Biodegradable polymer

• US 7,722,894 B2
• Filed: 10/21/2002
• Issued: 05/25/2010
• Est. Priority Date: 10/22/2001
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Wang, Yadong, Langer, Robert, Ameer, Guillermo
• Primary Examiner(s): Wax; Robert A
• Assistant Examiner(s): Barham; Bethany
• Application Number:
  US10/277,562
• Publication Number:
  US 20030118692A1
• Time in Patent Office: 2,773 Days
• Field of Search: 424/422
• US Class Current: 424/422
• 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 biocompatible, biodegradable elastomeric crosslinked polymer comprising glycerol and a diacid, wherein the polymer has a cross-link density of 1% up to less than about 40%, which can be obtained by polycondensation and crosslinking of glycerol and diacid at 120°

C. under an inert atmosphere with reduction in pressure for 24 to 48 hours until the desired crosslinking is reached.

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

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

4. 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.

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

6. The polymer of claim 5, wherein the diacid includes a carbon chain having greater than 15 carbon atoms.

7. The polymer of claim 6, wherein the diacid includes a carbon chain having greater than 20 carbon atoms.

8. The polymer of claim 7, wherein the diacid includes a carbon chain having greater than 25 carbon atoms.

9. 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.

10. The polymer of claim 1, wherein the polymer has a cross-link density of less than 30%.

11. The polymer of claim 10, wherein the polymer has a cross-link density of less than 20%

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

15. The polymer of claim 14, wherein the Young'"'"'s modulus of the polymer is less than 1 MPa.

16. The polymer of claim 15, wherein the Young'"'"'s modulus of the polymer is less than 0.5 MPa.

17. The polymer of claim 16, wherein the polymer has a modulus less than 100 kPa.

18. The polymer of claim 7, wherein the polymer has a modulus less than 10 kPa.

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

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

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

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

23. The polymer of claim 22, wherein the biomolecule is selected from the group consisting of growth factors, cell adhesion sequences, polynucleotides, polysaccharide, polypeptide, an extracellular matrix component, and any combination of the above.

24. The polymer of claim 22, wherein the biomolecule, a hydrophilic group, a hydrophobic group, a non-protein organic group, an acid, a small molecule, a bioactive molecule, or any combination of the above 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.

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

26. The polymer of claim 25, wherein the second polymer is biocompatible.

27. The polymer of claim 25, wherein the second polymer is biodegradable or non-biodegradable.

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

29. The polymer of claim 28, wherein a receptor is covalently linked to the chromophore or interposed between the chromophore and the polymer.

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

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

32. The polymer of claim 1, wherein the polymer has a shape selected from particles, tube, sphere, strand, coiled strand, capillary network, film, fiber, mesh, and sheet.

33. A stent, comprising the polymer of claim 1.

34. The stent of claim 33, further comprising a bioactive agent disposed within the polymer.

35. The stent of claim 34, wherein the bioactive agent is covalently or non-covalently linked to the polymer.

36. A stent, comprising:

the polymer of claim 1, and

a second polymer

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

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

38. The stent of claim 36, further comprising a bioactive agent.

39. The stent of claim 38, wherein the bioactive agent is covalently or non-covalently linked to the polymer, the second polymer, or both.

52. The polymer of claim 1, wherein the Young'"'"'s modulus of the polymer is less than 5 MPa.

53. The polymer of claim 1, further comprising reducing the pressure from 1 Torr to 40 mTorr over 5 hours.

54. The polymer of claim 1, further comprising curing the polymer at 120°

C. at 40 mTorr for 24-48 hours.

12. The polymer of 11, wherein the polymer has a cross-link density of less than 10%.

13. The polymer of claim 12 wherein the polymer has a cross-link density of 5%.

40. A method of producing a polymer, comprising:

combining glycerol and a diacid to form a mixture;

holding the mixture under conditions equivalent to a temperature of 120°

C. in an inert atmosphere at a pressure of 1 Torr to 40 mTorr until the mixture forms a crosslinked polymer having a pre-determined crosslinking density of 1% up to less than about 40%.

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

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

43. The method of claim 40, wherein the step of combining further comprises adding a porogen to the mixture.

44. The method of claim 43, wherein the porogen is selected from the group consisting of azodicarboimide, an alkali halide salt, and a water-soluble salt.

45. The method of claim 44, further comprising soaking the polymerized mixture in water to leach out the porogen.

46. The method of claim 40, further comprising modifying hydroxyl groups on the polymer with a member selected from the group consisting 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.

47. The method of claim 40, 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.

48. The method of claim 47, further comprising covering the relief pattern in the polymer to form covered channels.

49. The method of claim 48, wherein the cover comprises an elastomeric co-polymer of glycerol and a diacid.

50. The method of claim 47, 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.

51. The method of claim 47, comprising

combining 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; and

holding the mixture at a temperature of 120°

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