WO1991011148A1 - Procede et dispositif d'administration locale de substances biologiquement actives - Google Patents

Procede et dispositif d'administration locale de substances biologiquement actives Download PDF

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Publication number
WO1991011148A1
WO1991011148A1 PCT/DK1991/000022 DK9100022W WO9111148A1 WO 1991011148 A1 WO1991011148 A1 WO 1991011148A1 DK 9100022 W DK9100022 W DK 9100022W WO 9111148 A1 WO9111148 A1 WO 9111148A1
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WO
WIPO (PCT)
Prior art keywords
bone
prosthesis
united
healing
apertures
Prior art date
Application number
PCT/DK1991/000022
Other languages
English (en)
Inventor
Troels Torp Andreassen
Jørgen Peter Holmberg JØRGENSEN
Bue Kruse Bak
Original Assignee
Troels Torp Andreassen
Joergensen Joergen Peter Holmb
Bue Kruse Bak
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 Troels Torp Andreassen, Joergensen Joergen Peter Holmb, Bue Kruse Bak filed Critical Troels Torp Andreassen
Publication of WO1991011148A1 publication Critical patent/WO1991011148A1/fr

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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
    • A61L27/50—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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/72—Intramedullary pins, nails or other devices
    • 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
    • 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
    • A61F2/32—Joints for the hip
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/80—Cortical plates, i.e. bone plates; Instruments for holding or positioning cortical plates, or for compressing bones attached to cortical plates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/86—Pins or screws or threaded wires; nuts therefor
    • A—HUMAN NECESSITIES
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    • 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
    • A61F2/32—Joints for the hip
    • A61F2/36—Femoral heads ; Femoral endoprostheses
    • A61F2/3662—Femoral shafts
    • A61F2/367—Proximal or metaphyseal parts of shafts
    • 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
    • A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
    • A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
    • 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
    • A61F2/32—Joints for the hip
    • A61F2/34—Acetabular cups
    • A61F2002/3401—Acetabular cups with radial apertures, e.g. radial bores for receiving fixation screws
    • 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
    • A61F2/32—Joints for the hip
    • A61F2/34—Acetabular cups
    • A61F2002/3469—Acetabular cups with non-radial inner bores or canals
    • 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
    • A61F2/32—Joints for the hip
    • A61F2/36—Femoral heads ; Femoral endoprostheses
    • A61F2/3662—Femoral shafts
    • A61F2002/3678—Geometrical features
    • A61F2002/368—Geometrical features with lateral apertures, bores, holes or openings, e.g. for reducing the mass, for receiving fixation screws or for communicating with the inside of a hollow shaft
    • 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
    • A61F2/32—Joints for the hip
    • A61F2/36—Femoral heads ; Femoral endoprostheses
    • A61F2/3662—Femoral shafts
    • A61F2002/3678—Geometrical features
    • A61F2002/3694—Geometrical features with longitudinal bores
    • 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
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00574—Coating or prosthesis-covering structure made of carbon, e.g. of pyrocarbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00796—Coating or prosthesis-covering structure made of a phosphorus-containing compound, e.g. hydroxy(l)apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
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    • 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
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a method for local admini- stration of biologically active substances enhancing the hea ⁇ ling of bone fractures or of a bone and a prosthesis to be united and a device which can be used carrying out the met ⁇ hod. Furthermore, the invention relates to an agent for use for local administration for enhancing the healing bone frac- tures or of a bone and a prosthesis to be united and to the use of human growth hormone, thyroid hormone, growth factors, morphogens, cell growth stimulants and/or antibiotic(s) for this purpose.
  • Bone formation, healing of fractures, and healing of prothe- ses such as joint prostheses are depending on basal biologi ⁇ cal processes which seem to be related. These processes which have not yet been explained in detail are being studied in ⁇ tensively, partly to understand the biological correlations, and partly to develop "biological tools" enabling influencing or stimulating the processes of healing.
  • a trauma elicits release of bone-derived growth factors fro the bone matrix as well as other local growth factors fro the surrounding tissue and the blood.
