Blood compatible nanomaterials and methods of making and using the same

• US 20100239673A1
• Filed: 08/01/2006
• Published: 09/23/2010
• Est. Priority Date: 08/01/2005
• Status: Abandoned Application

• Current Assignee: Rensselaer Polytechnic Institute
• Original Assignee: Rensselaer Polytechnic Institute
• Inventors: Park, TaeJoon, Murugesan, Saravanababu, Linhardt, Robert J.
• Application Number:
  US11/497,838
• Publication Number:
  US 20100239673A1
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 13/12 of the kidneys

Abstract

The invention provides blood compatible nanomaterials, biomaterials prepared therewith and blood compatible medical devices fabricated using the biomaterials of the invention. The invention further provides methods of making and using the nanomaterials, biomaterials and medical devices of the invention for the diagnosis, prevention and treatment of medical conditions. The invention further provides methods of using room temperature ionic liquids to make blood compatible nanomaterials.

Claims

1. Blood compatible nanomaterials.

2. The nanomaterials of claim 1 wherein the nanomaterials comprises:

carbon, polymeric compounds, block-polymeric compounds, non-polymeric compounds, metallic compounds, non-metallic compounds, or composites.

3. The nanomaterials of claim 1 in the shapes of hollow or solid, spheres, ellipsoids, fibers, wires, pyramids, prisms, tubes or any combination thereof.

4. The nanomaterials of claim 1 wherein the nanomaterials are in the shape of nanotubes.

5. The nanotubes of claim 4 wherein the nanotubes are single-walled nanotubes, double-walled nanotubes (DWNTs) or multi-walled nanotubes (MWNTs).

6. The nanomaterials of claim 1 comprising carbohydrates.

7. The nanomaterials of claim 1 comprising glycosaminoglycans.

8. The nanomaterials of claim 7 wherein the glycosaminoglycans are heparan sulfate, heparin, dermatan sulfate, keratan sulfate hyaluronate, chondroitin sulfate, derivatives thereof, hybrids thereof, or any combinations thereof.

9. The nanomaterials of claim 1 comprising a composite.

10. The nanomaterials of claim 9 wherein the composite comprises a modified or unmodified carbohydrate matrix having an agent homogenously distributed therein.

11. The nanomaterials of claim 10 wherein the agent is an anticoagulant, antithrombogenic, antibiotic, diagnostic, imaging agent, radioactive agent, fluorescent agent or anticancer agent.

12. The nanomaterials of claim 11 wherein the agent is heparan sulfate, heparin, dermatan sulfate, keratan sulfate hyaluronate, chondroitin sulfate, derivatives thereof, hybrids thereof, or any combinations thereof.

13. The nanomaterials of claim 10 wherein the matrix is modified or unmodified cellulose, hemicellulose, inulin, chitin, chitotsan, glycogen, starch, pectin, carageenan, fucan, or fucoidin.

14. The nanomaterials of claim 9 wherein the composite is in the form of a film, a membrane, a fiber, a sphere, a wire, a rod, an extruded shape, a molded shape, or any combination thereof.

15. A method of making a composite of claim 9 comprising the steps of:

(a) dissolving a matrix material in a first ionic liquid;

(b) dissolving at least one agent in at least one ionic liquid wherein at least one ionic liquid having an agent dissolved therein is different from the first ionic liquid of step (a);

(c) combining the first ionic liquid of step (a) with the at least one ionic liquid of step (b) and mixing to form a combined solution comprising the matrix material and at least one agent; and

(d) fabricating the combined solution of step (c) in the form of a composite nanomaterial.

16. The method of claim 15 further comprising the step of removing at least a portion of the residual ionic liquid after step (c) or step (d).

17. The method of claim 16 wherein the removing step comprises washing the solid composite with a cosolvent after step (d).

18. The method of claim 16 wherein the removing step comprises extracting the ionic liquid from the combined solution of (c) with a cosolvent.

19. The method of claim 18 wherein the removing step comprises extracting the ionic liquid from the composite after step (d).

