CA2283240C - Electrode with improved signal to noise ratio - Google Patents

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) an 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) provided an overall enhanced signal after sensing for a given period of time.

Description

The invention relates generally to the field of electrodes for electrochemical meuurements, specifically elecvodes used in the biomedical fields to measure concentrations of biomedically significant compounds.
~ c~,~,u_ do of t_h_r,~ nvention The amount of a chentical in a given volume of solution can be measured with an electrode. An decvode is the component in an electrochemical cell in contact with tha elecvolyte medium through which current can flow by electronic movement.
Elxvodes, 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, where they are dippod in the electrolyte;
1.5 in medical devices, where the elecvode 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 movements 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 217 semisolid (e.g., in the form of a gel). Common elecvolytes include sulfuric acid and sodium chloride, which ionize in solution. Electrolytes used in the medical field must have a pH that is suffciently 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 2S electrochemical reactions (oxidation or reduction) at the surface of the electrode. The rate at which the electrochemical reactions take place is relatcc! w the reactivity of the species, the dccorode material, the ~lecvical potential applied to the clcevode, and the rate at which the elccvochemically active species is transported to the elaxrode surface.
In unstirred electrolytes, such as quiescent liquid solutions and gel electrolytes, 3C1 diffusion is the main process of transport of electrochemically active species to the elamnde surface. The exact nature of the diffusion process is deterrninad by the geometry of the electrode (e.g., planar disk, cylindrical, or spherical), and the geometry of the electrolyte (e.g., semiinfinitc 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 electradc is in a substantially perpendicular direction, whereas at the alges of the disk electrode the diffusion comes from both perpendicular and radial directions. The combination of these two different diffusion paaerns makes the total current collected at the disk electrode.
The present invention makes use of a unique geometry of the electrode surfice such that the diffusion of the electrochemically active species in the radial and axial diraxion 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.
An electrode assembly is disclosed that includes a multicotnponent 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 it~roved 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 oomact 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 15 working elxocode surfacx, and the signal is enhanced by allowing diffusion to ale working eloctrode surfaces via two and preferably three dimensions, e.g., (1) normal to the train 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 edgy are provided within the area being monitored. In the presetlce 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 them was only diffusion directly perper~icular to the main surface plane of the elxtrodc of int~a~at.

The invention features an electrode subassembly comprised of interconnected elearode 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 substa~ially 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 1~D the working electrode surface.
Another object of the invention is to provide an elf subassembly composed of a working electrode comprised of substantially discontinuous working electrode surfaces for ux with an electrode assembly to measure accurately, consistently, and quickly a diffused elecuochemical 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 elxuode 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, andlor an ionically corduaive material (e.g., an 2U 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 ~quivaleot to a solid electrode bui only using one half or less of the surface area of a~ solid electrode.
Another advantage of the iavention is thu the elf can be used to measure very 2h low eoiycenaations of an electrochemical signal in an clocxrolyt~ (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 elecuoosmotic electrode (e.g., iontophoresis or reverse iootophoresis elxdrodes) can be used electrically to draw glucose into the hydrogel. Glucose oxidase (GOD) contained in 3U the hydrogel converts the glucose into gluconic acid and hydrogen peroxide.
The electrode subassembly catalyzes the hydrogen peroxide into an clx~al signal. This system allows for the continuous and accurate measurement of an inflow of a very small amoum 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 elecuode 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 ~cm to 250 dam.
These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading tt~ 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.
Figure 1 is an overhead schematic view of a conventional electrode one dimensional working electrode.
Figure 2 is an overhead schematic view of a two dimensional working elxtrodc.
Figure 3 is an overhead schematic view of a three dimensional working electrode.
Figure 4 is an overhead schematic view of one embodiment of an electrode assembly of the invention.
Figure 5 is a schematic diagram of the chemical reactions involved in converting glucose to an elxtrical signal.
Figure 6 is an overhead plan view of a simple "strip" embodiment of a working electrode of the invention.
Figure 7 is an overhead view of another sitaple embodiment of a "strip"
configuration of a working elearode of the invention.
Figure 8 is yet another embodiment of a simple "strip" embodiment of a working clearode of the invention.
Figure 9 is an overhead view of a simple "checkerboard" embodiment of a working electrode of the invention.

