US20020098222A1 - Bone paste - Google Patents
Bone paste Download PDFInfo
- Publication number
- US20020098222A1 US20020098222A1 US08/816,079 US81607997A US2002098222A1 US 20020098222 A1 US20020098222 A1 US 20020098222A1 US 81607997 A US81607997 A US 81607997A US 2002098222 A1 US2002098222 A1 US 2002098222A1
- Authority
- US
- United States
- Prior art keywords
- composition
- bone
- gelatin
- dbm
- mixtures
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- 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
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
- A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
- A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/043—Mixtures of macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
-
- 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
-
- 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
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
-
- 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
- A61L27/26—Mixtures of macromolecular compounds
-
- 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
-
- 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
-
- 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
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
-
- 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
- A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
- A61F2/2875—Skull or cranium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
- A61F2/4455—Joints for the spine, e.g. vertebrae, spinal discs for the fusion of spinal bodies, e.g. intervertebral fusion of adjacent spinal bodies, e.g. fusion cages
-
- 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
- A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
-
- 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
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
- A61F2002/3006—Properties of materials and coating materials
- A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30621—Features concerning the anatomical functioning or articulation of the prosthetic joint
- A61F2002/30622—Implant for fusing a joint or bone material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00179—Ceramics or ceramic-like structures
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00179—Ceramics or ceramic-like structures
- A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00329—Glasses, e.g. bioglass
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
- A61F2310/00383—Gelatin
-
- 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
- This invention relates to a new osteogenic, osteoinductive composition for use in the field of orthopedic medicine to achieve bone fusions, fusion of implants to bone, filing of bone defects, or any other application in which an osteoinductive, osteogenic composition is desirable.
- Osteogenic bone grafting materials may be separated into two classes, namely those which are osteoconductive, and those which are osteoinductive. While the exact definition of these terms remains a matter of debate, it can be said that osteoconductive implants “conduct” bone growth across defects when implanted into osseous tissue. (Einhorn). Osteoinductive implants, on the other hand, have the ability to “induce” cells in the area to generate bone of their own accord. (Einhorn). These osteoinductive implants will cause the generation of bone even when they are implanted into non-osseous tissue (e.g. subcutaneous or intramuscular implantation). (Einhorn; Benedict; Strates; Urist).
- FIG. 1 provides a list of relevant properties of selected bone graft materials.
- the other category of bone grafting materials currently available is encompassed by autograft or allograft bone. If not too harshly processed, these materials are generally osteoinductive. (Yazdi). Since they are tissue transplants, their use imposes certain risks. Autografts have been associated with harvest site morbidity in excess of 20%. (Younger). Frozen or freeze-dried allografts induce some immune response, and if not properly screened, can be associated with disease transmission. (Hordin). The last variety of allografts is demineralized bone matrix.
- DBM Demineralized Bone Matrix
- DBM has the ability to induce the formation of bone even in non-osseous tissues within 4 weeks.
- the standard technique for determining the activity of DBM is to implant it subcutaneously or intramuscularly. (Nathan). It is believed that the major active factor in DBM is one or more bone morphogenetic proteins (BMP), (see U.S. Pat. No. 4,294,753, herein incorporated by reference).
- BMP bone morphogenetic proteins
- Other growth factors including but not limited to TGF-beta, (see U.S. Pat. No. 5,422,340, herein incorporated by reference), platelet derived growth factor (PDGF), and the like, may be important for this function also.
- Bioglass® is a bone grafting material which is a SiO 2 , Na 2 O, CaO, P 2 O 5 glass which has the ability to produce a bio-active surface layer of hydroxylapatite carbonate within minutes of implantation. (Hench).
- a bone paste would be osteoconductive (i.e. it conducts bone cells into a region) and osteoinductive (i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone).
- osteoconductive i.e. it conducts bone cells into a region
- osteoinductive i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone.
- bone pastes known in the art are osteoconductive, with only weak osteoinductive effects. Accordingly, such known pastes are inadequate for filling of large voids and frequently do not effect proper bone formation even in small voids. All currently available bone pastes, including those that exhibit some osteoinductive activity, are difficult to handle, do not adequately remain at the site of implantation, or both.
- one commercially available product GRAFTON®, (see U.S. Pat. No. 5,484,601) is a non-cross-linkable composition of demineralized bone powder suspended in a polyhydroxy compound (e.g. glycerol) or esters thereof, optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble.
- glycerol e.g. glycerol
- esters thereof optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble.
- U.S. Pat. Nos. 5,236,456 and 5,405,390 outline an “osteogenic” gel composition which is made from demineralized bone matrix (DBM) by treating with concentrated acid (3 M HCl) and heating to between 40 and 50° C.
- DBM demineralized bone matrix
- the patent briefly describes mixing the gel with DBM and several other components.
- the method of manufacturing the gel composition is such that it produces mostly collagen fibers (i.e. the temperature elevation is insufficient to produce gelatin). As a result, the collagen fibers are not soluble in neutral solutions.
- the patent specifies that the collagen must be dissolved in acid of low pH (e.g. HCl or 1% acetic acid, at a pH of less than 4.0).
- compositions of low pH are not typically very compatible with biological implantations. It is also noted that at column 5, line 20, and column 6, line 15, it is specified that the temperature at which the gel solidifies is 0-5° C., which precludes gellation in vivo.
- U.S. Pat. No. 4,440,750 (Glowacki and Pharris) outlines a standard enzymatic technique for extracting collagen from tissue using Pepsin.
- a highly refined collagen is obtained from animal sources, which is then reconstituted prior to forming the working composition.
- the collagen will not readily cross-link without the addition of other chemicals (e.g. aldehydes, chondroitin sulfate), which they do not specify in the composition. There is no mention of a set temperature or any reference to cross-linking behavior.
- a bone repair material having good structural strength was disclosed.
- the material comprised a demineralized bone matrix which had been surface activated by treatment with glutaraldehyde or like cross-linking agent to increase the binding thereof to biocompatible matrices.
- the resulting material has such a rigid structure that, prior to implantation into a biological recipient, the material may be machined.
- the bone paste of the present invention meets the needs in the art by providing a material that is easy to handle and store, which adheres to the site of implantation, displays both osteoconductive and osteoinductive activities, is thermally cross-linkable, and is substantially bioabsorbable.
- the composition is provided as a gel which contains mineral and protein components which have been clinically shown to induce rapid bone ingrowth.
- the composition may be delivered to the surgeon in a pre-loaded syringe, ready for use.
- the gel is easily formable into any shape, and is adhesive.
- the gel desirably hardens as a rubbery solid, which does not wash away or migrate from the site of implantation.
- the implant material becomes completely incorporated into the biological system.
- the mode of making and using this composition is set forth in detail below.
- a bone paste useful in the orthopaedic arts for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, arthrodesis of spinal or other joints, including spinal fusion procedures, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising gelatin and additional osteogenic components.
- the gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
- demineralized bone preferably derived from the species into which the bone paste is to be implanted.
- bioactive glass ceramic BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
- Demineralized bone has been shown to be highly effective in inducing bone formation.
- the gelatin provides a cross-linkable, adhesive and easily manipulated matrix in which the osteoconductive and osteoinductive elements of the composition are carried.
- Other factors such as antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, dextran, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof or any other material found to add to the desirable properties of the essential composition of this invention may be included.
- the composition may be freeze-dried or pre-constituted, and may be provided in a convenient dispensing device, such as a pre-loaded syringe.
- the gel is preferably in a liquid or highly malleable state at temperatures above about 40° C., but sets up as a hard gel at or preferably slightly above the body temperature of the organism into which it is implanted (e.g. at 38° C. in humans).
- FIG. 1 is a chart of existing bone grafting materials.
- FIG. 2 represents a bone demineralization process
- FIG. 3 is a graph of the kinematic viscosity (centistokes) versus concentration (%) for human gelatin processed at various temperatures in phosphate buffered saline solution (PBS).
- PBS phosphate buffered saline solution
- FIG. 4A is a photomicrograph of a section of an implant comprising demineralized bone matrix (DBM) without any carrier after four weeks intramuscularly in a rat.
- DBM demineralized bone matrix
- FIG. 4B is a photomicrograph of a section of an implant comprising 33% DBM in gelatin (i.e. the paste of this invention) after four weeks intramuscularly in a rat.
- composition of this invention its method of preparation and use are applicable to such compositions for use in any vertebrate species. Nonetheless, because human use is considered likely to be the principal orthopedic application of this new material, the following description concentrates on exemplying this material for human applications.
- the composition of this invention comprises gelatin and additional osteogenic components.
- the gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
- demineralized bone preferably derived from the species into which the bone paste is to be implanted.
- bioactive glass ceramic BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
- the composition is fluid at a first temperature (e.g., above 38° C.) and becomes thermally cross-linked at or just above a second temperature, corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans).
- a first temperature e.g., above 38° C.
- a second temperature corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans).
- thermoally cross-linked or “thermally cross-linkable” are used herein to describe the property of a composition which contains molecules which, at or below a given temperature and concentration, associate in such a fashion as to result in gelation of a solution containing these molecules.
- substantially bioabsorbable is used herein to describe the property of a material able to cooperate in and become incorporated with new bone formation. Accordingly, for example, demineralized bone matrix which has been chemically cross-linked with an agent such as glutaraldehyde, is not considered to be substantially bioabsorbable. However, demineralized bone matrix itself, bioactive glass or like ceramics, gelatin, and bone morphogenetic factors are all considered to be substantially bioabsorbable as they cooperate in new bone formation, rather than purely providing structural rigidity or support.
- the gelatin acts as a carrier phase and has the ability to thermally cross-link over a very small temperature range. This thermal cross-linking reaction is largely controlled by physical entanglement and hydrogen bonding between chains, and so is dependant on concentration and temperature. (Sperling). Additionally, since gelatin has been used extensively in the medical market, its in vivo properties are thoroughly studied. (McDonald). The gel-foam sponge is the most familiar application of this biopolymer. Studies have indicated that gelatin is only mildly antigenic upon implantation, and is comparable in some of its properties to collagen, (McDonald). However, collagen does not exhibit the thermal cross-linking property so important to the composition of this invention.
- the bioactive glass such as BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, calcined bone, tricalcium phosphate, or like material, is included to enhance the range of manipulable characteristics of strength and osteogenesis (osteoinduction and osteoconduction) exhibited by the composition.
- gelatin The manufacture of gelatin is based on the partial hydrolysis of collagen.
- Collagen is available from skin, bone, cartilage, tendon and other connective tissue. Skin and bone yield Type I and Type III collagen molecules, while tendon yields nearly pure Type I collagen, and cartilage yields a mixture of Type II and rarer types of collagen molecules.
- Gelatin molecules resemble collagen triple helices, however, they are partially hydrolyzed. As a result, in solution they have little organization. But, as the solution cools, the gelatin molecules begin to form helical structures. As the solution cools further, the viscosity increases and a phase transformation from a solution to a gel occurs. This phase change is reversible when heat is added.
- the set time and set temperature of a gelatin solution are dependent on the concentration of gelatin in solution, the molecular weight, or intrinsic viscosity, of the gelatin molecules, and the pH of the solution. At the isoelectric point, or the pH at which the gelatin molecules are electrically neutral, the set time is the shortest.
- Collagen can be partially hydrolyzed by several methods.
- the Type A process is the simplest and most rapid process, in which dilute acid (e.g. less than 1 M HCl) is used to partially hydrolyze the collagen.
- Type A processing is generally used with porcine skin and demineralized bovine bone.
- the Type B process uses an alkaline solution to partially hydrolyze the collagen.
- Type B processing is generally used with bovine hide and demineralized bovine bone.
- enzymes such as pepsin, may be used to partially hydrolyze collagen. Pepsin preferentially cleaves peptide bonds between aromatic amino acids. Pepsin also acts as an esterase, but amides of amino acids are not hydrolyzed.
- the gelatin is prepared from the bones of the species into which the compositions are to be implanted, by crushing and defatting the bones followed by soaking for about 24 hours in approximately 300 mg/L pepsin in a 0.5 M acetic acid at 33° C.
- the pH of the resulting solution is brought to 9.0 with sodium hydroxide to denature the pepsin, then it is returned to 7.0 with hydrochloric acid.
- the temperature of the solution is raised to 60° C. for about 15 to 30 minutes and returned to 4° C. to effect denaturation of remaining collagen and complete conversion to gelatin.
- the resulting solution is filtered to remove particulates and dialyzed against distilled water for 48 hours in a 50K-100K molecular weight cut-off (50K-100K MWCO) dialysis membrane.
- 50K-100K MWCO 50K-100K molecular weight cut-off dialysis membrane.
- the gelatin is redissolved in phosphate buffered saline (PBS) or water to an effective concentration of about 30-45 weight percent of gelatin in solution.
- PBS phosphate buffered saline
- the gelatin content of the composition is desirably between about 20-45% (w/w).
- the gelatin may be derived from the same or different species than that into which the composition is to be implanted.
- human, porcine, bovine, equine, or canine gelatin is derived from collagen sources such as bone, skin, tendons, or cartilage, and may then be mixed with DBM or other osteogenic materials.
- the collagen is converted to gelatin via, liming, acidification or by enzymatic extraction, for example by pepsin or like enzymatic treatment, followed by denaturation by heat or other means.
- the gelatin may be derived from tissue by mastication of the tissue, followed by an extended treatment capable of breaking cross-links in the long collagen chains.
- the tissue is ground then soaked for about 24-72 hours at between about 2-40° C. in dilute acid, such as 0.1 normal acetic acid.
- dilute acid such as 0.1 normal acetic acid.
- an enzyme such as pepsin at a sufficiently high concentration is added.
- Pepsin concentrations of between about 10-20,000 i.u./liter, 100-2,000 i.u/liter, or like concentrations are added to the dilute acid at the start of the treatment, with the period of treatment being adjusted according to the enzyme concentration used.
- Solids are removed from the composition, for example by centrifugation, and the supernatant material in solution having a molecular weight of about 50,000 daltons or higher is retained.
- This may be achieved by any of a number of methods known in the art including, but not limited to, dialyzing the supernatant in a 50,000 dalton molecular weight cut-off membrane against several changes of solution, ultrafiltration against a membrane having a like molecular weight cut-off, (MWCO) or gel permeation chromatography through a medium having a 50,000 dalton molecular mass cut-off.
- MWCO molecular weight cut-off
- the gelatin solution resulting from the foregoing extraction is preferably denatured, for example by heat-treatment to above about 50° C.
