KR20170096267A

KR20170096267A - A method for preparation of a metallic implant comprising biocompatable fluoride ceramic coating

Info

Publication number: KR20170096267A
Application number: KR1020160017283A
Authority: KR
Inventors: 김현이; 송주하; 천광희
Original assignee: 서울대학교산학협력단
Priority date: 2016-02-15
Filing date: 2016-02-15
Publication date: 2017-08-24
Also published as: KR101822255B1

Abstract

The present invention relates to a method for producing a metal implant containing a fluorine-based ceramic coating layer, including a step of forming a coating layer by depositing fluorine-based ceramic such as fluorinated calcium or fluorinated magnesium on a surface of a metal implant base material. The present invention further relates to a biocompatible antibacterial implant consisting of: the metal implant base material; and a fluorine-based ceramic coating layer formed on the surface of the metal implant base material.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a method for preparing a metal implant comprising a biocompatible fluorocarbon ceramic coating layer,

The present invention relates to a method for manufacturing a metal implant including a fluorine-based ceramic coating layer, and a metal implant base, including a step of forming a coating layer by depositing fluorine-based ceramics on the surface of a metal implant base material; And a fluorine-based ceramic coating layer formed on the surface of the substrate.

Materials for implant implant such as medical implant, artificial hip joint and osteoporosis are metal materials such as titanium, stainless steel alloy, cobalt-chromium alloy, bioactive ceramic materials such as alumina and zirconia, bioactive ceramic materials such as hydroxyapatite Is widely used. Among these implantable implant materials, the bioactive metal or alloy is superior in strength, fatigue resistance and molding processability to other materials such as ceramics and polymers, and for the purpose of regenerating and treating bone defects and loosening sites, , Which is the most widely used biomaterial in orthopedics and plastic surgery. The metals or alloys are iron, chromium, nickel, stainless steel, cobalt alloys, titanium, titanium alloys, zirconium, niobium, tantalum, gold and silver. Among them, they are superior in corrosion resistance to other metal materials and stable in human tissues Titanium and titanium alloys are most widely used for dental, orthopedic and plastic surgery implant materials.

In the past few years, attempts have been made to increase the surface area of a metal or alloy, to change surface topography, or to improve osseointegration through physical, chemical, and biological surface treatments . Osteointegration refers to the direct and functional coupling between a patient's own bone tissue and implanted implants, and a robust fusion of the bone and implant surfaces is an important factor for improving the durability of the implants in the body and for prolonged clinical functioning.

Since the 1990s, a variety of surface modifications have been routinely attempted to improve fusion with bone tissue, minimize bone resorption around metal or alloy implants, and improve affinity and adhesion to surrounding soft tissues. In particular, the most widely used surface treatment methods for titanium and titanium alloys include metal bead sintering (V. Amigo et al., J. Mater. Process. Technol., 2003, 141 (1): 117-122) Blasting and acid treatment (JE Feighan et al., J. Bone Joint Surg. Am., 1995, 77 (9): 1380-1395), alkali immersion and heat treatment (HM Kim et al., J. Mater. Med., 1997, 8 (6): 341-347). Hydroxyapatite coating (C. Popa et al., J. Mater. Sci. Mater. Med., 2005, 16 (12): 1165-1171). , J. Am. Prosthodont., 2007, 45 (1): 85-97), ion implantation (TR Rautray et al., J. Biomed. Biomater., 2010, 93 (2): 581-591). Recently, the most widely used method is SLA (sandblasted, large grit, acid etched) method.

Dental implants consist of three parts: an artificial root inserted into the bone tissue, an abutment connecting the root and the artificial tooth, and an artificial tooth. Up to now, The abutment is in direct contact with the tissue, and as described above, the micro-surface irregularities are formed by etching the interface between the tissue and the implant or by applying an additional substance to increase the contact area with the tissue, Has been concentrating on improving the biocompatibility by coating this excellent calcium phosphate ceramics.

However, there have been reports of various adverse effects in the use of abutment. Especially, inflammatory side effects such as periodontitis infection due to periodontal bacteria infection have been reported between the gums and the surface of the abdomen exposed to the outside, so that antibacterial and / or anti- The need for implants with a high degree of freedom is emerging.

