Claims for Patent: 9,132,208

Summary for Patent: 9,132,208

Title:	Composition for a tissue repair implant and methods of making the same
Abstract:	The invention is directed to a process for making a tissue repair implant having a porous sponge-like structure to repair bone, cartilage, or soft tissue defects by producing a connective tissue homogenate from one or more connective tissues; mixing the connective tissue homogenate with a carrier solution to produce a connective tissue carrier; optionally mixing one or more natural or synthetic bone fragements with said connective tissue carrier to produce a tissue repair mixture; freezing or freeze-drying the tissue repair mixture to produce a porous sponge-like structure and create a three-dimensional framework to entrap the natural or synthetic bone fragments, treating the frozen or freeze-dried porous sponge-like structure with one or more treatment solutions to produce a stabilized porous sponge-like structure. A crudely fragmented connective tissue from one or more connective tissues is optionally mixed with the tissue repair mixture before freezing or freeze-drying. The tissue repair implant having a porous sponge-like structure is optionally combined with one or more bioactive supplements or one or more agents that have bioactive supplement binding site(s) to increase the affinity of growth factors, differentiation factor, cytokines, or anti-inflammatory agents to the tissue repair implant. The invention is further directed toward applying such tissue repair implant for tissue repair.
Inventor(s):	Chen; Silvia S. (Virginia Beach, VA), Chen; Jingsong (Virginia Beach, VA), Wolfinbarger, Jr.; Lloyd (Norfolk, VA)
Assignee:	LifeNet Health (Virginia Beach, VA)
Application Number:	12/188,127
Patent Claims:	1. A process for preparing an osteoinductive tissue repair implant having a porous sponge-like structure comprising a. homogenizing one or more connective tissues to produce a connective tissue homogenate; b. mixing said connective tissue homogenate with a solution to produce a connective tissue carrier; c. mixing one or more bone fragments with said connective tissue carrier to produce a tissue repair mixture; d. freeze-drying said tissue repair mixture to produce a porous sponge-like structure and create a three-dimensional framework to entrap said bone fragments; and e. treating said freeze-dried porous sponge-like structure with one or more treatment solutions to produce said osteoinductive tissue repair implant, wherein said treatment solution comprises an ionic crosslinking agent. 2. The process of claim 1, wherein a connective tissue from one or more connective tissues is mixed with said tissue repair mixture before freeze-drying. 3. A process for preparing an osteoinductive tissue repair implant having a porous sponge-like structure comprising a. homogenizing one or more connective tissues to produce a connective tissue homogenate; b. mixing said connective tissue homogenate with a solution to produce a tissue repair mixture; c. freeze-drying said tissue repair mixture to produce a porous sponge-like structure and create a three-dimensional framework; and d. treating said freeze-dried porous sponge-like structure with one or more treatment solutions to produce said osteoinductive tissue repair implant, wherein said treatment solution comprises an ionic or enzymatic crosslinking agent, wherein said solution comprises a bioactive supplement selected from the group consisting of fibroblast growth factor (FGF), transforming growth factor (TGF), insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), parathyroid hormone-related protein (PTHrP), Indian hedgehog (Ihh), dexamethasone, insulin, transferrin, selenium, Insulin-Transferrin-Selenium (ITS), or ascorbate. 4. The process of claim 1, further comprising treating the osteoinductive tissue repair implant with a water replacing agent. 5. The process of claim 1, further comprising freeze-drying the osteoinductive tissue repair implant. 6. The process of claim 1, further comprising sterilizing the osteoinductive tissue repair implant. 7. The process of claim 1, wherein said three-dimensional framework is created by said connective tissue carrier. 8. The process of claim 1, further comprising combining said connective tissue homogenate, said connective tissue carrier, said tissue repair mixture, said porous sponge-like structure, or said osteoinductive tissue repair implant with one or more agents selected from the group consisting of growth factors, differentiation factors, cytokines, and anti-inflammatory agents. 