20. The method of claim 17 wherein the cosolvent is ethanol, isopropanol, methanol, water, hexanes, ethyl acetate, or acetonitrile.

21. The method of claim 17 wherein one or more of the ionic liquid are regenerated from the cosolvent by distillation.

22. The method of claim 15 further comprising drying the composite nanomaterial.

23. The method of claim 15 wherein the combining step is conducted at temperatures and under conditions in which the matrix and the agent are both stable.

24. The method of claim 15 wherein step (b) comprises at least two agents dissolved in at least two separate and different ionic liquids.

25. The method of claim 15 wherein step (b) comprises at least two agents dissolved in the same ionic liquid.

26. The method of claim 15 wherein the matrix is modified or unmodified cellulose, hemicellulose, inulin, chitin, chitotsan, glycogen, starch, pectin, carageenan, fucan, or fucoidin.

27. The method of claim 15 wherein the agent is heparan sulfate, heparin, dermatan sulfate, keratan sulfate hyaluronate, chondroitin sulfate, derivatives thereof, hybrids thereof, or any combinations thereof.

28. The method of claim 15 wherein the ionic liquids of step (a) or step (b) are selected from:

1-butyl, 3-methylimidazolium chloride [bmIm][Cl], 1-ethyl, 3-methylimidazolium benzoate ([emIm][ba]), 1-butyl, 3-methylimidazolium benzoate ([bmIm][ba]), and 1-butyl, 3-methylimidazolium hexafluorophosphate [bmIm][PF₆].

29. The method of claim 15 wherein the fabricating step comprises, casting to form molded shapes, films and membranes, electrospinning to provide fibers, or atomizing to form spheres and particles having smooth or textured surfaces.

30. The method of claim 26 wherein the matrix is cellulose and wherein the cellulose concentration in the first ionic liquid is between about 1% (w/w) and 50% (w/w).

31. The method of claim 30 wherein the agent is heparin and wherein the heparin concentration in the ionic liquid is between about 0.001 mg/mL and 0.5 mg/mL.

32. A biomaterial comprising the nanomaterials of claim 1.

33. A medical device comprising the nanomaterials of claim 1.

34. The medical device of claim 33 selected from the group consisting of:

intravascular medical devices;

extravascular medical devices, drug delivery devices, gene delivery devices, cell growth matrices, and any components thereof.

35. A composite comprising heparin homogenously distributed within a cellulose matrix.

36. The composite of claim 35 in the form of a nanomaterial.

37. The composite of claim 35 in the form of a fiber selected from hollow or solid nanofibers, microfibers, or macrofibers.

38. The composite of claim 37 wherein said fibers are fabricated to form a biomaterial.

39. The composite of claim 35 wherein the biomaterial is fabricated to form a blood compatible medical device for renal dialysis.

40. A method of treating a patient in need of renal dialysis comprising incorporating the medical device of claim 36 into the dialysis process.

41. The method of claim 40 wherein the patient has not been treated systemically with an anticoagulant prior to, or during dialysis.

42. A neoglycoprotein comprising at least one carbohydrate linked to a nanomaterial core.

43. The neoglycoprotein of claim 42 wherein the nanomaterial core comprises carbon, polymeric compounds, block-polymeric compounds, non-polymeric compounds, metallic compounds, non-metallic compounds, or composites spheres, full spheres, ellipsoids, fibers, wires, pyramids, prisms, tubes or any combination thereof.

44. The neoglycoprotein of claim 42 wherein the nanomaterial core comprises nanotubes.

45. The neoglycoprotein of claim 42 wherein the nanotubes are comprised of carbon.

46. The neoglycoprotein of claim 45 wherein the nanotubes are single-walled nanotubes (SWNTs), double-walled nanotubes (DWNTs) or multi-walled nanotubes MWNTs).

47. The neoglycoprotein of claim 42 wherein the carbohydrate is modified or unmodified cellulose, hemicellulose, inulin, chitin, chitotsan, glycogen, starch, pectin, carageenan, fucan, or fucoidin.

