CA2331824A1 - Test strip - Google Patents
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- CA2331824A1 CA2331824A1 CA002331824A CA2331824A CA2331824A1 CA 2331824 A1 CA2331824 A1 CA 2331824A1 CA 002331824 A CA002331824 A CA 002331824A CA 2331824 A CA2331824 A CA 2331824A CA 2331824 A1 CA2331824 A1 CA 2331824A1
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- CA
- Canada
- Prior art keywords
- electrode
- test strip
- working electrode
- disposable test
- working
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
- C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/004—Enzyme electrodes mediator-assisted
Abstract
An improved disposable test strip for use in amperometric measurement of analytes in complex liquid media, such as blood, which has three or more electrodes has been developed. This strip is designed so that different electrical potentials can be maintained between a common pseudo reference/counter electrode and each of the other electrodes upon the imposition of a common potential by an amperometric meter. This capability is imparted to the test strip by providing different circuit resistances for each of these other electrodes. The test strip can be utilized to measure a single analyte such as glucose with a background compensation via a "dummy" electrode or it can be used to measure the concentration of multiple analytes.
Description
WO 99/58709 PCTIGB!~9/01424 TEST STRIP
The measurement of analytes such as glucose in complex liquid media such as human blood by amperomeiric methods, using disposable test strips has become widely used and is currently employed in a number of commercial products. W certain configurations it is advantageous' to ~o improve the signal to noise ratio by employing a three electrode system in which one electrode selves as a pseudo referencelcounter electrode to establish a reference potential. Typically this is a silverlsilver chloride electrode. A second, working electrode is coated with an enzyme which promotes an oxidation or a reduction reaction with the intended anal;yte and is a mediator which transfers electrons between the enzyme and the electrode.
The third 'gdummy" electrode is coated with the mediator but not the enzyme and it provides a measure; of the current which arises from other than the oxidation reduction reaction involving the target: analyte. An exarnplle of such a system is described in U.S. Patent No. S,ti28,980 to Carter, et al.
WO 9915$709 PCTIGB!99101424 (incorporated by reference herein) and is utilized in the MediSense Q:ID
glucose meter.
The three electrode: system provides a good way to isolate the c:unrent which arises from the oxidation reduction reaction involving the target analyte such as glucose but it also imposes a higher current load on the pseudo reference/counter electrode. In some testing environments such as glucose meters used by diabetics in their homes it is impractical or impossible to pretreat the samples to remove possible interferants. Thus with home use glucose meters the diabetic simply applies a sample of whole io blood. Whole blood typically contains a number of electrochemically active species whose concentration may vary from person to person or even :from sample to sample from the same individual. The dummy electrode provides a measure of current arising from the presence of these interferants thus allowing a normalization 'which removes their contribution to the current ~ s measured at the working f:Iectrode. However, in such a three electrode configuration the current seen by the pseudo refen~encelcounter electrode includes contributions from both the working elea~trode and the dummy electrode. Thus in some cases the pseudo reference/counter .electrode sees a significantly greater current than it would in a two electrode configuration.
The pseudo reference/counter electrode: in such a configuration is, in fact, serving two roles which can be inconsistent if the current it sf:es becomes too great. It serves, on the one hand, to provide a constant half cell potential, i.e. a reference potential and, on the other hand, it also serves as a counter electrode balancing the electron transfer occurring at the v~rorking and dummy electrodes. For instance, in a typical glucose metermediator is becoming oxidized at the working and dummy electrodes so a reduction reaction needs to occur at the pseudo reference/counter electrode t~o balance the electron transfer. 'J~lith the typical Ag/Ag~~l pseudo reference/counter io electrode this involves the reduction of silver ions thus consuming (or reducing) silver chloride. If too much silver e:hloride is consumed the pseudo reference/counter electrode can no longer serve its furiction of providing a source of constant half cell potential. In other words, the potential difference between the two electrodf: reactions such as th.e is oxidation of a mediator at the working electrode and the reduction of silver at the pseudo reference/counter electrode will actually shift as the :reaction proceeds.
one approach is. to redesign the pseudo reference/counter electrode to handle higher current loads without displaying a significant shift in half cell ?o potential. This would normally mean increasing the size or silver WO 991587U9 . PCT/GB99/01424 concentration of the pseudo reference/counter electrode relative to the working and dummy electrodes. It is difficult to further reduce the; size of the working electrode because its size has already been minimized. It is limited by the economically acceptable procedures for reproducibly manufacturing millions of such disposable test strips. ~n the other hand;
increasing the size or silver concentration of t1':~e pseudo reference/counter electrode would significantly increase the cost: of such three electrode disposable strips because silver is the most expensive material used in the construction of such strips.
to Therefore, there is a need for three elecltrode disposable test strips for use in amperometric systems whose cost is comparable to two electrode test strips and yet have pseudo reference/counter electrodes with about the same stability as in the two electrode test strips.
It has been discovered that the current load on the pseudo referencelcounter counter electrode in a disposable test strip _for use in amperometric measurements with a three electrode system can be decreased zo and therefore its half cell potential better stabilized by increasing tile WO 99/58709 PCTIGB'99/01424 resistance of the dummy electrode. This allovvs three electrode test strips to give better performance without changing the operating characteristics of the meters in which they are used.
Increasing the resistance of the dummy electrode not only reduces the total current passing d-:crough the pseudo refere:ncelcounter electrode but it also changes the potential at the dummy electrode's interface with the sample. Thus it iS possible to have a three electrode system which can simultaneously measure the concentration oftwo analytes. The effective potential at the "dumzr~y" electrode with the higher total resistance can be io adjusted to be too low to effect an oxidation reduction reaction indicative of the concentration of one of the two target analytes.
It is preferred to have the resistance of the dummy electrode be at least 1000 ohms greater than that of the working electrode and it is especially preferred that the resistance differential be at least about 4000 is ohms.
It is also preferred that the resistance of the dummy electrode be increased by putting a resistance in series with the active electrode surface of this electrode. Thus both the area and nature of the active surface of the dummy electrode are kept similar or identical to that of the working zo electrode. This can readily be achieved by increasing the resistance of the WO 99/58709 PCT/GB.99/01424 conductive track which connects the active electrode surface to the meter which applies the potential and measures the resulting current. In the typical disposable strip for amperometric analyte measurement three electrode surfaces are present on one end of an elongate;d flat strip and three contact pads, one for each of the electrode surfaces, a:re present on the other end of the strip. Each electrode surface is connected to its contact pad by a conductive track. The contact pads serve as the means to establish electrical contact between the strip and the meter which applies the potential. and measures the resultant content. Th:e conductive tracks are typically covered io by an insulating layer to~prevent any short circuits between them.
It is particularly preferred to increase the resistance of the conductive track of the dummy electrode by narrowing its width. ff this conductive track is made of the same material as the worf;ing electrode's conductive track and has about tl~e same thickness as the conductive track of fibs i s working electrode it will have a higher resistance. Such a mechanism of increasing resistance is particularly easy to im:plernent in mass manufacturing.
WO 99158709 PCT/G~t99/01424 An example of the present invention will be described in accordance with the accompanying drawings, in which:
Figs. I a and 1 b are schematic diagraEms depicting the conductive layers of electrodes of disposable test strips having dummylsecond working electrodes with narrowed conductive layers;
Fig. 2 is a schematic diagram depicting the conductive layers of electrodes of a control disposable test strip ;
Fig. 3 is an exploded view of a disposable test strip ;
Fig. 4 is a perspective view of the assembled strip of Fig.. 3 ; end Fig. 5 is a series of plots of current i:n microamps versus tiime in seconds for a working electrode subjected to a;n initial potential of 400 milliVolts in the presence of a glucose contairung sample for various dummy electrode conf gurations.
The three electrode disposable test strip for the amperometric measurement of analytes in complex liquid media is optimized to improve the signal to s noise ratio without irn.posing an excessive cun-ent load on the reference/counter electrode by increasing the resistance of the dumrny electrode, i.e. the electrode which carries the electrochemical mediator also WO 99/5$709 PCTIGB!19/01424 utilized at the working electrode but which has no enzyme or other reactant selected to engage the analyte in an oxidation rf:duction reaction. A typical environment for the application of this concept is the three electrode test strip described in U.S. Patent No. 5,628,890 for the determination of glucose in whole blood samples.
Such a test strip is typically constructed of an elongated strip of a rigid electrically non-conducting material such as plastic. Suitable plastics include PVC, polycarbonate or polyester. Three conductive tracks are laid on this strip so as to establish independent conductive paths from one end to io the other. Each track temninates at the end adapted to be proximate ?to the meter used to apply electrical potential and meaisure the resulting currents with a contact pad that interfaces with the meter. At the distal end of the strip each track terminates in an electrode adapl:ed to contact the complex liquid medium which carries the analyte to be measured. A typical medium i s is whole human blood and a typical analyte is g;iucose.
The working electrode is a pad which is coated with both a substance designed to engage the target analyte in an oxidation-reduction reaction and a mediator adapted to transfer electrons between the pad and the oxidation reduction reaction. A typical substance is an enzyme adapted to promote the Zo oxidation of glucose, such as glucose oxidase, and the mediator is a compound which readily transfers electrons from the oxidation reduction reaction to the pad, such as a ferrocene derivative.
The "dummy" electrode is a pad which preferably has the same surface area as the working electrode and is coated with the same amount of the same mediator as the working electrode. The concept is to provide an environment in the immediate vicinity of this "dummy" electrode which is essentially identical to that of the working electrode except for the substance, typically an enzyme, adapted to react with the target ana:lyte.
Then the spurious electrochemical reactions which might occur at the to working electrode giving rise to noise are just as likely to occur at tl:re "dummy" electrode. Tlzus the signal arising from such spurious reactions can be determined by measurement at the "dununy" electrode and subtracted from the total signal measured at the working electrode. This provides an improved signal to noise ratio.
