WO2004049900A2 - Method for producing bone fracture fixation device with absorption delaying property - Google Patents

Method for producing bone fracture fixation device with absorption delaying property Download PDF

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Publication number
WO2004049900A2
WO2004049900A2 PCT/KR2003/002469 KR0302469W WO2004049900A2 WO 2004049900 A2 WO2004049900 A2 WO 2004049900A2 KR 0302469 W KR0302469 W KR 0302469W WO 2004049900 A2 WO2004049900 A2 WO 2004049900A2
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WO
WIPO (PCT)
Prior art keywords
bone
teeth
cortical bone
cortical
fixation device
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Application number
PCT/KR2003/002469
Other languages
French (fr)
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WO2004049900A3 (en
Inventor
Sung-Jin Choi
In-Hyuk Choi
Original Assignee
Sung-Jin Choi
In-Hyuk Choi
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Application filed by Sung-Jin Choi, In-Hyuk Choi filed Critical Sung-Jin Choi
Priority to AU2003279582A priority Critical patent/AU2003279582A1/en
Publication of WO2004049900A2 publication Critical patent/WO2004049900A2/en
Publication of WO2004049900A3 publication Critical patent/WO2004049900A3/en

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Classifications

    • 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
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/80—Cortical plates, i.e. bone plates; Instruments for holding or positioning cortical plates, or for compressing bones attached to cortical plates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/86—Pins or screws or threaded wires; nuts therefor
    • A61B17/866—Material or manufacture
    • 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
    • A61L27/34—Macromolecular 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A61L27/365—Bones
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00004—(bio)absorbable, (bio)resorbable, resorptive