Figure 1 ~) is a graph comparing the embodiment of Figure 7 with a single planar continuous working electrode surface.
Figure 11. is a graph comparing flux for an embodiment as per Figure 9 with a single planar continuous working electrode surface.
Figure 1 ~'. is a graph comparing various dimensional changes in "strip' and 'checkerboard" electrodes relative to a with a single planar continuous working electrode surface.
Before tbr, electrode of the present invention is described and disclosed it is to be understood that this invention is not limited to the particular components or coition described as such may, of course, vary. It is also to be understood that the terminology used berein is for the purpose of describing particular embodimenu only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.
It must be noted that as used in this specification and the appended claims, the singular forms 'a,' 'an' and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to 'a molecule' includes a plurality of mola;ules and different types of molecules.
Unless dcf'tned otherwise all technical and scientific terms used herein have the same meaning as comvmonly understood by one of ordinary skill in the art to which this inversion belongs. Although any materials or methods similar or equivalent to those descn'btd herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
Although ciocd publications may be published prior to the filing date such does not mesa that such publications ca>toot be antedatai by virtue of an earlier date of invention.
The term "electrode subassembly" mesas a working electrode comprised of a plurality or group of substantially discontinuous working elaxrode surfaces (e.g., components), .where the adjacent edges of the group of working electrode surfaces define as electrically insulating gap and wherein the group of working electrode surfaces allow for multidimensional diffusion. The woriang electrode surfaces (e.g., compotunu) can be configured in two or more strips to allow far two dimensional diffusion, or in two or more squares to allow for three dimensional diffusion.
The phrase "substantially discontinuous working electrode surfaces" or "substantially :S physically separated electrode surfaces" is meant to describe a working electrode that comprises a plurality of working electrode surfaces that are electrically connected, but otherwise substantially separated one from another (i.e., the adjacent edges of the working electrode surfaces of the working electrode are separated by an electrically insulating gap and the group of workimg electrode surfaces allow for multidimensional diffusion).
1O The term "electrode assembly" means an assembly comprised of k) an electrode subassembly, 2) an elearoosmotic electrode (e.g. , iontophoresis electrode), and 3) reference and counter electrodes. The electrode assembly can additionally include a substrate (e.g., a cezamic or polymeric substrate) to which the electrode assembly and electroosmotic, reference, and counter electrodes are attached.
1 ~ The term "working electrode" means one or more substantially discontinuous electrode surfaces) or components that are monitored to determine the amount of electrical signal generated at the combined surface which cover a defined area to be monitored. Tl~
amount of signal generated is correlated with the amount of a chemical compound prexnt in an electrolyte which contains a compound which generates the electrical signal on 2U contact with a surface of working electrode. The working electrode comprises substantially discont:irnwus catalytic surfaces which allow for multidimensional diffusion of compound to the catalytic surfaces. The catalytic surfaces are comprised of a material xlected from the group consisting of platinum, palladium, nickel, carbon, noble metals (e.g., gold), and oxides, dioxides and alloys thereof.
2S The term "electrically insulating gap" means the space defined by the adjacent edges of the outer perimeter of the area defined by the working electrode. The electrically insulating gap electrically isolates the individual surfaces or components fmm each otkxr by virtue of the width of the gap itself, andlor by virtue of an electrically insulating material contained within the gap.
30 The term "catalytic surface" or "catalytic face" are used interchangeably herein to mean the surface of the working electrode components that: k) is in contact with tlx surface of an electrolyte containing material through which the chemical signal flows from a source of chemical signal; 2) is comprised of a catalytic material (e.g., platim~m, palladium, or nickel and/or oxides, dioxides and alloys thereof); 3) catalyzes the conversion of the chemical signal into an electrical signal (i.e., an electrical current); and 4) defines the total working electrode surface arcs (all working electrode components) that, when composed of a catalytic material, is sufficient to drive the electrochemical reaction at a rate sufficient to generate a detectable, accurate electrical signal that is corretatable with the amount of chemical signal present in the electrolyte. Only that electrical signal generated at the catalytic surface of the working electrode is cornelatod with the amount of chemical signal present in the electrolyte.
1.0 The term "chemical signal," or "electrochemical signal," and the like arc used interchangeably and mean the chemical compound that is ultimately converted to an electrical signal at the catalytic faces of the working electrode components.
"Chemical signals" can be: 1 ) directly converted into an electrical current by chemical reaction at the catalytic faces of the electrode subassembly; or 2) indirectly converted into an electrical signal by the action of one or more catalysts. For example, the chemical signal glucose is indirectly converted into an electrical signal by reactions driven by two catalysts. A first catalyst glucose oxidase (GOD), which is present in the electrolyte containing material (e.g., a hydrogel patch), converts glucose into glueonic acid and hydrogen peroxide.
Hydrogen peroxide is then converted to a measured electrical current upon electrochemical oxidation by platinum (the second catalyst) on the catalytic faces of all of the working electrode components making up the electrode subassembly. Preferably, the chemical signal is generated by catalytic action on a biomedically significant compound (e.g., glucose).
'Ionically conductive material" or "medium" means a material that provides ionic cot~Ctivity, and through which electrochemically active species can diffuse.
The medium will allow diffusion in three dimeasions, i.e., normal to a planar surface of a working electrode component, normal to a length edge of the working elecuode component and normal to a width edge of a working elxtrode component. The ionical?y condt~ctivo material can be, for example, a solid, liquid, or semisolid (e.g., in the form of a gel) material that contains an electrolyte, which can be composed primarily of water and ions (e.g., sodium chloride), and generally comprises 5096 or more waver by weight.
The material can be in the form of a gel, a sponge or pad (e.g., soaked with an electrolytic solution), or any other material that can contain an electrolyte and allow passage of electrochemically active species, especially the chemical signal of interest, through it.
The invention must have some basic characteristics in order to be useful for its intended purpose, which is to detect a chemical signal in a manner such that the amount of signal detected can be related to the amount of signal in a given source, e.g., detect hydrogen peroxide generated by glucose oxidase (GOD) catalysis of glucose. The electrode assembly and medium must: (I) enable ions to flow in more than one dimension toward surfaces of the electrode subassembly; (2) be easy and inexpensive to manufacture;
(3) have a size such that the surface area of one face of the electrode assembly is in the range of about 0.1 cm2 to 8.0 cm2, and a thiclmess of less than 1 mm wherein all components of the electrode assembly are in substantially the same plane; and (4) include an electrode subassembly comprised of substantially discontinuous working electrode surfaces, e.g., separated working electrode components, which catalyze substantially all 1~ chemical signals which diffuse inward from the area surrounding the area defined by the electrode subassembly-all in a portable unit sufficiently small such that the unit can be worn as a watch is worn and weigh less than 0.25 kilograms.
As used herein, 'surface area" means the geomaric surface area (e.g., the geometric surface area of a circular electrode defined by the formula m~), without accounting for microscopic surface roughness that can contribute to the actual, three-dimensional surface area. The microscopic surface area is important in considering the actual, three-dimensional surface area available to, for example, drive the electrochemical conversion of the chemical signal to an electrical signal. The surface of an electrode subassembly is the sum of aU of the surface areas of each compancnt or surface of the working elxmode but not including any space or gap that exists between the components or between solid aneas of a substanrially discontirn~ous single working electrode surface.
For reasons that taay relate to factors such as the build up of undesired nnanerials in the electrode assembly and/or electrode subassembly, the electrode assembly andlor electrode subassembly must be easily replaceable (e.g., by a user) in a convenient manner.
In general, the electrode assembly and/or elearode subassembly is designed for use in continuous chemical signal sensing over a period ranging from about 1 day to I
month, preferably about 1 week to 2 weeks, more preferably about 2 weeks to 4 weeks or more.
_g..

