EP2071916A1 - Bio active ceramic coatings with excellent bio-compatibility and preaparation method thereof - Google Patents

Bio active ceramic coatings with excellent bio-compatibility and preaparation method thereof

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Publication number
EP2071916A1
EP2071916A1 EP07768796A EP07768796A EP2071916A1 EP 2071916 A1 EP2071916 A1 EP 2071916A1 EP 07768796 A EP07768796 A EP 07768796A EP 07768796 A EP07768796 A EP 07768796A EP 2071916 A1 EP2071916 A1 EP 2071916A1
Authority
EP
European Patent Office
Prior art keywords
coating
powder
hydroxyapatite
heat treatment
particles
Prior art date
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.)
Withdrawn
Application number
EP07768796A
Other languages
German (de)
French (fr)
Other versions
EP2071916A4 (en
Inventor
Dong-Soo Park
Byung-Dong Hahn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Institute of Machinery and Materials KIMM
Original Assignee
Korea Institute of Machinery and Materials KIMM
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Korea Institute of Machinery and Materials KIMM filed Critical Korea Institute of Machinery and Materials KIMM
Publication of EP2071916A1 publication Critical patent/EP2071916A1/en
Publication of EP2071916A4 publication Critical patent/EP2071916A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C26/00—Coating not provided for in groups C23C2/00 - C23C24/00
    • 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
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C24/00—Coating starting from inorganic powder
    • C23C24/08—Coating starting from inorganic powder by application of heat or pressure and heat
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C30/00—Coating with metallic material characterised only by the composition of the metallic material, i.e. not characterised by the coating process
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/3094—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/32—Joints for the hip
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00011—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00011—Metals or alloys
    • A61F2310/00017—Iron- or Fe-based alloys, e.g. stainless steel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00011—Metals or alloys
    • A61F2310/00023—Titanium or titanium-based alloys, e.g. Ti-Ni alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00185—Ceramics or ceramic-like structures based on metal oxides
    • A61F2310/00203—Ceramics or ceramic-like structures based on metal oxides containing alumina or aluminium oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00179—Ceramics or ceramic-like structures
    • A61F2310/00185—Ceramics or ceramic-like structures based on metal oxides
    • A61F2310/00239—Ceramics or ceramic-like structures based on metal oxides containing zirconia or zirconium oxide ZrO2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00796—Coating or prosthesis-covering structure made of a phosphorus-containing compound, e.g. hydroxy(l)apatite

Definitions

  • the present invention relates to a bioactive ceramic coating having excellent biocompatibility. More particularly, the present invention relates to a bioactive ceramic coating having excellent biocompatibility, which consists of crystalline grains, having an average diameter of less than 100 ran, and non-crystalline grains and has a crack-free and dense structure. The present invention is also concerned with a method of preparing the bioactive ceramic coating.
  • hydroxyapatite is known to be the most biologically compatible. Although hydroxyapatite has superior biocompatibility compared to other materials, it is not a preferred replacement for damaged bones owing to its low strength and fracture toughness.
  • Metallic materials or high-strength ceramic materials have high mechanical strength, but their biocompatibility is relatively low compared to hydroxyapatite. Thus, when such materials are implanted into the body while replacing damaged bones, it takes a long time for body cells to adhere to and grow on the surface thereof, thus delaying bone repair. Since the biocompatibility of artificial bone substitutes determines how easily and fast body cells adhere to and grow on the surface of artificial materials, it is dependent on their surface properties. Thus, if the surface of metallic materials and high-strength ceramic materials, which have high mechanical strength but low biocompatibility, are coated with hydroxyapatite, which has high biocompatibility, artificial bone substitute materials that are excellent in both mechanical strength and biocompatibility can be obtained. Many attempts have been made by many researchers worldwide to coat the surface of metallic or ceramic materials having high mechanical strength.
  • Plasma-spray coating involves spraying hydroxyapatite powder onto a prepared substrate along with a plasma-forming gas to form a coating.
  • the passage of plasma gas generates a plasma flame, which is as hot as 20,000 ° C, at which hydroxyapatite powder is partially melted.
  • the plasma spraying is problematic in that the substrate is also exposed to the high temperature, high residual stress is present at the interface between the coating and the substrate after cooling, and the device that is employed for coating is expensive.
  • U.S. Pat. Publication US2005/0181208 filed by Akedo et al. of Japan, discloses a method of coating a substrate with various ceramic powders including hydroxyapatite through aerosol deposition.
  • the method comprises crushing ceramic powders to provide ultrafine powders in which particles having a diameter of less than 50 run account for 10%-90% of total particles, subjecting the ultrafine powders to heat treatment at a temperature lower than the sintering temperature thereof so as to provide particles 50% or less of which are smaller than 50 run, and spraying the resulting powders onto a substrate or applying a mechanical impact force to the powders at room temperature to adhere the ceramic material to the substrate.
  • the present invention aims to provide a bioactive ceramic coating, such as a hydroxyapatite coating, calcium phosphate coating and mixtures thereof, having excellent biocompatibility and thus being suitable for use as a surgical implant or an artificial hip joint, and preparation methods thereof, the ceramic coating being provided on the surface of a metallic or ceramic material, consisting of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, and having a crack-free and dense structure.
  • a bioactive ceramic coating such as a hydroxyapatite coating, calcium phosphate coating and mixtures thereof, having excellent biocompatibility and thus being suitable for use as a surgical implant or an artificial hip joint, and preparation methods thereof, the ceramic coating being provided on the surface of a metallic or ceramic material, consisting of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, and having a crack-free and dense structure.
  • the present invention provides a bioactive ceramic coating, which is coated onto the surface of a metallic material or a ceramic material, including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 ⁇ m, and non-crystalline grains, and has a density of greater than 95% and a thickness ranging from 0.1 to 100 ⁇ m.
  • the present invention provides a method of preparing a bioactive ceramic coating comprising the steps of: (a) subjecting bioactive ceramic powder consisting of ultrafine particles to a first heat treatment at a temperature between 1,000 ° C and l,300 ° C; (b) applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 to 5 ⁇ m; (c) subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200 ° C and l,100 ° C; (d) coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in a vacuum atmosphere at room temperature; and (d) heat treatment after coating at a temperature between 200 ° C and 500 ° C.
  • the bioactive ceramic coating having excellent biocompatibility which is fabricated onto a metallic or ceramic material, consists of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, and has a crack-free and dense structure, thereby being useful in bone reconstruction, for example, as a surgical implant or an artificial hip joint.
