Ultrafiltration Membrane, Device, Bioartificial Organ, And Related Methods

• US 20090131858A1
• Filed: 01/10/2008
• Published: 05/21/2009
• Est. Priority Date: 01/10/2007
• Status: Active Grant

• Current Assignee: Cleveland Clinic Foundation
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Fissell, William H., Fleischman, Aaron, Goldman, Kenneth G., Roy, Shuvo
• Granted Patent: US 9,403,126 B2
• Time in Patent Office: Days
• US Class Current: 604/57
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61M 1/1623 Disposition or location of membranes relative to fluids
• CPC Class Codes: A61M 1/267 used for pumping
• CPC Class Codes: B01D 2257/70 Organic compounds not provided for in groups B01D2257/00 - B01D2257/602
• CPC Class Codes: B01D 2313/243 Pumps
• CPC Class Codes: B01D 2321/22 Electrical effects
• CPC Class Codes: B01D 2325/028 Microfluidic pore structures
• CPC Class Codes: B01D 61/145 Ultrafiltration
• CPC Class Codes: B01D 61/18 Apparatus therefor
• CPC Class Codes: B01D 61/20 Accessories; Auxiliary operations
• CPC Class Codes: B01D 67/0034 by micromachining techniques, e.g. using masking and etching steps, photolithography
• CPC Class Codes: B01D 67/0062 by micromachining techniques, e.g. using masking and etching steps, photolithography
• CPC Class Codes: B01D 67/0088 Physical treatment with compounds, e.g. swelling, coating or impregnation
• CPC Class Codes: G01N 1/4077 by other techniques involving separation of suspended solids
• CPC Class Codes: G01N 2001/4088 filtration

Abstract

The present invention relates to ultrafiltration. In particular, the present invention provides nanoporous membranes having pores for generating in vitro and in vivo ultrafiltrate, devices and bioartificial organs utilizing such nanoporous membranes, and related methods (e.g., diagnostic methods, research methods, drug screening). The present invention further provides nanoporous membranes configured to avoid protein fouling with, for example, a polyethylene glycol surface coating.

Claims

1. An ultrafiltration system comprising:

a) a membrane comprising a plurality of nanofabricated pores having a width less than 20 nanometers;

b) a housing containing said membrane; and

c) a fluid delivery passageway with a first end and a second end, said first end positioned outside of said housing, said second end positioned to deliver fluid across said membrane.

2. The system of claim 1, wherein said fluid is delivered across said membrane via perfusion pressure.

3. The system of claim 1, further comprising a pump configured to deliver said fluid across said membrane.

4. The system of claim 1, further comprising an actuator configured to decrease protein fouling of said nanofabricated pores.

5. The system of claim 1, further comprising a control component used to control/monitor extracellular fluid volume.

6. The system of claim 1, wherein said nanofabricated pores are arranged in the center of said membrane.

7. The system of claim 1, wherein said membrane has a porosity above 2%.

8. The system of claim 1, wherein the distance between each of said plurality of nanofabricated pores is within 200 nanometers.

9. The system of claim 1, wherein the length of said nanofabricated pores is less than 50 μ

m.

10. The system of claim 1, wherein said housing comprises a coating, said coating being biocompatible for in vivo use.

11. The system of claim 1, wherein said system further comprises one or more electrodes positioned on or near said membrane such that an electric field is generated in or near said pores.

12. The system of claim 1, wherein said housing has a length and a width, said length of said housing being less than 300 millimeters and said width of said housing being less than 300 millimeters.

13. The system of claim 1, wherein said membrane has a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan.

14. The system of claim 1, wherein said plurality of nanofabricated pores have a slit shape.

15. The system of claim 1, wherein the material of said membrane is selected from the group consisting of silicon, polysilicon, silicon carbide, ultrananocrystalline diamond, diamond-like-carbond (DLC), silicon dioxide, PMMA, SU-8, PTFE, titanium, silica, silicon nitride, polytetrafluorethylene, polymethylmethacrylate, polystyrene, and silicone.

16. An ultrafiltration system comprising:

a) a membrane comprising a plurality of nanofabricated pores, wherein said membrane has a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan;

b) a housing containing said membrane; and

c) a fluid delivery passageway with a first end and a second end, said first end positioned outside of said housing, said second end positioned to deliver fluid across said membrane.

17. The system of claim 16, wherein said fluid is delivered across said membrane via perfusion pressure.

18. The system of claim 16, further comprising a pump configured to deliver said fluid across said membrane.

19. The system of claim 16, further comprising an actuator configured to decrease protein fouling of said nanofabricated pores.

