Hydrolytically degradable polysaccharide hydrogels

Patent metadata

Field	Value
Publication number	US-11090387-B2
Application number	US-200913139537-A
Country	US
Kind code	B2
Filing date	Dec 8, 2009
Priority date	Dec 22, 2008
Publication date	Aug 17, 2021
Grant date	Aug 17, 2021

Abstract

Provided are polysaccharide compositions capable of controllable hydrolytic degradation and suitable for controlled release of therapeutic agents. Also provided are methods for synthesizing such compositions and a variety of applications in which the compositions may be used.

First claim

What is claimed:

1. A composition, comprising:
a polymer comprising a plurality of repeat units,
at least one repeat unit comprising
a biocompatible backbone comprising units of hyaluronic acid; and
a hydrolytically degradable linker disposed between the biocompatible backbone and a crosslinker group, wherein the hydrolytically degradable linker comprises one or more of units of lactic acid, caprolactone, glycolic acid, an anhydride, or an orthoester,
the crosslinker group covalently binding at least one repeat unit to a second repeat unit comprising methacrylate monomers;

wherein said repeat units are covalently bonded to one another, and
wherein the hydrolytically degradable linker degrades upon exposure to an aqueous medium.

2. The composition of claim 1 , further comprising a cell.

3. The composition of claim 2 , wherein the cell comprises a mammalian cell.

4. The composition of claim 2 , wherein the cell comprises a stem cell.

5. A method of synthesizing a macromer according to claim 1 , comprising:
reacting a first compound comprising methacrylate with a compound comprising lactide to give rise to a second compound comprising a methacrylic group, a lactic acid, and an OH end group;
converting the —OH end group to a carboxylic acid end group;
reacting the carboxylic acid end group to give rise to a functionalized end group; and
reacting the functionalized end group with a salt of an acidic polysaccharide, so as to give rise to a macromer comprising a polymerizing moiety and a hydrolytically degradable linker, wherein the hydrolytically degradable linker degrades upon exposure to an aqueous medium.

6. The method of claim 5 , wherein the converting the —OH end group to a carboxylic acid group comprises reaction with succinic anhydride in the presence of pyridine and dimethylaminopropylpyridine.

7. The method of claim 5 , wherein reacting the carboxylic acid group comprises reacting N-hydroxysuccinimide and dicyclyhexylcarbodiimide.

8. The method of claim 5 , wherein the salt of the acidic polysaccharide comprises tetrabutyl amine.

9. A method of controllably delivering an agent, comprising:
disposing a quantity of an agent within a polymeric composition according to claim 1 comprising a plurality of first repeat units,
at least one first repeat unit comprising
a biocompatible backbone comprising units of hyaluronic acid monomers; and
a hydrolytically degradable linker bound to the biocompatible repeat unit, to the polymerizing moiety, or to both,
wherein the hydrolytically degradable linker degrades upon exposure to an aqueous medium;
exposing the delivery composition to an aqueous medium so as to hydrolyze the hydrolytically degradable linker such at least a portion of the quantity of the agent is released from the polymeric composition

wherein said polymeric composition comprising a polymer comprising at least one of
(i) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one lactic acid being disposed between the hyaluronic acid and the methacrylate, or
(ii) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one caprolactone being disposed between the hyaluronic acid and the methacrylate.

10. The method of claim 9 , further comprising contacting the delivery composition to a tissue of a subject.

11. The method of claim 10 , further comprising disposing a capping material along at least a portion of the delivery composition such that release of the agent is preferentially directed into the tissue.

12. The method of claim 11 , wherein the capping material has a density greater than that of the delivery composition.

13. The method of claim 9 , wherein the agent comprises a stem cell, a cytokine, a chemotherapeutic, or any combination thereof.

14. A composition of claim 1 , consisting essentially of:
a polymer comprising a plurality of repeat units,
at least one repeat unit comprising
a biocompatible backbone comprising units of hyaluronic acid; and
a hydrolytically degradable linker disposed between the biocompatible backbone and a crosslinker group, wherein the hydrolytically degradable linker comprises one or more of lactic acid, caprolactone, glycolic acid, and anhydride or an ester,
the crosslinker group covalently binding at least one repeat unit to a second repeat unit

wherein said composition further comprises, comprising a polymer comprising at least one of
(i) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one lactic acid being disposed between the hyaluronic acid and the methacrylate, or
(ii) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one caprolactone being disposed between the hyaluronic acid and the methacrylate.

15. A composition of claim 1 , consisting essentially of:
a polymer comprising a plurality of repeat units,
at least one repeat unit comprising
a biocompatible backbone comprising units of hyaluronic acid; and
a hydrolytically degradable linker disposed between the biocompatible backbone and a crosslinker group, wherein the hydrolytically degradable linker comprises one or more of lactic acid, caprolactone, glycolic acid, and anhydride or an ester,
the crosslinker group covalently binding at least one repeat unit to a second repeat unit;

wherein said composition further comprises a polymer comprising at least one of
(i) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one lactic acid being disposed between the hyaluronic acid and the methacrylate, or
(ii) at least one repeat unit that comprises hyaluronic acid and a methacrylate, at least one caprolactone being disposed between the hyaluronic acid and the methacrylate; and

a plurality of cells.

16. The composition of claim 1 , wherein the first repeat unit and the second repeat unit are different on the basis of the formulas of their backbones, their polymerizable groups, or on the basis of the hydrolytically degradable linkers, or a combination thereof.

17. The composition of claim 16 , wherein the first repeat unit and the second repeat unit differ on the basis of the formulas of their hydrolytically degradable linkers.

Assignees

• Burdick Jason Alan
• Sahoo Sujata
• Chung Cindy
• Univ Pennsylvania

Inventors

• Burdick Jason Alan
• Sahoo Sujata
• Chung Cindy

Classifications

• A61L2300/414

  Growth factors · CPC title

• C12N5/0663

  Bone marrow mesenchymal stem cells (BM-MSC) · CPC title

• A61L27/58

  Materials at least partially resorbable by the body · CPC title

• A61L2300/604

  Biodegradation · CPC title

• A61L2300/426

  Immunomodulating agents, i.e. cytokines, interleukins, interferons · CPC title