  • FIG. 1 is a graph showing the particle size distribution of hydroxyapatite powder that is two-step heat-treated according to an embodiment of the present invention
  • FIG. 2 is a schematic presentation of a coating apparatus for applying hydroxyapatite powder according to an embodiment of the present invention
  • FIG. 3 is a cross-sectional SEM micrograph of a hydroxyapatite coating, which is fabricated on a substrate using the coating apparatus of FIG. 2, the SEM micrograph showing that the coating is highly dense and rarely porous;
  • FIG. 4 shows a TEM micrograph and an electron beam diffraction pattern of a hydroxyapatite coating according to an embodiment of the present invention
  • FIG. 5 is a surface SEM micrograph of a hydroxyapatite coating that is further heat-treated after two-step heat treatment according to an embodiment of the present invention
  • FIG. 6 is a graph showing the X-ray diffraction patterns of a hydroxyapatite coating before and after additional heat treatment according to an embodiment of the present invention, the X-ray diffraction showing the crystallinity of the coating;
  • FIG. 7 is a photo of a hydroxyapatite coating as a comparative example
  • FIG. 8 is a graph showing the particle size distribution of fluoridated hydroxyapatite powder that is two-step heat-treated according to an embodiment of the present invention.
  • FIG. 9 is a SEM micrograph of a fluoridated hydroxyapatite coating according to an embodiment of the present invention.
  • FIG. 10 is an energy-dispersive X-ray spectrum (EDS) of a fluoridated hydroxyapatite coating according to an embodiment of the present invention
  • FIG. 11 is a surface SEM micrograph of a fluoridated hydroxyapatite coating that is further heat-treated after two-step heat treatment according to an embodiment of the present invention
  • FIG. 12 is a graph showing the particle size distribution of ⁇ -tricalcium phosphate powder that is two- step heat-treated according to an embodiment of the present invention.
  • FIG. 13 is a surface SEM micrograph of a ⁇ -tricalcium phosphate coating according to an embodiment of the present invention.
  • FIG. 14 is a graph showing the X-ray diffraction pattern of a ⁇ -tricalcium phosphate coating according to an embodiment of the present invention.
  • FIG. 15 is a surface SEM micrograph of a ⁇ -tricalcium phosphate coating that is further heat-treated after two- step heat treatment according to an embodiment of the present invention.
  • FIG. 16 is a graph showing the cell viability on a hydroxyapatite coating according to an embodiment of the present invention
  • FIG. 17 is a graph showing the alkaline phosphatase (ALP) activity of human bone marrow stem cells on a hydroxyapatite coating according to an embodiment of the present invention.
  • ALP alkaline phosphatase
  • the present invention is directed to a bioactive ceramic coating having excellent biocompatibility.
  • a bioactive ceramic e.g., hydroxyapatite, fluoridated hydroxyapatite, ⁇ -tricalcium phosphate and mixtures thereof
  • a metallic material or a ceramic material including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 ⁇ m, and noncrystalline grains, and has a density of greater than 95% and a thickness ranging from 0.1 to 100 ⁇ m.
  • the metallic material or the ceramic material, including alumina or zirconia serves as a substrate material that supports the bioactive ceramic coating of the present invention.
  • the substrate material is not particularly limited, but is preferably stainless steel, titanium or an alloy thereof, and more preferably a titanium metal.
  • Crystalline particles in the coating have an average diameter less than 0.1 ⁇ m, and preferably ranging from 0.1 ⁇ m to 0.001 ⁇ m, within which the functions of osteoblasts are remarkably enhanced, leading to new bone synthesis, thereby accelerating recovery from bone damage.
  • the ceramic coating preferably has a thickness ranging from 0.1 ⁇ m to 100 ⁇ m.
  • the ceramic coating is less than 0.1 ⁇ m thick, it is difficult to uniformly coat the entire surface of a substrate material.
  • the thickness exceeds 100 ⁇ m, the coating is easily detached and does not have uniform thickness.
  • the bioactive ceramic coating has an internal density of greater than 95%, that is, from 95% to 100%, which aids in the attachment and proliferation of osteoblasts on the coating leading to new bone synthesis.
  • the present invention provides a method of preparing a bioactive ceramic coating having excellent biocompatibility.
  • the bioactive ceramic coating has increased crystallinity through first and second heat treatment steps for powder preparation and an additional third heat treatment step, which is performed after coating formation.
  • the method comprises the steps of: (a) subjecting bioactive ceramic powder, consisting of ultrafine particles, to a first heat treatment at a temperature between l,000 ° C and l,300 ° C; (b) applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 to 5 ⁇ m; (c) subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200 ° C and l,100 ° C; and (d) coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in a vacuum atmosphere at room temperature.
  • Step (a) includes subjecting hydroxyapatite powder or calcium phosphate powder or mixtures thereof consisting of ultrafine particles to the first heat treatment at a temperature between l,000 ° C and l,300 ° C.
  • the bioactive ceramic raw material powder is commercially available.
  • the raw material powder may have an average particle diameter from 10 ran to 20 nm, but the present invention is not limited thereto because it is enough merely to adjust the size of powder particles to a range approximate to the desired final particle diameter through the first heat treatment.
  • bioactive ceramic raw material powder suitable for use in the present invention examples include hydroxyapatite (HA), fluoridated hydroxyapatite (FHA) and tri-calcium phosphate (TCP) powders.
  • HA hydroxyapatite
  • FHA fluoridated hydroxyapatite
  • TCP tri-calcium phosphate
  • the first heat treatment is carried out at a relatively high temperature, preferably between l,000 ° C and l,300 ° C. Within this temperature range, the resulting primary powder has an average particle diameter ranging from 5 ⁇ m to 20 ⁇ m, which is approximate to the desired final particle diameter.
  • Step (b) includes applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 ⁇ m to 5 ⁇ m.
  • the mechanical impact force applied increases the amount of cracking, or internal energy stored as dislocations in fine crystals constituting the raw material particles, and to reduce the impact force or pressure that is required to break up the coating material ultrafine particles, which is applied upon the post-step coating formation, thereby facilitating the crushing of particles upon coating formation.
  • the powder particles first heat-treated at step (a) preferably have an average particle diameter ranging from 0.1 ⁇ m to 5 ⁇ m after a mechanical impact force is applied thereto.
  • Step (c) includes subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200 ° C and l,100 ° C.
  • the powder obtained through the second heat treatment has an average particle diameter ranging from 3 ⁇ m to 5 ⁇ m, and particles greater than 5 ⁇ m in diameter have a volume fraction of less than 50%, preferably less than 35%, and more preferably less than 20%, relative to the total amount of particles. This is important because the powder thus obtained is pulverized at the post-step powder spray coating within the above range so as to provide a coating having a desired grain size distribution of less than 100 nm.
  • Step (d) includes spraying and coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in vacuum atmosphere at room temperature.
  • the coating apparatus comprises a powder suspension container 1, in which a gas inlet is provided at a lower part thereof and which contains the bioactive ceramic coating powder of the present invention; a nozzle outlet 3 which communicates with the powder suspension container 1 through a nozzle, is provided at an opposite terminal end of the nozzle and allows the bioactive ceramic coating powder to be sprayed therethrough onto a metallic substrate 4, such as titanium or an alloy thereof, or a ceramic substrate 4, such as alumina or zirconia; a vacuum pump 5 which controls the level of vacuum of a vacuum chamber 2; and a motor stage 6 which moves in a right-and-left direction so as to provide an uniform coating on the substrate 4.
