US20020035402A1 - Osteoinductive ceramic materials - Google Patents
Osteoinductive ceramic materials Download PDFInfo
- Publication number
- US20020035402A1 US20020035402A1 US09/999,029 US99902901A US2002035402A1 US 20020035402 A1 US20020035402 A1 US 20020035402A1 US 99902901 A US99902901 A US 99902901A US 2002035402 A1 US2002035402 A1 US 2002035402A1
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- US
- United States
- Prior art keywords
- ceramic material
- osteoinductive biomaterial
- osteoinductive
- acid
- biomaterial
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 230000002138 osteoinductive effect Effects 0.000 title claims abstract description 38
- 229910010293 ceramic material Inorganic materials 0.000 title claims abstract description 34
- 239000012620 biological material Substances 0.000 claims abstract description 33
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- 239000000463 material Substances 0.000 claims description 36
- 239000007943 implant Substances 0.000 claims description 32
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- 239000002253 acid Substances 0.000 claims description 19
- 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 18
- 210000000988 bone and bone Anatomy 0.000 claims description 17
- 238000005245 sintering Methods 0.000 claims description 17
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 15
- 230000011164 ossification Effects 0.000 claims description 15
- 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 claims description 15
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 4
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- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 2
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
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- LCSKNASZPVZHEG-UHFFFAOYSA-N 3,6-dimethyl-1,4-dioxane-2,5-dione;1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1.CC1OC(=O)C(C)OC1=O LCSKNASZPVZHEG-UHFFFAOYSA-N 0.000 description 1
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 description 1
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- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C11/00—Multi-cellular glass ; Porous or hollow glass or glass particles
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C14/00—Glass compositions containing a non-glass component, e.g. compositions containing fibres, filaments, whiskers, platelets, or the like, dispersed in a glass matrix
- C03C14/004—Glass compositions containing a non-glass component, e.g. compositions containing fibres, filaments, whiskers, platelets, or the like, dispersed in a glass matrix the non-glass component being in the form of particles or flakes
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C4/00—Compositions for glass with special properties
- C03C4/0007—Compositions for glass with special properties for biologically-compatible glass
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
- C04B38/0051—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof characterised by the pore size, pore shape or kind of porosity
- C04B38/0064—Multimodal pore size distribution
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
- C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
- C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/924—Material characteristic
- Y10S623/926—Synthetic
Definitions
- the invention relates to an osteoinductive material and to a process for preparing said material.
- Calcium phosphates such as hydroxyapatite are known to be osteoconductive, or bioactive. This means that they-act as a template along which bone growth can occur. Further, bone formation can directly take place at the surface of the material, and a strong bond is obtained with bone tissue. Osteoinductivity, on the other hand, is regarded as a property of materials that induce the formation of bone tissue. In the past, this property has only been described in connection with materials that contain osteoinductive, proteinaceous factors such as bone morphogenetic proteins (BMP's).
- BMP's bone morphogenetic proteins
- the present invention aims to provide a material having an improved osteoinductivity. It is an object of the invention to provide a material that is suitable to be used as an implant in living organisms and to function as a (temporary) substitute for bone tissue. Thus, the material should be both biocompatible and biodegradable.
- the invention relates to an osteoinductive biomaterial, which is based on a ceramic material and which has a total porosity of 20 to 90%, wherein macropores are present having a size ranging from 0.1 to 1.5 mm, and wherein micropores are present having a size ranging from 0.05 to 20 ⁇ m.
- the material of the invention shows excellent osteoinductive behaviour in living tissue.
- the formation of bone tissue at the surface of the material of the invention assists in a favourable acceptation of an implant made of said material.
- the formation of the bone tissue accelerates the recovery of any damage in the bone structure, which forms the reason for applying the implant.
- An osteoinductive biomaterial according to the invention is based on a ceramic material.
- the biomaterial may for instance be a medical implant formed of a ceramic material. It is also possible that the biomaterial is a medical implant of a different material, such as a metal or a polymeric material, on which the ceramic material is present in the form of a coating.
- Another possibility is described by M. L. Gaillard and C. A. van Blitterswijk in J. Mater. Sci., Materials in Medicine, 5:695-701 (1994). This possibility concerns a copolymer having hydrogel-like properties, which may be calcified in the presence of calcium and phosphate ions.
- any ceramic material that is both sufficiently biocompatible and sufficiently biodegradable to be used as an implant in living tissue can be used.
- the ceramic material is capable of providing a calcium phosphate surface, either in vitro or in vivo, which has the present specific surface structure. It is further preferred that the ceramic material is capable of adsorbing biologically active agents, such as growth factors (BMP's etc.), either in vitro or in vivo.
- Suitable examples of ceramic materials include calcium phosphates, glass ceramics and materials containing calcium phosphates and/or glass ceramics.
- the ceramic material is a calcium phosphate.
- Preferred calcium phosphates are octacalcium phosphate, apatites, such as hydroxyapatite and carbonate apatite, whitlockites, such as ⁇ -tricalcium phosphate and tricalcium phosphate, and combinations thereof.
- An important aspect of the invention is the physical structure of the osteoinductive biomaterial.
- the material comprises both macropores and micropores.
- the total porosity ranges from 20 to 90%, preferably from 40 to 70%.
- the macropores of the material have a size of from 0.1 to 1.5 mm. Preferably, the size of the macropores lies between 0.2 and 1 mm. It has been found that the indicated sizes of the macropores have a significant beneficial influence on the osteoinductive character of the material. Further preferred is that the macropores are interconnected.
