Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products

• US 5,798,113 A
• Filed: 05/24/1995
• Issued: 08/25/1998
• Est. Priority Date: 04/25/1991
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Vasooncellos, 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:
  US08/449,524
• Time in Patent Office: 1,189 Days
• Field of Search: 424/451, 424/520, 424/93.1, 424/93.7, 424/422, 424/423, 424/424, 424/426, 424/427, 424/430, 424/434, 424/437, 424/489, 424/490, 514/814, 514/2, 514/866
• 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 providing a biologically active molecule or metabolic or immunologic function to a patient, comprising implanting into the body of the patient at least one immunoisolatory vehicle comprising a core comprising a volume in excess of 1 μl and at least about 10⁴ living cells dispersed in a biocompatible matrix formed of a hydrogel or extracellular matrix components, said cells being capable of secreting a biologically active product or of providing a metabolic or immunologic function to the patient; and an external jacket surrounding said core, said jacket being formed from a thermoplastic or hydrogel, said jacket being free of said cells projecting externally therefrom, said jacket being biocompatible and having a molecular weight cutoff permitting passage of molecules between the patient and the core through said jacket to provide said biologically active product of function.

Claims

1. A method of providing a biologically active molecule or metabolic or immunologic function to a patient, comprising implanting into the body of the patient at least one immunoisolatory vehicle comprising:

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

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

(b) an external jacket surrounding said core, said jacket being greater than 5 microns thick, said jacket being formed from a hydrogel that does not ionically 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 between the patient and the core through said jacket to provide said biologically active product or function.

4. The method of any one of claims 1, 2 or 3 in which said implantation is performed subcutaneously.

5. The method of claim 4 in which said cells produce insulin.

6. The method of claim 4 in which said cells are actively dividing Beta cells.

7. The method of claim 4 in which said cells comprise islets of Langerhans.

8. The method of any one of claims 1, 2, or 3 wherein the biologically active molecule is an analgesic or a pain-reducing substance.

9. The method of any one of claims 1, 2, or 3 wherein the immunoisolatory vehicle is implanted into the ventricle of the brain of the patient.

10. The method of any one of claims 1, 2, or 3 wherein the patient is an aged individual.

11. The method of any one of claims 1 or 2 wherein the core 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.

15. The method of any one of claims 1, 2 or 3 wherein the biologically active molecule is selected from the group consisting of enkephalins, catecholamines, opioid peptides, and mixtures thereof.

16. The method of any one of claims 1, 2 or 3 wherein the biologically active product is selected from the group consisting of antibodies, enzymes, trophic factors, growth factors, hormones and biological response modifiers.

17. The method of claim 16 wherein the biologically active product is a cytokine or lymphokine.

18. The method of any one of claims 1, 2 or 3 wherein the biologically active product is a neurotransmitter.

19. The method of claim 18 wherein the neurotransmitter selected from the group consisting of dopamine, L-dopa, gamma aminobutyric acid, serotonin, acetylcholine, noradrenaline, epinephrine and glutamic acid.

20. The method of any one of claims 1, 2 or 3 wherein the biologically active product is dopamine.

21. The method of any one of claims 1, 2 or 3 wherein the 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.

22. The method of any one of claims 1, 2 or 3 wherein the biologically active product is insulin, parathyroid hormone, interleukin 3, erythropoietin, albumin, transferrin or Factor VIII.

23. The method of any one of claims 1, 2 or 3 wherein accessory cells are coisolated with the cells in the core.

24. The method of any one of claims 1, 2 or 3, wherein the cells are adrenal chromaffin cells.

25. The method of any one of claims 1, 2 or 3, wherein the cells are primary cells.

26. The method of any one of claims 1, 2 or 3, 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.

27. The method of any one of claims 1, 2 or 3, wherein the cells are neural progenitor stem cells.

28. The method of claim 1, 2 or 3 wherein the jacket is between 5 and 200 μ

m thick.

29. The method of claim 1, 2 or 3 wherein the jacket has a molecular weight cutoff between 50 kD and 2000 kD.

30. The method of claim 1, 2 or 3 wherein the jacket is shaped to form a hollow fiber.

31. The method of claim 1, 2 or 3 wherein the jacket is shaped to form a flat sheet.

32. The method of claim 1, 2 or 3 wherein more than one vehicle but fewer than 10 vehicles are implanted in the patient.

33. The method of claim 1, 2 or 3 wherein the cells are allogeneic or syngeneic to the patient.

2. A method of providing a biologically active molecule or metabolic or immunologic function to a patient, comprising implanting into the body of the patient at least one immunoisolatory vehicle comprising:

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

l and at least about 10⁴ living 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) 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 between the patient and core through said jacket to provide the biologically active product or function.

13. The method of claim 2 or 3 wherein the jacket is selected from the group consisting of polyacrylonitrile-polyvinylchloride, polyacrylonitrile, polymethylmethacrylate, polyvinyldifluoride, polyolefins, polysulfones and celluloses.

14. The method of claim 2 or 3 wherein the jacket further comprises a hydrophilic or hydrophobic additive.

3. A method of providing a biologically active molecule or metabolic or immunologic function to a patient, comprising implanting into the body of the patient at least one implantable and retrievable immunoisolatory vehicle comprising:

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

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

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

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