  • These factors of whic a number is known, some of which may be synthesized using ge- netically modyfied organisms, elicits 1) an increased metabo ⁇ lism in the area, 2) changes of the secretion of superior hormones, and 3) a specific reaction leading to differentia ⁇ tion of primitive cells to form bone cells and proliferation of these. This specific reaction depends on the interaction between several polypeptide growth factors being dependant on hormones.
  • Such substances could be administered locally to the broken bone or bone-prosthesis interface during an operation, op ⁇ tionally supplemented with later local injections.
  • WO89/0369 discloses a bone cement comprising a cell growth stimulant
  • the hGH may be introduced to the bone cement interface through a supplementary drainage tube whic could be inserted to the cement.
  • the purpose of the admini stration of hGH according to WO89/03695 is to stimulate th proliferation of bone cells into the cement phase in order t have an increased strength and there is no indication of car rying out the present invention, nor of obtaining the bene fits thereof.
  • the present invention relates to a method for local admini stration of a biologically active substance enhancing th healing of bone fractures or of a bone and a prosthesis to b united wherein the biologically active substance is admini stered directly to the bone surfaces to be healed or the in terface between a bone and a prosthesis which are to be uni ⁇ ted.
  • the biologically active compound is administered incorporated in a coating of a porous metal + hydroxyapatite on the surface of a prosthe ⁇ sis to be united with a bone.
  • the biologically active compounds may be administered by local injections which, however, may be somewhat troublesome to both the patient and the physici ⁇ an.
  • the biologically active substance is administered by conti ⁇ nuous or pulsatile infusion to the bone surfaces or the in ⁇ terface between a bone and a prosthesis to be healed.
  • Continous or pulsatile infusion of the biologically active substance may, according to the invention be carried out as a real continous infusion using a continous pump to administer the substance to the surfaces to be healed, e.g. using an electrically controlled pump or an osmotic pump delivering a measured dosis of the substance over a sufficient span of time, preferably up to 3 weeks, more preferred up to from 1 1/2 to 2 1/2 weeks, or by several administrations given through a device forming part of the invention using a syrin ⁇ ge or a pump capable of delivering an intermittent or pulsa ⁇ tile flow of the acitve substances.
  • the method of the invention may in certain cases be carried out as a systemic administration if it is judged to be appropriate by the physician considering the individual and state to be treated even though local administration is preferred.
  • the invention relates to a device for local ad- ministration of a biologically active substance enhancing the healing of bone fractures or of a bone and a prosthesis to be united, said device being in the form of a device stretching across or along the surfaces of bone or bone and prosthesi to be united and said device having apertures, communicatin with an the internal hollow space, at or near the surfaces t be united.
  • the device of the invention may, according to a further asp ect of the invention, be in the form of a hollow bone nail fixation plate, screw or prosthesis having apertures leadin to the surfaces to be united.
  • the device is in the form of a hollow bone nail or fixatio plate having apertures at the surface thereof at the level o the fractured bone to be healed.
  • the devic is in the form of an artificial joint having a securing mem ber having apertures at the surface thereof, said securin member being hollow or having internal canals communicatin with the apertures.
  • a further aspect of the invention is constituted by an agent for use for local administration for enhancing the healing of bone fractures or a bone and a prosthesis to be healed, said agent comprising human growth hormone, thyroid hormone, anti ⁇ biotic(s) and/or a local growth factor.
  • the substances to be used in the method of the invention may e.g. be human growth hormone (hGH) , thyroid hormone and/or bone derived growth factors such as bone derived growth fac ⁇ tor (BDGF) or human skeletal growth factor (hSGF) , local re ⁇ gulators of bone metabolism, growth regulator hormones, bone proteins such as bone morphogenic protein (BMP) , calcium- regulating hormones such as parathyroid hormone, Prostaglan- din E 2 , or growth stimulating factors such as insulin-like growth factor I (IGF-1) and insulin like growth factor II (IGF-II) , colony stimulating factor (CSF) , basic fibroblast growth factor (bFGF) , platelet derived growth factor (PDGF) , Factor XIII, transforming growth factor ⁇ (TGF- ⁇ ) , heparin binding growth factor, antibiotic(s) and/or epidermal growth factor (EGF) .
  • hGH human growth hormone
  • BDGF bone derived growth fac ⁇ tor
  • antibiotics are of importance when exchang ⁇ ing alloplasts often being performed due to infections about an existing prosthesis. Infections are also often one of the factors eliciting pseudoarthroses.
