WO2008050145A1

WO2008050145A1 - Measurement device

Info

Publication number: WO2008050145A1
Application number: PCT/GB2007/004111
Authority: WO
Inventors: Oliver Davies
Original assignee: SureSensors Ltd
Current assignee: SureSensors Ltd
Priority date: 2006-10-27
Filing date: 2007-10-29
Publication date: 2008-05-02
Anticipated expiration: 2009-04-27
Also published as: GB0621352D0

Abstract

An analyte measuring device for measuring the amount of analyte in a test sample, typically a biological fluid, the device comprising: analyte specific measuring means reactable with the analyte to generate a change indicative of the presence or the amount of analyte in the test sample, and storage sensitive means sensitive to storage conditions and responsive to contact with the test sample to indicate viability of the analyte specific measuring means. The analyte specific measuring means and the storage sensitive means both include at least one storage sensitive component that is the same.

Description

Measurement Device

The present invention relates to a method and device for measuring the concentration of a substance in a fluid, for example an analyte in a physiological fluid from a patient. Typically, the method and device of the present invention are for use by diabetics to measure the amount of glucose in a blood sample.

Background of the Invention

Diabetes is one of the most widespread non-infectious diseases. It is estimated that around 250 million people suffer from diabetes, equivalent to around 4% of the world's population. Furthermore, the prevalence of diabetes is increasing, particularly in developed countries due, in part, to increased obesity rates. The complications associated with diabetes include an increased risk of suffering a heart attack, stroke, blood circulation disorders, kidney damage, blindness and nerve conduction disorders which can result in foot or leg amputations.

Assessing the concentration of glucose in the blood is an established way of both diagnosing and managing diabetes. Diabetics, in particular insulin-dependent diabetics, are advised to monitor their blood glucose levels several times a day in order to adapt and improve treatment plans. Due to the number of times blood glucose levels should be measured, it is highly preferable that diabetics are able to self-monitor their blood glucose levels without the need for medical supervision. Because of this, self-monitoring glucose measuring devices have been developed. These are now very commonly used by diabetics to control and monitor their glucose levels.

Because inaccurate results can lead to the incorrect administration of insulin, it is very important that self-monitoring glucose measuring devices provide accurate results. Inaccurate results may lead to the improper control of blood glucose levels resulting in potentially dangerous side effects, such as hypoglycaemia and hyperglycaemia.

Indeed, there have been numerous patient injuries caused by inaccurate results from glucose detection devices. In extreme cases, the provision of consistently and significantly inaccurate results by blood glucose monitors to users can have fatal consequences Known self-monitoring glucose measuring devices generally comprise a measurement device and a disposable test strip, with the test strip typically including one or more chemical reagents. During manufacture, glucose monitoring test strips are usually calibrated by batch and an appropriate calibration code is assigned. This calibration code must be entered into the electronic measuring device, usually by the user, prior to use of that particular batch of test strips. Once a calibration code has been entered, the system can then correctly convert the response generated by a test strip into a correctly calibrated glucose reading. One of the major post-manufacture factors to affect the accuracy of the calibration code assigned to a glucose detection device is the instability of the reagents they contain. This can cause the calibration code to become inappropriate, which may result in an incorrect reading and the failure of the patient to take the necessary corrective measures need to avoid dangerously high or low glucose levels.

Many of the test strips used in glucose monitoring devices include chemicals and reagents, which are sensitive to storage conditions, such as certain mediator compounds, for example potassium ferricyanide (potassium hexacyanoferrate III), and analyte specific biological components such as the enzymes Glucose Oxidase and Glucose Dehydrogenase. Due to the sensitivity of these reagents , glucose-monitoring systems generally have a limited shelf life. Test strips that are older than the prescribed shelf life are likely to provide inaccurate readings as a result of the effects of prolonged storage on the storage sensitive reagents that they contain. Such effects are commonly accelerated by factors, including exposure to sunlight, radiation, excessive heat (>30°C) and humidity (>1%RH).

