CA2101556C - Growth factor containing matrix for the treatment of cartilage lesions - Google Patents
Growth factor containing matrix for the treatment of cartilage lesions Download PDFInfo
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- CA2101556C CA2101556C CA002101556A CA2101556A CA2101556C CA 2101556 C CA2101556 C CA 2101556C CA 002101556 A CA002101556 A CA 002101556A CA 2101556 A CA2101556 A CA 2101556A CA 2101556 C CA2101556 C CA 2101556C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
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- A—HUMAN NECESSITIES
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- 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
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/51—Lyases (4)
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- A—HUMAN NECESSITIES
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/626—Liposomes, micelles, vesicles
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/84—Bones; tendons; teeth; cartilage
Abstract
Methods and compositions are provided for the treatment and repair of defects or lesions in the cartilage of humans and other animals. The defect or lesion in the cartilage may be first treated with an enzyme to remove proteoglycans from the defect area.
To induce cartilage formation, the defect is filled or otherwise dressed with a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix filling the defect contains a proliferation agent at a concentration sufficient to stimulate proliferation of repair cells and a transforming factor in an appropriate delivery system to release the transforming factor at a concentration sufficient to transform repair cells in the matrix and defect area into cartilage-producing chondrocytes. The matrix may also contain a chemotactic agent to attract repair cells. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.
To induce cartilage formation, the defect is filled or otherwise dressed with a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix filling the defect contains a proliferation agent at a concentration sufficient to stimulate proliferation of repair cells and a transforming factor in an appropriate delivery system to release the transforming factor at a concentration sufficient to transform repair cells in the matrix and defect area into cartilage-producing chondrocytes. The matrix may also contain a chemotactic agent to attract repair cells. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.
Description
.. .A A , . WO 92/ 13565 GROWTH FACTOR CONTAINING MATRIX FOR THE TREATMENT OF CARTILAGE
LESIONS
TECI~Ba'IC~t. FIELD OF THE INVENTION
This invention relmtes to the treatment and repair of defects or lesions in cartilage. More specifically, this invention relates to methods for treating defects or lesions (used interchangeably 1o herein) in cartilage and to compositions comprising a biodegradable matrix containing one or more proliferating agents to promote proliferation of repair cells to form new stable cartilage tissue. The compositions and methods of this invention are particularly useful in the treatment of osteoarthritis and other diseases and traumas that produce cartilage injury.
Joints are one of the common ways bones in the skeleton are connected. The ends of normal articulated bones are covered by articular cartilage tissue, which permits practically frictionl=ss movement of the bones with respect to one another [L. 6~eiss, ed., Cell and Tissue Biolocv (hunchen: Urban and Schwarzenburg, 1988) p. 247.
Articular cartilage is characterized by a particular structural organization. It consists of ~" W _ , WO 92/13565 ' ~ ~ ~ ~~'' C~~" ~ p~'/US92/00840 , , specialized cells (chondrocytes) embedded in an intercellular material (often referred to in the literature as the "cartilage matrix") which is rich in proteoglycans, collagen fibrils of predominantly type II, other proteins, and water [Buckwalter et al., "Articular Cartilage: Injury and Repair," in jajurv and Repair of the Husculoskel tit cr,ft Tissues (park Ridge, I11.: llmerican llcademy of Orthopaedic Surgeons Symposium, 1987) p. 465]. Cartilage tissue is neither to innervated nor penetrated by the vascular. or lymphatic systems. However, in the mature joint of adults, the underlying subchondral bone tissue, which forms a narrow, continuous plate between the bone tissue and the cartilage, is innervated and vascularized. Beneath this bone plate, the bone tissue forms trabeculae;
containing the marrow. In immature faints, articular cartilage is underlined by only primary bone trabeculae. Jl portion of the meniscal tissue fn joints also consists of cartilage whose make-up is similar to 2o articular cartilage [Bsaupre, J~. et al., clin.~Orthofl.
Rel. Res., pp. 72-76 (1986)].
Tvo types of defects or lesions are recognized in cartilage tissue, i.e., full-thickness defects and superficial defects. These defects differ not only in the extent of physical damage to the cartilage., but also in the nature of the repair response each type~of lesion can elicit.
Full-thickness defects extend to the subchondral bone and can cause severe pain since the 3o bone plate contains sensory nerve endings. Such defects generally arise from severe trauma or during the late stages of degenerative joint disease, such as osteoarthritis. Full-thickness defects may, on occasion, lead to bleeding and the induction of a repair reaction from the subchondral bone [Buckwalter WO 92/13565 ~ ' ~ ~ PCT/US92/00840 et al., "Articular Cartilage: Composition, Structure, Response to Injury, and hethoda of Facilitating Repair," in articular Cartilage and Knee Joint Function: Basic Science and l~rrthroscoov (New York:
Raven Press, 1990) pp, i9-56]. The repair tissue formed is a vascularized fibrous type of cartilage with insufficient biomechanical properties, and does not persist on a long-term basis [Buckwalter et al. (1990), supra].
Superficial defects in the articular cartilage tissue are restricted to the cartilage tissue itself. Such defects are notorious because they do not heal and show no propensity for repair reactions.
These defects may appear as fissures, divots, or clefts in the surface of the cartilage, or they may have a "crab-meat" appearance in the affected tissue.
They contain no~bleeding vessels (blood spots) such as are seen in full-thickness defects. Superficial defects may have no known cause, but often they are the result of mechanical derangements which lead to a wearing down of the cartilaginous tissue, hechanical derangements may be caused by trauma to the joint, e:g., a displacement of torn meniscus tissue into the joint, meniscectomy, a laxation of the joint by a torn ligament, malalignment of joints, or bone fracture, or by hereditary diseases. Superficial defects are also characteristic of early stages of degenerative joint diseases, such as osteoarthritis. Since the cartilage tissue is not innervated (Ham~s Histolow (9th ed.) (Philadelphia: J.B. Lippincott Co. 1987), pp. 266-272]
or vascularized, superficial defects are not painful.
However, although painless; superficial defects do not heal and often degenerate into full-thickness defects.
It is generally believed that because articular cartilage lacks a vasculature, damaged ,.. .. ' , 'z ~, ~ ~ ~. ~ ~ PCf/US92/00840 cartilage tissue does not receive sufficient or proper stimuli to elicit a repair response [Webber et al., "Intrinsic Repair Capabilities of Rabbit Meniscal Fibrocartilage: A Cell Culture Model", (30th Ann.
Orthop. Res. Soc., Atlanta, Feb. 1984); Webber et al., Z,. Orthoo. Res., ~, pp. 36-42 (1985)). It is theorized that the chondrocytes in the cartilaginous tissue are normally not exposed to sufficient amounts of repair-stimulating agents such as growth factors and fibrin clots typically present in damaged vascularized tissue.
One approach that has been used to expose damaged cartilage tissue to repair stimuli involves drilling or scraping through the cartilage into the subchondral bone to cause bleeding [Buckwalter et al.
(1990), ,8y~]. Unfortunately, the repair response of the tissue to such surgical trauma is usually comparable to that observed to take place naturally in full-thickness defects that cause bleeding, viz., formation of a fibrous type of cartilage which exhibits insufficient biomechanical properties and which does not persist on a long-term basis [8uckwalter et al.
(1990) , su~ira) A variety of growth factors have been isolated and are now available for research and biomedical applications [see e.g., Rizzino, A., )~
Biol., y~Q, pp. 411-22 (1988)]. Some of these growth factors, such as transforming growth factor beta (TGF-B), have been reported to promote formation of cartilage-specific molecules, such as type II collagen 3o and cartilage-specific proteoglycans, in embryonic rat mesenchymal cells in vitro [e. g., Seyedin et al., Proc.
Natl. Acad. Sci. USA, g~, pp. 2267-?1 (1985); Seyedin et al., J. Biol. Chem., j~~, pp. 5693-95 (1986);
Seyedin et al., J. Biol. Chem., ~, pp. 1946-19'9 (1987)).
~ WO 92/13565 Millions of patients have been diagnosed as having osteoarthritis, i.e., as having degenerating defects or lesions in their articular cartilage.
Nevertheless, despite claims of various methods to 5 elicit a repair response in damaged cartilage, none of these treatments has received substantial application (Buckwalter et al. (1990), ~; Knutson et al., J. Bone and Joint Surc., ~~e-B, p. 795 (1986); lCnutson et al., J, Bone and Joint Sura., 67-HB, p. 47 (1985);
Knutson et al., Clin. Orthoo., ~, p. 202 (1984);
Harquet, clan. Orthoc., ~,ø,.p. 102 (1980).]. llnd such treatments have generally provided only temporary relief. Systemic use o! "chondroprotective agents" has also been purported to arrest the progression of osteoarthritis and to induce relief of pain. However, such agents have not been shown to promote repair of lesions or defects in cartilage tissue.
To date, treatment of patients suffering from osteoarthritis has been directed largely to symptomatic relief through the use of analgesics and anti=
inflammatory agents. without a treatment that will elicit repair of superficial defects in articular cartilage, the cartilage frequently wears down to the subchondral bone plate. 1~t this phase of the disease, i.e., severe osteoarthritis, the unremitting nature of the pain and the significant compromise of function often dictates that the entire joint be excised and replaced with an artificial joint of metal and/or plastic. Some one-half million procedures comprising joint resection and replacement with an artificial joint are currently performed on knees and hips each year. (See e.g., Graves, E.J., "1988 Summary; National Hospital Discharge Survey", advanced Data From Vital and Health Statistics, ~, pp, 1-12 (June 19, 1990)].
. ~ ~ ~ ~ ~ ~~ ~ y PCf/US92/00840 There is, therefore, a need for a reliable treatment for cartilage defects which can induce repair and regeneration of stable cartilage and prevent the progression of superficial cartilage defects or lesions into severe osteoarthritis.
The present invention solves the problems referred to above by providing effective therapeutic methods and compositions to induce the repair of lesions in cartilage of humans and other animals. Use of the methods and compositions of this invention also prevents the progression of traumatic lesions and early forms of osteoarthritis which would otherwise lead to severe osteoarthritis with unremitting pain and loss of effective joint function lending to probable resection and replacement~of the joint.
In general outline, the methods of this invention far repairing cartilage defects comprise filling or otherwise dressing a defect in the cartilage with a composition of this invention comprising (1) a biodegradable matrix or matrix-forming material, (2) a proliferation agent to promote the proliferation of repair cells in the matrix and defect area, and, in certain embodiments, (3) a chemotactic agent to attract repair cells to the matrix and defect area, and (4) a transforming factor in an appropriate delivery system which will release the transforming factor at an appropriate time to promote differentiation (i.e., transformation) of the repair cells in the matrix or defect area into chondrocytes which produce new stable cartilage tissue. Alternatively, the transforming factor may be added to the defect site separately at the appropriate time.
(,i WO 92/13565 i~'~ ~ ~ ~ ~ ~ PGT/US92/0084(1 Treatment of cartilage defects can be effected during a single arthroscopic or surgical procedure using the methods of this invention.
According to certain methods of this invention, after identification of the defect, the defect is treated by the steps of (1) filling the defect area with an enzyme, which degrades the proteoglycans present on the surface of the defect, (2) removing the enzyme, and (3) dressing the defect with a composition comprising a matrix, a proliferation agent, and a transforming factor in an appropriate delivery system.
In order that the invention may be more fully understood, the following detailed description is provided. In the description the following terms are used.
ArthroscoDV -- as used herein, refers to the use of an arthroscope to examine or perform surgery on a joint.
Cartilave -- as used herein, refers to a type of connective tissue that contains chondrocytes embedded in an intercellular material (often referred to as the "cartilage matrix") comprising fibrils of .
collagen (predominantly type II collagen along with other minor types, e.g:, types IX and XI), various proteoglycans (e.g., chondroitinsulfate-, keratansulfate-, and dermatansulfate proteoglycans), other proteins, and water. Cartilage as used herein includes articular and meniscal cartilage. Articular cartilage covers the surfaces of the portions of bones in joints and allows movement in joints without direct bone-to-bone contact, and thereby prevents wearing down and damage to apposing bone surfaces. Host normal healthy articular cartilage is also described as ,._, ~ _ , WO 92/13565 ' ~ '~ ~ ~ ~ ~ ~ PCT/US92/00840 "hyaline", i.e., having a characteristic frosted glass appearance. Meniscal cartilage is usually found in joints which are exposed to concussion as well as movement. Such locations of meniscal cartilage include the temporo-mandibular, sterno-clavicular, acromio-clavicular, wrist and knee joints [Gray s Anatomy (New York: Bounty Booka, 1977)].
Cell adhesion,yromoting factor -- as used herein, refers to any compound or composition, including fibronectin and other peptides as small as tetrapeptides which comprise the tripeptide Arg-Gly-Asp, which mediates the adhesion of cells to extracellular material [Ruoslathi at al., pp. 517-518 (1986)].
Chemotactic Acent -- as used herein, refers to any compound or composition, including peptides, proteins, glycoproteins and glycosaminoglycan chains, which is capable of attracting cells in standard in vitro chemotactic assays [e. g., Wahl et al., Proc.
Natl . Acad. Sci . USl~, ~,, pp. 5788-92 ( 1987 ) Postlewaite et al., J. Exm. Med., ,~, pp. 2'51-56 (1987); Moore et al., Int. J. Tiss. Reac., pp. 301-07 (1989)].
Chondrocyrtes -- as used herein, refers to cells which are capable of producing components of cartilage tissue, e.g., type II cartilaginous fibrils and fibers and proteoglycans.
Fibroblast growth factor lFGF1 -- any member of the family of FGF polypeptides [Gimenez-Gallego et al., Biochem. Biorhvs. Res. Commun., ~, pp. 541-548 (1986); Thomas et al., Trends Biochem. Sci., ~, pp. 81-84 (1986)] or derivatives thereof, obtained from natural, synthetic or recombinant sources, which exhibits the ability to stimulate DNA synthesis and cell division in vitro (for assays see, e.g., Gimenez-Gallego et al., 1986, supra; Canalis et al., J. Clin.
I. v~, $1, pp. 1572-1577 (1988)) of a variety of cells, including primary fibroblasts, chondrocytes, vascular and corneal endothelial cells, osteoblasts, myoblasts, smooth muscle and glial cells [Thomas et al., 1986, ), FGFs may be classified as acidic (aFGF) or basic (bFGF) FGF, depending on their isoelectric points (pI).
as used herein, refers to a porous composite, solid or semi-solid biodegradable substance having pores or spaces sufficiently large to allow cells to populate the matrix. The term matrix includes matrix-forming materials, 1.e., materials which can form matrices within the defect site in cartilage.
Matrix-forming materials may require addition of a polymerizing agent to form a matrix, such as adding thrombin to a solution containing fibrinogen to form a fibrin matrix.
Proliferation lmitoaen'~,; Aaent -- as used herein, refers to any compound or composition, including peptides, proteins, and glycoproteins, which is capable of stimulating proliferation of cells in vitro. In vitro assays to determine the proliferation (mitogenic) activity of peptides, polypeptides and other compounds are well-known in the art [see, e.g., Canalis et al., J. Clin. I...ve~r_=~ pp, 1572-77 (1988);
Gimenez-Gallego et al., Hiochem. Biophvs. Rep- Commun 1~, pp. 541-548 (1986); Rizzino, "Soft Agar Growth Assays for Transforming Growth Factors and Mitogenic Peptides", in Methods Enzvmol , 146A (New Ye~rk:
Academic Press, 198?), pp, 341-52; Dickson et al., .
"Assay of Mitogen-Induced Effects on Cellular Incorporation of Precursors for Scavengers, ~g Novo, and Net DNA Synthesis", in Methods Enzvmoi., 146A
(New York: Academic Press, 1987), pp, 329-40]. One WO 92/13565 c t:' x'' v PCT/US92/00840 .
standard method to determine the proliferation (mitogenic) activity of a compound or composition is to assay it in vitro for its ability to induce anchorage-independent growth of nontransformed cells in soft agar [e. g., Rizzino, 1987, surra]. Other mitogenic activity assay systems are also known [e. g., Gimenez-Gallego et al., 1986, eyrra; Canalis et al., 1988, ~pra;
Dickson et al., 1987, ~pra].
Rerair Ceil -- as used herein, refers to a cell which, when exposed to appropriate stimuli, wilt differentiate and be transformed into a chondrocyte.
Repair cells include mesenchymal cells, fibroblasts, fibroblast-like cells, macrophages, and dedifferentiated chondrocytes.
Transforming Factor -- as used herein, refers to any peptide, polypeptide, protein, or any other compound or composition which induces differentiation of a repair cell into a chondrocyte. The ability of the compound or composition to induce or stimulate production of cartilage-specific proteoglycans and type II collagen by cells can be determined by in vitro assays known in the art [Seyedin et al., Proc. Nati.
Acad. Sci. USA, $,g,, pp. 2267-71 (1985); Seyedin et al., Path. Immunoi. Res., 1, pp. 38-42 (1987)].
T~anaf9~mina Growth Factor Aeta tTC_:F-g~ --any member of the family of TGF-8 polypeptides [Derynck, R. et al., Nature, ~,ø, pp. 701-705 (1985);
Roberts et al., "The transforming growth factor-B~s", In peptide Growth factors and their receptors I
(Berlin: Springer Verlag, 1990), p. 419)] or derivatives thereof, obtained from natural, synthetic or recombinant sources, which exhibits the characteristic TGF-B ability to stimulate normal rat kidney (NRK) cells to grow and form colonies in a soft agar assay [Roberts et al., 1984, ~pra] and which is ~ ~ CA 02101556 2001-09-10 capable of inducing transformation of repair cells into chondrocytes as evidenced by the ability to induce or stimulate production of cartilage-specific proteoglycans and type II collagen by cells in vitro [Seyedin et al., 1985, supra].
This invention relates to compositions and methods for treating defects or lesions in cartilage.
The compositions of this invention comprise a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix also contains a proliferation agent to stimulate the proliferation of repair cells in the matrix.
Preferably, the proliferation agent also series as a chemotactic agent to attract repair cells to the matrix. Alternatively, the matrix may contain a chemotactic agent in addition to the proliferation agent. In one preferred embodiment of this invention, the matrix also contains an appropriate concentration of a transforming factor, the transforming factor being contained within or in association with a delivery system which effects release of the transforming factor at the appropriate time to transform the proliferated repair cells in the matrix into chondrocytes which produce stable cartilage tissue. The matrix may also contain a cell adhesion promoting factor.
Matrix materials useful in the methods and compositions of this invention for filling or otherwise dressing the defect in the cartilage include fibrinogen (activated with thrombin to form fibrin in the defect or lesion), collagen, Sepharose, gelatin and any other biodegradable material which forms a matrix with pores sufficiently large to allow repair cells to populate and proliferate within the matrix and which can be degraded and replaced with cartilage during the repair process.
* Trade--mark WO 92/13565 ~~ ~ ;~ '~ ~ PCT/US92/00840 The matrices useful in the compositions and methods of this invention may be preformed or may be formed in situ, for example, by polymerizing compounds and compositions such as fibrinogen to form a fibrin matrix. Matrices that may be preformed include collagen (e. g., collagen sponges and collagen fleece), chemically modified collagen, gelatin beads or sponges, a gel-forming substance such as S~pharose, any other gel-forming or composite substance that is composed of a biodegradable matrix material that will fill the defect and allow repair cells to populate the matrix, or mixtures of the above.
In a preferred embodiment of this invention, the matrix is formed using a matrix-forming material, preferably a solution of fibrinogen, to which is added thrombin to initiate polymerization shortly before use.
1~ fibrinogen concentration of 0.5-5 mg/ml of an aqueous buffer solution may be used. Preferably, a fibrinogen solution of 1 mg/ml of an aqueous buffer solution is 2o used. Polymerization of this fibrinogen solution in the defect area yields a matrix with a pore size sufficiently large (e.g., approximately 50-200 um) so that repair cells are free to populate the matrix and proliferate in order to fill the volume of the defect that the matrix occupies. Preferably, a sufficient amount of thrombin is added to the fibrinogen solution shortly before application in order to allow enough time for the surgeon to deposit the material in the defect area prior to completion of polymerization.
3o Typically, the thrombin concentration should be such that polymerization is achieved within a few to several (2-4) minutes since exposure of cartilage to air for lengthy periods of time has been shown to cause damage [Mitchell et al., J. Bone sToint Su~,q_, T_y~, pp. 89-95 (1989)]. Excessive amounts of thrombin should not be used since thrombin has the ability to cleave growth factor molecules and inactivate them. Thrombin solutions of 10-500 units per ml, and preferably 100 units per ml, of an aqueous buffer solution may be prepared for addition to the fibrinogen solution. In a preferred embodiment of this invention, approximately 20 ~l of thrombin (loo ~/ml) are mixed with each ml of a fibrinogen solution (1 mg/ml) approxiaately 200 seconds before filling the defect. Polymerization will occur more slowly if a lower concentration of thrombin is added. It will be appreciated that the amount of thrombin solution needed to achieve fibrin polymerization within 2-4 minutes can be given only approximately, since it depends upon the environmental temperature, the temperature of the thrombin solution, the temperature of the fibrinogen solution, etc. The polymerization of the thrombin-activated matrix solution filling the defect is easily monitored by observing the thrombin-induced polymerization of an external sample of the fibrinogen solution.
Preferably, in the compositions and methods of this invention, fibrin matrices are formed from autologous fibrinogen molecules, i.e., fibrinogen molecules derived from the blood of the same mammalian species~as the species to be treated. Non-immunogenic fibrinogen from her species may also be used.
When collagen is used as a matrix material, sufficiently viscous solutions can be made, e.g., using Collagen-Vliess~ ("fleece") or gelatine-blood-mixtures, and there is no need for a polymerizing agent.
Collagen matrices may also be used with a fibrinogen solution activated with a polymerizing agent so that a combined matrix results.
Polymerizing agents may also be unnecessary when other biodegradable compounds are used to form the WO 92/13565 r~ ~ ~ ~ ~ ;~ ~ PCf/US92/00840 matrix. For example, Sepharose solutions may be chosen that will be liquid matrix solutions at 39-42~C and become solid (1.e., gel-like) at 35-38~C. The Sepharose should also be at concentrations such that the gel filling the cartilage defect has a mesh size to allow repair cells to freely populate the matrix and defect area.
In the compositions of this invention, one or more proliferation (mitogenic) agents may be added to l0 the matrix solution. The proliferation agent or agents should be present in an appropriate concentration range to have a proliferative effect on repair cells in the matrix filling the defect (see Examples section).
Preferably, the same agent should also have a chemotactic effect on the cells (as in the case of TGF-B); however, a factor having exclusively a proliferative effect may be used. Alternatively, to produce chemotactic cell immigration, followed by induction of cell proliferation, two different agents may be used, each one having just one of those specific effects (either chemotactic or proliferative).