- the denatured protein is then stored in a frozen state or it may be freeze-dried or precipitated, for example in a volatile organic solvent, and reconstituted in a solution, such as an isotonic saline solution, at a concentration of between about 30-45% (w/w) gelatin.
- the demineralized bone is preferably in a powdered form, and is preferably composed of particles in the size range between about 80-850 ⁇ m in diameter.
- Methods for producing demineralized bone powder are known in the art (see for example U.S. Pat. No. 5,405,390, herein incorporated by reference for this purpose), and are not, therefore, elaborated here.
- Demineralized bone powder extracted by standard techniques, is mixed with the gelatin solution prepared as described above, to form a composition comprising about 0-40% (w/w) demineralized bone powder.
- bone morphogenetic proteins reduce the percentage of DBM required in the composition.
- the BMP is preferably present at a concentration of between about 0.0001 to 0.1 mg/ml, 0.001 mg/ml to 0.01 mg/ml, or like concentration, depending on the amount of DBM present (0-40% w/w).
- the final composition preferably comprises gelatin having a viscosity of about 3600 centipoise at 44° C. (when measured in the linear range of a viscosity/sheer rate plot—0.87/s), or a kinematic viscosity of about 0.7 centistokes at 44° C.
- concentration of the gelatin in the carrier phase i.e. absent added osteogenic components
- the concentration of the gelatin in the carrier phase is preferably about 30-45% (w/w), (approximately 50-60% w/v), to ensure that gelation at 38° C. will occur in a reasonable amount of time.
- different temperatures may be required. These needs are accommodated by altering the gelatin concentration, increasing the concentration if a higher gel temperature is desired, and lowering the concentration if a lower gel temperature is desired.
- the DBM content of the composition is defined herein by the concentration required to obtain bone formation similar to that seen with DBM alone. We have found that about 5-40% (w/w) DBM in the composition is effective. Anything lower than about 5% seems to do very little by way of bone formation, unless added BMPs (component iii) are present in the composition, in which case the DBM concentration may be substantially reduced or eliminated altogether.
- BMPs component iii
- the weight percent of DBM in the composition may be manipulated up or down. In addition, it will be recognized that, depending on the species into which the composition is implanted, the DBM weight percent may need to be adjusted up or down.
- composition according to this invention may act as a carrier for cortical, cancellous or cortical and cancerous bone chips. Such compositions are useful for fling larger bone voids.
- these bone chips when they are not demineralized, they provide an added spectrum of biological properties not exhibited by the gelatin alone or the gelatin plus osteogenic components (i-iv). When present, it is preferred for such bone chips to be in the size range of about 80 ⁇ m to about 10 mm.
- the composition of gelatin and osteogenic components (i-iv) is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form.
- Such forms would desirably take the form of vertebral disks, acetabular hemispheres, tubes, ellipsoid shapes for void filling, and intramedullary plugs, which are useful to plug the intramedullary canal of various bones (i.e. the marrow containing portion of the bone) to prevent bone cement from entering healthy bone tissue.
- These forms are produced, for example, by raising the temperature of the composition above its liquefaction temperature (e.g. about 45° C.), and allowing the composition to gel in a mold of appropriate shape.
- the gelatin content is preferably made as high as possible to ensure that the form remains solid upon grafting into a vertebrate recipient.
- the source of collagen was from demineralized human cortical bone powder in the size range of 250-850 ⁇ m.
- the demineralized bone matrix powder (DBM), 0.5 M. acetic acid solution, and pepsin were added to a centrifuge tube.
- the centrifuge tube was tumbled for 24 hours at the desired temperature: 4° C., 30° C., 33° C. or 37° C.
- the pH was adjusted to 9.0 then down to 7.0 with 1 N NaOH and 1N HCl, respectively, deactivating the pepsin.
- the solution was placed in a 60° C. water bath for 15 minutes, then quenched in ice water.
- the solution was centrifuged and the supernatant was poured into dialysis membrane tubing with a 1000 Daltons molecular weight cut off. The supernatant was dialyzed to obtain a 1000:1 dilution factor, frozen and lyophilized until completely dry. This experiment was performed in quintuplicates for each temperature.
- the kinematic viscosities (centistokes) were graphed versus concentration of human gelatin solution, FIG. 3.
- the linear regression was extrapolated to zero to determine the kinematic viscosity at zero concentration.
- the optimum processing temperature was determined by the temperature that yielded the highest solution viscosity at zero concentration, largest slope of the linear regression, greatest yield, and lastly, the gelatin that produced a solid bone composite at slightly above human body temperature.
- the human gelatin processed at 30° C. had the highest slope on the kinematic viscosity versus concentration plot, 0.40 (centistokes/%), followed by the human gelatin processed at 4° C., 0.26 (centistokes/%), the human gelatin processed at 33° C., 0.21 (centistokes/%), and lastly the human gelatin processed at 37° C., 0.17 (centistokes/%), Table 1.
- the set temperatures for various bone paste compositions were determined, Table 2. Human gelatin made from DBM via pepsin at 33° C., 35° C., and 37° C. was used in the bone paste compositions. Gelatin concentrations were varied from 19 w/w % of total composite to 25 w/w % of total composite (corresponding to 40 w/v % to 60 w/v % gelatin in the carrier matrix) in a pH 7.4 phosphate buffered saline solution (PBS). All bone paste composites tested contained DBM at a concentration of 33 w/w % of the total composite.
- PBS pH 7.4 phosphate buffered saline solution
- the critical concentration of gelatin in a bone paste composite that was solid at slightly above human body temperature, 38° C. to 39° C. was 25 w/w % of the total composite for human gelatin, processed at 33° C., and with 33 w/w % of the composite being DBM, the remainder being PBS.
- the human gelatin processed at 33° C. had a zero concentration kinematic viscosity of 0.71 centistokes.
- Human gelatin solutions of lower kinematic viscosities were found to have critical concentrations in excess of about 25 w/w %.
- gelatins with viscosities higher than about 0.71 centistokes are expected to thermally cross-link at concentrations lower than about 25% (w/w).
- This study demonstrates that the bone paste of this invention is osteoinductive.
- this study demonstrates particle sizes for the DBM component of the composition which operate well in promoting new bone growth in an animal into which it is implanted.
- the intra-muscular rat model is the standard model for testing the osteoinductivity of demineralized bone and other osteoinductive factors. Strates et al. have used this model for many years (Strates).
- the femurs, tibiae, and fibulae were harvested from fresh-killed (within 24 hours, refrigerated at 4° C.) Sprague-Dawley rats.
- the diaphyses were cut from the bones and the marrow removed from the mid-shaft with a dissecting probe and sterile water wash.
- Mid-shaft segments were then demineralized in 0.6 M. HCl for 24 hours at 4° C. with the mass ratio of bone to acid maintained at ⁇ fraction (1/10) ⁇ or lower.
- the bone segments were lyophilized and then mixed with dry ice and ground in a lab-scale bone mill. DBM powder was sieved and the fraction from 125-450 ⁇ m was retained.
- a carrier matrix of 50% (w/v) gelatin was made by heating phosphate buffered saline (PBS) to 60° C. and then adding powdered porcine gelatin (Sigma, 300 bloom) and stirring vigorously. Carrier matrix was allowed to age for 15 minutes (to even out the distribution of gelatin in solution) and then it was allowed to cool to 50° C. DBM was added to the gelatin solution at this point in the following amounts: 0 (negative control), 15, 19, 24, and 33% w/w of the total composite. The composite was blended thoroughly by hand mixing.
- PBS phosphate buffered saline
- powdered porcine gelatin Sigma, 300 bloom
- Implants were prepared by ejecting a thread of composite onto a petri dish. These threads were cut into short segments ( ⁇ 4 mm.), weighed, and placed into sterile petri dishes. Positive controls were prepared by pelletizing DBM mixed with PBS in a centrifuge. To maintain pellet integrity during the hazards of surgery, these pellets were frozen and implanted as such.
- Each muscle was notched to mark the superior side of the animal and placed into a labeled petri dish.
- the muscle was X-rayed with mammography equipment, using mammography film (DuPont).
- Roentgenograms were analyzed using a digital camera attached to an Apple LCII equipped with NIH Image 4.1 software. Images were thresholded to highlight the implant shadow and then the area of the shadow was determined by pixel counting.
- FIGS. 4A and 4B provide photomicrographs of sections of implants after four weeks in vivo in the rat intramuscular model. We found that 33% (w/w) DBM in gelatin carrier (FIG.
- FIG. 4A DBM (FIG. 4A).
- 10 is mature bone, as evidenced by red stain uptake from Masson's stain
- 20 is new cartilage formation, as evidenced by uptake of blue stain from Masson's stain and the presence of cells
- 30 is residual DBM, as evidenced by uptake of blue stain and the absence of cells, from which all cartilagenous and bone structures in the muscle cross section arose
- 40 is immature bone, as evidenced by light blue staining and the presence of cells.
- the cells seen are osteoclasts, degrading the newly formed cartilage, and osteoblasts, laying down new bone.
- vascular infiltration in the mature bone is evident in the Masson's stained sections, from which the black and white prints were made.
- GraftonTM contains only 8% DBM in a glycerol carrier.
- This example provides one procedure for the manufacture of bone paste from gelatin and demineralized bone. As fractions of the total mass of composition desired, the following components are weighed (percentages given are of total composite weight): Dry demineralized bone: 0-40% (w/w) Lyophilized thermally 20-45% (w/w) cross-linkable gelatin: BIOGLASS ®: 0-40% (w/w) bone morphogenetic protein: 0.001 mg/ml
- compositions are thoroughly blended while dry, and the balance of the composition mass is made up by addition of water, phosphate buffered saline, or any other physiologically acceptable liquid carrier.
- the composition may be packaged in this form or lyophilized for later reconstruction with water.
- the malleable properties of the composition are achieved by heating the composition to a temperature sufficient to exceed the liquefaction point of the gelatin, and then allowing the composition to cool to the temperature at which it gels.
Abstract
Description
- 1. Field of the Invention
- This invention relates to a new osteogenic, osteoinductive composition for use in the field of orthopedic medicine to achieve bone fusions, fusion of implants to bone, filing of bone defects, or any other application in which an osteoinductive, osteogenic composition is desirable.
- 2. Background
- More than 100,000 bone grafting procedures are performed every year in the United States alone. (Cornell). In the majority of reconstruction procedures, the graft material is used as a filler between bone particles in the belief that continuous contact between particles of bone leads to more rapid and complete healing at the repair site (as well as greater mechanical integrity). (Bloebaum). In the cases of bone augmentation and spinal fusion, these bone grafts may make up the entire structure of the graft, since there are no bone fragments in the area. With the possible exception of one product (whose use guidelines do not allow this), all bone grafting materials require surgical placement with the requisite incisions.
- Osteogenic bone grafting materials may be separated into two classes, namely those which are osteoconductive, and those which are osteoinductive. While the exact definition of these terms remains a matter of debate, it can be said that osteoconductive implants “conduct” bone growth across defects when implanted into osseous tissue. (Einhorn). Osteoinductive implants, on the other hand, have the ability to “induce” cells in the area to generate bone of their own accord. (Einhorn). These osteoinductive implants will cause the generation of bone even when they are implanted into non-osseous tissue (e.g. subcutaneous or intramuscular implantation). (Einhorn; Benedict; Strates; Urist).
- All of the artificially produced bone-grafting materials available today fall in the osteoconductive category of grafts. Among these are Bioglass®, Norian®, Collagraft®, corraline hydroxyapatite, powdered hydroxyapatite, crystalline and amorphous hydroxyapatite (hydroxyl apatite), and a number of other products. All of these implants rely on their similarity to natural bone hydroxyapatite. A likely mechanism for bone conduction lies in the ability of these materials to enhance diffusion of trophic factors and cells over their very large surface areas and the mechanical support which they provide to growing tissues. FIG. 1 provides a list of relevant properties of selected bone graft materials.
- The other category of bone grafting materials currently available is encompassed by autograft or allograft bone. If not too harshly processed, these materials are generally osteoinductive. (Yazdi). Since they are tissue transplants, their use imposes certain risks. Autografts have been associated with harvest site morbidity in excess of 20%. (Younger). Frozen or freeze-dried allografts induce some immune response, and if not properly screened, can be associated with disease transmission. (Hordin). The last variety of allografts is demineralized bone matrix.
- Demineralized Bone Matrix (DBM) was first described by Senn in 1889. (Senn). It was rediscovered, largely by accident, and thoroughly studied by Urist and Strates in the late 1960's. (Strates; Urist). It has since become a major product of tissue banks around the world. As the name implies, it is bone which has been demineralized by treatment with acid. A detailed outline of the process for producing this product is provided in FIG. 2.
- DBM has the ability to induce the formation of bone even in non-osseous tissues within 4 weeks. (Strates; Urist; Lasa). The standard technique for determining the activity of DBM is to implant it subcutaneously or intramuscularly. (Nathan). It is believed that the major active factor in DBM is one or more bone morphogenetic proteins (BMP), (see U.S. Pat. No. 4,294,753, herein incorporated by reference). Other growth factors, including but not limited to TGF-beta, (see U.S. Pat. No. 5,422,340, herein incorporated by reference), platelet derived growth factor (PDGF), and the like, may be important for this function also.
- Bioglass® is a bone grafting material which is a SiO2, Na2O, CaO, P2O5 glass which has the ability to produce a bio-active surface layer of hydroxylapatite carbonate within minutes of implantation. (Hench).
- Two problems are associated with the use of DBM or Bioglass. Both of these materials are supplied as large particles, and do not always stay in the area into which they are implanted. (Scarborough; Frenkel). Also, due to their coarse nature, they are hard to mold and handle in the operating room. Accordingly, there is the need for a product which does not allow for particle migration, while also being easier to use in the operating environment.
- As noted in table 1, in recent years, several bone-filling surgical pastes have become commercially available. These products range from simple mixtures of saline with a sand-like powder to a recently released gel, known as GRAFTON®, a glycerol-based, non-cross-linkable composition. All of these products are used in orthopedics to repair bone defects, such as voids, cavities, cracks etc. Such defects may be the result of trauma or may be congenital, and the known pastes may be used to patch or fill such defects, or build upon existing bony structures. The ultimate goal of such treatments is that the paste will induce bone formation to replace the paste while retaining the form created by the surgeon when applying the paste.
