110 is less than 0.01 times the diameter d, the height is very low, so that the surface roughness is low and bone adhesion is not easy, and the groove 110 is more than 0.5 times because it is made in a hemispherical shape. There is no number. Therefore, the ratio of diameter d: height h = 1: 0.01 to 0.5 is most preferred.

The surface of the metal base material 100 obtained through the steps S1a and S2a is passivated from metal to metal oxide and can be used immediately. When manufacturing a biograft metal, stent or implant in the prior art, the process of passivating the titanium in the form of titanium oxide suitable for biomaterials and prevent oxidation. The passivation process in the form of titanium oxide was carried out by exposing the biograft metal to high temperature or boiling in hot water. However, in the case of the present invention, a groove may be formed on the surface while passivating the metal base material 100 in the form of titanium oxide through anodization.

If necessary, you can further proceed as follows.

The heat treatment is performed to form an oxide film 300 on the surface of the metal base material 100 (S3a).

An oxide film 300 is formed on the surface of the metal base material 100 by heat-treating the metal base material 100 having the grooves 110 formed on the surface thereof. Here, the oxide film 300 may include fine pores in or inside the oxide film 300 including the grooved oxide 310 and the oxide fine hole 311 formed along the groove 110 and the micropores 111 of the metal base material 100. It means the oxide film 300 formed. The oxide film 300 is preferably a thin film having a thickness of 10 to 1,000nm, if the thickness of the thin film is less than 10nm does not mean that the heat treatment separately, if the thickness exceeds 1,000nm the oxide film 300 by the external force the metal base material (100) ) May deviate.

The oxide film 300 is in an amorphous state when the surface of the metal base material 100 on which the grooves 110 are formed is not heat treated, and becomes an crystalline surface when heat treated. As such, by changing to a crystalline surface, physicochemical properties such as hydrophilicity, hardness, strength, and thickness of the oxide film 300 can be controlled. The oxide film 300 is formed with a hemispherical groove oxide 310 including a microscopic oxide hole 311, the heat treatment temperature for forming the groove oxide 310 is preferably made at 200 to 1200 ℃, such a temperature In crystalline oxide film 300 is formed. If the heat treatment temperature is less than 200 ℃ amorphous oxide film is formed, if it exceeds 1200 ℃ may deform the metal base material 100.

The hemispherical groove oxide 310 formed in the oxide film 300 preferably has a diameter of 10 to 1,000 nm. When the diameter of the grooved oxide 310 is less than 10 nm, the biological binding force is not high, and the grooved oxide 310 larger than 1,000 nm may be effectively formed in a chemical or physical manner. The diameter of the grooves 310 may be adjusted through condition control of anodization. In addition, the surface of the groove oxide 310 itself is also formed with a rough surface having a fine microscopic oxide hole 311 of several nanometers in size. Through such heat treatment, the crystalline titanium oxide film 300 is formed to have a higher hardness and a thickness of 10 nm or more, which is relatively thicker than the amorphous titanium oxide film, thereby improving biocompatibility and hydrophilicity.

In the case of titanium (Ti), an amorphous titanium oxide (TiO ₂ ) thin film having a thickness of 2 to 5 nm is formed on a surface of a native oxide layer formed naturally after the titanium oxide nanotubes 200 are removed through anodization. . When heat-treated at 200 to 1200 ° C., an anatase crystal phase is formed at about 200 ° C. or more, and a rutile crystal phase oxide film 300 is formed at 700 ° C. or more. The hardness is in order of rutile>anatase> amorphous, and by heat treatment, the thickness of the oxide film 300 can be increased to 10 nm or more. That is, as the heat treatment is performed, the hardness of the metal surface on which the hemispherical grooves 310 are formed may be increased, and the thickness of the oxide film 300 suitable for the living body may be increased.

In the first embodiment, the hemispherical groove 110 is formed on the surface only by anodizing the metal base material 100. In the second embodiment, the anodization is performed with sandblasting. In the manufacturing method according to the second embodiment, first, as shown in FIG. 5, the surface of the metal base material is sandblasted (S1b).

Sandblasting is a type of spray processing, and sandblast media used here are small diameter glass spheres, silicon, sea sand, metal particles, and the like. Sandblasting is a process of forming a fine groove surface on the surface by hitting the sandblast medium by spraying with air or dropping by gravity. That is, sandblasting particles of 1 to 100 μm are prepared to form micro-sized grooves on the surface of the metal base material, and sandblasted to the surface of the metal base material using a pressure of 0.45 to 0.65 kgf / cm ² . In the case where the sand blasting pressure 0.45kgf / cm ² is less than mothamyeo not form a groove of a desired size has not been sand-blast media to properly blow the metal base material, cause a damage to a part of the metal base material exceeds the 0.65kgf / cm ² have. Thereafter, the sandblast media is washed to remove all of the metal substrate surface. Through this process, a large micro recess of 50 to 500 μm size is formed on the surface of the metal base material. In the case of micro grooves, it is difficult to form grooves of less than 50 μm by using sand blasting, and when they exceed 500 μm, the grooves are not suitable because they are large enough to affect the metal base material.

Thereafter, a process of anodizing the metal base material including the micro grooves is performed. Anodizing the metal base material (S2b) and removing the titanium oxide nanotubes to form hemispherical grooves on the surface of the metal base material (S3b). Is the same as step S1a and step S2a of the first embodiment, and further description is omitted. Through this process, hemispherical nano grooves are formed in the micro grooves by anodization.

