Biodegradable Elastomers

• US 20090047256A1
• Filed: 01/12/2007
• Published: 02/19/2009
• Est. Priority Date: 01/12/2006
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Zumbuehl, Andreas, Nijst, Christiaan, Bruggeman, Joost P., Karp, Jeffrey M., Ferreira, Lino Da Silva, Bettinger, Christopher J., Kim, Sonia J., Burdick, Jason
• Granted Patent: US 8,143,042 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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: A61K 35/48 Reproductive organs
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: C08G 63/6854 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08J 2367/00 Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08J2377/12; of polyester-imides C08J2379/08; Derivatives of such polymers
• CPC Class Codes: C08J 2367/07 having terminal carbon-to-carbon unsaturated bonds
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08J 3/246 Intercrosslinking of at least two polymers
• CPC Class Codes: C08K 5/0025 Crosslinking or vulcanising agents; including accelerators
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 67/07 having terminal carbon-to-carbon unsaturated bonds
• CPC Class Codes: C12N 11/082 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C12N 11/087 Acrylic polymers
• CPC Class Codes: C12N 11/096 : Polyesters; Polyamides

Abstract

The present inventions in various aspects provide elastic biodegradable polymers. In various embodiments, the polymers are formed by the reaction of a multifunctional alcohol or ether and a difunctional or higher order acid to form a pre-polymer, which is cross-linked to form the elastic biodegradable polymer. In preferred embodiments, the cross-linking is performed by functionalization of one or more OR groups on the pre-polymer backbone with vinyl, followed by photopolymerization to form the elastic biodegradable polymer composition or material. Preferably, acrylate is used to add one or more vinyls to the backbone of the pre-polymer to form an acrylated pre-polymer. In various embodiments, acrylated pre-polymers are co-polymerized with one or more acrylated co-polymers.

Claims

1. An elastomeric composition comprising a cross-linked polyester, the cross-linked polyester comprising:

a polymeric unit of the general formula (ω

-B-)_n cross-linked between at least a portion of the A components of the polyester, at least a portion of the cross-links forming a dioic acid ester;

wherein,

A represents a substituted or unsubstituted ester,

B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities; and

n represents an integer greater than 1.

2. The composition of claim 1, wherein the cross-linked polyester comprises a portion that can be represented by the general formula (I)

3. The composition of claim 2, wherein p=8, q=8 and v=4.

4. The composition of claim 1, wherein the average ratio of the number of cross-links to the number of (-A-B-)_n polymeric units is less than about 0.4.

5. The composition of claim 1, wherein the average ratio of the number of cross-links to the number of (-A-B-)_n polymeric units is greater than about 0.5.

6. The composition of claim 1, wherein the at least a portion of the cross-links forming a dioic acid ester comprise one or more substituted or unsubstituted alkylester functionalities.

7. The composition of claim 1, wherein the at least a portion of the cross-links forming a dioic acid ester comprise one or more substituted or unsubstituted carbonic acid alkylester functionalities.

8. The composition of claim 1, wherein the cross-linked polyester comprises

a polymeric unit of the general formula (ω

-B-)_n cross-linked to a substituted or unsubstituted alkane through at least a portion of the A components of the polyester, at least a portion of the cross-links forming an acid ester;

wherein,

A represents a substituted or unsubstituted ester,

B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities; and

n represents an integer greater than 1.

9. A biodegradable material formed from the composition of claim 1, the material having a tensile Young'"'"'s modulus less than about 1.5 MPa when measured according to ASTM standard D412-98a.

10. A biodegradable material formed from the composition of claim 1, the material having a tensile Young'"'"'s modulus greater than about 0.05 MPa and an elongation of greater than about 45%, both when measured according to ASTM standard D412-98a.

11. A biodegradable material formed from the composition of claim 1, the material having a Young'"'"'s modulus in the range between about 0.4 MPa and about 0.55 MPa when measured according to ASTM standard D412-98a.

12. A biodegradable material formed from the composition of claim 1, the material having a maximum elongation greater than about 170%.

