Biocompatible substrate for facilitating interconnections between stem cells and target tissues and methods for implanting same

• US 8,808,687 B2
• Filed: 07/12/2011
• Issued: 08/19/2014
• Est. Priority Date: 07/12/2010
• Status: Active Grant

• Current Assignee: California Institute of Technology, Regents of the University of California (University of California), University of Southern California
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Humayun, Mark, Ahuja, Ashish, Tai, Yu-Chong, Hinton, David, Grubbs, Robert, Clegg, Dennis, Johnson, Lincoln V., Hikita, Sherry T.
• Primary Examiner(s): Lankford, Blaine
• Assistant Examiner(s): Clarke, Trent R
• Application Number:
  US13/181,279
• Publication Number:
  US 20120009159A1
• Time in Patent Office: 1,134 Days
• US Class Current: 424/93.7
• CPC Class Codes: A61K 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61L 2430/00 Materials or treatment for tissue regeneration
• CPC Class Codes: A61L 2430/16 for reconstruction of eye parts, e.g. intraocular lens, cornea
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/3808 Endothelial cells
• CPC Class Codes: A61L 27/3813 Epithelial cells, e.g. keratinocytes, urothelial 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 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C08L 65/04 Polyxylenes
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 83/08 containing silicon bound to organic groups containing atoms other than carbon, hydrogen and oxygen
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 2535/00 Supports or coatings for cell culture characterised by topography
• CPC Class Codes: C12N 5/0621 Eye cells, e.g. cornea, iris pigmented cells photoreceptors C12N5/062
• CPC Class Codes: Y10T 428/24479 : including variation in thickness

Abstract

Disclosed herein are substrates for cell delivery to target tissues requiring treatment for various diseases that induce cell death, damage or loss of function. The substrates are configured to provide seeded cells, including stem cells, with a structural support that allows interconnection with and transmission of biological signals between the cells and the target tissue.

Claims

1. A substrate for cellular therapy to treat diseased or damaged ocular tissue, comprising:

a solid planar parylene substrate configured for implantation into a human eye, the substrate comprising

a long axis and a short axis; and

a distinct parylene apical surface for the growth of a population of human embryonic stem cell-derived RPE cells, and a distinct parylene basal surface;

wherein the apical surface has a thickness ranging from about 0.1 to about 5 microns allowing passage of molecules having a molecular weight of up to about 75 kilodaltons and has an integrally formed continuous raised lip positioned around the perimeter to reduce migration of human stem cell-derived RPE cells off the apical surface; and

wherein the basal surface comprises a plurality of supporting protrusions, the supporting protrusions being periodic, columnar in shape, and running longitudinally along the length of the long axis of the basal surface of the substrate and the basal surface is configured to prevent the growth of blood vessels through said basal surface to said apical surface.

2. The substrate of claim 1, wherein the parylene of said apical surface is selected from the group consisting of parylene A, parylene AM, ammonia treated parylene, and parylene C.

3. The substrate of claim 1, wherein the parylene of said inhomogeneous basal surface comprises a polymer selected from the group consisting of parylene A, parylene AM, ammonia treated parylene, and parylene C.

4. The substrate of claim 1, wherein one or more of said apical surface and said inhomogeneous basal surface is treated with one or more of matrigel, poly-L-dopamine, vitronectin, or retronectin.

5. The substrate of claim 1, wherein the height of said supporting protrusions ranges from about 1 μ

m to about 500 μ

m.

6. The substrate of claim 1, wherein one or more of said parylene apical surface and said parylene inhomogeneous basal surface are oxygen-treated.

7. The substrate of claim 1, wherein said continuous raised lip has a height ranging from about 10 to about 1000 microns.

8. The substrate of claim 1, wherein said continuous raised lip has a width ranging from about 10 to about 1000 microns.

9. The substrate of claim 1, wherein the long axis and the short axis of parylene substrate each range from about 0.3 mm to about 7 mm.

10. The substrate of claim 1, wherein said parylene inhomogeneous basal surface is treated with vitronectin.

11. The substrate of claim 1, wherein said parylene apical surface is treated with vitronectin.

12. The substrate of claim 1, wherein the damaged or diseased ocular tissue comprises ocular tissue afflicted with an outer retinal degenerative disease is selected from the group consisting of dry AMD, wet AMD, Stargardt'"'"'s disease, Leber'"'"'s Congenital Ameurosis, and retinitis pigmentosa.

13. The substrate of claim 1, wherein the substrate is suitable for implantation into the subretinal space of the eye of a subject.

14. The substrate claim 1, wherein upon implantation into the human eye, RPE cells on said substrate functionally interdigitate with the outer segments of the photoreceptors of the eye.

23. The substrate of claim 1, wherein the damaged or diseased ocular tissue comprises ocular tissue afflicted with an outer retinal degenerative disease is selected from the group consisting of dry AMD, wet AMD, Stargardt'"'"'s disease, Leber'"'"'s Congenital Ameurosis, and retinitis pigmentosa.

15. A substrate for cellular therapy to treat diseased or damaged ocular tissue, comprising:

a solid planar parylene substrate configured for implantation into a human eye, the substrate comprising

a long axis and a short axis; and

a distinct parylene apical surface for the growth of a population of human embryonic stem cell-derived RPE cells, and a distinct parylene basal surface;

wherein the apical surface has a thickness ranging from about 0.1 to about 5 microns allowing passage of molecules having a molecular weight of up to about 75 kilodaltons; and

wherein the basal surface comprises a plurality of supporting protrusions, the supporting protrusions being periodic, columnar in shape, and running longitudinally along the length of the long axis of the basal surface of the substrate, the supporting protrusions providing structural rigidity along the long axis and permitting flexibility along the shorter axis, and the basal surface is configured to prevent the growth of blood vessels through said basal surface to said apical surface.

16. The substrate of claim 15, wherein the parylene of said apical surface is selected from the group consisting of parylene A, parylene AM, ammonia treated parylene, and parylene C.

17. The substrate of claim 15, wherein the parylene of said inhomogeneous basal surface comprises a polymer selected from the group consisting of parylene A, parylene AM, ammonia treated parylene, and parylene C.

18. The substrate of claim 15, wherein one or more of said apical surface and said inhomogeneous basal surface is treated with one or more of matrigel, poly-L-dopamine, vitronectin, or retronectin.

19. The substrate of claim 15, wherein the height of said supporting protrusions ranges from about 1 μ

m to about 500 μ

m.

20. The substrate of claim 15, wherein the long axis and the short axis of parylene substrate each range from about 0.3 mm to about 7 mm.

21. The substrate of claim 15, wherein said parylene inhomogeneous basal surface is treated with vitronectin.

22. The substrate of claim 15, wherein said parylene apical surface is treated with vitronectin.

24. The substrate of claim 15, wherein the substrate is suitable for implantation into the subretinal space of the eye of a subject.