WO2001008714A1 - Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques - Google Patents

Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques Download PDF

Info

Publication number
WO2001008714A1
WO2001008714A1 PCT/US2000/020630 US0020630W WO0108714A1 WO 2001008714 A1 WO2001008714 A1 WO 2001008714A1 US 0020630 W US0020630 W US 0020630W WO 0108714 A1 WO0108714 A1 WO 0108714A1
Authority
WO
WIPO (PCT)
Prior art keywords
bone
graft
composition
cartilage
nucleic acid
Prior art date
Application number
PCT/US2000/020630
Other languages
English (en)
Inventor
John F. Wironen
Jamie M. Grooms
Original Assignee
Regeneration Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneration Technologies, Inc. filed Critical Regeneration Technologies, Inc.
Priority to MXPA02000877A priority Critical patent/MXPA02000877A/es
Priority to CA002379663A priority patent/CA2379663A1/fr
Priority to EP00952271A priority patent/EP1202755A1/fr
Priority to JP2001513444A priority patent/JP2003505205A/ja
Priority to AU64998/00A priority patent/AU6499800A/en
Publication of WO2001008714A1 publication Critical patent/WO2001008714A1/fr

Links

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
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • 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
    • 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
    • A61F2/30756—Cartilage endoprostheses
    • 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
    • A61F2/446—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 having a circular or elliptical cross-section substantially parallel to the axis of the spine, e.g. cylinders or frustocones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—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
    • A61L27/3612—Cartilage, synovial fluid
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61F2/442—Intervertebral or spinal discs, e.g. resilient
    • 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
    • A61F2/46—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2/4603—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor for insertion or extraction of endoprosthetic joints or of accessories thereof
    • A61F2/4611—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor for insertion or extraction of endoprosthetic joints or of accessories thereof of spinal prostheses
    • 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
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A61F2002/2839—Bone plugs or bone graft dowels
    • 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
    • A61F2002/30108—Shapes
    • A61F2002/30199—Three-dimensional shapes
    • A61F2002/30224—Three-dimensional shapes cylindrical
    • 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
    • A61F2002/30108—Shapes
    • A61F2002/30199—Three-dimensional shapes
    • A61F2002/30224—Three-dimensional shapes cylindrical
    • A61F2002/30235—Three-dimensional shapes cylindrical tubular, e.g. sleeves
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30772—Apertures or holes, e.g. of circular cross section
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30772—Apertures or holes, e.g. of circular cross section
    • A61F2002/30774—Apertures or holes, e.g. of circular cross section internally-threaded
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30795—Blind bores, e.g. of circular cross-section
    • A61F2002/30813—Stepped or enlarged blind bores, e.g. having discrete diameter changes
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30841—Sharp anchoring protrusions for impaction into the bone, e.g. sharp pins, spikes
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/3085—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves with a threaded, e.g. self-tapping, bone-engaging surface, e.g. external surface
    • A61F2002/30866—Rounded threads
    • 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
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30878—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves with non-sharp protrusions, for instance contacting the bone for anchoring, e.g. keels, pegs, pins, posts, shanks, stems, struts
    • A61F2002/30891—Plurality of protrusions
    • A61F2002/30892—Plurality of protrusions parallel
    • 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
    • A61F2002/448—Joints for the spine, e.g. vertebrae, spinal discs comprising multiple adjacent spinal implants within the same intervertebral space or within the same vertebra, e.g. comprising two adjacent spinal implants
    • 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
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063—Three-dimensional shapes
    • A61F2230/0069—Three-dimensional shapes cylindrical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the present invention relates to bone, cartilage and other tissue implant materials as vehicles for delivery of nucleic acid compositions.
  • bone and cartilage implants are treated with nucleic acids actively encoding osteogenic (osteoinductive or osteoconductive) gene products, including but not limited to bone mo ⁇ hogenic proteins, cartilage derived mo ⁇ hogenic proteins, growth factors, and combinations thereof.
  • Spinal fusion is indicated to provide stabilization of the spinal column for painful spinal motion and disorders such as structural deformity, traumatic instability, degenerative instability, and post-resection iatrogenic instability. Fusion, or arthrodesis, is achieved by the formation of an osseous bridge between adjacent motion segments. This can be accomplished within the disc space, anteriorly between contiguous vertebral bodies or posteriorly between consecutive transverse processes, laminae or other posterior aspects of the vertebrae.
  • An osseous bridge, or fusion mass is biologically produced by the body upon skeletal injury. This normal bone healing response is used by surgeons to induce fusion across abnormal spinal segments by recreating spinal injury conditions along the fusion site and then allowing the bone to heal. A successful fusion requires the presence of osteogenic or osteopotential cells, adequate blood supply, sufficient inflammatory response, and appropriate preparation of local bone. This biological environment is typically provided in a surgical setting by decortication, or removal of the outer, cortical bone to expose the vascular, cancellous bone, and the deposition of an adequate quantity of high quality graft material.
  • a fusion or arthrodesis procedure is often performed to treat an anomaly involving an intervertebral disc.
  • Intervertebral discs located between the endplates of adjacent vertebrae, stabilize the spine, distribute forces between vertebrae, and cushion vertebral bodies.
  • a normal intervertebral disc includes a semi-gelatinous component, the nucleus pulposus, which is surrounded and confined by an outer, fibrous ring called the annulus fibrosis. In a healthy, undamaged spine, the annulus fibrosis prevents the nucleus pulposus from protruding outside the disc space.
  • Spinal discs may be displaced or damaged due to trauma, disease or aging.
  • Disruption of the annulus fibrosis allows the nucleus pulposus to protrude into the vertebral canal, a condition commonly referred to as a hemiated or ruptured disc.
  • the extruded nucleus pulposus may press on the spinal nerve, which may result in nerve damage, pain, numbness, muscle weakness and paralysis.
  • Intervertebral discs may also deteriorate due to the normal aging process or disease. As a disc dehydrates and hardens, the disc space height will be reduced leading to instability of the spine, decreased mobility and pain.
  • 316L stainless steel has a stiffness of 193 Gpa.
  • Cortical bone on the other hand, has a stiffness value of about 17 Gpa.
  • bone as an implant also allows excellent postoperative imaging because it does not cause scattering like metallic implants on CT or MRI imaging.
  • the Cloward dowel is a circular graft made by drilling an allogeneic or autogeneic plug from the illium.
  • Cloward dowels are bicortical, having porous cancellous bone between two cortical surfaces.
  • Such dowels have relatively poor biomechanical properties, in particular a low compressive strength. Therefore, the Cloward dowel is not suitable as an intervertebral spacer without internal fixation due to the risk of collapsing prior to fusion under the intense cyclic loads of the spine.
  • Bone dowels having greater biomechanical properties have been produced and marketed by Regeneration Technologies, Inc., (RTI), 1 Innovation Drive, Alachua, Florida 32615, and have been patented, see U.S. Patent No. 5,814,084.
  • RTI Regeneration Technologies, Inc.
  • Unicortical dowels from allogeneic femoral or tibial condyles are available.
  • RTI has also developed a diaphysial cortical dowel having superior mechanical properties, which forms the basis of the 5,814,084 patent (the '814 patent).
  • This dowel also provides the further advantage of having a naturally preformed cavity formed by the existing meduallary canal of the donor long bone. The cavity can be packed with osteogenic materials such as bone or bioceramic.
  • Bone mo ⁇ hogenetic proteins a class of osteoinductive factors from bone matrix, are capable of inducing bone formation when implanted in a fracture or surgical bone site.
  • Recombinantly produced human bone mo ⁇ hogenetic protein-2 (rhBMP-2) has been demonstrated in several animal models to be effective in regenerating bone in skeletal defects. The use of such proteins has led to a need for appropriate carriers and fusion spacer designs.
  • bone graft substitutes such as bioceramics
  • the challenge has been to develop a bone graft substitute which avoids the disadvantages of metal implants and bone grafts while capturing the advantages of both.
  • Calcium phosphate ceramics are biocompatible and do not present the infectious or immuno logical concerns of allograft materials. Ceramics may be prepared in any quantity, which is a great advantage over autograft and even allograft bone graft material.
  • bioceramics are osteoconductive, stimulating osteogenesis in bony sites. Bioceramics provide a porous matrix which further encourages new bone growth.
  • ceramic implants typically lack the strength to support high spinal loads and therefore require separate fixation before the fusion.
  • hydroxyapatite(HA) and tricalcium phosphate (TCP) ceramics have been most commonly used for bone grafting.
  • Hydroxyapatite is chemically similar to inorganic bone substance and biocompatible with bone.
