Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane

• US 5,837,234 A
• Filed: 06/07/1995
• Issued: 11/17/1998
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Neurotech USA, Inc. (Woodbrook Group Holdings, Inc.)
• Original Assignee: Cytotherapeutics, Inc.
• Inventors: Lysaght, Michael, Baurmeister, Ulrich, Wechs, Friedbert, Rottger, Henning, Gentile, Frank T., Winn, Shelley R.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/488,317
• Time in Patent Office: 1,259 Days
• Field of Search: 535/174, 535/180, 535/182, 535/240.22, 535/240.241, 535/240.282, 535/382, 535/395, 535/401, 424/93.7, 424/424
• US Class Current: 424/93.7
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61K 35/22 Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• CPC Class Codes: A61K 35/33 Fibroblasts
• 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: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: B01D 69/1411 containing dispersed material in a continuous matrix
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C08L 81/06 Polysulfones; Polyethersulfones
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres

Abstract

A bioartificial organ for implanting to provide a therapeutic effect is prepared containing a core of living cells encapsulated in a foam-like membrane having three regions: a dense, fine-pored, permselective inner region, a middle region that lacks macrovoids and a fine-pored outer region. The membrane has a molecular weight cutoff that permits passage to nutrients to the cells but not passage of the cells. Preferably, the membrane is made of polyether sulfone, pores range in size between 0.02 μm and 2.0 μm and have polyhedrally symmetric boundaries and are arranged asymmetrically from one surface to the other. The membrane has an asymmetry factor AF relative to the maximum pore diameter of 0.01 to 2.0 and a ratio of the maximum mean free path length to the diameter of the largest pore of greater than 3. The membrane can be hydrophobic or hydrophilic. The bioartificial organ is formed by coextrusion or by stepwise assembly by forming the cell core and then applying the membrane. A polyether sulfone membrane is prepared from a solution containing by weight 12 to 35% polyether sulfone and 15 to 65% ε-caprolactam, and optionally 0 to 85% latent solvent, 0 to 15% thickner, to 5% non-solvent and 0 to 1% auxiliaries. Cells encapsulated can be cells that produce a neurotransmitter such as dopamine or a biologically active factor such as CNTF, NGF, GDNF, endorphins, catecholamines or enkephalins.

Claims

1. A bioartificial organ comprising:

(a) a cell core of one or more living cells, and

(b) an encapsulating, permselective polyether sulfone membrane shaped to define an internal volume, the cell core of one or more living cells being disposed within the internal volume, the membrane comprising a dense, fine-pored permselective inner region next to the cell core, a middle region that lacks macrovoids, and a fine-pored outer region,

wherein the fine-pored inner and outer regions of the membrane are interconnected through the middle region via a system of open pores to define an open network structure across the thickness of the membrane, said membrane having a molecular weight cutoff permitting passage of nutrients, but not the passage of cells thereacross to maintain viability of the cell core, and said membrane having pores ranging in size between 0.02 μ

m and 2.0 μ

m, the pores have polyhedrally symmetric boundaries and being arranged asymmetrically from one surface of the membrane to the other surface, asymmetry factor AF relative to the maximum pore diameter being 0.01 to 2.0, and ratio of the maximum mean free path length to the diameter of the largest pore being greater than 3.

2. The bioartificial organ of claim 1 wherein the membrane is hydrophilic.

3. The bioartificial organ of claim 1 wherein said cell is a dividing cell.

4. The bioartificial organ of claim 3 wherein said cell produces ciliary neurotrophic factor.

5. The bioartificial organ of claim 3 or 4 wherein said cell is a BHK cell.

6. The bioartificial organ of claim 1 wherein said membrane is microporous.

14. A method of providing a biologically active molecule to a recipient, comprising implanting at least one bioartificial organ according to any one of claims 1,2,3 into an implantation site in a recipient, sufficient to provide a therapeutically effective amount of the biologically active molecule.

15. The method of claim 14 wherein the biologically active molecule is selected from the group consisting of ciliary neurotrophic factor, nerve growth factor and glial derived neurotrophic factor.

16. The method of claim 14 wherein the biologically active molecule is ciliary neurotrophic factor.

17. The method of claim 14 wherein the biologically active molecule is selected from the group consisting of endorphins, catecholamines and enkephalins.

18. The method of claim 14 wherein the implantation site is the cerebral spinal fluid.

7. A method of forming a bioartificial organ comprising the step of encapsulating a cell core comprising one or more living cells capable of producing a biologically active product, the step of encapsulating the cell core comprising surrounding the cell core with an encapsulating permselective polyether sulfone membrane, the membrane shaped to define an internal volume, and the membrane comprising a fine-pored permselective inner region next to the cell core, a middle region that lacks macrovoids, and a fine-pored outer region,

wherein the fine-pored inner and outer regions of the membrane are interconnected through the middle region via a system of open pores that define an open network structure across the thickness of the membrane, said membrane having a molecular weight cutoff permitting passage of nutrients, but not the passage of cells, thereacross to maintain viability of the cell core, and said membrane having pores ranging in size between 0.02 μ

m and 2.0 μ

m, the pores have polyhedrally symmetric boundaries and being arranged asymmetrically from one surface of the membrane to the other surface, asymmetry factor AF relative to the maximum pore diameter being 0.01 to 2.0, and ratio of the maximum mean free path length to the diameter of the largest pore being greater than 3.

8. The method of claim 7 wherein the membrane is formed by coextrusion.

9. The method of claim 7 wherein the membrane is hydrophilic.

10. The method of claim 7 wherein said cell is a dividing cell.

11. The method of claim 10 wherein said cell produces CNTF.

12. The method of claim 10 wherein said cell is a BHK cell.

13. The method of claim 7 wherein said membrane is microporous.