WO2007074968A1 - Implant dentaire revêtu d'une protéine morphogénique osseuse recombinée et procédé de revêtement de celui-ci - Google Patents

Implant dentaire revêtu d'une protéine morphogénique osseuse recombinée et procédé de revêtement de celui-ci Download PDF

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Publication number
WO2007074968A1
WO2007074968A1 PCT/KR2006/004234 KR2006004234W WO2007074968A1 WO 2007074968 A1 WO2007074968 A1 WO 2007074968A1 KR 2006004234 W KR2006004234 W KR 2006004234W WO 2007074968 A1 WO2007074968 A1 WO 2007074968A1
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WIPO (PCT)
Prior art keywords
implant
coated
bone morphogenic
morphogenic protein
dental implant
Prior art date
Application number
PCT/KR2006/004234
Other languages
English (en)
Inventor
Soo Hong Kim
Original Assignee
Cowellmedi Co., Ltd.
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
Priority claimed from KR1020060059457A external-priority patent/KR100736826B1/ko
Application filed by Cowellmedi Co., Ltd. filed Critical Cowellmedi Co., Ltd.
Priority to US11/719,740 priority Critical patent/US7879092B2/en
Publication of WO2007074968A1 publication Critical patent/WO2007074968A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
    • A61C8/0013—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy with a surface layer, coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
    • A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
    • A61C8/0016—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy polymeric material
    • 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
    • A61F2310/00976—Coating or prosthesis-covering structure made of proteins or of polypeptides, e.g. of bone morphogenic proteins BMP or of transforming growth factors TGF
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses

Definitions

  • the present invention relates to a dental implant coated with recombinant bone morphogenic protein and a coating method thereof, and more particularly to a dental implant having a recombinant bone morphogenic protein coated on the processed surface thereof, which, when implanted into the jawbone, enables undifferentiated adult cells around the implant site to be rapidly differentiated into osteoblasts so as to induce osteoconductive healing to thereby reduce a healing period, as well as a coating method thereof.
  • osteoblasts derived from the surrounding bone tissue differentiate into new bone tissue in an osteoconductive and osteoinductive healing process.
  • the new bone tissue adheres closely to the implant surface, so that the osseointegration of the implant with the surrounding bone tissue occurs to resist masticatory forces.
  • the blood clots serve to stop the bleeding by blocking the broken blood vessels from an external environment and to store the released grown factors and acts to provide a temporary substrate for cell migration such that various cells required for bone formation or the treatment of inflammations can migrate to sites to be treated. Then, an angiogenesis process and a fibrous tissue formation process progress over about 4 weeks, while granulation tissue is formed and help undifferentiated cells to differentiate into osteoblasts. Then, the osteoblasts differentiate and develop into bone cells to form woven bone. The time required up to the formation of the woven bone is known to be about 2 months.
  • the formation of the woven tissue is a phenomenon that abnormally rapidly occurs due to a wound, the histological structure thereof is irregular compared to that of normal bone tissue, and thus the bone density thereof is also relatively low.
  • the bone cells thereof are replaced with lamella bone having hard bone tissue.
  • the implant is connected with the surrounding bone tissue, while the deposition of bone on the implant is completed and osseointegration between the implant and the bone tissue is completed through a bone remodeling process, so that the implant performs functions under normal forces.
  • the time required for adaptation to the implant is 2-4 months depending on persons.
  • the time for the bone tissue adhered to the interface with the implant to reach a level capable of mastication is 3-5 months for the lower jaw and 6-8 months for the upper jaw.
  • This process is called a healing period , in which bone cells naturally undergo a healing process in a normal human body.
  • external stimuli such as inflammations or occlusal forces to the inserted implant should be limited such that the adhesion of bone tissue to the implant can be successively achieved. For this reason, a patient cannot masticate food for a long period of time and must continue to maintain oral hygiene performance to prevent infections.
  • technology for rapidly differentiating the surrounding undifferentiated adult cells into bone cells have been studied and developed in various ways.