~ s The pseudo reference/counter electrode i.s a pad with a maternal such as silver/silver chloride which has both the oxidized and reduced form of a species to provide an essentially constant half cell potential. So long as the relative proportions of the reduced and oxidized form of this species such as silver and silver chloride are not substantially changed the half cell potential Zo of this electrochemical couple will remain relatively constant. This facilitates being able to maintain a known constant oxidation or redv~uction potential at the working electrode. This allows; a production batch of disposable test strips to have a common calibration.
In the typical situation the disposable strips are utilized with a meter which functions to cozrelate the amount of cuzz~ent observed upon ttoe application of an external potential to the contact pads of the disposable strip to the amount of analyte present. This meter is designed to assume certain electrical characteristics will be observed upon the application of this external potential. One such assumption is that the amount of current ~o observed will decrease monotonically with time. If the current does. not decay in the expected manner the meter is programmed to abort the test. If the half cell potential of the pseudo referenceicounter electrode such as a silver/silver chloride electrode shifts the current characteristics may indeed fail to meet the expectations programmed into the meter causing an aborted i s test.
For example the lhalf cell potential of the: silver/silver chloride electrode will shift if the proportion of silver to silver chloride is changed.
As current flows through this electrode silver is either reduced or oxidized, depending on the nature of the reaction occurring at the working electrode.
zo In the typical meter for sensing glucose concentration glucose is oxidized at the working electrode reducing the mediator. The mediator then transfers the electron or electrons it has gained in this reduction reaction to its electrode pad. These electrons are then taken up at the pseudo reference/counter electrode. In the typical case this is a silver/silver chloride electrode and the electrons are taken up by the reduction of silver ions transforming silver chloride to silver metal.
If a sufficient amount of current passes through such a pseudo reference/counter electrode the proportion of silver to silver chloridE: will change enough to cause a noticeable change in the half cell potential of this io electrode. If this change becomes large enough the current at the working electrode may no longer decay monotonically. This in tum will cause the meter to sense an error condition and abort the test.
The current at the; working electrode arises from the oxidatior.~
reduction reaction involving the target analyte and the subsequent transfer of is electrons by the mediator. In the typical glueos~e meter glucose is oxidized by glucose oxidase and the mediator, for instance a ferrocene derivative, then transfers the electrons liberated by the oxidation of the glucose to its electrode pad. In detail the glucose oxidase becomes reduced by oxidizing the glucose in the sample which is exposed to tlhe disposable test strip and ?o then is reoxidized by reducing the mediator. The mediator in turn becomes WO 99J58709 PCT/GB'99/OI424 reoxidized by transferring electrons through it:. electrode pad to the circuit with the pseudo reference/counter electrode. r~'ormally the current arising from this transfer decays monotonically in accordance with the Cottrell equation as the mediator in reasonable diffusion distance to the electrode pad which was reduced by reaction with glucose oxidase is reoxidized.
However, this behavior' is dependent upon the potential at the working electrode being held at or above a certain potential relative to the pseudo referencelcounter electrode. If the potential at this pseudo reference/counter electrode shifts,the behavior at the working electrode may no longer follow ~o this pattern.
The disposable strips are typically designed so that the pseudo reference/counter electrode does not undergo such a potential shift. For instance this electrode can be made large enough that the current generated by the analyte concentrations typically encounl:ered does not consume ~s enough silver ions to cause such a shift.
The use of a third, "dummy" electrode, however, imposes an additional current load on the pseudo reference:/counter electrode. In the typical glucose meter where an oxidation reaction occurs at the working , electrode, the reduction. reaction occurring at the pseudo reference%;ounter ?o electrode must balance not only the oxidation reaction at the working electrode but also any oxidation reaction occurring at the "dummy"
electrode. This additional burden may be sufficient to shift the half:-cell potential of the pseudo reference/counter electrode out of its design range.
This is a particular problem in glucose rrleters which utilize an initially reduced mediator such as a ferrocene derivative. In such a meter there is an initial high current load as the mediator is oxidized at both the working and "dummy" electrodes. if there is also a high level of glucose in the sample being tested, there will also be a fairly high current load from the reoxidation of mediator initially reduced as a result of the oxidation of the io glucose. The combined current load has a tendlency to adversely efi:ect the half cell potential of the pseudo referencelcounter electrode.
The total current Load on the pseudo reference/counter electrode can be reduced by increasirng the resistance in the overall circuit. However, it is impractical to change the resistance in the circuit involving the working ~ s electrode. The meters used with the disposable; test strips of presenl:
concern are calibrated to correlate the level of current in the working electrode circuit after sometime period or over some fixed time interval after exposu7re of the test strip to the sample to the concentration of target analyte. Then the meters are distributed to a large number of users who expect to use l:he Zn meters with the disposable test strips for a number of years. Thus it is m impractical to make any change in such test strips which would reg~uire a corresponding change in the meter with which they are used.
It has, however, been found that the resistance in the "dummy"
electrode circuit can be increased without advc:rseiy effecting the interaction between the disposable test strip and its meter. The function of the "dummy" electrode is to allow subtraction from the total signal or current at the working electrode of that portion attributable to superious oxidation-reduction reactions with species in the complex liquid medium other than the target analyte. This subtraction is only of conc:em at the time or over the ~o interval during which the current at the working electrode is measured for correlation to the analyte concentration. Typically such measurements are made after the resistamc:e of the overall system is comparatively high after most of the oxidation at the working electrode has already occurred.. It has been discovered that at this point the difference in electrochemical is environments at the working and "dummy" electrodes is insufficient to adversely effect the function of the dummy electrode.
The relative difference in electrochemical environment between the working electrode and a "dummy" electrode with added resistance does tend to decrease as a test cycle proceeds. As the mE:diator subject to reoxidation Zo at the working electrode decreases the effective resistance in the working ~a electrode circuit increases, i.e. there are few species to support electron transfer. Thus although there will always be a fixed difference in resistance between the working and "dummy" electrodes circuits the percentage difference will decrease as the effective resistance in the working electrode circuit increases.
In an alternative embodiment, the three e~iectrode arrangement is used to simultaneously measure the concentration oiF two analytes. In this case there are two working electrodes and one pseudo reference/counter electrode. The first working electrode is designed to operate with a first io substance that engages one of the target analytes in an oxidation reduction reaction at a relatively flow potential. The second working electrodf: is designed to operate with a second substance that engages the other target analyte in an oxidation reduction reaction only at a higher potential. For ease in manufacturing both working electrodes are typically coated with i s both substances and appropriate mediators. However, the test strip is designed so that the second substance which is coated on the fast warking electrode remains inactive. In particular, the electrical resistance in the circuit path from the contact pad connected to the first working electrode through the first working electrode is significantly greatly than the c~Iectrical ~o resistance in the circuit path from the contact pad connected to the :second ~s WO 99/5$709 PCTIGB99/01424 working electrode through the working electrode. Thus when a certain electrical potential is applied to the contact pads of both electrodes relative to the pseudo reference/counter electrode, the effective potential at: the first working electrode is less than that at the second working electrode, some of the potential drop having been expended traversing the higher circuit resistance.
The two analyte embadirnent is applied to the simultaneous measurement of ketones and glucose by utilizing an enzyme mediator system far the ketones which operates at +200mV and an enzyme mediator io system for the glucose which operates at +400mv. In particular, h~~droxy butyrate dehydrogenase (HBDH) with a nicotinamide adenine dinucleotide (NADH) cofactor and a 1,10-phenanthroline c~uinone ( 1,10 PQ) mE:diator is used for the ketones and glucose oxidase with a ferrocene derivative mediator is used for the glucose.
~ s The low operating potential of the HBD~H/NADH/ 1,10 PQ system is a significant advantage for an analyte like ketones which has a limited linear response range. In the case of ketones a linear response is typically expected only over a range of between about 0 and 8 m;illi Molar. By :operating at a low potential interference from other species which might undergo an Zo oxidation reduction reaiction at a higher potential is avoided. In other words, 1 fi the probability that another chemical species in the sample might lbecome oxidized and deliver electrons to the first working electrode thus making a superious contribution to the current sensed at this electrode is minimized.
The potential at the first working electrode is adjusted so that upon the application of a 400mV potential between the; second working electrode and the reference/counter electrode the potential between this first working electrode and the reference/counter electrode is 200mV. This adjustment is effected by increasing the resistance of the circuit path involving this electrode relative to that involving the second. working electrode by an io appropriate amount in one of the ways discussed hereinabove.
The current sensed at the fzrst working electrode is the result of the oxidation of ketones while that sensed at the second working electrode is the result of the oxidation of both ketones and glucose. The amount o~f current at each electrode carp then be employed in a sample simultaneous equation to is determine the concentration of ketones and glucose in the same sample.
It is, of course, possible to coat only the first working electrode with the ketones sensitive chemistry and to coat or.~ly the second working electrode with only the glucose sensitive chernistry. This would be expected to result in higher manufacturing costs. Typically the disposable test strips Zo are manufactured by a series of printing steps so that applying different E~
chemistries to each working electrode would require additional printing steps.
A particular application of the concept of a high resistance clammy electrode to the measurement of glucose is ilhustrated in Figures 1 through 5.
s In the strips illustrated, the working electrode and the dummy electrode each had a surface area of 6.612 square millimeter:> while the pseudo reference/counter elecitrode had a surface area. of 4.18 square millin:neters.
The conductive tracks which connect the contact pads to the electrode pads are in most cases 0.$Ol millimeters. In two cases the conductive track to associated with the dummy electrode was narrowed to 0.510 millimeters and 0.305 millimeters, as illustrated in Figures Ia and Ib.
