Catalytic reactive oxygen species scavenger hydrogel
A medical device (e.g., an analyte sensor) that may be implanted within a living animal (e.g., a human) and may be used to measure an analyte (e.g., glucose or oxygen) in a medium (e.g., interstitial fluid, blood, or intraperitoneal fluid) within the animal. The medical device may include a polymer covering at least a portion of a surface of the medical device and a plurality of reactive oxygen species (ROS) scavenger molecules covalently linked to the polymer (e.g., to reduce degradation of an analyte indicator including the polymer).
1 . A sensor for measurement of an analyte in a medium within a living animal comprising:
a sensor housing;
an analyte indicator covering at least a portion of the sensor housing, and the analyte indicator comprises a polymer; and
a plurality of reactive oxygen species (ROS) scavenger molecules covalently linked to the polymer, wherein the ROS scavenger molecules comprise
or a combination thereof.
2 . The sensor of claim 1 , wherein each of the plurality of reactive oxygen species (ROS) scavenger molecules is covalently linked to the polymer via a monomer spacer molecule attached to the polymer.
3 . The sensor of claim 2 , wherein the polymer has a backbone, and the monomer spacer is covalently linked to the backbone of the polymer.
4 . The sensor of claim 3 , wherein the polymer comprises co-monomers of at least monomers according to Formula Ia: ABC [Formula Ia],
wherein A is an analyte indicator monomer, B is a acrylate, methacrylate, acrylamide, or methacrylamide monomer, C is a polyethylene glycol monomer, wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, and C is 1 to 99% by weight of Formula Ia.
5 . The sensor of claim 3 , wherein the polymer comprises co-monomers of four monomers according to Formula Ia: ABCD [Formula Ia],
wherein A is an analyte indicator monomer, B is a acrylate, methacrylate, acrylamide, or methacrylamide monomer, C is a polyethylene glycol monomer, D is a compound or a monomer containing boronate or boronic acid moieties, wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight of Formula Ia.
6 . The sensor of claim 5 , wherein the compound or the monomer containing boronate or boronic acid moieties is selected from the group consisting of: a compound of formula II:
R—B(OH) 2 [Formula II], wherein R in Formula II is a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 , wherein R 1 and R 2 are identical or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, wherein Formula II optionally comprises spacer or linker between R and B,
a phenylboronic acid compound
wherein one or more R in the phenylboronic acid compound is independently a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, optionally comprising a spacer or linker between R and B,
a boronate compound of Formula III:
wherein R in Formula III is independently a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, and wherein X and Y=alkyl, wherein Formula III optionally comprises spacer or linker between R and B, and
a combination thereof.
7 . The sensor of claim 6 , wherein the spacer or linker between R and B is a C 1 -C 20 linear or branched alkyl or alkoxy.
8 . The sensor of claim 5 , wherein the compound containing boronate or boronic acid moieties is selected from the group consisting of: 2-acrylamidophenylboronic acid, 3-(Acrylamido)phenylboronic acid, 4-vinylboronic acid containing moieties, and (3-methacrylamidophenyl)boronic acid.
9 . The sensor of claim 3 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group.
10 . The sensor of claim 9 , wherein the poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group is covalently linked to an acrylate, methacrylate, acrylamide, or methacrylamide group of the polymer.
11 . The sensor of claim 3 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a flexible spacer having a repeating group selected from the group consisting of:
and a combination thereof, wherein R 1 is a reactive group and wherein n is 1 to 1000.
12 . The sensor of claim 11 , wherein the reactive group is
wherein R is the repeating group.
13 . The sensor of claim 1 , wherein the ROS scavenger molecules further comprise a reactive group attached thereto, wherein the reactive group is a primary amine, a thiol, or an alkyne group.
14 . The medical device sensor of claim 2 , wherein the plurality of ROS scavenger molecules are covalently linked to the monomer spacer molecule via a coupling bond selected from an amide bond, a carbon-thiol bond, a malamide-thiol bond, or a triazole bond.
15 . The sensor of claim 14 , wherein the coupling bond is formed between a reactive group RG 1 of the monomer spacer molecule and a reactive group RG 2 of the ROS scavenger molecules and is selected from the group consisting of:
Resulting
RG 1
RG 2
Bond
a)
H 2 N—R
Acid
Primary Amine
Amide
b)
Double
Thiol
Carbon-Thiol
Carbon Bond
c)
Maleimide
Thiol
Malamide-
Thiol
d)
Azide
Alkyne
Triazole.
16 . The sensor of claim 1 , wherein the ROS scavenger molecules reduce a degradation rate of the analyte indicator comprising the polymer.
17 . The sensor of claim 1 , wherein the sensor comprises at least one drug eluting polymer matrix that covers a portion of the sensor housing.