- the micropores of the material have a size of from 0.05 to 20 ⁇ m.
- the micropores are at least located in the macropores.
- the formation of bone tissue is highly promoted.
- a preferred range for the size of the micropores is from 0.5 and 10 ⁇ m.
- the micropores are at least present in the surface of the macropores.
- the microporosity of the material's surface preferably lies between 40 and 60%.
- the biomaterial preferably consists of crystals.
- the size of the crystals is similar to the size of the micropores.
- the biomaterial has a preferable microrugosity.
- the size of the crystals lies preferably between 0.05 and 20 ⁇ m, more preferably between 0.5 and 10 ⁇ m.
- the osteoinductive biomaterial according to the invention may advantageously be used in applications where bone formation is desired.
- the material may be used for the manufacture of medical implants, particular implants for bone substitution.
- the material may further be used for the manufacture of a scaffold for tissue engineering a bone equivalent.
- the invention further relates to processes for preparing an osteoinductive biomaterial as described above.
- the osteoinductive biomaterial may be prepared by sintering a ceramic material under such conditions, that an osteoinductive biomatieral as described above is obtained.
- the ceramic material is, before the sintering, in a calcined state.
- the sintering is preferably performed at a temperature between 1000 and 1275° C., treated with an aqueous solution of an organic acid and washed to remove the acid.
- the sintering is carried out at a temperature between 1150 and 1250° C.
- the duration of the sintering step may suitably be chosen between 6 and 10 hours, preferably between 7 and 9 hours. It has further been found advantageous to perform the sintering while the ceramic material is submersed in a powder of the ceramic material. This beneficially affects the reactivity of the surface of the material, and consequently also the bioactivity (dissolution, re-precipitation).
- the material is preferably ground with sandpaper, such as Si—C sandpaper, to remove chemical surface impurities.
- the material is treated with an aqueous solution of an acid.
- Suitable acids in this regard are any etching acids, i.e. any acids which lead to a slight dissolution of the calcium phosphate based material.
- the use of the following acids has been found to lead to extremely favourable results: maleic acid, hydrochloric acid, phosphoric acid, and combinations thereof.
- the concentration of the acid in the solution is preferably chosen such that the pH of the solution lies between 0 and 4, more preferably between 1 and 3.
- the ceramic material is washed to remove the acid.
- the washing may suitably be performed using ethanol, water or a combination thereof.
- osteoinductive biomaterial it is preferred to subject the obtained osteoinductive biomaterial to a sterilisation treatment, such as a steam sterilisation.
- a slurry of a powder of the ceramic material in an aqueous solution of a negative replica forming agent which during sintering burns or evaporates, is sintered under such conditions that an osteoinductive biomaterial as described above is obtained.
- Suitable negative replica forming agents include hydrogen peroxide, baking powder or bicarbonate. Preferably, hydrogen peroxide is used.
- the powder is added to an aqueous solution of the negative replica forming agent to form a slurry.
- concentration of the negative replica forming agent in the slurry preferably lies between 0.5 and 15 wt. %, more preferably between 1 and 5 wt. %, based on the weight of the solution.
- the powder is added in a ratio of between 0.5 to 5, preferably 1 to 3 grams per 1 millilitre of the solution.
- the slurry may then be cast in a mould having a desired shape and size and sintered.
- the sintering is preferably carried out at a temperature between 800 and 1300° C., more preferably between 1000 and 1200° C. for a period of up to 12 hours. Care should be taken that the sintering period is not so long that a dense material is obtained.
- HA hydroxyapatite
- FIG. 1 A: HA sintered at 1300° C. (FIG. 1)
- FIGS. 1 - 4 are 2500 ⁇ enlarged; FIGS. 5 and 6 are 81.5 ⁇ enlarged.
- HA1250 1250° C.
- HA1300 1300° C.
- the HA1300 was prepared by a subsequent sintering of HA1250 blocks, for 8 hours at 1300° C. (the temperature was raised from room temperature by 100° C. per hour, kept constant for 8 hours, and lowered by 100° C. per hour to room temperature), while submersed in HA powder to obtain a surface reactive layer.
- HA1300 contained approximately 10-12% by weight of ⁇ -tricalcium phosphate.
- the implants were excises. Six implants of each material type were placed in Karnovsky's fixative for at least one week (4° C.), while the seventh implant was stored at ⁇ 70° C. for biochemical analysis. The fixed implants were subsequently dehydrated through a series of ethanol and embedded in Methyl Methacrylate. Semithin sections were cut on a modified innerlock diamond saw, perpendicular to the longitudinal plane of the implants, and examined by light microscopy for de novo bone formation.
- a 2.0 M solution (A) of calcium nitrate tetra-hydrate (AR) in distilled water (AD) was prepared.
- a 2.0 M second solution (B) was prepared of diammonium hydrogen phosphate (AR) was prepared in distilled water (AD). Under stirring and adjusting the pH just over 8.0 using ammonia (AR), the second solution (B) was slowly added to the first solution (A) in a ratio of 1.63:1 (vol/vol).
- the obtained mixed solution was kept overnight in a cupboard at ambient temperature. The next day, the pH of the solution was adjusted to over 10.00 using ammonia. The solution was left to age at ambient temperature.
- the BCP powder was mixed with a 3.0% aqueous hydrogen peroxide solution at a ratio of 1 gram powder in 1 ml solution.