Definitions

  • the present invention relates to a method for producing a bone fracture fixation device which is used to fix a fractured bone within a living body when treatment bone fractures of humans and animals.
  • the present invention relates to a method for producing a bone fracture fixation device with absorption delaying property, which induces the formation of new bone so as to make the incorporation of a bone fracture using cortical bone or tooth collected from a human body or animal and fixes a fractured bone firmly until the new bone is slowly absorbed and decomposed (hereinafter, referred to as "absorption-delayed") in a living body to completely union the bone fracture, and which needs no operation of removing the fixation device after healing the bone fracture.
  • Bone fracture fixation devices are largely divided into external bone fracture fixation devices that are mounted outside a living body and internal bone fracture fixation devices that are mounted inside a living body.
  • the present invention relates to internal fixation devices of them.
  • fixation devices made of metal such as titanium or stainless steel have been most widely used.
  • the fixation devices can be made in various shapes such as a plate, pin, screw, etc.
  • the above metallic fixation devices are problematic in that they exist as a foreign substance after a bone fracture is healed thus to require a re-operation for removing them.
  • the pain of the patient gets bigger and he or she has to bear expenses for the operation and accept the risk of the re-operation.
  • the fixation devices have no function at all for inducing the formation of new bone so as to quickly proceed the incorporation of bone fracture in a living body.
  • fixation devices made of biologically decomposable polymer such as polyglycolic acid, polygelatin, polydioxanone, polylactide and the like are being partly used.
  • fixation devices are decomposed in a living body, so a re-operation for removing it can be omitted. But, it is difficult to use it for healing a bone fracture of a long bone such as a leg bone due to its small strength, and it has no function for inducing the formation of new bone so as to quickly proceed the incorporation of bone fractures.
  • fixation devices of the biologically decomposable polymer are weak in strength, thus they have been restrictively used mainly for treatment bone fractures such as facial bone, jaw bone, finger bone, toe bone and the like or as a sutures.
  • U.S. Patent No. 5,968,047 discloses fixation devices made of human or animal cortical bone.
  • the U.S. Patent only refers to a biological activity material overally representing every biological components contained in bone, but does not clearly state bone morphogenetic proteins facilitating the formation of new bone. Also, it does not state at all a treatment method for preserving the bone morphogenetic proteins (BMP) without damaging and a method for suppressing or removing immunologically reactive material components.
  • BMP bone morphogenetic proteins
  • the application claims the shapes of a plate, a screw and a pin as fixation devices without describing whether the fixation devices of cortical bone have been absorbed or their absorption process. Especially, it claims the excellence of the shape of a screw formed of cortical bone from a functional viewpoint.
  • the fixation devices In a case that every organic materials or proteins and immunologically reactive materials excepting hydroxy apatites are removed from cortical bone, the fixation devices remained as foreign substances without being decomposed in a living body. Thus, like the fixation devices made of steel, the cortical bone has no choice but to be re-operated for removal after healing bone fractures, or have no choice but to remain permanently.
  • absorption delaying fixation devices using cortical bone was adapted. But, these materials have no fixing force or supporting force because they are absorbed or weakened at an early time, thus they are restrictively used for fixing jaw bone, facial bone, finger bone, toe bone and the like that do not require a large fixing force and has a small momentum.
  • the present invention has been developed for the purpose of solving the foregoing problems and thus it is an object of the present invention to provide a method for producing a bone fracture fixation device with absorption delaying property, which can firmly fix a bone fracture portion until the bone fracture is completely conglutinated since the fixation device is absorption-delayed in a living body to thus and which can omit a re-operation since the fixation device is completely biologically decomposed after the incorporation of the bone fracture.
  • BMP bone morphogenetic protein
  • the present invention provides a method for making a fixation device of cortical bone or teeth to be absorption-delayed in a living body, a method for suppressing immunological rejection and a method for preventing BMP in the fixation device from being damaged.
  • soft tissue having an immunologically rejection mechanism is removed by a manual work or mechanical method from cortical bone or teeth collected from a human body or animal within 24 hours after death.
  • the cortical bone or teeth can be used as they are immediately after collecting them from a human body or animal within 24 hours after death, or can be used after being refrigerated or frozen after the collection.
  • the soft tissue of the cortical bone or teeth includes muscles, periosteum, marrow, blood vessel, cancellous bone or the like being adhered to the cortical bone or teeth.
  • the reason why the soft tissue is removed from the cortical bone or teeth is to remove or suppress an immunologically reactive material in fixation devices to the maximum so as to avoid the cortical bone or teeth from being absorbed and decomposed too quickly in a living body (that is to say, so as to delay absorption).
  • BMP is a bone morphogenetic protein that is contained in cortical bone or teeth and has the function of deriving osteoblast cells from mesenchymal cells or stem cells so as to form new bone. Since Urist discovered in 1965 that BMP extracted from cortical bone of dead cattle is implanted into the muscle of a rabbit to thus form new bone, BMP materials have been recently made into products. Such BMP offers an implantation effect mainly by adding BMP to implants of bone to form new bone.
  • the cortical bone or teeth of which soft tissue is removed is cut and molded using sodium azide or an electrolyte cooling water to thus produce a fixation device.
  • Fixation devices produced by the method of this invention include all shapes of a plate, a pin, a screw or the like.
  • the reason why sodium azide or an electrolyte cooling water is used upon cutting and molding in the present invention is to prevent BMP from being damaged or denatured by a heat generated upon cutting and molding the cortical bone or teeth. More preferably, the heat generated upon cutting and molding the cortical bone or teeth is
  • the electrolyte cooling water includes a lactic Ringer's solution cooling water, a Hartmann cooling water or a Ringer's solution or the like which are composed of an electrolyte component similar to a living body.
  • the electrolyte solution maintains the BMP function, and the electrolyte cooling water added with lactic acid is more effective to improve local acidosis caused by inflammation of foreign substance reaction.
  • the ultrasonic washer has the function of generating several hundred thousand of bubbles per one second by a negative pressure phenomenon and a vibrating effect to separate and remove foreign substances adhered to the substrate and destruct cells. Therefore, in the sodium azide or electrolyte solution treatment process, it is more effective to separate the immunologically reactive material in fine pores of the cortical bone or teeth by the ultrasonic washer and then enucleate the same by the suction apparatus.
  • Fig. 13 shows no osteoblast cells and blood cells observed in a circular or elliptical Haversian cannal wherein ultrasonication was carried out in the electrolyte solution treatment process, while Fig. 12 shows osteoblast cells and blood cells observed wherein ultrasonication was not carried out.
  • molded cortical bone or teeth is immersed in a mixed solution of chloroform and methanol for more than two days to thus suppress immunological rejection.
  • fat is expelled from cortical bone or teeth by immersing the cortical bone or teeth in the mixed solution for more than two days, and fixation devices are allowed to be absorption-delayed in a living body by maximally suppressing the rejection function of an immunologically reactive material remaining in the cortical bone or teeth.
  • the present invention is characterized in that a mixed solution of chloroform and methanol is used so as to avoid the damage of BMP in the cortical bone or teeth.
  • chloroform and methanol are preferably mixed at a ratio of 1 : 1.
  • fixation devices cortical bone or teeth defatted by being immersed in the mixed solution of chloroform and methanol are
