WO1996010426A1 - Greffon osteoplastique - Google Patents
Greffon osteoplastique Download PDFInfo
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- WO1996010426A1 WO1996010426A1 PCT/JP1995/001970 JP9501970W WO9610426A1 WO 1996010426 A1 WO1996010426 A1 WO 1996010426A1 JP 9501970 W JP9501970 W JP 9501970W WO 9610426 A1 WO9610426 A1 WO 9610426A1
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- acid
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- bmp
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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- 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
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- 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
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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- 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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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- 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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/222—Gelatin
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- 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
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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- 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
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- 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
- A61L27/56—Porous materials, e.g. foams or sponges
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- 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
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- 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
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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- 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
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- 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
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the present invention relates to an osteogenic implant containing an osteoinductive factor, and a composite porous body that can be used as a carrier for an osteoinductive factor.
- an osteogenic implant characterized in that an osteoinductive factor is carried on a composite porous body obtained by applying a bioabsorbable polymer material to the surface of a porous structure made of a bioabsorbable hydrophilic material.
- a composite porous body useful as a carrier for osteoinductive factors.
- Bone morphogenetic protein acts on undifferentiated mesenchymal cells in subcutaneous or muscular tissue to differentiate them into chondroblasts or osteoblasts and form cartilage or bone. It is a protein. BMP was discovered as a substance exhibiting ectopic osteoinductive activity in the demineralized bone matrix, but was not isolated and its specific structure remained unknown. However, genetic engineering techniques have cloned the gene encoding human BMP and revealed its amino acid sequence. Human BMPs were also found to constitute a family of multiple closely related proteins whose amino acid sequences had homology, and many types of recombinant human osteoinductive factors (rhBMPs) were 242, pp. 1528-1534 (1988); Proc. Atl. Acad.
- the carrier for BMP since the carrier for BMP is implanted in a living body together with BMP, it is required to have properties such as low toxicity, low carcinogenicity, and low antigenicity without impairing the BMP activity, and furthermore, the availability is easy. It is also desirable to have biodegradability in some cases.
- Examples of the technologies that have already been proposed include, for example, an implant in which BMP is supported on a carrier made of atelocollagen (Japanese Patent Application Laid-Open No. 62-89629), a support of ceramic material impregnated with BMP and a collagen carrier. Transplant (JP-A-60-253455), a composition comprising rh BMP, a porous biodegradable polymer and autologous blood (US Pat. No. 5,171,579).
- implants consisting only of BMP and collagen carrier have insufficient moldability and lack of strength, and are rapidly degraded in the living body, so that their shape is not sufficiently maintained in the living body and bone formation is not always sufficient.
- a non-degradable or slowly degrading substance such as a ceramic material
- a carrier in order to improve moldability and shape retention in a living body
- these substances may be removed from the body.
- problems such as remaining without being absorbed into the bone and inhibiting the formation of uniform bone tissue, or the possibility that the residual carrier may cause bone resorption due to bone remodeling and the like.
- a composition comprising a porous biodegradable polymer and autologous blood has been desired to be further improved in terms of operability during operation and moldability.
- a bone graft substitute composition carrying is disclosed.
- the skeletal structure that maintains the structure is PLA, and the pores are filled with hyaluronic acid gel.
- ⁇ polylactic acid having interconnected voids '' which forms the skeletal structure of the composition described in this publication, remains for at least 90 days after transplantation and maintains physical properties. It is clear that the substance remains in the living body for a long time. Further, since the composition described in this publication uses a PLA sponge, it has rigid and brittle properties, low plasticity and elasticity, and is insufficient in moldability and operability at the time of implantation.
- Japanese Patent Application Laid-Open No. Hei 3-23864 discloses a collagen sponge having a polylactic acid system embedded therein useful as a filler for living tissue
- German Patent No. 3,841,397 discloses a collagen sponge comprising a polyester sponge.
- a sustained-release pharmaceutical carrier coated with is disclosed.
- BMP bone formation implants.
- an osteogenic implant that is excellent in moldability and shape maintenance in a living body, has excellent operability during surgery, and uses BMP that is excellent in new bone formation.
- Disclosure of the invention The inventors of the present invention aimed at creating an osteogenic implant to which BMP was applied, which was excellent in moldability and shape maintenance in a living body, excellent in operability during surgery, and excellent in new bone formation.
- an osteoinductive factor is carried on a composite porous body having a surface layer made of a bioabsorbable polymer material on the surface of a porous structure made of a bioabsorbable hydrophilic material.
- the present inventors have found that an osteogenic implant achieves the above object, and have completed the present invention.
- the present invention provides a bio-absorbable hydrophilic material composed of one or more compounds selected from the group consisting of gelatin, hyaluronic acid, and a hyaluronic acid derivative. Bioabsorption of one or more selected from the group consisting of polylactic acid / polyglycolic acid copolymer and poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid copolymer
- the present invention also relates to a composite porous body provided with a conductive polymer material.
- FIG. 1 schematically shows a partial cross-sectional view of a typical embodiment of an osteogenic implant according to the present invention. That is, the implant 1 for bone formation of the present invention,
- a composite porous body 4 composed of a porous structure 2 made of a bioabsorbable hydrophilic material, and a surface layer 3 made of a bioabsorbable polymer material formed on its surface;
- the bone formation implant 1 includes a large number of holes 6. These holes 6 are continuous and open to the outside.
- the partial cross-sectional view shown in FIG. 1 is a schematic view, and the shape, size, and the like of each component are not limited to the illustrated embodiment.
- the transplant of the present invention is mainly used by transplanting it to a site where bone (including cartilage) is to be formed in a living body.
- BMP acts on the implanted site to induce bone formation.
- the composite porous body itself gradually absorbs in vivo and is replaced by new bone, while retaining the BMP locally and serving as a delivery system for forming a desired form of bone.
- the osteoinductive factor (BMP) which can be used in the present invention is a protein having an activity of acting on undifferentiated mesenchymal cells to differentiate them into chondrocytes and osteoblasts and forming cartilage or bone. If it is, there is no particular limitation, and its preparation method is not limited.