  • BMPs recombinant human bone morphogenic proteins
  • Methods of medical surgery using such recombinant bone morphogenic proteins (BMPs) are applied used in a wide range of fields, one of which is implant surgery. Disclosure of Invention Technical Problem
  • Korean Patent Publication No. 2005-58452 discloses an implant for implantation into either a bone tissue or a bone tissue supplemented with a bone substitute material.
  • the surface of the implant which comes into contact with bone tissue or grows around bone tissue or together with bone tissue, comprises a first-type region and a second-type region different from the first-type region, in which the first-type surface region is formed of compounds having the effects of bone integration, inflammation inhibition, infection treatment and growth stimulation effects so as to have a structure suitable for the growth of bone tissue.
  • the first-type surface region is, for example, a biologically compatible surface made of, for example, titanium, and can be formed to have a structure suitable for the growth of bone tissue. Also, this surface can be additionally coated with a material containing calcium phosphate, can be modified with, for example, phosphate or peptide sequences and/or is made of a material, which can contain, for example a gel or polymer containing growth factors. For this reason, there are problems in that, in order to coat the growth-stimulating factors on the implant surface, the implant surface must be coated with either the calcium phosphate- containing material for fixing the growth-stimulation factors onto the implant surface or a fixture such as a gel or polymer containing the growth-stimulating factors.
  • the present invention aims to develop a method for coating recombinant bone morphogenic proteins (BMPs) on the surface of an implant, such that the coated implant enables to undifferentiated adult cells around the surgical site of the implant to be rapidly differentiated into osteoblasts so as to induce osteoconductive healing to thereby reduce a healing period.
  • BMPs bone morphogenic proteins
  • an object of the present invention is to provide a dental implant coated with recombinant bone morphogenic protein, which is obtained by coating the implant surface directly with recombinant bone morphogenic proteins by freeze drying in a negative-pressure atmosphere, without using a fixture for fixing the recombinant bone morphogenic proteins on the implant surface, and which, when the implant is implanted into the jawbone, enables undifferentiated adult cells around the implant site to be rapidly differentiated into osteoblasts so as to induce osteoconductive healing to thereby reduce a healing period, as well as a coating method thereof.
  • Another object of the present invention is to provide a dental implant coated with recombinant bone morphogenic protein, which does not employ any adhesive polymer for coating, and thus does not substantially cause a tissue inflammatory reaction for absorbing the polymer, as well as a coating method thereof.
  • Still another object of the present invention is to provide a dental implant coated with recombinant bone morphogenic protein, which is obtained by either embossing the implant surface with ceramic balls, or forming a sheet structure on the implant surface using calcium triphosphate or forming fine pores on the implant surface by anodic oxidation, and then coating recombinant bone morphogenic protein on the treated implant surface, such that the recombinant bone morphogenic protein is not easily detached from the implant surface during the surgical implantation of the implant, as well as a coating method thereof.
  • Yet another object of the present invention is to provide a dental implant coated with recombinant bone morphogenic protein, which has little or no side effects resulting from the bone morphogenic protein, because a minimum amount of the protein locally acts on tissue around the implant site, as well as a coating method thereof.
  • Still another further object of the present invention is to provide a dental implant coated with recombinant bone morphogenic protein, in which the bone morphogenic protein show pharmacological effects to enable undifferentiated adult cells around the implant to be differentiated into osteoblasts so as to induce enhanced osteoconductive healing, to thereby significantly reduce the osseointegration period of the implant, as well as a coating method thereof.
  • the implant surface having fine pores formed thereon is coated with the recombinant bone morphogenic protein by freeze drying in a negative-pressure atmosphere.
  • the coating film formed of the recombinant bone morphogenic protein is fixed to the fine pores formed on the implant surface, it is not peeled from the implant surface.
  • the implant does not employ any adhesive polymer for coating, and thus does not substantially cause a tissue inflammatory reaction for the absorption of the polymer.
  • recombinant bone morphogenic protein BMP-2 penetrates between the ceramic balls formed on the dental implant surface, the sheet structures of calcium triphosphate or the fine pores formed by anodic oxidation, so as to form a coating film.
  • the recombinant bone morphogenic protein BMP-2 is not detached from the dental implant surface even during the surgical implantation of the implant.
  • the recombinant bone morphogenic protein coated on the surface of the dental implant is coated mainly on the deep valley of the implant surface, it can be prevented from being peeled due to mechanical friction during the surgical implantation of the implant.
