Biodegradable Photoluminescent Polymers

• US 20110183435A1
• Filed: 06/18/2009
• Published: 07/28/2011
• Est. Priority Date: 06/20/2008
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Gautam, Santosh, Yang, Jian
• Granted Patent: US 8,530,611 B2
• Time in Patent Office: Days
• US Class Current: 436/501
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/3891 as distinct cell layers
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified 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: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 283/006 on to polymers provided for in C08G18/00 C08F283/004 takes precedence
• CPC Class Codes: C08F 289/00 Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds not provided for in groups C08F251/00 - C08F287/00
• CPC Class Codes: C08F 290/00 Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08G 18/4236 containing only aliphatic groups
• CPC Class Codes: C08G 18/4283 Hydroxycarboxylic acid or ester
• CPC Class Codes: C08G 18/4646 containing one nitrogen atom in the ring
• CPC Class Codes: C08G 18/4676 containing sulfur
• CPC Class Codes: C08G 18/73 acyclic
• CPC Class Codes: C08G 2230/00 Compositions for preparing biodegradable polymers
• CPC Class Codes: C08G 63/6854 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08G 63/6858 Polycarboxylic acids and polyhydroxy compounds in which at least one of the two components contains aliphatic unsaturation
• CPC Class Codes: C08G 63/914 derived from polycarboxylic acids and polyhydroxy compounds
• CPC Class Codes: C08J 2367/04 Polyesters derived from hydroxy carboxylic acids, e.g. lactones C08J2367/06 takes precedence
• CPC Class Codes: C08J 5/18 Manufacture of films or sheets
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 5/0691 : Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels

Abstract

The present invention describes a novel elastomeric biodegradable photoluminescent polymer (BPLP). The BPLPs of the present invention possess great processability and tunable fluorescence emission characteristics and are cell-compatible and biodegradable. The BPLPs of the present invention can serve as both implant materials and bioimaging probes.

Claims

1. An aliphatic biodegradable photoluminescent polymer (BPLP) composition comprising:

a degradable oligomer, wherein the oligomer is synthesized from a biocompatible multifunctional monomer, a diol, and an amino acid;

wherein the amino acid is linked as a side chain to the BPLP backbone wherein the fluorescence emanates from a 6-membered ring formed by a carboxylic acid, an alpha carbon, and an amino group of the amino acid;

wherein the carboxylic acid, the alpha carbon, and the amino groups bend backwards to join the polymer backbone via an esterification reaction.

3. The composition of claim 1 wherein the biocompatible multifunctional monomer comprises citric acid, the diol comprises 1,8-octanediol, and the amino acid comprises cysteine or serine.

5. The composition of claim 1 wherein the diols comprises saturated aliphatic diols, C3-C12 diols, macrodiols, hydrophilic diols, hydrophobic diols or any combinations thereof.

6. The composition of claim 1 wherein the diols are selected from a group comprising of 1,8-octanediols, ethylene glycol, propylene glycol, macrodiols, poly(ethylene glycol), poly(propylene glycol) 1,3-propanediol, ethanediol, and cis-1,2-cyclohexanediol.

9. The composition of claim 1, wherein the BPLP is optionally crosslinked;

wherein the crosslinking is achieved by radical polymerization initiated by photoinitiators or redox initiators.

2. (canceled)

4. (canceled)

7. (canceled)

8. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. A method of making an aliphatic biodegradable photoluminescent polymer (BPLP) comprising the steps of:

mixing a biocompatible multifunctional monomer, a diol, and an amino acid to form a mixture;

raising the temperature of the mixture to melt the mixture; and

lowering the temperature of the mixture with stirring to form the aliphatic BPLP.

18. The method of claim 16, wherein the biocompatible multifunctional monomer comprises citric acid, the diol comprises 1,8-octanediol, and the amino acid comprises cysteine or serine.

17. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. A method of making a cross-linked biodegradable photoluminescent polymer (CBPLP) comprising the steps of:

dissolving a biodegradable photoluminescent polymer in an organic solvent to form a solution;

casting the solution in a mold;

evaporating the solvent; and

post-polymerizing the BPLP to forms the CBPLP.

24. (canceled)

25. (canceled)

26. A method of making one or more aliphatic biodegradable photoluminescent polymer (BPLP) nanoparticles comprising the steps of:

dissolving a BPLP in an organic solvent to form a solution;

adding the solution dropwise to deionized water with stirring; and

evaporating the organic solvent to form the one or more aliphatic (BPLP) nanoparticles.

28. The method of claim 26, wherein the biocompatible multifunctional monomer comprises citric acid.

27. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. (canceled)

36. A urethane-doped biodegradable photoluminesecent polyester (UBPLP) comprising:

a degradable oligomer, wherein the oligomer is synthesized from a biocompatible multifunctional monomer, a diol;

an amino acid, and a di-isocyanate;

wherein the amino acid is linked as a side chain to the BPLP backbone.