  • the specific antibiotic(s) and the dosis regimen is determined by the physician in consideration of the individu ⁇ al and the specific infection to be treated and the severity thereof.
  • the bone fractures for which the present invention invention is especially advantageous are complicated fractures which need a rapid development of strength, fractures with delayed union or non-union as well as fractures in elderly people.
  • Fig.l shows cross sectional view of an embodiment of a bone nail according to the invention
  • Fig.2 shows a general outline of a bone nail according to the invention located in the tibia of a rat.
  • Fig.3 shows a detail of a bone nail according to the inven- tion
  • Fig.4 shows a general outline of an embodiment of a hip joint prosthesis according to the invention.
  • Fig.5 shows a photo of a rat tibia comprising a nail,
  • Fig.6 shows a general outline of a fixation plate according to the invention.
  • Fig.7 shows an X-ray picture of a rat having nail according to the invention in tibia and an osmotic pump
  • the bone nail shown in Fig.l comprises a hollow member 1 be ⁇ ing closed in one end 2.
  • the apertures 4 are preferably located evenly spaced at the circumference of the nail and preferably in a level corresponding to the fracture zone of the bone in which the nail has been inserted in order to secure the ends of the broken bone.
  • a nail according to the invention may e.g. have 3 apertures located at the circumference.
  • Fig.2 the bone nail 1 is inserted in a tibia 6 of a rat.
  • the tibia has a standard fracture 7 and the nail 5 is placed in such a manner that the apertures 3 are located at level with the fracture.
  • Fig.3 in which a photo shows a detail of a hole in a nail according to the invention.
  • This embodiment has been made from a cannula being closed in the distant end and which has been provided with holes using spark erosion using tungsten wire in kerosene.
  • the holes may also be made using laserdrilling as described in published International Patent Application No. WO89/0420.
  • the hip joint prosthesis comprises a head 8 and a securing member 9 to be secured to the femur.
  • the se ⁇ curing member 9 has one or more canals 10 leading to aper ⁇ tures 3 at the surface of the securing member.
  • the acetabular component 11 may also have one or more canal(s) 10 leading to apertures 3 at the surface to be united with the bone.
  • the biologically active substances may be administered through the canals 10 to provide the local effect by diffusing throu ⁇ gh the apertures 3.
  • Fig.6 shows a fixation plate 12 according to the invention secured to a bone 13 having a fracture 14 using screws 15.
  • the fixation plate 12 comprises canals 10 leading to aper ⁇ tures 3 at the surface of the fixation plate near the frac ⁇ ture to be healed.
  • the fixation plate also comprises an adap ⁇ ter 16 communicating with the canals 10 for connecting a sy- ringe or pump for administrring the biologically active sub ⁇ stance(s) .
  • a photo shows an X-ray picture of a rat having a nail according to the invention placed in the broken tibia and an osmotic pump implanted un- der the skin at the back.
  • the connecting polyethylene tubing is not visible on X-ray pictures.
  • the control groups were injected with saline. After 40 days of fracture healing, the rats were killed and the fractured and the correspondin non-fractured bones were tested in a materials testing machi ⁇ ne using a destructive three-point bending procedure. The results appear from the below Table I.
  • growth hormone stimulates the mechanical strength development in healing diaphyseal fractures in the rat, when a total dose of 2 g/kg BW/day is given in 2 daily injections.
  • An increased strength observed in the non-frac- tured bones seems to be a quantitative phenomenon.
  • the rats were randomized into 6 groups: no injections, 0.9% NaCl (volume corresponding to b-hGH-treated groups), 0.08, 0.4, 2.0 and 10 mg b-hGH/kg/day given in 2 daily doses, starting one week prior to fracture and continuing until testing.
  • Bio ⁇ mechanical testing was carried out in a materials testing machine by a three-point bending procedure. Load and deform tion was recorded continously, and maximum load, stiffne and energy absorption were calculated. The results appe from the below Table II.
  • the effect of growth hormone administration during differen phases of fracture repair was investigated in a rat model
  • the biomechanical properties of healing tibial fractures was investigateed after 40 days of healing.
