WO1990009783A1 - Systeme d'acheminement a liberation regulee de facteurs bioactifs - Google Patents

Systeme d'acheminement a liberation regulee de facteurs bioactifs Download PDF

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Publication number
WO1990009783A1
WO1990009783A1 PCT/US1990/000900 US9000900W WO9009783A1 WO 1990009783 A1 WO1990009783 A1 WO 1990009783A1 US 9000900 W US9000900 W US 9000900W WO 9009783 A1 WO9009783 A1 WO 9009783A1
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Prior art keywords
composition
bioactive substance
matrix
animal
group
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Application number
PCT/US1990/000900
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English (en)
Inventor
Cato T. Laurencin
Paul A. Lucas
Glenn T. Syftestad
Abraham Domb
Julianne Glowacki
Robert S. Langer
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Massachusetts Institute Of Technology
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Publication of WO1990009783A1 publication Critical patent/WO1990009783A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
    • C08G67/04—Polyanhydrides
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • Presently available systems for the sustained release of drugs are generally polymeric compositions where the drug or agent is either an integral part of the polymer matrix or layered or contained as a discrete portion of the device.
  • the drug or agent is either an integral part of the polymer matrix or layered or contained as a discrete portion of the device.
  • Folkman and Langer in U.S. Patent 4,291,797 describe a delivery device for macromolecules in which the macromolecule is interspersed throughout the polymer matrix.
  • Hutchinson describes a delivery vehicle formed of polylactide polymer and an acid stable polypeptide interspersed in the matrix.
  • Higuchi in U.S. Patent 3,625,214 describes a sustained release drug delivery device according to a defined release profile by layering the drug and a bioerodible polymer.
  • the invention relates to a composition and method for the controlled administration of a bioactive substance to a local cell population in a subject.
  • the composition comprises a bioerodible, surface-eroding polymer having the bioactive substance interspersed throughout the matrix, which erodes in the biological environment, releasing the bioactive substance to the selected area.
  • the invention also includes a method for delivering water-soluble local-acting substances, particularly proteins, to a specific site in the body of an animal.
  • composition and method of the invention allows water-soluble proteins to interact with local cell populations. These proteins are soluble in the physiological environment, and are generally
  • the present composition releases soluble proteins directly to a selected site in a concentration sufficient to permit the proteins to interact with the local cell population.
  • the surface-eroding polymers used in the present composition are biocompatible and bioerode in the physiological environment, allowing heterogeneous degradation from the surface of the device, which leads to near zero-order release kinetics.
  • the degradation products of the surface-eroding polymers are non-mutagenic, non-cytotoxic and have a low teratogenic potential.
  • the present invention provides a system for the controlled or sustained release of bioactive substances which interact with local cell populations at a physiological site.
  • the composition is formed from a bioerodible, surface-eroding polymer and the bioactive substance.
  • controlled release of the substance may be either continuous or discontinuous.
  • composition of the present invention comprises a bioerodible polymer matrix and a
  • matrix denotes a carrier, polymeric phase for the interspersed bioactive substance, which bioerodes in the environment of use, releasing the bioactive substance.
  • Bioerodible polymers suitable for use in the present invention are polymers which break down or disintegrate over a prolonged period of time when placed in contact with biological fluids.
  • Surface-eroding bioerodible polymers are preferred for use in the present composition.
  • Surface-eroding polymers are, generally, polymers having hydrophobic backbones and hydrolytic linkages, which bioerode from the surface at a constant rate in a biological environment.
  • Surface eroding polymers include polyanhydrides and polyorthoesters.
  • Polyanhydride polymers are particularly useful for the present compositions.
  • polymers have several properties which are desirable in a biodegradable, polymeric controlled-release system. These polymers have a hydrophobic backbone and a water labile linkage, which allows
  • the water-labile anhydride linkage provides the basis for the use of a variety of backbones, each having a unique degradation rate.
  • the rate of degradation in vivo can be controlled by controlling the length and composition of the polymer backbone.
  • polyanhydrides which can be used in the present invention include poly[bis(p-carboxyphenoxy) propane anhydride] (PCPP) and poly[bis(p-carboxy) methane anhydride] (PCPM). Co-polymers of polyanhydrides with other substances can also be used.
  • PCPP-SA co-polymer of PCPP and sebacic acid
  • PCPP-SA co-polymer of PCPP and sebacic acid
  • the degradation products of the polyanhydrides are non-mutagenic and non-toxic.
  • Invivo toxicity studies have shown that polyanhydrides have excellent local system biocompatibility.