  • the freeze drying treatment is carried out so that the moisture content can be below 5% is to stop the metabolism of every organic materials such as enzyme or protein, thereby preventing the damage and denaturalization of BMP in the cortical bone or teeth and facilitating the absorption of ethylene oxide gas. Additionally, upon a sterilization treatment for preventing microbial penetration and contamination, ethylene oxide gas not affecting BMP is employed.
  • the cortical bone or teeth treated by chloroform and methanol may be reserved by quickly freezing at a temperature less
  • an absorption delaying material or biologically decomposable polymer is selectively coated on the entire surface of cortical bone or teeth that has been immersed, defatted and freeze-dried or on the surface where cortical bone or teeth and host bone are not bonded each other.
  • biologically decomposable polymer is coated on the entire surface of cortical bone or teeth is to allow fixation devices to start absorption after bone fracture is completely self-healed.
  • the above-mentioned absorption delaying material includes collagen, ceramics and the biologically decomposable polymer includes polyglycolic acid, polyglactic 910, polydioxanone, polyglyconate, poliglecaprone 25 and the like.
  • the fixation devices of cortical bone or teeth coated with an absorption delaying material or biologically decomposable polymer When the fixation devices of cortical bone or teeth coated with an absorption delaying material or biologically decomposable polymer is inserted into a living body and used, the coated absorption delaying material and the biologically decomposable polymer are fully absorbed firstly in the living body respectively by macrophage cells and by hydrolysis, and then the decomposition and absorption of cortical bone or teeth occur, thus the absorption delaying effect of the fixation devices can be maximized.
  • the coating thickness of the absorption delaying material or biologically decomposable polymer it is possible to effectively control the absorption period of cortical bone or teeth.
  • BMP or other bone formation inducing materials can be added to cortical bone.
  • the present invention is characterized in that: [i] soft tissue of cortical bone or teeth is removed by a mechanical method or the like, [ii] an immunologically reactive material is suppressed (defatted) by immersing the cortical bone or teeth in a mixed solution of chloroform and methanol for a long time, [iii] mounting and using a suction apparatus or ultrasonic washer upon an electrolyte solution treatment after optional molding, [iv] the cortical bone or teeth is freeze-dried at a temperature less than -40°C, [v] an absorption delaying material or a biologically decomposable polymer is optionally coated on the cortical bone or teeth, and [vi] optionally, an antigenic material is extracted or an antigenicity depressing material is added.
  • the present invention is characterized in that: [i] fresh cortical bone or teeth is colleted and used, [ii] a solution not affecting BMP is used upon removing an immunological reactive material from the cortical bone or teeth, [iii] bone formation inducing materials are protected and heat generation is suppressed by using sodium azide or an electrolyte cooling water upon cutting and molding the cortical bone or teeth, [iv] the cortical bone or teeth is freeze-dried so that its moisture content can be below 5%, [v] the cortical bone or teeth is sterilized with ethylene oxide gas not affecting BMP, [vi] the cortical bone or teeth optionally treated with chloroform and methanol is quickly frozen at a temperature less
  • fixation devices produced in the present invention contain BMP originally or are added with BMP to induce and facilitate the formation of new bone, thereby enabling the reduction of a bone fracture healing time. In addition, they are slowly absorbed and decomposed (absorption-delayed) in a living body, thus there is no need for re-operation for removing the fixation devices and a fracture bone can be firmly fixed until the bone fracture is completely incorporated.
  • a sterilized, packaged product is immersed in an electrolyte solution before the fixation devices are used for a bone fracture fixation, thereby supplementing the moisture content.
  • Fig. 1 is a radiograph taken right after an operation as in Example 1 ;
  • Fig. 2 is a radiograph taken after 8 weeks since the operation as in Example 1;
  • Fig. 3 is a radiograph taken after 22 weeks since the operation as in Example 1;
  • Fig. 4 is a radiograph taken right after an operation as in
  • Fig. 5 is a radiograph taken after 12 weeks since the operation as in Example 2
  • Fig. 6 is a radiograph taken after 22 weeks since the operation as in Example 2;
  • Fig. 7 is a radiograph taken right after an operation as in Example 3.
  • Fig. 8 is a radiograph taken after 6 weeks since the operation as in Example 3.
  • Fig. 9 is a radiograph taken after 22 weeks since the operation as in Example 3.
  • Fig. 10 is a radiograph taken right after an operation using a titanium bone plate and a screw as in Comparative Example 1 ;
  • Fig. 11 is a radiograph taken after 22 weeks since the operation as in Comparative Example 1 ;
  • Fig. 12 is a photograph of cortical bone that is not ultrasonicated in the step of an electrolyte solution treatment
  • Fig. 13 is a photograph of cortical bone that is ultrasonicated in the step of an electrolyte solution treatment.
  • Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then immersed in a mixed solution (1 : 1) of chloroform and methanol for five days, then
  • FIG. 1 A radiograph taken right after the operation is as shown in Fig. 1 , a radiograph taken after 8 weeks since the operation is as shown in Fig. 2, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 3. As shown in Fig.
  • Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then the molded material is immersed in a bathtub of an electrolyte solution, and then immersed in a mixed solution (1: 1) of chloroform and methanol for six days.
  • a suction apparatus and an ultrasonic washer are mounted to the bathtub of the electrolyte solution to carry out suction treatment and ultrasonication along with immersion. Continually, the immersed molded material is freeze-dried so that the moisture content can be 4%
  • a fixation device of cortical bone There is carried out an operation of fixing using the fixation device a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 4mm interval is caused.
  • a radiograph taken right after the operation is as shown in Fig. 4, a radiograph taken after 12 weeks since the operation is as shown in Fig. 5, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 6.
  • Fig. 5 it can be known that, after 12 weeks since the operation, the formation of new bone is induced from a bone fragment side of the defective portion, thus the defective portion begins to be filled, and about a half the thickness of the bone plate is absorbed in a living body.
  • Example 3 Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then immersed in a mixed solution (1 : 1) of chloroform and methanol for five days, and then freeze-dried so that the moisture content can be 5% at -90°C.
  • polyglicolic acid biologically decomposable polymer
  • a fixation device of cortical bone There is carried out an operation of fixing using the fixation device a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 3mm interval is caused.
  • a radiograph taken right after the operation is as shown in Fig. 7, a radiograph taken after 6 weeks since the operation is as shown in Fig. 8, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 9.
  • Fig. 7 A radiograph taken right after the operation is as shown in Fig. 7
  • a radiograph taken after 6 weeks since the operation is as shown in Fig. 8
  • a radiograph taken after 22 weeks since the operation is as shown in Fig. 9.
  • a conventional fixation device of a plate and screw shape made of titanium By using a conventional fixation device of a plate and screw shape made of titanium, there is carried out an operation of fixing a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 2mm interval is caused.
  • a radiograph taken right after the operation is as shown in Fig. 10, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 1 1.
  • Fig. 1 1 it can be known that, no new bone is formed on the defective portion even after 22 weeks since the operation, the defective portion is not incorporated at all, and the bone plate is not absorbed in the living body at all.
  • the fixation devices produced by the method of the present invention can induce the formation of new bone to thus reduce a healing period.
  • they are slowly absorbed and decomposed in a living body, thus a defective portion can be fixed firmly until a bone fracture is completely incorporated. Therefore, they are useful for the treatment of a long bone such as arm or leg bone, and there is no need for a re-operation for removing the fixation devices, thereby reducing operation costs and patient's pains.

