Hydrogel compositions comprising encapsulated cells and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2017196818-A1
Application number	US-201515321458-A
Country	US
Kind code	A1
Filing date	Jun 30, 2015
Priority date	Jun 30, 2014
Publication date	Jul 13, 2017
Grant date	—

Abstract

The present invention provides injectable compositions comprising cells encapsulated in hydrogel capsules and methods of preparing these compositions. The present invention also provides methods for using these compositions to promote hematopoiesis and to treat or prevent cardiovascular and immunological disorders in a subject.

First claim

1 . A composition comprising a plurality of hydrogel capsules, wherein
at least 90% of said hydrogel capsules in said composition comprise a cell and a hydrogel encapsulating said cell, wherein said hydrogel encapsulating said cell has a thickness of less than 20 microns.

2 . The composition of claim 1 , wherein at least 70% of said hydrogel capsules comprise a single cell.

3 . The composition of claim 1 , wherein the cell is a mesenchymal stem cell (MSC) or a progenitor thereof, a hematopoietic stem cell (HSC) or a progenitor thereof, or an endothelial progenitor cell.

4 . (canceled)

5 . The composition of claim 1 , wherein the hydrogel comprises at least one polymer selected from the group consisting of alginate, agarose, poly(ethylene glycol dimethacrylate), polylactic acid, polyglycolic acid, PLGA, gelatin, collagen, agarose, pectin, poly(lysine), polyhydroxybutyrate, poly-epsilon-caprolactone, polyphosphazines, poly(vinyl alcohol), poly(alkylene oxide), poly(ethylene oxide), poly(allylamine), poly(acrylate), poly(4-aminomethylstyrene), pluronic polyol, polyoxamer, poly(uronic acid), poly(anhydride) and poly(vinylpyrrolidone).

6 . (canceled)

7 . The composition of claim 5 , wherein the polymer is alginate.

8 . The composition of claim 5 , wherein the polymer comprises polymer chains cross-linked to each other using a divalent or trivalent cation selected from the group consisting of Ca 2+ , Mg 2+ , Sr 2+ , Ba 2+ , Be 2+ and Al 3+ .

9 . (canceled)

10 . The composition of claim 8 , wherein the divalent cation is Ca 2+ .

11 . The composition of claim 2 , wherein the diameter of said hydrogel capsule comprising a single cell is between about 10 and 500 micron.

12 . (canceled)

13 . The composition of claim 5 , wherein the hydrogel comprises a first polymer and a second polymer.

14 . The composition of claim 13 , wherein the first polymer is alginate and the second polymer is collagen or fibrin.

15 . A method of preparing a composition comprising a plurality of hydrogel capsules, the method comprising:
a) contacting a cell with a moiety capable of adhering to a cell and comprising a cross-linking catalyst; and b) contacting the cell and the moiety with at least one polymer comprising a plurality of polymer chains;
wherein the cross-linking catalyst catalyzes a reaction that cross-links said plurality of polymer chains, thereby forming a composition comprising a plurality of hydrogel capsules, wherein at least 90% of said hydrogel capsules in said composition comprise a cell and a hydrogel encapsulating said cell, wherein said hydrogel encapsulating said cell has a thickness of less than 20 microns.

16 . The method of claim 15 , wherein the cross-linking catalyst is a divalent or trivalent cation selected from the group consisting of Ca 2+ , Mg 2+ , Sr 2+ , Ba 2+ , Be 2+ and Al 3+ .

17 . (canceled)

18 . The method of claim 15 , wherein said moiety is a nanoparticle.

19 . The method of claim 18 , wherein said nanoparticle is a CaCO 3 nanoparticle.

