Implantable biocompatable immunoisolatory vehicle for delivery of selected therapeutic products

• US 6,083,523 A
• Filed: 09/04/1998
• Issued: 07/04/2000
• Est. Priority Date: 04/25/1991
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Lysaght, Michael J., Emerich, Dwaine F., Aebischer, Patrick, Sanberg, Paul R., Dionne, Keith E., Vasconcellos, Alfred V., Gentile, Frank T., Christenson, Lisa, Scharp, David W., Hegre, Orion D., Hoffman, Diane, Lacy, Paul E.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/148,671
• Time in Patent Office: 669 Days
• Field of Search: 424/424, 424/493, 424/497, 264/4.1, 435/1.1, 435/177, 435/178, 435/179, 435/180, 435/182
• US Class Current: 424/424
• CPC Class Codes: A61K 2035/126 Immunoprotecting barriers, e.g. jackets, diffusion chambers
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• 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 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• 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: 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 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C12N 2510/02 : Cells for production
• CPC Class Codes: C12N 5/0012 : Cell encapsulation
• CPC Class Codes: C12N 5/0062 : General methods for three-dimensional culture
• CPC Class Codes: C12N 5/0614 : Adrenal gland
• CPC Class Codes: C12N 5/0656 : Adult fibroblasts
• CPC Class Codes: C12N 5/0677 : Three-dimensional culture, tissue culture or organ culture; Encapsulated cells

Abstract

An immunoisolatory vehicle for the implantation into an individual of cells which produce a needed product or provide a needed metabolic function. The vehicle is comprised of a core region containing isolated cells and materials sufficient to maintain the cells, and a permselective, biocompatible, peripheral region free of the isolated cells, which immunoisolates the core yet provides for the delivery of the secreted product or metabolic function to the individual.

Claims

1. An implantable immunoisolatory vehicle for providing a biologically active product or function to an individual, the immunoisolatory vehicle comprising:

(a) a core comprising a volume in excess of 1 μ

l and at least 10⁴ living cells dispersed in a biocompatible liquid, said cells being capable of secreting a selected biologically active product or of providing a selected biological function to an individual; and

(b) an external permselective jacket surrounding said core, said jacket being greater than 5 microns thick and formed from a hydrogel that does not tonically bond to a polymer of opposite charge on the core during formation of the jacket, said jacket being free of said cells projecting, externally therefrom, said jacket being biocompatible and having a molecular weight cutoff permitting passage of molecules to and from the core through said jacket to provide said biologically active product or function.

2. The immunoisolatory vehicle of claim 1 in which said hydrogel comprises alginate cross-linked with a multivalent ion.

3. The immunoisolatory vehicle of claim 1 wherein said vehicle is of sufficient size and durability for retrieval after implantation.

4. The immunoisolatory vehicle of claim 1 in which said cells are selected from the group consisting of insulin-producing cells, adrenal chromaffin cells, antibody-secreting cells, fibroblasts, astrocytes, Beta cell lines, and Chinese hamster ovary cells.

5. The immunoisolatory vehicle of claim 1 in which the cells are derived from a cell bank.

6. The immunoisolatory vehicle of claim 1 in which the interface between said core and jacket are free of an intermediate layer of fibrogenic material linking said core and jacket.

18. The immunoisolatory vehicle of claims 1 or 7 wherein said vehicle is a flat sheet.

19. The immunoisolatory vehicle of claims 1 or 7 wherein said external jacket is in substantially flat or tubular form.

20. The immunoisolatory vehicle of claims 1 or 7 wherein said cells are allogeneic to said individual.

21. The immunoisolatory vehicle of claims 1 or 7 wherein said cells secrete antibodies.

22. The immunoisolatory vehicle of claims 1 or 7 wherein the biologically active product is an analgesic or pain-reducing substance.

23. The immunoisolatory vehicle of claims 1 or 7, wherein said cells are capable of secreting a biologically active product selected from the group consisting of growth factor, trophic factor, or both.

