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WO1999033415A1 - Compositions a base d'osteopontine activant la reparation osseuse - Google Patents

Compositions a base d'osteopontine activant la reparation osseuse Download PDF

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Publication number
WO1999033415A1
WO1999033415A1 PCT/US1998/027808 US9827808W WO9933415A1 WO 1999033415 A1 WO1999033415 A1 WO 1999033415A1 US 9827808 W US9827808 W US 9827808W WO 9933415 A1 WO9933415 A1 WO 9933415A1
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WO
WIPO (PCT)
Prior art keywords
composition
bone
osteopontin
growth
polymer
Prior art date
Application number
PCT/US1998/027808
Other languages
English (en)
Inventor
Dale R. Peterson
Nancy Nousek-Goebl
Todd P. Glancy
Original Assignee
Depuy Orthopaedics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Depuy Orthopaedics, Inc. filed Critical Depuy Orthopaedics, Inc.
Priority to JP2000526176A priority Critical patent/JP2001527030A/ja
Priority to AU20214/99A priority patent/AU748002B2/en
Priority to EP98965015A priority patent/EP1043963A4/fr
Publication of WO1999033415A1 publication Critical patent/WO1999033415A1/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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30667—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
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • 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
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • This invention relates to implantable biocompatible compositions that induce the repair of damaged or diseased bone or cartilage or other connective tissues upon contact of the damaged or diseased tissues with the composition in vivo. More particularly the present invention is directed to the use of a composition comprising an effective amount of osteopontin to induce endogenous repair of damaged or diseased bone and cartilage tissues.
  • Extracellular bone matrix contains predominantly mineral (hydroxyapatite) and an organic matrix, where the major component of the organic matrix is collagen type I.
  • the remaining components of bone matrices include a number of less abundant non-collagenous proteins and growth factors. For example, since the mid-1960's the osteoinductive activity of both demineralized bone matrix (DBM) and bone morphogenetic protein (BMP) has been studied. See, for example, S.
  • DBM demineralized bone matrix
  • BMP bone morphogenetic protein
  • Osteopontin is an adhesive glycoprotein which binds calcium and collagen, and in particular binds very tightly to hydroxyapatite. Osteopontin is found in secreted bone matrix and has been proposed to play a role in bone repair and remodeling including the nucleation of the hydroxyapatite crystals during matrix mineralization, osteoblast attachment, and binding and activating of osteoblasts during bone remodeling.
  • the mature protein contains a cell-binding Arg-Gly-Asp (RGD) sequence.
  • osteopontin This sequence has been termed the "cell-binding motif because it is via this sequence that adhesion molecules bind cells to the extra-cellular matrix. Accordingly it is anticipated that osteopontin will participate in the attachment of bone cells to the matrix. Osteopontin is structurally similar to bone sialoprotein and is enriched at the mineralization front of newly formed bone in the metaphysis. The protein can be isolated from warm blooded vertebrate bone and cartilage tissues using standard extraction techniques known to those skilled in the art. The expression of osteopontin is correlated with mineralization in bone and cartilage and its expression is stimulated by growth factors such as TGF ⁇ .
  • osteopontin also is enriched at bone surfaces facing osteoclasts and that osteopontin mRNA predominates in osteoblasts close to the metaphyseal/diaphyseal border where osteoblastic bone resorption is particularly pronounced. Osteopontin apparently also is produced by chondrocytes in calcified cartilage, by bone marrow cells, and by osteoblasts in fetal rat bone. Accordingly, it has been suggested that osteopontin has a role in biological mineralization.
  • a composition comprising osteopontin is used to enhance the ability of endogenous cells to repair bone and cartilage tissues in a warm-blooded vertebrate species.
  • the disclosed composition is administered to a warm-blooded species, either by implanting or injecting the composition, for in vivo contact with the site in need of repair.
  • the present invention is directed to compositions comprising osteopontin in a substantially pure form, and the use of such compositions to enhance the repair of bone and cartilage defects in vivo.
  • osteopontin is intended to include native osteopontin protein isolated from human or other warm- blooded vertebrates, naturally occurring isoforms of osteopontin, recombinant protein produced from osteopontin encoding nucleic acid sequences, and protein fragments/peptides of osteopontin proteins.
  • osteopontin gene is defined herein to include any nucleic acid sequence encoding for osteopontin, including the native gene sequences isolated from human or other warm-blooded vertebrates, any nucleic acid sequences encoding active fragments of bone sialoprotein protein, or any recombinant derivative thereof.