In some cases, a third embodiment using a sand blasted, larg-grit, acid etched (SLA) method and an anodization method may be performed instead of the sandblasting method as the second embodiment. As shown in FIG. 6, in the step S1c of performing the SLA method on the metal base material, an etching process is performed by immersing the metal base material in which the grooves of several hundred micro sizes are formed on the surface through sand blasting. Through the etching process, it is possible to obtain an intermediate groove having a size of 1 to 50 μm, which is a smaller groove than a micro groove obtained through sandblasting. In the case of the intermediate groove, it is difficult to form a groove of less than 1 μm through acid etching, and when it exceeds 50 μm, sandblasting and acid etching do not have a meaning because there is no difference from a large groove.

After acid etching, washing is sequentially performed with a base wash to neutralize the acid, an acid used for neutralization, and water or distilled water to remove the base, and a washing process of particles used for sand blasting is also performed. After this, the step of anodizing the same metal base material as the first embodiment and the second embodiment (S2c) and the step of removing the titanium oxide nanotubes to form hemispherical grooves on the surface of the metal base material (S3c) are performed. Thus, through the third embodiment, the middle groove is formed in the micro groove, and the hemispherical nano groove is formed in the middle groove.

The fourth embodiment, which is another embodiment, is a technique for preventing anodization in some regions of the metal base material, and includes the following steps. As shown in FIG. 7, first, a polymer protective layer is formed on a part of the surface of the metal base material (S1d).

A metal base material for preparing a biograft metal, an implant, or a stent is prepared, and a polymer protective layer is formed to prevent anodization on a part of the surface of the metal base material. This step is performed when there is a region in the surface of the metal base material that does not want to be anodized, and this step may not be performed when anodizing the entire surface of the metal base material.

In the case of an implant, there may be a region requiring a high biobinding force and a region not requiring the biobinding force according to the shape. Accordingly, the region requiring high bio-binding force performs anodization, and the region that does not require bio-binding force or the region that does not require grooves form a polymer protective layer so that anodization does not occur. In the case of the stent, the inner surface of the stent is preferably smooth so that blood can flow smoothly through the inside of the stent. For this purpose, a polymer protective layer is formed on the inner wall of the stent so that the inner wall is not anodized.

The polymer protective layer is a polydimethylsiloxane (PDMS), polymethylmethacrylate (PMMA), polyimide (PI), polyethylene terephthalate (PET), polyethersulfone (PES), polyethylene naphthalate (PEN), It is preferably selected from the group consisting of polystyrene (PS), polyurethane (PU), polyamide (PA), fiber reinforced plastic (FRP), and mixtures thereof.

Anodizing the base metal to form titanium oxide nanotubes on the surface (S2d).

A titanium oxide nanotube is formed on the surface by anodizing a metal base material having a polymer protective layer formed on a portion of the surface or the polymer protective layer not present. In the case of the metal base material on which the polymer protective layer is formed, the anodized electrolyte is in contact with the region excluding the polymer protective layer, and titanium oxide nanotubes are formed in the area where the electrolyte is in contact. The step of anodizing the metal base material to form the titanium oxide nanotubes on the surface may use the same method as in step S1a of the first embodiment, thereby detailed description thereof will be omitted.

The polymer protective layer on the surface of the metal base material is removed (S3d).

When anodization is completed on the surface of the metal base material, the polymer protective layer protecting the surface of the metal base material is removed to prevent anodization. The polymer protective layer can be simply removed using a cleaning solution such as acetone or the like. The step of removing the polymer protective layer is preferably removed immediately after anodization, but in some cases, may be removed after the final biograft metal is finally manufactured. In other words, this step may be performed at any stage or after anodization.

Subsequently, the step of removing the titanium oxide nanotubes to form hemispherical grooves on the surface of the metal base material (S4d) and the step of performing heat treatment to form an oxide film on the surface of the metal base material (S5d) are the same as in the steps S2a and S3a of Example 1 Detailed description is omitted because it is made. The fourth embodiment may use the biograft metal, implant or stent obtained through these steps, but if necessary to carry a hydrophilic drug, the following steps may be further proceeded.

The oxide film is changed into a hydrophilic state (S6d).

When a hydrophobic drug is injected in a hydrophobic state without changing the oxide film into a hydrophilic state, when a biotransplantable metal, implant or stent including the same is inserted into the living body, the hydrophobic drug may be rapidly released from the biograft metal, implant or stent in contact with the living body. It is released all at once. If the drug is released in a short time, the release concentration of the drug is increased, which has a harmful effect on the living body. Therefore, a hydrophilic drug is used to release the drug slowly, and the surface of the biograft metal, implant or stent is also preferably hydrophilic. As a method of changing the oxide film formed on the surface of the metal base material into a hydrophilic state, UV having a wavelength of 300 to 400 nm at a speed of 1 to 20 m / min is used by using a UV lamp having an intensity of 0.1 to 10 J / cm 2 for the oxide film. It is preferable to process. In addition to the UV treatment, methods such as a hydrothermal treatment process and a plasma treatment process, which can change the oxide film into a hydrophilic state, can be used without limitation.

The drug is injected into the groove of the oxide film (S7d).

In order to delay the release of the drug, the oxide film is changed to hydrophilic, and a hydrophilic drug is injected into the groove to allow the drug to smoothly flow into the hydrophilic groove. The hydrophilic drug is preferably a hydrophilic polymer drug that inhibits the proliferation of neointimal cells.

Drugs can be used in various ways depending on the use of the implant or stent, it is preferable to use bisphosphonate-based drugs in order to increase the biobinding force in the implant. In some cases, bisphosphonate-based drugs and antibiotics may be mixed, and bisphosphonate-based drugs are used to suppress osteoclast production in vivo. have. In addition, bisphosphonate drugs cause metabolic changes such as inhibition of intestinal calcium migration, inhibition of 1,25 (OH) ₂ D production, inhibition of glycolysis, inhibition of cell growth, and changes in acidic and alkaline phosphatides.