  • a minimum amount of the protein coated on the implant surface locally acts on tissue around the implant site, the protein has little or no side effects.
  • FlG. 1 is a cross-sectional view of a dental implant coated with recombinant bone morphogenic protein according to the prior art.
  • FlG. 2 is a 20-fold enlarged SEM photograph showing a state in which a recombinant bone morphogenic protein was coated on a dental implant surface using a method like the example of FlG. 1.
  • FlG. 3 is a 20-fold enlarged SEM photograph showing a state in which a recombinant bone morphogenic protein was coated on a dental implant surface using a method like the example of FlG. 1 in a manner different from the state of FlG. 2.
  • FlG. 4 is a perspective view of another implant coated with recombinant bone morphogenic protein according to the prior art.
  • FlG. 5 is a 2,000-fold enlarged SEM photograph showing a state in which fine pores having a size of 0.1-6 D were formed on a dental implant surface by anodic oxidation treatment according to the present invention.
  • FIG. 6 is a 2,000-fold enlarged SEM photograph showing a state in which fine pores having a size of 0.1-6 D, which are different from those of FlG. 5, were formed on a dental implant surface by anodic oxidation treatment according to the present invention.
  • FlG. 7 is a 3,000-fold enlarged SEM photograph showing a state in which fine pores having a size of 0.1-6 D were formed on a dental implant surface by spark-anodic oxidation according to the present invention.
  • FIG. 8 is a 2,000-fold enlarged SEM photograph showing a state where the photograph of FIG. 7 was seen in inclined direction.
  • FIG. 9 is a 2,000-fold enlarged SEM photograph showing a state in which an unsaturated protein solution was coated on a dental implant surface according to the present invention and, as a result, the protein solution was encapsulated into less than 1 D of fine pores distributed on the valley of the surface.
  • FIG. 10 is 2,000-fold enlarged SEM photograph showing a state in which a saturated protein solution was coated on a dental implant surface according to the present invention and, as a result, a surplus of the protein mass was bound to the protein film coated on less than 1 D of fine pores.
  • FIG. 11 is a photograph showing a 0.5-ml polypropylene tube.
  • FlG. 12 is a photograph showing a 1.5-ml polypropylene tube.
  • FlG. 13a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface before coating the implant surface with ceramic balls.
  • FIG. 13b is a 3,000-fold enlarged SEM photograph showing a dental implant surface before its coating with ceramic balls, but after its coating with a recombinant bone morphogenic protein solution.
  • FIG. 14a is a 20-fold enlarged SEM photograph showing the surface of a dental implant surface coated with ceramic balls.
  • FlG. 14b is a 3,000-fold enlarged SEM photograph showing the state of a ceramic ball-coated dental implant surface after coating a recombinant bone morphogenic protein on the surface.
  • FIG. 15a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface before its coating with calcium triphosphate.
  • FIG. 15b is a 3,000-fold enlarged SEM photograph showing the state of a dental implant surface before its coating with calcium triphosphate, but after its coating with recombinant bone morphogenic protein.
  • FIG. 14a is a 20-fold enlarged SEM photograph showing the surface of a dental implant surface coated with ceramic balls.
  • FlG. 14b is a 3,000-fold enlarged SEM photograph showing the state of a ceramic ball-coated dental implant surface after coating a recombinant bone morphogenic protein on the surface.
  • FIG. 16a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface coated with calcium triphosphate.
  • FIG. 16b is a 3,000-fold enlarged photograph of a calcium triphosphate-coated dental implant surface after coating a recombinant bone morphogenic protein on the surface.
  • FIG. 17a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface before anodic oxidation treatment.
  • FIG. 17b is a 3,000-fold enlarged SEM photograph showing the state of a dental implant surface before anodic oxidation treatment, but after coating a recombinant bone morphogenic protein on the surface.
  • FIG. 17a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface coated with calcium triphosphate.
  • FIG. 16b is a 3,000-fold enlarged photograph of a calcium triphosphate-coated dental implant surface after coating a recombinant bone morphogenic protein on the surface.