The effects of ageing on the accuracy of known glucose devices are widely acknowledged. In an attempt to minimise the likelihood of inaccurate readings as a result of the effects of aging and poor storage, the shelf life of current glucose detection devices is limited, typically to 18 to 21 months from the date of the test strip manufacture. This limited life is a problem for countries or regions that have a non- optimal supply chain. It is also recommended that current glucose devices are stored under specific conditions, and particularly to avoid storage conditions of elevated temperatures (greater than 22⁰C) and high humidity (greater then 60%RH). This can be a problem for glucose biosensors sold and distributed to countries with hot and/or humid climates.

Some attempts have been made to address the issue of product sensitivity to storage conditions, for example as described in United States Patent Application

2005/0123441. In this application, it is recognised that many active components of a diagnostic test system may become damaged through the effects of incorrect or prolonged storage. In an attempt to identify when such damage occurs, an additional storage sensitive compound is incorporated within the reagent system. A signal derived from the storage sensitive compound within the reagent system is measured and its magnitude used to estimate the potential damage caused to the active reagent system.

Whilst United States Patent Application 2005/0123441 goes some way towards identifying potential active reagent system damage as a result of adverse storage conditions some crucial drawbacks exist. Firstly, the actual damage to the active diagnostic measuring reagents cannot be measured. Instead, changes that occur to a separate storage sensitive compound, which plays no part in the diagnostic measurement reaction, are measured. As a result, the actual level of damage to the functional active reagent system due to adverse storage conditions can only be inferred from the signal generated by the storage sensitive reagent. It is thus only possible to estimate potential damage to the active functional reagent system. This is not ideal since the system may over or under estimate the effects of storage on the active reagents and thus not accurately determine the level of damage. Furthermore, the reagent used to indicate the effects of adverse storage conditions has to have the same sensitivity as the active reagents to all possible damaging conditions, such as temperature, humidity, light, radiation etc. Where the storage sensitive reagent shows differing sensitivity to any of these factors from the active reagents the system may not accurately reflect the true damage to the active measuring reagents. A further drawback is that there is no facility for correcting the result provided by the diagnostic test system for the effects of incorrect or adverse storage. Summary of the Invention

The present invention seeks to address many of the problems associated with the effects of storage on the accuracy of many diagnostic test strips. The device of the present invention seeks to ensure that, where the active reagents contained within the device have been adversely affected by poor or prolonged storage, the system does not provide an inaccurate result to the user. Moreover the present invention seeks to provide means for accurately detecting and where appropriate optionally correcting for the effects of poor storage on the active reagents disposed on or in a diagnostic test strip. In order to correct for the effects of poor or prolonged storage on the active reagents the actual damage to at least one of the active reagents is measured thus allowing the system to accurately correct the final result to take in to account this reagent damage.

According to a first aspect of the present invention there is provided an analyte measuring device for measuring the amount of analyte in a test sample, typically a biological fluid, comprising: analyte specific measuring means contactable with the analyte to generate a change indicative of the amount of analyte in the test sample and storage sensitive measuring means responsive to contact with the test sample to generate a measurable change indicative of the viability of the analyte specific measuring means, wherein the storage sensitive measuring means compriseat least one reagent contained within the analyte specific measuring means that is involved in the measurement of the analyte as the storage sensitive measuring component.

The reagent used on the storage sensitive measuring means should be at least as sensitive to storage as the other reagents on the analyte specific measuring means otherwise the system may produce a low reading on the storage sensitive measuring means when there is damage to other reagents on the analyte specific measuring means.

The storage sensitive measuring means provides information as to the overall effect of any harmful storage conditions that the test strip has been subjected to, for example combinations of time, temperature, humidity, radiation etc. The response from the storage sensitive measuring means may be compared with a predetermined threshold value. The threshold can be set according to the sensitivity of the reagents common to both of the analyte specific measuring means and the storage sensitive measuring means. In the event that the threshold is exceeded, for example if the measured response is equal to or greater than the threshold, the measurement is automatically abandoned, and the test strip is discarded. In the event that the threshold is not exceeded, a result is provided since the test strip is known to be viable.