9. A method of repairing defects in bone, cartilage, or soft tissue comprising implanting the osteoinductive tissue repair implant prepared by the process of claim 1 at the site of defect. 10. An osteoinductive tissue repair implant having a porous sponge-like structure prepared by the process of claim 1, wherein the pore size is larger than about 50 microns. 11. An osteoinductive tissue repair implant having a porous sponge-like structure prepared by the process of claim 1, wherein the void volume is from about 10% to about 95%. 12. An osteoinductive tissue repair implant having a porous sponge-like structure prepared by the process of claim 1, wherein the void volume is from about 30% to about 80%. 13. The process of claim 1, wherein said osteoinductive tissue repair implant having a porous sponge-like structure is in the form of rod, sheet, cube, tube, particle, sphere, ellipsoid, wedge, or ribbon. 14. The process of claim 1, wherein said connective tissue homogenate is made from one more connective tissue(s) of human origins. 15. The process of claim 1, wherein said connective tissue is obtained from fascia, cartilage, tendon, ligament, pericardium, fat, urethra, small intestine, dermis, bone or a mixture of two or more of the above. 16. The process of claim 1, wherein said connective tissue in the connective tissue homogenate is cleaned and disinfected. 17. The process of claim 15, wherein said connective tissue is devitalized to remove cellular components. 18. The process of claim 16, wherein said connective tissue is freeze-dried. 19. The process of claim 1, wherein producing said connective tissue homogenate is carried out by homogenizing said connective tissue at a temperature from about 15.degree. C. to about 100.degree. C. for a period of time of about 0.5 minutes to about 30 minutes. 20. The process of claim 19, wherein said connective tissue is homogenized in solution. 21. The process of claim 1, wherein the weight percentage of said connective tissue homogenate in said osteoinductive tissue repair implant is no more than 80% in the dry state. 22. The process of claim 1, wherein the weight percentage of said connective tissue homogenate in said osteoinductive tissue repair implant is no more than 50% in the dry state. 23. The process of claim 1, wherein the weight percentage of said connective tissue homogenate in said osteoinductive tissue repair implant is no more than 20% in the dry state. 24. The process of claim 1, wherein said solution in step b comprises one or more polysaccharides selected from the group consisting of alginate, propylene glycol alginate, native or crosslinked chitosan, starch, cellulose and its derivatives, xanthan gum, dextran, carrageenan, hyaluronic acid, condroitin sulfate, locust bean gum, gum tragacanth, gum arabic, curdlan, pullulan, scleroglucan, or lower methoxylpectin. 25. The process of claim 1, wherein said solution in step b comprises (i) salts of calcium, barium, aluminum, strontium, copper, zinc, magnesium, manganese, cobalt, or iron; or (ii) glutaraldehyde, glyceraldehyde, genipin, glucose or ribose, poly(ethylene glycol) diepoxide crosslinker, poly(ethylene glycol) diglycidyl ether, ethyl(dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS), transglutaminase, ethylenediamine, lysyl oxidase, hexamethylene diisocyanate (HMDIC); dimethyl suberimidate (DMS), dimethyl-3-3'-dithiobispropionimidate (DTBP), or acryl azide. 26. The process of claim 1, wherein said solution in step b comprises a material selected from the group consisting of collagen, gelatin, agarose, hyaluronic acid, fibrin, chitin, biotin, avidin, proteoglycans, laminin, fibronectin, elastin, heparin, glycerol, sucrose octasulfate, polyethylene glycol, polymethylmethacrylate, polyurethane, acryloilmorpholine, N,N-dimethyl acrylamide, N-vinyl pyrrolidone and tetrahydrofurfuryl methacrylate, hydroxyapatite, hyaluronan, alginate, polyurethane, polylactic acid, or a combination comprising at least one of the foregoing polymers. 27. The process of claim 1, wherein said solution in step b comprises a bioactive supplement selected from the group consisting of fibroblast growth factor (FGF), transforming growth factor (TGF), insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), parathyroid hormone-related protein (PTHrP), Indian hedgehog (Ihh), dexamethasone, insulin, transferrin, selenium, Insulin-Transferrin-Selenium (ITS), or ascorbate. 