JP2008080102A - Implant - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an implant connectable quickly and more surely to an osseous tissue by swiftly prompting the neogenesis of the osseous tissue. <P>SOLUTION: The implant has a metal oxide layer with photocatalytic activity and bioaffinity on the surface of an implant material. The implant having the metal oxide layer with the bioaffinity on its surface enables an increase in its adhesion area with an osteoblast when it is imbedded in vivo eventually improving the cellular adhesion and the cellular breeding of the implant. This can swiftly prompt the neogenesis of the osseous tissue to enable the quick and more accurate connection of the implant to the osseous tissue. The implant with the metal oxide layer formed on its surface also has the photocatalytic activity to enable the complete removal and the detoxification of the infectious lesion by disinfecting bacteria sticking to the surface of the implant. Thus, the regeneration of a bone is possible despite the contamination of the implant and the implant also proves effective for the treatment of the ambient inflammation of the implant. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an implant, and more particularly to an implant that can be more reliably combined with bone tissue in a short period of time.

  A treatment method for reconstructing a tooth lost due to caries or periodontal disease with an implant has been widely recognized due to its high predictability. For example, pure titanium or a titanium alloy is used as the material of the implant, but until the implant embedded in the jaw bone can support the occlusal force (until the bone tissue is bonded to the implant), usually 3 months in the lower jaw, A healing period of 6 months is required in the upper jaw. For this reason, the lengthening of the treatment period is a factor that makes patients and surgeons frustrated.

  Therefore, attempts have been made to modify the surface of various implants in order to shorten the healing period and achieve a more reliable connection between the bone tissue and the implant. Specifically, sand blasting, anodic oxidation, acid etching, and the like have been studied, but these methods are intended to enhance bone tissue renewal by imparting a certain roughness to the implant surface, Many of the implants currently on the market are roughened implants.

In recent years, in addition to the surface roughening described above, methods for chemically modifying the surface have been studied. For example, sandblasting and fluoride-treated titanium implants have been proposed, and it has been reported that bone tissue formation is enhanced (Patent Document 1, Non-Patent Documents 1 and 2). In addition, titanium implants that have been sandblasted and acid-etched are immediately sealed in isotonic saline so that significant bone and implants are maintained while maintaining high levels of sterility and surface energy until the pack is opened. There is also a report that it becomes possible to combine with (Non-patent Documents 3 and 4).
JP 2005-533552 A JE Ellingsen, CB Johansson, A. Wennerberg and A. Holmen, Improved retention and bone-to-lmplant contact with fluoride-modified titanium implants, Int J Oral Maxillofac Implants 19 (2004), pp. 659-666 Lyndon F. Cooper, Yongsheng Zhou, Jun Takebe, Juanli Guo, Armin Abron, Anders Holmen and Jan Eirik Ellingsen, Fluoride modification effects on osteoblast behavior and bone formation at TiO2 grit-blasted cp titanium endosseous implants, Biomaterials 27 (6), ( 2006), pp. 926-936 Germanier Y, Tosatti S, Broggini N, Textor M, Buser D., Enhanced bone apposition around biofunctionalized sandblasted and acid-etched titanium implant surfaces.A histomorphometric study in miniature pigs.Germanier, Clin.Oral Implants Res. 2006 Jun; 17 ( 3): 251-257 Buser D, Broggini N, Wieland M, Schenk RK, Denzer AJ, Cochran DL, Hoffmann B, Lussi A, Steinemann SG, Enhanced bone apposition to a chemically modified SLA titanium surface., J Dent Res. 2004 Jul; 83 (7) : 529-533

  However, none of the above-mentioned implants is necessarily sufficient in clinical practice, and there is a demand for the development of an implant that rapidly enhances bone tissue formation and can be more reliably combined with bone tissue in a short period of time.

  The present invention has been made in view of such circumstances, and a problem to be solved is to provide an implant that can rapidly enhance bone tissue renewal and can be more reliably combined with bone tissue in a short period of time. is there.

  As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by providing an implant comprising a metal oxide layer having photocatalytic activity and biocompatibility on the surface of the implant material, The present invention has been completed.