  • ⁇ -tricalcium phosphate is rapidly degraded in vivo and is too weak to provide support under the cyclic loads of the spine until fusion occurs.
  • developing an implant having the biomechanical properties of metal and the biological properties of bone without the disadvantages of either has been extremely difficult or impossible. It recently became apparent that natural bone mineral is not actually as close to the chemistry and structure of hydroxyapatite as was previously believed.
  • Natural bone mineral contains carbonate ions, magnesium, sodium, hydrogenophosphate ions and trace elements. Bone mineral also has a different crystalline structure than HA. Other details of bone chemistry are disclosed in U.S. Patent No. 4,882,149 to Spector. Mimicking the chemistry and microstructure of bone is important to obtain a beneficial modulus of elasticity and resorbption rate.
  • this invention which provides bone or cartilage matrix compositions as a delivery vehicle for nucleic acids, meets a need long felt in the art, as there are substantial disadvantages to use of proteins to induce bone or cartilage repair or formation which are overcome by delivery of nucleic acids encoding such proteins.
  • bone or cartilage graft compositions comprising expressible nucleic acids encoding cartilage or bone growth or repair factors.
  • the invention provides reduced antigenicity bone (RAB) in combination with nucleic acids actively encoding cartilage or bone inducing factors, (osteogenic or chondrogenic factors).
  • RAB reduced antigenicity bone
  • compositions of this invention are prepared and used to replace damaged, diseased or otherwise compromised tissues, either in the spine or in any number of other biological locations.
  • shaped or formed chondrogenic or osteogenic (osteoconductive or osteoinductive) compositions are provided wherein demineralized bone or cartilage, mineralized bone or cartilage, or pastes comprising mineralized or demineralized bone and cartilage, are provided as delivery vehicles for osteogenic or chondrogenic expressible nucleic acids.
  • methods are disclosed for conducting various surgical procedures using the compositions of this invention.
  • One object of the invention is to provide a bone graft implant having substantially natural mineral structure, reduced antigenicity (reduced immunogenicity), enhanced safety and osteoinductive potential.
  • Another object of the invention is to provide a cartilage graft implant having substantially natural mineral structure, reduced antigenicity (reduced immunogenicity), enhanced safety and osteoinductive or chondrogenic potential.
  • Another object of the invention is to provide spacers for engagement between vertebrae which restore the intervertebral disc space and which support the vertebral column while encouraging bone ingrowth and avoiding stress shielding.
  • Another object of the invention is to provide pins, suture anchors, interference screws, demineralized bone implants, including but not limited to ligaments, oral maxilofacial plates, dowels, posterior lumbar interbody fusion implants, trauma screws and plates, pericardium (for dura, plura, shoulder patch and perioligaments), wedges, chips and pastes comprising bone, cartilage or other tissues, alone or in combination with nucleic acids encoding growth factors, including but not limited to bone mo ⁇ hogenetic proteins, cartilage derived mo ⁇ hogenetic proteins, tissue growth factor (betal and the like).
  • demineralized bone implants including but not limited to ligaments, oral maxilofacial plates, dowels, posterior lumbar interbody fusion implants, trauma screws and plates, pericardium (for dura, plura, shoulder patch and perioligaments), wedges, chips and pastes comprising bone, cartilage or other tissues, alone or in combination with nucleic acids encoding growth factors, including but not limited to bone mo ⁇
  • One benefit of the present invention is that it solves many of the problems associated with the use of bone and other graft materials, either from allograft or xenograft materials.
  • the antigen removal process disclosed herein removes immunogenic and potentially disease causing agents while retaining the natural microstructure of bone and other tissues described herein. This feature allows the use of allograft or xenograft, which is available in virtually unlimited supply. Fortifying the graft with nucleic acids encoding nucleic acids which actively encode bone or cartilage growth factors or osteogenic proteins, makes the graft osteoinductive, thereby making the pain and risk of harvesting autograft unnecessary.
  • An additional benefit is that the invention provides a stable scaffold for bone, cartilage or other tissue ingrowth as the process of fusion or new cartilage or tissue generation occurs.
  • a further object and another benefit of this invention is that it allows the use of bone grafts without the need for metal cages or internal fixation, due to the increased speed of fusion.
  • FIG. 1 is a top perspective view of a bone dowel implant according to US Patent No. 5,814,084, treated according to the method of the present invention to include nucleic acids encoding growth factors.
  • FIG. 2 shows bilateral dowel placement between L5 and the sacrum, using a bone dowel such as that shown in figure 1 , including nucleic acids encoding bone growth factors.
  • FIG. 3 is a perspective view of a cortical bone dowel such as that shown in figure 1, having a chamber and a threaded external feature, and including nucleic acids encoding osteogenic factors.
  • FIG. 4 is a side perspective view of a bone dowel according to this invention.
  • FIG. 5 is a cross-section of a bone dowel of this invention.
  • FIG. 6 is a side elevational view of the bone dowel shown in FIG. 5.
  • FIG. 7 is a cortical bone ring packed with an osteogenic material including nucleic acids encoding osteogenic factors.
  • FIG. 8 is a representation of a cortical bone ring embodiment provided by this invention.
  • FIG. 9 is another embodiment of a cortical bone ring provided by this invention.
  • the present invention provides bone and cartilage graft compositions, spacers and surgical procedures.
  • the bone graft compositions include bone or cartilage grafts, in combination with nucleic acids encoding an osteogenic material, such as a bone mo ⁇ hogenic protein (BMP), cartilage derived mo ⁇ hogenic protein, growth factors, peptides (e.g. pi 5).
  • BMP bone mo ⁇ hogenic protein
  • cartilage derived mo ⁇ hogenic protein growth factors
  • peptides e.g. pi 5
  • delivery of nucleic acids encoding desirable gene products results in uptake of such nucleic acids and expression of the encoded proteins.
  • the nucleic acids may be so-called naked DNA or RNA, comprising appropriate transcription and translation start and stop signals, as are known in the art.
  • the nucleic acid may also comprise viral replication signals, and may include recombinant viral vectors encoding nucleic acids or genes, the expression of which is desired in a given implant location.
  • This invention also provides pins, suture anchors, interference screws, demineralized or mineralized bone implants, including but not limited to ligaments, oral maxilofacial plates, dowels, posterior lumbar interbody fusion implants, trauma screws and plates, pericardium (for dura, plura, shoulder patch and perioligaments), wedges, chips and pastes comprising reduced antigenicity bone, cartilage or other tissues, in combination with nucleic acids encoding growth factors, including but not limited to bone mo ⁇ hogenetic proteins, cartilage derived mo ⁇ hogenetic proteins, tissue growth factor (betal and the like).
  • ligaments including but not limited to ligaments, oral maxilofacial plates, dowels, posterior lumbar interbody fusion implants, trauma screws and plates, pericardium (for dura, plura, shoulder patch and perioligaments), wedges, chips and pastes comprising reduced antigenicity bone, cartilage or other tissues, in combination with nucleic acids encoding growth factors, including but not limited to bone mo ⁇ h
  • the bone grafts according to this invention may be treated according to the method disclosed herein to remove all of the cellular material, fat and non-collagenous protein that is otherwise associated with bone graft compositions.
  • free collagen is also removed, leaving structural or bound collagen which is associated with bone mineral to form the trabecular struts of bone.
  • Such bone implant material while depleted of non-collagenous proteins and non-structural collagens and is defatted, still contains the natural crystalline structure of bone. Therefore, such bone graft compositions of this invention have the natural microstructure of bone without the risk of disease transmission or significant immunogenicity or antigenicity.
  • the natural crystalline structure of bone is maintained by the presence of structural collagen in association with the natural bone minerals.
  • a bone graft material with preferred physical and biological characteristics, including the ability to deliver nucleic acids, without attendant immunogenicity or antigenicity.
  • the presence of structural collagen and the natural mineral structure of bone results in an elasticity and radioopacity which is identical or nearly identical to bone.
  • the material has sufficient resilience and elasticity to retain a formed body and yet remains rigid enough to maintain an open space between bone portions to result in a fusion mass.
  • Demineralized bone matrix or autograft bone treated with nucleic acids may also be employed, but if xenograft bone is to be used, it is preferred that non-collagenous, non- structural proteins are removed.
  • the composite is an ideal bone graft substitute.
  • the composite has the natural calcium phosphate structure of bone. This facilitates inco ⁇ oration and substitution of the graft material, giving the composites a desirable resorbption rate of a few months. This compares favorably to the resorbption rates of known materials which are typically either too fast, slow or unpredictable. For example, allograft typically is resorbed within 12-60 months but may, on the other hand, resorb too quickly before fusion can occur due to an immunogenic response by the patient.
  • the combination of nucleic acids encoding BMP and other osteogenic factors with the graft material according to this invention provides the osteoinductive potential of autograft without the need for a harvesting surgical procedure at a secondary location, where morbidity may occur.
