WO2000074690A1 - Bone graft substitute composition - Google Patents
Bone graft substitute composition Download PDFInfo
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- WO2000074690A1 WO2000074690A1 PCT/US2000/002780 US0002780W WO0074690A1 WO 2000074690 A1 WO2000074690 A1 WO 2000074690A1 US 0002780 W US0002780 W US 0002780W WO 0074690 A1 WO0074690 A1 WO 0074690A1
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- bone
- graft substitute
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- 239000000203 mixture Substances 0.000 title claims abstract description 107
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 68
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 27
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims abstract description 25
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims abstract description 21
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 239000008223 sterile water Substances 0.000 claims abstract description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 8
- 239000011780 sodium chloride Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims abstract description 6
- -1 methycellulose Polymers 0.000 claims abstract description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000001103 potassium chloride Substances 0.000 claims abstract description 4
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims abstract description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims abstract description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002953 phosphate buffered saline Substances 0.000 claims abstract description 3
- 210000002805 bone matrix Anatomy 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 claims description 12
- 239000012530 fluid Substances 0.000 claims description 9
- 230000003628 erosive effect Effects 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 239000012867 bioactive agent Substances 0.000 claims description 2
- 210000001185 bone marrow Anatomy 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 230000000921 morphogenic effect Effects 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 239000004372 Polyvinyl alcohol Substances 0.000 abstract 1
- 229920002451 polyvinyl alcohol Polymers 0.000 abstract 1
- 239000000463 material Substances 0.000 description 29
- 238000009472 formulation Methods 0.000 description 15
- 230000007547 defect Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 241000282465 Canis Species 0.000 description 7
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 5
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 230000002262 irrigation Effects 0.000 description 4
- 238000003973 irrigation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 238000005336 cracking Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000004816 latex Substances 0.000 description 3
- 229920000126 latex Polymers 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000011505 plaster Substances 0.000 description 3
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011507 gypsum plaster Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000002962 histologic effect Effects 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000000035 BCA protein assay Methods 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- QMGYPNKICQJHLN-UHFFFAOYSA-M Carboxymethylcellulose cellulose carboxymethyl ether Chemical compound [Na+].CC([O-])=O.OCC(O)C(O)C(O)C(O)C=O QMGYPNKICQJHLN-UHFFFAOYSA-M 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000005667 attractant Substances 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 239000004068 calcium phosphate ceramic Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000031902 chemoattractant activity Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
-
- 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
- A61L27/40—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
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
-
- 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
- A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Inorganic Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Botany (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Developmental Biology & Embryology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Composite Materials (AREA)
- Materials Engineering (AREA)
- Materials For Medical Uses (AREA)
Abstract
A bone graft substitute composition comprising calcium sulfate; a mixing solution selected from the group consisting of sterile water, sodium chloride, phosphate buffered saline, potassium chloride, and sodium sulfate; and a plasticizing substance selected from the group consisting of carboxymethylcellulose, polyvinyl alcohol, methycellulose, and hydroxypropyl methylcellulose.
Description
SPECIFICATION
BONE GRAFT SUBSTITUTE COMPOSITION
BACKGROUND OF THE INVENTION:
The present invention relates, in general, to bone graft substitute compositions. Calcium sulfate has been clinically used for many years as a bone void filler with successful results.
Hanker et al . , U.S. Patent 4,619,655, issued October 28, 1986, discloses an animal implant comprising a scaffold material composed of plaster of Paris and a non- bioresorbable calcium material (such as calcium phosphate ceramic particles) bound with the plaster of Paris; a method of inserting such a composition in fluid or semisolid form into the appropriate body location of an animal (e.g., about a fracture locus); and a method of inserting a preform of such composition into the appropriate location of an animal (e.g., at the locus of a fracture) .