- human BMP produced by genetic recombination technology is preferable because a large amount of material with stable clinical safety such as immunity and quality can be obtained. That is, a transformant (cell or microorganism) containing a recombinant DNA containing a nucleotide sequence encoding a human osteoinductive factor is cultured, and the recombinant human osteoinductive factor produced by the transformant is isolated and purified. It is a recombinant human bone inducing factor (rhBMP).
- rhBMP human bone inducing factor
- rhBMP human osteoinductive factors
- rhBMP-2 include, for example, rhBMP-2, rhBMP-3, rhBMP-4 (also referred to as rhBMP-2B), rhBMP-5, rhBMP-6, Examples thereof include rhBMP-7, rhBMP-8, rhBMP-9, and heterodimers of rhBMP, or modified or partially deleted forms thereof.
- rhBMP-2 Preferably rh BMP-2.
- rhBMPs can be expressed in mammalian cells (eg, CHO cells), microorganisms (eg, E. coli), yeast cells, and the like.
- the rh BMP has already been established for mass production and purification.
- Rh BMP-2 has a certain power.
- Other roBMPs can be produced, purified and used in the same way.
- the already known purified rh BMP-2 is a dimeric protein with a molecular weight of about 30,000. Each monomer has a high-mannose-type sugar chain at residue A sn 56 [Abstract Sci nt Interraction Symposium of Protein Society, San Diego, CA (1992). )]
- the composite porous body constituting the support of the osteogenic implant according to the present invention comprises a porous structure and a surface layer as described above.
- the porous structure is the implant of the present invention. It is a structure having a skeleton that is the basis of a porous structure.
- the specific structure of the porous structure is not particularly limited, and the implant manufactured using the porous structure constitutes an arbitrary porous structure such as a sponge, a mesh, or a fiber. It only needs to have a basic structure that can handle it.
- the surface layer is a layer provided on at least a part of the surface of the porous structure, and forms a composite porous body integrally with the porous structure.
- the preferred surface layer is one that is uniformly applied to the entire surface of the porous structure in the form of a film along the porous structure. Further, it is more preferable that the surface layer itself has a finer porous structure.
- the osteogenic implant according to the present invention has the above-described porous structure, blood and cells in a living body quickly enter the pores of the porous body after being implanted, and are suitable for bone formation.
- An environment is formed throughout the implant (ie, not only on the outer surface of the implant, but also on the pores inside the implant), and the BMP carried on the implant surface and in the Z 'or pores is rapidly released. After that, the porous structure and the BMP carried in the Z or surface layer are gradually released with the absorption of the porous structure and / or the surface layer.
- bone is formed not only on the surface of the implant, but also in the pores inside the implant and also in the resorbed portion of the implant.
- the bioabsorbable hydrophilic material in the present invention includes biocompatibility (that is, low toxicity, low foreign body reaction in a living body, and good affinity with living tissue), bioabsorbability (ie, , Biodegradable), hydrophilic, but low in water solubility or insoluble in water, and is solid at room temperature and has moldability.
- biocompatibility that is, low toxicity, low foreign body reaction in a living body, and good affinity with living tissue
- bioabsorbability ie, , Biodegradable
- hydrophilic but low in water solubility or insoluble in water, and is solid at room temperature and has moldability.
- the material has such properties.
- gelatin, hyaluronic acid, a hyaluronic acid derivative for example, polyion of hyaluronic acid with chitosan, polyaminogalactosamine, triethanolamine alginate, gelatin, casein, keratin, collagen, myosin and / or fipro
- collagen for example, see JP-A-6-73103
- collagen derivatives for example, succinylated collagen, methylated collagen
- chitosan for example, methylpyrrolidone chitosan
- Polyaminogalactosamine for example, trialginate alginate Examples include min, casein, keratin, myosin, and fibrin.
- the above-mentioned bioabsorbable hydrophilic materials can be used alone or in combination of two or more.
- any conventionally known porous body can be used.
- the porous gelatin material it is preferable to use a porous material prepared by dissolving gelatin in water, bubbling, freeze-drying and preparing a sponge.
- a porous gelatin body having a pore size of about 50 to 500 111, a density of 10 to 100 mg / ml, and a porosity of 90% or more has its own weight. Because it can absorb about 30 times more water than water, it is actually used as a hemostatic agent, and it is easily absorbed in tissues, so it may be embedded in the body and has no antigenicity. It is most preferred because it is known to be a safe material.
- the collagen porous material used as the porous structure may be a sponge-shaped porous material derived from low antigenic atelocollagen by a known method [for example, Helistat (trade name: Marion Laboratories, Inc.) Is preferred.
- Examples of the porous body of the hyaluronic acid derivative include a sponge composed of a gelatin Z-hyaluronic acid polyion complex (JP-A-6-73103), and examples of the porous body of the hyaluronic acid include hyaluronic acid.
- the hyaluronic acid porous material and the chitosan derivative porous material solidified and formed by a known method include, for example, a chitosan derivative described in Carbohydrate Polymers, 20, 99-106 (1993).
- a porous body can be used.
- the porous structure can be in any shape (eg, sponge, mesh, or fibrous) and has an average pore size of preferably 10 to 1 000 m, more preferably Preferably, the porous body has a porosity of 50 to 500 m, preferably 50% or more, more preferably 70% or more, and still more preferably 90% or more.
- the bioabsorbable polymer material of the present invention includes biocompatibility (ie, low toxicity, low foreign body reaction in vivo, and good affinity with living tissue), bioabsorbability (ie, It is a polymer material that is solid at room temperature, has moldability, and has a certain strength. There is no particular limitation on the polymer having such properties. Specifically, a hydrophobic polymer which is manufactured artificially, has biocompatibility and biodegradability, and has bioabsorbability, for example, polylactic acid, polylactic acid-polyglycolic acid copolymer, poly [bis (P-carboxifoxy) propane] Copolymer of anhydride (PC PP) and sebacic acid [J.
- biocompatibility ie, low toxicity, low foreign body reaction in vivo, and good affinity with living tissue
- bioabsorbability ie, It is a polymer material that is solid at room temperature, has moldability, and has a certain strength.