Two different conductive layer prints a:re illustrated in Figs. I a (Track A) and I b (Track B). A control conductive layer print, in which tree working and dummy electrodes have the same resistance, is shown in Fig. ~~.
a s Referring to Figs. 1 a, 1 b and 2, the electrode configuration on the sensor strips has three printed layers of electrically conducting carbon ink: 2. The layers define the positions of the pseudo reference/counter electrode 4, the working electrode 5, the dummy electrode Sa and electrical cantacts 3.
Referring to Fig. 2, working electrode _'i has a track width l fi that is zo equal to track width 16a of dummy electrode Sa. Equal track widths 16 and ~s WO 99!58709 PCTIGB99/01424 1 ba give the working electrode and dummy electrode equal resistances.
Referring to Figs. 1 a and 1 b, track widths 1 f b and 16c of dummy electrode 5a are narrower than track width 16a of the control in Fig. 2. The conductive Iayer of dummy electrode 5a is nacTOwed in order to increase the s resistance of the dummy electrode relative to t:he working electrode resistance. Track width 16c is smaller than track width 16b. Thus, the resistance of dummy electrode 5a in Track A yig. l a) is greater than the resistance of dummy electrode 5a in Track B (dig. ib).
to The composition of the conductive layers can also affect the resistance of the electrodes. Generally, the conductive layers of the electrodes are printed at the same tirr.~e with the same ink. The conductive layers can be printed with a low carbon-content ink or a high carbon-content ink. Low carbon-content had a carbon content of between 30 and 3 I weight percent is and a resin content of between 7 and 9 weight percent. The high c;3rbon-content ink has a carbon content of between 42 and 45 weight percent, and a resin content of between '~ and 9 weight percent.
A suitable electrode sensor strip is illustrated in Figs. 3 and 4.
Referring to Figs. 3 and 4, the electrode support I, an elongated strip of Zo plastic material (e.g., PVC, polycarbonate, or ;polyester) supports tlZree WO 99158709 PCT/GB!99/01424 printed tracks of electrically conducting carbon ink 2. These printed tracks define the positions of the pseudo reference/counter electrode 4, of the working electrode S, of the dummy electrode :pa, and of the electrical contacts 3 that are inserted into an appropriate measurement device (not s shown). The conductive layer of dummy electrode Sa is narrowed in order to increase the resistance of the dummy electrode relative to the wcarking electrode.
The elongated portions of the conductive tracks are each overlaid with silverlsilver chloride particle tracks 6a and 6b., with the enlarged exposed io area overlying 4, and Eb and 4 together forming the pseudo reference/counter eleci:rode. The conductive track or Iayer for dummy electrode Sa is not overlaid with silver/silver chloride. This further increases the resistance of the dummy electrode. The conductive tracks are :further overlaid with a layer of hydrophobic electrically insulating material 7 that ~ s leaves exposed only th.e positions of the pseudo reference/counter .electrode, the working electrode .and the dummy electrode, and the contact areas. This hydrophobic insulating material prevents short circuits. Because tl'nis insulating material is hydrophobic, it can confine the sample-~to the. exposed electrodes. A prefezTed insulating material is available as POLYP~LAST~' ?o (Sericol Ltd., Broadsta~irs, Kent, IlK).
ao WO 99/58709 PCTlGB991U1424 The working electrode working area 8 its formed from an irk: that includes a mixture of an enzyme, a mediator, and a conductive material.
The dummy electrode working area is formed. from ink that includes a mixture of a mediator and a conductive material without enzyme. The s respective inks are applied to the positions 5 and Sa of carbon traclks 2 as discrete areas of fixed length. Alternatively, instead of an enzyme, electrode layer 8 can contain a substrate catalytically reactive with an enzyme to be assayed. The conductive material in a preferred embodiment includes particulate carbon having the redox mediator adsorbed thereon.
io A printing ink is formed as an aqueous solution of the conductor and adsorbed redox mediator. For the working electrode, it also includes the enzyme or, alternatively, a substrate. When the analyte to be mea:>ured is blood glucose, the enzyme is preferably glucc>se oxidase, and the redox i s mediator is a ferrocene derivative.
The inl: can be screen printed. The ink can include a polysaccharide (e.g., a guar gum or an alginate), a hydrolyzed gelatin, an enzyme stabilizer (e.g., glutamate or trehalose), a film-forming ;polymer (e.g., a polyvinyl alcohol), a conductive filler (e.g., carbon), a redox mediator (e.g., ferrocene ~o or a ferrocene derivative), a defoaming agent" a buffer, and an enzyme or a WO 99/5$709 PCT/GB'99/01424 substrate. The ini: printed on a dummy electrode lacks the enzymf: or the substrate.
The pseudo reference/counter electrode: 5b is situated relative to the working electrode 8 and dummy electrode 8a such that it is in a non-ideal position for efficient electrochemical function. The electrodes are arranged not to minimize the effect of the resistance of~ the solution on the overall resistance of the circuit (as is conventional). Positioning the pseudo referencelcounter electrode downstream of the working electrode leas the advantage of preventing completion of a circuit (and thus detectioo~ of a io response) before the working electrode has bE:en completely covered by sample.
The electrode area is overlaid by a fine grade mesh 9. This mesh protects the printed components from physical damage. It also heJ(ps the sample to wet the pseudo reference/counter electrode and working; electrode ~s by reducing the surface tension of the sample, thereby allowing it to spread evenly over the electrodes. Preferably, this rr~esh layer extends over the whole length of the sample path, between and including, the application point and the electrode area. Preferably, this mesh is constructed of finely woven nylon strands. Alternatively, any woven or non-woven material can zo be used, provided it does not occlude the surface of the electrode such that nozmal diffusion is obstructed. The thickness of the mesh is selected so that the resulting sample depth is sufficiently small to produce a high solution resistance. Preferably, the fabric is not more than 70 urn in thicknfas.
Preferably the mesh has a percent open area of about 40 to about 4:5%, a s mesh count of about ~5 to about 1 i S per cm, a. fiber diameter of about 20 to about 40 p.m, and a thickness of from about 40 to about 60 pm. A suitable mesh is I~1Y64 HC mesh, available from Sefar (formerly ZBF), CH-8803, Ruschlikon, Switzerland.
The mesh can be surfactant coated. This is only necessary if the mesh io material itself is hydrophobic (for example, nylon or polyester). If a hydrophilic mesh is used, the surfactant coating can be omitted. Any suitable surfactant can be used to coat the mesh, so long as it allows adequate even spreading of the sample. A preferred surfactant is FC 170C
FLUORAD° fluorochemical surfactant (3M, ,3t. Paul, MN).
FLUORAD° is ~ s a solution of a fluoroaliphatic oxyethylene adduct, lower polyethylene glycols, 1,4-dioxane, and water. A preferred surfactant loading for most applications is from about 15-20 ug/mg of mesh. The preferred surfactant loading will vary depending on the type of mesh and surfactant used and the sample to be analyzed. It can be determined empirically by observing flow zo of the sample through the mesh with different levels of surfactant.
WO 99/58709 PCT/GB!99/01424 A second layer of coarser surfactant coated mesh 10 is applied over the first mesh. This second mesh layer controls the influx of the saimple as it travels from the application point toward the F>seudo reference/cownter and working electrode areas by providing a space .into which the displaced air s within the sample transfer path can move as the sample moves prel:erentially along the lower fine grade mesh layer 9 and partially in mesh layer 10. The spacing of the larger fibers of the secondary mesh layer, perpendicular to the direction of sample flow, helps to control the :>ample flow by presenting repeated physical bazxiers to the movement of the sample as it travels io through the transfer path. The regular pattern of the mesh fibers ensures that the sample progresses in stages and that only samples with sufficient volume to generate an accurate: response are able to pass all the way along the pathway and reach the pseudo reference/count:er electrode.
~ s Preferably, mesh 10 is of a woven consl:ruction, so that it preaents a regular repeating pattern of mesh fzbers both perpendicular to and parallel to the longest aspect of the strip. Generally, the second mesh layer should be substantially thicker than the first mesh, with liarger diameter-mesh fibers and larger apertures between them. The large~~ mesh preferably has a ?o thickness of from 100 to 1000 pm, with a thiciicness of from 100 to I 50 ~m ~a WO 99/5$709 PCT/GB99/01424 being most preferred_ A preferred mesh has a percent open area of about 50 to about SSf%, a mesh ~:ount of from about 45 'to about 55 per cm, amd a fiber diameter of from about SS to about b5 p.m. A preferred mesh is NY 151 HC
mesh, also available from Sefar, CH-8803, Rushchlikon, Switzerland.
s Mesh 10 is also provided with a coating; of a suitable surfactant {unless the mesh itself is hydrophilic). Preferably, it is the same surfactant as that on the first mesh layer. The loading of surfactant is lower on mesh than on mesh 9, providing a further barrier to movement of samiple past the transverse fibers of mesh 10. In general, a~ loading of 1-10 p.ghng of io mesh is preferred.
The mesh layers 9 and 10 are held in place by layers of hydrophobic electrically insulating ink 11. These layers can be applied by screen printing the ink over a portion of the peripheries of the: meshes. Together, the layers and mesh surround and define a suitable sample transfer path 12 for the 1 s sample to travel from the application point at the furthest end of the strip towards the working electrode and pseudo reference/counter electrode. The ink impregnates the mesh outside of path 12. The insulating material thus defines sample transfer path 12 by not allowing sample to infiltratf: the area of mesh covered by the layers of insulating material. A preferred insulating ~S
WO 99/58709 PCT/GB!~9/01424 ink f or impregnating the mesh layers is SERIt~ARD° (Sericol, Ltdl., Broadstairs, Kent, UK).
The upper part of the electrode is enclosed by a liquid/vapor impermeable cover membrane 13. This can be a flexible tape made of s polyester or similar material which includes a small aperture 14 to allow access ofthe applied sample to the underlying; surfactant coated mesh layers.