Proliferation (mitogenic) agents useful in the compositions and methods of this invention for stimulating the proliferation of repair cells include transforming growth factors ("TGFs") such as TGF-aS and TGF-Bs; insulin-like growth factor ("IGF I"); acidic or basic fibroblast growth factors ("FGFs"); platelet-derived growth factor ("PDGF"); epidermal growth factor ("EGF"); and hemopoietic growth factors, such as interleukin 3 ("IL-3") (Rizzino, 1987, s~ ra; Canalis et al., supra, 1988; Growth factors in biolocv and medicine, Ciba Foundation Symposium, ~ø (New York:
John Wiley i~ Sons, 1985); Baserga, R., ed., Cell ra owth and division (Oxford: IRL Press, 1985); Sporn, H.A. and Roberts, A.B., eds., Peptide crowt factors and their recectors, Vols. I and II (Berlin: Springer-Verlag, 1990)]. However, these particular examples are not limiting. hny compound or composition which is capable of stimulating the proliferation of cells as 5 demonstrated by an in vitro assay for cell proliferation is useful as a proliferation agent in this invention. Sucb assays are known in the art [e. g., Canalis et al., 1988, ; Gimenez-Gallego et al., 1986, sierra; Gickson et al., 1987, 10 Rizzino, 1987, suzira].
Chemotactic agents useful in the compositions and methods of this invention for attracting repair cells include, for example, TGF-Bs, FGFs (acid or basic), PDGF, tumor necrosis factors (e. g., TNF-a, TNF-15 B) and proteoglycan degradation products, such as glycosaminoglycan chains [Roberts et al. (1990), sera;
Growth factors fn bfoloavr an medicine, Ciba Foundation ~r~~sium, ~ø (New York, John wiley 1 Sons, 1985); R.
Baserga, ed., Cell,growth and' division (Oxford: IRL
Press, 1985)]. Assays to determine the chemotactic ability of polypeptides and other compounds are known in the art [e. g., Postlewaite et al., 1987, suflra; wahl et al., 1987, sutra; Moore et al., 1989, supra].
In a preferred embodiment of this invention, the matrix contains TGF-B as the proliferation agent and as the chemotactic agent. In particular, TGF-BI or TGF-BII may be used as the proliferation and chemotactic agent. Other TGF-B forms (e. g., TGF-BIII, TGF-BIV, TGF-BV, etc.) or polypeptides having TGF-B
activity [see Roberts, 1990, sgpra] may also be useful for this purpose, as well as other forms of this substance to be detected in the future, and other growth factors. For use as the proliferation agent and chemotactic agent, TGF-B molecules are dissolved or suspended in the matrix at a concentration of ~ ~ ~, ~~? y ~ PCT/US92/00840 preferably 2-50 ng~ml of matrix solution, and most preferably, 2-10 ng/ml of matrix solution. It will be appreciated that the preferred concentration of TGF-B
that will stimulate proliferation of repair cells may vary with the particular animal to ba treated.
A transforming factor or factors may also be present in the matrix solution so that after repair cells have populated the aatrix, the transforming factor will be released into the defect site in a concentration sufficient to promote differentiation (i.e., transformation) of the repair cells into chondrocytes which form new stable cartilage tissue.
Proper timing of the release of the transforming factor is particularly important if the transforming factor can inhibit or interfere with the effectiveness of the proliferation agent (see Roberts et al. (1990), ~pra].
Transforming factors useful in the compositions and methods of this invention include any peptide, polypeptide, protein or any other compound or 2o composition which induces differentiation of repair cells into chondrocytes which produce cartilage-specific proteoglycans and type II collagen. The ability of a compound or composition to induce or stimulate production of cartilage-specific .
proteoglycans and type II collagen in cells can be determined using assays known in the art (e. g., Seyedin et al., 1985, supra; Seyedin et al., 1987, supra]. The transforming factors useful in the compositions and methods of this invention include, for example, TGF-Bs, TGF-as and FGFs (acid or basic). These transforming factors may be used singly or in .
combination. In,addition, TGF-B may be used in combination with EGF.
The properly timed release of the transforming factor may be achieved by packaging the WO 92/13565 Pcrius9iioosao transforming factor in or with an~~p ~ p~riate delivery system. Delivery systems useful in the compositions and methods of this invention include liposomes, bioerodible polymers, carbohydrate-based corpuscles, fibers such as collagen which are chemically linked to heparin sulfate proteoglycans or other such molecules to which transforming factors bind spontaneously, and osmotic pumps. Delivery systems such as liposomes, bioerodible polymers, fibers with bound transforming 1o factors and carbohydrate-based corpuscles containing the transforming agent may be mixed with the matrix solution used to fill the defect. These systems are known and available in the art (see p. Johnson and J. G. Lloyd-Jones, eds., Drug Deliverv~y (Chichester, England: Ellis Horwood Ltd., 1987)x.
Liposomes may be prepared according to the procedure of Kim et al., Biochem. Bionhvs. l~cta, , 12$ pp. 339-348 (1983). Other liposome preparation procedures may also be used. Additional factors for stimulating chondrocytes to synthesize the cartilage tissue components may be included with the transforming factor in the delivery system.
In a preferred embodiment of this invention, the matrix contains TGF-B as the proliferation and.
chemotactic~agent, and contains TGF-8 packaged in a delivery system as the transforming factor. In particular, TGF-BI or TGF-BII may be used as the proliferation and chemotactic agent and as the transforming factor. Other TGF-B forms (e. g., TGF-BIII, TGF-BIV, TGF-BV, etc.) or polypeotides having TGF-B activity (see Roberts, 1990, supra) may also be useful for this purpose, as well as other forms c.f this substance to be detected in the future, and other growth factors.
WO 92/13565 ~ ~ ~ ~ ~ ~ ~ PCT/US92/00840 In a preferred embodiment, a TGF-B
concentration of preferably 2-50 ng/ml of matrix solution, and most preferably, 2-10 ng/ml of matrix solution, is used as a proliferation agent and ac a chemotactic agent. A substantially higher concentration of TGF-a is also present in a subsequently releasable form in the matrix composition as a transforming factor. Preferably, the subsequent concentration of TGF-B is greater than 200 ng/ml of matrix and, most preferably, is greater than 500 ng/ml of matrix. It will be appreciated that the preferred concentration of TGF-B to induce differentiation of repair cells may vary with the particular animal to be treated.
It is necessary to stagger the exposure of the repair cells to the two concentration ranges of TGF-8, since TGF-B at relatively high concentrations (e.'g., greater than 200 ng/ml of matrix solution) may not only transform repair cells into chondrocytes, but also will inhibit chemotactic attraction of repair cells; whereas at relatively low concentrations (e. g., 2-10 ng/ml), TGF-B attracts repair cells and stimulates their proliferation, but will not induce transformation of repair cells into chondrocytes which produce cartilage tissue.
In a preferred embodiment of this invention, in order to obtain the sequence of chemotaxis and proliferation, followed by transformation, TGF-B is present both in a free, unencapsulated form and in an encapsulated, or otherwise sequestered, form in the matrix. Preferably, for the purpose of attracting and inducing proliferation of repair cells in the matrix and defect area, TGF-B molecules are dissolved or suspended in the matrix at a concentration of 2-10 ng/ml of matrix solution. To promote transformation of WO 92113565 ~ " '~ ~ ' ~ ~ PCT/US92/00&l0 repair cells in the matrix into chondrocytes, TGF-B
molecules are also present in the matrix sequestered in multivesicular liposomes according to the method of Kim et al., 1983, ~pra, at a concentration of greater than 200 ng/ml of matrix solution, and preferably at a concentration of greater than 500 ng/ml. The TGF-B-loaded liposomes are disrupted when the attracted repair cells have populated the aatrix and have started to degrade the matrix. During the degradation of the matrix, the repair cells ingest and/or degrade the liposomes, resulting in the release of TGF-B at concentrations sufficient to induce the transformation of repair cells into chondrocytes.
The required two-stage delivery of chemotactic and proliferating versus transforming concentrations of TGF-B may also be achieved by combining transforming concentrations of TGF-B with a bioerodible polymer. 711ternatively, a pump, and preferably an implanted osmotic pump, may be used to control the concentration of TGF-8 in the defect and matrix. In this embodiment of the invention, the pump controls the concentration of TGF-B in the matrix, i.e., the pump may release TGF-B at an initial chemotactic and proliferation stimulating concentration and at a subsequent transforming concentration.
Preferably, the transforming concentration of TGF-B is delivered by the pump approximately 1 to 2 weeks post-operatively. Delivery of the transforming factor into the defect volume is preferably localized to the matrix in the defect site.
The proliferation agents and, when used, the transforming factors in the compositions of this invention are applied in the defect site within the biodegradable matrix. Their presence is thus restricted to a very localized site. This is done to WO 92/13565 ~ ~ ~ ~ ~ PCT/US92/00840 avoid their free injection or infusion into a joint space. Such free infucion may produce the adverse effect of stimulating the cells of the synovial membrane to produce joint effusion.
5 Fibronectin or any other compound, including peptides as small as tstrapeptides, that contain the amino acid sequence l~rg-Gly-lisp, may be used as cell adhesion promoting factors [Ruoslathi et al., 1986, in order to enhance the initial adhesion of i0 repair cells to the matrix deposited in the defsct site. Fibrin and certain collagen matrices already contain this sequence [Ruoslathi et al., 1986, When other biodegradable matrices are used, such cell adhesion promoting factors may be mixed with the matrix 15 material before the matrix is used to dress the defect.
Peptides containing Arg-Gly-7lap may also be chemically coupled to the matrix material (e.g., to its fibers or meshes) or to a compound added to the matrix, such as albumin.
20 The compositions hereinbefore described are useful in methods to induce cartilage formation at a selected site of defect or lesion in cartilage tissue of an animal.
The methods of this invention allow for a treatment of cartilage defects in animals, including humans, that is simple to administer and is restricted in.location to the affected joint area. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.
To carry out the methods of treating defects or lesions in cartilage according to this invention, a defect or lesion,is identified, prepared, and dressed with a biodegradable matrix composition according to this invention. A.proliferation (mitogenic) agent is present in the matrix composition at an appropriate WO 92/t3565 '~ ~ ~ ~j PCT/US92/00840 concentration to stimulate the proliferation of repair cells in the matrix and defect or lesion. The same agent may also, at this concentration, serve as a chemotactic agent to attract repair cells, provided that the factor used has a combined effect with respect to cell proliferation and chemotaxis (as does TGF-B at 2-10 ng/ml of matrix). Alternatively, two different agents may be present in the matrix, one with a specific proliferative effect, and the other with a specific chemotactic effect. In an alternative embodiment, after the defect area is dressed with the biodegradable matrix, the proliferation agent and, if desired, a chemotactic agent, may be injected directly into the matrix-filled defect area.
in a subsequent step, the repair cells in the matrix are exposed to a transforming factor at the appropriate time at a concentration sufficient to transform the repair cells into chondrocytes which produce stable cartilage tissue. This may be accomplished by including an appropriate delivery system containing the transforming factor within the matrix composition as described above. Alternatively, the transforming agent may be delivered by injection directly into the matrix-filled defect area at the appropriate time. The transforming concentration should be made available to the cells approximately 1 to 2 weeks following the initial implantation of the biodegradable matrix into the defect area. Additional factors may be added to the delivery system or directly 3o injected in order to better promote synthesis of the cartilage matrix components at this time point.
Cartilage defects or lesions in animals are readily identifiable visually during arthroscopic examination of the joint or during simple examination of the lesion or defect during open surgery. Cartilage ,,.~ . ..
WO 91/13565 ~ ~ ~ ~- ~ ~ ~crius9iioosao defects may also be identified inferentially by using computer aided tomography (GT scanning), X-ray examination, magnetic resonance imaging (l~tI), analysis of synovial fluid or serum markers, or by any other procedure known in the art.
Once a defect has been identified, the surgeon may elect to surgically modify the defect to enhance the ability of the defect to physically retain the solutions and matrix material that are added in the treatment methods described herein. Preferably-, instead of having a flat or shallow concave geometry, the defect has or is shaped to have vertical edges or is undercut in order to better retain the solutions and matrix materials added in the treatment methods described herein.
In addition to the above aechanical measures, which will improve aatrix adherence to the defect site, chemical measures may also enhance matrix adhesion.
Such measures include degrading the superficial layers of cartilage proteoglycans on the defect surface to expose the collagen fibrils of the cartilage so that they may interact with the collagen fibrils of the matrix (when a collagenous matrix is used) or with the fibrin fibrils of the matrix (when a fibrin matrix is used): The proteoglycans on the surface of the cartilage not only tend to interfere with adherence of a fibrin or other biodegradable matrix to the cartilage, but also inhibit thrombin activity locally.
advantageously, proteoglycan degradation products may also have a chemotactic effect on repair cells [Moore, J~.R. et al., Int. J. Tiss. Reac.. XI161, pp. 301-307 (1989)].
Fu;thermore, the adhesion of the matrix to the cartilage of the defect can also be enhanced by .using fibrin glue (i.e., blood factor XIII or fibrin WO 92/13565 ~ ~ ~ ~ ~ ~ ~ pGT/US92/00840 stabilization factor) to promote chemical bonding (cross-linking) of the fibrils of the matrix to the cartilage collagen fibrils on the defect surface [see Gibble et al., Transfusion, 30(8), pp. 741-47 (1990)).
The enzyme transglutaminase may be used to the same effect [see, e.g., Ichinose et al., J. Biol. Chem., 265(23), pp. 13411-14 (1990); "Transglutaminase,~ ~ds:
V. A. Najjar and L. Lorand, Hartinus ~lijhoff Publishers (Boston, 1984)]. Other compounds that can promote adhesion of extracellular materials may also be used.
According to one embodiment of the methods of this invention, the surface of the defect is dried by blotting the area using sterile absorbent tissue, and the defect volume is filled with a sterile enzyme solution for a period of 2-l0 minutes to degrade the proteoglycans present on the surface of the cartilage and locally within approximately 1 to 2 hum deep from the surface of the defect. Various enzymes may be used, singly or in combination, in sterile buffered aqueous solutions to degrade the proteoglycans. The pH
of the solution should be adjusted to optimize enzyme activity.
Enzymes useful to degrade the proteoglycans in the methods of this invention include chondroitinase ABC, chondroitinase AC, hyaluronidase, pepsin, trypsin, chymotrypsin, papain, pronase, stromelysin and Staph V8 protease. The appropriate concentration of a particular enzyme or combination of enzymes will depend on the activity of the enzyme solution.
In a preferred embodiment of this invention, the defect is filled with a sterile solution of chondroitinase ABC at a concentration of 1 U/ml and digestion is allowed to proceed for 4 minutes. The preferred concentration of chondroitinase ABC was :determined by examining with an electron microscope rabbit joint cartilage tissue which had been treated with various concentrations of enzyme for various periods of time as described in Example :. Any other enzyme used should be employed at a concentration for a time period such that only superficial proteoglycans down to a depth of about i-2 ~m are degraded.
The amount of time the enzyme solution is applied should be kept to a minimum to effect the degradation of the proteoglycans predominantly in the l0 repair area. For chondroitinase A8C at a concentration of 1 U/ml, a digestion period longer than 10 minutes may result in the unnecessary and potentially harmful degradation of the proteoglycans outside the defect area. Furthermore, digestion times longer than 10 minutes contribute excessively to the overall time of the procedure. The overall time of the procedure .
should be kept to a minimum, especially during open arthrotomy, because cartilage may be damaged by exposure to air [Mitchell et al., (1989), ~yp~). For 2o these reasons, in the embodiments of the methods of this invention that include the step of degradation of proteoglycans by enzymatic digestion, digestion times of less than 10 minutes are preferred and digestion times of less than 5 minutes are most preferred.
According to the methods of this invention, after the enzyme has degraded the proteoglycans from the surface of the defect, the enzyme solution should be removed from the defect area. Removal of the enzyme solution may be effected by using an aspirator equipped with a fine suction tip followed by sponging with cottonoid. Alternatively, the enzyme solution may be removed by sponging up with cottonoid alone.
Following removal of the enzyme solution, the defect should be rinsed thoroughly, preferably three ;times, with sterile physiologic saline (e.g., 0.15 M
25 ~1~~.5~~
NaCl). The rinsed defect site should then be dried.
Sterile gauze or cottonoid may be used to dry the defect site.
Alternatively, or in addition to the enzyme treatment step, the defect site say be dressed with a compound, such as fibrin glue or transglutaminase, to enhance adhesion of the matrix to the defect site. In a preferred embodiment, fibrin glue or transglutaminase is applied to the defect site after the defect site has 1o been rinsed and dried following enzyme treatment.
According to the methods of this invention, the defect site is next dressed with a composition of this invention, described herein, to fill the defect preferably to its edges with the matrix composition such that a flat plane is formed. The composition comprises a matrix material and a proliferation agent and, if desired, a chemotactic agent. The composition used in this step may also contain, packaged in an appropriate delivery system, a transforming factor. In the most preferred method of the invention, the matrix contains a proliferation agent, a chemotactic agent (which may be identical to the proliferation agent) and a transforming factor which is packaged in or associated with a delivery system that releases the' transforming factor, at a time that the repair calls populating the matrix have begun remodelling the intercellular substance, at a concentration that transforms the repair cells into chondrocytes.
Preferred compositions are described above.
If the matrix does not contain proliferation and chemotactic agent(s), the agents) may be injected directly into the matrix-filled defect area in order to deliver the preferred concentrations to promote chemotaxis and proliferation of repair cells.
Preferably, in this embodiment of the invention, after .~'~' ~ ~ PCT/US92/00840 dressing the defect with the matrix, TGF-B is injected locally into the matrix to give a concentration of 2-10 ng/ml of matrix. Injection should be localized to the matrix-filled defect area to avoid exposure of cells of the synovial membrane to growth factors which could lead to cell proliferation and joint effusion.
J~fter the defect site is dressed with the matrix composition (and, in the case of fibrin matrices, once the matrix has solidified) and, if to required, the proliferation agent has been injected into the matrix-filled defect site, the joint capsule and skin incisions may be closed and the arthroscopy or open surgery terminated.
If the transforming factor is not present in the matrix in an appropriate delivery system, the transforming factor may be added directly into the matrix approximately 1-2 weeks postoperatively, for example, by injection or by an osmotic pump, at a concentratipn sufficient to transform repair cells into chondrocytes. Preferably, in this embodiment of the invention, TGF-B is added directly into the matrix approximately one week post-operatively to give a concentration of greater than 200 ng/ml, and most preferably greater than 500 ng/ml of matrix.
The methods described herein for repairing defects in articular cartilage are most effective when the defect does not extend to the bone beneath the cartilage. The methods described herein may also be used for repairing defects in meniscal cartilage tissue.
In order that the invention described herein may be more fully understood, the following examples are set forth. _ It should be understood that these examples are for illustrative purposes and are not to be construed as limiting this invention in any manner.
r Enzyme Testinc for Proteocrlvc~r m~~~oval In order to promote and improve matrix adherence along superficial defect surfaces of articular cartilage tissue, proteoglycan molecules within the superficial cartilage matrix may be removed enzymatically, in order to expose the collagen fibrillar network to externally applied matrices and to migrating repair cells. Various proteases and to glycosaminoglycan-degrading enzymes are suitable to be used for this purpose, but pH conditions should be controlled to provide maximal activity for each enzyme.
In this example, we tested chondroitinase ABC
(0.5-5 U/ml) and trypsin (0.5-4~j for their ability to effect proteoglycan removal. Knee joints from freshly slaughtered rabbits, obtained from a local butcher, were employed. Mechanically-created superficial cartilage defects were exposed to the enzyme solutions for a period of 4 minutes. Solutions were then removed with absorbent tissue and the defect sites rinsed thoroughly with physiologic saline. Following this procedure, cartilage tissue was fixed immediately in 2t (v/v) glutaraldehyde solution (buffered with 0.05 M
sodium cacodylate, pH 7.4) containing o.7~ (w/v) ruthenium hexamine trichloride (RHT) for histological examination. The post-fixation medium consisted of a it RHT-osmium tetroxide solution (buffered with 0.1 M
sodium cacodylate). Tissue was dehydrated in a graded series of ethanol and embedded in Epon 812. Thin sections were cut, stained with uranyl acetate and lead citrate, and examined in an electron microscope. In these sections, RHT-fixed (i.e., precipitated) proteoglycans appeared as darkly-staining granules.
Enzyme concentrations removing a superficial layer of 4 ..
WO 92/13565 '~ ~ ~ ~ ~ ~ ~~ PCT/US92/00840 .._, proteoglycans no more than i-2 um in thickness were defined as optimal (deeper penetration of enzymes could affect the underlying chondrocytes). Chondroitinase ABC was found to be optimally active at a concentration of approximately 1 U/ml. Trypsin was found to be optimally active at a concentration of approximately 2.5t. The optimal activity range for other glycosaminoglycanases or proteases may be determined in a similar manner. Any buffer may be used in conjunction with the enzyme provided that it is non-toxic and that its maximal buffering capacity occurs at a pH value close to that required for maximal enzyme activity.
Matrix Adhe~Eence to Superficial Defects The possibility of promoting matrix adhesion along defect surfaces by controlled enzyme digestion of superficial cartilage proteoglycans was investigated.
Defects were created in the knee joints of three mature rabbits by cutting with a planing knife. These defects were not enzyme treated. The defects were filled with a fibrin matrix, formed by mixing 20 ~1 of a thrombin solution (100 U/ml aqueous buffer) with each ml of fibrinogen solution (1 mg/ml aqueous buffer) approximately 200 second before filling the defect.
The rabbits were sacrificed after 1 month and the knee joints examined to determine the extent to which the fibrin matrix had adhered to the defect site. The results were compared to those achieved in rabbits whose defects had been treated with chondroitinase ABC
(1 U/ml for 4 minutes) before the defect was filled , with fibrin matrix (see Examples 3, 4 and 5).
The fibrin matrices deposited in defect areas left untreated with an enzyme exhibited low .affinity to ~, ~ ~, ;~ ~ ~ PGT/US92/00840 adhere to the defect surface. Following enzyme treatment, the sticking capacity of the fibrin matrices (determined indirectly by measuring mechanical strength to adhere, i.e., by testing the easiness with which the matrix could be pushed away manually with the tip of a forceps, and indirectly by noting the number of defects in which the matrix successfully remained sticking throughout the experiment) was significantly increased.
The low affinity of matrices for the defect surfaces in l0 the absence of enzyme treatment probably is due to a local inhibition of matrix adhesion by proteoglycan molecules and an inhibition of fibrin polymerization.
Soth of these effects are prevented by enzymatic removal of superficial proteoglycans along the defect surface area.
Application of Growth Factors to Defect Sites to Provide Chemotactic Stimulation of Repair Cell Migration into Defect hreas and Induction of Repair Cell Proliferation Various growth factors were tested for their usefulness in stimulating chemotactic migration of repair cells to the defect area in order to accomplish healing of the defect.
The growth factors employed included a) epidermal growth factor (EGF), b) basic fibroblast growth factor (bFGF), c) insulin-like growth factor I
(IGF I), d) human growth hormone (hGH) and e) transforming growth factor-8 (TGF-B) at concentrations of between 5-10 ng/ml.