Abstract

The present invention discloses a method for producing a bone fracture fixation device with absorption delaying property which is used for healing bone fractures of humans and animals. The method comprises the steps of: [i] removing soft tissue from fresh cortical bone or teeth; [ii] molding the cortical bone or teeth using sodium azide or an electrolyte cooling water; [iii] immersing the cortical bone or teeth in a mixed solution of chloroform and methanol for more than two days; [iv] freeze-drying the immersed cortical bone or teeth; and [v] sterilizing the freeze-dried molded cortical bone or teeth with ethylene oxide gas and packaging the same. The bone fracture fixation device with absorption delaying property produced according to the present invention is superior in fixing force until bone fracture is incorporated since it is slowly absorbed and decomposed in a human or animal body.

Description

METHOD FOR PRODUCING BONE FRACTURE FIXATION DEVICE WITH ABSORPTION DELAYING PROPERTY
TECHNICAL FIELD The present invention relates to a method for producing a bone fracture fixation device which is used to fix a fractured bone within a living body when treatment bone fractures of humans and animals.
More particularly, the present invention relates to a method for producing a bone fracture fixation device with absorption delaying property, which induces the formation of new bone so as to make the incorporation of a bone fracture using cortical bone or tooth collected from a human body or animal and fixes a fractured bone firmly until the new bone is slowly absorbed and decomposed (hereinafter, referred to as "absorption-delayed") in a living body to completely union the bone fracture, and which needs no operation of removing the fixation device after healing the bone fracture.
Bone fracture fixation devices are largely divided into external bone fracture fixation devices that are mounted outside a living body and internal bone fracture fixation devices that are mounted inside a living body. The present invention relates to internal fixation devices of them.
As the most firm and definite method for an internal bone fracture fixation, the method defined in AO/ASIF (Arbeitsgemeinschaft fur Osteosynthesefragen / Association for the Study of Internal Fixation) is known. BACKGROUND ART
Up to now, internal bone fracture fixation devices (hereinafter, referred to as 'fixation devices') made of metal such as titanium or stainless steel have been most widely used. The fixation devices can be made in various shapes such as a plate, pin, screw, etc.
However, the above metallic fixation devices are problematic in that they exist as a foreign substance after a bone fracture is healed thus to require a re-operation for removing them. In case of re-operation, the pain of the patient gets bigger and he or she has to bear expenses for the operation and accept the risk of the re-operation. Furthermore, the fixation devices have no function at all for inducing the formation of new bone so as to quickly proceed the incorporation of bone fracture in a living body.
To overcome the above problem, fixation devices made of biologically decomposable polymer such as polyglycolic acid, polygelatin, polydioxanone, polylactide and the like are being partly used.
The above-mentioned fixation devices are decomposed in a living body, so a re-operation for removing it can be omitted. But, it is difficult to use it for healing a bone fracture of a long bone such as a leg bone due to its small strength, and it has no function for inducing the formation of new bone so as to quickly proceed the incorporation of bone fractures.
The fixation devices of the biologically decomposable polymer are weak in strength, thus they have been restrictively used mainly for treatment bone fractures such as facial bone, jaw bone, finger bone, toe bone and the like or as a sutures.
U.S. Patent No. 5,968,047 discloses fixation devices made of human or animal cortical bone.
However, the U.S. Patent only refers to a biological activity material overally representing every biological components contained in bone, but does not clearly state bone morphogenetic proteins facilitating the formation of new bone. Also, it does not state at all a treatment method for preserving the bone morphogenetic proteins (BMP) without damaging and a method for suppressing or removing immunologically reactive material components. In addition, the application claims the shapes of a plate, a screw and a pin as fixation devices without describing whether the fixation devices of cortical bone have been absorbed or their absorption process. Especially, it claims the excellence of the shape of a screw formed of cortical bone from a functional viewpoint. According to the references, it is known that, in a case cortical bone is implanted in a living body, an inflammatory reaction occurs in cortical bone due to heterologous protein or foreign substances even if there is only a small quantity of immunologically reactive material in the cortical bone, and the absorption of graft bone occurs due to the action of macrophage cells and osteoclast cells.
In a case that every organic materials or proteins and immunologically reactive materials excepting hydroxy apatites are removed from cortical bone, the fixation devices remained as foreign substances without being decomposed in a living body. Thus, like the fixation devices made of steel, the cortical bone has no choice but to be re-operated for removal after healing bone fractures, or have no choice but to remain permanently. In a reference related to a bone plate, it is reported an example in which absorption delaying fixation devices using cortical bone was adapted. But, these materials have no fixing force or supporting force because they are absorbed or weakened at an early time, thus they are restrictively used for fixing jaw bone, facial bone, finger bone, toe bone and the like that do not require a large fixing force and has a small momentum.
DISCLOSURE OF INVENTION
The present invention has been developed for the purpose of solving the foregoing problems and thus it is an object of the present invention to provide a method for producing a bone fracture fixation device with absorption delaying property, which can firmly fix a bone fracture portion until the bone fracture is completely conglutinated since the fixation device is absorption-delayed in a living body to thus and which can omit a re-operation since the fixation device is completely biologically decomposed after the incorporation of the bone fracture. It is another object of the present invention to provide a method for producing a bone fracture fixation device with absorption delaying property that is made of cortical bone or teeth, the bone fracture fixation device with absorption delaying property having the function of inducing and facilitating the formation of new bone so as to quickly proceed the incorporation of bone fracture because the fixation device contains bone morphogenetic protein (hereinafter, referred to as BMP).