Such bisphosphonate drugs include etidronate (1-ethane-1-hydroxy-1,1-bisphosphonate), pamidronate (3-amino-1-hydroxy-propylidene bisphosphonate), and alendronate (4). -amino-1-hydroxy-butylidene bisphosphonate), ibandronate, 1-hydroxy-3- [methyl (pentyl) amino] propane-1,1-diyl bisphosphonate), and mixtures thereof. Do.

In addition, the antibiotic is preferably selected from the group consisting of tetracycline (tetracycline), vancomycin (vancomycin), amoxicillin, clavulanic acid and mixtures thereof.

Unlike the fourth embodiment, the manufacturing method of the fifth embodiment is identical to the steps S1d to S4d as shown in FIG. 8, but there is a difference in the process after the step of forming grooves on the surface of the metal base material.

Forming a polymer protective layer on a portion of the surface of the metal base material (S1e), anodizing the metal base material to form titanium oxide nanotubes on the surface (S2e), and removing the polymer protective layer on the surface of the metal base material (S3e). After removing the titanium oxide nanotubes to form grooves on the surface of the metal base material (S4e), in the fifth embodiment, a biocompatible material is coated on the surface of the metal base material (S5e).

The biocompatible material is further coated on the surface of the metal base material in order to increase the biocompatibility, the biocompatibility, the strength, and the like. When a thin coating layer is formed on the surface of the metal base material using a biocompatible material, grooves are also formed in the coating layer by the grooves of the metal base material.

The biocompatible material may be a biocompatible metal, a biocompatible ceramic, a biocompatible polymer, or the like. Biocompatible materials and elements include magnesium (Mg), calcium (Ca), phosphorus (P), zinc (Zn), iron (Fe), chromium (Cr), nickel (Ni), stainless steel, and cobalt ( Co), titanium (Ti), zirconium (Zr), niobium (Nb), tantalum (Ta), gold (Au), silver (Ag) and a mixture thereof are preferably selected. Hydroxyapatite (HAp), biphasic calcium phosphate ceramics, bioactive glass, zirconia (ZrO ₂ ), alumina (Al ₂ O ₃ ), titania (TiO ₂ ), silicon carbide (SiC), silicon nitride (Si ₃ N ₄ ), and mixtures thereof. In addition, the biocompatible polymers are polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polycaprolactone (poly-e- caprolactone, PCL) and mixtures thereof.

As a method of coating the biocompatible material on the surface of the metal base material, an electron beam deposition method or an electrolytic coating method is preferable. In addition to this, any method capable of coating may be used without limitation.

The electron beam deposition method is a method of depositing a biocompatible material on a metal base material which is a deposition base material by irradiating an electron beam to a biocompatible material located in an electron beam deposition apparatus, and is generally used as a method of depositing a metal. When using this method, even a metal having a high melting point can be easily deposited, and at the same time, there is an advantage in that a dense and uniform coating can be performed.

The electron beam may be generated at an electron beam deposition current of 100 to 150 mA. If the electron beam is less than 100 mA, the energy is so small that the electron beam is generated so that the rate at which the biocompatible material is deposited is very low and the process is not efficient. In addition, the biocompatible material may be overflowed if it exceeds 150 mA, thereby reducing the durability of the electron beam deposition equipment.

In addition, the electron beam deposition rate in the electron beam deposition process is preferably 1 to 1.5 Å / s. If the deposition rate is less than 1 Å / s, the amount of biocompatible materials deposited is too small, the process is inefficient, exceeding 1.5 Å / s In this case, the uniformity may be reduced when the biocompatible material to be deposited is laminated.

The electrolytic coating method, which is another method of coating a biocompatible material, is a method of coating a biocompatible material by immersing a metal base material in an aqueous solution containing the biocompatible material and then greeting the electricity with the aqueous solution.

Herein, the aqueous solution containing the biocompatible material is preferably selected from the group consisting of a hydroxyapatite (HAp) solution, a calcium solution, a phosphate solution, and a mixture thereof. Here, the calcium solution refers to a solution containing calcium in an ionic form, calcium phosphate, calcium acetate monohydrate (CA), calcium acetate hydrate (calcium acetate hydrate), calcium acetate (calcium) acetate) and mixtures thereof, but is not limited thereto. In addition, the phosphate solution means a solution in which the phosphate is contained in the aqueous solution in the form of ions, glycerophosphate disodium salt pentahydrate (GP), glycerol phosphate calcium salt, glycerophosphate disodium Preferably, the salt hydrate is selected from the group consisting of glycerophosphate disodium salt hydrate, glycerol phosphate disodium salt, and mixtures thereof.

It is preferable that aqueous solution is 25-300 degreeC in temperature. If the temperature is less than 25 ℃ the activity of the electrolytic ions may be lowered kinetics disadvantageously, if the temperature exceeds 300 ℃ may cause a problem of excessive manufacturing energy release.

Through this step, in the fifth embodiment, a biocompatible metal, an implant or a stent coated with a biocompatible material on the surface of the metal base material can be obtained, and in the case of the drug release implant or the stent, as in the steps S6d and S7d of the fourth embodiment Changing the coating layer to a hydrophilic state (S6e) and the step of injecting a drug into the groove of the hydrophilic coating layer (S7e) can be further proceeded.

In the manufacturing method according to the sixth embodiment, as shown in FIG. 9, forming a polymer protective layer on a part of the surface of the metal base material (S1f), and forming titanium oxide nanotubes on the surface by anodizing the metal base material ( S2f), removing the polymer protective layer on the surface of the metal base material (S3f), and removing the titanium oxide nanotubes to form grooves on the surface of the metal base material (S4f) are the same as in the fourth and fifth embodiments. Although the following steps are made, there is a difference in applying the fourth embodiment and the fifth embodiment together.

In the sixth embodiment, as in the fourth embodiment, after forming grooves on the surface of the metal base material (S4f), heat treatment is performed to form titanium oxide nanotubes on the surface of the metal base material (S5f).