Each of these factors was applied locally to defects produced'in the knee following chondroitinase l~rBC treatment and rinsing as described in Example 2. A
total of ten animals (two per growth factor) were 'utilized. Each growth factor was able to ~~ PCT/US92/00840 chemotactically attract or locally stimulate proliferation of repair cells to the defect surfaces sufficiently to completely cover the defect surfaces.
However, the cells were only present on the surfaces of 5 the defects, and in no instance was proliferation of the repair cells adequate to fill the defect volume.
(It is believed that the proteoglycan degradation products by themselves, i.e., without the addition of any other agent, exert a sufficient 10 chemotactic effect to attract repair cells to the defect. Irloore, A.R. et al. [Int. J. Tiss. Reac., XI(bl, pp. 301-107, 1989] have shown that proteoglycan degradation products have chemotactic effects per se.) 15 Application to Defect Sites of Growth Factors Entrapped in Biodegradable Matrices to Provide Chemotactic Stimulation of Repair Cell Migration into Defect Areas and Induction of Repair Cell Proliferation 2o Since local application of a growth factor under the conditions of Example 3 in no instance induces repair cell proliferation adequate to fill the defect volume, the experiment was repeated using the same growth factors, but this time the growth factors 25 were entrapped in biodegradable matrices. The biodegradable matrices used were fibrin, collagen and Sepharose. Sufficient quantities of matrices containing growth factor were applied to fill the defect volumes completely.
30 Fibrin matrices were formed by mixing 20 ~cl of a thrombin solution (100 U/ml of an aqueous buffer solution: Veronah acetate buffer, pH 7.0) with each ml of fibrinogen solution (1 mg/ml of an aqueous buffer solution: 0.05M Tris, pH 7.4, O.iH NaCl) approximately 200 seconds prior to filling the defect. For collagen '~ ~ ~ ~ ~ ~ ~ PCT/US92/00840 matrices, sufficiently viscous solutions were made using Colagen-Vliess~ or gelatine-blood-mixtures. For Sepharose matrices, defects were filled with liquid solutions of Sepharoae at 39-42~C. Upon cooling (35-38~C), a Sepharose aatrix was formed in the defect.
Thirty rabbits (two for each type of matrix and growth factor) were utilized for this experiment.
In all cases where the deposited matrix remained adherent to the defect, it became completely populated to by fibroblast-like repair cello. This situation was found to exist as early as eight to ten days post-operatively. Ho further changes occurred in the structural organization of the repair tissue up to four weeks post-operatively, except that the biodegradable matrices became remodelled by the repair cells and replaced by a loose, connective tissue type of extracellular matrix.
Transformation of this tissue to cartilage tissue did not occur.
2 o EycAMPI,E ~
Application to Defect Sites of Growth Factors Entrapped in Biodegradable Matrices to Provide Chemotactic Stimulation of Repair Cell Migration into Defect Areas and Induction of Repair Cell Proliferation Followed by Timed, Local Release of a Transforming Factor at a Secondary Stage to Provide Transformation of the Defect Site into Hyaline CartilaEge The observation that matrices within the defect volume were completely filled with repair cells following application of growth factor, and that these cells were able to remodel the deposited matrix (see Example 4), prompted the investigation of the effects of introducing a transforming factor (such as TGF-8) in an encapsulated form (e.g., liposomes) from which the transforming factor would be released when the matrix WO 92/13565 r G~ ' PCT/US92/00840 was completely populated with repair cells that had begun to remodel the intercellular structure.
TGF-B was mixed into the fibrinogen solution (1 mg/ml) at a low concentration (e.g., 2-10 ng/ml) for the purpose of promoting the initial chemotactic and proliferative effects. TGF-8 was also encapsulated in liposomes according to the method of Rim et al. (1983) supra. These TGF-B containing liposomes were added to the same fibrinogen solution in a concentration adequate to provide, when the liposomes were ruptured and the TGF-B was released, the higher concentration of 100-1000 ng of TGF-B per ml of fibrinogen for the purpose of promoting transformation of the repair cells into chondrocytes and transformation of the matrix-filled defect into cartilage during a secondary stage when the repair cells populating the fibrin matrix have begun to remodel~the intercellular substance.
Ten mature rabbits, in which superficial knee joint articular cartilage defects were produced as in Example 2, were treated by application of this~mixture of fibrinogen containing free and liposome-encapsulated TGF-8 to the defect site. In the various experiments in this series of experiments, the concentration of free TGF-B was maintained in the range from 2-10 ng/ml of fibrinogen while the concentration of encapsulated TGF-8 was varied to provide (upon release of the TGF-B
from the liposomes) a concentration between 100 and 1000 ng TGF-B/ml fibrinogen in 100 ng steps. Formation of hyaline cartilage tissue occurred at the treatment 3o sites in all cases. The most reproducible results were obtained at concentrations of above 200 ng encapsulated TGF-8/ml fibrinogen solution, and preferably above 500 ng TGF-B/ml of fibrinogen solution.
~~.pl~aJ~
Determination of the Time Point of Tissue Transformation In this experiment, a group of six mature rabbits were subjected to knee surgery to produce superficial defects as in Example 2. A full treatment scheme for superficial defect repair was applied, i.e., treatment with chondroitinase ABC (1 U/ml for 4 minutes), followed by filling the defect site with fibrin matrix (1 mg/ml fibrinogen solutian, 20 ~l 100 U/ml thrombin solution per ml of fibrinogen solution) containing free TGF-B (-2-10 ng/ml) and liposome encapsulated TGF-B (-800 ng/ml). Three rabbits were sacrificed at eight, ten and twelve days postoperatively, the remaining three at twenty, twenty-four and twenty-eight days. Transformation of the primitive, fibroblast-like repair cell tissue into hyaline cartilage tissue occurred between days twelve and twenty in this animal model. This was determined on the basis of histological examination. At-days eight to twelve, loose fibrous repair tissue was still present (the applied fibrin matrix being partially or completely remodelled), whereas at day twenty and subsequently, the defect space was partially or .
completely filled with hyaline cartilage tissue.
Application of Cartilage Repair Procedures in a Mini-Dlq Model The experimental procedures utilised in the rabbit model, supra, were applied to a larger animal model, the mini-pig. Superficial defects (0.6 mm wide, 0.6 mm deep and approximately 10-15 mm long) were created in four mature mini-pigs (2-4 years old, 80-110 lbs.) by cutting with a planing knife in the WO 92/13565 PCT/US92/00840 _ patellar groove and on the medial condyle. The defects were then treated with chondroitinase JsrBC (1 U/ml for 4 minutes, as used for rabbits, ;~ynra). The enzyme solution was removed, the defect dried, rinsed with physiological saline, then dried again. The defect sites were then filled with a fibrinogen matrix solution. The fibrinogen matrix solution used in this experiment contained 2-6 ng of free TGF-8 per ml, and 1500-2000 ng of liposome-encapsulated TGF-8 per ml of fibrinogen solution. Prior to filling the defects, thrombin was added to the matrix solution as described above in the rabbit experiment.
The mini-pigs were sacrificed 6 weeks postoperatively, and the sites of the matrix-filled defects were examined histologically. All sites showed healing, i.e., formation of hyaline cartilage tissue at the treatment site.
LESIONS
TECI~Ba'IC~t. FIELD OF THE INVENTION
This invention relmtes to the treatment and repair of defects or lesions in cartilage. More specifically, this invention relates to methods for treating defects or lesions (used interchangeably 1o herein) in cartilage and to compositions comprising a biodegradable matrix containing one or more proliferating agents to promote proliferation of repair cells to form new stable cartilage tissue. The compositions and methods of this invention are particularly useful in the treatment of osteoarthritis and other diseases and traumas that produce cartilage injury.
Joints are one of the common ways bones in the skeleton are connected. The ends of normal articulated bones are covered by articular cartilage tissue, which permits practically frictionl=ss movement of the bones with respect to one another [L. 6~eiss, ed., Cell and Tissue Biolocv (hunchen: Urban and Schwarzenburg, 1988) p. 247.
Articular cartilage is characterized by a particular structural organization. It consists of ~" W _ , WO 92/13565 ' ~ ~ ~ ~~'' C~~" ~ p~'/US92/00840 , , specialized cells (chondrocytes) embedded in an intercellular material (often referred to in the literature as the "cartilage matrix") which is rich in proteoglycans, collagen fibrils of predominantly type II, other proteins, and water [Buckwalter et al., "Articular Cartilage: Injury and Repair," in jajurv and Repair of the Husculoskel tit cr,ft Tissues (park Ridge, I11.: llmerican llcademy of Orthopaedic Surgeons Symposium, 1987) p. 465]. Cartilage tissue is neither to innervated nor penetrated by the vascular. or lymphatic systems. However, in the mature joint of adults, the underlying subchondral bone tissue, which forms a narrow, continuous plate between the bone tissue and the cartilage, is innervated and vascularized. Beneath this bone plate, the bone tissue forms trabeculae;
containing the marrow. In immature faints, articular cartilage is underlined by only primary bone trabeculae. Jl portion of the meniscal tissue fn joints also consists of cartilage whose make-up is similar to 2o articular cartilage [Bsaupre, J~. et al., clin.~Orthofl.
Rel. Res., pp. 72-76 (1986)].
Tvo types of defects or lesions are recognized in cartilage tissue, i.e., full-thickness defects and superficial defects. These defects differ not only in the extent of physical damage to the cartilage., but also in the nature of the repair response each type~of lesion can elicit.
Full-thickness defects extend to the subchondral bone and can cause severe pain since the 3o bone plate contains sensory nerve endings. Such defects generally arise from severe trauma or during the late stages of degenerative joint disease, such as osteoarthritis. Full-thickness defects may, on occasion, lead to bleeding and the induction of a repair reaction from the subchondral bone [Buckwalter WO 92/13565 ~ ' ~ ~ PCT/US92/00840 et al., "Articular Cartilage: Composition, Structure, Response to Injury, and hethoda of Facilitating Repair," in articular Cartilage and Knee Joint Function: Basic Science and l~rrthroscoov (New York:
Raven Press, 1990) pp, i9-56]. The repair tissue formed is a vascularized fibrous type of cartilage with insufficient biomechanical properties, and does not persist on a long-term basis [Buckwalter et al. (1990), supra].
Superficial defects in the articular cartilage tissue are restricted to the cartilage tissue itself. Such defects are notorious because they do not heal and show no propensity for repair reactions.
These defects may appear as fissures, divots, or clefts in the surface of the cartilage, or they may have a "crab-meat" appearance in the affected tissue.
They contain no~bleeding vessels (blood spots) such as are seen in full-thickness defects. Superficial defects may have no known cause, but often they are the result of mechanical derangements which lead to a wearing down of the cartilaginous tissue, hechanical derangements may be caused by trauma to the joint, e:g., a displacement of torn meniscus tissue into the joint, meniscectomy, a laxation of the joint by a torn ligament, malalignment of joints, or bone fracture, or by hereditary diseases. Superficial defects are also characteristic of early stages of degenerative joint diseases, such as osteoarthritis. Since the cartilage tissue is not innervated (Ham~s Histolow (9th ed.) (Philadelphia: J.B. Lippincott Co. 1987), pp. 266-272]
or vascularized, superficial defects are not painful.
However, although painless; superficial defects do not heal and often degenerate into full-thickness defects.
It is generally believed that because articular cartilage lacks a vasculature, damaged ,.. .. ' , 'z ~, ~ ~ ~. ~ ~ PCf/US92/00840 cartilage tissue does not receive sufficient or proper stimuli to elicit a repair response [Webber et al., "Intrinsic Repair Capabilities of Rabbit Meniscal Fibrocartilage: A Cell Culture Model", (30th Ann.
Orthop. Res. Soc., Atlanta, Feb. 1984); Webber et al., Z,. Orthoo. Res., ~, pp. 36-42 (1985)). It is theorized that the chondrocytes in the cartilaginous tissue are normally not exposed to sufficient amounts of repair-stimulating agents such as growth factors and fibrin clots typically present in damaged vascularized tissue.
One approach that has been used to expose damaged cartilage tissue to repair stimuli involves drilling or scraping through the cartilage into the subchondral bone to cause bleeding [Buckwalter et al.
(1990), ,8y~]. Unfortunately, the repair response of the tissue to such surgical trauma is usually comparable to that observed to take place naturally in full-thickness defects that cause bleeding, viz., formation of a fibrous type of cartilage which exhibits insufficient biomechanical properties and which does not persist on a long-term basis [8uckwalter et al.
(1990) , su~ira) A variety of growth factors have been isolated and are now available for research and biomedical applications [see e.g., Rizzino, A., )~
Biol., y~Q, pp. 411-22 (1988)]. Some of these growth factors, such as transforming growth factor beta (TGF-B), have been reported to promote formation of cartilage-specific molecules, such as type II collagen 3o and cartilage-specific proteoglycans, in embryonic rat mesenchymal cells in vitro [e. g., Seyedin et al., Proc.
Natl. Acad. Sci. USA, g~, pp. 2267-?1 (1985); Seyedin et al., J. Biol. Chem., j~~, pp. 5693-95 (1986);
Seyedin et al., J. Biol. Chem., ~, pp. 1946-19'9 (1987)).
~ WO 92/13565 Millions of patients have been diagnosed as having osteoarthritis, i.e., as having degenerating defects or lesions in their articular cartilage.
Nevertheless, despite claims of various methods to 5 elicit a repair response in damaged cartilage, none of these treatments has received substantial application (Buckwalter et al. (1990), ~; Knutson et al., J. Bone and Joint Surc., ~~e-B, p. 795 (1986); lCnutson et al., J, Bone and Joint Sura., 67-HB, p. 47 (1985);
Knutson et al., Clin. Orthoo., ~, p. 202 (1984);
Harquet, clan. Orthoc., ~,ø,.p. 102 (1980).]. llnd such treatments have generally provided only temporary relief. Systemic use o! "chondroprotective agents" has also been purported to arrest the progression of osteoarthritis and to induce relief of pain. However, such agents have not been shown to promote repair of lesions or defects in cartilage tissue.
To date, treatment of patients suffering from osteoarthritis has been directed largely to symptomatic relief through the use of analgesics and anti=
inflammatory agents. without a treatment that will elicit repair of superficial defects in articular cartilage, the cartilage frequently wears down to the subchondral bone plate. 1~t this phase of the disease, i.e., severe osteoarthritis, the unremitting nature of the pain and the significant compromise of function often dictates that the entire joint be excised and replaced with an artificial joint of metal and/or plastic. Some one-half million procedures comprising joint resection and replacement with an artificial joint are currently performed on knees and hips each year. (See e.g., Graves, E.J., "1988 Summary; National Hospital Discharge Survey", advanced Data From Vital and Health Statistics, ~, pp, 1-12 (June 19, 1990)].
. ~ ~ ~ ~ ~ ~~ ~ y PCf/US92/00840 There is, therefore, a need for a reliable treatment for cartilage defects which can induce repair and regeneration of stable cartilage and prevent the progression of superficial cartilage defects or lesions into severe osteoarthritis.
The present invention solves the problems referred to above by providing effective therapeutic methods and compositions to induce the repair of lesions in cartilage of humans and other animals. Use of the methods and compositions of this invention also prevents the progression of traumatic lesions and early forms of osteoarthritis which would otherwise lead to severe osteoarthritis with unremitting pain and loss of effective joint function lending to probable resection and replacement~of the joint.
In general outline, the methods of this invention far repairing cartilage defects comprise filling or otherwise dressing a defect in the cartilage with a composition of this invention comprising (1) a biodegradable matrix or matrix-forming material, (2) a proliferation agent to promote the proliferation of repair cells in the matrix and defect area, and, in certain embodiments, (3) a chemotactic agent to attract repair cells to the matrix and defect area, and (4) a transforming factor in an appropriate delivery system which will release the transforming factor at an appropriate time to promote differentiation (i.e., transformation) of the repair cells in the matrix or defect area into chondrocytes which produce new stable cartilage tissue. Alternatively, the transforming factor may be added to the defect site separately at the appropriate time.
(,i WO 92/13565 i~'~ ~ ~ ~ ~ ~ PGT/US92/0084(1 Treatment of cartilage defects can be effected during a single arthroscopic or surgical procedure using the methods of this invention.
According to certain methods of this invention, after identification of the defect, the defect is treated by the steps of (1) filling the defect area with an enzyme, which degrades the proteoglycans present on the surface of the defect, (2) removing the enzyme, and (3) dressing the defect with a composition comprising a matrix, a proliferation agent, and a transforming factor in an appropriate delivery system.
In order that the invention may be more fully understood, the following detailed description is provided. In the description the following terms are used.
ArthroscoDV -- as used herein, refers to the use of an arthroscope to examine or perform surgery on a joint.
Cartilave -- as used herein, refers to a type of connective tissue that contains chondrocytes embedded in an intercellular material (often referred to as the "cartilage matrix") comprising fibrils of .
collagen (predominantly type II collagen along with other minor types, e.g:, types IX and XI), various proteoglycans (e.g., chondroitinsulfate-, keratansulfate-, and dermatansulfate proteoglycans), other proteins, and water. Cartilage as used herein includes articular and meniscal cartilage. Articular cartilage covers the surfaces of the portions of bones in joints and allows movement in joints without direct bone-to-bone contact, and thereby prevents wearing down and damage to apposing bone surfaces. Host normal healthy articular cartilage is also described as ,._, ~ _ , WO 92/13565 ' ~ '~ ~ ~ ~ ~ ~ PCT/US92/00840 "hyaline", i.e., having a characteristic frosted glass appearance. Meniscal cartilage is usually found in joints which are exposed to concussion as well as movement. Such locations of meniscal cartilage include the temporo-mandibular, sterno-clavicular, acromio-clavicular, wrist and knee joints [Gray s Anatomy (New York: Bounty Booka, 1977)].
Cell adhesion,yromoting factor -- as used herein, refers to any compound or composition, including fibronectin and other peptides as small as tetrapeptides which comprise the tripeptide Arg-Gly-Asp, which mediates the adhesion of cells to extracellular material [Ruoslathi at al., pp. 517-518 (1986)].
Chemotactic Acent -- as used herein, refers to any compound or composition, including peptides, proteins, glycoproteins and glycosaminoglycan chains, which is capable of attracting cells in standard in vitro chemotactic assays [e. g., Wahl et al., Proc.
Natl . Acad. Sci . USl~, ~,, pp. 5788-92 ( 1987 ) Postlewaite et al., J. Exm. Med., ,~, pp. 2'51-56 (1987); Moore et al., Int. J. Tiss. Reac., pp. 301-07 (1989)].
Chondrocyrtes -- as used herein, refers to cells which are capable of producing components of cartilage tissue, e.g., type II cartilaginous fibrils and fibers and proteoglycans.
Fibroblast growth factor lFGF1 -- any member of the family of FGF polypeptides [Gimenez-Gallego et al., Biochem. Biorhvs. Res. Commun., ~, pp. 541-548 (1986); Thomas et al., Trends Biochem. Sci., ~, pp. 81-84 (1986)] or derivatives thereof, obtained from natural, synthetic or recombinant sources, which exhibits the ability to stimulate DNA synthesis and cell division in vitro (for assays see, e.g., Gimenez-Gallego et al., 1986, supra; Canalis et al., J. Clin.
I. v~, $1, pp. 1572-1577 (1988)) of a variety of cells, including primary fibroblasts, chondrocytes, vascular and corneal endothelial cells, osteoblasts, myoblasts, smooth muscle and glial cells [Thomas et al., 1986, ), FGFs may be classified as acidic (aFGF) or basic (bFGF) FGF, depending on their isoelectric points (pI).
as used herein, refers to a porous composite, solid or semi-solid biodegradable substance having pores or spaces sufficiently large to allow cells to populate the matrix. The term matrix includes matrix-forming materials, 1.e., materials which can form matrices within the defect site in cartilage.
Matrix-forming materials may require addition of a polymerizing agent to form a matrix, such as adding thrombin to a solution containing fibrinogen to form a fibrin matrix.
Proliferation lmitoaen'~,; Aaent -- as used herein, refers to any compound or composition, including peptides, proteins, and glycoproteins, which is capable of stimulating proliferation of cells in vitro. In vitro assays to determine the proliferation (mitogenic) activity of peptides, polypeptides and other compounds are well-known in the art [see, e.g., Canalis et al., J. Clin. I...ve~r_=~ pp, 1572-77 (1988);
Gimenez-Gallego et al., Hiochem. Biophvs. Rep- Commun 1~, pp. 541-548 (1986); Rizzino, "Soft Agar Growth Assays for Transforming Growth Factors and Mitogenic Peptides", in Methods Enzvmol , 146A (New Ye~rk:
Academic Press, 198?), pp, 341-52; Dickson et al., .
"Assay of Mitogen-Induced Effects on Cellular Incorporation of Precursors for Scavengers, ~g Novo, and Net DNA Synthesis", in Methods Enzvmoi., 146A
(New York: Academic Press, 1987), pp, 329-40]. One WO 92/13565 c t:' x'' v PCT/US92/00840 .
standard method to determine the proliferation (mitogenic) activity of a compound or composition is to assay it in vitro for its ability to induce anchorage-independent growth of nontransformed cells in soft agar [e. g., Rizzino, 1987, surra]. Other mitogenic activity assay systems are also known [e. g., Gimenez-Gallego et al., 1986, eyrra; Canalis et al., 1988, ~pra;
Dickson et al., 1987, ~pra].
Rerair Ceil -- as used herein, refers to a cell which, when exposed to appropriate stimuli, wilt differentiate and be transformed into a chondrocyte.
Repair cells include mesenchymal cells, fibroblasts, fibroblast-like cells, macrophages, and dedifferentiated chondrocytes.
Transforming Factor -- as used herein, refers to any peptide, polypeptide, protein, or any other compound or composition which induces differentiation of a repair cell into a chondrocyte. The ability of the compound or composition to induce or stimulate production of cartilage-specific proteoglycans and type II collagen by cells can be determined by in vitro assays known in the art [Seyedin et al., Proc. Nati.
Acad. Sci. USA, $,g,, pp. 2267-71 (1985); Seyedin et al., Path. Immunoi. Res., 1, pp. 38-42 (1987)].
T~anaf9~mina Growth Factor Aeta tTC_:F-g~ --any member of the family of TGF-8 polypeptides [Derynck, R. et al., Nature, ~,ø, pp. 701-705 (1985);
Roberts et al., "The transforming growth factor-B~s", In peptide Growth factors and their receptors I
(Berlin: Springer Verlag, 1990), p. 419)] or derivatives thereof, obtained from natural, synthetic or recombinant sources, which exhibits the characteristic TGF-B ability to stimulate normal rat kidney (NRK) cells to grow and form colonies in a soft agar assay [Roberts et al., 1984, ~pra] and which is ~ ~ CA 02101556 2001-09-10 capable of inducing transformation of repair cells into chondrocytes as evidenced by the ability to induce or stimulate production of cartilage-specific proteoglycans and type II collagen by cells in vitro [Seyedin et al., 1985, supra].
This invention relates to compositions and methods for treating defects or lesions in cartilage.
The compositions of this invention comprise a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix also contains a proliferation agent to stimulate the proliferation of repair cells in the matrix.
