Methods and compositions of a bioartificial kidney suitable for use in vivo or ex vivo

• US 5,549,674 A
• Filed: 10/08/1993
• Issued: 08/27/1996
• Est. Priority Date: 03/02/1992
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Humes, H. David, Cieslinski, Deborah A.
• Primary Examiner(s): Dodson, Shelley A.
• Application Number:
  US08/133,436
• Time in Patent Office: 1,054 Days
• Field of Search: 435/240.2, 435/240.21, 514/12, 600/36, 604/6, 604/35, 604/48, 604/319, 623/1, 623/11, 623/12
• US Class Current: 623/23.65
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• 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 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: C12M 21/08 for producing artificial tissue or for ex-vivo cultivation of tissue prostheses A61F2/00, grafts A61L27/00
• CPC Class Codes: C12M 23/06 Tubular C12M23/08, C12M23/16 take precedence
• CPC Class Codes: C12M 25/02 Membranes; Filters filters or filtration in general B01D24/00-B01D41/00
• CPC Class Codes: C12M 29/04 Filters; Permeable or porous membranes or plates, e.g. dialysis
• CPC Class Codes: C12M 29/16 Hollow fibers hollow fiber modules in general B01D63/02
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2501/15 Transforming growth factor beta (TGF-β)
• CPC Class Codes: C12N 2501/385 of the family of the retinoic acid recptor, e.g. RAR, RXR; Peroxisome proliferator-activated receptor [PPAR]
• CPC Class Codes: C12N 2502/256 Renal cells
• CPC Class Codes: C12N 2502/28 Vascular endothelial cells
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2533/54 Collagen; Gelatin
• CPC Class Codes: C12N 5/0687 Renal stem cells; Renal progenitors
• CPC Class Codes: C12N 5/069 Vascular Endothelial cells
• CPC Class Codes: C12N 5/0697 Artificial constructs associating cells of different lineages, e.g. tissue equivalents blood vessels C12N5/0691

Abstract

A novel cell seeded hollow fiber bioreactor is described as a potential bioartificial kidney. Renal cells are seeded along a hollow fiber in a perfused bioreactor to reproduce the ultrafiltration function and transport function of the kidney. Maintenance of tissue specific function and ultrastructure suggest that this bioreactor provides an economical device for treating renal failure as well as studying renal tubululogenesis in vitro.

Claims

1. A bioartificial filtration device suitable for filtering blood, comprising at least one semipermeable hollow fiber in a chamber defined by a housing, wherein said one surface of said fiber is coated with a layer of endothelial cells, epithelial cells, or a combination thereof, wherein said cells are non-immortalized cells, and wherein said hollow fiber is in fluid communication with blood inlet and outlet, and wherein said housing is elaborated with a blood filtrate outlet.

2. The bioartificial filtration device according to claim 1, wherein said hollow fiber is internally coated with a composition comprising said endothelial, epithelial cells or a combination thereof and at least one extracellular matrix component.

3. The bioartificial filtration device according to claim 1, wherein said hollow fibers are coated internally with a composition comprising said endothelial cells and at least one extracellular matrix component.

4. The bioartificial filtration device according to claim 3, wherein said endothelial cells are transfected with a gene encoding a compound with anticoagulant activity.

5. The bioartificial filtration device according to claim 4, wherein said gene encodes hirudin.

6. The bioartificial filtration device according to claim 4, wherein said gene encodes a peptide with hirudin-like properties.

7. The bioartificial filtration device according to claims 2 or 3, wherein said extracellular matrix component is a member selected from the group consisting of Type I collagen, Type IV collagen, laminin, proteoglycan, fibronectin, and combinations thereof.

8. The bioartificial filtration device according to claim 1, wherein said semipermeable hollow fiber is formed from a biocompatible polymer.

9. The bioartificial filtration device according to claim 8, wherein said biocompatible polymer is selected from the group consisting of polyacrylonitrile, cellulose, polycarbonate, polymethylmethacrylate, polysulphone, cellulose acetate, acrylic copolymer and ethylene vinyl copolymer.