Accordingly, studies have been made to impart antimicrobial properties to the surfaces of implants by using silver, which is known to have excellent antibacterial properties, or by supporting antibiotics. Specifically, a method of coating silver on the surface or utilizing silver nanoparticles has been attempted. However, when the silver is used, the antimicrobial activity can be greatly improved, but the risk of necrosis of the surrounding tissue cells due to the cytotoxicity of silver itself is high . In the meantime, the method of coating antibiotics on the surface of the implants, or applying antibiotics to the pores of the implants in the case of porous materials, shows that antibiotics are rapidly released early due to weak adhesion between the antibiotics and the surface of the implants, And it is disadvantageous that it can exhibit cytotoxicity by antibiotics due to such rapid release.

The inventors of the present invention have made intensive researches to find out a method of manufacturing an implant that can improve the biocompatibility and modify the surface of a metal implant while minimizing cytotoxicity and exhibit antibacterial and / or anti-inflammatory activity. As a result, It has been found that not only the biocompatibility is improved but also the proliferation of fungi such as Escherichia coli and / or Staphylococcus aureus can be significantly reduced, .

In order to solve the above problems, the present invention provides a method of manufacturing a metal implant including a fluorine-based ceramic coating layer, which comprises depositing fluorine-based ceramics on the surface of a metal implant base to form a coating layer.

The present invention also relates to a metal implant substrate; And a fluorine-based ceramic coating layer formed on the surface of the substrate.

The present inventors have found that when a fluorocarbon ceramic is coated on a surface of a metal implant base material to a predetermined thickness by using a deposition process, the biocompatibility of the implant is improved and the antibacterial and / or anti-inflammatory activity can be continuously exhibited. Accordingly, in order to improve the biocompatibility of the prior art, it has been desired to have an excellent biocompatibility without performing complicated processes such as forming a microstructure on the surface of an implant, It is possible to provide an implant that can exhibit continuous antibacterial and / or anti-inflammatory activity without the use of silver or an implant containing an antibiotic.

The "implant" is also referred to as an implant or implant, and includes a man-made device that is adapted to replace lost biological tissue, to support damaged biological tissue, or to act as tissue. Since the surface of the implant is in contact with the body, it can be made of biomedical material such as titanium, silicon or apatite. If desired, the implant may include an electronic device therein, such as, for example, a pacemaker or a cochlear implant. Or may be bioactive, such as a subcutaneous drug delivery device in the form of implantable pills or drug-eluting stents. The implant may be accompanied by side effects such as infection, inflammation and pain, as it is intended to be inserted into the body. In addition, when inserted into the body, it may be recognized as a foreign substance, causing a rejection reaction, or causing a coagulation or an allergic reaction. Therefore, it is very important to select materials that minimize these side effects.