For analyte specific biological components that have a high degree of sensitivity to storage conditions the threshold value can be set suitably low. For analyte specific biological components that are more robust the predetermined to a higher level. Because the storage sensitive measuring means contains at least one of the active reagents from the analyte specific measuring means then the reading from the storage sensitive measuring means gives real information about the level of damage to that reagent on the analyte specific measuring means. Hence, if the threshold is exceeded this is an accurate indication that there is too much damage on the analyte specific measuring means for its reading to be reliable.

The storage sensitive measuring means may comprise a measurement element and a storage sensitive component. In this case, the response is made up, in large part by the response generated from the storage sensitive component present on the on the storage sensitive measuring element. The greater the severity of the storage conditions that the test strip has been subjected to the greater the response generated by the storage sensitive measuring element.

The reagent composition of the storage sensitive measuring means may be substantially the same as the reagent composition of the analyte specific measuring means minus the analyte specific reaction component.

The system can be arranged to correct the overall response for the effects of aging, for example by subtracting the response from the storage sensitive measuring means from the response of the analyte specific measuring means. The analyte specific measuring means may comprise a working electrode containing potassium ferricyanide. The storage sensitive measuring means may comprise a separate storage sensitive measuring electrode also containing potassium ferricyanide. Preferably, the potassium ferricyanide on the working electrode and the storage sensitive measuring electrode are present in the same amounts on both measuring electrodes. Since the potassium ferricyanide will convert to potassium ferrocyanide at the same rate on both the working electrode and the storage sensitive measuring electrode, increases in response from the storage sensitive measuring electrode are proportional to increases in the analyte independent response for the working electrode.

The predetermined threshold value for the storage sensitive measuring electrode can be set such that the threshold is reached, through the conversion of potassium ferricyanide to potassium ferrocyanide on the storage sensitive measuring element, before there is any damage to the analyte specific biological component disposed on the working electrode. Unwanted extra response from the working electrode that is generated by the conversion of potassium ferricyanide to potassium ferrocyanide can be removed by subtracting the response generated on the storage sensitive measuring electrode from the working electrode response. This extends the shelf life of the test strips with little or no risk that the results provided are inaccurately low as a result of damage to the analyte specific biological component so long as the storage sensitive electrode reading threshold has not been exceeded

The storage sensitive measuring means may comprise a plurality of storage sensitive measuring elements disposed on the test strip along with the analyte specific measuring means. By having a plurality of storage sensitive measuring elements disposed on the test strip it is possible to generate a plurality of storage dependent readings thus providing a greater assurance of the overall test strip efficacy. The plurality of readings may be compared to provide a more precise determination of the test strip's viability.

The plurality of storage sensitive measuring elements may be disposed on the test strip such that one storage sensitive measuring element is positioned at the proximal end of the test strip reaction zone and another at the distal end of the test strip reaction zone. By comparing these two storage sensitive measuring element readings at the end of the test is possible to determine that the entire test strip reaction zone is viable. If the both proximal and distal storage sensitive measuring element readings are below the predetermined threshold limit, a comparison of the two readings will allow the system to further assess the testing event for full functionality. For instance substantially different proximal and distal storage sensitive measuring element readings may be caused by either a damaged test strip or by the application of an insufficient amount of test sample to the test strip measuring zone. Both of these failure modes are likely to result in inaccurate test reading. Where the readings from the proximal and distal storage sensitive measuring elements are substantially different the system may be configured to automatically reject the test result.

The storage sensitive measuring element may be identical to the analyte specific measuring element except that it does not contain an analyte specific biological component. The storage sensitive measuring element is preferably formed from the same material as the analyte specific measuring element.

For an electrochemically based embodiment of the present invention there is typically little variation in the resistance, oxidation potential, electrochemical area and topology (i.e. roughness) of the material of the analyte specific measuring electrode and the storage sensitive measuring electrode(s).

Preferably, there is a variation of less than 10% in the abovementioned properties of the materials of the first and second electrodes; more suitably a variation of less than 5%; advantageously a variation of less than 1% most advantageously a variation of less than 0.5%; of the abovementioned properties of the material of the first and second electrodes.