Preferably, the proliferation agent also series as a chemotactic agent to attract repair cells to the matrix. Alternatively, the matrix may contain a chemotactic agent in addition to the proliferation agent. In one preferred embodiment of this invention, the matrix also contains an appropriate concentration of a transforming factor, the transforming factor being contained within or in association with a delivery system which effects release of the transforming factor at the appropriate time to transform the proliferated repair cells in the matrix into chondrocytes which produce stable cartilage tissue. The matrix may also contain a cell adhesion promoting factor.
Matrix materials useful in the methods and compositions of this invention for filling or otherwise dressing the defect in the cartilage include fibrinogen (activated with thrombin to form fibrin in the defect or lesion), collagen, Sepharose, gelatin and any other biodegradable material which forms a matrix with pores sufficiently large to allow repair cells to populate and proliferate within the matrix and which can be degraded and replaced with cartilage during the repair process.
* Trade--mark WO 92/13565 ~~ ~ ;~ '~ ~ PCT/US92/00840 The matrices useful in the compositions and methods of this invention may be preformed or may be formed in situ, for example, by polymerizing compounds and compositions such as fibrinogen to form a fibrin matrix. Matrices that may be preformed include collagen (e. g., collagen sponges and collagen fleece), chemically modified collagen, gelatin beads or sponges, a gel-forming substance such as S~pharose, any other gel-forming or composite substance that is composed of a biodegradable matrix material that will fill the defect and allow repair cells to populate the matrix, or mixtures of the above.
In a preferred embodiment of this invention, the matrix is formed using a matrix-forming material, preferably a solution of fibrinogen, to which is added thrombin to initiate polymerization shortly before use.
1~ fibrinogen concentration of 0.5-5 mg/ml of an aqueous buffer solution may be used. Preferably, a fibrinogen solution of 1 mg/ml of an aqueous buffer solution is 2o used. Polymerization of this fibrinogen solution in the defect area yields a matrix with a pore size sufficiently large (e.g., approximately 50-200 um) so that repair cells are free to populate the matrix and proliferate in order to fill the volume of the defect that the matrix occupies. Preferably, a sufficient amount of thrombin is added to the fibrinogen solution shortly before application in order to allow enough time for the surgeon to deposit the material in the defect area prior to completion of polymerization.
3o Typically, the thrombin concentration should be such that polymerization is achieved within a few to several (2-4) minutes since exposure of cartilage to air for lengthy periods of time has been shown to cause damage [Mitchell et al., J. Bone sToint Su~,q_, T_y~, pp. 89-95 (1989)]. Excessive amounts of thrombin should not be used since thrombin has the ability to cleave growth factor molecules and inactivate them. Thrombin solutions of 10-500 units per ml, and preferably 100 units per ml, of an aqueous buffer solution may be prepared for addition to the fibrinogen solution. In a preferred embodiment of this invention, approximately 20 ~l of thrombin (loo ~/ml) are mixed with each ml of a fibrinogen solution (1 mg/ml) approxiaately 200 seconds before filling the defect. Polymerization will occur more slowly if a lower concentration of thrombin is added. It will be appreciated that the amount of thrombin solution needed to achieve fibrin polymerization within 2-4 minutes can be given only approximately, since it depends upon the environmental temperature, the temperature of the thrombin solution, the temperature of the fibrinogen solution, etc. The polymerization of the thrombin-activated matrix solution filling the defect is easily monitored by observing the thrombin-induced polymerization of an external sample of the fibrinogen solution.
Preferably, in the compositions and methods of this invention, fibrin matrices are formed from autologous fibrinogen molecules, i.e., fibrinogen molecules derived from the blood of the same mammalian species~as the species to be treated. Non-immunogenic fibrinogen from her species may also be used.
When collagen is used as a matrix material, sufficiently viscous solutions can be made, e.g., using Collagen-Vliess~ ("fleece") or gelatine-blood-mixtures, and there is no need for a polymerizing agent.
Collagen matrices may also be used with a fibrinogen solution activated with a polymerizing agent so that a combined matrix results.
Polymerizing agents may also be unnecessary when other biodegradable compounds are used to form the WO 92/13565 r~ ~ ~ ~ ~ ;~ ~ PCf/US92/00840 matrix. For example, Sepharose solutions may be chosen that will be liquid matrix solutions at 39-42~C and become solid (1.e., gel-like) at 35-38~C. The Sepharose should also be at concentrations such that the gel filling the cartilage defect has a mesh size to allow repair cells to freely populate the matrix and defect area.
In the compositions of this invention, one or more proliferation (mitogenic) agents may be added to l0 the matrix solution. The proliferation agent or agents should be present in an appropriate concentration range to have a proliferative effect on repair cells in the matrix filling the defect (see Examples section).
Preferably, the same agent should also have a chemotactic effect on the cells (as in the case of TGF-B); however, a factor having exclusively a proliferative effect may be used. Alternatively, to produce chemotactic cell immigration, followed by induction of cell proliferation, two different agents may be used, each one having just one of those specific effects (either chemotactic or proliferative).
Proliferation (mitogenic) agents useful in the compositions and methods of this invention for stimulating the proliferation of repair cells include transforming growth factors ("TGFs") such as TGF-aS and TGF-Bs; insulin-like growth factor ("IGF I"); acidic or basic fibroblast growth factors ("FGFs"); platelet-derived growth factor ("PDGF"); epidermal growth factor ("EGF"); and hemopoietic growth factors, such as interleukin 3 ("IL-3") (Rizzino, 1987, s~ ra; Canalis et al., supra, 1988; Growth factors in biolocv and medicine, Ciba Foundation Symposium, ~ø (New York:
John Wiley i~ Sons, 1985); Baserga, R., ed., Cell ra owth and division (Oxford: IRL Press, 1985); Sporn, H.A. and Roberts, A.B., eds., Peptide crowt factors and their recectors, Vols. I and II (Berlin: Springer-Verlag, 1990)]. However, these particular examples are not limiting. hny compound or composition which is capable of stimulating the proliferation of cells as 5 demonstrated by an in vitro assay for cell proliferation is useful as a proliferation agent in this invention. Sucb assays are known in the art [e. g., Canalis et al., 1988, ; Gimenez-Gallego et al., 1986, sierra; Gickson et al., 1987, 10 Rizzino, 1987, suzira].
Chemotactic agents useful in the compositions and methods of this invention for attracting repair cells include, for example, TGF-Bs, FGFs (acid or basic), PDGF, tumor necrosis factors (e. g., TNF-a, TNF-15 B) and proteoglycan degradation products, such as glycosaminoglycan chains [Roberts et al. (1990), sera;
Growth factors fn bfoloavr an medicine, Ciba Foundation ~r~~sium, ~ø (New York, John wiley 1 Sons, 1985); R.
Baserga, ed., Cell,growth and' division (Oxford: IRL
Press, 1985)]. Assays to determine the chemotactic ability of polypeptides and other compounds are known in the art [e. g., Postlewaite et al., 1987, suflra; wahl et al., 1987, sutra; Moore et al., 1989, supra].
In a preferred embodiment of this invention, the matrix contains TGF-B as the proliferation agent and as the chemotactic agent. In particular, TGF-BI or TGF-BII may be used as the proliferation and chemotactic agent. Other TGF-B forms (e. g., TGF-BIII, TGF-BIV, TGF-BV, etc.) or polypeptides having TGF-B
activity [see Roberts, 1990, sgpra] may also be useful for this purpose, as well as other forms of this substance to be detected in the future, and other growth factors. For use as the proliferation agent and chemotactic agent, TGF-B molecules are dissolved or suspended in the matrix at a concentration of ~ ~ ~, ~~? y ~ PCT/US92/00840 preferably 2-50 ng~ml of matrix solution, and most preferably, 2-10 ng/ml of matrix solution. It will be appreciated that the preferred concentration of TGF-B
that will stimulate proliferation of repair cells may vary with the particular animal to ba treated.
A transforming factor or factors may also be present in the matrix solution so that after repair cells have populated the aatrix, the transforming factor will be released into the defect site in a concentration sufficient to promote differentiation (i.e., transformation) of the repair cells into chondrocytes which form new stable cartilage tissue.
Proper timing of the release of the transforming factor is particularly important if the transforming factor can inhibit or interfere with the effectiveness of the proliferation agent (see Roberts et al. (1990), ~pra].
Transforming factors useful in the compositions and methods of this invention include any peptide, polypeptide, protein or any other compound or 2o composition which induces differentiation of repair cells into chondrocytes which produce cartilage-specific proteoglycans and type II collagen. The ability of a compound or composition to induce or stimulate production of cartilage-specific .
proteoglycans and type II collagen in cells can be determined using assays known in the art (e. g., Seyedin et al., 1985, supra; Seyedin et al., 1987, supra]. The transforming factors useful in the compositions and methods of this invention include, for example, TGF-Bs, TGF-as and FGFs (acid or basic). These transforming factors may be used singly or in .
combination. In,addition, TGF-B may be used in combination with EGF.
The properly timed release of the transforming factor may be achieved by packaging the WO 92/13565 Pcrius9iioosao transforming factor in or with an~~p ~ p~riate delivery system. Delivery systems useful in the compositions and methods of this invention include liposomes, bioerodible polymers, carbohydrate-based corpuscles, fibers such as collagen which are chemically linked to heparin sulfate proteoglycans or other such molecules to which transforming factors bind spontaneously, and osmotic pumps. Delivery systems such as liposomes, bioerodible polymers, fibers with bound transforming 1o factors and carbohydrate-based corpuscles containing the transforming agent may be mixed with the matrix solution used to fill the defect. These systems are known and available in the art (see p. Johnson and J. G. Lloyd-Jones, eds., Drug Deliverv~y (Chichester, England: Ellis Horwood Ltd., 1987)x.
Liposomes may be prepared according to the procedure of Kim et al., Biochem. Bionhvs. l~cta, , 12$ pp. 339-348 (1983). Other liposome preparation procedures may also be used. Additional factors for stimulating chondrocytes to synthesize the cartilage tissue components may be included with the transforming factor in the delivery system.
In a preferred embodiment of this invention, the matrix contains TGF-B as the proliferation and.
chemotactic~agent, and contains TGF-8 packaged in a delivery system as the transforming factor. In particular, TGF-BI or TGF-BII may be used as the proliferation and chemotactic agent and as the transforming factor. Other TGF-B forms (e. g., TGF-BIII, TGF-BIV, TGF-BV, etc.) or polypeotides having TGF-B activity (see Roberts, 1990, supra) may also be useful for this purpose, as well as other forms c.f this substance to be detected in the future, and other growth factors.
WO 92/13565 ~ ~ ~ ~ ~ ~ ~ PCT/US92/00840 In a preferred embodiment, a TGF-B
concentration of preferably 2-50 ng/ml of matrix solution, and most preferably, 2-10 ng/ml of matrix solution, is used as a proliferation agent and ac a chemotactic agent. A substantially higher concentration of TGF-a is also present in a subsequently releasable form in the matrix composition as a transforming factor. Preferably, the subsequent concentration of TGF-B is greater than 200 ng/ml of matrix and, most preferably, is greater than 500 ng/ml of matrix. It will be appreciated that the preferred concentration of TGF-B to induce differentiation of repair cells may vary with the particular animal to be treated.
It is necessary to stagger the exposure of the repair cells to the two concentration ranges of TGF-8, since TGF-B at relatively high concentrations (e.'g., greater than 200 ng/ml of matrix solution) may not only transform repair cells into chondrocytes, but also will inhibit chemotactic attraction of repair cells; whereas at relatively low concentrations (e. g., 2-10 ng/ml), TGF-B attracts repair cells and stimulates their proliferation, but will not induce transformation of repair cells into chondrocytes which produce cartilage tissue.
In a preferred embodiment of this invention, in order to obtain the sequence of chemotaxis and proliferation, followed by transformation, TGF-B is present both in a free, unencapsulated form and in an encapsulated, or otherwise sequestered, form in the matrix. Preferably, for the purpose of attracting and inducing proliferation of repair cells in the matrix and defect area, TGF-B molecules are dissolved or suspended in the matrix at a concentration of 2-10 ng/ml of matrix solution. To promote transformation of WO 92113565 ~ " '~ ~ ' ~ ~ PCT/US92/00&l0 repair cells in the matrix into chondrocytes, TGF-B
molecules are also present in the matrix sequestered in multivesicular liposomes according to the method of Kim et al., 1983, ~pra, at a concentration of greater than 200 ng/ml of matrix solution, and preferably at a concentration of greater than 500 ng/ml. The TGF-B-loaded liposomes are disrupted when the attracted repair cells have populated the aatrix and have started to degrade the matrix. During the degradation of the matrix, the repair cells ingest and/or degrade the liposomes, resulting in the release of TGF-B at concentrations sufficient to induce the transformation of repair cells into chondrocytes.
The required two-stage delivery of chemotactic and proliferating versus transforming concentrations of TGF-B may also be achieved by combining transforming concentrations of TGF-B with a bioerodible polymer. 711ternatively, a pump, and preferably an implanted osmotic pump, may be used to control the concentration of TGF-8 in the defect and matrix. In this embodiment of the invention, the pump controls the concentration of TGF-B in the matrix, i.e., the pump may release TGF-B at an initial chemotactic and proliferation stimulating concentration and at a subsequent transforming concentration.
Preferably, the transforming concentration of TGF-B is delivered by the pump approximately 1 to 2 weeks post-operatively. Delivery of the transforming factor into the defect volume is preferably localized to the matrix in the defect site.
The proliferation agents and, when used, the transforming factors in the compositions of this invention are applied in the defect site within the biodegradable matrix. Their presence is thus restricted to a very localized site. This is done to WO 92/13565 ~ ~ ~ ~ ~ PCT/US92/00840 avoid their free injection or infusion into a joint space. Such free infucion may produce the adverse effect of stimulating the cells of the synovial membrane to produce joint effusion.
5 Fibronectin or any other compound, including peptides as small as tstrapeptides, that contain the amino acid sequence l~rg-Gly-lisp, may be used as cell adhesion promoting factors [Ruoslathi et al., 1986, in order to enhance the initial adhesion of i0 repair cells to the matrix deposited in the defsct site. Fibrin and certain collagen matrices already contain this sequence [Ruoslathi et al., 1986, When other biodegradable matrices are used, such cell adhesion promoting factors may be mixed with the matrix 15 material before the matrix is used to dress the defect.
Peptides containing Arg-Gly-7lap may also be chemically coupled to the matrix material (e.g., to its fibers or meshes) or to a compound added to the matrix, such as albumin.
20 The compositions hereinbefore described are useful in methods to induce cartilage formation at a selected site of defect or lesion in cartilage tissue of an animal.
The methods of this invention allow for a treatment of cartilage defects in animals, including humans, that is simple to administer and is restricted in.location to the affected joint area. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.
To carry out the methods of treating defects or lesions in cartilage according to this invention, a defect or lesion,is identified, prepared, and dressed with a biodegradable matrix composition according to this invention. A.proliferation (mitogenic) agent is present in the matrix composition at an appropriate WO 92/t3565 '~ ~ ~ ~j PCT/US92/00840 concentration to stimulate the proliferation of repair cells in the matrix and defect or lesion. The same agent may also, at this concentration, serve as a chemotactic agent to attract repair cells, provided that the factor used has a combined effect with respect to cell proliferation and chemotaxis (as does TGF-B at 2-10 ng/ml of matrix). Alternatively, two different agents may be present in the matrix, one with a specific proliferative effect, and the other with a specific chemotactic effect. In an alternative embodiment, after the defect area is dressed with the biodegradable matrix, the proliferation agent and, if desired, a chemotactic agent, may be injected directly into the matrix-filled defect area.
in a subsequent step, the repair cells in the matrix are exposed to a transforming factor at the appropriate time at a concentration sufficient to transform the repair cells into chondrocytes which produce stable cartilage tissue. This may be accomplished by including an appropriate delivery system containing the transforming factor within the matrix composition as described above. Alternatively, the transforming agent may be delivered by injection directly into the matrix-filled defect area at the appropriate time. The transforming concentration should be made available to the cells approximately 1 to 2 weeks following the initial implantation of the biodegradable matrix into the defect area. Additional factors may be added to the delivery system or directly 3o injected in order to better promote synthesis of the cartilage matrix components at this time point.
Cartilage defects or lesions in animals are readily identifiable visually during arthroscopic examination of the joint or during simple examination of the lesion or defect during open surgery. Cartilage ,,.~ . ..
WO 91/13565 ~ ~ ~ ~- ~ ~ ~crius9iioosao defects may also be identified inferentially by using computer aided tomography (GT scanning), X-ray examination, magnetic resonance imaging (l~tI), analysis of synovial fluid or serum markers, or by any other procedure known in the art.
Once a defect has been identified, the surgeon may elect to surgically modify the defect to enhance the ability of the defect to physically retain the solutions and matrix material that are added in the treatment methods described herein. Preferably-, instead of having a flat or shallow concave geometry, the defect has or is shaped to have vertical edges or is undercut in order to better retain the solutions and matrix materials added in the treatment methods described herein.
In addition to the above aechanical measures, which will improve aatrix adherence to the defect site, chemical measures may also enhance matrix adhesion.
Such measures include degrading the superficial layers of cartilage proteoglycans on the defect surface to expose the collagen fibrils of the cartilage so that they may interact with the collagen fibrils of the matrix (when a collagenous matrix is used) or with the fibrin fibrils of the matrix (when a fibrin matrix is used): The proteoglycans on the surface of the cartilage not only tend to interfere with adherence of a fibrin or other biodegradable matrix to the cartilage, but also inhibit thrombin activity locally.
advantageously, proteoglycan degradation products may also have a chemotactic effect on repair cells [Moore, J~.R. et al., Int. J. Tiss. Reac.. XI161, pp. 301-307 (1989)].
Fu;thermore, the adhesion of the matrix to the cartilage of the defect can also be enhanced by .using fibrin glue (i.e., blood factor XIII or fibrin WO 92/13565 ~ ~ ~ ~ ~ ~ ~ pGT/US92/00840 stabilization factor) to promote chemical bonding (cross-linking) of the fibrils of the matrix to the cartilage collagen fibrils on the defect surface [see Gibble et al., Transfusion, 30(8), pp. 741-47 (1990)).
The enzyme transglutaminase may be used to the same effect [see, e.g., Ichinose et al., J. Biol. Chem., 265(23), pp. 13411-14 (1990); "Transglutaminase,~ ~ds:
V. A. Najjar and L. Lorand, Hartinus ~lijhoff Publishers (Boston, 1984)]. Other compounds that can promote adhesion of extracellular materials may also be used.
According to one embodiment of the methods of this invention, the surface of the defect is dried by blotting the area using sterile absorbent tissue, and the defect volume is filled with a sterile enzyme solution for a period of 2-l0 minutes to degrade the proteoglycans present on the surface of the cartilage and locally within approximately 1 to 2 hum deep from the surface of the defect. Various enzymes may be used, singly or in combination, in sterile buffered aqueous solutions to degrade the proteoglycans. The pH
of the solution should be adjusted to optimize enzyme activity.
Enzymes useful to degrade the proteoglycans in the methods of this invention include chondroitinase ABC, chondroitinase AC, hyaluronidase, pepsin, trypsin, chymotrypsin, papain, pronase, stromelysin and Staph V8 protease. The appropriate concentration of a particular enzyme or combination of enzymes will depend on the activity of the enzyme solution.
In a preferred embodiment of this invention, the defect is filled with a sterile solution of chondroitinase ABC at a concentration of 1 U/ml and digestion is allowed to proceed for 4 minutes. The preferred concentration of chondroitinase ABC was :determined by examining with an electron microscope rabbit joint cartilage tissue which had been treated with various concentrations of enzyme for various periods of time as described in Example :. Any other enzyme used should be employed at a concentration for a time period such that only superficial proteoglycans down to a depth of about i-2 ~m are degraded.
The amount of time the enzyme solution is applied should be kept to a minimum to effect the degradation of the proteoglycans predominantly in the l0 repair area. For chondroitinase A8C at a concentration of 1 U/ml, a digestion period longer than 10 minutes may result in the unnecessary and potentially harmful degradation of the proteoglycans outside the defect area. Furthermore, digestion times longer than 10 minutes contribute excessively to the overall time of the procedure. The overall time of the procedure .
should be kept to a minimum, especially during open arthrotomy, because cartilage may be damaged by exposure to air [Mitchell et al., (1989), ~yp~). For 2o these reasons, in the embodiments of the methods of this invention that include the step of degradation of proteoglycans by enzymatic digestion, digestion times of less than 10 minutes are preferred and digestion times of less than 5 minutes are most preferred.
According to the methods of this invention, after the enzyme has degraded the proteoglycans from the surface of the defect, the enzyme solution should be removed from the defect area. Removal of the enzyme solution may be effected by using an aspirator equipped with a fine suction tip followed by sponging with cottonoid. Alternatively, the enzyme solution may be removed by sponging up with cottonoid alone.
Following removal of the enzyme solution, the defect should be rinsed thoroughly, preferably three ;times, with sterile physiologic saline (e.g., 0.15 M
25 ~1~~.5~~
NaCl). The rinsed defect site should then be dried.
Sterile gauze or cottonoid may be used to dry the defect site.
Alternatively, or in addition to the enzyme treatment step, the defect site say be dressed with a compound, such as fibrin glue or transglutaminase, to enhance adhesion of the matrix to the defect site. In a preferred embodiment, fibrin glue or transglutaminase is applied to the defect site after the defect site has 1o been rinsed and dried following enzyme treatment.
According to the methods of this invention, the defect site is next dressed with a composition of this invention, described herein, to fill the defect preferably to its edges with the matrix composition such that a flat plane is formed. The composition comprises a matrix material and a proliferation agent and, if desired, a chemotactic agent. The composition used in this step may also contain, packaged in an appropriate delivery system, a transforming factor. In the most preferred method of the invention, the matrix contains a proliferation agent, a chemotactic agent (which may be identical to the proliferation agent) and a transforming factor which is packaged in or associated with a delivery system that releases the' transforming factor, at a time that the repair calls populating the matrix have begun remodelling the intercellular substance, at a concentration that transforms the repair cells into chondrocytes.
Preferred compositions are described above.
If the matrix does not contain proliferation and chemotactic agent(s), the agents) may be injected directly into the matrix-filled defect area in order to deliver the preferred concentrations to promote chemotaxis and proliferation of repair cells.
Preferably, in this embodiment of the invention, after .~'~' ~ ~ PCT/US92/00840 dressing the defect with the matrix, TGF-B is injected locally into the matrix to give a concentration of 2-10 ng/ml of matrix. Injection should be localized to the matrix-filled defect area to avoid exposure of cells of the synovial membrane to growth factors which could lead to cell proliferation and joint effusion.
J~fter the defect site is dressed with the matrix composition (and, in the case of fibrin matrices, once the matrix has solidified) and, if to required, the proliferation agent has been injected into the matrix-filled defect site, the joint capsule and skin incisions may be closed and the arthroscopy or open surgery terminated.
