Multiple-layer immune barrier for donor cells

• US 9,446,168 B2
• Filed: 06/06/2011
• Issued: 09/20/2016
• Est. Priority Date: 06/07/2010
• Status: Active Grant

• Current Assignee: Beta-O2 Technologies Ltd.
• Original Assignee: Beta-O2 Technologies Ltd.
• Inventors: Bremer, Yehezkel, Barkai, Uriel, Rotem, Avi, Neufeld, Tova
• Primary Examiner(s): Barham, Bethany
• Assistant Examiner(s): Lazaro, Dominic
• Application Number:
  US13/153,721
• Publication Number:
  US 20110300191A1
• Time in Patent Office: 1,933 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A01N 1/0231 Chemically defined matrices, e.g. alginate gels, for immobilising, holding or storing cells, tissue or organs for preservation purposes; Chemically altering or fixing cells, tissue or organs, e.g. by cross-linking, for preservation purposes
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• 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 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/00 Materials for grafts or prostheses or for coating grafts or prostheses dental prostheses A61C13/00; shape or structure of prostheses A61F2/00; use of preparations for artificial teeth A61K6/80; artificial kidneys A61M1/14
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/36 containing ingredients of undetermined constitution or reaction products thereof , e.g. transplant tissue, natural bone, extracellular matrix isolated natural compounds, e.g. collagen A61L27/24
• CPC Class Codes: A61L 27/505 Stabilizers
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: C12N 5/0012 Cell encapsulation
• CPC Class Codes: C12N 5/0676 Pancreatic cells
• CPC Class Codes: Y10S 623/915 Method or apparatus for preparing biological material

Abstract

A system is provided, including a plurality of donor cells and a first alginate structure that encapsulates the plurality of donor cells. The first alginate structure has a guluronic acid concentration of between 64% and 74%. The system additionally includes a second alginate structure that surrounds the first alginate structure, the second alginate structure having a mannuronic acid concentration of between 52% and 60%. A selectively-permeable membrane is coupled at least in part to the second alginate structure. Other embodiments are also described.

Claims

1. An implantable device comprising:

a housing; and

a multi-layer immune barrier supported by the housing, wherein the multi-layer immune barrier comprises;

a membrane-alginate structure, the membrane-alginate structure being a selectively-permeable hydrophilized membrane having pores impregnated with a cross-linked alginate; and

a tissue-alginate layer positioned over the membrane-alginate structure, the tissue-alginate layer being a cross-linked alginate encapsulating a plurality of cells,

wherein the housing comprises a cover, wherein the tissue-alginate layer is disposed within the housing, and the membrane-alginate structure is coupled to the cover.

2. The implantable device of claim 1, wherein the alginate of the tissue-alginate layer has a guluronic acid concentration of between 64% and 74%.

3. The implantable device of claim 2, wherein the guluronic acid concentration of the tissue-alginate layer is between 67% and 71%.

4. The implantable device of claim 1, wherein the alginate of the membrane-alginate structure has a mannuronic acid concentration of between 52% and 60%.

5. The implantable device of claim 4, wherein the mannuronic acid concentration of the membrane-alginate structure is between 54% and 58%.

6. The implantable device of claim 1, wherein the plurality of cells is selected from the group consisting of beta cells, alpha cells, hepatic cells, hepatocytes, neural cells, neuroendocrine cells, renal cortex cells, vascular endothelial cells, thyroid cells, parathyroid cells, adrenal cells, thymic cells, adrenal cells, ovarian cells, genetically-engineered cells, cloned cells, stem cells and testicular cells.

7. The implantable device of claim 1, wherein the plurality of cells comprises cells of pancreatic islets.

8. The implantable device of claim 1, wherein the tissue-alginate layer has a thickness of 300-700 microns.

9. The implantable device of claim 1, wherein the tissue-alginate layer has a dry matter content between 1.8 and 4.2%.

10. The implantable device of claim 1, wherein the membrane-alginate structure has a dry matter content of between 3.0 and 7.0%.

11. The implantable device of claim 1, wherein the plurality of cells comprise cells that are disposed in a plurality of pancreatic islets, and wherein the tissue-alginate layer encapsulates that plurality of pancreatic islets at a density of between 1000 and 6500 islet equivalents (IEQ) per square cm.

12. The implantable device of claim 1, wherein the plurality of cells comprise cells that are disposed in a plurality of pancreatic islets, and wherein the tissue-alginate structure encapsulates that plurality of pancreatic islets at a density of between 1500 and 6000 islets per square cm.

13. The implantable device claim 11, wherein the tissue-alginate layer encapsulates the plurality of pancreatic islets at a density of between 3500 and 4500 islets per square cm.

14. The implantable device claim 1, wherein the selectively-permeable hydrophilized membrane has a pore size of up to 0.5 microns.

15. The implantable device of claim 1, further comprising:

a gas permeable membrane;

an oxygen reservoir; and

one or more oxygen delivery tubes in fluid communication with the oxygen reservoir,

wherein the oxygen reservoir is a space within the housing configured for oxygen to be stored from the oxygen delivery tubes.

16. The implantable device of claim 15, further comprising:

a plurality of fluid-injection ports disposed remotely from the housing, and coupled to the housing by respective oxygen delivery tubes, the fluid-injection ports comprising at least in part a penetrable surface for receiving a needle therethrough, and configured to receive gaseous oxygen from a source of gaseous oxygen, and to facilitate passage of gaseous oxygen to the plurality of cells while the housing is disposed within a body of a subject.

17. An implantable device comprising:

a housing;

a multi-layer immune barrier supported by the housing, wherein the multi-layer immune barrier comprises;

a membrane-alginate structure, the membrane-alginate structure being a selectively-permeable hydrophilized membrane having pores impregnated with a cross-linked High-M alginate; and

a tissue-alginate layer positioned over the membrane-alginate structure, the tissue-alginate layer being an alginate encapsulating a plurality of pancreatic islet cells, wherein the alginate is a High-G alginate,

wherein the housing comprises a cover, wherein the tissue-alginate layer is disposed within the housing, and the membrane-alginate structure is coupled to the cover;

an oxygen reservoir for storing gaseous oxygen within the housing;

one or more oxygen delivery tubes in fluid communication with the oxygen reservoir; and

a plurality of fluid-injection ports disposed remotely from the housing, and coupled to the housing by respective oxygen delivery tubes, the fluid-injection ports comprising at least in part a penetrable surface for receiving a needle therethrough, and configured to receive gaseous oxygen from a source of gaseous oxygen, and to facilitate passage of gaseous oxygen to the plurality of pancreatic islet cells while the housing is disposed within a

body of a subject.