Gitelis, U.S. Patent 5,147,403, issued September 15, 1992, discloses a method or technique for implanting a prosthesis comprising the steps of first preparing the surface of a bone to receive the prosthesis, then applying a calcium sulfate suspension in free flowing form to the prepared bone surface, and then seating the prosthesis to the coated bone surface. Randolph, U.S. Patents 5,614,206, issued March 25, 1997, and 5,807,567, issued September 15, 1998, disclose processes for preparing pellets by mixing of calcium sulfate, water and other medicaments to provide controlled
release of calcium sulfate and medicaments.
Snyder, U.S. Patent 5,425,769, issued June 20, 1995, discloses a composition for an artificial bone substitute material consisting of collagen m a calcium sulfate matrix which can be rendered porous by a foaming agent . The composition is adaptable for osseous repair by adjusting the collagen and calcium sulfate m varying ratios to suit particular applications and including admixtures of growth factors. Sottosanti, U.S. Patent 5,366,507, discloses a composition for use m bone tissue regeneration, the composition containing a barrier material and a graft material. The barrier material can be calcium sulfate, while the graft material may consist of a composite graft material containing demmeralized, freeze-dried, allogenic bone and calcium sulfate.
Sottosanti, U.S. Patent 5,569,308, discloses a method for use m bone tissue regeneration including first filling a graft site with graft material, and then placing a layer of barrier material over at least a portion of the graft material . The barrier material can be calcium sulfate, while the graft material may consist a composite graft material containing demmeralized, freeze-dried, allogenic bone and calcium sulfate. Hanker et al , "Setting of Composite
Hydroxylapatite/Plaster Implants with Blood for Bone Reconstruction," Proceedings of the 44 th Annual Meeting of the Electron Mi croscopy Soci ety of America , Copyright 1986, discloses using blood as the only moistening agent a plaster or plaster/HA mixture as long as accelerator salts are utilized, and suggests that the putty-like consistency of such compositions offers distinct advantages m moldability and workability.
Osteotech, Inc., of Shrewsbury, New Jersey, markets a bone graft substitute under the mark Grafton® . It is comprised of demmeralized bone matrix and glycerol as a carrier material. The carrier material, glycerol, is a viscous, gel-like, weak alcohol that is hydrophilic and water soluble. It is recognized by the Food and Drug Administration as a "Generally Regarded As Safe" substance .
DePuy, Inc., of Warsaw, Indiana, markets a bone graft substitute under the mark DynaGraft . It is comprised of demmeralized bone matrix and poloxamer as a carrier material . Poloxamer is a reverse phase polymer which becomes more viscous with increasing temperature .
Nothing m the known prior art discloses or suggests the present invention. More specifically, nothing m the known prior art discloses or suggests a bone graft substitute composition including calcium sulfate, a mixing solution such as sterile water, and a plasticiz g substance such as carboxymethylcellulose , and having an extended set time and sufficient robustness to withstand fluid impact with minimal erosion.
BRIEF SUMMARY OF THE INVENTION: A basic concept of the present invention is to provide bone graft substitute composition having an extended set time and sufficient robustness to withstand fluid impact with minimal erosion for expanded clinical applications . The bone graft substitute composition of the present invention comprises, m general, calcium sulfate; a mixing solution such as sterile water; and a plasticizmg substance such as carboxymethylcellulose.
One object of the present invention is to provide a bone graft substitute composition that can be mixed into a paste and then loaded into a syringe and ejected for an extended period of time (e.g., more than ten minutes) .
Another object of the present invention is to provide a bone graft substitute composition that can be mixed into a putty and then handled and formed into desired shapes for an extended period of time (e.g., more than ten minutes) .
DETAILED DESCRIPTION OF THE INVENTION:
The bone graft substitute composition of the present invention comprises, general, a quantity of calcium sulfate, a quantity of fluid (e.g., sterile water), and a quantity of a plasticizmg substance (e.g., carboxymethylcellulose) which provides a resultant composition that is robust and has an extended set time. The extended set time of the resultant composition provides a useful working time of at least 10 minutes to allow sufficient time for a surgeon to properly apply the bone graft substitute composition, while the robustness of the resultant composition allows the implanted composition to withstand the typical pressure of body fluids, irrigation fluids and/or suctionmg with minimal material erosion, disintegration or dissolution.
