WO2023032947A1 - 生体適合性材料およびその製造方法 - Google Patents
生体適合性材料およびその製造方法 Download PDFInfo
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- WO2023032947A1 WO2023032947A1 PCT/JP2022/032506 JP2022032506W WO2023032947A1 WO 2023032947 A1 WO2023032947 A1 WO 2023032947A1 JP 2022032506 W JP2022032506 W JP 2022032506W WO 2023032947 A1 WO2023032947 A1 WO 2023032947A1
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- Prior art keywords
- substrate
- metal film
- biocompatible
- film
- calcium
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- 239000000560 biocompatible material Substances 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims description 44
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 239000000758 substrate Substances 0.000 claims abstract description 138
- 229910052751 metal Inorganic materials 0.000 claims abstract description 117
- 239000002184 metal Substances 0.000 claims abstract description 117
- 239000012890 simulated body fluid Substances 0.000 claims abstract description 26
- 230000005660 hydrophilic surface Effects 0.000 claims abstract description 25
- 210000001124 body fluid Anatomy 0.000 claims abstract description 18
- 238000004090 dissolution Methods 0.000 claims abstract description 18
- 239000010839 body fluid Substances 0.000 claims abstract description 14
- 239000011575 calcium Substances 0.000 claims description 124
- 229910052791 calcium Inorganic materials 0.000 claims description 114
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 104
- 239000011777 magnesium Substances 0.000 claims description 84
- 150000002500 ions Chemical class 0.000 claims description 53
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 52
- 229910052749 magnesium Inorganic materials 0.000 claims description 46
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 41
- 239000000463 material Substances 0.000 claims description 40
- 239000012981 Hank's balanced salt solution Substances 0.000 claims description 35
- 238000004544 sputter deposition Methods 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 230000003746 surface roughness Effects 0.000 claims description 13
- 239000004053 dental implant Substances 0.000 claims description 12
- 238000005477 sputtering target Methods 0.000 claims description 12
- 210000000988 bone and bone Anatomy 0.000 claims description 11
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 8
- 239000010936 titanium Substances 0.000 claims description 8
- 229910052719 titanium Inorganic materials 0.000 claims description 8
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 6
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 6
- 239000002953 phosphate buffered saline Substances 0.000 claims description 6
- 238000004140 cleaning Methods 0.000 claims description 5
- 238000010335 hydrothermal treatment Methods 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 238000007743 anodising Methods 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 238000005422 blasting Methods 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000001185 bone marrow Anatomy 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- 239000000788 chromium alloy Substances 0.000 claims description 3
- 210000003722 extracellular fluid Anatomy 0.000 claims description 3
- 210000002751 lymph Anatomy 0.000 claims description 3
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 210000002966 serum Anatomy 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- 229910001256 stainless steel alloy Inorganic materials 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 238000004113 cell culture Methods 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims 1
- 230000000717 retained effect Effects 0.000 abstract 1
- 238000007654 immersion Methods 0.000 description 31
- 239000000047 product Substances 0.000 description 26
- 238000000576 coating method Methods 0.000 description 18
- 230000001681 protective effect Effects 0.000 description 18
- 239000011248 coating agent Substances 0.000 description 17
- 239000010410 layer Substances 0.000 description 16
- 238000002441 X-ray diffraction Methods 0.000 description 12
- 239000007943 implant Substances 0.000 description 12
- 239000011521 glass Substances 0.000 description 10
- 229910052586 apatite Inorganic materials 0.000 description 9
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 9
- 238000005498 polishing Methods 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000919 ceramic Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000002149 energy-dispersive X-ray emission spectroscopy Methods 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 238000001139 pH measurement Methods 0.000 description 4
- 230000035882 stress Effects 0.000 description 4
- 230000008646 thermal stress Effects 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 229910045601 alloy Inorganic materials 0.000 description 3
- 239000000956 alloy Substances 0.000 description 3
- 239000011247 coating layer Substances 0.000 description 3
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- 238000010586 diagram Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 239000013081 microcrystal Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- -1 zirconia Chemical compound 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
- 241001422033 Thestylus Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001755 magnetron sputter deposition Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000010883 osseointegration Methods 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 208000008312 Tooth Loss Diseases 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 238000002048 anodisation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000002659 electrodeposit Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 210000004195 gingiva Anatomy 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000013528 metallic particle Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 238000013032 photocatalytic reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000550 scanning electron microscopy energy dispersive X-ray spectroscopy Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/06—Titanium or titanium alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/30—Inorganic materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
Definitions
- the present invention relates to a biocompatible material provided with a protective film, specifically a metal film, on a substrate, and the protective film, specifically the metal film, maintains the hydrophilicity of the substrate until it is used in a biological environment.
- the present invention relates to a biocompatible material comprising a biocompatible substrate that is hydrophilic; and a metal film provided on the substrate, the metal film having a dissolution property of dissolving in a predetermined liquid.
- the present invention also relates to a method for producing the biocompatible material.
- Patent Document 1 discloses a technique for imparting an activated surface with superhydrophilicity by removing organic contaminants adhering to a titanium-based biological implant with ultraviolet light immediately before surgery.
- a special device is required to irradiate the bioimplant with ultraviolet light at the surgical site, and the operation during surgery is complicated.
- Patent Document 2 discloses a technique of coating a solution containing a drug on an implant hydrophilized by ultraviolet irradiation.
- drug-containing coatings tend to deteriorate when stored in the atmosphere.
- Patent Document 3 a dental implant with a hydroxyapatite coating is sealed in a container, sterilized with radiation, and stored. Disclosed is a technique for removing impurities adhering to a surface at a surgical site.
- an increase in the number of procedures at the time of surgery is complicated, and there is a possibility that an unforeseen situation may arise because the impurity removal step is entrusted to the clinical site.
- Patent Document 4 discloses a technology that maintains antibacterial properties and hydrophilicity for a long period of time by forming an oxide composed of titanium and iodine on the base material surface. However, since this technology maintains hydrophilicity using the photocatalytic reaction of titanium oxide, it cannot maintain hydrophilicity in a dark place such as inside a container.
- Patent Document 5 discloses a technique for imparting antibacterial properties and hydrophilicity by directly fixing a hydrophilic organic compound on a metal surface.
- this technology directly electrodeposits polymers onto metals, it is difficult to uniformly apply the polymer to complex shapes.
- it since it is a soft polymer, local detachment and breakage cannot be avoided during screw insertion.
- Patent Document 6 discloses a technology of a solution and a preservation kit that can maintain a hydrophilic state by anodization, hydrothermal treatment, ultraviolet irradiation, plasma irradiation, and the like.
- the above-described group of techniques shows that the hydrophilic state can be maintained only in a solution, and in order to maintain it, it must be stored in a container containing the solution.
- Patent Document 7 discloses a technique in which a Mg-rich layer integrated with a substrate is provided on ceramics, and the film ensures hydrophilicity. Immediately after production, it exhibits superhydrophilicity and has a contact angle of 0°, but when exposed to the atmosphere, it gradually loses its hydrophilicity and reaches a contact angle of 40° or more in 5 days or more.
- Patent Document 8 discloses a technique in which a Ca-rich layer is provided on ceramics and hydrophilicity is ensured by the film. In this case as well, the film exhibits superhydrophilicity immediately after production and has a contact angle of 0°, but when exposed to the air, it gradually loses its hydrophilicity, and after several weeks, the contact angle reaches 40° or more. Note that the films of Patent Documents 7 and 8 are stable and insoluble because they are compounds. Therefore, a storage method or a relatively short expiration date must be provided to maintain the hydrophilicity of this membrane.
- Patent Literature 9 discloses techniques relating to implants and coating layers such as calcium-containing magnesium and trace amounts of iron and nickel.
- an object of the present invention is to provide a technique that does not require a storage container or solution for maintaining hydrophilicity and does not require a step of imparting hydrophilicity at the surgical site.
- an object of the present invention is to protect a hydrophilic substrate with a protective film, specifically a metal film, and to protect the biocompatible material with the protective film, specifically a metal film, when using the biocompatible material in a biological environment.
- Another object of the present invention is to provide a biocompatible material which dissolves the metal film and can be used while maintaining the hydrophilicity of the protected hydrophilic substrate.
- Another object of the present invention is to provide a method for producing the above biocompatible material in addition to or in addition to the above objects.
- ⁇ 1> a biocompatible substrate having a hydrophilic surface; and a metal film provided on the surface of the substrate, the metal film having a dissolution property of dissolving in body fluid or simulated body fluid;
- a biocompatible material having ⁇ 2> In the above item ⁇ 1>, when the biocompatible material is brought into contact with a body fluid or simulated body fluid, the metal film is dissolved, and the biocompatible substrate having a hydrophilic surface is preferably exposed.
- the bodily fluid is at least one selected from the group consisting of blood, lymph, bone marrow fluid, and interstitial fluid
- the pseudo-bodily fluid is physiological saline or phosphate-buffered saline.
- PBS physiological saline or phosphate-buffered saline.
- HBSS Hank's Balanced Salt Solution
- SBF plasma solution
- cell culture solution cell culture solution
- Eagle (MEM) solution DMEM solution
- serum medium serum medium.