- PHB polyhydroxybutyric acid
- PGP Polyhydroxypropionic acid
- PCPP polycarboxylic acid
- SCPP poly [bis (p-carboxyphenoxy) propane] anhydride
- the aforementioned bioabsorbable polymer materials can be used alone or in combination of two or more.
- the bioabsorbable polymer material is dissolved in an appropriate solvent, and this is attached to the surface and inside of the porous structure by any method.
- an appropriate solvent for example, polylactic acid (PLA) or polylactic acid / polyglycolic acid copolymer (PLGA), especially polylactic acid having an average molecular weight of 5,000 to 150,000, or polylactic acid having an average molecular weight of 5,000 to 150,000 (molar ratio) Is dissolved in an organic solvent at a concentration of 0.2 to 20% (w / w), preferably 1 to 6% (w / w).
- the layer made of bioabsorbable polymer material has a porous structure Applying the solution to the porous structure by any method (eg, spraying or coating, preferably impregnated) capable of forming up to the surface and the surface of each internal pore, and further drying (eg, ventilation drying) (Preferably freeze-drying).
- any method eg, spraying or coating, preferably impregnated
- further drying eg, ventilation drying
- an organic solvent for preparing the bioabsorbable polymer material solution for example, dioxane, acetone, ethyl acetate, dimethylformamide or glacial acetic acid can be used.
- additives for example, a gelling agent, surfactant, if desired, for the purpose of improving the loading of BMP on the composite porous body obtained from the porous structure and the surface layer by the method described above.
- Agents, stabilizers, and Z or pH adjusters can be used as appropriate.
- the gelling agent include hyaluronic acid, carboxymethylcellulose (sodium), gelatin, collagen, gel-form polylactic acid / polyethylene glycol copolymer, and autologous blood. More can be added at the time of BMP addition or before BMP addition.
- a surfactant can be added to the porous structure and Z or the surface layer, and is preferably added to the surface layer made of a bioabsorbable polymer material. When it is added to the surface layer, it can be added when the bioabsorbable polymer material is applied, or can be added (or washed) after the bioabsorbable polymer material is applied. When it is added to the porous structure, it can be added at the time of preparing the structure or before the surface layer is applied.
- the surfactant is preferably a nonionic surfactant, more preferably a polyoxyethylene sorbin alkyl ester such as polysorbate 80 or polysorbate 20.
- a surfactant especially, polysorbate 80
- a surfactant especially, polysorbate 80
- 0.1 to 10% by weight, preferably 0.05 to 2% by weight, of the surfactant is added to the surface of the surface layer, or the cleaning treatment is performed with a solution containing the surfactant.
- the stabilizer include amino acids and saccharides such as glycine
- examples of the pH regulator include pharmaceutically acceptable organic acids and mineral acids such as citric acid. Can also be added in the same manner as the above-mentioned gelling agent and surfactant.
- the composite porous body having a surface layer made of a bioabsorbable polymer material on the surface of a porous structure made of a bioabsorbable hydrophilic material has an average pore diameter of preferably 10 to 1,000 m, more preferably The porosity is preferably 40% or more, more preferably 60% or more, and still more preferably 80% or more.
- the composite porous body maintains a porous structure in a living body for a certain period of time, allows cells to enter, provides a place for bone formation, and is gradually decomposed and absorbed and disappears completely. is there.
- the composite porous body of the present invention may be subjected to a sterilization treatment if necessary.
- the sterilization method may be any method that is medically acceptable, and examples include radiation sterilization, ethylene oxide gas sterilization, and dry heat sterilization.
- the BMP has at least a part of the composite porous body, that is, the surface of the composite porous body, the inside of the composite porous body (in other words, the porous structure). (Inside the body and / or inside the surface layer) and Z or in the pore space of the composite porous body.
- a bioabsorbable hydrophilic material has a good absorbency for a BMP aqueous solution and a good BMP adsorptivity, and thus has an excellent BMP supportability.
- bioabsorbable polymer materials are hydrophobic, BMP's absorbability and adsorptivity are improved, especially when they contain surfactants or are surface-treated with surfactants.
- a base such as a gelling agent may be added before or simultaneously with the addition of BMP in order to enhance the BMP supportability on the surface of the composite porous body.
- the method for supporting BMP on the composite porous body of the present invention is not particularly limited as long as BMP can be preferably supported on the entire composite porous body.
- BMP can be added at any stage of the production process of the composite porous body. For example, BMP is added during the manufacturing process of the porous structure Force, BMP can be added to the surface of the porous structure when it is completed, or BMP can be added together when the surface layer is applied. BMP can also be added when treating the composite porous body with a gelling surfactant.
- the BMP may be added by impregnating the BMP solution to obtain an implant as it is, or by drying the impregnated body by freeze-drying or the like. When a dry transplant is used, it is moistened with water for injection or physiological saline at the time of use (at the time of transplantation). .
- the content of each component per 1 m1 of the implant is not particularly limited.
- the bioabsorbable hydrophilic material forming the porous structure is Usually, it is 50 Omg or less, preferably 30 Omg or less, more preferably 5 to 10 Omg, and the bioabsorbable polymer material forming the surface layer is usually 50 Omg or less, preferably 30 Omg or less, more preferably Is 5 to 20 Omg, and BMP may be any concentration as long as it exhibits an osteoinductive effect.However, when rhBMP-2 is used, it is usually 0.01 mg or more, preferably 0.1 mg or more. It is 0.1 to 20 mg, more preferably 0.1 to 5. Omg.
- One example of a preferred embodiment of the osteogenic implant according to the present invention is as follows. That is, when a BMP aqueous solution is impregnated into a composite porous body consisting of a porous structure made of a gelatin porous body and a surface layer of polylactic acid / polyglycolic acid copolymer (PLGA), a part of the BMP solution becomes It passes through the micropores in the PLGA surface layer and is adsorbed inside the PLGA, and is further adsorbed on the gelatin porous matrix inside. If necessary, dry by freeze-drying. Thus, an osteogenic implant of the present invention can be obtained that carries BMP on the entire composite porous material.
- PLGA polylactic acid / polyglycolic acid copolymer
- BMP is released into the living body from the surface of the implant, and further, as the PLGA is absorbed and the gelatin porous body is absorbed, the internal BMP is absorbed. BMP is also released gradually.