The bone graft substitute composition of the present invention may comprise a mixture of calcium sulfate; a mixing solution selected from the group consisting of sterile water, inorganic salts, and cationic surface active agents including sodium chloride, phosphate buffered saline, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate, and sodium acetate, etc.; and a plasticizmg
substance selected from the group consisting of cellulose derivatives including sodium carboxymethylcellulose, methycellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxethylcellulose and cellulose acetate butyrate, and higher molecular weight alcohols including glycerol and vinyl alcohols, etc. The bone graft substitute composition may include demmeralized bone matrix. One formulation of the composition may be approximately 100 parts calcium sulfate by weight, 11.1 parts carboxymethylcellulose by weight, 185.2 parts water by weight, and 69.4 parts demmeralized bone matrix by weight. Another formulation of the composition may be approximately 100 parts calcium sulfate by weight, 6.3 parts carboxymethylcellulose by weight, and 31 parts water by weight. Another formulation of the composition may be approximately 100 parts calcium sulfate by weight, 1.2 parts carboxymethylcellulose by weight, and 31 parts water by weight . Another formulation of the composition may be approximately 80-120 parts calcium sulfate by weight, 1-40 parts carboxymethylcellulose by weight, and 21-250 parts water by weight. The composition may include a bioactive agent selected from the group consisting of demmeralized bone matrix, growth factors, hyaluronic acid, bone morphogenic proteins, bone autograft, and bone marrow, etc. The composition may include sodium bicarbonate. For example, the composition may include 0.1-2% sodium bicarbonate by weight for creating a porous structure m the resultant composition. Possible embodiments of the bone graft substitute composition of the present invention may include at least one additive selected from the group consisting of antiviral agent, antimicrobial agent, antibiotic agent, ammo acid, peptide, vitamin, inorganic element, protein synthesis co-factor, hormone, endocrine
tissue, synthesizer, enzyme, polymer cell scaffolding agent with parenchymal cells, angiogenic drug, demmeralized bone powder, collagen lattice, antigenic agent, cytoskeletal agent, mesenchymal stem cells, bone digester, antitumor agent, cellular attractant, fibronectin, growth hormone, cellular attachment agent, immunosuppressant , nucleic acid, surface active agent, hydroxyapatite, penetration enhancer, bone allograft, and chunks, shards, and/or pellets of calcium sulfate.
Preferred Embodiment 1 : An mjectable bone graft substitute composition having the following preferred formulation: 100 parts by weight of medical grade calcium sulfate hemihydrate (MGCSH) , 11.1 parts by weight of carboxymethylcellulose (CMC), 69.4 parts by weight of demmeralized bone matrix (DBM) , and 162 parts by weight of sterile water.
The preferred method for mixing this putty bone graft substitute composition comprises the following steps: (1) dry blend the powder components (i.e., the calcium sulfate hemihydrate, carboxymethylcellulose, and demmeralized bone matrix) ; (2) add the sterile water; and (3) mix or stir all components for approximately 30 seconds to one minute or until the desired putty-like consistency is achieved.
The resultant mjectable bone graft substitute composition has the following characteristic/criteria:
Handability — the resultant composition should (a) be a single cohesive bolus; (b) be able to be handled and manipulated with minimal to no material transfer
(sticking) to latex gloved hand; (c) be able to be handled without material crumbling or falling apart; and (d) exhibit minimal cracking or "tearing" with extreme
manipulation, e.g., hard squeezing;
Ejectability — the resultant composition should, (a) be able to be easily manipulated, e.g., rolled into a long cylinder or other suitable shape, so as to be manually placed into an appropriate injection apparatus, e.g., a syringe; and (b) be able to be ejected through a 1/8 inch (0.3175 centimeter) diameter orifice with relatively little pressure required; and
Robustness — the resultant composition, after being placed or injected into or onto the desired location, should be able to withstand body fluids, reasonable irrigation fluids and/or suctionmg with minimal material erosion, disintegration or dissolution.