- the resulting slurry was poured into a mould consisting of a plastic container (diameter 38 mm, height 60 mm). The mould was placed in an oven at 60° C. for foaming and drying. Next, the dry porous blocks were carefully removed from the container and sintered at 1100° C. for 10 hours (the temperature was raised from room temperature to 1100° C. in 10 hours, and after sintering, the temperature was decreased to room temperature in the same time frame.)
- BCP biphasic calcium phosphate
- BCP blocks machined from BCP ceramic body as obtained above were polished into cylinders (5 mm diameter, 6 mm length).
- the implants were ultrasonically washed with 70% ethanol for 15 minutes, with demineralised water twice (15 minutes each), dried at 50° C., and then steam sterilised (121° C.) for 30 minutes before implantation.
- the surgical procedure was performed under general anaesthesia (30 mg pentobarbital sodium/kg body weight) and under sterile conditions. After shaving, the skin was sterilised with iodine and 70% ethanol. With a scalpel, a longitudinal incision was made in the skin. By a blunt separation, the thigh muscle was disposed. Again, with a scalpel, a small longitudinal incision was made in the thigh muscle and a muscle pouch was obtained by blunt separation. One BCP cylinder was inserted into the muscle pouch (one BCP implant was implanted in each dog). The surgical procedure was finished by suturing the muscle pouch and skin in layers with silk thread. The animals were intramuscularly injected with 1.6 million units penicillin 3 times in 3 days.
- Soft tissue implantation (both intramuscularly and subcutaneously) is the study model of osteoinduction.
- the bone formation in BCP ceramic followed intramuscular implantation showed that the tested BCP is osteoinductive.
- a mixture was prepared of SiO 2 (relative amount 29.4% in weight, AR, particle size 0.5-10 microns), NaHCO 3 (relative amount 34.1% in weight, AR), CaCO 3 (relative amount 28.6% in weight, AR) and Na 2 HPO 4 (relative amount 7.9% in weight, AR). This mixture was sintered for 10 hours at 1000° C. and for 2 hours at 1300° C. After cooling, a glass ceramic material was obtained.
- the glass ceramic was broken mechanically into small particles, which were subsequently ball-milled to a fine powder.
- the powder was sieved through a 200 mesh filter.
- the glass ceramic powder was mixed with a 3.0% aqueous hydrogen peroxide solution at a ratio of 2.4 gram powder in 1 ml solution.
- the resulting slurry was poured into a plastic container (diameter 38 mm, height 60 mm).
- the mould was placed in an oven at 50° C. for foaming and drying.
- the dry porous blocks were sintered at 800-1000° C. for 2 hours (the increase in temperature was 5° C./min.) . Eventually, the blocks were allowed to cool naturally in the oven.
Abstract
The invention relates to an osteoinductive biomaterial, which is based on a ceramic material and which has a total porosity of 20 to 90%, wherein macropores are present having a size ranging from 0.1 to 1.5 mm, and wherein micropores are present having a size ranging from 0.05 to 20 μm. The invention further relates to a process for preparing said osteoinductive biomaterial.
Description
- The invention relates to an osteoinductive material and to a process for preparing said material.
- Calcium phosphates such as hydroxyapatite are known to be osteoconductive, or bioactive. This means that they-act as a template along which bone growth can occur. Further, bone formation can directly take place at the surface of the material, and a strong bond is obtained with bone tissue. Osteoinductivity, on the other hand, is regarded as a property of materials that induce the formation of bone tissue. In the past, this property has only been described in connection with materials that contain osteoinductive, proteinaceous factors such as bone morphogenetic proteins (BMP's).
- Recently, however, several studies have been reported that indicate a possible osteoinductive capacity of calcium phosphates when implanted intramuscularly in dogs or baboons. Generally, it is assumed that the presence of a porous structure and a specific geometry of the implant plays a crucial role in the osteoinductive character of the implant.
- Yamasaki et al., in Biomaterials 1992, vol. 13, no. 5, 308-312, have described to have found heterotopic bone formation around porous hydroxyapatite ceramic granules, but not around dense granules. The porous granules had a size between 200 and 600 μm, and a continuous and interconnected microporosity ranging in diameter from 2 to 10 μm.
- The present invention aims to provide a material having an improved osteoinductivity. It is an object of the invention to provide a material that is suitable to be used as an implant in living organisms and to function as a (temporary) substitute for bone tissue. Thus, the material should be both biocompatible and biodegradable.
- Surprisingly, it has been found that this object is achieved by the provision of a ceramic material having both macropores and micropores of specific sizes. Hence, the invention relates to an osteoinductive biomaterial, which is based on a ceramic material and which has a total porosity of 20 to 90%, wherein macropores are present having a size ranging from 0.1 to 1.5 mm, and wherein micropores are present having a size ranging from 0.05 to 20 μm.
- The material of the invention shows excellent osteoinductive behaviour in living tissue. The formation of bone tissue at the surface of the material of the invention assists in a favourable acceptation of an implant made of said material. Moreover, the formation of the bone tissue accelerates the recovery of any damage in the bone structure, which forms the reason for applying the implant.