The metal base material having grooves formed on the surface is heat-treated to form an oxide film on the metal base material surface. A plurality of grooves are formed in the oxide film, and the heat treatment temperature for forming the grooves is preferably performed at 200 to 1200 ° C. as in the fourth embodiment, and a crystalline thin film is formed at this temperature.

The grooves formed in the oxide film preferably have a diameter of 10 to 1,000 nm similarly to the grooves. If the diameter of the grooved oxide is less than 10nm, the bio-binding force is not high, and if the diameter of the grooved oxide is greater than 1,000 nm, the grooves may be interlocked with each other, thereby making it difficult to obtain uniform grooves. The diameter of the grooves can be controlled by the diameter of the grooves or by controlling the heat treatment temperature. In addition, a rough surface having fine pores of several nanometers in size is formed at the same time as the surface of the grooved oxide itself.

The biocompatible material is coated on the surface of the oxide film (S6f).

The biocompatible material is further coated on the surface of the oxide film in order to increase biocompatibility, biocompatibility, strength, and the like. When the coating layer is formed on the surface of the oxide film using a biocompatible material, the groove shape is also formed on the coating layer by the groove of the oxide film. As the biocompatible material, any of the materials described in Example 5 can be used.

When the biocompatible material is coated after the heat treatment is performed to form the oxide film, the strength is increased by the oxide film, and the strength and biocombination force are increased by the biocompatible material.

Through these steps, in the sixth embodiment, a biograft metal, an implant, or a stent coated with a biocompatible material on the oxide film surface may be obtained. In the case of a drug release implant or stent, the coating layer may be similar to the steps S6d and S7d of the fourth embodiment. Changing to a hydrophilic state (S7f) and the step of injecting a drug into the groove of the hydrophilic coating layer (S8f) can be further proceeded.

Hereinafter, embodiments of the present invention will be described in more detail.

Example 1 is a method of anodizing the surface of a metal base material made of pure titanium metal or titanium alloy to form hemispherical grooves on the surface. Here, the surface of the metal base material before the surface treatment may be confirmed through FIG. 10.

As shown in FIG. 11, when a positive electrode is a titanium (Ti) metal base material 100 and a negative electrode is an insoluble platinum (Pt, 10) metal, a DC voltage is applied to both ends and anodized, so that the titanium oxide nanotubes are formed on a metal surface. Can be formed on top. Before anodizing, first, the metal base material 100 is immersed in ethanol and acetone in an ultrasonic cleaner in turn, and then washed for 2 minutes. Subsequently, the titanium (Ti) metal base material 100 to be anodized in the electrolyte and the insoluble platinum 10 metal as a counter electrode are dipped in the electrolyte 20 as shown in FIG. 11. In this case, the electrolyte solution was an electrolyte solution 20 in which 0.01 to 10 wt% of ammonium fluoride (NH ₄ F) salt was added to a mixture of ethylene glycol and water, and the temperature of the electrolyte solution 20 was 10 to 10. Applying an applied voltage of 10 to 200V at a constant voltage for 1 to 300 minutes while maintaining 80 ℃ to obtain a titanium oxide nanotube of 200nm or more. Titanium oxide obtained by the anodic oxidation (TiO ₂₎ nanotubes can be seen to preferably formed of a bar, titanium oxide nanotubes shown in FIG.

The sample obtained by anodizing is immersed in water for 1 hour and washed. After washing, in order to remove the titanium oxide nanotubes obtained by anodizing from the metal matrix, they were immersed in a hydrogen peroxide (H ₂ O ₂ ) solution and washed again with an ultrasonic cleaner for 5 minutes while maintaining 20 to 100 ° C. After dipping and washing for 5 minutes with an ultrasonic cleaner, it is finally dipped in ethanol and washed for 5 minutes with an ultrasonic cleaner. The washed samples are stored after drying in a hot air dryer. This removes the titanium oxide nanotubes formed on the surface of the metal base material, and the surface has a hemispherical groove as shown in FIG. 13. In further expansion, it can be seen that micropores are formed in the hemispherical grooves as shown in FIGS. 14 and 15. FIG. 16 shows XPS results of comparing the original metal matrix surface with the surface removed after anodizing to form titanium oxide nanotubes. XPS results show that after the nanopatterning process, the surface is more oxidized to titanium oxide and impurities such as lead (Pb) are removed as shown in Table 1. Lead may remain on the surface during the manufacturing process, but may be removed from the surface of the metal substrate in the process of removing the titanium oxide nanotubes after anodizing as in the present invention. At this time, impurities other than lead are also removed.

Table 1

name	Before Nano Patterning (At.%)	After Nano Patterning (At.%)
C1s	47.5	47.85
Ca2p	0.29	-
F1s	0.33	0.41
K2p	-	-
Nis	1.09	1.06
O1s	34.18	36.9
Pb4f	0.13	-
S2p	0.42	-
Si2p	1.16	0.6
Ti2p	14.4	13.12
Zn2p3	0.51	0.06

FIG. 17 illustrates an AFM (atomic force microscope) image of the metal base material from which anodized titanium oxide nanotubes are removed, and it can be seen that nano-sized grooves are uniformly formed.

If necessary, the thickness of the titanium oxide oxide film may be increased to about 10 nm to 1,000 nm by heat-treating the metal matrix sample at 200 to 1200 ° C.

Example 2 is a restable blast media (RBM) process for sandblasting a metal base material made of pure titanium metal or an alloy and then anodizing to form grooves on the surface of the metal base material.

First, the metal base material is fixed so as not to be moved by pressure, and then sandblasting the media including calcium phosphate particles having a grain size of sand such as 180 to 425 μm to the metal base material at an appropriate pressure using a spray nozzle. Surface treatment. The sand is using a pressure of 0.45 to 0.65kgf / cm ² is made as sand blasting. The surface treatment is performed for 10 to 25 seconds, and the treated metal base material is washed in the ultrasonic cleaner for about 5 minutes. Thus, the sandblasting surface-treated metal base material can be confirmed through FIG.

