Encapsulated cell device

• US 5,976,780 A
• Filed: 06/02/1998
• Issued: 11/02/1999
• Est. Priority Date: 07/16/1996
• Status: Expired due to Term

• Current Assignee: Kumarpal A. Shah
• Original Assignee: Kumarpal A. Shah
• Inventors: Shah, Kumarpal A.
• Primary Examiner(s): SAUNDERS, DAVID A
• Application Number:
  US09/089,174
• Time in Patent Office: 518 Days
• Field of Search: 424/93.7, 424/424, 424/425, 427/2.14, 427/2.24, 435/1.1, 435/177, 435/178, 435/182, 435/400
• US Class Current: 435/1.1
• 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: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres

Abstract

A macroencapsulation device for somatic cells using ultrapurified Na alginate and polysulfone hollow fibers of 30 kDa molecular weight cutoff. Ultrapurified Na alginate material is used which has a high `G` content, low endotoxin content, low divalent metal toxins and low protein impurities. Islet cells prior to being encapsulated, are irrigated with Hank'"'"'s modified solution (without Ca and Mg) containing gentamycin, vancomycin and amphotericin B and then passed through a leukoabsorb filter to reduce the donor antigen load of passenger leukocytes and to reduce the bioburden of microorganisms including viruses. Encapsulation is done in RPMI 1640 tissue culture fluid containing necessary nutritional supplements and ATP source of energy. The open ends of the fiber are covered with a porous membrane. To further improve biocompatibility, the outer wall of the polysulfone is lightly gelled with alginate gel. Such double gelled, encapsulated fibers do not affect diffusion of glucose or insulin across the hollow fibers.

Claims

1. A transplantation or implantation device comprising

a hollow polysulfone fiber having ends and a fiber wall with a porosity which selectively allows nutritional, gaseous, and metabolic substances to pass therethrough and which only allows passage of substances having a molecular weight less than about 30,000 Daltons, and

a mixture of viable, somatic, mammalian cells and alginate gel suspended within said fiber.

2. The device of claim 1, wherein said wall is devoid of macrovoids and has a porosity which prevents donor antigens and cytokines from passing through said wall.

3. The device of claim 1, wherein said fiber includes a sulfonic polymer for inhibiting complement activation.

4. The device of claim 1, wherein said somatic cells are selected from the group consisting of neural, endocrine and hepatic cells.

5. The device of claim 1, wherein said cells are substantially free from passenger leukocytes.

6. The device of claim 1, wherein said mixture includes a soluble sulfonic polymer.

7. The device of claim 6, wherein said soluble sulfonic polymer comprises sodium polystrene sulfonate.

8. A transplantation or implantation device comprising

a hollow polysulfone fiber having ends and a fiber wall with a porosity which selectively allows nutritional, gaseous, and metabolic substances to pass therethrough and

a mixture of viable, somatic, mammalian cells and alginate gel suspended within said fiber, wherein said alginate comprises ultrapurified alginate which is substantially free of divalent metal toxins and has (i) an endotoxin content of less than 750 EU/g, (ii) a protein content of less than 0.2%, and (iii) a G monomer, dimer and trimer content of greater than 60%.

9. The device of claim 8, wherein said alginate has a viscosity of approximately 322 mPas, a pH of approximately 5.9, a loss on drying factor of approximately 8.7%, a heavy metals content of less than 74 parts per million, an arsenic content of less than 0.5 parts per million, a lead content of less than 7 parts per million, and an iron content of less than 58 parts per million.

10. The device of claim 8, wherein said gel is exposed at the ends of the fiber, and

wherein the device comprises a porous membrane cross-linked to said exposed gel.

11. The device of claim 10, wherein said porous membrane only allows passage of substances having a molecular weight less than about 50,000 Daltons.

12. The device of claim 11, wherein said porous membrane is selected from the group consisting of poly-L-lysine, chitosan and polyethylenimine.

13. The device of claim 11, wherein said wall has a porosity which only allows passages of substances having a molecular weight less than about 30,000 Daltons.

14. The device of claim 13, wherein said porous membrane is made of poly-L-lysine.

15. The device of claim 10, including an exterior gel coating over said wall and said porous membrane.

16. The device of claim 15, wherein the exterior gel coating cross-links to the porous membrane.

17. The device of claim 15, wherein said porous membrane comprises poly-L-lysine and said gel coating comprises alginate.

18. The device of claim 8, wherein said mixture includes modified Hank'"'"'s solution devoid of Ca and Mg and enriched with fetal calf serum and adenine.

19. The device of claim 8, wherein said mixture includes antibiotics.

20. The device of claim 19, wherein the antibiotics comprise gentamycin, vancomycin and amphotericin B.

21. The device of claim 19, wherein the antibiotics are selected from the group consisting of gentamycin, vancomycin, amphotericin B, and combinations thereof.

22. The device of claim 21, wherein the cells comprise islet cells.

23. A transplantation or implantation device comprising

a biocompatible hollow fiber having ends and a fiber wall with a porosity which selectively allows nutritional, gaseous and metabolic substances to pass therethrough and which only allows passage of substances having a molecular weight less than about 30,000 Daltons;

a mixture of viable, somatic, mammalian cells and a biocompatible viscous carrier disposed within said fiber and exposed at the ends thereof; and

a biocompatible porous membrane cross-linked to the exposed mixture.

24. The device of claim 23, wherein the porosity of the membrane selectively allows nutritional, gaseous and metabolic substances to pass therethrough.

25. The device of claim 23, wherein said porous membrane is made from a solution containing a cross-linking agent.

26. The device of claim 25, wherein the degree of cross-linking is such as to produce a desired porosity of the membrane.

27. The device of claim 26, wherein the concentration of the cross-linking agent in the solution, the molecular weight of the cross-linking agent, and the contact time between the mixture and the solution are so controlled as to produce a desired degree of cross-linking.

28. The device of claim 27, wherein the solution contains about a 1% volume concentration of between 14,000 and 25,000 molecular weight cross-linking agent and the contact time is about 2 minutes or less.

29. The device of claim 28, wherein said porous membrane has a porosity which only allows passage of substances having a molecular weight less than about 50,000 Daltons.

30. The device of claim 28, wherein the cross-linking agent is selected from the group consisting of poly-L-lysine, chitosan and polyethylenimine.

31. The device of claim 23, wherein said fiber is made of polysulfone.

32. The device of claim 23, wherein said fiber includes a sulfonic polymer for inhibiting complement activation.

33. A transplantation of implantation device comprising

a biocompatible hollow fiber having ends and a fiber wall with a porosity which selectively allows nutritional, gaseous and metabolic substances to pass therethrough;

a mixture of viable, somatic, mammalian cells and a biocompatible viscous carrier disposed within said fiber and exposed at the ends thereof, wherein said viscous carrier is ultrapurified alginate which is substantially free of divalent metal toxins and has (i) an endotoxin content of less than 750 EU/g, (ii) a protein content of less than 0.2%, and iii) a G monomer, dimer and trimer content of greater than 60%; and

a biocompatible porous membrane cross-linked to the exposed mixture.

34. The device of claim 33, wherein said viscous carrier includes a soluble sulfonic polymer.

35. The device of claim 34, wherein said soluble sulfonic polymer comprises sodium polystrene sulfonate.

36. The device of claim 33, wherein said porous membrane comprises poly-L-lysine.

37. The device of claim 33, comprising a outer gel coating covering said fiber and said porous membrane.

38. The device of claim 37, wherein said outer gel coating comprises alginate.