13. A biodegradable material formed from the composition of claim 1, wherein the biodegradable material is one or more of non-toxic to humans, biocompatible and bioabsorbable.

44. An elastic biodegradable material formed from a composition of claim 1 or claim 14, further comprising one or more of a growth factor, cell adhesion sequence, polynucleotide, polysaccharide, polypeptide, an extracellular matrix component, and combinations thereof.

45. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the elastic biodegradable material is seeded with one or more connective tissue cells, organ cells, muscle cells, nerve cells, and combinations thereof.

46. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the elastic biodegradable material is seeded with one or more 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.

47. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein a chromophore is covalently linked to the cross-linked polyester.

48. The elastic biodegradable material of claim 45, wherein a receptor is covalently linked to the chromophore or interposed between the chromophore and the cross-linked polyester.

49. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the elastic biodegradable material is porous.

50. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the composition comprises a porogen.

51. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the composition comprises a bioactive agent.

52. An elastic biodegradable material formed from a composition of claim 1 or claim 14, wherein the elastic biodegradable material is in the form of a particle, tube, sphere, strand, coiled strand, capillary network, film, fiber, mesh, or sheet.

14. An elastomeric composition comprising a cross-linked polyester, the cross-linked polyester comprising:

a polymeric unit of the general formula (-A-B-)_n cross-linked between at least a portion of the A components of the polyester, the cross-link forming a link comprising at least a portion of the general formula -(D)_k-C-;

wherein

A represents a substituted or unsubstituted ester,

B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities;

C represents a substituted or unsubstituted dioic acid ester;

D represents one or more of a substituted or unsubstituted ester;

n represents an integer greater than 1; and

k represents an integer greater than 0.

15. The composition of claim 14, wherein the cross-linked polyester comprises at least a portion that can be represented by the general formula (II)

16. The composition of claim 15, wherein p=8, q=8 and v=4.

17. The composition of claim 14, wherein the average ratio of the number of cross-links to the number of (-A-B-)_n polymeric units is less than about 0.4.

18. The composition of claim 14, wherein the average ratio of the number of cross-links to the number of (-A-B-)_n polymeric units is greater than about 0.5.

19. The composition of claim 14, wherein the cross-linked polyester comprises a polymeric unit of the general formula (-A-B-)_n cross-linked to a substituted or unsubstituted alkane through at least a portion of the A components of the polyester, at least a portion of the cross-links forming an acid ester;

wherein,

A represents a substituted or unsubstituted ester,

B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities; and

n represents an integer greater than 1.

20. A biodegradable material formed from the composition of claim 14, the material having a tensile Young'"'"'s modulus less than about 17 MPa when measured according to ASTM standard D412-98a.

21. A biodegradable material formed from the composition of claim 14, the material having a tensile Young'"'"'s modulus greater than about 0.6 MPa and an elongation of greater than about 20%, both when measured according to ASTM standard D412-98a.

22. A biodegradable material formed from the composition of claim 14, the material having a tensile Young'"'"'s modulus greater than about 0.25 MPa when measured according to ASTM standard D412-98a and a swelling in water of greater than about 1%.

23. A biodegradable material formed from the composition of claim 14, the material having a tensile Young'"'"'s modulus greater than about 0.25 MPa when measured according to ASTM standard D412-98a and a swelling in water of greater than about 40%.

24. A biodegradable material formed from the composition of claim 14, the material having a Young'"'"'s modulus in the range between about 0.4 MPa and about 0.55 MPa when measured according to ASTM standard D412-98a.

25. A biodegradable material formed from the composition of claim 14, the material having a maximum elongation greater than about 60%.

26. A biodegradable material formed from the composition of claim 14, wherein the biodegradable material is one or more of:

non-toxic to humans, biocompatible and bioabsorbable.

27. An elastomeric biodegradable material formed from a cross-linked polyester, the elastomeric biodegradable material having a degradation rate that is substantially non-monotonic as a function of overall cross-link density.

