Polysaccharide biomaterials and methods of use thereof

• US 20030021762A1
• Filed: 06/25/2002
• Published: 01/30/2003
• Est. Priority Date: 06/26/2001
• Status: Active Grant

• Current Assignee: BioInteractions Ltd.
• Original Assignee: BioInteractions Ltd.
• Inventors: Luthra, Ajay K., Hudson, John O., Sandhu, Shivpal S.
• Granted Patent: US 8,101,196 B2
• Time in Patent Office: Days
• US Class Current: 424/78.32
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/0064 Hydrogels or hydrocolloids
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08B 37/0069 Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08L 39/06 Homopolymers or copolymers of N-vinyl-pyrrolidones
• CPC Class Codes: D04B 21/205 Elongated tubular articles of small diameter, e.g. coverings or reinforcements for cables or hoses
• CPC Class Codes: D10B 2403/0122 Smooth surfaces, e.g. laminated or coated
• CPC Class Codes: D10B 2509/06 Vascular grafts; stents

Abstract

The invention includes a medical hydrogel made from polymerized polysaccharide macromers. The macromers are preferably polysaccharides decorated with polymerizable groups, for example, methacrylates. The macromers may also be made into polymers of at least two macromers polymerized together. These polymers are preferably multi-armed or high-molecular weight and used for medical uses, for example, making coatings on medical devices. Macromers of N-vinylpyrrolidone are also disclosed herein.

Claims

1. A medical apparatus comprising a plurality of polysaccharide macromers polymerized into a three-dimensional crosslinked hydrogel that defines a hollow cylinder, wherein the cylinder is formed during polymerization of the polysaccharide macromers.

2. The medical apparatus of claim 1 wherein the polysaccharide macromers before polymerization comprise at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

3. The medical apparatus of claim 1 wherein the polysaccharide macromers include at least one macromer chosen from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

4. The medical apparatus of claim 1 wherein the polysaccharide macromers include polysaccharide macromers having at least two polymerizable groups.

5. The medical apparatus of claim 1 wherein the hydrogel further comprises at least one polymerized monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

6. The medical apparatus of claim 1 wherein the hydrogel comprises at least about 5% polysaccharide by weight when dehydrated.

7. The medical apparatus of claim 1 wherein the cylinder further comprises a tube of a non-hydrogel material encapsulated in the wall.

8. The medical apparatus of claim 7 wherein the tube comprises a material chosen from the group consisting of silicone polymer, woven fabric, knitted fabric, polyester, polyamide, fluorocarbon, polyethylene, polycarbonate, polyurethane, and polystyrene.

9. The medical apparatus of claim 8 further comprising an impermeable barrier between the tube and the interior surface of the central lumen, wherein the barrier is encapsulated by the hydrogel.

10. The medical apparatus of claim 8 further comprising a permeable barrier between the tube and the interior surface of the central lumen, wherein the barrier is encapsulated by the hydrogel.

11. The medical apparatus of claim 1 wherein the cylinder has a central lumen that has a diameter of less than about 6 mm.

12. The medical apparatus of claim 1 wherein the cylinder has an exterior surface that is free of any materials covalently bonded to thereto.

13. A biocompatible encapsulation for an inert medical device comprising a plurality of polysaccharide macromers polymerized into a three-dimensional crosslinked hydrogel that encapsulates the medical device.

14. The encapsulation of claim 13 wherein the polysaccharide macromers before polymerization comprise at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

15. The encapsulation of claim 13 wherein the polysaccharide macromers include at least one macromer chosen from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

16. The encapsulation of claim 13 wherein the hydrogel further comprises at least one polymerized monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

17. A medical apparatus comprising a plurality of heparin macromers polymerized into a three-dimensional crosslinked hydrogel that defines a hollow cylinder having an exterior, wherein the cylinder is formed during polymerization of the heparin macromers and the exterior is free of covalently bonds to another material.

18. The medical apparatus of claim 17 wherein the heparin macromers before polymerization comprise at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, and monomers having sulphonate groups.

19. The encapsulation of claim 17 wherein the hydrogel further comprises at least one polymerized monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

20. The medical apparatus of claim 17 wherein the hydrogel comprises at least about 5% heparin by weight when dehydrated.

21. The medical apparatus of claim 17 wherein the cylinder further comprises a tube of a non-hydrogel material encapsulated therein.