18 . A method of fabricating a sensor for measurement of an analyte in a medium within a living animal, the method comprising:
applying an analyte indicator to a sensor housing of the sensor such that the applied analyte indicator covers at least a portion of the sensor housing, wherein the analyte indicator comprises a polymer; and
coupling a plurality of reactive oxygen species (ROS) scavenger molecules covalently to the polymer, wherein the ROS scavenger molecules comprise
or a combination thereof.
19 . The method of claim 18 , wherein the polymer comprises co-monomers of at least monomers of A) an analyte indicator monomer, B) at least one acrylate, methacrylate, acrylamide, or methacrylamide monomer having a monomer spacer and a reactive group at an end thereof, and C) a polyethylene glycol monomer.
20 . The method of claim 19 , wherein coupling the plurality of ROS scavenger molecules covalently to the polymer comprises coupling the plurality of ROS scavenger molecules covalently to the reactive group of the analyte indicator such that each of the plurality of ROS scavenger molecules is covalently linked to the analyte indicator via the monomer spacer.
21 . The method of claim 19 , wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, and C is 1 to 99% by weight of the polymer.
22 . The method of claim 19 , wherein the polymer comprises co-monomers of four monomers according to Formula Ia: ABCD [Formula Ia],
wherein A is the analyte indicator monomer, B is the at least one acrylate, methacrylate, acrylamide, or methacrylamide monomer having the monomer spacer and a reactive group at an end thereof, C is the polyethylene glycol monomer, and D is a compound or monomer containing boronate or boronic acid moieties, wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight of Formula Ia.
23 . The method of claim 22 , wherein the compound or monomer containing boronate or boronic acid moieties is selected from the group consisting of: a compound of formula II:
R—B(OH) 2 [Formula II], wherein R in Formula II is a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 , wherein R 1 and R 2 are identical or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, wherein Formula II optionally comprises a spacer or linker between R and B,
a phenylboronic acid compound
wherein one or more R in the phenylboronic acid compound is independently a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, optionally comprising a spacer or linker between R and B,
a boronate compound of Formula III:
wherein R in Formula III is a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, and wherein X and Y=alkyl, wherein Formula III optionally comprises spacer or linker between R and B, and
a combination thereof.
24 . The method of claim 23 , wherein the spacer or linker between R and B is a C 1 -C 20 linear or branched alkyl or alkoxy.
25 . The method of claim 23 , wherein the compound containing boronate or boronic acid moieties is selected from the group consisting of: 2-acrylamidophenylboronic acid, 3-(Acrylamido)phenylboronic acid, 4-vinylboronic acid containing moieties, (3-methacrylamidophenyl)boronic acid, and a combination thereof.
26 . The method of claim 23 , wherein the compound containing boronate or boronic acid moieties is provided at a molar ratio of 0.1 to 100 to analyte indicator monomer.
27 . The method of claim 20 , wherein the polymer has a backbone, and the monomer spacer is covalently linked to the backbone of the polymer.
28 . The method of claim 27 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group.
29 . The method of claim 28 , wherein the poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group is covalently linked to an acrylate, methacrylate, acrylamide, or methacrylamide group of the analyte indicator.
30 . The method of claim 27 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a flexible spacer having a repeating group selected from the group consisting of:
and a combination thereof, wherein R 1 is a reactive group and wherein n is 1 to 1000.
31 . The method of claim 30 , wherein the reactive group is
wherein R is the repeating group.
32 . The method of claim 18 , wherein the ROS scavenger molecules further comprise a reactive group attached thereto, wherein the reactive group is a primary amine, a thiol, or an alkyne group.
33 . The method of claim 20 , wherein the plurality of ROS scavenger molecules are covalently linked to the monomer spacer molecule via a coupling bond, wherein the coupling bond is an amide bond, a carbon-thiol bond, a malamide-thiol bond, or a triazole bond.
34 . The method of claim 33 , wherein the coupling bond is formed between a reactive group RG 1 of the monomer spacer molecule and a reactive group RG 2 of the ROS scavenger molecules selected from the group consisting of:
Resulting
RG 1
RG 2
Bond
a)
H 2 N—R
Acid
Primary Amine
Amide
b)
Double
Thiol
Carbon-Thiol
Carbon Bond
c)
Maleimide
Thiol
Malamide-
Thiol
d)
Azide
Alkyne
Triazole.