That is, the present invention is as follows.
(1) An implant comprising a metal oxide layer having photocatalytic activity and biocompatibility on the surface of an implant material.
(2) The implant according to (1) above, wherein the metal oxide layer is formed by an anodic oxidation method and treated with a fluoride.
(3) The implant according to (2) above, wherein the fluoride is ammonium hydrogen fluoride.
(4) The implant according to (1), wherein the metal oxide layer is formed by a plasma source ion implantation film formation method and is annealed at a temperature higher than 650 ° C.
(5) The above (1) to (1), wherein the metal oxide layer is composed of any one of titanium oxide, tin oxide, zinc oxide, bismuth trioxide, tungsten trioxide, ferric oxide, and strontium titanate. The implant according to any one of 4).
(6) The implant according to any one of (1) to (5), which is a dental implant.
(7) The implant according to any one of (1) to (6), wherein the implant is used after being irradiated with light.
(8) The implant according to any one of (1) to (6) above, wherein at least a part is brought into contact with bone tissue to promote bone tissue formation.
(9) The implant according to any one of (1) to (6) above, wherein at least a portion is brought into contact with bone tissue to enhance cell adhesion and / or cell proliferation.
(10) The implant according to any one of (1) to (6) above, wherein at least a part is brought into contact with the bone tissue and irradiated with light to promote the regeneration of the bone tissue.
(11) The implant according to any one of (1) to (6) above, wherein at least a portion is brought into contact with bone tissue and irradiated with light to suppress inflammation around the implant.

Since the implant of the present invention is provided with a metal oxide layer having biocompatibility on the surface thereof, it becomes possible to increase the adhesion area with osteoblasts when implanted in a living body, and the cell adhesion of the implant And cell proliferation can be improved. As a result, bone tissue renewal is rapidly enhanced, and bone tissue and implant can be more reliably combined in a short period of time. Therefore, the healing period can be shortened.
Moreover, since the metal oxide layer formed on the surface of the implant of the present invention also has photocatalytic activity, it is possible to sterilize bacteria and the like attached to the surface of the implant to completely remove the infected foci and to detoxify it. Thereby, even if the implant is contaminated, re-bone formation is possible, and it is also effective for treating peri-implantitis.
Therefore, the implant of the present invention is useful not only in the dental field (dental implant) but also in the surgical field (including orthopedics and plastic surgery).

Hereinafter, preferred embodiments of the present invention will be described in detail.
First, the implant of the present invention will be described.
The implant of the present invention is characterized in that a metal oxide layer having photocatalytic activity and biocompatibility is provided on the surface of the implant material.

The material of the implant material is not particularly limited as long as it is used for medical purposes, and examples thereof include metals, alloys, glass, ceramics, plastics, and composite materials.
Examples of the metal include titanium, tin, zinc, bismuth, tungsten, iron, niobium, tantalum, and zirconium, and titanium is particularly preferable.
Examples of the alloy include titanium alloy, cobalt-chromium-molybdenum alloy, titanium-aluminum-vanadium alloy, stainless steel, iron-chromium nickel alloy, vitalium, gold alloy, and silver alloy. Among them, stainless steel, titanium alloy, A cobalt-chromium-molybdenum alloy and a titanium-aluminum-vanadium alloy are preferred.
Examples of the glass include soda lime glass, lead glass, borosilicate glass, silica glass, alkali barium glass, aluminoborosilicate glass, borate glass, and quartz glass.
Examples of the ceramic include alumina, zirconia, aluminum nitride, silicon nitride, silicon carbide, sialon, and hydroxyapatite (calcium phosphate). Among these, alumina is preferable.

Plastics include polyolefin resins (eg, polyethylene, polypropylene), polystyrene resins (eg, polystyrene, AS resin, ABS resin), fluororesins (eg, polytetrafluoroethylene), vinyl chloride resins, acrylic resins, polyamide resins. , Polycarbonate, polyphenylene oxide, polyester resin (for example, PET, PBT), polyimide resin, epoxy resin, and silicone resin.
Examples of the composite material include FRP in which a thermosetting resin (for example, unsaturated polyester or epoxy resin) is reinforced with fibers, and FRTP in which a thermoplastic resin (for example, polyamide or polycarbonate) is reinforced with fibers. Examples thereof include glass fiber, carbon fiber, aramid fiber, and boron fiber.
Of these, metals and ceramics are preferably used as the material of the implant material. In addition, when an implant material is comprised with a several material, each material may differ.