After such tithe, the electrode is preferably designred so that it is disposable (e.g., can be readily detached from the monitoring device and rrplacod with a new electrode subassembly and/or electrode assembly). Accordingly, the electrode assembly must have some structural integrity, and provide for the detection of the chemical signal of interest.
In that the electrode asxmbly and sensor housing containiag the decaode assembly is preferably small (e.g., hand held, e.g., the size of a watch to be worn on the wrist of a patient and weighing about 0.25 kilograms or less). If desired, the electrode assembly and electrode subassembly can be particularly thin, e.g., in the rangy of 0.25 ~m to 250 ~cm.
In order to measure accurately the amount of a chemical sigaal (e.g., the amourn of hydrogen peroxide generated by GOD catalysis of glucose) and be sufficiently large to be manipulated, the electrode assembly cannot be too thin and cannot be too small.
The overall surface area of the complete electrode assembly (which includes the electrode subassembly) on a single surface should be in the range of about 0.25 ctrt2 to about 8 cm2, preferably about 0.50 cm? to 2 cm2.
~,a~,~of the Electrode~$~;ply Figures 1, 2, and 3 are overhead schematic views of exemplary embodimenu of an elxtrode subassembly. The embodiments of Figures 1, 2 and 3 allow migration to electrode surface (2) from one, two and three dimensions respectively. Figures 2 and 3 show embodimenu of the invention. The basic structural components of the electrode subassembly are the working electrode comprised of substantially dixontinuous working electrode surfaces as per Figures 2 and 3. Thex componeacs can be configured in a variety of ways.
Some of the basic configurations of the working elearodc eomg~oneats are shown within Figures 1, 2, 3, 4, 6, 7, 8 and 9. Figure 1 shows a basic configuration wherein the atmw leading towards tlx working electrode 1 is int~dod to t~prexat elearochemical signal diffusing toward the surface of the working electrode 1 from a dirxtion normal to the page on which the electrode 1 is drawn. Thus, electrochemical signal diffuses toward the surface of the working cloctrode 1 via a single dimension. These bane conrxpts are followed per the present invention. However, per the prcxnt inverxtion, electrochemical signal can diffuse to a surface or edge of the working elearode 1 via two different and preferably three different dimensions.
_g_ As shown in Figure 2 the working electrode 1 includes working electrode component strips 6, 7, 8 and 9, which are separated from each other by gaps 10, 11 and 12. In this "strip" configuration it is possible to detect electrochemical signal diffusing to the working elxtrode 1 via the path normal to the page as per Figure 1 and signal which diffuses in a direction substantially parallel to the page (from top to bottom) as shown by the arrows within the gaps 10, 11 and 12.
A more preferred embodiment of the invention is shown within Figure 3 wherein the elxtrochemical signal can diffuse toward the working electrode 1 via three different dimensions. More specifically, the working electrode 1 inches substantially separate discontinuous surface areas 13, 14, 15, 16, 17 and 18. These surface areas are separated from each other by gaps such as gaps 19 and 20. Thus, per this configuration electrochemical signal can diffuse to a surface of a working electrode component from a direction normal to 'the page as per Figure 1. Further, elearochemical signal can diffuse to a surface or edge of a working electrode component via a direction parallel to the page in the toplbottom direction as per the arrow in the gap 19 which is similar to that shown in Figure 2. Lastly, electrochemical signal can diffuse to a stu~aCe or edge of a working electrode from a direction parallel to a line drawn to t!x side edges of the page as per the arrow shown in the gap 20. Thus, electrochemical signal diffuses to the working electrode components 13-18 via three different dimensions: (1) normal to the planar surface; (2) normal to a length edge; and (3) normal to a width edge.
Electrodes which are used in order to sense elxuochmoical signals, and in particular biosensors are often oano~promised by the in6aent background signal that is present whey these sensors are used. This background signal or noise is geaetally due to o~tidation of a moral ele~ode surface. Accordingly, the noise is proportional too the of electrode surface area. In order to reduce the noise it is possible to decrease the surface area of the electrode. However, by dxreasing the surface area the signal is decreased thus the signal to noise ratio is not imgmvod.
In each of Figures 1, 2, and 3 the working elaxrode has a s<irfaae area smaller than if this electrode were a continuous solid due to the presenx of the gaps between the substantially discontinuous surface areas of the working eleexrode. Thus, the configuration in Figure 2 creates less noise than that of Figure 1. and ~ ~~8~on in Figure 3 creates less noise than that of Figure 2. Even though dx configurations of Figures 2 and 3 create less noise. they can actually generate an enhanced signal when the reading is taken over a defined (i.e.. limited or fuute) period of time as compared with the signal generated by the configuration of Figure 1. The enhance signal is created by receiving electrochemical signal from two or three directions as opposed to substantially only o~
S direction as per tlx system of Figure 1.
Regardless of the configuration of the working ola~~rode 1 it is consnvctnd and operates in essentially the same manner. Thus, before describing the particular details of the operation of particatlar embodimerns such as those shown in Figures 2 and 3, a general description of the working elxtrode is provided.
The basic "strip' configuration of wot~king electrodes of the present invention are shown within Figures 6, 7 and 8. The configurations differ only in that the 'gap" is different for each configuration. In Figure 6 each strip 6 a~ 7 has a width of 125 microns and the gap IO has a width of 125 microns. In Figure 7 each strip b and 7 has a width of 125 microns and the gap 10 has a width of 250 microns. In Figure 8 each strip 6 and 7 has a width of 125 microns and the gap 10 has a width of 500 microm. Figure I