35 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
36 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
37 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
38 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises,
39 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
40 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
41 . The sensor of claim 1 , wherein the ROS scavenger molecules comprises
42 . The method of claim 18 , wherein the ROS scavenger molecules comprises
43 . The method of claim 18 , wherein the ROS scavenger molecules comprises
44 . The method of claim 18 , wherein the ROS scavenger molecules comprises
45 . The method of claim 18 , wherein the ROS scavenger molecules comprises,
46 . The method of claim 18 , wherein the ROS scavenger molecules comprises
47 . The method of claim 18 , wherein the ROS scavenger molecules comprises
48 . The method of claim 18 , wherein the ROS scavenger molecules comprises
49 . A sensor for measurement of an analyte in a medium within a living animal comprising:
a sensor housing;
an analyte indicator covering at least a portion of the sensor housing, wherein the analyte indicator comprises a polymer; and
a plurality of reactive oxygen species (ROS) scavenger molecules covalently linked to the polymer via a monomer spacer molecule attached to the polymer, wherein the plurality of ROS scavenger molecules are covalently linked to the monomer spacer molecule via a coupling bond, wherein the coupling bond is an amide bond, a carbon-thiol bond, a malamide-thiol bond, or a triazole bond.
50 . The sensor of claim 49 , wherein the polymer has a backbone, and the monomer spacer is covalently linked to the backbone of the polymer.
51 . The sensor of claim 50 , wherein the polymer comprises co-monomers of at least monomers according to Formula Ia: ABC [Formula Ia],
wherein A is an analyte indicator monomer, B is a acrylate, methacrylate, acrylamide, or methacrylamide monomer, C is a polyethylene glycol monomer, wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, and C is 1 to 99% by weight of Formula Ia.
52 . The sensor of claim 50 , wherein the polymer comprises co-monomers of four monomers according to Formula Ia: ABCD [Formula Ia],
wherein A is an analyte indicator monomer, B is a acrylate, methacrylate, acrylamide, or methacrylamide monomer, C is a polyethylene glycol monomer, D is a compound or a monomer containing boronate or boronic acid moieties, wherein A is 0.01 to 10% by weight, B is 1 to 99% by weight, C is 1 to 99% by weight, and D is 0.01 to 99% by weight of Formula Ia.
53 . The sensor of claim 52 , wherein the compound or the monomer containing boronate or boronic acid moieties is selected from the group consisting of: a compound of formula II:
R—B(OH) 2 [Formula II], wherein R in Formula II is a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 , wherein R 1 and R 2 are identical or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, wherein Formula II optionally comprises a spacer or linker between R and B,
a phenylboronic acid compound
wherein one or more R in the phenylboronic acid compound is independently a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, optionally comprising a spacer or linker between R and B,
a boronate compound of Formula III:
wherein R in Formula III is a hydrogen, hydroxyl, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, or NR 1 R 2 wherein R 1 and R 2 , identical or different, each represent a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an amino group, an aryl group, a heteroaryl, a cyclic group, a multicyclic group, a carboxylic acid, a vinyl group, an acrylate group, an acryloyl group, or a methacrylate group, and wherein X and Y=alkyl, wherein Formula III optionally comprises a spacer or linker between R and B, and
a combination thereof.
54 . The sensor of claim 53 , wherein the spacer or linker between R and B is a C 1 -C 20 linear or branched alkyl or alkoxy.
55 . The sensor of claim 52 , wherein the compound containing boronate or boronic acid moieties is selected from the group consisting of: 2-acrylamidophenylboronic acid, 3-(Acrylamido)phenylboronic acid, 4-vinylboronic acid containing moieties, (3-methacrylamidophenyl)boronic acid, and a combination thereof.
56 . The sensor of claim 50 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group.
57 . The sensor of claim 56 , wherein the poly(ethylene), poly(ethylene glycol), poly(vinyl alcohol), poly(pyrrolidone), poly(acrylamide), poly(acrylic acid), or poly(amine) group is covalently linked to an acrylate, methacrylate, acrylamide, or methacrylamide group of the polymer.
58 . The sensor of claim 50 , wherein the monomer spacer covalently linked to the backbone of the polymer comprises a flexible spacer having a repeating group selected from the group consisting of:
and a combination thereof, wherein R 1 is a reactive group and wherein n is 1 to 1000.
59 . The sensor of claim 58 , wherein the reactive group is
wherein R is the repeating group.
60 . The sensor of claim 49 , wherein the ROS scavenger molecules comprise
or a combination thereof.
61 . The sensor of claim 60 , wherein the ROS scavenger molecules further comprise a reactive group attached thereto, wherein the reactive group is a primary amine, a thiol, or an alkyne group.
62 . The sensor of claim 49 , wherein the coupling bond is formed between a reactive group RG 1 of the monomer spacer molecule and a reactive group RG 2 of the ROS scavenger molecules selected from the group consisting of:
Resulting
RG 1
RG 2
Bond
a)
H 2 N—R
Acid
Primary Amine
Amide
b)
Double
Thiol
Carbon-Thiol
Carbon Bond
c)
Maleimide
Thiol
Malamide-
Thiol
d)
Azide
Alkyne
Triazole.
63 . The sensor of claim 49 , wherein the sensor comprises at least one drug eluting polymer matrix that covers a portion of the sensor housing.