- the implant of the present invention may be prepared by supporting BMP at the time of use, or may be stored under appropriate conditions until the time of use after supporting the BMP. Departure
- the clear implant can be implanted into the affected area using methods known in the art to repair various bone or cartilage defects. That is, it can be applied to a living body in the same manner as a conventionally known transplant, and can be appropriately applied according to the ordinary method of a person skilled in the art according to the purpose, use, applicable site, condition of a patient, and the like. it can.
- the implant of the present invention substantially defines the shape of the new bone to be formed. That is, bone formation occurs corresponding to the shape of the implant. Therefore, it is desirable to mold the implant of the present invention along a shape expected to form bone. Further, the transplant of the present invention does not require removal operation after transplant operation.
- Various osteogenic implants according to the present invention may be used alone or in combination of two or more. Further, the transplant of the present invention may be used in combination with another known transplant.
- the reinforcing material is, for example, a biocompatible film for fixing the implant, such as a collagen film or a Goatex film or a polylactic acid film used for the GTR method. Fixtures (especially bones) such as metal plates, osteosynthesis pins or nails, etc. These reinforcements can be removed surgically after bone formation, if necessary. Further, it may be used in combination with another known transplant.
- the present invention provides a bio-absorbable hydrophilic material composed of one or more compounds selected from the group consisting of gelatin, hyaluronic acid, and a hyaluronic acid derivative. Bioabsorption of one or more selected from the group consisting of polylactic acid / polyglycolic acid copolymer and poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid copolymer
- the present invention also relates to a composite porous body provided with a conductive polymer material.
- bioabsorbable hydrophilic material gelatin, and a gelatin / hyaluronic acid polyion complex
- a bioabsorbable polymer material polylactic acid having an average molecular weight of 500 to 1500, and an average molecular weight of 5
- a composite porous body comprising one or more compounds selected from the group consisting of Further, it is more preferable that a surfactant is further added to the surface layer of the composite porous body.
- a composite porous body in which the porous structure is a gelatin sponge having an average pore diameter of 50 to 500 Um and a porosity of 90% or more.
- the porous substrate and the surface layer are composed of a bioabsorbable hydrophilic material and a bioabsorbable polymer material, respectively. It has been conventionally known that each of these materials can serve as a BMP carrier by itself, even in L and shift.
- bioabsorbable hydrophilic materials such as gelatin and collagen, are soft and easily deformed, and decompose rapidly in vivo, and are decomposed and absorbed in one to two weeks. Therefore, it is not possible to obtain an implant that maintains its shape in a living body for a certain period of time, and in some cases, it is difficult to obtain a bone having a desired shape.
- the bioabsorbable polymer material is hydrophobic, it is inferior in BMP supportability.
- the force having biocompatibility is weaker than biocompatibility such as collagen.
- it has some hardness, it has low plasticity, is brittle and has insufficient moldability, and has the disadvantage that it is brittle and easily breaks even in a wet state after implantation.
- a carrier having both biocompatibility and strength by coating a porous bioabsorbable polymer material with collagen or the like having excellent biocompatibility.
- a carrier in practice, is inferior in plasticity, brittle, has insufficient moldability and operability, and is not satisfactory.
- the present inventors have surprisingly found that such a carrier has poor biocompatibility.
- the bone formation implant of the present invention in which BMP is supported on a composite porous body in which a surface of an absorbent polymer material is coated on a gelatin sponge or the like, has good biocompatibility and hydrophilicity, and also has good BMP supportability. I found it to be excellent.
- the implant of the present invention is rich in elasticity and excellent in operability and adaptability during surgery. Met. Furthermore, it has been found that the implant of the present invention can obtain good bone formation at an early stage not only in the peripheral portion but also in the central portion of the implant, and has excellent bone formation ability. That is, the implant for bone formation of the present invention exhibits excellent features not found in the conventional implants carrying BMP as described below.
- the osteogenic implant of the present invention is a flexible carrier having appropriate elasticity, is easy to mold, is not brittle, does not collapse, and can be molded into any shape. It can be formed into a shape and wound, or packed into a hole of a specific shape, easily fits into the shape of the bone defect, and has excellent operability and adaptability.
- the implant of the present invention has appropriate strength and elasticity, and can maintain a constant shape for a long period of time during storage in vitro and for a necessary period after implantation in the living body.
- it is possible to secure a space for forming a bone and to form a bone having a desired shape.
- It is also highly hydrophilic, has good penetration of bodily fluids (cells, blood, etc.) throughout the transplant, and maintains its porous shape for a certain period of time after implantation, making it necessary for bone cell growth.
- a stable microenvironment can be provided. BMP adsorption is good, BMP loading is excellent, BMP can be released in vivo in a sustained manner, and BMP does not leak out of the carrier. It takes the shape of a street.
- the bone is gradually absorbed into the living body and replaced by new bone, so that the implant itself does not remain in the living body for a long period of time, and good bone tissue is formed. You.
- the irritation at the transplantation site is weak, and there is no formation of bloody sickness observed in the PLGA carrier.
- the in vivo absorption of the transplant of the present invention varies depending on the size, shape, site of application, type of polymer, concentration, etc., but is almost completely absorbed in the body in about 3 to 12 weeks.
- the use of the transplant of the present invention enables favorable new bone formation. That is, as shown in the test examples described later, the formation of new bone by the implant of the present invention occurs early not only in the periphery of the implant but also in the center of the implant. It was confirmed that. This suggests that the implant of the present invention has a favorable environment suitable for bone formation even inside the implant. Further, as described above, the composite porous body of the present invention is a flexible carrier having good biocompatibility and hydrophilicity, excellent supportability of an active substance such as BMP, and suitable elasticity.
- the composite porous body of the present invention can maintain a constant shape and strength for a long period of time during storage outside a living body and for a necessary period after transplantation into a living body. Furthermore, after a certain period of time, it is gradually absorbed by the living body and does not remain in the living body for a long period of time. The irritation at the transplant site is also weak, and it is useful as a biomaterial.
- a sustained-release carrier for active substances such as polypeptides as a temporary substitute for living tissues such as bone and cartilage, or as a carrier for implants for forming living tissues such as bone and cartilage.