  The shape of the implant material may be any shape such as a plate shape, a columnar shape, a cylindrical shape, and a screw shape, and is not particularly limited.

The metal oxide is not particularly limited as long as it has photocatalytic activity and biocompatibility. For example, titanium oxide, tin oxide, zinc oxide, bismuth trioxide, tungsten trioxide, ferric oxide, titanate Strontium is mentioned, and titanium oxide is particularly preferable. The crystal form of titanium oxide may be anatase or rutile. Further, it may be a mixture of anatase and rutile, or a mixture of anatase, rutile and amorphous. In that case, a material containing anatase as a main component is suitable. Among these, as titanium oxide, a single-phase anatase or a mixture containing anatase as a main component and having a high degree of crystallinity is preferable.
The crystal form of the metal oxide can be confirmed by measuring X-ray diffraction, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, or the like. For example, anatase-type titanium oxide preferably used in the present invention exhibits (004) preferential orientation in X-ray diffraction. Further, the crystallinity can be confirmed based on the half width of the X-ray diffraction peak (2θ), and the smaller the half width, the higher the crystallinity.

  The thickness of the metal oxide layer is not particularly limited as long as it exhibits a photocatalytic action and does not impair the biocompatibility, and is preferably 5 μm or less, more preferably 4 μm, and even more preferably 3 μm. When the thickness exceeds 5 μm, foreign matter reaction due to peeling of the metal oxide layer, allergic reaction due to elution of metal ions, and the like may be caused and biocompatibility may be impaired. In order to sufficiently exhibit the photocatalytic action, the thickness of the metal oxide layer is preferably 0.2 μm or more, and more preferably 0.3 μm or more.

  In this specification, the photocatalytic activity means that in the valence band when irradiated with light (short wavelength light) having energy larger than the energy gap between the conduction electron band and the valence band of the metal oxide crystal. The property that can generate conduction electrons and holes by the excitation of electrons, and the biocompatibility is that without causing a harmful reaction such as a foreign body reaction when an implant is implanted in the living body. It is a property that can be adapted to enhance bone tissue renewal.

  The implant of the present invention can exhibit the following effects due to the metal oxide layer having photocatalytic activity and biocompatibility. That is, since the implant of the present invention is imparted with hydrophilicity that can contribute to biocompatibility, the adhesion area with osteoblasts is increased when implanted in a living body, and cell adhesion and cell proliferation of the implant are increased. Can be improved. As a result, bone tissue formation is rapidly promoted, and it becomes possible to bond the bone tissue and the implant more firmly in a short period of time. Therefore, the healing period can be shortened. The imparting of hydrophilicity will be described later.

  In the implant of the present invention, for example, the metal oxide coated on the surface by light irradiation is excited to generate chemical species such as free radicals, and the chemical species attached to the surface are decomposed and sterilized by the chemical species. Photocatalytic activity. Therefore, the implant of the present invention can be sterilized only by light irradiation, so that a special sterilization operation is not required, and also has the above-described biocompatibility, and thus has excellent convenience. In clinical practice, “peri-implantitis” develops due to factors such as bone quality, bone mass, occlusal force, and bacterial infection, and bone tissue formed to support the corner implant may be absorbed. In order to treat inflammation, it is indispensable not only to completely remove the infected lesion, but also to make the implant surface as clean as possible (detoxification). The rough-surfaced implants currently on the market are unable to completely remove the infected lesion or detoxify the implant surface due to its complicated surface shape, and therefore the treatment of peri-implantitis becomes extremely difficult. . On the other hand, in the present invention, even an implant having a rough surface can be decomposed and sterilized only by irradiating light without damaging the implant surface, and can be made into a clean state. Due to the excellent affinity, re-bone formation is possible even for contaminated implants. Therefore, it is expected as a completely new treatment for peri-implantitis.