The impermeable cover membrane encloses the exposed working electrode and pseudo reference/counter electrode. Thus., it maintains the available sample space over the electrodes at a fixed height which is equivalent to the io thickness of both mesh layers 9 and 10. This ensures that the solution resistance is kept at a high level. Any sample thickness up to the maximum depth of the two mesh layers is adequate in this respect. Aperture 14 is positioned overlying the furthest end of the of>en mesh area, remote from the pseudo reference/counter electrode 6b, such drat the exposed area of mesh is beneath the aperture can be used as a point of access or application for the-liquid sample to be measured. The aperture can be of any suitable size large enough to allow sufficient volume of sample to pass through to the mesh layers. It should not be so large as to expose any of the area of the electrodes. The aperture is formed in the covE:r membrane by any suitable Zo method {e.g., die puncihing). The cover membrane is affixed to the. strip 2E~
WO 99/58709 PCT/GB!~9/01424 along a specific section, not including the electrodes, the sample transfer path or application area, using a suitable method of adhesion. Preferably this is achieved by coating the underside of a polyester tape with a layer of hot melt glue which is then heat welded to the electrode surface. Th.e hot s melt glue layer is typically of a coating weight between 10-50 g/m2, preferably from 20 to 30 g/mz. Pressure sensitive glues or other equivalent methods of adhesion may also be used. Care should be taken when the tape is applied, the heat and pressure applied to the cover membrane can melt the SERICARD° .and can cause it to smear onto adjoining areas.
io The upper surface of the cover membrane can also be usefully provided with a layer of~ silicone or other hydrophobic coating which helps to drive the applied sample onto the portion of exposed surfactant coated mesh at the application ;point and thus make the: application of small volumes of sample much simpler.
is In use, a disposable test strip of the invention is connected, via electrode contacts 3, to a meter {not shown). A sample is applied to aperture 14, and moves along the sample transfer path 12. The progress of the sample is sufficiently impeded by mesh Layer 10 to allow the sample to form a uniform Zo front rather than flowing non-uniformly. Air is displaced thorough the upper WO 99/58709 PCTIGB!99101424 portion of mesh layer 10 to and through aperture 14. The sample first covers working electrode 5 in its entirety, and only then. approaches and covers pseudo reference/countelvelectrode 4. This com~aletes the circuit and causes a response to be detected by the measuring device.
The effect of increasing the resistance of a dummy electrode in a system for measuring glucose in a whole blood sample was electronically modeled. In particular, Ivledisense G2a disposable test strips which utilize glucose ~oxidase and a, ferrocene mediator were tested using venous lblood spiked with glucose to a concentration of 15m1VJ~. The electronics was used io to simulate the effect of :having a dummy electrode with each of five added resistances from zero to infinity (no dummy electrode). An initial potential relative to the pseudo reference/counter electrodLe of 400 mV was imposed on the working electrode and the content at the working electrode wzEs monitored over time. The results were reported in Figure 5.
t s Figure 5 illustrates that as the resistance increases so does the current at the working electrode. This is an indirect indication that the half cell potential of the pseudo referencelcounter electrode is being stabilized. In an ideal situation the current at the working electrode should be independent of the resistance of the dununy electrode and should just depend upon l~:he rate Zo at which glucose is oxidized. However, in the real world the extra current ~s WO 99/58709 PCT/GB!99/01424 load imposed on the pseudo referencelcounter electrode by the dummy electrode does cause an observable shift in the half cell potential of the pseudo reference/counter electrode. This in turn has an effect upon t:he current observed at the working electrode. As th.e potential difference between the working and pseudo reference/counter electrodes decreases because of this shift so does the current at the working electrode.
In addition, under some conditions the current decay at the working electrode departs from the expected model. In particular, it is expected the current will decrease monotonicly with time and tend to exhibit the behavior io predicted by the Cottrell equation. However, under certain conditions when the dummy electrode is :imposing a significant current load on the pseudo reference/counter electrode the current at the working electrode departs from classical behavior and may actually increase with time over some short time period. This is clearly illustrated in the lowest most curve of Figure 5, z s which represents a disposable test strip in which there is no resistance differential between the circuit path involving the working electrode and that involving the dummy electrode.
The glucose meters with which the disposable test strips of present concern are typically used have electronic features designed to detect invalid zo test results. One of these check features is a monitoring of the current decay at the working electrode. if this decay is not mor~otonic the meter will report an error condition and abort the test.
Thus increasing the resistance of the dummy electrode has been shown to be effective in decreasing the likelihood of a non-monotonic current decay at the working electrode and the ccansequent abortion of a test.
The measurement of analytes such as glucose in complex liquid media such as human blood by amperomeiric methods, using disposable test strips has become widely used and is currently employed in a number of commercial products. W certain configurations it is advantageous' to ~o improve the signal to noise ratio by employing a three electrode system in which one electrode selves as a pseudo referencelcounter electrode to establish a reference potential. Typically this is a silverlsilver chloride electrode. A second, working electrode is coated with an enzyme which promotes an oxidation or a reduction reaction with the intended anal;yte and is a mediator which transfers electrons between the enzyme and the electrode.
The third 'gdummy" electrode is coated with the mediator but not the enzyme and it provides a measure; of the current which arises from other than the oxidation reduction reaction involving the target: analyte. An exarnplle of such a system is described in U.S. Patent No. S,ti28,980 to Carter, et al.
WO 9915$709 PCTIGB!99101424 (incorporated by reference herein) and is utilized in the MediSense Q:ID
glucose meter.
The three electrode: system provides a good way to isolate the c:unrent which arises from the oxidation reduction reaction involving the target analyte such as glucose but it also imposes a higher current load on the pseudo reference/counter electrode. In some testing environments such as glucose meters used by diabetics in their homes it is impractical or impossible to pretreat the samples to remove possible interferants. Thus with home use glucose meters the diabetic simply applies a sample of whole io blood. Whole blood typically contains a number of electrochemically active species whose concentration may vary from person to person or even :from sample to sample from the same individual. The dummy electrode provides a measure of current arising from the presence of these interferants thus allowing a normalization 'which removes their contribution to the current ~ s measured at the working f:Iectrode. However, in such a three electrode configuration the current seen by the pseudo refen~encelcounter electrode includes contributions from both the working elea~trode and the dummy electrode. Thus in some cases the pseudo reference/counter .electrode sees a significantly greater current than it would in a two electrode configuration.
The pseudo reference/counter electrode: in such a configuration is, in fact, serving two roles which can be inconsistent if the current it sf:es becomes too great. It serves, on the one hand, to provide a constant half cell potential, i.e. a reference potential and, on the other hand, it also serves as a counter electrode balancing the electron transfer occurring at the v~rorking and dummy electrodes. For instance, in a typical glucose metermediator is becoming oxidized at the working and dummy electrodes so a reduction reaction needs to occur at the pseudo reference/counter electrode t~o balance the electron transfer. 'J~lith the typical Ag/Ag~~l pseudo reference/counter io electrode this involves the reduction of silver ions thus consuming (or reducing) silver chloride. If too much silver e:hloride is consumed the pseudo reference/counter electrode can no longer serve its furiction of providing a source of constant half cell potential. In other words, the potential difference between the two electrodf: reactions such as th.e is oxidation of a mediator at the working electrode and the reduction of silver at the pseudo reference/counter electrode will actually shift as the :reaction proceeds.
one approach is. to redesign the pseudo reference/counter electrode to handle higher current loads without displaying a significant shift in half cell ?o potential. This would normally mean increasing the size or silver WO 991587U9 . PCT/GB99/01424 concentration of the pseudo reference/counter electrode relative to the working and dummy electrodes. It is difficult to further reduce the; size of the working electrode because its size has already been minimized. It is limited by the economically acceptable procedures for reproducibly manufacturing millions of such disposable test strips. ~n the other hand;
increasing the size or silver concentration of t1':~e pseudo reference/counter electrode would significantly increase the cost: of such three electrode disposable strips because silver is the most expensive material used in the construction of such strips.
to Therefore, there is a need for three elecltrode disposable test strips for use in amperometric systems whose cost is comparable to two electrode test strips and yet have pseudo reference/counter electrodes with about the same stability as in the two electrode test strips.
It has been discovered that the current load on the pseudo referencelcounter counter electrode in a disposable test strip _for use in amperometric measurements with a three electrode system can be decreased zo and therefore its half cell potential better stabilized by increasing tile WO 99/58709 PCTIGB'99/01424 resistance of the dummy electrode. This allovvs three electrode test strips to give better performance without changing the operating characteristics of the meters in which they are used.
Increasing the resistance of the dummy electrode not only reduces the total current passing d-:crough the pseudo refere:ncelcounter electrode but it also changes the potential at the dummy electrode's interface with the sample. Thus it iS possible to have a three electrode system which can simultaneously measure the concentration oftwo analytes. The effective potential at the "dumzr~y" electrode with the higher total resistance can be io adjusted to be too low to effect an oxidation reduction reaction indicative of the concentration of one of the two target analytes.
It is preferred to have the resistance of the dummy electrode be at least 1000 ohms greater than that of the working electrode and it is especially preferred that the resistance differential be at least about 4000 is ohms.
It is also preferred that the resistance of the dummy electrode be increased by putting a resistance in series with the active electrode surface of this electrode. Thus both the area and nature of the active surface of the dummy electrode are kept similar or identical to that of the working zo electrode. This can readily be achieved by increasing the resistance of the WO 99/58709 PCT/GB.99/01424 conductive track which connects the active electrode surface to the meter which applies the potential and measures the resulting current. In the typical disposable strip for amperometric analyte measurement three electrode surfaces are present on one end of an elongate;d flat strip and three contact pads, one for each of the electrode surfaces, a:re present on the other end of the strip. Each electrode surface is connected to its contact pad by a conductive track. The contact pads serve as the means to establish electrical contact between the strip and the meter which applies the potential. and measures the resultant content. Th:e conductive tracks are typically covered io by an insulating layer to~prevent any short circuits between them.