  • a powder suspension container 1 in which a gas inlet is provided at a lower part thereof and which contains the bioactive ceramic coating powder of the present invention
  • a nozzle outlet 3 which communicates with the powder suspension container 1 through a nozzle, is provided at an opposite terminal end of the nozzle and allows the bioactive ceramic coating powder to be sprayed therethrough onto a metallic substrate 4,
  • the bioactive ceramic powder prepared in step (c) is placed into the powder suspension container 1, and is shattered by shaking the powder suspension container 1 longitudinally or through other movements, for example, vibration using a vibrator, while a suitable amount of oxygen is supplied through the gas inlet provided in the bottom of the powder suspension container 1.
  • the oxygen supplied into the powder suspension container 1 passes through the nozzle and arrives at the nozzle outlet 3 in the vacuum chamber 2 while carrying the suspended bioactive ceramic particles.
  • the bioactive ceramic particles are sprayed through the nozzle outlet in a direction perpendicular to the substrate to be coated, for example, onto the titanium metal substrate 4, which is placed in the vacuum chamber 2, which is maintained in a vacuum state at ambient temperature (about 25 ° C), thereby forming a coating that consists of crystalline grains, having a grain size distribution of less than 100 nm, and non-crystalline grains, and has a thickness ranging from 0.1 ⁇ m to 100 ⁇ m.
  • the vacuum chamber 4 is preferably maintained in a vacuum state ranging from 0.1 torr to 3X10 ⁇ 2 torr. Within this range of vacuum state, the coating is composed of crystalline grains and non-crystalline grains, as desired, and has a density of greater than 95%, and preferably 95% to 100%.
  • the present method may further include subjecting the coating obtained at step (d) to an additional third heat treatment at a temperature lower than 500 ° C, preferably between 500 ° C and 300 ° C, for 30 to 60 minutes.
  • the third heat treatment may be carried out in air atmosphere. As shown in FIGS. 5 and 6, the bioactive ceramic coating has much higher crystallinity than that before the heat treatment .
  • the resulting bioactive ceramic coating consists of crystalline grains, having an average diameter of less than 0.1 ⁇ m, and non-crystalline grains, and has a thickness ranging from 0.1 ⁇ m to 100 ⁇ m.
  • HA powder having an average primary particle diameter of 12 ran, which was commercially purchased, was heated in air at 1200 ° C for 2 hrs to provide an average particle diameter of 16.6 ⁇ m.
  • the HA powder was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, thereby crushing the particles to an average particle diameter of 3.2 ⁇ m and a maximum particle diameter of less than 30 ⁇ m.
  • the crushed HA powder was then heat-treated at 900 ° C for 2 hrs to yield HA powder for powder spray coating.
  • FIG. 1 shows the particle size distribution of the HA powder thus obtained.
  • the HA powder had an average particle diameter of 3.9 ⁇ m, while particles greater than 5 ⁇ m in diameter had a volume fraction of 32% relative to all particles.
  • the HA powder prepared as described above was placed into the powder dispersion container 1 of FIG. 2.
  • the powder dispersion container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder dispersion container 1.
  • the oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered HA particles.
  • the HA particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate.
  • the vacuum chamber 2 was maintained at a vacuum level of 2X10 "2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
  • FIG. 4 shows the TEM micrograph and the electron beam diffraction pattern of the formed hydroxyapatite layer.
  • the hydroxyapatite layer was present as a mixture of crystalline grains and non-crystalline grains, and the crystalline grains had an ultrafine size, less than several tens of nanometers. It is advantageous for bone reconstruction for hydroxyapatite to be present in a mixed state of crystalline grains and non-crystalline grains (H. Wang, N. Eliaz, Z. Xiang, H. P. Hsu, M. Spector, L.W. Hobbs, Biomaterials 27 (2006) 4192-4203) .
  • the HA coating As shown in the SEM micrograph of FIG. 3 and the TEM micrograph of FIG. 4, showing the fine structure of the HA coating, the HA coating was found to be highly dense and almost crack-free.
  • the HA coating on the titanium metal substrate, prepared in Example 1 was subjected to a third heat treatment for 1 hr in ambient atmosphere at 350 "C (Example 2- a), 450 ° C (Example 2-b) and 500 “C (Example 2-c) .
  • Examples 2-a, 2-b and 2-c were examined through scanning electron microscopy, and the resulting SEM micrographs are given in FIG. 5. As shown in FIG. 5, specimens of Examples 2-a, 2-b and 2-c were found to be maintained intact with no cracking.
  • Example 2-c specimens of Example 1 and Example 2-c were evaluated for X-ray diffraction patterns, and the results are given in FIG. 6. As shown in FIG. 6, the Example 2-c specimen exhibited a diffraction intensity greater than that of the Example 1 specimen, and had a new crystal peak. These results indicated that the crystallinity of the Example 2-c specimen was improved more than before the third heat treatment.
  • Ca3(PC> 4 ) 2 calcium fluoride (CaF 2 )/ which were commercially purchased and had an average primary particle diameter of about 20 run at a molar ratio of 3:1.
  • Calcium fluorapatite (FA) powder and hydroxyapatite (HA) powder were mixed and heated in air at 1200 ° C for 2 hrs.
  • the powder mixture was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, and was then heat-treated at 900 ° C for 2 hrs, thereby yielding fluoridated hydroxyapatite (FHA, Ca 1 O (PO 4 ) 6F 2x (OH) 2 -2x) powder for powder spray coating.
  • FIG. 8 shows the particle size distribution of the FHA powder thus obtained.
  • the FHA powder had an average particle diameter of 4.08 ⁇ m, while particles greater than 5.2 ⁇ m in diameter had a volume fraction of 37% relative to the total particles.
  • the FHA powder prepared as described above was placed into the powder suspension container 1 of FIG. 2.
  • the powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder dispersion container 1.
  • the oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered FHA particles.
  • the FHA particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate.
  • the vacuum chamber 2 was maintained at a vacuum level of 2 X ICT 2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
  • the formed coating was analyzed using scanning electron microscopy (SEM) , transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS) . As shown in FIG. 9, the FHA coating was found to be 10 ⁇ m thick and dense.
  • FIG. 10 is the energy-dispersive X-ray spectrum of the formed HFA layer. As shown in FIG. 10, fluorine atoms were detected in the membrane, thereby confirming that the prepared membrane was the HFA layer.
  • the FHA coating on the titanium metal substrate, prepared in Example 3, was subjected to a third heat treatment for 1 hr in ambient atmosphere at 500 ° C.
  • the FHA coating was then examined through scanning electron microscopy, and the resulting SEM micrograph is given in FIG. 11.
  • EXAMPLE 5 Preparation of ⁇ -tricalcium phosphate coating (1) Two-step heat treatment ⁇ -tricalcium phosphate (Ca 3 (PO 4 ) 2) powder having an average primary particle diameter of 20 run, which was commercially purchased, was heated in air at 1200 ° C for 2 hrs. The powder was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, and was then heat-treated at 900 ° C for 2 hrs, thereby yielding ⁇ - tricalcium phosphate ( ⁇ -TCP) powder for powder spray coating.