  • the characteristics of polyanhydride drug carriers for systemic drugs is described by Leong et al. Leong et al., J. Biomed. Mat. Res., 19:941-955 (1985), Leong et al. J. Biomed. Mat. Res., 20:51-64 (1986).
  • Polyanhydride delivery vehicles of the present invention can be used to deliver highly soluble bioactive factors or substances which regulate local cellular events. These factors are generally characterized in that in vitro they produce a response in a cell population, but do not produce a response when used directly in vivo. These substances or factors must be in the vicinity of the cells which they act upon to be effective. These factors are generally water-soluble polypeptides or proteins, which, when introduced into a physiological environment in vivo, are soluble in the environment, and so become too diluted to act locally. Bioactive factors having these characteristics include factors involved in wound healing or angiogenesis, such as TGF-beta, EGF, FGF and PDGF, which act upon local cell populations.
  • water as used herein (e.g., watersoluble), includes biological fluids, saline and physiologically acceptable buffer.
  • bioactive factors which promote chondrogenesis and osteogenesis are used.
  • the protein(s) involved in chondrogenesis/osteogenesis interact with the local cells to influence their proliferation and cytodifferentiation.
  • Transmembrane experiments have shown that the bioactive factor(s) responsible for the chondro-osteoinduction are soluble in body fluids. Nogami and Urist, Calcif. Tissue Res., 19:153-163 (1975); Urist et al., Arch. Surg.,
  • Osteogenesis is initiated by an interaction between diffusable bone matrix-derived bioactive factor(s) and local ingrowing cell populations.
  • Demineralized bone matrix may be viewed as a "natural" sustained release vehicle which releases the soluble bioactive factor(s) in an effective manner.
  • the present invention allows the dose and rate of release of bioactive factors exhibited by pieces of demineralized bone matrix to be mimicked.
  • the chondro/osteogenic water-soluble proteins used in the present embodiment of the invention are a complex mixture of proteins. Although considerable research has been done to isolate the chondro/osteogenic protein from bone matrix, to date no protein has been unequivocally purified to homogeneity. Urist et al., Proc. Nat'1. Acad. Sci.
  • the polyanhydride polymers may prove an even more useful delivery vehicle.
  • composition of the present invention can be used in manufacturing controlled-release delivery vehicles, which can be manufactured by recognized methods for preparing controlled-release vehicles. See, U.S. 4,391,727; U.S. 4,767,628. In one
  • the present compositions were formed by mixing the selected anhydride polymer and the bioactive factors. Briefly, the polyanhydride polymers or co-polymers were synthesized by art-recognized techniques. Leong et al. , J. Biomed.
  • particle size range of from about 90 to about 150 ⁇ m .
  • the water-soluble proteins i.e. , bioactive factors
  • the relative proportions of polymer to protein will vary depending upon the activity of the protein and the end use of the delivery vehicles. Generally, the protein is present in an amount sufficient, upon release, to interact with the local cell population.
  • the proportion of polymer or co-polymer to protein suitable for the purpose of the present invention will range from about 10% by weight to about 90% by weight of polymer to about 90% to 10% by weight of protein.
  • the preferred amount of protein is from about 20% to about 60% by weight, formulated with sufficient polymer matrix to give 100 parts by weight of the composition.
  • the mixture of protein and polymer is then molded to form delivery vehicles, which can be shaped in a wide variety of shapes, sizes and forms for delivering the selected bioactive factors to the environemnt of use.
  • delivery vehicles can be shaped as buccal and oral devices or
  • vaginal and intrauterine devices or articles subcutaneous implants or intramuscular devices of cylinderical, bullet, elliptical,
  • the polymer matrix acts as a support for the surrounding bone, or cartilage tissue.
  • the composition of the present invention can be formulated for delivering a soluble, bioactive factor to a local cell population to produce the desired localized effect.
  • the composition can be used in animals, including warm-blooded animals, humans, primates, farm and sport animals, laboratory animals, reptiles and amphibians.
  • the amount of bioactive factor is, in one embodiment, the amount necessary to affect the local cell population, or an excess of that amount.
  • the article can contain from about 5 mg to about 30 mg of protein.
  • the articles made from the composition of the present invention can be manufactured by standard techniques, such as casting or compression molding. Other methods of shaping polymeric materials into articles having the desired size and shape are well known.
  • the dried polymer is blended with the protein in the desired proportion, and the mixture is pressed into circular disks by compression molding. Compression molded articles can then be further sectioned into pieces having the desired dimensions.