  • FIG. 17a
  • FIG. 18a is a 20-fold enlarged SEM photograph showing the state of a dental implant surface after anodic oxidation treatment.
  • FIG. 18b is a 3,000-fold enlarged SEM photograph showing the state of an anodic oxidized dental implant surface after coating a recombinant bone morphogenic protein on the surface.
  • a method for coating a recombinant bone morphogenic protein on the surface of a dental implant comprises:
  • BMP solution preparation step 4 mg of recombinant bone morphogenic protein to 1 ml of acidic buffer solution (BMP solution preparation step); [42] iii) placing 6OD of the BMP solution of said step ii) in a 0.5-ml volume polypropylene tube and immersing in the polypropylene tube the implant having fine pores formed on the surface thereof (implant immersion step); [43] iv) placing the polypropylene tube having the implant immersed therein in a 1.5-ml volume polypropylene tube, sealing the 1.5-ml volume tube, and freezing the 1.5-ml volume tube in a freezer at -75 + 0.5 °C for 3-4 hours (first freezing step);
  • the second freeze-drying step is followed by a step of packaging the polypropylene tube in an aseptic environment and storing the packaged tube at room temperature or in a refrigerator in a dehumidified atmosphere (storage step).
  • the surface of the implant used in said step i) can be selected from the group consisting of an implant surface having a surface shape modified with a titanium oxide layer; an implant surface coated with titanium balls or ceramic balls, and an implant surface coated with calcium triphosphate.
  • dental implants having surfaces treated by other general methods can also be used in said step i).
  • Said implant having a surface shape modified with a titanium oxide layer is obtained by coating titanium on an implant surface subjected to electro-chemical treatment, mechanical sandblasting or chemical acid corrosion.
  • Said electro-chemical treatment is carried out in the following manner.
  • the electrolyte solution is placed in an electrolytic bath, in which a cathode and an anode are electrically connected with a titanium rod and the implant, respectively.
  • the implant is subjected to anodic oxidation treatment by applying constant current in conditions of current density of 1-10 A/dm and voltage of 150-250 V.
  • this oxide coating film formed on the implant surface has 0.1-6 D of fine pores formed therein.
  • the distance between the cathode and the anode is set at 5 cm, and the temperature of the electrolyte solution is 20 °C.
  • FIG. 7 The fine pores formed on the implant surface by the above spark-anodic oxidation process are shown in detail in a photograph in FIG. 7.
  • the fine pores having a size of 0.1-6 D are formed on the implant surface as a result of the spark-anodic oxidation.
  • FIG. 8 shows the observation of the fine pores of FIG. 7 in an inclined direction. As shown in FIG. 8, fine pores having a size of more than 1 D have a crater higher than that of the surrounding fine pores, whereas fine pores having a size of less than 1 D are distributed in deep valleys between great craters.
  • said implant having a surface coated with titanium balls or ceramic balls is prepared in the following manner. First, an implant body is prepared by mechanical cutting, and then the surface of the implant body is coated with titanium balls or ceramic balls by a high-temperature spraying process using a plasma spray such that it can show a roughness of about 15D.
  • the recombinant bone morphogenic protein solution is prepared by adding 4 mg of recombinant bone morphogenic protein to 1 ml of acidic buffer solution.
  • the term "acidic buffer solution” refers to a MES (2- ⁇ N-morpholino ⁇ ethanesulfonic acid) buffer solution having an acidity of 5.0. If the amount of the recombinant bone morphogenic protein, which is added to the acidic buffer solution, is less than 4 mg, the effect of the BMP protein can be reduced, because the amount of the coated BMP is too low.
  • the recombinant bone mor- phogenetic protein used herein is preferably a BMP-2 in terms of functions.
  • the implant having the fine pores formed thereon is immersed in the recombinant bone morphogenic protein solution prepared in said step ii), such that the recombinant bone morphogenic solution can be coated in the fine pores.
  • FIG. 9 The process, in which the recombinant bone morphogenic protein solution is coated in the fine pores, is shown in a photograph in FIG. 9.
  • the protein solution is first encapsulated into less than 1 D of fine pores distributed at the valley of the surface.
  • a surplus of the protein in the form of a mass is bound to the protein film coated in the fine pores having a size of less than 1 D.