- Desirably, a bone paste would be osteoconductive (i.e. it conducts bone cells into a region) and osteoinductive (i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone). In general, bone pastes known in the art are osteoconductive, with only weak osteoinductive effects. Accordingly, such known pastes are inadequate for filling of large voids and frequently do not effect proper bone formation even in small voids. All currently available bone pastes, including those that exhibit some osteoinductive activity, are difficult to handle, do not adequately remain at the site of implantation, or both.
- Thus, one commercially available product, GRAFTON®, (see U.S. Pat. No. 5,484,601) is a non-cross-linkable composition of demineralized bone powder suspended in a polyhydroxy compound (e.g. glycerol) or esters thereof, optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble.
- U.S. Pat. Nos. 5,236,456 and 5,405,390 (O'Leary and Prewett) outline an “osteogenic” gel composition which is made from demineralized bone matrix (DBM) by treating with concentrated acid (3 M HCl) and heating to between 40 and 50° C. The patent briefly describes mixing the gel with DBM and several other components. However, the method of manufacturing the gel composition is such that it produces mostly collagen fibers (i.e. the temperature elevation is insufficient to produce gelatin). As a result, the collagen fibers are not soluble in neutral solutions. To obtain a gel, the patent specifies that the collagen must be dissolved in acid of low pH (e.g. HCl or 1% acetic acid, at a pH of less than 4.0). However, compositions of low pH are not typically very compatible with biological implantations. It is also noted that at
column 5,line 20, andcolumn 6, line 15, it is specified that the temperature at which the gel solidifies is 0-5° C., which precludes gellation in vivo. - U.S. Pat. No. 4,440,750 (Glowacki and Pharris) outlines a standard enzymatic technique for extracting collagen from tissue using Pepsin. A highly refined collagen is obtained from animal sources, which is then reconstituted prior to forming the working composition. The collagen will not readily cross-link without the addition of other chemicals (e.g. aldehydes, chondroitin sulfate), which they do not specify in the composition. There is no mention of a set temperature or any reference to cross-linking behavior.
- In U.S. Pat. Nos. 4,394,370 and 4,472,840, (Jefferies), complexes of reconstituted collagen with demineralized bone or solubilized bone morphogenetic protein, optionally cross-linked with glutaraldehyde, were reported to be osteogenic when implanted in vivo. The reconstituted collagen of these patents is pulverized, lyophilized, microcrystalline collagen which has been dialyzed to remove the hydrochloric acid used in collagen preparation. Accordingly, the composition of those patents does not involve the conversion of collagen to gelatin prior to formation of the composition. Hence, the composition would not exhibit the thermal cross-linking behaviour of the instant composition.
- In U.S. Pat. No. 4,678,470 (Nashef et al.) disclosed a non-resorbable bone-grafting material comprising demineralized bone matrix that had been cross-linked by treatment with glutaraldehyde, or like cross-lining agent, suspended in a gelatinous or semi-solid carrier. Given that the demineralized bone of that patent is chemically cross-linked, its bone inductive properties are considered to be destroyed and the composition essentially forms a structural filler or matrix into which recipient bone may grow.
- In WO 89/04646 (Jefferies), a bone repair material having good structural strength was disclosed. The material comprised a demineralized bone matrix which had been surface activated by treatment with glutaraldehyde or like cross-linking agent to increase the binding thereof to biocompatible matrices. The resulting material has such a rigid structure that, prior to implantation into a biological recipient, the material may be machined.
- The bone paste of the present invention meets the needs in the art by providing a material that is easy to handle and store, which adheres to the site of implantation, displays both osteoconductive and osteoinductive activities, is thermally cross-linkable, and is substantially bioabsorbable. Preferably, the composition is provided as a gel which contains mineral and protein components which have been clinically shown to induce rapid bone ingrowth. The composition may be delivered to the surgeon in a pre-loaded syringe, ready for use. Preferably, at a first temperature, the gel is easily formable into any shape, and is adhesive. Once inside the biological milieu, or at a second lower temperature, the gel desirably hardens as a rubbery solid, which does not wash away or migrate from the site of implantation. Upon ingrowth of bone, the implant material becomes completely incorporated into the biological system. The mode of making and using this composition is set forth in detail below.
- A bone paste useful in the orthopaedic arts, for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, arthrodesis of spinal or other joints, including spinal fusion procedures, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising gelatin and additional osteogenic components. The gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
- (i) demineralized bone, preferably derived from the species into which the bone paste is to be implanted; or
- (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
- (iii) bone morphogenetic protein, TGF-beta, PDGF, or mixtures thereof, natural or recombinant; or
- (iv) mixtures of (i)-(iii).
- Where present (ii) or like material is included to enhance the range of manipulable characteristics of strength and osteoinduction exhibited by the composition. Where present, (iii) reduces the need for demineralized bone, which otherwise provides a source of osteoinductive factors.
- Demineralized bone has been shown to be highly effective in inducing bone formation. The gelatin provides a cross-linkable, adhesive and easily manipulated matrix in which the osteoconductive and osteoinductive elements of the composition are carried. Other factors, such as antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, dextran, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof or any other material found to add to the desirable properties of the essential composition of this invention may be included.
- The composition may be freeze-dried or pre-constituted, and may be provided in a convenient dispensing device, such as a pre-loaded syringe. The gel is preferably in a liquid or highly malleable state at temperatures above about 40° C., but sets up as a hard gel at or preferably slightly above the body temperature of the organism into which it is implanted (e.g. at 38° C. in humans).
- FIG. 1 is a chart of existing bone grafting materials.
- FIG. 2 represents a bone demineralization process.
- FIG. 3 is a graph of the kinematic viscosity (centistokes) versus concentration (%) for human gelatin processed at various temperatures in phosphate buffered saline solution (PBS).
- FIG. 4A is a photomicrograph of a section of an implant comprising demineralized bone matrix (DBM) without any carrier after four weeks intramuscularly in a rat.
- FIG. 4B is a photomicrograph of a section of an implant comprising 33% DBM in gelatin (i.e. the paste of this invention) after four weeks intramuscularly in a rat.
- It will be appreciated by those skilled in the art that the specifics of the composition of this invention, its method of preparation and use are applicable to such compositions for use in any vertebrate species. Nonetheless, because human use is considered likely to be the principal orthopedic application of this new material, the following description concentrates on exemplying this material for human applications.
- The composition of this invention comprises gelatin and additional osteogenic components. The gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
- (i) demineralized bone, preferably derived from the species into which the bone paste is to be implanted; or
- (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
- (iii) bone morphogenetic protein, TGF-beta, PDGF, or mixtures thereof, natural or recombinant; or
- (iv) mixtures of (i)-(iii).
- The composition is fluid at a first temperature (e.g., above 38° C.) and becomes thermally cross-linked at or just above a second temperature, corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans).
- The terms “thermally cross-linked” or “thermally cross-linkable” are used herein to describe the property of a composition which contains molecules which, at or below a given temperature and concentration, associate in such a fashion as to result in gelation of a solution containing these molecules.
- The term “substantially bioabsorbable” is used herein to describe the property of a material able to cooperate in and become incorporated with new bone formation. Accordingly, for example, demineralized bone matrix which has been chemically cross-linked with an agent such as glutaraldehyde, is not considered to be substantially bioabsorbable. However, demineralized bone matrix itself, bioactive glass or like ceramics, gelatin, and bone morphogenetic factors are all considered to be substantially bioabsorbable as they cooperate in new bone formation, rather than purely providing structural rigidity or support.
- The gelatin acts as a carrier phase and has the ability to thermally cross-link over a very small temperature range. This thermal cross-linking reaction is largely controlled by physical entanglement and hydrogen bonding between chains, and so is dependant on concentration and temperature. (Sperling). Additionally, since gelatin has been used extensively in the medical market, its in vivo properties are thoroughly studied. (McDonald). The gel-foam sponge is the most familiar application of this biopolymer. Studies have indicated that gelatin is only mildly antigenic upon implantation, and is comparable in some of its properties to collagen, (McDonald). However, collagen does not exhibit the thermal cross-linking property so important to the composition of this invention.
- Where present, the bioactive glass, such as BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, calcined bone, tricalcium phosphate, or like material, is included to enhance the range of manipulable characteristics of strength and osteogenesis (osteoinduction and osteoconduction) exhibited by the composition.
- The manufacture of gelatin is based on the partial hydrolysis of collagen. Collagen is available from skin, bone, cartilage, tendon and other connective tissue. Skin and bone yield Type I and Type III collagen molecules, while tendon yields nearly pure Type I collagen, and cartilage yields a mixture of Type II and rarer types of collagen molecules. Gelatin molecules resemble collagen triple helices, however, they are partially hydrolyzed. As a result, in solution they have little organization. But, as the solution cools, the gelatin molecules begin to form helical structures. As the solution cools further, the viscosity increases and a phase transformation from a solution to a gel occurs. This phase change is reversible when heat is added.
- The set time and set temperature of a gelatin solution are dependent on the concentration of gelatin in solution, the molecular weight, or intrinsic viscosity, of the gelatin molecules, and the pH of the solution. At the isoelectric point, or the pH at which the gelatin molecules are electrically neutral, the set time is the shortest.
- Collagen can be partially hydrolyzed by several methods. The Type A process is the simplest and most rapid process, in which dilute acid (e.g. less than 1 M HCl) is used to partially hydrolyze the collagen. Type A processing is generally used with porcine skin and demineralized bovine bone. The Type B process uses an alkaline solution to partially hydrolyze the collagen. Type B processing is generally used with bovine hide and demineralized bovine bone. Finally, enzymes, such as pepsin, may be used to partially hydrolyze collagen. Pepsin preferentially cleaves peptide bonds between aromatic amino acids. Pepsin also acts as an esterase, but amides of amino acids are not hydrolyzed.
- As one example of this method, the gelatin is prepared from the bones of the species into which the compositions are to be implanted, by crushing and defatting the bones followed by soaking for about 24 hours in approximately 300 mg/L pepsin in a 0.5 M acetic acid at 33° C. The pH of the resulting solution is brought to 9.0 with sodium hydroxide to denature the pepsin, then it is returned to 7.0 with hydrochloric acid. The temperature of the solution is raised to 60° C. for about 15 to 30 minutes and returned to 4° C. to effect denaturation of remaining collagen and complete conversion to gelatin. The resulting solution is filtered to remove particulates and dialyzed against distilled water for 48 hours in a 50K-100K molecular weight cut-off (50K-100K MWCO) dialysis membrane. After lyophilization, the gelatin is redissolved in phosphate buffered saline (PBS) or water to an effective concentration of about 30-45 weight percent of gelatin in solution.
- The gelatin content of the composition is desirably between about 20-45% (w/w). The gelatin may be derived from the same or different species than that into which the composition is to be implanted. For example, human, porcine, bovine, equine, or canine gelatin is derived from collagen sources such as bone, skin, tendons, or cartilage, and may then be mixed with DBM or other osteogenic materials. As noted above, the collagen is converted to gelatin via, liming, acidification or by enzymatic extraction, for example by pepsin or like enzymatic treatment, followed by denaturation by heat or other means. The gelatin may be derived from tissue by mastication of the tissue, followed by an extended treatment capable of breaking cross-links in the long collagen chains. In one embodiment, the tissue is ground then soaked for about 24-72 hours at between about 2-40° C. in dilute acid, such as 0.1 normal acetic acid. Preferably, an enzyme such as pepsin at a sufficiently high concentration is added. Pepsin concentrations of between about 10-20,000 i.u./liter, 100-2,000 i.u/liter, or like concentrations are added to the dilute acid at the start of the treatment, with the period of treatment being adjusted according to the enzyme concentration used. Solids are removed from the composition, for example by centrifugation, and the supernatant material in solution having a molecular weight of about 50,000 daltons or higher is retained. This may be achieved by any of a number of methods known in the art including, but not limited to, dialyzing the supernatant in a 50,000 dalton molecular weight cut-off membrane against several changes of solution, ultrafiltration against a membrane having a like molecular weight cut-off, (MWCO) or gel permeation chromatography through a medium having a 50,000 dalton molecular mass cut-off. It will be recognized by those skilled in the art that the higher the MWCO of the gelatin, the lower the yield. Accordingly, lower MWCO gelatin preparations, down to abut 1000 dalton MWCO's could be used, recognizing that undesirable low molecular weight species might thereby be retained.
- The gelatin solution resulting from the foregoing extraction is preferably denatured, for example by heat-treatment to above about 50° C. The denatured protein is then stored in a frozen state or it may be freeze-dried or precipitated, for example in a volatile organic solvent, and reconstituted in a solution, such as an isotonic saline solution, at a concentration of between about 30-45% (w/w) gelatin.
- The demineralized bone is preferably in a powdered form, and is preferably composed of particles in the size range between about 80-850 μm in diameter. Methods for producing demineralized bone powder are known in the art (see for example U.S. Pat. No. 5,405,390, herein incorporated by reference for this purpose), and are not, therefore, elaborated here. Demineralized bone powder, extracted by standard techniques, is mixed with the gelatin solution prepared as described above, to form a composition comprising about 0-40% (w/w) demineralized bone powder. Where present, bone morphogenetic proteins (BMP) reduce the percentage of DBM required in the composition. The BMP is preferably present at a concentration of between about 0.0001 to 0.1 mg/ml, 0.001 mg/ml to 0.01 mg/ml, or like concentration, depending on the amount of DBM present (0-40% w/w).
- The final composition preferably comprises gelatin having a viscosity of about 3600 centipoise at 44° C. (when measured in the linear range of a viscosity/sheer rate plot—0.87/s), or a kinematic viscosity of about 0.7 centistokes at 44° C. The concentration of the gelatin in the carrier phase (i.e. absent added osteogenic components) is preferably about 30-45% (w/w), (approximately 50-60% w/v), to ensure that gelation at 38° C. will occur in a reasonable amount of time. Naturally, those skilled in the art will recognize that, depending on the species of the organism into which the composition is to be implanted, different temperatures may be required. These needs are accommodated by altering the gelatin concentration, increasing the concentration if a higher gel temperature is desired, and lowering the concentration if a lower gel temperature is desired.
- The DBM content of the composition is defined herein by the concentration required to obtain bone formation similar to that seen with DBM alone. We have found that about 5-40% (w/w) DBM in the composition is effective. Anything lower than about 5% seems to do very little by way of bone formation, unless added BMPs (component iii) are present in the composition, in which case the DBM concentration may be substantially reduced or eliminated altogether. Naturally, based on this disclosure, those skilled in the art will recognize that by addition of different concentrations and compositions of bone morphogenetic proteins or other osteogenic or osteoinductive factors, the weight percent of DBM in the composition may be manipulated up or down. In addition, it will be recognized that, depending on the species into which the composition is implanted, the DBM weight percent may need to be adjusted up or down.