compares the flux readings obtained for a configuration as per Figure 7 with a single piece planar working electrode. As is shown in Figure 10 the flan is substantially increased at or near the edges.
As described above with reference to Figures 6, 7 and 8 (and Figures 1, 2 and 3); the electrode subassembly can also be configured in a variety of ways with rcspxt to the configuration of the electrically insulating gap. The electrically insulating gap 3 can be an empty space between the working electrodes, tine width of the gap serving clearically to isolate the two electrodes. Alternatively, the electrically insulating gap can ovatain an elearically insulating material of substantially the same thic>mess as the worfcing electrodes, and separating the working el~rodes. The decuicxlly insulsring material can be configured as a single pied, or can be present as several smaller pieces of material positioned at various points along the working electrodes' adjacent edges. The electrically insulating manorial can contact substantially the entire perinoetet of the adjacent elcctzodes' edges, or contact only portions of one or both of the working eiecuvde edges.
Alternatively, the electrically insulating material can be an area of substrate between the two electrodes on which no electrically cotxluctive material is coated (e.g., the ceramic -l1-substrate orno which the elecorode assembly is printed can xrve as the electrically insulating material).
In a preferred embodiment, the working electrode surfaces and the electrically insulating gaps are provided in a "checkerboard" configuration. An electrode subassembly that has a checkerboard configuration is one is which 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 (e.g., square) gaps. In a checkerboard configuration, the working electrode surfaces are configured in a repeating pattern. A schematic representation of an exemplary ekectrode subassembly having a IO checkerboard configuration is provided in Fig. 9, and a variety of methods can be used to produce such a subassembly. For example, the working electrode components can be pravidod as a plurality of strips that are configured parallel to each other.
Working clecuode surfaces then are configured as a plurality of square-shaped regions by depositing strips of eloetrically insulating material onto the strips of working electrodes, and at 90°
1.5 angles relative to the strips of working elxirodes. Those skilled in the art will recognize that, as is described about for the construction of an ela~ode subassembly in general, alternate methods can be used to produce an electrode subasxmbly having a checkerboard configuration. For example, several small pieces of electrically insulating material can be used to produce the checkerboard, or a single piece of elxa~ically insulating material 20 having square holes can be placed over a working electrode component(s).
When present in a checkerboard configuration, the working electrode surfaces preferably each are configured as squares having a width of about 125 Ecm. .
In general, tt~ width of the electrically insulating gap (andlor the width and location 25 of the daxrically emulating material contained in the gap) will vary according to a variety of factors such as the thickness of a ionically conductive material (e.g., hydrogel patch) used with the electrode assembly, the diffusion charattcristics of the chemical signal to be detxted by the decuode subassembly for a given gcom~ty, the size of the cla.-trodc subassembly, and the duration of the sensing period (l.c., monitoring period).
For 30 example, where the elxtrode assembly is uxd with an ekxxrolytic hydrogel patch having a thickness in the range of about 14 dun to 1000 ~cm and tbc electrically insulating gap has a width in the range of about 10 ~m to 1,000 Vim. In a preferred embodiment, the ionically conductive material is from about 5 mil to 30 mil thick and the gap is about 5 mil wide.
The working electrode includes catalytic material on its catalytic surface, preferably Pt. Pt0 and/or PtOZ. The catalytic surface of the working electrode is the face of the electrode in contact with the electrolyte (e.g., a hydrogel patch) and which is responsible for conversion of chemical signal to electrical signal, and thus the face which constitutes the minimal portion of the electrode that must be composed of the catalytic material. The catalytic material of the catalytic surface is the material that promotes conversion of the chemical signal into an electrical signal. Exemplary catalytic materials include carbon as well as platinum, palladium, gold, iridium, or other nobel metal. Where the chemical signal to be detected is hydrogen peroxide (e.g., generated by catalysis of glucose by GOD), the preferred catalytic materials on the catalytic surfaces of the working electrodes are platinum, palladium, iridium, or other nobel metal, more preferably platinum or l5 oxides, dioxides or alloys thereof.
The working electrode can be porous or nonporous, preferably nonporous. The working electrode can be trade of catalytic material (e.g., stamped from a thin sheet of platinum). Although the electrode can be conmucted from a single piece of material the working electrode must provide multiple substantially discontinuous working electrode surfaces to allow for multidirectional flow to the edges of the working electrode. The working electrode can be plated (e.g., electmlytic or nonelectrolytic plating), coated, printed, photolithographic ally deposited, or otherwise afFtxed to a substrate using methods well known in the art for application of a thin metal layer on a surface. The substrate can be dosed of any insulating material (c.g., a ceramic, plastic (e.g., polyethylene, 2,5 polypropylene), or polymeric material) to which the clecvode assembly can be affixed.
Preferably the electrode subassembly, more preferably the complete electrode assembly, is affixed to a plastic or ceramic substrate.
Preferably, the elxtrode subassembly and electrode assembly are tnanufacnued in a manner that is the most economical without compromising electrode performance (e.g., the ability of the electrodes to catalyze the chemical signal, andlor conduct an electrical current, or the ability to manipulate the electrodes by hand without breaking or othetwisc compromising the operability of the electrode).