  • compositions of the present invention can be utilized in a method for inducing the repair of damaged or defective tissues of a warm-blooded vertebrate. More particularly, osteopontin can be used to repair the tissues of orthopedic and non- orthopedic wound sites, including bone, cartilage, tendon, ligament, muscle, skin and other soft tissues.
  • compositions of the present invention are used to effectively repair fractures and fill or bridge bone defects including for example, craniofacial defects or periodontal defects, joint fractures, chondral defects, superficial chondral defects, full thickness defects, osteochondritis dissecans, minuscule tears, ligament tears, tendon tears, muscle lesions, myotendinitis junction lesions, skeletal reconstruction following secondary bone loss to infection or neoplasm, and the treatment of various bone or cartilaginous diseases such as osteoporosis.
  • Osteopontin may enhance the repair of these tissues either directly or indirectly.
  • osteopontin may increase new bone formation at a localized site by directly stimulating osteoblast activity (i.e., by enhancing matrix production or by recruiting additional osteoblast cells), by increasing angiogenesis, or by inhibiting osteoclast resorption.
  • the compositions of the present invention may participate in the recruitment of bone progenitor cells or bioactive agents to the localized site either by selective binding of osteopontin to the progenitor cells or the bioactive agent, or osteopontin may participate in the recruitment of cells through chemotaxis.
  • osteopontin can be used in a wound repair context in combination with a carrier material such as a ceramic or polymer, including the use of proteins such as collagen as the carrier material.
  • a carrier material such as a ceramic or polymer
  • proteins such as collagen
  • osteopontin can be combined with autologous cells (such as bone or cartilage progenitor cells) or autologous proteins (such as fibrin).
  • compositions of the present invention comprise a delivery vehicle and a bioactive mixture comprising an effective amount of a substantially pure osteopontin.
  • the compositions of the present invention comprise a delivery vehicle and a bioactive mixture comprising an osteopontin gene.
  • Delivery vehicles suitable for use in delivering bioactive agents to bone and cartilage in vivo are well known to those skilled in the art.
  • the delivery vehicle comprises a polymer matrix, and the polymer matrix is formed from one or more biocompatible polymers.
  • biocompatible means that the polymer is non-toxic, non-mutagenic and elicits a minimal to moderate inflammatory reaction.
  • the biocompatible polymer is also biodegradable and completely degrades in a controlled manner into non-toxic residues.
  • the polymer matrix serves as a delivery vehicle for the bioactive mixture, concentrating the bioactive agent at a localized site of administration and controlling the release of the bioactive composition.
  • the controlled delivery and release of osteopontin to localized bone and cartilage sites is based on the use of biodegradable, biocompatible polymers in combination with bioactive molecules to achieve both efficacious release of molecules and removal of the polymer from the treatment site within a physiologically useful time period.
  • a variety of polymers can be used to form the implant for the purposes of delivering bioactive molecules to a predetermined in vivo site, including polyesters, polyvinyl acetate, polyacrylates, polyorthoesters, polyhydroxyethylmethacrylate (polyhema) and polyanhydrides.
  • polyesters polyvinyl acetate, polyacrylates, polyorthoesters, polyhydroxyethylmethacrylate (polyhema) and polyanhydrides.
  • One of the advantages of polyesters in such applications is that they are both biodegradable and biocompatible. Aliphatic polyesters have been widely used in the area of biomaterials for implantable drug delivery devices, sutures, and general tissues supports, after injury or surgery.
  • polyesters traditionally of greatest interest for localized delivery of biomaterials are derived from lactide, glycolide, and e-caprolactone monomers, with a fairly broad range of degradation profiles accessible through various termonomer combinations.
  • the ester linkages in these aliphatic polyesters are hydrolytically and/or enzymatically labile and render the polymers degradable in aqueous environments.
  • polymers such as polyester anhydrides or ionomers are used.
  • other polymers such as polylactic acid and polyorthoesters can also be used.
  • the polymer matrix comprises collagen fibers. Collagen has been reported to exhibit bioactive properties and enhances the repair of bone and cartilage tissues in vivo. Accordingly collagen fiber can function as both as a component of the delivery system as well as an active agent of the present bone and cartilage repair compositions.
  • Other polymer suitable for use in forming the polymer matrix comprise fibrins, starches, alginate and hyaluronic acid.