It is still another object of the present invention to provide a method for producing a bone fracture fixation device with absorption delaying property using cortical bone or teeth collected from an animal or human, which [i] securely fixes and supports a fractured bone, [ii] does not act as a foreign substance to a living body and does not need to be re-operated for removing the fixation device because it is biologically decomposed after bone fracture healing, and [iii] induces and facilitates the formation of new bone because it contains BMP. For this, the present invention provides a method for making a fixation device of cortical bone or teeth to be absorption-delayed in a living body, a method for suppressing immunological rejection and a method for preventing BMP in the fixation device from being damaged. To achieve the above objects, there is provided a method for producing a bone fracture fixation device with absorption delaying property according to the present invention, comprising the steps of:
[i] removing soft tissue having an immunological rejection mechanism from cortical bone or teeth collected from a human body or animal within 24 hours since death by a manual work or a mechanical method;
[ii] molding the cortical bone or teeth using sodium azide or an electrolyte cooling water;
[iii] immersing the molded cortical bone or teeth in a mixed solution of chloroform and methanol for more than two days to suppress immunological rejection and defat the cortical bone or teeth;
[iv] freeze-drying the defatted cortical bone or teeth at a
temperature less than -40°C so that the moisture content can be below 5%; and
[v] sterilizing the freeze-dried molded cortical bone or teeth with ethylene oxide gas and packaging the same.
Hereinafter, the present invention will be described in detail.
Firstly, soft tissue having an immunologically rejection mechanism is removed by a manual work or mechanical method from cortical bone or teeth collected from a human body or animal within 24 hours after death.
At this time, the cortical bone or teeth can be used as they are immediately after collecting them from a human body or animal within 24 hours after death, or can be used after being refrigerated or frozen after the collection. The soft tissue of the cortical bone or teeth includes muscles, periosteum, marrow, blood vessel, cancellous bone or the like being adhered to the cortical bone or teeth.
The reason why a fresh cortical bone or teeth is collected from a human body or animal within 24 hours after death is to avoid BMP in the cortical bone or teeth from being damaged.
In addition, the reason why the soft tissue is removed from the cortical bone or teeth is to remove or suppress an immunologically reactive material in fixation devices to the maximum so as to avoid the cortical bone or teeth from being absorbed and decomposed too quickly in a living body (that is to say, so as to delay absorption).
BMP is a bone morphogenetic protein that is contained in cortical bone or teeth and has the function of deriving osteoblast cells from mesenchymal cells or stem cells so as to form new bone. Since Urist discovered in 1965 that BMP extracted from cortical bone of dead cattle is implanted into the muscle of a rabbit to thus form new bone, BMP materials have been recently made into products. Such BMP offers an implantation effect mainly by adding BMP to implants of bone to form new bone.
Next, the cortical bone or teeth of which soft tissue is removed is cut and molded using sodium azide or an electrolyte cooling water to thus produce a fixation device.
Fixation devices produced by the method of this invention include all shapes of a plate, a pin, a screw or the like.
The reason why sodium azide or an electrolyte cooling water is used upon cutting and molding in the present invention is to prevent BMP from being damaged or denatured by a heat generated upon cutting and molding the cortical bone or teeth. More preferably, the heat generated upon cutting and molding the cortical bone or teeth is
controlled not to exceed 70°C. A cooled sodium azide solution is employed for suppressing microbial activities, extracting water soluble non-collagenic protein agents and carrying out a washing operation without affecting BMP in cortical bone. More preferably, the electrolyte cooling water includes a lactic Ringer's solution cooling water, a Hartmann cooling water or a Ringer's solution or the like which are composed of an electrolyte component similar to a living body. The electrolyte solution maintains the BMP function, and the electrolyte cooling water added with lactic acid is more effective to improve local acidosis caused by inflammation of foreign substance reaction. To remove an immunologically reactive material more effectively, it is more preferable to immerse molded cortical bone or teeth in a bathtub of the electrolyte solution where a suction apparatus and /or an ultrasonic washer are mounted. The ultrasonic washer has the function of generating several hundred thousand of bubbles per one second by a negative pressure phenomenon and a vibrating effect to separate and remove foreign substances adhered to the substrate and destruct cells. Therefore, in the sodium azide or electrolyte solution treatment process, it is more effective to separate the immunologically reactive material in fine pores of the cortical bone or teeth by the ultrasonic washer and then enucleate the same by the suction apparatus.
Additionally, after the above process, it is more effective to optionally remove antigenic materials or add BMP protecting materials in order to suppress an immune reaction and activate BMP materials. As a protectant of BMP, N-ethylmaleimide and the like can be used. Fig. 13 shows no osteoblast cells and blood cells observed in a circular or elliptical Haversian cannal wherein ultrasonication was carried out in the electrolyte solution treatment process, while Fig. 12 shows osteoblast cells and blood cells observed wherein ultrasonication was not carried out.
Next, molded cortical bone or teeth is immersed in a mixed solution of chloroform and methanol for more than two days to thus suppress immunological rejection. In the present invention, fat is expelled from cortical bone or teeth by immersing the cortical bone or teeth in the mixed solution for more than two days, and fixation devices are allowed to be absorption-delayed in a living body by maximally suppressing the rejection function of an immunologically reactive material remaining in the cortical bone or teeth.
