Electrode with improved signal to noise ratio

Abstract

An electrode assembly for sensing an electrochemical signal diffused from a source to a working electrode which is comprised of a plurality of substantially separated working electrode surfaces is disclosed. The electrode of the invention is comprised of 1) a working electrode made up of a plurality of working electrode surfaces or components and 2) a electrically insulating gap defined by adjacent edges of 1) insulating the working electrode surfaces or components from each other. The working electrode components are configured to receive electrochemical signal from two or preferably three dimensions simultaneously. The working electrode components configured over the same surface as a single electrode provide (1) an improved signal to noise ratio as compared to a single electrode by reducing noise, and (2) provide an overall enhanced signal after sensing for a given period of time.

Description

FIELD OF THE INVENTION

The invention relates generally to the field of electrodes for electrochemical measurements, specifically electrodes used in the biomedical fields to measure concentrations of biomedically significant compounds.

BACKGROUND OF THE INVENTION

The amount of a chemical in a given volume of solution can be measured with an electrode. An electrode is the component in an electrochemical cell in contact with the electrolyte medium through which current can flow by electronic movement. Electrodes, which are essential components of both galvanic (current producing) and electrolytic (current using) cells, can be composed of a number of electrically conductive materials, e.g., lead, zinc, aluminum, copper, iron, nickel, mercury, graphite, gold, or platinum. Examples of electrodes are found in electric cells, wherein they are dipped in the electrolyte; in medical devices, where the electrode is used to detect electrical impulses emitted by the heart or the brain; and in semiconductor devices, where they perform one or more of the functions of emitting, collecting, or controlling the movement of electrons and ions.

The electrolyte can be any substance that provides ionic conductivity, and through which electrochemically active species can diffuse. Electrolytes can be solid, liquid, or semisolid (e.g., in the form of a gel). Common electrolytes include sulfuric acid and sodium chloride, which ionize in solution. Electrolytes used in the medical field must have a pH that is sufficiently close to that of the tissue in contact with the electrode (e.g., skin) so as not to cause harm to the tissue over time.

Electrochemically active species that are present in the electrolyte can undergo electrochemical reactions (oxidation or reduction) at the surface of the electrode. The rate at which the electrochemical reactions take place is related to the reactivity of the species, the electrode material, the electrical potential applied to the electrode, and the rate at which the electrochemically active species is transported to the electrode surface.

In unstirred electrolytes, such as quiescent liquid solutions and gel electrolytes, diffusion is the main process of transport of electrochemically active species to the electrode surface. The exact nature of the diffusion process is determined by the geometry of the electrode (e.g., planar disk, cylindrical, or spherical), and the geometry of the electrolyte (e.g., semiinfinite large volume, thin disk of gel, etc.) For example, diffusion of electrochemically active species to a spherical electrode in a semiinfinite volume of electrolyte differs from diffusion of electrochemically active species to a planar disk electrode. At the center of the disk electrode the diffusion of the electroactive species towards the electrode is in a substantially perpendicular direction, whereas at the edges of the disk electrode the diffusion comes from both perpendicular and radial directions. The combination of these two different diffusion patterns makes the total current collected at the disk electrode.

The present invention makes use of a unique geometry of the electrode surface such that the diffusion of the electrochemically active species in the radial and axial direction gives a total signal higher than if there was only diffusion in the axial direction, thus allowing the use of a decreased surface area of the electrode surface, particularly for the case of an electrolyte of finite volume.

