JP2015016231A - Biological implant - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biological implant which does not decrease in antibacterial action due to machine work, and can be made at lower costs.SOLUTION: A biological implant is made by molding a resin comprising at least one inorganic antimicrobial material selected from the group consisting of copper, zinc, silver, and their salt and oxide, and calcium phosphate material.

Description

  The present invention relates to a living body implant, and more particularly to a living body implant used for an artificial tooth root, an artificial skull, or the like.

  In order to repair a tooth that has been lost due to caries, periodontal disease, or the like, an implant treatment is performed in which an artificial tooth root serving as a root is embedded in the alveolar bone of the jaw and a dental crown is loaded on the artificial tooth root.

  Artificial dental roots used for implant treatment are generally a two-piece type composed of a fixture embedded in the jawbone and an abutment attached to the fixture and functioning as an abutment for attaching a prosthesis, There is a one-piece type that combines char and abutment. In general, titanium or a titanium alloy having excellent bone healing properties is used for the artificial root. The artificial dental root is embedded in the alveolar bone, and is fixed to the alveolar bone by healing of the alveolar bone around the artificial dental root.

  However, as a result of bacteria entering the alveolar bone through the gap between the artificial tooth root and the gingiva and being infected, the artificial tooth root may be shaken and removed. However, the antibacterial measures for artificial tooth roots have not been fully studied. However, as an antibacterial method for medical devices, a method has been proposed in which a titanium alloy is used as a substrate and a coating of an antibacterial metal such as silver is formed using a cathodic arc plasma deposition method (Patent Document 1).

JP 2009-524479 A

However, even if an artificial tooth root having a film formed using the method of Patent Document 1 is used, the following problems occur.
Artificial dental roots are often ground after being shipped from the manufacturing site in order to adapt to the patient's individual biological shape in a hospital, clinic or dental laboratory. That is, the antibacterial coating is scraped because the fixture is scraped using a dental grinding bar or the like for the one-piece type and the abutment for the two-piece type. In addition, when attaching and removing the crown, repeated mounting and removal of the crown to adjust the occlusal height of the crown causes the side surface of the artificial tooth root that contacts the crown to be shaved and the coating to be removed. It is shaved. As a result, there is a problem that the antibacterial action is lost and the artificial tooth root is easily infected. Further, in recent years, a technique of cutting the artificial tooth root is also used to remove the infection when the surrounding of the artificial tooth root is infected after the operation. In this case as well, the antibacterial properties and bone affinity expected for the artificial tooth root surface are lost by cutting the surface.

  In addition, even when applied to an artificial skull, if the periphery of the artificial skull is shaved for size adjustment, the coating is also scraped, resulting in a problem that the antimicrobial action is lost and the artificial skull is easily infected.

  In addition, the method of using the cathodic arc plasma deposition method for film production has a problem that the apparatus and process are complicated and the cost is high.

  Therefore, the present invention has been made to solve the above-mentioned problems, and to provide a lower-cost living body implant that does not lose its antibacterial action even by machining.

  In order to solve the above problems, the biological implant of the present invention comprises a resin containing at least one inorganic antibacterial material selected from the group consisting of copper, zinc, silver, salts and oxides thereof, and calcium phosphate-based materials. It is formed by molding.

  According to the present invention, it is possible to provide a lower-cost biological implant without reducing the antibacterial action even by machining.

  Hereinafter, the biological implant of the present invention will be described in detail.

  As the resin used in the present invention, a thermoplastic resin or a thermosetting resin can be used, but it is preferable to use a thermoplastic resin having more excellent moldability.

(Thermoplastic resin)
The thermoplastic resin used in the present invention is not particularly limited as long as it is a high-strength thermoplastic resin that can be used for medical purposes. For example, ultra high molecular weight polyethylene, polypropylene, polytetrafluoroethylene, polyamide, polyacetal, polycarbonate, polybutylene terephthalate, polyethylene terephthalate, polysulfone, polyethersulfone, liquid crystal polymer, polyetheretherketone (PEEK), polyimide, polyamideimide, Mention may be made of acrylic resins and copolymers containing these polymers as partial structures. A methacrylic resin or PEEK is preferable, and PEEK is more preferable.

(Thermosetting resin)
Examples of the thermosetting resin include polyurethane, phenol resin, melamine resin, urea resin, unsaturated polyester resin, diallyl phthalate resin, silicone resin, fluorine resin, and epoxy resin. A thermosetting resin can also be used 1 type or in mixture of 2 or more types as needed.