  • the composition of the polymer used to form the delivery vehicle matrix, as well as the molecular weight and physical properties of the polymer, can be varied according to the application.
  • hydrophobic polyanhydrides can be used where it is desirable to increase the time of degradation.
  • Compounds can be mixed into, or polymerized with the polymer as required for additional strength or other desirable physical properties, using materials known to those skilled in the art from studies involving bone cements.
  • tricalcium phosphate or other ceramic type materials that provide better physical handling can be added to the composition.
  • the polymer should release the material over a period of approximately 3 to 42 days (generally 6 weeks are required for sufficient repair to occur in humans before the bone is capable of bearing weight).
  • the polymer should also degrade completely over a period no longer than about sixteen to twenty weeks. Release and degradation times will depend in part upon the polymer used and the bioactive materials to be released.
  • the delivery vehicle comprises polyester ionomers (salts of carboxy-terminated polyesters).
  • the polyester ionomers exhibit good solubility even at higher molecular weights dictated by implant structural/functional requirements.
  • the polyesters are prepared from and degrade into naturally occurring metabolites for enhanced biocompatibility.
  • the polyester ionomers are prepared from the corresponding carboxy-terminated polyesters by neutralization or partial neutralization with biocompatible, pharmaceutically acceptable salt-forming bases.
  • the delivery vehicle comprises biodegradable carboxy-terminated polyesters in combination with the corresponding ionomers.
  • the physical properties of polyester ionomers can be controlled by the degree of neutralization of the corresponding carboxy-terminated polyesters and to some extent by selection of the neutralizing base.
  • the polyester ionomers can be used alone or in combination with their carboxy-terminated polyester precursor for use in construction of a biocompatible delivery vehicle for tissue repair and/or prolonged release of biologically active compounds.
  • polyester ionomers as delivery vehicles is described in U.S. Patent No. 5,668,288, the disclosure of which is incorporated herein by reference.
  • the polyester ionomers is a divalent residue of a polyester.
  • the polyester can comprise a homopolymer, copolymer, or terpolymer of biocompatible hydroxy acids, for example, lactic acid, gly colic acid, e -hydroxy caproic acid, and ⁇ -hydroxy valeric acid.
  • the polyester can be formed using copolymerization of a polyhydric alcohol and a biocompatible polycarboxylic acid. Most typically such copolymers are formed between dihydric alcohols, for example, propylene glycol for biocompatibility and biocompatible dicarboxylic acids.
  • the bioactive component of the present compositions comprises osteopontin, optionally combined with a pharmaceutically acceptable carrier, solubilizing agent, or filler material.
  • osteopontin should be administered at a concentration ranging from about 10 ng to about 1 mg/ml of the defect area.
  • osteopontin is administered in a concentration ranging from about 5 ug to about 100 ug/ml of the defect area.
  • tricalcium phosphate, hydroxyapatite, gypsum, or other suitable physiological mineral sources can be combined with the compositions to assist in repair of damaged or diseased bone.
  • a physiological compatible mineral comprises up to 80% of the bioactive mix of the present composition.
  • the physiological compatible mineral may comprises about 5% to about 50% of the bioactive mix, and more preferably comprises about 5% to 30% of the bioactive mix.
  • the present compositions can be combined with known pharmaceuticals and bioactive agents to create a delivery system for the local treatment of bone disorders or diseases.
  • the bioactive component of the present compositions can be further combined with growth factors, growth factor binding proteins or eukaryotic cells.
  • suitable growth factors comprise: fibroblast growth factor, transforming growth factor (e.g., TGF- ⁇ ,), bone morphogenetic protein, epidermal growth factor or platelet-derived growth factor.
  • growth factor binding proteins are insulin-like growth factor binding proteins (IGFBP's) such as IGFBP's 3 and 5.
  • suitable eukaryotic cells comprise bone marrow cells, osteoblasts and mesenchymal stem cells.
  • the bioactive composition of the present invention can further include an osteogenic agent that stimulates or accelerates generation of bone upon implantation into a bone defect site.
  • osteogenic agents comprise demineralized bone powder, morselized cancellous bone, aspirated bone marrow, bone or cartilage forming cells, and other bone sources.
  • the bioactive compositions of the present invention are utilized in one embodiment for stimulating the growth of bone and cartilage tissues at a predetermined localized site in a warm-blooded vertebrate.
  • the method comprises contacting the site in need of repair with a composition comprising substantially pure osteopontin.