- the simulated body fluid is preferably Hank's balanced salt solution.
- hydrophilicity means that the water droplet contact angle is 90° or less, preferably 50° or less, more preferably 30° or less, and most preferably 20° or less. is good.
- the metal film preferably contains at least one metal selected from the group consisting of Mg, Ca, Zn and Fe.
- the metal film contains magnesium and optionally calcium, and when the total weight of magnesium and calcium is 100% by weight, calcium is 0 to 40%. %, preferably 0.8-35% by weight, more preferably 5-35% by weight, even more preferably 15-35% by weight, most preferably 25-35% by weight.
- the protective film is preferably free of Mg 2 Ca.
- the protective film preferably has an amorphous portion.
- the substrate is at least one selected from the group consisting of pure titanium, cobalt-chromium alloys, stainless steel and titanium alloys, zirconia, alumina, calcium phosphate and magnesia. is good.
- the surface roughness Ra of the substrate is preferably 50 ⁇ m or less, preferably 40 ⁇ m or less, more preferably 30 ⁇ m or less.
- the shape of the biocompatible material is columnar, cylindrical, truncated conical, and conical, and a screw-like threaded portion is provided in part of the shape. It is preferably one selected from the group consisting of rectangular parallelepiped and cubic shapes, block shapes with partially inclined surfaces, and wedge shapes.
- the biocompatible material is an artificial bone material, an intraosseous fixation device material, a dental implant material, an orthodontic anchor screw material, an intramedullary nail material, and a vertebrae. It is preferably one selected from the group consisting of interbody fixation materials.
- a method for producing a biocompatible material (A) providing a biocompatible substrate; (B) hydrophilizing the surface of the biocompatible substrate; and (C) forming a metal film on the surface of the biocompatible substrate; a biocompatible substrate having a hydrophilic surface; and a metal film provided on the surface of said substrate.
- the step (C) is (C1) preparing a sputtering target comprising a metal film precursor; and (C2) using the sputtering target to form a metal film by sputtering on the biocompatible substrate obtained in step (B). forming a; should have
- the step (C1) is (C1a) a step of preparing a sputtering target comprising magnesium and optionally calcium
- the step (C2) includes (C2a) using the sputtering target to set the temperature of the biocompatible substrate obtained in the step (B) to 130°C or lower, preferably 90°C or lower, more preferably 60°C or lower. forming a metal film comprising magnesium and optionally calcium on the biocompatible substrate by sputtering, wherein the total weight of magnesium and calcium is 100% by weight, and calcium is in the range of 0 to 40% by weight; There is good.
- the step (B) includes acid treatment, blasting, anodizing, hydrothermal treatment, ultraviolet irradiation, plasma irradiation, laser irradiation, radiation irradiation, and ion irradiation. It is preferably at least one selected from the group consisting of: ⁇ 18>
- the step (B) is ion irradiation, and the ion irradiation power product is 0.4 W min/cm 2 or more, preferably 0.8 W min/cm 2 .
- a hydrophilic substrate is protected with a protective film, specifically a metal film, and when a biocompatible material is used in a biological environment, the protective film, specifically a metal film, is used.
- a biocompatible material is used in a biological environment
- the protective film specifically a metal film
- the present invention can provide a method for producing the above biocompatible material in addition to or in addition to the above effects.
- FIG. 4 shows X-ray diffraction profiles of an Mg film, an Mg10% Ca film, an Mg20% Ca film, and an Mg30% Ca film obtained using targets. At a power product of 0, 0.495, 0.99, 2.85 or 5.36 W min/cm 2 for smooth plate zirconia AF, rough plate zirconia AR, and glass substrate B.
- FIG. 4 is a diagram showing a water droplet contact angle on a surface irradiated with ions.
- Smooth plate-shaped zirconia AF or AF2 was irradiated with ions at a power product of 0.99 W min/cm 2 and then coated with a Mg 30% Ca film by sputtering within one week after coating, and within one week after coating.
- the water droplet contact angle immediately after removal of the film after storage for months, 2 months, 4 months, 7 months and 15 months is shown.
- FIG. 10 is a diagram showing pH measurement results as a dissolution rate evaluation in HBSS( ⁇ ) immersion for smooth zirconia A-F2 with Mg film, Mg20% Ca film and Mg30% Ca film.
- FIG. 10 is a diagram showing pH measurement results as a dissolution rate evaluation in HBSS( ⁇ ) immersion for smooth zirconia A-F2 with Mg film, Mg20% Ca film and Mg30% Ca film.
- Photographs of smooth plate-shaped zirconia AF photographs of samples coated with Mg30% Ca film by sputtering after applying ion irradiation to smooth plate-shaped zirconia AF at a power product of 5.36 Wmin / cm 2
- Smooth plate-shaped zirconia AF was subjected to ion irradiation at a power product of 5.36 Wmin/cm 2 and then coated with a Mg 30% Ca film by sputtering.
- I took it out.
- the present application provides a biocompatible material comprising a biocompatible substrate having a hydrophilic surface; and a metal film provided on the surface of the substrate and having a dissolution property of dissolving in a predetermined liquid. .
- the present application also provides a method of making the biocompatible material.
- Biocompatible material comprising a biocompatible substrate having a hydrophilic surface; and a metal film provided on the surface of the substrate, the metal film having a dissolution property of dissolving in a body fluid or simulated body fluid.
- biocompatible material refers to a property that is held in the body and poses no problem in terms of biosafety.
- a biocompatible material of the present invention has a biocompatible substrate.
- the biocompatible substrate has a hydrophilic surface with a water droplet contact angle of 90° or less, preferably 50° or less, more preferably 30° or less, and most preferably 20° or less. is good.
- the water droplet contact angle can be measured by a conventionally known method. For example, a droplet is dropped on the sample surface, and the angle formed by the sample surface and the droplet is measured by the ⁇ /2 method. can. More specifically, it can be measured 30 seconds after the droplet contacts the sample surface.
- the biocompatible substrate is not particularly limited as long as it has the above-mentioned "biocompatibility".
- examples include metals such as pure titanium, cobalt-chromium alloys, stainless steel and titanium alloys, and ceramics such as zirconia, alumina, calcium phosphate, and magnesia. can include, but are not limited to.
- the biocompatible substrate is preferably pure titanium, titanium alloys and zirconia, more preferably ceramics, and even more preferably zirconia. In the present invention, even if the biocompatible substrate is non-conductive ceramics, when the metal film and body fluid or simulated body fluid come into contact with each other, the metal film dissolves and the surface of the biocompatible substrate is exposed, resulting in hydrophilicity. It is possible to demonstrate sexuality.
- the biocompatible substrate preferably has a surface roughness (arithmetic mean roughness) Ra of 50 ⁇ m or less, preferably 40 ⁇ m or less, more preferably 30 ⁇ m or less.
- Surface roughness Ra can be measured by a conventionally known method, for example, according to JIS B0601:2013.
- a reference length and an evaluation length are defined according to Ra value categories.
- the reference length and evaluation length for 0.1 ⁇ Ra( ⁇ m) ⁇ 2 are 0.8 mm and 2.0 mm, respectively. If the reference length cannot be measured continuously due to interference between the stylus and the object, use the reference length in the category lower than the Ra value of the object, and measure the total number of times the evaluation length is exceeded. and its average value can be Ra.
- the biocompatible material of the present invention has a metal film on the surface of the biocompatible substrate.
- Metal films have dissolution properties that dissolve in body fluids or simulated body fluids.
- the metal film of the present invention is biocompatible in that when the biocompatible material is brought into contact with a body fluid or a simulated body fluid, the biocompatible substrate and the metal film are not integrated, the metal film dissolves, and the surface is hydrophilic.
- the substrate should be exposed.
- bodily fluids include, but are not limited to, blood, lymph, bone marrow fluid, interstitial fluid, and the like.
- physiological saline phosphate buffered saline (PBS), Hank's balanced salt solution (HBSS), SBF solution, plasma liquid, cell culture medium, Eagle (MEM) solution, DMEM solution, and serum medium etc., but not limited to these.
- PBS phosphate buffered saline
- HBSS Hank's balanced salt solution
- SBF plasma liquid
- cell culture medium cell culture medium
- Eagle (MEM) solution DMEM solution
- serum medium etc.
- the metal film of the present invention has the property of dissolving in body fluids or simulated body fluids. Therefore, when a biocompatible material having the metal film on its surface is implanted in the body, the metal film dissolves and becomes hydrophilic. The surface of the substrate having it is exposed, and high adhesiveness to living tissue can be exhibited.
- the metal film of the present invention is brought into contact with a body fluid or a simulated body fluid to dissolve the metal film, thereby forming a biocompatible substrate having a hydrophilic surface. By exposing, it is also possible to exhibit high adhesiveness to living tissue.
- the metal film can be dissolved when the biocompatible material is used, preferably during use, so that the hydrophilic surface of the biocompatible substrate exerts the desired effect.
- the metal film should have the dissolution properties of a) dissolving in 5% hydrochloric acid, and b) more preferably dissolving in Hank's Balanced Salt Solution.
- Hank's Balanced Salt Solution There are four types of Hank's balanced salt solutions, depending on whether they contain "Ca and Mg" and whether they contain "phenol red”. Red-free and "Ca and Mg"-free are preferred.