The implant of the present invention may be made of a pure titanium metal, a titanium alloy, a nickel-titanium alloy, a cobalt-chromium alloy, a stainless steel, or a simple combination thereof. For example, the titanium alloy may be aluminum (Al), tantalum (Ta), niobium (Nb), vanadium (Va), zirconium (Zr), tin (Sn), molybdenum molybdenum (Mo), silicon (Si), gold (Au), palladium (Pd), copper (Cu), platinum (Pt) and silver But it is not limited thereto. More preferably, it may be an alloy mainly containing titanium and containing at least one other metal. For example, an alloy containing aluminum and vanadium; An alloy comprising aluminum and niobium; An alloy including niobium and zirconium; Alloys comprising aluminum, molybdenum and vanadium; Alloys comprising aluminum, vanadium and tin; Alloys comprising niobium, tantalum and zirconium; Alloys comprising niobium, tantalum and tin; Alloys comprising niobium, tantalum, and molybdenum; Aluminum, zirconium, molybdenum and silicon; Aluminum, tin, zirconium, molybdenum and silicon; Aluminum, tin, zirconium, niobium, molybdenum and silicon; Alloys comprising aluminum, molybdenum, tin and silicon; Alloys comprising aluminum, tin, zirconium and molybdenum; Aluminum, vanadium, chromium, zirconium and molybdenum; Alloys comprising molybdenum, niobium, aluminum and silicon; Alloys comprising vanadium, chromium, tin and aluminum; Or an alloy with palladium, but is not limited thereto. Ti-8Al-1Mo-1V, Ti-6Al-6V-2Sn, Ti-35.3Nb-5.1Ta-7.1Zr, Ti-6Al- Ti-29Nb-13Ta-4Mo, Ti-29Nb-13Ta-2Sn, Ti-29Nb-13Ta-4.6Sn, Ti-6Al-2Sn-4Zr-2Mo-0.0Si, Ti-5.5Al-3.5Sn-3Zr-1Nb-0.5Mo-0.3Si, Ti-4Al-4Mo-2Sn-0.5Si, Ti-4Al-4Mo-4Sn-0.5Si, Ti-6Al-2Sn-4Zr-6Mo, Ti- 3Al-0.2Si, Ti-15V-3Cr-3Sn-3Al or Ti / Pd, but not limited to, titanium alloys that can be used in an implant.

The deposition of the fluorine-based ceramic may be performed by physical vapor deposition (PVD). Since the physical vapor deposition method does not involve a chemical reaction like chemical vapor deposition, it can be easily performed. In addition, by using the physical vapor deposition method, there is an advantage that a coating layer can be formed by adjusting the thickness to be thicker or thicker as compared with the case of simply dipping in a solution.

For example, in the manufacturing method of the present invention, the deposition of the fluorine-based ceramic can be performed until the thickness of the coating layer becomes 50 nm to 10000 nm. For example, when the coating layer has a thickness exceeding 10000 nm, the coating layer may be deformed or destroyed due to deformation of the substrate or heat treatment conditions. If the thickness is less than 50 nm, the effect of the deposited ceramic may be insignificant. As shown in FIG.

The fluorocarbon-based ceramic may be calcium fluoride or magnesium fluoride, but is not limited thereto. The metal layer can be deposited on the metal implant substrate by physical vapor deposition to form a coating layer, and any material having biocompatibility can be used without limitation.

In the physical vapor deposition method, when a metal fluoride substrate to be coated and a fluorinated ceramic target as a material to be deposited are placed in a chamber and an electron beam is generated in the chamber, atoms and ions generated as the fluorinated ceramic target melts and decomposes at a high temperature The metal layer is naturally bonded on the surface of the metal implant base to form a coating layer. The above-described performing process is merely an example, and can be carried out by using methods known in the art without limitation.

For example, the physical vapor deposition may be performed at a pressure of 1 x 10 < ^-3 > Torr or less. When performed at a pressure higher than the above range, atoms and ions decomposed from the ceramic target may not be uniformly deposited due to a low degree of vacuum. At this time, it is preferable that the temperature in the chamber is maintained at 100 DEG C or higher. When the deposition is performed at a temperature lower than the above range, the bonding force between the substrate and the coating layer is weakened, and the formed coating layer may be easily peeled off.

Preferably, the metal implant base material is prepared by etching at least a surface to be coated of the metal implant base material. By the etching, the adhesion with the coating layer which is subsequently deposited can be improved. The etching may be performed using ions of an inert gas such as argon or neon, but is not limited thereto. For example, when a metal implant substrate is placed in a chamber and an inert gas such as argon is implanted, and an ion beam current is applied while maintaining the pressure inside the chamber appropriately, argon ions are generated, whereby the metal implant base surface can be etched.

In addition, the metal implant substrate may be prepared by polishing and then cleaning the surface prior to etching. For example, the polishing may be performed by a polishing cloth, a polishing agent, or an electrolytic polishing, but the present invention is not limited thereto and can be carried out using known methods known in the art. The substrate thus polished is preferably washed before etching.

The polishing and etching may be performed in order of polishing and etching in order to improve adhesion of the fluorinated ceramic coating layer to be deposited later, and in some cases, polishing may be omitted and only etching may be performed.

