Layered non-fouling, antimicrobial antithrombogenic coatings
View Patent ↗Substrates, optionally coated with an undercoating, having grafted thereto one or more non-fouling materials are described herein. The non-fouling, polymeric material can be grafted to a variety of functionalized substrate materials, particularly polymeric substrates and/or polymeric undercoatings immobilized on a substrate. The compositions described herein are highly resistant protein absorption, particularly in complex media and retain a high degree of non-fouling activity over long periods of time. The compositions described herein may also demonstrate antimicrobial and/or anti-thrombogenic activity. The non-fouling material can be grafted to a functionalized substrate, or optionally from an undercoating on the substrate, preferably without significantly affecting the mechanical and/or physical properties of the substrate material.
1. A composition comprising a functionalized substrate in the form of a medical device containing lumens, cavities, porous structures, or combinations thereof, the functionalized substrate having a polymeric undercoat immobilized thereon and a non-fouling polymeric topcoat copolymer covalently bound to the polymeric undercoat, the polymeric undercoat being between the functionalized substrate and the non-fouling polymeric topcoat copolymer, wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are polyether moieties or phosphorylcholine, sulfobetaine or carboxybetaine zwitterionic moieties, the polymeric undercoat and the non-fouling polymeric topcoat copolymer comprising complementary reactive functional groups wherein the non-fouling polymeric topcoat copolymer is covalently bound to the polymeric undercoat via covalent bonds formed by the complementary reactive functional groups.
2. The composition of claim 1 , wherein the substrate comprises a polymer and the polymer is selected from the group consisting of polystyrene and substituted polystyrenes, poly(urethane)s, polyacrylates and polymethacrylates, polyacrylamides and polymethacrylamides, polyesters, polysiloxanes, polyethers, poly(orthoester), poly(carbonates), poly(hydroxyalkanoate)s, polyfluorocarbons, silicones, epoxy resins, polyamides and copolymers thereof, nylon, polyalkenes, phenolic resins, natural and synthetic elastomers, adhesives and sealants, polyolefins, polysulfones, polyacrylonitrile, polysaccharides, and combinations thereof.
3. The composition of claim 2 , wherein the polymer is polyurethane or polycarbonate-based polyurethanes.
4. The composition of claim 2 wherein the complementary reactive functional groups are epoxy-amine, isocyanate-carboxyl, glycidyl-anhydride, amine-anhydride, silanol-silanol, isocyanate-amine, carboxyl-amine, or hydroxyl-carboxyl.
5. The composition of claim 1 , wherein the complementary reactive functional groups are epoxy-amine, isocyanate-carboxyl, glycidyl-anhydride, amine-anhydride, silanol-silanol, isocyanate-amine, carboxyl-amine, or hydroxyl-carboxyl.
6. The composition of claim 5 , wherein the polymeric undercoat comprises a homopolymer or copolymer formed by condensation or radical polymerization of one or more monomers selected from the group consisting of acrylates, acrylamides, vinyl compounds, di, tri-, and tetra-isocyanates, alcohols, amines, thiocyanates, lactones, lactams, and combinations thereof.
7. The composition of claim 6 , wherein the polymeric undercoat comprises a homopolymer or copolymer formed by condensation or radical polymerization of one or more acrylate monomers.
8. The composition of claim 7 , wherein the polymeric undercoat comprises a copolymer of glycidyl methacrylate (GMA), 2-hydroxypropyl methacrylate (HPMA), lauryl methacrylate (LMA), and trimethoxysilyl methacrylate (TMOSMA).
9. The composition of claim 1 , wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are phosphorylcholine, sulfobetaine or carboxybetaine zwitterionic moieties.
10. The composition of claim 1 , wherein the non-fouling polymeric topcoat copolymer further comprises one or more polymerized monomers selected from the group consisting of acrylates, acrylamides, vinyl compounds, di, tri-, and tetra-isocyanates, alcohols, amines, thiocyanates, lactones, lactams, and combinations thereof.
11. The composition of claim 10 , wherein the non-fouling polymeric topcoat copolymer comprises 25-70 mol % sulfobetaine methacrylate, 10-50 mol % glycidyl methacrylate methacrylate, and 0-50 mol % 2-hydroxypropyl methacrylate.
12. The composition of claim 1 , wherein the non-fouling polymeric topcoat copolymer is grafted to the polymeric undercoat through a tether.
13. The composition of claim 12 , wherein the tether is part of the non-fouling polymeric topcoat copolymer.
14. The composition of claim 12 , wherein the tether is a moiety immobilized on the polymeric undercoat.
15. The composition of claim 1 , wherein the non-fouling polymeric topcoat copolymer is in the form of a brush or a comb.