- the dissolution property in 5% hydrochloric acid is preferably one or both of the following i) and ii) when 2 mg of the protective film is immersed in 50 ml of 5% hydrochloric acid.
- the time for the concentration of the substance dissolved from the protective film to become almost constant due to the immersion time is 0.3 seconds or more, preferably 0.5 to 20 seconds, more preferably 0.5 to 10 seconds after immersion.
- the time for 2 mg of the protective film to be almost dissolved is 0.5 seconds or longer, preferably 1 to 60 seconds, more preferably 1 to 30 seconds after immersion.
- the "substance dissolved from the protective film" depends on the components of the protective film.
- substantially dissolved means that the substrate is exposed on 90% or more of the surface.
- the exposure ratio can be evaluated from the photograph of the appearance, and when it is difficult to distinguish between the film and the substrate, the evaluation can be made by analysis using EDX or the like.
- the dissolution property of dissolving in a Hank's balanced salt solution is such that, for example, when 2 mg of the protective film is immersed in the Hank's balanced salt solution, either one or both of iii) and iv) below are preferably satisfied.
- iii) When immersed in 40 ml of Hank's balanced salt solution, the time for the concentration of the substance dissolved from the protective film to become almost constant with the immersion time is 0.5 hours or more, preferably 1 to 72 hours, more preferably 1 to 72 hours after immersion.
- the time for 2 mg of the protective film to be almost dissolved after immersion is 1 hour or more, preferably 2 to 672 hours, more preferably 3 to 336 hours, most preferably 4 to 168 hours. It's time.
- the terms "substance that dissolves from the metal film” and “substantially dissolve” have the same definitions as above.
- the metal film preferably contains at least one metal selected from the group consisting of Mg, Ca, Zn and Fe.
- the protective film may be an alloy composed of two or more selected from these metals.
- the metal film may further have a species selected from the group consisting of B, C, N and P.
- the alloy may further contain a species selected from the group consisting of B, C, N and P.
- the metal film comprises magnesium and optionally calcium, wherein calcium is 0-40% by weight, preferably 0.8-35% by weight, more preferably 0.8-35% by weight, where the total weight of magnesium and calcium is 100% by weight. should be 5-35% by weight, more preferably 15-35% by weight, most preferably 25-35% by weight.
- the higher the calcium content the larger the region of the amorphous structure. When the calcium content is 10% by weight, a sharp peak derived from crystals is observed, but when the calcium content is 20% by weight, a broad halo pattern derived from the amorphous structure is observed.
- a low-intensity peak that seems to be derived from microcrystals is observed in it, and at 25% by weight or more, almost no crystal-derived peaks are observed, and at 30% by weight, only a broad halo pattern derived from an amorphous structure is observed.
- the biocompatible membrane of the present application contains calcium, a large portion thereof has a substantially amorphous structure.
- the compatible membrane dissolves uniformly in body fluids or simulated body fluids, facilitating uniform exposure of the hydrophilic surface of the substrate.
- the target is manufactured by sputtering, it is preferable that the content of calcium is within 35% by weight for ease of target manufacturing.
- the metal membranes of the present application consist essentially of magnesium and optionally calcium, preferably magnesium and optionally calcium.
- “consisting only of” means that it is composed only of the components described in “-”.
- “consisting essentially only of” may include components other than those described in “ ⁇ ”, but the components may be composed only of those described in “ ⁇ ”. It means that it may be included as long as it does not cause
- the metal film is preferably Mg 2 Ca free.
- Mg 2 Ca-free means that no peak due to Mg 2 Ca is observed in X-ray diffraction analysis, preferably diffraction peaks generated from the substrate and Mg 2 Ca crystals respectively.
- each diffraction peak is separated by 1° or more in X-ray analysis using a cobalt (Co) tube), and no peaks based on Mg 2 Ca are observed at diffraction angles. No peaks should be observed in the range of 36-37° by X-ray analysis.
- the metal film should have an amorphous portion.
- amorphous means that sharp peaks are not observed in X-ray diffraction analysis.
- the biocompatible material of the present application has the above-described biocompatible substrate; and the above-described metal film; but may have other layers.
- the layer include, but are not limited to, an anodizing layer for titanium or a titanium alloy, a hydrothermal treatment layer, and the like. It may also have one or more layers on top of said membrane, i.e. on the side opposite the substrate.
- the shape of the biocompatible material of the present invention is not particularly limited. and a cube, a block shape such as a rectangular parallelepiped and a cube having a partially inclined surface, and a wedge shape.
- the field of application of the biocompatible material of the present invention is not particularly limited, but examples include artificial bone materials, intraosseous fixation device materials, dental implant materials, orthodontic anchor screw materials, intramedullary nail materials, and vertebrae. It is preferably one selected from the group consisting of interbody fixation materials. Examples include, but are not limited to, artificial bones, pins, wires, bolts, screws, washers, intramedullary nails, vertebral body spacers, and the like.
- the present application provides methods of making the biocompatible materials described above.
- the method comprises (A) providing a biocompatible substrate; (B) hydrophilizing the surface of the biocompatible substrate; and (C) forming a metal film on the surface of the biocompatible substrate; By these steps, a biocompatible material having a biocompatible substrate with a hydrophilic surface and a metal film provided on the surface of the substrate can be produced.
- substrate here.
- the "metal film” is not limited as long as it is a film that protects a hydrophilic substrate, but it is preferably the one described above.
- the (A) step is a step of preparing a biocompatible substrate.
- the "biocompatible substrate" described above may be purchased commercially, or the commercially purchased product may be formed into a desired shape.
- conventionally known methods can be used for the grinding method and the polishing method.
- the (B) step is a step of hydrophilizing the surface of the biocompatible substrate.
- the step (B) is preferably at least one selected from the group consisting of acid treatment, blasting, anodizing, hydrothermal treatment, ultraviolet irradiation, plasma irradiation, laser irradiation, radiation irradiation, and ion irradiation.
- the step (B) is preferably ion irradiation.
- the ion irradiation power product is 0.4 W ⁇ min/cm 2 or more, preferably 0.8 W ⁇ min/cm 2 or more, more preferably 2.5 W ⁇ min/cm 2 or more, and still more preferably 5 W ⁇ min/cm 2 or more. cm 2 or more, most preferably 5 to 32 W ⁇ min/cm 2 .
- the step (C) is a step of forming a metal film on the surface of the biocompatible substrate, that is, on the hydrophilized surface.
- the step (C) is not particularly limited as long as the metal film is formed while maintaining the hydrophilicity of the hydrophilized surface.
- step (C) step (C1) preparing a sputtering target comprising a metal film precursor; and (C2) using the sputtering target to form a metal film by sputtering on the biocompatible substrate obtained in step (B). forming a; should have
- step (C1) is (C1a) providing a sputter target comprising magnesium and optionally calcium
- step (C2) sputtering is performed using the sputtering target (C2a) at a temperature of 130° C. or lower, preferably 90° C. or lower, more preferably 60° C. or lower to the biocompatible substrate obtained in step (B).
- step (C2) is a step of forming a metal film having magnesium and optionally calcium on the surface of a biocompatible substrate and having 0 to 40% by weight of calcium when the total weight of magnesium and calcium is 100% by weight. , is good.
- a magnetron sputtering device is preferably used as the sputtering device.
- a magnetron sputtering system uses a magnetic field to efficiently deposit sputtered particles (metallic particles) generated by colliding argon ions against the target with a strong magnet (magnetron) behind the target. be able to.
- the desired film can be formed at a constant deposition rate.
- Magnesium-based metal films have a coefficient of linear expansion that is at least three times greater than that of zirconium, titanium, and titanium alloys, which serve as substrates.
- Tensile stress occurs at the interface on the film side, making the film easy to peel off. Therefore, in order to prevent the film from peeling off after the film formation and to prevent harmful stress from remaining when the implant is embedded, the temperature of the substrate during sputtering is set to a certain temperature or less, that is, 130° C. or less, preferably 90° C. or less. By controlling the temperature to preferably 60° C. or lower, a film with high adhesion can be formed.
- the above temperature can be estimated by calculating the thermal stress as follows. That is, the interfacial stress (thermal stress) that occurs when the temperature is lowered from the sputtering temperature to room temperature can be expressed approximately as shown in Equation 1 below.
- ⁇ T temperature difference between substrate temperature Td during sputtering and room temperature Tr
- ⁇ 1 average linear expansion coefficient of the substrate between temperatures Tr and Td
- ⁇ 2 between temperatures Tr and Td
- E 1 average elastic modulus of the substrate between temperatures Tr and Td
- E 2 average elastic modulus of the film between temperatures Tr and Td.
- the substrate is zirconia
- the coating film is pure magnesium
- the linear expansion coefficients are 8 ⁇ 10 ⁇ 6 and 25 ⁇ 10 ⁇ 6
- the elastic moduli are 210 GPa and 40 GPa, respectively.
- the proof stress of pure magnesium is generally said to be about 90 to 100 MPa
- the shear yield strength is about 50 MPa.
- the temperature difference should be 100 degrees or less.