Anodization is carried out using a sandblasted metal substrate. Anodization is performed in the same manner as in Example 1 by immersing a metal base material as an anode and platinum as a cathode in an electrolyte and applying a voltage to obtain titanium oxide nanotubes of 200 nm or more on the surface of the metal base material.

The titanium oxide nanotubes obtained through anodization are sequentially immersed in hydrogen peroxide water, water and ethanol, and then washed using an ultrasonic cleaner, thereby removing the titanium oxide nanotubes. In this manner, the metal base material having grooves formed on the surface thereof can obtain a surface having micro grooves of 100 μm and nano grooves of several to several hundred nanometers. 19 and 20 are surfaces removed only part of the titanium oxide nanotubes after sandblasting and anodizing, titanium oxide nanotube shape is left on the surface is not removed, as shown in the figure, evenly formed hemispherical grooves It can be seen that. This step can confirm the surface change as shown in FIG. 22 shows that the nanopattern grooves are formed on the surface while maintaining the micro grooves and the intermediate grooves on the hemispherical surface by anodizing the SLA and then removing the titanium oxide nanotubes.

Example 2 is a process of forming grooves on the surface of the metal base material by anodizing the metal base material made of pure titanium metal or alloy after SLA (Sand blasted, Larg-grit, Acid etched) method.

First, the metal base material is fixed so as not to be moved by the pressure, and then sandblasted aluminum metal (Al ₂ O ₃ ) having a grain size of sand such as 100 μm to the metal base material at an appropriate pressure using a spray nozzle. Surface treatment At this time, the aluminum oxide is sandblasted using a pressure of 0.45 to 0.65kgf / cm ² . Thereafter, the sandblasted metal matrix is immersed in an acid and the surface is etched to form grooves of several micrometers. Thereafter, neutralization washing is performed through a base to neutralize the acid used for etching, and washing with water or distilled water is performed once more to remove the base used for neutralization washing. Thereafter, an additional cleaning process is performed to completely remove the aluminum oxide used in sandblasting.

Anodization is carried out using sandblasted and etched metal substrates. Anodization is performed in the same manner as in Example 1 by immersing a metal base material as an anode and platinum as a cathode in an electrolyte and applying a voltage to obtain titanium oxide nanotubes of 200 nm or more on the surface of the metal base material.

The titanium oxide nanotubes obtained through anodization are sequentially immersed in water, hydrogen peroxide and ethanol, and then washed using an ultrasonic cleaner, thereby removing the titanium oxide nanotubes. In this manner, the metal base material having grooves formed on the surface may obtain a surface having micro grooves of 100 μm, intermediate grooves of several micrometers, and nano grooves of several to several hundred nanometers.

In Example 4, the metal base material made of pure titanium metal or alloy is anodized in the same manner as in Example 1, a groove is formed on the surface of the metal base material, and heat treatment is performed to increase the thickness of the oxide film.

Anodization is performed in the same manner as in Example 1 by dipping the metal base material as an anode and platinum as a cathode in an electrolyte and applying a voltage to obtain a nanotube structure of 200 nm or more on the surface of the metal base material. After immersing in water, hydrogen peroxide and alcohol, ultrasonic cleaning for 5 minutes to remove the titanium oxide nanotubes. After removing the titanium oxide nanotubes and dried for 10 minutes in 100 ℃ oven, heat treatment for 1 hour in 300 ℃ electric furnace. After the heat treatment, the thickness of the oxide film was increased to about 50 nm.

Example 5

A metal base material made of titanium (Ti) metal having an implant or stent shape is immersed in ethanol and acetone in an ultrasonic cleaner and washed for 2 minutes. After cleaning, the metal base is dried and PDMS (Polymethylsiloxane) is coated on the metal base where anodization is not desired. Thereafter, spot welding is performed on titanium metal to make an electrode point to anodize the surface of the metal base material. Subsequently, a titanium metal base material, which is an anodization target, and a platinum (Pt) metal, a counter electrode, are immersed in the electrolyte. In this case, the electrolyte used was an electrolyte in which 0.01 to 10 wt% NH ₄ F and 1 to 50 vol% H ₂ O were added to ethylene glycol, and the temperature of the electrolyte was maintained at room temperature.

When a direct current voltage is applied to both ends with a titanium metal base material as an anode and an insoluble platinum metal as a cathode, the surface of the titanium metal base material is anodized with titanium oxide (TiO ₂ ). At this time, the DC voltage is applied to a constant voltage of 10 to 200V for 10 to 300 minutes, the anodized titanium oxide is formed on the surface of the metal substrate titanium oxide nanotubes having a thickness of several microns or more.

Anodized metal base material is removed using PDMS coated on the inner wall surface using acetone. The PDMS coated surface is not anodized and the smooth surface is maintained. Next, the titanium oxide nanotubes obtained through anodization are removed from the metal base material. The anodized titanium nanotubes are immersed in a 30 wt% hydrogen peroxide (H ₂ O ₂ ) solution for 10 minutes under an ultrasonic cleaner. Through this method, the titanium oxide nanotubes formed on the surface of the metal base material are removed, and grooves are formed on the surface thereof.

Titanium oxide nanotubes are removed to heat the titanium metal base material with grooves formed on the surface at 200 to 1200 ° C. to form an oxide film having grooves that are nano size grooves of about 10 to 1,000 nm. Heat treatment was performed in a kiln at a temperature to form a titanium metal matrix having a thin film having a thickness of about 100 nm.