The surface area of the first and second electrodes may be different. The surface area of the first and second electrodes may be the same.

The analyte may be glucose, cholesterol, alcohol or free fatty acids. Preferably the analyte is β-D-Glucose. The fluid may be blood, urine, interstitial fluid, plasma, serum, saliva or spinal fluid. The enzyme is generally Glucose Oxidase or Glucose Dehydrogenase. The first detection device may comprise 0.01 to 10 i.u.of enzyme.

Preferably, the device further comprises a background sensor for measuring the effect of substances that interfere with the analye specific measurement means and the storage sensitive means. The background sensor may comprise a background electrode.

The analyte sensitive measuring means and the storage sensitive measuring means may be disposed together on a single test strip. Where a background electrode is employed, this too would be provided on the same single test strip.

According to a yet another aspect of the present invention, there is provided an analyte measuring device for measuring the amount of analyte in a test sample, typically a biological fluid, comprising: analyte specific measuring means contactable with the analyte to generate a change indicative of the amount of analyte in the test sample; storage sensitive measuring means responsive to contact with the test sample to generate a measurable change indicative of the viability of the analyte specific measuring means, and correction means for correcting the measured amount of analyte in the test sample indicated by the analyte specific measuring means using the measurement at the storage sensitive measuring means.

According to a further aspect of the present invention there is provided a method of measuring the amount of analyte in a fluid sample from a patient comprising the steps of: obtaining a fluid sample from a patient; contacting the fluid sample with a analyte measurement means reactable with the analyte to generate a response; and contacting the fluid with storage sensitive measuring means responsive to contact with the test sample to indicate the viability of the analyte specific measuring means.

The method may include the step of comparing the storage sensitive measuring element response with a predetermined threshold value, wherein if the storage sensitive measuring element response is above the threshold value the test is abandoned. The threshold value represents an unacceptable level of sensor damage as a result of poor or prolonged storage. By comparing the storage sensitive measuring element response to the threshold value the user can be assured that the device has not been compromised during storage.

Where the storage sensitive measuring element response is less than the threshold value the method may comprise a calibration step wherein the storage sensitive measuring element response is subtracted from the analyte specific measuring element signal to provide a measure of the amount of analyte in the fluid sample.

Preferably, there is a delay of less than ten minutes between contacting the first and second electrodes with the fluid and obtaining the measurement of the amount of analyte in the fluid sample.

Where the analyte to be measured is glucose, preferably the delay is less than 5 to 15 seconds between contacting the first and second electrodes with the fluid and obtaining the measurement of the amount of glucose in the fluid; advantageously 1 to 5 seconds.

Where the device is an electrochemical device, preferably the analyte measurement means and the storage sensitive measurement means are at the same voltage immediately prior to contact with the fluid.

Brief Description of the Drawings Various aspects of the invention will now be described by way of example only with reference to the accompanying drawings, of which:

Figure 1 is a plan view of a device for measuring analyte in a sample; Figure 2 is a plan view of an electrochemical device for measuring analyte in a sample; Figure 3 is a plan view of another electrochemical device for measuring analyte in a sample,

Figure 4 is a plan view of yet another electrochemical device for measuring analyte in a sample and Figure 5 is a plan view of still another electrochemical device for measuring analyte in a sample.

Specific Description of the Drawings Figure 1 shows a device 10 for measuring the amount of analyte in a sample, the device 10 having an analyte specific measuring element 12 and a storage sensitive measuring element 14 on a disposable test strip 16. The device 10 is usable in cooperation with a measurement meter (not shown). The analyte specific measuring element 12 is operable to allow the quantity of analyte of interest to be determined. The storage sensitive measuring element 14 is sensitive to storage conditions and can be used to provide a measure of the viability of the analyte specific measuring element. Included in both the storage sensitive measuring element 14 and the analyte specific measuring element 12 is the same storage sensitive active component. In some embodiments, the storage sensitive measuring element 14 and the analyte specific measuring element 12 are identical except that the storage sensitive element does not include any analyte specific reagent. Typically, the test strip 16 is provided in sealed packaging, for example a desiccated vial or foil packaging. Ideally, the packaging should not be opened by the user until within 5 minutes or less of being used. However due to the incorporation of the storage sensitive measuring element the test strip of the present invention is less susceptible.