- active substances such as polypeptides
- a temporary substitute for living tissues such as bone and cartilage
- implants for forming living tissues such as bone and cartilage.
- it is useful as a carrier for the bone formation implant carrying BMP. The following tests and results for proving the excellent effects of the osteogenic implant of the present invention are shown.
- Examples of the transplant of the present invention include: (A) a transplant prepared in Example 1 using a gelatin sponge having absorbed a solution containing 2% by weight of a D, L-lactic acid-Z glycolic acid copolymer [hereinafter referred to as “transplant”. Body (A)], (B) In Example 1, D, L Implants prepared using a gelatin sponge having absorbed a solution containing 4% by weight of acid / glycolic acid copolymer [hereinafter referred to as implant (B)], and (C) D, L in Example 2.
- -Lactic acid-glycolic acid copolymer An implant prepared using a gelatin sponge absorbed with a solution containing 4% by weight [hereinafter referred to as an implant (C)].
- Transplants containing 1 or about 80 ⁇ g / 100 ⁇ were used.
- transplants containing the above-mentioned transplants ( ⁇ :), ( ⁇ ) and (C), which did not contain rhBMP-2 were prepared and transplanted in the same manner.
- Tissue extraction was performed at 1, 2, 3, and 4 weeks after transplantation.
- the extirpated tissues were subjected to calcium content measurement (atomic absorption method), soft X-ray photography, pQCT (quantitative computer-linked tomography for peripheral bone), and histological observation to evaluate the degree of bone formation.
- the excised tissue was immersed in 2N hydrochloric acid for 2 days or more, calcium was extracted, and the calcium content was measured by an atomic absorption method.
- FIG. 2 shows the change over time in the calcium content of the transplant.
- the group containing 20 g / 100 il of rh BMP-2 (indicated by 20 g in FIG. 2) and the group containing 80 g / 1001 (80 ⁇ . g)
- the calcium content of all transplants (A), (B) and (C) increased over time after one week from transplantation, and in most groups was less than three weeks. Showed the maximum value after 4 weeks.
- the value increased depending on the dose of rh BMP-2.
- wk is the elapsed time (weeks) after transplantation.
- PQCT was used to search for calcium distribution in the excised tissue. According to the search results of the calcium distribution in the vertical section of the extracted tissue, not only the surface layer of the implant but also the distribution of mottled calcium inside the implant were observed, and the bone along the hole of the implant was observed. Tissue formation was suggested.
- FIGS. Fig. 6 is a histological image (80x) of a section obtained by vertically cutting the central portion of the extracted tissue
- Fig. 7 is a histological image (66x) of a section cut in the horizontal direction.
- bone tissue stained red by HE black portions in FIGS.
- Figure 8 is an enlarged view of Figure 7 (330x).
- bone marrow tissue consisting of capillaries, bone marrow cells, and adipose tissue is also located in the bone matrix gap.
- We it was found that one week after the transplant, the porous transplant almost remained, but an image in which some gelatin began to be absorbed was observed.
- Two weeks after the transplantation an image in which the gelatin part was further absorbed was observed, and three weeks after the transplantation, most of the gelatin part was absorbed.
- PLGA remained as a thin layer inside the implant, and after 4 weeks, an image of a colorless and transparent thin layer lining large and small holes showing the persistence was observed. Furthermore, no changes such as hemorrhage, necrosis, and edema were observed in the tissues surrounding the implant of the present invention, indicating that the implant has weak local irritation.
- the transplant of the present invention maximized the osteoinduction by rh BMP-2 after 3 weeks from the transplantation or later, and furthermore, in the implant, It was confirmed that the compound had excellent bone inducing ability capable of inducing good bone tissue. It was also recognized that the implant of the present invention was gradually absorbed and shrunk in vivo, and had low local irritation.
- Example 23 A porous implant produced in Example 23 as an implant of the present invention in the same manner as in the above-mentioned Transplant Test Example 1, which contains rh BMP-2 at 0.1111 / 1111 or 0.4 mg / m]. The test was performed using the transplant. As a control, similarly, the following transplants containing 0.1 mg mgml or 0.4 mg m ⁇ 1 of rhBMP-2 were prepared and transplanted.
- a PLGA sponge (pore size: 100-500 ⁇ m, porosity: 90%) was added with rh BMP-2 solution and blood in a ratio of 1: An implant in which the solution mixed in 9 was dropped and absorbed.
- FIG. 9 The electron micrograph of the implant of the present invention without BMP added, that is, the composite porous body, is shown in FIG. 9, and the electron microscopic photographs of the carriers used for the comparative implants A and B without BMP are also shown in FIGS. It is shown in Figure 11.
- Tissue extraction was performed at 1, 2, 3 and 4 weeks after transplantation. After measuring the wet weight of the excised tissue, calcium content was measured (atomic absorption method) and histological observation was performed to evaluate the degree of bone formation.
- the comparative graft A showed good osteogenesis, but a bloody stomach formation and swelling were observed in the center, and the comparative graft B lacked the strength at the time of implantation and was brittle.
- the carrier was split due to lack of strength even after implantation, and formation and swelling of bloody cysts were observed.
- the implant of the present invention had flexibility and operability at the time of implantation. After implantation, bone tissue having almost the same shape and size as that of the implant was induced, and almost no swollen bloody stomach was formed.
- the calcium content / wet weight ratio of the excised tissue was the highest compared to other carriers.
- Nippon White Kin A 1.5 cm long full thickness defect was created in the right ulna of a heron (16-20 weeks old, male), and a D, L-lactate lactone was added to a gelatin sponge in Example 3 as a transplant of the present invention in the defect.
- An implant containing about 0.1 mg / ml or 0.4 mg / ml of rBMP-2 was implanted into the composite porous material having absorbed a solution containing 4% by weight of glycolic acid copolymer.
- Post-operative plain X-rays and CT scans of the defect using PQCT were performed over time to observe calcium distribution. After 12 weeks, they were sacrificed, paraffin sections were prepared after formalin fixation and decalcification, and histologically examined.
