WO1991011148A1 - A method and device for local administration of biologically active substances - Google Patents
A method and device for local administration of biologically active substances Download PDFInfo
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- 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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- Prior art keywords
- bone
- prosthesis
- united
- healing
- apertures
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/30—Inorganic materials
- A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61F2/367—Proximal or metaphyseal parts of shafts
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- 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
- 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
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
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- 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
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- 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
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- 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
- A61L2300/43—Hormones, e.g. dexamethasone
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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
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- 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.
Abstract
The invention relates to a method for local administration of biologically active substance(s) enhancing the healing of bone fractures or of a bone and a prosthesis to be united directly to the bone surfaces to be healed or the interface between a bone and a prosthesis which are to be united, and a device and an agent for use in such a method. Furthermore, the use of human growth hormone, thyroid hormone, antibiotic(s) and/or local growth factors for the preparation of a pharmaceutical preparation for enhancing the healing of bone fractures or of a bone and a prosthesis to be united is described.
Description
TITLE
A Method and Device for Local Administration of Biologically Active Substances.
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.
BACKGROUND OP THE INVENTION
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.
Materials of prostheses and materials and principles of oste- osynthesis have been undergoing a drastic development aiming at adapting the mechanical properties of the materials to the demands of the human bone, offering suitable patterns of load and increasing the biocompatibility (e.g. by reducing the liberation of ions from the materials) .
Even though the development of design of prostheses and m terials of osteosynthesis will proceed it is clear that "bi ological tools" will be absolutely necessary in the futu bone surgery as the biological processes are hampered by number of conditions as well as in elderly people. In thes cases even the most advanced design of materials will not b sufficient. When inserting prostheses having high loading especially hip joints, knee joints, or ankle joints is i crucial to have a very quick inset of healing and a rapi development of strength as it is essential for the patient to avoid confinement to bed as early as possible in order t avoid thrombosis. At the same time is essential to avoid mo vements of the parts to be united in the first period afte the operation in order to avoid the formation of fibrous tis sue around the prosthesis reducing the binding strength an thus increasing the risk that the prosthesis will work loose Such working loose now often implies that the prosthesis ha become loose after 5 to 15 years.
There is a wish to avoid using bone cement when implantin prostheses such as hip joints as all the old bone cement mus be removed from the internal of the bone in case a prosthesi is to be replaced due to working loose. Thus it is tried t adapt the bone parts to have a press fit with the prosthesi in order to avoid the use of bone cement, and it has bee proposed to provide the prosthesis with a coating of porou metal, titanium fiber mesh and/or hydroxyapatite in order t have a better bony ingrowth for fixation of the prosthesis.
The sequence of biological responses in bone healing in it broad sense may be outlined as follows:
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.
If it is desired to use such growth factors to stimulate the healing of bone fractures or healing of a bone and a prosthe- sis to be united with the bone, one could utilize systemic administration thereof. However, this route of administration is not desirable due to the high doses which must be used, both from an economical point of view and due to the consi¬ derable rise og undesired side effects due to systemic ad i- nistration of biologically very potent substances in high doses.
Such substances could be administered locally to the broken bone or bone-prosthesis interface during an operation, op¬ tionally supplemented with later local injections. However, this implies that the substance applied should have a very high potency or may and be able to be kept in place for a sufficient time to carry out its function, and local injec¬ tions are imprecise and increase the risk of infections.
It would also be possible to coat the prosthesis/osteosynth- esis material with a vehicle which slowly releases the active substance or to add the active substance to bone cement. This approach is not convenient as the vehicle must not be toxic to the tissue, must not take up any substantial room which would leave a dead space on the surface and thus interfere with the healing. The slow release of the active substance(s) from a coating or a bone cement renders it very difficult to control the rate of release. Furthermore, the (passive) rele¬ ase of the active substance(s) or growth factor(s) from a vehicle or a bone cement would not make possible the admini-
stration of combinations of active substanc (s) and/or growt factor(s) in a specific sequence.