The analyte specific measuring element 12 and the storage sensitive measuring element 14 are stored and tested under identical conditions. This means that the storage sensitive measuring element 14 can be used to provide a measure of the impact of the storage conditions on the analyte specific measurement means.

Typically a threshold value is set for measurements at the storage sensitive element 14, which when exceeded indicates that the analyte specific measurement element 12 cannot be trusted to provide accurate results.

In use, the test strip 16 is removed from the packaging, inserted into the measurement meter and the sample is applied. Where the analyte is glucose, approximately 0.1 to 10 μl of sample fluid may be used, preferably 0.1 to 3 μl. Where the device is being used as an immunoassay, approximately 5 to 20 μl of the sample fluid (typically blood, plasma or serum) may be used. The meter then performs a test and reads the result from the analyte specific measurement element and the storage sensitive measuring element. If the storage sensitive measuring element 14 result is greater than a pre-determined threshold then the test is rejected. If the storage sensitive measuring element 14 result is less than the threshold then the reading from analyte specific measurement element 12 can be used to provide the test result. Any suitable measurement technique could be used, but in a preferred embodiment, electrochemical measurements are used.

Figure 2 shows a device 18 for making electrochemical measurements of a biological sample, in this case to determine the quantity of glucose in blood. This has an analyte sensitive working sensor 20, a storage sensitive measuring sensor 22 and a shared electrode 24, which is used as a counter / reference. The analyte sensitive working sensor 20 comprises an electrode on which is a layer of enzyme reagent that comprises an enzyme and an electron mediator, in this case potassium ferricyanide. The storage sensitive measuring sensor 22 has an electrode with a storage sensitive component, in this case potassium ferricyanide, but no enzyme. The potassium ferricyanide on the analyte sensitive working electrode 20 and the storage sensitive electrode 22 are present in the same amounts on both measuring electrode. Potassium ferricyanide is more sensitive to storage than the other active ingredients on the analyte sensitive working sensor. Because of this, an increase in the storage sensitive measuring sensor response will be seen before the other active reagents on the analyte sensitive working sensor are damaged to the extent that the test results are compromised. Each of the analyte sensitive working electrode 20, the storage sensitive measuring electrode 22 and the reference electrode 24 is electrically insulated from the others and connected to its own measurement terminal 26, 28, 30. These terminals 26, 28, 30 are provided to allow electrical measurements to be made by a suitable measuring device. Typically, the test strip 18 is fabricated so that fluid is drawn into by capillary action. Techniques for making this type of strip are well known.

As mentioned previously, potassium ferricyanide is sensitive to storage conditions. In adverse conditions, potassium ferricyanide (potassium hexacyanoferrate III) converts to potassium ferrocyanide (potassium hexacyanoferrate II). This conversion causes an increase in response from the storage sensitive measuring electrode. This storage related increase in response is proportional to the storage related increase in response at the analyte sensitive working electrode 20, since the potassium ferricyanide on the analyte sensitive working electrode 20 will convert to potassium ferrocyanide at the same rate on both the working electrode 24 and the storage sensitive measuring electrode 22. Hence, by measuring the response of the storage sensitive measuring electrode 22, a measure of the viability of the analyte sensitive working electrode 20 can be made. In some circumstances the response from the analyte specific measuring electrode 20 can be corrected for the effects of storage using the response form the storage sensitive measuring electrode 22.

