Implantable Tissue Compositions and Method

• US 20070254005A1
• Filed: 08/24/2005
• Published: 11/01/2007
• Est. Priority Date: 08/26/2004
• Status: Active Grant

• Current Assignee: Chandraskekhar Pathak, Sanjay Thigle
• Original Assignee: Pathak Holdings, LLC
• Inventors: Pathak, Chandraskekhar, Thigle, Sanjay
• Granted Patent: US 7,919,112 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 2430/20 for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3608 Bone, e.g. demineralised bone matrix [DBM], bone powder
• CPC Class Codes: A61L 27/3612 Cartilage, synovial fluid
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/3633 : Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3641 : characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3683 : subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3687 : characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/38 : containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/52 : Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 : Materials at least partially resorbable by the body
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Novel implantable tissue fixation methods and compositions are disclosed. Methods and compositions of tissue, fixed using polymeric and/or variable length crosslinks, and di- or polymercapto compounds are described. Also described are the methods and compositions wherein the tissue is fixed using biodegradable crosslinkers. Methods and compositions for making radioopaque tissue are also described. Methods and compositions to obtain a degradable implantable tissue-synthetic biodegradable polymer composite are also described. Compositions and methods of incorporating substantially water-insoluble bioactive compounds in the implantable tissue are also disclosed. The use of membrane-like implantable tissue to make an implantable drug delivery patch are also disclosed. Also described are the compositions and methods to obtain a coated implantable tissue. Medical applications implantable tissue such as heart valve bioprosthesis, vascular grafts, meniscus implant, drug delivery patch are also disclosed.

Claims

1-26. -26. (canceled)

27. A method of crosslinking an implantable tissue having tissue functional groups comprising:

selecting a tissue suitable for implantation into a patient;

introducing into the tissue an organic functional small molecule compound comprising a functional group and an unsaturated group;

reacting the functional group of the compound with a tissue functional group to form a covalent bond between the compound and the tissue;

introducing into the tissue a monomer that is a polymerizable monomer or a cyclic dimerizable monomer; and

reacting the unsaturated group with the monomer to form a polymer that comprises covalent bonds to a plurality of tissue functional groups.

28. The method of claim 27 wherein the compound comprises no more than one tissue functional group.

29. The method of claim 27 wherein a plurality of the compounds each form a covalent bond between the compound and the tissue and also contribute an unsaturated group to the polymer that comprises covalent bonds to a plurality of tissue functional groups.

30. The method of claim 27 wherein the compound comprises a plurality of functional groups that each react with a tissue functional group to form the covalent bonds to the plurality of the tissue functional groups.

31. The method of claim 27 wherein the monomer is the free radical polymerizable monomer and is chosen from the group consisting of, acrylamide, methacrylamide, acrylate and methacrylate.

32. The method of claim 31 wherein the monomer is the acrylate and is a member of the group consisting of methyl acrylate, butyl acrylate, stearyl acrylate, and glycidyl acrylate.

33. The method of claim 27 wherein the monomer is the cyclic dimerizable monomer.

34. The method of claim 27, wherein the monomer comprises a sulfonate group, pyrrolidinone group or a phosphorylcholine group.

35. The method of claim 27 wherein the tissue functional group is an amine, carboxylic acid, hydroxyl, or thiol.

36. The method of claim 34 wherein the functional group of the compound reacts with the amine, carboxylic acid, hydroxyl or the thiol.

37. The method of claim 27 wherein the organic functional small molecule compound comprises a plurality of the unsaturated groups before reacting with the monomer.

38. The method of claim 27, wherein reacting the unsaturated group with the monomer is initiated by exposing the tissue in vitro to ultraviolet light visible light, thermal energy, gamma radiation, or electron beam radiation.

39. The method of claim 27, wherein the polymer is a linear soluble polymer, a thermosensitive polymer, a biodegradable polymer, a polymer that is fluorinated, or a polymer that comprises silicone.