- An osteoinductive biomaterial according to the invention is based on a ceramic material. The biomaterial may for instance be a medical implant formed of a ceramic material. It is also possible that the biomaterial is a medical implant of a different material, such as a metal or a polymeric material, on which the ceramic material is present in the form of a coating. Another possibility is described by M. L. Gaillard and C. A. van Blitterswijk in J. Mater. Sci., Materials in Medicine, 5:695-701 (1994). This possibility concerns a copolymer having hydrogel-like properties, which may be calcified in the presence of calcium and phosphate ions.
- In principle, any ceramic material that is both sufficiently biocompatible and sufficiently biodegradable to be used as an implant in living tissue can be used. Preferably, the ceramic material is capable of providing a calcium phosphate surface, either in vitro or in vivo, which has the present specific surface structure. It is further preferred that the ceramic material is capable of adsorbing biologically active agents, such as growth factors (BMP's etc.), either in vitro or in vivo. Suitable examples of ceramic materials include calcium phosphates, glass ceramics and materials containing calcium phosphates and/or glass ceramics.
- Preferably, the ceramic material is a calcium phosphate. Preferred calcium phosphates are octacalcium phosphate, apatites, such as hydroxyapatite and carbonate apatite, whitlockites, such as α-tricalcium phosphate and tricalcium phosphate, and combinations thereof.
- An important aspect of the invention is the physical structure of the osteoinductive biomaterial. The material comprises both macropores and micropores. The total porosity ranges from 20 to 90%, preferably from 40 to 70%.
- The macropores of the material have a size of from 0.1 to 1.5 mm. Preferably, the size of the macropores lies between 0.2 and 1 mm. It has been found that the indicated sizes of the macropores have a significant beneficial influence on the osteoinductive character of the material. Further preferred is that the macropores are interconnected.
- The micropores of the material have a size of from 0.05 to 20 μm. Preferably, the micropores are at least located in the macropores. In accordance with this embodiment, the formation of bone tissue is highly promoted. A preferred range for the size of the micropores is from 0.5 and 10 μm. In a preferred embodiment, the micropores are at least present in the surface of the macropores. The microporosity of the material's surface preferably lies between 40 and 60%.
- In accordance with the invention, the biomaterial preferably consists of crystals. Preferably, the size of the crystals is similar to the size of the micropores. When this is the case, the biomaterial has a preferable microrugosity. Thus, the size of the crystals lies preferably between 0.05 and 20 μm, more preferably between 0.5 and 10 μm.
- The osteoinductive biomaterial according to the invention may advantageously be used in applications where bone formation is desired. Thus, the material may be used for the manufacture of medical implants, particular implants for bone substitution. The material may further be used for the manufacture of a scaffold for tissue engineering a bone equivalent.
- The invention further relates to processes for preparing an osteoinductive biomaterial as described above.
- In a first embodiment, the osteoinductive biomaterial may be prepared by sintering a ceramic material under such conditions, that an osteoinductive biomatieral as described above is obtained. The ceramic material is, before the sintering, in a calcined state. The sintering is preferably performed at a temperature between 1000 and 1275° C., treated with an aqueous solution of an organic acid and washed to remove the acid.
- Preferably, the sintering is carried out at a temperature between 1150 and 1250° C. The duration of the sintering step may suitably be chosen between 6 and 10 hours, preferably between 7 and 9 hours. It has further been found advantageous to perform the sintering while the ceramic material is submersed in a powder of the ceramic material. This beneficially affects the reactivity of the surface of the material, and consequently also the bioactivity (dissolution, re-precipitation).
- After the sintering, the material is preferably ground with sandpaper, such as Si—C sandpaper, to remove chemical surface impurities.
- Subsequently, the material is treated with an aqueous solution of an acid. Suitable acids in this regard are any etching acids, i.e. any acids which lead to a slight dissolution of the calcium phosphate based material. The use of the following acids has been found to lead to extremely favourable results: maleic acid, hydrochloric acid, phosphoric acid, and combinations thereof. The concentration of the acid in the solution is preferably chosen such that the pH of the solution lies between 0 and 4, more preferably between 1 and 3.
- After the acid treatment, which preferably lasts between 3 and 15 minutes, the ceramic material is washed to remove the acid. The washing may suitably be performed using ethanol, water or a combination thereof.
- Finally, it is preferred to subject the obtained osteoinductive biomaterial to a sterilisation treatment, such as a steam sterilisation.
- In a second embodiment, a slurry of a powder of the ceramic material in an aqueous solution of a negative replica forming agent, which during sintering burns or evaporates, is sintered under such conditions that an osteoinductive biomaterial as described above is obtained. Suitable negative replica forming agents include hydrogen peroxide, baking powder or bicarbonate. Preferably, hydrogen peroxide is used.
- Thus, first, the powder is added to an aqueous solution of the negative replica forming agent to form a slurry. The concentration of the negative replica forming agent in the slurry preferably lies between 0.5 and 15 wt. %, more preferably between 1 and 5 wt. %, based on the weight of the solution. The powder is added in a ratio of between 0.5 to 5, preferably 1 to 3 grams per 1 millilitre of the solution. The slurry may then be cast in a mould having a desired shape and size and sintered. The sintering is preferably carried out at a temperature between 800 and 1300° C., more preferably between 1000 and 1200° C. for a period of up to 12 hours. Care should be taken that the sintering period is not so long that a dense material is obtained.
- The invention will now be elucidated by the following, non-restrictive examples.