To allow the storage sensitive electrode 22 to provide an indication of, and potentially correct for, the effects of storage, a predetermined threshold is selected so that is reached, through the conversion of potassium ferricyanide to potassium ferrocyanide on the storage sensitive measuring element 22, before there is any damage to the analyte specific biological component disposed on the working electrode 20. For analyte specific biological components that have a high degree of sensitivity to storage conditions the threshold value can be set suitably low. For analyte specific biological components that are more robust the predetermined threshold can be set to a higher level. If the storage sensitive electrode 22 measurement is greater than the threshold then the system rejects the test, as there is a chance that the biological component of the analyte specific measuring electrode 20 will have been damaged. If the storage sensitive 22 reading is less than the pre-determined threshold, then it can be used to correct the analyte specific reading for detrimental effects caused by storage. Where the storage sensitive measuring electrode 22 and the analyte specific measuring electrode 20 are the same size this can be done by simply subtracting the measurement at the storage sensitive electrode 22 from the measurement at the analyte specific measurement electrode 20. Where the two electrodes 20 and 22 are different sizes the reading from the storage sensitive measuring electrode 22 must be appropriately scaled before subtraction from the analyte specific measurement electrode reading.

In use, the test strip 18 is removed from its packaging, and inserted into a measuring device, which applies a potential of about 400 mV between the counter/reference sensor part 24 and both the analyte specific working sensor part 20 and the storage sensitive sensor part 22 via the terminals. A sample of the fluid under test is then applied. Where the analyte is glucose, approximately 0.1 to 10 μl of sample fluid may be used, preferably 0.1 to 3 μl. Where the device 18 is being used as an immunoassay, approximately 5 to 20 μl of the sample fluid (typically blood, plasma or serum) may be used. Capillary action draws the sample, for example blood, along the sample chamber and over the counter/reference sensor part, the working sensor part and the storage sensitive part. After a predetermined time, preferably less than 15 seconds, the electric current passed by each working sensor part is measured.

When a potential is applied between the analyte specific measurement electrode 20 and the counter electrode 24, a current is generated by the transfer of electrons from the substance being measured (the enzyme substrate), via the enzyme and the mediator to the surface of the electrode. The current generated is proportional to both the area of the sensor part and also the concentration of glucose in the test sample. Since the area of the working sensor part is known, the electric current should be proportional to the glucose concentration.

When a potential is applied between the storage sensitive measurement electrode 22 and the counter electrode 24, a current is generated that is representative of the quantity of potassium ferrocyanide present at the storage sensitive measuring electrode. The meter reads the result from the storage sensitive measuring electrode 22. If this result is greater than the pre-determined threshold then the test is rejected. If the result is less than the threshold then the reading from the analyte specific measurement electrode is corrected using the storage sensitive reading. When the analyte specific and storage sensitive electrodes 20 and 22 respectively are the same size then merely subtracting the storage sensitive reading from the analyte specific reading corrects for effects of storage.

This embodiment may be used not only to determine the viability of the test strip through assessment of the response generated by the storage sensitive measuring element 22, but also to substantially extend the time period over which the test strip 18 will provide accurate results by removing unwanted extra response from the working electrode that is generated by the presence of the potassium ferrocyanide created by the effects of poor storage. This provides a prolonged shelf life compared to existing glucose monitoring systems and dramatically reduces the likelihood of the system providing inaccurate results due to test strip damage caused by poor or prolonged storage.

Figure 3 shows another embodiment. This is similar to that of Figure 2, but includes two storage sensitive electrodes 22a and 22b on opposing sides of the analyte specific working electrode 20 and the counter electrode 24, i.e. one at each end of the reaction zone. As well as providing the features described with reference to Figure 2, in this embodiment the storage sensitive electrodes 22a and 22b are used to more confidently assess test strip viability and / or damage by providing two or more storage sensitive electrode readings. This can be done because the test strip might be damaged more at one end than at the other, and with only one storage sensitive electrode the reading may be low when in fact there may be greater damage to the working electrode 20. Having two storage sensitive electrodes 22a and 22b at opposite ends of the reaction zone limits the likelihood of damage to the working electrode 20 going undetected. Such readings may also be used to ensure that the test strip has been fully covered with test sample and that there is no physical damage to the measuring sensors by comparing the readings from the proximal storage sensitive electrode with the distal storage sensitive electrode.