The film is irradiated with UV to change the hydrophilic surface so that the drug is injected into the oxide groove of the oxide film. The UV is treated at a speed of 10 m / min using a UV lamp having a strength of 1 J / cm 2. The hydrophilic drug is injected into the groove of the oxide film of which the surface is hydrophilic to finally prepare a biograft metal, and the biograft metal is applied to an implant or stent.

A metal base material made of titanium (Ti) metal having an implant or stent shape is immersed in ethanol and acetone in an ultrasonic cleaner and washed for 2 minutes. After cleaning, the metal base is dried and PDMS (Polymethylsiloxane) is coated on the metal base where anodization is not desired. Thereafter, spot welding is performed on titanium metal to make an electrode point to anodize the surface of the metal base material. Subsequently, a titanium metal base material, which is an anodization target, and a platinum (Pt) metal, a counter electrode, are immersed in the electrolyte. The electrolyte used was ethylene glycol (Ethylene glycol) 0.01 to 10wt% NH ₄ F and the electrolyte of from 1 to the composition is added 50vol% H ₂ O, the temperature of the electrolyte is kept to room temperature.

When a direct current voltage is applied to both ends with a titanium metal base material as an anode and an insoluble platinum metal as a cathode, the surface of the titanium metal base material is anodized with titanium oxide (TiO ₂ ). At this time, the DC voltage is applied to a constant voltage of 10 to 200V for 10 to 300 minutes, the anodized titanium oxide is formed of titanium oxide nanotubes having a thickness of several microns or more on the surface of the metal base material.

Anodized metal base material is removed using PDMS coated on the inner wall surface using acetone. The PDMS coated surface is not anodized and the smooth surface is maintained.

Next, the titanium oxide nanotubes obtained through anodization were removed from the titanium metal matrix. In order to remove the titanium oxide nanotubes, anodized titanium metal substrate was placed in a 30 wt% hydrogen peroxide (H ₂ O ₂ ) solution under an ultrasonic cleaner. Immerse for 10 minutes.

Titanium oxide nanotubes are removed to mount the titanium metal base material having grooves on the surface of the inner upper side of the vacuum chamber. Niobium (Nb), one of the biocompatible materials, is disposed under the vacuum chamber, and the pressure inside the vacuum chamber is maintained at about 5 × 10 ⁻⁷ Torr. In order to generate an electron beam irradiated to niobium metal, the electron beam deposition current was applied for 9 hours while varying from 100 to 150 mA. This adjusted the current value in order to maintain the rate drop over time when niobium deposition was carried out at a rate of 1 mA / s. As a result, a niobium layer, which is a biocompatible material having a thickness of 3 μm, is formed on the surface of the metal matrix.

Such biograft metals, implants, and stents are anodized to remove the anodized surface after anodizing the surface of the metal base material, thereby preventing the anodized surface from being peeled off and thus decreasing the somatic cell necrosis or bone fusion. In addition, when implanting a metal biomaterial with hemispherical grooves formed through surface anodization of the metal base material, it has an advantage of maximizing surface area and increasing surface roughness, thereby having excellent biocompatibility, chemical compatibility and mechanical compatibility. .

The present invention relates to a metal for biotransplantation, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method having a nanopatterning groove surface, and more particularly, after anodizing the surface of the metal base material. A groove is formed on the surface to remove the anodized titanium oxide film and prevents the nanopatterning groove surface from leaking out of the living body, a method for manufacturing a metal, a metal manufacturing method, an implant, an implant manufacturing method, a stent and a stent manufacturing method Available in the field.

Claims

Anodizing a metal base material made of titanium metal or titanium alloy to form titanium oxide nanotubes;

And removing the titanium oxide nanotubes to form grooves on the surface of the metal base material.
The method of claim 1,

The anodizing to form titanium oxide nanotubes,

A method for producing a metal for transplantation with a nanopatterned groove, characterized in that the metal base material is immersed in an electrolyte solution containing fluoride (F − ) ions.
The method of claim 2,

The electrolyte solution containing fluoride ions,

Salts containing fluoride ions; At least one solvent of an inorganic acid, an organic acid, a polymer alcohol; a method for producing a bio-transplant metal having a nano-patterned groove surface comprising a.
The method of claim 3, wherein

The salt is a method for producing a bio-grafted metal having a nano-patterned groove surface characterized in that it comprises at least one of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium fluoride (NH 4 F).
The method of claim 3, wherein

The solvent is nano-patterned, characterized in that it comprises at least one of phosphoric acid (H 3 PO 4 ), sulfuric acid (H 2 SO 4 ), nitric acid (HNO 3 ), glycerol (glycerol), ethylene glycol (ethylene glycol) A method for producing a biotransplant metal having a groove surface.
The method of claim 1,

After the step of forming the groove on the metal base material surface,

Heat treating the metal base material to form an oxide film having a thickness of 10 nm to 1,000 nm on the surface of the metal base material.
The method of claim 6,

The heat treatment is a biotransplantation metal manufacturing method having a nanopatterning groove surface, characterized in that at 200 ℃ to 1200 ℃.
The method of claim 1,

The groove has a hemispherical shape,

10. A method for producing a bio-transplant metal having a nanopatterning groove surface, characterized in that the diameter has a size of 10nm to 1,000nm.
The method of claim 1,

The groove has a hemispherical shape,

The hemispherical groove has a nano-patterned groove surface characterized in that it further comprises a nanopore (pore) of several nanometers in size on the surface.
The method of claim 1,

The removal of the titanium oxide nanotubes is a method for producing a bio-grafted metal having a nano-patterned groove surface characterized in that the metal base material is immersed in hydrogen peroxide (H 2 O 2 ) to remove by ultrasonic cleaning.
The method of claim 1,

The removal of the titanium oxide nanotubes are immersed in an organic acid or an aqueous base solution to remove the nanopatterning grooves, characterized in that the manufacturing method of the metal for biografting.
The method of claim 1,