  • ⁇ -TCP ⁇ - tricalcium phosphate
  • FIG. 12 shows the particle size distribution of the ⁇ - TCP powder thus obtained.
  • the ⁇ -TCP powder had an average particle diameter of 4.1 ⁇ m, while particles greater than 5 ⁇ m in diameter had a volume fraction of 38% relative to the total particles.
  • the ⁇ -TCP powder prepared as described above, was placed into the powder suspension container 1 of FIG. 2.
  • the powder suspension container 1 was reciprocated longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1.
  • the oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered ⁇ -TCP particles .
  • the ⁇ -TCP particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate.
  • the vacuum chamber 2 was maintained at a vacuum level of 2X10 "2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
  • the formed ⁇ -TCP coating was analyzed using scanning electron microscopy (SEM) and X-ray diffraction. As shown in FIG. 13, the ⁇ -TCP coating was found to be 10 ⁇ m thick and dense. FIG. 14 shows an X-ray diffraction pattern of the formed ⁇ -TCP coating.
  • the ⁇ -TCP coating on the titanium metal substrate, prepared in Example 5, was subjected to a third heat treatment for 1 hr in ambient atmosphere at 500 ° C
  • the ⁇ -TCP coating was then examined through scanning electron microscopy, and the resulting SEM micrograph is given in FIG. 15.
  • Hydroxyapatite powder which was commercially purchased, was heated in air at 1200 ° C for 2 hrs . Then, the hydroxyapatite powder was placed into the powder suspension container 1 of FIG. 2.
  • the powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1.
  • the oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered hydroxyapatite particles .
  • the hydroxyapatite particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate.
  • the vacuum chamber 2 was maintained at a vacuum level of 1 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
  • Hydroxyapatite powder which was commercially purchased, was heated in air at 1200 ° C for 2 hrs and ball- milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container.
  • the ground hydroxyapatite powder was dried at 120 ° C for 8 hrs.
  • the hydroxyapatite powder was placed into the powder suspension container 1 of FIG. 2.
  • the powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1.
  • the oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered hydroxyapatite particles.
  • the hydroxyapatite particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate.
  • the vacuum chamber 2 was maintained at a vacuum level of 1 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
  • the formed HA coating was not dense, and had poor adhesion to the substrate.
  • MG-63 cells osteoblast-like cell line, American Type Culture Collection (ATCC) No. CRL-1427, USA
  • ATCC American Type Culture Collection
  • HA/Ti HA-coated titanium substrate
  • the cells were cultured in Dulbecco's Modified Eagle Medium (DMEM, Gibco, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, USA) and 1% penicillin/streptomycin (P/S; Hyclone, USA) in an incubator at 37 ° C under 5% CO 2 .
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • cell proliferation was examined using an MTT assay (Cell Proliferation Kit I, Boehringer Mannheim, Mannheim, Germany) .
  • MTT assay Cell Proliferation Kit I, Boehringer Mannheim, Mannheim, Germany
  • the absorbance was measured at 595 nm using an ELISA reader (Synergy HT, Bio-Tek Instruments, Inc, Winooski, VT, USA) .
  • the HA-coated Ti substrate As shown in Table 1 and FIG. 16, compared to the non- coated titanium substrate, the HA-coated Ti substrate (HA/Ti) exhibited improvements in cell proliferation of 7%, 6% and 23% after 1, 3 and 5 days, respectively. These results indicated that the HA coating had more favorable cell viability.
  • the differentiation behavior of human bone marrow stem cells on HA coatings was determined by assaying the ALP activity of the cells.
  • hBMSC human bone marrow stem cells
  • ALP alkaline phosphatase
  • the cells were cultured in a differentiation medium, which was Dulbecco' s Modified Eagle Medium/low glucose (DMEM/LG, Gibco, USA) supplemented with 10% FBS (Gibco, USA) and 1% penicillin/streptomycin (P/S; Hyclone, USA) and were supplemented with 10 "8 M of dexamethasone, 10 mM of ⁇ - glycerophosphate and 50 ⁇ g/ml of L-ascorbic acid, in an incubator at 37 ° C under 5% CO 2 .
  • DMEM/LG Dulbecco' s Modified Eagle Medium/low glucose
  • FBS Gibco, USA
  • P/S penicillin/streptomycin
  • the ALP activity an early marker of osteoblastic differentiation, was determined by measuring absorbance at 405 nm using an ELISA reader (Synergy HT, Bio- Tek Instruments, Inc, Winooski, VT, USA) .
  • HA-coated titanium substrates of Examples 1, 2-a and 2-b compared to the non- coated Ti, HA-coated titanium substrates of Examples 1, 2-a and 2-b exhibited higher ALP activity.
  • the HA-coated Ti substrate that was additionally heat-treated at 350 ° C (Example 2-a) displayed the highest ALT activity.

Abstract

Disclosed herein are a bioactive ceramic coating having excellent biocompatibility and a preparation method thereof. The bioactive ceramic coating is coated onto a metallic material or a ceramic material, including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 μm, and non-crystalline grains, and has a density of greater than 95% and a thickness ranging from 0.1 to 100 μm. Since the bioactive ceramic coating is present at a mixed state of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, has a crack-free and dense structure, and has excellent biocompatibility, it is useful in bone reconstruction, for example, as a surgical implant or an artificial hip joint.

Description

[DESCRIPTION]
[invention Title]
BIO ACTIVE CERAMIC COATINGS WITH EXCELLENT BIO- COMPATIBILITY AND PREPARATION METHOD THEREOF
[Technical Field]
The present invention relates to a bioactive ceramic coating having excellent biocompatibility. More particularly, the present invention relates to a bioactive ceramic coating having excellent biocompatibility, which consists of crystalline grains, having an average diameter of less than 100 ran, and non-crystalline grains and has a crack-free and dense structure. The present invention is also concerned with a method of preparing the bioactive ceramic coating.
[Background Art]
Human and animal bones which have been damaged through injury or disease are reconstructed by replacing them with artificial materials. Commonly used synthetic bone substitute materials include metallic materials, such as stainless steel and titanium, and ceramic materials, such as zirconia, alumina and hydroxyapatite (Cas (PO4)SH) . Of them, hydroxyapatite is known to be the most biologically compatible. Although hydroxyapatite has superior biocompatibility compared to other materials, it is not a preferred replacement for damaged bones owing to its low strength and fracture toughness.
Metallic materials or high-strength ceramic materials have high mechanical strength, but their biocompatibility is relatively low compared to hydroxyapatite. Thus, when such materials are implanted into the body while replacing damaged bones, it takes a long time for body cells to adhere to and grow on the surface thereof, thus delaying bone repair. Since the biocompatibility of artificial bone substitutes determines how easily and fast body cells adhere to and grow on the surface of artificial materials, it is dependent on their surface properties. Thus, if the surface of metallic materials and high-strength ceramic materials, which have high mechanical strength but low biocompatibility, are coated with hydroxyapatite, which has high biocompatibility, artificial bone substitute materials that are excellent in both mechanical strength and biocompatibility can be obtained. Many attempts have been made by many researchers worldwide to coat the surface of metallic or ceramic materials having high mechanical strength.