In addition, the present invention is characterized in that a mixed solution of chloroform and methanol is used so as to avoid the damage of BMP in the cortical bone or teeth. At this time, chloroform and methanol are preferably mixed at a ratio of 1 : 1.
In addition, materials, such as pure alcohol, acetone, etc., that are insoluble to BMP, carry out a defatting action, extract antigenicity depressing materials or depress antigenicity, can be used as a solvent. Next, the fixation devices (cortical bone or teeth) defatted by being immersed in the mixed solution of chloroform and methanol are
freeze-dried at a temperature less than -40°C so that their moisture
content can be below 5%, and then sterilized and packaged with an ethylene oxide gas, thereby to produce final fixation devices. The reason why the cortical bone or teeth is quickly freeze-dried
at a temperature less than -40°C is to suppress the damage of residual BMP and precool the cortical bone or teeth for freeze drying treatment. The reason why the freeze drying treatment is carried out so that the moisture content can be below 5% is to stop the metabolism of every organic materials such as enzyme or protein, thereby preventing the damage and denaturalization of BMP in the cortical bone or teeth and facilitating the absorption of ethylene oxide gas. Additionally, upon a sterilization treatment for preventing microbial penetration and contamination, ethylene oxide gas not affecting BMP is employed.
Optionally, the cortical bone or teeth treated by chloroform and methanol may be reserved by quickly freezing at a temperature less
than -20°C. Upon quick freezing, it is the most effective to use liquid
nitrogen of - 196°C.
To improve the absorption delaying effect of fixation devices much more, it is more preferably that an absorption delaying material or biologically decomposable polymer is selectively coated on the entire surface of cortical bone or teeth that has been immersed, defatted and freeze-dried or on the surface where cortical bone or teeth and host bone are not bonded each other. The reason why biologically decomposable polymer is coated on the entire surface of cortical bone or teeth is to allow fixation devices to start absorption after bone fracture is completely self-healed. The reason why biologically decomposable polymer is coated on the surface where cortical bone or teeth and host bone are not bonded each other is because the formation of new bone on a bone fracture surface is stimulated on the contact surface between a cortical bone or teeth plate and a fractured bone to thus facilitate the healing of bone fracture, and because the bioabsorption and biodegradation of cortical bone or teeth does not occur thereon.
The above-mentioned absorption delaying material includes collagen, ceramics and the biologically decomposable polymer includes polyglycolic acid, polyglactic 910, polydioxanone, polyglyconate, poliglecaprone 25 and the like.
When the fixation devices of cortical bone or teeth coated with an absorption delaying material or biologically decomposable polymer is inserted into a living body and used, the coated absorption delaying material and the biologically decomposable polymer are fully absorbed firstly in the living body respectively by macrophage cells and by hydrolysis, and then the decomposition and absorption of cortical bone or teeth occur, thus the absorption delaying effect of the fixation devices can be maximized. By adjusting the coating thickness of the absorption delaying material or biologically decomposable polymer, it is possible to effectively control the absorption period of cortical bone or teeth.
Additionally, to strengthen the new bone formation inducing ability of fixation devices, BMP or other bone formation inducing materials can be added to cortical bone.
As explained above, in order to suppress immunological rejection and absorption-delay cortical bone or teeth, the present invention is characterized in that: [i] soft tissue of cortical bone or teeth is removed by a mechanical method or the like, [ii] an immunologically reactive material is suppressed (defatted) by immersing the cortical bone or teeth in a mixed solution of chloroform and methanol for a long time, [iii] mounting and using a suction apparatus or ultrasonic washer upon an electrolyte solution treatment after optional molding, [iv] the cortical bone or teeth is freeze-dried at a temperature less than -40°C, [v] an absorption delaying material or a biologically decomposable polymer is optionally coated on the cortical bone or teeth, and [vi] optionally, an antigenic material is extracted or an antigenicity depressing material is added.
Additionally, in order to induce the formation of new bone, the present invention is characterized in that: [i] fresh cortical bone or teeth is colleted and used, [ii] a solution not affecting BMP is used upon removing an immunological reactive material from the cortical bone or teeth, [iii] bone formation inducing materials are protected and heat generation is suppressed by using sodium azide or an electrolyte cooling water upon cutting and molding the cortical bone or teeth, [iv] the cortical bone or teeth is freeze-dried so that its moisture content can be below 5%, [v] the cortical bone or teeth is sterilized with ethylene oxide gas not affecting BMP, [vi] the cortical bone or teeth optionally treated with chloroform and methanol is quickly frozen at a temperature less
than -20°C and freeze-reserved, and [vii] a BMP materials or a bone
formation inducing material is optionally added to the cortical bone. The fixation devices produced in the present invention contain BMP originally or are added with BMP to induce and facilitate the formation of new bone, thereby enabling the reduction of a bone fracture healing time. In addition, they are slowly absorbed and decomposed (absorption-delayed) in a living body, thus there is no need for re-operation for removing the fixation devices and a fracture bone can be firmly fixed until the bone fracture is completely incorporated.
In order to increase the strength of the fixation devices produced by the method of the present invention much more, it is more preferable that a sterilized, packaged product is immersed in an electrolyte solution before the fixation devices are used for a bone fracture fixation, thereby supplementing the moisture content.
BRIEF DESCRIPTION OF THE DRAWINGS These and other features, aspects, and advantages of preferred embodiments of the present invention will be more fully described in the following detailed description, taken accompanying drawings. In the drawings:
Fig. 1 is a radiograph taken right after an operation as in Example 1 ;
Fig. 2 is a radiograph taken after 8 weeks since the operation as in Example 1;
Fig. 3 is a radiograph taken after 22 weeks since the operation as in Example 1; Fig. 4 is a radiograph taken right after an operation as in
Example 2;
Fig. 5 is a radiograph taken after 12 weeks since the operation as in Example 2; Fig. 6 is a radiograph taken after 22 weeks since the operation as in Example 2;
Fig. 7 is a radiograph taken right after an operation as in Example 3;
Fig. 8 is a radiograph taken after 6 weeks since the operation as in Example 3;
Fig. 9 is a radiograph taken after 22 weeks since the operation as in Example 3;
Fig. 10 is a radiograph taken right after an operation using a titanium bone plate and a screw as in Comparative Example 1 ;
Fig. 11 is a radiograph taken after 22 weeks since the operation as in Comparative Example 1 ;
Fig. 12 is a photograph of cortical bone that is not ultrasonicated in the step of an electrolyte solution treatment; and Fig. 13 is a photograph of cortical bone that is ultrasonicated in the step of an electrolyte solution treatment.
BEST MODES FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Example, but not limited thereto.
Example 1
Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then immersed in a mixed solution (1 : 1) of chloroform and methanol for five days, then
freeze-dried so that the moisture content can be 5% at -90°C, and then
sterilized with ethylene oxide gas and packaged, thereby producing a fixation device of cortical bone. There is carried out an operation of fixing using the fixation device a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 3mm interval is caused. A radiograph taken right after the operation is as shown in Fig. 1 , a radiograph taken after 8 weeks since the operation is as shown in Fig. 2, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 3. As shown in Fig. 2, it can be known that, after 8 weeks since the operation, the formation of new bone is induced from a bone fragment side of the defective portion, thus the defective portion begins to be filled, and about a half the thickness of the bone plate is absorbed in a living body. In addition, as shown in Fig. 3, it can be known that, after 22 weeks since the operation, the defective portion is fully filled and incorporated, and about three quarters of the bone plate, i.e., portions that are not contacted with host bone, is absorbed in a living body.
Example 2
Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then the molded material is immersed in a bathtub of an electrolyte solution, and then immersed in a mixed solution (1: 1) of chloroform and methanol for six days. A suction apparatus and an ultrasonic washer are mounted to the bathtub of the electrolyte solution to carry out suction treatment and ultrasonication along with immersion. Continually, the immersed molded material is freeze-dried so that the moisture content can be 4%
at -80°C, and then sterilized with ethylene oxide gas and packaged,
thereby producing a fixation device of cortical bone. There is carried out an operation of fixing using the fixation device a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 4mm interval is caused. A radiograph taken right after the operation is as shown in Fig. 4, a radiograph taken after 12 weeks since the operation is as shown in Fig. 5, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 6. As shown in Fig. 5, it can be known that, after 12 weeks since the operation, the formation of new bone is induced from a bone fragment side of the defective portion, thus the defective portion begins to be filled, and about a half the thickness of the bone plate is absorbed in a living body. In addition, as shown in Fig. 6, it can be known that, after 22 weeks since the operation, the defective portion is fully filled and incorporated, and almost every portions of the bone plate are absorbed in a living body. Example 3 Soft tissue is removed by a manual work from cortical bone collected from a dog after 20 hours of death, then molded in the form of a plate using an electrolyte cooling water, then immersed in a mixed solution (1 : 1) of chloroform and methanol for five days, and then freeze-dried so that the moisture content can be 5% at -90°C.
Continually, polyglicolic acid (biologically decomposable polymer) is coated at a thickness of 1mm on the surface of the immersed cortical bone where the cortical bone and host bone are not bonded each other, and then sterilized with ethylene oxide gas and packaged, thereby producing a fixation device of cortical bone. There is carried out an operation of fixing using the fixation device a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 3mm interval is caused. A radiograph taken right after the operation is as shown in Fig. 7, a radiograph taken after 6 weeks since the operation is as shown in Fig. 8, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 9. As shown in Fig. 8, it can be known that, after 6 weeks since the operation, the formation of new bone is induced from a bone fragment side of the defective portion, thus the defective portion begins to be filled, and the bone plate keeps its original thickness. In addition, as shown in Fig. 9, it can be known that, after 22 weeks since the operation, the defective portion is fully filled and incorporated, and the outer portions of the bone plate of the cortical bone begins to be absorbed. Comparative Example 1
By using a conventional fixation device of a plate and screw shape made of titanium, there is carried out an operation of fixing a bone shaft portion of a dog ulna where a transverse bone fracture with a defective portion of a 2mm interval is caused. A radiograph taken right after the operation is as shown in Fig. 10, and a radiograph taken after 22 weeks since the operation is as shown in Fig. 1 1. As shown in Fig. 1 1 , it can be known that, no new bone is formed on the defective portion even after 22 weeks since the operation, the defective portion is not incorporated at all, and the bone plate is not absorbed in the living body at all.
INDUSTRIAL APPLICABILITY
The fixation devices produced by the method of the present invention can induce the formation of new bone to thus reduce a healing period. In addition, they are slowly absorbed and decomposed in a living body, thus a defective portion can be fixed firmly until a bone fracture is completely incorporated. Therefore, they are useful for the treatment of a long bone such as arm or leg bone, and there is no need for a re-operation for removing the fixation devices, thereby reducing operation costs and patient's pains.