- Four different types of porous hydroxyapatite (HA) discs (approximately 6×6×2 mm in size) were prepared:
- A: HA sintered at 1300° C. (FIG. 1)
- B: HA sintered at 1250° C. (FIG. 2)
- C: HA sintered at 1300° C., and treated with acid (FIGS. 3 and 5)
- D: HA sintered at 1250° C., and treated with acid (FIGS. 4 and 6).
- FIGS.1-4 are 2500× enlarged; FIGS. 5 and 6 are 81.5× enlarged.
- Two types of porous calcium phosphate blocks (18×18×25 mm) were prepared by sintering hydroxyapatite at either 1250° C. (HA1250; white colour) or 1300° C. (HA1300; blue colour). The HA1300 was prepared by a subsequent sintering of HA1250 blocks, for 8 hours at 1300° C. (the temperature was raised from room temperature by 100° C. per hour, kept constant for 8 hours, and lowered by 100° C. per hour to room temperature), while submersed in HA powder to obtain a surface reactive layer. HA1300 contained approximately 10-12% by weight of β-tricalcium phosphate. The sides of all blocks were ground with #220 Si—C sandpaper to remove chemical surface impurities, and the blocks were cut in 4 parts of approximately 8×8×25 mm. A total of twenty, 2 mm thick sections were prepared from each material type. The corners of each material (HA1250 and HA1300) were placed in 2.5% maleic acid for 10 minutes. Subsequently, all sections (40 in total) were ultrasonically cleaned/washed for 5 minutes in alcohol (70%) and distilled water respectively, individually packaged and sterilised by steam sterilisation.
- Four pockets were created in the paravertrebal muscle in the back of 7 goats (2 pockets left and 2 pockets right from the spinal cord) for each of the four implants. the implants were inserted in a randomised manner in each pocket, ensuring that each implant type is only present once in each goat. Each material type was evaluated in sevenfold for statistical analysis, which necessitates the use of 7 goats.
- Seven adult Dutch milk goats (approximately 40-60 kg; CAE/CL arthritis free and examined by a veterinary surgeon) were obtained from a professional stock breeder, and kept in quarantine for 4 weeks prior to the experiment. Prior to surgery, the goats were weighed and amphicilin 20% (2 ml/50 kg body weight) was administered by intramuscular injection. The surgical procedure was performed under general inhalation anaesthesia. After an intravenous injection of Thiopental, a mixture of nitrous oxide, oxygen and fluothane maintained anaesthesia. Left and right, 10 cm from the spinal cord, the back of each goat was shaved at two places, respectively. For each of the four intramuscular implantation sites (in each goat), an incision of approximately 3 cm was made, followed by blunt dissection until the muscle fascia of the paravertrebal muscle was reached. using a Mayo scissors, an incision of 15 mm was made in the muscle fascia and an intramuscular pocket was subsequently prepared by blunt dissection followed by implant insertion. The muscle fascia and skin were closed in separate layers using vicryl 3-0 sutures. Six months post-operatively, the animals were sacrificed using an intravenously administered overdose of thiopental and potassium chloride.
- After sacrificing the animals, the implants were excises. Six implants of each material type were placed in Karnovsky's fixative for at least one week (4° C.), while the seventh implant was stored at −70° C. for biochemical analysis. The fixed implants were subsequently dehydrated through a series of ethanol and embedded in Methyl Methacrylate. Semithin sections were cut on a modified innerlock diamond saw, perpendicular to the longitudinal plane of the implants, and examined by light microscopy for de novo bone formation.
- After the six months implantation time, histology revealed that a thin fibrous tissue capsule surrounded the HA samples. The adjoining muscle tissue had a normal appearance. None of the HA1250 and HA1300 sample revealed signs of degradation. With the acid treated HA1250 samples, some loosened HA particles could be observed at the periphery of the implant, while abundant surface degradation was observed with the acid treated HA1300. Especially at the outer surface of these implants, many loosened HA particles were present in the surrounding tissues. Noteworthy is the finding that particularly at both the outer surface and the pore surfaces of acid treated HA1250 implants, numerous individual mononucleated and multinucleated giant cells were present that were more or less cubicoidal in morphology. Furthermore, in the acid treated HA1250 samples, de novo bone formation was apparent. This bone tissue was normal in appearance and contained osteoblasts and osteocytes. None of the other materials revealed any bone formation.
- A 2.0 M solution (A) of calcium nitrate tetra-hydrate (AR) in distilled water (AD) was prepared. A 2.0 M second solution (B) was prepared of diammonium hydrogen phosphate (AR) was prepared in distilled water (AD). Under stirring and adjusting the pH just over 8.0 using ammonia (AR), the second solution (B) was slowly added to the first solution (A) in a ratio of 1.63:1 (vol/vol).
- The obtained mixed solution was kept overnight in a cupboard at ambient temperature. The next day, the pH of the solution was adjusted to over 10.00 using ammonia. The solution was left to age at ambient temperature.
- After 30 days, the clear solution was tipped to leave a slurry which was washed five times. with distilled water (AD). Next, the slurry was filtered over 3 filter papers (2* #3 and 1* #1) under negative pressure. The cake in the filter was washed three times with distilled water (AD) while taken care that in between each washing cycle the filter cake was dry but not broken. The cake was then dried in an oven at 50° C. and ground to a powder. The resulting powder was sieved over a 140 mesh sifter to obtain a biphasic calcium phosphate (BCP) powder.
