Biodegradable polymer

• US 20030118692A1
• Filed: 10/21/2002
• Published: 06/26/2003
• Est. Priority Date: 10/22/2001
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert, Wang, Yadong, Ameer, Guillermo
• Granted Patent: US 7,722,894 B2
• Time in Patent Office: Days
• US Class Current: 426/6
• CPC Class Codes: C08G 63/12 derived from polycarboxylic acids and polyhydroxy compounds

Abstract

A biodegradable polymer comprising a condensation polymer of glycerol and a diacid. The polymer may be adapted for use as a tissue engineering construct. For example, it may be seeded with cells or molecules may be attached to it to modify the metabolism and proliferation of cells or to modify the degradation rate and/or mechanism of the polymer. The polymer may also be exploited in a variety of medical and non-medical applications.

Claims

1. A polymer comprising a biodegradable condensation polymer of glycerol and a diacid, wherein the polymer has a tensile elastic modulus of 5 MPa or less.

2. The polymer of claim 1, wherein the polymer is biocompatible.

3. The polymer of claim 1, wherein the polymer is an elastomer.

4. The polymer of claim 1, wherein the ratio of the glycerol to the diacid is between 1 and 1.5.

5. The polymer of claim 1, wherein the diacid is sebacic acid.

6. The polymer of claim 1, wherein the diacid is selected from malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, and azelaic acid.

7. The polymer of claim 1, wherein the diacid includes a carbon chain having greater than 10 carbon atoms.

8. The polymer of claim 7, wherein thediacid includes a carbon chain having greater than 15 carbon atoms.

9. The polymer of claim 8, wherein the diacid includes a carbon chain having greater than 20 carbon atoms.

10. The polymer of claim 9, wherein the diacid includes a carbon chain having greater than 25 carbon atoms.

11. The polymer of claim 1, wherein the diacid includes one or more double bonds, an aromatic group, an amine, a hydroxyl group, a halogen atom, an aliphatic side chain, or any combination of the above.

12. The polymer of claim 1 wherein the polymer is cross-linked.

13. The polymer of claim 12, wherein the polymer has a cross-link density of less than 40%

14. The polymer of claim 13, wherein the polymer has a cross-link density of less than 30%.

15. The polymer of claim 14, wherein the polymer has a cross-link density of less than 20%

21. The polymer of claim 1, wherein the Young'"'"'s modulus of the polymer is less than 3 MPa.

22. The polymer of claim 21, wherein the Young'"'"'s modulus of the polymer is less than 1 MPa.

23. The polymer of claim 22, wherein the Young'"'"'s modulus of the polymer is less than 0.5 MPa.

24. The polymer of claim 23, wherein the polymer has a modulus less than 100 kPa.

25. The polymer of claim 24, wherein the polymer has a modulus less than 10 kPa.

26. The polymer of claim 1, wherein the ultimate tensile strength of the polymer is greater than 0.5 MPa.

27. The polymer of claim 1, wherein the polymer has a maximum elongation greater than 250%.

28. The polymer of claim 1, wherein, when the polymer is exposed to an aqueous environment, the polymer is characterized by surface erosion.

29. The polymer of claim 1, further comprising a member of a biomolecule, a hydrophilic group, a hydrophobic group, a non-protein organic group, an acid, a small molecule, a bioactive molecule, and any combination of the above.

30. The polymer of claim 29, wherein the biomolecule is selected from growth factors, cell adhesion sequences, polynucleotides, polysaccharide, polypeptide, an extracellular matrix component, and any combination of the above.

31. The polymer of claim 29, wherein the member is linked to the polymer through a member of a covalent bond, a hydrogen bond, an electrostatic interaction, a hydrophobic interaction, and a van der Waals interaction.

32. The polymer of claim 1, wherein the polymer is seeded with cells selected from the group consisting of connective tissue cells, organ cells, muscle cells, nerve cells, and any combination thereof.

33. The polymer of claim 32, wherein the cells are selected from the group consisting of tenocytes, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiac muscle cells, skeletal muscle cells, islet cells, nerve cells, hepatocytes, kidney cells, bladder cells, urothelial cells, chondrocytes, and bone-forming cells.

34. The polymer of claim 1, wherein the polymer further comprises a second polymer as a mixture or adduct.

35. The polymer of claim 34, wherein the second polymer is biocompatible.

36. The polymer of claim 34, wherein the second polymer is biodegradable or non-biodegradable.

37. The polymer of claim 1, wherein a chromophore is covalently linked to the polymer.

38. The polymer of claim 37, wherein a receptor is covalently linked to the chromophore or interposed between the chromophore and the polymer.

39. The polymer of claim 1, wherein the polymer is adapted and constructed to be porous.

40. The polymer of claim 1, wherein the polymer further comprises a porogen mixed into the polymer.

41. The polymer of claim 1, wherein the polymer is adapted and constructed to have a shape selected from particles, tube, sphere, strand, coiled strand, capillary network, film, fiber, mesh, and sheet.

