Cell encapsulating device containing a cell displacing core for maintaining cell viability

• US 5,980,889 A
• Filed: 08/05/1997
• Issued: 11/09/1999
• Est. Priority Date: 08/10/1993
• Status: Expired due to Term

• Current Assignee: W. L. Gore & Associates (W.L. Gore & Associates)
• Original Assignee: Gore Hybrid Technologies, Inc.
• Inventors: Mish, Stanley L., Butler, Mark D.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/906,367
• Time in Patent Office: 826 Days
• Field of Search: 435/177, 435/180, 435/182, 435/325, 435/382, 435/395, 435/401, 435/403, 435/402, 435/70.1, 435/70.3, 435/71.1, 435/71.2, 424/423, 424/93.7
• US Class Current: 424/93.7
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Abstract

Cell encapsulating devices capable of maintaining large numbers of viable cells are provided containing an inert, substantially cell-free core that displaces cells, a permeable membrane and a zone for maintaining cells. The permeable membrane surrounds the core such that the zone of cells is bounded by the core and the permeable membrane. The cell zone may contain a support means for cell attachment and the core may have an outer boundary containing a material that promotes cell adhesion. Preferably, the cell zone has a thickness such that at least about 10% of the cells, more preferably at least about 50% or 80%, in a cell layer located closest to the outer boundary of the core remain viable. The thickness is preferably less than 500 microns such as 25 to 250 microns or 50 to 100 microns. The devices are suitable for implantation into an individual in need of treatment and are capable of supplying therapeutic substances to such individuals.

Claims

1. An enclosable cell encapsulating device comprising:

a) an outer permeable membrane wherein said permeable membrane allows for passage into said device of nutrients external to said device and wastes of cells and desirable cell products out of said device without permitting passage of cells therethrough;

b) a cell displacing core situated in said device so as to displace cells from a region centrally located in said device, said core being substantially cell free;

c) a cell zone capable of containing cells, said cell zone having a thickness extending from said permeable membrane to an outer boundary of said cell displacing core, said thickness being sufficiently narrow to support the viability of cells; and

d) a sealable opening for receiving cells, which when sealed forms a completely enclosed cell encapsulation device.

2. The device according to claim 1 wherein said permeable membrane excludes cells and molecules of an immune system.

3. The device according to claim 2 further comprising a support means for providing a site for cell attachment in the cell zone.

4. The device according to claim 3 wherein the support means is comprised of a porous PTFE material, a dextran material, a collagen material, a polyester material or a polystyrene material.

5. The device according to claim 3 wherein the support means is a random network, a trabecular network, microspheres or fibrous mattes.

6. The device according to claim 3 wherein the outer boundary of the core is porous and the interior region of the core is substantially cell free.

7. The device according to claim 2 wherein the outer boundary of the core is comprised of a material which promotes cell adhesion.

8. The device according to claim 7 wherein the material to promote cell adhesion is collagen, poly-L-lysine, laminin, fibronectin or porous PTFE.

9. The device according to claim 2 wherein the permeable membrane and the core are both cylindrical having longitudinal axes which are substantially parallel to each other.

10. The device of claim 2 wherein the core is substantially centrally located within the permeable membrane.

11. The device according to claim 10 wherein the cell zone thickness is less than about 500 microns.

12. The device according to claim 11 wherein the cell zone thickness is from about 25 to about 250 microns.

13. The device according to claim 12 wherein the cell zone thickness is from about 50 to about 100 microns.

14. The device according to claim 2 wherein the permeable membrane is comprised of porous polytetrafluoroethylene (PTFE) or hydrogel.

15. The device according to claim 14 wherein the permeable membrane comprises a hydrogel with an average thickness of between about 15 and about 25 microns.

16. The device according to claim 2 wherein the core comprises an inert, cell-free material made from polytetrafluoroethylene (PTFE), polydimethylsiloxane, polyurethane, polyester, polyamide, polysaccharides, hydrophilic polyacrylonitrile or a copolymer of polyacrylonitrile and acrylamide.

17. The device according to claim 1 wherein said core comprises a swellable material that expands from an initial dimension to an enlarged final dimension upon exposure to water.

18. The device according to claim 1 wherein said device further comprises cells in said cell zone.

19. The device according to claim 1 wherein said thickness of the cell zone is less than about 500 microns.

20. The device according to claim 19 wherein said thickness of the cell zone averages about 25 to 250 microns.

21. The device according to claim 20 wherein said thickness of the cell zone averages about 50 to 100 microns.

22. The device according to claim 1 further comprising a porous network positioned between said core and said permeable membrane.

23. The enclosable cell encapsulation device according to claim 1 wherein said cell displacing core has a radial dimension greater than the thickness of the cell zone.

24. The device according to claim 23 wherein said permeable membrane excludes cells and molecules of an immune system.

25. The device according to claim 23 wherein said core comprises a swellable material that expands from an initial dimension to an enlarged final dimension upon exposure to water.

26. The device according to claim 23 wherein said device further comprises cells in said cell zone.

27. The device according to claim 23 further comprising a porous network positioned between said core and said permeable membrane.

28. The device according to claim 1 wherein the thickness of the cell zone supports the viability of at least about 10% of the cells in a cell layer located closet to the outer boundary of the core.

29. The device according to claim 28 wherein the thickness of the cell zone supports the viability of at least about 50% of the cells in a cell layer located closest to the outer boundary of the core.

30. The device according to claim 29 wherein the cell zone thickness is from about 50 to about 100 microns.

31. The device according to claim 30 further comprising a support means for attachment of cells to the core.

32. The device according to claim 31 wherein the support means is a random network, a trabecular network, microspheres or fibrous mattes.

