Biosensor membranes composed of polymers containing heterocyclic nitrogens
View Patent ↗Novel membranes comprising various polymers containing heterocyclic nitrogen groups are described. These membranes are usefully employed in electrochemical sensors, such as amperometric biosensors. More particularly, these membranes effectively regulate a flux of analyte to a measurement electrode in an electrochemical sensor, thereby improving the functioning of the electrochemical sensor over a significant range of analyte concentrations. Electrochemical sensors equipped with such membranes are also described.
1. A membrane for use in an electrochemical sensor, comprising:
a crosslinker; and
a polymer having the formula:
wherein the solid horizontal line represents a polymer backbone;
A is an alkyl substituted with a water-soluble constituent;
D is selected from a group consisting of phenylalkyl, alkoxystyrene, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, a poly(ethylene glycol)-containing constituent, and a polyhydroxyl-containing constituent; and
each of n, l, p and q is independently a positive number.
2. The membrane of claim 1 , wherein A is negatively charged.
3. The membrane of claim 1 , wherein A is selected from a group consisting of a sulfonate, a carboxylate, and a phosphate.
4. The membrane of claim 1 , wherein A is selected from a group consisting of sulfopropyl, sulfobutyl, carboxypropyl, and carboxypentyl.
5. The membrane of claim 1 , wherein A is of the formula L-G, where L is a C2-C12 linear or branched alkyl linker and G is a negatively charged carboxy or sulfonate.
6. The membrane of claim 5 , wherein L is substituted with an aryl, alkoxy, alkenyl, alkynyl, —F, —Cl, —OH, aldehyde, ketone, ester, or amide.
7. The membrane of claim 1 , wherein D is styrene or C1-C18 alkyl methacrylate.
8. The membrane of claim 1 , wherein the polymer has a formula selected from a group consisting of:
9. The membrane of claim 1 , wherein an average molecular weight of the polymer is above about 50,000.
10. The membrane of claim 1 , wherein an average molecular weight of the polymer is above about 200,000.
11. The membrane of claim 1 , wherein an average molecular weight of the polymer is above about 1,000,000.
12. The membrane of claim 1 , wherein the polymer further comprises a B-containing copolymer such that the polymer has the formula:
wherein B is a modifier and m is a positive number.
13. The membrane of claim 12 , wherein B is selected from a group consisting of a chelator, a negatively charged constituent, a hydrophobic hydrocarbon constituent, a hydrophilic hydroxyl or polyhydroxy constituent, a silicon polymer, and a poly(ethylene glycol).
14. The membrane of claim 12 , wherein B is a poly(ethylene glycol) having a molecular weight of from about 100 to about 20,000.
15. The membrane of claim 12 , wherein the polymer has a formula selected from a group consisting of:
16. The membrane of claim 12 , wherein [n/(n+m+l+p)]×100% is from about 1% to about 25%.
17. The membrane of claim 12 , wherein [m/(n+m+l+p)]×100% is from about 1% to about 15%.
18. The membrane of claim 12 , wherein [l/(n+m+l+p)]×100% is from about 20% to about 90%.
19. The membrane of claim 12 , wherein [p/(n+m+l+p)]×100% is from about 1% to about 50%.
20. The membrane of claim 1 or 12 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of pyridine, imidazole, oxazole, thiazole, pyrazole, and any derivative thereof.
21. The membrane of claim 1 or 12 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, 2-vinylimidazole, and 4-vinylimidazole.
22. The membrane of claim 1 or 12 sufficient to limit a flux of glucose or lactate thereacross.
23. The membrane of claim 1 or 12 sufficient to limit a flux of glucose or lactate thereacross in vivo.
24. The membrane of claim 1 or 12 , wherein the crosslinker comprises at least one epoxide reactive group.
25. The membrane of claim 1 or 12 , wherein the crosslinker has a molecular weight of from about 200 to about 2000.
26. The membrane of claim 1 or 12 , wherein the crosslinker is a derivative of poly(ethylene glycol) or poly(propylene glycol).
27. The membrane of claim 1 or 12 , wherein a weight ratio of the polymer to the crosslinker is from about 4:1 to about 32:1.
28. The membrane of claim 1 or 12 , wherein a weight ratio of the polymer to the crosslinker is from about 8:1 to about 16:1.
29. The membrane of claim 1 , further comprising a layer of poly(ethylene glycol).
30. An electrochemical sensor, comprising:
a working electrode comprising:
a sensing layer in contact with a conductive material of the electrode;
a membrane disposed over the sensing layer, the membrane comprising a crosslinker and a polymer having the formula:
wherein the solid horizontal line represents a polymer backbone;
A is an alkyl substituted with a water-soluble constituent;
D is selected from a group consisting of phenylalkyl, alkoxystyrene, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, a poly(ethylene glycol)containing constituent, and a polyhydroxyl-containing constituent; and
each of n, l, p and q is independently a positive number; and
a counter electrode in electrochemical communication with the working electrode.