Therefore, the implant of the present invention is appropriately subjected to light irradiation before or after implant implantation in order to enhance photocatalytic activity and biocompatibility. The light to be irradiated varies depending on the type of metal oxide, but light having a wavelength necessary for developing photocatalytic activity and biocompatibility is irradiated. For example, in the case where the metal oxide layer is made of titanium oxide, light in the ultraviolet region with a normal wavelength of 254 to 400 nm, preferably 300 to 400 nm is irradiated, and the illuminance is 3 mW / cm ² or less. In order to irradiate such ultraviolet rays, for example, a lamp having a UVA or UVB light source can be used. Moreover, irradiation time is 1 minute-24 hours normally. The longer the irradiation time, the more reliably the photocatalytic activity and biocompatibility can be expressed. However, it may be difficult to obtain an effect commensurate with the irradiation time even if the irradiation time exceeds 24 hours. Also, by irradiating the implant with ultraviolet rays for 2 hours, the photocatalytic activity and biocompatibility are maintained for 24 hours, so the irradiation time is 1 minute to 5 hours, preferably 1 to 4 hours, depending on the purpose of use. Preferably, it can be set to 1 to 2 hours.

  In the present invention, an implant is a substitute for an artificially produced organ / tissue for implantation in a site that has suffered a defect or trauma, as long as it is at least partially in contact with bone tissue. The concept is not particularly limited and includes not only the dental field but also the surgical field. Specific examples include plates, intramedullary nails, screws, artificial joints, various screws, pins, instruments, wires, washers, nuts, rods, hooks, cables, bands, anchors, buttons, clips, and plugs.

Next, the manufacturing method of the implant of this invention is demonstrated.
First, an implant material having a desired shape and made of a desired material is prepared according to the purpose of use. Next, a metal oxide layer is formed on the surface of the implant material. And in order to provide photocatalytic activity and / or biocompatibility, a metal oxide layer is processed by the method mentioned later.

(Formation of metal oxide layer)
The method for forming the metal oxide layer is not particularly limited as long as the metal oxide layer can be formed on the surface of the implant material. For example, the following anodic oxidation method or plasma source ion implantation film forming method is preferably used. .

(Anodic oxidation method)
In the electrolyte solution, a metal or alloy implant material is used as an anode, stainless steel or the like is used as a cathode, a voltage is applied between both electrodes to perform electrolysis, and the surface of the implant material that is the anode is chemically oxidized. A metal oxide film is formed.
In the anodic oxidation method, for example, a sulfuric acid-phosphoric acid-hydrogen peroxide solution, a sulfuric acid-hydrogen peroxide solution, or the like is used as the electrolyte solution, and among them, a sulfuric acid-phosphoric acid-hydrogen peroxide solution is preferable. The concentration of the electrolyte is, for example, 1.3 to 1.7 mol / l sulfuric acid, 0.1 to 0.5 mol / l phosphoric acid, 0.1 hydrogen peroxide in the case of a sulfuric acid-phosphoric acid-hydrogen peroxide solution. It is prepared in the range of ˜0.5 mol / l.

The film forming conditions in the anodic oxidation method are not uniform depending on the type of metal oxide to be formed, the material of the implant or the type and concentration of the electrolyte, but are as follows, for example.
Voltage: 50 to 250V, preferably 150 to 200V
Current density: 0.1 to 0.5 mA / cm ² , preferably 0.2 to 0.4 mA / cm ²
-Temperature: 10-40 ° C, preferably 20-30 ° C
In the anodic oxidation method, by adjusting the electrolyte concentration, voltage, current density, etc., a metal oxide layer having a desired crystal structure, orientation, thickness, etc. can be easily and inexpensively without using a special manufacturing apparatus. Can be formed. For example, when a titanium oxide layer is formed, a titanium oxide layer made of a mixture of anatase, rutile and amorphous is formed.

(Plasma source ion implantation deposition method)
[1] The implant material is insulated and fixed in the vacuum container, and then the metal alkoxide is heated and vaporized and introduced into the vacuum container as a raw material gas, and at the same time maintained in a reduced pressure state. Next, high frequency is transmitted to an antenna installed in the vacuum vessel to generate plasma by high frequency discharge. Then, by repeatedly applying a negative pulse voltage to the implant material, ions in the plasma are implanted into the surface of the implant material, and a metal oxide film is formed.
[2] After the implant material is insulated and fixed in the vacuum container and the pressure is reduced, the metal alkoxide is heated and vaporized and introduced into the vacuum container as a raw material gas. Next, a negative DC voltage is applied within a voltage range that does not cause discharge in the implant material with respect to the ground potential, and plasma is generated around the implant material without using the electrode antenna, and is superimposed on the DC voltage. A negative pulse voltage is applied to the ground potential. Then, ions in the plasma atmosphere are implanted into the surface of the implant material, and a metal oxide film is formed.