28. The process of claim 1, wherein said solution in step b comprises a bioactive supplement selected from the group consisting of cytokine of granulocyte/macrophage colony stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor (TNF)-.alpha., interleukin (IL)-1.beta., IL-4, IL-6, IL-8, IL-10, secretory leukocyte protease inhibitor (SLPI), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein (MIP)-1.alpha., MIP-2, IL-18, angiopoietin, keratinocyte Growth Factor (KGF), endothelin, interferon regulatory factor (IFN)-.alpha., or IFN-.beta.. 29. The process of claim 1, wherein said solution in step b comprises a bioactive supplement selected from the group consisting of anti-inflammatory agent of an IL-1.alpha.R antibody, TNF-.alpha. receptor antagonist, cyclooxygenase-2 specific inhibitors, mitogen-activated protein (MAP) kinase inhibitors, NO synthase inhibitors, nuclear factor (NF)-.kappa.B inhibitors, or inhibitors of matrix metalloproteinease (MMP). 30. The process of claim 29, wherein said bioactive supplement is extracted from tissue selected from the group consisting of demineralized bone matrix, basement membrane, or submucosa matrix. 31. The process of claim 1, wherein said solution in step b comprises an antioxidant selected from the group consisting of sodium nitroprusside, cartilage matrix glycoprotein (CMGP), vitamins C, vitamin E, selenium, N-Acetylcysteine (NAC) estradiol, glutathione, melatonin, resveratrol, flavonoid, carotene, aminoguanidine, or lycopene. 32. The process of claim 1, wherein said solution in step b comprises a photoactive agent selected from the group consisting of a xanthene dye, naphthalimide compounds, riboflavin-5-phosphate, N-hydroxypyridine-2-(1H)-thione, N-(20-ethylaminoethyl)-4-amino-1,8-naphthalimide, bis-diazopyruvamide, N,N9-bis(3-diazopyruvoyl)-2,29-(ethylenedioxy)bis-(ethylamine) (DPD); diazopyruvoyl (DAP); methylene blue, erythrosin, phloxime, thionine, methylene green, rose Bengal, acridine orange, xanthine dye, and thioxanthine dyes, ethyl eosin, eosin Y, or a combination comprising at least one of the foregoing photoactive agents. 33. The process according to 32, wherein said photoactive agent is activated by UV light or a laser. 34. The process of claim 24, wherein the weight percentage of said polysaccharides in said osteoinductive tissue repair implant is no more than 20% in the dry state. 35. The process of claim 24, wherein the weight percentage of said polysaccharides in said osteoinductive tissue repair implant is no more than 5% in the dry state. 36. The process of claim 1, wherein said bone fragments comprise non-demineralized bone, partially demineralized bone, demineralized bone, ceramics, hydroxyapatite, calcium phosphate, calcium sulfate, calcium carbonate, or a combination of two or more of the above. 37. The process of claim 1, said bone fragments are from human or animals. 38. The process of claim 1, wherein said bone fragments are in the form of particles, fibers, rods, or cubes. 39. The process of claim 38, wherein said particles have an average particle size of about 125 micron to about 2000 micron. 40. The process of claim 38, wherein said fibers have an average width of 0.1 to 2 mm and an average length of about 0.3 mm to about 100 mm. 41. The process of claim 38, wherein said rods have average width of 0.5 to 5 mm and an average length of about 1 mm to about 100 mm. 42. The process of claim 38, wherein said cubes have an average volume of about 0.001 mm.sup.3 to an average volume of about 1000 mm.sup.3. 43. The process of claim 36, wherein said demineralized bone has a residual calcium content from about 1% to about 4%. 44. The process of claim 1, wherein the weight percentage of said bone fragments in said osteoinductive tissue repair implant is about 0.1% to about 95% in the dry state. 45. The process of claim 1, wherein the weight percentage of said bone fragments in said osteoinductive tissue repair implant is about 10% to about 90% in the dry state. 46. The process of claim 1, wherein the weight percentage of said bone fragments in said osteoinductive tissue repair implant is about 30% to about 80% in the dry state. 47. The process of claim 1, wherein said tissue repair mixture is placed in a mold before said freeze-drying step. 48. The process of claim 1, wherein said tissue repair mixture is processed under negative hydrostatic pressure before freeze-drying. 