The working electrode can have the catalytic material over all electrode surfaces.
Alternatively, only the catalytic faces of the electrode subassembly have the catalytic material. Preferably, the catalytic material is platinum or a platinum-containing material which is present on at least the catalytic surface of the working electrode.
The electrode assembly and/or electrode subassembly can include additional materials that enhance the performance, handleabiiity; andlor durability of the electrode assembly and/or electrode subassembly. For example, the working electrode can be coated with a material that serves to decrease the interference of other species in the electrolyte with the measurement of electric current at the working electrode, andlor decrease the rate of oxidation of the catalytic material on the working electrodes' catalytic surfaces.
The relative size (i.e., diameter, surfact area, thickness, etc.) of the working electrode and its individual components can vary according to a variety of factors, including the dimensions of the surface through which the chemical signal is to be detected (e.g., the size of a hydmgel patch through which the chemical signal is drawn), or the size constraints of a monitoring electrode assembly used in connection with the electrode subassembly. If desired, the working electrode including each of its components can be quite thin, with a thickness in the range of 0.25 hem to 250 ~cm.
Regardless of the embodiment used, all of the electrode subassemblies of the invention include (l) a working electrode comprised of a plurality of substantially discontinuous working electrode surfaces, allowing for measurement of multidirectional dif~'usion from a medium to the working electrode surfaces and (ii) an electrically insulating gap defined by the adjacent edges of the working electrode, which gap isolates the working electrode surfaces from each other. The relative proportions of each of the components (e.g., the width, stuface areas, and geometries of the working electrode, and the width of the insulating gap) is such that substantially au chemical signal diffusing toward an outer edge of area defined by a working electrode surface allows for measureme~ of chemical diffused from multiple directions relative to a working electrode The electrode subassembly is normally used in an electrode assembly which includes additional components such as: a) an electroosmotic electrode (e.g., an iontophoresis or reverse iontophoresis electrode); b) a counter electrode; and c) a reference electrode. The electroosmotic electrode can be used electrically to draw electrochemical compounds from a sourer through material comprising water, enzyme and electrolyte, and to the area of the electrode subassembly. In general, practical and physical limitations of the system require that the electroosmotic electrode and the electrode subassembly be used alternately (i.e., current is present in the electroosmotic electrode or the electric current generated at the electrode subassembly is measured). Alternatively, diffusion of the chemical signal into the ionically conductive material can occur independent of the electroosmotic electrode (e.g., by passive diffusion).
The electrode assembly may comprise additional components. The electrode assembly may additionally comprise a chemical signal-impermeable mask which is positioned in the chemical signal transport path so as to inhibit substantially all chemical signal transport from the chemical signal source having an undesirable vector component relative to a plane of the mask and the catalytic faces of the working electrodes. Use of chemical signal-impermeable masks is not necessary to the operability of the invention and, in some cases, may not be desirable. Exemplary cheraicai signal-impermeable masks ate disclosed within United States Patent 5,735,273, issued April 7, 1998, and which application discloses inventions which were invented under an obligation to assign rights to the same entity as that to which the rights in the present invention were invented under an obligation to assign.
a0 The electrode subassembly can be operated by connecting the electrodes such that the working electrode (including all of its components) are connected as two conventional working electrodes, along with appmpriau counter and reference elec~odcs, to a standard potentiostat circuit(s). A potentiostat is an electrical circuit used in elecuochemicat measur~em~en<s when a working electrode is biased at a po~tentiaLs versus a reference electrode. For t>x purpose of the present invention, the elearical current mavsured at the working electrode of the electrode subassembly is the~current that is correlated with an amount of chemical signal.