It is particularly preferred to increase the resistance of the conductive track of the dummy electrode by narrowing its width. ff this conductive track is made of the same material as the worf;ing electrode's conductive track and has about tl~e same thickness as the conductive track of fibs i s working electrode it will have a higher resistance. Such a mechanism of increasing resistance is particularly easy to im:plernent in mass manufacturing.
WO 99158709 PCT/G~t99/01424 An example of the present invention will be described in accordance with the accompanying drawings, in which:
Figs. I a and 1 b are schematic diagraEms depicting the conductive layers of electrodes of disposable test strips having dummylsecond working electrodes with narrowed conductive layers;
Fig. 2 is a schematic diagram depicting the conductive layers of electrodes of a control disposable test strip ;
Fig. 3 is an exploded view of a disposable test strip ;
Fig. 4 is a perspective view of the assembled strip of Fig.. 3 ; end Fig. 5 is a series of plots of current i:n microamps versus tiime in seconds for a working electrode subjected to a;n initial potential of 400 milliVolts in the presence of a glucose contairung sample for various dummy electrode conf gurations.
The three electrode disposable test strip for the amperometric measurement of analytes in complex liquid media is optimized to improve the signal to s noise ratio without irn.posing an excessive cun-ent load on the reference/counter electrode by increasing the resistance of the dumrny electrode, i.e. the electrode which carries the electrochemical mediator also WO 99/5$709 PCTIGB!19/01424 utilized at the working electrode but which has no enzyme or other reactant selected to engage the analyte in an oxidation rf:duction reaction. A typical environment for the application of this concept is the three electrode test strip described in U.S. Patent No. 5,628,890 for the determination of glucose in whole blood samples.
Such a test strip is typically constructed of an elongated strip of a rigid electrically non-conducting material such as plastic. Suitable plastics include PVC, polycarbonate or polyester. Three conductive tracks are laid on this strip so as to establish independent conductive paths from one end to io the other. Each track temninates at the end adapted to be proximate ?to the meter used to apply electrical potential and meaisure the resulting currents with a contact pad that interfaces with the meter. At the distal end of the strip each track terminates in an electrode adapl:ed to contact the complex liquid medium which carries the analyte to be measured. A typical medium i s is whole human blood and a typical analyte is g;iucose.
The working electrode is a pad which is coated with both a substance designed to engage the target analyte in an oxidation-reduction reaction and a mediator adapted to transfer electrons between the pad and the oxidation reduction reaction. A typical substance is an enzyme adapted to promote the Zo oxidation of glucose, such as glucose oxidase, and the mediator is a compound which readily transfers electrons from the oxidation reduction reaction to the pad, such as a ferrocene derivative.
The "dummy" electrode is a pad which preferably has the same surface area as the working electrode and is coated with the same amount of the same mediator as the working electrode. The concept is to provide an environment in the immediate vicinity of this "dummy" electrode which is essentially identical to that of the working electrode except for the substance, typically an enzyme, adapted to react with the target ana:lyte.
Then the spurious electrochemical reactions which might occur at the to working electrode giving rise to noise are just as likely to occur at tl:re "dummy" electrode. Tlzus the signal arising from such spurious reactions can be determined by measurement at the "dununy" electrode and subtracted from the total signal measured at the working electrode. This provides an improved signal to noise ratio.
~ s The pseudo reference/counter electrode i.s a pad with a maternal such as silver/silver chloride which has both the oxidized and reduced form of a species to provide an essentially constant half cell potential. So long as the relative proportions of the reduced and oxidized form of this species such as silver and silver chloride are not substantially changed the half cell potential Zo of this electrochemical couple will remain relatively constant. This facilitates being able to maintain a known constant oxidation or redv~uction potential at the working electrode. This allows; a production batch of disposable test strips to have a common calibration.
In the typical situation the disposable strips are utilized with a meter which functions to cozrelate the amount of cuzz~ent observed upon ttoe application of an external potential to the contact pads of the disposable strip to the amount of analyte present. This meter is designed to assume certain electrical characteristics will be observed upon the application of this external potential. One such assumption is that the amount of current ~o observed will decrease monotonically with time. If the current does. not decay in the expected manner the meter is programmed to abort the test. If the half cell potential of the pseudo referenceicounter electrode such as a silver/silver chloride electrode shifts the current characteristics may indeed fail to meet the expectations programmed into the meter causing an aborted i s test.
For example the lhalf cell potential of the: silver/silver chloride electrode will shift if the proportion of silver to silver chloride is changed.
As current flows through this electrode silver is either reduced or oxidized, depending on the nature of the reaction occurring at the working electrode.
zo In the typical meter for sensing glucose concentration glucose is oxidized at the working electrode reducing the mediator. The mediator then transfers the electron or electrons it has gained in this reduction reaction to its electrode pad. These electrons are then taken up at the pseudo reference/counter electrode. In the typical case this is a silver/silver chloride electrode and the electrons are taken up by the reduction of silver ions transforming silver chloride to silver metal.
If a sufficient amount of current passes through such a pseudo reference/counter electrode the proportion of silver to silver chloridE: will change enough to cause a noticeable change in the half cell potential of this io electrode. If this change becomes large enough the current at the working electrode may no longer decay monotonically. This in tum will cause the meter to sense an error condition and abort the test.
The current at the; working electrode arises from the oxidatior.~
reduction reaction involving the target analyte and the subsequent transfer of is electrons by the mediator. In the typical glueos~e meter glucose is oxidized by glucose oxidase and the mediator, for instance a ferrocene derivative, then transfers the electrons liberated by the oxidation of the glucose to its electrode pad. In detail the glucose oxidase becomes reduced by oxidizing the glucose in the sample which is exposed to tlhe disposable test strip and ?o then is reoxidized by reducing the mediator. The mediator in turn becomes WO 99J58709 PCT/GB'99/OI424 reoxidized by transferring electrons through it:. electrode pad to the circuit with the pseudo reference/counter electrode. r~'ormally the current arising from this transfer decays monotonically in accordance with the Cottrell equation as the mediator in reasonable diffusion distance to the electrode pad which was reduced by reaction with glucose oxidase is reoxidized.
However, this behavior' is dependent upon the potential at the working electrode being held at or above a certain potential relative to the pseudo referencelcounter electrode. If the potential at this pseudo reference/counter electrode shifts,the behavior at the working electrode may no longer follow ~o this pattern.
The disposable strips are typically designed so that the pseudo reference/counter electrode does not undergo such a potential shift. For instance this electrode can be made large enough that the current generated by the analyte concentrations typically encounl:ered does not consume ~s enough silver ions to cause such a shift.
The use of a third, "dummy" electrode, however, imposes an additional current load on the pseudo reference:/counter electrode. In the typical glucose meter where an oxidation reaction occurs at the working , electrode, the reduction. reaction occurring at the pseudo reference%;ounter ?o electrode must balance not only the oxidation reaction at the working electrode but also any oxidation reaction occurring at the "dummy"
electrode. This additional burden may be sufficient to shift the half:-cell potential of the pseudo reference/counter electrode out of its design range.
This is a particular problem in glucose rrleters which utilize an initially reduced mediator such as a ferrocene derivative. In such a meter there is an initial high current load as the mediator is oxidized at both the working and "dummy" electrodes. if there is also a high level of glucose in the sample being tested, there will also be a fairly high current load from the reoxidation of mediator initially reduced as a result of the oxidation of the io glucose. The combined current load has a tendlency to adversely efi:ect the half cell potential of the pseudo referencelcounter electrode.
The total current Load on the pseudo reference/counter electrode can be reduced by increasirng the resistance in the overall circuit. However, it is impractical to change the resistance in the circuit involving the working ~ s electrode. The meters used with the disposable; test strips of presenl:
concern are calibrated to correlate the level of current in the working electrode circuit after sometime period or over some fixed time interval after exposu7re of the test strip to the sample to the concentration of target analyte. Then the meters are distributed to a large number of users who expect to use l:he Zn meters with the disposable test strips for a number of years. Thus it is m impractical to make any change in such test strips which would reg~uire a corresponding change in the meter with which they are used.
It has, however, been found that the resistance in the "dummy"
electrode circuit can be increased without advc:rseiy effecting the interaction between the disposable test strip and its meter. The function of the "dummy" electrode is to allow subtraction from the total signal or current at the working electrode of that portion attributable to superious oxidation-reduction reactions with species in the complex liquid medium other than the target analyte. This subtraction is only of conc:em at the time or over the ~o interval during which the current at the working electrode is measured for correlation to the analyte concentration. Typically such measurements are made after the resistamc:e of the overall system is comparatively high after most of the oxidation at the working electrode has already occurred.. It has been discovered that at this point the difference in electrochemical is environments at the working and "dummy" electrodes is insufficient to adversely effect the function of the dummy electrode.
The relative difference in electrochemical environment between the working electrode and a "dummy" electrode with added resistance does tend to decrease as a test cycle proceeds. As the mE:diator subject to reoxidation Zo at the working electrode decreases the effective resistance in the working ~a electrode circuit increases, i.e. there are few species to support electron transfer. Thus although there will always be a fixed difference in resistance between the working and "dummy" electrodes circuits the percentage difference will decrease as the effective resistance in the working electrode circuit increases.