- the film formation temperature is preferably 130° C. or less, and the film is formed at 60° C. or less considering the double safety factor of 90° C. or less, and the approximately three times safety factor. is preferred.
- the ion cleaning process is a process in which impurities on the surface are removed at the atomic level by bombarding the surface of the substrate with argon ions or the like while appropriately adjusting the bias in a vacuum, specifically in a vacuum chamber. is. By performing this appropriately, the adhesion of the metal film can be stabilized and the surface of the substrate can be activated.
- the production method of the present invention may have steps other than the above (A) to (D).
- steps other than the above (A) to (D) For example, as described above, after the (A) step and before the (B) step, a step of shaping the "biocompatible substrate" into a desired shape, and a step of grinding and/or polishing the surface of the shape may be included.
- the step of providing the layer is preferably provided after the step (B) and before the step (C).
- Substrate materials for implants are zirconia AF and AF2 in the form of smooth plates with a thickness of 3 mm ⁇ 10 mm ⁇ 10 mm, which are generally ground on one plane, and micro-grid grooves on the surface.
- a rough-surfaced plate-like zirconia AR was used, the surface of which was roughened by forming a .
- a glass substrate B having a thickness of 1.2 mm ⁇ 26 mm ⁇ 76 mm was also used in order to examine the details of the characteristics of the formed metal film.
- the surface roughness of each sample was measured with reference to JIS B0601:2013, with a reference length of 0.8 mm, an evaluation length of 4.0 mm, and cutoff values of ⁇ c0.8 mm and ⁇ s0.25 ⁇ m.
- the surface roughness was measured in two directions parallel and perpendicular to the grinding direction and averaged. Table 1 summarizes the surface roughness values for each sample.
- Ion irradiation in a vacuum chamber was used to form a hydrophilic surface.
- the pressure was reduced to a predetermined value, harmful gases were removed from the chamber, and then argon gas was sealed.
- the power product of ion irradiation was 0 (untreated), 0.495, 0 99, 2.8 or 5.36 W ⁇ min/cm 2 under five conditions.
- the sputtering target four kinds of ingots manufactured by melting pure magnesium and pure magnesium and pure calcium in a predetermined ratio were machined into disk shapes having a diameter of about 120 mm.
- the three types of ingots have a calcium content of 0% by weight (Mg), 10% by weight (Mg10%Ca), 20% by weight (Mg20%Ca) or 30% by weight (Mg30%Ca).
- the amount was magnesium.
- % of calcium amount is the ratio of calcium weight when the sum of calcium weight and magnesium weight is 100% by weight, and is represented by the following weight %.
- Calcium weight % calcium weight/(magnesium weight+calcium weight) ⁇ 100. Similar to Mg10% Ca, etc., using pure magnesium and pure calcium, we prototyped targets with a calcium content of 40% by weight (Mg40% Ca) or 50% by weight (Mg50% Ca). Alternatively, it could not be used because cracks occurred during machining and it was partially damaged.
- the substrate was placed on the stage of the sputtering apparatus so as to face the sputtering target. It was placed so that the ground or roughened surface faced upward.
- the temperature of the substrate was kept at room temperature, the pressure of argon was 1 to 10 mTorr, the sputtering voltage and the substrate bias were adjusted to adjust the film formation process (deposition) time, and the smooth plates A to F and the rough surface were used. Plates AR and glass substrate B were set in the same chamber. Smooth plates A-F2 were also performed with the glass substrate B placed in the same chamber.
- magnesium alone (Mg) is sputtered to 20% by weight (Mg20% Ca) and 30% by weight (Mg30% Ca).
- Ca magnesium-only film
- Mg film a film with a calcium content of 20% by weight
- Mg30% Ca film a film with a calcium content of 30% by weight
- the thickness of the film was measured by actually measuring the step between the film-formed portion on the substrate and the masked portion where the film was not formed by the stylus method. Also, the weight of the film was calculated by subtracting the weight of the substrate AF, AR or AF2 before sputtering from the weight of the sample after sputtering each film.
- FIG. 1 shows that after ion irradiation was applied to the glass substrate B at a power product of 0.99 W min/cm 2 , magnesium alone (Mg) and calcium content of 10% by weight (Mg 10% Ca) and 20% by weight were applied by sputtering.
- % (Mg20% Ca) and 30% by weight (Mg30% Ca) targets respectively, a magnesium-only film (Mg film) and a calcium content of 10% by weight (Mg10% Ca film).
- 8 shows X-ray diffraction profiles of a film with a calcium content of 20% by weight (Mg 20% Ca film) and a film with a calcium content of 30% by weight (Mg 30% Ca film).
- the Mg film is crystalline, the Mg10% Ca film is crystalline with low crystallinity, the Mg20% Ca film has a mixed structure of microcrystals and amorphous, and the Mg30% Ca film is non-crystalline. found to be crystalline.
- the amount of calcium added to magnesium exceeds 0.8% by weight, calcium does not form a solid solution in magnesium and Mg 2 Ca precipitates.
- the presence of intermetallic compounds such as Mg 2 Ca was not observed in any of the films.
- no difference was observed in the film structure detected due to the difference in ion irradiation intensity.
- FIG. 2 shows the power product of 0, 0.495, 0.99, 2.8 or 5.36 W min for smooth plate-shaped zirconia AF, rough plate-shaped zirconia AR, and glass substrate B.
- /cm 2 indicates the water droplet contact angle on the ion-irradiated surface.
- sputtering was performed to protect the ion-irradiated surface with a metal film.
- the sample coated with the metal film was wrapped in medicine wrapping paper and stored in the atmosphere for two months, the water droplet contact angle of the substrate immediately after removing the metal film was measured.
- the substrate was immersed and shaken in 50 ml of a 5% hydrochloric acid aqueous solution for about 10 seconds to dissolve the film until the entire surface of the substrate was exposed. After additional cleaning by immersing and shaking in another ultrapure water for about 10 seconds, it was dried by blowing with argon gas.
- Table 3 shows that smooth plate-like zirconia AF and rough plate-like zirconia AR were subjected to hydrophilization treatment by ion irradiation at power products of 0.495, 0.99, and 5.36 W min/cm 2 . Water drop contact angle after 2 months after application. Further, the smooth plate-shaped zirconia AF and the rough plate-shaped zirconia AR were subjected to hydrophilization treatment by ion irradiation at power products of 0.495, 0.99, and 5.36 Wmin/cm 2 , and then sputtered. shows the water droplet contact angle immediately after removing the metal film in the above-described process after two months of protection by covering with a Mg30% Ca film.
- Table 4 shows smooth plate-shaped zirconia A to F, which were subjected to hydrophilization treatment by ion irradiation at a power product of 0.99 W min/cm 2 and then sputtered to obtain Mg film, Mg20% Ca film, or Mg30% Ca film.
- the water droplet contact angles are shown immediately after removing the metal films in the process described above after two months of protection by coating each of the films.
- smooth plate-shaped zirconia A-F2 was irradiated with ions at a power product of 0.99 W min/cm 2 and then sputtered to coat with a Mg30% Ca film for 7 months and 15 months immediately after coating.
- the water droplet contact angle is shown immediately after the film has had its metal film removed by the process described above.
- a zirconia AR in the form of a rough surface plate was subjected to ion irradiation with a power product of 0.99 W min/cm 2 and then sputtered to form a Mg30% Ca film within one week from immediately after coating. Water droplet contact angles are shown immediately after removing their metal films in the above-described process after storage in air for 1 month, 2 months and 4 months.
- the water droplet contact angle of rough zirconia that has not been subjected to ion irradiation is 70° or more at maximum, whereas the water droplet contact angle of rough zirconia that has been subjected to ion irradiation is 5° or less at the lowest. It exhibits superhydrophilicity. Also, in smooth zirconia with a lower substrate surface roughness, the difference in water droplet contact angle before and after ion irradiation is smaller. Therefore, by appropriately combining the substrate surface roughness and the presence or absence of ion irradiation or the conditions thereof, it is possible to provide the water droplet contact angle required for each implant site.
- each of the smooth zirconia coated with three kinds of metal films with different chemical components and structures and the metal films removed has a water droplet contact angle of 20 ° or less, which is highly hydrophilic. show gender. Therefore, it can be seen that the hydrophilic surface can be protected regardless of the type of metal film.
- the protective performance of the Mg20% Ca film and the Mg30% Ca film having an amorphous structure is slightly lower than that of the crystalline Mg film (magnesium only film). Are better. Therefore, by using a metal film having an amorphous structure, better protection performance can be exhibited.
- HBSS(-) solution without phenol red
- Fuji Film Wako Pure Chemical containing no calcium or magnesium
- the simulated body fluid volume was 40 ml or 400 ml. Therefore, assuming that the apparent surface area ignoring the influence of surface roughness is 220 mm 2 , the pseudo body fluid volume per unit area of the film in contact with the solution is 0.182 ml/mm 2 or 0.0182 ml/mm 2 , respectively. be.
- Dissolution rates were evaluated from pH measurements using the glass electrode method.
- a desktop pH tester HORIBA, F-74) and a GRT composite electrode (9615S-10D, HORIBA) were used for pH measurement.