In Based on the description above and in tlx figures, it will be recognized that the electrode subassembly and electrode assembly of the invention can be configured in a variety of different forms, and from a variety of different materials.
However, the elearodes will have certain defined mechanical, electrical, chemical and diffusion characteristics.
1:i Mechanically the electrode assembly and electrode subassembly will have sufficient saucairal irgegrity such that it can be readily handlod by baunan fingers without significant handling difficulties or significantly compromising the performance of the electrode.
Further, where the electrode subassembly is used in conjunction with an ionically cot>ductive material (e.g., a hydrogel patch), it may be desirable to remove the material 2Q from the electrode. Thus, it may be desirable to design the electrode assembly so that the patch can be removed froth the electrode assembly andJor electrode subassembly without signifuantty degrading the surface of any of the elaarodrs, or adhering to any of the electrodes in a manner that makes it difficult to remove completely all patch material from the face of any of the electrodes. The electrode subassembly and/or electrode assembly 25~ can be provided as a unit separate from the any other component of a monitoring device (e.g., a glucose monitoring device). In such an embodinocm a bonding pad or a pad that contacts a pin connxtor member 4 as per Figures 1,~ and 3 is used. The member 4 makes it possible readily to connect and disconnxt the electrode assembly from the remainder of the device. Alternatively, the iorrically conductive material and the electrode subassembly 3a aadlor electrode assembly can be provided as a singk unit and the member 4 can be use!
elaxrically to connect the unit into the device and complete the device.

