Combination therapy to promote wound healing

Patent metadata

Field	Value
Publication number	US-2016175485-A1
Application number	US-201414913284-A
Country	US
Kind code	A1
Filing date	Aug 19, 2014
Priority date	Aug 27, 2013
Publication date	Jun 23, 2016
Grant date	—

Abstract

Methods for increasing and/or promoting wound healing, wound re-epithelialization and dermal regeneration of epithelial tissues and cutaneous wounds by administration to a subject of an extracellular matrix scaffold or Scaffold for Dermal Regeneration (SDR) populated with beta adrenergic receptor antagonist pre-conditioned mesenchymal stem cells (MSCs) are provided. Compositions and kits comprising an extracellular matrix scaffold (ECMS) populated with beta adrenergic receptor antagonist pre-conditioned mesenchymal stem cells (MSCs) are also provided.

First claim

What is claimed is:

1 . An extracellular matrix scaffold comprising mesenchymal stem cells (MSCs) which have been contacted and/or pre-conditioned with a beta adrenergic receptor antagonist.

2 . The extracellular matrix scaffold of claim 1 , wherein the MSCs have been cultured in medium comprising a beta adrenergic receptor antagonist.

3 . The extracellular matrix scaffold of claim 2 , wherein the MSCs have been cultured at least 24 hours in medium comprising a beta adrenergic receptor antagonist.

4 . The extracellular matrix scaffold of any one of claims 1 to 3 , wherein the MSCs have been cultured under hypoxic conditions.

5 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the antagonist has a Kd for a beta-3 adrenergic receptor that is about 100 or more times greater than a Kd of the antagonist for a non-beta-3 adrenergic receptor.

6 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the beta adrenergic receptor antagonist is a non-selective antagonist for β1 and β2 adrenergic receptors.

7 . The extracellular matrix scaffold of claim 6 , wherein the beta adrenergic receptor antagonist is selected from carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, and mixtures, analogs and salts thereof.

8 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the beta adrenergic receptor antagonist is a selective antagonist for β1 adrenergic receptors.

9 . The extracellular matrix scaffold of claim 8 , wherein the beta adrenergic receptor antagonist is selected from acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, nebivolol, and mixtures, analogs and salts thereof.

10 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the beta adrenergic receptor antagonist is a selective antagonist for β2 adrenergic receptors.

11 . The extracellular matrix scaffold of claim 10 , wherein the beta adrenergic receptor antagonist is selected from butoxamine and ICI-118,551.

12 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the beta adrenergic receptor antagonist is selected from the group consisting of timolol, labetalol, dilevelol, propanolol, carvedilol, nadolol, carteolol, penbutolol, sotalol, ICI-118,551, butoxamine, and mixtures, analogs and salts thereof.

13 . The extracellular matrix scaffold of any one of claims 1 to 4 , wherein the beta adrenergic receptor antagonist is substantially free of activity as a beta-3 adrenergic receptor agonist.

14 . The extracellular matrix scaffold of any one of claims 1 to 13 , wherein the beta adrenergic receptor antagonist is cross-linked to the scaffold.

15 . The extracellular matrix scaffold of any one of claims 1 to 14 , wherein the MSCs are adipose-derived MSCs (Ad-MSCs).

16 . The extracellular matrix scaffold of any one of claims 1 to 13 , wherein the MSCs are bone-marrow-derived MSCs (BM-MSCs).

17 . A kit comprising an extracellular matrix scaffold of any one of claims 1 to 16 .

18 . A method of promoting, facilitating, and/or increasing healing, closure, re-epithelization and/or dermal regeneration of an epithelial and/or cutaneous wound in a subject in need thereof, comprising placing, implanting, suturing or embedding onto or into the wound an extracellular matrix scaffold of any one of claims 1 to 16 .

19 . The method of claim 18 , wherein the subject has diabetes.

20 . The method of any one of claims 18 to 19 , wherein the subject is a human.

21 . The method of any one of claims 18 to 20 , wherein the wound comprises an incision, laceration, abrasion, or ulcer.

22 . The method of any one of claims 18 to 21 , wherein the wound is a chronic wound.

23 . The method of any one of claims 18 to 22 , the wound comprises a venous stasis ulcer, a diabetic foot ulcer, a neuropathic ulcer, or a decubitus ulcer.

24 . The method of any one of claims 18 to 20 , wherein the wound comprises a wound resulting from surgical wound dehiscence.

25 . The method of any one of claims 18 to 20 , wherein the wound comprises a burn.

26 . The method of any one of claims 18 to 24 , wherein the epithelial wound comprises skin.

27 . The method of any one of claims 18 to 26 , wherein the MSCs are autologous to the subject.

28 . The method of any one of claims 18 to 26 , wherein the MSCs are syngeneic to the subject.

29 . The method of any one of claims 18 to 26 , wherein the MSCs are allogeneic to the subject.

30 . The method of any one of claims 18 to 26 , wherein the MSCs are xenogeneic to the subject.

31 . The method of any one of claims 18 to 30 , wherein the wound is sterile.

32 . The method of any one of claims 18 to 30 , wherein the wound is not sterile.

33 . The method of any one of claims 18 to 32 , wherein the beta adrenergic receptor antagonist is applied multiple times to the extracellular matrix scaffold that has been sutured, embedded or implanted into the wound.

Assignees

• Univ California

Inventors

• Isseroff Roslyn Rivkah
• Dasu Ravi Krishna Mohan
• Ramirez Sandra

Classifications

• A61L2300/436

  of receptors · CPC title

• A61K35/28

  Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells · CPC title

• A61L27/3633 Primary

  Extracellular matrix [ECM] · CPC title

• A61L27/3834

  Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells · CPC title

• A61L27/3895

  using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions · CPC title