SUMMARY OF THE INVENTION

An electrode assembly is disclosed that includes a multicomponent working electrode subassembly comprised of a plurality of substantially physically separated working electrode surfaces (e.g., a plurality of working electrode components). When surfaces of the working electrode subassembly are configured over an area that is equal to the area of a single piece working electrode, the multicomponent electrode will provide an improved signal to noise ratio due to reduced noise, and will provide an enhanced signal when measuring signal from a finite amount of medium over a finite amount of time. A working electrode of the invention provides a substantially discontinuous surface area in contact with a medium through which a compound will diffuse in response to a current. Noise created by the electrode material is reduced by reducing the surface area per individual working electrode surface, and the signal is enhanced by allowing diffusion to multiple working electrode surfaces via two and preferably three dimensions, e.g., (1) normal to the main surface plane, (2) normal to the length edge, and (3) normal to the width edge. By using a substantially discontinuous surface, a large number of edges are provided within the area being monitored. In the presence of edges, the flux for the species of interest is significantly higher (at the edge, due to radial diffusion) thus giving a higher overall flux over the area of interest that is greater than that if there was only diffusion directly perpendicular to the main surface plane of the electrode of interest.

The invention features an electrode subassembly comprised of interconnected electrode surfaces that form a working electrode, with each of the electrode components being separated from the others by an electrically insulating gap.

An object of the invention is to provide a working electrode comprised of substantially discontinuous working electrode surfaces or components and thereby obtain signal from three dimensions which provide an improved signal to noise ratio.

Another object is to provide a method for measuring an electrochemical signal by providing substantially discontinuous working electrode surfaces or components that detect the flux of the electrochemical signal in two or more preferably three directions relative to the working electrode surface.

Another object of the invention is to provide an electrode subassembly composed of a working electrode comprised of substantially discontinuous working electrode surfaces for use with an electrode assembly to measure accurately, consistently, and quickly a diffused electrochemical signal, and achieve an accurate measurement of the electrochemical signal within a matter of seconds to minutes.

Another object of the invention is to provide an electrode assembly with a bonding pad or a pad that contacts a pin connector that can be readily connected and disconnected from a power source and monitoring device, thus allowing for replacement of the electrode assembly, electrode subassembly, and/or an ionically conductive material (e.g., an electrolytic gel) used with the electrode assembly.

An advantage of the working electrode is that it provides an improved signal to noise ratio by reducing noise and allowing a signal to be produced equivalent to a solid electrode but only using one half or less of the surface area of a solid electrode.

Another advantage of the invention is that the electrode can be used to measure very low concentrations of an electrochemical signal in an electrolyte (i.e., an ionically conductive material). For example, the electrode can be used in conjunction with a hydrogel system for monitoring glucose levels in a subject (e.g., a human). An electroosmotic electrode (e.g., iontophoresis or reverse iontophoresis electrodes) can be used electrically to draw glucose into the hydrogel. Glucose oxidase (GOD) contained in the hydrogel converts the glucose into gluconic acid and hydrogen peroxide. The electrode subassembly catalyzes the hydrogen peroxide into an electrical signal. This system allows for the continuous and accurate measurement of an inflow of a very small amount of glucose in an electrolyte (e.g., glucose concentrations 10,500, or 1,000 or more times less than the concentration of glucose in blood).

Another advantage is that the electrode assembly and electrode subassembly are easily and economically produced.

A feature of the electrode subassembly of the invention is that it is small and flat, having a total surface area in the range of about 0.1 cm² to 8.0 cm². If desired, the electrode subassembly can also be quite thin, such that it has a thickness in the range of about 0.25 μm to 250 μm.

These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the composition, components and size of the invention as set forth below, reference being made to the accompanying drawings forming a part hereof wherein like numbers refer to like components throughout.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an overhead schematic view of a conventional one dimensional working electrode.

FIG. 2 is an overhead schematic view of a two dimensional working electrode.

FIG. 3 is an overhead schematic view of a three dimensional working electrode.

FIG. 4 illustrates an example of an operating circuit using working electrode 1, reference electrode 21, and counter electrode 22 with a power source 23 and monitoring device 24. The power source 23 is used to provide voltage to the reference 21 and working 1 electrode to drive the conversion of chemical signal to electrical signal at the catalytic, multidimensional faces of the working 1 electrode. The power source 23 also maintains a fixed potential at the working electrode 1 (where, for example, hydrogen peroxide is converted to molecular oxygen, hydrogen ions, and electrons), which is compared with the potential of the reference electrode 21 during monitoring. The operating circuit also maintains an electrical potential on the working electrode 1 for catalysis of chemical signal that diffuses toward the working electrode 1. The working electrode 1 is electrically connected to a counter electrode 22. The counter electrode 22 consumes electrons generated at the working electrode. The current generated at the working electrode 1 is measured at a position between the working 1 and counter 22 electrode.1 measured relative to the reference electrode 21 as exemplified in FIG. 4 . The electrical current generated at the working electrode 1 is correlated to the amount of glucose in the hydrogel patch, and extrapolated to the concentration of glucose in the subject's bloodstream.

