Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core

• US 5,874,099 A
• Filed: 05/24/1995
• Issued: 02/23/1999
• Est. Priority Date: 04/25/1991
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Vasoohcellos, Alfred V., Emerich, Dwaine F., Aebischer, Patrick, Sanberg, Paul R., Dionne, Keith E., Lysaght, Michael J., Gentile, Frank T., Christenson, Lisa, Scharp, David W., Hegre, Orion D., Hoffman, Diane, Lacy, Paul E.
• Primary Examiner(s): Bawa, Raj
• Application Number:
  US08/449,837
• Time in Patent Office: 1,371 Days
• Field of Search: 424/422, 424/423, 424/424, 424/426, 424/427, 424/430, 424/434, 424/437, 424/489, 424/490
• US Class Current: 424/422
• 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

A method of forming an implantable and retrievable immunoisolatory vehicles is disclosed, the method comprising the steps of first forming a core comprising a volume of at least 1 μl and at least 10⁴ cells capable of providing a biologically active product or metabolic or immunologic function, said cells being dispersed in a biocompatible hydrogel or extracellular matrix, and then forming around the core a surrounding external biocompatible thermoplastic or hydrogel jacket free of said cells projecting externally thereof, said jacket having molecular weight cutoff permitting passage of molecules to and from the core through said jacket to provide said biologically active product or function.

Claims

1. A method of forming an implantable and retrievable immunoisolatory vehicle, the method comprising the steps of:

(a) forming a core comprising a volume of at least 1 μ

l and at least 10⁴ cells capable of secreting a biologically active product or providing a metabolic or immunologic, function in a biocompatible hydrogel matrix, and

(b) forming an external permselective jacket of hydrogel around said core in direct contact with said hydrogel matrix, said jacket hydrogel comprising a hydrogel that does not ionically bond to a hydrogel 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 molecule or function.

2. The method of claim 1 in which said jacket is formed by cross-linking of the jacket hydrogel and core hydrogel.

6. The method of claim 1 or 5 in which said jacket hydrogel comprises alginate.

10. The method of claims 1 or 3 wherein the core matrix is selected from the group consisting of alginate, collagen, laminin-containing hydrogels, agarose, cellulose, methylcellulose, block copolymer of ethylene-vinylalcohol, sodium polystyrene sulfonate, vinyl-methyl-tribenzyl ammonium chloride, phosphazene, and polyvinylalcohol.

13. The method of claims 1, 3 or 4 wherein the biologically active product is selected from the group consisting of antibodies, enzymes, trophic factors, growth factors, hormones, biological response modifiers, cytokines, lymphokine and neurotransmitters.

14. The method of claims 1, 3 or 4 wherein the biologically active product is selected from the group consisting of enkephalins, catecholamines, opioid peptides, and mixtures thereof.

15. The method claims 1, 3 or 4 wherein the biologically active product is an analgesic or a pain-reducing substance.

16. The method of claims 1, 3 or 4 wherein the biologically active product is a neurotransmitter.

17. The method of claims 1, 3 or 4 wherein accessory cells are coisolated with the cells in the core.

18. The method of claims 1, 3, or 4 wherein the cells are primary cells.

19. The method of claims 1, 3, or 4 wherein the 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.

20. The method of claim 18 wherein the insulin producing cells are selected from the group consisting of Beta cells and islets of Langerhans.

21. The method of claim 1, 3 or 4 wherein the cells are neural stem cells.

22. The method of claim 1, 3 or 4 wherein the cells are adrenal chromaffin cells.

23. The method of claims 1, 3, or 4 wherein the core has a volume in excess of 10 μ

l.

24. The method of claim 1, 3 or 4 wherein the jacket is between 5 and 200 μ

m thick.

25. The method of claim 1, 3 or 4 wherein the jacket has a molecular weight cutoff is between 50 kD and 2000 kD.

26. The method of claim 1, 3 or 4 wherein the jacket is shaped to form a hollow fiber.

27. The method of claim 1, 3 or 4 wherein the jacket is shaped to form a flat sheet.

28. The method of claims 1 or 4 wherein the jacket is selected from the group consisting of alginate, collagen, laminin-containing hydrogels, agarose, cellulose, methylcellulose, block copolymer of ethylene-vinylalcohol, sodium polystyrene sulfonate, vinyl-methyl-tribenzyl ammonium chloride, phosphazene, and polyvinylalcohol.

3. A method of forming an implantable and retrievable immunoisolatory vehicle, the method comprising the steps of:

(a) forming a core comprising a volume of at least 1 μ

l and at least 10⁴ cells dispersed in a biocompatible hydrogel matrix, said cells being capable of secreting a biologically active product or of providing a metabolic or immunologic function to the patient; and

(b) forming an external 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 biologically active product or function.

8. The method of claims 3 or 4 wherein the jacket is selected from the group consisting of polyacrylonitrile-polyvinylchloride, polyacrylonitrile, polymethylmethacrylate, polyvinyldifluoride, polyolefins, polysulfones and celluloses.

9. The method of claim 3 or 4 wherein the jacket further composes a hydrophilic or hydrophobic additive.

11. The method of claim 3 wherein the core matrix is selected from the group consisting of collagen, laminin, glycoaminoglycans, protcoglycans, fibronectin, elastin, and mixtures thereof.

12. The method of claim 11 wherein the glycosaminoglycans are selected from the group consisting of hyaluronic acid, chondroitin sulfate, heparin, and heparin sulfate.

4. A method of forming an implantable and retrievable immunoisolatory vehicle, the method comprising the steps of:

(a) forming a core comprising a volume of at least 1 μ

l and at least 10⁴ cells capable of providing a biologically active product or metabolic or immunologic function, said cells being dispersed in a biocompatible extracellular matrix, and

(b) forming around the core a surrounding external biocompatible thermoplastic or hydrogel jacket free of said cells projecting externally thereof, said jacket having molecular weight cutoff permitting passage of molecules to and from the core through said jacket to provide said biologically active product or function.

5. The method of claim 4 in which said jacket is formed of a hydrogel.

7. The method of claim 4 in which said jacket is formed of a thermoplastic.