25. The immunoisolatory vehicle of claims 1 or 7, wherein said cells are derived from a pathogen free animal.

26. The immunoisolatory vehicle of claims 1 or 7, wherein said jacket further comprises a hydrophilic or hydrophobic additive.

27. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is selected from the group consisting of enkephalins, catecholamines, opioid peptides, and mixtures thereof.

28. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is selected from the group consisting of antibodies, enzymes, trophic factors, growth factors, hormones and biological response modifiers.

29. The immunoisolatory vehicle of claim 28, wherein said biologically active product is a cytokine or lymphokine.

30. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is a neurotransmitter.

32. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is dopamine.

33. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is selected from the group consisting of nerve growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor, neurotrophin-3, platelet derived growth factor, epidermal growth factor, neurotensin and Substance P.

34. The immunoisolatory vehicle of claims 1 or 7, wherein said biologically active product is insulin, parathyroid hormone, interleukin 3, erythropoietin, albumin, transferrin or Factor VIII.

35. The immunoisolatory vehicle of claims 1 or 7, wherein accessory cells are co-isolated with the cells in said core.

36. The immunoisolatory vehicle of claims 1 or 7, wherein said cells are adrenal chromaffin cells.

37. The immunoisolatory vehicle of claims 1 or 7, wherein said molecular weight cutoff is between 50-2000 kD.

38. The immunoisolatory vehicle of claims 1 or 7, wherein said jacket is between about 10 and 200 microns thick.

39. The immunoisolatory vehicle of claims 1 or 7, wherein said liquid comprises a nutrient medium.

40. The immunoisolatory vehicle of claim 39, wherein said liquid further comprises fetal bovine serum or equine serum.

7. An immunoisolatory vehicle for providing a biologically active product or function to an individual, the immunoisolatory vehicle comprising:

(a) a core comprising a volume in excess of 1 μ

l and at least 10⁴ living cells dispersed in a biocompatible liquid, said cells being capable of secreting biologically active product or of providing a biological function to an individual; and

(b) an external permselective jacket surrounding said core, said jacket comprising a biocompatible thermoplastic, said jacket being immunoisolatory and having a molecular weight cutoff permitting passage of molecules to and from the core through said jacket to provide said biological product or function.

8. The immunoisolatory vehicle of claim 7 in which said cells are selected from the group consisting of insulin-producing cells, adrenal chromaffin cells, antibody-secreting cells, fibroblasts, astrocytes, Beta cell lines, and Chinese hamster ovary cells.

9. The immunoisolatory vehicle of claim 7 in which said jacket is formed of a hydrogel material.

10. The immunoisolatory vehicle of claim 7 in which the interface between said core and jacket is free of an intermediate layer of fibrogenic material linking said core and jacket.

11. The immunoisolatory vehicle of claim 7 in which said core and said external jacket form an interface substantially free of direct ionic bonding.

12. The immunoisolatory vehicle of claim 7 in which said external jacket is a non-spherical shape.

13. The immunoisolatory vehicle of claim 7 in which said molecular weight cutoff is above about 100 kD.

14. The immunoisolatory vehicle of claim 7 in which said cells are formed by aggregating naturally occurring individual cells or cell clusters into an improved diffusional aggregate form adapted for increased packing per unit volume.

15. The immunoisolatory vehicle of claim 7 in which said cell clusters are selected from the group consisting of pancreatic islets, adrenal chromaffin cells and insulin secreting cell lines.

16. The immunoisolatory vehicle of claim 7 in which said jacket is formed of a hydrogel material.

17. The implantable vehicle of claim 7 wherein said cells secrete nerve growth factor.

24. The immunoisolatory vehicle of claim 7, wherein said cells comprise cells from a cell bank.

31. The immunoisolatory vehicle of claim 24, wherein said neurotransmitter is selected from the group consisting of dopamine, L-dopa, gamma aminobutyric acid, serotonin, acetylcholine, noradrenaline, epinephrine and glutamic acid.