- the implant of the present invention was excellent in resilience to deformation, easily implanted in a bone defect, and excellent in operability. Radiopaque images were observed 2 weeks after the operation, and fusion between the tomograms was observed at 3 to 4 weeks. Observation by pQCT showed that bone formation progressed toward the inside of the carrier by 3 to 6 weeks after the operation, and then the bone in the center was resorbed. This is considered to be a finding suggesting the formation of cortical bone and bone marrow cavity following remodeling, and it was confirmed from histological findings that bone having such a structure was formed. In addition, the fusion rate and bone formation were dose-dependent.
- the implant of the present invention had the largest amount of BMP adsorbed per same volume, adsorbing about 1.5 times the amount of PLA sponge and gelatin sponge.
- the adsorption rate with respect to the total amount was about 70%, which was better than 50 Q0 for PLA sponge and 60% for gelatin sponge.
- the implant of the present invention induces bone formation promptly in a living body, and further, the entire implant is gradually replaced with new bone, completely eliminating the remaining of the implant, and producing good bone tissue. It can be formed and has excellent operability and moldability during adaptation. Therefore, in order to repair various bone or cartilage defects caused by trauma, disease, congenital defects, etc., it can be applied to an affected area by a method known in the art.
- the implant of the present invention when implanted in a living body, has low inflammability and excellent biocompatibility, and can repair bone or cartilage in a state close to nature.
- the implant of the present invention can be applied to various fields, for example, for trauma such as fracture, tumor or disease such as inflammatory, degenerative or necrotic bone disease, and surgery such as brain surgery or orthopedic surgery. Repair of bone or cartilage defect sites by accompanying bone extraction, promotion of healing of various fractures, formation of bone around artificial implants such as artificial joints, artificial bones or artificial dental roots, promotion of fixation when using human implants, spine Bone replacement in orthopedic fields such as promoting fixation and leg extension, cartilage regeneration, joint reconstruction, bone or cartilage replacement in plastic surgery fields, or bone, cartilage or cement repair in the dental field. It is suitable for increasing the size of bones for use in an implant. BRIEF DESCRIPTION OF THE FIGURES
- FIG. 1 is an explanatory view schematically showing a partial cross-sectional structure of a typical embodiment of the implant of the present invention.
- FIG. 2 is a graph showing a time-dependent change in calcium content when the transplant of the present invention is transplanted.
- FIG. 3 is a soft X-ray photograph of the transplant (A) of the present invention containing rhBMP-2 (20 g / 1001) three weeks after transplantation.
- FIG. 4 is a soft X-ray photograph of the transplant (B) of the present invention containing rhBMP-2 (20 ⁇ g1001) three weeks after transplantation.
- FIG. 5 is a soft X-ray photograph of the transplant (C) of the present invention containing rhBMP-2 (20 ⁇ g / 100 ⁇ 1) three weeks after transplantation.
- FIG. 6 is a cross-sectional view of a tissue image ( ⁇ 80) of a vertically-excised tissue of the transplant (C) of the present invention (containing 100 g of rhBMP-12 containing 20 gZ100) three weeks after transplantation.
- FIG. 7 is a cross-sectional view of a tissue image (66 ⁇ ) of a horizontally-excised tissue of the transplant (C) of the present invention (containing 100 g of rhBMP-12 containing 20 gZ100 l) three weeks after the transplantation.
- Fig. 8 is a partially enlarged view (330x) of Fig. 7.
- FIG. 9 is an electron micrograph ( ⁇ 35) of the composite porous body of the present invention.
- FIG. 10 is an electron micrograph ( ⁇ 50) of the carrier used for comparative implant A.
- FIG. 11 is an electron micrograph ( ⁇ 35) of the carrier used for comparative implant B.
- rhBMP-2 manufactured by Genetics Institute (also used in the following examples): 1 [2 mg / m1 to 8 mgZml; 5% glycine, 0.5% sucrose, 5mM sodium chloride, 5mM glutamate, 0.01% polysorbate 80; pH 4.5: 1 solution and blood mixed 1: 9 About 200 1 of the prepared solution was dropped and absorbed to obtain a porous bone transplant of the present invention containing rhBMP-2 (20 gZ100 ⁇ l to 80 ⁇ gZ100).
- Example 2 Example 2
- O g or 4. 0 g was added to a polysorbate 80 in advance to a concentration of 0.1% by weight, and added to 1,4 dioxane [Reagent: I, manufactured by Kanto Chemical Co., Ltd., and dissolved by heating to obtain 10 Om 1.
- the solution is added dropwise to a gelatin sponge (sbonzel) of 7 cmx10 cmx1 cm until the polymer solution cannot be absorbed. (Approximately 70 ml).
- the gelatin sponge that had absorbed the polymer solution was frozen at ⁇ 30, and dried at 0.1 mbar to obtain a composite porous body. Then, a solution of sodium hyaluronate derived from cockscomb (manufactured by Wako Pure Chemical Industries, Ltd.) at 0.25% by weight was added dropwise and wetted, followed by freeze-drying by a known method.
- rh BMP-2 “2 mg Zml 8 8 mg / 1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate , 0.01% polysorbate 80; pH 4.5: 1 solution and blood mixed in a ratio of 1: 9, about 2001 was dropped and absorbed, and rhBMP-2 (2O Example 3 A porous bone graft of the present invention containing gZlOO1 to 80 gZ100il) was obtained.
- Og or 4.0 g was added to 1,4-dioxane (a reagent manufactured by Kanto Chemical Co., Ltd.) to which polysorbate 80 was previously added to a concentration of 0.1% by weight, and dissolved by heating to 10 Om 1. After the polymer solution was cooled to room temperature, the solution was added dropwise to a 7 cm ⁇ 10 cm ⁇ 1 cm gelatin sponge (sbonzel) until the polymer solution could not be absorbed, and moistened (about 7 Om 1).
- the gelatin sponge having absorbed the polymer solution was frozen with -30, and dried at 0.1 mbar to obtain a composite porous body.
- rh BMP-2 0.1 mgZml to 0.8 mgZml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, ⁇ 0.1% polysol A solution of about 7 Om1 was dropped and absorbed, and then lyophilized by a known method to obtain a porous bone graft of the present invention.
