In-situ chemistry stack for continuous glucose sensors

• US 10,324,058 B2
• Filed: 04/28/2016
• Issued: 06/18/2019
• Est. Priority Date: 04/28/2016
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Inventors: Rao, Ashwin K., Pesantez, Daniel E.
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US15/141,446
• Publication Number:
  US 20170315077A1
• Time in Patent Office: 1,146 Days
• CPC Class Codes: A61B 2562/125 characterised by the manufacture of electrodes
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: C12Q 1/002 Electrode membranes
• CPC Class Codes: C12Q 1/003 Functionalisation
• CPC Class Codes: C12Q 1/006 for glucose
• CPC Class Codes: G01N 27/307 Disposable laminated or multilayered electrodes G01N27/3272 takes precedence
• CPC Class Codes: G01N 27/3272 Test elements therefor, i.e. disposable laminated substrates with electrodes, reagent and channels optical biosensors G01N33/52

Abstract

Embodiments of the invention provide an in-situ polymerization technique for creating a glucose sensor chemistry stack. An analyte sensor comprises a crosslinked polymer matrix in contact with an electrode. The crosslinked polymer matrix is formed by exposing ultraviolet (UV) light to a polymer matrix mixture comprising a plurality of hydroxyethyl methacrylate (HEMA) monomers, one or more di-acrylate crosslinkers, one or more UV photoinitiators, and an oxidoreductase. The oxidoreductase is covalently linked to the crosslinked polymer matrix. In typical embodiments, the oxidoreductase is a glucose oxidase-acrylate bioconjugate. In one or more embodiments, the analyte sensor apparatus further comprises a glucose limiting membrane positioned over the crosslinked polymer matrix. The glucose limiting membrane is formed by exposing ultraviolet (UV) light to a glucose limiting membrane mixture comprising a plurality of hydroxyethyl methacrylate (HEMA) monomers, one or more di-acrylate crosslinkers, one or more UV photoinitiators, ethylene glycol, and water.

Claims

1. An analyte sensor apparatus comprising:

a crosslinked polymer matrix disposed on a working electrode, wherein the crosslinked polymer matrix is formed in-situ on an electroactive surface of the working electrode by exposing a polymerization reaction mixture to ultraviolet (UV) light, wherein;

(a) the polymerization reaction mixture comprises;

a plurality of hydroxyethyl methacrylate (HEMA) monomers;

one or more di-acrylate crosslinkers;

one or more UV photoinitiators; and

glucose oxidase; and

(b) the polymerization reaction mixture is exposed to the (UV) light so that the glucose oxidase is covalently linked to the crosslinked polymer matrix,

the analyte sensor apparatus further comprising;

a glucose limiting membrane disposed over the crosslinked polymer matrix, wherein the glucose limiting membrane is formed in-situ over the crosslinked polymer matrix by exposing a membrane reaction mixture to ultraviolet (UV) light, wherein;

the membrane reaction mixture comprises;

a plurality of hydroxyethyl methacrylate (HEMA) monomers;

one or more di-acrylate crosslinkers;

one or more UV photoinitiators;

ethylene glycol; and

water.

2. The apparatus of claim 1, wherein the glucose oxidase comprises a glucose oxidase-acrylate bioconjugate.

3. The apparatus of claim 2, wherein the glucose oxidase-acrylate bioconjugate comprises 10-80 mol % of the crosslinked polymer matrix.

4. The apparatus of claim 2, wherein the glucose oxidase-acrylate bioconjugate is formed by reacting glucose oxidase with acryloyl-PEG-(N-hydroxy succinimide) in a respective mole ratio ranging from 1:

1 to 1;

10.

5. The apparatus of claim 4, wherein the glucose oxidase is reacted with acryloyl-PEG-(N-hydroxy succinimide) in a respective mole ratio of 1:

4.

6. The apparatus of claim 1, wherein the di-acrylate crosslinker comprises an ethylene glycol.

7. The apparatus of claim 1, wherein the UV photoinitiator is 2,2,-dimethoxy-2-phenylacetophenone (DMPA) or a phosphine blend.

8. The apparatus of claim 1, wherein the glucose limiting membrane comprises a polyethylene glycol (PEG)-methacrylate, a methyl methacrylate, a poly(2-hydroxyethyl methacrylate) (polyHEMA), and/or a methacryloyl phosphorylcholine (MPC).

9. A method of forming a working electrode in an analyte sensor apparatus, the method comprising:

(a) forming a monomer mixture on an electroactive surface of the electrode, the monomer mixture comprising;

a plurality of hydroxyethyl methacrylate (HEMA) monomers;

one or more di-acrylate crosslinkers;

one or more UV photoinitiators; and

glucose oxidase;

(b) polymerizing the monomer mixture with ultraviolet (UV) light so as to form a crosslinked polymer matrix on the electrode, wherein the glucose oxidase is covalently linked to the crosslinked polymer matrix;

(c) forming a glucose limiting membrane mixture over the crosslinked polymer matrix, the membrane mixture comprising;

a plurality of hydroxyethyl methacrylate (HEMA) monomers;

one or more di-acrylate crosslinkers;

one or more UV photoinitiators;

ethylene glycol; and

water; and

(d) polymerizing the glucose limiting membrane mixture with ultraviolet (UV) light to form a glucose limiting membrane.

10. The method of claim 9, wherein the membrane mixture is deposited over the crosslinked polymer matrix using a spin, slot or spray coating method.

11. The method of claim 9, wherein polymerizing the monomer mixture with ultraviolet (UV) light comprises masking an area of the deposited monomer mixture so as to prevent the monomer mixture from forming a crosslinked polymer matrix over a sensor substrate area.

12. The method of claim 9, wherein the glucose oxidase is a glucose oxidase-acrylate bioconjugate.

13. The method of claim 12, wherein the glucose oxidase-acrylate bioconjugate comprises 10-80 mol % of the crosslinked polymer matrix.

14. The method of claim 12, wherein the glucose oxidase-acrylate bioconjugate is formed by reacting glucose oxidase with acryloyl-PEG-(N-hydroxy succinimide) in a respective mole ratio ranging from 1:

1 to 1;

10.

15. The method of claim 14, wherein the glucose oxidase is reacted with acryloyl-PEG-(N-hydroxy succinimide) in a respective mole ratio of 1:

4.

16. The method of claim 9, wherein amounts of the di-acrylate crosslinker and amounts of HEMA monomers are selected so as to control the cross-link density of the crosslinked glucose limiting membrane, thereby controlling the glucose permeability of the glucose limiting membrane.

17. The method of claim 9, wherein the working electrode:

(a) comprises a plurality of layers that does not include an adhesion promoting layer;

(b) comprises a plurality of layers that does not include a separate layer consisting essentially of an albumin; and

/or

(c) comprises a crosslinked polymer matrix formed by a process that does not use glutaraldehyde.

18. The method of claim 9, wherein the glucose limiting membrane further comprises polyethylene glycol (PEG)-methacrylate, methyl methacrylate, poly(2-hydroxyethyl methacrylate) (polyHEMA), or methacryloyl phosphorylcholine (MPC).