Cartilage repair systems and applications utilizing a glycosaminoglycan mimic

• US 9,180,166 B2
• Filed: 04/29/2011
• Issued: 11/10/2015
• Est. Priority Date: 03/12/2010
• Status: Active Grant

• Current Assignee: New Jersey Institute of Technology
• Original Assignee: New Jersey Institute of Technology
• Inventors: Arinzeh, Treena, Collins, George, Modak, Piyush, Tseng, Ling-Fang
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US13/097,657
• Publication Number:
  US 20110274742A1
• Time in Patent Office: 1,656 Days
• Field of Search: None
• US Class Current: 1/1
• 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 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• 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 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: C08L 1/02 Cellulose; Modified cellulose
• CPC Class Codes: C08L 1/16 Esters of inorganic acids
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C12N 2533/72 Chitin, chitosan
• CPC Class Codes: C12N 2533/78 Cellulose
• CPC Class Codes: C12N 5/0655 Chondrocytes; Cartilage
• CPC Class Codes: D01D 5/0007 Electro-spinning non-woven fabrics produced by electro-spinning D04H1/728
• CPC Class Codes: D01F 2/24 from cellulose derivatives
• CPC Class Codes: D01F 9/00 : Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments

Abstract

The present invention relates to hydrogel or scaffold compositions and methods of use for cell growth and/or regenerative medicine. The hydrogel comprises a water soluble cellulose compound and, in certain aspects, a fibrous or filamentous matrix. The hydrogels as described provide a support or scaffold that promotes, facilitates, and/or enhances progenitor or stem cell growth and/or differentiation. In addition, the hydrogel is useful for tissue, e.g., cartilage, regeneration and repair.

Claims

1. A composite hydrogel composition for facilitating cell growth or differentiation in cartilage comprising from 1% to 10% by weight of a water soluble anionic cellulose, and from 1% to 10% by weight of a polycationic polysaccharide, wherein the anionic water soluble cellulose forms a hydrogel, and wherein the polycationic polysaccharide forms a self-assembled fiber or filament network on the cellulose hydrogel, wherein the composition mimics the natural extracellular matrix of cartilage;

and a mesenchymal stem cell (MSC) contained in or on the hydrogel, wherein the composition facilitates cell growth or differentiation of the MSC, wherein the water soluble anionic cellulose is sodium cellulose sulfate having from about 18% to about 20% sulfation.

2. The composition of claim 1, wherein the sodium cellulose sulfate is sulfated on at least one position of the glucose unit selected from the group consisting of positions 2, 3, 6, and combinations thereof.

3. The composition of claim 2, wherein the composition further comprises a cellulose sulfate compound with from about 6% to about 12% sulfation, or a cellulose sulfate compound having from about 13% to about 17% sulfation or a combination thereof.

4. The composition of claim 2, wherein the sodium cellulose sulfate is sulfated at positions 2, 3 and 6 of the glucose unit.

5. The composition of claim 1, wherein the polycationic polysaccharide is chitosan.

6. The composition of claim 5, wherein the chitosan has a molecular weight of from about 190 kilodalton (kDa) to about 310 kDa.

7. The composition of claim 1, wherein the hydrogel retains from about 1.5% to about 2% by weight of water.

8. The composition of claim 5, wherein the chitosan fibers in the hydrogel form interfiber spacings of from 10 μ

m to about 1 mm.

9. The composition of claim 8, wherein the interfiber spacings are from 100 μ

m to about 1 mm.

10. The composition of claim 1, further comprising a cation, wherein the polymer network is complexed or stabilized by ionic interactions.

11. The composition of claim 10, wherein the cation is at least one of calcium, magnesium, iron(II), manganese(II) or a combination thereof.

12. The composition of claim 1, further comprising a chemical cross-linking agent.

13. The composition of claim 12, wherein the chemical cross-linking agent is a diglycidyl ether.

14. The composition of claim 13, wherein the diglycidyl ether is isosorbide diglycidyl ether.

15. The composition of claim 14, wherein the diglycidyl ether is diisosorbide bisepoxide.

16. The composition of claim 1, further comprising a pH buffer.

17. The composition of claim 1, comprising an MSC-derived, differentiated cell.

18. The composition of claim 17, wherein the MSC-derived, differentiated cell expresses aggregan or type II collagen or both.

19. The composition of claim 1, further comprising a growth factor.

20. The composition of claim 19, wherein the growth factor is transforming growth factor beta (TGF-β

).

21. The composition of claim 1, wherein the hydrogel is pre-formed in vitro.

22. The composition of claim 1, wherein the hydrogel is formed in vivo or in situ.

23. The composition of claim 1, wherein the composition is adapted for injection in vivo and/or in situ in a subject, and wherein the injectable hydrogel is capable of facilitating cell growth or differentiation.

24. The composition of claim 1, wherein the fiber or filament is an electrospun fiber or filament.

29. A method of treating or repairing cartilage tissue in a subject in need of such repair, the method comprising administering to said subject an effective amount of a hydrogel composition according to claim 1.

30. A method of treating arthritis in a subject in need of such treatment, the method comprising administering to said subject an effective amount of a hydrogel according to claim 1.

25. A composite hydrogel composition for facilitating mesenchymal stem cell growth or differentiation comprising a polymer network comprising from about 1% to about 10% (w/w) of a sodium cellulose sulfate compound, from about 1% to about 10% (w/w) of chitosan, wherein the sodium cellulose sulfate has from about 18% to about 20% sulfation, and wherein the polymer network-fiber matrix forms a cell attachment surface that facilitates mesenchymal stem cell growth or differentiation.

26. A method of preparing the hydrogel composition of claim 25 comprising the steps of:

admixing an aqueous solution having from about 1% to about 10% (w/w) of a sodium cellulose sulfate compound, and from about 1% to about 10% (w/w) of chitosan, wherein the chitosan forms fiber or filament matrix, and wherein the sodium cellulose sulfate and chitosan forms a polyionic complex.

27. The method of claim 26, comprising the step of seeding an isolated differentiable human mesenchymal stem cell (hMSC) on the hydrogel composition.

28. The method of claim 27, comprising the step of growing the hMSCs so that the isolated differentiable hMSCs differentiate into a mature cell phenotype on the hydrogel.