  • the osteoinductive composites of this invention enhance bone growth into and inco ⁇ oration of the graft, resulting in fusion more quickly than would occur using bone or cartilage graft material alone. Allograft alone typically requires many months to inco ⁇ orate and sometimes is never fully inco ⁇ orated, but is merely encased within the patient's bone. The quicker fusion, occurring within about five months, provided by this invention compensates for the less desirable biomechanical properties of graft and makes the use of internal fixation and metal interbody fusion devices unnecessary.
  • the spacers of this invention are not required to support the cyclic loads of the spine for very long because of the quick fusion rates which reduce the biomechanical demands on the spacer.
  • the compositions of this invention may be used with internal fixation devices or may be reinforced as needed, see WO98/56319, hereby inco ⁇ orated by reference.
  • the graft may be autogeneic, allogeneic or xenogeneic.
  • the components of bone which could cause disease or prompt the patient's body to reject the graft are removed by the treatment process disclosed herein.
  • Xenogenic bone such as bovine, ovine, porcine, canine, equine or other bone, is available in virtually unlimited supply.
  • osteogenic factors are also available in unlimited supply thanks to recombinant DNA technology. Therefore, the present invention solves all of the problems associated with autograft, allograft and xenograft, including supply, immunogenicity, disease transmission and the need for surgical procedures at secondary sites.
  • bone mineral is an excellent carrier for osteogenic factors, such as nucleic acids encoding BMP's, CDMP's, peptides (e.g. pi 5) and like factors.
  • Hydroxyapatite which is similar in chemical composition to the mineral in cortical bone, is an osteogenic factor-binding agent which controls the rate of delivery of certain proteins to the fusion site.
  • Calcium phosphate compositions such as hydroxyapatite are thought to bind bone mo ⁇ hogenic proteins and prevent BMP from prematurely dissipating from the spacer before fusion can occur.
  • the cartilage and bone implant- nucleic acid compositions of this invention have the advantage of including a load bearing member composed of bone or cartilage which naturally binds and provides controlled delivery of nucleic acids encoding osteogenic factors such as bone mo ⁇ hogenic proteins, without at the same time inducing undesirable immune responses in the recipient thereof.
  • This invention also capitalizes on the discovery that cortical bone, like metal, can be conveniently machined into the various shapes disclosed herein.
  • the load bearing members define threads on an outer surface.
  • Threads provide several advantages that were previously only available with metal implants. Threads allow better control of spacer insertion than can be obtained with a smooth surface. This allows the surgeon to more accurately position the spacer, which is extremely important around the critical neurological and vascular structures of the spinal column.
  • Threads and the like also provide increased surface area which facilitates the process of bone healing and creeping substitution for replacement of the donor bone material and fusion. These features also increase post-operative stability of the spacer by engaging the adjacent vertebral endplates and anchoring the spacer to prevent expulsion. This is a major advantage over smooth grafts. Surface features also stabilize the bone-spacer interface and reduce micromotion to facilitate inco ⁇ oration and fusion. Methods for producing such external bone features are disclosed in U.S. Patent No. 5,814,084, hereby inco ⁇ orated by reference.
  • the graft compositions of this invention can be prepared according to methods disclosed herein. Bone of human or animal source is obtained according to known procedures.
  • the bone is cleaned to remove tissue and blood and is then treated with agents to remove cellular material, fats, noncollagenous proteins, and optionally, to remove non-structural collagens.
  • Typical agents include alcohols and peroxides.
  • the bone material is also treated to remove free collagen, leaving only bound or structural collagen in association with bone minerals. This reduces immunogenicity/antigenicity, without compromising the structural integrity of the bone material.
  • One preferred agent for removing free collagen and associated non-structural antigenic proteins and any remaining fat is a chaotropic agent, such as urea, guanidinium hydrochloride, Triton X-
  • the bone graft bone material is then preferably washed with sterile, deionized water and terminally sterilized by suitable methods, including but not limited to gamma irradiation, vapor-phase peroxide treatment, and the like.
  • Allograft, autograft, or xenograft bone dowels or other appropriately shaped implants can be packaged fresh frozen or freeze-dried, preferably freeze dried.
  • Sterilization can be provided via aseptic processing or terminally sterilized by ETO, E-beam, or gamma irradiation preferably gamma irradiation.
  • Gamma irradiation allows the procurement and processing of allograft or xenograft under less rigorous environmentally controlled conditions since terminal sterilization offers a significantly higher degree of sterility.
  • the graft according to this invention may be treated to remove all of the non-collagenous bone proteins leaving a non-immunogenic, disease-free, graft implant material having the natural mineral, microcrystalline structure of bone, with a consistency which retains desired forms.
  • the composition of this invention is preferred because it has a microstructure which is the closest to natural bone of all of the known treated bone products.
  • This bone product also has the radioopacity of natural bone and does not show the dense white image of the bone products of Spector and Geistlich.
  • the product of this invention also provides superior resorbability, particularly when combined with nucleic acid encoding osteogenic factors. Resorbption has been found to advantageously occur within several months as opposed to several years required for the Spector and Garlich materials or the few weeks of the Urist product. When the material is combined with nucleic acids encoding a bone growth factor, the resorbption time is ample for forming the bony bridge required for fusion and bone healing.
  • the bone or cartilage materials of this invention are combined with an osteogenic composition or material containing nucleic acids which actively encode a bone growth factor, proteins or peptides.
  • Osteogenic nucleic acids can be applied to the bone material by impregnating the graft with a solution including osteogenic nucleic acid compositions.
  • the allograft, autograft or xenograft is allowed to soak for sufficient time to allow the allograft, autograft or xenograft to absorb the nucleic acid.
  • Additional nucleic acid could be used with the allograft, autograft or xenograft produced according to the method of this invention by the inco ⁇ oration of the nucleic acid in a delivery vehicle placed around or in the allograft.
  • nucleic acid encoding an osteogenic composition can be packed into a chamber defined within a body of the material.
  • the nucleic acids may be combined with appropriate protein growth factors.
  • the various osteogenic factors, growth factors, proteins, peptides or nucleic acids may be forced into the interstices of the bone or other cartilage implants under vacuum or pressure, or by oscillation between high and low pressure in an appropriate chamber or vessel.
  • the composition may be applied by the surgeon during surgery or the spacer may be supplied with the composition preapplied. In such cases, the osteogenic composition may be stabilized for transport and storage such as by freeze-drying.
  • the stabilized composition can be rehydrated and/or reactivated with a sterile fluid such as saline or water or with body fluids applied before or after implantation.
  • a freeze- dried bone or cartilage matrix may be simply reconstituted in a composition comprising expressible nucleic acids, alone or in combination with protein, peptide or other growth factors, antibiotics, antineoplastics, antiinflammatories or the like.
  • the thus reconstituted implant may then be directly implanted into an appropriate recipient or it may be freeze- dried in combination with the applied and absorbed osteogenic composition.
  • the thus treated implant may be treated with or cultured with various cell-types to provide a cell-coated matrix inco ⁇ orating expressible nucleic acids.
  • osteoogenic composition means virtually any material that promotes bone growth or healing, including natural, synthetic and recombinant proteins, hormones and the like, cells expressing such factors, and nucleic acids actively encoding such factors.
  • actively encoding is meant the inclusion in a nucleic acid construct of all required signals, including transcriptional promoters and terminators, enhancers, and the like, as known in the art, in order to achieve efficient expression of encoded factors.
  • the osteogenic compositions used in this invention preferably comprise an amount of nucleic acid actively encoding growth factors sufficient to stimulate or induce bone growth or healing of a substantially pure bone inductive factor such as a bone mo ⁇ hogenetic protein in a pharmaceutically acceptable carrier.
  • the preferred osteoinductive factors include, but are not limited to, nucleic acids encoding recombinant human bone mo ⁇ hogenic proteins (rhBMPs), CDMPs, and nucleic acids encoding such factors.
  • the nucleic acid encodes bone mo ⁇ hogenetic protein rhBMP-2, rhBMP-4 or heterodimers thereof.
  • the concentration of nucleic acid encoding rhBMP-2 or other growth factors may be between about 1 ng - 1 mg per gram of implant.
  • Nucleic Acids encoding any bone mo ⁇ hogenetic protein is contemplated including bone mo ⁇ hogenetic proteins designated as BMP-1 through BMP-13, CDMP1 and CDMP2, and various growth factors know in the aft to be beneficial for the induction of bone growth and tissue regeneration.
  • Nucleic acids encoding BMPs are known in the art and may be prepared by one skilled in the art as described in U.S. Patent Nos.
  • nucleic acids encoding growth factors disclosed in U.S. patent No. 5,763,416, stimulating factors as disclosed in U.S. Patent No. 5,854,207, or 5,899,936, in WO97/38729; WO95/22611 or WO99/06563 are also hereby inco ⁇ orated by reference for use in combination with bone or cartilage matrices as disclosed herein.