- We have found in in vivo studies that the compositions with DBM contents from 15 to 33% all produce calcified tissue. We have found that there is a good correlation between the amount of DBM in the composition and the level of bone induction, as long as the DBM concentration is greater than about 19% (w/w). About 38-40% (w/w) is the upper mass limit for DBM. Accordingly, 0-40% (w/w) DBM, and more preferably 5-30% (w/w), 7-33%(w/w) or 15-25% (w/w) is desirable for this component.
- We have observed histologically that, subsequent to implantation into an animal, the gelatin phase is totally absorbed within about 2 weeks. Additionally, cartilage and mineralized bone formed within two weeks, with mature bone being evident by about the fourth week. The animals in these studies did not exhibit any gross health problems or any indications of irritation, hematoma, soreness, fever, or weight loss during the study. The composition according to this invention, whether it comprises gelatin and osteogenic components (i-iv) may act as a carrier for cortical, cancellous or cortical and cancerous bone chips. Such compositions are useful for fling larger bone voids. In addition, when these bone chips are not demineralized, they provide an added spectrum of biological properties not exhibited by the gelatin alone or the gelatin plus osteogenic components (i-iv). When present, it is preferred for such bone chips to be in the size range of about 80 μm to about 10 mm.
- In a further embodiment of this invention, the composition of gelatin and osteogenic components (i-iv) is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form. Such forms would desirably take the form of vertebral disks, acetabular hemispheres, tubes, ellipsoid shapes for void filling, and intramedullary plugs, which are useful to plug the intramedullary canal of various bones (i.e. the marrow containing portion of the bone) to prevent bone cement from entering healthy bone tissue. These forms are produced, for example, by raising the temperature of the composition above its liquefaction temperature (e.g. about 45° C.), and allowing the composition to gel in a mold of appropriate shape. For such forms, the gelatin content is preferably made as high as possible to ensure that the form remains solid upon grafting into a vertebrate recipient.
- Those skilled in the art will recognize the many orthopedic applications of the bone paste of this invention. However, by way of illustration rather than limitation, for purposes of arthrodesis of the spine, one particularly preferred mode of using this composition would be at an early stage of vertebral disk degeneration or subsequent to trauma. Diagnosis of trauma or degeneration is followed by formation of a small orifice, or a plurality of small orifices in the intervertebral cartilage at the site of degeneration. The bone paste is then injected into the intervertebral space to induce arthrodesis. A similar procedure could be used with other joints or bone damage.
- Having generally described the invention, the following examples are provided to show specific features and applications of the invention. It should be recognized that this invention is in no way limited to the specifics of the examples as set forth below, and that the limits of this invention are defined by the claims which are appended hereto.
- In this experiment, the source of collagen was from demineralized human cortical bone powder in the size range of 250-850 μm. The demineralized bone matrix powder (DBM), 0.5 M. acetic acid solution, and pepsin were added to a centrifuge tube. The centrifuge tube was tumbled for 24 hours at the desired temperature: 4° C., 30° C., 33° C. or 37° C. The pH was adjusted to 9.0 then down to 7.0 with 1 N NaOH and 1N HCl, respectively, deactivating the pepsin. The solution was placed in a 60° C. water bath for 15 minutes, then quenched in ice water. The solution was centrifuged and the supernatant was poured into dialysis membrane tubing with a 1000 Daltons molecular weight cut off. The supernatant was dialyzed to obtain a 1000:1 dilution factor, frozen and lyophilized until completely dry. This experiment was performed in quintuplicates for each temperature.
- The kinematic viscosities of dilute concentrations of gelatin, 0.0625 w/v %, 0.125 w/v %, 0.25 w/v %, and 0.5 w/v % in phosphate buffered saline solutions (pH 7.4 at 25° C.), were measured with an Ubbelhode viscometer at 44° C. The kinematic viscosities of human gelatin processed at 4° C., 30° C., 33° C., and 37° C., were measured in duplicates, except for 33° C. which was only measured once. The kinematic viscosities (centistokes) were graphed versus concentration of human gelatin solution, FIG. 3. The linear regression was extrapolated to zero to determine the kinematic viscosity at zero concentration. The optimum processing temperature was determined by the temperature that yielded the highest solution viscosity at zero concentration, largest slope of the linear regression, greatest yield, and lastly, the gelatin that produced a solid bone composite at slightly above human body temperature.
- As the processing temperature increased, the yield of gelatin, normalized for the same pepsin to DBM ratio (0.03% (w/v) pepsin/1 g DBM), increased. The kinematic viscosity at zero concentration, or y-intercept, followed a reverse trend. As the processing temperatures increased, the extrapolated kinematic viscosities decreased, Table 1.
- The human gelatin processed at 30° C. had the highest slope on the kinematic viscosity versus concentration plot, 0.40 (centistokes/%), followed by the human gelatin processed at 4° C., 0.26 (centistokes/%), the human gelatin processed at 33° C., 0.21 (centistokes/%), and lastly the human gelatin processed at 37° C., 0.17 (centistokes/%), Table 1.
- In order to correlate the kinematic viscosities to molecular weight of gelatin, the kinematic viscosities must be translated into intrinsic viscosities. However, the intrinsic viscosities were undefined due to the polyelectrolytic nature of gelatin. As a result, a direct relationship between viscosity and molecular weight of human gelatin can not be made.
TABLE 1 Physical properties of human gelatin and human gelatin in phosphate buffered saline solution. Human gelatin was processed at 4° C., 30° C., 33° C., and 37° C., resulting from 1 g of DBM and 0.03 w/v % pepsin solution in 0.5 N acetic acid: Human Slope of Gelatin Linear Processed Average Yield Extrapolated Regression r2 Value of at Various Percent by y-intercept (centistokes/ Linear Temp. Weight (centistokes) %) Regression 4° C. 6% (n = 5) 0.72 (trial 0.26 (trial 0.985 ( trial 1 & 2) 1 & 2) 1 & 2) 30° C. 18% (n = 5) 0.71 (trial 0.40 (trial 0.993 ( trial 1 & 2) 1 & 2) 1 & 2) 33° C. 30% (n = 4) 0.71 (trial 1) 0.21 (trial 1) 0.994 (trial 1) 37° C. 60% (n = 5) 0.70 (trial 0.17 (trial 0.996 ( trial 1 & 2) 1 & 2) 1 & 2) - The set temperatures for various bone paste compositions were determined, Table 2. Human gelatin made from DBM via pepsin at 33° C., 35° C., and 37° C. was used in the bone paste compositions. Gelatin concentrations were varied from 19 w/w % of total composite to 25 w/w % of total composite (corresponding to 40 w/v % to 60 w/v % gelatin in the carrier matrix) in a pH 7.4 phosphate buffered saline solution (PBS). All bone paste composites tested contained DBM at a concentration of 33 w/w % of the total composite. Different ambient temperatures were used to test whether the bone paste was solid or liquid, 45° C., 43° C., 41° C., 40° C., 38° C., and 35.5° C. The set temperature was determined both by subsequent lowering of the ambient temperature and raising of the ambient temperature.
TABLE 2 Ambient temperatures corresponding to solidified (non-syringe-able) bone paste composites. Human Gelatin as a Percent of Total 37° C. Process 35° C. Process 33° C. Process Composite Weight Temp Temp Temp 25 w/w % <35.5° C. <35.5° C. 40° C. 24 w/w % <35.5° C. <35.5° C. <35.5° C. 22 w/w % <35.5° C. <35.5° C. <35.5° C. 21 w/w % <35.5° C. <35.5° C. <35.5° C. 19 w/w % <35.5° C. <35.5° C. <35.5° C. - Accordingly, the critical concentration of gelatin in a bone paste composite that was solid at slightly above human body temperature, 38° C. to 39° C., was 25 w/w % of the total composite for human gelatin, processed at 33° C., and with 33 w/w % of the composite being DBM, the remainder being PBS. The human gelatin processed at 33° C. had a zero concentration kinematic viscosity of 0.71 centistokes. Human gelatin solutions of lower kinematic viscosities were found to have critical concentrations in excess of about 25 w/w %. Correspondingly, gelatins with viscosities higher than about 0.71 centistokes are expected to thermally cross-link at concentrations lower than about 25% (w/w).
- This study demonstrates that the bone paste of this invention is osteoinductive. In addition, this study demonstrates particle sizes for the DBM component of the composition which operate well in promoting new bone growth in an animal into which it is implanted.
- The intra-muscular rat model is the standard model for testing the osteoinductivity of demineralized bone and other osteoinductive factors. Strates et al. have used this model for many years (Strates).
- As noted in Example 1 above, we determined that for gelation at 38° C., a gelatin solution concentration of 40-60% w/v (30-45% w/w of the solution absent added osteogenic components) is required. At this concentration, gelatin acting as a carrier matrix thermally cross-links at 38° C. within approximately 8 minutes. In this study we addressed the question of how much DBM must be present in this fixed 40-60% gelatin carrier matrix to induce bone formation which favorably compares with positive controls. We compared 4 different compositions of a DBM/Gelatin composite with both positive and negative controls in a rat intra-muscular model.
- A. Implant Preparation:
- The femurs, tibiae, and fibulae were harvested from fresh-killed (within 24 hours, refrigerated at 4° C.) Sprague-Dawley rats. The diaphyses were cut from the bones and the marrow removed from the mid-shaft with a dissecting probe and sterile water wash. Mid-shaft segments were then demineralized in 0.6 M. HCl for 24 hours at 4° C. with the mass ratio of bone to acid maintained at {fraction (1/10)} or lower. The bone segments were lyophilized and then mixed with dry ice and ground in a lab-scale bone mill. DBM powder was sieved and the fraction from 125-450 μm was retained.
- A carrier matrix of 50% (w/v) gelatin was made by heating phosphate buffered saline (PBS) to 60° C. and then adding powdered porcine gelatin (Sigma, 300 bloom) and stirring vigorously. Carrier matrix was allowed to age for 15 minutes (to even out the distribution of gelatin in solution) and then it was allowed to cool to 50° C. DBM was added to the gelatin solution at this point in the following amounts: 0 (negative control), 15, 19, 24, and 33% w/w of the total composite. The composite was blended thoroughly by hand mixing.
- Implants were prepared by ejecting a thread of composite onto a petri dish. These threads were cut into short segments (˜4 mm.), weighed, and placed into sterile petri dishes. Positive controls were prepared by pelletizing DBM mixed with PBS in a centrifuge. To maintain pellet integrity during the hazards of surgery, these pellets were frozen and implanted as such.
- B. Rat Surgery:
- Young Sprague-Dawley rats (200-410 g) were anesthetized with 86 mg/kg Ketamine, and 13 mg/kg Xylazine administered intramuscularly (in the thigh). A parallel-mid-line incision was made from the tip of the sternum to just above the groin. The lateral aspects of the rectus abdominus were accessed by blunt dissection to either side of the animal. Three short incisions were made in the muscle on each side and the implants inserted, followed by 1 to 2 stitches with Prolene¤ 3-0 suture (to mark the location and prevent the ejection of the implant mass). One positive or one negative control as well as two experimental compositions were inserted on each side. Implant locations were random except that each rat had one positive control on one side and one negative control on the contralateral side.
- Animals were returned to their cages and provided food and water ad-lib. All members of the study group were kept for 4 weeks except one animal (R1) which was sacrificed after 2 weeks for histology.
- After 4 weeks, animals were sacrificed with an overdose of Nembutal. The rectus abdominus was removed by sharp dissection, removing as much tissue as possible.
- C. Explant Analysis:
- Each muscle was notched to mark the superior side of the animal and placed into a labeled petri dish. The muscle was X-rayed with mammography equipment, using mammography film (DuPont). Roentgenograms were analyzed using a digital camera attached to an Apple LCII equipped with NIH Image 4.1 software. Images were thresholded to highlight the implant shadow and then the area of the shadow was determined by pixel counting.
- Two of each variety of explant were removed from the muscle and fixed in 10% buffered formalin. Histological sections were taken and consecutive sections were stained with H&E and Masson's trichrome stain. These histological samples were examined by a qualified pathologist.
- Remaining explants were cut from the muscle tissue and ashed in a muffle furnace for 4.5 hours at 700-750° C. Ash weight was determined and normalized to original implant weight. Ash was dissolved in 1.0N HCl and analyzed for calcium content by atomic absorption spectroscopy.
- All analyses were conducted in a blinded manner with decoding done only after processing of the data was complete.
- D. Histology:
- Two week histology samples of 15% and 19% DBM composites indicated that bone formation was occurring, even at this early date. The route of bone formation is not readily apparent, but appears to be endochondral. Four week histology samples revealed that mature bone was formed at the site of implantation. The quality of bone formed was comparable to that of natural bone as shown by the ash and percent calcium analyses. All implants containing DBM were found to lead to the production of some bone. Those containing greater than about 20% DBM yielded the highest quality bone. FIGS. 4A and 4B provide photomicrographs of sections of implants after four weeks in vivo in the rat intramuscular model. We found that 33% (w/w) DBM in gelatin carrier (FIG. 4B) according to this invention produced as much new bone as pure, 100% DBM (FIG. 4A). In these figures, the following structures are evident:10 is mature bone, as evidenced by red stain uptake from Masson's stain; 20 is new cartilage formation, as evidenced by uptake of blue stain from Masson's stain and the presence of cells; 30 is residual DBM, as evidenced by uptake of blue stain and the absence of cells, from which all cartilagenous and bone structures in the muscle cross section arose; and 40 is immature bone, as evidenced by light blue staining and the presence of cells. The cells seen are osteoclasts, degrading the newly formed cartilage, and osteoblasts, laying down new bone. In addition, vascular infiltration in the mature bone is evident in the Masson's stained sections, from which the black and white prints were made.