- The BCP powder was mixed with a 3.0% aqueous hydrogen peroxide solution at a ratio of 1 gram powder in 1 ml solution. The resulting slurry was poured into a mould consisting of a plastic container (diameter 38 mm, height 60 mm). The mould was placed in an oven at 60° C. for foaming and drying. Next, the dry porous blocks were carefully removed from the container and sintered at 1100° C. for 10 hours (the temperature was raised from room temperature to 1100° C. in 10 hours, and after sintering, the temperature was decreased to room temperature in the same time frame.)
- To test the osteoinductivity of the above prepared biphasic calcium phosphate (BCP), BCP cylinders were implanted in the thigh muscles of dogs for 90 days. Bone formation induced by BCP was analysed with histology, back scattered electron microscopy (BSE) and energy disperse X-ray (EDX) microanalysis.
- 1. Preparation of the implants:
- BCP blocks machined from BCP ceramic body as obtained above were polished into cylinders (5 mm diameter, 6 mm length). The implants were ultrasonically washed with 70% ethanol for 15 minutes, with demineralised water twice (15 minutes each), dried at 50° C., and then steam sterilised (121° C.) for 30 minutes before implantation.
- 2. Animal preparation:
- Eight healthy dogs (male and female, 2-6 years old, 10-15 kg) were selected and used to test the osteoinductivity of BCP.
- 3. Surgical procedure:
- The surgical procedure was performed under general anaesthesia (30 mg pentobarbital sodium/kg body weight) and under sterile conditions. After shaving, the skin was sterilised with iodine and 70% ethanol. With a scalpel, a longitudinal incision was made in the skin. By a blunt separation, the thigh muscle was disposed. Again, with a scalpel, a small longitudinal incision was made in the thigh muscle and a muscle pouch was obtained by blunt separation. One BCP cylinder was inserted into the muscle pouch (one BCP implant was implanted in each dog). The surgical procedure was finished by suturing the muscle pouch and skin in layers with silk thread. The animals were intramuscularly injected with 1.6 million units penicillin 3 times in 3 days.
- 4. Sample harvest:
- Ninety days after surgery, the dogs were sacrificed by an overdose of pentobarbital sodium, and the implanted samples with surrounding tissues were harvested and immediately fixed in 4% buffered (pH=7.4) formaldehyde. A total of 8 samples were collected from 8 dogs.
- 5. Histological preparation:
- The fixed samples were washed with PBS (3 changes of PBS, 2 days each), then dehydrated with series ethanol solution (70%, 80%, 90%, 96% and 100% X2) and embedded in MMA. Thin undecalcified sections (10-20 micrometer) were made and stained with Methylene Blue and Basic Fuchsin for histological observation. Some sections were coated with carbon and observed with BSE and EDX.
- 6. Results:
- Incidence of bone formation
- Bone formation was found in all samples (8 in 8) Identification of induced bone
- Histologically, bone was found in the pores inside the implants. Mineralised bone matrix, osteoblast seams and osteocytes were obvious. BSE observation showed that the bone tissue was mineralised and contained osteocyte lacunas, EDX analysis showed that the mineralised tissues were composed of Ca and P.
- 7. Conclusion
- Soft tissue implantation (both intramuscularly and subcutaneously) is the study model of osteoinduction. The bone formation in BCP ceramic followed intramuscular implantation showed that the tested BCP is osteoinductive.
- A mixture was prepared of SiO2 (relative amount 29.4% in weight, AR, particle size 0.5-10 microns), NaHCO3 (relative amount 34.1% in weight, AR), CaCO3 (relative amount 28.6% in weight, AR) and Na2HPO4 (relative amount 7.9% in weight, AR). This mixture was sintered for 10 hours at 1000° C. and for 2 hours at 1300° C. After cooling, a glass ceramic material was obtained.
- The glass ceramic was broken mechanically into small particles, which were subsequently ball-milled to a fine powder. The powder was sieved through a 200 mesh filter. The glass ceramic powder was mixed with a 3.0% aqueous hydrogen peroxide solution at a ratio of 2.4 gram powder in 1 ml solution. The resulting slurry was poured into a plastic container (diameter 38 mm, height 60 mm). The mould was placed in an oven at 50° C. for foaming and drying. Next, the dry porous blocks were sintered at 800-1000° C. for 2 hours (the increase in temperature was 5° C./min.) . Eventually, the blocks were allowed to cool naturally in the oven.
- To test the osteoinductivity of the above prepared glass ceramics, glass ceramic cylinders were implanted in the thigh muscles of dogs for 90 days. Bone formation induced by glass ceramics was analysed with histology, back scattered electron microscopy (BSE) and energy disperse X-ray (EDX) microanalysis.
- 1. Preparation of the implants:
- Glass ceramic blocks machined from glass ceramic body as prepared above were polished into cylinders (5 mm diameter, 6 mm length). The implants were ultrasonically washed with 70% ethanol for 15 minutes, with demineralised water twice (15 minutes each), dried at 50° C., and then steam sterilised (121° C.) for 30 minutes before implantation.
- 2. Animal preparation:
- Eight health dogs (male and female, 2-6 years old, 10-15 kg) were selected and used to test the osteoinductivity of glass ceramic.
- 3. Surgical procedure:
- Surgery was performed under general anaesthesia (30 mg pentobarbital sodium/kg body weight) and under sterile conditions. After shaving, the skin was sterilised with iodine ethanol and 70% ethanol. With a scalpel, a longitudinal incision was made in the skin. By a blunt separation, the thigh muscle was disposed. Again, with a scalpel, a small longitudinal incision was made in the thigh muscle, a muscle pouch was obtained by blunt separation. One glass ceramic cylinder was inserted into the muscle pouch (one implant was implanted in each dog). The surgical procedure was finished by suturing the muscle pouch and skin with silk thread in layers. The animals were intramuscularly injected with 1.6 million units penicillin for 3 days.