  • nucleic acids actively including bone calcification factors such as in U.S. Patent No. 5,635,374 (hereby inco ⁇ orated by reference) may also be included in the graft compositions of this invention.
  • the choice of carrier material for the osteogenic nucleic acid composition is based on the application desired, biocompatibihty, biodegradability, and interface properties.
  • the bone growth inducing composition can be introduced into the pores of the bone material in any suitable manner.
  • the composition may be injected into the pores of the graft.
  • the composition is dripped onto the graft or the graft is soaked in or sprayed with a solution containing an effective amount of the composition to stimulate osteoinduction.
  • the osteogenic composition is infused into the bone under elevated or reduced pressure, or both. All of the method for introducing proteins as disclosed in U.S. Patent No.
  • 5,854,207 are hereby inco ⁇ orated by reference as methods for introducing nucleic acids into bone or cartilage matrices.
  • the pores of the matrix are exposed to the composition for a period of time sufficient to allow the nucleic acid osteogenic composition to thoroughly soak, coat and infuse into the graft.
  • the osteogenic factor preferably a nucleic acid encoding a BMP
  • the carrier may be any suitable medium capable of delivering the nucleic acids to the graft.
  • the medium is supplemented with a buffer solution as is known in the art.
  • nucleic acid encoding rhBMP-2 is suspended or admixed in a carrier, such as water, saline, MFR buffer, liquid collagen or injectable bicalcium phosphate.
  • a carrier such as water, saline, MFR buffer, liquid collagen or injectable bicalcium phosphate.
  • nucleic acid encoding BMP is applied to the pores of the graft and then lypholized or freeze-dried.
  • the nucleic acid graft-BMP composition can then be stored in a sterile container, at room temperature, or at decreased temperature for storage and transport.
  • the osteoinductive nucleic acids can be added at the time of surgery.
  • osteoinductive protein carriers known in the art are available to deliver nucleic acids to a chamber defined within the bone or cartilage material or to locations around the implantation site of the bone material.
  • Potential carriers include calcium sulphates, polylactic acids, polyanhydrides, collagen, calcium phosphates, polymeric acrylic esters, polyphoazines, polyamines, polycarbonates, and the like, and demineralized bone.
  • the carrier may be any suitable carrier capable of delivering the nucleic acids, alone or in combination with proteins, peptides or other biologically active agents. Most preferably, the carrier is capable of being eventually resorbed into the body.
  • One preferred carrier is an absorbable collagen sponge marketed by Integra LifeSciences Co ⁇ oration under the trade name Helistat® Absorbable Collagen Hemostatic Agent.
  • Another preferred carrier is an open cell polylactic acid polymer (OPLA).
  • Other potential matrices for the compositions may be biodegradable and chemically defined calcium sulfates, calcium phosphates such as tricalcium phosphate (TCP) and hydroxyapatite (HA) and including injectable bicalcium phosphates (BCP), and polyanhydrides.
  • Other potential materials are biodegradable and are biologically derived, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components.
  • the osteoinductive material may also be an admixture of nucleic acids encoding BMP and a polymeric acrylic ester carrier, such as polymethylmethacrylate, polyvinylacetate, polyhydroxyethyl methacrylate, and the like.
  • a polymeric acrylic ester carrier such as polymethylmethacrylate, polyvinylacetate, polyhydroxyethyl methacrylate, and the like.
  • the carriers are preferably provided as a sponge which can be compressed into the chamber or as strips or sheets which may be folded to conform to the chamber.
  • the carrier has a width and length which are each slightly greater than the width and length of the chamber.
  • the carrier is soaked with a nucleic acid encoding rhBMP-2 solution and then compressed into the chamber.
  • the sponge is held within the chamber by the compressive forces provided by the sponge against the wall of the dowel. It may be preferable for the carrier to extend out of the openings of the chamber to facilitate contact of the osteogenic composition with the highly vascularized tissue surrounding the fusion site.
  • the carrier can also be provided in several strips sized to fit within the chamber. The strips can be placed one against another to fill the interior. As with the folded sheet, the strips can be arranged within the spacer in several orientations.
  • the osteogenic material whether provided in a sponge, a single folded sheet or in several overlapping strips, has a length corresponding to the length and width of the chamber.
  • a preferred carrier is a biphasic calcium phosphate ceramic. Hydroxyapatite/tricalcium phosphate ceramics are preferred because of their desirable bioactive properties and degradation rates in vivo. The preferred ratio of hydroxyapatite to tricalcium phosphate is between about 0:100 and about 65:35. Any size or shape ceramic carrier which will fit into the chambers defined in the load-bearing member are contemplated. Ceramic blocks are commercially available from Sofamor Danek Group, B. P. 4-62180 Rang-du-Fliers, France and Bioland, 132 Route d: rock, 31100 Toulouse, France. Of course, rectangular and other suitable shapes are contemplated. The osteoinductive factor is introduced into the carrier in any suitable manner.
  • the carrier may be soaked in a solution containing the factor.
  • the present invention also provides spacers for maintaining a space between adjacent bones.
  • the spacers include a body composed of bone or cartilage graft in combination with a nucleic acid encoding bone growth factor.
  • the bone source is any suitable bone material preferably of vertebrate origin, including tibial, f ⁇ bial, humeral, iliac, etc.
  • the graft bodies of this invention include flat spacers, bone dowels, cortical rings, bone chips and any other suitably shaped bone pieces.
  • a preferred body is obtained from the diaphysis of a long bone having a medullary canal which forms a natural chamber in the graft.
  • the invention provides a spacer 10 for maintaining a space between adjacent bones in a patient.
  • the spacer 10 includes a load- bearing member or body 11 sized and shaped to fit within the space.
  • the body 11 is preferably composed of a natural bone or cartilage material which has optimally been processed to remove associated non-collagenous bone proteins.
  • the bone material contains native collagen materials and naturally associated bone minerals but is substantially free from native non-collagenous protein.
  • demineralized or partially demineralized bone may be used.
  • the chemical composition of the bone material allows it to resiliently retain a shaped body.
  • the shape of the body is preferably formed, and the body machined to have desired surface features, before the bone material is processed according to the methods of this invention. However, in some embodiments a mass of bone is treated as disclosed herein, and then is shaped or machined to form a particular body.
  • the body 11 is shaped as a dowel. Dowel shaped bodies are sometimes preferred when the bones are vertebrae to be fused.
  • the dowel 10 includes a wall 12 sized for engagement within the intervertebral space (rVS) to maintain the IVS in proper physiologic orientation.
  • the wall 12 defines an outer engaging surface 13 for contacting the adjacent vertebrae.
  • the wall 12 is preferably cylindrical, so that the bone dowel 10 has a diameter d which is larger than the height h of the IVS between adjacent vertebrae V or the height of the space between the lowest lumbar vertebrae L5 and the sacrum S as depicted in Figure 2.
  • the body is a bone dowel 20 which includes a wall 22 having an engagement surface 23.
  • the wall 22 defines a chamber 25 therethrough.
  • the load-bearing member is a bone graft obtained from the diaphysis of a long bone having a medullary canal which forms the chamber 25.
  • Such dowels are available from Regeneration Technologies, Inc., 1 Innovation Drive, Alachua, Florida 32615.
  • the chamber 25 can be packed with an osteogenic composition comprising nucleic acids encoding BMP, CDMP and the like to stimulate osteoinduction.
  • the chamber 25 is preferably defined through a pair of outer engaging surfaces 23 so that the composition has maximum contact with the endplates of the adjacent vertebrae. Referring now to FIG.
  • the spacer 20 preferably includes a solid protective wall 26 which is positionable to protect the spinal cord from escape or leakage of material packed within the chamber 25.
  • the protective wall 26 is posterior.
  • the osteogenic composition has a length which is greater than the length of the chamber ( Figures 5 and 6) and the composition is disposed within the chamber 25 to contact the end plates of adjacent vertebrae when the spacer 20 is implanted between the vertebrae. This provides better contact of the composition with the end plates to stimulate osteoinduction.
  • the dowel 20 includes an outer engaging surface 23 defining threads 24.
  • the dowel 10 is provided with a tool-engaging hole 19 in a wall 18 opposite the solid protective wall 16.
  • the tool engaging hole 19 is provided in a surface of the dowel which is adjacent the surgeon and opposite the initial thread 17.
  • the tool engaging tool hole 19 would be provided in the anterior surface of the dowel 10.
  • Other machined features are contemplated in the outer or bone engaging surfaces 23. Such machine features include surface roughenings such as knurlings and ratchetings.
  • the spacers of this invention can be inserted using conventional techniques and known tools. In accordance with additional aspects of the present invention, methods for implanting an interbody fusion spacer, such as the spacer 20, are contemplated.
  • the spacers of this invention can also be inserted using laporoscopic technology as described in Sofamor Danek USA's Laproscooic Bone Dowel Surgical Technique, 1995, 1800 Pyramid Place, Memphis, Tennessee 38132,1-800-933-2635.