The most widely known method is a coating technique based on plasma spraying. Plasma-spray coating involves spraying hydroxyapatite powder onto a prepared substrate along with a plasma-forming gas to form a coating. The passage of plasma gas generates a plasma flame, which is as hot as 20,000°C, at which hydroxyapatite powder is partially melted. When the melted particles are adhered onto the substrate, they are allowed to harden to form a coating. However, the plasma spraying is problematic in that the substrate is also exposed to the high temperature, high residual stress is present at the interface between the coating and the substrate after cooling, and the device that is employed for coating is expensive. In particular, when the substrate is a metal that oxidizes at high temperature, the plasma spray coating process is carried out in a vacuum, and thus requires a more expensive device. A great deal of research has been done to apply a coating of hydroxyapatite onto a metallic or ceramic substrate using other methods, but none of the attempts provides a dense and crack-free hydroxyapatite coating (M. Sato, M.A. Sambito, A. Aslani, N.M. Kalkhoran, E. B. Slamovich, T.J. Webster, Biomaterials 27 (2006) 2358-69) .
U.S. Pat. Publication US2005/0181208, filed by Akedo et al. of Japan, discloses a method of coating a substrate with various ceramic powders including hydroxyapatite through aerosol deposition. The method comprises crushing ceramic powders to provide ultrafine powders in which particles having a diameter of less than 50 run account for 10%-90% of total particles, subjecting the ultrafine powders to heat treatment at a temperature lower than the sintering temperature thereof so as to provide particles 50% or less of which are smaller than 50 run, and spraying the resulting powders onto a substrate or applying a mechanical impact force to the powders at room temperature to adhere the ceramic material to the substrate.
However, in the literature: T. Fujihara, M. Tsukamoto, N. Abe, S. Miyake, T. Ohji, J. Akedo, Vacuum 73 (2004) 629- 33, when hydroxyapatite powder is coated onto a substrate using an aerosol deposition method, the spraying of the powder in a direction perpendicular to the substrate does not create a dense hydroxyapatite coating. In addition, as described in the Comparative Examples of the present invention, when ultrafine hydroxyapatite powder is thermally treated at a temperature lower than the sintering temperature thereof (1200*0), and then sprayed, a dense hydroxyapatite coating cannot be obtained.
According to a recent report, when the artificial bioceramic material hydroxyapatite is composed of ultrafine particles less than 100 run in size, the function of osteoblasts (bone forming cells) is greatly promoted, leading to new bone synthesis, thereby accelerating recovery from bone damage (TJ. Webster, C. Ergun, R. H. Doremus, R. W. Siegel, R. Bozios, Biomaterials 21 (2000) 1803- 10) . Hence, if hydroxyapatite as a surface coating is composed of ultrafine particles having a crystalline grain (crystallite) size of less than 100 nm, a greatly improved coating can be formed.
[Disclosure] [Technical Problem] Accordingly, the present invention aims to provide a bioactive ceramic coating, such as a hydroxyapatite coating, calcium phosphate coating and mixtures thereof, having excellent biocompatibility and thus being suitable for use as a surgical implant or an artificial hip joint, and preparation methods thereof, the ceramic coating being provided on the surface of a metallic or ceramic material, consisting of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, and having a crack-free and dense structure.
[Technical Solution]
In order to accomplish the above objects, the present invention provides a bioactive ceramic coating, which is coated onto the surface of a metallic material or a ceramic material, including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 μm, and non-crystalline grains, and has a density of greater than 95% and a thickness ranging from 0.1 to 100 μm.
In addition, the present invention provides a method of preparing a bioactive ceramic coating comprising the steps of: (a) subjecting bioactive ceramic powder consisting of ultrafine particles to a first heat treatment at a temperature between 1,000°C and l,300°C; (b) applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 to 5 μm; (c) subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200°C and l,100°C; (d) coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in a vacuum atmosphere at room temperature; and (d) heat treatment after coating at a temperature between 200°C and 500°C.
[Advantageous Effects]
In accordance with the present invention, the bioactive ceramic coating having excellent biocompatibility, which is fabricated onto a metallic or ceramic material, consists of crystalline grains, having an average diameter of less than 100 nm, and non-crystalline grains, and has a crack-free and dense structure, thereby being useful in bone reconstruction, for example, as a surgical implant or an artificial hip joint.
[Description of Drawings] FIG. 1 is a graph showing the particle size distribution of hydroxyapatite powder that is two-step heat-treated according to an embodiment of the present invention; FIG. 2 is a schematic presentation of a coating apparatus for applying hydroxyapatite powder according to an embodiment of the present invention;
FIG. 3 is a cross-sectional SEM micrograph of a hydroxyapatite coating, which is fabricated on a substrate using the coating apparatus of FIG. 2, the SEM micrograph showing that the coating is highly dense and rarely porous;
FIG. 4 shows a TEM micrograph and an electron beam diffraction pattern of a hydroxyapatite coating according to an embodiment of the present invention; FIG. 5 is a surface SEM micrograph of a hydroxyapatite coating that is further heat-treated after two-step heat treatment according to an embodiment of the present invention;
FIG. 6 is a graph showing the X-ray diffraction patterns of a hydroxyapatite coating before and after additional heat treatment according to an embodiment of the present invention, the X-ray diffraction showing the crystallinity of the coating;
FIG. 7 is a photo of a hydroxyapatite coating as a comparative example;
FIG. 8 is a graph showing the particle size distribution of fluoridated hydroxyapatite powder that is two-step heat-treated according to an embodiment of the present invention;
FIG. 9 is a SEM micrograph of a fluoridated hydroxyapatite coating according to an embodiment of the present invention;
FIG. 10 is an energy-dispersive X-ray spectrum (EDS) of a fluoridated hydroxyapatite coating according to an embodiment of the present invention; FIG. 11 is a surface SEM micrograph of a fluoridated hydroxyapatite coating that is further heat-treated after two-step heat treatment according to an embodiment of the present invention;
FIG. 12 is a graph showing the particle size distribution of β-tricalcium phosphate powder that is two- step heat-treated according to an embodiment of the present invention;
FIG. 13 is a surface SEM micrograph of a β-tricalcium phosphate coating according to an embodiment of the present invention;
FIG. 14 is a graph showing the X-ray diffraction pattern of a β-tricalcium phosphate coating according to an embodiment of the present invention;
FIG. 15 is a surface SEM micrograph of a β-tricalcium phosphate coating that is further heat-treated after two- step heat treatment according to an embodiment of the present invention;
FIG. 16 is a graph showing the cell viability on a hydroxyapatite coating according to an embodiment of the present invention; and FIG. 17 is a graph showing the alkaline phosphatase (ALP) activity of human bone marrow stem cells on a hydroxyapatite coating according to an embodiment of the present invention.
[Best Mode] The present invention is directed to a bioactive ceramic coating having excellent biocompatibility.