48. The method of claim 42 wherein the neoglycoprotein is blood compatible.

49. The method of claim 42 wherein the neoglycoprotein is a neoproteoglycan.

50. A solution comprising a mixture of a matrix material dissolved in a first ionic liquid in combination with at least one agent dissolved in at least one different ionic liquid wherein the matrix and the agent remain stable in the solution mixture.

51. The solution of claim 50 wherein the matrix material is cellulose and the agent is heparin.

52. The solution of claim 51 wherein upon removal of the ionic liquid, the solution mixture forms a composite having a cellulose matrix with heparin homogenously distributed therein.

53. The solution of claim 50 wherein upon removal of the ionic liquid, the solution mixture forms a composite comprising the matrix with the agent homogenously distributed therein.

54. A method of making a composite comprising the steps of:

(a) dissolving a matrix material in a first ionic liquid;

(b) dissolving at least one agent in at least one ionic liquid wherein at least one ionic liquid having an agent dissolved therein is different from the first ionic liquid of step (a);

(c) combining the first ionic liquid of step (a) with the at least one ionic liquid of step (b) and mixing to form a combined solution comprising the matrix material and at least one agent; and

(d) fabricating the combined solution of step (c) in the form of a composite nanomaterial.

55. The method of claim 54 further comprising the step of removing at least a portion of the residual ionic liquid after step (c) or step (d).

56. The method of claim 55 wherein the removing step comprises washing the solid composite with a cosolvent after step (d).

57. The method of claim 55 wherein the removing step comprises extracting the ionic liquid from the combined solution of (c) with a cosolvent.

58. The method of claim 55 wherein the removing step comprises extracting the ionic liquid from the composite after step (d).

59. The method of claim 55 wherein the removing step requires a cosolvent and the cosolvent is ethanol, isopropanol, methanol, water, hexanes, ethyl acetate, or acetonitrile.

60. The method of claim 59 wherein one or more of the ionic liquids are regenerated from the cosolvent by distillation.

61. The method of claim 54 further comprising drying the composite nanomaterial.

62. The method of claim 54 wherein the combining step is conducted at temperatures and under conditions in which the matrix and the agent are both stable.

63. The method of claim 54 wherein step (b) comprises at least two agents dissolved in at least two separate and different ionic liquids.

64. The method of claim 54 wherein step (b) comprises at least two agents dissolved in the same ionic liquid.

65. The method of claim 54 wherein the matrix is modified or unmodified cellulose, hemicellulose, inulin, chitin, chitotsan, glycogen, starch, pectin, carageenan, fucan, or fucoidin.

66. The method of claim 54 wherein the agent is heparan sulfate, heparin, dermatan sulfate, keratan sulfate hyaluronate, chondroitin sulfate, derivatives thereof, hybrids thereof, or any combinations thereof.

67. The method of claim 54 wherein the ionic liquids of step (a) or step (b) are selected from:

1-butyl, 3-methylimidazolium chloride [bmIm][Cl], 1-ethyl, 3-methylimidazolium benzoate ([emIm][ba]), 1-butyl, 3-methylimidazolium benzoate ([bmIm][ba]), and 1-butyl, 3-methylimidazolium hexafluorophosphate [bmIm][PF₆].

68. The method of claim 54 wherein the fabricating step comprises, casting to form molded shapes, films and membranes, electrospinning to provide fibers, or atomizing to form spheres and particles having smooth or textured surfaces.

69. The method of claim 65 wherein the matrix is cellulose and wherein the cellulose concentration in the first ionic liquid is between about 1% (w/w) and 50% (w/w).

70. The method of claim 66 wherein the agent is heparin and wherein the heparin concentration in the ionic liquid is between about 0.001 mg/mL and 0.5 mg/mL.

71. The method of claim 54 wherein the agent is an anticoagulant, antithrombogenic, antibiotic, diagnostic agent, imaging agent, radioactive agent, fluorescent agent or anticancer agent.

72. A composite prepared in accordance with the method of claim 54.

73. The composite of claim 72 wherein the composite is a nano-sized material, a microsized material or a macro-sized material.