33. The device according to claim 32 wherein the support means is made from porous PTFE, dextran, collagen, polyester or polystyrene.

34. The device according to claim 30 further comprising insulin secreting cells.

35. The device according to claim 28 wherein the thickness of the cell zone supports the viability of at least about 80% of the cells in a cell layer located closest to the outer boundary of the core.

36. A method of preparing cell products comprising

culturing cells in vitro in the device according to claim 1 so as to allow cell products to diffuse out of the device and into culture medium surrounding the device;

and

purifying the cell product from the culture medium.

37. The method of claim 36 wherein the cell product is insulin.

38. A method for providing a therapeutic substance to an individual in need of treatment wherein the therapeutic substance is produced by a population of cells contained in an implantable cell encapsulating device, said method comprising inserting into an individual in need of treatment the device according to claim 18 wherein the cells contained within the device provide the therapeutic substance to the individual.

39. The method according to claim 38 wherein the core and the permeable membrane are proportioned to provide a diffusion length parameter (DLP), measured on a planar cross-section of the device taken perpendicular to a long axis of the core and passing through the core, cell zone and permeable membrane at a point along the long axis of the core, wherein the cell zone is sufficiently thick to contain at least one cell layers, and

wherein the DLP is defined as the ratio of an area of the cell zone wherein the area is the total area of the cell zone of the cross-section, divided by a perimeter of the cell zone of the cross-section wherein the perimeter is defined as the length of the inside surface of the permeable membrane on the cross-section, is less than about 500 microns.

40. The method according to claim 39 wherein the cells in the device produce insulin as the therapeutic substance.

41. A device for providing substances from cells contained in the device, said device comprising

a cell displacing core having a substantially cell free interior region and an outer boundary surrounding the interior region and a long axis, wherein said core is situated in said device so as to displace cells from a region centrally located in said device;

a cell zone containing cells, said cell zone substantially surrounding the core and extending from the outer boundary of the core to an inside surface of a permeable membrane, said cell zone being sufficiently narrow to support the viability of cells in cell layer located closest to the outer boundary of the core having a minimum cell thickness of at least one cell layer and a maximum cell thickness which is defined by a diffusion length parameter (DLP) wherein said DLP is less than about 500 microns,

the permeable membrane having inside and outside surfaces and a long axis substantially parallel to the long axis of the core, and surrounding the cell zone, and

a sealable opening for inserting cells, and

wherein said DLP is measured on a planar cross-section of the device taken perpendicular to the long axis of the core and passing through the core, cell zone and permeable membrane at a point along the long axis of the core wherein the cell zone is sufficiently thick to contain at least one cell layer, and wherein the DLP is defined as the ratio of an area of the cell zone wherein the area is the total area of the cell zone of the cross-section, divided by a perimeter of the cell zone of the cross-section wherein the perimeter is defined as the length of the inside surface of the permeable membrane on the cross section.

42. The device according to claim 41 wherein the diffusion length parameter ranges from about 25 to about 250 microns.

43. The device according to claim 42 wherein the diffusion length parameter ranges from about 50 to about 100 microns.

44. The device according to claim 41 wherein the cell zone thickness is such that at least about 10% of the cells in a cell layer located closest to the outer boundary of the core remain viable.

45. The device according to claim 44 wherein the cell zone thickness is such that at least about 50% of the cells in a cell layer located closest to the outer boundary of the core remain viable.

46. The device according to claim 45 wherein the cell zone thickness is such that at least about 80% of the cells in a cell layer located closest to the outer boundary of the core remain viable.

47. The device according to claim 43 further comprising a support means for attachment of cells.

48. The device according to claim 47 wherein the form of the support means is a random network, a trabecular network, fibrous mattes or microspheres.

49. The device according to claim 47 wherein the material for producing the solid support means is made from porous PTFE, dextran, collagen, polyester or polystyrene.

50. The device according to claim 49 wherein the cells comprise insulin secreting cells.

51. The device according to claim 41 wherein the permeable membrane is made from porous polytetrafluoroethylene (PTFE) or hydrogel.

52. The device according to claim 51 wherein the permeable membrane comprises a hydrogel with an average thickness of between about 15 and about 25 microns.

53. The device according to claim 41 wherein the core comprises an inert, cell-free material made from polytetrafluoroethylene (PTFE), polydimethylsiloxane, polysaccharides, poluurethane, polyester, ployamide, hydrophilic polyacrylonitrile or a copolymer of polyacrylonitrile and acrylamide.

54. The device according to claim 41 wherein the core and the permeable membrane are substantially spherical.

55. A method of producing a device for containing cells for the production of a therapeutic substance, the method comprising

providing an exterior membrane impermeable to cells but permeable to both nutrients and the therapeutic substance produced by the cells and wherein the membrane forms a lumen;

providing a cell-impermeable core to be inserted into the lumen of the exterior;

introducing the core into the lumen of the exterior membrane to create a cell zone for maintaining cells, said cell having a thickness extending from said permeable membrane to an outer boundary of said cell displacing core and being sufficiently narrow to support the viability of cells in a cell layer closest to the outer boundary of the core, and wherein said core is situated in said device so as to displace cells from a region centrally located in said device;

introducing cells into the cell zone; and

sealing the exterior membrane so that the exterior membrane surrounds the core, the cell zone and the cells therein.

56. The method according to claim 55 further comprising a swelling step to enlarge the core to a final volume.

57. The method according to claim 55 further comprising inserting the device into an individual whereby the cells are sustained by nutrients from the individual and the therapeutic substance is provided to the individual by the cells.