The coating of a bioactive ceramic (e.g., hydroxyapatite, fluoridated hydroxyapatite, β-tricalcium phosphate and mixtures thereof) is coated onto the surface of a metallic material or a ceramic material, including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 μm, and noncrystalline grains, and has a density of greater than 95% and a thickness ranging from 0.1 to 100 μm. The metallic material or the ceramic material, including alumina or zirconia, serves as a substrate material that supports the bioactive ceramic coating of the present invention. The substrate material is not particularly limited, but is preferably stainless steel, titanium or an alloy thereof, and more preferably a titanium metal.
Crystalline particles in the coating have an average diameter less than 0.1 μm, and preferably ranging from 0.1 μm to 0.001 μm, within which the functions of osteoblasts are remarkably enhanced, leading to new bone synthesis, thereby accelerating recovery from bone damage.
The ceramic coating preferably has a thickness ranging from 0.1 μm to 100 μm. When the ceramic coating is less than 0.1 μm thick, it is difficult to uniformly coat the entire surface of a substrate material. When the thickness exceeds 100 μm, the coating is easily detached and does not have uniform thickness.
The bioactive ceramic coating has an internal density of greater than 95%, that is, from 95% to 100%, which aids in the attachment and proliferation of osteoblasts on the coating leading to new bone synthesis.
In addition, the present invention provides a method of preparing a bioactive ceramic coating having excellent biocompatibility. With the method, the bioactive ceramic coating has increased crystallinity through first and second heat treatment steps for powder preparation and an additional third heat treatment step, which is performed after coating formation.
The method comprises the steps of: (a) subjecting bioactive ceramic powder, consisting of ultrafine particles, to a first heat treatment at a temperature between l,000°C and l,300°C; (b) applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 to 5 μm; (c) subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200°C and l,100°C; and (d) coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in a vacuum atmosphere at room temperature.
Step (a) includes subjecting hydroxyapatite powder or calcium phosphate powder or mixtures thereof consisting of ultrafine particles to the first heat treatment at a temperature between l,000°C and l,300°C. The bioactive ceramic raw material powder is commercially available. The raw material powder may have an average particle diameter from 10 ran to 20 nm, but the present invention is not limited thereto because it is enough merely to adjust the size of powder particles to a range approximate to the desired final particle diameter through the first heat treatment.
Examples of the bioactive ceramic raw material powder suitable for use in the present invention include hydroxyapatite (HA), fluoridated hydroxyapatite (FHA) and tri-calcium phosphate (TCP) powders.
The first heat treatment is carried out at a relatively high temperature, preferably between l,000°C and l,300°C. Within this temperature range, the resulting primary powder has an average particle diameter ranging from 5 μm to 20 μm, which is approximate to the desired final particle diameter.
Step (b) includes applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 μm to 5 μm. The mechanical impact force applied increases the amount of cracking, or internal energy stored as dislocations in fine crystals constituting the raw material particles, and to reduce the impact force or pressure that is required to break up the coating material ultrafine particles, which is applied upon the post-step coating formation, thereby facilitating the crushing of particles upon coating formation.
For this, the powder particles first heat-treated at step (a) preferably have an average particle diameter ranging from 0.1 μm to 5 μm after a mechanical impact force is applied thereto.
The mechanical impact force is applied, for example, using a ball mill, but the present invention is not limited thereto. Step (c) includes subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200°C and l,100°C.
At step (c) , which is carried out in order to prepare bioactive ceramic powder for aerosol powder spray coating at the post-step, the powder obtained through the second heat treatment has an average particle diameter ranging from 3 μm to 5 μm, and particles greater than 5 μm in diameter have a volume fraction of less than 50%, preferably less than 35%, and more preferably less than 20%, relative to the total amount of particles. This is important because the powder thus obtained is pulverized at the post-step powder spray coating within the above range so as to provide a coating having a desired grain size distribution of less than 100 nm.
Step (d) includes spraying and coating the bioactive ceramic powder obtained at step (c) onto the surface of a metallic material or a ceramic material, including alumina or zirconia, in vacuum atmosphere at room temperature.
The coating of the bioactive ceramic powder on a substrate may be performed using a coating apparatus, which is shown in FIG. 2. Referring to FIG. 2, the coating apparatus comprises a powder suspension container 1, in which a gas inlet is provided at a lower part thereof and which contains the bioactive ceramic coating powder of the present invention; a nozzle outlet 3 which communicates with the powder suspension container 1 through a nozzle, is provided at an opposite terminal end of the nozzle and allows the bioactive ceramic coating powder to be sprayed therethrough onto a metallic substrate 4, such as titanium or an alloy thereof, or a ceramic substrate 4, such as alumina or zirconia; a vacuum pump 5 which controls the level of vacuum of a vacuum chamber 2; and a motor stage 6 which moves in a right-and-left direction so as to provide an uniform coating on the substrate 4.
In order to fabricate a ceramic coating on the substrate using the coating apparatus, the bioactive ceramic powder prepared in step (c) is placed into the powder suspension container 1, and is shattered by shaking the powder suspension container 1 longitudinally or through other movements, for example, vibration using a vibrator, while a suitable amount of oxygen is supplied through the gas inlet provided in the bottom of the powder suspension container 1. The oxygen supplied into the powder suspension container 1 passes through the nozzle and arrives at the nozzle outlet 3 in the vacuum chamber 2 while carrying the suspended bioactive ceramic particles. The bioactive ceramic particles are sprayed through the nozzle outlet in a direction perpendicular to the substrate to be coated, for example, onto the titanium metal substrate 4, which is placed in the vacuum chamber 2, which is maintained in a vacuum state at ambient temperature (about 25°C), thereby forming a coating that consists of crystalline grains, having a grain size distribution of less than 100 nm, and non-crystalline grains, and has a thickness ranging from 0.1 μm to 100 μm.
The vacuum chamber 4 is preferably maintained in a vacuum state ranging from 0.1 torr to 3X10~2 torr. Within this range of vacuum state, the coating is composed of crystalline grains and non-crystalline grains, as desired, and has a density of greater than 95%, and preferably 95% to 100%.
The present method may further include subjecting the coating obtained at step (d) to an additional third heat treatment at a temperature lower than 500°C, preferably between 500°C and 300°C, for 30 to 60 minutes. The third heat treatment may be carried out in air atmosphere. As shown in FIGS. 5 and 6, the bioactive ceramic coating has much higher crystallinity than that before the heat treatment .
The resulting bioactive ceramic coating consists of crystalline grains, having an average diameter of less than 0.1 μm, and non-crystalline grains, and has a thickness ranging from 0.1 μm to 100 μm.
[Mode for Invention]
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention. EXAMPLE 1: Preparation of hydroxyapatite (HA) coating
(1) Two-step heat treatment
Hydroxyapatite (HA) powder having an average primary particle diameter of 12 ran, which was commercially purchased, was heated in air at 1200°C for 2 hrs to provide an average particle diameter of 16.6 μm. The HA powder was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, thereby crushing the particles to an average particle diameter of 3.2 μm and a maximum particle diameter of less than 30 μm. The crushed HA powder was then heat-treated at 900°C for 2 hrs to yield HA powder for powder spray coating.