- E. Compositional Analysis:
- There was no statistically significant difference, using a 2σ test, in ash content between the negative control, the positive control, or compositions comprising 15% or 19% (w/w) DBM. This does not necessarily imply that these compositions do not work (examination of the Roentgenograms obviates this conclusion). Rather, it indicates that the sensitivity of the ash method does not allow the detection of the difference. Examination of the data for the 24% and 33% composites indicates that they are significantly better than 19%, 15%, and the negative controls, and are not significantly different from the (positive) control, see Table 3:
TABLE 3 Composition % Yield Ash/g (% DBM) Implant Standard Deviation 0 {− control} 10.1 9 (n = 6) 15 5.5 12.7 (n = 6) 19 11.9 12.2 (n = 6) 24 34.5 14.9 (n = 5) 33 30.0 8.0 (n = 4) 100 {+ control} 31.9 8.8 (n = 6) - F. Atomic Absorption Spectroscopy:
- The atomic absorption spectroscopy of ashed compositions of DBMI/gelatin composites yielded the amount of calcium in the samples. The 15% and 19% compositions did not show a statistically significant difference from the negative controls. However, it is expected that with greater assay sensitivity, positive effects of DBM at concentrations as low as about 7% (w/w) in gelatin carrier would be measurable. The average calcium content produced by compositions greater than or equal to 24% appeared to be proportional to the amount of DBM, by weight, in the composition:
TABLE 4 Comparison between the atomic absorption spectroscopy results of ashed samples of six different DBM/gelatin composites explanted from rats after 4 weeks in vivo. Composition Average Ca (% DBM w/w) Content/gram Standard Deviation (σ) 0 {(−) control} 1.2 1.2 (n = 6) 15 3.9 2.4 (n = 4) 19 7.3 7.5 (n = 4) 24 23.1 8.7 (n = 3) 33 28.0 4.4 (n = 4) 100 {(+) 81.3 30.0 (n = 5) control} - G. X-Ray Digital Analysis:
- Gross examination/comparison of the x-rays reveals that the 24% and 33% compositions are not significantly different from the (+) controls. The 15% and 19% compositions do not appear to generate significant bone. However, it is expected that with greater assay sensitivity, positive effects of DBM at concentrations as low as about 7% (w/w) in gelatin carrier would be measurable. No bone formation was apparent on the x-rays at the locations of the (−) controls. Accordingly, we conclude that DBM at a concentration of between about 24% to 33% (w/w) in gelatin is active in inducing bone formation. These same data indicate that concentrations of DBM below about 20% are less effective in generating significant bone in comparison to positive controls. It is noted that Grafton™ contains only 8% DBM in a glycerol carrier.
TABLE 5 Composition Normalized Area (% of (% DBM w/w) + ve control) Standard Deviation (σ) 0 {(−) control} 0 0 (n = 10) 15 2.8 1.9 (n = 7) 19 4.1 4.2 (n = 7) 24 33.0 15.2 (n = 10) 33 36.7 14.9 (n = 10) 100 {(+) 100 43.1 (n = 10) control} - This example provides one procedure for the manufacture of bone paste from gelatin and demineralized bone. As fractions of the total mass of composition desired, the following components are weighed (percentages given are of total composite weight):
Dry demineralized bone: 0-40% (w/w) Lyophilized thermally 20-45% (w/w) cross-linkable gelatin: BIOGLASS ®: 0-40% (w/w) bone morphogenetic protein: 0.001 mg/ml - These components are thoroughly blended while dry, and the balance of the composition mass is made up by addition of water, phosphate buffered saline, or any other physiologically acceptable liquid carrier. The composition may be packaged in this form or lyophilized for later reconstruction with water. The malleable properties of the composition are achieved by heating the composition to a temperature sufficient to exceed the liquefaction point of the gelatin, and then allowing the composition to cool to the temperature at which it gels.
- Cornell, C.Techniques in
Orthopaedics 1992, 7, 55-63. - Bloebaum, R. D.Human Bone Ingrowth and Materials; Bloebaum, R. D., Ed.; Society for Biomaterials: Denver, Colo., 1996.
- Einhorn, T. A.Enhancement of Bone Repair Using Biomaterials; Einhorn, T. A., Ed.; Society for Biomaterials: Denver, Colo., 1996.
- Benedict, J. J.The Role of Carrier Matrices on Bone Induction In Vivo; Benedict, J. J., Ed.; Society for Biomaterials: Denver, Colo., 1996.
- Strates, B.; Tiedeman, J.European Journal of
Experimental Musculoskeletal Research 1993, 2, 61-67. - Urist, M. R.Bone Morphogenetic Protein; Urist, M. R., Ed.; W. B. Saunders Co.: Philadelphia, 1992, pp 70-83.
- Yazdi, M.; Bernick, S.; Paule, W.; Nimni, M.Clinical Orthopaedics and Related Research 1991, 262, 281-285.
- Younger, E.; Chapman, M.Journal of
Orthopaedic Trauma 1989, 3, 192-195. - Hardin, C. K.Otolaringologic Clinics of North America 1994, 27, 911-925.
- Senn, N.The American Journal of the Medical Sciences 1889, 98, 219-243.
- Urist, M. R.; Huo, Y. K; Brownell, A. G.; Hohl, W. M.; Buyske, J.; Lietze, A.; Tempst, P.; Hunkapiller, M.; DeLange, R. J.Procedures of the National Acadamy of Sciences, USA 1984, 81, 371-375.
- Urist, M. R.; Chang, J. J.; Lietze, A.; Huo, Y. K.; Brownell, A. G.; DeLang, R. J.Methods in Enzymology 1987, 146, 294-313.
- Lasa, C.; Hollinger, J.; Droham, W.; MacPhee, M.Plastic and Reconstructive Surgery 1995, 96, 1409-1417.
- Nathan, R.; Bentz, H.; Armstrong, R.; Piez, K; Smestad, T.; Ellingsworth, L.; McPherson, J.; Seyedin, S.Journal of
Orthopaedic Research 1988, 6, 324-334. - Hench, L. L.; Andersson, O. H.Bioactive Glasses; Hench, L. L.; Andersson, O. H., Ed.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 1993, pp 41-63.
- Scarborough, N.Bone Repair Using Allografts; Scarborough, N., Ed.; Society for Biomaterials, 1996.
- Frenkel, S. R.; Moskovich, R.; Spivak, J.; Zhang, Z. H.; Prewett, A. B.Spine 1993, 18, 1634-1639.
- Sperling, L. H.Introduction to Physical Polymer Science; John Wiley and Sons, Inc.: New York, 1992.
- McDonald, T. O.; Britton, B.; Borgmann, A. R.; Robb, C. A.
Toxicology 1977, 7, 37-44. - Culling, C. F. A.; Allison, R. T.; Barr, W. T.Cellular Pathology Technique; 4 ed.; Butterworths: London, 1985.
- U.S. Pat. No. 5,481,601
- U.S. Pat. No. 5,236,456
- U.S. Pat. No. 5,405,390
- U.S. Pat. No. 4,440,750
- U.S. Pat. No. 4,394,370
- U.S. Pat. No. 4,472,840
- U.S. Pat. No. 4,678,470
- WO 89/04646
Claims (37)
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/816,079 US20020098222A1 (en) | 1997-03-13 | 1997-03-13 | Bone paste |
CA002280745A CA2280745A1 (en) | 1997-03-13 | 1998-03-12 | Bone paste |
HU0001811A HUP0001811A3 (en) | 1997-03-13 | 1998-03-12 | Bone paste and method for preparation thereof |
SK1257-99A SK125799A3 (en) | 1997-03-13 | 1998-03-12 | Bone paste |
JP53981998A JP2001514565A (en) | 1997-03-13 | 1998-03-12 | Bone paste |
PL98335800A PL335800A1 (en) | 1997-03-13 | 1998-03-12 | Bone paste |
AU65528/98A AU6552898A (en) | 1997-03-13 | 1998-03-12 | Bone paste |
EP98911607A EP0984797A1 (en) | 1997-03-13 | 1998-03-12 | Bone paste |
PCT/US1998/004904 WO1998040113A1 (en) | 1997-03-13 | 1998-03-12 | Bone paste |
US11/152,548 US8652503B2 (en) | 1997-03-13 | 2005-06-14 | Bone paste |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/816,079 US20020098222A1 (en) | 1997-03-13 | 1997-03-13 | Bone paste |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/152,548 Continuation US8652503B2 (en) | 1997-03-13 | 2005-06-14 | Bone paste |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020098222A1 true US20020098222A1 (en) | 2002-07-25 |
Family
ID=25219628
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/816,079 Abandoned US20020098222A1 (en) | 1997-03-13 | 1997-03-13 | Bone paste |
US11/152,548 Expired - Lifetime US8652503B2 (en) | 1997-03-13 | 2005-06-14 | Bone paste |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/152,548 Expired - Lifetime US8652503B2 (en) | 1997-03-13 | 2005-06-14 | Bone paste |
Country Status (9)
Country | Link |
---|---|
US (2) | US20020098222A1 (en) |
EP (1) | EP0984797A1 (en) |
JP (1) | JP2001514565A (en) |
AU (1) | AU6552898A (en) |
CA (1) | CA2280745A1 (en) |
HU (1) | HUP0001811A3 (en) |
PL (1) | PL335800A1 (en) |
SK (1) | SK125799A3 (en) |
WO (1) | WO1998040113A1 (en) |
Cited By (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030113360A1 (en) * | 1999-12-22 | 2003-06-19 | Ludwig Baumgartner | Method for producing a bone material enriched with bone growth factors |
US20040146543A1 (en) * | 2002-08-12 | 2004-07-29 | Shimp Lawrence A. | Synthesis of a bone-polymer composite material |
US6773699B1 (en) | 2001-10-09 | 2004-08-10 | Tissue Adhesive Technologies, Inc. | Light energized tissue adhesive conformal patch |
US6780840B1 (en) | 2001-10-09 | 2004-08-24 | Tissue Adhesive Technologies, Inc. | Method for making a light energized tissue adhesive |
WO2004071547A1 (en) * | 2003-02-12 | 2004-08-26 | Ethicon Gmbh | Bone filling material comprising anabolic steroid |
EP1464345A2 (en) * | 2003-04-03 | 2004-10-06 | Dennis W. Szymaitis | Bone growth and adjacent tissue regeneration composition |
US20050008620A1 (en) * | 2002-10-08 | 2005-01-13 | Shimp Lawrence A. | Coupling agents for orthopedic biomaterials |
US20050008672A1 (en) * | 2002-12-12 | 2005-01-13 | John Winterbottom | Formable and settable polymer bone composite and method of production thereof |
US6875427B1 (en) | 2001-10-09 | 2005-04-05 | Tissue Adhesive Technologies, Inc. | Light energized tissue adhesive |
US20050084542A1 (en) * | 2003-04-11 | 2005-04-21 | Rosenberg Aron D. | Osteoinductive bone material |
US6939364B1 (en) * | 2001-10-09 | 2005-09-06 | Tissue Adhesive Technologies, Inc. | Composite tissue adhesive |
US20050209696A1 (en) * | 2004-01-16 | 2005-09-22 | Jo-Wen Lin | Implant frames for use with settable materials and related methods of use |
US6992172B1 (en) * | 1999-11-12 | 2006-01-31 | Fibrogen, Inc. | Recombinant gelatins |
US20060051427A1 (en) * | 2004-03-02 | 2006-03-09 | Nanotherapeutics, Inc. | Compositions for repairing bone and methods for preparing and using such compositions |
US20060067971A1 (en) * | 2004-09-27 | 2006-03-30 | Story Brooks J | Bone void filler |
US20060074422A1 (en) * | 2004-09-27 | 2006-04-06 | Story Brooks J | Suture anchor and void filler combination |
US20060083769A1 (en) * | 2004-10-14 | 2006-04-20 | Mukesh Kumar | Method and apparatus for preparing bone |
US20060084602A1 (en) * | 2004-10-14 | 2006-04-20 | Lynch Samuel E | Platelet-derived growth factor compositions and methods of use thereof |
US20060204544A1 (en) * | 2002-05-20 | 2006-09-14 | Musculoskeletal Transplant Foundation | Allograft bone composition having a gelatin binder |
US20060233849A1 (en) * | 2005-04-13 | 2006-10-19 | Simon Bruce J | Composite bone graft material |
US20060233851A1 (en) * | 2005-04-13 | 2006-10-19 | Ebi, L.P. | Composite bone graft material |
US7132110B2 (en) | 2001-08-30 | 2006-11-07 | Isotis Orthobiologics, Inc. | Tissue repair compositions and methods for their manufacture and use |
US20060280803A1 (en) * | 2004-10-14 | 2006-12-14 | Mukesh Kumar | Method and apparatus for repairing bone |
US20070191963A1 (en) * | 2002-12-12 | 2007-08-16 | John Winterbottom | Injectable and moldable bone substitute materials |
US20070190083A1 (en) * | 2006-02-01 | 2007-08-16 | Scifert Jeffrey L | Medical implants with reservoir (s), and materials preparable from same |
US20070202191A1 (en) * | 2006-02-27 | 2007-08-30 | Mark Borden | Bone graft materials derived from mineralized gelatin |
US20070202190A1 (en) * | 2006-02-27 | 2007-08-30 | Mark Borden | Bone graft materials derived from mineralized gelatin |
US20080028992A1 (en) * | 2004-04-15 | 2008-02-07 | Lee Dosuk D | Delayed-Setting Calcium Phosphate Pastes |
US20080069852A1 (en) * | 2006-01-19 | 2008-03-20 | Shimp Lawrence A | Porous osteoimplant |
US20080195476A1 (en) * | 2007-02-09 | 2008-08-14 | Marchese Michael A | Abandonment remarketing system |
US20080221701A1 (en) * | 2007-03-09 | 2008-09-11 | Jipin Zhong | Osteostimulative settable bone graft putty |
US20090142385A1 (en) * | 2007-12-04 | 2009-06-04 | Warsaw Orthopedic, Inc. | Compositions for treating bone defects |
US20090246244A1 (en) * | 2008-03-27 | 2009-10-01 | Warsaw Orthopedic, Inc. | Malleable multi-component implants and materials therefor |
US7718616B2 (en) | 2006-12-21 | 2010-05-18 | Zimmer Orthobiologics, Inc. | Bone growth particles and osteoinductive composition thereof |
US20100129421A1 (en) * | 2007-01-15 | 2010-05-27 | Hans Biomed.Cor | Composition for promoting bone regeneration and restoration |
US7799754B2 (en) | 2004-10-14 | 2010-09-21 | Biomimetic Therapeutics, Inc. | Compositions and methods for treating bone |
