Tissue engineered uterus

• US 20030096406A1
• Filed: 11/15/2002
• Published: 05/22/2003
• Est. Priority Date: 11/16/2001
• Status: Active Grant

• Current Assignee: Anthony J. Atala
• Original Assignee: Children's Medical Center Corporation
• Inventors: Atala, Anthony, Yoo, James J.
• Granted Patent: US 7,049,057 B2
• Time in Patent Office: Days
• US Class Current: 435/366
• 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: A61L 2430/22 for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3679 Hollow organs, e.g. bladder, esophagus, urether, uterus, intestine
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3813 Epithelial cells, e.g. keratinocytes, urothelial cells
• CPC Class Codes: A61L 27/3826 Muscle cells, e.g. smooth muscle cells
• CPC Class Codes: A61L 27/3886 comprising two or more cell types
• CPC Class Codes: A61L 27/3891 as distinct cell layers
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C12N 2500/84 from mammals
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2502/1347 Smooth muscle cells
• CPC Class Codes: C12N 2502/243 Cells of the female genital tract, non-germinal ovarian cells
• CPC Class Codes: C12N 2533/40 Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06
• CPC Class Codes: C12N 5/0697 Artificial constructs associating cells of different lineages, e.g. tissue equivalents blood vessels C12N5/0691

Abstract

The invention is directed to compositions and methods for reconstructing artificial female reproductive organs. The constructs and methods of the invention can be used for ameliorating congenital malformations and disorders of female reproductive tract using tissue engineered female reproductive organs, such as the uterus, vagina, cervix, and fallopian tubes. These tissue engineered female reproductive organs can be generated by perfusing cultured cell populations derived from cells of the female reproductive tissues, such as uterine, vaginal, cervical, fallopian tube epithelial cells as well as smooth muscle cells.

Claims

1. A method of constructing an artificial uterus comprising:

providing a biocompatible matrix;

perfusing the biocompatible matrix with a first cell population, the first cell population comprising a uterine epithelial cell population;

perfusing the biocompatible matrix with a second cell population comprising a different cell type than the first cell population; and

culturing the cell populations in the biocompatible matrix;

to thereby create an artificial uterus, uterine tissue structure, or uterine segment.

2. The method of claim 1, wherein the method further comprises perfusing the biocompatible matrix with at least one additional cell population.

3. The method of claim 1, wherein the second cell population is a substantially homogenous smooth muscle cell population.

4. The method of claim 1, wherein the first cell population is a substantially homogenous cervical epithelial cell population, whereby the artificial uterine segment formed is a cervix.

5. The method of claim 1, wherein the method further comprises purfusing the first and second cell populations on separate matrix layers and combining the matrix layers after perfusion.

6. The method of claim 1, wherein the artificial uterus or uterine tissue has uterine epithelial cells deposited on a surface of the matrix and smooth muscle cells deposited on another surface of the matrix.

7. The method of claim 1, wherein the method further comprises selecting a biocompatible matrix that comprises a polymer.

8. The method of claim 1, wherein the method further comprises selecting a biocompatible matrix that comprises a decellularized structure.

9. The method of claim 1, wherein the biocompatible matrix is formed from at least one material selected from the group consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

10. The method of claim 1, wherein the biocompatible matrix is polyglycolic acid (PGA).

11. A method of reconstructing, repairing, augmenting or replacing a uterus in a subject comprising:

providing a biocompatible matrix;

perfusing the biocompatible matrix with a first cell population, the first cell population comprising a uterine epithelial cell population;

perfusing the biocompatible matrix with a second cell population comprising a different cell type than the first cell population;

culturing the cell populations in the biocompatible matrix; and

implanting the cell perfused biocompatible matrix in the subject;

to thereby create an artificial uterus, uterine tissue structure, or segment thereof in the subject in need of uterus reconstruction, repair, augmentation or replacement.

12. The method of claim 11, wherein the second cell population comprises a substantially homogenous smooth muscle cell population.

13. The method of claim 11, wherein the first cell population comprises a substantially homogenous cervical epithelial cell population, whereby the artificial uterine segment formed is a cervix.

14. The method of claim 11, wherein the biocompatible matrix comprises a polymer.

15. The method of claim 11, wherein the biocompatible matrix comprises a decellularized structure.

16. The method of claim 11, wherein the biocompatible matrix is formed from at least one material selected from the group of materials consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

17. The method of claim 11, wherein the biocompatible matrix is polyglycolic acid (PGA).

18. An artificial uterus construct comprising:

an implantable, biocompatible matrix, which has been perfused with a uterine epithelial cell population and with a smooth muscle cell population, such that the uterine epithelial cell population attaches to the smooth muscle cell population forming a tissue structure having compliance of normal uterus tissue.

19. The construct of claim 18, wherein the biocompatible matrix is formed from at least one material selected from the group consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

20. The construct of claim 18, wherein the biocompatible material is polyglycolic acid (PGA).

21. The method of claim 18, wherein the biocompatible matrix comprises a polymer.

22. The method of claim 18, wherein the biocompatible matrix comprises a decellularized structure.

23. The construct of claim 18, wherein the biocompatible matrix is perfused with at least one additional cell population.

