WO2000047114A1 - Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene - Google Patents
Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene Download PDFInfo
- Publication number
- WO2000047114A1 WO2000047114A1 PCT/US2000/003151 US0003151W WO0047114A1 WO 2000047114 A1 WO2000047114 A1 WO 2000047114A1 US 0003151 W US0003151 W US 0003151W WO 0047114 A1 WO0047114 A1 WO 0047114A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bmp
- collagen
- fibrillar
- solution
- bone
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
Definitions
- this invention relates to a delivery system for bone morphogenic proteins.
- Bone is a living, dynamic tissue with substantial capacity for regeneration. Through the tightly-controlled, ongoing processes of formation and reso ⁇ tion, bone is involved in the regulation of serum calcium, is able to remodel in order to respond to changes in physical stress placed upon it, and is able to repair both micro fractures and substantial fractures within its structure. These processes are controlled, at least in part, by the large number of growth factors present in the bone matrix. These factors include basic and acidic fibroblast growth factor, insulin-like growth factors I and II, the superfamily of transforming growth factors beta (TGF ⁇ ), platelet derived growth factors, and bone mo ⁇ hogenic proteins.
- TGF ⁇ transforming growth factors beta
- the bone mo ⁇ hogenic proteins are now known to include a large family of proteins within the TFG ⁇ superfamily of growth and differentiation factors.
- Members of the BMP family have been determined to be key signaling molecules in embryogenesis, in species ranging from Drosophila to humans. They are involved in delivering positional information as well as the development of hard tissues (bones and teeth) and soft tissues.
- BMPs When implanted into adult animals, several of the BMPs have been shown to initiate the complex cellular process resulting in the induction of bone through both the endochondral and intramembranous bone formation pathways.
- the invention features a method for delivering a bone mo ⁇ hogenic protein to a tissue site, the method involving: (a) combining the bone mo ⁇ hogenic protein (BMP) with a soluble collagen; and (b) administering the BMP-collagen solution to the tissue site, whereby, upon contact with the tissue, the collagen solution is converted to a collagen gel.
- BMP bone mo ⁇ hogenic protein
- the BMP-collagen solution is administered by injection; the tissue site is bone or cartilage; the site has a defect; the defect is treated by BMP delivery; the collagen solution, upon administration to the tissue, is converted to a collagen gel within 180 seconds, more preferably, within 120 seconds, and, most preferably, within 90 seconds: the soluble collagen includes a fibrillar component and forms a fibrillar matrix: the fibrillar component is at a concentration of between 0.01-2.0%, more preferably, 0.1 -0.8% (fibrillar collagen solids (w/v)); the BMP-collagen solution is at approximately pH 5.5-7.5, preferably, approximately 6.0-6.5; and the bone mo ⁇ hogenic protein is selected from the TGF ⁇ superfamily, e.g., BMP-1 , BMP-2 (BMP-2A), BMP-3 (osteogenin), BMP-4 (BMP-2B), BMP-5. BMP-6, BMP-7, osteoinductive factor (OIF), BMP-8, BMP-9, BMP
- the invention features a bone mo ⁇ hogenic protein (BMP)-collagen solution, whereby, upon administration to a tissue, the solution is converted to a collagen gel.
- BMP bone mo ⁇ hogenic protein
- this BMP-collagen solution is injectable; the BMP-collagen solution, upon administration to a tissue, is converted to a collagen gel within 180 seconds, more preferably, within 120 seconds, and, most preferably, within 90 seconds; the BMP-collagen solution includes a fibrillar component and forms a fibrillar matrix; the fibrillar component is at a concentration of 0.01 -2.0%, more preferably, 0.1-0.8% (fibrillar collagen solids (w/v)); the BMP-collagen solution is at approximately pH 5.5-7.5, more preferably, at approximately pH 6.0-6.5; and the bone mo ⁇ hogenic protein is selected from the TGF ⁇ superfamily, e.g., BMP-1 , BMP-2 (BMP-2 A), BMP-3 (osteogenin), BMP-4 (BMP-2B), BMP-5, BMP-6, BMP-7, osteoinductive factor (OIF), BMP-8, BMP-9, BMP- 10, BMP- 12, BMP- 13, and BMP- 14.
