Diffusion layer for an enzymatic in vivo sensor

Patent metadata

Field	Value
Publication number	US-10422765-B2
Application number	US-201314027493-A
Country	US
Kind code	B2
Filing date	Sep 16, 2013
Priority date	Mar 28, 2011
Publication date	Sep 24, 2019
Grant date	Sep 24, 2019

Abstract

Electrode systems are disclosed for measuring the concentration of an analyte under in vivo conditions, where the systems includes an electrode with immobilized enzyme molecules and an improved diffusion barrier that controls diffusion of the analyte from body fluid surrounding the electrode system to the enzyme molecules. Methods of making and using the system also are disclosed.

First claim

The invention claimed is:

1. An electrode system for measuring the concentration of an analyte under in vivo conditions, the system comprising:
an electrode with immobilized enzyme molecules; and
a diffusion barrier that controls diffusion of the analyte from an exterior of the electrode system to the immobilized enzyme molecules, wherein the diffusion barrier comprises a block copolymer having at least one hydrophilic block and at least one hydrophobic block, wherein the at least one hydrophilic block is made from hydrophilic monomeric units selected from the group consisting of hydrophilic (meth)acrylesters with a polar —OH, —OCH 3 or —OC 2 H 2 group, hydrophilic (meth)acrylamides, (meth)acrylic acid, and combinations thereof, wherein the at least one hydrophilic block and the at least one hydrophobic block are covalently linked to one another, and wherein the at least one hydrophobic block has a glass transition temperature between 40° C. and 100° C.

2. The electrode system of claim 1 , wherein:
(i) the at least one hydrophilic block of the block copolymer has a length selected from the group consisting of from about 50 to about 200 monomeric units, from about 150 to about 300 monomeric units, from about 100 to about 150 monomeric units, and from about 200 to about 250 monomeric units; and/or
(ii) the at least one hydrophobic block of the block copolymer has a length selected from the group consisting of from about 50 to about 200 monomeric units, from about 150 to about 250 monomeric units, from about 80 to about 150 monomeric units, and from about 170 to about 200 monomeric units.

3. The electrode system of claim 1 , wherein (i) if the hydrophilic monomeric units for the at least one hydrophilic block are hydrophilic (meth)acrylesters with a polar —OH, —OCH 3 or —OC 2 H 2 group, they are selected from the group consisting of 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate (HEMA), 2-methoxyethyl acrylate, 2-methoxyethyl methacrylate, 2-ethoxyethyl acrylate, 2-ethoxyethyl methacrylate, 2- or 3-hydroxypropyl acrylate, 2- or 3-hydroxypropyl methacrylate (2- or 3-HPMA), 2- or 3-methoxypropyl acrylate, 2- or 3-methoxypropyl methacrylate, 2- or 3-ethoxypropyl acrylate, 2- or 3-ethoxypropyl methacrylate, 1- or 2-glycerol acrylate, 1- or 2-glycerol methacrylate, (ii) if the hydrophilic monomeric units for the at least one hydrophilic block are hydrophilic (meth)acrylamides, then they are selected from the group consisting of acrylamide, methacrylamide, an N-alkyl- or N,N-dialkyl acrylamide, and an N-alkyl- or N,N-dialkyl methylamide wherein the alkyl comprises 1-3 C-atoms, (iii) if the hydrophilic monomeric units for the at least one hydrophilic block are (meth)acrylic acid, they are selected from the group consisting of acrylic acid, methacrylic acid, and (iv) combinations of (i) to (iii).

4. The electrode system of claim 1 , wherein the at least one hydrophilic block comprises at least two different hydrophilic monomeric units, wherein at least one of the hydrophilic monomeric units is a non-ionic hydrophilic monomeric unit and at least one of the hydrophilic monomeric units is an ionic hydrophilic monomeric unit, and wherein the ionic hydrophilic monomeric unit is present in a molar amount of from about 1 mol-% to about 20 mol-%.

5. The electrode system of claim 1 , wherein the at least one hydrophobic block is made from monomeric units selected from the group consisting of hydrophobic (meth)acrylesters, styrene-based monomers, and combinations thereof.