24. A method of reducing infertility in a subject comprising:

providing a biocompatible matrix;

perfusing the biocompatible matrix with a first cell population, the first cell population comprising a uterine epithelial cell population;

perfusing the biocompatible matrix with a second cell population comprising a different cell type than the first cell population;

culturing the cell populations in the biocompatible matrix, such that an artificial uterus is formed;

depositing a fertilized egg in the artificial uterus;

implanting the artificial uterus in the subject;

to thereby create an artificial uterus in the subject, whereby the artificial uterus supports the growth of the deposited fertilized egg.

25. A method of constructing an artificial fallopian tube comprising:

providing a biocompatible matrix;

perfusing the biocompatible matrix with a first cell population, the first cell population comprising a fallopian tube epithelial cell population;

perfusing the biocompatible matrix with a second cell population comprising a different cell type than the first cell population; and

culturing the cell populations in the biocompatible matrix;

to thereby create an artificial fallopian tube or fallopian tube tissue structure.

26. The method of claim 25, wherein the method further comprises perfusing the biocompatible matrix with at least one additional cell population.

27. The method of claim 25, wherein the second cell population comprises a substantially homogenous smooth muscle cell population.

28. The method of claim 25, wherein the method further comprises perfusing the first and second cell populations on separate matrix layers and combining the matrix layers after perfusion.

29. The method of claim 25, wherein the artificial fallopian tube or fallopian tube tissue has fallopian tube epithelial cells deposited on a surface of the matrix and smooth muscle cells deposited on another outer surface of the matrix.

30. The method of claim 25, wherein the method further comprises selecting a biocompatible matrix that comprises a polymer.

31. The method of claim 25, wherein the method further comprises selecting a biocompatible matrix that comprises a decellularized structure.

32. The method of claim 25, wherein the biocompatible matrix is formed from at least one material selected from the group consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

33. The method of claim 25, wherein the biocompatible matrix is polyglycolic acid (PGA).

34. The method of claim 25, wherein the biocompatible matrix is coated with a biocompatible and biodegradable shaped setting material.

35. A method of reconstructing, repairing, augmenting or replacing a fallopian tube in a subject comprising:

providing a biocompatible matrix;

perfusing the biocompatible matrix with a first cell population, the first cell population comprising a fallopian tube epithelial cell population;

perfusing the biocompatible matrix with a second cell population comprising a different cell type than the first cell population;

culturing the cell populations in the biocompatible matrix; and

implanting the cell perfused biocompatible matrix in the subject;

to thereby create an artificial fallopian tube or fallopian tube tissue structure in the subject in need of fallopian tube reconstruction, repair, augmentation or replacement.

36. The method of claim 35, wherein the method further comprises perfusing the biocompatible matrix with at least one additional cell population.

37. The method of claim 35, wherein the second cell population comprises a substantially homogenous a smooth muscle cell population.

38. The method of claim 35, wherein the method further comprises perfusing the first and second cell populations on separate matrix layers and combining the matrix layers after perfusion.

39. The method of claim 35, wherein the artificial fallopian tube or fallopian tube tissue has fallopian tube epithelial cells deposited on a surface of the matrix and smooth muscle cells deposited on another surface of the matrix.

40. The method of claim 35, wherein the method further comprises selecting a biocompatible matrix that comprises a polymer.

41. The method of claim 35, wherein the method further comprises selecting a biocompatible matrix that comprises a decellularized structure.

42. The method of claim 35, wherein the biocompatible matrix is formed from at least one material selected from the group consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

43. The method of claim 35, wherein the biocompatible matrix is polyglycolic acid (PGA).

44. The method of claim 35, wherein the biocompatible matrix is coated with a biocompatible and biodegradable shaped setting material.

45. An artificial fallopian tube construct comprising:

an implantable, biocompatible matrix, which has been perfused with a fallopian tube epithelial cell population and with a smooth muscle cell population, such that the fallopian tube epithelial cell population attaches to the muscle cell population forming the artificial fallopian tube tissue structure.

46. The construct of claim 45, wherein the biocompatible matrix is formed from at least one material selected from the group of materials consisting of cellulose ether, cellulose, cellulosic ester, fluorinated polyethylene, poly-4-methylpentene, polyacrylonitrile, polyamide, polyamideimide, polyacrylate, polybenzoxazole, polycarbonate, polycyanoarylether, polyester, polyestercarbonate, polyether, polyetheretherketone, polyetherimide, polyetherketone, polyethersulfone, polyethylene, polyfluoroolefin, polyglycolic acid, polyimide, polyolefin, polyoxadiazole, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polysulfide, polysulfone, polytetrafluoroethylene, polythioether, polytriazole, polyurethane, polyvinyl, polyvinylidene fluoride, regenerated cellulose, silicone, urea-formaldehyde, copolymers and physical blends thereof.

47. The construct of claim 45, wherein the biocompatible material is polyglycolic acid (PGA).

48. The method of claim 45, wherein the biocompatible matrix comprises a polymer.

49. The method of claim 45, wherein the biocompatible matrix comprises a decellularized structure.

50. The construct of claim 45, wherein the biocompatible matrix is perfused with at least one additional cell population.