  • Devices of this invention can be conveniently inco ⁇ orated into Sofamor Danek's laproscopic bone dowel system that facilitates anterior interbody fusions with an approach that is much less surgically morbid than the standard open anterior retroperitoneal approaches.
  • This system includes templates, trephines, dilators, reamers, ports and other devices required for laproscopic dowel insertion.
  • the body may also include other shapes such as cortical rings as shown in Figure 7.
  • Such cortical rings 50 are obtained by a cross-sectional slice of the diaphysis of a long bone and include a superior surface 51 and an inferior surface 52.
  • the graft shown in Figure 7 includes an outer surface 53 which is adjacent and between the superior 51 and inferior 52 surfaces.
  • bone growth through-holes 53a are defined through the outer surface 53 to facilitate fusion.
  • the holes 53a allow mesenchymal stem cells to creep in and bone growth protein and nucleic acids encoding such proteins to diffuse out of the graft. This facilitates bone graft inco ⁇ oration and possibly accelerates fusion by forming anterior and lateral bone bridging outside and through the device.
  • the outer surface 53 defines a tool-engaging hole 54 for receiving an implanting tool.
  • at least one of the superior and/or inferior surfaces 51, 52 are roughened for gripping the end plates of the adjacent vertebrae.
  • the surface roughenings may include teeth 56 on ring 50' as shown in Figure 8 or waffle pattern 57 as shown on ring 5O" in Figure 9.
  • the ring 50 may be trimmed for a more uniform geometry as shown in Figure 7 or left in place as shown in Figure 9.
  • the graft can also be formed into a square shape to be conveniently inco ⁇ orated into current surgical procedures such as, the Smith-Robinson technique for cervical fusion (Smith, M.D., G.W. and R.A. Robinson, M.D., "The Treatment of Certain Cervical-Spine Disorders By Anterior Removal Of The Intervertebral Disc And Interbody Fusion", J. Bone And Joint Surgery, 40-A:607-624 (1958) and Cloward, M.D., R.B., "The Anterior Approach For Removal Of Ruptured Cervical Disks", in meeting of the Harvey Cushing Society, Washington, D.C., April 22, 1958).
  • the surgeon prepares the endplates of the adjacent vertebral bodies to accept a graft after the disc has been removed.
  • the endplates are generally prepared to be parallel surfaces with a high-speed burr.
  • the surgeon then typically sculpts the graft to fit tightly between the bone surfaces so that the graft is held by compression between the vertebral bodies.
  • the bone graft is intended to provide structural support and promote bone ingrowth to achieve a solid fusion of the affected joint.
  • the spacers of this invention avoid the need for this graft sculpting as spacers of known size and dimensions are provided.
  • This invention also avoids the need for a donor surgery because the osteoinductive properties of autograft are provided by the allograft or xenograft implants prepared according to the present invention.
  • the spacers are combined with osteoinductive materials including but not limited to nucleic acids actively encoding growth factors that make allograft or xenograft implants osteoinductive. Therefore, the spacers of this invention speed the patient's recovery by reducing surgical time, avoiding a painful donor surgery and inducing quicker fusion.
  • osteoinductive materials including but not limited to nucleic acids actively encoding growth factors that make allograft or xenograft implants osteoinductive. Therefore, the spacers of this invention speed the patient's recovery by reducing surgical time, avoiding a painful donor surgery and inducing quicker fusion.
  • the bone graft material may be allograft or xenograft, selected from bovine, porcine, equine, ovine, canine or the like.
  • This procedure removes proteins, fats, polysaccharides, glycosaminoglycans and other non- collagenous antigens from bone matrix, and may be conducted in any order of steps, although carrying the process out in the order provided herein has provided consistently excellent results.
  • autograft or allograft bone or cartilage material is used as the nucleic acid delivery matrix.
  • This procedure is followed to de-fat the bone tissue, to remove blood and other proteins, and to inactivate microorganisms that might be present in or on the bone. Prior to initiating this treatment, the bone was cleaned of any attached adventitious tissue.
  • the bone tissue was placed into a container, covered with peroxide solution, and permitted to soak with agitation, sonication or both for about 15 minutes.
  • the peroxide solution and removed debris was decanted, and the bone tissue was rinsed with warm sterile water.
  • Treatment at this stage with a TNBP/Triton X-100 or like solutions, such as hydrogen peroxide/SDS helps to remove additional non-structural proteins and residual fat.
  • the bone tissue was placed into a container, covered with acetone, and heated to between about 35 to 40 degrees centigrade, and permitted to soak with agitation for about 15 minutes. This step was repeated until no fat was visible in the solution after being allowed to cool (three to five cycles is usually adequate).
  • the bone tissue was then rinsed with sterile water and permitted to dry.
  • Variations on this treatment may include use of 99% isopropanol, hexane, and combinations of these solvents.
  • Treatment of the graft at this or a different stage of the process with acetic or other acid is useful to produce a slightly demineralized bone graft of reduced antigenicity, with concomitant effects on the graft strength, growth factor binding capacity, resorbability, removal of acid soluble proteins and loosely associated collagens, and further reductions in antigenicity.
  • the graft is preferably contacted for about thirty minutes with acid, e.g. 1% acetic acid, with the acid being introduced into an evacuated chamber containing the graft, such that uniform acid penetration occurs. If inorganic acids are used, e.g.
  • the acid strength or period of acid contact should be reduced, to avoid complete demineralization of the graft.
  • urea solution 6 M
  • Non-collagenous proteins were extracted from the bone tissue for approximately 48 hours, with agitation.
  • the urea/protein solution was then decanted, and the bone tissue was rinsed with sterile water, several times(about three) using at least a two-fold volume of water.
  • the foregoing procedure was conducted with bovine bone blocks and cancellous chips. Bone cubes of 1 cm were cut from bovine condyles. As a final sterilization step, the thus treated bone was subjected to lyophilization and then gamma irradiation. Bone implant material treated according to this procedure was implanted into a primate model. Little or no adverse immune response (swelling, inflammation) was detected. Furthermore, bone implant treated in this manner was soaked with bone mo ⁇ hogenic protein and implanted in a primate model. Excellent induction of new bone growth into and around the implant bovine bone was detected, without adverse immune response.
  • guanidinium hydrochloride TritonX-100, Tween, TNBP and the like, optionally including combinations of chaotropic agents and surfactants such as SDS (sodium dodecyl sulfate).
  • SDS sodium dodecyl sulfate
  • examples of conditions for use of these agents include use of 4 M guanidinium hydrochloride, and 1% TNBP/TritonX-100.
  • a consenting donor i.e., donor card or other form of acceptance to serve as a donor
  • These tests may be conducted by any of a number of means conventional in the art, including but not limited to ELISA assays, PCR assays, or hemagglutination.
  • Such testing follows the requirements of: (i) American Association of Tissue Banks, Technical Manual for Tissue Banking, Technical Manual - Musculoskeletal Tissues, pages M19-M20; (ii) The Food and Drug Administration, Interim Rule, Federal Register/Vol. 50, No.
  • the donor In addition to a battery of standard biochemical assays, the donor, or their next of kin, was interviewed to ascertain whether the donor engaged in any of a number of high risk behaviors such as having multiple sexual partners, suffering from hemophilia, engaging in intravenous drug use etc. After the donor was ascertained to be acceptable, the bones useful for obtention of the dowels were recovered and cleaned.
  • a dowel was obtained as a transverse plug from the diaphysis of a long bone using a diamond tipped cutting bit which was water cleaned and cooled.
  • the bit was commercially available (Starlite, Inc) and had a generally circular nature and an internal vacant diameter between about 10 mm to about 20 mm.
  • the machine for obtention of endo- and cortical dowels consisted of a pneumatic driven miniature lathe which is fabricated from stainless steel and anodized aluminum. It has a spring-loaded carriage which travels parallel to the cutter. The carriage rides on two runners which are 1.0 inch stainless rods and has a travel distance of approximately 8.0 inches. One runner has set pin holes on the running rod which will stop the carriage from moving when the set pin is placed into the desired hole.
  • the carriage is moveable from side to side with a knob which has graduations in metric and in English. This allows the graft to be positioned.
  • On this carriage is a vice which clamps the graft and holds it in place while the dowel is being cut.
  • the vice has a cut out area in the jaws to allow clearance for the cutter.
  • the lathe has a drive system which is a pneumatic motor with a valve controller which allows a desired RPM to be set.
  • the carriage is manually pulled back and locked in place with a set pin.
  • the graft is loaded into the vice and is aligned with the cutter.
  • the machine is started and the RPM is set, by using a knob on the valve control.
  • the set pin which allows the graft to be loaded onto the cutter to cut the dowel. Once the cutter has cut all the way through the graft the carriage will stop on a set pin.
  • sterile water is used to eject dowel out of the cutter. It is fully autoclavable and has a stainless steel vice and/or clamping fixture to hold grafts for cutting dowels.
  • the graft can be positioned to within 0.001" of an inch which creates dowel uniformity during the cutting process.
  • the cutter used in conjunction with the above machine can produce dowels ranging from 5 mm to 30 mm diameters and the sizes of the cutters are 10.6 mm; 11.0 mm; 12.0 mm; 13.0 mm; 14.0 mm; 16.0 mm; and 18.0 mm.
  • the composition of the cutters is stainless steel with a diamond powder-cutting surface which produces a very smooth surface on the wall of the dowels.