  • 1.5-ml volume polypropylene tube as shown in FIG. 12 refers to a tube having a volume greater than that of the 0.5-ml volume polypropylene tube.
  • the 1.5-ml volume polypropylene tube containing the coated implant is frozen in a freezer at a temperature of -75 0.5 °C for 3-4 hours, such that the recombinant bone morphogenic protein coated in the fine pores can be fixed to the fine pores.
  • Said step v) is carried out to evaporate water from the recombinant bone morphogenic protein coated in the fine pores as shown in the photograph of FIG. 5 or 6.
  • This step is preferably performed by opening the lid of the 1.5-ml volume polypropylene tube frozen in the freezer, placing the opened tube in a freeze dryer pre- cooled to 75 5 °C, and freeze-drying the tube in the freeze dryer at a pressure of 0.05 0.005 torr for 8 hours.
  • FIG. 5 is a 2,000-fold enlarged SEM photograph showing a state in which fine pores having a size of 0.1-6 D were formed on the implant surface by spark-anodic oxidation treatment according to the present invention.
  • FIG. 6 is a 2,000-fold enlarged SEM photograph showing a state in which fine pores having a size of 0.1-6 D, different from those of FlG. 5, were formed on the implant surface by spark- anodic oxidation treatment according to the present invention.
  • the following dental implant samples were prepared: a dental implant sample coated with ceramic balls (sample 1; FlG. 14a); a dental implant sample coated with calcium triphosphate (sample 2; FlG. 16a); and a dental implant sample subjected to anodic oxidation (sample 3; FlG. 18a). Also, as samples for comparison with said samples 1 to 3, the following dental implant samples were prepared: a dental implant sample before being coated with ceramic balls (sample 4; FlG. 13a); a dental implant sample before coating with calcium triphosphate (sample 5; FlG. 15a); and a dental implant sample before being subjected to anodic oxidation treatment (sample 6; FlG. 17b).
  • BMP-2 according to the following conditions. Specifically, in Examples 1 to 3, the recombinant bone morphogenic protein was coated on the surface of each of the dental implant samples 1 to 3, and in Comparative Examples 1 to 3, the recombinant bone morphogenic protein was coated on the surface of each of the dental implant samples 4 to 6.
  • the 0.5-ml volume polypropylene tubes each having the implant immersed therein were placed in six 1.5-ml volume polypropylene tubes, respectively, sealed and then frozen in a freezer at -75 + 0.5 °C for 3 hours.
  • the lid of each of the frozen 1.5-ml volume polypropylene tubes was opened and the opened tubes were placed in a freeze dryer pre-cooled to a temperature of -75 + 5 °C, in which the tubes were freeze- dried at a pressure of 0.05 + 0.005 torr for 8 hours.
  • the lids of the tubes were immediately closed, and the tubes were stored in a refrigerator to prevent contamination and moisture absorption.
  • the recombinant bone morphogenic protein was penetrated and impregnated between the ceramic balls, suggesting that the recombinant bone morphogenic protein BMP-2 was attached in a state where it cannot be easily detached even during the implantation of the dental implant.
  • the recombinant bone morphogenic protein BMP-2 was detached to the dental implant surface in a state where it can be easily detached during the implantation of the dental implant.
  • the recombinant bone morphogenic protein BMP-2 was penetrated between the ceramic balls or calcium triphosphate sheet structures coated on the dental implant surface or between the fine pores formed by anodic oxidation, so as to form a coating film of the protein, suggesting that the recombinant bone morphogenic protein BMP-2 was attached in a state where it cannot be easily detached even during the implantation of the dental im plant.
  • the present invention provides a dental implant coated with recombinant bone morphogenic protein, which is obtained by processing the surface of a dental implant, coating the processed surface with a solution containing recombinant bone morphogenic protein molecules, and freeze-drying the coated implant in a negative- pressure atmosphere.
  • the implant to be coated with recombinant bone morphogenic protein on the surface thereof may be any implant treated according to a suitable surface treatment method.
  • the implant to be coated with recombinant bone morphogenic protein can be selected from the group consisting of an implant having a surface modified with a titanium oxide layer, an implant having a surface coated with titanium balls or ceramic balls, and an implant having a surface coated with calcium triphosphate.