- the sample was immersed in 40 ml of HBSS (-) solution kept at 37° in an air bath type constant temperature device, and the pH was measured after 1 hour, 3 hours, 6 hours, 12 hours and 24 hours. bottom.
- the pH was measured after immersion in 400 ml of HBSS (-) solution kept at 37 ° in an air bath type constant temperature device, after 6 hours, 24 hours and 168 hours, it was taken out, and the exposed surface was identified and an XRD device ((D8ADVANCE, BRUKER), and SEM EDX (JSM5900LVM, JEOL) was used to identify the exposed surface.
- FIG. 4 shows the results of pH measurement as a dissolution rate evaluation in HBSS ( ⁇ ) immersion for smooth zirconia A-F2 with Mg film, Mg20% Ca film and Mg30% Ca film.
- the calculated value of the amount of magnesium and calcium components per unit volume mol/cm 3 in the Mg film, Mg20% Ca film and Mg30% Ca film when the film thickness is 5.28 ⁇ m and the total cross-sectional area is 220 mm 2 is shown.
- FIG. 5 shows the XRD measurement results of smooth zirconia A-F2 with a Mg film before immersion in HBSS(-) and after immersion for 6 hours, 24 hours and 168 hours, respectively.
- the ratio of the diffraction intensity Im from the (0 0 -2) plane of the magnesium film and the diffraction intensity Iz from the (1 0 -1) plane of the zirconia substrate was calculated.
- Table 6 shows the value obtained by subtracting the Im/Iz after 168 hours from the peak intensity ratio Im/Iz obtained from the peak intensity ratio Im/Iz, and the estimated value of the film thickness based on the relationship between the intensity ratio and the value of the film thickness T after 0 hour. shown in If the relationship between immersion time and film thickness is approximated by an exponential function, the change in film thickness with immersion time can be roughly predicted by the following equation.
- Fig. 6 shows appearance photographs of samples taken out from smooth zirconia A-F2 with Mg30% Ca film before immersion in HBSS (-), 6 hours and 168 hours after immersion, and EDX of the sample surface taken out after 6 hours of immersion. Analytical results are shown.
- Table 7 shows the identification results obtained from FIG.
- the sample taken out after 6 hours of immersion was covered with a metallic color layer, black or white layer, and there were almost no areas where polishing scratches on the substrate could be observed, and the surface of the biocompatible substrate was not exposed. .
- In the sample taken out after 24 hours of immersion almost no metal-colored layer was observed, more polishing scratches on the substrate were observed, and more of the biocompatible substrate surface was exposed.
- polishing scratches on the substrate were observed over the entire surface, and the surface of the biocompatible substrate was exposed over the entire surface.
- FIG. 5 Table 6, FIG. 6, and Table 7 reveal the following.
- occlusion with dentures cannot be performed until sufficient osseointegration occurs. Therefore, there is a demand for early osteosynthesis of dental implants. From FIG. 4 and Table 5, it can be seen that after immersion in the simulated body fluid, the metal film is ionized immediately after immersion, resulting in a sudden change in pH, reaching a maximum pH of 9.5 or higher after 24 hours. Therefore, it can be seen that dissolution of the membrane occurs early after implantation in the bone.
- the film thickness rapidly decreases immediately after immersion, and the film thickness hardly changes after 24 hours of immersion, but all of the metal film dissolves within 168 hours.
- the substrate was hardly exposed after 6 hours of immersion, but the substrate was gradually exposed thereafter, and the substrate was exposed on all sides at least within 168 hours of immersion. I understand. Therefore, after a dental implant whose hydrophilic surface is protected by a metal film is implanted, the film dissolves early, exposing the activated surface, thereby promoting early osseointegration.
- the amount of the HBSS(+) solution was adjusted so that the equilibrium pH after elution of the sputtering film was 8.0 or less.
- substrates not subjected to ion irradiation and sputtering were tested by immersing them in two kinds of solutions, HBSS(+) and HBSS(+) after Mg30% Ca film elution.
- HBSS(+) and HBSS(+) As a simulated body fluid immersion test, each sample was immersed in 500 ml of simulated body fluid, held in a constant temperature bath at 37° C. for one week, and then removed from the solution.
- FIG. 7 is a photograph of smooth plate-shaped zirconia AF, which was coated with a Mg30% Ca film by sputtering after being subjected to ion irradiation with a power product of 5.36 W min/cm 2 to the smooth plate-shaped zirconia AF.
- a photograph of a sample, and a sample coated with a Mg30% Ca film by sputtering after ion irradiation with a power product of 5.36 W min/cm 2 on smooth plate-shaped zirconia AF was immersed in a simulated body fluid. Photograph after removal from HBSS(+) after a week.