  In the plasma source ion implantation film forming method, for example, a vacuum pump can be used in order to reduce the pressure. Moreover, as a metal alkoxide, the alkoxide containing the metal which should form a metal oxide layer can be used. For example, when forming a titanium oxide layer, a titanium alkoxide having 2 to 10 carbon atoms in the alkoxy group can be used. Specifically, titanium tetraethoxide, titanium tetraisopropoxide, titanium tetrabutoxide, and the like can be given. Among these, titanium tetraisopropoxide is preferable because the deposition rate of titanium oxide is high and the crystal structure of the alignment film can be easily controlled.

Film formation conditions in the plasma source ion implantation film formation method are not uniform depending on the type of metal oxide to be formed, the material of the implant material, and the like, but are as follows, for example.
(Deposition conditions of [1] above)
Decompression degree: 0.1 to 10 Pa, preferably 0.5 to 5 Pa
Implant material temperature: room temperature to 400 ° C., preferably room temperature to 300 ° C.
High frequency output: 20 to 500 W, preferably 50 to 300 W
Pulse voltage: -2 to -50 kV, preferably -10 to -30 kV
-Pulse frequency: 0.05 to 5 kHz, preferably 0.1 to 2 kHz
Pulse time: 2.5 to 200 μs, preferably 5 to 100 μs
(Deposition conditions of [2] above)
Decompression degree: 0.1 to 10 Pa, preferably 0.5 to 5 Pa
Implant material temperature: room temperature to 400 ° C., preferably room temperature to 300 ° C.
Pulse voltage: -2 to -50 kV, preferably -10 to -30 kV
-Pulse frequency: 0.05 to 5 kHz, preferably 0.1 to 2 kHz
Pulse time: 2.5 to 200 μs, preferably 5 to 100 μs
DC voltage: -0.1 to -5 kV, preferably -0.5 to -4 kV

  In the plasma source ion implantation deposition method, the desired crystal structure can be obtained regardless of the material and shape of the implant material by adjusting the vaporization temperature of the raw material and its supply amount, the implant material temperature, the pulse voltage, the direct current voltage, etc. It is possible to uniformly form a metal oxide having orientation, thickness and the like on the entire surface. When forming a titanium oxide layer, it becomes easy to obtain titanium oxide containing anatase as a main component.

  Next, after forming a metal oxide layer by a plasma source ion implantation film forming method, it is desirable to anneal the metal oxide layer. Thereby, photocatalytic activity and biocompatibility can be improved further. For example, the annealing is performed at a temperature of more than 600 ° C. (preferably more than 650 ° C., more preferably more than 650 ° C. to 750 ° C.) for 0.5 to 5 hours (preferably 1 to 2 hours). In addition, when forming the titanium oxide layer, the present inventors have a single-phase anatase or anatase as a main component by annealing at a temperature of more than 650 ° C. (for example, 654 ° C.), 700 ° C. or 750 ° C. In addition, it has been found that titanium oxide having a high degree of crystallinity can be obtained reliably, and that the higher the annealing temperature, the more the photocatalytic activity and biocompatibility are enhanced.

  By adopting the plasma source ion implantation film formation method or the anodic oxidation method as the metal oxide formation method, a metal oxide that has good adhesion to the implant material and is difficult to peel off can be obtained. And metal ion elution can be suppressed. This prevents harmful reactions such as foreign body reactions when implanted in a living body.