16. The composition of claim 1 , wherein the non-fouling polymeric topcoat copolymer, the polymeric undercoat, the functionalized substrate, or combinations thereof have immobilized thereon one or more bioactive agents.
17. The composition of claim 13 , wherein the one or more bioactive agents are immobilized covalently or non-covalently on the non-fouling topcoat copolymer, the polymeric undercoat, the functionalized substrate, or combinations thereof.
18. The composition of claim 17 , wherein the one or more bioactive agents are immobilized to the non-fouling topcoat copolymer, the polymeric undercoat, the functionalized substrate, or combinations thereof, through a tether.
19. The composition of claim 1 , wherein the composition reduces fouling by greater than 80% after storage in phosphate buffered saline (PBS) containing protein, media, or serum at 37° C. for a period of at least 7 days compared to uncoated substrate.
20. The composition of claim 1 , wherein the composition is biocompatible.
21. The composition of claim 1 , wherein the composition is antimicrobial.
22. The composition of claim 1 , wherein the composition is anti-thrombogenic.
23. The composition of claim 1 wherein the composition retains greater than 80% of its original anti-thrombogenic activity, in PBS containing serum for a time of 30 days.
24. The composition of claim 1 , wherein the medical device is a vascularly inserted catheter selected from the group consisting of a peripherally inserted central catheter (PICC), central venous catheter (CVC), and hemodialysis catheter.
25. The composition of claim 1 , wherein the tensile strength, modulus, device dimensions, or combinations thereof are within 20% of the tensile strength, modulus, device dimensions, or combinations thereof of the uncoated substrate.
26. A method of making a composition in the form of a medical device containing lumens, cavities, porous structures, or combinations thereof, the method comprising immobilizing a polymeric undercoat having reactive functional groups on the medical device and grafting a non-fouling polymeric topcoat copolymer to the immobilized polymeric undercoat, the non-fouling polymeric topcoat copolymer having reactive functional groups, the undercoat reactive functional groups and the non-fouling polymeric topcoat copolymer reactive functional groups being complementary wherein the non-fouling polymeric topcoat copolymer is covalently bound to the polymeric undercoat via covalent bond formation between the complementary reactive functional groups and more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are polyether moieties or phosphorylcholine, sulfobetaine or carboxybetaine zwitterionic moieties.
27. The method of claim 26 , wherein the non-fouling polymeric topcoat copolymer is grafted to the immobilized undercoat using one or more polymerized monomers having unsaturated bonds.
28. The method of claim 26 wherein the medical device is a vascularly inserted catheter selected from the group consisting of a peripherally inserted central catheter (PICC), central venous catheter (CVC), and hemodialysis catheter.
29. The method of claim 26 wherein the substrate comprises a polymer and the polymer is selected from the group consisting of polystyrene and substituted polystyrenes, poly(urethane)s, polyacrylates and polymethacrylates, polyacrylamides and polymethacrylamides, polyesters, polysiloxanes, polyethers, poly(orthoester), poly(carbonates), poly(hydroxyalkanoate)s, polyfluorocarbons, silicones, epoxy resins, polyamides and copolymers thereof, nylon, polyalkenes, phenolic resins, natural and synthetic elastomers, adhesives and sealants, polyolefins, polysulfones, polyacrylonitrile, polysaccharides, and combinations thereof.
30. The method of claim 26 wherein the substrate comprises a polymer and the polymer is polyurethane or a polycarbonate-based polyurethane.
31. The method of claim 26 wherein the complementary reactive functional groups are epoxy-amine, isocyanate-carboxyl, glycidyl-anhydride, amine-anhydride, silanol-silanol, isocyanate-amine, carboxyl-amine, or hydroxyl-carboxyl.
32. The method of claim 26 wherein the polymeric undercoat comprises a homopolymer or copolymer formed by condensation or radical polymerization of one or more acrylate monomers.
33. The method of claim 26 wherein the non-fouling polymeric topcoat copolymer is a random copolymer or a block copolymer.
34. The method of claim 26 wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are polyether moieties.
35. The method of claim 26 wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are a phosphorylcholine, sulfobetaine, or carboxybetaine zwitterionic moiety.
36. The method of claim 26 wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are a sulfobetaine or carboxybetaine zwitterionic moiety.
37. The composition of claim 1 wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are a phosphorylcholine, sulfobetaine, or carboxybetaine zwitterionic moiety.
38. The composition of claim 37 wherein more than 35 mole % of the polymerized monomers comprised by the non-fouling polymeric topcoat copolymer are a sulfobetaine or carboxybetaine zwitterionic moiety.