20. The system of claim 16, wherein said nanofabricated pores are arranged in the center of said membrane.

21. The system of claim 16, wherein said membrane has a porosity above 2%.

22. The system of claim 16, further comprising a control component used to control/monitor extracellular fluid volume.

23. The system of claim 16, said plurality of nanofabricated pores having a width less than 20 nanometers.

24. The system of claim 16, wherein the distance between each of said plurality of nanofabricated pores is within 200 nanometers.

25. The system of claim 16, wherein the length of said nanofabricated pores is less than 50 μ

m.

26. The system of claim 16, wherein said housing comprises a coating, said coating being biocompatible for in vivo use.

27. The system of claim 16, wherein said system further comprises one or more electrodes positioned on or near said membrane such that an electric field is generated in or near said pores.

28. The system of claim 16, wherein said housing has a length and a width, said length of said housing being less than 300 millimeters and said width of said housing being less than 300 millimeters.

29. The system of claim 16, wherein said plurality of nanofabricated pores have a slit shape.

30. The system of claim 16, wherein the material of said membrane is selected from the group consisting of silicon, polysilicon, silicon carbide, ultrananocrystalline diamond, diamond-like-carbond (DLC), silicon dioxide, PMMA, SU-8, PTFE, titanium, silica, silicon nitride, polytetrafluorethylene, polymethylmethacrylate, polystyrene, and silicone.

31. An ultrafiltration system comprising:

a) a membrane comprising a plurality of nanofabricated pores having a width less than 20 nanometers;

said membrane having a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan;

b) a housing containing said membrane and said electrode; and

c) a fluid delivery passageway with a first end and a second end, said first end positioned outside of said housing, said second end positioned to deliver fluid across said membrane.

32. The system of claim 31, wherein said fluid is delivered across said membrane via perfusion pressure.

33. The system of claim 31, further comprising a pump configured to deliver said fluid across said membrane.

34. The system of claim 31, further comprising an actuator configured to decrease protein fouling of said nanofabricated pores.

35. The system of claim 31, wherein said nanofabricated pores are arranged in the center of said membrane.

36. The system of claim 31, wherein said membrane has a porosity above 2%.

37. The system of claim 31, wherein the material of said membrane is selected from the group consisting of silicon, polysilicon, silicon carbide, ultrananocrystalline diamond, diamond-like-carbond (DLC), silicon dioxide, PMMA, SU-8, PTFE, titanium, silica, silicon nitride, polytetrafluorethylene, polymethylmethacrylate, polystyrene, and silicone.

38. The system of claim 31, further comprising a control component used to control/monitor extracellular fluid volume.

39. The system of claim 31, wherein the distance between each of said plurality of nanofabricated pores is within 200 nanometers.

40. The system of claim 31, wherein the length of said nanofabricated pores is less than 50 μ

m.

41. The system of claim 31, wherein said housing comprises a coating, said coating being biocompatible for in vivo use.

42. The system of claim 31, wherein said system further comprises one or more electrodes positioned on or near said membrane such that an electric field is generated in or near said pores.

43. The system of claim 31, wherein said housing has a length and a width, said length of said housing being less than 300 millimeters and said width of said housing being less than 300 millimeters.

44. The system of claim 31, wherein said plurality of nanofabricated pores have a slit shape.

45. A method of filtering a biological fluid comprising:

a) providing;

i) a biological fluid; and

ii) an ultrafiltration system comprising;

a) a membrane comprising a plurality of nanofabricated pores having a width less than 20 nanometers;

said membrane having a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan;

b) a housing containing said membrane and said electrode; and

c) a fluid delivery passageway with a first end and a second end, said first end positioned outside of said housing, said second end positioned to deliver fluid across said membrane;

b) transferring said biological fluid into said first end of said delivery passageway; and

c) passing said fluid across said membrane to generated filtered fluid.

46. The method of claim 45, wherein said fluid is delivered across said membrane via perfusion pressure.

47. The method of claim 45, further comprising a pump configured to deliver said fluid across said membrane.

48. The method of claim 45, further comprising an actuator configured to decrease protein fouling of said nanofabricated pores.

49. The method of claim 45, wherein said nanofabricated pores are arranged in the center of said membrane.

50. The method of claim 45, wherein said membrane has a porosity above 2%.

51. The method of claim 45, wherein said ultrafiltration system further comprises a control component used to control/monitor extracellular fluid volume.