20 . The method of claim 15 , wherein the at least one polymer is selected from the group consisting of alginate, agarose, poly(ethylene glycol dimethacrylate), polylactic acid, polyglycolic acid, PLGA, gelatin, collagen, agarose, pectin, poly(lysine), polyhydroxybutyrate, poly-epsilon-caprolactone, polyphosphazines, poly(vinyl alcohol), poly(alkylene oxide), poly(ethylene oxide), poly(allylamine), poly(acrylate), poly(4-aminomethylstyrene), pluronic polyol, polyoxamer, poly(uronic acid), poly(anhydride) and poly(vinylpyrrolidone).

21 . (canceled)

22 . The method of claim 15 , wherein the cell is a mesenchymal stem cell (MSC) or a progenitor thereof, a hematopoietic stem cell (HSC) or a progenitor thereof, or an endothelial progenitor cell.

23 . (canceled)

24 . A method of administering at least one protein factor produced by a cell to a subject in need thereof, the method comprising administering to said subject a composition comprising a plurality of hydrogel capsules, wherein at least 90% of said hydrogel capsules in said composition comprise a cell and a hydrogel encapsulating said cell, wherein said hydrogel encapsulating said cell has a thickness of less than 20 microns.

25 . The method of claim 24 , wherein the cell is a mesencymal stem cell (MSC) or a progenitor thereof.

26 . The method of claim 24 , wherein the hydrogel in each cell containing hydrogel capsule is characterized by a stiffness of about 0.1 to about 500 kPa.

27 . (canceled)

28 . The method of claim 24 , wherein
said at least one protein factor is naturally produced by said cell; or said at least one protein factor is not naturally produced by said cell, and wherein said cell has been genetically engineered to produce said at least one protein factor; or wherein said cell has been genetically engineered to modify expression of at least one protein factor.

29 - 30 . (canceled)

31 . The method of claim 25 , wherein said at least one protein factor is
a hematopoietic factor selected from the group consisting of stem cell factor (SCF), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-7 (IL-7), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), erythropoietin, thrombopoietin, collagen-I, interleukin-11 (IL-11), angiopoietin-1 and transforming growth factor-beta (TGF-beta); or a cardiovascular regeneration factor selected from the group consisting of vascular endothelial growth factor (VEGF), stromal cell derived factor 1 (SDF-1), tumor necrosis factor-inducible gene 6 protein (TSG-6), interleukin-6 (IL-6), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF or FGF-2), insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), thrombospondin-4, secreted frizzled-related protein 2 (Sfrp2), matrix metalloproteinase 9 (MMP-9), tissue inhibitior of metalloproteinases (TIMP) metallopeptidase inhibitor 2 (TIMP-2), monocyte chemotactic protein 1 (MCP-1), thrombospondin 1 (TSP-1), chemokine (C-X-C motif) ligand 6 (CXCL6) and interferon gamma-induced protein 10 (IP-10); or a GVHD suppression factor selected from the group consisting of transforming growth factor-beta (TGF-beta), hepatocyte growth factor (HGF), prostaglandin E2 (PGE2), galectin and indoleamine 2,3-dioxygenase (IDO).

32 - 38 . (canceled)

39 . The method of claim 24 , wherein the composition is administered by a route selected from the group consisting of intravenous infusion, intrabone infusion, intramuscular injection, subcutaneous implantation, intraperitoneal injection, intracardial injection, intratracheal administration, topical application and oral administration.

40 . (canceled)

41 . The method of claim 31 , wherein the subject has undergone bone marrow transplantation or HSC transplantation; or wherein the subject suffers from cancer, an immune deficiency disorder, or a blood disease.

42 - 47 . (canceled)

48 . A method for treating or preventing a cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a composition comprising a plurality of hydrogel capsules, wherein at least 90%

Assignees

• Harvard College

Inventors

• Shin Jae-Won
• Mao Angelo S
• Utech Stefanie
• Weitz David A
• Mooney David J
• Uzun Oktay

Classifications

• A61K35/28

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

• A61K9/4816 Primary

  Wall or shell material · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/5036

  Polysaccharides, e.g. gums, alginate; Cyclodextrin · CPC title

• C12N11/10

  the carrier being a carbohydrate · CPC title