  • sterile water is used to cool and remove debris from graft and/or dowel as the dowel is being cut (hydro infusion). The water travels down through the center of the cutter to irrigate as well as clean the dowel under pressure. In addition, the water aids in ejecting the dowel from the cutter.
  • the dowel was then removed from the medullary canal of the dowel and the cavity cleaned to create a chamber.
  • the chamber interior may be scraped or machined as desired and may be filled with desired osteogenic materials, including allograft, autograft, ceramic, growth factors and the like.
  • the final machined product may be stored, frozen or freeze-dried and vacuum-sealed for later use.
  • the dowel is constructed with a nucleic acid encoding BMP.
  • the dowel is constructed with a mixture of nucleic acids encoding a variety of different growth factors.
  • a diaphysial cortical bone dowel is prepared as described above.
  • the plug is then machined, preferably in a class 10 clean room, to the dimensions desired.
  • the machining is preferably conducted on a lathe such as a jeweler's lathe or machining tools may be specifically designed and adapted for this pu ⁇ ose.
  • a hole is then drilled through the anterior wall of the dowel. The hole is then tapped to receive a threaded insertion tool.
  • the thus-prepared dowel is treated with a nucleic acid as described in Example 2.
  • a threaded bone dowel is obtained through the methods described above.
  • a vial containing 4.0 mg of lypholized nucleic acid encoding rhBMP-2 is constituted with 1 mL sterile water (Abbott Laboratories) for injection to obtain a 4.0 mg/mL solution as follows:
  • the dilution scheme below is followed to obtain the appropriate rhBMP-2 nucleic acid concentration. This dilution provides sufficient volume for two dowels.
  • the dilutions are performed as follows: 1. Using a 5-cc syringe, transfer 4.0 mL of MFR 906 buffer (Genetics Institute) into a sterile vial.
  • a bone implant is lyophilized, and then brought into contact with a solution containing nucleic acids encoding osteogenic proteins, growth factors, in order to reconstitute the lyophilized bone dowel.
  • the dowel draws the nucleic acids encoding growth factors or other osteogenic compositions, natural or recombinant, into the interstices of the bone matrix.
  • the composition of nucleic acid may also include proteins, peptides or other biologically active constituents.
  • Freeze dried nucleic acid encoding rhBMP-2 is reconstituted with sterile water for injection as in Example 4.
  • a sterile allograft or xenograft bone dowel is transferred to a sterile "soaking" container.
  • Reconstituted nucleic acid encoding rhBMP-2 is added to the soaking container so that the allograft is completely submersed in the solution.
  • the allograft or xenograft bone dowel is allowed to soak in the rhBMP-2 encoding nucleic acid solution for 30-60 minutes so that the graft absorbs the nucleic acid, and any other components added to the solution.
  • autograft, allograft or xenograft is contacted with nucleic acids encoding such factors under vacuum with swirling for about 15 minutes.
  • a threaded dowel is obtained through the methods of Examples 1-5.
  • a vial containing 4 .0 mg of lypholized nucleic acid encoding rhBMP-2 is constituted with 1 mL sterile water or saline solution for injection to obtain a 4.0 mg/mL solution as follows:
  • the rhBMP-2 nucleic acid solution is applied to a Helistat sponge (Genetics Institute) as follows:
  • a threaded dowel is obtained through the methods of Examples 1-5.
  • a vial containing 4.0 mg of lypholized nucleic acid encoding rhBMP-2 is constituted with 1 mL sterile water or saline solution for injection to obtain a 4.0 mg/mL solution as follows: 1. Using a 3-cc syringe and 22G needle, slowly inject 1.0 mL sterile water for injection into the vial containing lypholized rhBMP-2 nucleic acid.
  • Allograft or xenograft bone chips are harvested, processed and prepared according to Example 1 to produce allograft or xenograft bone chips.
  • Freeze dried nucleic acid encoding rhBMP-2 is reconstituted with sterile water or saline for injection as described in Example 4.
  • the sterile allograft or xenograft bone chips are transferred to the sterile "soaking" container.
  • the bone chips are first lyophilized, so that upon contact with the BMP nucleic acid solution, the bone chips reconstitute, thereby soaking up the BMP nucleic acid solution into the interstices of the chips.
  • Reconstituted rhBMP-2 nucleic acid is placed into the soaking container so that the allograft or xenograft is completely submersed.
  • the allograft or xenograft bone chips are soaked in the rhBMP-2 nucleic acid solution for 30-60 minutes.
  • the allograft or xenograft bone chips are removed from the soaking container and placed into the posterolateral gutters of the level of the spine to be fused, or into any other bony location where bone fusion or repair is desired.
  • This procedure may be employed to make a gelatin nucleic acid sponge by injecting gelatin into bone chips prepared as described above and then lyophilizing the composition.
  • the efficiency of loading of BMP or other growth factor encoding nucleic acids is enhanced when contact is made with the graft under vacuum.
  • a cortical ring is obtained as a cross-sectional slice of the diaphysis of a human long bone and then optionally prepared using the methods described in Example 1 to produce a cortical ring of reduced antigenicity.
  • the cortical ring is fashioned into a square hollow ring.
  • the ring is packed with an osteogenic composition comprising nucleic acids actively encoding growth factors as described in the foregoing EXAMPLES.
  • a D-shaped cervical spacer is obtained as a cross-sectional slice of a diaphysis of a long bone and treated according to the method of Example 1.
  • the exterior surfaces of the walls are formed by machining the slice to a D-shape.
  • the engaging surfaces of the spacer are provided with knurlings by a standard milling machine.
  • a hole is then drilled through the anterior wall of the spacer. The hole is then tapped to engage a threaded insertion tool.
  • the chamber of the spacer is then packed with an osteogenic nucleic acid composition as described in the foregoing EXAMPLES.
  • the cervical spine is approached anteriorly according to known surgical techniques.
  • the composite material of this invention including osteogenic factor encoding nucleic acids is placed within the interdiscal space.
  • EXAMPLE 12 POSTEROLATERAL FUSION
  • the spine is approached posterolaterially according to known surgical techniques.
  • the composite material of this invention is including osteogenic factor encoding nucleic acids placed between portions of adjacent vertebrae.
  • Processed allograft or xenograft chips infused with nucleic acid are added to a binding matrix to hold the chips together, improving their handling characteristics.
  • the chips are added to gelatin and water to form a paste or slurry and then, optionally, freeze dried into a sheet or any other desired form.
  • the surgeon hydrates the gelatin, graft, nucleic acid composite with a solution, optionally containing nucleic acids encoding osteoinductive factors.
  • the nucleic acid solution could be freeze dried on a hemostatic or other biologically acceptable sponge during manufacture.
  • Alternative binding matrix materials include gelatin, glycosaminoglycans, hyaluronic acid, polymers, proteins and other suitable materials.
  • compositions described herein may have applications in diverse areas of the orthopedic arts.
  • pre-formed shapes may be prepared using appropriately proportioned quantities of bone that has been demineralized, gelatin, growth factors and the like.
  • Compositions wherein gelatin is present at a sufficiently high concentration that the composition is in a semi-liquid, malleable solid or viscous liquid above normal body temperature of a recipient, but becomes a gel or solid at normal body temperature, upon implantation into the recipient are highly desirable.
  • gelatin concentrations of between about one to twenty-five percent are typically sufficient, depending on the average molecular weight of the gelatin employed in such compositions.
  • compositions wherein gelatin is present at a sufficiently high concentration that the composition is a solid at a temperature above normal body temperature of a recipient but is a malleable solid at a slightly higher temperature, such that a solid of substantially any desired form may be made a the higher temperature, and upon implantation into a recipient, the composition maintains the formed shape are also highly desirable.
  • gelatin concentrations of between about ten and forty percent are sufficient for this pu ⁇ ose, depending on the molecular weight of the gelatin employed for such compositions.
  • the nucleic acid encoding growth factors may be added to the binding matrix.
  • the combination of a nucleic acid encoding bone growth factor with a bone or cartilage graft provides superior results as compared with other known implant materials. Quicker fusion rates provide enhanced mechanical strength sooner.
  • the graft of this invention is an excellent nucleic acid carrier which provides controlled release of BMP encoding nucleic acids or other osteogenic compositions, including growth factors, cartilage derived mo ⁇ hogenic proteins, nucleic acids encoding BMPs or other growth factors, to the fusion site.
  • the presence of structural collagen and the natural mineral structure of bone results in an elasticity and radioopacity which is identical or nearly identical to bone.
  • the material has sufficient resilience and elasticity to retain a formed body and yet remains rigid enough to maintain an open space between bone portions to result in a fusion mass.
  • cartilage implants, reduced antigenicity cartilage implants, and other tissues may be produced by treating such tissues with nucleic acids encoding any desirable factor, including but not limited to osteogenic factor, angiogenic factors, and the like.
  • the antigenicity of such tissues may be reduced by appropriate treatment with chaotropic agents, as described above for bone.
  • the thus-treated cartilage and other tissues are then contacted with various nucleic acids encoding growth factors, cells, proteins, antifungals, antibiotics, antineoplastics, analgesics, and the like, as described above.