Published International Patent Application No. WO89/0369 discloses a bone cement comprising a cell growth stimulant In the specification it is mentioned that instead of mixin hGH with the cement, 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.
BRIEF DESCRIPTION OF THE INVENTION
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.
It has now been shown, that administration of hGH during the healing of fractured bones or bone defects will speed up the healing giving a more rapid development of a firm cohesion between the surfaces to be united within the first weeks which is crucial to the healing.
It has also surprisingly been found that bone fractures in elderly individuals heal very rapidly when using the method of the invention.
According to one aspect of the invention 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.
According to the invention, the biologically active compounds may be administered by local injections which, however, may be somewhat troublesome to both the patient and the physici¬ an.
According to a a preferred second aspect of the invention, 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.
However, 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.
Furthermore, 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.
In accordance with a still further aspect of the inventio 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.
According to yet another aspect of the invention 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 E2, 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 β (TGF-β) , heparin binding growth factor, antibiotic(s) and/or epidermal growth factor (EGF) .
Administration of antibiotics is 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. When administering antibi¬ otics, 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.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described more in detail below with referen¬ ce to the drawings in which
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, and
Fig.7 shows an X-ray picture of a rat having nail according to the invention in tibia and an osmotic pump
DETAILED DESCRIPTION OF THE INVENTION
The bone nail shown in Fig.l comprises a hollow member 1 be¬ ing closed in one end 2. In the wall of the member 1 there are holes or apertures 3 communicating with the inner space 4 of the nail. 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. During the healing the biologically active substance(s) is (are) administered through the nail being introduced through the open end 5 of the nail, e.g. using a syringe or a pump, whereafter the sub¬ stance diffuses through the apertures 4 and exercises its healing effect directly at the broken surfaces to be healed.
In 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.
Reference is made to 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.
An embodiment of a hip joint according to the invention is shown in Fig.4. 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) .
Reference is made to fig.7 in which 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 invention will be further described in the below Examples which are only to be considered as explaining the invention and not as limiting the invention, the scope of which is set forth in the appended claims.
EXAMPLE 1
INCREASE OF THE STRENGTH OF INTACT BONES AND HEALING TIBIA FRACTURES IN RAT (DUE TO ADMINISTRATION OF GROWTH HORMONE) . The aim of the study was to investigate the influence of exo genous growth hormone administration on the biomechanica properties of healing diaphyseal fractures in the rat. In 90 day-old female Wistar rats a standardized tibial fracture wa produced in the right tibia and non-rigid fixation was esta blished using a K-wire as intramedullary nail. Two g of bio synthetic human growth hormone (b-hGH) per kg body weight pe day was given in 2 daily injections starting one week befor fracture and continuing until testing. 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.
Table 1
Differences noted between growth hormone injected and con- trols after 40 days treating:
Group Max.load Stiffness Max.stress (N) (N/mm) (N/mm2)
Control 21.9 ± 5.7 86 ± 39 15.3 ± 7.8 (n=8)
+ b-hGH 98.3 ± 8.3 365 ± 36 41.3 ± 8.6 (n=8)
Mean (S.E.M.); 2p < 0.05; 2p < 0.01.
In the growth hormone injected animals, maximun load and stiffness of the intact bones had increased 40 days post fracture compared to the saline injected controls, but there was no difference in terms of stress values, modulus of ela- sticity or normalized energy absorption.
In conclusion, 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.
EXAMPLE 2
THE INFLUENCE OF THE DOSIS OF GROWTH HORMONE ON FRACTURE HEALING IN THE RAT
Growth hormone stimulates the proliferation of chondrocytes in vivo and in vitro. Growth hormone also stimulates weight gain and longitudinal bone growth depending on the dose and freqency of administration. Experimental fractures of long bones heal through a stage of cartilaginous callus if the mechanical conditions are not absolutely stable. The aim of the study was to investigate the effect of different doses of biosynthetic human growth hormone (b-hGH) on the mechanical strength development in healing experimental fractures. In 90-day-old female Wistar rats, a closed fracture was pro¬ duced by three-point bending 2 mm above the tibio-fibular junction in the right tibia. Closed medullary nailing was performed, and the bones were left to heal for 40 days. 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.