Claims

1. A method for producing a bone fracture fixation device with absorption delaying property, comprising the steps of: [i] removing soft tissue having an immunological rejection mechanism from cortical bone or teeth collected from a human body or animal within 24 hours since death by a manual work or a mechanical method;
[ii] molding the cortical bone or teeth using sodium azide or an electrolyte cooling water;
[iii] immersing the molded cortical bone or teeth in a mixed solution of chloroform and methanol for more than two days to suppress immunological rejection and defat the cortical bone or teeth;
[iv] freeze-drying the defatted cortical bone or teeth at a
temperature less than -40°C so that the moisture content can be below 5%; and
[v] sterilizing the freeze-dried molded cortical bone or teeth with ethylene oxide gas and packaging the same.
2. The method of claim 1 , wherein the cortical bone or teeth is one that is refrigerated or frozen after being collected from a human body or animal within 24 hours since death.
3. The method of claim 1 , wherein the soft tissue includes muscles, periosteum, marrow, blood vessel, cancellous bone or the like being adhered to the cortical bone or teeth.
4. The method of claim 1 , wherein chloroform and methanol is mixed at a ratio of 1 : 1.
5. The method of claim 1 , wherein the molded cortical bone or teeth is suction-treated and/ or ultrasonicated in a sodium azide or electrolyte solution after the molding.
6. The method of claim 1 , wherein an absorption delaying material or a biologically decomposable polymer is coated on the cortical bone or teeth immersed in the mixed solution of chloroform and methanol and freeze-dried.
7. The method of claim 6, wherein the absorption delaying material or the biologically decomposable polymer is coated on the surface where the cortical bone or teeth and host bone are not bonded each other.
8. The method of claim 6 or 7, wherein the biologically decomposable polymer is one of polyglycolic acid, polyglactin 910, polydioxanone or polyglyconate or poliglecaprone 25.
9. The method of claim 6 or 7, wherein the absorption delaying material is collagen.
10. The method of claim 1 , wherein the bone fracture fixation device is used after being immersed in the sodium azide or electrolyte cooling solution.
1 1. The method of claim 1 , wherein the bone fracture fixation device is formed in a plate, bar, pin or screw shape.
12. The method of claim 1 or 10, wherein the electrolyte cooling water is a Ringer's solution, a lactic Ringer's solution or a Hartmann solution.
13. The method of claim 1, wherein the cortical bone or teeth treated with chloroform and methanol is quickly frozen at a temperature
from -20°C to -200°C to be freeze-preserved.
14. The method of claim 1, wherein a BMP protecting material is added to the cortical bone or teeth.
15. The method of claim 1, wherein a BMP or a new bone formation inducing material is added to cortical bone or teeth.
16. The method of claim 1 , wherein an antigenic material is extracted from cortical bone or an antigenicity depressing material is added to cortical bone or teeth.
PCT/KR2003/002469 2002-12-04 2003-11-17 Method for producing bone fracture fixation device with absorption delaying property WO2004049900A2 (en)

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EP2641622A2 (en) * 2010-10-27 2013-09-25 Cosmobiomedicare Co., Ltd. Method for producing a bone transplant material, and bone transplant material produced by same
EP2641622A4 (en) * 2010-10-27 2014-11-19 Cosmobiomedicare Co Ltd Method for producing a bone transplant material, and bone transplant material produced by same
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EP3643334A1 (en) * 2018-10-26 2020-04-29 Miron Research and Development in Dentistry, LLC Non-resorbable bone allografts and method for making same

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AU2003279582A1 (en) 2004-06-23

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