Prior to forming the titanium oxide nanotubes,

Sandblasting the surface of the metal base material further comprises,

The sandblasting step,

A method for manufacturing a bio-transplant metal having a nanopatterned groove surface, by hitting sandblasted media against the surface of the metal base material to form micro grooves of 50 μm to 500 μm on the surface of the metal base material.
The method of claim 1,

Prior to forming the titanium oxide nanotubes,

A method for manufacturing a biograft metal having a nanopatterned groove surface further comprising surface treating the metal base material through a sand blasted, large-grit, acid etched (SLA) method.
The method of claim 1,

Prior to forming the titanium oxide nanotubes,

Forming a polymer protective layer to prevent anodization on a portion of the surface of the metal base material,

After forming the titanium oxide nanotubes,

And removing the polymer protective layer.
The method of claim 1,

After the step of forming a groove on the metal base material surface,

The method for producing a bio-transplant metal having a nano-patterned groove surface further comprising the step of coating a biocompatible material on the surface of the metal base material.
The method of claim 1,

After the step of forming a groove on the metal base material surface,

Heat-treating the metal base material to form an oxide film on the surface of the metal base material;

The method of manufacturing a bio-transplant metal having a nano-patterned groove surface characterized in that it further comprises the step of coating a biocompatible material on the surface of the oxide film.
The method according to any one of claims 15 and 16,

Coating the biocompatible material comprises:

A method for producing a biotransplant metal having a nanopatterning groove surface, using an electron beam deposition method or an electrolytic coating method.
The method of claim 17,

The electrolytic coating method,

And immersing the metal base material in an aqueous solution containing the biocompatible material and applying electricity to the aqueous solution to coat the biocompatible material.
The method of claim 1,

After the step of forming a groove on the metal base material surface,

Changing the surface of the metal base material to a hydrophilic state;

The method of manufacturing a bio-grafted metal having a nano-patterned groove surface further comprises the step of injecting a drug into the groove of the metal base material is hydrophilic.
The method of claim 19,

The drug is a method for producing a bio-transplant metal having a nano-patterned groove surface, characterized in that the hydrophilic polymer drug.
Anodizing a metal base material made of titanium metal or titanium alloy to form titanium oxide nanotubes, and removing the titanium oxide nanotubes, grooves are formed on the surface of the metal base material. .
The method of claim 21,

The groove has a hemispherical shape,

The groove is a ratio of diameter and height is diameter: height = 1: 0.01 to 0.5, the diameter of the hemispherical groove has a nanopatterned groove surface having a nanopatterning groove surface, characterized in that the size.
The method of claim 21,

The groove is a nano-transplanting metal having a nano-patterned groove surface characterized in that it further comprises a micro-pores of several nanometers in size.
The method of claim 21,

The metal base material has a nanopatterning groove surface, characterized in that it further comprises an oxide film of 10nm to 1,000nm thickness.
The method of claim 21,

The metal base material is a biograft metal having a nano patterning groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro grooves of 50㎛ to 500㎛ size larger than the intermediate groove .
The method of claim 21,

The surface of the metal base material in which the grooves are formed is a hydrophilic state, and the biopatterning metal having a nanopatterning groove surface, characterized in that the hydrophilic polymer drug is injected into the grooves of the metal base material which is hydrophilic.
A biograft metal having a nanopatterned groove surface, characterized in that it comprises a metal base material having a hemispherical groove formed on the surface.
The method of claim 27,

The hemispherical groove has a ratio of diameter and height in diameter: height = 1: 0.01 to 0.5, and the hemispherical groove has a nanopatterning groove surface, characterized in that it has a size of 10nm to 1,000nm.
The method of claim 27,

The hemispherical groove has a nanopatterned groove surface, characterized in that it further comprises micropores of several nanometers in size.
The method of claim 27,

The metal base material has a nanopatterning groove surface, characterized in that it further comprises an oxide film of 10nm to 1,000nm thickness.
The method of claim 27,

The metal base material is a biograft metal having a nano patterning groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro grooves of 50㎛ to 500㎛ size larger than the intermediate groove .
The method of claim 27,

The surface of the metal base material in which the grooves are formed is a hydrophilic state, and the biopatterning metal having a nanopatterning groove surface, characterized in that the hydrophilic polymer drug is injected into the grooves of the metal base material which is hydrophilic.
Anodizing an implant body made of titanium metal or a titanium alloy to form titanium oxide nanotubes;

Removing the titanium oxide nanotubes to form grooves on the surface of the implant body, wherein the implant has a nanopatterning groove surface.
The method of claim 33,

After forming the groove on the surface of the implant body,

And heat treating the implant body to form an oxide film having a thickness of 10 nm to 1,000 nm on the surface of the implant body.
The method of claim 33,

The heat treatment is an implant manufacturing method having a nano patterning groove surface, characterized in that at 200 ℃ to 1200 ℃.
The method of claim 33,

The groove has a hemispherical shape,

10 nm to 1,000 nm in diameter, the hemispherical groove is an implant having a nano patterning groove surface characterized in that it further comprises a micropore (pore) of several nanometers on the surface.
The method of claim 33,

Prior to forming the titanium oxide nanotubes,

Further comprising sandblasting the implant body surface,

The sandblasting step,

A method for manufacturing an implant having a nanopatterning groove surface, wherein sandblast media is hitting the surface of the implant body to form micro grooves of 50 μm to 500 μm on the surface of the implant body.
The method of claim 33,

Prior to forming the titanium oxide nanotubes,

The method of manufacturing an implant having a nano-patterned groove surface further comprises the step of surface treatment of the implant body through a sand blasted, large-grit, acid etched (SLA) method.
An implant having a nanopatterned groove surface, wherein an implant body made of titanium metal or a titanium alloy is anodized to form titanium oxide nanotubes, and the titanium oxide nanotubes are removed to form grooves on the surface of the implant body.
The method of claim 39,