  • implants having surfaces treated by other general methods can also be used.
  • the phrase "implant having a surface modified with a titanium oxide layer” refers to an implant having a surface subjected to electro-chemical treatment, mechanical sandblasting treatment, or chemical acid corrosion treatment so as to increase the surface area of the implant. Also, the phrase “implant having a surface coated with titanium balls or ceramic balls” refers to an implant having an increased surface area achieved by attaching microscopic-size grains made of titanium or ceramic material to the implant surface at high temperature.
  • current density and voltage magnitude in treating the implant surface by spark-anodic oxidation are preferably 1-10 A/dm and 150-250 V, respectively.
  • the voltage in the anodic oxidation treatment increased with the passage of time in a constant current condition so as to generate sparks, and at a voltage of about 240 V, the current density in the anodic oxidation treatment was maintained at a substantially constant level. This is believed to be because the sparks occurred due to dielectric breakdown at the surface of the barrier layer, so that the growth of the coating film was very slow or was not increased.
  • the surface pattern of the formed oxide coating film varies with a change in the current density.
  • a very compact oxide coating layer is initially formed on the surface of the metal, and this layer becomes a barrier layer interfering with the flow of electric current with the passage of time, and then continues to grow with an increase in voltage while forming a porous surface layer.
  • the initial coating layer is broken by spark discharge and, at the same time, restored, while the initial oxide coating layer is locally heated to dissolve the surface of the coating layer.
  • innumerable pores which can be regarded as traces of the spark discharge, are created out of the barrier layer, while the total thickness of the coating layer increases.
  • anions in the electrolyte are incorporated into the coating layer by an electric field. If the magnitude of voltage is less than 150 V, the surface of the implant will not be sufficiently anodic-oxidized, so that the thickness of the oxide coating layer becomes too small, and thus, fine pores will not be sufficiently formed on the implant surface. On the other hand, if the magnitude of voltage exceeds 250 V, the surface of the implant will be excessively oxidized, so that the thickness of the oxide coating layer becomes too large, while the implant surface becomes too rough without the formation of fine pores.
  • Another implant which can be used in the present invention, is the implant coated with titanium balls or ceramic balls.
  • the implant coated with titanium balls is obtained by preparing an implant body by mechanical cutting, and coating dissolved titanium to the surface of the implant body with a plasma spray using a high-temperature spraying process. It is known that this implant surface shows a roughness of about 15D and can strongly resist rotatory powder, and osteoblasts well adhere to this implant surface. Also, this implant surface is larger in surface area than a machined surface, and thus is relatively advantageous. In addition, in an implant having a machined surface, the length thereof is emphasized, whereas, in the implant having a titanium plasma sprayed surface (TPS), the diameter thereof is of more importance than the length thereof.
  • TPS titanium plasma sprayed surface
  • the recombinant bone morphogenic protein which is coated on the implant having the above-described surface, is preferably BMP-2.
  • the recombinant bone morphogenic protein BMP-2 which is used in the present invention, is a homodimer made of a combination of two peptide molecules each consisting of 114 amino acids shown in Table 2 below.
  • A alanine
  • R arginine
  • N asparagines
  • C cystein
  • Q glutamine
  • E glutamic acid
  • G glycine
  • H histidine
  • I isoleucine
  • L leucine
  • K lysine
  • M methionine
  • F phenylalanine
  • P praline
  • S serine
  • T threonine
  • W tryptophane
  • Y tyrosine
  • V valine.
  • the protein BMP-2 which is used in the present invention, is made in osteoblasts and released to the extracellular substrate, in which it stimulates itself and the surrounding cells to form bone.
  • BMP-2 is purified and grafted into parts other than bone
  • the BMP protein stimulates the surrounding cells to form bone, so that new bone tissue is formed at the grafted parts.
  • the BMP protein binds to a BMP receptor in the membrane of susceptible cells to act as a system of transferring a signal into the cells by extracellular stimulation.
  • the BMP-2 protein dominates in the ability to differentiate cells into bone cells, compared to a property to grow cells.