US7943573B2 (en) | 2008-02-07 | 2011-05-17 | Biomimetic Therapeutics, Inc. | Methods for treatment of distraction osteogenesis using PDGF |
US8106008B2 (en) | 2006-11-03 | 2012-01-31 | Biomimetic Therapeutics, Inc. | Compositions and methods for arthrodetic procedures |
US8114841B2 (en) | 2004-10-14 | 2012-02-14 | Biomimetic Therapeutics, Inc. | Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix |
US8147860B2 (en) | 2005-12-06 | 2012-04-03 | Etex Corporation | Porous calcium phosphate bone material |
US8492335B2 (en) | 2010-02-22 | 2013-07-23 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods for the treatment of tendinopathies |
US8551525B2 (en) | 2010-12-23 | 2013-10-08 | Biostructures, Llc | Bone graft materials and methods |
US8613938B2 (en) | 2010-11-15 | 2013-12-24 | Zimmer Orthobiologics, Inc. | Bone void fillers |
US8690874B2 (en) | 2000-12-22 | 2014-04-08 | Zimmer Orthobiologics, Inc. | Composition and process for bone growth and repair |
US8870954B2 (en) | 2008-09-09 | 2014-10-28 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries |
US8926710B2 (en) | 2010-10-25 | 2015-01-06 | Warsaw Orthopedic, Inc. | Osteoinductive bone graft injectable cement |
US9138508B2 (en) | 2006-02-27 | 2015-09-22 | Globus Medical, Inc. | Bone graft materials derived from mineralized gelatin |
US9144631B2 (en) | 2003-01-27 | 2015-09-29 | Benedicte Asius | Ceramic-based injectable implants which are used to fill wrinkles, cutaneous depressions and scars, and preparation method thereof |
US9161967B2 (en) | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
US9265830B2 (en) | 2011-04-20 | 2016-02-23 | Warsaw Orthopedic, Inc. | Implantable compositions and methods for preparing the same |
US9463264B2 (en) | 2014-02-11 | 2016-10-11 | Globus Medical, Inc. | Bone grafts and methods of making and using bone grafts |
US9486483B2 (en) | 2013-10-18 | 2016-11-08 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9539286B2 (en) | 2013-10-18 | 2017-01-10 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9579421B2 (en) | 2014-02-07 | 2017-02-28 | Globus Medical Inc. | Bone grafts and methods of making and using bone grafts |
US9642891B2 (en) | 2006-06-30 | 2017-05-09 | Biomimetic Therapeutics, Llc | Compositions and methods for treating rotator cuff injuries |
WO2018009091A1 (en) * | 2016-07-04 | 2018-01-11 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "НОВОСИБИРСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ТРАВМАТОЛОГИИ И ОРТОПЕДИИ ИМ. Я.Л.ЦИВЬЯНА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГБУ "ННИИТО им. Я.Л. ЦИВЬЯНА" МИНЗДРАВА РОССИИ) | Method for producing bone-plastic material |
US10016529B2 (en) | 2015-06-10 | 2018-07-10 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
US10207027B2 (en) | 2012-06-11 | 2019-02-19 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US10532131B2 (en) * | 2006-02-17 | 2020-01-14 | NuVasive Netherlands B.V. | Osteoinductive calcium phosphates |
CN111564213A (en) * | 2020-05-12 | 2020-08-21 | 成都铂润信息技术有限公司 | Health state early warning method and system suitable for ruminant livestock |
CN114509535A (en) * | 2021-12-27 | 2022-05-17 | 安徽丰原明胶有限公司 | Method for detecting maturity of ossein in bone gelatin production |
CN114569787A (en) * | 2021-04-13 | 2022-06-03 | 健诺维(成都)生物科技有限公司 | Bone repair material and preparation method and application thereof |
US11426489B2 (en) | 2015-06-10 | 2022-08-30 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
CN114984308A (en) * | 2022-06-28 | 2022-09-02 | 奥精医疗科技股份有限公司 | Cleft lip and palate repair material and preparation method thereof |
US11896736B2 (en) | 2020-07-13 | 2024-02-13 | Globus Medical, Inc | Biomaterial implants and methods of making the same |
Families Citing this family (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020076429A1 (en) * | 1998-01-28 | 2002-06-20 | John F. Wironen | Bone paste subjected to irradiative and thermal treatment |
US20040081704A1 (en) * | 1998-02-13 | 2004-04-29 | Centerpulse Biologics Inc. | Implantable putty material |
US20030147860A1 (en) | 2002-02-07 | 2003-08-07 | Marchosky J. Alexander | Compositions and methods for forming and strengthening bone |
AU770196B2 (en) | 1999-02-04 | 2004-02-12 | Warsaw Orthopedic, Inc. | Osteogenic paste compositions and uses thereof |
US7371408B1 (en) | 1999-06-07 | 2008-05-13 | Wright Medical Technology, Inc. | Bone graft substitute composition |
AU782394B2 (en) * | 1999-06-29 | 2005-07-21 | J. Alexander Marchosky | Compositions and methods for forming and strengthening bone |
US20010037091A1 (en) | 1999-12-29 | 2001-11-01 | Wironen John F. | System for reconstituting pastes and methods of using same |
AU2001236632A1 (en) * | 2000-02-03 | 2001-08-14 | Regeneration Technologies, Inc. | Extraction of growth factors from tissue |
US7182781B1 (en) | 2000-03-02 | 2007-02-27 | Regeneration Technologies, Inc. | Cervical tapered dowel |
AU2001248766A1 (en) | 2000-04-19 | 2001-10-30 | Shionogi And Co., Ltd. | Process for preparation of sulfonamide derivatives and crystals thereof |
US9387094B2 (en) | 2000-07-19 | 2016-07-12 | Warsaw Orthopedic, Inc. | Osteoimplant and method of making same |
AU2001280962A1 (en) * | 2000-08-01 | 2002-02-13 | Regeneration Technologies, Inc. | Diaphysial cortical dowel |
US6576249B1 (en) * | 2000-11-13 | 2003-06-10 | El Gendler | Bone putty and method |
WO2002058755A2 (en) * | 2001-01-25 | 2002-08-01 | Regeneration Technologies, Inc. | Injectable porous bone graft materials |
US20020176893A1 (en) * | 2001-02-02 | 2002-11-28 | Wironen John F. | Compositions, implants, methods, and kits for closure of lumen openings, repair of ruptured tissue, and for bulking of tissue |
US6685626B2 (en) | 2001-02-02 | 2004-02-03 | Regeneration Technologies, Inc. | Compositions, devices, methods, and kits for induction of adhesions |
TWI267378B (en) | 2001-06-08 | 2006-12-01 | Wyeth Corp | Calcium phosphate delivery vehicles for osteoinductive proteins |
ES2181593B2 (en) * | 2001-06-14 | 2004-04-16 | Universidad Complutense De Madrid | METHOD FOR OBTAINING USEFUL BIOACTIVE IMPLANTS AS CONTROLLED RELEASE SYSTEMS OF ANTIBIOTICS. |
US7105182B2 (en) | 2001-07-25 | 2006-09-12 | Szymaitis Dennis W | Periodontal regeneration composition and method of using same |
US20030026770A1 (en) | 2001-07-25 | 2003-02-06 | Szymaitis Dennis W. | Periodontal regeneration composition and method of using same |
US7371409B2 (en) | 2001-09-06 | 2008-05-13 | Wright Medical Technology, Inc. | Bone graft substitute composition |
US7357947B2 (en) * | 2001-09-10 | 2008-04-15 | Biomet, Inc. | Bone graft material incorporating demineralized bone matrix and lipids |
AU2002308204B9 (en) | 2001-11-19 | 2008-06-12 | Scil Technology Gmbh | Device having osteoinductive and osteoconductive properties |
CA2480839C (en) | 2002-03-29 | 2011-01-04 | Wright Medical Technology, Inc. | Bone graft substitute composition |
US7166133B2 (en) | 2002-06-13 | 2007-01-23 | Kensey Nash Corporation | Devices and methods for treating defects in the tissue of a living being |
AU2003240196A1 (en) | 2002-06-20 | 2004-01-23 | Nicolaas Duneas | Osteoinductive biomaterials |
US7291179B2 (en) | 2002-06-24 | 2007-11-06 | Wright Medical Technology, Inc. | Bone graft substitute composition |
US6652887B1 (en) | 2002-06-24 | 2003-11-25 | Wright Medical Technology, Inc. | Bone graft substitute composition |
ES2260685T3 (en) | 2002-09-10 | 2006-11-01 | Scil Technology Gmbh | METALLIC IMPLANT COVERED, TO A REDUCED OXYGEN CONCENTRATION, WITH OSTEOINDUCTING PROTEIN. |
US7582309B2 (en) | 2002-11-15 | 2009-09-01 | Etex Corporation | Cohesive demineralized bone compositions |
US7507257B2 (en) | 2003-02-04 | 2009-03-24 | Wright Medical Technology, Inc. | Injectable resorbable bone graft material, powder for forming same and methods relating thereto for treating bone defects |
NZ544050A (en) | 2003-06-11 | 2009-03-31 | Osteotech Inc | Osteoimplants and methods for their manufacture |
US7771755B2 (en) | 2003-09-12 | 2010-08-10 | Wyeth | Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins |
JP2005211477A (en) * | 2004-01-30 | 2005-08-11 | Gunze Ltd | Support for regenerative medicine |
WO2006026731A1 (en) | 2004-08-30 | 2006-03-09 | Spineovations, Inc. | Method of treating spinal internal disk derangement |
US8127770B2 (en) | 2004-08-30 | 2012-03-06 | Spineovations, Inc. | Method of using an implant for treament of ligaments and tendons |
US7250550B2 (en) | 2004-10-22 | 2007-07-31 | Wright Medical Technology, Inc. | Synthetic bone substitute material |
DE602006016956D1 (en) | 2005-04-06 | 2010-10-28 | Mallinckrodt Inc | Systems and methods for managing information regarding medical fluids and containers therefor |
US8025903B2 (en) | 2005-09-09 | 2011-09-27 | Wright Medical Technology, Inc. | Composite bone graft substitute cement and articles produced therefrom |
ES2402651T3 (en) | 2005-09-09 | 2013-05-07 | Agnovos Healthcare, Llc | Cement substitute for bone graft of composite material and articles produced from it |
DE102006033168A1 (en) | 2006-07-10 | 2008-01-17 | Gelita Ag | Use of gelatin and a crosslinking agent for the preparation of a crosslinking therapeutic composition |
DE102006033167A1 (en) | 2006-07-10 | 2008-01-24 | Gelita Ag | Use of gelatin and a crosslinking agent for the preparation of a crosslinking medical adhesive |
US20080096976A1 (en) * | 2006-10-24 | 2008-04-24 | Neville Alleyne | Method of treating spinal internal disk derangement |
AU2013203287B2 (en) * | 2006-11-03 | 2015-12-17 | Biomimetic Therapeutics, Llc. | Compositions and methods for arthrodetic procedures |
PT3345607T (en) * | 2006-12-29 | 2022-11-21 | Ossifi Mab Llc | Methods of altering bone growth by administration of sost or wise antagonist or agonist |
US9700584B2 (en) * | 2007-12-21 | 2017-07-11 | Rti Surgical, Inc. | Osteoinductive putties and methods of making and using such putties |
EP2080528B1 (en) | 2008-01-17 | 2014-06-25 | Tadeusz Cieslik | Preparation for regeneration of postoperative and post-traumatic bone defects |
US8469961B2 (en) | 2008-03-05 | 2013-06-25 | Neville Alleyne | Methods and compositions for minimally invasive capsular augmentation of canine coxofemoral joints |
US9248165B2 (en) | 2008-11-05 | 2016-02-02 | Hancock-Jaffe Laboratories, Inc. | Composite containing collagen and elastin as a dermal expander and tissue filler |
US9320761B2 (en) | 2008-12-18 | 2016-04-26 | Vivex Biomedical, Inc. | Bone induction system and methods |
WO2011008111A1 (en) * | 2009-07-17 | 2011-01-20 | Tadeusz Cieslik | Preparation for regeneration of postoperative, post-traumatic bone defects and method for implantation of this preparation |
WO2011137292A2 (en) * | 2010-04-30 | 2011-11-03 | University Of Maryland, Baltimore | Injectable, load-bearing cell/microbead/calcium phosphate bone paste for bone tissue engineering |
US10130736B1 (en) | 2010-05-14 | 2018-11-20 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
US9352003B1 (en) | 2010-05-14 | 2016-05-31 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
WO2012018241A2 (en) * | 2010-08-05 | 2012-02-09 | Um In Woong | Method for processing bone graft material using teeth, and bone graft material processed thereby |
EP2789353B1 (en) * | 2011-12-05 | 2018-08-15 | Hitachi Chemical Company, Ltd. | Membrane for inducing regeneration of bone/tissue, and method for producing same |
US9180116B2 (en) | 2012-07-19 | 2015-11-10 | Cayman Chemical Company, Inc. | Difluorolactam compounds as EP4 receptor-selective agonists for use in the treatment of EP4-mediated diseases and conditions |
WO2014110284A1 (en) | 2013-01-09 | 2014-07-17 | Bacterin International, Inc. | Bone graft substitute containing a temporary contrast agent and a method of generating such and a method of use thereof |
US9539363B2 (en) * | 2014-04-24 | 2017-01-10 | Warsaw Orthopedic, Inc. | Collagen matrix |
ES2693579T3 (en) | 2015-01-16 | 2018-12-12 | Spineovations, Inc. | Method of treatment of the intervertebral disc |
US10531957B2 (en) | 2015-05-21 | 2020-01-14 | Musculoskeletal Transplant Foundation | Modified demineralized cortical bone fibers |
AU2017254618B2 (en) | 2016-04-19 | 2021-04-01 | Warsaw Orthopedic, Inc. | An implantable composite containing carbonated hydroxyapatite |
KR102285323B1 (en) * | 2017-10-11 | 2021-08-03 | 포항공과대학교 산학협력단 | Bone graft substitutes based on coccoliths and carbonated hydroxyapatite synthesized from coccoliths |
US11285177B2 (en) * | 2018-01-03 | 2022-03-29 | Globus Medical, Inc. | Allografts containing viable cells and methods thereof |
CN110302431A (en) * | 2019-06-21 | 2019-10-08 | 湖北联结生物材料有限公司 | A kind of injectable type bioactivity glass of the DBM containing decalcified bone matrix and its preparation method and application |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3034852A (en) | 1960-01-26 | 1962-05-15 | Japan Leather Mfg Co Ltd | Solubilization of insoluble collagen fibers and reconstitution thereof |