- Table 8 shows the samples coated with a Mg 30% Ca film by sputtering after applying ion irradiation to smooth plate-shaped zirconia AF at power products of 0.495, 0.99 and 5.36 W min/cm 2 respectively.
- the sample was immersed in HBSS(+), removed from the HBSS(+) one week later, and photographed with a microscope (VHX7000, KEYENCE) from a direction tilted 15 degrees from the axis perpendicular to the sample. It is a value calculated by image analysis of the metal film remaining portion, the area fraction of the portion not covered with HAp while the base material is exposed, and the HAp coverage based on the image obtained by synthesizing the matching portions.
- FIG. 8 is an image used when calculating the area fractions of the power products of 0.495 and 5.36 W ⁇ min/cm 2 for the smooth materials (AF) in Table 8.
- FIG. 8 When another sample with a power product of 0.495 and 0.99 was immersed in HBSS(+) for 3 weeks and taken out, no residual metal film was observed. On the other hand, the area fraction of the portion where the base material was exposed and was not covered with HAp was found to be approximately the same as that when immersed in HBSS(+) for one week.
- a dental implant that has undergone a hydrophilization treatment that exhibits high hydrophilicity and whose hydrophilic surface is protected by a metal film, the activated surface is spontaneously exposed in vivo, and the entire apatite formation occurs. It is possible to encourage early bone formation.
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Abstract
Description
具体的には、本発明は、親水性である生体適合性基体;及び前記基体上に備えられる金属膜であって所定の液で溶解する溶解特性を有する金属膜;を有する生体適合性材料に関する。
また、本発明は、該生体適合性材料の製造方法に関する。
歯根用インプラントのスクリュー部と骨との接合性が不十分なことに起因して、埋入後にゆるみが発生しやすいことから、スクリュー部と骨細胞との接着性の改善が求められている。
また、歯根用インプラントと歯肉との接触部(アバットメント部)において、細菌の付着に起因する炎症が発生しやすいことから、アバットメント部への細菌の付着を抑制する技術が求められている。
また、基材の表面粗さと親水性とは密接な関係がある。表面粗さが粗いほど接触面積が大きくなるため、表面状態の変化に敏感となる。
したがって、表面粗さが粗いほど、その親水性を長期間保持することは難しい。
特許文献9は、カルシウムを含有させたマグネシウム及び微量の鉄とニッケル等であるインプラント及びコーティング層に関する技術を開示する。しかしながら、同技術では不溶性のMg2Caが含まれていることから、生体内に取り込まれて危害を及ぼす可能性がある。また、同技術におけるコーティング層は完全に溶解せずに、コーティング層を介して基材と骨とが接着する。したがって、基体の親水性が骨との接着性に関係することはない。
具体的には、本発明の目的は、親水性を有する基体を保護膜、具体的には金属膜で保護し、生体適合性材料を生体環境下で使用する際には該保護膜、具体的には該金属膜を溶解させ、保護された親水性を有する基体を親水性を保持したままで使用することができる生体適合性材料を提供することにある。
また、本発明の目的は、上記目的の他に、又は上記目的に加えて、上記生体適合性材料の製造方法を提供することにある。
<1> 表面が親水性である生体適合性基体;及び
前記基体の表面に備えられる金属膜であって、体液または擬似体液で溶解する溶解特性を有する金属膜;
を有する、生体適合性材料。
<2> 上記<1>において、生体適合性材料を体液または擬似体液に接触させると金属膜が溶解し、表面が親水性である生体適合性基体が露出するのがよい。
<4> 上記<1>~<3>のいずれかにおいて、擬似体液が、ハンクス平衡塩溶液であるのがよい。
<6> 上記<1>~<5>のいずれかにおいて、金属膜が、Mg、Ca、Zn及びFeからなる群から選ばれる少なくとも1種の金属を有してなるのがよい。
<8> 上記<7>において、保護膜がMg2Caフリーであるのがよい。
<9> 上記<1>~<8>のいずれにおいて、保護膜が非晶質部分を有するのがよい。
<11> 上記<1>~<10>のいずれにおいて、基体の表面粗さRaが、50μm以下、好ましくは40μm以下、より好ましくは30μm以下であるのがよい。
<13> 上記<1>~<12>のいずれにおいて、生体適合性材料が、人工骨材料、骨内固定器具材料、歯科用インプラント材料、歯科矯正用アンカースクリュー材料、髄内釘材料、及び椎体間固定材料からなる群から選ばれる1種であるのがよい。
(A)生体適合性基体を準備する工程;
(B)生体適合性基体の表面を親水化する工程;及び
(C)前記生体適合性基体の表面上に金属膜を形成する工程;
を有することにより、表面が親水性である生体適合性基体;及び前記基体の表面に備えられる金属膜;を有する生体適合性材料を製造する、上記方法。
(C1)金属膜前駆体を有してなるスパッタターゲットを準備する工程;及び
(C2)前記スパッタターゲットを用いて、前記(B)工程で得られた生体適合性基体上に、スパッタリングにより金属膜を形成する工程;
を有するのがよい。
前記(C2)工程が、(C2a)前記スパッタターゲットを用いて、前記(B)工程で得られた生体適合性基体の温度を130℃以下、好ましくは90℃以下、より好ましくは60℃以下として、スパッタリングにより前記生体適合性基体にマグネシウム及び任意にカルシウムを有してなり、マグネシウムとカルシウムとの合計の重量を100重量%とすると、カルシウムが0~40重量%有する金属膜を形成する工程である、のがよい。
<18> 上記<14>~<17>のいずれかにおいて、(B)工程が、イオン照射であり、イオン照射電力積で0.4W・min/cm2以上、好ましくは0.8W・min/cm2以上、より好ましくは2.5W・min/cm2以上、さらに好ましくは5W・min/cm2以上、最も好ましくは5~32W・min/cm2であるのがよい。
<19> 上記<14>~<18>のいずれかにおいて、(B)工程後であって(C)工程前に、(D)生体適合性基体の表面をイオンクリーニングする工程;をさらに有するのがよい。
具体的には、本発明により、親水性を有する基体を保護膜、具体的には金属膜で保護し、生体適合性材料を生体環境下で使用する際には該保護膜、具体的には該金属膜を溶解させ、保護された親水性を有する基体を親水性を保持したままで使用することができる生体適合性材料を提供することができる。
また、本発明により、上記効果の他に、又は上記効果に加えて、上記生体適合性材料の製造方法を提供することができる。
本願は、表面が親水性である生体適合性基体;及び
該基体の表面に備えられる金属膜であって所定の液に溶解する溶解特性を有する金属膜;を有する、生体適合性材料を提供する。
また、本願は、該生体適合性材料の製造方法を提供する。
本願は、表面が親水性である生体適合性基体;及び
該基体の表面に備えられる金属膜であって、体液または擬似体液で溶解する溶解特性を有する金属膜;を有する、生体適合性材料を提供する。
なお、本願において「生体適合性」とは、生体内に保持して生体安全上問題ないとされている特性をいう。
本発明の生体適合性材料は、生体適合性基体を有する。
該生体適合性基体は、その表面が親水性であり、該親水性は、水滴接触角が90°以下、好ましくは50°以下、より好ましくは30°以下、最も好ましくは20°以下であるのがよい。
なお、水滴接触角は、従来公知の方法で測定することができ、例えば、液滴を試料表面に滴下し、試料面と液滴とがなす角を測定するθ/2法により測定することができる。より具体的には、液滴が試料面に接触した後、30秒後に測定することができる。
表面粗さRaは、従来公知の方法により測定することができ、例えばJIS B0601:2013に準拠して測定することができる。同規格ではRa値の区分に応じて基準長さ及び評価長さが定められている。例えば、0.1<Ra(μm)≦2の基準長さ及び評価長さはそれぞれ0.8mm及び2.0mmである。スタイラスと測定物との干渉によって基準長さを連続的に測定できない場合には、対象物のRa値よりも低い区分の基準長さを使用し、トータルして評価長さ以上となる回数を測定し、その平均値をRaとすることができる。
本発明の生体適合性材料は、生体適合性基体の表面に金属膜を有する。
金属膜は、体液または擬似体液で溶解する溶解特性を有する。
本発明の金属膜は、生体適合性材料を体液または擬似体液に接触させると、生体適合性基体と該金属膜が一体化しておらず該金属膜が溶解し、表面が親水性である生体適合性基体が露出するのがよい。
ここで、体液として、血液、リンパ液、骨髄液、及び組織液などを挙げることができるがこれらに限定されない。また、疑似体液として、生理食塩水、リン酸緩衝生理食塩水(PBS)、ハンクス平衡塩溶液(HBSS)、SBF溶液、血漿液、細胞培養液、Eagle(MEM)溶液、DMEM溶液、及び血清培地などを挙げることができるがこれらに限定されない。