52. The method of claim 45, wherein the material of said membrane is selected from the group consisting of silicon, polysilicon, silicon carbide, ultrananocrystalline diamond, diamond-like-carbond (DLC), silicon dioxide, PMMA, SU-8, PTFE, titanium, silica, silicon nitride, polytetrafluorethylene, polymethylmethacrylate, polystyrene, and silicone.

53. The method of claim 45, wherein said filtered fluid is substantially free of proteins.

54. The method of claim 45, wherein said filtered fluid comprises hemofiltered fluid.

55. The method of claim 45, further comprising the step of d) transferring said filtered fluid into a subject.

56. The method of claim 45, wherein the distance between each of said plurality of nanofabricated pores is within 200 nanometers.

57. The method of claim 45, wherein the length of said nanofabricated pores is less than 50 μ

m.

58. The method of claim 45, wherein said plurality of nanofabricated pores have a slit shape.

59. An implantable ultrafiltration device comprising:

a) a membrane comprising a plurality of nanofabricated pores having a width less than 20 nanometers;

said membrane having a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan;

b) a biocompatible housing containing said membrane; and

c) a fluid delivery passageway with a first end and a second end, said first end positioned outside of said housing, said second end positioned to delivery fluid across said membrane.

60. The device of claim 59, wherein said fluid is delivered across said membrane via perfusion pressure.

61. The device of claim 59, further comprising a pump configured to deliver said fluid across said membrane.

62. The device of claim 59, further comprising an actuator configured to decrease protein fouling of said nanofabricated pores.

63. The device of claim 59, wherein said nanofabricated pores are arranged in the center of said membrane.

64. The device of claim 59, wherein said membrane has a porosity above 2%.

65. The device of claim 59, further comprising a control component used to control/monitor extracellular fluid volume.

66. The device of claim 59, wherein the material of said membrane is selected from the group consisting of silicon, polysilicon, silicon carbide, ultrananocrystalline diamond, diamond-like-carbond (DLC), silicon dioxide, PMMA, SU-8, PTFE, titanium, silica, silicon nitride, polytetrafluorethylene, polymethylmethacrylate, polystyrene, and silicone.

67. The device of claim 59, wherein the distance between each of said plurality of nanofabricated pores is within 200 nanometers.

68. The device of claim 59, wherein the length of said nanofabricated pores is less than 50 μ

m.

69. The device of claim 59, wherein said plurality of nanofabricated pores have a slit shape.

70. The device of claim 59, wherein said housing comprises a coating, said coating being biocompatible for in vivo use.

71. The device of claim 59, further comprising a population of cells attached to said membrane.

72. The device of claim 71, wherein said cells are selected from the group consisting of renal tubule cells, pancreatic cells, hepatic cells, thyroid cells, adrenal cells, parathyroid cells, pituitary cells, hypothalamic cells, gonadal cells, prokaryotic cells, duodenal cells, gastric cells, intestinal cells, muscle cells, fibroblast cells, and endothelial cells.

73. The device of claim 59, wherein said housing has physical dimensions that permit said device to be used in a human subject, in vivo.

74. The device of claim 59, further comprising one or more sensors associated with said membrane, wherein said sensor is configured to monitor filtration parameters.

75. The device of claim 74, wherein said one or more sensors are selected from the group consisting of a pressure sensor configured to monitor transmembrane pressure, a proteins sensor configured to monitor protein leakage/membrane breakdown, an optical blood sensor configured to monitor membrane rupture, and urea sensor configured to monitor urea clearance.

76. A method of creating an implantable ultrafiltration device comprising adding a plurality of nanofabricated pores having a width of less than 200 nanometers onto the surface of a membrane, wherein said nanofabricated pores are positioned in the center of said membrane surface.

77. The method of claim 76, wherein said adding is accomplished with nanolithography.

78. The method of claim 76, wherein said membrane has a surface coating selected from the group consisting of polyethylene glycol, oligosaccharide surfactant polymers, heparin, and hyaluronan.

79. The method of claim 76, wherein said membrane has a porosity above 2%.

80. The method of claim 77, wherein said nanolithography is imprinting.

81. The method of claim 76, wherein said less than 200 nanometers is less than 100 nanometers.

82. The method of claim 76, wherein said less than 200 nanometers is less than 50 nanometers.

83. The method of claim 76, wherein said less than 200 nanometers is less than 20 nanometers.

84. The method of claim 76, wherein said less than 200 nanometers is less than 10 nanometers.