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. An implant comprising:
a first hydrogel comprising a first 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 channels comprising multiple hardened, cross-linked regions within the first hydrogel.
2. The implant 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 implant of claim 1 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
4. The implant 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 implant of claim 1 , further comprising a bioactive agent.
6. The implant of claim 1 , wherein the initiator is selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.
7. The implant of claim 6 , wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.
8. The implant of claim 1 , wherein the first hydrogel has a modulus of from about 5 kPa to about 500 kPa, and the second hydrogel has a modulus of from about 50 kPa to about 5,000 kPa.
9. The implant of claim 1 , wherein the first hydrogel degrades over a period of from about 4 weeks to about 10 weeks, and the second hydrogel degrades over a period of from about 6 weeks to about 6 months.
10. The implant of claim 1 , wherein the multiple channels form a mesh.
11. A composite hydrogel composition comprising:
a first hydrogel comprising a first 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 channels comprising multiple hardened, cross-linked regions within the first hydrogel.
12. The composite hydrogel composition of claim 11 , 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.
13. The composite hydrogel composition of claim 11 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
14. The composite hydrogel composition of claim 11 , 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.
15. The composite hydrogel composition of claim 11 , wherein the initiated precursor reacts with an initiator selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof, to further crosslink the second hydrogel.
16. The composite hydrogel composition of claim 15 , wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.
17. The composite hydrogel composition of claim 11 , further comprising a bioactive agent.
18. A method of forming an implant comprising:
contacting a first reactive precursor with a second reactive precursor and an initiated precursor comprising at least one vinyl group;
crosslinking the first reactive precursor and the second reactive precursor to form a first hydrogel; and
exposing a portion of the hydrogel to an initiator to initiate crosslinking of the initiated precursor to form a second hydrogel comprising channels comprising multiple hardened, cross-linked regions within the first hydrogel.
19. The method of claim 18 , wherein a mask is utilized to selectively expose the initiated precursor to the initiator.
20. The method of claim 18 , wherein the multiple hardened cross-linked regions form a mesh.
21. The method of claim 18 , wherein the first reactive precursor comprises electrophilic groups and the second reactive precursor comprises nucleophilic groups.
22. The method of claim 18 , wherein the first reactive precursor, the second reactive precursor, or both, comprise 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 18 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
24. The method of claim 18 , 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 18 , wherein the initiator is selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof, to further crosslink the second hydrogel.
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. A kit comprising:
a first reactive precursor comprising electrophilic groups, a second reactive precursor comprising nucleophilic groups, and an initiated precursor comprising at least one vinyl group;
an initiator to initiate crosslinking of the initiated precursor;
a mold for forming an implant by placing the first reactive precursor, the second reactive precursor, and the initiated precursor therein; and
an initiator mask to selectively expose the initiated precursor to the initiator.
28. The kit of claim 27 , wherein the first reactive precursor, the second reactive precursor, or both, comprise 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.
29. The kit of claim 27 , wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.
30. The kit of claim 27 , 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.
31. The kit of claim 27 , wherein the initiator is selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.
32. The kit of claim 31 , wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.