If the transforming factor is not present in the matrix in an appropriate delivery system, the transforming factor may be added directly into the matrix approximately 1-2 weeks postoperatively, for example, by injection or by an osmotic pump, at a concentratipn sufficient to transform repair cells into chondrocytes. Preferably, in this embodiment of the invention, TGF-B is added directly into the matrix approximately one week post-operatively to give a concentration of greater than 200 ng/ml, and most preferably greater than 500 ng/ml of matrix.
The methods described herein for repairing defects in articular cartilage are most effective when the defect does not extend to the bone beneath the cartilage. The methods described herein may also be used for repairing defects in meniscal cartilage tissue.
In order that the invention described herein may be more fully understood, the following examples are set forth. _ It should be understood that these examples are for illustrative purposes and are not to be construed as limiting this invention in any manner.
r Enzyme Testinc for Proteocrlvc~r m~~~oval In order to promote and improve matrix adherence along superficial defect surfaces of articular cartilage tissue, proteoglycan molecules within the superficial cartilage matrix may be removed enzymatically, in order to expose the collagen fibrillar network to externally applied matrices and to migrating repair cells. Various proteases and to glycosaminoglycan-degrading enzymes are suitable to be used for this purpose, but pH conditions should be controlled to provide maximal activity for each enzyme.
In this example, we tested chondroitinase ABC
(0.5-5 U/ml) and trypsin (0.5-4~j for their ability to effect proteoglycan removal. Knee joints from freshly slaughtered rabbits, obtained from a local butcher, were employed. Mechanically-created superficial cartilage defects were exposed to the enzyme solutions for a period of 4 minutes. Solutions were then removed with absorbent tissue and the defect sites rinsed thoroughly with physiologic saline. Following this procedure, cartilage tissue was fixed immediately in 2t (v/v) glutaraldehyde solution (buffered with 0.05 M
sodium cacodylate, pH 7.4) containing o.7~ (w/v) ruthenium hexamine trichloride (RHT) for histological examination. The post-fixation medium consisted of a it RHT-osmium tetroxide solution (buffered with 0.1 M
sodium cacodylate). Tissue was dehydrated in a graded series of ethanol and embedded in Epon 812. Thin sections were cut, stained with uranyl acetate and lead citrate, and examined in an electron microscope. In these sections, RHT-fixed (i.e., precipitated) proteoglycans appeared as darkly-staining granules.
Enzyme concentrations removing a superficial layer of 4 ..
WO 92/13565 '~ ~ ~ ~ ~ ~ ~~ PCT/US92/00840 .._, proteoglycans no more than i-2 um in thickness were defined as optimal (deeper penetration of enzymes could affect the underlying chondrocytes). Chondroitinase ABC was found to be optimally active at a concentration of approximately 1 U/ml. Trypsin was found to be optimally active at a concentration of approximately 2.5t. The optimal activity range for other glycosaminoglycanases or proteases may be determined in a similar manner. Any buffer may be used in conjunction with the enzyme provided that it is non-toxic and that its maximal buffering capacity occurs at a pH value close to that required for maximal enzyme activity.
Matrix Adhe~Eence to Superficial Defects The possibility of promoting matrix adhesion along defect surfaces by controlled enzyme digestion of superficial cartilage proteoglycans was investigated.
Defects were created in the knee joints of three mature rabbits by cutting with a planing knife. These defects were not enzyme treated. The defects were filled with a fibrin matrix, formed by mixing 20 ~1 of a thrombin solution (100 U/ml aqueous buffer) with each ml of fibrinogen solution (1 mg/ml aqueous buffer) approximately 200 second before filling the defect.
The rabbits were sacrificed after 1 month and the knee joints examined to determine the extent to which the fibrin matrix had adhered to the defect site. The results were compared to those achieved in rabbits whose defects had been treated with chondroitinase ABC
(1 U/ml for 4 minutes) before the defect was filled , with fibrin matrix (see Examples 3, 4 and 5).
The fibrin matrices deposited in defect areas left untreated with an enzyme exhibited low .affinity to ~, ~ ~, ;~ ~ ~ PGT/US92/00840 adhere to the defect surface. Following enzyme treatment, the sticking capacity of the fibrin matrices (determined indirectly by measuring mechanical strength to adhere, i.e., by testing the easiness with which the matrix could be pushed away manually with the tip of a forceps, and indirectly by noting the number of defects in which the matrix successfully remained sticking throughout the experiment) was significantly increased.
The low affinity of matrices for the defect surfaces in l0 the absence of enzyme treatment probably is due to a local inhibition of matrix adhesion by proteoglycan molecules and an inhibition of fibrin polymerization.
Soth of these effects are prevented by enzymatic removal of superficial proteoglycans along the defect surface area.
Application of Growth Factors to Defect Sites to Provide Chemotactic Stimulation of Repair Cell Migration into Defect hreas and Induction of Repair Cell Proliferation Various growth factors were tested for their usefulness in stimulating chemotactic migration of repair cells to the defect area in order to accomplish healing of the defect.
The growth factors employed included a) epidermal growth factor (EGF), b) basic fibroblast growth factor (bFGF), c) insulin-like growth factor I
(IGF I), d) human growth hormone (hGH) and e) transforming growth factor-8 (TGF-B) at concentrations of between 5-10 ng/ml.
Each of these factors was applied locally to defects produced'in the knee following chondroitinase l~rBC treatment and rinsing as described in Example 2. A
total of ten animals (two per growth factor) were 'utilized. Each growth factor was able to ~~ PCT/US92/00840 chemotactically attract or locally stimulate proliferation of repair cells to the defect surfaces sufficiently to completely cover the defect surfaces.
However, the cells were only present on the surfaces of 5 the defects, and in no instance was proliferation of the repair cells adequate to fill the defect volume.
(It is believed that the proteoglycan degradation products by themselves, i.e., without the addition of any other agent, exert a sufficient 10 chemotactic effect to attract repair cells to the defect. Irloore, A.R. et al. [Int. J. Tiss. Reac., XI(bl, pp. 301-107, 1989] have shown that proteoglycan degradation products have chemotactic effects per se.) 15 Application to Defect Sites of Growth Factors Entrapped in Biodegradable Matrices to Provide Chemotactic Stimulation of Repair Cell Migration into Defect Areas and Induction of Repair Cell Proliferation 2o Since local application of a growth factor under the conditions of Example 3 in no instance induces repair cell proliferation adequate to fill the defect volume, the experiment was repeated using the same growth factors, but this time the growth factors 25 were entrapped in biodegradable matrices. The biodegradable matrices used were fibrin, collagen and Sepharose. Sufficient quantities of matrices containing growth factor were applied to fill the defect volumes completely.
30 Fibrin matrices were formed by mixing 20 ~cl of a thrombin solution (100 U/ml of an aqueous buffer solution: Veronah acetate buffer, pH 7.0) with each ml of fibrinogen solution (1 mg/ml of an aqueous buffer solution: 0.05M Tris, pH 7.4, O.iH NaCl) approximately 200 seconds prior to filling the defect. For collagen '~ ~ ~ ~ ~ ~ ~ PCT/US92/00840 matrices, sufficiently viscous solutions were made using Colagen-Vliess~ or gelatine-blood-mixtures. For Sepharose matrices, defects were filled with liquid solutions of Sepharoae at 39-42~C. Upon cooling (35-38~C), a Sepharose aatrix was formed in the defect.
Thirty rabbits (two for each type of matrix and growth factor) were utilized for this experiment.
In all cases where the deposited matrix remained adherent to the defect, it became completely populated to by fibroblast-like repair cello. This situation was found to exist as early as eight to ten days post-operatively. Ho further changes occurred in the structural organization of the repair tissue up to four weeks post-operatively, except that the biodegradable matrices became remodelled by the repair cells and replaced by a loose, connective tissue type of extracellular matrix.
Transformation of this tissue to cartilage tissue did not occur.
2 o EycAMPI,E ~
Application to Defect Sites of Growth Factors Entrapped in Biodegradable Matrices to Provide Chemotactic Stimulation of Repair Cell Migration into Defect Areas and Induction of Repair Cell Proliferation Followed by Timed, Local Release of a Transforming Factor at a Secondary Stage to Provide Transformation of the Defect Site into Hyaline CartilaEge The observation that matrices within the defect volume were completely filled with repair cells following application of growth factor, and that these cells were able to remodel the deposited matrix (see Example 4), prompted the investigation of the effects of introducing a transforming factor (such as TGF-8) in an encapsulated form (e.g., liposomes) from which the transforming factor would be released when the matrix WO 92/13565 r G~ ' PCT/US92/00840 was completely populated with repair cells that had begun to remodel the intercellular structure.
TGF-B was mixed into the fibrinogen solution (1 mg/ml) at a low concentration (e.g., 2-10 ng/ml) for the purpose of promoting the initial chemotactic and proliferative effects. TGF-8 was also encapsulated in liposomes according to the method of Rim et al. (1983) supra. These TGF-B containing liposomes were added to the same fibrinogen solution in a concentration adequate to provide, when the liposomes were ruptured and the TGF-B was released, the higher concentration of 100-1000 ng of TGF-B per ml of fibrinogen for the purpose of promoting transformation of the repair cells into chondrocytes and transformation of the matrix-filled defect into cartilage during a secondary stage when the repair cells populating the fibrin matrix have begun to remodel~the intercellular substance.
Ten mature rabbits, in which superficial knee joint articular cartilage defects were produced as in Example 2, were treated by application of this~mixture of fibrinogen containing free and liposome-encapsulated TGF-8 to the defect site. In the various experiments in this series of experiments, the concentration of free TGF-B was maintained in the range from 2-10 ng/ml of fibrinogen while the concentration of encapsulated TGF-8 was varied to provide (upon release of the TGF-B
from the liposomes) a concentration between 100 and 1000 ng TGF-B/ml fibrinogen in 100 ng steps. Formation of hyaline cartilage tissue occurred at the treatment 3o sites in all cases. The most reproducible results were obtained at concentrations of above 200 ng encapsulated TGF-8/ml fibrinogen solution, and preferably above 500 ng TGF-B/ml of fibrinogen solution.
~~.pl~aJ~
Determination of the Time Point of Tissue Transformation In this experiment, a group of six mature rabbits were subjected to knee surgery to produce superficial defects as in Example 2. A full treatment scheme for superficial defect repair was applied, i.e., treatment with chondroitinase ABC (1 U/ml for 4 minutes), followed by filling the defect site with fibrin matrix (1 mg/ml fibrinogen solutian, 20 ~l 100 U/ml thrombin solution per ml of fibrinogen solution) containing free TGF-B (-2-10 ng/ml) and liposome encapsulated TGF-B (-800 ng/ml). Three rabbits were sacrificed at eight, ten and twelve days postoperatively, the remaining three at twenty, twenty-four and twenty-eight days. Transformation of the primitive, fibroblast-like repair cell tissue into hyaline cartilage tissue occurred between days twelve and twenty in this animal model. This was determined on the basis of histological examination. At-days eight to twelve, loose fibrous repair tissue was still present (the applied fibrin matrix being partially or completely remodelled), whereas at day twenty and subsequently, the defect space was partially or .
completely filled with hyaline cartilage tissue.
Application of Cartilage Repair Procedures in a Mini-Dlq Model The experimental procedures utilised in the rabbit model, supra, were applied to a larger animal model, the mini-pig. Superficial defects (0.6 mm wide, 0.6 mm deep and approximately 10-15 mm long) were created in four mature mini-pigs (2-4 years old, 80-110 lbs.) by cutting with a planing knife in the WO 92/13565 PCT/US92/00840 _ patellar groove and on the medial condyle. The defects were then treated with chondroitinase JsrBC (1 U/ml for 4 minutes, as used for rabbits, ;~ynra). The enzyme solution was removed, the defect dried, rinsed with physiological saline, then dried again. The defect sites were then filled with a fibrinogen matrix solution. The fibrinogen matrix solution used in this experiment contained 2-6 ng of free TGF-8 per ml, and 1500-2000 ng of liposome-encapsulated TGF-8 per ml of fibrinogen solution. Prior to filling the defects, thrombin was added to the matrix solution as described above in the rabbit experiment.
The mini-pigs were sacrificed 6 weeks postoperatively, and the sites of the matrix-filled defects were examined histologically. All sites showed healing, i.e., formation of hyaline cartilage tissue at the treatment site.
Claims (33)
1. A composition for the treatment or repair of defects or lesions in cartilage comprising a biodegradable matrix or matrix-forming material used to dress the area of the defect or lesion in the cartilage; the matrix or matrix-forming material containing:
a proliferation agent at an appropriate concentration to stimulate the proliferation of repair cells in the matrix and the area of the defect or lesion; and a transforming factor associated with a delivery system and at an appropriate concentration such that upon subsequent delivery of the transforming factor to the proliferated repair cells in the matrix and defect, the repair cells are transformed into chondrocytes that produce cartilage tissue.
a proliferation agent at an appropriate concentration to stimulate the proliferation of repair cells in the matrix and the area of the defect or lesion; and a transforming factor associated with a delivery system and at an appropriate concentration such that upon subsequent delivery of the transforming factor to the proliferated repair cells in the matrix and defect, the repair cells are transformed into chondrocytes that produce cartilage tissue.
2. The composition according to claim 1 further comprising a chemotactic agent at an appropriate concentration to attract repair cells to the matrix and defect area.
3. The composition according to claim 2, wherein the chemotactic agent is selected from the group consisting of TGF-.beta.s, FGFs, PDGF, TNF-.alpha., TNF-.beta.
and proteoglycan degradation products.
and proteoglycan degradation products.
4. The composition according to claim 1 or 2 wherein the proliferation agent is selected from the group consisting of TGF-.beta.s, FGFs, IGF I, PDGF, EGF, TGF-.alpha.s, human growth hormone and hemopoietic growth factors.
5. The composition according to claim 1 or 2 wherein the transforming factor is selected from the group consisting of TGF-.beta.s, TGF-.alpha.s, FGFs, and combinations thereof, and TGF-.beta. in combination with EGF.
6. The composition according to claim 1 or 2, wherein the biodegradable matrix used to fill the defect area is selected from the group consisting of fibrin, collagen, gelatin, Sepharose* or combinations thereof.
7. The composition according to claim 2, wherein the proliferation agent, the chemotactic agent and the transforming factor are selected from the group consisting of TGF-.beta.s.
8. The composition according to claim 1 or 2, wherein the transforming factor is a mixture of one or more transforming factors.
9. The composition according to claim 7, wherein the proliferation and chemotactic agent is TGF-.beta. at a concentration of 2-50 ng/ml in the matrix and the transforming factor is TGF-.beta. associated with an appropriate delivery system which provides a concentration of TGF-.beta. of greater than 200 ng/ml in the matrix.
10. The composition according to claim 1 or 2, wherein the delivery system is selected from the group consisting of liposomes, bioerodible polymers, collagen fibers chemically linked to heparin sulfate proteoglycans, and carbohydrate-based corpuscles.
* Trade-mark
* Trade-mark
11. A composition for the treatment or repair of defects or lesions in cartilage comprising:
a fibrin matrix formed by adding thrombin to a fibrinogen solution, TGF-.beta. present at a concentration of 2-10 ng/ml of fibrinogen solution as a proliferation and chemotactic agent to stimulate proliferation of and attract repair cells in the matrix and defect, and TGF-.beta. encapsulated in liposomes and present at a concentration of greater than 200 ng/ml of fibrinogen solution as a transforming factor that is subsequently delivered to the proliferated repair cells to transform the repair cells into chondrocytes that produce cartilage tissue.
a fibrin matrix formed by adding thrombin to a fibrinogen solution, TGF-.beta. present at a concentration of 2-10 ng/ml of fibrinogen solution as a proliferation and chemotactic agent to stimulate proliferation of and attract repair cells in the matrix and defect, and TGF-.beta. encapsulated in liposomes and present at a concentration of greater than 200 ng/ml of fibrinogen solution as a transforming factor that is subsequently delivered to the proliferated repair cells to transform the repair cells into chondrocytes that produce cartilage tissue.
12. The composition according to claim 1 or 2 further comprising a cell adhesion promoting factor comprising the tripeptide Arg-Gly-Asp.
13. The use of any one of the compositions of claims 1-12 in the manufacture of a medicament for the treatment of superficial defects in cartilage.
14. The use of a composition according to claim 1 or 2 in the manufacture of a medicament for inducing cartilage formation at a selected site in the cartilage tissue of an animal.
15. The use of a composition according to claim 11 in the manufacture of a medicament for inducing cartilage formation at a selected site in cartilage tissue of an animal.
16. Use of a biodegradable matrix in the manufacture of a medicament for treating defects or lesions in cartilage in animals, said biodegradable matrix containing an effective amount of a proliferation agent to stimulate proliferation of repair cells, an effective amount of a chemotactic agent to attract repair cells to the matrix and defect, and an effective amount of a transforming factor associated with a delivery system to transform repair cells into chondrocytes.
17. Use of a biodegradable matrix in the manufacture of a medicament for treating defects or lesions at a selected site in cartilage in animals, said biodegradable matrix containing an effective amount of a chemotactic agent to attract repair cells to the matrix and defect or lesion and an effective amount of a proliferation agent to stimulate proliferation of repair cells, said biodegradable matrix being adapted for use with a transforming factor to be delivered into the matrix, approximately 1-2 weeks after filling the defect with the matrix, at a concentration sufficient to transform repair cells into chondrocytes.
18. The use according to claim 16 or 17, said biodegradable matrix adapted for use with fibrin glue or transglutaminase to cover the surface of the defect to be filled with the biodegradable matrix.
19. The use of an agent to remove proteoglycan from the surface of a defect in the manufacture of a medicament for treating defects or lesions in cartilage in animals, said agent being adapted for filling the defect to remove proteoglycan from the surface of the defect, and adapted for removal before dressing the defect with a biodegradable matrix containing an effective amount of a proliferation agent to stimulate proliferation of repair cells and containing a transforming factor associated with a delivery system that releases the transforming factor at a concentration sufficient to transform repair cells into chondrocytes.
20. The use of an agent to remove proteoglycan from the surface of a defect in the manufacture of a medicament for treating defects or lesions in cartilage in animals, said agent being adapted for filling the defect to remove proteoglycan from the surface of the defect, and adapted for removal before dressing the defect with a biodegradable matrix containing an effective amount of a proliferation agent to stimulate proliferation of repair cells, and delivering a transforming factor into the matrix approximately 1-2 weeks after filling the defect, at a concentration sufficient to transform repair cells into chondrocytes.
21. The use according to claim 19 or 20, said biodegradable matrix adapted for use with fibrin glue or transglutaminase to cover the surface of the defect or lesion to be filled with the biodegradable matrix.
22. The use according to claim 19 or 20 wherein the biodegradable matrix also contains a chemotactic agent at a concentration sufficient to attract repair cells to the matrix and area of the defect or lesion in cartilage.
23. The use of claim 19 or 20 in which the agent to remove proteoglycan from the surface of the defect is selected from the group consisting of chondroitinase ABC, chondroitinase AC, hyaluronidase, pepsin, papain, trypsin, chymotrypsin, pronase, stromelysin and Staph V8 protease.
24. The use of claim 22 wherein the proliferation agent, the chemotactic agent, and the transforming factor are TGF-.beta..
25. The use of claim 19 in which the delivery system for the delivery of the transforming factor is selected from the group consisting of liposomes, bioerodible polymers, collagen fibers chemically linked to heparin sulfate proteoglycans, and carbohydrate-based corpuscles.
26. The use of claim 16, 17, 19 or 20 in which the biodegradable matrix is selected from the group consisting of fibrin, collagen, gelatin, Sepharose or combinations thereof.
27. The use according to claim 16, 17, 19 or 20 wherein the biodegradable matrix is fibrin which is formed by addition of thrombin to a solution of fibrinogen immediately before filling the defect or lesion with the fibrinogen solution.
28. The use according to claim 22 wherein the proliferation agent and the chemotactic agent is TGF-.beta. at a concentration of 2-10 ng/ml of matrix, and the transforming factor is TGF-.beta. encapsulated in liposomes and present at a concentration of greater than 200 ng/ml of matrix.
29. The use according to claim 19 or 20 wherein the agent to remove proteoglycan from the surface of the defect is chondroitinase ABC, and the defect is filled for 4 minutes with a solution comprising chondroitinase ABC at a concentration of 1 unit/ml.
30. The use according to claim 16, 17, 19 or 20 wherein the biodegradable matrix further contains a cell adhesion promoting factor comprising the tripeptide Arg-Gly-Asp.
31. The use of a sterile solution of chondroitinase ABC in the manufacture of a medicament for treating defects or lesions in cartilage in animals, said solution being adapted for filling the defect or lesion area with a sterile solution of chondroitinase ABC at a concentration of 1 unit/ml for 4 minutes, and adapted for removal before rinsing the defect area with sterile physiologic saline, drying the defect area, adding 2 units of thrombin to each ml of a matrix-forming solution comprising 1 mg/ml of fibrinogen, and containing TGF-.beta. at a concentration of 2-10 ng/ml, and TGF-.beta. in liposomes at. a concentration greater than 200 ng/ml, and filling the defect with the matrix-forming solution immediately after addition of the thrombin.
32. The use according to claim 31, said solution adapted for use with fibrin glue or transglutaminase to cover the surface of the defect to be filled with the matrix-forming solution.