In an alternative embodiment, the three e~iectrode arrangement is used to simultaneously measure the concentration oiF two analytes. In this case there are two working electrodes and one pseudo reference/counter electrode. The first working electrode is designed to operate with a first io substance that engages one of the target analytes in an oxidation reduction reaction at a relatively flow potential. The second working electrodf: is designed to operate with a second substance that engages the other target analyte in an oxidation reduction reaction only at a higher potential. For ease in manufacturing both working electrodes are typically coated with i s both substances and appropriate mediators. However, the test strip is designed so that the second substance which is coated on the fast warking electrode remains inactive. In particular, the electrical resistance in the circuit path from the contact pad connected to the first working electrode through the first working electrode is significantly greatly than the c~Iectrical ~o resistance in the circuit path from the contact pad connected to the :second ~s WO 99/5$709 PCTIGB99/01424 working electrode through the working electrode. Thus when a certain electrical potential is applied to the contact pads of both electrodes relative to the pseudo reference/counter electrode, the effective potential at: the first working electrode is less than that at the second working electrode, some of the potential drop having been expended traversing the higher circuit resistance.
The two analyte embadirnent is applied to the simultaneous measurement of ketones and glucose by utilizing an enzyme mediator system far the ketones which operates at +200mV and an enzyme mediator io system for the glucose which operates at +400mv. In particular, h~~droxy butyrate dehydrogenase (HBDH) with a nicotinamide adenine dinucleotide (NADH) cofactor and a 1,10-phenanthroline c~uinone ( 1,10 PQ) mE:diator is used for the ketones and glucose oxidase with a ferrocene derivative mediator is used for the glucose.
~ s The low operating potential of the HBD~H/NADH/ 1,10 PQ system is a significant advantage for an analyte like ketones which has a limited linear response range. In the case of ketones a linear response is typically expected only over a range of between about 0 and 8 m;illi Molar. By :operating at a low potential interference from other species which might undergo an Zo oxidation reduction reaiction at a higher potential is avoided. In other words, 1 fi the probability that another chemical species in the sample might lbecome oxidized and deliver electrons to the first working electrode thus making a superious contribution to the current sensed at this electrode is minimized.
The potential at the first working electrode is adjusted so that upon the application of a 400mV potential between the; second working electrode and the reference/counter electrode the potential between this first working electrode and the reference/counter electrode is 200mV. This adjustment is effected by increasing the resistance of the circuit path involving this electrode relative to that involving the second. working electrode by an io appropriate amount in one of the ways discussed hereinabove.
The current sensed at the fzrst working electrode is the result of the oxidation of ketones while that sensed at the second working electrode is the result of the oxidation of both ketones and glucose. The amount o~f current at each electrode carp then be employed in a sample simultaneous equation to is determine the concentration of ketones and glucose in the same sample.
It is, of course, possible to coat only the first working electrode with the ketones sensitive chemistry and to coat or.~ly the second working electrode with only the glucose sensitive chernistry. This would be expected to result in higher manufacturing costs. Typically the disposable test strips Zo are manufactured by a series of printing steps so that applying different E~
chemistries to each working electrode would require additional printing steps.
A particular application of the concept of a high resistance clammy electrode to the measurement of glucose is ilhustrated in Figures 1 through 5.
s In the strips illustrated, the working electrode and the dummy electrode each had a surface area of 6.612 square millimeter:> while the pseudo reference/counter elecitrode had a surface area. of 4.18 square millin:neters.
The conductive tracks which connect the contact pads to the electrode pads are in most cases 0.$Ol millimeters. In two cases the conductive track to associated with the dummy electrode was narrowed to 0.510 millimeters and 0.305 millimeters, as illustrated in Figures Ia and Ib.
Two different conductive layer prints a:re illustrated in Figs. I a (Track A) and I b (Track B). A control conductive layer print, in which tree working and dummy electrodes have the same resistance, is shown in Fig. ~~.
a s Referring to Figs. 1 a, 1 b and 2, the electrode configuration on the sensor strips has three printed layers of electrically conducting carbon ink: 2. The layers define the positions of the pseudo reference/counter electrode 4, the working electrode 5, the dummy electrode Sa and electrical cantacts 3.
Referring to Fig. 2, working electrode _'i has a track width l fi that is zo equal to track width 16a of dummy electrode Sa. Equal track widths 16 and ~s WO 99!58709 PCTIGB99/01424 1 ba give the working electrode and dummy electrode equal resistances.
Referring to Figs. 1 a and 1 b, track widths 1 f b and 16c of dummy electrode 5a are narrower than track width 16a of the control in Fig. 2. The conductive Iayer of dummy electrode 5a is nacTOwed in order to increase the s resistance of the dummy electrode relative to t:he working electrode resistance. Track width 16c is smaller than track width 16b. Thus, the resistance of dummy electrode 5a in Track A yig. l a) is greater than the resistance of dummy electrode 5a in Track B (dig. ib).
to The composition of the conductive layers can also affect the resistance of the electrodes. Generally, the conductive layers of the electrodes are printed at the same tirr.~e with the same ink. The conductive layers can be printed with a low carbon-content ink or a high carbon-content ink. Low carbon-content had a carbon content of between 30 and 3 I weight percent is and a resin content of between 7 and 9 weight percent. The high c;3rbon-content ink has a carbon content of between 42 and 45 weight percent, and a resin content of between '~ and 9 weight percent.
A suitable electrode sensor strip is illustrated in Figs. 3 and 4.
Referring to Figs. 3 and 4, the electrode support I, an elongated strip of Zo plastic material (e.g., PVC, polycarbonate, or ;polyester) supports tlZree WO 99158709 PCT/GB!99/01424 printed tracks of electrically conducting carbon ink 2. These printed tracks define the positions of the pseudo reference/counter electrode 4, of the working electrode S, of the dummy electrode :pa, and of the electrical contacts 3 that are inserted into an appropriate measurement device (not s shown). The conductive layer of dummy electrode Sa is narrowed in order to increase the resistance of the dummy electrode relative to the wcarking electrode.
The elongated portions of the conductive tracks are each overlaid with silverlsilver chloride particle tracks 6a and 6b., with the enlarged exposed io area overlying 4, and Eb and 4 together forming the pseudo reference/counter eleci:rode. The conductive track or Iayer for dummy electrode Sa is not overlaid with silver/silver chloride. This further increases the resistance of the dummy electrode. The conductive tracks are :further overlaid with a layer of hydrophobic electrically insulating material 7 that ~ s leaves exposed only th.e positions of the pseudo reference/counter .electrode, the working electrode .and the dummy electrode, and the contact areas. This hydrophobic insulating material prevents short circuits. Because tl'nis insulating material is hydrophobic, it can confine the sample-~to the. exposed electrodes. A prefezTed insulating material is available as POLYP~LAST~' ?o (Sericol Ltd., Broadsta~irs, Kent, IlK).
ao WO 99/58709 PCTlGB991U1424 The working electrode working area 8 its formed from an irk: that includes a mixture of an enzyme, a mediator, and a conductive material.
The dummy electrode working area is formed. from ink that includes a mixture of a mediator and a conductive material without enzyme. The s respective inks are applied to the positions 5 and Sa of carbon traclks 2 as discrete areas of fixed length. Alternatively, instead of an enzyme, electrode layer 8 can contain a substrate catalytically reactive with an enzyme to be assayed. The conductive material in a preferred embodiment includes particulate carbon having the redox mediator adsorbed thereon.
io A printing ink is formed as an aqueous solution of the conductor and adsorbed redox mediator. For the working electrode, it also includes the enzyme or, alternatively, a substrate. When the analyte to be mea:>ured is blood glucose, the enzyme is preferably glucc>se oxidase, and the redox i s mediator is a ferrocene derivative.
The inl: can be screen printed. The ink can include a polysaccharide (e.g., a guar gum or an alginate), a hydrolyzed gelatin, an enzyme stabilizer (e.g., glutamate or trehalose), a film-forming ;polymer (e.g., a polyvinyl alcohol), a conductive filler (e.g., carbon), a redox mediator (e.g., ferrocene ~o or a ferrocene derivative), a defoaming agent" a buffer, and an enzyme or a WO 99/5$709 PCT/GB'99/01424 substrate. The ini: printed on a dummy electrode lacks the enzymf: or the substrate.
The pseudo reference/counter electrode: 5b is situated relative to the working electrode 8 and dummy electrode 8a such that it is in a non-ideal position for efficient electrochemical function. The electrodes are arranged not to minimize the effect of the resistance of~ the solution on the overall resistance of the circuit (as is conventional). Positioning the pseudo referencelcounter electrode downstream of the working electrode leas the advantage of preventing completion of a circuit (and thus detectioo~ of a io response) before the working electrode has bE:en completely covered by sample.
The electrode area is overlaid by a fine grade mesh 9. This mesh protects the printed components from physical damage. It also heJ(ps the sample to wet the pseudo reference/counter electrode and working; electrode ~s by reducing the surface tension of the sample, thereby allowing it to spread evenly over the electrodes. Preferably, this rr~esh layer extends over the whole length of the sample path, between and including, the application point and the electrode area. Preferably, this mesh is constructed of finely woven nylon strands. Alternatively, any woven or non-woven material can zo be used, provided it does not occlude the surface of the electrode such that nozmal diffusion is obstructed. The thickness of the mesh is selected so that the resulting sample depth is sufficiently small to produce a high solution resistance. Preferably, the fabric is not more than 70 urn in thicknfas.
Preferably the mesh has a percent open area of about 40 to about 4:5%, a s mesh count of about ~5 to about 1 i S per cm, a. fiber diameter of about 20 to about 40 p.m, and a thickness of from about 40 to about 60 pm. A suitable mesh is I~1Y64 HC mesh, available from Sefar (formerly ZBF), CH-8803, Ruschlikon, Switzerland.
The mesh can be surfactant coated. This is only necessary if the mesh io material itself is hydrophobic (for example, nylon or polyester). If a hydrophilic mesh is used, the surfactant coating can be omitted. Any suitable surfactant can be used to coat the mesh, so long as it allows adequate even spreading of the sample. A preferred surfactant is FC 170C
FLUORAD° fluorochemical surfactant (3M, ,3t. Paul, MN).