  • Polyanhydrides have demonstrated the characteristics necessary for a successful delivery vehicle of os teo genic factors. They released the inductive protein(s) at an effective dose over a time period coincident with the accumulation of host target cells, as evidenced by the appearance of cartilage and/or bone at the ectopic site. In addition, there was rapid ingrowth of host tissue to promote direct interaction of bioactive factors with the target cells.
  • the polymers are biocompatible, and the composition is biodegradable so that it will ultimately be resorbed.
  • water-soluble proteins for use in the present invention although capable of inducing a biological effect in v i t ro do not induce an effect when implanted alone into the physiological site. Similiarly, the polymers themselves do not induce an effect when implanted alone. Only the combination of water-soluble proteins and polymer was effective.
  • Polyanhydride polymers have now been shown capable of delivering bioactive factors which act on local cell populations.
  • bioactive factors which act on local cell populations.
  • chondro/osteogenic factors bioactive factors such as TGF-beta, EGF, FGF, and PDGF which act upon local cell populations in would healing or angiogenesis, can be used in the present devices.
  • Water-soluble proteins were prepared from a 4 M guanidine hydrochloride extract of demineralized bovine cortical bone as described by Syftestad et al. Syftestad et al., Differentiation, 29:230-237 (1985). Briefly, mid-shaft femoral cortices of 1 year old steers were cleaned of adhering tissue and marrow, decalcified in 0.6 N HCl at 4°C, defatted in chloroform: methanol (1:1 v/v) and air dried. The bone matrix was extracted at 4°C in a solution of 4 M guanidine hydrochloride buffered with 50 mM Tris, pH 6.8, and containing enzyme inhibitors.
  • the extract was dialyzed at 4oC sequentially against solutions of decreasing ionic strength: 0.5 M guanidine hydrochloride, 50 mM Tris buffered saline, and distilled water. Precipitates which formed at each step were removed by centrifugation until only those proteins soluble in cold distilled water remained. This portion of the extract was
  • PCPP Poly[bis(p-carboxyphenoxy)propane anhydride]
  • PCPM poly[bis(p-carboxy)methane anhydride]
  • Conix Macro. Synth., 2:95-98 (1966); Leong et al., J. Biomed. Mat. Res., 19:941-955 (1985). Briefly, the dicarboxylic acid monomers were converted to the mixed anhydride by total reflux in acetic anhydride followed by recrystallization. The prepolymers were then subjected to melt polycondensation in vacuo under nitrogen sweep. Copolymers of PCPP and sebacic acid (SA) were obtained in a similar manner. The polymers were purified by extraction with anhydrous ether in a Soxhlet Extractor for several hours and were stored in a desicator over calcium chloride.
  • SA sebacic acid
  • Matrices incorporating water-soluble protein were formulated by compression molding.
  • the polymers were ground in a Micro Mill Grinder and sieved into a particle size range of 90-150 ⁇ m .
  • Twenty mg of water-soluble proteins were manually mixed with the polymer at the desired ratios (w/w) and the mixture pressed into circular discs in a Carver Test Cylinder Outfit at 30 Kpsi and room temperature.
  • Cartilage was identified by its typical
  • the water-soluble protein preparation from bovine bone matrix used in this study has been previously shown to consist of numerous Coomassie Blue stained protein bands ranging in size from 10 Kd to 100 Kd when subjected to SDS-PAGE. Syftestad et al., Differentiation, 29:230-237 (1985).
  • the water-soluble proteins are capable of inducing chondrogenesis in two in vitro assay systems: the stage 24 chick limb bud system (Syftestad and
  • this protein mixture can also induce ectopic endochondral ossification in the muscle of CBA/J mice.
  • 20 mg of lyophilized water-soluble proteins were implanted alone into a mouse thigh muscle, however, no signs of cartilage or bone formulation could be detected.
  • a "nodule" of connective tissue composed of fibroblastic cell types embedded in a loose extracellular matrix was present. This response is most probably due to the normal wound healing response and was not directly initiated by the implanted water-soluble proteins. By 16 days post-implantation, this connective tissue infiltrate has disappeared making it impossible to locate the original implant site.
  • PCPP was tested at protein loadings of 20% and 40%. At these loadings, the implants exhibited connective tissue 9 days post-implantation and were essentially indistinguishable from controls. No cartilage and/or bone was induced (Table 1).
  • PCPM was tested at a variety of loading with water-soluble proteins: 20, 30, 40 and 50%. Only the implants loaded with 30% protein exhibited cartilage and/or bone induction (Table 1). The others contained connective tissue and were essentially identical to implants of PCPM alone.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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  • Molecular Biology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On a mis au point une composition et un procédé de libération régulée de protéines solubles dans l'eau, comprenant une matrice polymère à érosion de surface ainsi que des facteurs bioactifs solubles dans l'eau. Ladite composition s'érode biologiquement dans l'environnement biologique du sujet à une vitesse régulée, libérant ainsi les protéines solubles dans l'eau à un rythme leur permettant d'avoir une action réciproque avec les populations cellulaires locales.
PCT/US1990/000900 1989-02-22 1990-02-22 Systeme d'acheminement a liberation regulee de facteurs bioactifs WO1990009783A1 (fr)