37. The composition of claim 36, wherein the biocompatible monomer comprises citric acid, the diol comprises 1,8-octanediol, the amino acid comprises cysteine or serine, and the di-isocyanate comprises Hexamethylene-1,6-di-isocyanate (HDI), or 1,4-Butane di-isocyanate (BDI).

38. The composition of claim 36, wherein the biocompatible multifunctional monomer comprises citric acid.

39. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

47. A method of making an a crosslinked urethane-doped biodegradable photoluminescent polyester (CUBPLP) comprising the steps of:

mixing a biocompatible multifunctional monomer and a diol to form a mixture;

raising the temperature of the mixture to melt the mixture;

lowering the temperature of the mixture with stirring to form an oligomer;

adding an amino acid to the oligomer with stirring to form a pre-BPLP-amino acid;

purifying the pre-BPLP-amino acid by dropwise addition to deionized water;

collecting an undissolved pre-BPLP-amino acid portion from the deionized water;

lyophilizing the collected pre-BPLP-amino acid to obtain purified pre-BPLP;

dissolving the purified pre-BPLP-amino acid in 1,4-dioxane to form a solution;

adding 1,6-hexamethyl diisocyanate (HDI) to the pre-BPLP-amino acid solution which may optionally contain one or more catalysts to form a pre-CUBPLP (UBPLP);

casting a film of the pre-CUBPLP (UBPLP) in a laminar airflow; and

placing the pre-CUBPLP (UBPLP) in an oven to obtain the CUBPLP.

48. The method of claim 47, wherein the biocompatible multifunctional monomer comprises citric acid, the diol comprises 1,8-octanediol, and the amino acid comprises cysteine or serine.

49. The method of claim 47, wherein the one or more catalysts are selected from a group comprising tin-based catalysts such as organotin catalysts, tin octanoate (stannous octanoate), dibutyl tin dilaurate and amine catalysts such DABCO (1,4-diazabicyclo[2.2.2]octane).

50. A method for fabricating crosslinked aliphatic biodegradable photoluminescent polymer (CBPLP) scaffolds comprising the steps of:

freeze-drying a BPLP solution in a mold; and

post polymerizing the freeze-dried solution in an oven to form a CBPLP scaffold.

51. A method of fabricating a small diameter blood vessel (SDBV) graft, wherein the SDBV graft comprises multiple crosslinked aliphatic biodegradable photoluminescent polymer (CBPLP) scaffolds;

comprising the steps of;

transferring first cells on a first CBPLP scaffold;

transferring second cells on a second CBPLP scaffold;

culturing the first and second CBPLP scaffolds for at least two days;

providing a CBPLP-ser tube;

constructing the SDBV graft by rolling the first CBPLP seeded with the first cell and the second CBPLP scaffold seeded with the second cell with the CBPLP-ser tube sequentially on a rod;

removing the rod to form a tubular graft;

seeding third cells onto the lumen of the tubular graft;

culturing the graft for at least 3 days in a coculture medium; and

assembling the graft in a perfusion bioreactor to form the CBPLP-SDBV graft.

52. The method of claim 51, further comprising the steps of:

mounting the grafts on one or more hollow posts in the perfusion chamber;

pumping a cell-culture medium with pulsing into the chamber;

wherein the cell-culture medium is in communication with the grafts; and

culturing the grafts for a specified period of time in the cell-culture medium.

53. The method of claim 51, wherein the first cells are human aortic fibroblast (HAFB) cells.

54. (canceled)

55. (canceled)

56. A fluorometric method for the detection of cationic polymers in a sample;

wherein the cationic polymer does not have a chromophore or lacks a chromophore absorbing above 200 nm;

comprising the steps of;

mixing the sample comprising the cationic polymer with an aqueous solution of a water-soluble biodegradable photoluminescent polymer (BPLP) or an organic solvent of a water-insoluble BPLP;

forming a complex between the cationic polymer in the sample and the water-soluble or water-insoluble BPLP;

measuring a fluorescence signal emanating from the complex of the cationic polymer with the water-soluble or water-insoluble BPLP;

mixing standard solutions comprising different concentrations of the cationic polymer with the with the water-soluble or water-insoluble BPLP solution;

forming complexes between the different concentrations of the cationic polymer and the water-soluble or water-insoluble BPLP;

measuring a fluorescence signal emanating from the complex of the different concentrations cationic polymer with the water-soluble or water-insoluble BPLP;

creating a calibration curve by plotting the fluorescence signal values of the complexes versus the different concentrations of the cationic polymer; and

calculating an unknown concentration of the cationic polymer in the sample based on the calibration curve.

57. The method of claim 56, wherein the cationic polymer is Polyquaternium-1,ω

-{4-[tris(2-hydroxyethyl)ammonio]-but-2-enylpoly(dimethylammoniobut-2enyl)}tris(2-hydroxyethyl)ammonium polychloride.

58. (canceled)