Hydrogel precursors having nanoparticles

• US 10,335,515 B2
• Filed: 10/20/2015
• Issued: 07/02/2019
• 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
• Primary Examiner(s): Coughlin, Matthew P
• Assistant Examiner(s): Wheeler, Thurman
• Application Number:
  US14/918,229
• Publication Number:
  US 20160038643A1
• Time in Patent Office: 1,351 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 shape retaining implantable hydrogel precursor composition comprising:

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

a photoinitiator; 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%;

the polymer nanoparticles are present from about 10% to about 40%; and

the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles is a non-flowable gel or paste and has a yield stress in Pa at zero shear rate s<sup>−

1</sup>, wherein;

the cross-linkable functional group is cross-linkable with the photoinitiator, and

the shape retaining implantable hydrogel precursor composition has a shape and shape retention thereof.

2. The composition of claim 1, wherein the hyaluronic acid polymer is a methacrylated hyaluronic acid polymer.

3. The composition of claim 2, wherein the methacrylated hyaluronic acid polymer has a molecular weight from about 500 kDa to about 1.8 MDa.

4. The composition of claim 1, wherein the polymer nanoparticles have a molecular weight of about 10 kDa to about 20 kDa.

5. The composition of claim 1, wherein the polymer nanoparticles have a particle size of about 10 nm to about 500 nm.

6. The composition of claim 1, wherein:

the polymer particles are present from about 10% to about 30%.

7. The composition of claim 1, wherein the ratio of cross-linkable hyaluronic acid polymer to polymer nanoparticles is from 1:

15 to about 2;

1.

8. The composition of claim 1, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles has shape memory at physiological temperatures.

9. The composition of claim 1, further comprising live cells in the cross-linkable polymer matrix.

10. The composition of claim 1, further comprising a biologically active agent in the cross-linkable polymer matrix.

11. The composition of claim 6, wherein the polymer nanoparticles are present from about 10% to about 20%.

12. The composition of claim 1, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles has a non-zero shear stress at a shear rate below 1 s⁻

1.

13. The composition of claim 11, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles has a yield stress of at least about 400 Pa to about 800 Pa.

14. The composition of claim 11, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles has a shear stress of about 500 Pa to about 1000 Pa at 1 s⁻

1 shear rate.

15. The composition of claim 11, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles has the following 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.

16. The composition of claim 1, wherein the cross-linkable hyaluronic acid polymer matrix having the polymer nanoparticles is an unflowable paste having a defined shape below the yield stress.

17. The composition of claim 1, further comprising particles of decellularized cartilage and/or cross-linkable decellularized cartilage in the cross-linkable polymer matrix.

18. The composition of claim 2, percent methacrylation of the methacrylated hyaluronic acid polymer is 5%-40%.