The composition, size and thickness of the electrode assembly can be varied and such variance can affect the time over which the electrode assembly can be used. For example, the hydrogel patches and the electrodes of the present invention used with the electrode assembly are generally designed so as to provide utility over a period of about 24 hours. After that time some deterioration in characteristics, sensitivity, and accuracy of the measurements from the electrode can be expected (e.g., due to accumulation of material on the face of the electrode subassembly), and the electrode subassembly and hydrogel patch should be replaced. The invention contemplates electrode assemblies which are used over a shorter period of time, e.g., 8 to 12 hours or a longer period of time, e.g., 1 to 30 days.

The substantially discontinuous working electrode surfaces of the invention can be used to obtain improved signal to noise ratio and enhanced signal over an finite time when measuring any chemical signal in an finite volume. More specifically, the working electrode of the invention can be used to carry out a method which comprises extracting any biomedically significant substance through the skin of a mammalian subject (e.g., a human patient) and reacting that substance with another substance or substances to form a product which is detectable electrochemically by the production of a signal, which signal is generated proportionally based on the amount of a biologically important or biomedically significant substance drawn into the patch. As indicated in the above-cited patents the ability to withdraw biochemically significant substances such as glucose through skin has been established (see U.S. Pat. Nos. 5,362,307 and 5,279,543). However, the amount of compound withdrawn is often so small that it is not possible to make meaningful use of such methodology in that the withdrawn material cannot be precisely measured and related to any standard. The present invention provides an electrode that is capable of detecting the electrochemical signal at very low levels in a manner that allows for direct, accurate correlation between the amount of signal generated and the amount of the molecule in the human subject.

The invention is remarkable in that it allows for the noninvasive detection and quick, accurate measurement of amounts of a biomedically relevant compound, e.g., glucose, at levels that are 1, 2, or even 3 orders of magnitude less than the concentration of that compound in blood. For example, glucose might be present in blood in a concentration of about 5 millimolar. However, the concentration of glucose in a hydrogel patch which is used to withdraw glucose through skin as described in the system above is on the order of 2 micromolar to 100 micromolar. Micromolar amounts are 3 orders of magnitude less than millimolar amounts. The ability accurately and quickly to detect glucose in such small concentrations is attained by constructing the electrode assembly and electrode subassembly with the components described herein and the configurations described herein.

Because the amount of signal to be measured may be very small and further because it may be important to measure changes quickly in that signal over short periods of time the multicomponent, multisurface electrode configuration of the invention is valuable in obtaining results. The electrodes of the invention can detect a smaller signal over a shorter period of time as compared to a continuous surface working electrode.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to use the electrode assemblies and subassemblies of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, particular components, etc.), but some deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, surface area is geometric surface area, temperature is in degrees centigrade, and pressure is at or near atmospheric pressure.

The data presented in these examples are computer-simulated (i.e., the data is generated from a computer model of the electrode assembly described herein). The computer model of the invention uses the following parameters:

• • peroxide diffusivity: 1.2×10⁻⁵ cm²/sec;
  • glucose diffusivity: 1.3×10⁻⁶ cm²/sec;
  • initial peroxide concentration=100 nmol/ml=100 μM;
  • thickness of stagnant layer on top of electrode (the gel layer)=600 microns;
  • electrode thickness=125 micron width for the strip configuration as per FIG. 7 and 125 micron squares for the checkerboard configuration as per FIG. 10;
  • gap (insulator)=125 microns, 250 microns and 500 microns for the strip configuration, as indicated in FIGS. 11, 12, and 13.