Preferred Embodiment 2 :
A putty bone graft substitute composition having the following preferred formulation: 100 parts by weight of medical grade calcium sulfate hemihydrate (MGCSH), 6.3 parts by weight of carboxymethylcellulose (CMC) , and 31 parts by weight of sterile water.
The preferred method for mixing this putty bone graft substitute composition comprises the following steps: (1) dry blend the powder components (i.e., the calcium sulfate hemihydrate, and carboxymethylcellulose); (2) add the sterile water; and (3) mix or stir all components for approximately 30 seconds to one minute or until the desired putty-like consistency is achieved.
The resultant putty bone graft substitute composition has the following characteristic/criteria: Handability — the resultant composition should
(a) be a single cohesive bolus; (b) be able to be handled and manipulated with minimal to no material transfer (sticking) to latex gloved hand; (c) be able to be handled
without material crumbling or falling apart; and (d) exhibit minimal cracking or "tearing" with extreme manipulation, e.g., hard squeezing; and
Robustness — the resultant composition, after being placed or injected into or onto the desired location, should be able to withstand body fluids, reasonable irrigation fluids and/or suctionmg with minimal material erosion, disintegration or dissolution.
Preferred Embodiment 3 :
A paste bone graft substitute composition having the following preferred formulation: 100 parts by weight of medical grade calcium sulfate hemihydrate (MGCSH), 1.2 parts by weight of carboxymethylcellulose (CMC) , and 31 parts by weight of sterile water.
The preferred method for mixing this putty bone graft substitute composition comprises the following steps: (1) dry blend the powder components (i.e., the calcium sulfate hemihydrate, and carboxymethylcellulose); (2) add the sterile water; and (3) mix or stir all components for approximately 30 seconds to one minute or until the desired putty-like consistency is achieved.
The resultant paste bone graft substitute composition has the following characteristic/criteria: Ejectability — the resultant composition should be able to be ejected through a 1/8 inch (0.3175 centimeter) diameter orifice with relatively little pressure required.
Preferred Embodiment 4:
A bone graft substitute composition having the following preferred formulation: approximately 80-120 parts medical grade calcium sulfate hemihydrate by weight,
approximately 21-250 parts sterile water by weight; and approximately 1-40 parts sodium carboxymethylcellulose by weight. This preferred formulation may include approximately 10-100 parts demmeralized bone matrix by weight .
The preferred method for mixing this bone graft substitute composition comprises the following steps: (1) dry blend the powder components (i.e., the calcium sulfate hemihydrate, and sodium carboxymethylcellulose, and, if included, the demmeralized bone matrix); (2) add the sterile water; and (3) mix or stir all components for approximately 30 seconds to one minute or until the desired consistency is achieved.
The resultant bone graft substitute composition has the following characteristic/criteria:
Handability — the resultant composition should: (a) be a single cohesive bolus; (b) be able to be handled and manipulated with minimal to no material transfer (sticking) to latex gloved hand; (c) be able to be handled without material crumbling or falling apart; and (d) exhibit minimal cracking or "tearing" with extreme manipulation, e.g., hard squeezing;
Ejectability — the resultant composition should: (a) be able to be easily manipulated, e.g., rolled into a long cylinder or other suitable shape, so as to be manually placed into an appropriate injection apparatus, e.g., a syringe; and (b) be able to be ejected through a 1/8 inch (0.3175 centimeter) diameter orifice with relatively little pressure required; and Robustness — the resultant composition, after being placed or injected into or onto the desired location, should be able to withstand body fluids, reasonable irrigation fluids and/or suctionmg with
minimal material erosion, disintegration or dissolution.
Tests : The majority of tests done to date on the bone graft substitute composition of the present invention basically consist of mixing a specific formulation and then assessing and recording the mixing, handling, consistency, and m ectability properties of the resultant material.