71. A drug delivery device comprising the polymer of claim 1 and at least one moiety selected from a small molecule and a bioactive agent.

72. The drug delivery device of claim 71, wherein the moiety is covalently or non-covalently attached to the polymer.

73. The drug delivery device of claim 71, wherein the device is adapted and contructed to be implanted in the abdominal region of a patient, and wherein the moiety is an anti-inflammatory agent.

74. A cardiac stent, comprising:

an expandable metal mesh; and

a coating comprising the polymer of claim 1.

75. The cardiac stent of claim 74, further comprising a member of a small molecule and a bioactive agent disposed within the coating.

76. The cardiac stent of claim 75, wherein the member is covalently or non-covalently linked to the polymer.

77. A cardiac stent, comprising:

the polymer of claim 1, and

a second polymer

wherein the two polymers are combined in a mixture or adduct.

78. The cardiac stent of claim 77, wherein the second polymer is biodegradable or non-biodegradable.

79. The cardiac stent of claim 77, further comprising a member of a small molecule and a bioactive agent.

80. The cardiac stent of claim 79, wherein the member is covalently or non-covalently linked to the polymer, the second polymer, or both.

81. An absorbent garment comprising a liquid pervious topsheet, a backsheet comprising the polymer of claim 1, and a liquid absorbent core disposed between the topsheet and the backsheet.

82. The absorbent of claim 81, wherein the polymer is degradable in a landfill.

83. The absorbent garment of claim 81, wherein the garment is a member of the group consisting of diaper, incontinence protector, sanitary napkin, panty liner, and surgical dressing.

84. A biodegradable adhesive, comprising the polymer of claim 1, wherein the cross-link density of the condensation polymer is less than 1%.

85. The adhesive of claim 84, wherein the cross-link density of the polymer is less than 0.5%.

86. The adhesive of claim 85, wherein the cross-link density of the polymer is less than 0.05%.

87. A chewing gum comprising the polymer of claim 1 and a member of a flavoring agent, a colorant, and both of the above.

88. The chewing gum of claim 87, further comprising a member of a small molecule, at least one nutrient, and both of the above.

89. The chewing gum of claim 88, wherein the member is covalently or non-covalently attached to the polymer.

90. An inflatable balloon comprising the polymer of claim 1, wherein the balloon is degradable in an outdoor environment.

91. A fishing lure comprising the polymer of claim 1 and a hook, wherein the polymer degrades after exposure to an aqueous environment.

92. A fishing fly comprising the polymer of claim 1 and a hook, wherein the polymer degrades after exposure to an aqueous environment.

93. A disposable bag comprising the polymer of claim 1, wherein the polymer degrades in a landfill.

16. The polymer of 15, wherein the polymer has a cross-link density of less than 10%.

17. The polymer of claim 16 wherein the polymer has a cross-link density of 5%.

18. The biodegradable polymer of claim 17, wherein the polymer has a cross-link density of less than 1%.

19. The polymer of claim 18, wherein the polymer has a cross-link density of less than 0.5%.

20. The polymer of claim 19, wherein the polymer has a cross-link density of less than 0.05%.

42. A polymer comprising a biodegradable condensation polymer of glycerol and a diacid, wherein the polymer is an elastomer.

43. A tissue engineering construct comprising an elastomeric biodegradable condensation polymer of glycerol and a diacid.

44. The tissue engineering construct of claim 43, wherein the ratio of the glycerol to the diacid is between 1 and 1.5.

45. The tissue engineering construct of claim 43, wherein the diacid is sebacic acid.

46. The tissue engineering construct of claim 43, wherein the diacid is selected from malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, and azelaic acid.

47. The tissue engineering construct of claim 43, wherein the diacid includes a carbon chain having greater than 10 carbon atoms.

48. The tissue engineering construct of claim 47, wherein diacid includes a carbon chain having greater than 15 carbon atoms.

49. The tissue engineering construct of claim 48, wherein diacid includes a carbon chain having greater than 20 carbon atoms.

50. The tissue engineering construct of claim 49, wherein diacid includes a carbon chain having greater than 25 carbon atoms.

51. The tissue engineering construct of claim 43, wherein the diacid includes one or more double bonds, an aromatic group, an amine, a hydroxyl group, a halogen atom, an aliphatic side chain, or any combination of the above.