Preferably, the elxtrode assembly will optimally operate at a gH which is relatively close to that of the solid or electrolyte in which the electrode subassembly is in contact (e.g.. human skin (about pH 7) or the hydrogel patch) and at least within a range of from about pH 4 to pH 9. In general, the working operates at a current level in the range of 0.1 nanoamp to 1 milliamp.
~liht The present invention is useful in connection with the detection of biologically significant molecules such as glucose which are moved through human skin using a technique known as electroosmosis. The basic concept of moving a molecule such as a glucose through human skin is disclosed within U.S. Patent 5,362,307, issued November 8, 1994, and U.S. Patent 5,279,543, issued January 18. 1994, disclosing the basic concept of moving molecules such as glucose through human skin by means of elecaoosmosis. The concept of converting the very small amounts of molecules such as glucose which can be extracted through the skin in order to create a current by use of glucose oxidasc is disclosed within European patent application EP 95925261.0 now granted as EP 0 766 578, issued on October 4, 2000; and hydroget parches suitable for use with the prestnt invention are disclosed within pending European application EP 96924493.8;
cacti of which applications disclose inventions which were invented under an obligation to assign rights to the same entity as that to which the rights in the present invention were invented under an obligation to assign.
The elearode subassembly of the invention can be ustd as part of an ckctrode assembly (e.g., with refazacn, cou~r, and elecuoosmotic elauoda) for mea.SUrrment of a biomedically important compound (e.g., glucose). For example, as shown in Figure 4, the electrode subassembly comprises! of a multiconiponcnt working elxttodc 1 can be placed within a elcctroosmotic electrode 25, a reference cla~~odc 21 and a catat~er elxtrode 22. The elecdroosmotic 25, reference 21 and counter 22 eketrodes are connoaod by leads 26, 27 and 28, respectively, to a power source and monitoring device.
A
hydrogel patch, which is the electrochemical conducting medium, is placed in contact with the elatrode assembly and the entire assembly placed onto an area of mammalian (e.g., human) skin. An eloctricat current is sent through the elcccroosmotic clatrode, thereby drawing molecules, including glucose, through the patient's skin and into the hydrogel patch.
(:FNF ATIj~,r . -~F- ,TRrC~ tICNA~
Glucose oxidase (GOD), contained in the hydrogel patch, catalyzes the conversion of glucose into gluconic acid a~ hydrogen peroxide as descrt'bcd above and shown in Figure 5. Tlic hydrogen peroxide is then catalyzed at the electrode subassembly to 2 electrons, molecular oxygen, and 2 hydrogen ions, and the electric currtnt ge~rated at the working electrode.
The electrical current generated at the working electrode 1 is correlated to the amount of glucose in the hydrogel patch, and extrapolated to the coition of gh~cose 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 hydrogcl patches and the electrodes of the present invention used with the electrode assanbly are generally designed so as to provide utility over a period of about 24 hours.
After that time some deterioration in c6aractcristics, sensitivity, and accuracy of the measurements from the elecorode can be expected (e.g., due to accumulation of material on the face of the electrode subassembly), and the electrode subossembly and hydrogel patch should be replaced. T'he invention contemplates elxtrode 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 dixontinuous working electrode surfaces of the invetuion 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 vohitne. More spxifically, the working elearode of the invention tin be used ~ carry out a method which oomprisa extracting any biomedically significant substance through the skin of a mammalian subject (e.g., a human patient) a~ reacting that substance with another substance or substances to form a pmducx which is detxtable electrochemically by the production of a signal, which signal is generated proportionally based on the amount of a biologicagy itaportaat or biomedically significant substance drawn into the parch. As indicated in the above-cited patents the ability to withdraw biochemically significant substat>ces such as ghrcose through skin has ban established (sx U.S. Patent Nos. 5,362,307 and 5,279,543). However, the amount of cocnpouad withdrawn is often so small that it is not possible to make mmniagful use of such methodology in that the withdrawn material cannot be precisely measured and related to any standard. The prcxnt invention provides an electrode that is capable of detceting 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 announts of a biomedically relevant compound, e.g., glucose, at levels that arc 1, 2, or even 3 orders of magnitude less than the cotxentration of that compound is blood. For example, glucose might be present in blood in a concentration of about 5 tnillimolar. However, the concentration of gh~cose is a hydroget patch which is used to withdraw glucox through skin as dcsctlbed in the system above is on the order of 2 micromotar to 100 micromolar. Micxomolar amounts are 3 orders of magnitude less than tnillimolar amounts. The ability accurately and quickly to detect glucose iu such small concentrations is attained by constructing the electrode assembly and electrode subassembly with the components described herein and the configurations described herein.
t3ecaux the amount of signal to be treasured may be very small and further because it may be important to treasure changts quickly in that signal over short periods of time the multicompo~nt, multisurface electrode configuration of the invention is valuable in obtaining results. The clue of the invention can detect a smaller signal over a shorter period of time as compared to a continuous surface working electrode.
The following examples are put forth so as to provide those of ordinary skill in ttx an with a complete disclosure and ion of how to use the electrode assemblies and subassemblies of the prexnt invention, and are not intaoded w limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accut~acy with respect to mmnbas used (e.g., amounts, particular components, ere.), but some deviations should be aaouz~d for. Unless indicated othcrwist, parts are parts by weight, surface area is geomenric 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 diffusiviry: 1.2 x 105 cm2/sec;
glucose diffusiviry: 1.3 x 10'~ cm2/sec;
initial peroxide concentration = 100 tunoUml = 100 ~M;
thickness of stagnant layer on top of electrode (the gel layer) = 600 microns;
electrode thickness = 125 micron width for the strip configuration as per Figure 6 and 125 micron squares for the checkerboard co~guration as per Figure 9:
gap (insulator) = 125 microns. 250 microns and 500 microns for the strip configuration, as indicated in Figures 10, 11, and 12.
Fx_ am~rle 1: sect of ages and ~dLl Diffusion on Peroxide FILx at an Flyctrode Surface Figure 10 provides a computer simulation of the effect of edges and radial diffusion IS 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-P~~ide Flux on a Checker Board Electrode Figure 11 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 pctvxide flux on a planar electrode (with 1D diffusion only). The curves are noratalized for the same surface area of the e. Also shown is the ratio of the flux for checkerboard divided by thre flwc 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.
Figure 12 is a graph of a computer simulation of results comparing a normalized ratio of mesh to solid elxandGS over time. This simulation shows the peroxide fhuc for slotted and square electrodes (1~ with spacing (S) relative (normalized) to the peroxide flux for a 1D planar elxtrode. 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 (24)