(Inorganic antibacterial material)
The inorganic antibacterial material used in the present invention is at least one inorganic antibacterial material selected from the group consisting of copper, zinc, silver, their salts and oxides, and calcium phosphate materials. These inorganic antibacterial materials are contained dispersed in a resin. Examples of the salt include carbonates, phosphates, and oxalates of copper, zinc, and silver, and carbonates are preferable. The inorganic antibacterial material may be used alone or in combination of two or more. When using 1 type, it is preferable to use silver, its salt, or its oxide. Moreover, when using 2 or more types, it is preferable to use silver and its salt, or silver and its oxide. In addition, a composite material in which the calcium phosphate material includes at least one selected from the group consisting of copper, zinc, silver, and salts and oxides thereof can also be used. Further, a calcium phosphate material containing silver or a salt thereof or an oxide thereof is preferable. As this composite material, a composite powder produced by a wet method, a firing method or a thermal spraying method can be used. Since this composite material contains a calcium phosphate-based material, it is preferable because bone formation occurs at an early stage when it is embedded in bone.

The size of the inorganic antibacterial material may be any size as long as it can be dispersed in the resin. For example, the average particle size (D ₅₀ ) is 200 μm or less. Moreover, content of the inorganic antibacterial material in a biological implant is 1 to 70 weight%. For example, in the case of Ag ₂ O, the average particle size is 2 to 200 μm, preferably 2 to 100 μm, and the content is 2 to 50% by weight, preferably 5 to 20% by weight. When the average particle diameter is larger than 200 μm or the content exceeds 50% by weight, the resin surface becomes rough, which is not preferable.

  In the living body implant of the present invention, an inorganic antibacterial material is dispersed and contained in a resin, so that even if the surface is shaved by machining or the like, a new inorganic antibacterial material appears on the surface, so that the antibacterial action is not lost. In addition, the contained inorganic antibacterial material gradually elutes and exhibits an antibacterial action over a long period of time. Moreover, when it uses for an artificial tooth root, the infection from an intraoral area can be prevented through the side peripheral surface of the artificial tooth root which contacts a crown. Moreover, even if the side peripheral surface of the artificial tooth root that contacts the crown is ground, it has an effect of having antibacterial properties without reducing the mechanical strength. Further, when used for an artificial skull, when the periphery of the artificial skull is cut for size adjustment, it can be easily cut and has antibacterial properties as compared with an artificial skull made of ceramics.

  When the thermoplastic resin is used, the living body implant of the present invention can use various molding methods such as extrusion molding, injection molding, calendar molding, and blow molding, and can be manufactured at a lower cost. A 3D printer method can also be used.

You may manufacture the inorganic antibacterial material used for this invention by the wet method, a baking method, or a thermal spraying method. A preferred inorganic antibacterial material for producing by a wet method, a firing method or a thermal spraying method is calcium phosphate containing at least one selected from silver and its oxide, silver and its carbonate, or silver, its salt and its oxide It is a system material. As the calcium phosphate material, one or a mixture of two or more selected from the group consisting of hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate and quaternary calcium phosphate can be used. Preferably, it is hydroxyapatite. The calcium phosphate-based material also has an action of promoting bone formation, and by using the calcium phosphate-based material in combination, the amount of silver or Ag ₂ O can be reduced, so that it can be manufactured at a lower cost.

(Manufacture of inorganic antibacterial materials by plasma spraying method)
Examples of the thermal spraying method include a flame spraying method, a high-speed flame spraying method, a plasma spraying method, and a cold spray method, but the plasma spraying method is preferable. Although the plasma spraying conditions are not particularly limited, for example, a method described in the following document can be used.
“Mechanical, In Vitro Antibiotic and Biological Prooferts of Plasma SprayedSilver-Doped Hydroxyapatite Coating”, Mangal Rpy et al. (ACS Appl.
As the plasma spraying conditions, for example, thermal spraying can be performed at an operating output of 25 kW, a mixed gas of primary gas Ar and secondary gas Ar—H, and a spraying distance of 110 mm. In the present invention, a mixed powder of silver and / or a salt thereof or an oxide thereof and a calcium phosphate material is used for the plasma spray material. After cooling, the plasma sprayed coating is peeled from the base material and pulverized to obtain a plasma sprayed composite powder.

  The silver concentration in the plasma sprayed composite powder can be adjusted by changing the amount of the silver raw material to be blended with the calcium phosphate material used as the plasma spray material. The silver concentration in the plasma sprayed composite powder is 0.05 wt% to 3.00 wt%, preferably 0.05 wt% to 2.50 wt%, more preferably 0.05 wt% to 1.00 wt%. More preferably, it is 0.1% by weight to 1.00% by weight. It is because antibacterial property is not enough when it is smaller than 0.05% by weight. Moreover, it is because it will show a toxicity to a biological tissue when larger than 3.00 weight%.