FIG. 1 shows the particle size distribution of the HA powder thus obtained. As shown in FIG. 1, the HA powder had an average particle diameter of 3.9 μm, while particles greater than 5 μm in diameter had a volume fraction of 32% relative to all particles.
(2) Formation of HA coating
The HA powder prepared as described above was placed into the powder dispersion container 1 of FIG. 2. The powder dispersion container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder dispersion container 1. The oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered HA particles. The HA particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate. The vacuum chamber 2 was maintained at a vacuum level of 2X10"2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm. (3) Evaluation The formed coating was analyzed using scanning electron microscopy (SEM) , transmission electron microscopy (TEM) and X-ray diffraction. As shown in FIG. 3, the HA coating was found to be 40 μm thick and dense. FIG. 4 shows the TEM micrograph and the electron beam diffraction pattern of the formed hydroxyapatite layer. As shown in FIG. 4, the hydroxyapatite layer was present as a mixture of crystalline grains and non-crystalline grains, and the crystalline grains had an ultrafine size, less than several tens of nanometers. It is advantageous for bone reconstruction for hydroxyapatite to be present in a mixed state of crystalline grains and non-crystalline grains (H. Wang, N. Eliaz, Z. Xiang, H. P. Hsu, M. Spector, L.W. Hobbs, Biomaterials 27 (2006) 4192-4203) .
As shown in the SEM micrograph of FIG. 3 and the TEM micrograph of FIG. 4, showing the fine structure of the HA coating, the HA coating was found to be highly dense and almost crack-free.
EXAMPLE 2: Third heat treatment of the HA coating
The HA coating on the titanium metal substrate, prepared in Example 1, was subjected to a third heat treatment for 1 hr in ambient atmosphere at 350 "C (Example 2- a), 450°C (Example 2-b) and 500 "C (Example 2-c) .
Specimens of Examples 2-a, 2-b and 2-c were examined through scanning electron microscopy, and the resulting SEM micrographs are given in FIG. 5. As shown in FIG. 5, specimens of Examples 2-a, 2-b and 2-c were found to be maintained intact with no cracking.
In addition, specimens of Example 1 and Example 2-c were evaluated for X-ray diffraction patterns, and the results are given in FIG. 6. As shown in FIG. 6, the Example 2-c specimen exhibited a diffraction intensity greater than that of the Example 1 specimen, and had a new crystal peak. These results indicated that the crystallinity of the Example 2-c specimen was improved more than before the third heat treatment.
EXAMPLE 3: Preparation of fluoridated hydroxyapatite coating
(1) Two-step heat treatment First, calcium fluorapatite (FA, Caio (PO4) 6F2) was synthesized from a mixture of β-tricalcium phosphate
(Ca3(PC>4)2) and calcium fluoride (CaF2)/ which were commercially purchased and had an average primary particle diameter of about 20 run at a molar ratio of 3:1. Calcium fluorapatite (FA) powder and hydroxyapatite (HA) powder were mixed and heated in air at 1200 °C for 2 hrs. The powder mixture was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, and was then heat-treated at 900°C for 2 hrs, thereby yielding fluoridated hydroxyapatite (FHA, Ca1O (PO4) 6F2x(OH) 2-2x) powder for powder spray coating.
FIG. 8 shows the particle size distribution of the FHA powder thus obtained. As shown in FIG. 8, the FHA powder had an average particle diameter of 4.08 μm, while particles greater than 5.2 μm in diameter had a volume fraction of 37% relative to the total particles. (2) Formation of FHA coating
The FHA powder prepared as described above was placed into the powder suspension container 1 of FIG. 2. The powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder dispersion container 1. The oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered FHA particles. The FHA particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate. The vacuum chamber 2 was maintained at a vacuum level of 2 X ICT2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm. (3) Evaluation
The formed coating was analyzed using scanning electron microscopy (SEM) , transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS) . As shown in FIG. 9, the FHA coating was found to be 10 μm thick and dense. FIG. 10 is the energy-dispersive X-ray spectrum of the formed HFA layer. As shown in FIG. 10, fluorine atoms were detected in the membrane, thereby confirming that the prepared membrane was the HFA layer.
EXAMPLE 4: Third heat treatment of the FHA coating
The FHA coating on the titanium metal substrate, prepared in Example 3, was subjected to a third heat treatment for 1 hr in ambient atmosphere at 500 °C. The FHA coating was then examined through scanning electron microscopy, and the resulting SEM micrograph is given in FIG. 11.
EXAMPLE 5: Preparation of β-tricalcium phosphate coating (1) Two-step heat treatment β-tricalcium phosphate (Ca3 (PO4) 2) powder having an average primary particle diameter of 20 run, which was commercially purchased, was heated in air at 1200°C for 2 hrs. The powder was ball-milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container, and was then heat-treated at 900°C for 2 hrs, thereby yielding β- tricalcium phosphate (β-TCP) powder for powder spray coating.
FIG. 12 shows the particle size distribution of the β- TCP powder thus obtained. As shown in FIG. 12, the β-TCP powder had an average particle diameter of 4.1 μm, while particles greater than 5 μm in diameter had a volume fraction of 38% relative to the total particles.
(2) Formation of β-TCP coating The β-TCP powder, prepared as described above, was placed into the powder suspension container 1 of FIG. 2. The powder suspension container 1 was reciprocated longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1. The oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered β-TCP particles . The β-TCP particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate. The vacuum chamber 2 was maintained at a vacuum level of 2X10"2 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm. (3) Evaluation
The formed β-TCP coating was analyzed using scanning electron microscopy (SEM) and X-ray diffraction. As shown in FIG. 13, the β-TCP coating was found to be 10 μm thick and dense. FIG. 14 shows an X-ray diffraction pattern of the formed β-TCP coating.
EXAMPLE 6: Third heat treatment of the β-TCP coating
The β-TCP coating on the titanium metal substrate, prepared in Example 5, was subjected to a third heat treatment for 1 hr in ambient atmosphere at 500°C The β-TCP coating was then examined through scanning electron microscopy, and the resulting SEM micrograph is given in FIG. 15.
COMPARATIVE EXAMPLE 1: Preparation of hydroxyapatite coating
Hydroxyapatite powder, which was commercially purchased, was heated in air at 1200 °C for 2 hrs . Then, the hydroxyapatite powder was placed into the powder suspension container 1 of FIG. 2. The powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1. The oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered hydroxyapatite particles . The hydroxyapatite particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate. The vacuum chamber 2 was maintained at a vacuum level of 1 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm. When the HA powder was sprayed onto the substrate, no coating was formed on the substrate.
