Control of cell growth in a bioartificial organ with extracellular matrix coated microcarriers

• US 5,858,747 A
• Filed: 05/23/1995
• Issued: 01/12/1999
• Est. Priority Date: 07/20/1994
• Status: Expired due to Fees

• Current Assignee: Neurotech USA, Inc. (Woodbrook Group Holdings, Inc.)
• Original Assignee: Cytotherapeutics, Inc.
• Inventors: Holland, Laura M., Schinstine, Malcolm, Aebischer, Patrick, Shoichet, Molly S., Hammang, Joseph P., Doherty, Edward J., Gentile, Frank T., Winn, Shelley R., Cain, Brian M.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/447,810
• Time in Patent Office: 1,330 Days
• Field of Search: 435/178, 435/240.2, 435/240.22, 435/240.23, 435/240.24, 435/240.241, 435/240.242, 435/240.243, 435/182, 435/176, 435/177, 435/377, 435/382 , 435/395, 435/403, 435/289.1, 424/93.7, 424/93.21, 424/422
• US Class Current: 435/182
• 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: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/383 Nerve cells, e.g. dendritic cells, Schwann cells
• CPC Class Codes: A61L 27/3834 Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
• CPC Class Codes: A61L 27/3839 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3895 using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/82 Translation products from oncogenes
• CPC Class Codes: C08L 83/12 containing polyether sequences
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2510/04 Immortalised cells
• CPC Class Codes: C12N 2533/30 Synthetic polymers
• CPC Class Codes: C12N 2533/54 Collagen; Gelatin
• CPC Class Codes: C12N 2533/74 Alginate
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06

Abstract

Methods and compositions are provided for controlling cell distribution within an implantable bioartificial organ by exposing the cells to a treatment that inhibits cell proliferation, promotes cell differentiation, or affects cell attachment to a growth surface within the bioartificial organ. Such treatments include (1) genetically manipulating cells, (2) exposing the cells to a proliferation-inhibiting compound or a differentiation-inducing compound or removing the cells from exposure to a proliferation-stimulating compound or a differentiation-inhibiting compound; exposing the cells to irradiation, and (3) modifying a growth surface of the bioartificial organ with extracellular matrix molecules, molecules affecting cell proliferation or adhesion, or an inert scaffold, or a combination thereof. These treatments may be used in combination. The bioartificial organ typically has a semipermeable membrane encapsulating a cell-containing core, and is preferably immunoisolatory. Cells can be grown on microcarriers and then loaded into the bioartificial organ. The microcarriers may be coated with an extracellular matrix component such as collagen to cause decreased cell proliferation or increased cell differentiation. Microcarriers containing cells can be suspended in a proliferation inhibiting hydrogel matrix prior to encapsulation.

Claims

1. A method for controlling distribution of a core of living cells encapsulated by a biocompatible jacket in a bioartificial organ comprising growing the cells on microcarriers prior to encapsulation to produce microcarriers containing cells then loading the microcarriers containing cells in the bioartificial organ.

2. The method of claim 1 wherein the microcarriers are selected from the group consisting of dextran microcarriers, gelatin microcarriers and glass microcarriers.

3. The method of claim 1 wherein the cells are selected from the group consisting of primary cells and immortalized cell lines.

4. The method of claim 1 wherein the cells are modified to secrete a biologically active molecule.

5. The method according to claim 4 wherein the cells secrete a biologically active molecule from the group consisting of hormones, cytokines, growth factors, trophic factors, angiogenesis factors, antibodies, blood coagulation factors, lymphokines and enzymes.

6. The method according to claim 1 wherein the microcarriers containing cells are suspended in a proliferation inhibiting hydrogel matrix prior to encapsulation in the bioartificial organ.

7. A bioartificial organ comprising:

(a) a biocompatible jacket; and

(b) a core comprising of living cells grown on microcarriers prior to encapsulation to produce microcarriers containing cells said microcarriers containing cells then loaded into and encapsulated by the biocompatible jacket in the bioartificial organ.

8. The bioartificial organ of claim 7 wherein the microcarrier is selected from the group consisting of dextran microcarriers, gelatin microcarriers and glass microcarriers.

9. The bioartificial organ of claim 7 wherein the jacket comprises a material selected from the group consisting of polyacrylates, polyvinylidenes, polyvinyl chloride copolymers, polyurethanes, polystyrenes, polyamides, cellulose acetates, cellulose nitrates, polysulfones, polyphosphazenes, polyacrylonitriles, poly(acrylonitrile/covinyl chloride), copolymers thereof and mixtures thereof.

10. The bioartificial organ of claim 7 wherein the cells are selected from the group consisting of primary cells and immortalized cell lines.

11. The bioartificial organ of claim 7 wherein the microcarriers containing cells are suspended in a proliferation inhibiting hydrogel matrix prior to encapsulation in the bioartificial organ.