Thermoresponsive, biodegradable, elastomeric material
Provided are novel biocompatible copolymers and compositions comprising the copolymers. The copolymers and degradation products thereof are non-toxic and typically have an LCST between room temperature and 37° C. so that they are liquid at room temperature and gelled at 37° C. which facilitates their use in humans, for example for wound treatment and as a cellular growth matrix or niche. The copolymer comprises numerous ester linkages in its backbone so that the copolymers are erodeable in situ. Degradation products of the polymer are soluble and non-toxic. The copolymer is amine-reactive so that it can conjugate with proteins, such as collagen. Active ingredients, such as drugs, can be incorporated into compositions comprising the copolymer.
1. A copolymer comprising: an N-isopropylacrylamide residue; an acrylic acid residue; an acrylic acid N-hydroxysuccinimide ester residue; and a polyester macromer comprising hydroxyethyl methacrylate (HEMA) and trimethylene carbonate (TMC), wherein hydrogels comprising said copolymer have weight loss ranging from 16% to 84% over three weeks in phosphate-buffered saline at 37° C.; and
wherein the percent feed ratio of N-isopropylacrylamide:acrylic acid:acrylic acid N-hydroxysuccinimide ester:polyester macromer for the copolymer is 85: 6: 5: 4.
2. The copolymer of claim 1 , wherein the copolymer has a lower critical solution temperature below 37° C.
3. The copolymer of claim 1 , wherein the copolymer has a lower critical solution temperature of between 30° C. and 35° C.
4. The copolymer of claim 1 , wherein the copolymer has a lower critical solution temperature above 37° C. after its ester bonds are hydrolyzed.
5. The copolymer of claim 1 , wherein the ratio of hydroxyethyl methacrylate to trimethyl carbonate residues in the polyester macromer ranges from 1:1 to 1:10.
6. The copolymer of claim 5 , wherein the ratio of hydroxyethyl methacrylate and trimethyl carbonate residues in the polyester macromer ranges from 1:2 to 1:5.
7. The copolymer or claim 1 , further comprising one or both of a caprolactone and a glycolide residue.
8. The copolymer of claim 1 , further comprising an amine-containing compound attached to the copolymer.
9. The copolymer of claim 8 , wherein the amine-containing compound is collagen.
10. The copolymer of claim 8 , wherein the amine-containing compound is gelatin.
11. The copolymer of claim 9 , comprising between 1% wt and 10% wt collagen.
12. A composition comprising the copolymer of claim 1 , and an aqueous solvent.
13. The composition of claim 12 , wherein the aqueous solvent is one of water, saline and phosphate-buffered saline.
14. The composition of claim 12 , further comprising an active agent.
15. The composition of claim 14 , wherein the active agent is one or more of an antiseptic, an antibiotic, an analgesic, an anesthetic, a chemotherapeutic agent, a clotting agent, an anti-inflammatory agent, a metabolite, a cytokine, a chemoattractant, a hormone, a steroid, a protein and a nucleic acid.
16. The composition of claim 15 , wherein the active agent is a desmopressin.
17. The composition of claim 12 , further comprising a biological material selected from the group consisting of a cell, a protein, and a virus.
18. The composition of claim 17 , wherein the biological material is a cell.
19. The composition of claim 18 , wherein the cell is a progenitor cell or a stem cell.
20. A method of making a thermosensitive copolymer comprising co-polymerizing N-isopropylacrylamide; acrylic acid; acrylic acid N-hydroxysuccinimide ester; and a polyester macromer prepared from hydroxyethyl methacrylate and trimethyl carbonate monomers to make a copolymer,
wherein the percent feed ratio of N-isopropylacrylamide:acrylic acid:acrylic acid N-hydroxysuccinimide ester:polyester macromer for the copolymer is 85:6:5:4; and
wherein hydrogels comprising said copolymer have weight loss ranging from 16% to 84% over three weeks in phosphate buffered saline at 37° C.
21. The method of claim 20 , wherein the monomers are co-polymerized by free-radical polymerization.
22. The method of claim 20 , wherein the ratio of hydroxyethyl methacrylate to trimethyl carbonate residues in the polyester macromer ranges from 1:1 to 1:10.
23. The method of claim 20 , wherein the ratio of hydroxyethyl methacrylate to trimethyl carbonate residues in the polyester macromer ranges from 1:2 to 1:5.
24. The method of claim 20 , further comprising conjugating an amine-containing compound to the copolymer.
25. The method of claim 24 , wherein the amine-containing compound is collagen.
26. The method of claim 24 , wherein the amine-containing compound is gelatin.
27. The copolymer of claim 1 , having a tensile strength of 0.5 MPa to 1.14 MPa.
28. The copolymer of claim 8 , having a tensile strength greater than 0.3 MPa and an elongation at break greater than 340%.