  • the composition is surgically implanted at the site in need of repair and the composition comprises osteopontin and a polymer matrix, wherein the polymer matrix controls the release of osteopontin and concentrates osteopontin at the desired site.
  • the composition may be in an injectable form and the method of contacting the site in need of repair comprises injecting the composition into or adjacent to the site.
  • the injectable form of the present composition typically comprises osteopontin in combination with a pharmaceutically acceptable carrier.
  • the viscosity of the compositions can be adjusted by controlling the water content of the compositions or by the addition of pharmaceutically acceptable fillers or thickening agents known to those skilled in the art.
  • the injectable forms include collagen fibers and the viscosity of the composition is controlled by adjusting the pH of the composition to about 6.0 to about 7.5.
  • the compositions of the present invention can be combined with an effective amount antibiotics, chemotherapeutic agents, additional growth factors, antigens, antibodies, enzymes or hormones.
  • a composition comprising osteopontin and an antibiotic may be useful in the treatment of osteomyelitis, thereby reducing the need for and risk of parenteral antibiotics.
  • a composition comprising osteopontin and an antineoplastic agent could be used for the local treatment of bone neoplasm, or a composition comprising osteopontin and an osteogenic or other growth factor (e.g., osteogenin, bone morphogenetic protein, parathyroid hormone, or TGF ⁇ ) could be used to accelerate the repair of skeletal defects as occurs with excessive trauma and with skeletal deficiency disorders such as osteogenesis imperfecta and osteoporosis.
  • an osteogenic or other growth factor e.g., osteogenin, bone morphogenetic protein, parathyroid hormone, or TGF ⁇
  • compositions can be prepared in fluid forms for injection into a warm-blooded vertebrate.
  • the injectable forms are used to systemically treat a warm-blooded vertebrate and provide therapeutic value for conditions such as osteoporosis, arthritis or other pathogenic situations that involve bone and/or cartilage.
  • the injectable pharmaceutical formulation may be administered via the parenteral route, including subcutaneously, intraperitoneally, intramuscularly and intravenously.
  • parenteral dosage forms include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier.
  • the osteopontin compound is dissolved in a saline solution containing 5% of dimethyl sulfoxide and 10% Cremphor EL (Sigma Chemical Company). Additional solubilizing agents are well-known to those familiar with the art and can be utilized as pharmaceutical excipients for delivery of the osteopontin compounds.
  • Other delivery vehicles are contemplated for use in accordance with the present invention and can be used to administer the fluid forms of the present invention systemically to a warmblooded vertebrate.
  • the delivery vehicle may be an oral dosage form, an epidermal patch or other delivery vehicle known to those skilled in the art.
  • the model involves the formation of circular defects (approximately 6-8mm in diameter) in the parietal bones of adult (greater than 6 months in age) Sprague Dawley rats.
  • the defect is of a critical size such that the intraosseous wound would not heal by bone formation during the life of the animal.
  • the surgery is conducted with sterile technique, cap, mask, gown and gloves.
  • Ketoset Animals are sedated with a cocktail of Ketoset 10ml, with 0.15ml of lOOmg/ml Xylazine and 0.3ml of lOmg/ml acepromarine added, and the dosage is 0. lml/lOOg body weight. If additional sedation is needed Ketoset alone is used in 0.05 ml increments. After the rats are sedated, their heads are shaved from behind the ears to the tip of the nose and laterally, ventral to the ears. A three part scrub, alternating betadine and alcohol is performed. An ointment is placed in the eyes prior to scrubbing.
  • the animals are placed on V- trays with their heads positioned on a small stack of 4 x 4 gauze to make a level surgery site.
  • the animals are immobilized by taping them to the tray using strips of tape running across the nose, ears and back.
  • the tray with the immobilized animal is placed under a sterile drape on the surgery table.
  • a skin incision is made in the midline of the skull, the periosteum is scraped off and retracted to expose the midline site.
  • An 6 or 8mm trephine is used in a micro-drill under 40 pounds or less of pressure. Irrigation of the site while drilling is necessary to avoid thermal necrosis. As the bone is cut care is taken to avoid damage to the dura and sagittal sinus. The dura should be left intact if possible. If bleeding occurs the area is packed with gelfoam for a few minutes, then removed when bleeding stops. The defect edges are then scraped smooth.
  • a 6-8mm circle of gelfilm is placed between the brain and the composition comprising osteopontin.
  • the periosteal layer is sutured closed over the defect region using a 5-0 proline continuous suture pattern.