DE2657370C2 (en) | 1976-12-17 | 1982-11-11 | Hans Dr.med. Dr.med.dent. 8000 München Scheicher | Means for covering and / or filling in bone defects |
US4294753A (en) | 1980-08-04 | 1981-10-13 | The Regents Of The University Of California | Bone morphogenetic protein process |
CA1190855A (en) | 1980-09-03 | 1985-07-23 | Rolf W. Pfirrmann | Treatment of osteitis |
US4394370A (en) | 1981-09-21 | 1983-07-19 | Jefferies Steven R | Bone graft material for osseous defects and method of making same |
US4472840A (en) | 1981-09-21 | 1984-09-25 | Jefferies Steven R | Method of inducing osseous formation by implanting bone graft material |
US4440750A (en) | 1982-02-12 | 1984-04-03 | Collagen Corporation | Osteogenic composition and method |
GB8328074D0 (en) * | 1983-10-20 | 1983-11-23 | Geistlich Soehne Ag | Chemical compositions |
US4678470A (en) | 1985-05-29 | 1987-07-07 | American Hospital Supply Corporation | Bone-grafting material |
FR2601371B1 (en) | 1986-07-11 | 1989-05-12 | Merieux Inst | PROCESS FOR TREATING COLLAGEN WITH A VIEW TO, IN PARTICULAR, FACILITATING CROSS-LINKING AND COLLAGEN OBTAINED BY APPLICATION OF SAID PROCESS |
JPS63181770A (en) * | 1987-01-21 | 1988-07-26 | 永瀬 守 | Artificial bone cured and formed by mixing calcium triphosphate, acid, protein and water |
JPS6432371A (en) * | 1987-07-29 | 1989-02-02 | Nec Corp | Inter-processor communicator system |
CA1339083C (en) | 1987-11-13 | 1997-07-29 | Steven R. Jefferies | Bone repair material and delayed drug delivery system |
IT1215881B (en) | 1988-02-16 | 1990-02-22 | Giancarlo Foresti | OSTEOTROPIC ACTION SURGICAL AID. |
US4975526A (en) | 1989-02-23 | 1990-12-04 | Creative Biomolecules, Inc. | Bone collagen matrix for zenogenic implants |
JPH01288269A (en) * | 1988-05-16 | 1989-11-20 | Tonen Corp | Composite molding |
US5422340A (en) | 1989-09-01 | 1995-06-06 | Ammann; Arthur J. | TGF-βformulation for inducing bone growth |
US5073373A (en) | 1989-09-21 | 1991-12-17 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5290558A (en) | 1989-09-21 | 1994-03-01 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5236456A (en) | 1989-11-09 | 1993-08-17 | Osteotech, Inc. | Osteogenic composition and implant containing same |
US5206023A (en) * | 1991-01-31 | 1993-04-27 | Robert F. Shaw | Method and compositions for the treatment and repair of defects or lesions in cartilage |
US5356629A (en) | 1991-07-12 | 1994-10-18 | United States Surgical Corporation | Composition for effecting bone repair |
US5270300A (en) * | 1991-09-06 | 1993-12-14 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone |
JP2984112B2 (en) * | 1991-10-31 | 1999-11-29 | 京セラ株式会社 | Bone filler |
US5314476A (en) | 1992-02-04 | 1994-05-24 | Osteotech, Inc. | Demineralized bone particles and flowable osteogenic composition containing same |
JP3170339B2 (en) * | 1992-03-31 | 2001-05-28 | 京セラ株式会社 | Biotransplant material |
DE4216496C2 (en) * | 1992-05-19 | 1994-09-22 | Werner Prof Dr Med Sattel | Use of a lead body for insertion into a bone cavity, in particular in the medullary cavity of a long bone |
US5531791A (en) | 1993-07-23 | 1996-07-02 | Bioscience Consultants | Composition for repair of defects in osseous tissues, method of making, and prosthesis |
US5503558A (en) | 1993-11-12 | 1996-04-02 | Mcgill University | Osseointegration promoting implant composition, implant assembly and method therefor |
US5707962A (en) | 1994-09-28 | 1998-01-13 | Gensci Regeneration Sciences Inc. | Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof |
WO1996039203A1 (en) * | 1995-06-06 | 1996-12-12 | Gensci Regeneration Laboratories, Inc. | Modified osteogenic materials |
US5776193A (en) | 1995-10-16 | 1998-07-07 | Orquest, Inc. | Bone grafting matrix |
US20010037091A1 (en) * | 1999-12-29 | 2001-11-01 | Wironen John F. | System for reconstituting pastes and methods of using same |
-
1997
- 1997-03-13 US US08/816,079 patent/US20020098222A1/en not_active Abandoned
-
1998
- 1998-03-12 HU HU0001811A patent/HUP0001811A3/en unknown
- 1998-03-12 SK SK1257-99A patent/SK125799A3/en unknown
- 1998-03-12 CA CA002280745A patent/CA2280745A1/en not_active Abandoned
- 1998-03-12 EP EP98911607A patent/EP0984797A1/en not_active Withdrawn
- 1998-03-12 JP JP53981998A patent/JP2001514565A/en active Pending
- 1998-03-12 PL PL98335800A patent/PL335800A1/en unknown
- 1998-03-12 AU AU65528/98A patent/AU6552898A/en not_active Abandoned
- 1998-03-12 WO PCT/US1998/004904 patent/WO1998040113A1/en not_active Application Discontinuation
-
2005
- 2005-06-14 US US11/152,548 patent/US8652503B2/en not_active Expired - Lifetime
Cited By (137)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6992172B1 (en) * | 1999-11-12 | 2006-01-31 | Fibrogen, Inc. | Recombinant gelatins |
US7655615B2 (en) * | 1999-12-22 | 2010-02-02 | Tutogen Medical Gmbh | Method for producing a bone material enriched with bone growth factors |
US20030113360A1 (en) * | 1999-12-22 | 2003-06-19 | Ludwig Baumgartner | Method for producing a bone material enriched with bone growth factors |
US8690874B2 (en) | 2000-12-22 | 2014-04-08 | Zimmer Orthobiologics, Inc. | Composition and process for bone growth and repair |
US20060251729A1 (en) * | 2001-08-30 | 2006-11-09 | Isotis Orthobiologics, Inc. | Tissue repair compositions and methods for their manufacture and use |
US7132110B2 (en) | 2001-08-30 | 2006-11-07 | Isotis Orthobiologics, Inc. | Tissue repair compositions and methods for their manufacture and use |
US7811608B2 (en) | 2001-08-30 | 2010-10-12 | Isotis Orthobiologics, Inc. | Tissue repair compositions and methods for their manufacture and use |
US6780840B1 (en) | 2001-10-09 | 2004-08-24 | Tissue Adhesive Technologies, Inc. | Method for making a light energized tissue adhesive |
US6773699B1 (en) | 2001-10-09 | 2004-08-10 | Tissue Adhesive Technologies, Inc. | Light energized tissue adhesive conformal patch |
US6875427B1 (en) | 2001-10-09 | 2005-04-05 | Tissue Adhesive Technologies, Inc. | Light energized tissue adhesive |
US6939364B1 (en) * | 2001-10-09 | 2005-09-06 | Tissue Adhesive Technologies, Inc. | Composite tissue adhesive |
US20090269388A1 (en) * | 2002-05-20 | 2009-10-29 | Musculoskeletal Transplant Foundation | Allograft bone composition having a gelatin binder |
US20060204544A1 (en) * | 2002-05-20 | 2006-09-14 | Musculoskeletal Transplant Foundation | Allograft bone composition having a gelatin binder |
US8771719B2 (en) | 2002-08-12 | 2014-07-08 | Warsaw Orthopedic, Inc. | Synthesis of a bone-polymer composite material |
AU2003262660B2 (en) * | 2002-08-12 | 2009-07-16 | Warsaw Orthopedic, Inc. | Synthesis of a bone-polymer composite material |
US20040146543A1 (en) * | 2002-08-12 | 2004-07-29 | Shimp Lawrence A. | Synthesis of a bone-polymer composite material |
SG145565A1 (en) * | 2002-08-12 | 2008-09-29 | Osteotech Inc | Synthesis of a bone-polymer composite material |
EP2392359A3 (en) * | 2002-08-12 | 2012-03-07 | Warsaw Orthopedic, Inc. | Synthesis of a bone-polymer composite material |
WO2004014452A3 (en) * | 2002-08-12 | 2004-08-26 | Osteotech Inc | Synthesis of a bone-polymer composite material |
AU2009202477B2 (en) * | 2002-08-12 | 2012-08-23 | Warsaw Orthopedic, Inc. | Synthesis of a bone-polymer composite material |
US20050008620A1 (en) * | 2002-10-08 | 2005-01-13 | Shimp Lawrence A. | Coupling agents for orthopedic biomaterials |
US7270813B2 (en) | 2002-10-08 | 2007-09-18 | Osteotech, Inc. | Coupling agents for orthopedic biomaterials |
US8686064B2 (en) | 2002-10-08 | 2014-04-01 | Warsaw Orthopedic, Inc. | Coupling agents for orthopedic biomaterials |
US20080063684A1 (en) * | 2002-12-12 | 2008-03-13 | John Winterbottom | Formable and Settable Polymer Bone Composite and Methods of Production Thereof |
US7291345B2 (en) | 2002-12-12 | 2007-11-06 | Osteotech, Inc. | Formable and settable polymer bone composite and method of production thereof |
US10080661B2 (en) | 2002-12-12 | 2018-09-25 | Warsaw Orthopedic, Inc. | Injectable and moldable bone substitute materials |
US20070191963A1 (en) * | 2002-12-12 | 2007-08-16 | John Winterbottom | Injectable and moldable bone substitute materials |
US9333080B2 (en) | 2002-12-12 | 2016-05-10 | Warsaw Orthopedic, Inc. | Injectable and moldable bone substitute materials |
US9308292B2 (en) | 2002-12-12 | 2016-04-12 | Warsaw Orthopedic, Inc. | Formable and settable polymer bone composite and methods of production thereof |
US9107751B2 (en) | 2002-12-12 | 2015-08-18 | Warsaw Orthopedic, Inc. | Injectable and moldable bone substitute materials |
US20050008672A1 (en) * | 2002-12-12 | 2005-01-13 | John Winterbottom | Formable and settable polymer bone composite and method of production thereof |
US9144631B2 (en) | 2003-01-27 | 2015-09-29 | Benedicte Asius | Ceramic-based injectable implants which are used to fill wrinkles, cutaneous depressions and scars, and preparation method thereof |
WO2004071547A1 (en) * | 2003-02-12 | 2004-08-26 | Ethicon Gmbh | Bone filling material comprising anabolic steroid |
EP1464345A3 (en) * | 2003-04-03 | 2006-03-29 | Dennis W. Szymaitis | Bone growth and adjacent tissue regeneration composition |
EP1464345A2 (en) * | 2003-04-03 | 2004-10-06 | Dennis W. Szymaitis | Bone growth and adjacent tissue regeneration composition |
US20050084542A1 (en) * | 2003-04-11 | 2005-04-21 | Rosenberg Aron D. | Osteoinductive bone material |
US8454988B2 (en) | 2003-04-11 | 2013-06-04 | Etex Corporation | Osteoinductive bone material |
US20080188946A1 (en) * | 2003-04-11 | 2008-08-07 | Etex Corporation | Osteoinductive bone material |
US8221781B2 (en) | 2003-04-11 | 2012-07-17 | Etex Corporation | Osteoinductive bone material |
US8012210B2 (en) | 2004-01-16 | 2011-09-06 | Warsaw Orthopedic, Inc. | Implant frames for use with settable materials and related methods of use |
US20050209696A1 (en) * | 2004-01-16 | 2005-09-22 | Jo-Wen Lin | Implant frames for use with settable materials and related methods of use |
US7829105B2 (en) | 2004-03-02 | 2010-11-09 | Nanotherapeutics, Inc. | Compositions for repairing bone |
US7846459B2 (en) | 2004-03-02 | 2010-12-07 | Nanotherapeutics, Inc. | Methods for preparing compositions for repairing bone |
US20060051427A1 (en) * | 2004-03-02 | 2006-03-09 | Nanotherapeutics, Inc. | Compositions for repairing bone and methods for preparing and using such compositions |
US20080014279A1 (en) * | 2004-03-02 | 2008-01-17 | Nanotherapeutics, Inc. | Methods for Preparing Compositions for Repairing Bone |
US8216359B2 (en) | 2004-04-15 | 2012-07-10 | Etex Corporation | Delayed-setting calcium phosphate pastes |
US20080028992A1 (en) * | 2004-04-15 | 2008-02-07 | Lee Dosuk D | Delayed-Setting Calcium Phosphate Pastes |
US20060067971A1 (en) * | 2004-09-27 | 2006-03-30 | Story Brooks J | Bone void filler |
US20060074422A1 (en) * | 2004-09-27 | 2006-04-06 | Story Brooks J | Suture anchor and void filler combination |
US9545377B2 (en) | 2004-10-14 | 2017-01-17 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods of use thereof |
US20060084602A1 (en) * | 2004-10-14 | 2006-04-20 | Lynch Samuel E | Platelet-derived growth factor compositions and methods of use thereof |
US20060280803A1 (en) * | 2004-10-14 | 2006-12-14 | Mukesh Kumar | Method and apparatus for repairing bone |
US11318230B2 (en) | 2004-10-14 | 2022-05-03 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods of use thereof |
US8114841B2 (en) | 2004-10-14 | 2012-02-14 | Biomimetic Therapeutics, Inc. | Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix |
US7473678B2 (en) | 2004-10-14 | 2009-01-06 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods of use thereof |
US11571497B2 (en) | 2004-10-14 | 2023-02-07 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods of use thereof |
US20060083769A1 (en) * | 2004-10-14 | 2006-04-20 | Mukesh Kumar | Method and apparatus for preparing bone |
US20070259814A1 (en) * | 2004-10-14 | 2007-11-08 | Lynch Samuel E | Platelet Derived Growth Factor and Methods of Use Thereof |
US7670384B2 (en) | 2004-10-14 | 2010-03-02 | Biomet Manufacturing Corp. | Bone graft composition comprising a bone material and a carrier comprising denatured demineralized bone |
US10258566B2 (en) | 2004-10-14 | 2019-04-16 | Biomimetic Therapeutics, Llc | Compositions and methods for treating bone |
US7799754B2 (en) | 2004-10-14 | 2010-09-21 | Biomimetic Therapeutics, Inc. | Compositions and methods for treating bone |
US11364325B2 (en) | 2004-10-14 | 2022-06-21 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods of use thereof |