Example 1

Effect of Edges and Radial Diffusion on Peroxide Flux at an Electrode Surface

FIG. 11 provides a computer simulation of the effect of edges and radial diffusion on peroxide flux at an electrode surface. This simulation shows that the peroxide flux on a slotted discontinuous electrode is higher at all positions, and particularly so at and near the edges, as compared to the peroxide flux for a planar electrode.

Example 2

Peroxide Flux on a Checker Board Electrode

FIG. 12 provides a computer simulation of peroxide flux on a “checker board” electrode; radial and planar diffusion are compared with radial diffusion only. This simulation shows the peroxide flux on a checkerboard relative to the peroxide flux on a planar electrode (with ID diffusion only). The curves are normalized for the same surface area of the electrode. Also shown is the ratio of the flux for checkerboard divided by the flux for the planar electrode. This ratio curve clearly shows that there is a significant advantage in using a discontinuous surface (such as a checkerboard) as compared to a planar electrode.

Example 3

Comparison of Checker Board, Slotted, and Solid Electrodes

FIG. 13 is a graph of a computer simulation of results comparing a normalized ratio of mesh to solid electrodes over time. This simulation shows the peroxide flux for slotted and square electrodes (E) with spacing (S) relative (normalized) to the peroxide flux for a 1D planar electrode. In all cases, the results are normalized so that the electrodes have the same surface area. The conclusion from this graph is that the checkerboard (square) electrode is best, followed by the 125 micron/250 micron space slotted electrode, and so on for the remaining electrodes.

Claims

1. A method of measuring the amount or concentration of a chemical signal in a mammalian subject, the method comprising the steps of:

contacting the skin of the mammalian subject with a first surface of a hydrogel medium through which a chemical signal can diffuse in response to a current, said hydrogel comprising water, electrolyte, and an enzyme, wherein the thickness of said hydrogel is in the range of 10 μm to 1,000 μm;

contacting an electrode assembly to a second surface of the medium, the assembly comprising a working electrode comprised of a plurality of substantially physically separated electrode surfaces and an electroosmotic electrode, wherein (i) the working electrode surfaces are separated by a gap having a width in a range of 10 μm to 1,000 μm, (ii) an electrically insulating material is positioned in each gap separating the electrode surfaces, (iii) the working electrode is characterized by a substantially planar configuration, and (iv) the working electrode has a thickness in a range of 0.25 μm to 250 μm;

providing current to the electroosmotic electrode sufficient to create diffusion of a chemical signal across the mammalian subject's skin, through the medium and to the working electrode in a first dimension direction and a second dimension direction;

providing a voltage to each of the working electrode surfaces of the working electrode sufficient to drive electrochemical detection of chemical signal which generates an electrical current at the working electrode surfaces, wherein said electrical current is generated at the working electrode surfaces by electrochemical oxidation of hydrogen peroxide producing an electrical signal;

measuring the electrical current generated at the working electrode surfaces; and

correlating the measured current to the amount or concentration of chemical signal in the mammalian subject.

2. The method of claim 1, wherein the electrode surfaces are configured as elongated rectangular strips parallel to each other and separated from each other by elongated rectangular gaps.

3. The method of claim 1, wherein diffusion of chemical signal further occurs in a third dimension direction substantially normal to the second dimension direction.

4. The method of claim 3, wherein the electrode surfaces are configured in a regular pattern of planar surfaces and gaps.

5. The method of claim 1, wherein each working electrode surface is comprised of a compound selected from the group consisting of platinum, platinum alloy, oxides and dioxides thereof.

6. The method of claim 1, wherein the electrode assembly further comprises a counter electrode and a reference electrode and wherein the counter electrode and a reference electrode are positioned in substantially the same plane as the working electrode, the counter electrode being electrically connected to the working electrode, and the reference electrode being positioned such that a substantially constant electrical potential is maintained on the reference electrode relative to the working electrode.

7. The method of claim 6, wherein the working electrode, counter electrode, reference electrode, and electroosmotic electrode are concentrically aligned with each other and wherein the working electrode is operated at a current level in the range of 0.1 nanoamp to 1 milliamp.

8. The method of claim 6, wherein the medium comprises a hydrogel having a surface in contact with a surface of the working electrode, the counter electrode, the reference electrode, and the electroosmotic electrode.

9. The method of claim 1, wherein the chemical signal is glucose.

10. The method of claim 1, wherein the working electrode surfaces are provided as a plurality of square-shaped regions, with the working electrode surfaces being isolated from each other by a plurality of rectangular gaps.

11. The method of claim 10, wherein the rectangular gaps are squares.

12. A method of measuring the amount or concentration of glucose in a human patient, comprising the steps of:

contacting the skin of the patient with a first surface of a hydrogel medium through which glucose diffuses, said hydrogel comprising water, electrolyte and glucose oxidase, wherein (i) glucose oxidase catalyzes a reaction resulting in conversion of glucose to gluconic acid, (ii) the thickness of said hydrogel is in the range of 10 μm to 1,000 μm;

contacting an electrode assembly to a second surface of the hydrogel medium, the assembly comprising a working electrode comprised of a plurality of substantially physically separated working electrode planar surfaces and an electroosmotic electrode, wherein (i) the working electrode surfaces are separated by a gap having a width in a range of 10 μm to 1,000 μm, (ii) an electrically insulating material is positioned in each gap separating the electrode surfaces, (iii) the working electrode is characterized by a substantially planar configuration, and (iv) the working electrode has a thickness in a range of 0.25 μm to 250 μm;

providing current to the electroosmotic electrode sufficient to draw ions through the skin of the patient along with glucose wherein the working electrode planar surfaces are configured such that the glucose is drawn in a first direction normal to the planar surfaces and in a second direction substantially parallel to the planar surfaces;

providing a voltage to each of the working electrode surfaces sufficient to drive electrochemical detection of a product of the reaction of glucose and glucose oxidase which generates an electrical current at the working electrode surfaces;

measuring the electrical current at the working electrode surfaces; and

correlating the measured current to the amount or concentration of glucose in the patient.

13. The method of claim 12 wherein the working electrodes are configured such that the glucose is further drawn in a third direction substantially parallel to the planar surfaces and substantially perpendicular to the second direction.

14. A hydrogel and electrode assembly for use in a glucose monitoring device, comprising:

a hydrogel comprised of water, electrolyte and glucose oxidase, wherein (a) glucose oxidase catalyzes a reaction resulting in conversion of glucose to gluconic acid, and (b) the thickness of said hydrogel is in the range of 10 μm to 1,000 μm; and

an electrode assembly comprising a working electrode that comprises a plurality of substantially physically separated working electrode planar surfaces, wherein (i) each working electrode surface comprises a catalytic surface and is separated from adjacent working electrode surfaces by a gap, said gap having a width in a range of 10 μm to 1,000 μm, (ii) an electrically insulating material is positioned in each gap separating the electrode surfaces, (iii) the working electrode is characterized by a substantially planar configuration, (iv) the working electrode has a thickness in a range of 0.25 μm to 250 μm, and v) a voltage may be provided to each of the working electrode surfaces sufficient to drive electrochemical detection of a product of the reaction of glucose and glucose oxidase which generates an electrical current at the working electrode surfaces.

15. The hydrogel and electrode assembly of claim 14, which further comprises a counter electrode and a reference electrode, each being positioned in substantially the same plane as the working electrode, the counter electrode being electrically connected to the working electrode, and the reference electrode being positioned such that a substantially constant electrical potential is maintained on the reference electrode relative to the working electrode.

16. The hydrogel and electrode assembly of claim 15, wherein the working electrode surfaces are provided as a plurality of square-shaped regions, with the working electrode surfaces being isolated from each other by a plurality of rectangular gaps.

17. The hydrogel and electrode assembly of claim 16, wherein the rectangular gaps are squares.

18. The hydrogel and electrode assembly of claim 14, wherein the electrode surfaces are configured as elongated rectangular strips parallel to each other and separated from each other by elongated rectangular gaps.