  • the skin is then closed with staples. Animals are recovered in an incubator to avoid hypothermia, and once the animals are walking, they are returned to their cages.
  • compositions of the present invention were administered directly to the localized in vivo defect site (the calvaria defect site in the rat calvaria defect model) of adult rats through the use of ALZET osmotic pumps.
  • ALZET osmotic pumps ALZA Scientific Products Palo Alto, California
  • the pumps were connected to a catheter wherein the catheter directs delivery of the pump's contents (osteopontin) into the calvaria defect to provide a local dose of about 17 ug/ml of total defect volume.
  • the osmotic pumps were assembled prior to implantation.
  • the pump assembly was first filled with the osteopontin composition by attaching a syringe containing the solution to be delivered to the catheter tubing and filling the osmotic pump with the solution to be delivered.
  • the filled osmotic pump is fitted onto its flow moderator.
  • the pump assembly is then incubated in sterile saline (0.9%) at 37°C for at least 4-6 hours. Optimal results are obtained by priming overnight. This step ensures that the osmotic pump is pumping continuously prior to implantation and minimizes the chance of clotting within the cannula or occlusion by tissue during delivery of the test agent.
  • the assembly is then implanted into the host animal.
  • the rat was anesthetized (e.g., with an intraperitoneal injection of a solution of sodium pentobarbital, 40-50 mg/kg) and the pump apparatus was implanted into a subcutaneous pocket in the midscapular area of the back of the rat.
  • the skin over the implantation site was shaved and washed, and a mid-scapular incision is made into the back of the animal.
  • a hemostat was inserted into the incision and, by opening the jaws of the hemostat, the subcutaneous tissue was spread to create a pocket for the pump.
  • the pocket should be large enough to allow some free movement of the pump (e.g., 1 cm longer than the pump).
  • a filled pump was inserted into the pocket and connected to a catheter. The distal end of the catheter is placed into the calvaria defect for direct delivery of the osteopontin composition to the defect. The pump insertion site is then closed with wound clips or sutures.
  • Table 1 describes the experimental procedures used to analyze the in vivo bone growth response of rats to osteopontin. The following abbreviations are used: BW, beginning weight; SAC date, sacrifice date; DOB, date of birth; TX, treatment. Table 1
  • osteopontin into a rat calvarial defect via the osmotic pump method enhances new bone formation.
  • the osteopontin compositions of the present invention can also be administered intravenously to provide systemic administration of the composition.
  • Such systemic administration may provide therapeutic value for orthopedic conditions such as osteoporosis or other pathogenic conditions involving bone or cartilage.
  • the ALZET pumps can deliver fluid compositions directly into the venous or arterial circulation via a catheter. ALZET pumps have been shown to pump successfully against arterial pressure with no reduction in flow. The following procedure details placement of a catheter in the external jugular vein. In many cases this site is preferable because of its size and ease of access, however, other sites may be used successfully.
  • An osmotic pump flow moderator is connected to one end of a catheter (inside diameter ⁇ 0.07 cm).
  • the catheter should be 25% longer than the distance between the site of subcutaneous pump implantation (the midscapular region) and the site where the catheter enters the external jugular vein.
  • the flow moderator and catheter is filled by attaching a syringe filled with osteopontin composition to the free end of the catheter.
  • the osmotic pump is filled with the osteopontin composition and fitted onto the flow moderator.
  • the syringe which was used to fill the catheter can now be detached and the flow moderator inserted until the white flange is flush with the surface of the pump.
  • the pump and catheter should be completely filled and free of air bubbles.
  • the filled pump and catheter are incubated in sterile saline (0.9%) at 37°C for at least 4-6 hours. This step ensures that the osmotic pump is pumping continuously prior to implantation, minimizing the possibility of clotting and catheter occlusion during delivery of the test agent.
  • the complete assembly is then implanted into the animal as follows.
  • the ventral portion of the animal's neck is shaved and cleaned and the neck is incised to one side of the midline, and the tissues spread along the head to tail axis.
  • blunt dissection the external jugular vein is located just beneath the skin and is elevated and cleaned for a distance of 1.5 cm.
  • a silk ligature (3.0) is then placed around the head end of the cleaned vein and tied, and all large branches of the vein are tied off, but not cut.
  • Two loose, overhand knots are placed at the heart end of the vein.