- BMP-1 B
- tissue is meant an aggregation of similarly specialized cells in an organism, preferably, mammalian, and, most preferably, human, where the cells are exposed to the organism's extracellular fluid, and are united in performance of a function within an organism.
- fibrillar component is meant an insoluble fibrillar collagen component wherein the collagen molecules interact in a quarter-stagger array to form microfibrils which themselves aggregate by side-to-side and end-to-end association to form stabilized collagen fibrils.
- the fibrillar component exhibits a collagen solid content ranging from about 0.1 -2.0% (w/v) fibrillar collagen solids.
- fibrillar collagen solids the dry collagen solid content of the fibrillar component in terms of percent fibrillar solids.
- the collagen solids Prior to addition to a soluble collagen formulation, the collagen solids are suspended in solution at a concentration ranging from 10-100 mg/ml, preferably 40 mg/ml. The collagen solid suspension is then added to the soluble collagen formulation for a final collagen solid concentration of 0.1 -2.0%, or 1 -20 mg/ml.
- the collagen delivery systems described herein are biocompatible, readily available, and stable in solution at neutral pH. These properties allow for the homogeneous dispersion of active BMP peptides, injectable administration of these peptides through a fine gauge needle (for example, a 30 gauge needle), sufficient density to fill a bone defect and to remain in place until gelation and fibril formation, and substantial BMP delivery for the maintenance of the active peptide in the bone matrix for a period of time sufficient to promote healing.
- a fine gauge needle for example, a 30 gauge needle
- FIGURE 1 is a graph demonstrating recombinant human BMP-2 retention following injection in combination with either the presently-described rapidly polymerizing collagen containing a 20% fibrillar collagen component, buffer, or a collagen sponge.
- an injectable deliver ⁇ ' system for BMPs which involves an initially soluble collagen which is capable of rapid polymerization.
- the low viscosity of the initial collagen solution allows homogeneous mixing of the introduced BMP and administration to a site by injection.
- the rapid polymerization characteristic allows for targeted delivery of the peptide to specific tissue sites and in concentrations which may be readily controlled through the choice of BMP concentration in the soluble collagen mixture.
- any collagen which exhibits the properties of an initially soluble state followed by rapid polymerization may be used in the invention. Because this delivery system is optimally designed for use in mammalian systems, rapid polymerization preferably occurs at temperatures and pH's which approximate the physiological conditions of the recipient mammal. For humans, this collagen preferably polymerizes in a range of about 36°-39°C and at a pH of about 6.5-7.5.
- collagens for use in the invention are described in DeVore & Eiferman (U.S. Patent No. 5,492,135.) These collagens are initially soluble in form and, upon exposure to physiological fluids, undergo rapid polymerization. Such collagen solutions have been prepared at concentrations ranging from 10 mg/ml to over 70 mg/ml and at pH's ranging from about 6.0-8.0.
- Fibrillar collagen may be reconstituted from animal sources, such as bovine hide, using methods described, for example, in Borel and Randoux, Frontiers in Matrix Biology, Vol. 10, pages 1-58, In Methods of Connective Tissue Research, Eds. Robert, Moczar, and Moczar, S. Karger, Basel, 1985. Fibrillar collagen may also be prepared from human or animal tissue sources using the method of Kelman and DeVore (U.S. Patent Nos. 4,969,912 and 5,322,802.) Concentrations of the fibrillar collagen component may range from about 0.01 -2.0% (collagen solids (w/v)).
- the injectable collagen systems described herein may be used to deliver any bone mo ⁇ hogenic protein selected from the TGF ⁇ superfamily, including, without limitation, BMP- 1 , BMP-2 (BMP-2A), BMP-3 (osteogenin). BMP-4 (BMP-2B), BMP-5. BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP- 1 1 , BMP-12, BMP- 13, BMP-14 and osteoinductive factor (OIF).
- the bone mo ⁇ hogenic protein is BMP-2.