The groove has a hemispherical shape,

The groove is an implant having a nano patterning groove surface, the ratio of diameter and height is diameter: height = 1: 0.01 to 0.5, the diameter of the hemispherical groove has a size of 10nm to 1,000nm.
The method of claim 39,

The groove has a nanopatterning groove surface, characterized in that it further comprises a micro-pores of several nanometers in size.
The method of claim 39,

The metal base material is an implant having a nano patterning groove surface, characterized in that further comprises an oxide film of 10nm to 1,000nm thickness.
The method of claim 39,

The implant body is an implant having a nano-patterned groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro groove of 50㎛ to 500㎛ size larger than the intermediate groove is formed.
An implant having a nanopatterned groove surface comprising an implant body having a hemispherical groove formed on the surface thereof.
The method of claim 44,

The hemispherical groove has a diameter-to-height ratio of diameter: height = 1: 0.01 to 0.5, and the hemispherical groove has an nanopatterning groove surface, characterized in that it has a size of 10nm to 1,000nm.
The method of claim 44,

The hemispherical groove is an implant having a nano-patterned groove surface, characterized in that it further comprises micropores of several nanometers in size.
The method of claim 44,

The implant body has a nano-patterned groove surface, characterized in that further comprises an oxide film of 10nm to 1,000nm thickness.
The method of claim 44,

The implant body is an implant having a nano-patterned groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro groove of 50㎛ to 500㎛ size larger than the intermediate groove is formed.
Anodizing a stent body made of titanium metal or a titanium alloy to form titanium oxide nanotubes;

Removing the titanium oxide nanotubes to form a groove (groove) on the surface of the stent body, characterized in that it comprises a nano patterning groove surface having a stent manufacturing method.
The method of claim 49,

After forming the groove on the surface of the stent body,

And heat-treating the stent body to form an oxide film having a thickness of 10 nm to 1,000 nm on the surface of the stent body.
The method of claim 49,

The groove has a hemispherical shape,

A method for producing a stent having a nanopatterning groove surface, wherein the diameter has a size of 10 nm to 1,000 nm.
The method of claim 49,

The groove has a hemispherical shape,

The hemispherical groove is a stent manufacturing method having a nano-patterned groove surface characterized in that it further comprises a micropore (pore) of several nanometers in size on the surface.
The method of claim 49,

Prior to forming the titanium oxide nanotubes,

Forming a polymer protective layer to prevent anodization on a portion of the surface of the stent body,

After forming the titanium oxide nanotubes,

The method of claim 1, further comprising removing the polymer protective layer.
The method of claim 49,

After the step of forming a groove in the stent body surface,

The method of manufacturing a stent having a nanopatterning groove surface further comprising the step of coating a biocompatible material on the surface of the stent body.
The method of claim 49,

After the step of forming a groove in the stent body surface,

Heat treating the stent body to form an oxide film on the surface of the stent body;

The method of manufacturing a stent having a nano-patterned groove surface further comprises the step of coating a biocompatible material on the surface of the oxide film.
The method of any one of claims 54 and 55,

Coating the biocompatible material comprises:

A method of manufacturing a stent having a nanopatterning groove surface, using an electron beam deposition method or an electrolytic coating method.
The method of claim 49,

After the step of forming a groove in the stent body surface,

Changing the surface of the stent body to a hydrophilic state;

The method of manufacturing a stent having a nano-patterned groove surface further comprises the step of injecting a drug into the groove of the stent body is hydrophilic.
The method of claim 49,

The drug is a method for producing a stent having a nano patterning groove surface, characterized in that the hydrophilic polymer drug.
A stent having a nanopatterned groove surface, wherein the stent body made of titanium metal or titanium alloy is anodized to form titanium oxide nanotubes, and the titanium oxide nanotubes are removed to form grooves on the surface of the stent body.
The method of claim 59,

The groove has a hemispherical shape,

The groove has a diameter-to-height ratio of diameter: height = 1: 0.01 to 0.5, and the diameter of the hemispherical groove has a nanopatterning groove surface, characterized in that it has a size of 10 nm to 1,000 nm.
The method of claim 59,

The groove has a nano-patterned groove surface, characterized in that it further comprises micropores of several nanometers in size.
The method of claim 59,

The stent body has a nano patterning groove surface, characterized in that further comprises an oxide film of 10nm to 1,000nm thickness.
The method of claim 59,

The stent body has a nano patterning groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro grooves of 50㎛ to 500㎛ size larger than the intermediate groove is formed.
The method of claim 59,

The surface of the stent body in which the grooves are formed is a hydrophilic state, and a hydrophilic polymer drug is injected into the grooves of the hydrophilic stent body.
A stent having a nanopatterned groove surface comprising a stent body having a hemispherical groove formed on its surface.
66. The method of claim 65,

The hemispherical groove has a diameter and height ratio of diameter: height = 1: 0.01 to 0.5, and the hemispherical groove has a nanopatterning groove surface, characterized in that it has a size of 10 nm to 1,000 nm.
66. The method of claim 65,

The hemispherical groove has a nanopatterned groove surface, characterized in that it further comprises micropores of several nanometers in size.
66. The method of claim 65,

The stent body has a nano patterning groove surface, characterized in that further comprises an oxide film of 10nm to 1,000nm thickness.
66. The method of claim 65,

The stent body has a nano patterning groove surface, characterized in that the intermediate groove of 1㎛ to 50㎛ size larger than the groove, and the micro grooves of 50㎛ to 500㎛ size larger than the intermediate groove is formed.
66. The method of claim 65,

The surface of the stent body in which the grooves are formed is a hydrophilic state, and a hydrophilic polymer drug is injected into the grooves of the hydrophilic stent body.