- 4. Sample harvest:
- Ninety days after surgery, the dogs were sacrificed by a pentobarbital sodium overdose, and the implanted samples were harvested with surrounding tissues and immediately fixed in 4% buffered (pH=7.4) formaldehyde. A total of 8 samples were collected from 8 dogs.
- 5. Histological preparation:
- The fixed samples were washed with PBS (3 changes of PBS, 2 days each), then dehydrated with series ethanol solution (70%, 80%, 90%, 96% and 100% X2) and embedded in MMA. Thin undecalcified sections (10-20 micrometer) was made and stained with Methylene Blue and Basic Fuchsin for histological observation. Some sections were coated with carbon and observed with BSE and EDX.
- 6. Results:
- Incidence of bone formation
- Bone formation was found in 6 samples of 8 Identification of induced bone
- Histologically, bone was found in the pores inside the implants. Mineralised bone matrix, osteoblast seam and osteocytes were obvious. BSE observation showed that the bone tissues were mineralised with osteocyte lacunas, EDX analysis showed that the mineralised tissues were composed of Ca and P.
- 7. Conclusion:
- Soft tissue implantation (both intramuscularly and subcutaneously) is the study model of osteoinduction. The bone formation in glass ceramic followed intramuscular implantation showed that the tested glass ceramic is osteoinductive.
Claims (21)
1. An osteoinductive biomaterial comprising at least one ceramic material having a total porosity of between about 20% to about 90%, with the ceramic material including macropores having a size ranging from about 0.1 mm to about 1.5 mm, and with the ceramic material including micropores having a size ranging from about 0.05 μm to about 20 μm.
2. The osteoinductive biomaterial according to claim 1 , wherein the macropores range in size from between about 0.2 mm to about 1.0 mm.
3. The osteoinductive biomaterial according to claim 1 , wherein the micropores range in size from between about 0.5 μm to about 10 μm.
4. The osteoinductive biomaterial according to claim 1 , wherein the total porosity is between about 40% to about 70%.
5. The osteoinductive biomaterial according to claim 1 comprising crystals having a crystal size of between about 0.05 μm to about 20 μm.
6. The osteoinductive biomaterial according to claim 1 comprising crystals having a crystal size of between about 0.5 μm to about 10 μm.
7. The osteoinductive biomaterial according to claim 1 , wherein the ceramic material includes a material having one or more members selected from the group consisting of calcium phosphate and glass ceramic.
8. The osteoinductive biomaterial according to claim 1 , wherein the ceramic material is one or more calcium phosphates selected from the group consisting of octacalcium phosphate, apatites, hydroxyapatite, carbonate apatite, whitlockites, β-tricalcium phosphate and α-tricalcium phosphate.
9. A process for preparing an osteoinductive biomaterial comprising sintering a ceramic material at a temperature of between about 1000° C. to about 1275° C. to produce a sintered ceramic material, treating the sintered ceramic material with an aqueous solution of at least one acid, and washing the sintered ceramic material to remove the acid.
10. The process according to claim 9 , wherein the at least one acid is selected from the group consisting of maleic acid, hydrochloric acid, and phosphoric acid.
11. The process according to claim 9 , wherein the aqueous solution has a pH between about 0 to about 4.
12. The process according to claim 9 , wherein the sintered ceramic material is washed with one or more of ethanol or water.
13. A process for preparing an osteoinductive biomaterial comprising preparing a slurry including a powdered ceramic material and an aqueous solution including one or more negative replica forming agents, and sintering the slurry at a temperature of between about 800° C. to about 1200° C.
14. The process according to claim 13 , wherein the one or more negative replica forming agents is hydrogen peroxide.
15. A process according to claim 9 further including the step of sterilizing the osteoinductive biomaterial.
16. A process according to claim 13 further including the step of sterilizing the osteoinductive biomaterial.
17. An osteoinductive biomaterial prepared by sintering a ceramic material at a temperature of between about 1000° C. to about 1275° C. to produce a sintered ceramic material, treating the sintered ceramic material with an aqueous solution of at least one acid, and washing the sintered ceramic material to remove the acid.
18. An osteoinductive biomaterial prepared by preparing a slurry including a powdered ceramic material and an aqueous solution including one or more negative replica forming agents, and sintering the slurry at a temperature of between about 800° C. to about 1200° C.