6. The electrode system of claim 5 , wherein if the hydrophobic monomeric units for the at least one hydrophobic block are (meth)acrylesters, they are selected from the group consisting of methyl acrylate, methyl methacrylate (MMA), ethyl acrylate, ethyl methacrylate (EMA), n- or i-propyl acrylate, n- or i-propyl methacrylate, n-butyl acrylate, n-butyl methacrylate (BUMA), neopentyl acrylate, neopentyl methacrylate, and combinations thereof.

7. The electrode system of claim 1 , wherein the at least one hydrophobic block comprises at least two different hydrophobic monomeric units.

8. The electrode system of claim 7 , wherein the at least one hydrophobic block has a glass transition temperature of about 40° C. to about 80° C.

9. The electrode system of claim 1 , wherein the molar ratio of hydrophilic block:hydrophobic block is in a range selected from the group consisting of about 75% (hydrophilic):25% (hydrophobic) to about 25% (hydrophilic):75% (hydrophobic), from about 65% (hydrophilic):35% (hydrophobic) to about 35% (hydrophilic):65% (hydrophobic), and from about 60% (hydrophilic):40% (hydrophobic) to about 40% (hydrophilic):60% (hydrophobic).

10. The electrode system of claim 1 further comprising:
a counter electrode having an electrical conductor; and
a working electrode having an electric conductor on which the immobilized enzyme molecules and the diffusion barrier are arranged.

11. The electrode system of claim 10 , wherein the immobilized enzyme molecules are present in the form of multiple fields arranged on the conductor of the working electrode at a distance from each other.

12. The electrode system of claim 1 , wherein the diffusion barrier forms a layer covering an enzyme layer with a thickness selected from the group consisting of about 2 μm to about 20 μm, of about 5 μm to about 20 μm, and of about 10 μm to about 15 μm.

13. The electrode system of claim 1 , wherein an enzyme layer and the diffusion barrier are covered by a spacer, and wherein the spacer is a copolymer of (meth)acrylates comprising more than 50 mol-% hydrophilic monomeric units.

14. The electrode system of claim 1 , wherein the diffusion barrier comprises only one block copolymer.

15. The electrode system of claim 1 , wherein the diffusion barrier further comprises a plasticizer.

16. The electrode system of claim 1 , wherein the diffusion barrier has an effective diffusion coefficient (D eff ) for glucose selected from the group consisting of ≥10 −10 cm 2 /s, ≥5·10 −10 cm 2 /s, and ≥10 −9 cm 2 /s.

17. An insertable or implantable sensor configured for measuring glucose, the sensor comprising:
a flexible and biocompatible substrate;
the electrode system of claim 1 applied on the substrate;
a potentiostat applied on the substrate and in electrical communication with the electrode system; and
an amplifier applied on the substrate and in electrical communication with the electrode system for amplifying measuring signals of the electrode system,
wherein the immobilized enzyme molecules are glucose oxidase or glucose dehydrogenase.

18. A method of making a diffusion barrier for an enzymatic electrode, the method comprising the steps of:
providing a solution of block copolymer in a solvent or a solvent mixture to a prefabricated electrode system having the enzymatic electrode, wherein the block copolymer comprises at least one hydrophilic block and at least one hydrophobic block covalently linked to one another as the block copolymer, and wherein the at least one hydrophilic block is made from hydrophilic monomeric units selected from the group consisting of hydrophilic (meth)acrylesters with a polar —OH, —OCH 3 or —OC 2 H 2 group, hydrophilic (meth)acrylamides, (meth)acrylic acid, and combinations thereof; and
drying the solution into the diffusion barrier for the enzymatic electrode, wherein the at least one hydrophobic block has a glass transition temperature between 40° C. and 100° C.

19. The method of claim 18 , wherein:
(i) the at least one hydrophilic block of the block copolymer has a len

Assignees

• Roche Diabetes Care Inc

Inventors

• Staib Arnulf
• Thiele Marcel
• Koelker Karl-Heinz
• Rieger Ewald

Classifications

• C12Q1/006

  for glucose · CPC title

• C12Q1/002 Primary

  Electrode membranes · CPC title

• A61B5/14532

  for measuring glucose, e.g. by tissue impedance measurement · CPC title

• A61B5/14865

  invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors · CPC title

• A61B5/1486

  using enzyme electrodes, e.g. with immobilised oxidase · CPC title