DIRECTED STEM CELL RECRUITMENT

• US 20110097379A1
• Filed: 05/11/2009
• Published: 04/28/2011
• Est. Priority Date: 05/09/2008
• Status: Active Grant

• Current Assignee: Wake Forest University Health Sciences
• Original Assignee: Wake Forest University Health Sciences
• Inventors: Lee, Sang Jin, Atala, Anthony, Yoo, James, Van Dyke, Mark
• Granted Patent: US 9,694,055 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• 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: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/26 for kidney reconstruction
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 13/12 of the kidneys

Abstract

The invention is directed to methods of inducing cell recruitment and tissue regeneration at a target site in a subject. It is also based, in part, on the discovery that a subject'"'"'s own biologic resources and environmental conditions can be used for in situ tissue regeneration and thereby reduce or eliminate the need for donor cell procurement and ex vivo manipulation of such donor cells. Methods are disclosed for recruitment of a subject'"'"'s own stem cells to a target region by inducing a sustained positive pressure at a target site, such as the kidney, thereby increasing the number of pluripotent cells capable of differentiating to regenerate the target tissue.

Claims

1. Use of a biocompatible substance as an implant to recruit pluripotent cells to a target site within a body structure and induce tissue regeneration within the body structure.

2. The use according to claim 1, wherein the biocompatible substance creates a hyperbaric environment at the target site such that native pluripotent cells migrate to the site.

3. The use according to claim 1, wherein the biocompatible substance further provides a scaffold for attachment of pluripotent cells.

4. The use according to claim 3, wherein the biocompatible substance further comprises a hydrogel that is sufficiently porous to allow cell infiltration.

5. The use according to claim 1, wherein the biocompatible substance further comprises a hydrogel formulated to expand by water absorption following implantation at the target site to provide a sustained positive pressure at the target site.

6. The use according to claim 1, wherein the biocompatible substance further comprises a solution having a collagen concentration from about 1 mg/mL to about 30 mg/mL.

7. The use according to claim 1, wherein the biocompatible substance further comprises at least one adjuvant selected from the group of growth factors, cytokines, enzymes, collagen reducing agents, antibiotics and anti-inflammatory agents.

8. The use according to claim 7, wherein the adjuvant further comprises an anti-inflammatory agent.

9. The use according to claim 1, wherein the biocompatible substance further comprises a collagen synthetase inhibitor.

10. The use according to claim 1, wherein the biocompatible substance further comprises an injectable composition.

11. A method of inducing cell recruitment to a target site of a subject comprising:

delivering a biocompatible substance to a target site within a body structure to produce positive pressure within the target site; and

maintaining positive pressure at the target site, whereby pluripotent cells are recruited to the target site.

12. The method of claim 11, wherein the step of delivering the biocompatible substance further comprises delivering a substantially cell-free polymeric biocompatible substance.

13. The method of claim 11, wherein the step of delivering the biocompatible substance further comprises delivering a collagen biocompatible substance.

14. The method of claim 13, wherein the collagen biocompatible substance is a solution having a collagen concentration from about 1 mg/mL to about 30 mg/mL.

15. The method of claim 14, wherein the collagen solution thermogels at about 37°

C.

16. The method of claim 11, wherein the step of delivering the biocompatible substance further comprises delivering a hydrogel biocompatible substance.

17. The method of claim 11, wherein the positive pressure is maintained in a range from about 5 cmH₂O to about 70 cmH₂O for at least one hour after injection at the target site.

18. The method of claim 11, wherein the step of delivering the biocompatible substance further comprises delivering a biocompatible substance with a viscosity between about about 5 cP to about 1×

10⁸ cP at 25°

C.

19. The method of claim 11, wherein the step of delivering the biocompatible substance into the target site comprises injecting the substance into the target site.

20. The method of claim 11, wherein the step of delivering the biocompatible substance into the target site comprises surgically implanting the substance at the target site.

21. A method of kidney regeneration comprising:

injecting a substantially cell-free biocompatible substance into a target site in a kidney, wherein the biocompatible substance creates a hyperbaric environment at the target site;

maintaining positive pressure at the target site for at least one hour to recruit pluripotent cells to the target site; and

inducing differentiation of the pluripotent cells, wherein differentiation produces new glomeruli structures within the kidney.

22. A method of inducing in situ tissue regeneration at a target site of a subject comprising:

delivering a biocompatible substance to the target site to produce a positive pressure within a body structure,

maintaining the positive pressure at the target site for a period of time, whereby the number of pluripotent cells at the target site is increased,

delivering at least one adjuvant to a target site; and

promoting differentiation of the pluripotent cells to regenerate the tissue at the target site.

23. The method of claim 22, wherein the biocompatible substance comprises a substantially cell-free, injectable biocompatible polymeric substance.

24. The method of claim 22, wherein the adjuvant is incorporated into the biocompatible substance.

25. The method of claim 22, wherein the adjuvant further comprises an anti-inflammatory agent, such as, for example, dexamethasone.

26. The method of claim 22, wherein the adjuvant further comprises collagen synthetase inhibitor, such as, for example, collagenase.