FLUORAD° is ~ s a solution of a fluoroaliphatic oxyethylene adduct, lower polyethylene glycols, 1,4-dioxane, and water. A preferred surfactant loading for most applications is from about 15-20 ug/mg of mesh. The preferred surfactant loading will vary depending on the type of mesh and surfactant used and the sample to be analyzed. It can be determined empirically by observing flow zo of the sample through the mesh with different levels of surfactant.
WO 99/58709 PCT/GB!99/01424 A second layer of coarser surfactant coated mesh 10 is applied over the first mesh. This second mesh layer controls the influx of the saimple as it travels from the application point toward the F>seudo reference/cownter and working electrode areas by providing a space .into which the displaced air s within the sample transfer path can move as the sample moves prel:erentially along the lower fine grade mesh layer 9 and partially in mesh layer 10. The spacing of the larger fibers of the secondary mesh layer, perpendicular to the direction of sample flow, helps to control the :>ample flow by presenting repeated physical bazxiers to the movement of the sample as it travels io through the transfer path. The regular pattern of the mesh fibers ensures that the sample progresses in stages and that only samples with sufficient volume to generate an accurate: response are able to pass all the way along the pathway and reach the pseudo reference/count:er electrode.
~ s Preferably, mesh 10 is of a woven consl:ruction, so that it preaents a regular repeating pattern of mesh fzbers both perpendicular to and parallel to the longest aspect of the strip. Generally, the second mesh layer should be substantially thicker than the first mesh, with liarger diameter-mesh fibers and larger apertures between them. The large~~ mesh preferably has a ?o thickness of from 100 to 1000 pm, with a thiciicness of from 100 to I 50 ~m ~a WO 99/5$709 PCT/GB99/01424 being most preferred_ A preferred mesh has a percent open area of about 50 to about SSf%, a mesh ~:ount of from about 45 'to about 55 per cm, amd a fiber diameter of from about SS to about b5 p.m. A preferred mesh is NY 151 HC
mesh, also available from Sefar, CH-8803, Rushchlikon, Switzerland.
s Mesh 10 is also provided with a coating; of a suitable surfactant {unless the mesh itself is hydrophilic). Preferably, it is the same surfactant as that on the first mesh layer. The loading of surfactant is lower on mesh than on mesh 9, providing a further barrier to movement of samiple past the transverse fibers of mesh 10. In general, a~ loading of 1-10 p.ghng of io mesh is preferred.
The mesh layers 9 and 10 are held in place by layers of hydrophobic electrically insulating ink 11. These layers can be applied by screen printing the ink over a portion of the peripheries of the: meshes. Together, the layers and mesh surround and define a suitable sample transfer path 12 for the 1 s sample to travel from the application point at the furthest end of the strip towards the working electrode and pseudo reference/counter electrode. The ink impregnates the mesh outside of path 12. The insulating material thus defines sample transfer path 12 by not allowing sample to infiltratf: the area of mesh covered by the layers of insulating material. A preferred insulating ~S
WO 99/58709 PCT/GB!~9/01424 ink f or impregnating the mesh layers is SERIt~ARD° (Sericol, Ltdl., Broadstairs, Kent, UK).
The upper part of the electrode is enclosed by a liquid/vapor impermeable cover membrane 13. This can be a flexible tape made of s polyester or similar material which includes a small aperture 14 to allow access ofthe applied sample to the underlying; surfactant coated mesh layers.
The impermeable cover membrane encloses the exposed working electrode and pseudo reference/counter electrode. Thus., it maintains the available sample space over the electrodes at a fixed height which is equivalent to the io thickness of both mesh layers 9 and 10. This ensures that the solution resistance is kept at a high level. Any sample thickness up to the maximum depth of the two mesh layers is adequate in this respect. Aperture 14 is positioned overlying the furthest end of the of>en mesh area, remote from the pseudo reference/counter electrode 6b, such drat the exposed area of mesh is beneath the aperture can be used as a point of access or application for the-liquid sample to be measured. The aperture can be of any suitable size large enough to allow sufficient volume of sample to pass through to the mesh layers. It should not be so large as to expose any of the area of the electrodes. The aperture is formed in the covE:r membrane by any suitable Zo method {e.g., die puncihing). The cover membrane is affixed to the. strip 2E~
WO 99/58709 PCT/GB!~9/01424 along a specific section, not including the electrodes, the sample transfer path or application area, using a suitable method of adhesion. Preferably this is achieved by coating the underside of a polyester tape with a layer of hot melt glue which is then heat welded to the electrode surface. Th.e hot s melt glue layer is typically of a coating weight between 10-50 g/m2, preferably from 20 to 30 g/mz. Pressure sensitive glues or other equivalent methods of adhesion may also be used. Care should be taken when the tape is applied, the heat and pressure applied to the cover membrane can melt the SERICARD° .and can cause it to smear onto adjoining areas.
io The upper surface of the cover membrane can also be usefully provided with a layer of~ silicone or other hydrophobic coating which helps to drive the applied sample onto the portion of exposed surfactant coated mesh at the application ;point and thus make the: application of small volumes of sample much simpler.
is In use, a disposable test strip of the invention is connected, via electrode contacts 3, to a meter {not shown). A sample is applied to aperture 14, and moves along the sample transfer path 12. The progress of the sample is sufficiently impeded by mesh Layer 10 to allow the sample to form a uniform Zo front rather than flowing non-uniformly. Air is displaced thorough the upper WO 99/58709 PCTIGB!99101424 portion of mesh layer 10 to and through aperture 14. The sample first covers working electrode 5 in its entirety, and only then. approaches and covers pseudo reference/countelvelectrode 4. This com~aletes the circuit and causes a response to be detected by the measuring device.
The effect of increasing the resistance of a dummy electrode in a system for measuring glucose in a whole blood sample was electronically modeled. In particular, Ivledisense G2a disposable test strips which utilize glucose ~oxidase and a, ferrocene mediator were tested using venous lblood spiked with glucose to a concentration of 15m1VJ~. The electronics was used io to simulate the effect of :having a dummy electrode with each of five added resistances from zero to infinity (no dummy electrode). An initial potential relative to the pseudo reference/counter electrodLe of 400 mV was imposed on the working electrode and the content at the working electrode wzEs monitored over time. The results were reported in Figure 5.
t s Figure 5 illustrates that as the resistance increases so does the current at the working electrode. This is an indirect indication that the half cell potential of the pseudo referencelcounter electrode is being stabilized. In an ideal situation the current at the working electrode should be independent of the resistance of the dununy electrode and should just depend upon l~:he rate Zo at which glucose is oxidized. However, in the real world the extra current ~s WO 99/58709 PCT/GB!99/01424 load imposed on the pseudo referencelcounter electrode by the dummy electrode does cause an observable shift in the half cell potential of the pseudo reference/counter electrode. This in turn has an effect upon t:he current observed at the working electrode. As th.e potential difference between the working and pseudo reference/counter electrodes decreases because of this shift so does the current at the working electrode.
In addition, under some conditions the current decay at the working electrode departs from the expected model. In particular, it is expected the current will decrease monotonicly with time and tend to exhibit the behavior io predicted by the Cottrell equation. However, under certain conditions when the dummy electrode is :imposing a significant current load on the pseudo reference/counter electrode the current at the working electrode departs from classical behavior and may actually increase with time over some short time period. This is clearly illustrated in the lowest most curve of Figure 5, z s which represents a disposable test strip in which there is no resistance differential between the circuit path involving the working electrode and that involving the dummy electrode.
The glucose meters with which the disposable test strips of present concern are typically used have electronic features designed to detect invalid zo test results. One of these check features is a monitoring of the current decay at the working electrode. if this decay is not mor~otonic the meter will report an error condition and abort the test.
Thus increasing the resistance of the dummy electrode has been shown to be effective in decreasing the likelihood of a non-monotonic current decay at the working electrode and the ccansequent abortion of a test.
Claims (23)
1. A disposable test strip suitable for attachment to the signal readout circuitry of a meter which performs an amperometric test to detect a current representative of the concentration of an analyte in a complex liquid medium comprising:
(a) a working electrode which comprises an electrode pad coated with both a substance designed to engage said analyte in an oxidation-reduction reaction and a mediator compound which will transfer electrons between the oxidation-reduction reaction and the electrode pad;
(b) a dummy electrode which comprises an electrode pad which is coated with about the same amount of mediator compound as the working electrode but lacks the substance which engages the analyte in the oxidation-reduction reaction;
(c) a pseudo reference/counter electrode which comprises an electrode pad coated with a material which contains both the oxidized and reduced form of a chemical species which is designed to undergo a reduction or oxidation reaction to balance the opposite reaction at the working and dummy electrodes; and (d) three conductive tracks, each of which extends from a contact pad adapted to interface with said readout circuitry to one of the electrode pads and which is in electrical contact with both its contact pad and its electrode pad;
wherein the electrical resistance in the circuit path from the contact pad connected to the dummy electrode through the dummy electrode is significantly greater than the electrical resistance in the circuit path from the contact pad connected to the working electrode through the working electrode.
(a) a working electrode which comprises an electrode pad coated with both a substance designed to engage said analyte in an oxidation-reduction reaction and a mediator compound which will transfer electrons between the oxidation-reduction reaction and the electrode pad;
(b) a dummy electrode which comprises an electrode pad which is coated with about the same amount of mediator compound as the working electrode but lacks the substance which engages the analyte in the oxidation-reduction reaction;
(c) a pseudo reference/counter electrode which comprises an electrode pad coated with a material which contains both the oxidized and reduced form of a chemical species which is designed to undergo a reduction or oxidation reaction to balance the opposite reaction at the working and dummy electrodes; and (d) three conductive tracks, each of which extends from a contact pad adapted to interface with said readout circuitry to one of the electrode pads and which is in electrical contact with both its contact pad and its electrode pad;
wherein the electrical resistance in the circuit path from the contact pad connected to the dummy electrode through the dummy electrode is significantly greater than the electrical resistance in the circuit path from the contact pad connected to the working electrode through the working electrode.