10. The bioartificial filtration device according to claim 1, wherein said semipermeable hollow fiber has a molecular weight cut-off of less than 66,000 Daltons.

11. The bioartificial filtration device according to claim 1, wherein said semipermeable hollow fiber has an ultrafiltration coefficient greater than 20 mL/hr,Torr, m².

12. The bioartificial filtration device according to claim 11, wherein said semipermeable hollow fiber has an ultrafiltration coefficient of from 20-100 mL/hr,Torr, m².

13. The bioartificial filtration device according claim 1, comprising a plurality of said coated semipermeable hollow fibers.

56. The filtration device according to claim 2, wherein hirudin, a hirudin fragment, or hirulog is covalently linked to said fibers.

14. A bioartificial filtration device suitable for filtering blood, comprising a bundle of semipermeable hollow fibers in a chamber defined by a housing, wherein said fibers are coated internally with a layer of endothelial or epithelial cells, wherein opposite ends of said hollow fibers are connected to perfusion inlet and outlet ports and wherein said housing contains a blood filtrate outlet.

15. A bioartificial filtration device suitable for filtering blood, comprising at least one semipermeable hollow fiber embedded in extracellular matrix, said fiber in fluid communication with a blood filtrate outlet, wherein one end of said hollow fiber is sealed.

16. The bioartificial filtration device according to claim 15, wherein said semipermeable hollow fiber is formed from a biocompatible polymer.

17. The bioartificial filtration device according to claim 16, wherein said biocompatible polymer is selected from the group consisting of polyacrylonitrile, cellulose, polycarbonate, polymethylmethacrylate, polysulphone, cellulose acetate, acrylic copolymer and ethylene vinyl copolymer.

18. The bioartificial filtration device according to claim 15, wherein said semipermeable hollow fiber has a molecular weight cut-off of less than 66,000 Daltons.

19. The bioartificial filtration device according to claim 15, wherein said semipermeable hollow fiber has an ultrafiltration coefficient greater than 20 mL/hr,Torr.

20. The bioartificial filtration device according to claim 19, wherein said semipermeable hollow fiber has an ultrafiltration coefficient of from 20-100 mL/hr,Torr.

21. The bioartificial filtration device according to claim 15, wherein said extracellular matrix is impregnated with an angiogenic factor.

22. The bioartificial filtration device according to claim 15, wherein said filtration device further comprises a means to deliver angiogenic factors into proximity with said fiber.

23. The bioartificial filtration device according to either claim 21 or 22, wherein said angiogenic factors are selected from the group consisting of acidic fibroblast growth factor (FGF), basic FGF, FGF-5 hepatocyte growth factor, and vascular endothelial growth factor.

24. The bioartificial filtration device according to claim 15, comprising a multitude of said coated semipermeable hollow fibers.

25. A bioartificial filtration device suitable for filtering blood, comprising a plurality of semipermeable hollow fibers which are in close proximity to a capillary network, wherein one end of said hollow fibers is sealed, and the opposite end is in fluid communication with a blood filtrate outlet.

26. A bioartificial tubule processing unit suitable for processing blood filtrate, comprising a semipermeable hollow fiber which is coated internally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

27. The bioartificial tubule processing device according to claim 26, wherein said hollow fiber is coated internally with a composition comprising said renal tubule cells and at least one extracellular matrix component.

28. The bioartificial tubule processing device according to claim 27, wherein said extracellular matrix component is a member selected from the group consisting of Type I collagen, Type IV collagen, laminin, Matrigel, proteoglycan, fibronectin, and combinations thereof.

29. The bioartificial tubule processing device according to claim 26, wherein said renal tubule cells are in a confluent monolayer.

30. The bioartificial tubule processing device according to claim 26, wherein said semipermeable hollow fibers are formed from a biocompatible polymer.

31. The bioartificial tubule processing device according to claim 30, wherein said biocompatible polymer is selected from the group consisting of polyacrylonitrile, cellulose, polycarbonate, polymethylmethacrylate, polysulphone, cellulose acetate, acrylic copolymer and ethylene vinyl copolymer.