28. The elastomeric biodegradable material of claim 27, wherein the cross-linked elastomeric polyester comprises:

a polymeric unit of the general formula (-A-B-)_n cross-linked between at least a portion of the A components of the polyester, the cross-link forming a link comprising at least a portion of the general formula -(D)_k-C-;

wherein

A represents a substituted or unsubstituted ester,

B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities;

C represents a substituted or unsubstituted dioic acid ester;

D represents one or more of a substituted or unsubstituted ester;

n represents an integer greater than 1; and

k represents an integer greater than 0.

29. An elastomeric biodegradable material of claim 27, wherein the degradation rate is the in vivo degradation rate

30. An elastomeric biodegradable material of claim 27, wherein the degradation rate is the in vitro degradation rate in phosphate buffer saline (PBS), or in acidic or alkaline conditions.

31. A method for forming a biodegradable elastomeric material, comprising the steps of:

(a) reacting a first component comprising two or more functionalities of the general formula —

OR, where R of each group is independently hydrogen or alkyl, with a second component comprising two or more acid ester functionalities to form a mixture of pre-polymers having a molecular weight in the range between about 300 Da and about 75,000 Da;

(b) reacting the mixture of pre-polymers with an acrylate to form a mixture of acrylated pre-polymers; and

(c) irradiating the acrylated pre-polymer mixture with ultraviolet light to cross-link at least a portion of the acrylated pre-polymers and form a biodegradable elastomeric material;

wherein the pre-polymer mixture is not heated above about 45°

C. during irradiation.

32. The method of claim 31, wherein the acrylate comprises one or more of

33. The method of claim 31, wherein the pre-polymer mixture is not heated above about 25°

C. during irradiation.

34. The method of claim 31, wherein step (b) comprises adding to the reaction one or more of an acrylated dextran, acrylated hyaluronic acid, acrylated chitosan, and acrylated poly(ethylene glycol).

42. A method of forming a medical device comprising the steps of:

injecting an acrylated pre-polymer of claim 31 at a site where the medical device is desired; and

irradiating the injected acrylated pre-polymer with ultraviolet light to form a medical device.

43. The method of claim 42, wherein the medical device provides delivery of a bioactive agent over time.

35. A method for forming a biodegradable elastomeric material, comprising the steps of:

(a) providing a solution comprising;

a first component comprising two or more functionalities of the general formula —

OR, where R of each group is independently hydrogen or alkyl; and

a second component comprising two or more acid ester functionalities;

(b) forming a reaction mixture by adding diisopropyl azodicarboxylate and triphenylphosphine to the pre-polymer solution to crosslink at least a portion of the pre-polymers to form a biodegradable elastomeric material;

wherein, the reaction mixture is not heated above about 25°

C.

36. The method of claim 35, wherein the step of forming a reaction mixture comprises adding a mono-acid to provide an ester linked side chain in the biodegradable elastomeric material.

37. The method of claim 35, wherein the step of forming a reaction mixture comprises adding a mono-alcohol to provide an ether linked side chain in the biodegradable elastomeric material.

38. The method of claim 35, wherein the second component is a substituted or unsubstituted dioic acid ester.

39. The method of claim 35, wherein the second component of the pre-polymer comprises an amino ester functionality and the biodegradable elastomeric material comprises a poly-β

-amino ester polymer.

40. A method for forming a biodegradable elastomeric material, comprising the steps of:

(a) providing a solution comprising;

a first component comprising two or more functionalities of the general formula —

OR, where R of each group is independently hydrogen or alkyl; and

a second component comprising two or more acid ester functionalities;

(b) crosslinking at least a portion of the pre-polymers by thermal initiated polymerization using a thermal initiator, by redox-pair initiated polymerization, or both, wherein the crosslinking reaction is conducted at a temperature of less than about 25°

C.

41. A method for forming a biodegradable elastomeric material, comprising the steps of:

(a) providing a solution comprising;

a first component comprising two or more functionalities of the general formula —

OR, where R of each group is independently hydrogen or alkyl; and

a second component comprising two or more acid ester functionalities;

(b) crosslinking at least a portion of the pre-polymers with a Michael-type addition reaction using a bifunctional sulfhydryl compound, wherein the crosslinking reaction is conducted at a temperature of less than about 25°

C.