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US31395389A 1989-02-22 1989-02-22
US313,953 1994-09-28

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990015586A2 (fr) * 1989-06-05 1990-12-27 Massachusetts Institute Of Technology Polymeres pouvant s'eroder biologiquement pour liberation de medicaments dans les os
WO1992013565A1 (fr) * 1991-01-31 1992-08-20 Shaw, Robert, Francis Matrice contenant un facteur de croissance pour le traitement de lesions du cartilage
EP0530804A1 (fr) * 1991-09-06 1993-03-10 Shaw, Robert Francis Trousses et méthodes pour le traitement et pour la réparation des lésions ou des défauts de cartilage ou d'os
EP0568651A1 (fr) * 1991-02-01 1993-11-10 Massachusetts Institute Of Technology Melanges de polymeres biodegradables pour apport medicamenteux
US5328695A (en) * 1983-03-22 1994-07-12 Massachusetts Institute Of Technology Muscle morphogenic protein and use thereof
WO1996018411A1 (fr) * 1994-12-16 1996-06-20 Massachusetts Institute Of Technology Liberation localisee de facteurs favorisant la survie de cellules transplantees
EP0591392B1 (fr) * 1991-06-21 1996-09-11 Genetics Institute, Inc. Compositions pharmaceutiques de proteines osteogeniques
WO1998056312A1 (fr) * 1997-06-13 1998-12-17 Scimed Life Systems, Inc. Protheses endovasculaires avec plusieurs couches d'une composition polymere biodegradable
US5935594A (en) * 1993-10-28 1999-08-10 Thm Biomedical, Inc. Process and device for treating and healing a tissue deficiency
US5981825A (en) * 1994-05-13 1999-11-09 Thm Biomedical, Inc. Device and methods for in vivo culturing of diverse tissue cells
WO2002085422A1 (fr) * 2001-04-25 2002-10-31 Eidgenössische Technische Hochschule Zürich Matrices pour l'administration de medicaments destinees a ameliorer la cicatrisation
US6569172B2 (en) 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6592599B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6866668B2 (en) 1998-08-14 2005-03-15 Verigen Transplantation Service International (“VTSL”) AG Methods, instruments and materials for chondrocyte cell transplantation
US7659273B2 (en) 2001-05-23 2010-02-09 Mitsubishi Tanabe Pharma Corporation Composition for accelerating bone fracture healing
US8226942B2 (en) 2007-12-28 2012-07-24 Kuros Biosurgery Ag PDGF fusion proteins incorporated into fibrin foams
US8252794B2 (en) 2001-05-23 2012-08-28 Mitsubishi Tanabe Pharma Corporation Composition for regenerative treatment of cartilage disease

Citations (1)

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WO1989000855A1 (fr) * 1987-07-31 1989-02-09 Massachusetts Institute Of Technology Polyanhydrides ayant des proprietes de degradation hydrolytiques ameliorees

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1989000855A1 (fr) * 1987-07-31 1989-02-09 Massachusetts Institute Of Technology Polyanhydrides ayant des proprietes de degradation hydrolytiques ameliorees

Non-Patent Citations (2)

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Title
Proc. Natl. Acad. Sci. USA, Vol. 84, October 1987, (Washington, D.C. US), T.K. SAMPATH et al.: "Isolation of Osteogenin, an Extracellular Matrixassociated, bone-Inductive Protein, by Heparin Affinity Chromatography", pages 7109-7113 *
Proc. Natl. Acad. Sci. USA, Vol. 85, December 1988, (Washington, D.C., US), E.A. WANG et al.: "Purification and Characterization of other Distinct bone-Inducing Factors", pages 9484-9488 *

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328695A (en) * 1983-03-22 1994-07-12 Massachusetts Institute Of Technology Muscle morphogenic protein and use thereof
WO1990015586A2 (fr) * 1989-06-05 1990-12-27 Massachusetts Institute Of Technology Polymeres pouvant s'eroder biologiquement pour liberation de medicaments dans les os
WO1990015586A3 (fr) * 1989-06-05 1991-03-21 Massachusetts Inst Technology Polymeres pouvant s'eroder biologiquement pour liberation de medicaments dans les os
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
WO1992013565A1 (fr) * 1991-01-31 1992-08-20 Shaw, Robert, Francis Matrice contenant un facteur de croissance pour le traitement de lesions du cartilage
US5368858A (en) * 1991-01-31 1994-11-29 Robert F. Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage
CN1056083C (zh) * 1991-01-31 2000-09-06 罗伯特弗朗西斯肖 治疗及修复软骨缺损或损伤的方法及组合物
EP0568651A1 (fr) * 1991-02-01 1993-11-10 Massachusetts Institute Of Technology Melanges de polymeres biodegradables pour apport medicamenteux
EP0568651A4 (en) * 1991-02-01 1996-11-27 Nova Pharm Corp Biodegradable polymer blends for drug delivery
EP0591392B1 (fr) * 1991-06-21 1996-09-11 Genetics Institute, Inc. Compositions pharmaceutiques de proteines osteogeniques
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