Method for controlling proliferation and differentiation of cells encapsulated within bioartificial organs

• US 5,795,790 A
• Filed: 05/23/1995
• Issued: 08/18/1998
• Est. Priority Date: 07/20/1994
• Status: Expired due to Term

• Current Assignee: Neurotech USA, Inc. (Woodbrook Group Holdings, Inc.)
• Original Assignee: Cytotherapeutics, Inc.
• Inventors: Aebischer, Patrick, Shoichet, Molly S., Hammang, Joseph P., Doherty, Edward J., Gentile, Frank T., Holland, Laura M., Winn, Shelley R., Cain, Brian M., Schinstine, Malcolm
• Primary Examiner(s): Naff, David M.
• Application Number:
  US08/448,201
• Time in Patent Office: 1,183 Days
• Field of Search: 435/177, 435/178, 435/240.7, 435/240.22, 435/240.23, 435/240.24, 435/240.241, 435/240.242, 435/240.243, 435/180, 435/182, 424/93.7
• US Class Current: 435/382
• 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 thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• 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 a 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. In a preferred treatment, cells are exposed to and then removed from exposure to a proliferation-stimulating and differentiation inhibiting compound prior to encapsulation of the cells in a semipermeable biocompatible jacket to form a bioartificial organ. Upon in vivo implantation of the bioartificial organ in a host, cellular proliferation is inhibited and cellular differentiation is promoted.

Claims

1. A method for controlling distribution of cells within a bioartificial organ comprising encapsulated cells, said method comprising exposing the cells to and then removing the cells from exposure to a proliferation-stimulating and differentiation-inhibiting compound prior to encapsulation such that cellular proliferation is inhibited and cellular differentiation is promoted in the absence of said compound upon in vivo implantation in a host.

2. The method according to claim 1, wherein the proliferation-stimulating and differentiation-inhibiting compound is selected from the group consisting of EGF, TGF-α

, and amphiregulin, and the cells are neural stem cells.

3. The method according to claim 1, wherein the proliferation-stimulating and differentiation-inhibiting compound is a mixture of a member of the FGF family of growth factors and at least one member of the CNTF or NGF family of growth factors, and the cells are neural stem cells.

4. The method according to claim 1, wherein the proliferation-stimulating and differentiation-inhibiting compound is a multilineage growth factor and the cells are hematopoietic stem cells.

5. The method according to claim 1, wherein the cells are selected from the groups consisting of primary cells and immortalized cell lines.

6. A bioartificial organ comprising:

(a) a biocompatible jacket; and

(b) a core of living cells encapsulated by the biocompatible jacket wherein said cells are cells that have been exposed to and then removed from exposure to a proliferation-stimulating and differentiation-inhibiting compound prior to encapsulation in the bioartificial organ such that cellular proliferation is inhibited and cellular differentiation is promoted in the absence of said compound upon in vivo implantation in a host.

7. The bioartificial organ of claim 6, wherein the cells are selected from the group consisting of primary cells and immortalized cell lines.

8. The bioartificial organ of claim 6, wherein the proliferation-stimulating and differentiation-inhibiting compound is selected from the group consisting of EGF, TGF-α

, and amphiregulin, and the cells are neural stem cells.

9. The bioartificial organ of claim 6, wherein the proliferation-stimulating and differentiation-inhibiting compound is a mixture of a member of FGF family of growth factors and at least one member of the CNTF or NGF family of growth factors, and the cells are neural stem cells.

10. The bioartificial organ of claim 6, wherein the proliferation-stimulating and differentiation-inhibiting compound is a multilineage growth factor and the cells are hematopoietic stem cells.