Circulation system

• US 9,506,024 B2
• Filed: 08/05/2011
• Issued: 11/29/2016
• Est. Priority Date: 08/06/2010
• Status: Active Grant

• Current Assignee: Tissuse GmbH
• Original Assignee: Tissuse GmbH
• Inventors: Hoffmann, Silke, Marx, Uwe, Lindner, Gerd, Horland, Reyk, Lauster, Roland
• Primary Examiner(s): HOBBS, MICHAEL L
• Application Number:
  US13/814,673
• Publication Number:
  US 20130295598A1
• Time in Patent Office: 1,943 Days
• Field of Search: 435/29, 435/303.1, 435/366
• US Class Current: 1/1
• 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 23/16 Microfluidic devices; Capillary tubes integrated microfluidic structures B01L3/5027; microreactors B01J19/0093
• 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: C12M 29/08 Air lift
• CPC Class Codes: C12M 29/16 Hollow fibers hollow fiber modules in general B01D63/02
• CPC Class Codes: C12N 5/0691 Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels

Abstract

A self-contained circulation system, which supports the formation of capillaries in capillary growth sections and allows the formation of micro organoids and/or micro tissue sections for monitoring the effect of one or more test compounds and determining efficacy, side-effects, biosafety, metabolites, mode of action or organ regeneration as well as methods of establishing such micro organoids and/or micro tissue in the self-contained circulation system.

Claims

1. A self-contained fluid circulation system, comprising:

a. a capillary growth chamber enclosing at least one capillary growth section, the capillary growth chamber having at least two micro inlets and at least two micro outlets which provide and remove fluid from the capillary growth section, the at least one capillary growth section including a tissue culture space oriented between the micro inlets and micro outlets and a neovascularization region adjacent to the tissue culture space remote from the micro inlets and micro outlets,

b. a directional fluid pumping device having an inlet and an outlet,

c. an arteriolar transport channel connecting the directional fluid pumping device output and the at least two micro inlets and a venular transport channel connecting the directional fluid pumping device inlet and the at least two micro outlets to form a fluid circulation loop, and

d. a biocompatible matrix which forms a growth scaffold oriented within the at least one capillary growth section of the capillary growth chamber,

wherein the fluid in the circulation system passes from the micro inlets through the a biocompatible matrix in the capillary growth section and out through the micro outlets in order to form capillaries within biocompatible matrix,

wherein the neovascularization region is has a distance from at least 100 μ

m and up to 500 μ

m from the micro inlets and/or micro outlets to impair the growth of capillaries.

2. The circulation system of claim 1, wherein the capillary growth chamber has two spaced apart capillary growth sections having two spaced apart sets of the micro inlets and micro outlets feeding two tissue culture spaces.

3. The circulation system of claim 1, wherein the capillary growth chamber is at least in part gas permeable.

4. The circulation system of claim 1, wherein the biocompatible matrix comprises at least one of a semi-solid, biocompatible matrix and semi-solid, biocompatible hollow fibres.

5. The circulation system of claim 4, wherein the biocompatible matrix comprises micro channels, structures and/or networks, which allow formation of capillaries by endothelial cells.

6. The circulation system of claim 1, wherein neovascularization region is devoid of micro inlets and outlets.

7. The circulation system of claim 1, wherein the capillary growth chamber further comprises an extra-capillary fluid and/or waste collector.

8. The circulation system of claim 7, wherein the extra-capillary fluid and/or waste collector is separated from the biocompatible matrix and/or biocompatible hollow fibre by a cell retention membrane or by cell exclusion channels.

9. The circulation system of claim 8, wherein at least one sensor is arranged in the extra capillary fluid and/or waste collector.

10. The circulation system according to claim 1, further comprising capillaries and/or organoids formed in the capillary growth section.

11. The circulation system according to claim 1, wherein two or more different tissues and/or organoids are maintained within one self-contained system, which are perfused by the same circulating fluid.

12. The circulation system according to claim 1, wherein the sub-section space is sufficiently far removed from corresponding micro inlets and micro outlets such that the formation of capillaries is impaired in this sub-section during the initial establishment of capillaries in the capillary growth section.

13. The circulation system according to claim 1, wherein the neovascularization region has a distance from at least 100 μ

m and up to 300 μ

m from the micro inlets and/or micro outlets.

14. The circulation system according to claim 1, wherein the arteriolar transport channel branches of at least once to connect with the at least two inlets, and the venular transport channel branches of at least once to connect with the at least two outlets, respectively.

15. The circulation system of claim 14, wherein the combined cross-sectional area of the arteriolar channels after the branching point is essentially identical to the cross-sectional area of the arteriolar channel in front of the branching point and/or the combined cross-sectional area of the venular transport channels after the branching point is essentially identical to the cross-sectional area of the venular channel in front of the branching point.

16. The circulation system of claim 14, wherein the combined cross-sectional area of all inlets is essentially identical to the cross-sectional area of said arteriolar channel and/or arteriolar channels and the combined cross-sectional area of all outlets is essentially identical to the cross-sectional area of said venular channel and/or venular channels, preferably are the cross-sectional areas of arteriolar and venular channels identical.

17. The circulation system according to claim 1, wherein the arteriolar transport channel is gas permeable.

18. The circulation system according to claim 1, wherein the a capillary growth chamber is provided with a removable translucent cover to allow microscopic inspection of the capillary growth in the biocompatible matrix and to facilitate the placement of tissue in the biocompatible matrix in the space adjacent to the capillary growth section having impaired capillary growth.

19. A method of establishing a circulation system according to claim 1, comprising the steps of

a. seeding endothelial cells into the circulation system, and

b. incubating at least until capillaries have formed in the capillary growth section and/or until an endothelial cell layer has formed in the transport channels and/or until an endothelial cell layer has covered all inner surfaces of the pumping device.

20. The method of establishing a circulation system according to claim 19, wherein the method further comprises the step of injecting whole blood into said circulation system.

21. The method of establishing a circulation system according to claim 19, wherein step b) is carried out under shear force.