- Og or 4.0 g to a polysorbate in advance. 80 was added to 0.1% by weight of 1,4-dioxane [a reagent manufactured by Kanto Chemical Co., Ltd.], and the mixture was dissolved by heating to 100 ml. After the polymer solution was cooled to room temperature, the solution was added dropwise to a 7 cm ⁇ 10 cm ⁇ 1 cm gelatin sponge (sbonzel) until the polymer solution could not be absorbed, and moistened (about 7 Om 1).
- the gelatin sponge having absorbed the polymer solution was frozen at ⁇ 30 and dried at 0.1 mbar to obtain a composite porous body.
- an aqueous solution containing 0.2% by weight of gelatin (a reagent manufactured by Bio-Rad Co., Ltd.) was added dropwise and wetted, followed by freeze-drying by a known method to obtain rh BMP-2 (0. 1 mg / m1 to 0.8 mg / m1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamic acid, 0.01% polysorbate 80; PH4.5] solution approx. 7 Om 1 was dropped and absorbed to obtain a porous bone graft of the present invention.
- the gelatin sponge having absorbed the polymer solution was frozen at ⁇ 30 and dried at 0.1 lmbar to obtain a composite porous body.
- rhBMP-2 containing 0.2% by weight of gelatin (a reagent manufactured by Bio-Rad Co., Ltd.) [0.1 mgZml to 0.8 mg / ml; 5% sucrose, 5 mM sodium chloride, 5 mM glutamic acid, ⁇ . 0.1% polysorbate 80; pH 4.5]
- a solution of about 70 ml was dropped and absorbed by a known method. After freeze-drying, a porous bone graft of the present invention was obtained.
- Og or 4.0 g is preliminarily polysorbate 80 was added to 1,4 dioxane [reagent manufactured by Kanto Chemical Co., Ltd.] added to a concentration of 0.1% by weight, and dissolved by heating to obtain 100 m 1.
- the polymer solution was added dropwise to a gelatin sponge (sbonzel) of 7 cmx10 cmx1 cm until the polymer solution could not be absorbed, and moistened (about 7 Om 1).
- rhBMP-2 containing 0.2% by weight of sodium hyaluronate derived from cockscomb (manufactured by Wako Pure Chemical Industries, Ltd.) [0.1 mg mg / ml to 0.8 mg / ml; 2.5% glycine , 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01 Q'0 polysorbate 80; pH 4.5 j solution About 70 ml was dropped and absorbed. It was freeze-dried by a known method to obtain a porous bone graft of the present invention.
- Example 8
- the gelatin sponge having absorbed the polymer solution was frozen at ⁇ 30, and dried at 0.1 mbar to obtain a composite porous body.
- an aqueous solution containing 0.2% by weight of cockroach-derived sodium hyaluronate [manufactured by Wako Pure Chemical Industries, Ltd.] was added dropwise and wetted, and freeze-dried by a known method.
- -2 [0.1 mgZml to 0.8 mgZml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamic acid, 0.01% polysorbate 80; pH 4. 5] About 70 ml of the solution was dropped and absorbed to obtain a porous bone graft of the present invention.
- Polysorbate 80 was added to glacial acetic acid [Reagent manufactured by Kanto Chemical Co., Ltd.] to which 0.1% by weight was added and dissolved to obtain 10 Om 1.
- the polymer solution was cooled to room temperature, it was dropped on a 7 cm ⁇ 10 cm ⁇ 1 cm gelatin sponge (sponzel) until the polymer solution could not be absorbed, and the polymer solution was wetted (about 70 m 1). Next, the gelatin sponge having absorbed the polymer solution was frozen at ⁇ 30 and then dried at 0.1 mbar.
- Rh BM P—2 [0.1 mg / m 1 to 0.8 mg 1; 2.5 on gelatin sponge (sponzel) of 7 cm mx l 0 cm mx l cm. 'Glycine, 0.5% sucrose, 5mM sodium chloride, 5mM glutamic acid, 0.01% polysorbate 80; pH 4.5] Approximately 70 ml of the solution was dropped and absorbed.
- rh BMP-2 prepared by a known method (0.1 mg / ml to 0.8 mg Zml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0 mM 0.1% polysorbate 80; pH 4.5]
- the lyophilized powder of the solution was added to the polymer solution in an amount of 20 mg to 80 mg as rhBMP-2 and stirred, and rhBMP was added.
- — 2 suspension A liquid was prepared.
- the rhBMP-2 suspension was dropped on a 7 cmxl O cmxlcm gelatin sponge (sponzel) until the suspension could not be absorbed, and moistened (about 7 Om1).
- the gelatin sponge having absorbed the polymer solution was frozen at ⁇ 30 and dried at 0.1 mbar to obtain a porous bone graft of the present invention.
- Example 1 2 Example 1 2
- rh BMP—2 [0.1 mg / ml to 0.8 mg / m 1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% polysorbate 8 0; pH 4.5]
- a solution of about 7 Om1 was added dropwise and freeze-dried by a known method to obtain rh BMP-2 (0.2 mg / m1 to 1.6 mg / m1).
- the resulting porous bone graft of the present invention was obtained.
- rh BMP-2 (0.1 lm gZml to 0.8 mg gZml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% polysorbate 8 0; pH 4.5]
- a solution of about 7 Om1 was dropped and absorbed, and lyophilized by a known method to obtain a porous bone graft of the present invention.
- the base 80 was added to 1,4-dioxane [reagent manufactured by Kanto Chemical Co., Ltd.] added at 0.1% by weight and dissolved to make 100 ml. After the polymer solution is cooled to room temperature, the solution is added dropwise to a 7.5 cmx10 cm x 0.3 cm collagen sponge (Helistat, manufactured by Marion Laboratories, Inc.) until the polymer solution can no longer be absorbed.
- the gelatin sponge having absorbed the polymer solution was frozen at 130 ° C., and dried at 0.1 mbar to obtain a composite porous material.rh BMP-2 (0.1 mg) / m] ⁇ 0. 8 m gZm l; 2. 5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamic acid, 0. 0 1 0 / ⁇ polysorbate one Bok 8 0; p H4.5] About 22.5 ml of the solution was dropped and absorbed, and lyophilized by a known method to obtain a porous bone graft of the present invention.