- the protein is added to the collagen solution to a desired concentration, and the solution is administered to the appropriate tissue site.
- combinations of two or more BMPs may be administered simultaneously, or the BMP may be combined with other compounds which encourage bone formation, for example, hydroxyapatite, calcium phosphate, or other non-collagen materials such as coral powder.
- the collagen-BMP solution is administered to a site, for example, the site of a bone or collagen defect by syringe injection or surgical placement.
- the injectable collagen-BMP delivery system described herein is ideally suited to the treatment and repair of bone defects (for example, injury, fracture, or non-union fracture) or cartilage defects or injury.
- the collagen-BMP preparation can also be applied to increase bone density in the treatment of osteoporosis.
- BMP-2 recombinant human BMP-2 was used. Experiments were conducted to determine whether the addition of BMP in buffer (pH 4.5) would impede gelation or fibril formation. BMP was added to collagen at a 1 : 1 ratio, mixed using two syringes attached by a syringe adaptor, and then injected into a 0.8% saline solution. The still viscous mixture sank to the bottom of the solution. Gelation and fibril formation occurred within 1 minute of introduction into the saline.
- the 20% fibrillar collagen formulation had greater BMP retention at the implantation site than did the 10% fibrillar formulation. Indeed, the 20% fibrillar collagen formulation retained 60% of the BMP retained using a surgically-implanted sponge (a standard treatment) and 150% of that retained following BMP-buffer injections. Comparative retention was consistent for up to nearly 200 hours post- implantation ( Figure 1).
- Rapidly polymerizing collagen formulations containing 20% fibrillar bovine collagen matrix and BMP (mixed with ,25 I-BMP) were also injected into bone-groove defects in rabbit forelimb long bones (80 ⁇ g BMP/200 ⁇ l aliquot).
- Surgically-implanted sponges containing BMP and injections of BMP in buffer were used as non-collagen controls.
- Animals were examined radiographically at 3, 24, 47, 72, 100, 170, and 190 hours post-treatment, as well as at 2, 3, and 4 weeks post-treatment. At 4 weeks, the implant sites and surrounding bone were removed for histological examination.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne un procédé d'apport d'une protéine osseuse morphogénétique à un tissu consistant : (a) à combiner la protéine osseuse morphogénétique (BMP) avec un collagène soluble ; et (b) à administrer cette solution au tissu, au contact duquel cette solution se transforme en collagène gélifié. Cette invention concerne également l'utilisation de ce procédé pour traiter les anomalies osseuses ou celles des cartilages. De plus, cette invention propose des solutions BMP-collagènes utiles à cet effet.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU29847/00A AU2984700A (en) | 1999-02-12 | 2000-02-07 | Injectable collagen-based delivery system for bone morphogenic proteins |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11993999P | 1999-02-12 | 1999-02-12 | |
US60/119,939 | 1999-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000047114A1 true WO2000047114A1 (fr) | 2000-08-17 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/003151 WO2000047114A1 (fr) | 1999-02-12 | 2000-02-07 | Systeme d'apport de proteines osseuses morphogenetiques par injection de collagene |
Country Status (2)
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AU (1) | AU2984700A (fr) |
WO (1) | WO2000047114A1 (fr) |
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WO2002051449A2 (fr) * | 2000-12-22 | 2002-07-04 | Sulzer Biologics Inc. | Composition et methode de croissance et de reparation osseuse |
US20030143207A1 (en) * | 2001-10-18 | 2003-07-31 | Livesey Stephen A. | Remodeling of tissues and organ |
WO2003094835A2 (fr) | 2002-05-09 | 2003-11-20 | Prochon Biotech Ltd. | Variantes de fgf et leurs procedes d'utilisation |