(Give photocatalytic activity and / or biocompatibility)
In order to impart photocatalytic activity and / or biocompatibility to the metal oxide layer formed on the surface of the implant material, the metal oxide layer is treated by the following method.
When a metal oxide layer is formed by an anodic oxidation method, the metal oxide layer is treated with fluoride. Examples of the fluoride include fluorine-containing ammonium such as ammonium hydrogen fluoride and ammonium fluoride, sodium hydrogen fluoride, and hydrogen fluoride. Of these, fluorine-containing ammonium is preferable, and ammonium hydrogen fluoride is more preferable. These are usually used in the form of an aqueous solution, and the anodized implant is immersed in the aqueous solution or an aqueous solution is applied. The fluoride concentration in the aqueous solution is usually 1% or less, preferably 0.1 to 0.2%, more preferably 0.15 to 0.18%. “%” Means% by weight. Processing temperature is 4-60 degreeC normally, Preferably it is 10-40 degreeC, More preferably, it is 20-30 degreeC. The treatment time is usually 2 to 15 minutes, preferably 3 to 10 minutes, more preferably 4 to 6 minutes.
When the metal oxide layer is made of, for example, titanium oxide, only amorphous titanium oxide is eluted by the fluoride treatment. Thereby, it can be set as the anatase-rich titanium oxide by which hydrophilicity was provided to the surface.

  When a metal oxide layer is formed by a plasma source ion implantation film formation method, the metal oxide layer is irradiated with light. Thereby, hydrophilicity is provided to the implant surface. The light to be irradiated differs depending on the type of metal oxide, but the light having a wavelength necessary for developing the photocatalytic action is irradiated. For example, when the metal oxide layer is made of titanium oxide, the same ultraviolet light as described above is irradiated.

Thus, by providing biocompatibility to the surface of the implant by the above treatment, the adhesion area with osteoblasts increases when implanted in the living body, and the cell adhesion and cell proliferation of the implant are improved. . As a result, bone tissue renewal is rapidly promoted, and the bone tissue and the implant can be firmly bonded in a short period of time.
According to the above manufacturing method, such a useful implant can be provided simply and inexpensively, and therefore, its technical significance is extremely large.

  Examples of the present invention will be described in detail below, but the present invention is not limited to these examples. “%” Indicates% by weight unless otherwise specified.

(Example 1)
A titanium disk (diameter 8 mm, thickness 1.5 mm) was anoded in a sulfuric acid-phosphoric acid-hydrogen peroxide aqueous electrolyte at a final voltage of 200 V, a current density of 0.3 mA / cm ² , an energization time of 10 minutes, and a temperature of 30 ° C. Oxidized to form a titanium oxide layer on the surface. Subsequently, the surface layer of amorphous titanium oxide was eluted with 0.175% ammonium hydrogen fluoride for 5 minutes. From the X-ray diffraction, XPS, and Raman spectroscopy, it was confirmed that the crystal structure of titanium oxide was anatase-rich. The thickness of the titanium oxide layer was about 3 μm.

(Example 2)
A titanium disk (the disk shape and dimensions are the same as in Example 1) was insulated and fixed in the plasma source ion implantation apparatus, and titanium tetraisopropoxide gas was introduced under reduced pressure. Next, plasma was generated by high frequency discharge, and a negative pulse voltage was repeatedly applied to the disk to form a titanium oxide layer on the disk surface simultaneously with oxygen ion implantation. The disk on which the titanium oxide layer was formed was heated at 654 ° C. for 1 hour. X-ray diffraction, XPS and Raman spectroscopy confirmed that the crystal structure of titanium oxide was a single-phase anatase. The X-ray diffraction pattern is shown in FIG. In FIG. 1, “A” is a diffraction peak characteristic of anatase type crystals. Moreover, the film thickness of the titanium oxide layer was about 70 to 700 nm.

The film formation conditions for titanium oxide are as follows.
・ Decompression degree: 1.3 Pa
-Implant material temperature: 100-300 ° C
・ High frequency output: 50W
・ Pulse voltage: -20kV
・ Pulse frequency: 100Hz
・ Pulse time: 50μs

(Example 3)
A titanium disk (diameter 10 mm, thickness 2 mm) was ground with 1200-grid water-resistant abrasive paper to make the surface roughness uniform, and then ultrasonically washed with trichlorethylene, 95% ethanol, and distilled water for 15 minutes each. Next, the obtained titanium disk was anodized in a sulfuric acid-phosphoric acid-hydrogen peroxide aqueous electrolyte at a final voltage of 200 V, a current density of 0.3 mA / cm ² , an energization time of 10 minutes, and a temperature of 30 ° C. A titanium oxide layer was formed. Subsequently, the surface layer of amorphous titanium oxide was eluted with 0.175% ammonium hydrogen fluoride for 5 minutes. From the X-ray diffraction, XPS, and Raman spectroscopy, it was confirmed that the crystal structure of titanium oxide was anatase-rich. The thickness of the titanium oxide layer was about 3 μm.

