Renal tissue regeneration

• US 9,694,055 B2
• Filed: 05/11/2009
• Issued: 07/04/2017
• Est. Priority Date: 05/09/2008
• Status: Active Grant

• Current Assignee: Wake Forest University Health Sciences
• Original Assignee: Wake Forest University Health Sciences
• Inventors: Atala, Anthony, Yoo, James, Van Dyke, Mark, Lee, Sang Jin
• Primary Examiner(s): Moloye, Titilayo
• Application Number:
  US12/991,811
• Publication Number:
  US 20110097379A1
• Time in Patent Office: 2,976 Days
• 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. A method of inducing renal progenitor cell recruitment to the kidney parenchyma of a subject comprising:

obtaining a substantially cell-free biocompatible collagen thermogel that will thermogel as it reaches body temperature and maintain a viscosity greater than water for more than 1 hour when gelled;

chilling the substantially cell-free biocompatible collagen thermogel below its gelation temperature;

injecting the chilled, substantially cell-free biocompatible collagen thermogel into the kidney parenchyma of the subject with an injection needle;

measuring the pressure in the kidney parenchyma during injection with a pressure sensor;

continuing injection of the chilled, substantially cell-free biocompatible collagen thermogel until a positive pressure in a range from about 5 cmH20 to about 20 cmH20 in the kidney parenchyma is obtained by the injecting step;

maintaining the positive pressure for at least one hour after injection due to gelation of the substantially cell-free biocompatible collagen thermogel as it reaches body temperature; and

creating a hyperbaric environment caused by the step of injecting the substantially cell-free biocompatible collagen thermogel into the kidney parenchyma, whereby renal progenitor cells are recruited to the kidney parenchyma.

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

3. The method of claim 1, wherein the viscosity of the biocompatible collagen thermogel is between about 5 cP to about 1×

10⁸ cP at 25°

C.

9. The method according to claim 1, further comprising performing the method of claim 1 multiple times over a period of time.

4. A method of kidney regeneration comprising:

obtaining a substantially cell-free biocompatible collagen thermogel that will thermogel as it reaches body temperature and maintain a viscosity greater than water for more than 1 hour when gelled;

chilling the substantially cell-free biocompatible collagen thermogel below its gelation temperature;

injecting the chilled, substantially cell-free biocompatible collagen thermogel into the kidney parenchyma of a subject with an injection needle;

measuring the pressure in the kidney parenchyma during injection with a pressure sensor;

continuing injection of the chilled substantially cell-free biocompatible collagen thermogel at the kidney parenchyma until a positive pressure in a range from about 5 cmH20 to about 20 cmH20 is obtained by the injecting step;

creating a hyperbaric environment in the kidney parenchyma caused by the step of injecting the substantially cell-free biocompatible collagen thermogel; and

maintaining the positive pressure in the kidney parenchyma for at least one hour due to gelation of the substantially cell-free biocompatible collagen thermogel as it reaches body temperature, whereby renal progenitor cells are recruited to the kidney parenchyma and differentiate into new glomeruli structures within the kidney parenchyma one week after the step of injection.

10. The method according to claim 4, further comprising performing the method of claim 4 multiple times over a period of time.

5. A method of inducing in situ renal tissue regeneration in the kidney parenchyma of a subject comprising:

obtaining a substantially cell-free biocompatible collagen thermogel that will thermogel as it reaches body temperature and maintain a viscosity greater than water for more than 1 hour when gelled;

chilling the substantially cell-free biocompatible collagen thermogel below its gelation temperature;

injecting the chilled substantially cell-free biocompatible collagen thermogel and at least one adjuvant into the kidney parenchyma of the subject with an injection needle;

measuring the pressure during injection with a pressure sensor;

continuing injection of the chilled substantially cell-free biocompatible collagen thermogel and adjuvant until a positive pressure in a range from about 5 cmH20 to about 20 cmH20 is obtained by the injecting step;

maintaining the positive pressure in the kidney parenchyma for a period of time due to gelation of the substantially cell-free biocompatible collagen thermogel as it reaches body temperature, whereby renal progenitor cells are recruited to the kidney parenchyma and differentiate into renal tissue one week after the step of injection.

6. The method of claim 5, wherein the adjuvant is incorporated into the biocompatible collagen thermogel.

7. The method of claim 5, wherein the adjuvant comprises an anti-inflammatory agent comprising dexamethasone.

8. The method of claim 7, wherein the anti-inflammatory agent comprises a collagen synthetase inhibitor.

11. The method according to claim 5, further comprising performing the method of claim 5 multiple times over a period of time.