Formulation Tests:
Injectable Bone Graft Substitute Composition: Formulations with various types and amounts of carboxymethylcellulose and demmeralized bone matrix have been tested. Specific examples include: (1) carboxymethylcellulose percentages of 1-10% by weight; (2) types of carboxymethylcellulose have included high viscosity, medium viscosity, and low viscosity from 3 vendors (e.g., Aqualon® 7HF PH sodium carboxymethylcellulose from Hercules Incorporated, Hercules Plaza, 1313 North Market Street, Wilmington, DE 19894-0001); (3) carboxymethylcellulose sterilized by gamma or electronic beam sterilization (medium and low doses); (4) demmeralized bone matrix percentages up to 65% by volume; (5) differently processed demmeralized bone matrix, air dried and freeze dried; (6) demmeralized bone matrix from two vendors (e.g., human freezed dried demmeralized bone matrix from AlloSource, 8085 E. Harvard Ave . , Denver, CO 80231); and (7) animal demmeralized bone matrix, including bovine and canine. For all these formulations, varying amounts of water, between 31-200 parts by weight, have been tested. The mixing, handling, consistency, and mjectability properties were assessed and formulas chosen such that
they met the mixing, handability, ejectability, and robustness characteristics/criteria stated heremabove. Paste And Putty Bone Graft Substitute Composition: These were the first tests done and included formulations with compositions having 100 parts by weight medical grade calcium sulfate hemihydrate, and between 1-10% by weight carboxymethylcellulose, and between 31-200 parts by weight water. As was the case with the mjectable bone graft substitute composition, mixing, handability, consistency, mjectability, and robustness properties were assessed for the different formulations. Specific tests have included: (1) varying the carboxymethylcellulose percentages from 0.25 % up to 10% by weight, (2) using inorganic salt solutions including 2% sodium chloride (NaCl) by weight, 2-4% sodium sulfate (Na2S04) by weight, and 2% potassium chloride (KCl) by weight.
As with the mjectable bone graft substitute composition, varying amounts of water, 31-200 parts by weight, were used.
Example 1 : The osteomductive properties of the mjectable bone graft substitute composition have been studied using an athymic mouse-intramuscular implantation model. This animal model is widely accepted as the "gold standard" for assessing osteomductive characteristics of bone graft materials. In this model, a given amount of material is surgically placed into a muscular site. After an implantation period of four weeks, the osteomductive response is assessed using various analytical methods, lncludling radiography, biochemical analysis (alkaline phosphatase levels and calcium content) , and histomorphometry .
In this study, four athymic (nude) male mice (Harlan Sprague Dawley, Inc.) were used for each material group. Two muscle pouches were formed m the right and left gluteal muscles of each mouse and implanted with either- 1) pellets which were manufactured using the composition given m Preferred Embodiment 1, or 2 ) twenty (20) mg of demmeralized bone matrix which had been rehydrated with lsotomc saline (0.9% NaCl) . The pellets made from Preferred Embodiment 1 were 3.0 mm m diameter, 2.5 mm m height and 25 mg in weight.
After twenty-eight (28) days the animals were sacrificed and the materials explanted. The explants were analyzed for osteomductive potential by assessing the alkaline phosphatase activity and for new bone growth by histomorphometπc analysis of histologic sections.
Samples to be analyzed for alkaline phosphatase activity were minced, sonicated, and extracted with water saturated butanol . The extracts were assayed for protein content using a Pierce BCA Protein Assay Kit (Pierce Chemical Co.) and measuring the conversion of para- nitrophenylphosphate (pNPP) to para-nitrophenol (pNP) with time. The results were expressed as umole pNP formed/mm/ug tissue protein.
Samples intended for histomorphometπc analyses were prepared using standard histological procedures. The percent viable bone (new bone formation) was quantitated employing computer software (Adobe Photo Shop 3.0.4 and HNIH 1.61), m conjunction with a microscope equipped with a video camera. Data was reported as percent viable bone relative to the total cross-sectional area analyzed. The alkaline phosphatase levels (umole pNP formed/mm/ug tissue protein) and percent viable bone results for the groups of mice implanted with DBM only and
with mjectable putty manufactured using the composition given m Preferred Embodiment 1 are shown m Table 1.