  • the belly of sharp, curved iris scissors the mid-portion of the vein is grasped, elevated and cut, so that an ellipsoidal piece of the vein wall is removed.
  • the free end of the catheter is inserted into the hole in the vein wall, and advanced gently to the level of the heart (about 2 cm in an adult rat).
  • the proximal (heart-end) ligatures are tied snugly around the catheter, being careful not to crimp the catheter.
  • the distal (head-end) ligature is then tied around the catheter. The ends of all three ligatures are then cut off close to the knots.
  • a hemostat is then used to tunnel over the neck creating a pocket on the back of the animal in the midscapular region.
  • the pump is positioned into this pocket, allowing the catheter to reach over the neck to the external jugular vein with sufficient slack to permit free head and neck movement.
  • the incision in the skin of the neck is then closed with 2 or 3 wound clips or with sutures.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention porte sur une composition bioactive activant la réparation des tissus conjonctifs endommagés ou malades lorsque ces tissus sont en contact avec la composition in vivo. La présente invention porte notamment sur l'utilisation d'une composition comprenant une quantité efficace d'ostéopontine permettant d'activer la réparation des os endommagés ou malades.
PCT/US1998/027808 1997-12-31 1998-12-30 Compositions a base d'osteopontine activant la reparation osseuse WO1999033415A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000526176A JP2001527030A (ja) 1997-12-31 1998-12-30 骨修復効果を向上するためのオステオポンチンを基剤とする組成物
AU20214/99A AU748002B2 (en) 1997-12-31 1998-12-30 Osteopontin-based compositions for enhancing bone repair
EP98965015A EP1043963A4 (fr) 1997-12-31 1998-12-30 Compositions a base d'osteopontine activant la reparation osseuse

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US7024697P 1997-12-31 1997-12-31
US60/070,246 1997-12-31

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037858A1 (fr) * 1999-11-24 2001-05-31 Transtissue Technologies Gmbh Substrats pouvant etre implantes, permettant de soigner des tissus conjonctifs
WO2002009735A3 (fr) * 2000-08-01 2002-10-03 Univ Washington Procedes et dispositifs servant a moduler la reaction a une blessure
EP1328286A1 (fr) * 2000-10-05 2003-07-23 New Zealand Dairy Board Compositions pour la sante osseuse derivees du lait
WO2007068252A2 (fr) * 2005-12-16 2007-06-21 Arla Foods Amba Formulations d'osteopontine bovine pour l'amelioration du processus de cicatrisation des plaies
US7767221B2 (en) 2004-03-05 2010-08-03 The Trustees Of Columbia University In The City Of New York Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone
WO2012117120A1 (fr) 2011-03-03 2012-09-07 Arla Foods Amba Procédé d'isolement de l'ostéopontine à l'aide de charges d'alimentation concentrées
US8864843B2 (en) 2007-02-12 2014-10-21 The Trustees Of Columbia University In The City Of New York Biomimmetic nanofiber scaffold for soft tissue and soft tissue-to-bone repair, augmentation and replacement
WO2016179089A1 (fr) * 2015-05-01 2016-11-10 Rensselaer Polytechnic Institute Échafaudage nano-composite biomimétique pour réparation de fracture et cicatrisation améliorées
US11110199B2 (en) 2013-04-12 2021-09-07 The Trustees Of Columbia University In The City Of New York Methods for host cell homing and dental pulp regeneration

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040106896A1 (en) * 2002-11-29 2004-06-03 The Regents Of The University Of California System and method for forming a non-ablative cardiac conduction block
CN114957404B (zh) * 2022-05-17 2023-04-25 四川大学 一种多肽及其在促进骨修复中的用途

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US5158934A (en) * 1989-09-01 1992-10-27 Genentech, Inc. Method of inducing bone growth using TGF-β
US5372503A (en) * 1993-04-27 1994-12-13 Dental Marketing Specialists, Inc. Method for installation of a dental implant
US5533836A (en) * 1993-03-29 1996-07-09 Zymogenetics, Inc. Compositions and methods for stimulating the growth of osteoblasts
US5824651A (en) * 1993-05-10 1998-10-20 Universite De Montreal Process for modification of implant surface with bioactive conjugates for improved integration