5 Table II
Increased maximum load and stiffness of fractures treat with b-hGH in doses of 2 mg/kg/day and 10 mg/kg/day after days healing as compared with controls:
10 Treatment n Maximun load Stiffness (N) (N/mm)
1) no injections 13 37.2 ± 6.5 171.0 ± 31.0
2) 0.9%NaCl 14 30.2 ± 4.9 138.0 ± 24.2 153) b-hGH 0.08 mg/kg/day 10 35.6 ± 8.2 166.0 ± 39.3
4) b-hGH 0.4 mg/kg/day 15 34.9 ± 5.8 179.7 ± 30.5
5) b-hGH 2.0 mg/kg/day 10 55.3 ± 10.2* 219.9 ± 31.8*
6) b-hGH 10 mg/kg/day 13 69.3 ± 8.4** 323. 0 ± 30. 0**
20 Mean values ± SEM; 2p < 0.05; 2p < 0.01
Conclusion: Biosynthetic human growth hormone administere twice a day accelerates the mechanical strength developmen in healing rat tibial fractures when given subcutaneously i doses of 2 mg/kg/day and 10 mg/kg/day.
5 EXAMPLE 3
THE EFFECT OF GROWTH HORMONE ON DIFFERENT PHASES OF FRACTUR REPAIR IN THE RAT.
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. In group (1) , maximum load and stiffness of the healing fractures increased to 165% and 175%, respectively, compared to the control group. In group (2), maximum load, stiffness, maximum stress, and ener¬ gy absorption at ultimate load increased to 222%, 175%, 171%, and 247%, respectively, compared to the control group. In group (3) , no statistically detectable effects were found. The results indicate: 1) that the stimulating effect of b- hGH on fracture healing is most pronounced during the first part of the healing period, 2) that no further effect will be obtained if the b-hGH administration is extended for the en¬ tire healing period, and 3) that pretreatment is not a prere¬ quisite for obtaining a stimulating effect of b-hGH on frac- ture healing.
EXAMPLE 4
THE INFLUENCE OF GROWTH HORMONE ON FRACTURE HEALING IN AGED RATS.
It has been found that diaphyseal fractures in aged rats hea- led much slower than fractures in young adult rats. The pre¬ sent investigation was carried out in order to elucidate whether growth hormone influences the healing of tibial frac¬ tures in old rats, as it has been found that bone morphogene- tic protein (BMP) is growth hormone dependent. Two-year-old male Wistar rats were used for the experiment. A standardized tibial fracture was produced 2-4 mm above the tibiofibular junction and the fracture was stabilized with an intramedullary K-wire. The animals were randomized for growth
hormone administration (2.7 mg b-hGH/kg/day in two daily i jections) or saline injections. Groups of animals were term nated and tested after 40 or 80 days of fracture healing. T results appear from the below Table III.
Table III
Effect of growth hormone (b-hGH, 2.7 mg/kg BW/day in tw daily doses) on the mechanical properties of healing tibia fractures in 2-year-old rats:
Experimental Ultimate load Stiffness Ultimate stres group (N) (N/mm) . N/mm2)
40 days healing 16.3 ± 2.1 68.7 ± 25.3 10.20 ± 2.73 control (n=12) 40 days healing 21.0 ± 3.1 96.2 ± 26.6 11.33 ± 1.85 b-hGH (n=13)
80 days healing *48.01 ± 11.0 237 ± 60 36.5 ± 6.8 control (n=12)
80 days healing 85.4 ± 8.5* 387 ± 33 57.7 ± 6.8 b-hGH (n=ll)
Mean values ± SEM; 2__ < 0.05; 2j> < 0.01
Conclusion: The administration of growth hormone stimulate the mechanical strength development in healing tibial frac tures in the aged rat.