22. The medical apparatus of claim 21 wherein the tube comprises a material chosen from the group consisting of silicone polymer, woven fabric, knitted fabric, polyester, polyamide, fluorocarbon, polyethylene, polycarbonate, polyurethane, and polystyrene.

23. The medical apparatus of claim 21 wherein the cylinder has a lumen with a diameter of less than about 6 mm.

24. A biocompatible coating system for a medical device comprising a coating on the device that includes a plurality of multi-armed polymers polymerized from more than one polyvinylpyrrolidone macromer.

25. The biocompatible coating of claim 24 wherein the plurality of multi-armed polymers further comprises methacrylate monomers.

26. The system of claim 24 wherein the medical device is chosen from the group consisting of a wire, a tube, a coil, a spring, stent, catheter, balloon, and an implantable device.

27. The system of claim 24 wherein the medical device has an exterior surface made of a material chosen from the group consisting of metal, plastic, hydrogel, ceramic, or a combination thereof.

28. A material for medical uses comprising a multi-armed polymer polymerized from more than one polyvinylpyrrolidone macromer.

29. The biocompatible coating of claim 28 wherein the plurality of multi-armed polymers further comprises polymerized methacrylate monomers.

30. A preparation of a modified polysaccharide polymer soluble in a solvent, the modified polymer comprising at least two polysaccharide macromers polymerized together to form the modified polymer, wherein the modified polymer is soluble and has a multi-armed structure.

31. The preparation of claim 30 wherein the polysaccharide macromers are polymerized by the reaction of chemical moieties chosen from the group from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer, and wherein the polymer is in an isolatable form.

32. The preparation of claim 30 wherein the polysaccharide is heparin.

33. The preparation of claim 30 wherein the polysaccharide macromers include at least one macromer chosen from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

34. The preparation of claim 30 wherein the polysaccharides macromers are polymerized in a solvent chosen from the group consisting of aqueous solvents, organic solvents, and mixtures thereof.

35. The preparation of claim 30 wherein the polymers are complexed with cations.

36. The preparation of claim 30 disposed in an organic solvent.

37. The preparation of claim 30 disposed as a coating.

38. The preparation of claim 30 wherein the modified polysaccharide polymer further comprises a polymerizable chemical group.

39. The preparation of claim 30 wherein the modified polysaccharide polymer further comprises a chemical group for forming a covalent bond with a surface.

40. A method of making a medical apparatus comprising preparing a plurality of polysaccharide macromers and polymerizing the macromers into a three-dimensional crosslinked hydrogel that defines a hollow cylinder, wherein the cylinder is formed during polymerization of the polysaccharide macromers.

41. The method of claim 40 further comprising choosing the polysaccharide macromers before polymerization to include at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

42. The method of claim 40 further comprising choosing the polysaccharide macromers to include at least one macromer chosen from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

43. The method of claim 40 further comprising polymerizing the macromers in the presence of at least one monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

44. The method of claim 40 further comprising encapsulating a tube of a non-hydrogel material encapsulated in the wall of the cylinder.

45. The method of claim 40 further comprising choosing the tube to contain at least one material chosen from the group consisting of silicone polymer, woven fabric, knitted fabric, polyester, polyamide, fluorocarbon, polyethylene, polycarbonate, polyurethane, and polystyrene.

46. The method of claim 45 further comprising further placing a impermeable barrier between the tube and the interior surface of the central lumen, and encapsulating the barrier in the hydrogel.

47. The method of claim 45 further comprising further placing a permeable barrier between the tube and the interior surface of the central lumen, and encapsulating the barrier in the hydrogel.

48. The method of claim 40 further comprising making the cylinder to have a central lumen with a diameter of less than about 6 mm.

49. The method of claim 40 further comprising making the cylinder to have an exterior surface that is free of any materials covalently bonded to thereto.

50. A biocompatible encapsulation method for an inert medical device comprising polymerizing a plurality of polysaccharide macromers into a three-dimensional crosslinked hydrogel and encapsulates the medical device in the hydrogel.

51. The method of claim 50 further comprising choosing the polysaccharide macromers to include at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

52. The method of claim 50 further comprising choosing the polysaccharide macromers to include at least one macromer from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

53. The method of claim 50 further comprising polymerizing the macromers with at least one polymerized monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

54. A method of making a medical apparatus comprising polymerizing a plurality of heparin macromers into a three-dimensional crosslinked hydrogel and thereby making a hollow cylinder having an exterior, wherein the cylinder is formed during polymerization of the heparin macromers and the exterior is not covalently bonded to another material.