32. A bioartificial tubule processing device according to claim 27, comprising a plurality of said coated semipermeable hollow fibers.

33. A bioartificial tubule processing device suitable for processing blood filtrate, comprising a plurality of semipermeable hollow fibers which are internally coated with a layer of renal tubule cells, wherein one end of said hollow fibers is connected to a blood filtrate inlet and the opposite end of said hollow fibers is connected to a urine outlet.

34. A bioartificial tubule processing device suitable for processing blood filtrate, comprising a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated externally with a layer of renal tubule cells, wherein one end of said fiber is sealed and the opposite end of said fiber is in fluid communication with a reabsorbate outlet, and wherein said housing is further elaborated with a blood filtrate inlet and a urine outlet.

35. The bioartificial tubule processing device according to claim 34, wherein said hollow fiber is coated externally with a composition comprising said renal tubule cells and at least one extracellular matrix component.

36. The bioartificial tubule processing device according to claim 35, wherein said extracellular matrix component is a member selected from the group consisting of Type I collagen, Type IV collagen, laminin, Matrigel, proteoglycan, fibronectin, and combinations thereof.

37. The bioartificial tubule processing device according to claim 34, wherein said renal tubule cells are in a confluent monolayer.

38. The bioartificial tubule processing device according to claim 34, wherein said semipermeable hollow fiber is formed from a biocompatible polymer.

39. The bioartificial tubule processing device according to claim 38, wherein said biocompatible polymer is selected from the group consisting of polyacrylonitrile, cellulose, polycarbonate, polymethylmethacrylate, polysulphone, cellulose acetate, acrylic copolymer and ethylene vinyl copolymer.

40. The bioartificial tubule processing device according to 34, comprising a plurality of said hollow fibers.

41. A bioartificial tubule processing device suitable for processing blood filtrate, comprising a plurality of semipermeable hollow fibers in a chamber defined by a housing, wherein said fibers are coated externally with a layer of renal tubule cells, wherein opposite ends of said fibers are connected to a blood filtrate inlet and perfusion outlet, and wherein said housing is further elaborated with a urine outlet.

42. A bioartificial blood purification device comprising a filtration device and a tubule processing device,

wherein said filtration device comprises a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated internally with a layer of endothelial cells, epithelial cells, or a combination thereof, wherein said hollow fiber is in fluid communication with blood inlet and outlet, and wherein said housing is elaborated with a blood filtrate outlet,

wherein said filtration device is in fluid communication with a tubule processing device which comprises a semipermeable hollow fiber which is coated internally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

43. The bioartificial blood purification device according to claim 42, wherein said filtration device and said tubule processing device comprise a plurality of said semipermeable hollow fibers.

44. A bioartificial blood purification device comprising a filtration device and a tubule processing device,

wherein said filtration device comprises a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated internally with a layer of endothelial cells, epithelial cells, or a combination thereof, wherein said hollow fiber is in fluid communication with blood inlet and outlet, and wherein said housing is elaborated with a blood filtrate outlet,

wherein said filtration device is in fluid communication with said tubule processing device which comprises a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated externally with a layer of renal tubule cells, wherein one end of said fiber is sealed and the opposite end of said fiber is in fluid communication with a reabsorbate outlet, and wherein said housing is further elaborated with a blood filtrate inlet and a urine outlet.

45. The bioartificial blood purification device according to claim 44, wherein said filtration device and said tubule processing device comprise a plurality of said semipermeable hollow fibers.

46. A bioartificial blood purification device comprising a filtration device and a tubule processing device,

wherein said filtration device comprises a semipermeable hollow fiber embedded in extracellular matrix, wherein said fiber is in fluid communication with a blood filtrate outlet and is sealed at one end,

and wherein said filtration device is in fluid communication with said tubule processing device which comprises a semipermeable hollow fiber which is coated internally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

47. The bioartificial blood purification device according to claim 46, wherein said filtration device and said tubule processing device comprise a plurality of said semipermeable hollow fibers.