In the manufacturing method of the present invention, in order to improve the biocompatibility, a substrate having nanometer and / or micrometer-level microstructure on the surface of a metal implant base may be used. For this purpose, a machined method, an atmospheric pressure plasma treatment, a vacuum plasma treatment, a high temperature plasma treatment, a metal bead sintering method beads sintering method, particle blasting method, acid treatment, alkali treatment, anodic oxidation method, ion implantation method, or a combination thereof But it is not limited thereto.

The present invention also provides a biocompatible antibacterial implant comprising a metal implant base material and a fluoric ceramic coating layer formed on the base material surface. The implant may be manufactured according to the metal implant manufacturing method of the present invention, but is not limited thereto.

The implant may be inserted into a living body to replace damaged tissue, or may be used to promote regeneration of the tissue. Or to support or treat damaged or missing skeletal tissue. A support, joint, and bone fixation device for regenerating and supporting hard tissue such as dental and orthopedic implants, abutments, artificial bones, artificial joints, small bones of the jawbone and facial area, fillers, porcelain, , Spinal processing devices, and the like. Preferably, the implant of the present invention can be used as an artificial tooth root, an artificial root, an artificial joint, or an artificial bone, but is not limited thereto.

The implant may be in the form of a wholly or partly similar tooth, a screw, a block, a plate, a film, a filament, a membrane, a mesh, a woven fabric, a nonwoven, a knit, a grain, a particle, a bolt, a nut, But it is not limited thereto.

In a specific embodiment of the present invention, it has been confirmed that the precursor bone cells adhere well to the surface of the implant according to the present invention and are cultured while expanding. Fungi cultured with the implant, such as E. coli or Staphylococcus aureus, Respectively. This indicates that the implant according to the present invention has excellent biocompatibility and has antimicrobial activity against fungi, in particular, Escherichia coli and Staphylococcus aureus. Therefore, the implant according to the present invention is a biocompatible antibacterial implant, and can be effectively used for dental implants particularly susceptible to infection of fungi.

The method of the present invention can improve the biocompatibility of an implant by depositing a fluoride ceramic on the surface of a metal implant base to uniformly form a coating layer with a predetermined thickness. In addition, silver or antibiotics used for imparting antimicrobial activity may show short-term antimicrobial activity, but they have disadvantages such as adverse effects on normal cells due to cytotoxicity, On the other hand, since the implant containing the fluorine-based ceramic coating layer formed on the surface of the present invention can maintain antimicrobial activity continuously, it is possible to prevent inflammation or the like caused by fungi without side effects such as cell necrosis. Therefore, And can be usefully applied to dental implants.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view for explaining an example of a method of forming a biocompatible fluorine-based ceramic coating layer in the manufacturing method of the present invention.
2 is a view showing a surface shape of a specimen coated with calcium fluoride and magnesium fluoride on a titanium substrate according to an embodiment of the present invention, which is observed with a scanning electron microscope (SEM).
FIG. 3 is a cross-sectional view of a specimen coated with calcium fluoride and magnesium fluoride on a titanium substrate according to an embodiment of the present invention observed by SEM.
4 is a diagram showing a crystal structure of a specimen coated with calcium fluoride and magnesium fluoride on a titanium substrate according to an embodiment of the present invention by X-ray diffraction.
5 is a graph showing cell adhesion of calcium fluoride and magnesium fluoride on a titanium substrate according to an embodiment of the present invention.
6 is a graph showing the antibacterial effect of calcium fluoride and magnesium fluoride on a titanium substrate according to an embodiment of the present invention. A titanium substrate (bare Ti substrate) was used as a negative control, and a titanium substrate coated with silver was used as a positive control.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Manufacturing example 1: Preparation of titanium substrate

Prior to introducing the fluorine-based ceramic coating layer, the titanium substrate was polished and etched to improve the adhesion with the coating layer. Specifically, a pure titanium substrate (pure Ti: CP-Ti) in the form of a flat plate of 10 mm x 10 mm x 1 mm was prepared and the vapor deposition surface of the substrate to which the coating layer was introduced was polished to 4,000 times using SiC paper Polished with a 1 μm diamond slurry, polished to a 1 μm level, and cleaned by ultrasonication in ethanol and acetone. Thereafter, the cleaned substrate was placed in the etching chamber, argon gas (Ar gas) was injected into the chamber, and an ion beam current of 90 V-2A was applied while maintaining the chamber internal pressure at 1 × 10 ^-3 Torr, Ar ⁺ ions were generated to etch the substrate surface. And maintained for 30 minutes under the above etching conditions.