なお、本発明の金属膜は、生体適合性材料を使用する前、好ましくは使用直前に、体液または擬似体液に接触させて該金属膜が溶解し、表面が親水性である生体適合性基体が露出させることによっても、生体組織への高い接着性を発揮することができる。
ハンクス平衡塩溶液は、「Ca及びMg」の含有・不含、「フェノールレッド」の含有・不含により、4種存在するが、このうち、フェノールレッド不含であるのがよく、好ましくはフェノールレッド不含・「Ca及びMg」不含であるのがよい。
i)保護膜から溶解する物質の濃度が浸漬時間によりほぼ一定になる時間が、浸漬後、0.3秒以上、好ましくは0.5~20秒、より好ましくは0.5~10秒である;
ii)前記保護膜2mgがほぼ溶解する時間が、浸漬後0.5秒以上、好ましくは1~60秒、より好ましくは1~30秒である。
なお、「保護膜から溶解する物質」は、保護膜の成分に依存する。また、「ほぼ溶解する」とは、表面の90%以上で基体が露出していることを意味する。ここで、膜と基体の判別が容易な場合は外観写真から露出率を評価でき、膜と基体の判別が困難な場合はEDXなどを用いた分析で評価できる。
iii)ハンクス平衡塩溶液40mlに浸漬したとき、保護膜から溶解する物質の濃度が浸漬時間によりほぼ一定になる時間が、浸漬後、0.5時間以上、好ましくは1~72時間、より好ましくは2~48時間である;
iv)ハンクス平衡塩溶液400mlに浸漬したとき、前記保護膜2mgがほぼ溶解する時間が、浸漬後1時間以上、好ましくは2~672時間、より好ましくは3~336時間、最も好ましくは4~168時間である。
なお、「金属膜から溶解する物質」及び「ほぼ溶解する」という語句については、上記した定義と同じである。
また、金属膜は、B、C、N及びPからなる群から選ばれる種をさらに有してもよい。なお、金属膜が合金からなる場合、該合金がB、C、N及びPからなる群から選ばれる種をさらに有してもよい。
スパッタリングにより製造する場合は、ターゲット製造の容易さより、カルシウムが35重量%以内であることが好ましい。
また、この場合、金属膜は、Mg2Caフリーであるのがよい。ここで、「Mg2Caフリー」とは、X線回折分析において、Mg2Caに基づくピークが観察されない程度であることを意味し、好ましくは基体とMg2Caとの結晶それぞれから生じる回折ピークが重ならない(コバルト(Co)管球を用いたX線分析でそれぞれの回折ピークが1°以上離れている)回折角でMg2Caに基づくピークが観察されない、例えば、Co管球を用いたX線分析で36~37°の範囲にピークが観察されないのが良い。
金属膜は、非晶質部分を有するのがよい。ここで、「非晶質」とは、X線回折分析において、シャープなピークが観察されないことをいう。
本願の生体適合性材料は、上述の生体適合性基体;及び上述の金属膜;を有するが、それ以外の層を有してもよい。
例えば、生体適合性基体と金属膜との間に1つ又は複数の親水化を目的とした層を有してもよい。該層として、例えばチタンあるいはチタン合金に対する陽極酸化処理層、水熱処理層等を挙げることができるがこれらに限定されない。また、上述の膜の上部、すなわち基体とは反対側に1つ又は複数の層を有してもよい。
本願は、上述した生体適合性材料の製造方法を提供する。
該方法は、
(A)生体適合性基体を準備する工程;
(B)生体適合性基体の表面を親水化する工程;及び
(C)前記生体適合性基体の表面上に金属膜を形成する工程;
を有し、これらの工程により、表面が親水性である生体適合性基体;及び前記基体の表面に備えられる金属膜;を有する生体適合性材料を製造することができる。
なお、ここで、「生体適合性基体」は上述したものを用いることができる。
また、「金属膜」は、親水性の基体を保護する膜であれば限定されないが、上述したものであるのが好ましい。
(B)工程は、酸処理、ブラスト処理、陽極酸化、水熱処理、紫外線照射、プラズマ照射、レーザー照射、放射線照射、及びイオン照射からなる群から選ばれる少なくとも1種であるのがよい。
特に、(B)工程は、イオン照射であるのが好ましい。この場合、イオン照射電力積で0.4W・min/cm2以上、好ましくは0.8W・min/cm2以上、より好ましくは2.5W・min/cm2以上、さらに好ましくは5W・min/cm2以上、最も好ましくは5~32W・min/cm2であるのがよい。
親水化した表面の親水性を保持させつつ金属膜が形成されるのであれば、(C)工程は特に限定されない。
(C1)金属膜前駆体を有してなるスパッタターゲットを準備する工程;及び
(C2)前記スパッタターゲットを用いて、前記(B)工程で得られた生体適合性基体上に、スパッタリングにより金属膜を形成する工程;
を有するのがよい。
(C2)工程が、(C2a)該スパッタターゲットを用いて、(B)工程で得られた生体適合性基体の温度を130℃以下、好ましくは90℃以下、より好ましくは60℃以下として、スパッタリングにより生体適合性基体の表面にマグネシウム及び任意にカルシウムを有してなり、マグネシウムとカルシウムとの合計の重量を100重量%とすると、カルシウムが0~40重量%有する金属膜を形成する工程である、のがよい。
マグネトロンスパッタ装置は、ターゲットの後方に強力な磁石(マグネトロン)を配置し、アルゴンイオンをターゲットに衝突さえることで発生させたスパッタ粒子(金属粒子)を、磁場を利用して基体に効率よく堆積させることができる。このとき、スパッタ電圧、基体のバイアス、装置内の圧力、さらに基体材の温度を調整することで、目的とする膜を一定の成膜速度で形成することができる。
純マグネシウムの耐力は、一般に約90~100MPaといわれているので、せん断降伏強さはおよそ50MPaとなる。少なくともこの値以下に上記の熱応力を抑えるためには、温度差を100度以下にするのがよい。例えば使用温度を体温として36℃とすると、成膜温度は130℃以下で行うのがよく、2倍の安全率90℃以下、また約3倍の安全率を考慮すると60℃以下で成膜することが好ましい。
また、例えば、基体と金属膜との間に層を設ける場合、該層を設ける工程を(B)工程後(C)工程前に設けるのがよい。
以下、本発明について、実施例を用いて具体的に説明するが、本発明は該実施例によってのみ限定されるものではない。
インプラントを想定した基体材料として、片平面において一般的な研削加工を施した、厚さ3mm×10mm×10mmの平滑プレート状のジルコニアA-F、A-F2、並びに表面にミクロな格子状の溝を形成することで表面を粗面化した、粗面プレート状のジルコニアA-Rを用いた。なお、形成された金属膜の特性の詳細を調べるために厚さ1.2mm×26mm×76mmのガラス基体Bも用いた。
親水性面を形成するため、真空チャンバ内におけるイオン照射を用いた。イオン照射のプロセスは、まず、所定の値まで減圧し、チャンバ内の有害ガスを取り除いた後、アルゴンガスを封入した。放電に必要な電圧および基体バイアスを適度に調整することによって、イオン照射の電力積(電力W×時間(min)/断面積(cm2))として、0(未処理)、0.495、0.99、2.8又は5.36W・min/cm2の5種類の条件で実施した。
イオン照射に引き続き、同真空チャンバ内でスパッタリングを実施した。スパッタターゲットには、純マグネシウム、および純マグネシウムと純カルシウムを所定の割合で溶解して製造した4種類のインゴットを、機械加工して直径が約120mmのディスク形状に加工したものを用いた。インゴットの3種類は、カルシウム量を0重量%(Mg)、10重量%(Mg10%Ca)、20重量%(Mg20%Ca)又は30重量%(Mg30%Ca)としたものであり、残りの量はマグネシウムであった。ここで、カルシウム量の%は、カルシウム重量とマグネシウム重量との合計を100重量%としたときのカルシウム重量の割合であり、以下の重量%で表される。
カルシウム重量%=カルシウム重量/(マグネシウム重量+カルシウム重量)×100。
なお、Mg10%Caなどと同様に、純マグネシウムと純カルシウムを用いて、カルシウム量を40重量%(Mg40%Ca)又は50重量%(Mg50%Ca)とするターゲットを試作したが、溶製時あるいは機械加工時にクラックが生じて部分的に破損したため、使用できなかった。
基体の温度を室温のままとし、アルゴンの圧力は1~10 mTorrで行い、スパッタ電圧及び基体のバイアスを調整して成膜プロセス(デポジション)時間を調整し、平滑プレートA-F、粗面プレートA-R及びガラス基体Bを同一チャンバ内に設定して実施した。また、平滑プレートA-F2もガラス基体Bを同一チャンバ内に設置して実施された。
表2に、電力積0.99W・min/cm2でイオン照射を施した後、スパッタリングにより、マグネシウムのみ(Mg)、カルシウム量をそれぞれ20重量%(Mg20%Ca)及び30重量%(Mg30%Ca)としたターゲットを用いてそれぞれ得られた、マグネシウムのみの膜(Mg膜)、カルシウム量を20重量%とした膜(Mg20%Ca膜)及びカルシウム量を30重量%とした膜(Mg30%Ca膜)の厚さと重量を示す。得られた膜の厚さは、各基体と同一チャンバ内で処理をしたガラス基体Bにスパッタリングしたサンプルを用いて次のように測定した。すなわち、基体上の成膜した部分と上述のマスキングを施して成膜させない部分との段差を、触針法により実測することにより膜の厚さを測定した。また、膜の重量は、各膜をスパッタリングした後のサンプル重量からスパッタリングする前の基体A-F、A-RあるいはA-F2の重量を差し引いて計算した。
図1は、ガラス基体Bに電力積0.99W・min/cm2でイオン照射を施した後、スパッタリングにより、マグネシウムのみ(Mg)、カルシウム量をそれぞれ10重量%(Mg10%Ca)、20重量%(Mg20%Ca)及び30重量%(Mg30%Ca)としたターゲットを用いてそれぞれ得られた、マグネシウムのみの膜(Mg膜)、カルシウム量を10重量%とした膜(Mg10%Ca膜)、カルシウム量を20重量%とした膜(Mg20%Ca膜)及びカルシウム量を30重量%とした膜(Mg30%Ca膜)のX線回折プロファイルである。
これらの結果より、Mg膜は結晶質であり、Mg10%Ca膜は結晶性の低い結晶質であり、Mg20%Ca膜は微結晶と非晶質の混合組織であり、Mg30%Ca膜は非晶質であることがわかった。一般的にマグネシウムに対するカルシウムの添加量が0.8重量%を越えるとカルシウムはマグネシウムに固溶せずにMg2Caが析出する。しかし、いずれの膜においてもMg2Caなどの金属間化合物の存在は認められなかった。また、図示しないが、イオン照射強度の違いによって検出された膜構造に違いは認められなかった。
基材又は膜の上に約5μlの純水を滴下し、表面張力によって水滴が丸く盛り上がった程度を滴下面に対して垂直な方向からCCDカメラで撮影した。液面と固体面とのなす水滴接触角として、一般的なθ/2法を用いて、液滴の左右端点と液滴頂点とを結ぶ直線と、固体表面のなす角度を求め、それを2倍することで算出した。また、基材の研磨方向に沿って水滴が拡がる傾向があったため、基材の研磨方向と平行な方向から接触角を測定した場合と、基材の研磨方向と垂直な方向からそれを測定した場合の2方向から測定し、それらを平均した値を水滴接触角とした。
さらに、平滑プレート状のジルコニアA-F、粗面プレート状のジルコニアA-Rについて、電力積0.495、0.99、5.36Wmin/cm2でイオン照射による親水化処理を施した後スパッタリングにより、Mg30%Ca膜を被覆して保護し2か月間経過した後、上述した工程でそれらの金属膜を除去した直後の水滴接触角を示す。