  The average particle size of the plasma spray composite powder is 10 μm or less, preferably 1 to 7 μm, and the content in the biological implant is 2 to 50% by weight, preferably 5 to 20% by weight.

  The biological implant of the present invention includes not only an artificial tooth root and an artificial skull but also an iliac spacer, an artificial vertebral body, an artificial vertebral body spacer, an intercostal block, an artificial joint, and the like.

  Hereinafter, the present invention will be described in more detail using experimental examples.

Experimental Example 1.
(1) Antibacterial test (test piece preparation)
Ag ₂ O (manufactured by Merck) having a different average particle diameter was used as the inorganic antibacterial material, and biocompatible (ISO 10993) certified medical PEEK (manufactured by TECAPEEK CLASSIX) was used as the thermoplastic resin. Ag ₂ O used was dried at 150 ° C. for 6 hours. The content of Ag ₂ O is such that 10% by weight, were premixed Ag ₂ O and PEEK. Next, the mixed raw material was put into a heating mold having a heater wound outside (the cross section was a cylinder), the temperature of the mold was raised to the melting temperature of PEEK (342 ° C.), and PEEK was melted. After natural cooling, the product was taken out from the mold, and a cylindrical molded body was taken out. A test piece of 50 mm × 50 mm × 2 mm was produced from the cylindrical molded body by cutting. Incidentally, Ag 2 average particle diameter (D ₅₀₎ of the _O used was measured using a Shimadzu laser diffraction particle size distribution measuring apparatus.

(Test method)
In accordance with JIS Z2801, “Antimicrobial processed product—antibacterial test method / antibacterial effect”, antibacterial evaluation against MRSA (methicillin-resistant Staphylococcus aureus) was performed, and the following antibacterial activity values were obtained. However, assuming that this antibacterial member is used in vivo, bovine serum was used instead of 1/500 normal broth medium for the purpose of simulating the biological environment. The culture temperature was also changed from 35 ° C to 37 ° C. Incubation was performed in the dark for 24 hours.

The antibacterial activity value (R) is a value indicating the difference in the logarithmic value of the number of viable bacteria after inoculating and culturing bacteria in the antibacterial processed product and the unprocessed product, and is defined by the following formula.
Antibacterial activity value = log [(average value of viable cell count after 24 hours of unprocessed test piece) / (average value of viable cell count after 24 hour of antibacterial processed test piece)]
For example, an antibacterial activity value R of 7 indicates that the number of bacteria has become 1/10 ⁷ before the test. According to JIS standards, when the antibacterial activity value is 2 or more, it is determined that the antibacterial activity is effective.

(2) Cell adhesion test (preparation of test piece)
Similarly to the test piece of the antibacterial test, a PEEK cylindrical molded body containing Ag ₂ O was prepared, and a φ14 mm × 1 mm test piece was prepared from the cylindrical molded body by cutting.

(Test method)
After pre-culturing the mouse-derived osteoblast precursor cell line MC3T3-E1, α-MEM + 1
Seeds were placed on test specimens immersed in 0% FBS. After culturing for 2 hours at 37 ° C. with 5% CO ₂ , the cytoskeleton and nucleus were fluorescently stained, and the cell diameter ratio after the test was determined. The cell ratio after the test is the ratio of PEEK alone (comparative example not containing silver) to the cell diameter, which is obtained by taking a photograph, measuring the diameters of many cells in the photograph, and averaging them. The smaller the cell ratio, the higher the toxicity of silver to cells. In this test, a cell ratio of 90% or more was determined to be low in cytotoxicity.

(result)
Table 1 shows the results of the antibacterial test and cell adhesion test. In the comprehensive judgment, the case where the antibacterial activity value was 2 or more and the cell ratio was 90% or more was evaluated as ◯, and other cases were evaluated as ×. When the average particle size of Ag ₂ O was in the range of ₂ to 200 μm, excellent antibacterial activity and low cytotoxicity were exhibited. Further, when the content of Ag ₂ O was 2 to 50% by weight, excellent antibacterial activity and low cytotoxicity were exhibited.