Example 1: Preparation of titanium implants containing calcium fluoride coating layer

A titanium substrate prepared by polishing and etching according to Preparation Example 1 was placed in a process chamber of equipment for physical vapor deposition and a CaF ₂ (calcium fluoride) target as a deposition material was sintered at 1200 ° C for 3 hours The pellets were placed in a crucible and placed in a chamber. The chamber was sealed and a 5 mM electron beam was generated to fuse the target in the chamber to deposit a fluorocarbon coating layer in which atoms and / or ions were naturally bonded on the substrate. At this time, a vacuum state of 9.0 × 10 ^-4 Torr was initially formed, and a vacuum pressure of 1.0 × 10 ^-3 Torr was maintained at the time of deposition. During the deposition process, the temperature inside the chamber was about 160 ° C, and the deposition rate was adjusted to 3 to 4 Å.

Example 2. Preparation of Titanium Implant with a Fluorinated Magnesium Coating Layer

A magnesium fluoride coating layer was deposited on a titanium substrate in the same manner as in Example 1 except that a MgF ₂ (magnesium fluoride) target was sintered at 1100 ° C for 3 hours as a deposition material and used in a pellet form .

Experimental Example 1: Characterization of fluorine-based ceramic coating layer

The surface and cross-section of the calcium fluoride-coated magnesium fluoride coated titanium substrate were observed with a scanning electron microscope, and the results are shown in FIGS. 2 and 3. Specifically, as shown in Figs. 2 and 3, the calcium fluoride and magnesium fluoride coating layers were uniformly formed over the entire substrate. Further, as shown in FIG. 3, when the conditions of Examples 1 and 2 were used, it was confirmed that a coating layer was formed to a thickness of about 500 nm.

Further, an X-ray diffraction pattern was obtained using an X-ray diffractometer, and the results are shown in FIG. As shown in FIG. 4, the black pattern showing the X-ray diffraction pattern of calcium fluoride showed the characteristic spectrum of calcium fluoride at 28 ° and 47 °, the red pattern showing the X-ray diffraction pattern of the magnesium fluoride was 26 ° And a characteristic spectrum of magnesium fluoride at 43 °. This indicates that no phase other than calcium fluoride and magnesium fluoride is formed in the coating process according to the present invention.

Experimental Example 2: Biocompatibility of fluorine-based ceramic coating layer

In order to confirm the biocompatibility by introducing the fluoric ceramic coating layer, a cell adhesion experiment was carried out. Prior to the experiment, substrates coated with calcium fluoride and magnesium fluoride, respectively, were washed with ethanol and disinfected with ultraviolet light. A certain number of cells were dispensed on the two types of fluorocarbon ceramic coated substrates, cultured for a predetermined period, and then their morphology was observed to confirm cell adhesion.

Specifically, MC3T3-E1 cells, pre-osteoblast cell lines, were seeded on 3 × 10 ⁴ specimens and cultured for 1 day. After incubation, protein fixation and dehydration were performed, and the shape of the cells attached on the substrate was observed using a scanning electron microscope. The results are shown in FIG. As shown in FIG. 5, the cells cultured on the substrate coated with calcium fluoride and magnesium fluoride adhered to the substrate surface and cultured / propagated while expanding laterally, indicating that these fluorocarbon-based ceramic coating layers had biocompatibility .