US7621963B2 (en) | 2005-04-13 | 2009-11-24 | Ebi, Llc | Composite bone graft material |
US20060233851A1 (en) * | 2005-04-13 | 2006-10-19 | Ebi, L.P. | Composite bone graft material |
US20060233849A1 (en) * | 2005-04-13 | 2006-10-19 | Simon Bruce J | Composite bone graft material |
US8147860B2 (en) | 2005-12-06 | 2012-04-03 | Etex Corporation | Porous calcium phosphate bone material |
US8545858B2 (en) | 2005-12-06 | 2013-10-01 | Etex Corporation | Porous calcium phosphate bone material |
US20080069852A1 (en) * | 2006-01-19 | 2008-03-20 | Shimp Lawrence A | Porous osteoimplant |
US9034356B2 (en) | 2006-01-19 | 2015-05-19 | Warsaw Orthopedic, Inc. | Porous osteoimplant |
US20070190083A1 (en) * | 2006-02-01 | 2007-08-16 | Scifert Jeffrey L | Medical implants with reservoir (s), and materials preparable from same |
US9320708B2 (en) | 2006-02-01 | 2016-04-26 | Warsaw Orthopedic, Inc. | Medical implants with reservoir(s) |
US7824703B2 (en) | 2006-02-01 | 2010-11-02 | Warsaw Orthopedics, Inc. | Medical implants with reservoir(s), and materials preparable from same |
US9931435B2 (en) | 2006-02-01 | 2018-04-03 | Warsaw Orthopedic, Inc. | Medical implants with reservoir(s), and materials preparable from same |
US20100298815A1 (en) * | 2006-02-01 | 2010-11-25 | Warsaw Orthopedic, Inc. | Medical implants with reservoir(s), and materials preparable from same |
US8697114B2 (en) | 2006-02-01 | 2014-04-15 | Jeffrey L. Scifert | Medical implants with reservoir(s), and materials preparable from same |
US10532131B2 (en) * | 2006-02-17 | 2020-01-14 | NuVasive Netherlands B.V. | Osteoinductive calcium phosphates |
US20200108180A1 (en) * | 2006-02-17 | 2020-04-09 | NuVasive Netherlands B.V. | Osteoinductive Calcium Phosphates |
US11590263B2 (en) * | 2006-02-17 | 2023-02-28 | NuVasive Netherlands B.V. | Osteoinductive calcium phosphates |
US9138508B2 (en) | 2006-02-27 | 2015-09-22 | Globus Medical, Inc. | Bone graft materials derived from mineralized gelatin |
US7785634B2 (en) | 2006-02-27 | 2010-08-31 | Globus Medical, Inc. | Bone graft materials derived from mineralized gelatin |
US7892577B2 (en) | 2006-02-27 | 2011-02-22 | Globus Medical, Inc. | Bone graft materials derived from mineralized gelatin |
WO2007101171A3 (en) * | 2006-02-27 | 2008-08-21 | Globus Medical Inc | Bone graft materials derived from mineralized gelatin |
US20110104299A1 (en) * | 2006-02-27 | 2011-05-05 | Mark Borden | Bone graft materials derived from mineralized gelatin |
US20070202190A1 (en) * | 2006-02-27 | 2007-08-30 | Mark Borden | Bone graft materials derived from mineralized gelatin |
US20070202191A1 (en) * | 2006-02-27 | 2007-08-30 | Mark Borden | Bone graft materials derived from mineralized gelatin |
US8394419B2 (en) | 2006-02-27 | 2013-03-12 | Global Medical, Inc. | Bone graft materials derived from mineralized gelatin |
US8658197B2 (en) | 2006-04-14 | 2014-02-25 | Warsaw Orthopedic, Inc. | Disruptable medical implants with reservoir (s), and materials preparable from same |
US11058801B2 (en) | 2006-06-30 | 2021-07-13 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
US9642891B2 (en) | 2006-06-30 | 2017-05-09 | Biomimetic Therapeutics, Llc | Compositions and methods for treating rotator cuff injuries |
US9161967B2 (en) | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
US10456450B2 (en) | 2006-06-30 | 2019-10-29 | Biomimetic Therapeutics, Llc | Compositions and methods for treating rotator cuff injuries |
US8399409B2 (en) | 2006-11-03 | 2013-03-19 | Biomimetic Therapeutics Inc. | Compositions and methods for arthrodetic procedures |
US8106008B2 (en) | 2006-11-03 | 2012-01-31 | Biomimetic Therapeutics, Inc. | Compositions and methods for arthrodetic procedures |
US8742072B2 (en) | 2006-12-21 | 2014-06-03 | Zimmer Orthobiologics, Inc. | Bone growth particles and osteoinductive composition thereof |
US7718616B2 (en) | 2006-12-21 | 2010-05-18 | Zimmer Orthobiologics, Inc. | Bone growth particles and osteoinductive composition thereof |
US8192751B2 (en) * | 2007-01-15 | 2012-06-05 | Hans Biomed.Cor | Composition for promoting bone regeneration and restoration |
US20100129421A1 (en) * | 2007-01-15 | 2010-05-27 | Hans Biomed.Cor | Composition for promoting bone regeneration and restoration |
US20080195476A1 (en) * | 2007-02-09 | 2008-08-14 | Marchese Michael A | Abandonment remarketing system |
US20080221701A1 (en) * | 2007-03-09 | 2008-09-11 | Jipin Zhong | Osteostimulative settable bone graft putty |
US9433704B2 (en) | 2007-03-09 | 2016-09-06 | Novabone Products, Llc | Osteostimulative settable bone graft putty |
US9056150B2 (en) | 2007-12-04 | 2015-06-16 | Warsaw Orthopedic, Inc. | Compositions for treating bone defects |
US10441679B2 (en) | 2007-12-04 | 2019-10-15 | Warsaw Orthopedic, Inc. | Compositions for treating bone defects |
US10080819B2 (en) | 2007-12-04 | 2018-09-25 | Warsaw Orthopedic, Inc | Compositions for treating bone defects |
US20090142385A1 (en) * | 2007-12-04 | 2009-06-04 | Warsaw Orthopedic, Inc. | Compositions for treating bone defects |
US7943573B2 (en) | 2008-02-07 | 2011-05-17 | Biomimetic Therapeutics, Inc. | Methods for treatment of distraction osteogenesis using PDGF |
US8349796B2 (en) | 2008-02-07 | 2013-01-08 | Biomimetic Therapeutics Inc. | Methods for treatment of distraction osteogenesis using PDGF |
US20090246244A1 (en) * | 2008-03-27 | 2009-10-01 | Warsaw Orthopedic, Inc. | Malleable multi-component implants and materials therefor |
US9730982B2 (en) | 2008-03-27 | 2017-08-15 | Warsaw Orthopedic, Inc. | Malleable multi-component implants and materials therefor |
US8840913B2 (en) | 2008-03-27 | 2014-09-23 | Warsaw Orthopedic, Inc. | Malleable multi-component implants and materials therefor |
US8870954B2 (en) | 2008-09-09 | 2014-10-28 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries |
US11135341B2 (en) | 2008-09-09 | 2021-10-05 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor composition and methods for the treatment of tendon and ligament injuries |
US11235030B2 (en) | 2010-02-22 | 2022-02-01 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods for the treatment of tendinopathies |
US8492335B2 (en) | 2010-02-22 | 2013-07-23 | Biomimetic Therapeutics, Llc | Platelet-derived growth factor compositions and methods for the treatment of tendinopathies |
US8926710B2 (en) | 2010-10-25 | 2015-01-06 | Warsaw Orthopedic, Inc. | Osteoinductive bone graft injectable cement |
US8613938B2 (en) | 2010-11-15 | 2013-12-24 | Zimmer Orthobiologics, Inc. | Bone void fillers |
US8551525B2 (en) | 2010-12-23 | 2013-10-08 | Biostructures, Llc | Bone graft materials and methods |
US9220596B2 (en) | 2010-12-23 | 2015-12-29 | Biostructures, Llc | Bone graft materials and methods |
US9849215B2 (en) | 2011-04-20 | 2017-12-26 | Warsaw Orthopedic, Inc. | Implantable compositions and methods for preparing the same |
US9265830B2 (en) | 2011-04-20 | 2016-02-23 | Warsaw Orthopedic, Inc. | Implantable compositions and methods for preparing the same |
US10792397B2 (en) | 2012-06-11 | 2020-10-06 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US10207027B2 (en) | 2012-06-11 | 2019-02-19 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US9486483B2 (en) | 2013-10-18 | 2016-11-08 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US10022474B2 (en) | 2013-10-18 | 2018-07-17 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US11771804B2 (en) | 2013-10-18 | 2023-10-03 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US11116874B2 (en) | 2013-10-18 | 2021-09-14 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9539286B2 (en) | 2013-10-18 | 2017-01-10 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9579421B2 (en) | 2014-02-07 | 2017-02-28 | Globus Medical Inc. | Bone grafts and methods of making and using bone grafts |
US9463264B2 (en) | 2014-02-11 | 2016-10-11 | Globus Medical, Inc. | Bone grafts and methods of making and using bone grafts |
US10016529B2 (en) | 2015-06-10 | 2018-07-10 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
US11426489B2 (en) | 2015-06-10 | 2022-08-30 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
WO2018009091A1 (en) * | 2016-07-04 | 2018-01-11 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "НОВОСИБИРСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ТРАВМАТОЛОГИИ И ОРТОПЕДИИ ИМ. Я.Л.ЦИВЬЯНА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГБУ "ННИИТО им. Я.Л. ЦИВЬЯНА" МИНЗДРАВА РОССИИ) | Method for producing bone-plastic material |
CN111564213A (en) * | 2020-05-12 | 2020-08-21 | 成都铂润信息技术有限公司 | Health state early warning method and system suitable for ruminant livestock |
US11896736B2 (en) | 2020-07-13 | 2024-02-13 | Globus Medical, Inc | Biomaterial implants and methods of making the same |
CN114569787A (en) * | 2021-04-13 | 2022-06-03 | 健诺维(成都)生物科技有限公司 | Bone repair material and preparation method and application thereof |
CN114569787B (en) * | 2021-04-13 | 2022-11-18 | 健诺维(成都)生物科技有限公司 | Bone repair material and preparation method and application thereof |
CN114509535A (en) * | 2021-12-27 | 2022-05-17 | 安徽丰原明胶有限公司 | Method for detecting maturity of ossein in bone gelatin production |
CN114984308A (en) * | 2022-06-28 | 2022-09-02 | 奥精医疗科技股份有限公司 | Cleft lip and palate repair material and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2280745A1 (en) | 1998-09-17 |
WO1998040113A1 (en) | 1998-09-17 |
JP2001514565A (en) | 2001-09-11 |
EP0984797A1 (en) | 2000-03-15 |
HUP0001811A3 (en) | 2001-02-28 |
SK125799A3 (en) | 2000-08-14 |
HUP0001811A2 (en) | 2000-10-28 |
US8652503B2 (en) | 2014-02-18 |
AU6552898A (en) | 1998-09-29 |
PL335800A1 (en) | 2000-05-22 |
US20070003593A1 (en) | 2007-01-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8652503B2 (en) | Bone paste | |
US20020018796A1 (en) | Thermally sterilized bone paste | |
US20020076429A1 (en) | Bone paste subjected to irradiative and thermal treatment | |
EP1127581B1 (en) | Malleable paste for filling bone defects | |
US6911212B2 (en) | Malleable putty and flowable paste with allograft bone having residual calcium for filling bone defects | |
US7045141B2 (en) | Allograft bone composition having a gelatin binder | |
US6437018B1 (en) | Malleable paste with high molecular weight buffered carrier for filling bone defects | |
USRE39587E1 (en) | Malleable paste for filling bone defects | |
CA2457372C (en) | Composition for filling bone defects | |
USRE38522E1 (en) | Malleable paste for filling bone defects | |
US5510396A (en) | Process for producing flowable osteogenic composition containing demineralized bone particles | |
US6458375B1 (en) | Malleable paste with allograft bone reinforcement for filling bone defects | |
US20090269388A1 (en) | Allograft bone composition having a gelatin binder | |
US20120205274A1 (en) | Allograft bone composition having a gelatin binder | |
US11433159B2 (en) | Hydratable and flowable implantable compositions and methods of making and using them | |
AU2299502A (en) | Bone paste | |
MXPA99008331A (en) | Bone paste | |
CZ323699A3 (en) | Bone paste | |
AU784006B2 (en) | Malleable paste for filling bone defects | |
AU2008200841A1 (en) | Composition For Filling Bone Defects |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: UNIVERSITY OF FLORIDA TISSUE BANK, INC., FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WIRONEN, JOHN F.;GROOMS, JAMIE M.;REEL/FRAME:008580/0302 Effective date: 19970313 |
|
AS | Assignment |
Owner name: FLORIDA, UNIVERSITY OF, FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:WIRONEN, JOHN F.;REEL/FRAME:008727/0305 Effective date: 19970505 Owner name: WIRONEN, JOHN F., FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:UNIVERSITY OF FLORIDA TISSUE BANK, INC.;REEL/FRAME:008727/0274 Effective date: 19970505 |
|
AS | Assignment |
Owner name: UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC., F Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FLORIDA, UNIVERSITY OF;REEL/FRAME:008682/0221 Effective date: 19970606 |
|
AS | Assignment |
Owner name: REGENERATION TECHNOLOGIES, INC., FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SOUTHEAST TISSUE ALLIANCE, INC.;UNIVERSITY OF FLORIDA ORTHOPAEDIC TISSUE BANK, INC.;UNIVERSITY OF FLORIDA TISSUE BANK, INC.;REEL/FRAME:015796/0186 Effective date: 20050121 Owner name: REGENERATION TECHNOLOGIES, INC.,FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SOUTHEAST TISSUE ALLIANCE, INC.;UNIVERSITY OF FLORIDA ORTHOPAEDIC TISSUE BANK, INC.;UNIVERSITY OF FLORIDA TISSUE BANK, INC.;REEL/FRAME:015796/0186 Effective date: 20050121 |
|
AS | Assignment |
Owner name: RTI BIOLOGICS, INC., FLORIDA Free format text: CHANGE OF NAME;ASSIGNOR:REGENERATION TECHNOLOGIES, INC., A DELAWARE CORPORATION;REEL/FRAME:020858/0167 Effective date: 20080227 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |