US2005118230A1PendingUtilityA1

Methods and compositions for regenerating connective tissue

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Assignee: ENCELLE INCPriority: Oct 22, 2003Filed: Oct 22, 2004Published: Jun 2, 2005
Est. expiryOct 22, 2023(expired)· nominal 20-yr term from priority
Inventors:Ronald Stewart HillRichard Chris KlannFrancis Vincent Lamberti
A61P 7/02A61P 37/06A61P 31/04A61P 29/00A61P 31/12A61P 19/04A61P 19/02A61L 26/0057A61L 27/3645A61K 38/1875A61L 26/0052A61L 27/26A61L 27/52A61K 35/32A61L 27/3834A61K 38/014A61L 26/008A61L 27/3608A61L 2430/10A61L 27/48
60
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Claims

Abstract

Connective tissue regenerative compositions and methods of repairing and regenerating connective tissue using such compositions are provided. The compositions generally comprise a bioactive hydrogel matrix comprising a polypeptide, such as gelatin, and a long chain carbohydrate, such as dextran. The hydrogel matrix may further include polar amino acids, as well as additional beneficial additives. Advantageously, the compositions include further components, such as osteoinductive or osteoconductive materials, medicaments, stem or progenitor cells, and three-dimensional structural frameworks. The compositions are useful for regenerating connective tissue, and can be administered to an area having injury to, or a loss of, connective tissue, such as bone, cartilage, tendon, and ligament.

Claims

exact text as granted — not AI-modified
1 . A method for regenerating connective tissue comprising administering a bioactive hydrogel matrix to a site in need of connective tissue regeneration, wherein the bioactive hydrogel matrix comprises a polypeptide and a long chain carbohydrate.  
     
     
         2 . The method of  claim 1 , wherein the polypeptide is a tissue-derived or synthetic polypeptide.  
     
     
         3 . The method of  claim 2 , wherein the polypeptide is a tissue-derived polypeptide derived from tissue selected from the group consisting of collagens, gelatins, agarose, alginate, keratin, decorin, aggrecan, and glycoproteins.  
     
     
         4 . (canceled)  
     
     
         5 . The method of  claim 1 , wherein the polypeptide has a molecular mass of about 3,000 to about 3,000,000 Da.  
     
     
         6 . (canceled)  
     
     
         7 . The method of  claim 1 , wherein the long chain carbohydrate is a polysaccharide or a sulfated polysaccharide.  
     
     
         8 . (canceled)  
     
     
         9 . The method of  claim 7 , wherein the polysaccharide is selected from the group consisting of glycosaminoglycans and glucosaminoglycans.  
     
     
         10 . The method of  claim 7 , wherein the polysaccharide is selected from the group consisting of dextran, dextrin, heparan, heparin, hyaluronic acid, chondroitin, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, and chitosan.  
     
     
         11 . (canceled)  
     
     
         12 . The method of  claim 1 , wherein the long chain carbohydrate has a molecular mass of about 2,000 to about 8,000,000 Da.  
     
     
         13 . (canceled)  
     
     
         14 . The method of  claim 1 , wherein the polypeptide is gelatin and the long chain carbohydrate is dextran.  
     
     
         15 - 19 . (canceled)  
     
     
         20 . The method of  claim 14 , wherein the gelatin is present at a concentration of about 0.01 to about 40 mM.  
     
     
         21 - 23 . (canceled)  
     
     
         24 . The method of  claim 14 , wherein the dextran is present at a concentration of about 0.01 to about 10 mM.  
     
     
         25 . The method of  claim 1 , wherein the bioactive hydrogel matrix further comprises one or more components selected from the group consisting of polar amino acids, polar amino acid analogues or derivatives, divalent cation chelators, and combinations thereof.  
     
     
         26 . The method of  claim 25 , wherein the bioactive hydrogel matrix further comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.  
     
     
         27 . The method of  claim 26 , wherein the polar amino acids are present at a concentration of about 3 to about 150 mM.  
     
     
         28 . The method of  claim 26 , wherein the polar amino acids are present at a concentration of about 10 to about 65 mM.  
     
     
         29 . The method of  claim 26 , wherein the polar amino acids are selected from the group consisting of L-cysteine, L-glutamic acid, L-lysine, L-arginine, and mixtures thereof.  
     
     
         30 - 33 . (canceled)  
     
     
         34 . The method of  claim 25 , wherein the bioactive hydrogel matrix further comprises ethylenediaminetetraacetic acid or a salt thereof.  
     
     
         35 . The method of  claim 34 , wherein the ethylenediaminetetraacetic acid or salt thereof is present at a concentration of about 0.01 to about 10 mM.  
     
     
         36 . The method of  claim 1 , wherein the bioactive hydrogel matrix further comprises at least one osteoinductive or osteoconductive material.  
     
     
         37 . The method of  claim 36 , wherein the at least one osteoinductive or osteoconductive material is selected from the group consisting of demineralized bone matrix (DBM), bone morphogenetic proteins (BMPs), transforming growth factors (TGFs), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), platelet-derived growth factors (PDGFs), epidermal growth factors (EGFs), vascular endothelial growth factors (VEGFs), vascular permeability factors (VPFs), cell adhesion molecules (CAMs), calcium aluminate, hydroxyapatite, coralline hydroxyapatite, alumina, zirconia, aluminum silicates, calcium phosphate, tricalcium phosphate, calcium sulfate, polypropylene fumarate, bioactive glass, porous titanium, porous nickel-titanium alloy, porous tantalum, sintered cobalt-chrome beads, ceramics, collagen, autologous bone, allogenic bone, xenogenic bone, coralline, and derivates or combinations thereof.  
     
     
         38 . The method of  claim 1 , wherein the bioactive hydrogel matrix further comprises at least one medicament selected from the group consisting of antivirals, antibacterials, anti-inflammatories, immunosuppressants, analgesics, anticoagulants, and healing promotion agents.  
     
     
         39 . The method of  claim 1 , wherein the bioactive hydrogel matrix further comprises cells selected from the group consisting of stem cells, progenitor cells, and mixtures thereof.  
     
     
         40 . The method of  claim 1 , wherein, following said administering step, the bioactive hydrogel matrix is at least partially contained within a three-dimensional structural framework.  
     
     
         41 . The method of  claim 40 , wherein the three-dimensional structural framework includes a bioreabsorbable or non-bioreabsorbable material.  
     
     
         42 . (canceled)  
     
     
         43 . The method of  claim 40 , wherein the three-dimensional framework includes a material selected from the group consisting of coralline, metals, sponge, bioactive glass, ceramics, calcium salts, collagen, keratin, fibrinogen, alginate, chitosan, allogenic bone, autologous bone, hyaluronan, polyethylene, poly(vinylidene fluoride), poly(tetrafluoroethylene), poly(vinyl alcohol), poly(hydroxyalkanoate), poly(ethylene terephthalate), poly(butylene terephthalate), poly(methyl methacrylate), poly(hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(dimethyl siloxane), polydioxanone, and polypyrrole, poly(glycolic acid), poly(lactic acids), poly(ethylene oxides), poly(lactide-co-glycolides), poly(s-caprolactone), polyanhydrides, polyphosphazenes, poly(ortha-esters), and polyimides, and combinations thereof.  
     
     
         44 . The method of  claim 40 , wherein the three-dimensional structural framework includes a metal cage.  
     
     
         45 . The method of  claim 40 , wherein the three-dimensional structural framework includes a collagen sponge.  
     
     
         46 . The method of  claim 1 , wherein the bioactive hydrogel matrix is administered in dehydrated form such that body fluids re-hydrate the bioactive hydrogel matrix.  
     
     
         47 . The method of  claim 1 , wherein the bioactive hydrogel matrix is in dehydrated form and the method further comprises re-hydrating the bioactive hydrogel matrix with a re-hydrating fluid prior to said administering step.  
     
     
         48 . The method of  claim 47 , wherein the re-hydrating fluid includes cells selected from the group consisting of stem cells, progenitor cells, and mixtures thereof.  
     
     
         49 . The method of  claim 46 , wherein the dehydrated bioactive hydrogel matrix is in particulate form.  
     
     
         50 . The method of  claim 49 , wherein the dehydrated bioactive hydrogel matrix is combined with at least one osteoinductive or osteoconductive material prior to said administering step.  
     
     
         51 . The method of  claim 50 , wherein the at least one osteoinductive or osteoconductive material is in the form of a putty or paste.  
     
     
         52 . The method of  claim 1 , wherein the bioactive hydrogel matrix is in crosslinked form, the long chain carbohydrate being covalently crosslinked to the polypeptide.  
     
     
         53 - 54 . (canceled)  
     
     
         55 . A connective tissue regenerative composition comprising: 
 a) a bioactive hydrogel matrix comprising: 
 i. a polypeptide, and  
 ii. a long chain carbohydrate; and  
   b) a three-dimensional structural framework at least partially containing the bioactive hydrogel matrix.    
     
     
         56 . The composition of  claim 55 , wherein the polypeptide is a tissue-derived or synthetic polypeptide.  
     
     
         57 . The composition of  claim 56 , wherein the polypeptide is a tissue-derived polypeptide derived from tissue selected from the group consisting of collagens, gelatins, keratin, decorin, aggrecan, and glycoproteins.  
     
     
         58 . (canceled)  
     
     
         59 . The composition of  claim 55 , wherein the polypeptide has a molecular mass of about 3,000 to about 3,000,000 Da.  
     
     
         60 . (canceled)  
     
     
         61 . The composition of  claim 55 , wherein the long chain carbohydrate is a polysaccharide or a sulfated polysaccharide.  
     
     
         62 . (canceled)  
     
     
         63 . The composition of  claim 61 , wherein the polysaccharide is selected from the group consisting of glycosaminoglycans and glucosaminoglycans.  
     
     
         64 . The composition of  claim 61 , wherein the polysaccharide is selected from the group consisting of dextran, heparan, heparin, hyaluronic acid, alginate, agarose, carageenan, amylopectin, amylose, glycogen, starch, cellulose, chitin, and chitosan.  
     
     
         65 . (canceled)  
     
     
         66 . The composition of  claim 55 , wherein the long chain carbohydrate has a molecular mass of about 2,000 to about 8,000,000 Da.  
     
     
         67 . (canceled)  
     
     
         68 . The composition of  claim 55 , wherein the polypeptide is gelatin and the long chain carbohydrate is dextran.  
     
     
         69 - 73 . (canceled)  
     
     
         74 . The composition of  claim 68 , wherein the gelatin is present at a concentration of about 0.01 to about 40 mM.  
     
     
         75 - 77 . (canceled)  
     
     
         78 . The composition of  claim 68 , wherein the dextran is present at a concentration of about 0.01 to about 10 mM.  
     
     
         79 . The composition of  claim 55 , wherein the bioactive hydrogel matrix further comprises one or more components selected from the group consisting of polar amino acids, polar amino acid analogues or derivatives, divalent cation chelators, and combinations thereof.  
     
     
         80 . The composition of  claim 79 , wherein the bioactive hydrogel matrix further comprises at least one polar amino acid selected from the group consisting of tyrosine, cysteine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, lysine, histidine, and mixtures thereof.  
     
     
         81 . The composition of  claim 80 , wherein the polar amino acids are present at a concentration of about 3 to about 150 mM.  
     
     
         82 . The composition of  claim 80 , wherein the polar amino acids are present at a concentration of about 10 to about 65 mM.  
     
     
         83 . The composition of  claim 80 , wherein the polar amino acids are selected from the group consisting of L-cysteine, L-glutamic acid, L-lysine, L-arginine, and mixtures thereof.  
     
     
         84 - 87 . (canceled)  
     
     
         88 . The composition of  claim 79 , wherein the bioactive hydrogel matrix further comprises ethylenediaminetetraacetic acid or a salt thereof.  
     
     
         89 . The composition of  claim 88 , wherein the ethylenediaminetetraacetic acid or salt thereof is present at a concentration of about 0.01 to about 10 mM.  
     
     
         90 . The composition of  claim 55 , wherein the three-dimensional structural framework comprises a bioreabsorbable or non-bioreabsorbable material.  
     
     
         91 . (canceled)  
     
     
         92 . The composition of  claim 55 , wherein the three-dimensional structural framework includes a material selected from the group consisting of coralline, metals, sponge, bioactive glass, ceramics, calcium salts, collagen, keratin, fibrinogen, alginate, chitosan, hyaluronan, allogenic bone, autologous bone, polyethylene, poly(vinylidene fluoride), poly(tetrafluoroethylene), poly(vinyl alcohol), poly(hydroxyalkanoate), poly(ethylene terephthalate), poly(butylene terephthalate), poly(methyl methacrylate), poly(hydroxyethyl methacrylate), poly(N-isopropylacrylamide), poly(dimethyl siloxane), polydioxanone, and polypyrrole, poly(glycolic acid), poly(lactic acids), poly(ethylene oxides), poly(lactide-co-glycolides), poly(s-caprolactone), polyanhydrides, polyphosphazenes, poly(ortha-esters), polyimides, and combinations thereof.  
     
     
         93 . The composition of  claim 55 , wherein the three-dimensional structural framework includes a metal cage.  
     
     
         94 . The composition of  claim 55 , wherein the three-dimensional structural framework includes a collagen sponge.  
     
     
         95 . The composition of  claim 55 , wherein at least a portion of the bioactive hydrogel matrix is in crosslinked form, the polypeptide being covalently crosslinked to the long chain carbohydrate.  
     
     
         96 . The composition of  claim 95 , wherein the crosslinked hydrogel matrix comprises at least a portion of the three-dimensional structural framework.  
     
     
         97 . The composition of  claim 96 , wherein at least a portion of the crosslinked hydrogel matrix is dehydrated.  
     
     
         98 . A connective tissue regenerative composition comprising: 
 a) a bioactive hydrogel matrix comprising: 
 i. a polypeptide, and  
 ii. a long chain carbohydrate; and  
   b) at least one osteoinductive or osteoconductive material.    
     
     
         99 . The composition of  claim 98 , wherein the at least one osteoinductive or osteoconductive material is selected from the group consisting of demineralized bone matrix (DBM), bone morphogenetic proteins (BMPs), transforming growth factors (TGFs), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), platelet-derived growth factors (PDGFs), epidermal growth factors (EGFs), vascular endothelial growth factors (VEGFs), vascular permeability factors (VPFs), cell adhesion molecules (CAMs), calcium aluminate, hydroxyapatite, coralline hydroxyapatite, alumina, zirconia, aluminum silicates, calcium phosphate, tricalcium phosphate, calcium sulfate, polypropylene fumarate, bioactive glass, porous titanium, porous nickel-titanium alloy, porous tantalum, sintered cobalt-chrome beads, ceramics, collagen, autologous bone, allogenic bone, xenogenic bone, coralline, and derivates or combinations thereof.  
     
     
         100 . The composition of  claim 98 , wherein the at least one osteoinductive or osteoconductive material is present at a concentration of about 0.01 volume percent to about 90 volume percent, based upon the total volume of the composition.  
     
     
         101 . The composition of  claim 100 , wherein the at least one osteoinductive or osteoconductive material is present at a concentration of about 50 volume percent to about 80 volume percent, based upon the total volume of the composition.  
     
     
         102 . (canceled)  
     
     
         103 . The composition of  claim 98 , wherein the polypeptide is gelatin and the long chain carbohydrate is dextran.  
     
     
         104 . The composition of  claim 98 , wherein the bioactive hydrogel matrix further comprises one or more components selected from the group consisting of polar amino acids, polar amino acid analogues or derivatives, divalent cation chelators, and combinations thereof.  
     
     
         105 . The composition of  claim 98 , wherein the composition is dehydrated.  
     
     
         106 . The composition of  claim 98 , wherein the bioactive hydrogel matrix is dehydrated.  
     
     
         107 . The composition of  claim 106 , wherein the dehydrated bioactive hydrogel matrix is in particulate form.  
     
     
         108 . The composition of  claim 107 , wherein the at least one osteoinductive or osteoconductive material is in the form of a putty or paste.  
     
     
         109 . The composition of  claim 98 , wherein at least a portion of the bioactive hydrogel matrix is in crosslinked form, the polypeptide being covalently crosslinked to the long chain carbohydrate.  
     
     
         110 . A connective tissue regenerative composition comprising: 
 a) a bioactive hydrogel matrix comprising: 
 i. a polypeptide, and  
 ii. a long chain carbohydrate; and  
   b) cells selected from the group consisting of stem cells, progenitor cells, and mixtures thereof.    
     
     
         111 . The composition of  claim 110 , wherein the cells are adipose-derived adult stem (ADAS) cells.  
     
     
         112 . The composition of  claim 110 , wherein the cells are mesenchymal stem cells.  
     
     
         113 . The composition of  claim 110 , wherein the cells are present at a concentration of about 10,000 to about 1,000,000 cells per ml of bioactive hydrogel matrix.  
     
     
         114 - 115 . (canceled)  
     
     
         116 . The composition of  claim 110 , wherein the bioactive hydrogel matrix is dehydrated.  
     
     
         117 . The composition of  claim 116 , wherein the dehydrated bioactive hydrogel matrix is in particulate form.  
     
     
         118 . The composition of  claim 110 , wherein the polypeptide is gelatin and the long chain carbohydrate is dextran.  
     
     
         119 . The composition of  claim 110 , wherein the bioactive hydrogel matrix further comprises one or more components selected from the group consisting of polar amino acids, polar amino acid analogues or derivatives, divalent cation chelators, and combinations thereof.  
     
     
         120 . The composition of  claim 110 , wherein at least a portion of the bioactive hydrogel matrix is in crosslinked form, the polypeptide being covalently crosslinked to the long chain carbohydrate.  
     
     
         121 . A method for attaching a first connective tissue to a second connective tissue at a point of attachment, the method comprising: 
 a) coating at least a portion of at least one of said first and second connective tissue with a bioactive hydrogel matrix comprising: 
 i. a polypeptide; and  
 ii. a long chain carbohydrate;  
   b) contacting said first connective tissue to said second connective tissue at a point of attachment; and    c) suturing said first connective tissue to said second connective tissue.    
     
     
         122 . The method of  claim 121 , wherein said polypeptide is gelatin and said long chain carbohydrate is dextran.  
     
     
         123 . The method of  claim 121 , wherein at least a portion of the bioactive hydrogel matrix is in crosslinked form, the polypeptide being covalently crosslinked to the long chain carbohydrate.  
     
     
         124 . The method of  claim 121 , wherein the first connective tissue comprises bone, and the second connective tissue comprises tendon or ligament.  
     
     
         125 . The method of  claim 121 , wherein the first and second connective tissue both comprise tendon or ligament.  
     
     
         126 . The method of  claim 1 , wherein the site in need of connective tissue regeneration is the natural joint of a patient, the joint being affected by a degenerative disease.

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