Abstract

La présente invention porte sur des tissus, notamment mais pas exclusivement, sur des implants osseux et de cartilage utilisés comme matrices de support pour administrer des acides nucléiques biologiquement actifs sur des sites où ces tissus doivent être implantés. Lors de l'implantation, les acides nucléiques associés aux implants sont absorbés par des cellules dans le site d'implantation et sont exprimés de façon à produire des facteurs de croissance, des facteurs régénérateurs et analogues codés par les acides nucléiques. De cette manière, par exemple, l'acide nucléique code une protéine morphogénétique osseuse ou analogue, la vitesse d'induction osseuse, de conduction ou de cicatrisation, et la vitesse de formation du cartilage ou réparation étant ainsi améliorées sans qu'il y ait besoin de fabriquer, purifier, isoler et administrer des facteurs de croissance de protéine ou de peptide.
PCT/US2000/020630 1999-07-28 2000-07-28 Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques WO2001008714A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MXPA02000877A MXPA02000877A (es) 1999-07-28 2000-07-28 Matriz de hueso o cartilago como un vehiculo para suministro de acido nucleico.
CA002379663A CA2379663A1 (fr) 1999-07-28 2000-07-28 Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques
EP00952271A EP1202755A1 (fr) 1999-07-28 2000-07-28 Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques
JP2001513444A JP2003505205A (ja) 1999-07-28 2000-07-28 核酸送達ビヒクルとしての軟骨マトリクス又は骨マトリクス
AU64998/00A AU6499800A (en) 1999-07-28 2000-07-28 Cartilage or bone matrix as a nucleic acid delivery vehicle

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US36320899A 1999-07-28 1999-07-28
US09/363,208 1999-07-28
US58599700A 2000-06-02 2000-06-02
US09/585,997 2000-06-02

Publications (1)

Publication Number Publication Date
WO2001008714A1 true WO2001008714A1 (fr) 2001-02-08

Family

ID=27001962

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/020630 WO2001008714A1 (fr) 1999-07-28 2000-07-28 Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques

Country Status (6)

Country Link
EP (1) EP1202755A1 (fr)
JP (1) JP2003505205A (fr)
AU (1) AU6499800A (fr)
CA (1) CA2379663A1 (fr)
MX (1) MXPA02000877A (fr)
WO (1) WO2001008714A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009644A2 (fr) * 2000-07-31 2002-02-07 Cornell Research Foundation, Inc. Procede pour ameliorer la densite ou la formation osseuse
FR2812553A1 (fr) * 2000-07-19 2002-02-08 Geistlich Soehne Ag Combinaison de collagene et de matiere osseuse pour la reparation de lesions articulaires
WO2002098332A1 (fr) * 2001-02-16 2002-12-12 Sulzer Spine-Tech Inc. Implants osseux et procedes associes
WO2002098329A1 (fr) * 2001-05-31 2002-12-12 Bioteck Srl Greffe biomedicale pour structures squelettiques
EP1283063A1 (fr) * 2001-08-10 2003-02-12 Ed. Geistlich Söhne Ag Für Chemische Industrie Matrice collagénique pour la régénération des tissus contenant du matériel génétique d'activité therapeutique
WO2002065957A3 (fr) * 2001-02-16 2003-04-17 David A Hanson Implants osseux et procedes associes
FR2866237A1 (fr) * 2004-02-13 2005-08-19 Biobank Procede de traitement de tissus osseux et biomateriaux implantables.
WO2008064840A1 (fr) 2006-11-30 2008-06-05 Markus Schlee Procédé de fabrication d'un implant
US8501396B2 (en) 2001-11-05 2013-08-06 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8530149B2 (en) 2001-11-05 2013-09-10 Medgenics Medical Israel Ltd Dermal micro-organs, methods and apparatuses for producing and using the same
US8685635B2 (en) 2002-11-05 2014-04-01 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8858981B2 (en) 1997-10-10 2014-10-14 Ed. Geistlich Soehne Fuer Chemistrie Industrie Bone healing material comprising matrix carrying bone-forming cells
US8877175B2 (en) 2006-09-14 2014-11-04 Medgenics Medical Israel Ltd. Long lasting drug formulations
US8911763B2 (en) 1997-10-10 2014-12-16 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material and method
US9034315B2 (en) 1997-10-10 2015-05-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Cell-charged multi-layer collagen membrane
US9107896B2 (en) 2001-11-05 2015-08-18 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US9127084B2 (en) 2006-09-14 2015-09-08 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9155749B2 (en) 2006-09-14 2015-10-13 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9265609B2 (en) 2013-01-08 2016-02-23 Warsaw Orthopedic, Inc. Osteograft implant
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
US10172651B2 (en) 2012-10-25 2019-01-08 Warsaw Orthopedic, Inc. Cortical bone implant
CN111492223A (zh) * 2017-12-29 2020-08-04 豪夫迈·罗氏有限公司 组织样品制备系统
US11369473B2 (en) 2019-04-08 2022-06-28 Loubert S. Suddaby Extended release immunomodulatory implant to facilitate bone morphogenesis
US11779683B2 (en) 2019-04-08 2023-10-10 Loubert S. Suddaby Extended release immunomodulatory implant to facilitate bone morphogenesis

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060111779A1 (en) * 2004-11-22 2006-05-25 Orthopedic Development Corporation, A Florida Corporation Minimally invasive facet joint fusion
US20100023129A1 (en) * 2008-07-22 2010-01-28 Guo-Feng Xu Jawbone prosthesis and method of manufacture
DE102010048710B4 (de) * 2010-03-30 2013-05-23 3T Textiltechnologietransfer Gmbh Implantat mit einer Sandwich-Struktur
RU2642250C2 (ru) * 2012-07-31 2018-01-24 Гайстлих Фарма Аг Гидрофильный содержащий фосфатную группу дегидратированный частично очищенный материал для замещения кости

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820305A (en) 1986-11-03 1989-04-11 Harms Juergen Place holder, in particular for a vertebra body
US4878915A (en) 1987-01-22 1989-11-07 Brantigan John W Surgical prosthetic implant facilitating vertebral interbody fusion
US4961740A (en) 1988-10-17 1990-10-09 Surgical Dynamics, Inc. V-thread fusion cage and method of fusing a bone joint
US5013649A (en) * 1986-07-01 1991-05-07 Genetics Institute, Inc. DNA sequences encoding osteoinductive products
US5015247A (en) 1988-06-13 1991-05-14 Michelson Gary K Threaded spinal implant
US5044104A (en) 1989-04-13 1991-09-03 Rehau Ag & Co. Label mounting apparatus
US5147402A (en) 1990-12-05 1992-09-15 Sulzer Brothers Limited Implant for ingrowth of osseous tissue
US5192327A (en) 1991-03-22 1993-03-09 Brantigan John W Surgical prosthetic implant for vertebrae
US5670336A (en) * 1988-04-08 1997-09-23 Stryker Corporation Method for recombinant production of osteogenic protein
WO1997038729A1 (fr) * 1996-04-12 1997-10-23 The Regents Of The University Of Michigan Procede de transfert de genes in vivo pour la guerison de plaies
US5688678A (en) * 1990-05-16 1997-11-18 Genetics Institute, Inc. DNA encoding and methods for producing BMP-8 proteins
WO1998012322A1 (fr) * 1996-09-18 1998-03-26 Genetics Institute, Inc. Compositions de proteines-16 morphogenetiques osseuses
US5763416A (en) * 1994-02-18 1998-06-09 The Regent Of The University Of Michigan Gene transfer into bone cells and tissues
WO1998056433A1 (fr) * 1997-06-11 1998-12-17 Sdgi Holdings, Inc. Composites de greffes osseuses et ecarteurs
WO1999011664A1 (fr) * 1997-09-05 1999-03-11 Genetics Institute, Inc. Cellules genetiquement manipulees qui expriment des proteines morphogenetiques d'os
WO1999029718A2 (fr) * 1997-12-10 1999-06-17 Genetics Institute, Inc. Compositions a base de proteine morphogenetique osseuse (bmp) du type bmp-17 et bmp-18