31. The electrochemical sensor of claim 30 , wherein A is negatively charged.
32. The electrochemical sensor of claim 30 , wherein A is selected from a group consisting of a sulfonate, a carboxylate, and a phosphate.
33. The electrochemical sensor of claim 30 , wherein A is selected from a group consisting of sulfopropyl, sulfobutyl, carboxypropyl, and carboxypentyl.
34. The electrochemical sensor of claim 30 , wherein A is of the formula L-G, where L is a C2-C12 linear or branched alkyl linker and G is a negatively charged carboxy or sulfonate.
35. The electrochemical sensor of claim 34 , wherein L is substituted with an aryl, alkoxy, alkenyl, alkynyl, —F, —Cl, —OH, aldehyde, ketone, ester, or amide.
36. The electrochemical sensor of claim 30 , wherein D is styrene or C1-C18 alkyl methacrylate.
37. The electrochemical sensor of claim 30 , wherein the polymer has a formula selected from a group consisting of:
38. The electrochemical sensor of claim 30 , wherein an average molecular weight of the polymer is above about 50,000.
39. The electrochemical sensor of claim 30 , wherein an average molecular weight of the polymer is above about 200,000.
40. The electrochemical sensor of claim 30 , wherein an average molecular weight of the polymer is above about 1,000,000.
41. The electrochemical sensor of claim 30 , wherein the polymer further comprises a B-containing copolymer such that the polymer has the formula:
wherein B is a modifier and m is a positive number.
42. The electrochemical sensor of claim 41 , wherein B is selected from a group consisting of a chelator, a negatively charged constituent, a hydrophobic hydrocarbon consitituent, a hydrophilic hydroxyl or polyhydroxy constituent, a silicon polymer, and a poly(ethylene glycol).
43. The electrochemical sensor of claim 41 , wherein B is a poly(ethylene glycol) having a molecular weight of from about 100 to about 20,000.
44. The electrochemical sensor of claim 41 , wherein the polymer has a formula selected from a group consisting of:
45. The electrochemical sensor of claim 41 , wherein [n/(n+m+l+p)]×100% is from about 1% to about 25%.
46. The electrochemical sensor of claim 41 , wherein [m/(n+m+l+p)]×100% is from about 1% to about 15%.
47. The electrochemical sensor of claim 41 , wherein [l/(n+m+l+p)]×100% is from about 20% to about 90%.
48. The electrochemical sensor of claim 41 , wherein [p/(n+m+l+p)]×100% is from about 1% to about 50%.
49. The electrochemical sensor of claim 30 or 41 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of pyridine, imidazole, oxazole, thiazole, pyrazole, and any derivative thereof.
50. The electrochemical sensor of claim 30 or 41 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, 2-vinylimidazole, and 4-vinylimidazole.
51. The electrochemical sensor of claim 30 or 41 , wherein the membrane is sufficient to limit a flux of glucose or lactate thereacross.
52. The electrochemical sensor of claim 30 or 41 , wherein the membrane is sufficient to limit a flux of glucose or lactate thereacross in vivo.
53. The electrochemical sensor of claim 30 or 41 , wherein the crosslinker comprises at least one epoxide reactive group.
54. The electrochemical sensor of claim 30 or 41 , wherein the crosslinker has a molecular weight of from about 200 to about 2000.
55. The electrochemical sensor of claim 30 or 41 , wherein the crosslinker is a derivative of poly(ethylene glycol) or poly(propylene glycol).
56. The electrochemical sensor of claim 30 or 41 , wherein a weight ratio of the polymer to the crosslinker is from about 4:1 to about 32:1.
57. The electrochemical sensor of claim 30 or 41 , wherein a weight ratio of the polymer to the crosslinker is from about 8:1 to about 16:1.
58. The electrochemical sensor of claim 30 , wherein the membrane further comprises a layer of poly(ethylene glycol).
59. The electrochemical sensor of claim 30 , wherein the sensing layer comprises an enzyme, an enzyme stabilizer, and a crosslinker.
60. The electrochemical sensor of claim 30 , wherein the sensing layer comprises an enzyme, a polymeric mediator, and a crosslinker.
61. A membrane for use in an electrochemical sensor, comprising:
a crosslinker; and
a polymer having the formula:
wherein the solid horizontal line represents a polymer backbone;
A is a strong acid; and
each of n, l and q is independently a positive number.
62. The membrane of claim 61 , wherein A is such that the heterocyclic nitrogen to which it is attached is zwitterionic.
63. The membrane of claim 61 , wherein A is a stronger acid than carboxylic acid.
64. The membrane of claim 61 , wherein the polymer further comprises a B-containing copolymer such that the polymer has the formula:
wherein B is a modifier and m is a positive number.