  • BMP-2 binds to BMP receptor (BMPR-II and BMPR-I) proteins in the cell membrane
  • signaling proteins Smadl, Smad5 and Smad8 are phosphorylated to form a complex with Smad4.
  • This complex moves into the nucleus and activates a transcription regulator such as RunX2.
  • the activated transcription regulator activates various genes associated with bone formation so as to initiate bone formation.
  • the bone-inducing ability of BMP-2 was already demonstrated in preclinical models and evaluated in clinical trials. In some cases, the effect of BMP-2 on osseointegration is also shown to be superior to the effect of an autogenous bone graft.
  • rhBMP-2 recombinant human bone morphogenic protein-2
  • BMP-2 recombinant human bone morphogenic protein-2
  • BMP-2 acts as a key protein. Because BMP is a protein produced in human beings, it is made in human beings in a necessary amount in case of need, even if it is not administered from an external source.
  • BMP is normally formed by cells in a woven bone formation process and secreted to stimulate itself and the surrounding cells to promote bone formation.
  • cells must receive a signal in order to produce any protein, steps of making that signal sequentially occur.
  • rhBMP-2 from an external source results in the effect of reducing previous steps.
  • woven bone occurs to induce subsequent processes and then disappears, and these induction and disappearance processes are repeated such that hard bone tissue is formed. Therefore, according to the present invention, rhBMP-2, which induces hard bone tissue, is administered from an external source, and thus a healing period can be reduced.
  • the woven bone-forming step is entered before completion of the formation of granulation tissue, which occurs over about 2 months, and also a period for transition from woven bone into lamella bone is reduced.
  • the surgical implantation of the implant coated with rhBMP-2 has a disadvantage in that healing can be can be achieved within a short period (less than 2 weeks) without considering the time required for general implants to be stabilized.
  • the rhBMP-2 protein which is used in the present invention, is coated on the implant surface using a freeze-drying technique.
  • the implant surface will be surrounded by blood clots. If the rhBMP-2 protein on the implant surface is present in a liquid phase, it has a high likelihood to be easily washed out before formation of blood clots even with a trace amount of blood or body fluid.
  • this risk can be reduced, because rhBMP-2 is coated on the implant surface by freeze-drying.
  • rhBMP-2 is stored in blood clots while it can be prevented from being rapidly released, it induces bone cells and blood vessel cells at local sites, and thus an early healing mechanism is entered. Also, as described above, the initial healing process is reduced, so that the osseointegration of the implant is just performed due to the proliferation of bone cells and blood vessel cells.
  • the freeze-drying process in the present invention consists of a first freezing step, followed by a second freeze-drying step.
  • the first freezing step is preferably carried out in a freezer at -75 + 0.5 °C or higher for 3-4 hours. If the freezing temperature is higher than -74.5 °C or the freezing time is shorter than 3 hours, sufficient freezing cannot be achieved, so that, when vacuum is applied in the second freeze-drying step, the protein solution can be lost. On the other hand, the freezing temperature is lower than 75.5 °C or the freezing time exceeds 4 hours, sufficient freezing will be ensured, but any increased freezing effect resulting from the lowering of the freezing temperature or the increase in the freezing time will not be obtained.
  • the second freeze-drying step is preferably carried out by placing the sample in a freezing dryer pre-cooled to 75 + 5 °C and freeze-drying the sample at a pressure of 0.05 + 0.005 torr for 8 hours.
  • These temperature and pressure range conditions are the most preferred conditions where the sample can be sufficiently dried within 8 hours. If the freeze drying time in said temperature and pressure range conditions is less than 8 hours, complete drying will not be achieved due to the insufficient evaporation of water, and thus, when the implant is exposed to room temperature, the protein will be present as a solution due to the remaining water, so as to increase the risk of the lose and contamination of the protein. On the other hand, the freezing time in said temperature and pressure conditions exceeds 8 hours, sufficient drying will be achieved, but any increased freezing effect resulting from the increase in the freezing time will not be obtained.
  • the present invention provides the dental implant coated with recombinant bone morphogenic protein and the method for coating the protein on the dental implant. More particularly, the present invention provides the dental implant having recombinant bone morphogenic protein coated on the processed surface thereof, which, when implanted into the jawbone, enables undifferentiated adult cells around the implant site to rapidly differentiate into osteoblasts so as to induce osteo- conductive healing to thereby reduce a healing period, as well as a coating method thereof.

