HYDROGEL PRECURSORS HAVING NANOPARTICLES

• US 20190314554A1
• Filed: 05/31/2019
• Published: 10/17/2019
• Est. Priority Date: 09/25/2013
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: DETAMORE, Michael, BECK, Emily, GEHRKE, Stevin, BERKLAND, Cory
• Granted Patent: US 11,000,630 B2
• Time in Patent Office: Days
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 2430/32 for nerve reconstruction
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/3817 Cartilage-forming cells, e.g. pre-chondrocytes
• CPC Class Codes: A61L 27/383 Nerve cells, e.g. dendritic cells, Schwann cells
• 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 27/48 with macromolecular fillers
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• 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: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

An implantable hydrogel precursor composition can include: a cross-linkable polymer matrix that is biocompatible; and a plurality of polymer particles in the cross-linkable polymer matrix. The cross-linkable polymer matrix can include a cross-linkable hyaluronic acid polymer that has cross-linkable functional groups. The hyaluronic acid polymer can be a methacrylated hyaluronic acid polymer. The methacrylated hyaluronic acid polymer can have a molecular weight from about 500 kDa to about 1.8 MDa. The polymer particles can include a cross-linked hyaluronic acid. The cross-linkable polymer matrix having the polymer particles has a yield stress. The cross-linkable polymer matrix having the polymer particles has shape retention at physiological temperatures. The composition can include live cells in the cross-linkable polymer matrix. The composition can include a biologically active agent in the cross-linkable polymer matrix.

Claims

1. A method of forming a hydrogel implant, comprising:

providing an implantable hydrogel precursor composition that has a yield stress at zero shear rate, the implantable hydrogel precursor composition comprising;

a cross-linkable polymer matrix that is biocompatible; and

a plurality of polymer particles in the cross-linkable polymer matrix;

implanting the hydrogel precursor composition into a body of a subject such that the hydrogel precursor composition has a shape and shape retention while in the body; and

crosslinking the cross-linkable polymer matrix to form a hydrogel containing the plurality of polymer particles that has the shape.

2. The method of claim 1, further comprising shaping the hydrogel precursor composition to have the shape with shape retention while in the body.

3. The method of claim 2, further comprising:

placing the hydrogel precursor in a defect in a tissue in the body; and

crosslinking the cross-linkable polymer in the defect.

4. The method of claim 3, wherein while in the defect, the hydrogel precursor composition retains the shape without leaking or flowing out of the defect.

5. The method of claim 2, further comprising shaping the hydrogel precursor composition with an instrument to obtain the shape.

6. The method of claim 3, wherein the defect is in a cartilage tissue, a bone tissue, or a nerve tissue.

7. The method of claim 1, further comprising:

placing cells within the hydrogel precursor composition; and

performing the crosslinking with the cells within the cross-linking composition.

8. The method of claim 1, further comprising:

providing a cross-linkable polymer matrix that is biocompatible; and

mixing a plurality of polymer particles into the cross-linkable polymer matrix.

9. The method of claim 3, further comprising forming the defect in the tissue.

10. The method of claim 8, further comprising:

providing a bioactive agent; and

mixing the bioactive agent into the cross-linkable polymer matrix.

11. The method of claim 1, further comprising:

regenerating bone with the hydrogel;

regenerating cartilage with the hydrogel;

or

regenerating nerves with the hydrogel.

12. The method of claim 11, further comprising treating a full or partial thickness cartilage defect with the hydrogel.

13. The method of claim 1, wherein the cross-linkable polymer matrix includes a cross-linkable hyaluronic acid polymer that has cross-linkable functional groups.

14. The method of claim 13, wherein the hyaluronic acid polymer is a methacrylated hyaluronic acid polymer.

15. The method of claim 14, wherein the methacrylated hyaluronic acid polymer has a molecular weight from about 500 kDa to about 1.8 MDa.

16. The composition of claim 1, wherein the polymer particles include a cross-linked hyaluronic acid.

17. The method of claim 16, wherein the hyaluronic acid polymer particles have a molecular weight of about 10 kDa to about 20 kDa.

18. The method of claim 1, wherein the implantable hydrogel precursor composition comprises:

a cross-linkable hyaluronic acid polymer having a cross-linkable functional group forming a cross-linkable polymer matrix that is biocompatible; and

a plurality of polymer nanoparticles in the cross-linkable polymer matrix, wherein the polymer nanoparticles are cross-linked hyaluronic acid,

wherein;

the cross-linkable hyaluronic acid polymer is present from about 2% to about 10%; and

the polymer nanoparticles are present from about 10% to about 40%.

19. The method of claim 18, wherein:

the polymer nanoparticles have a molecular weight of about 10 kDa to about 20 kDa;

the polymer nanoparticles have a particle size of about 10 nm to about 500 nm; and

a ratio of cross-linkable hyaluronic acid polymer to polymer nanoparticles is from 1;

15 to about 2;

1.

20. The method of claim 18, wherein the implantable hydrogel precursor composition comprises:

live cells; and

/or

a biologically active agent.

21. The method of claim 18, wherein the implantable hydrogel precursor composition comprises:

a non-zero shear stress at a shear rate below 1 s<sup>−

1</sup>;

a shear stress of about 500 Pa to about 1000 Pa at 1 s<sup>−

1</sup> shear rate;

a yield stress of at least about 400 Pa to about 800 Pa; and

/or

a storage modulus;

about 400 Pa to about 1100 Pa at an initial phase, about 10 Pa to about 400 Pa at a disruption phase, and about 500 Pa to about 1200 Pa at a recovery phase.