Example 4
A titanium disk (the disk dimensions are the same as in Example 3) was ground with 1200-grid water-resistant abrasive paper to make the surface uniform, and then ultrasonically washed with trichlorethylene, 95% ethanol, and distilled water for 15 minutes each. . Next, the obtained titanium disk was insulated and fixed, and titanium tetraisopropoxide gas was introduced under reduced pressure. Next, plasma was generated by high frequency discharge, and a negative pulse voltage was repeatedly applied to the disk to form a titanium oxide layer on the disk surface simultaneously with oxygen ion implantation. The film forming conditions are the same as in Example 2. The disk on which the titanium oxide layer was formed was heated at 654 ° C. for 1 hour. X-ray diffraction, XPS and Raman spectroscopy confirmed that the crystal structure of titanium oxide was a single-phase anatase. The thickness of the titanium oxide layer was about 70 to 700 nm.

[Evaluation test]
(Evaluation of photocatalytic activity)
Methylene blue decoloration test The titanium disks obtained in Examples 1 and 2 and the untreated titanium disk (cont1) were each immersed in a 10 ppm methylene blue aqueous solution and irradiated with light under black light as a UVA light source for 2 hours. Next, the degree of decolorization of the methylene blue aqueous solution after light irradiation was measured by measuring the absorbance at a wavelength of 664 nm with a spectrophotometer. The results are shown in Table 1.
Moreover, the titanium disk obtained in Examples 3 to 4 and the untreated titanium disk (cont2) were each immersed in a 10 ppm methylene blue aqueous solution and irradiated with light under black light as a UVA light source for 24 hours. Next, the degree of decolorization of the methylene blue aqueous solution after light irradiation was measured by measuring the absorbance at a wavelength of 664 nm with a spectrophotometer. The results are shown in Table 2.
Methylene blue is decomposed by the active oxygen species generated by light irradiation, and changes from the original blue color to colorless and transparent. Therefore, the smaller the absorbance, the higher the photocatalytic activity.

(Hydrophilicity evaluation)
Deionized water was dropped onto the surfaces of the titanium disks obtained in Examples 1 to 4 and untreated titanium disks (cont1 and 2), and the water contact angle was measured with a contact angle meter (manufactured by Kyowa Interface Science). The measurement results of Examples 1-2 and cont1 are shown in Table 1, and the measurement results of Examples 3-4 and cont2 are shown in Table 2. In addition, it means that hydrophilicity is so favorable that a water contact angle is small.

(Cell culture test)
(I) The titanium disk obtained in Examples 1 and 2 and the untreated titanium disk (cont1) irradiated with UV, and (ii) the titanium disk obtained in Examples 1 and 2 and untreated A titanium disk that was shielded from light and was not irradiated with UV was prepared, and then cell culture was performed using these six kinds of titanium discs.
Similarly, (i) the titanium disk obtained in Examples 3 to 4, and an untreated titanium disk (cont2) irradiated with UV, and (ii) the titanium disk obtained in Examples 3 to 4 And untreated titanium discs that were shielded from light and not irradiated with UV were prepared, and then cell culture was performed using these six types of titanium discs.
Mouse-derived myoblasts (C2C12) capable of differentiating into osteoblasts were used as cultured cells, and cultured in a 24-well dish according to a conventional method. Subsequently, a cell adhesion test and a cell proliferation test were performed according to the following procedures.

(1) Cell adhesion test After fixing 30 minutes after culturing, non-adherent cells were washed and subjected to nuclear staining with Propidium Iodide. Then, the number of adherent cells on the titanium disk was measured with an electron microscope (manufactured by Hitachi, Ltd.), and the adherent cells were also observed. The number of adherent cells is shown in Table 3 as an average value per 0.025 mm ² for Examples 1 to 2 and cont1 titanium disks irradiated with UV in (i) above, and subjected to UV irradiation in (i) above. The titanium disks of Examples 3 to 4 and cont2 are shown in Table 4 as average values per 1 mm ² .
Moreover, the result of having observed the adherent cell about the titanium disk irradiated with UV by said (i) is shown to FIGS. 2 is an SEM view of cells attached to the titanium disk obtained in Example 1, FIG. 3 is an SEM view of cells attached to the titanium disk obtained in Example 2, and FIG. It is a SEM figure of the cell which adhered. For the titanium disk not irradiated with UV (ii), the same results as in cont1 and cont2 were obtained.