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EP0891421A4 (fr) * 1996-03-18 2001-07-25 Univ Pennsylvania Substrat de materiau bioactif pour une fixation et une fonction cellulaires accrues
US6416774B1 (en) * 1996-05-09 2002-07-09 The Trustees Of The University Of Pennsyvania Hollow bone mineral-like calcium phosphate particles
EP0929322A1 (fr) * 1996-09-30 1999-07-21 Children's Medical Center Corporation Procedes et compositions de programmation d'une matrice organique en vue d'un remodelage au sein d'un tissu cible

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Publication number Priority date Publication date Assignee Title
US5158934A (en) * 1989-09-01 1992-10-27 Genentech, Inc. Method of inducing bone growth using TGF-β
US5533836A (en) * 1993-03-29 1996-07-09 Zymogenetics, Inc. Compositions and methods for stimulating the growth of osteoblasts
US5372503A (en) * 1993-04-27 1994-12-13 Dental Marketing Specialists, Inc. Method for installation of a dental implant
US5824651A (en) * 1993-05-10 1998-10-20 Universite De Montreal Process for modification of implant surface with bioactive conjugates for improved integration

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037858A1 (fr) * 1999-11-24 2001-05-31 Transtissue Technologies Gmbh Substrats pouvant etre implantes, permettant de soigner des tissus conjonctifs
US6602294B1 (en) 1999-11-24 2003-08-05 Transtissue Technologies Gmbh Implantable substrates for the healing and protection of connecting tissue, preferably cartilage
WO2002009735A3 (fr) * 2000-08-01 2002-10-03 Univ Washington Procedes et dispositifs servant a moduler la reaction a une blessure
EP1328286A1 (fr) * 2000-10-05 2003-07-23 New Zealand Dairy Board Compositions pour la sante osseuse derivees du lait
JP2004510742A (ja) * 2000-10-05 2004-04-08 ニュージーランド　デアリー　ボード 乳汁から誘導された骨の健康用組成物
EP1328286A4 (fr) * 2000-10-05 2004-09-29 New Zealand Dairy Board Compositions pour la sante osseuse derivees du lait
US7767221B2 (en) 2004-03-05 2010-08-03 The Trustees Of Columbia University In The City Of New York Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone
US9427495B2 (en) 2004-03-05 2016-08-30 The Trustees Of Columbia University In The City Of New York Multi-phased, biodegradable and oesteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone
WO2007068252A3 (fr) * 2005-12-16 2007-08-30 Arla Foods Amba Formulations d'osteopontine bovine pour l'amelioration du processus de cicatrisation des plaies
WO2007068252A2 (fr) * 2005-12-16 2007-06-21 Arla Foods Amba Formulations d'osteopontine bovine pour l'amelioration du processus de cicatrisation des plaies
US8864843B2 (en) 2007-02-12 2014-10-21 The Trustees Of Columbia University In The City Of New York Biomimmetic nanofiber scaffold for soft tissue and soft tissue-to-bone repair, augmentation and replacement
US10265155B2 (en) 2007-02-12 2019-04-23 The Trustees Of Columbia University In The City Of New York Biomimmetic nanofiber scaffold for soft tissue and soft tissue-to-bone repair, augmentation and replacement
WO2012117120A1 (fr) 2011-03-03 2012-09-07 Arla Foods Amba Procédé d'isolement de l'ostéopontine à l'aide de charges d'alimentation concentrées
WO2012117119A1 (fr) 2011-03-03 2012-09-07 Arla Foods Amba Procédé d'isolement de l'ostéopontine à l'aide de charges d'alimentation contenant des espèces cmp ou caséine
US9181325B2 (en) 2011-03-03 2015-11-10 Arla Foods Amba Method for isolating osteopontin using concentrated feeds
US9181316B2 (en) 2011-03-03 2015-11-10 Arla Foods Amba Method for isolating osteopontin using feeds containing CMP or casein species
US11110199B2 (en) 2013-04-12 2021-09-07 The Trustees Of Columbia University In The City Of New York Methods for host cell homing and dental pulp regeneration
WO2016179089A1 (fr) * 2015-05-01 2016-11-10 Rensselaer Polytechnic Institute Échafaudage nano-composite biomimétique pour réparation de fracture et cicatrisation améliorées
US12274809B2 (en) 2015-05-01 2025-04-15 Rensselaer Polytechnic Institute Biomimetic nano-composite scaffold for enhanced bone healing and fracture repair

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JP2001527030A (ja) 2001-12-25
AU748002B2 (en) 2002-05-30
EP1043963A1 (fr) 2000-10-18
EP1043963A4 (fr) 2001-02-07
AU2021499A (en) 1999-07-19

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