33. The use according to claim 31 wherein the TGF-.beta. in liposomes is at a concentration of greater than 500 ng/ml.
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Application Number | Priority Date | Filing Date | Title |
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US07/648,274 US5206023A (en) | 1991-01-31 | 1991-01-31 | Method and compositions for the treatment and repair of defects or lesions in cartilage |
US648,274 | 1991-01-31 | ||
PCT/US1992/000840 WO1992013565A1 (en) | 1991-01-31 | 1992-01-30 | Growth factor containing matrix for the treatment of cartilage lesions |
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CA2101556A1 CA2101556A1 (en) | 1992-08-01 |
CA2101556C true CA2101556C (en) | 2002-07-23 |
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Application Number | Title | Priority Date | Filing Date |
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CA002101556A Expired - Fee Related CA2101556C (en) | 1991-01-31 | 1992-01-30 | Growth factor containing matrix for the treatment of cartilage lesions |
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US (2) | US5206023A (en) |
EP (1) | EP0569541B1 (en) |
JP (2) | JPH06505258A (en) |
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CA (1) | CA2101556C (en) |
DE (1) | DE69202332T2 (en) |
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NZ (1) | NZ260125A (en) |
TW (1) | TW214514B (en) |
WO (1) | WO1992013565A1 (en) |
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Families Citing this family (398)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5023090A (en) * | 1989-08-16 | 1991-06-11 | Levin Robert H | Topical compositions containing LYCD and other topically active medicinal ingredients for the treatment of ACNE |
US5837539A (en) * | 1990-11-16 | 1998-11-17 | Osiris Therapeutics, Inc. | Monoclonal antibodies for human mesenchymal stem cells |
US5811094A (en) * | 1990-11-16 | 1998-09-22 | Osiris Therapeutics, Inc. | Connective tissue regeneration using human mesenchymal stem cell preparations |
US6010696A (en) * | 1990-11-16 | 2000-01-04 | Osiris Therapeutics, Inc. | Enhancing hematopoietic progenitor cell engraftment using mesenchymal stem cells |
US5486359A (en) * | 1990-11-16 | 1996-01-23 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells |
US6197325B1 (en) | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6117425A (en) | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
US7196054B1 (en) | 1990-11-27 | 2007-03-27 | The American National Red Cross | Methods for treating wound tissue and forming a supplemented fibrin matrix |
US6054122A (en) | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
US5616311A (en) * | 1991-01-15 | 1997-04-01 | Hemosphere, Inc. | Non-crosslinked protein particles for therapeutic and diagnostic use |
US6391343B1 (en) | 1991-01-15 | 2002-05-21 | Hemosphere, Inc. | Fibrinogen-coated particles for therapeutic use |
US5853746A (en) * | 1991-01-31 | 1998-12-29 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier |
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 |
US5674844A (en) * | 1991-03-11 | 1997-10-07 | Creative Biomolecules, Inc. | Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases |
US7056882B2 (en) | 1991-03-11 | 2006-06-06 | Curis, Inc. | Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases |
SE9101853D0 (en) * | 1991-06-17 | 1991-06-17 | Jonas Wadstroem | IMPROVED TISSUE ASHESIVE |
US6440427B1 (en) * | 1991-06-17 | 2002-08-27 | Biovitrum Ab | Tissue treatment composition comprising fibrin or fibrinogen and biodegradable and biocompatible polymer |
DE4125400C2 (en) * | 1991-07-31 | 2000-08-17 | Edwin Klaus | Use of insoluble collagen for the treatment of degenerative, non-inflammatory joint processes |
US5270300A (en) * | 1991-09-06 | 1993-12-14 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone |
US5171579A (en) * | 1991-10-11 | 1992-12-15 | Genetics Institute, Inc. | Formulations of blood clot-polymer matrix for delivery of osteogenic proteins |
US6013853A (en) * | 1992-02-14 | 2000-01-11 | The University Of Texas System | Continuous release polymeric implant carrier |
US5876452A (en) * | 1992-02-14 | 1999-03-02 | Board Of Regents, University Of Texas System | Biodegradable implant |
JPH07503869A (en) * | 1992-02-14 | 1995-04-27 | ボード・オヴ・リージェンツ,ザ・ユニヴァーシティ・オヴ・テキサス・システム | Multiphasic bioerodible implant materials or carriers and methods of manufacture and use thereof |
CA2093836A1 (en) * | 1992-04-24 | 1993-10-25 | Wayne Gombotz | Biodegradable tgf-.beta. delivery system for bone regeneration |
IL105529A0 (en) * | 1992-05-01 | 1993-08-18 | Amgen Inc | Collagen-containing sponges as drug delivery for proteins |
CA2103943A1 (en) * | 1992-08-21 | 1994-02-22 | A. Gregory Bruce | Composition and methods for the generation of bone |
CN1091315A (en) * | 1992-10-08 | 1994-08-31 | E·R·斯奎布父子公司 | Fibrin sealant compositions and using method thereof |
US5320102A (en) * | 1992-11-18 | 1994-06-14 | Ciba-Geigy Corporation | Method for diagnosing proteoglycan deficiency in cartilage based on magnetic resonance image (MRI) |
ES2225828T3 (en) * | 1993-03-12 | 2005-03-16 | The American National Red Cross | SUPPLEMENTED FABRIC SEALANTS, PRODUCTION AND USE PROCEDURES. |
US5549904A (en) * | 1993-06-03 | 1996-08-27 | Orthogene, Inc. | Biological adhesive composition and method of promoting adhesion between tissue surfaces |
US5368051A (en) * | 1993-06-30 | 1994-11-29 | Dunn; Allan R. | Method of regenerating articular cartilage |
US5916557A (en) * | 1993-11-12 | 1999-06-29 | The Trustees Of Columbia University In The City Of New York | Methods of repairing connective tissues |
AU1176595A (en) * | 1993-11-12 | 1995-05-29 | International Technology Management Associates, Ltd. | Methods of repairing connective tissues |
US5591625A (en) * | 1993-11-24 | 1997-01-07 | Case Western Reserve University | Transduced mesenchymal stem cells |
DE69530914T2 (en) * | 1994-02-17 | 2004-03-11 | New York Blood Center, Inc. | BIOLOGICAL BIOADHESIVE PREPARATIONS CONTAINING FIBRINE ADHESIVE AND LIPOSOMES, METHODS FOR THEIR PRODUCTION AND USE |
JP4259610B2 (en) * | 1994-04-08 | 2009-04-30 | キューエルティー・ユーエスエイ・インコーポレーテッド | Liquid delivery composition |
US5644026A (en) * | 1994-05-03 | 1997-07-01 | La Jolla Cancer Research Foundation | Epitaxin, a cell motility factor |
US5723331A (en) * | 1994-05-05 | 1998-03-03 | Genzyme Corporation | Methods and compositions for the repair of articular cartilage defects in mammals |
WO1995030742A1 (en) * | 1994-05-05 | 1995-11-16 | Genzyme Corporation | Methods and compositions for the repair of articular cartilage defects in mammals |
US6017891A (en) * | 1994-05-06 | 2000-01-25 | Baxter Aktiengesellschaft | Stable preparation for the treatment of blood coagulation disorders |
US5906827A (en) * | 1994-06-03 | 1999-05-25 | Creative Biomolecules, Inc. | Matrix for the manufacture of autogenous replacement body parts |
PT952792E (en) * | 1994-06-06 | 2003-12-31 | Osiris Therapeutics Inc | BIOMATRIZ FOR REGENERATION OF FABRICS |
JPH07328108A (en) * | 1994-06-10 | 1995-12-19 | Ajinomoto Co Inc | Organic tissue adhesive and blood coagulant |
US6695848B2 (en) | 1994-09-02 | 2004-02-24 | Hudson Surgical Design, Inc. | Methods for femoral and tibial resection |
US8603095B2 (en) | 1994-09-02 | 2013-12-10 | Puget Bio Ventures LLC | Apparatuses for femoral and tibial resection |
US5728676A (en) * | 1994-09-08 | 1998-03-17 | Ciba-Geigy Corporation | Use of insulin-like growth factors I and II for inhibition of inflammatory response |
US6911216B1 (en) * | 1994-10-12 | 2005-06-28 | Genzyme Corporation | Targeted delivery via biodegradable polymers |
EP0785774B1 (en) * | 1994-10-12 | 2001-01-31 | Focal, Inc. | Targeted delivery via biodegradable polymers |
US5585007A (en) | 1994-12-07 | 1996-12-17 | Plasmaseal Corporation | Plasma concentrate and tissue sealant methods and apparatuses for making concentrated plasma and/or tissue sealant |
EP0796115A1 (en) * | 1994-12-07 | 1997-09-24 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US20050186673A1 (en) * | 1995-02-22 | 2005-08-25 | Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie | Collagen carrier of therapeutic genetic material, and method |
GB9503492D0 (en) | 1995-02-22 | 1995-04-12 | Ed Geistlich S Hne A G F R Che | Chemical product |
IL112834A (en) * | 1995-03-01 | 2000-12-06 | Yeda Res & Dev | Pharmaceutical compositions for controlled release of soluble receptors |
US5693341A (en) * | 1995-03-16 | 1997-12-02 | Collagen Corporation | Affinity bound collagen matrices for the delivery of biologically active agents |
US5658588A (en) * | 1995-03-31 | 1997-08-19 | University Of Cincinnati | Fibrinogen-coated liposomes |
US6638912B2 (en) | 1995-05-01 | 2003-10-28 | The Regents Of The University Of California | Peptide compositions mimicking TGF-β activity |
US5780436A (en) * | 1995-05-01 | 1998-07-14 | The Regents Of The University Of California | Peptide compositions with growth factor-like activity |
US5661127A (en) * | 1995-05-01 | 1997-08-26 | The Regents Of The University Of California | Peptide compositions with growth factor-like activity |
US7112320B1 (en) | 1995-06-07 | 2006-09-26 | Andre Beaulieu | Solid wound healing formulations containing fibronectin |
US5655546A (en) * | 1995-06-07 | 1997-08-12 | Halpern; Alan A. | Method for cartilage repair |
US6528483B2 (en) | 1995-06-07 | 2003-03-04 | André Beaulieu | Method of producing concentrated non-buffered solutions of fibronectin |
US6482231B1 (en) * | 1995-11-20 | 2002-11-19 | Giovanni Abatangelo | Biological material for the repair of connective tissue defects comprising mesenchymal stem cells and hyaluronic acid derivative |
US5840848A (en) * | 1996-01-05 | 1998-11-24 | Autoimmune, Inc. | Method for preparation of type II collagen |
US5842477A (en) * | 1996-02-21 | 1998-12-01 | Advanced Tissue Sciences, Inc. | Method for repairing cartilage |
US6645945B1 (en) | 1996-03-05 | 2003-11-11 | Depuy Acromed, Inc. | Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors |
US20110207666A1 (en) * | 1996-03-05 | 2011-08-25 | Depuy Spine, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US5942499A (en) * | 1996-03-05 | 1999-08-24 | Orquest, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US6221854B1 (en) * | 1996-03-05 | 2001-04-24 | Orquest, Inc. | Method of promoting bone growth with hyaluronic acid and growth factors |
US6008013A (en) * | 1996-07-05 | 1999-12-28 | University Of Rochester | Chondrocyte proteins |
JP3638614B2 (en) * | 1996-07-25 | 2005-04-13 | ジェンザイム・コーポレーション | Chondrocyte medium composition and culture method |
US6666892B2 (en) * | 1996-08-23 | 2003-12-23 | Cook Biotech Incorporated | Multi-formed collagenous biomaterial medical device |
ES2208974T3 (en) * | 1996-08-23 | 2004-06-16 | Cook Biotech, Inc. | PROTESIS OF GRAFT, MATERIALS AND METHODS. |
US8716227B2 (en) | 1996-08-23 | 2014-05-06 | Cook Biotech Incorporated | Graft prosthesis, materials and methods |
US20060025786A1 (en) * | 1996-08-30 | 2006-02-02 | Verigen Transplantation Service International (Vtsi) Ag | Method for autologous transplantation |
US5989269A (en) * | 1996-08-30 | 1999-11-23 | Vts Holdings L.L.C. | Method, instruments and kit for autologous transplantation |
US5759190A (en) * | 1996-08-30 | 1998-06-02 | Vts Holdings Limited | Method and kit for autologous transplantation |
US6569172B2 (en) * | 1996-08-30 | 2003-05-27 | Verigen Transplantation Service International (Vtsi) | Method, instruments, and kit for autologous transplantation |
US20020173806A1 (en) * | 1996-08-30 | 2002-11-21 | Verigen Transplantation Service International (Vtsi) Ag | Method for autologous transplantation |
US7534263B2 (en) | 2001-05-25 | 2009-05-19 | Conformis, Inc. | Surgical tools facilitating increased accuracy, speed and simplicity in performing joint arthroplasty |
US7618451B2 (en) * | 2001-05-25 | 2009-11-17 | Conformis, Inc. | Patient selectable joint arthroplasty devices and surgical tools facilitating increased accuracy, speed and simplicity in performing total and partial joint arthroplasty |
US8556983B2 (en) | 2001-05-25 | 2013-10-15 | Conformis, Inc. | Patient-adapted and improved orthopedic implants, designs and related tools |
US8771365B2 (en) | 2009-02-25 | 2014-07-08 | Conformis, Inc. | Patient-adapted and improved orthopedic implants, designs, and related tools |
US8882847B2 (en) | 2001-05-25 | 2014-11-11 | Conformis, Inc. | Patient selectable knee joint arthroplasty devices |
US8480754B2 (en) | 2001-05-25 | 2013-07-09 | Conformis, Inc. | Patient-adapted and improved articular implants, designs and related guide tools |
US8735773B2 (en) | 2007-02-14 | 2014-05-27 | Conformis, Inc. | Implant device and method for manufacture |
US9603711B2 (en) | 2001-05-25 | 2017-03-28 | Conformis, Inc. | Patient-adapted and improved articular implants, designs and related guide tools |
US8617242B2 (en) | 2001-05-25 | 2013-12-31 | Conformis, Inc. | Implant device and method for manufacture |
US8083745B2 (en) | 2001-05-25 | 2011-12-27 | Conformis, Inc. | Surgical tools for arthroplasty |
US8545569B2 (en) | 2001-05-25 | 2013-10-01 | Conformis, Inc. | Patient selectable knee arthroplasty devices |
US8234097B2 (en) | 2001-05-25 | 2012-07-31 | Conformis, Inc. | Automated systems for manufacturing patient-specific orthopedic implants and instrumentation |
US20070233269A1 (en) * | 2001-05-25 | 2007-10-04 | Conformis, Inc. | Interpositional Joint Implant |
US7468075B2 (en) * | 2001-05-25 | 2008-12-23 | Conformis, Inc. | Methods and compositions for articular repair |
US20020098222A1 (en) | 1997-03-13 | 2002-07-25 | John F. Wironen | Bone paste |
AU7481098A (en) * | 1997-05-13 | 1998-12-08 | Case Western Reserve University | Osteoarthritis cartilage regeneration using human mesenchymal stem ce lls |
US7524335B2 (en) * | 1997-05-30 | 2009-04-28 | Smith & Nephew, Inc. | Fiber-reinforced, porous, biodegradable implant device |
AU738334B2 (en) | 1997-05-30 | 2001-09-13 | Osteobiologics, Inc. | Fiber-reinforced, porous, biodegradable implant device |
WO1999003419A1 (en) * | 1997-07-21 | 1999-01-28 | The Board Of Trustees Of The University Of Illinois | Modifying tissue surfaces by liquid crystal formation |
AUPO832597A0 (en) * | 1997-07-30 | 1997-08-21 | Cardiac Crc Nominees Pty Limited | Wound treatment compositions |
US7923250B2 (en) | 1997-07-30 | 2011-04-12 | Warsaw Orthopedic, Inc. | Methods of expressing LIM mineralization protein in non-osseous cells |
EP1007673B1 (en) | 1997-07-30 | 2008-12-17 | Emory University | Novel bone mineralization proteins, dna, vectors, expression systems |
US6025327A (en) | 1997-08-08 | 2000-02-15 | Biocell Technology, Llc | Hydrolyzed collagen type II and use thereof |
US6511958B1 (en) | 1997-08-14 | 2003-01-28 | Sulzer Biologics, Inc. | Compositions for regeneration and repair of cartilage lesions |
ATE220564T1 (en) * | 1997-08-14 | 2002-08-15 | Sulzer Innotec Ag | COMPOSITION AND DEVICE FOR REPAIRING CARTILAGE TISSUE IN VIVO CONSISTING OF NANOCAPSULES WITH OSTEOINDUCTIVE AND/OR CHONDROINDUCTIVE FACTORS |
US6306432B1 (en) * | 1997-09-08 | 2001-10-23 | Chiron Corporation | High and low load formulations of IGF-I in multivesicular liposomes |
US20030180263A1 (en) * | 2002-02-21 | 2003-09-25 | Peter Geistlich | Resorbable extracellular matrix for reconstruction of bone |
US9034315B2 (en) * | 1997-10-10 | 2015-05-19 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Cell-charged multi-layer collagen membrane |
US20050186283A1 (en) * | 1997-10-10 | 2005-08-25 | Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie | Collagen carrier of therapeutic genetic material, and method |
US8858981B2 (en) * | 1997-10-10 | 2014-10-14 | Ed. Geistlich Soehne Fuer Chemistrie Industrie | Bone healing material comprising matrix carrying bone-forming cells |
GB9721797D0 (en) * | 1997-10-14 | 1997-12-17 | Univ Cardiff | Materials and methods relating to cartilage repair |
US6197586B1 (en) | 1997-12-12 | 2001-03-06 | The Regents Of The University Of California | Chondrocyte-like cells useful for tissue engineering and methods |
US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
CA2349562A1 (en) | 1998-03-06 | 1999-09-10 | Crosscart, Inc. | Soft tissue xenografts |
US6972041B1 (en) | 1998-03-16 | 2005-12-06 | Crosscart, Inc. | Bone xenografts |
US6383732B1 (en) | 1999-02-11 | 2002-05-07 | Crosscart, Inc. | Method of preparing xenograft heart valves |
US20030147860A1 (en) | 2002-02-07 | 2003-08-07 | Marchosky J. Alexander | Compositions and methods for forming and strengthening bone |
JP2002510646A (en) * | 1998-04-03 | 2002-04-09 | カイロン コーポレイション | Use of IGFI for treating articular cartilage disorders |
US6835377B2 (en) | 1998-05-13 | 2004-12-28 | Osiris Therapeutics, Inc. | Osteoarthritis cartilage regeneration |
US7252818B2 (en) | 1998-07-24 | 2007-08-07 | Cardiovascular Biotherapeutics, Inc. | Method of producing biologically active human acidic fibroblast growth factor and its use in promoting angiogenesis |
KR20040077968A (en) * | 1998-08-14 | 2004-09-07 | 페리겐 트란스플란타치온 서비스 인터나치오날 (파우테에스이) 아게 | Methods, instruments and materials for chondrocyte cell transplantation |
DE19841698A1 (en) * | 1998-09-11 | 2000-03-16 | Curative Technologies Gmbh | Composition for accelerating healing of tissue damage in cartilage or wounds, comprises thrombocyte growth factor, fibrin or fibrinogen and polymer |
AU772012B2 (en) | 1998-09-14 | 2004-04-08 | Board Of Trustees Of The Leland Stanford Junior University | Assessing the condition of a joint and preventing damage |
US7239908B1 (en) | 1998-09-14 | 2007-07-03 | The Board Of Trustees Of The Leland Stanford Junior University | Assessing the condition of a joint and devising treatment |
US6630457B1 (en) | 1998-09-18 | 2003-10-07 | Orthogene Llc | Functionalized derivatives of hyaluronic acid, formation of hydrogels in situ using same, and methods for making and using same |
EP1117422B1 (en) * | 1998-10-06 | 2005-09-28 | Stryker Corporation | Use of op-1 for the preparation of a pharmaceutical composition for repairing a defect locus in a non articular cartilage tissue of a mammal |
US7067144B2 (en) * | 1998-10-20 | 2006-06-27 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
US6110484A (en) | 1998-11-24 | 2000-08-29 | Cohesion Technologies, Inc. | Collagen-polymer matrices with differential biodegradability |
US8882850B2 (en) * | 1998-12-01 | 2014-11-11 | Cook Biotech Incorporated | Multi-formed collagenous biomaterial medical device |
EP1051116B8 (en) * | 1998-12-01 | 2009-06-10 | Washington University | Embolization device |
WO2000040613A1 (en) | 1999-01-06 | 2000-07-13 | Genentech, Inc. | Insulin-like growth factor (igf) i mutant variants |
CN101385851A (en) * | 1999-02-01 | 2009-03-18 | 遗传研究所公司 | Methods and compositions for healing and repair of articular cartilage |
US6267786B1 (en) * | 1999-02-11 | 2001-07-31 | Crosscart, Inc. | Proteoglycan-reduced soft tissue xenografts |
WO2000048550A2 (en) * | 1999-02-16 | 2000-08-24 | Sulzer Biologics, Inc. | Device and method for regeneration and repair of cartilage lesions |
US6197061B1 (en) | 1999-03-01 | 2001-03-06 | Koichi Masuda | In vitro production of transplantable cartilage tissue cohesive cartilage produced thereby, and method for the surgical repair of cartilage damage |
WO2000054797A2 (en) | 1999-03-17 | 2000-09-21 | Novartis Ag | Pharmaceutical compositions comprising tgf-beta |
US20040059416A1 (en) * | 1999-06-22 | 2004-03-25 | Murray Martha M. | Biologic replacement for fibrin clot |
US6964685B2 (en) * | 1999-06-22 | 2005-11-15 | The Brigham And Women's Hospital, Inc. | Biologic replacement for fibrin clot |
AU5754800A (en) * | 1999-06-22 | 2001-01-09 | Brigham And Women's Hospital | Biologic replacement for fibrin clot for intra-articular use |
DE60039301D1 (en) * | 1999-07-21 | 2008-08-07 | Omeros Corp | RINSE SOLUTIONS AND METHODS FOR PAIN-INHIBITING, INFLAMMATION-INHIBITING AND INHIBITION OF CARTILAGE REMOVAL |
US6179840B1 (en) | 1999-07-23 | 2001-01-30 | Ethicon, Inc. | Graft fixation device and method |
US20020095157A1 (en) * | 1999-07-23 | 2002-07-18 | Bowman Steven M. | Graft fixation device combination |
US20020116063A1 (en) * | 1999-08-02 | 2002-08-22 | Bruno Giannetti | Kit for chondrocyte cell transplantation |
US6579469B1 (en) | 1999-10-29 | 2003-06-17 | Closure Medical Corporation | Cyanoacrylate solutions containing preservatives |
EP1099443A1 (en) | 1999-11-11 | 2001-05-16 | Sulzer Orthopedics Ltd. | Transplant/implant device and method for its production |
US6623963B1 (en) | 1999-12-20 | 2003-09-23 | Verigen Ag | Cellular matrix |
US20030095993A1 (en) * | 2000-01-28 | 2003-05-22 | Hanne Bentz | Gel-infused sponges for tissue repair and augmentation |