(2) Cell proliferation test BrdU (bromodeoxyuridine) was administered 24 hours after culture, immunofluorescent staining with FITC conjugated anti-BrdU antibody was performed, the number of cell proliferation was counted, and the ratio of the number of dividing cells to the number of adherent cells (%). Table 3 shows the results of cell proliferation tests on Examples 1-2 and cont1 titanium disks irradiated with UV in (i) above, and Examples 3-4 and cont2 titanium disks irradiated with UV in (i) above. Table 4 shows the results of the cell proliferation test.

(Bone implantation test)
A titanium oxide layer was formed on titanium implants used in actual clinical practice in the same manner as in Examples 1 and 2, and then irradiated with light under a black light as a UVA light source for 24 hours. Titanium implants obtained in this way (titanium implants in which a titanium oxide layer is formed by a film forming method corresponding to Examples 1 and 2 are referred to as Examples 5 and 6, respectively) and untreated titanium implants (Cont3) was embedded in the rabbit tibia, and the bone contact rate was measured from tissue sections after 2 weeks and 6 weeks. The results are shown in Table 5.
Fig. 5 shows an optical micrograph of the contact portion between the bone tissue and the titanium implant when two weeks have passed after the titanium implant is implanted. (A) is a bone tissue and cont3 titanium implant. And (b) is an optical micrograph of the contact portion between the bone tissue and the titanium implant of Example 6. In the figure, C represents cortical bone, and NB represents a new part of bone tissue.
In addition, although the bone contact rate was shown as a ratio (%) of the bone tissue which contacts the implant surface, it can be used as an index of bone affinity of the implant.

  From the above results, the titanium disk on which the titanium oxide layer is formed has at least 1.7 times or more (preferably 2.1 times or more) cell adhesion due to its significantly superior hydrophilicity than the untreated titanium disk. ), It was confirmed that the cell proliferation was improved by at least 1.4 times (preferably 1.7 times or more). In addition, the SEM image of the titanium disk on which the titanium oxide layer was formed showed a state in which the cell morphology was thin and wide and the titanium disk had progressed, and it was confirmed that the cell affinity was dramatically improved. Furthermore, in the titanium implant in which the titanium oxide layer was formed, a significantly higher bond between the bone tissue and the implant was observed from an extremely early stage of 2 weeks after implantation, compared with the control.

It is a figure which shows the X-ray-diffraction pattern of the titanium oxide layer formed in the titanium disk in Example 2. FIG. 2 is a view showing an SEM image of cells attached to the titanium disk obtained in Example 1. FIG. 6 is a view showing an SEM image of cells attached to the titanium disk obtained in Example 2. FIG. It is a figure which shows the SEM image of the cell adhering to the titanium disk of cont. (A) is a figure which shows the optical microscope photograph which image | photographed the contact part of the bone tissue and the titanium implant of cont3, (b) is the optical which image | photographed the contact part of the bone tissue and the titanium implant of Example 6. It is a figure which shows a microscope picture.

Claims (7)

  An implant comprising a metal oxide layer having photocatalytic activity and biocompatibility on the surface of an implant material.   The implant according to claim 1, wherein the metal oxide layer is formed by an anodic oxidation method and treated with a fluoride.   The implant of claim 2, wherein the fluoride is ammonium hydrogen fluoride.   The implant according to claim 1, wherein the metal oxide layer is formed by a plasma source ion implantation film formation method and is annealed at a temperature higher than 650 ° C.   The metal oxide layer is formed of any one of titanium oxide, tin oxide, zinc oxide, bismuth trioxide, tungsten trioxide, ferric oxide, and strontium titanate. The implant according to Item.   The implant according to any one of claims 1 to 5, which is a dental implant. The implant according to any one of claims 1 to 6, which is used after being irradiated with light.