Table 1 - Osteomductive Results
Alkaline Phosphatase Levels and Percent Viable Bone
Example 2 : A study was performed on canines to evaluate healing of bone defects using materials with the composition given Preferred Embodiment 1. The DBM used m these compositions was fresh frozen canine DBM (Veterinarian Transplant Services, Seattle, WA) . Two methods were used to produce the test materials. The first material group consisted of a blend of DBM, calcium sulfate, and CMC powder that was irradiated sterilized, while the second group mixed canine DBM with the calcium sulfate-CMC blend at the time of surgery.
In this canine animal model, large medullary cylindrical defects (13 mm diameter x 50 mm length) were created bilaterally m the proximal humeri by drilling axially through the greater tubercle. Six to 7 cc of test
material were injected into prepared cavities using a large-bore catheter-tip syringe. Left humeri received the premixed material that hand been sterilized and the right humeri received the material mixed mtraoperatively which utilized non- irradiated canine DBM. Radiographs of the humeri were obtained preoperative, immediately postoperative, and at 2 , 3, and 6 weeks. Following euthanasia after 6 weeks, the explanted humeri were sectioned transversely, radiographed, and processed for plastic imbedded undecalcifled histology. The histologic sections were stained with basic fuchsm and toluidme blue and examined by light microscopy.
Post -operative radiographs revealed all test materials to be well contained m the prepared cavities. Normal would healing occurred and there were no postoperative infections. Serial clinical radiographs showed a progressive decrease m materials density with time, no difference was evident between the right and left sides . Contact radiographs of the cut sections demonstrated no difference m pattern or density of bone filling the right and left defects, non-irradiated and irradiated canine DBM materials groups, respectively. Serial sections for all the dogs showed between 30-100% filling of the defect, with one dog showing almost complete filling for all sections.
Histologically, the nature of new bone formation and the amount of residual material were similar m the right and left defects. In the peripheral one-third of the defects, new bone was present at the margins and haversian surfaces of abundant DBM particles. Residual calcium sulfate was evident, incorporated withm slender bone trabeculae, independent of DBM particles. New bone
formation in the central aspect of the defects was more variable, with some vascular fibrosus tissue shown. No foreign body or inflammatory response was seen in any of the slides, indicating that the materials had extremely good biocompatibilty .
Thus, materials with compositions given in Preferred Embodiment 1 were shown to be well tolerated by the bone and to heal a large medullary defect 30-100% at six weeks with viable new bone in a canine bone defect model . Although the present invention has been described and illustrated with respect to preferred embodiments and preferred uses therefor, it is not to be so limited since modifications and changes can be made therein which are within the full intended scope of the invention.
Claims
1. A bone graft substitute composition comprising: (a) calcium sulfate; (b) a mixing solution selected from the group consisting of sterile water, inorganic salts, and cationic surface active agents including sodium chloride, phosphate buffered saline, potassium chloride, sodium sulfate, ammonium sulfate, ammonium acetate, and sodium acetate; and
(c) a plasticizing substance selected from the group consisting of cellulose derivatives including sodium carboxymethylcellulose, methycellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxethylcellulose and cellulose acetate butyrate, and higher molecular weight alcohols including glycerol and vinyl alcohols.
2. The bone graft substitute composition of claim 1 in which is included demineralized bone matrix.
3. The bone graft substitute composition of claim 2 m which said composition is approximately 40% demineralized bone matrix by dry weight.
4. The bone graft substitute composition of claim 2 m which said composition is approximately 100 parts calcium sulfate by weight, 11.1 parts carboxymethylcellulose by weight, 162 parts water by weight, and 69.4 parts demineralized bone matrix by weight.