EXAMPLE 5
LOCAL ADMINISTRATION OF A LIQUID SUBSTANCE TO A FRACTURE BONE BY MEANS OF AN IMPLANTED MINIOSMOTIC PUMP AND A HOLLO
INTRAMEDULLARY BONE NAIL HAVING APERTURES AT THE LEVEL OF THE FRACTURE.
The feasibility of local administration of a liquid substance for a sufficient period of time to a fractured bone through a hollow bone nail having apertures communicating with the in¬ ternal canal at the level of the facture has been investiga¬ ted in an experimental model.
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 μ 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. (Alzetβ 2ML4) was implanted under the skin at the back of the rats and connected to the bone nail by means of medical grade po¬ lyethylene tubing. The miniosmotic pumps contained 2 ml of saline and was capable of delivering a continous flow of 55 μl 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.
Claims
1. A method for local administration of biologically acti substance(s) enhancing the healing of bone fractures or of bone and a prosthesis to be united wherein the biologicall active substance(s) is(are) administered directly to the bo surfaces to be healed or the interface between a bone and prosthesis which are to be united.
2. A method as claimed in claim 1, wherein the biologicall active substance(s) is(are) administered incorporated in coating of a porous metal and hydroxyapatit on the surface o a prosthesis to be united with a bone.
3. A method as,claimed in claim 1, wherein the biologicall active substance(s) is(are) administered by continuous o pulsatile infusion to the bone surfaces or the interface bet ween a bone and a prosthesis to be healed.
4. A device for local administration of a biologically ac tive substance enhancing the healing of bone fractures or o a bone and a prosthesis to be united, said device being i the form of a device stretching across or along the surface of bone or bone and prosthesis to be united and said devic having apertures, communicating with an internal hollow spa ce, at or near the surfaces to be united.
5. A device as claimed in claim 4 being in the form of hollow bone nail, fixation plate, screw, or prosthesis havin apertures leading to the surfaces to be united.
6. A device as claimed in claim 5 being in the form of hollow bone nail having" apertures at the surface thereof a the level of the fractured bone to be healed.
7. A device as claimed in claim 5 being in the form of an artificial joint having a securing member having apertures at the surface thereof, said securing member being hollow or having internal canals communicating with the apertures.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DK027390A DK27390D0 (en) | 1990-02-02 | 1990-02-02 | METHOD AND APPARATUS FOR ADMINISTRATING BIOLOGICALLY ACTIVE SUBSTANCES |
DK273/90 | 1990-02-02 |
Publications (1)
Publication Number | Publication Date |
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WO1991011148A1 true WO1991011148A1 (en) | 1991-08-08 |
Family
ID=8091689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/DK1991/000022 WO1991011148A1 (en) | 1990-02-02 | 1991-01-25 | A method and device for local administration of biologically active substances |
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AU (1) | AU7324391A (en) |
DK (1) | DK27390D0 (en) |
WO (1) | WO1991011148A1 (en) |
ZA (1) | ZA91759B (en) |
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WO1998051354A2 (en) * | 1997-05-15 | 1998-11-19 | Stryker Corporation | Compositions for morphogen-induced osteogenesis |
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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 |
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-
1990
- 1990-02-02 DK DK027390A patent/DK27390D0/en not_active Application Discontinuation
-
1991
- 1991-01-25 WO PCT/DK1991/000022 patent/WO1991011148A1/en unknown
- 1991-01-25 AU AU73243/91A patent/AU7324391A/en not_active Abandoned
- 1991-02-01 ZA ZA91759A patent/ZA91759B/en unknown
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Also Published As
Publication number | Publication date |
---|---|
DK27390D0 (en) | 1990-02-02 |
AU7324391A (en) | 1991-08-21 |
ZA91759B (en) | 1992-07-29 |
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