Abstract

La présente invention concerne un implant dentaire comprenant une protéine morphogénique osseuse recombinée appliquée sur la surface traitée dudit implant. Lorsqu'il est implanté dans la mâchoire, cet implant permet de différencier rapidement en ostéoblastes des cellules adultes indifférenciées autour du site d'implantation de façon à induire une cicatrisation ostéoconductrice, d'où la réduction d'une période de cicatrisation. L'invention concerne également un procédé de revêtement de cet implant. Selon l'invention, la protéine morphogénique osseuse BMP-2 recombinée pénètre entre des boules de céramique formées sur la surface de l'implant dentaire, des structures en feuille de triphosphate de calcium ou des pores fins formés par oxydation anodique, de manière à former un film de revêtement. Ainsi, la protéine morphogénique osseuse BMP-2 recombinée ne se détache pas de la surface de l'implant dentaire même pendant l'implantation chirurgicale de l'implant. Par ailleurs, étant donné que la protéine morphogénique osseuse recombinée appliquée sur la surface de l'implant dentaire est d'abord appliquée essentiellement sur le sillon profond de la surface de l'implant, elle ne peut pas être arrachée sous l'action du frottement mécanique pendant l'implantation chirurgicale de l'implant. De plus, étant donné qu'une quantité minimale de la protéine appliquée sur la surface de l'implant agit localement sur le tissu autour du site d'implantation, les effets secondaires de la protéine sont très faibles, voire nuls. Cette protéine présente des effets pharmacologiques permettant de différencier des cellules adultes indifférenciées en ostéoblastes de façon à induire une cicatrisation ostéoconductrice améliorée, d'où une réduction considérable de la période d'osséointégration de l'implant.
PCT/KR2006/004234 2005-12-26 2006-10-19 Implant dentaire revêtu d'une protéine morphogénique osseuse recombinée et procédé de revêtement de celui-ci WO2007074968A1 (fr)

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KR10-2005-0129577 2005-12-26
KR20050129577 2005-12-26
KR10-2006-0059457 2006-06-29
KR1020060059457A KR100736826B1 (ko) 2005-12-26 2006-06-29 재조합 골형성 촉진 단백질을 도포한 치과용 임플란트 및그 도포 방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055630A1 (fr) * 2006-11-06 2008-05-15 Clinical House Europe Gmbh Implant dentaire doté d'un revêtement
US20110313539A1 (en) * 2009-08-25 2011-12-22 Prostec Co., Ltd. Medical supplies and method of producing the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824651A (en) * 1993-05-10 1998-10-20 Universite De Montreal Process for modification of implant surface with bioactive conjugates for improved integration
US20040038180A1 (en) * 2002-08-23 2004-02-26 Woodwelding Ag Implant, in particular a dental implant
KR20040032297A (ko) * 2002-10-09 2004-04-17 (주)아미티에 생분해성 골접합용 코팅 임플란트
US20050079469A1 (en) * 2003-08-21 2005-04-14 Yasumasa Akagawa Method for fixing an implant, fixing member for the implant and implant composite

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824651A (en) * 1993-05-10 1998-10-20 Universite De Montreal Process for modification of implant surface with bioactive conjugates for improved integration
US20040038180A1 (en) * 2002-08-23 2004-02-26 Woodwelding Ag Implant, in particular a dental implant
KR20040032297A (ko) * 2002-10-09 2004-04-17 (주)아미티에 생분해성 골접합용 코팅 임플란트
US20050079469A1 (en) * 2003-08-21 2005-04-14 Yasumasa Akagawa Method for fixing an implant, fixing member for the implant and implant composite

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055630A1 (fr) * 2006-11-06 2008-05-15 Clinical House Europe Gmbh Implant dentaire doté d'un revêtement
US20110313539A1 (en) * 2009-08-25 2011-12-22 Prostec Co., Ltd. Medical supplies and method of producing the same
US10668187B2 (en) 2009-08-25 2020-06-02 Prostec Co., Ltd. Medical supplies and method of producing the same

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