55. The method of claim 54 further comprising choosing the heparin macromers to have at least one polymerizable group chosen from the set consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, and monomers having sulphonate groups.

56. The method of claim 54 further comprising polymerizing the macromers with at least one polymerized monomer chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

57. The method of claim 54 further comprising making the hydrogel to be at least about 5% heparin by weight when dehydrated.

58. The method of claim 54 further comprising encapsulating a tube of a non-hydrogel material into the cylinder.

59. The method of claim 54 further comprising using a tube made from at least one material chosen from the group consisting of silicone polymer, woven fabric, knitted fabric, polyester, polyamide, fluorocarbon, polyethylene, polycarbonate, polyurethane, and polystyrene.

60. The method of claim 59 further comprising making the cylinder with a lumen having a diameter of less than about 6 mm.

61. A method of coating a medical device comprising:

providing a plurality of polyvinylpyrrolidone macromers,

polymerizing the macromers into a multi-armed polyvinylpyrrolidone material, and

applying the material onto the medical device.

62. The method of claim 61 further comprising disposing the crosslinked polyvinylpyrrolidone material in an organic solvent before applying the coating to the medical device.

63. The method of claim 61 further comprising applying the coating by a process chosen from the group consisting of dipping, spraying, and drying.

64. A method of making a polysaccharide polymer comprising

providing polymerizable polysaccharide macromers,

synthetically polymerizing the macromers with each other to form a group of polymers having an average length of at least two macromers per polymer, and

isolating the polymers.

65. The method of claim 64 further comprising a step of choosing the polymerizable polysaccharide macromers to each have an average of at least one chemical moiety chosen from the group consisting of polyhydroxyethylmethylacrylates, methyl methacrylates, methacrylates, acrylates, photopolymerizable monomers, monomers with hydroxyl groups, monomers with glycerol groups, monomers with polyoxyalkylene ether groups, monomers with polypropylene oxide groups, monomers with vinyl groups, monomers with zwitterionic groups, monomers with silicone groups, monomers having sulphate groups, monomers having sulphonate groups, and heparin monomer.

66. The method of claim 64 wherein the polysaccharide is chosen to be heparin.

67. The method of claim 64 wherein the polysaccharide macromers are chosen to include at least one macromer chosen from the group consisting of macromers of glycosaminoglycans, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and proteoglycans.

68. The method of claim 64 further comprising polymerizing the polysaccharides macromers in a solvent chosen from the group consisting of aqueous solvents, organic solvents, and mixtures thereof.

69. The method of claim 64 further comprising complexing the polymers with cations.

70. The method of claim 64 further comprising disposing the polymers in an organic solvent.

71. The method of claim 64 wherein the polymers in the group are made to be multi-armed by the polymerization process and are soluble in a solvent.

72. A method of making a coating on a medical device comprising

providing a group of polysaccharide polymers synthetically polymerized from at least two polysaccharide macromers, the polymers having an average length of at least two macromers per polymer,

disposing the polymers in a solvent to make a mixture, and

contacting the medical device with the mixture.

73. The method of claim 72 further comprising complexing the polymers with a cation and choosing the solvent to be an organic solvent.

74. The method of claim 72 further comprising making the polymers with functional groups that are reactable with the medical device to form a covalent bond.

75. The method of claim 72 further comprising reacting the functional groups with the medical device to forma covalent bond between the polymers and the surface.

76. The method of claim 72 further comprising making the polymers with polymerizable groups.

77. The method of claim 76 further comprising polymerizing the polymers after the mixture has contacted the surface.

78. The method of claim 72 wherein the medical device is a tube.

79. A medical device for use as a blood vessel comprising a tubular member having a fabric layer and a crosslinked hydrogel layer made from a plurality of polymerized polysaccharide macromers, the hydrogel layer being disposed on a luminal surface of the tubular member and having a thickness of less than 10 μ

m.

80. A medical device for use as a blood vessel comprising a tubular member having a fabric layer and a crosslinked hydrogel coating made from a plurality of polymerized polysaccharide macromers, the hydrogel layer being disposed on at least a luminal surface of the tubular member and having a thickness of less than 10 μ

m.

81. The medical device of claim 80 wherein the fabric contains a plurality of fabric strands and the hydrogel layer conforms to the strands without covering the interstitial spaces between the strands.

82. The medical device of claim 80 further comprising a polymeric material disposed between the fabric and the hydrogel layer, with the hydrogel layer being in contact with the polymeric material.