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5013649A (en) * 1986-07-01 1991-05-07 Genetics Institute, Inc. DNA sequences encoding osteoinductive products
US4820305A (en) 1986-11-03 1989-04-11 Harms Juergen Place holder, in particular for a vertebra body
US4878915A (en) 1987-01-22 1989-11-07 Brantigan John W Surgical prosthetic implant facilitating vertebral interbody fusion
US5670336A (en) * 1988-04-08 1997-09-23 Stryker Corporation Method for recombinant production of osteogenic protein
US5015247A (en) 1988-06-13 1991-05-14 Michelson Gary K Threaded spinal implant
US4961740B1 (en) 1988-10-17 1997-01-14 Surgical Dynamics Inc V-thread fusion cage and method of fusing a bone joint
US4961740A (en) 1988-10-17 1990-10-09 Surgical Dynamics, Inc. V-thread fusion cage and method of fusing a bone joint
US5026373A (en) 1988-10-17 1991-06-25 Surgical Dynamics, Inc. Surgical method and apparatus for fusing adjacent bone structures
US5044104A (en) 1989-04-13 1991-09-03 Rehau Ag & Co. Label mounting apparatus
US5688678A (en) * 1990-05-16 1997-11-18 Genetics Institute, Inc. DNA encoding and methods for producing BMP-8 proteins
US5147402A (en) 1990-12-05 1992-09-15 Sulzer Brothers Limited Implant for ingrowth of osseous tissue
US5192327A (en) 1991-03-22 1993-03-09 Brantigan John W Surgical prosthetic implant for vertebrae
US5763416A (en) * 1994-02-18 1998-06-09 The Regent Of The University Of Michigan Gene transfer into bone cells and tissues
WO1997038729A1 (fr) * 1996-04-12 1997-10-23 The Regents Of The University Of Michigan Procede de transfert de genes in vivo pour la guerison de plaies
WO1998012322A1 (fr) * 1996-09-18 1998-03-26 Genetics Institute, Inc. Compositions de proteines-16 morphogenetiques osseuses
WO1998056433A1 (fr) * 1997-06-11 1998-12-17 Sdgi Holdings, Inc. Composites de greffes osseuses et ecarteurs
WO1999011664A1 (fr) * 1997-09-05 1999-03-11 Genetics Institute, Inc. Cellules genetiquement manipulees qui expriment des proteines morphogenetiques d'os
WO1999029718A2 (fr) * 1997-12-10 1999-06-17 Genetics Institute, Inc. Compositions a base de proteine morphogenetique osseuse (bmp) du type bmp-17 et bmp-18

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8911763B2 (en) 1997-10-10 2014-12-16 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material and method
US8858981B2 (en) 1997-10-10 2014-10-14 Ed. Geistlich Soehne Fuer Chemistrie Industrie Bone healing material comprising matrix carrying bone-forming cells
US9034315B2 (en) 1997-10-10 2015-05-19 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Cell-charged multi-layer collagen membrane
NL1018560C2 (nl) * 2000-07-19 2003-08-19 Geistlich Soehne Ag Combinatie van botmateriaal en collageen voor het repareren van beschadigde gewrichten.
FR2812553A1 (fr) * 2000-07-19 2002-02-08 Geistlich Soehne Ag Combinaison de collagene et de matiere osseuse pour la reparation de lesions articulaires
ES2195731A1 (es) * 2000-07-19 2003-12-01 Geistlich Soehne Ag Producto mineral oseo en particulas para la reparacion de defectos de cartilagos y defectos oseos combinados.
US6939540B1 (en) 2000-07-31 2005-09-06 Cornell Research Foundation, Inc. Method of enhancing bone density
WO2002009644A3 (fr) * 2000-07-31 2003-02-27 Cornell Res Foundation Inc Procede pour ameliorer la densite ou la formation osseuse
WO2002009644A2 (fr) * 2000-07-31 2002-02-07 Cornell Research Foundation, Inc. Procede pour ameliorer la densite ou la formation osseuse
WO2002098332A1 (fr) * 2001-02-16 2002-12-12 Sulzer Spine-Tech Inc. Implants osseux et procedes associes
WO2002065957A3 (fr) * 2001-02-16 2003-04-17 David A Hanson Implants osseux et procedes associes
WO2002098329A1 (fr) * 2001-05-31 2002-12-12 Bioteck Srl Greffe biomedicale pour structures squelettiques
EP1283063A1 (fr) * 2001-08-10 2003-02-12 Ed. Geistlich Söhne Ag Für Chemische Industrie Matrice collagénique pour la régénération des tissus contenant du matériel génétique d'activité therapeutique
AU2002300450B2 (en) * 2001-08-10 2007-04-05 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Collagen Carrier of Therapeutic Genetic Material, and Method
US9468667B2 (en) 2001-11-05 2016-10-18 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8501396B2 (en) 2001-11-05 2013-08-06 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8530149B2 (en) 2001-11-05 2013-09-10 Medgenics Medical Israel Ltd Dermal micro-organs, methods and apparatuses for producing and using the same
US9107896B2 (en) 2001-11-05 2015-08-18 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8685635B2 (en) 2002-11-05 2014-04-01 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US8771291B2 (en) 2002-11-05 2014-07-08 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US9101595B2 (en) 2002-11-05 2015-08-11 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
US9572593B2 (en) 2003-05-01 2017-02-21 Medgenics Medical Israel Ltd. Dermal micro-organs, methods and apparatuses for producing and using the same
FR2866237A1 (fr) * 2004-02-13 2005-08-19 Biobank Procede de traitement de tissus osseux et biomateriaux implantables.
WO2005082432A1 (fr) * 2004-02-13 2005-09-09 Biobank Procede de traitement de tissus osseux et biomateriaux implantables
US9155749B2 (en) 2006-09-14 2015-10-13 Medgenics Medical Israel Ltd. Long lasting drug formulations
US8877175B2 (en) 2006-09-14 2014-11-04 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9687564B2 (en) 2006-09-14 2017-06-27 Medgenics Medical Israel Ltd. Long lasting drug formulations
US9127084B2 (en) 2006-09-14 2015-09-08 Medgenics Medical Israel Ltd. Long lasting drug formulations
WO2008064840A1 (fr) 2006-11-30 2008-06-05 Markus Schlee Procédé de fabrication d'un implant
EP2097046B1 (fr) * 2006-11-30 2013-04-24 SCHLEE, Markus Procédé de fabrication d'un implant
US10172651B2 (en) 2012-10-25 2019-01-08 Warsaw Orthopedic, Inc. Cortical bone implant
US10820999B2 (en) 2013-01-08 2020-11-03 Warsaw Orthopedic, Inc. Osteograft implant
US9265609B2 (en) 2013-01-08 2016-02-23 Warsaw Orthopedic, Inc. Osteograft implant
US9949832B2 (en) 2013-01-08 2018-04-24 Warsaw Orthopedic, Inc. Osteograft implant
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
CN111492223A (zh) * 2017-12-29 2020-08-04 豪夫迈·罗氏有限公司 组织样品制备系统
US11369473B2 (en) 2019-04-08 2022-06-28 Loubert S. Suddaby Extended release immunomodulatory implant to facilitate bone morphogenesis
US11779683B2 (en) 2019-04-08 2023-10-10 Loubert S. Suddaby Extended release immunomodulatory implant to facilitate bone morphogenesis

Also Published As

Publication number Publication date
MXPA02000877A (es) 2002-08-06
EP1202755A1 (fr) 2002-05-08
AU6499800A (en) 2001-02-19
CA2379663A1 (fr) 2001-02-08
JP2003505205A (ja) 2003-02-12

Similar Documents

Publication Publication Date Title
EP0988070B1 (fr) Composites de greffes osseuses et ecarteurs
WO2001008714A1 (fr) Cartilage ou matrice osseuse servant de vehicules pour administrer des acides nucleiques
US9999520B2 (en) Osteoimplant and method of making same
EP0955961B1 (fr) Ecarteurs vertebraux
US6761739B2 (en) Cortical and cancellous allograft spacer
US20120071983A1 (en) Bone grafts
JP2002503135A (ja) 補強された骨移植片代替物
JP2004503330A (ja) 骨インプラント及びその製法
CA2379665A1 (fr) Implants tissulaires a antigenicite reduite (rat)
US20120310348A1 (en) Bone grafts
AU773116B2 (en) Spinal spacer
CA2547680A1 (fr) Ecarteurs vertebraux

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2379663

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2002/000877

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 64998/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2000952271

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2000952271

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 2000952271

Country of ref document: EP