19. The hydrogel and electrode assembly of claim 14, wherein each working electrode surface is comprised of a compound selected from the group consisting of platinum, platinum alloy, oxides and dioxides thereof.

20. The hydrogel and electrode assembly of claim 14, wherein the electrode assembly further comprises an electroosmotic electrode, a counter electrode and a reference electrode and wherein the electroosmotic electrode, the counter electrode and a reference electrode are positioned in substantially the same plane as the working electrode, the counter electrode being electrically connected to the working electrode, and the reference electrode being positioned such that a substantially constant electrical potential is maintained on the reference electrode relative to the working electrode.

21. The hydrogel and electrode assembly of claim 20, wherein the working electrode, counter electrode, reference electrode, and the electroosmotic electrode are concentrically aligned with each other and wherein the working electrode is operated at a current level in the range of 0.1 nanoamp to 1 milliamp.

22. The hydrogel and electrode assembly of claim 20, wherein the hydrogel has a surface in contact with a surface on the working electrode, the counter electrode, the reference electrode, and the electroosmotic electrode.

23. A method of measuring the amount or concentration of a chemical signal in a mammalian subject, the method comprising the steps of:

contacting a first surface of an ionically conductive hydrogel with a skin surface of the mammalian subject, said hydrogel comprising water, electrolyte, and an enzyme, wherein the thickness of said hydrogel is in the range of 10 μm to 1,000 μm;

contacting an electrode assembly to a second surface of the hydrogel, the assembly comprising an electroosmotic electrode, a working electrode comprised of a plurality of substantially physically separated working electrode planar surfaces, a counter electrode, and a reference electrode, wherein (i) the working electrode surfaces are separated by a gap having a width in a range of 10 μm to 1,000 μm, (ii) an electrically insulating material is positioned in each gap separating the electrode surfaces, (iii) the working electrode is characterized by a substantially planar configuration, and (iv) the working electrode has a thickness in a range of 0.25 μm to 250 μm;

providing current to the electroosmotic electrode sufficient to draw the chemical signal across the mammalian subject's skin, through the hydrogel and to the working electrode;

providing a voltage to the working electrode planar surfaces sufficient to drive electrochemical detection of chemical signal which generates an electrical current at the working electrode surfaces, wherein said electrical current is generated at the working electrode surfaces by electrochemical oxidation of hydrogen peroxide producing an electrical signal;

measuring the electrical current generated at the working electrode; and

correlating the measured current to the amount or concentration of chemical signal in the mammalian subject.

24. A method of measuring the amount or concentration of glucose in a mammalian subject, the method comprising the steps of:

contacting a first surface of an ionically conductive hydrogel with a skin surface of the mammalian subject, said hydrogel comprising water, electrolyte and glucose oxidase, wherein (i) glucose oxidase catalyzes a reaction resulting in conversion of glucose to gluconic acid, and (ii) the thickness of said hydrogel is in the range of 10 μm to 1,000 μm;

contacting an electrode assembly to a second surface of the hydrogel, the assembly comprising an electroosmotic electrode, a working electrode comprised of a plurality of substantially physically separated working electrode planar surfaces, a counter electrode, and a reference electrode, wherein (i) the working electrode surfaces are separated by a gap having a width in a range of 10 μm to 1,000 μm, (ii) an electrically insulating material is positioned in each gap separating the electrode surfaces, (iii) the working electrode is characterized by a substantially planar configuration, and (iv) the working electrode has a thickness in a range of 0.25 μm to 250 μm;

providing current to the electroosmotic electrode sufficient to draw the glucose across the mammalian subject's skin and into the hydrogel;

providing a voltage to the working electrode planar surfaces sufficient to drive electrochemical detection of a product of the reaction of glucose and glucose oxidase which generates an electrical current at the working electrode surfaces;

measuring the electrical current generated at the working electrode; and

correlating the measured current to the amount or concentration of glucose in the mammalian subject.