図3に、平滑プレート状のジルコニアA-F、電力積0.99Wmin/cm2でイオン照射を施した後にスパッタリングにより、Mg30%Ca膜を被覆直後から1週間以内、被覆後1か月間、2か月間及び4か月間で保管した後、上述した工程でそれらの金属膜を除去した直後の水滴接触角を示す。
また、図3に、粗面プレート状のジルコニアA-R、電力積0.99W・min/cm2でイオン照射を施した後にスパッタリングにより、Mg30%Ca膜を被覆直後から1週間以内、被覆後1か月間、2か月間及び4か月間大気中で保管した後、上述した工程でそれらの金属膜を除去した直後の水滴接触角を示す。
例えば歯科インプラント材料などにおいて、スクリュー部のゆるみを防ぐためには骨と歯科インプラント材料とを直接接合することが重要であるが、それにはスクリュー部材料表面の親水性を向上させることが効果的である。また、アバットメント部における周囲炎を防ぐためには細菌を付着させないことが重要であるが、それにはアバットメント部材料表面の親水性を低下させる必要がある。
したがって、親水性面の保護は、金属膜の種類によらずなされることがわかる。
また、結晶質であるMg膜(マグネシウムのみの被膜)で保護した場合と比べて、非晶質構造を有すMg20%Ca膜及びMg30%Ca膜による保護の場合の方が、保護性能が若干優れている。
したがって、非晶質構造を有す金属膜を用いることでより優れた保護性能を発揮できる。
したがって、金属膜を被覆することによって、特殊な保管容器を使用せずに大気中で長期間そのまま保管することが可能である。
平滑プレート状のジルコニアA-F2に電力積0.99W・min/cm2でイオン照射を施した後にスパッタリングにより、Mg膜、Mg20%Ca膜及びMg30%Ca膜をつけたサンプルに対して、擬似体液中における溶解速度試験を行った。ここで、サンプルの上面と側面にスパッタリング膜がついており、下面にはついていない。
疑似体液の容量は40mlあるいは400mlを用いた。
したがって、表面粗さの影響を無視した見かけ上の表面積を220mm2とすると、被膜が溶液と接触する単位面積当たりの疑似体液容量は、それぞれ0.182ml/mm2あるいは0.0182ml/mm2である。
溶解速度は、ガラス電極法を用いたpH測定から評価した。pH測定には、卓上型pH試験機(HORIBA、F-74)、GRT複合電極(9615S-10D、HORIBA)を用いた。
また、膜厚5.28μm、総断面積220mm2とした場合のMg膜、Mg20%Ca膜及びMg30%Ca膜におけるマグネシウムおよびカルシウム成分の単位体積当たりの物質量mol/cm3の計算値を表5に示す。
図5に、Mg膜をつけた平滑ジルコニアA-F2に対するHBSS(-)浸漬前、浸漬6時間、24時間及び168時間後にそれぞれ取り出した後のXRD測定結果を示す。
浸漬時間と膜厚との関係を指数関数で近似すると、浸漬時間に伴う膜厚変化が次の式でおおよそ予測できる。
また、表7に、図6から得られた同定結果を示す。浸漬6時間後に取り出したサンプルでは、金属色の層、黒色あるいは白色の層で覆われており、基板の研磨キズが観察できる部分はほとんどなく、生体適合性の基体の表面は露出していなかった。浸漬24時間後に取り出したサンプルでは、金属色の層はほとんどなく、基板の研磨キズが観察できる部分が増え、生体適合性の基体表面の露出部分が増加した。さらに、浸漬168時間後のサンプルでは、全面が基板の研磨キズが観察でき、全面において生体適合性の基体の表面が露出していた。
例えば、歯科インプラントを顎骨に埋植した後、十分な骨接合が生じるまでの期間は義歯をつけた咬合ができない。そのため、歯科インプラントを早期に骨接合させることが求められている。図4、表5から、疑似体液に浸漬した後、浸漬直後に金属膜がイオン化することによって急激にpH変化が生じ、24時間後には最大でpH9.5以上になることがわかる。
したがって、骨内に埋植した後、早期に膜の溶解が生じることがわかる。
図6及び表7から、浸漬6時間後の時点ではまだほとんど基板は露出していないが、それ以降で徐々に基板が露出し、少なくとも浸漬168時間以内には、全ての面で基板が露出したことがわかる。
したがって、金属膜によって親水性面を保護された歯科インプラントを埋植した後、早期に膜が溶解し、活性化面を露出することで、早期骨接合を促すことが可能である。
平滑プレート状のジルコニアA-F及び粗面プレート状のジルコニアA-Rに電力積0.495、0.99及び5.36W・min/cm2でイオン照射を施した後にスパッタリングにより、Mg30%Ca膜をつけたそれぞれのサンプルに対して、擬似体液をもちいたin vitroの生体反応試験を行った。
擬似体液には、カルシウムおよびマグネシウムの含有されたハンクス平衡塩溶液(HBSS(+)溶液)を用いた。また、溶液中の平衡pHを生体内環境に近づけるため、スパッタリング膜溶出後の平衡pHが8.0以下となるようにHBSS(+)の溶液量を調整した。比較のためにイオン照射及びスパッタリングを施していない基体について、HBSS(+)及びMg30%Ca膜溶出後のHBSS(+)の2種類の溶液に浸漬した試験をおこなった。
擬似体液浸漬試験として、擬似体液500mlに各試料を浸漬させ、37℃の恒温槽中で1週間保持した後、サンプルを溶液から取り出した。
電力積0.495及び0.99の別のサンプルを3週間HBSS(+)に浸漬して取り出したところ、金属膜残存は認められなかった。一方、基材が露出したままHApで覆われなかった部分の面積分率は1週間HBSS(+)に浸漬した際のそれと同程度認められた。
また、イオン照射後スパッタリングを施していない基体については、HBSS(+)及び金属膜溶出後のHBSS(+)の2種類の溶液浸漬のいずれもHApの形成は認められなかった。
例えば、歯科インプラント材料表面に生体内で骨アパタイトが形成されると、骨アパタイトを介して骨接合がなされ、歯科インプラントを強固に骨接合させることができる。
図7から、イオン照射後に金属膜によって親水性面が保たれているジルコニアではアパタイトが全面に旺盛に形成されたが、イオン照射後に金属膜によって親水性が保たれなかったジルコニアではアパタイトが全く形成されなかった。
表8から、イオン照射電力積による親水化強度が異なる場合、金属膜によって親水性が保たれているサンプルの中でもHAp被覆率が異なることがわかった。さらに、より高い親水性を示すサンプルほど高いHAp被覆率を示す。親水化によって活性化された表面は、エネルギーが高い状態にある。親水性面が溶液内で露出されたジルコニアではアパタイトが形成され、親水化されていないジルコニアではアパタイトが形成されなかったことから、エネルギー状態の高い活性化表面が溶液内で露出することで、アパタイトの核が多量に形成され、全面に旺盛なアパタイトが形成されたと考えられる。
したがって、高い親水性を示す親水化処理を施し、金属膜によってその親水性面を保護された歯科インプラントを使用することで、生体内で自発的に活性化面が露出し、アパタイト形成を全面に促し、早期に骨形成させることが可能である。
Claims (19)
- 表面が親水性である生体適合性基体;及び
前記基体の表面に備えられる金属膜であって、体液または擬似体液で溶解する溶解特性を有する金属膜;
を有する、生体適合性材料。 - 前記生体適合性材料を体液または擬似体液に接触させると前記金属膜が溶解し、表面が親水性である生体適合性基体が露出する請求項1に記載の生体適合性材料。
- 前記体液が、血液、リンパ液、骨髄液、及び組織液からなる群から選ばれる少なくとも1種であり、前記疑似体液が生理食塩水、リン酸緩衝生理食塩水(PBS)、ハンクス平衡塩溶液(HBSS)、SBF溶液、血漿液、細胞培養液、Eagle(MEM)溶液、DMEM溶液、及び血清培地から選ばれた少なくとも1種である請求項1に記載の生体適合性材料。
- 前記擬似体液が、ハンクス平衡塩溶液である請求項1に記載の生体適合性材料。
- 前記親水性は、水滴接触角が90°以下である請求項1に記載の材料。
- 前記金属膜が、Mg、Ca、Zn及びFeからなる群から選ばれる少なくとも1種の金属を有してなる請求項1に記載の材料。
- 前記金属膜がマグネシウム及び任意にカルシウムを有してなり、マグネシウムとカルシウムとの合計の重量を100重量%とすると、カルシウムが0~40重量%有する請求項1に記載の材料。
- 前記金属膜がMg2Caフリーである請求項7に記載の材料。
- 前記金属膜が非晶質部分を有する請求項1に記載の材料。
- 前記基体が、純チタニウム、コバルトクロム合金、ステンレス鋼及びチタン合金、ジルコニア、アルミナ、リン酸カルシウム及びマグネシアからなる群から選ばれる少なくとも1種である請求項1に記載の材料。
- 前記基体の表面粗さRaが、50μm以下である請求項1に記載の材料。
- 前記生体適合性材料の形状が、円柱状、円筒状、円錐台状及び円錐状、並びに該形状の一部にスクリュー状のねじ部を備えた形状、直方体及び立方体、並びに一部傾斜面を有するブロック形状、及びくさび形状からなる群から選ばれる1種である請求項1に記載の材料。
- 前記生体適合性材料が、人工骨材料、骨内固定器具材料、歯科用インプラント材料、歯科矯正用アンカースクリュー材料、髄内釘材料、及び椎体間固定材料からなる群から選ばれる1種である請求項1に記載の材料。
- 生体適合性材料の製造方法であって、
(A)生体適合性基体を準備する工程;
(B)生体適合性基体の表面を親水化する工程;及び
(C)前記生体適合性基体の表面上に金属膜を形成する工程;
を有することにより、表面が親水性である生体適合性基体;及び前記基体の表面に備えられる金属膜;を有する生体適合性材料を製造する、上記方法。 - 前記(C)工程が、
(C1)金属膜前駆体を有してなるスパッタターゲットを準備する工程;及び
(C2)前記スパッタターゲットを用いて、前記(B)工程で得られた生体適合性基体上に、スパッタリングにより金属膜を形成する工程;
を有する請求項14に記載の方法。 - 前記(C1)工程が、(C1a)マグネシウム及び任意にカルシウムを有してなるスパッタターゲットを準備する工程であり、
前記(C2)工程が、(C2a)前記スパッタターゲットを用いて、前記(B)工程で得られた生体適合性基体の温度を130℃以下として、スパッタリングにより前記生体適合性基体にマグネシウム及び任意にカルシウムを有してなり、マグネシウムとカルシウムとの合計の重量を100重量%とすると、カルシウムが0~40重量%有する金属膜を形成する工程である、請求項15に記載の方法。 - 前記(B)工程が、酸処理、ブラスト処理、陽極酸化、水熱処理、紫外線照射、プラズマ照射、レーザー照射、放射線照射、及びイオン照射からなる群から選ばれる少なくとも1種である請求項14に記載の方法。
- 前記(B)工程が、イオン照射であり、イオン照射電力積で0.4W・min/cm2以上である請求項14に記載の方法。
- 前記(B)工程後であって前記(C)工程前に、(D)生体適合性基体の表面をイオンクリーニングする工程;をさらに有する請求項14に記載の方法。
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