Experimental example 2.
(1) Antibacterial test (test piece preparation)
A test piece was prepared in the same manner as in Example 1 except that a plasma spray composite powder of Ag-hydroxyapatite (hereinafter, hydroxyapatite is abbreviated as HA) was used instead of the Ag ₂ O powder. A powder obtained by mixing Ag (average particle size 10 μm, manufactured by Merck) and HA (made by Merck) at 10/90 (weight ratio) was sprayed by the following method.
The thermal spraying conditions were an operating output of 25 kW, a mixed gas of primary gas Ar and secondary gas Ar—H, and a spraying distance of 110 mm. Thermal spraying was performed on a pure titanium plate having a length of 10 cm, a width of 10 cm, and a thickness of 0.5 mm. After cooling, the plasma sprayed coating was peeled off from the pure titanium plate and pulverized to obtain a plasma sprayed composite powder. As a result, an Ag-HA sprayed composite powder containing 10% by weight of Ag was produced.
The antibacterial test was performed in the same manner as in Experimental Example 1.

(2) Cell adhesion test (preparation of test piece)
A test piece was prepared in the same manner as in Experimental Example 1 except that a sprayed composite powder of Ag-HA was used instead of the Ag ₂ O powder.
The cell adhesion test was performed in the same manner as in Experimental Example 1.

(result)
Table 2 shows the results of the antibacterial test and cell adhesion test. When the content of Ag-HA was 2 to 50% by weight, excellent antibacterial activity and low cytotoxicity were exhibited. Note that when the content of Ag-HA exceeds 50% by weight, it is difficult to prepare a mixed powder, and a test piece cannot be produced.

Experimental Example 3.
(1) Dissolution test (test piece preparation)
In the same manner as in the preparation of the test piece for antibacterial test of Experimental Example 1, a PEEK cylindrical molded body containing Ag ₂ O was manufactured, and a test piece of φ40 mm × 2 mm was manufactured from the cylindrical molded body by cutting.

(Test method)
In a plastic container, 100 ml of fetal bovine serum was added to one test piece and left at 37 ° C. After a predetermined time (4 hours, 12 hours, 24 hours, 48 hours), 1 ml is collected from the extract, centrifuged at 1000 rpm for 15 minutes and filtered through a 0.22 μm filter, and then filtrated with an ICP mass spectrometer. The silver ion concentration in the medium was measured.

  In addition, the antibacterial test and the cell adhesion test were performed on the test piece prepared in the present experimental example by the same method as in the first experimental example.

(result)
The measurement results of the silver ion concentration are shown in Table 3. It was confirmed that the silver elutes gradually and that when the silver concentration in the test piece increases, the eluted silver also increases.

Experimental Example 4.
(1) Dissolution test (test piece preparation)
A test piece was prepared in the same manner as in Experimental Example 3 except that a sprayed composite powder of Ag-HA was used instead of the Ag ₂ O powder.

(Test method)
The dissolution test was performed in the same manner as in Experimental Example 3.

  In addition, the antibacterial test and the cell adhesion test were performed on the test piece prepared in the present experimental example by the same method as in the first experimental example.

(result)
Table 5 shows the measurement results of the silver ion concentration. When Ag-HA spray composite powder is used, it is confirmed that silver is gradually eluted and that when the silver concentration in the test piece is increased, the eluted silver is also increased, as in the case of using Ag ₂ O. did. Since Ag in Ag-HA is 10 wt%, the amount of silver elution in Sample 25 is equivalent to that in Sample 23 (Ag ₂ O 20 wt%) even when Ag contained in the sample is 0.5 wt%. It can be seen that even if the silver content is small, it has an antibacterial effect.

  ADVANTAGE OF THE INVENTION According to this invention, even if the surface is shaved by grinding etc., the biological implant which can be manufactured at low cost, without antibacterial property falling can be provided. The biological implant of the present invention is not limited to an artificial tooth root, and can be widely used as other biological implants such as an artificial skull.

Claims (7)

  A biological implant formed by molding a resin containing at least one inorganic antibacterial material selected from the group consisting of copper, zinc, silver, salts and oxides thereof, and calcium phosphate materials.   The biological implant according to claim 1, wherein the inorganic antibacterial material is silver or a salt thereof or an oxide thereof.   The biological implant according to claim 1, wherein the inorganic antibacterial material is a calcium phosphate material containing at least one selected from the group consisting of copper, zinc, silver, and salts and oxides thereof.   The biological implant according to claim 3, wherein the inorganic antibacterial material is silver or a salt thereof or an oxide thereof and a calcium phosphate material.   The biological implant according to claim 1, wherein the resin is a thermoplastic resin.   The living body implant according to claim 5, wherein the thermoplastic resin is polyetheretherketone.   The biological implant according to any one of claims 1 to 6, wherein the biological implant is an artificial tooth root.