65. The membrane of claim 64 , wherein B is selected from a group consisting of a chelator, a negatively charged constituent, a hydrophobic hydrocarbon constituent, a hydrophilic hydroxyl or polyhydroxy constituent, a silicon polymer, and a poly(ethylene glycol).
66. The membrane of claim 61 or 64 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, 2-vinylimidazole, and 4-vinylimidazole.
67. The membrane of claim 61 or 64 sufficient to limit a flux of glucose or lactate thereacross.
68. The membrane of claim 61 or 64 sufficient to limit a flux of glucose or lactate thereacross in vivo.
69. The membrane of claim 61 or 64 , wherein the crosslinker comprises at least one epoxide reactive group.
70. The membrane of claim 61 or 64 , wherein the crosslinker has a molecular weight of from about 200 to about 2000.
71. The membrane of claim 61 or 64 , wherein the crosslinker is a derivative of poly(ethylene glycol) or poly(propylene glycol).
72. The membrane of claim 61 or 64 , wherein a weight ratio of the polymer to the crosslinker is from about 4:1 to about 32:1.
73. The membrane of claim 61 or 64 , wherein a weight ratio of the polymer to the crosslinker is from about 8:1 to about 16:1.
74. The membrane of claim 61 , wherein A is negatively charged.
75. The membrane of claim 61 , wherein A is an alkyl group substituted with a water soluble constituent.
76. The membrane of claim 61 , wherein A comprises a carboxy or sulfonate group.
77. The membrane of claim 61 , wherein A is selected from a group consisting of sulfopropyl, sulfobutyl, carboxypropyl, and carboxypentyl.
78. An electrochemical sensor, comprising:
a working electrode comprising:
a sensing layer in contact with a conductive material of the electrode;
a membrane disposed over the sensing layer, the membrane comprising a crosslinker and a polymer having the formula:
wherein the solid horizontal line represents a polymer backbone;
A is a strong acid and is negatively charged; and
each of n, l and q is independently a positive number; and
a counter electrode in electrochemical communication with the working electrode.
79. The electrochemical sensor of claim 78 , wherein A is such that the heterocyclic nitrogen to which it is attached is zwitterionic.
80. The electrochemical sensor of claim 78 , wherein A is a stronger acid than carboxylic acid.
81. The electrochemical sensor of claim 78 , wherein the polymer further comprises a B-containing copolymer such that the polymer has the formula:
wherein B is a modifier and m is a positive number.
82. The electrochemical sensor of claim 81 , wherein B is selected from a group consisting of a chelator, a negatively charged constituent, a hydrophobic hydrocarbon constituent, a hydrophilic hydroxyl or polyhydroxy constituent, a silicon polymer, and a poly(ethylene glycol).
83. The electrochemical sensor of claim 78 or 81 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of pyridine, imidazole, oxazole, thiazole, pyrazole, and any derivative thereof.
84. The electrochemical sensor of claim 78 or 81 , wherein at least one heterocyclic nitrogen constituent of the polymer is independently selected from a group consisting of 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 1-vinylimidazole, 2-vinylimidazole, and 4-vinylimidazole.
85. The electrochemical sensor of claim 78 or 81 sufficient to limit a flux of glucose or lactate thereacross.
86. The electrochemical sensor of claim 78 or 81 sufficient to limit a flux of glucose or lactose thereacross in vivo.
87. The electrochemical sensor of claim 78 or 81 , wherein the crosslinker comprises at least one epoxide reactive group.
88. The electrochemical sensor of claim 78 or 81 , wherein the crosslinker has a molecular weight of from about 200 to about 2000.
89. The electrochemical sensor of claim 78 or 81 , wherein the crosslinker is a derivative of poly(ethylene glycol) or poly(propylene glycol).
90. The electrochemical sensor of claim 78 or 81 , wherein a weight ratio of the polymer to the crosslinker is from about 4:1 to about 32:1.
91. The electrochemical sensor of claim 78 or 81 , wherein a weight ratio of the polymer to the crosslinker is from about 8:1 to about 16:1.
92. The electrochemical sensor of claim 78 , wherein the sensing layer comprises an enzyme, an enzyme stabilizer, and a crosslinker.
93. The electrochemical sensor of claim 78 , wherein the sensing layer comprises an enzyme, a polymeric mediator, and a crosslinker.
94. The electrochemical sensor of claim 78 , wherein A is negatively charged.
95. The electrochemical sensor of claim 78 , wherein A is an alkyl group substituted with a water soluble constituent.
96. The electrochemical sensor of claim 78 , wherein A comprises a carboxy or sulfonate group.
97. The electrochemical sensor of claim 78 , wherein A is selected from a group consisting of sulfopropyl, sulfobutyl, carboxypropyl, and carboxypentyl.