What is claimed is:

1. A hydrogel and electrode assembly for use in a glucose monitoring device, comprising:
an ionically conductive hydrogel comprised of water, electrolyte and glucose oxidase, wherein the glucose oxidase catalyzes a reaction resulting in conversion of glucose to gluconic acid, characterized in that the hydrogel has a thickness in the range of 10 µm to 1,000 µm; and an electrode assembly comprising a working electrode characterized in that the working electrode comprises a plurality of substantially physically separated working electrode planar surfaces, wherein (a) each working electrode surface comprises a catalytic surface and is separated from adjacent working electrode surfaces by a gap having a width in a range of 5 µm to 1,000 µm, (b) an electrically insulating material is positioned in each gap separating the working electrode surfaces, (c) the working electrode has a flat configuration having a thickness in a range of 0.25 µm to 250 µm, and (d) a voltage may be provided to the working electrode surfaces in an amount sufficient to drive electrochemical detection of a product of the reaction s glucose and glucose oxidase which generates an electrical current at the working electrode surfaces by electrochemical oxidase of hydrogen peroxide producing an electrical signal.

2. The hydrogel and electrode assembly of claim 1, wherein the working electrode surfaces are configured in a regular pattern of planar surfaces and gaps.

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

4. The hydrogel and electrode assembly of claim 1 or claim 2, 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.

5. The hydrogel and electrode assembly of claim 4, wherein the rectangular gaps are squares.

6. The hydrogel and electrode assembly of claim 1, wherein the working electrode planar surfaces are configured such that glucose is drawn in a first direction normal to the planar surfaces, a second direction substantially parallel to the planar surfaces, and a third direction substantially parallel to the planar surfaces and substantially perpendicular to the second direction.

7. The hydrogel and electrode assembly of claim 1, wherein each working electrode surface is comprised of a compound selected from the group consisting of platinum, platinum alloy, oxides and diodes thereof.

8. The hydrogel and electrode assembly of claim 1, wherein the working electrode has a surface area in the range of 0.1 cm2 to 8 cm2.

9. The hydrogel and electrode assembly of claim 1, wherein the electrode assembly further comprises a counter electrode and a reference electrode, and wherein the counter electrode and the reference electrode are positioned in substantially the same place 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.

10. The hydrogel and electrode assembly of claim 9, wherein the electrode assembly further comprises am electroosmotic electrode, and wherein the electroosmotic electrode is positioned in substantially the same plane as the working electrode, the counter electrode and the reference electrode.

11. The hydrogel and electrode assembly of claim 9 or claim 10, wherein the working electrode, the counter electrode, the reference electrode and, if present, 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.

12. The hydrogel and. electrode assembly of claim 9 or claim 10, wherein the hydrogel has a surface in contact with a surface an the working electrode, the counter electrode, the reference electrode and, if present, the electorosmotic electrode.

13. A method of measuring the amount of glucose in a mammalian subject, the method comprising the steps of:
(a) providing an ionically conductive hydrogel as claimed in claim 1 through which the glucose can diffuse in response to a current;
(b) contacting an electrode assembly as claimed in claim 1 to a surface of the hydrogel, the assembly comprising a working electrode that comprises of a plurality of substantially physically separated working electrode planar surfaces;
(c) providing a voltage to the working electrode surfaces in an amount sufficient to drive electrochemical detection of the glucose 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;
(d) measuring the electrical current generated at the working electrode surfaces; and (e) correlating the measured current to a concentration of glucose in the mammalian subject.

14. The method of claim 13, wherein the working electrode surfaces are configured in a regular pattern of planar surfaces and gaps.

15. The method of claim 13 or claim 14, wherein the working electrode surfaces are configured as elongated rectangular strips parallel to each other and separated from each other by elongated rectangular gaps,

16. The method of claim 13 or claim 14, 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 method of claim 16, wherein the rectangular gaps are squares.

18. The method o~ claim 13, wherein the working electrode planar surfaces are configured such that the glucose is drawn in a first direction normal to the planar surfaces, a second direction substantially parallel to the planar surfaces, and a third direction substantially parallel to the planar surfaces and substantially perpendicular to the second direction.

19. The method of claim 13, wherein the mammalian subject is a human.

20. The method of claim 13, wherein each working electrode surface is comprised of a compound selected from the group consisting of platinum, platinum alloy, oxides and dioxides thereof:

21. The method of claim 13, wherein the working electrode has a surface area in the range of 0.1 cm2 to 8 cm2.

22. The method of claim 13, wherein the electrode assembly further comprises a counter electrode and a reference electrode, and wherein the counter electrode and the 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.

23. The method of claim 22, wherein the working electrode, the counter electrode and the reference 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.

24. The method of claim 22, wherein the ionically conductive hydrogel is a hydrogel patch, the patch having a surface in contact with a surface of the working electrode, the counter electrode and the reference electrode.