49. The process of claim 1, further comprising treating said freeze-dried porous sponge-like structure with an additional treatment solution comprising chemical crosslinking agents; or photoactive agents. 50. The process of claim 1, wherein said ionic crosslinking agent comprise one or more metal ions selected from the group consisting of calcium, barium, aluminum, strontium, copper, zinc, magnesium, manganese, cobalt, or iron. 51. The process of claim 3, wherein said treatment solution comprises transglutaminase or lysyl oxidas. 52. The process of claim 49, wherein said chemical crosslinking agents comprise glutaraldehyde, glyceraldehyde, genipin, glucose, ribose, poly(ethylene glycol)diepoxide, poly(ethylene glycol)diglycidyl ether, EDC and NHS, or acryl azide. 53. The process of claim 1, wherein said treatment solution comprises a material selected from the group consisting of collagen, gelatin, agarose, modified hyaluronic acid, fibrin, chitin, biotin, avidin, demineralized bone matrix, proteoglycans, laminin, fibronectin, elastin, heparin, glycerol, sucrose octasulfate, polyethylene glycol, polymethylmethacrylate, polyurethane, acryloilmorpholine, N,N-dimethyl acrylamide, N-vinyl pyrrolidone and tetrahydrofurfuryl methacrylate, hydroxyapatite, hyaluronan, alginate, polyurethane, polylactic acid, or a combination comprising at least one of the foregoing materials. 54. The process of claim 8, wherein said one or more agents is incorporated in the treatment solution. 55. The process of claim 1, wherein said treatment solution comprises antioxidants. 56. The process of claim 1, wherein said treating step comprises treating said freeze-dried porous sponge-like structure with more than one treatment solutions simultaneously or sequentially to stabilize the porous sponge-like structure and further entrap said bone fragments. 57. The process of claim 1, wherein said treating step is carried out for a duration of about 5 minutes to about 16 hours. 58. The process of claim 1, wherein said treating step is carried out for a duration of about 15 minutes to about 120 minutes. 59. The process of claim 1, wherein said treating step is carried out for a duration of about 30 minutes to about 60 minutes. 60. The process of claim 6, wherein said sterilization is carried out using gamma irradiation, super critical solution, ethylene oxide, or electronic-beam. 61. A process for repairing a defect comprising implanting said osteoinductive tissue repair implant having a porous sponge-like structure according to claim 1 or 3 into a defect without rehydration to allow said osteoinductive tissue repair implant to absorb blood or fluid as well as autologous cells in situ. 62. A process for repairing a defect comprising rehydrating said osteoinductive tissue repair implant having a porous sponge-like structure according to claim 1 or 3 with a rehydrating solution; optionally seeding vital cells on said osteoinductive tissue repair implant to render said osteoinductive tissue repair implant vital; optionally culture said cell-seeded osteoinductive tissue repair implant before implantation; implanting said osteoinductive tissue repair implant into said defect. 63. The process of claim 62, wherein said rehydrating solution comprises blood or bone marrow aspirate, platelet rich plasma, enzymes, bioactive supplements, natural polymers, synthetic polymers, photoactive agents, antioxidants, crosslinking agents, antimicrobial agents, vital cells, one or more agents that have bioactive supplement binding site(s), or a mixture of two or more of the above. 64. The process of claim 62, wherein said vital cells comprise one or more than one type of cells from autologous or allograft bone marrow aspirate; stromal cells from bone marrow, stromal cells from fat, synovium, periostieum, perichondrium, muscle, dermis, umbilical cord blood, and Warton's jelly; or pericytes. 65. The process of claim 1 or 3, wherein said solution in step b comprises alginate. 66. The process of claim 1 or 3, further comprising cutting the one or more connective tissues prior to the homogenizing, wherein at least a part of the cut connective tissues is homogenized in step a. 67. The process of claim 1 or 3, wherein the treating is performed for a time period of 5 to 120 minutes.

Details for Patent 9,132,208

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-02-26