Experimental Example 3: Antimicrobial activity of fluorine-based ceramic coating layer

In order to confirm the antibacterial activity of the fluorine-based ceramic coated metal titanium substrate according to the present invention, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were dispensed at a predetermined density, Lt; / RTI > At this time, a silver-coated titanium substrate (positive control), which is a representative antimicrobial substance, was used instead of a pure titanium substrate (bare Ti, negative control) and a fluorine-based ceramics not containing a coating layer. Specifically, Escherichia coli and Staphylococcus aureus were each seeded on each substrate at a density of 3.2 x 10 ⁵ CFU / mL and 2.1 x 10 ⁵ CFU / mL, and cultured for 1 day. Bacteria cultured for 1 day were collected, transferred to a plate containing fresh culture medium, cultured again for 1 day, and the degree of propagation of the bacteria was confirmed. The cultured bacteria were observed under an optical microscope and the results are shown in Fig. Further, the concentration of each microorganism was measured, and the microbial reduction rate was deduced from the concentration of the microorganism cultured on the titanium substrate used as a negative control.

As shown in FIG. 6, it was confirmed that colonies and colonies grown with both E. coli and Staphylococcus aureus were filled in the plates cultured for one day on a pure titanium substrate used as a negative control and cultivated for 24 hours. However, in plates cultivated and cultivated on calcium fluoride or magnesium fluoride coated titanium substrates according to the present invention and plates cultivated and re-cultured on silver-coated titanium substrates used as a positive control, a significantly reduced number Colony was present. Particularly, when calcium fluoride coated substrate was used, the number of bacteria was decreased to a level similar to that of the positive control and little colonies were observed. The calcium fluoride-coated substrate exhibited a bacterial reduction rate of 99.9%, which is equivalent to that of the silver-coated substrate, for both of the two fungi. In the case of the fluorinated magnesium-coated substrate, And 73.8% and 69.7%, respectively.

Claims

A method for manufacturing a metal implant comprising a fluorine-based ceramic coating layer, comprising the steps of: forming a coating layer by depositing a fluoride ceramic on a surface of a metal implant base.

The method according to claim 1,
Wherein the fluorine-based ceramic is calcium fluoride or magnesium fluoride.

The method according to claim 1,
Wherein the deposition of the fluorine-based ceramic coating layer is performed until the thickness of the coating layer reaches 50 nm to 10000 nm.

The method according to claim 1,
Wherein the deposition of the fluorine-based ceramic is performed by physical vapor deposition (PVD).

5. The method of claim 4,
Wherein the physical vapor deposition is performed at a pressure of 1 x 10 < ^-3 > Torr or less.

5. The method of claim 4,
Wherein the physical vapor deposition is performed while maintaining the temperature in the chamber at 100 DEG C or higher.

The method according to claim 1,
Wherein the material of the metal implant base material is titanium, a titanium alloy, a nickel-titanium alloy, a cobalt-chromium alloy, a stainless steel, or a simple combination thereof.

8. The method of claim 7,
Wherein the alloy further comprises at least one metal selected from the group consisting of aluminum, tantalum, niobium, vanadium, zirconium, tin, molybdenum, silicon, gold, palladium, copper, platinum and silver.

The method according to claim 1,
Wherein the metal implant substrate is prepared by etching at least a surface to be coated of the metal implant substrate.

10. The method of claim 9,
Wherein the metal implant substrate is polished prior to etching and then cleaned to prepare.

11. The method of claim 10,
Wherein the polishing is performed by a polishing cloth, a polishing agent, or an electrolytic polishing.

10. The method of claim 9,
Wherein the etching is carried out using an inert gas ion.

13. The method of claim 12,
Wherein the inert gas is argon or neon.

Metal implant materials; And a fluorine-based ceramic coating layer formed on the surface of the substrate.

15. The method of claim 14,
A biocompatible antimicrobial implant according to any one of claims 1 to 13.

15. The method of claim 14,
Wherein the implant is a form that is wholly or partially similar to a tooth, a screw, a block, a plate, a film, a filament, a membrane, a mesh, a woven fabric, a nonwoven, a knit, a grain, a particle, a bolt, a nut, Biocompatible antimicrobial implants.

15. The method of claim 14,
Wherein the implant has antibacterial activity against E. coli or Staphylococcus aureus.