COMPARATIVE EXAMPLE 2: Preparation of hydroxyapatite coating
Hydroxyapatite powder, which was commercially purchased, was heated in air at 1200 °C for 2 hrs and ball- milled for 24 hrs using zirconia balls 5 mm in diameter and a plastic container. The ground hydroxyapatite powder was dried at 120°C for 8 hrs. Then, the hydroxyapatite powder was placed into the powder suspension container 1 of FIG. 2. The powder suspension container 1 was shaken longitudinally while oxygen was supplied at a rate of 10 L/min through the gas inlet provided in the bottom of the powder suspension container 1. The oxygen supplied into the powder suspension container 1 passed through the nozzle and arrived at the nozzle outlet 3 located in the vacuum chamber 2 while carrying the shattered hydroxyapatite particles. The hydroxyapatite particles were projected through the nozzle outlet 3 against the titanium metal substrate 4 in a direction perpendicular to the substrate. The vacuum chamber 2 was maintained at a vacuum level of 1 torr, and the nozzle outlet 3 was spaced apart from the substrate 4 by a distance of 5 mm.
As shown in FIG. 7, the formed HA coating was not dense, and had poor adhesion to the substrate.
TEST EXAMPLE 1: Evaluation of cell viability on the HA coating
The cell proliferation on the HA coating prepared in Example 1 was estimated. MG-63 cells (osteoblast-like cell line, American Type Culture Collection (ATCC) No. CRL-1427, USA) were seeded onto and allowed to grow on the HA-coated titanium substrate (HA/Ti) , prepared in Example 1, and a non- coated titanium substrate not having a HA coating.
The cells were cultured in Dulbecco's Modified Eagle Medium (DMEM, Gibco, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, USA) and 1% penicillin/streptomycin (P/S; Hyclone, USA) in an incubator at 37 °C under 5% CO2.
After 1, 3 and 5 days, cell proliferation was examined using an MTT assay (Cell Proliferation Kit I, Boehringer Mannheim, Mannheim, Germany) . The absorbance was measured at 595 nm using an ELISA reader (Synergy HT, Bio-Tek Instruments, Inc, Winooski, VT, USA) .
TABLE 1 Cell proliferation rates
As shown in Table 1 and FIG. 16, compared to the non- coated titanium substrate, the HA-coated Ti substrate (HA/Ti) exhibited improvements in cell proliferation of 7%, 6% and 23% after 1, 3 and 5 days, respectively. These results indicated that the HA coating had more favorable cell viability.
TEST EXAMPLE 2: Evaluation of differentiation of human bone marrow stem cells on the HA coating
The differentiation behavior of human bone marrow stem cells on HA coatings was determined by assaying the ALP activity of the cells. In order to evaluate the differentiation of human bone marrow stem cells (hBMSC) into osteoblasts by assaying the alkaline phosphatase (ALP) activity of the cells, hBMSC cells (PT-2501, Cambrex Bio Science Walkersville, Inc., USA) were seeded onto and allowed to grow on the HA-coated titanium substrate, prepared in Example 1, the HA-coating titanium substrates of Examples 2-a and 2-b, heat-treated at 350°C and 450 °C, respectively, and a titanium substrate not coated with an HA coating. The cells were cultured in a differentiation medium, which was Dulbecco' s Modified Eagle Medium/low glucose (DMEM/LG, Gibco, USA) supplemented with 10% FBS (Gibco, USA) and 1% penicillin/streptomycin (P/S; Hyclone, USA) and were supplemented with 10"8 M of dexamethasone, 10 mM of β- glycerophosphate and 50 μ g/ml of L-ascorbic acid, in an incubator at 37°C under 5% CO2.
After 21 days, the ALP activity, an early marker of osteoblastic differentiation, was determined by measuring absorbance at 405 nm using an ELISA reader (Synergy HT, Bio- Tek Instruments, Inc, Winooski, VT, USA) .
TABLE 2 Alkaline phosphatase activity
As shown in Table 2 and FIG. 17, compared to the non- coated Ti, HA-coated titanium substrates of Examples 1, 2-a and 2-b exhibited higher ALP activity. In particular, the HA-coated Ti substrate that was additionally heat-treated at 350°C (Example 2-a) displayed the highest ALT activity.

Claims

[CLAIMS] [Claim l]
A bioactive ceramic coating which is coated onto a metallic material or a ceramic material, including alumina or zirconia, consists of crystalline grains, having an average diameter of less than 0.1 μ m, and non-crystalline grains, and has a density of greater than 95% and athickness ranging from 0.1 μ mto lOO μ m.
[Claim 2]
A method of preparing a bioactive ceramic coating comprising the steps of:
(a) subjecting bioactive ceramic powder consisting of ultrafine particles to a first heat treatment at a temperature between 1 ,000 °C and 1 , 300 °C ;
(b) applying a mechanical impact force to the powder obtained at step (a) so as to crush powder particles and provide an average particle diameter ranging from 0.1 to 5 μ m;
(c) subjecting the powder obtained at step (b) to a second heat treatment at a temperature between 200 °C and 1,100 "C; and
(d) coating the bioactive ceramic powder obtained at step (c) onto a surface of a metallic material or a ceramic material, including alumina or zirconia, in a vacuum atmosphere at room temperature.
[Claim 3] The method as set forth in claim 2 , further comprising subjecting the coating obtained at step (d) to a third heat treatment at a temperature lower than about 500 °C for 30 to 60 minutes so as to increase crystallinity of the coating .
[Claim 4]
The method as set forth in claim 2, wherein the powder obtained through the first heat treatment of step (a) has an average particle diameter ranging from 5 μ m to 20 μ m.
[Claim 5]
The method as set forth in claim 2, wherein the bioactive ceramic powder of step (a) is hydroxyapatite (HA), fluoridated hydroxyapatite (FHA), β -tricalcium phosphate (β-TCP) powder or mixtures thereof.
[Claim 6]
The method as set forth in claim 2 , wherein the powder obtained through the second heat treatment has an average particle diameter ranging from 3 μ m to 5 μ m, and particles greater than 5 μ m in diameter have a volume fraction of less than 50% relative to the total particles.
[Claim 7]
The method as set forth in claim 2, wherein the coating at step (d) is performed at a vacuum level ranging from 0.1 torrto 3X10"2torr.
[Claim 8] A bioactive ceramic coating which is prepared according to any one of claims 2 to 6.
EP07768796A 2006-09-28 2007-07-18 Bio active ceramic coatings with excellent bio-compatibility and preaparation method thereof Withdrawn EP2071916A4 (en)

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KR101223015B1 (en) * 2008-12-24 2013-01-17 재단법인 포항산업과학연구원 The coating method of hydroxyapatite and coating apparatus
KR101081687B1 (en) 2008-12-30 2011-11-09 고려대학교 산학협력단 Method of fabricating bio-materials
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KR102002176B1 (en) * 2012-10-16 2019-07-23 (주)코미코 Method of manufacturing a hydroxyapatite powder for blast
CN103463681B (en) * 2013-09-16 2015-01-14 同济大学 Method for preparing biodegradable magnesium alloy surface modification fluoridated hydroxyapatite coating
KR102286394B1 (en) 2020-11-24 2021-08-06 주식회사 오스메딕 Method for hydroxyapatite coating of biomaterials and biomaterials coated by hydroxyapatite using the same
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