48. A bioartificial blood purification device comprising a filtration device and a tubule processing device,

wherein said filtration device comprises a semipermeable hollow fiber embedded in extracellular matrix, wherein said fiber is in fluid communication with a blood filtrate outlet and is sealed at one end,

and wherein said filtration device is in fluid communication with said tubule processing device which comprises a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated externally with a layer of renal tubule cells, wherein one end of said fiber is sealed and the opposite end of said fiber is in fluid communication with a reabsorbate outlet, and wherein said housing is further elaborated with a blood filtrate inlet and a urine outlet.

49. The bioartificial blood purification device according to claim 48, wherein said filtration device and said tubule processing device comprise a plurality of said semipermeable hollow fibers.

50. A bioartificial blood purification device comprising a device comprising a plurality of first and second types of semipermeable hollow fibers in a chamber defined by a housing with a urine outlet,

wherein the first type of said fibers provide filtration function, are internally coated with endothelial cells and are in fluid communication with blood inlet and outlet, and

wherein said the second type of said fibers provide reabsorption function, are coated externally with a layer of renal tubule cells, and have one end sealed and the opposite end in fluid communication with said perfusion outlet.

51. A bioartificial blood purification device comprising, in fluid communication with each other, (1) a hemodialyzer and (2) a bioartificial tubule processing device comprising a semipermeable hollow fiber which is coated internally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

52. A bioartificial blood purification device comprising, in fluid communication with each other, (1) a hemodialyzer and (2) a bioartificial tubule processing device comprising a semipermeable hollow fiber in a chamber defined by a housing, wherein said fiber is coated externally with a layer of renal tubule cells, wherein one end of said fiber is sealed and the opposite end of said fiber is in fluid communication with a reabsorbate outlet, and wherein said housing is further elaborated with a blood filtrate inlet and a urine outlet.

53. A bioartificial filtration device suitable for filtering blood, comprising:

at least one semipermeable membrane, coated on one surface with a layer of endothelial cells, epithelial cells or a combination thereof, in a chamber defined by a housing containing;

(i) a perfusion inlet supplying a flow of blood passed, and in fluid communication with, said one surface of said membrane and

(ii) a perfusion outlet for receiving blood which has flowed over said one surface of said membrane, and

(iii) a filtrate outlet for receiving filtrate in fluid communication with the surface opposite said cell coated surface of said membrane.

54. A bioartificial tubule processing device suitable for processing blood filtrate, comprising:

at least one semipermeable membrane, coated on one surface with a layer of renal tubule cells, in a chamber defined by a housing containing;

(i) a filtrate inlet supplying a flow of blood filtrate passed, and in fluid communication with, said one surface of said membrane and

(ii) a urine outlet for receiving blood filtrate which has flowed over said one surface of said membrane, and

(iii) a reabsorbate outlet in fluid communication with the surface opposite said cell coated surface of said membrane.

55. A bioartificial filtration device suitable for filtering blood, comprising a semipermeable hollow fiber in a chamber surrounded by a housing, wherein said fiber is coated with a layer of hirudin, hirudin fragments or hirulog, wherein said fiber is in fluid communication with blood inlet and a blood outlet, and wherein said housing is elaborated with a blood filtrate outlet.

57. A bioartificial tubule processing unit suitable for processing blood filtrate, comprising a semipermeable hollow fiber which is coated externally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

58. A bioartificial blood purification device comprising a filtration device and a tubule processing device,

wherein said filtration device comprises at least one semipermeable hollow fiber in a chamber defined by a housing, wherein said one surface of said fiber is coated with a layer of endothelial cells, epithelial cells, or a combination thereof, wherein said cells are non-immortalized cells, and wherein said hollow fiber is in fluid communication with blood inlet and outlet, and wherein said housing is elaborated with a blood filtrate outlet,

wherein said filtration device is in fluid communication with a tubule processing device which comprises at least one semipermeable hollow fiber which is coated externally with a layer of renal tubule cells, wherein said fiber is in fluid communication with a blood filtrate inlet and a urine outlet.

59. The device of claim 58, wherein said filtration device precedes said tubule processing device in said series.