  • Biosynthetic human growth hormone (b-hGH) 2.7 mg/kg body weight/day was given in two daily injections to three groups of rats: (1) for the entire healing period, (2) for the first 20 days and (3) for the last 20 days of healing.
  • Three corresponding groups of control rats were injected with saline.
  • maximum load and stiffness of the healing fractures increased to 165% and 175%, respectively, compared to the control group.
  • the bone nail was made from a stainless steel tube (a hypo ⁇ dermic needle) being closed at the tip by welding. At a di- stance of 9 mm from the free end of the needle, 3 circular holes spaced 120* and having a diameter of 70 ⁇ were made by spark erosion using a tungsten wire in kerosene. Standardized fractures were made in the tibia of 4-month-old rats and the bone nails were inserted into the marrow cavity of the frac- tured tibiae and used for fixation of the fractures as shown i Fig.7. X-rays were taken to make sure that the apertures were localized at the level of the fractures. A miniosmotic pump manufactured by Alza Corp., California, U.S.A.
  • the miniosmotic pumps contained 2 ml of saline and was capable of delivering a continous flow of 55 ⁇ l per day.
  • the systems were tested for a period of 2 weeks. Af er removal of bone nails, tubing and pumps, the systems were examined under microscope: It was found that apertures were still open in all the bone nails and that the pumps were still capable of delivering the saline solution through the apertures.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte à un procédé d'administration locale de substance(s) biologiquement active(s) servant à favoriser la guérison de fractures osseuses ou la jointure d'un os et d'une prothèse directement aux surfaces osseuses à réparer ou de l'interface entre un os et une prothèse, ainsi qu'à un dispositif et à un agent utilisables dans un tel procédé. Est en outre décrite l'utilisation d'une hormone de croissance humaine, de l'hormone thyroïdienne, d'antibiotique(s) et/ou de facteurs de croissance locale pour la préparation d'une composition pharmaceutique destinée à favoriser la réparation de fractures osseuses ou la jointure d'un os et d'une prothèse.
PCT/DK1991/000022 1990-02-02 1991-01-25 Procede et dispositif d'administration locale de substances biologiquement actives WO1991011148A1 (fr)

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DK027390A DK27390D0 (da) 1990-02-02 1990-02-02 Fremgangsmaade og apparat til administration af biologisk aktive stoffer
DK273/90 1990-02-02

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656767A1 (fr) * 1993-06-30 1995-06-14 Allan Reuben Dunn Procede pour regenerer le cartilage d'une articulation
WO1997017032A1 (fr) * 1995-11-09 1997-05-15 Genesis Orthopedics Appareil et procede permettant d'administrer une substance biologiquement active a un os
WO1998051354A2 (fr) * 1997-05-15 1998-11-19 Stryker Corporation Compositions pour osteogenese induite par des agents morphogenetiques
WO2001008717A1 (fr) * 1999-08-03 2001-02-08 Smith & Nephew, Inc. Dispositifs implantables a liberation regulee
EP1168988A1 (fr) * 1999-02-19 2002-01-09 James B. Grimes Proth se osseuse et son proc d d'implantation
US6648916B1 (en) 1997-12-10 2003-11-18 Sdgi Holdings, Inc. Osteogenic fusion device
US6761738B1 (en) 2000-09-19 2004-07-13 Sdgi Holdings, Inc. Reinforced molded implant formed of cortical bone
US6780192B2 (en) 2000-10-24 2004-08-24 Sdgi Holdings, Inc. Osteogenic packing device and method
WO2005007212A2 (fr) * 2003-07-10 2005-01-27 Friedrich-Baur-Gmbh Systeme de liberation de substance active a ajustage individuel