WO2006007780A1 (fr) * | 2004-07-22 | 2006-01-26 | Fang Xu | Matiere pour reparation d'os sous forme de gelatine injectable et son procede de preparation |
WO2008079672A2 (fr) * | 2006-12-19 | 2008-07-03 | Warsaw Orthopedic, Inc | Compositions de vecteur fluide et procédés d'utilisation |
US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
USRE42208E1 (en) | 2003-04-29 | 2011-03-08 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US8292968B2 (en) | 2004-10-12 | 2012-10-23 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
EP2716299A2 (fr) * | 2011-06-03 | 2014-04-09 | Chonnam National University Hospital | Peptide bfp4 favorisant la formation osseuse ou la vasculogenèse, et son application |
US8906110B2 (en) | 2007-01-24 | 2014-12-09 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
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US9271821B2 (en) | 2012-01-24 | 2016-03-01 | Lifecell Corporation | Elongated tissue matrices |
US9370536B2 (en) | 2012-09-26 | 2016-06-21 | Lifecell Corporation | Processed adipose tissue |
US9375513B2 (en) | 2011-04-14 | 2016-06-28 | Lifecell Corporation | Regenerative materials |
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US9532863B2 (en) | 2011-12-20 | 2017-01-03 | Lifecell Corporation | Sheet tissue products |
US9549805B2 (en) | 2011-12-20 | 2017-01-24 | Lifecell Corporation | Flowable tissue products |
US9687590B2 (en) | 2007-07-03 | 2017-06-27 | Histogenics Corporation | Double-structured tissue implant and a method for preparation and use thereof |
US9701940B2 (en) | 2005-09-19 | 2017-07-11 | Histogenics Corporation | Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof |
US9782436B2 (en) | 2012-04-24 | 2017-10-10 | Lifecell Corporation | Flowable tissue matrices |
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WO2002051449A2 (fr) * | 2000-12-22 | 2002-07-04 | Sulzer Biologics Inc. | Composition et methode de croissance et de reparation osseuse |
WO2002051449A3 (fr) * | 2000-12-22 | 2002-09-06 | Sulzer Biolog Inc | Composition et methode de croissance et de reparation osseuse |
US8690874B2 (en) | 2000-12-22 | 2014-04-08 | Zimmer Orthobiologics, Inc. | Composition and process for bone growth and repair |
JP2004520106A (ja) * | 2000-12-22 | 2004-07-08 | サルザー バイオロジクス インコーポレイテッド | 骨の成長および修復のための組成物ならびに方法 |
US20030143207A1 (en) * | 2001-10-18 | 2003-07-31 | Livesey Stephen A. | Remodeling of tissues and organ |
US7563769B2 (en) | 2002-05-09 | 2009-07-21 | ProChon Biotech, Ltd. | FGF variants and methods for use thereof |
US8916522B2 (en) | 2002-05-09 | 2014-12-23 | Prochon Biotech Ltd. | FGF-9 variants and methods of use thereof |
US9487568B2 (en) | 2002-05-09 | 2016-11-08 | Prochon Biotech Ltd. | FGF-2 variants and methods of use thereof |
WO2003094835A2 (fr) | 2002-05-09 | 2003-11-20 | Prochon Biotech Ltd. | Variantes de fgf et leurs procedes d'utilisation |
US8609823B2 (en) | 2002-05-09 | 2013-12-17 | ProChon Biotech, Ltd. | FGF-9 variants and methods for use thereof |
US8119783B2 (en) | 2002-05-09 | 2012-02-21 | Prochon Biotech Ltd. | FGF variants and methods for use thereof |
USRE42208E1 (en) | 2003-04-29 | 2011-03-08 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
USRE43258E1 (en) | 2003-04-29 | 2012-03-20 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US8221500B2 (en) | 2003-05-16 | 2012-07-17 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
WO2006007780A1 (fr) * | 2004-07-22 | 2006-01-26 | Fang Xu | Matiere pour reparation d'os sous forme de gelatine injectable et son procede de preparation |
US8292968B2 (en) | 2004-10-12 | 2012-10-23 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
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US8048857B2 (en) | 2006-12-19 | 2011-11-01 | Warsaw Orthopedic, Inc. | Flowable carrier compositions and methods of use |
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US8906110B2 (en) | 2007-01-24 | 2014-12-09 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
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AU2984700A (en) | 2000-08-29 |
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