EP1265630B1 (en) | 2000-03-24 | 2006-06-07 | Genentech, Inc. | Use of insulin for the treatment of cartilagenous disorders |
US6723335B1 (en) * | 2000-04-07 | 2004-04-20 | Jeffrey William Moehlenbruck | Methods and compositions for treating intervertebral disc degeneration |
DE60143517D1 (en) * | 2000-04-25 | 2011-01-05 | Osiris Therapeutics Inc | RESTORING THE RACES WITH MESENCHYMAL STEM CELLS |
WO2001082994A1 (en) * | 2000-04-28 | 2001-11-08 | Curis, Inc. | Methods and reagents for tissue engineering of cartilage in vitro |
US6645485B2 (en) * | 2000-05-10 | 2003-11-11 | Allan R. Dunn | Method of treating inflammation in the joints of a body |
EP1282437B1 (en) | 2000-05-16 | 2008-03-19 | Genentech, Inc. | Treatment of cartilage disorders |
DE10026480A1 (en) * | 2000-05-29 | 2001-12-13 | Augustinus Bader | Method of making a recipient-specific tissue graft or implant |
US7671018B2 (en) | 2000-08-30 | 2010-03-02 | University Of Delaware | Delivery system for heparin-binding growth factors |
EP2036495A1 (en) * | 2000-09-14 | 2009-03-18 | The Board of Trustees of The Leland Stanford Junior University | Assessing condition of a joint and cartilage loss |
AU9088801A (en) | 2000-09-14 | 2002-03-26 | Univ Leland Stanford Junior | Assessing the condition of a joint and devising treatment |
EP1927659B1 (en) | 2000-10-16 | 2010-01-27 | Genetech, Inc. | Wisp polypeptides and therapeutical applications thereof |
US6648911B1 (en) | 2000-11-20 | 2003-11-18 | Avantec Vascular Corporation | Method and device for the treatment of vulnerable tissue site |
US6852330B2 (en) | 2000-12-21 | 2005-02-08 | Depuy Mitek, Inc. | Reinforced foam implants with enhanced integrity for soft tissue repair and regeneration |
US6721142B1 (en) * | 2000-12-21 | 2004-04-13 | Western Digital (Fremont) Inc. | Non-corrosive GMR slider for proximity recording |
CA2365376C (en) * | 2000-12-21 | 2006-03-28 | Ethicon, Inc. | Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration |
US6599323B2 (en) | 2000-12-21 | 2003-07-29 | Ethicon, Inc. | Reinforced tissue implants and methods of manufacture and use |
US20020114795A1 (en) * | 2000-12-22 | 2002-08-22 | Thorne Kevin J. | Composition and process for bone growth and repair |
KR20040008125A (en) * | 2001-01-30 | 2004-01-28 | 오르쏘젠 인크. | Compositions and methods for the treatment and repair of defects or lesions in articular cartilage using synovial-derived tissue or cells |
AUPR289601A0 (en) * | 2001-02-05 | 2001-03-01 | Commonwealth Scientific And Industrial Research Organisation | Method of tissue repair |
ATE359094T1 (en) * | 2001-02-14 | 2007-05-15 | Genzyme Corp | BIOCOMPATIBLE FLEECE FOR HEMOSTASIS AND TISSUE BUILDING |
US8062377B2 (en) | 2001-03-05 | 2011-11-22 | Hudson Surgical Design, Inc. | Methods and apparatus for knee arthroplasty |
DE60230873D1 (en) * | 2001-04-25 | 2009-03-05 | Eidgenoess Tech Hochschule | MEDICAMENT RELEASING MATRICES FOR THE PROMOTION OF WOUND HEALING |
US6713085B2 (en) | 2001-04-27 | 2004-03-30 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Method and membrane for mucosa regeneration |
EP1392202A4 (en) * | 2001-05-07 | 2009-10-21 | Crosscart Inc | Submucosal xenografts |
US8439926B2 (en) * | 2001-05-25 | 2013-05-14 | Conformis, Inc. | Patient selectable joint arthroplasty devices and surgical tools |
ATE504264T1 (en) | 2001-05-25 | 2011-04-15 | Conformis Inc | METHODS AND COMPOSITIONS FOR REPAIRING THE SURFACE OF JOINTS |
AU2002335747B2 (en) * | 2001-09-15 | 2009-01-29 | Rush University Medical Center | Stratified cartilage tissue and methods to engineer same |
US20030165473A1 (en) * | 2001-11-09 | 2003-09-04 | Rush-Presbyterian-St. Luke's Medical Center | Engineered intervertebral disc tissue |
US7160725B2 (en) * | 2001-11-13 | 2007-01-09 | Curis, Inc. | Hedgehog signaling promotes the formation of three dimensional cartilage matrices |
US6780841B2 (en) | 2001-11-13 | 2004-08-24 | Biocell Technology, Llc | Hyaluronic acid and chondroitin sulfate based hydrolyzed collagen type II and method of making same |
CA2412012C (en) * | 2001-11-20 | 2011-08-02 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage |
US7232802B2 (en) | 2001-12-21 | 2007-06-19 | Zimmer Orthobiologics, Inc. | Compositions and methods for promoting myocardial and peripheral angiogenesis |
DE60232101D1 (en) * | 2001-12-28 | 2009-06-04 | Kyowa Hakko Kogyo Kk | |
US20030138873A1 (en) * | 2002-01-22 | 2003-07-24 | Koichi Masuda | Tissue engineered cartilage for drug discovery |
CA2472239A1 (en) * | 2002-01-22 | 2003-07-31 | Pfizer Inc. | 3-(imidazolyl)-2-aminopropanoic acids for use as tafi-a inhibitors for the treatment of thrombotic diseases |
AU2003212898B2 (en) * | 2002-02-01 | 2008-10-02 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
US20050171616A1 (en) * | 2002-02-04 | 2005-08-04 | Hsing-Wen Sung | Peritoneal regeneration with acellular pericardial patch |
US20060014284A1 (en) * | 2002-03-21 | 2006-01-19 | Thomas Graeve | Biomatrix and method for producting the same |
US20030215426A1 (en) * | 2002-04-02 | 2003-11-20 | William Marsh Rice University | Redifferentiated cells for repairing cartilage defects |
US7832566B2 (en) | 2002-05-24 | 2010-11-16 | Biomet Biologics, Llc | Method and apparatus for separating and concentrating a component from a multi-component material including macroparticles |
US7374678B2 (en) * | 2002-05-24 | 2008-05-20 | Biomet Biologics, Inc. | Apparatus and method for separating and concentrating fluids containing multiple components |
US7992725B2 (en) | 2002-05-03 | 2011-08-09 | Biomet Biologics, Llc | Buoy suspension fractionation system |
US20030205538A1 (en) * | 2002-05-03 | 2003-11-06 | Randel Dorian | Methods and apparatus for isolating platelets from blood |
US20060278588A1 (en) | 2002-05-24 | 2006-12-14 | Woodell-May Jennifer E | Apparatus and method for separating and concentrating fluids containing multiple components |
DE10392686T5 (en) | 2002-05-24 | 2005-07-07 | Biomet Mfg. Corp., Warsaw | Apparatus and method for separating and concentrating liquids containing multiple components |
US7845499B2 (en) | 2002-05-24 | 2010-12-07 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
US7622562B2 (en) * | 2002-06-26 | 2009-11-24 | Zimmer Orthobiologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
US20050130879A1 (en) * | 2002-07-02 | 2005-06-16 | Julia Hwang | Modifying tissue surfaces by liquid crystal formation |
JP4777650B2 (en) * | 2002-09-10 | 2011-09-21 | アメリカン ナショナル レッド クロス | Hemostatic bandage |
US20040136968A1 (en) * | 2002-09-27 | 2004-07-15 | Verigen Ag | Autologous cells on a support matrix for tissue repair |
CA2501041A1 (en) * | 2002-10-07 | 2004-04-22 | Conformis, Inc. | Minimally invasive joint implant with 3-dimensional geometry matching the articular surfaces |
US20040078090A1 (en) | 2002-10-18 | 2004-04-22 | Francois Binette | Biocompatible scaffolds with tissue fragments |
US7824701B2 (en) * | 2002-10-18 | 2010-11-02 | Ethicon, Inc. | Biocompatible scaffold for ligament or tendon repair |
WO2004039248A2 (en) * | 2002-10-31 | 2004-05-13 | The General Hospital Corporation | Repairing or replacing tissues or organs |
CN1780594A (en) * | 2002-11-07 | 2006-05-31 | 康复米斯公司 | Methods for determining meniscal size and shape and for devising treatment |
US20050118236A1 (en) * | 2002-12-03 | 2005-06-02 | Gentis Inc. | Bioactive, resorbable scaffolds for tissue engineering |
AU2004208038B2 (en) | 2003-01-30 | 2007-09-06 | Prochon Biotech Ltd. | Freeze-dried fibrin matrices and methods for preparation thereof |
WO2004075940A1 (en) * | 2003-02-26 | 2004-09-10 | Zimmer Orthobiologics, Inc. | Preparation for repairing cartilage tissue, especially articular cartilage defects |
US8197837B2 (en) | 2003-03-07 | 2012-06-12 | Depuy Mitek, Inc. | Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof |
US7794408B2 (en) * | 2003-03-28 | 2010-09-14 | Ethicon, Inc. | Tissue collection device and methods |
US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US7488348B2 (en) * | 2003-05-16 | 2009-02-10 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US8226715B2 (en) * | 2003-06-30 | 2012-07-24 | Depuy Mitek, Inc. | Scaffold for connective tissue repair |
US10583220B2 (en) * | 2003-08-11 | 2020-03-10 | DePuy Synthes Products, Inc. | Method and apparatus for resurfacing an articular surface |
US8034003B2 (en) | 2003-09-11 | 2011-10-11 | Depuy Mitek, Inc. | Tissue extraction and collection device |
US7611473B2 (en) * | 2003-09-11 | 2009-11-03 | Ethicon, Inc. | Tissue extraction and maceration device |
WO2005039662A2 (en) * | 2003-10-10 | 2005-05-06 | Kw2 Implantattechnologie Gmbh | Cartilage regeneration by generation of chondrons under high concentrations of magnesium |
EP1677844A1 (en) * | 2003-10-10 | 2006-07-12 | Coloplast A/S | A dressing |
US7316822B2 (en) * | 2003-11-26 | 2008-01-08 | Ethicon, Inc. | Conformable tissue repair implant capable of injection delivery |
US7901461B2 (en) * | 2003-12-05 | 2011-03-08 | Ethicon, Inc. | Viable tissue repair implants and methods of use |
ATE515245T1 (en) | 2003-12-11 | 2011-07-15 | Isto Technologies Inc | PARTICLE CARTILAGE SYSTEM |
CA2535169A1 (en) | 2003-12-31 | 2005-07-21 | Osteotech, Inc. | Improved bone matrix compositions and methods |
US7815645B2 (en) * | 2004-01-14 | 2010-10-19 | Hudson Surgical Design, Inc. | Methods and apparatus for pinplasty bone resection |
US20060030854A1 (en) | 2004-02-02 | 2006-02-09 | Haines Timothy G | Methods and apparatus for wireplasty bone resection |
US7857814B2 (en) * | 2004-01-14 | 2010-12-28 | Hudson Surgical Design, Inc. | Methods and apparatus for minimally invasive arthroplasty |
US8021368B2 (en) | 2004-01-14 | 2011-09-20 | Hudson Surgical Design, Inc. | Methods and apparatus for improved cutting tools for resection |
US8287545B2 (en) | 2004-01-14 | 2012-10-16 | Hudson Surgical Design, Inc. | Methods and apparatus for enhanced retention of prosthetic implants |
US8114083B2 (en) | 2004-01-14 | 2012-02-14 | Hudson Surgical Design, Inc. | Methods and apparatus for improved drilling and milling tools for resection |
WO2005077013A2 (en) | 2004-02-06 | 2005-08-25 | Georgia Tech Research Corporation | Surface directed cellular attachment |
US7910124B2 (en) * | 2004-02-06 | 2011-03-22 | Georgia Tech Research Corporation | Load bearing biocompatible device |
US11395865B2 (en) * | 2004-02-09 | 2022-07-26 | DePuy Synthes Products, Inc. | Scaffolds with viable tissue |
US8221780B2 (en) * | 2004-04-20 | 2012-07-17 | Depuy Mitek, Inc. | Nonwoven tissue scaffold |
US8137686B2 (en) | 2004-04-20 | 2012-03-20 | Depuy Mitek, Inc. | Nonwoven tissue scaffold |
US8657881B2 (en) * | 2004-04-20 | 2014-02-25 | Depuy Mitek, Llc | Meniscal repair scaffold |
DE102004024635A1 (en) * | 2004-05-12 | 2005-12-08 | Deutsche Gelatine-Fabriken Stoess Ag | Process for the preparation of moldings based on crosslinked gelatin |
US20050288796A1 (en) * | 2004-06-23 | 2005-12-29 | Hani Awad | Native soft tissue matrix for therapeutic applications |
US8512730B2 (en) | 2004-07-12 | 2013-08-20 | Isto Technologies, Inc. | Methods of tissue repair and compositions therefor |
US7335508B2 (en) * | 2004-07-22 | 2008-02-26 | Prochon Biotech Ltd. | Porous plasma protein matrices and methods for preparation thereof |
US7351423B2 (en) | 2004-09-01 | 2008-04-01 | Depuy Spine, Inc. | Musculo-skeletal implant having a bioactive gradient |
US7273756B2 (en) * | 2004-10-01 | 2007-09-25 | Isto Technologies, Inc. | Method for chondrocyte expansion with phenotype retention |
US7837740B2 (en) * | 2007-01-24 | 2010-11-23 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
WO2006050213A2 (en) * | 2004-10-29 | 2006-05-11 | Michalow Alexander E | Methods of promoting healing of cartilage defects and method of causing stem cells to differentiate by the articular chondrocyte pathway |
US7866485B2 (en) | 2005-02-07 | 2011-01-11 | Hanuman, Llc | Apparatus and method for preparing platelet rich plasma and concentrates thereof |
WO2006086199A1 (en) * | 2005-02-07 | 2006-08-17 | Hanuman Llc | Platelet rich plasma concentrate apparatus and method |
EP1848474B1 (en) | 2005-02-07 | 2013-06-12 | Hanuman LLC | Platelet rich plasma concentrate apparatus and method |
US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
AU2006282754A1 (en) | 2005-08-26 | 2007-03-01 | Zimmer, Inc. | Implants and methods for repair, replacement and treatment of joint disease |
CA2621153C (en) * | 2005-09-02 | 2016-10-18 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Method of repairing meniscal tears using a collagen membrane material |
WO2007035778A2 (en) | 2005-09-19 | 2007-03-29 | Histogenics Corporation | Cell-support matrix and a method for preparation thereof |
EP1764117A1 (en) | 2005-09-20 | 2007-03-21 | Zimmer GmbH | Implant for the repair of a cartilage defect and method for manufacturing the implant |
KR100720052B1 (en) | 2005-10-07 | 2007-05-18 | (주) 차바이오텍 | Microsphere or microbead coated with nanoparticle containing growth factor for regenerating cartilaginous tissue |
US20070135706A1 (en) * | 2005-12-13 | 2007-06-14 | Shimko Daniel A | Debridement method, device and kit |
US20090306776A1 (en) | 2006-01-25 | 2009-12-10 | Children's Medical Center Corporation | Methods and procedures for ligament repair |
TWI434675B (en) | 2006-02-06 | 2014-04-21 | Conformis Inc | Patient selectable joint arthroplasty devices and surgical tools |
US8623026B2 (en) | 2006-02-06 | 2014-01-07 | Conformis, Inc. | Patient selectable joint arthroplasty devices and surgical tools incorporating anatomical relief |
US9339278B2 (en) | 2006-02-27 | 2016-05-17 | Biomet Manufacturing, Llc | Patient-specific acetabular guides and associated instruments |
US7967868B2 (en) | 2007-04-17 | 2011-06-28 | Biomet Manufacturing Corp. | Patient-modified implant and associated method |
US8070752B2 (en) | 2006-02-27 | 2011-12-06 | Biomet Manufacturing Corp. | Patient specific alignment guide and inter-operative adjustment |
US9173661B2 (en) | 2006-02-27 | 2015-11-03 | Biomet Manufacturing, Llc | Patient specific alignment guide with cutting surface and laser indicator |
US10278711B2 (en) | 2006-02-27 | 2019-05-07 | Biomet Manufacturing, Llc | Patient-specific femoral guide |
US9345548B2 (en) | 2006-02-27 | 2016-05-24 | Biomet Manufacturing, Llc | Patient-specific pre-operative planning |
US8407067B2 (en) | 2007-04-17 | 2013-03-26 | Biomet Manufacturing Corp. | Method and apparatus for manufacturing an implant |
US9289253B2 (en) | 2006-02-27 | 2016-03-22 | Biomet Manufacturing, Llc | Patient-specific shoulder guide |
US20150335438A1 (en) | 2006-02-27 | 2015-11-26 | Biomet Manufacturing, Llc. | Patient-specific augments |
US8282646B2 (en) | 2006-02-27 | 2012-10-09 | Biomet Manufacturing Corp. | Patient specific knee alignment guide and associated method |
US8377066B2 (en) | 2006-02-27 | 2013-02-19 | Biomet Manufacturing Corp. | Patient-specific elbow guides and associated methods |
US8535387B2 (en) | 2006-02-27 | 2013-09-17 | Biomet Manufacturing, Llc | Patient-specific tools and implants |
US8608748B2 (en) | 2006-02-27 | 2013-12-17 | Biomet Manufacturing, Llc | Patient specific guides |
US8241293B2 (en) | 2006-02-27 | 2012-08-14 | Biomet Manufacturing Corp. | Patient specific high tibia osteotomy |
US8608749B2 (en) | 2006-02-27 | 2013-12-17 | Biomet Manufacturing, Llc | Patient-specific acetabular guides and associated instruments |
US9113971B2 (en) | 2006-02-27 | 2015-08-25 | Biomet Manufacturing, Llc | Femoral acetabular impingement guide |
US8591516B2 (en) | 2006-02-27 | 2013-11-26 | Biomet Manufacturing, Llc | Patient-specific orthopedic instruments |
US8473305B2 (en) | 2007-04-17 | 2013-06-25 | Biomet Manufacturing Corp. | Method and apparatus for manufacturing an implant |
US8568487B2 (en) | 2006-02-27 | 2013-10-29 | Biomet Manufacturing, Llc | Patient-specific hip joint devices |
US8092465B2 (en) | 2006-06-09 | 2012-01-10 | Biomet Manufacturing Corp. | Patient specific knee alignment guide and associated method |
US9907659B2 (en) | 2007-04-17 | 2018-03-06 | Biomet Manufacturing, Llc | Method and apparatus for manufacturing an implant |
US8298237B2 (en) | 2006-06-09 | 2012-10-30 | Biomet Manufacturing Corp. | Patient-specific alignment guide for multiple incisions |
US8603180B2 (en) | 2006-02-27 | 2013-12-10 | Biomet Manufacturing, Llc | Patient-specific acetabular alignment guides |
US8858561B2 (en) | 2006-06-09 | 2014-10-14 | Blomet Manufacturing, LLC | Patient-specific alignment guide |
US8864769B2 (en) | 2006-02-27 | 2014-10-21 | Biomet Manufacturing, Llc | Alignment guides with patient-specific anchoring elements |
US8133234B2 (en) | 2006-02-27 | 2012-03-13 | Biomet Manufacturing Corp. | Patient specific acetabular guide and method |
US9918740B2 (en) | 2006-02-27 | 2018-03-20 | Biomet Manufacturing, Llc | Backup surgical instrument system and method |
US8567609B2 (en) | 2006-05-25 | 2013-10-29 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
US8430813B2 (en) * | 2006-05-26 | 2013-04-30 | Depuy Spine, Inc. | Illuminated surgical access system including a surgical access device and integrated light emitter |
US9795399B2 (en) | 2006-06-09 | 2017-10-24 | Biomet Manufacturing, Llc | Patient-specific knee alignment guide and associated method |
WO2008019128A2 (en) * | 2006-08-04 | 2008-02-14 | Stb Lifesaving Technologies, Inc. | Solid dressing for treating wounded tissue |
CA2661389C (en) * | 2006-09-07 | 2016-04-12 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Method of treating bone cancer |
JP2010509943A (en) | 2006-09-28 | 2010-04-02 | チルドレンズ メディカル センター コーポレーション | Method of repairing tissue and collagen product therefor |
US8163549B2 (en) | 2006-12-20 | 2012-04-24 | Zimmer Orthobiologics, Inc. | Method of obtaining viable small tissue particles and use for tissue repair |
US7718616B2 (en) | 2006-12-21 | 2010-05-18 | Zimmer Orthobiologics, Inc. | Bone growth particles and osteoinductive composition thereof |
US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
US8328024B2 (en) | 2007-04-12 | 2012-12-11 | Hanuman, Llc | Buoy suspension fractionation system |
CA2684040C (en) | 2007-04-12 | 2016-12-06 | Isto Technologies, Inc. | Method of forming an implant using a mold that mimics the shape of the tissue defect site and implant formed therefrom |
JP5479319B2 (en) | 2007-04-12 | 2014-04-23 | バイオメット・バイオロジックス・リミテッド・ライアビリティ・カンパニー | Buoy suspension fractionation system |
CA2686820C (en) * | 2007-04-23 | 2016-06-28 | Baxter International Inc. | Fibrin compositions containing strontium compounds |
US20080269762A1 (en) * | 2007-04-25 | 2008-10-30 | Biomet Manufacturing Corp. | Method and device for repair of cartilage defects |
WO2008157412A2 (en) | 2007-06-13 | 2008-12-24 | Conformis, Inc. | Surgical cutting guide |
ES2327480B1 (en) * | 2007-06-15 | 2010-08-10 | Bioiberica, S.A. | "DISABLED FOR THE TREATMENT OF TENDONS, LIGAMENTS AND BONES". |
WO2009020612A1 (en) * | 2007-08-06 | 2009-02-12 | Stb Lifesaving Technologies, Inc. | Methods and dressing for sealing internal injuries |
US8062655B2 (en) * | 2007-08-31 | 2011-11-22 | Phillips Plastics Corporation | Composite scaffold structure |
US8265949B2 (en) | 2007-09-27 | 2012-09-11 | Depuy Products, Inc. | Customized patient surgical plan |
US8357111B2 (en) | 2007-09-30 | 2013-01-22 | Depuy Products, Inc. | Method and system for designing patient-specific orthopaedic surgical instruments |
EP2957244B1 (en) | 2007-09-30 | 2020-04-15 | DePuy Products, Inc. | Method of generating a customized patient-specific orthopaedic surgical instrumentation |
EP2227263A2 (en) * | 2007-12-28 | 2010-09-15 | Kuros Biosurgery AG | Pdgf fusion proteins incorporated into fibrin foams |
US20090181807A1 (en) * | 2008-01-16 | 2009-07-16 | Jason Miguel De Los Santos | Golfing aid |
EP2567692B1 (en) | 2008-02-27 | 2016-04-06 | Biomet Biologics, LLC | Use of a device for obtaining interleukin-1 receptor antagonist rich solutions |
US8337711B2 (en) | 2008-02-29 | 2012-12-25 | Biomet Biologics, Llc | System and process for separating a material |
WO2009111626A2 (en) | 2008-03-05 | 2009-09-11 | Conformis, Inc. | Implants for altering wear patterns of articular surfaces |
CA2717725A1 (en) * | 2008-03-05 | 2009-09-11 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
CA2721713C (en) | 2008-05-05 | 2019-07-09 | Novimmune Sa | Anti-il-17a/il-17f cross-reactive antibodies and methods of use thereof |
AU2009246474B2 (en) | 2008-05-12 | 2015-04-16 | Conformis, Inc. | Devices and methods for treatment of facet and other joints |
US8012077B2 (en) * | 2008-05-23 | 2011-09-06 | Biomet Biologics, Llc | Blood separating device |
WO2010087521A1 (en) | 2009-01-29 | 2010-08-05 | 独立行政法人理化学研究所 | Combined preparation for treating joint diseases |