- rh BMP-2 [0.1 mg / ml to 0.8 mg Z ml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% polysorbate 80; About 9 ml of a pH4.5: 1 solution was dropped and absorbed, and lyophilized by a known method to obtain a porous bone graft of the present invention.
- Example 18
- Og is ethyl acetate
- Og is ethyl acetate [Reagent manufactured by Kanto Chemical Co., Ltd.] and dissolved to make 100 ml, and a 7.5 cm x 1 O cm x O. 3 cm collagen sponge (He1 istat) (Marion Laboratories, Inc.) And dried under reduced pressure at room temperature to obtain a composite porous body.
- rh BMP-2 [0.1 mg / ml to 0.8 mg / ml; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01 % Polysorbate 80; pH 4.5] A solution of about 22.5 ml was dropped and absorbed, and lyophilized by a known method to obtain a porous bone graft of the present invention.
- Example 20
- the spongel having absorbed the polymer solution was frozen at 130 and freeze-dried at 0.1 mbbar to obtain a composite porous body.
- rh BMP-2 (0.12 mg / m1 to 5.9 mg / m1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.1% 0 1% polysorbate 80; pH 4.51 solution was dropped and absorbed, then lyophilized by a known method, and rhBMP-2 (0.1 mg / ml to 5.0 mg / ml). m 1) was obtained.
- 1,4-dioxane reagent manufactured by Kanto Chemical Co., Ltd.
- polysorbate 80 Was added to 1,4-dioxane (a reagent manufactured by Kanto Chemical Co., Ltd.) added to a concentration of 0.5% by weight, and dissolved by heating to 150 m 1. After cooling the polymer solution to room temperature, it is impregnated with a gelatin sponge (sbon
- Rh BMP-2 (0.12 mg / m 1 to 5.9 mg / m 1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% polysorbate 80; pH 4.5]
- a solution of approximately 6 Om1 was added dropwise and absorbed, and rh BMP-2 (0.1 mg / ml to 5. 0 mgZm!) was obtained.
- 4-Dioxane (Kanto Chemical Co., Ltd.) prepared by adding 12.0 in advance with 0.5% by weight of polysorbate 80 (Kanto Chemical Co., Ltd.). Was added and dissolved by heating to 150 m 1.
- the polymer solution is cooled to room temperature, it is impregnated with a gelatin sponge (sponzel) of 7 cm ⁇ 10 cm ⁇ 1 cm. Next, the sponge was immersed in the polymer solution, frozen at 45 °, and freeze-dried at 0.1 mbar.
- rh BMP -2 (0.12 mg Zml to 5.9 mg / m 1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% Polysorbate 80; pH 4.5] Approximately 60 ml of the solution was dropped and absorbed, then freeze-dried by a known method, and rhBMP-2 (0.1 mgZml to 5.0 mg / ml) was added. A porous bone graft of the present invention was obtained containing Example 26.
- Og is preliminarily polysorbate 80 (manufactured by Kanto Chemical Co., Ltd.) Was added to 1,4-dioxane (a reagent manufactured by Kanto Chemical Co., Ltd.) to which 0.5% by weight was added, and dissolved by heating to obtain 10 OmI. After the polymer solution was cooled to room temperature, it was dropped and wetted on a 7 cm ⁇ 10 cm ⁇ 1 cm gelatin sponge (sponzel) until the polymer solution could not be absorbed (about 7 Om 1).
- r hBMP-2 [0.1 2 mgZml ⁇ 5.9 mg / m 1; 2.5% glycine, 0.5% sucrose, 5 mM sodium chloride, 5 mM glutamate, 0.01% polysorbate 80 PH 4.5]
- the solution was absorbed by dropping about 6 Om1 and then freeze-dried by a known method to obtain rhBMBP-2 (0.1 mg / ml to 5.0 mg / m). ) was obtained.
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Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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JP8511609A JP2986551B2 (ja) | 1994-09-30 | 1995-09-28 | 骨形成用移植体 |
AU35778/95A AU3577895A (en) | 1994-09-30 | 1995-09-28 | Osteoplastic graft |
US08/817,409 US5830493A (en) | 1994-09-30 | 1995-09-28 | Bone-forming graft |
KR1019970701932A KR970706027A (ko) | 1994-09-30 | 1995-09-28 | 골 형성용 이식체(Osteoplastic graft) |
EP95932925A EP0784985A4 (en) | 1994-09-30 | 1995-09-28 | OSTEOPLASTIC TRANSPLANT |
MX9702305A MX9702305A (es) | 1994-09-30 | 1995-09-28 | Injerto formador de hueso. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP6/261980 | 1994-09-30 | ||
JP26198094 | 1994-09-30 |
Publications (1)
Publication Number | Publication Date |
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WO1996010426A1 true WO1996010426A1 (fr) | 1996-04-11 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/JP1995/001970 WO1996010426A1 (fr) | 1994-09-30 | 1995-09-28 | Greffon osteoplastique |
Country Status (9)
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US (1) | US5830493A (ja) |
EP (1) | EP0784985A4 (ja) |
KR (1) | KR970706027A (ja) |
CN (1) | CN1158573A (ja) |
AU (1) | AU3577895A (ja) |
CA (1) | CA2200052A1 (ja) |
MX (1) | MX9702305A (ja) |
TW (1) | TW369414B (ja) |
WO (1) | WO1996010426A1 (ja) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997045532A1 (en) * | 1996-05-28 | 1997-12-04 | Brown University Research Foundation | Hyaluronan based biodegradable scaffolds for tissue repair |
WO1997046267A1 (en) * | 1996-06-03 | 1997-12-11 | Gore Enterprise Holdings, Inc. | Materials and methods for the immobilization of bioactive species onto biodegradable polymers |
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Also Published As
Publication number | Publication date |
---|---|
AU3577895A (en) | 1996-04-26 |
US5830493A (en) | 1998-11-03 |
CN1158573A (zh) | 1997-09-03 |
EP0784985A1 (en) | 1997-07-23 |
TW369414B (en) | 1999-09-11 |
MX9702305A (es) | 1997-06-28 |
EP0784985A4 (en) | 2000-05-31 |
CA2200052A1 (en) | 1996-04-11 |
KR970706027A (ko) | 1997-11-03 |
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