Bio-artificial organ containing a matrix having hollow fibers for supplying gaseous oxygen

• US 6,372,495 B1
• Filed: 06/02/1998
• Issued: 04/16/2002
• Est. Priority Date: 10/06/1995
• Status: Expired due to Term

• Current Assignee: Academisch Ziekenhuis BIJ de Universiteit Van Amsterdam Academisch Medisch Centrum, Seed Capital Investments-2 B.V.
• Original Assignee: Seed Capital Investments-2 B.V.
• Inventors: Flendrig, Leonardus Marcus
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): MELLER, MICHAEL V
• Application Number:
  US09/051,273
• Time in Patent Office: 1,414 Days
• Field of Search: 435/395, 435/398, 435/399, 435/400, 435/289.1, 435/370, 435/177, 435/325
• US Class Current: 435/395
• CPC Class Codes: A61M 1/3472 with treatment of the filtrate
• CPC Class Codes: A61M 1/3489 by biological cells, e.g. bioreactor
• CPC Class Codes: C12M 21/08 for producing artificial tissue or for ex-vivo cultivation of tissue prostheses A61F2/00, grafts A61L27/00
• CPC Class Codes: C12M 23/06 Tubular C12M23/08, C12M23/16 take precedence
• CPC Class Codes: C12M 23/24 Gas permeable parts
• CPC Class Codes: C12M 25/02 Membranes; Filters filters or filtration in general B01D24/00-B01D41/00
• CPC Class Codes: C12M 25/10 Hollow fibers or tubes hollow fiber modules in general B01D63/02
• CPC Class Codes: C12M 25/14 Scaffolds; Matrices in general C12N5/0068
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06

Abstract

A bio-artificial organ system is provided comprising a wall surrounding a space which has a solid support for cell cultivation. The space includes a there dimensional matrix in the form of a highly porous sheet or mat and including a physiologically acceptable network of fibers or an open-pore foam structure; hydrophobic hollow fibers permeable to gaseous oxygen or gaseous carbon dioxide evenly distributed through the three dimensional matrix material and arranged in parallel running from one end of the matrix material to the other end of the matrix material. Cells obtained from organs are present in the extra fiber space for culture wherein the cells are provided with sufficient oxygenation and are maintained as small aggregates with three dimensional attachment.

Claims

1. A bio-artificial organ system comprising a wall surrounding a space, said space comprising:

(a) a solid support for cell cultivation consisting of a three dimensional matrix in the form of a highly porous sheet or mat, wherein the three dimensional matrix comprises a physiologically acceptable network or fibers or a physiologically acceptable open pore foam structure, wherein the matrix has a porosity of from 40 to about 95% and a pore size of from 10 μ

m to 100 μ

m, and an overall height of from 50 μ

m to about 200 μ

m; and

(b) conduits for supplying gaseous oxygen;

wherein said conduits are hollow fibers made of a hydrophobic material and having an outer diameter of 0.1 mm to 1.0 mm, wherein said hollow fibers are evenly distributed through the three dimensional matrix and are arranged in parallel running from one end of the matrix to the other end of the matrix, wherein the distance between individual hollow fibers is between 0.1 mm and 5 mm.

2. The bio-artificial organ system according to claim 1 wherein the cells are selected from the group consisting of liver cells, pancreas cells, kidney cells, parathyroid gland cells, and bone marrow cells.

3. The bio-artificial organ system according to claim 1 wherein the cells are selected from the group consisting of hum an cells and cells derived from non-human animals which are biologically compatible with a human.

4. The bio-artificial organ system according to claim 1 wherein the cells are liver cells selected from the group consisting of primary hepatocytes, immortalized liver cells, liver cell transformants, hepatoma cells, hepatoblasts, and cell lines derived therefrom.

5. The bio-artificial organ system according to claim 4 wherein said liver cells are primary hepatocytes.

6. The bio-artificial organ system according to claim 5 wherein said primary hepatocytes have been subjected to cryopreservation.

7. The bio-artificial organ system according to claim 1 further including at least one gas inlet and at least one gas outlet operably connected to said hollow fibers.

8. The bio-artificial organ system according to claim 1 wherein the hollow fibers are attached to the matrix sheet or mat by weaving said fibers into the matrix sheet or mat, glueing said fibers to said matrix sheet, by sewing said fibers onto the matrix sheet or mat, bonding said fibers to said matrix sheet or mat by means of ultrasound.

9. The bio-artificial organ according to claim 1 wherein said solid support is present in the form of at least one rolled or folded sheet or mat or at least two stacked sheets or mats.

10. A method for maintaining and/or cultivating organ cells comprising introducing said cells into the space of the bio-artificial organ according to claim 7 so that said cells adhere to the solid support, and keeping these cells under physiologically acceptable conditions while supplying gaseous oxygen or an oxygen containing gas through said at least one gas inlet operably connected to the hollow fibers.

11. The method according to claim 10 wherein, after the cells have been introduced into the space of the bio-artificial organ, the cells are immobilized on the solid support located in the bioartificial organ by rotating the bioartificial organ around an internal or an external longitudinal axis for a period of time sufficient to allow the cells to adhere to said solid support.

12. The method according to claim 11 wherein said rotating is around the external longitudinal axis.

13. The method according to claim 10 wherein the organ cells are liver cells selected from the group consisting of primary hepatocytes, immortalized liver cells, liver cell transformants, hepatoma cells, hepatoblasts, and cell lines derived therefrom.