US8170641B2 (en) | 2009-02-20 | 2012-05-01 | Biomet Manufacturing Corp. | Method of imaging an extremity of a patient |
US8808303B2 (en) | 2009-02-24 | 2014-08-19 | Microport Orthopedics Holdings Inc. | Orthopedic surgical guide |
US8808297B2 (en) | 2009-02-24 | 2014-08-19 | Microport Orthopedics Holdings Inc. | Orthopedic surgical guide |
US9017334B2 (en) | 2009-02-24 | 2015-04-28 | Microport Orthopedics Holdings Inc. | Patient specific surgical guide locator and mount |
US8187475B2 (en) | 2009-03-06 | 2012-05-29 | Biomet Biologics, Llc | Method and apparatus for producing autologous thrombin |
US8313954B2 (en) | 2009-04-03 | 2012-11-20 | Biomet Biologics, Llc | All-in-one means of separating blood components |
EP2419035B1 (en) | 2009-04-16 | 2017-07-05 | ConforMIS, Inc. | Patient-specific joint arthroplasty methods for ligament repair |
JP6053517B2 (en) | 2009-05-05 | 2016-12-27 | ノヴィミュンヌ エスア | Anti-IL-17F antibodies and methods for their use |
US9011800B2 (en) | 2009-07-16 | 2015-04-21 | Biomet Biologics, Llc | Method and apparatus for separating biological materials |
DE102009028503B4 (en) | 2009-08-13 | 2013-11-14 | Biomet Manufacturing Corp. | Resection template for the resection of bones, method for producing such a resection template and operation set for performing knee joint surgery |
EP2509539B1 (en) | 2009-12-11 | 2020-07-01 | ConforMIS, Inc. | Patient-specific and patient-engineered orthopedic implants |
JP4995888B2 (en) * | 2009-12-15 | 2012-08-08 | 株式会社神戸製鋼所 | Stainless steel arc welding flux cored wire |
US8632547B2 (en) | 2010-02-26 | 2014-01-21 | Biomet Sports Medicine, Llc | Patient-specific osteotomy devices and methods |
US9066727B2 (en) | 2010-03-04 | 2015-06-30 | Materialise Nv | Patient-specific computed tomography guides |
US8591391B2 (en) | 2010-04-12 | 2013-11-26 | Biomet Biologics, Llc | Method and apparatus for separating a material |
US9271744B2 (en) | 2010-09-29 | 2016-03-01 | Biomet Manufacturing, Llc | Patient-specific guide for partial acetabular socket replacement |
CA2817584C (en) | 2010-11-15 | 2018-01-02 | Zimmer Orthobiologics, Inc. | Bone void fillers |
US9968376B2 (en) | 2010-11-29 | 2018-05-15 | Biomet Manufacturing, Llc | Patient-specific orthopedic instruments |
EP2754419B1 (en) | 2011-02-15 | 2024-02-07 | ConforMIS, Inc. | Patient-adapted and improved orthopedic implants |
US9241745B2 (en) | 2011-03-07 | 2016-01-26 | Biomet Manufacturing, Llc | Patient-specific femoral version guide |
US8715289B2 (en) | 2011-04-15 | 2014-05-06 | Biomet Manufacturing, Llc | Patient-specific numerically controlled instrument |
US9675400B2 (en) | 2011-04-19 | 2017-06-13 | Biomet Manufacturing, Llc | Patient-specific fracture fixation instrumentation and method |
US8668700B2 (en) | 2011-04-29 | 2014-03-11 | Biomet Manufacturing, Llc | Patient-specific convertible guides |
US8956364B2 (en) | 2011-04-29 | 2015-02-17 | Biomet Manufacturing, Llc | Patient-specific partial knee guides and other instruments |
EP2757964B1 (en) | 2011-05-26 | 2016-05-04 | Cartiva, Inc. | Tapered joint implant and related tools |
US8532807B2 (en) | 2011-06-06 | 2013-09-10 | Biomet Manufacturing, Llc | Pre-operative planning and manufacturing method for orthopedic procedure |
US9084618B2 (en) | 2011-06-13 | 2015-07-21 | Biomet Manufacturing, Llc | Drill guides for confirming alignment of patient-specific alignment guides |
BR112013032144A2 (en) | 2011-06-16 | 2016-12-13 | Smith & Nephew Inc | surgical alignment using references |
US20130001121A1 (en) | 2011-07-01 | 2013-01-03 | Biomet Manufacturing Corp. | Backup kit for a patient-specific arthroplasty kit assembly |
US8764760B2 (en) | 2011-07-01 | 2014-07-01 | Biomet Manufacturing, Llc | Patient-specific bone-cutting guidance instruments and methods |
US8597365B2 (en) | 2011-08-04 | 2013-12-03 | Biomet Manufacturing, Llc | Patient-specific pelvic implants for acetabular reconstruction |
US9066734B2 (en) | 2011-08-31 | 2015-06-30 | Biomet Manufacturing, Llc | Patient-specific sacroiliac guides and associated methods |
US9295497B2 (en) | 2011-08-31 | 2016-03-29 | Biomet Manufacturing, Llc | Patient-specific sacroiliac and pedicle guides |
US9386993B2 (en) | 2011-09-29 | 2016-07-12 | Biomet Manufacturing, Llc | Patient-specific femoroacetabular impingement instruments and methods |
US9451973B2 (en) | 2011-10-27 | 2016-09-27 | Biomet Manufacturing, Llc | Patient specific glenoid guide |
EP2770918B1 (en) | 2011-10-27 | 2017-07-19 | Biomet Manufacturing, LLC | Patient-specific glenoid guides |
US9554910B2 (en) | 2011-10-27 | 2017-01-31 | Biomet Manufacturing, Llc | Patient-specific glenoid guide and implants |
US9301812B2 (en) | 2011-10-27 | 2016-04-05 | Biomet Manufacturing, Llc | Methods for patient-specific shoulder arthroplasty |
KR20130046336A (en) | 2011-10-27 | 2013-05-07 | 삼성전자주식회사 | Multi-view device of display apparatus and contol method thereof, and display system |
WO2013116744A1 (en) | 2012-02-01 | 2013-08-08 | Children's Medical Center Corporation | Biomaterial for articular cartilage maintenance and treatment of arthritis |
US9237950B2 (en) | 2012-02-02 | 2016-01-19 | Biomet Manufacturing, Llc | Implant with patient-specific porous structure |
US9486226B2 (en) | 2012-04-18 | 2016-11-08 | Conformis, Inc. | Tibial guides, tools, and techniques for resecting the tibial plateau |
US9675471B2 (en) | 2012-06-11 | 2017-06-13 | Conformis, Inc. | Devices, techniques and methods for assessing joint spacing, balancing soft tissues and obtaining desired kinematics for joint implant components |
US9642956B2 (en) | 2012-08-27 | 2017-05-09 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
AU2013342257B2 (en) | 2012-11-08 | 2018-08-30 | Smith & Nephew, Inc. | Improved reattachment of detached cartilage to subchondral bone |
AU2013342255B2 (en) | 2012-11-08 | 2017-05-04 | Smith & Nephew, Inc. | Methods and compositions suitable for improved reattachment of detached cartilage to subchondral bone |
US10245306B2 (en) | 2012-11-16 | 2019-04-02 | Isto Technologies Ii, Llc | Flexible tissue matrix and methods for joint repair |
US9060788B2 (en) | 2012-12-11 | 2015-06-23 | Biomet Manufacturing, Llc | Patient-specific acetabular guide for anterior approach |
US9204977B2 (en) | 2012-12-11 | 2015-12-08 | Biomet Manufacturing, Llc | Patient-specific acetabular guide for anterior approach |
US20140178343A1 (en) | 2012-12-21 | 2014-06-26 | Jian Q. Yao | Supports and methods for promoting integration of cartilage tissue explants |
EP3798226A1 (en) | 2013-02-01 | 2021-03-31 | Children's Medical Center Corporation | Collagen scaffolds |
US9839438B2 (en) | 2013-03-11 | 2017-12-12 | Biomet Manufacturing, Llc | Patient-specific glenoid guide with a reusable guide holder |
US9579107B2 (en) | 2013-03-12 | 2017-02-28 | Biomet Manufacturing, Llc | Multi-point fit for patient specific guide |
US9826981B2 (en) | 2013-03-13 | 2017-11-28 | Biomet Manufacturing, Llc | Tangential fit of patient-specific guides |
US9498233B2 (en) | 2013-03-13 | 2016-11-22 | Biomet Manufacturing, Llc. | Universal acetabular guide and associated hardware |
US9517145B2 (en) | 2013-03-15 | 2016-12-13 | Biomet Manufacturing, Llc | Guide alignment system and method |
US20140271589A1 (en) | 2013-03-15 | 2014-09-18 | Biomet Biologics, Llc | Treatment of collagen defects using protein solutions |
US9895418B2 (en) | 2013-03-15 | 2018-02-20 | Biomet Biologics, Llc | Treatment of peripheral vascular disease using protein solutions |
US9950035B2 (en) | 2013-03-15 | 2018-04-24 | Biomet Biologics, Llc | Methods and non-immunogenic compositions for treating inflammatory disorders |
US10208095B2 (en) | 2013-03-15 | 2019-02-19 | Biomet Manufacturing, Llc | Methods for making cytokine compositions from tissues using non-centrifugal methods |
US10143725B2 (en) | 2013-03-15 | 2018-12-04 | Biomet Biologics, Llc | Treatment of pain using protein solutions |
US20150112349A1 (en) | 2013-10-21 | 2015-04-23 | Biomet Manufacturing, Llc | Ligament Guide Registration |
US10282488B2 (en) | 2014-04-25 | 2019-05-07 | Biomet Manufacturing, Llc | HTO guide with optional guided ACL/PCL tunnels |
US9408616B2 (en) | 2014-05-12 | 2016-08-09 | Biomet Manufacturing, Llc | Humeral cut guide |
US9839436B2 (en) | 2014-06-03 | 2017-12-12 | Biomet Manufacturing, Llc | Patient-specific glenoid depth control |
US9561040B2 (en) | 2014-06-03 | 2017-02-07 | Biomet Manufacturing, Llc | Patient-specific glenoid depth control |
AU2015287920A1 (en) * | 2014-07-08 | 2017-01-19 | Mimedx Group, Inc. | Micronized wharton's jelly |
US9833245B2 (en) | 2014-09-29 | 2017-12-05 | Biomet Sports Medicine, Llc | Tibial tubercule osteotomy |
US9826994B2 (en) | 2014-09-29 | 2017-11-28 | Biomet Manufacturing, Llc | Adjustable glenoid pin insertion guide |
US10179191B2 (en) | 2014-10-09 | 2019-01-15 | Isto Technologies Ii, Llc | Flexible tissue matrix and methods for joint repair |
US10077420B2 (en) | 2014-12-02 | 2018-09-18 | Histogenics Corporation | Cell and tissue culture container |
US9820868B2 (en) | 2015-03-30 | 2017-11-21 | Biomet Manufacturing, Llc | Method and apparatus for a pin apparatus |
US9713810B2 (en) | 2015-03-30 | 2017-07-25 | Biomet Biologics, Llc | Cell washing plunger using centrifugal force |
EP3892241A1 (en) | 2015-03-31 | 2021-10-13 | Cartiva, Inc. | Drill bit for carpometacarpal implant |
CA2981061A1 (en) | 2015-03-31 | 2016-10-06 | Cartiva, Inc. | Hydrogel implants with porous materials and methods |
CA2981074C (en) | 2015-04-14 | 2023-03-28 | Cartiva, Inc. | Tooling for creating tapered opening in tissue and related methods |
US9757721B2 (en) | 2015-05-11 | 2017-09-12 | Biomet Biologics, Llc | Cell washing plunger using centrifugal force |
US10226262B2 (en) | 2015-06-25 | 2019-03-12 | Biomet Manufacturing, Llc | Patient-specific humeral guide designs |
US10568647B2 (en) | 2015-06-25 | 2020-02-25 | Biomet Manufacturing, Llc | Patient-specific humeral guide designs |
CN109348722B (en) | 2015-07-31 | 2022-04-08 | 宝洁公司 | Forming belt for forming non-woven fabric |
BR112018002059B1 (en) | 2015-07-31 | 2023-02-14 | The Procter & Gamble Company | PACKAGING OF ITEMS FOR PERSONAL CARE |
ES2720805T3 (en) | 2016-04-29 | 2019-07-24 | Reifenhaeuser Masch | Device and procedure for manufacturing nonwovens based on continuous filaments |
US10722310B2 (en) | 2017-03-13 | 2020-07-28 | Zimmer Biomet CMF and Thoracic, LLC | Virtual surgery planning system and method |
KR102245539B1 (en) | 2018-02-12 | 2021-04-29 | 주식회사 지앤피바이오사이언스 | Composition for increasing expression level of growth factor genes containing core-shell structured microparticles as effective component |
US11051829B2 (en) | 2018-06-26 | 2021-07-06 | DePuy Synthes Products, Inc. | Customized patient-specific orthopaedic surgical instrument |
CA3117214C (en) | 2018-11-01 | 2022-08-30 | Oil States Energy Services, L.L.C. | Valve with pressure differential seating |
US20230256138A1 (en) * | 2020-05-14 | 2023-08-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Composite product for the osteoarticular regeneration of cartilage lesion |
CN114984298A (en) * | 2022-07-18 | 2022-09-02 | 重庆大学 | Cartilage tissue adhesive and preparation method and application thereof |
Family Cites Families (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3966908A (en) * | 1973-11-29 | 1976-06-29 | Lescarden Ltd. | Method of treating degenerative joint afflictions |
US4761471A (en) * | 1980-08-04 | 1988-08-02 | The Regents Of The University Of California | Bone morphogenetic protein composition |
US4346709A (en) * | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
US4418691A (en) * | 1981-10-26 | 1983-12-06 | Massachusetts Institute Of Technology | Method of promoting the regeneration of tissue at a wound |
US4440750A (en) * | 1982-02-12 | 1984-04-03 | Collagen Corporation | Osteogenic composition and method |
IL68218A (en) * | 1983-03-23 | 1985-12-31 | Univ Ramot | Compositions for cartilage repair comprising embryonal chondrocytes |
CA1230591A (en) * | 1983-06-03 | 1987-12-22 | Charles A. Frolik | PURIFIED TRANSFORMING GROWTH FACTOR-.beta. DERIVED FROM HUMAN PLATELETS AND PLACENTAS |
JPS6028999A (en) * | 1983-06-30 | 1985-02-14 | Maruho Kk | Protein having cell proliferation accelerating action, its composition and its preparation |
US4795804A (en) * | 1983-08-16 | 1989-01-03 | The Regents Of The University Of California | Bone morphogenetic agents |
JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
US4804744A (en) * | 1984-01-04 | 1989-02-14 | International Genetic Engineering, Inc. | Osteogenic factors |
US4785079A (en) * | 1984-11-09 | 1988-11-15 | The Salk Institute For Biological Studies | Isolation of fibroblast growth factor |
US4956455A (en) * | 1984-03-05 | 1990-09-11 | The Salk Institute For Biological Studies | Bovine fibroblast growth factor |
US4609551A (en) * | 1984-03-20 | 1986-09-02 | Arnold Caplan | Process of and material for stimulating growth of cartilage and bony tissue at anatomical sites |
US4619913A (en) * | 1984-05-29 | 1986-10-28 | Matrix Pharmaceuticals, Inc. | Treatments employing drug-containing matrices for introduction into cellular lesion areas |
US4620327A (en) * | 1984-07-05 | 1986-11-04 | Caplan Arnold I | Process of adapting soluble bone protein for use in stimulating osteoinduction |
US4627982A (en) * | 1984-07-16 | 1986-12-09 | Collagen Corporation | Partially purified bone-inducing factor |
DE3588058T3 (en) * | 1984-07-16 | 2005-04-07 | Celtrix Pharmaceuticals, Inc., Palo Alto | Cartilage-inducing polypeptide factors from bone |
US4843063A (en) * | 1984-07-16 | 1989-06-27 | Collagen Corporation | Polypeptide cartilage-inducing factors found in bone |
US4888366A (en) * | 1984-10-24 | 1989-12-19 | Collagen Corporation | Inductive collagen-based bone repair preparations |
US4563350A (en) * | 1984-10-24 | 1986-01-07 | Collagen Corporation | Inductive collagen based bone repair preparations |
US4638045A (en) * | 1985-02-19 | 1987-01-20 | Massachusetts Institute Of Technology | Non-peptide polyamino acid bioerodible polymers |
US4886747A (en) * | 1985-03-22 | 1989-12-12 | Genentech, Inc. | Nucleic acid encoding TGF-β and its uses |
US4839215A (en) * | 1986-06-09 | 1989-06-13 | Ceramed Corporation | Biocompatible particles and cloth-like article made therefrom |
IL83003A (en) * | 1986-07-01 | 1995-07-31 | Genetics Inst | Osteoinductive factors |
US4877864A (en) * | 1987-03-26 | 1989-10-31 | Genetics Institute, Inc. | Osteoinductive factors |
US4931548A (en) * | 1987-01-30 | 1990-06-05 | Techne Corporation | Heterodimer form of transforming growth factor-beta |
AU626524B2 (en) * | 1987-05-29 | 1992-08-06 | Bristol-Myers Squibb Company | Cloning and expression of simian transforming growth factor- beta 1 |
US4846835A (en) * | 1987-06-15 | 1989-07-11 | Grande Daniel A | Technique for healing lesions in cartilage |
US4952404A (en) * | 1987-06-19 | 1990-08-28 | President And Fellows Of Harvard College | Promotion of healing of meniscal tissue |
US4952403A (en) * | 1987-06-19 | 1990-08-28 | President And Fellows Of Harvard College | Implants for the promotion of healing of meniscal tissue |
DE3727606A1 (en) * | 1987-08-19 | 1989-05-03 | Aesculap Ag | METHOD FOR PRODUCING A BONE REPLACEMENT MATERIAL |
NZ226170A (en) * | 1987-09-18 | 1990-07-26 | Ethicon Inc | Stable freeze-dried pharmaceutical composition containing epidermal growth factor |
US5221620A (en) * | 1987-10-06 | 1993-06-22 | Oncogen | Cloning and expression of transforming growth factor β2 |
EP0318184A1 (en) * | 1987-11-12 | 1989-05-31 | Schering Corporation | Acceleration of bone formation with GM-CSF |
CA1339083C (en) * | 1987-11-13 | 1997-07-29 | Steven R. Jefferies | Bone repair material and delayed drug delivery system |
US4863732A (en) * | 1987-12-16 | 1989-09-05 | Collagen Corporation | Injectable composition for inductive bone repair |
US5049659A (en) * | 1988-02-09 | 1991-09-17 | Dana Farber Cancer Institute | Proteins which induce immunological effector cell activation and chemattraction |
GB8803697D0 (en) * | 1988-02-17 | 1988-03-16 | Deltanine Research Ltd | Clinical developments using amniotic membrane cells |
JP2548414B2 (en) * | 1988-04-08 | 1996-10-30 | ストライカー・コーポレーション | Biosynthetic bone morphogenetic protein and osteogenic device containing the protein |
US4975526A (en) * | 1989-02-23 | 1990-12-04 | Creative Biomolecules, Inc. | Bone collagen matrix for zenogenic implants |
EP0418234B1 (en) * | 1988-06-08 | 1994-03-23 | Genentech, Inc. | NUCLEIC ACID ENCODING TGF-$g(b)3 AND ITS USE |
IL90683A0 (en) * | 1988-06-27 | 1990-01-18 | Yissum Res Dev Co | Osteogenic growth factors derived from regenerating bone marrow |
US4950483A (en) * | 1988-06-30 | 1990-08-21 | Collagen Corporation | Collagen wound healing matrices and process for their production |
US5108436A (en) * | 1988-09-29 | 1992-04-28 | Collagen Corporation | Implant fixation |
US5106626A (en) * | 1988-10-11 | 1992-04-21 | International Genetic Engineering, Inc. | Osteogenic factors |
IE61346B1 (en) * | 1988-11-02 | 1994-11-02 | Genentech Inc | A permeable material to fit around the teeth or gums of a mammal |
US5162430A (en) * | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
CA2005120A1 (en) * | 1988-12-15 | 1990-06-15 | Anthony F. Purchio | Tgf-beta 1/beta 2: a novel chimeric transforming growth factor-beta |
KR910700063A (en) * | 1988-12-20 | 1991-03-13 | 알. 더글라스 암스트롱 | Polypeptide-polymer conjugates having wound healing activity |
US4990336A (en) * | 1989-02-08 | 1991-02-05 | Biosearch, Inc. | Sustained release dosage form |
WO1990009783A1 (en) * | 1989-02-22 | 1990-09-07 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
AU5197790A (en) * | 1989-02-23 | 1990-09-26 | Cytotaxis, Inc. | Periodontal and bone regeneration factor, materials and methods |
EP0384731B1 (en) * | 1989-02-23 | 1996-12-18 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Osteogenic growth polypeptides identified from regenerating bone marrow |
US4944948A (en) * | 1989-02-24 | 1990-07-31 | Liposome Technology, Inc. | EGF/Liposome gel composition and method |
CA2016235C (en) * | 1989-05-09 | 2002-03-12 | Alan J. Fischman | Labeled chemotactic peptides to image focal sites of infection or inflammation |
ES2093647T3 (en) * | 1989-06-05 | 1997-01-01 | Massachusetts Inst Technology | BIOEROSIONABLE POLYMERS FOR THE RELEASE OF DRUGS IN THE BONES. |
US5158934A (en) * | 1989-09-01 | 1992-10-27 | Genentech, Inc. | Method of inducing bone growth using TGF-β |
US5043431A (en) * | 1989-09-11 | 1991-08-27 | Codon | Method and apparatus for the production of TGF-β |
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 |
-
1991
- 1991-01-31 US US07/648,274 patent/US5206023A/en not_active Expired - Lifetime
-
1992
- 1992-01-28 NZ NZ260125A patent/NZ260125A/en unknown
- 1992-01-29 IL IL10079992A patent/IL100799A/en not_active IP Right Cessation
- 1992-01-30 AU AU14128/92A patent/AU667032B2/en not_active Ceased
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- 1992-01-30 KR KR1019930702276A patent/KR100235391B1/en not_active IP Right Cessation
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- 1992-01-30 CA CA002101556A patent/CA2101556C/en not_active Expired - Fee Related
- 1992-01-30 JP JP4505748A patent/JPH06505258A/en not_active Withdrawn
- 1992-01-30 DK DK92906351.9T patent/DK0569541T3/en active
- 1992-01-30 AT AT92906351T patent/ATE121943T1/en not_active IP Right Cessation
- 1992-01-30 EP EP92906351A patent/EP0569541B1/en not_active Expired - Lifetime
- 1992-01-31 CN CN92101431A patent/CN1056083C/en not_active Expired - Fee Related
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- 1992-03-28 TW TW081102394A patent/TW214514B/zh active
- 1992-11-23 US US07/979,904 patent/US5368858A/en not_active Expired - Lifetime
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- 1993-07-30 NO NO932748A patent/NO307735B1/en not_active IP Right Cessation
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- 1998-06-18 HK HK98105693A patent/HK1006416A1/en not_active IP Right Cessation
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JP2004230184A (en) | 2004-08-19 |
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CN1064813A (en) | 1992-09-30 |
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NO932748D0 (en) | 1993-07-30 |
ATE121943T1 (en) | 1995-05-15 |
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WO1992013565A1 (en) | 1992-08-20 |
CN1056083C (en) | 2000-09-06 |
IL100799A (en) | 1996-10-16 |
EP0569541B1 (en) | 1995-05-03 |
IE67515B1 (en) | 1996-04-03 |
DK0569541T3 (en) | 1995-07-10 |
US5206023A (en) | 1993-04-27 |
US5368858A (en) | 1994-11-29 |
IL100799A0 (en) | 1992-09-06 |
NZ260125A (en) | 1997-07-27 |
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