2. The disposable test strip of Claim 1 wherein the greater electrical resistance in the dummy electrode circuit is provided by increasing the resistance of the conductive track connecting the dummy electrode to its contact pad.
3. The disposable test strip of Claim 1 or 2, further comprising an elongate support having a substantially flat, planar surface. arranged to be releasably attached to the readout circuitry.
4. The disposable test strip of Claim 3 wherein the three conductive tracks are created by coating conductive particles on the elongated support.
5. The disposable test strip of Claim 4 wherein the conductive particles comprise carbon.
6. The disposable test strip of Claim 4 or 5 wherein a greater electrical resistance is imparted to the conductive track connecting the dummy electrode to its contact pad by using a smaller volume of conductive particles in this track as compared to that used in the conductive track connecting the working electrode to its contact pad.
7. The disposable test strap of any one of Claims 2 to 6 wherein the conductive track connecting the dummy electrode to its contact pad is narrower than the conductive track connecting the working electrode to its contact pad.
8. The disposable test strip of any one of Claims 2 to 7 wherein the conductive track connecting the dummy electrode to its contact pad is thinner than the conductive track connecting the working electrode to its contact pad.
9. The disposable test strip of any one of Claims 2 to 8 wherein the conductive track connecting the dummy electrode to its contact pad has a different composition than the conductive track connecting the working electrode to its contact pad.
10. The disposable test strip of Claim 9 wherein both the conductive track connected to the dummy electrode and the conductive track connected to the working electrode are comprised of carbon particles but only the latter conductive track is coated with silver.
11. The disposable test strip of any one of Claims 2 to 10 wherein the conductive track connecting the dummy electrode to its contact pad is longer than the conductive track connecting the working electrode to its contact pad.
12. The disposable test strip of any one of the preceding claims wherein the analyte is glucose and the substance engaging the analyte in an oxidation reduction reaction is an enzyme.
13. The disposable test strip of Claim 12 wherein the enzyme is glucose oxidase.
14, The disposable test strip of any one of the preceding claims wherein the mediator is a ferrocene derivative.
15. The disposable test strip of any one of the preceding claims wherein said pseudo reference/counter electrode comprises an electrode pad coated with a mixture of silver and silver chloride.
16. The disposable test strap of any one of the preceding claims wherein the electrical resistance in said dummy electrode circuit is at. least 1000 ohms greater than in said working electrode circuit path.
17. A disposable test strip suitable for attachment to the signal readout circuitry of: a meter which performs an amperometric test to detect currents representative of the concentrations of multiple analytes in a liquid medium comprising:
(a) a first working electrode which comprises an electrode pad coated with both a substance designed to engage one of the multiple analytes in an oxidation-reduction reaction at a first electrical potential difference and a mediator compound which will transfer electrons between its oxidation-reduction reaction and its electrode pad;
(b) a second working electrode which comprises an electrode pad which is coated with both a substance designed to engage another of the multiple analytes in an oxidation-reduction reaction at a second electrical potential difference which is significantly greater than said first electrical potential difference and another mediator compound which will transfer electrons between its oxidation-reduction reaction and its electrode pad;
(c) a pseudo reference/counter electrode which comprises an electrode pad coated with a material which contains both the oxidized and reduced form of a chemical species which is designed to undergo a reduction or oxidation reaction to balance the opposite reactions at the first and second working electrodes; and (d) three conductive tracks, each of which extends from a contact pad intended to interface with said readout circuitry to one of the electrode pads and which is in electrical contact with both its contact pad and its electrode pad;
wherein the electrical resistance in the circuit path from the contact pad connected to the first working electrode through the first working electrode is significantly greater than the electrical resistance in the circuit path from the contact pad connected to the second working electrode through the second working electrode.
(a) a first working electrode which comprises an electrode pad coated with both a substance designed to engage one of the multiple analytes in an oxidation-reduction reaction at a first electrical potential difference and a mediator compound which will transfer electrons between its oxidation-reduction reaction and its electrode pad;
(b) a second working electrode which comprises an electrode pad which is coated with both a substance designed to engage another of the multiple analytes in an oxidation-reduction reaction at a second electrical potential difference which is significantly greater than said first electrical potential difference and another mediator compound which will transfer electrons between its oxidation-reduction reaction and its electrode pad;
(c) a pseudo reference/counter electrode which comprises an electrode pad coated with a material which contains both the oxidized and reduced form of a chemical species which is designed to undergo a reduction or oxidation reaction to balance the opposite reactions at the first and second working electrodes; and (d) three conductive tracks, each of which extends from a contact pad intended to interface with said readout circuitry to one of the electrode pads and which is in electrical contact with both its contact pad and its electrode pad;
wherein the electrical resistance in the circuit path from the contact pad connected to the first working electrode through the first working electrode is significantly greater than the electrical resistance in the circuit path from the contact pad connected to the second working electrode through the second working electrode.
18. The disposable test strip of Claim 17 wherein there are only two working electrodes.
19. The disposable test strip of Claim 17 or 18 wherein the pseudo reference/counter electrode comprises an electrode pad coated with a mixture of silver and silver chloride.
20, The disposable test strip of any one of Claims 17 to 19 wherein the first working electrode comprises an enzyme system adapted to engage ketones and a suitable mediator and the second working electrode comprises an enzyme suitable to engage glucose and a suitable mediator.
21. The disposable test strip of Claim 20 wherein the first working electrode comprises a HBDH/NADH/1,00 PQ
system and the second working electrode comprises glucose oxidase and a ferrocene based mediator.
system and the second working electrode comprises glucose oxidase and a ferrocene based mediator.
22. The disposable test strip of Claim 21 wherein the resistance in the first working electrode circuit is such that when a 400 mV potential exists between the second working electrode and the pseudo reference/counter electrode there is a 200 mV potential between the first working electrode and the pseudo reference/counter electrode.
23. A disposable test strip substantially as shown in or described with respect to Figures 1a, 1b, 3, 4 or 5 of the accompanying drawings.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9809963A GB2337122B (en) | 1998-05-08 | 1998-05-08 | Test strip |
| GB9809963.3 | 1998-05-08 | ||
| PCT/GB1999/001424 WO1999058709A1 (en) | 1998-05-08 | 1999-05-06 | Test strip |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2331824A1 true CA2331824A1 (en) | 1999-11-18 |
Family
ID=10831758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002331824A Abandoned CA2331824A1 (en) | 1998-05-08 | 1999-05-06 | Test strip |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US6540891B1 (en) |
| EP (1) | EP1075538A1 (en) |
| JP (1) | JP4439733B2 (en) |
| AR (2) | AR015075A1 (en) |
| AU (1) | AU758617B2 (en) |
| BR (1) | BR9910284A (en) |
| CA (1) | CA2331824A1 (en) |
| CO (1) | CO4890893A1 (en) |
| GB (1) | GB2337122B (en) |
| WO (1) | WO1999058709A1 (en) |
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| KR0151203B1 (en) * | 1994-12-08 | 1998-12-01 | 이헌조 | Multi-electrode type biosensor |
| US5628890A (en) * | 1995-09-27 | 1997-05-13 | Medisense, Inc. | Electrochemical sensor |
| JPH09201337A (en) * | 1996-01-25 | 1997-08-05 | Casio Comput Co Ltd | Glucose measuring device |
| US5708247A (en) * | 1996-02-14 | 1998-01-13 | Selfcare, Inc. | Disposable glucose test strips, and methods and compositions for making same |
-
1998
- 1998-05-08 GB GB9809963A patent/GB2337122B/en not_active Expired - Fee Related
-
1999
- 1999-05-06 BR BR9910284-6A patent/BR9910284A/en not_active IP Right Cessation
- 1999-05-06 CO CO99027698A patent/CO4890893A1/en unknown
- 1999-05-06 AU AU38358/99A patent/AU758617B2/en not_active Ceased
- 1999-05-06 AR ARP990102135A patent/AR015075A1/en not_active Application Discontinuation
- 1999-05-06 EP EP99920981A patent/EP1075538A1/en not_active Withdrawn
- 1999-05-06 CA CA002331824A patent/CA2331824A1/en not_active Abandoned
- 1999-05-06 JP JP2000548500A patent/JP4439733B2/en not_active Expired - Lifetime
- 1999-05-06 US US09/674,891 patent/US6540891B1/en not_active Expired - Lifetime
- 1999-05-06 WO PCT/GB1999/001424 patent/WO1999058709A1/en not_active Application Discontinuation
-
2000
- 2000-02-25 AR ARP000100816A patent/AR022757A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU3835899A (en) | 1999-11-29 |
| JP4439733B2 (en) | 2010-03-24 |
| AR022757A2 (en) | 2002-09-04 |
| GB9809963D0 (en) | 1998-07-08 |
| US6540891B1 (en) | 2003-04-01 |
| GB2337122A (en) | 1999-11-10 |
| EP1075538A1 (en) | 2001-02-14 |
| AR015075A1 (en) | 2001-04-11 |
| AU758617B2 (en) | 2003-03-27 |
| WO1999058709A1 (en) | 1999-11-18 |
| JP2002514744A (en) | 2002-05-21 |
| BR9910284A (en) | 2001-01-09 |
| GB2337122B (en) | 2002-11-13 |
| CO4890893A1 (en) | 2000-02-28 |
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| EEER | Examination request | ||
| FZDE | Dead |