52. The tissue engineering construct of claim 43, wherein the Young'"'"'s modulus of the polymer is less than 5 MPa.

53. The tissue engineering construct of claim 52, wherein the Young'"'"'s modulus of the polymer is less than 3 MPa.

54. The tissue engineering construct of claim 53, wherein the Young'"'"'s modulus of the polymer is less than 1 MPa.

55. The tissue engineering construct of claim 54, wherein the Young'"'"'s modulus of the polymer is less than 0.5 MPa.

56. The polymer of claim 55, wherein the polymer has a modulus less than 100 kPa.

57. The polymer of claim 56, wherein the polymer has a modulus less than 10 kPa.

58. The tissue engineering construct of claim 43, wherein the ultimate tensile strength of the polymer is greater than 0.5 MPa.

59. The tissue engineering construct of claim 43, wherein the polymer is characterized by surface erosion in vivo.

60. The tissue engineering construct of claim 43, wherein the polymer is porous.

61. The tissue engineering construct of claim 60, further comprising a porogen.

62. The tissue engineering construct of claim 43, wherein the tissue is selected from the group consisting of muscle tissue, connective tissue, nerve tissue, organ tissue, epithelial tissue and any combination of the above.

63. The tissue engineering construct of claim 62, wherein the tissue is a member of the group consisting of skin, lung, cardiac muscle, skeletal muscle, smooth muscle, heart valve, bone, nerve, kidney, bladder, liver, tendon, ligament, and pancreas tissue.

64. The tissue engineering construct of claim 43, wherein the polymer is formed into a member of the group consisting of particles, tube, sphere, strand, coiled strand, capillary network, film, fiber, mesh, and sheet.

65. The tissue engineering construct of claim 43, further comprising a member of a biomolecule, a hydrophilic group, a hydrophobic group, a non-protein organic group, an acid, a small molecule, a bioactive molecule, and any combination of the above.

66. The tissue engineering construct of claim 43, further comprising cells selected from the group consisting of connective tissue cells, organ cells, muscle cells, nerve cells, and any combination thereof.

67. The tissue engineering construct of claim 66, wherein the cells are selected from the group consisting of tenocytes, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiac muscle cells, skeletal muscle cells, islet cells, nerve cells, hepatocytes, kidney cells, bladder cells, urothelial cells, chondrocytes, and bone-forming cells.

68. The tissue engineering construct of claim 43, further comprising a second biocompatible polymer.

69. The tissue engineering construct of claim 68, wherein the second biocompatible polymer forms a mixture or adduct with the biocompatible condensation polymer.

70. The tissue engineering construct of claim 68, wherein the second biocompatible polymer is biodegradable or non-biodegradable.

94. A method of producing a polymer, comprising:

combining equal molar amounts of glycerol and a diacid to form a mixture;

holding the mixture at a temperature of 120°

C. in an inert atmosphere at a pressure of 1 Torr for 24 hours;

holding the mixture at a temperature of 120°

C. and a pressure of 40 mTorr until the mixture forms a polymer having a pre-determined crosslinking density.

95. The method of claim 94, wherein the mixture is held at a pressure of 40 mTorr for 24 hours.

96. The method of claim 94, wherein the mixture is held at a pressure of 40 mTorr for 48 hours.

97. The method of claim 94, wherein the step of combining further comprises adding a porogen to the mixture.

98. The method of claim 97, wherein the porogen is selected from azodicarboimide, an alkali halide salt, and a water-soluble salt.

99. The method of claim 98, further comprising soaking the polymerized mixture in water to leach out the porogen.

100. The method of claim 94, further comprising modifying hydroxyl groups on the polymer with a member of a biomolecule, a hydrophilic group, a hydrophobic group, a non-protein organic group, an acid, a small molecule, a bioactive agent, and any combination of the above.

101. The method of claim 94, further comprising:

providing a substrate having a predetermined pattern of grooves and channels and a sacrificial coating of a water-soluble material;

after the step of combining, casting the mixture over the substrate; and

after the mixture has the predetermined cross-link density, dissolving the sacrificial layer to free the polymer from the substrate, wherein the polymer has a relief pattern corresponding to the predetermined pattern.

102. The method of claim 101, further comprising covering the relief pattern in the polymer to form covered channels.

103. The method of claim 102, wherein the cover comprises an elastomeric co-polymer of glycerol and a diacid.

104. The method of claim 101, wherein the step of covering comprises providing a cover, disposing a partially polymerized equimolar mixture of glycerol and a diacid between the cover and the polymer, and cross-linking the equimolar mixture.

105. The method of claim 101, further comprising preparing a cover for the polymer having the relief by the steps of:

combining equal molar amounts of glycerol and a diacid to form a mixture;

holding the mixture at a temperature of 120°

C. in an inert atmosphere at a pressure of 1 Torr for 24 hours;

forming the mixture into a sheet;

disposing the sheet over the relief pattern in the polymer; and

holding the mixture at a temperature of 120°

C. in an inert atmosphere at a pressure of 1 Torr until the sheet has a predetermined cross-link density,

wherein the step of forming may be performed before or after the step of holding at a pressure of 1 Torr.