Hydrogel implants with varying degrees of crosslinking
View Patent ↗The present disclosure relates to a hydrogel composition and methods of using the same. The hydrogel composition may include precursors that react with each other upon contact as well as precursors that react upon contact with an initiator. In embodiments, the resulting hydrogels may have varying levels of crosslinking with both denser and less dense regions.
1. A composite hydrogel composition comprising:
a first hydrogel comprising a reactive precursor comprising a multi-arm polyether possessing electrophilic groups in combination with a second reactive precursor comprising nucleophilic groups; and
a second hydrogel comprising at least one initiated precursor comprising at least one vinyl group,
wherein the second hydrogel forms a disperse region within the first hydrogel.
2. The composite hydrogel composition of claim 1 , wherein the first reactive precursor, comprises a core selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, and combinations thereof, and wherein the second reactive precursor comprises a core comprising a component selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, polyvinyl alcohol, poly(vinyl pyrrolidinone), poly(amino acids), dextran, chitosan, alginates, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid, albumin, collagen, casein, gelatin, and combinations thereof.
3. The composite hydrogel composition of claim 1 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
4. The composite hydrogel composition of claim 1 , wherein the initiated precursor is selected from the group consisting of acrylic acid, methacrylic acid, phosphorylcholine containing monomers, furanone functional vinyl monomers, potassium sulfopropyl acrylate, potassium sulfopropyl methacrylate, n-vinyl pyrrolidone, hydroxyethyl methacrylate, vinyl monomers having a high refractive index, siloxane functional vinyl compounds, polyethylene glycol-silicone co-monomers having vinyl groups, tris acrylate, pyrrole, liquid crystalline vinyl monomers, liquid crystalline vinyl polymers, and combinations thereof.
5. The composite hydrogel composition of claim 1 , further comprising an initiator selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.
6. The composite hydrogel composition of claim 5 , wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.
7. The composite hydrogel composition of claim 1 , further comprising a bioactive agent.
8. The composite hydrogel composition of claim 7 , wherein the bioactive agent is in both the first hydrogel and the second hydrogel.
9. The composite hydrogel composition of claim 8 , wherein the bioactive agent in the first hydrogel is the same as the bioactive agent in the second hydrogel.
10. The composite hydrogel composition of claim 8 , wherein the bioactive agent in the first hydrogel is different than the bioactive agent in the second hydrogel.
11. The composite hydrogel composition of claim 8 , wherein the bioactive agent is released from the first hydrogel over a period of time from about 1 day to about 6 weeks, and the bioactive agent is released from the second hydrogel over a period of time from about 5 days to about 12 weeks.
12. The composite hydrogel composition of claim 1 , wherein the second hydrogel comprises from about 5% to about 30% by weight of the composite hydrogel composition.
13. The composite hydrogel composition of claim 1 , wherein the first hydrogel has a modulus of from about 5 kPa to about 50 kPa, and the second hydrogel has a modulus of from about 10 kPa to about 100 kPa.
14. The composite hydrogel composition of claim 1 , wherein the first hydrogel degrades over a period of from about 1 week to about 4 weeks, and the second hydrogel degrades over a period of from about 2 weeks to about 8 weeks.
15. The composite hydrogel composition of claim 1 , further comprising a barrier layer comprising a third hydrogel comprising at least one initiated precursor over at least a portion of the surface of the first hydrogel.
16. The composite hydrogel composition of claim 15 , wherein the second hydrogel and the third hydrogel comprise the same initiated precursor.
17. The composite hydrogel composition of claim 15 , wherein the third hydrogel layer directs delivery of a bioactive agent from the first hydrogel, the second hydrogel, or both, in a direction opposite the barrier layer.
18. A drug delivery device comprising the composite hydrogel composition of claim 1 .
19. The drug delivery device of claim 18 , wherein a bioactive agent is present in the drug delivery device in a form selected from the group consisting of liposomes, microspheres, microbubbles, and combinations thereof.
20. The drug delivery device of claim 19 , wherein a first bioactive agent is released from the first hydrogel over a period of from about 1 day to about 6 weeks, and a second bioactive agent is released from the second hydrogel over a period of from about 5 days to about 12 weeks.
21. A method for making the composite hydrogel composition of claim 1 comprising:
contacting a first hydrogel comprising a first reactive precursor comprising a multi-arm polyether possessing electrophilic groups, a second reactive precursor comprising nucleophilic groups, and a second hydrogel comprising at least one initiated precursor comprising at least one vinyl group to form a disperse region comprising the second hydrogel within the first hydrogel.
22. The method of claim 21 , wherein the first reactive precursor comprises a core selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, and combinations thereof, and wherein, the second reactive precursor, comprises a core comprising a component selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, polyvinyl alcohol, poly(vinyl pyrrolidinone), poly(amino acids), dextran, chitosan, alginates, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid, albumin, collagen, casein, gelatin, and combinations thereof.
23. The method of claim 21 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
24. The method of claim 21 , wherein the initiated precursor is selected from the group consisting of acrylic acid, methacrylic acid, phosphorylcholine containing monomers, furanone functional vinyl monomers, potassium sulfopropyl acrylate, potassium sulfopropyl methacrylate, n-vinyl pyrrolidone, hydroxyethyl methacrylate, vinyl monomers having a high refractive index, siloxane functional vinyl compounds, polyethylene glycol-silicone co-monomers having vinyl groups, tris acrylate, pyrrole, liquid crystalline vinyl monomers, liquid crystalline vinyl polymers, and combinations thereof.
25. The method of claim 21 , further comprising contacting the first hydrogel to an initiator selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.
26. The method of claim 25 , wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.
27. The method of claim 21 , wherein the second hydrogel layer further comprises a bioactive agent.