19. A medical implant comprising the osteoinductive biomaterial of claim 1 .
20. A scaffold for tissue engineering a bone equivalent comprising the osteoinductive biomaterial of claim 1 .
21. A method of inducing bone formation in a mammal comprising implanting the osteoinductive biomaterial of claim 1 into a mammal in a manner to induce bone formation on the osteoinductive biomaterial.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/999,029 US20020035402A1 (en) | 1998-09-15 | 2001-11-15 | Osteoinductive ceramic materials |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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EPEP98203084.3 | 1998-09-15 | ||
EP98203084 | 1998-09-15 | ||
US09/396,072 US6511510B1 (en) | 1998-09-15 | 1999-09-15 | Osteoinductive ceramic materials |
US09/999,029 US20020035402A1 (en) | 1998-09-15 | 2001-11-15 | Osteoinductive ceramic materials |
Related Parent Applications (1)
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US09/396,072 Continuation US6511510B1 (en) | 1998-09-15 | 1999-09-15 | Osteoinductive ceramic materials |
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US20020035402A1 true US20020035402A1 (en) | 2002-03-21 |
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Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US09/396,072 Expired - Lifetime US6511510B1 (en) | 1998-09-15 | 1999-09-15 | Osteoinductive ceramic materials |
US09/999,029 Abandoned US20020035402A1 (en) | 1998-09-15 | 2001-11-15 | Osteoinductive ceramic materials |
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Application Number | Title | Priority Date | Filing Date |
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US09/396,072 Expired - Lifetime US6511510B1 (en) | 1998-09-15 | 1999-09-15 | Osteoinductive ceramic materials |
Country Status (9)
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US (2) | US6511510B1 (en) |
EP (1) | EP0987032B1 (en) |
JP (1) | JP2000093504A (en) |
AT (1) | ATE283713T1 (en) |
AU (1) | AU766735B2 (en) |
CA (1) | CA2282075A1 (en) |
DE (1) | DE69922312T2 (en) |
DK (1) | DK0987032T3 (en) |
ES (1) | ES2248958T3 (en) |
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US20030171822A1 (en) * | 2000-08-04 | 2003-09-11 | Lo Wei Jen | Porous synthetic bone graft and method of manufacture thereof |
US7094371B2 (en) | 2000-08-04 | 2006-08-22 | Orthogem Limited | Porous synthetic bone graft and method of manufacture thereof |
US20060292198A1 (en) * | 2001-03-02 | 2006-12-28 | Stryker Corporation | Porous beta-tricalcium phosphate granules for regeneration of bone tissue |
US20030180376A1 (en) * | 2001-03-02 | 2003-09-25 | Dalal Paresh S. | Porous beta-tricalcium phosphate granules and methods for producing same |
US8173149B2 (en) | 2001-03-02 | 2012-05-08 | Stryker Corporation | Method for producing porous β-tricalcium phosphate granules |
US20050170012A1 (en) * | 2001-03-02 | 2005-08-04 | Stryker Corporation | Porous beta-tricalcium phosphate granules for regeneration of bone tissue |
US20090110743A1 (en) * | 2001-03-02 | 2009-04-30 | Dalal Paresh S | Porous beta-tricalcium phosphate granules and methods for producing same |
US8288452B2 (en) | 2003-05-15 | 2012-10-16 | Lo Wei J | Synthetic bone graft biomaterial |
WO2004101013A1 (en) * | 2003-05-15 | 2004-11-25 | Orthogem Limited | Biomaterial |
US20060122706A1 (en) * | 2003-05-15 | 2006-06-08 | Lo Wei J | Synthetic bone graft biomaterial |
US20050142518A1 (en) * | 2003-10-10 | 2005-06-30 | Bego Semados Gmbh & Co. Kg | Arrangement for restoring a periodontosis-induced bone defect |
US10286102B2 (en) | 2010-05-11 | 2019-05-14 | Howmedica Osteonics Corp | Organophosphorous, multivalent metal compounds, and polymer adhesive interpenetrating network compositions and methods |
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US8765189B2 (en) | 2011-05-13 | 2014-07-01 | Howmedica Osteonic Corp. | Organophosphorous and multivalent metal compound compositions and methods |
US10064892B2 (en) | 2013-07-18 | 2018-09-04 | Kuros Biosciences B.V. | Method for producing an osteoinductive calcium phosphate and products thus obtained |
US10561683B2 (en) | 2013-07-18 | 2020-02-18 | Kuros Biosciences B.V. | Method for producing an osteoinductive calcium phosphate and products thus obtained |
US11147836B2 (en) | 2013-07-18 | 2021-10-19 | Kuros Biosciences B.V. | Method for producing an osteoinductive calcium phosphate and products thus obtained |
US10537661B2 (en) | 2017-03-28 | 2020-01-21 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline calcium phosphate coating and methods for making the same |
US10537658B2 (en) | 2017-03-28 | 2020-01-21 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline gallium-containing hydroxyapatite coating and methods for making the same |
US11058799B2 (en) | 2017-03-28 | 2021-07-13 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline calcium phosphate coating and methods for making the same |
US11141505B2 (en) | 2017-03-28 | 2021-10-12 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline gallium-containing hydroxyapatite coating and methods for making the same |
US11793910B2 (en) | 2017-03-28 | 2023-10-24 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline calcium phosphate coating and methods for making the same |
US11793907B2 (en) | 2017-03-28 | 2023-10-24 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline gallium-containing hydroxyapatite coating and methods for making the same |
Also Published As
Publication number | Publication date |
---|---|
ATE283713T1 (en) | 2004-12-15 |
DE69922312T2 (en) | 2005-12-22 |
AU4746399A (en) | 2000-03-23 |
JP2000093504A (en) | 2000-04-04 |
DK0987032T3 (en) | 2005-03-21 |
ES2248958T3 (en) | 2006-03-16 |
EP0987032A1 (en) | 2000-03-22 |
AU766735B2 (en) | 2003-10-23 |
CA2282075A1 (en) | 2000-03-15 |
EP0987032B1 (en) | 2004-12-01 |
US6511510B1 (en) | 2003-01-28 |
DE69922312D1 (en) | 2005-01-05 |
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