40. A crosslinked tissue prepared according to claim 27.

41. The crosslinked tissue of claim 40 wherein the tissue has a shrink temperature greater than about 65°

C.

42. A method for forming a tissue and synthetic biodegradable polymer composite material, the method comprising the steps of:

selecting a tissue suitable for implantation into a patient;

infusing the tissue in vitro with a fluid that comprises an organic solvent and a synthetic biodegradable polymer dissolved in the fluid; and

evaporating the fluid and the solvent.

43. The method of claim 42 wherein the organic solvent is at least about 80% of the fluid by volume.

44. The method of claim 42 wherein the biodegradable polymer has a molecular weight from about 2000 to about 500000 and comprises a, polyhydroxy acid, a polylactone, a polyhydroxyalkanoate, a polyanhydride, a polyglycolide, a poly(orthocarbonate), a poly(carbonate), or a poly(phosphonate).

45. A method of claim 42 wherein infusing the tissue in vitro comprises selecting the biodegradable polymer to be a liquid or a solid with a melting point lower than about 70°

C.

46. The method of claim 42 wherein the biodegradable polymer comprises polyethylene glycol.

47. The method of claim 42 wherein the organic solvent comprises alcohol, acetone, tetrahydrofuran, benzene, toluene, xylene, chloroform, methylene chloride, dimethyl sulfoxide, n-vinyl pyrrolidinone, or dimethylacetamide.

48. The method of claim 42 wherein the tissue is crosslinked.

49. The method of claim 42 wherein the fluid further comprises a bioactive substance.

50. The method of claim 42 further comprising reacting biodegradable polymer functional groups with tissue functional groups to form covalent bonds with the tissue.

51. The method of claim 50 wherein the tissue functional groups are amines, carboxylic acids, hydroxyls, or thiols that react with the biodegradable polymer functional groups.

52. The method of claim 42 wherein the biodegradable polymer further comprises an unsaturated group at the time of the infusion.

53. A method for forming a coated implantable tissue comprising:

selecting a tissue suitable for implantation into a patient;

coating the tissue surface in vitro with a biodegradable hydrogel precursor and crosslinking the precursor to form a biodegradable hydrogel that coats the implantable tissue.

54. The method of claim 53, wherein the tissue is crosslinked.

55. The method of claim 53, wherein the hydrogel comprises a bioactive substance.

56. The method of claim 53 wherein the biodegradable hydrogel precursor comprises a polylactone, polyhydroxyacid, a polyhydroxyalkanoate, a polyanhydride, a polyglycolide, a poly(orthocarbonate), a poly(carbonate), or a poly(phosphonate), or a polyethylene glycol.

57. The method of claim 53, wherein the biodegradable hydrogel comprises a synthetic biodegradable polymer.

58. The method of claim 53 comprising introducing mammalian cells in vitro to the hydrogel.

59. A method for making an implantable tissue comprising:

growing mammalian cells on a scaffold to form a tissue of at least about 1 micron in thickness; and

at least partially decellularizing the tissue.

60. A method of forming a shape retaining implantable tissue comprising:

providing an implantable tissue;

infusing the tissue with polymerizable monomer;

conforming the infused tissue to a desired shape; and

polymerizing the monomer in the infused tissue until the shape of the tissue is substantially preserved.

61. A method of modifying an implantable substrate comprising tissue or collagen having substrate functional groups comprising:

selecting an implantable collagen substrate or an implantable tissue substrate;

introducing into the substrate a cyclic lactone or a hydroxyacid, and

initiating polymerization of the cyclic lactone or the hydroxyacid by the substrate functional groups.

62. The method of claim 61 wherein the cyclic lactone or cyclic carbonate is introduced into the substrate and the cyclic lactone comprises lactide, glycolide, caprolactone, dioxanone, trimethylene carbonate.

63. The method of claim 61 wherein the initiation is catalyzed by a metal organic catalyst.

64. A chemically modified implantable substrate of claim 61.