5. The bone graft substitute composition of claim 1 m which said composition is approximately 100 parts calcium sulfate by weight, 6.3 parts carboxymethylcellulose by weight, and 31 parts water by weight .
6. The bone graft substitute composition of claim 1 m which said composition is approximately 100 parts calcium sulfate by weight, 1.2 parts carboxymethylcellulose by weight, and 31 parts water by weight .
7. The bone graft substitute composition of claim 1 m which said composition is approximately 80-120 parts calcium sulfate by weight, 1-40 parts carboxymethylcellulose by weight, and 21-250 parts water by weight .
8. The bone graft substitute composition of claim 1 m which is included a bioactive agent selected from the group consisting of demmeralized bone matrix, growth factors, hyaluronic acid, bone morphogenic proteins, bone autograft, therapeutic agents, analgesics, and bone marrow, bone allograft, and parenchymal and mesenchymal cells .
9. The bone graft substitute composition of claim 1 m which is included sodium bicarbonate.
10. A bone graft substitute composition comprising: (a) calcium sulfate; (b) a mixing solution; and
(c) a plasticizmg substance for extending the set time of the resultant composition and for providing the resultant composition with sufficient robustness to withstand fluid impact with minimal erosion.
11. A bone graft substitute composition comprising:
(a) approximately 80-120 parts medical grade calcium sulfate hemihydrate by weight;
(b) approximately 21-250 parts sterile water by weight; and
(c) approximately 1-40 parts sodium carboxymethylcellulose by weight.
12. The bone graft substitute of claim 11 which is included approximately 10-100 parts demmeralized bone matrix by weight .
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE60039515T DE60039515D1 (en) | 1999-06-07 | 2000-02-02 | COMPOSITION FOR REPLACEMENT OF BONE RANSPLANT |
| EP00914492A EP1198236B1 (en) | 1999-06-07 | 2000-02-02 | Bone graft substitute composition |
| AU35876/00A AU780355B2 (en) | 1999-06-07 | 2000-02-02 | Bone graft substitute composition |
| CA002371612A CA2371612C (en) | 1999-06-07 | 2000-02-02 | Bone graft substitute composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/327,761 US7371408B1 (en) | 1999-06-07 | 1999-06-07 | Bone graft substitute composition |
| US09/327,761 | 1999-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000074690A1 true WO2000074690A1 (en) | 2000-12-14 |
Family
ID=23277952
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2000/002780 WO2000074690A1 (en) | 1999-06-07 | 2000-02-02 | Bone graft substitute composition |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US7371408B1 (en) |
| EP (1) | EP1198236B1 (en) |
| AU (1) | AU780355B2 (en) |
| CA (1) | CA2371612C (en) |
| DE (1) | DE60039515D1 (en) |
| WO (1) | WO2000074690A1 (en) |
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| WO2001066044A3 (en) * | 2000-03-03 | 2002-09-12 | Smith & Nephew Inc | Shaped particle and composition for bone deficiency and method of making the particle |
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| US8690874B2 (en) | 2000-12-22 | 2014-04-08 | Zimmer Orthobiologics, Inc. | Composition and process for bone growth and repair |
| KR100435419B1 (en) * | 2001-03-30 | 2004-06-10 | 주식회사 리젠 바이오텍 | Bone-filling composition for stimulating bone-forming and bone-consolidation comprising calcium sulfate and viscous biopolymers |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU780355B2 (en) | 2005-03-17 |
| CA2371612C (en) | 2008-07-29 |
| CA2371612A1 (en) | 2000-12-14 |
| EP1198236A4 (en) | 2004-04-07 |
| US20020110541A1 (en) | 2002-08-15 |
| EP1198236A1 (en) | 2002-04-24 |
| US20020071827A1 (en) | 2002-06-13 |
| AU3587600A (en) | 2000-12-28 |
| EP1198236B1 (en) | 2008-07-16 |
| US7371408B1 (en) | 2008-05-13 |
| DE60039515D1 (en) | 2008-08-28 |
| US7371410B2 (en) | 2008-05-13 |
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