US6998134B2 (en) 1998-09-11 2006-02-14 Gerhard Schmidmaier Biologically active implants
US7285135B2 (en) 1997-12-10 2007-10-23 Warsaw Orthopedic, Inc. Osteogenic fusion device
EP1881793A1 (fr) * 2005-05-19 2008-01-30 Unigene Laboratories, Inc. Procede permettant de stimuler la formation osseuse et sa preservation
WO2009147395A2 (fr) * 2008-06-05 2009-12-10 Corin Limited Cotyle prothétique
US7723291B2 (en) 2006-07-27 2010-05-25 Warsaw Orthopedic, Inc. Release of BMP, bioactive agents and/or cells via a pump into a carrier matrix
US7763270B2 (en) 2002-09-10 2010-07-27 Scil Technology Gmbh Metal implant coated under reduced oxygen concentration with osteoinductive protein
US8546334B2 (en) 2001-11-19 2013-10-01 Scil Technology Gmbh Device having osteoinductive and osteoconductive properties

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526909A (en) * 1984-01-09 1985-07-02 Regents Of The University Of California Polymethylmethacrylate delivery system for bone morphogenetic protein
EP0149540A2 (fr) * 1984-01-13 1985-07-24 Ed. Geistlich Söhne Ag Für Chemische Industrie Plaque d'ostéosynthèse
EP0198213A2 (fr) * 1985-03-15 1986-10-22 Yeda Research And Development Company, Ltd. Procédé et compositions contenant un dérivé de la vitamine D pour le traitement local de fractures osseuses
WO1987001595A1 (fr) * 1985-09-19 1987-03-26 Bloemer Alois Agent contenant des antibiotiques et son utilisation comme matiere plastique chirurgicale
EP0289314A2 (fr) * 1987-04-28 1988-11-02 Roche Diagnostics GmbH Emploi de IGF-II pour le traitement de désordres des os
WO1989003695A1 (fr) * 1987-10-23 1989-05-05 Novo-Nordisk A/S Ciment osseux
EP0360139A2 (fr) * 1988-09-17 1990-03-28 Boehringer Ingelheim Kg Dispositif d'ostéosynthèse et son procédé de fabrication
EP0366029A2 (fr) * 1988-10-25 1990-05-02 Takao Yamamuro Matériau pour la réparation des os et ciment osseux
WO1990011726A1 (fr) * 1989-03-31 1990-10-18 Vsesojuzny Nauchno-Issledovatelsky I Ispytatelny Institut Meditsinskoi Tekhniki Dispositif de restructuration d'un element manquant dans un os tubulaire

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526909A (en) * 1984-01-09 1985-07-02 Regents Of The University Of California Polymethylmethacrylate delivery system for bone morphogenetic protein
EP0149540A2 (fr) * 1984-01-13 1985-07-24 Ed. Geistlich Söhne Ag Für Chemische Industrie Plaque d'ostéosynthèse
EP0198213A2 (fr) * 1985-03-15 1986-10-22 Yeda Research And Development Company, Ltd. Procédé et compositions contenant un dérivé de la vitamine D pour le traitement local de fractures osseuses
WO1987001595A1 (fr) * 1985-09-19 1987-03-26 Bloemer Alois Agent contenant des antibiotiques et son utilisation comme matiere plastique chirurgicale
EP0289314A2 (fr) * 1987-04-28 1988-11-02 Roche Diagnostics GmbH Emploi de IGF-II pour le traitement de désordres des os
WO1989003695A1 (fr) * 1987-10-23 1989-05-05 Novo-Nordisk A/S Ciment osseux
EP0360139A2 (fr) * 1988-09-17 1990-03-28 Boehringer Ingelheim Kg Dispositif d'ostéosynthèse et son procédé de fabrication
EP0366029A2 (fr) * 1988-10-25 1990-05-02 Takao Yamamuro Matériau pour la réparation des os et ciment osseux
WO1990011726A1 (fr) * 1989-03-31 1990-10-18 Vsesojuzny Nauchno-Issledovatelsky I Ispytatelny Institut Meditsinskoi Tekhniki Dispositif de restructuration d'un element manquant dans un os tubulaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DERWENT'S ABSTRACT, No. 86-161 401/25; & SU,A,1 192 796, publ. week 8625, (KHELIMSKII A M). *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656767A4 (fr) * 1993-06-30 1997-11-12 Allan Reuben Dunn Procede pour regenerer le cartilage d'une articulation.
EP0656767A1 (fr) * 1993-06-30 1995-06-14 Allan Reuben Dunn Procede pour regenerer le cartilage d'une articulation
WO1997017032A1 (fr) * 1995-11-09 1997-05-15 Genesis Orthopedics Appareil et procede permettant d'administrer une substance biologiquement active a un os
US5871484A (en) * 1995-11-09 1999-02-16 General Orthopedics Apparatus and method for administering a biologically active substance to a bone
US6740120B1 (en) 1996-08-13 2004-05-25 James B. Grimes Bone prosthesis and method of Access
WO1998051354A2 (fr) * 1997-05-15 1998-11-19 Stryker Corporation Compositions pour osteogenese induite par des agents morphogenetiques
WO1998051354A3 (fr) * 1997-05-15 1999-03-11 Creative Biomolecules Inc Compositions pour osteogenese induite par des agents morphogenetiques
US7763079B2 (en) 1997-12-10 2010-07-27 Warsaw Orthopedic, Inc. Osteogenic fusion device
US8685102B2 (en) 1997-12-10 2014-04-01 Warsaw Orthopedic, Inc. Osteogenic fusion device
US6648916B1 (en) 1997-12-10 2003-11-18 Sdgi Holdings, Inc. Osteogenic fusion device
US8177848B2 (en) 1997-12-10 2012-05-15 Warsaw Orthopedic, Inc. Osteogenic fusion device
US7179293B2 (en) 1997-12-10 2007-02-20 Warsaw Orthopedic, Inc. Osteogenic fusion device
US7285135B2 (en) 1997-12-10 2007-10-23 Warsaw Orthopedic, Inc. Osteogenic fusion device
US10646622B2 (en) 1998-09-11 2020-05-12 Gerhard Schmidmaier Biologically active implants
US6998134B2 (en) 1998-09-11 2006-02-14 Gerhard Schmidmaier Biologically active implants
EP1168988A1 (fr) * 1999-02-19 2002-01-09 James B. Grimes Proth se osseuse et son proc d d'implantation
EP1168988A4 (fr) * 1999-02-19 2002-09-04 James B Grimes Proth se osseuse et son proc d d'implantation
WO2001008717A1 (fr) * 1999-08-03 2001-02-08 Smith & Nephew, Inc. Dispositifs implantables a liberation regulee
US7618460B2 (en) 2000-09-19 2009-11-17 Warsaw Orthopedic, Inc. Reinforced molded implant formed of cortical bone
US6761738B1 (en) 2000-09-19 2004-07-13 Sdgi Holdings, Inc. Reinforced molded implant formed of cortical bone
US7550011B2 (en) 2000-10-24 2009-06-23 Warsaw Orthopedic, Inc. Osteogenic packing device and method
US8177845B2 (en) 2000-10-24 2012-05-15 Warsaw Orthopedic, Inc. Osteogenic packing device and method
US6780192B2 (en) 2000-10-24 2004-08-24 Sdgi Holdings, Inc. Osteogenic packing device and method
US8546334B2 (en) 2001-11-19 2013-10-01 Scil Technology Gmbh Device having osteoinductive and osteoconductive properties
US8257728B2 (en) 2002-09-10 2012-09-04 Scil Technology Gmbh Metal implant coated under reduced oxygen concentration with osteoinductive protein
US7763270B2 (en) 2002-09-10 2010-07-27 Scil Technology Gmbh Metal implant coated under reduced oxygen concentration with osteoinductive protein
WO2005007212A3 (fr) * 2003-07-10 2005-03-31 Friedrich Baur Gmbh Systeme de liberation de substance active a ajustage individuel
WO2005007212A2 (fr) * 2003-07-10 2005-01-27 Friedrich-Baur-Gmbh Systeme de liberation de substance active a ajustage individuel
EP1881793A4 (fr) * 2005-05-19 2011-03-09 Unigene Lab Inc Procede permettant de stimuler la formation osseuse et sa preservation
EP1881793A1 (fr) * 2005-05-19 2008-01-30 Unigene Laboratories, Inc. Procede permettant de stimuler la formation osseuse et sa preservation
US7723291B2 (en) 2006-07-27 2010-05-25 Warsaw Orthopedic, Inc. Release of BMP, bioactive agents and/or cells via a pump into a carrier matrix
WO2009147395A3 (fr) * 2008-06-05 2010-01-28 Corin Limited Cotyle prothétique
WO2009147395A2 (fr) * 2008-06-05 2009-12-10 Corin Limited Cotyle prothétique

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AU7324391A (en) 1991-08-21
DK27390D0 (da) 1990-02-02
ZA91759B (en) 1992-07-29

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