When a viable test strip-measuring zone is fully and correctly covered with the test sample fluid both the proximal and distal storage sensitive measuring element readings should differ by no more than a predetermined limit. If they differ by more than this second predetermined limit, it can be inferred that either the test strip reaction zone has not been fully covered with the test sample fluid or that the measuring elements have been either damaged after manufacture or poorly formed during manufacture. Under such circumstances it is probable that the reading from the analyte dependent measuring element 20 will be inaccurate due to it being only partially covered by the test sample fluid or due to physical damage to the measuring element. In circumstances where the proximal and distal storage sensitive measuring element 22a and 22b readings are both below the predetermined storage related test strip viability threshold, but where they differ from each other by more than a second predetermined amount of percentage, the system may reject the test due to either insufficient sample application to the test strip reaction zone or due to test strip damage. In use of the embodiment of Figure 3, the test strip 18 is removed from the packaging, inserted into meter and the sample is applied. As before, where the analyte is glucose, approximately 0.1 to 10 μl of sample fluid may be used, preferably 0.1 to 3 μl, and where the device is being used as an immunoassay, approximately 5 to 20 μl of the sample fluid may be used. The meter then performs the test and reads the result from the storage sensitive electrodes 22a, 22b. At the end of the test the two readings are compared to provide a more accurate assessment of the damage to the whole of the test area. If the results from the proximal and distal storage sensitive electrodes 22a, 22b are greater then the predetermined storage related test strip viability threshold then the test is rejected. In addition if the results from the proximal and distal storage sensitive measuring electrodes 22a, 22b differ from each other by more then a predetermined percentage or amount then the test is rejected due to incomplete sample coverage. Preferably, the proximal and distal reading variation threshold is more than 20-60%. If the storage sensitive measuring electrode results are both less than the storage related test strip viability threshold, and if the two storage sensitive measuring electrode readings do not differ from each by more than the predetermined proximal and distal reading variation threshold then the analyte specific electrode reading may corrected using an average of the storage sensitive electrodes readings.

Although the storage sensitive measuring element response will be generated primarily from the storage sensitive component disposed thereon, for example potassium ferricyanide as described above, a portion of the storage sensitive measuring element response may also be generated from substances in the sample fluid other than the analyte causing an analyte independent response. Such substances may be termed interfering substances and include but are not limited to acetaminophen, ascorbic acid, vitamin C, gentisic acid and uric acid. Interfering substances are those substances in the test sample that react with the analyte specific electrode to create current that is not related to the analyte of interest leading to an overestimation of the concentration of the analyte if interest. These substances create current on both the analyte specific electrode and the storage sensitive electrode to the same degree and act to increase their responses. In embodiments where the storage sensitive electrode and the analyte specific electrode are identical, except that the storage sensitive electrode does not contain the analyte specific reagents, then any current generated on the storage sensitive electrode due to the presence of interfering substances will also be seen on the analyte specific electrode. Thus, the storage sensitive electrode can be used to simultaneously correct the analyte specific electrode response for the effects of damage caused by storage sensitivity and interfering substances. This can be done by subtracting the storage sensitive measuring electrode reading from the working electrode reading.

Because of the effect of interfering substances, it is possible for a test to be rejected on the basis of a high storage sensitive measuring element response when in fact there is no storage damage to the test strip. This could happen if the patient has a very high level of an interfering substance in his / her blood and / or if the threshold level for the storage sensitive measurement is set very low. To limit the effects of this, a separate background measurement electrode 32 may be provided for measuring interfering substances, as shown in Figure 4. This allows differentiation between the response created as a result of poor storage and that created by interfering substances. The background measurement electrode 32 is ideally identical to the storage sensitive electrode, but without any active components on it, i.e. no potassium ferricyanide or enzyme. When in use, the background electrode 32 would be at the same potential as the analyte specific working electrode 20 and the storage sensitive electrode 22. With only the bare electrode material in contact with the test sample the background response will be comprised exclusively of current generated by the direct electrochemical oxidation of interfering substances in the sample fluid, typically blood.

In use of the embodiment of Figure 4, the test strip is removed from the packaging, inserted into meter and the sample is applied. As before, where the analyte is glucose, approximately 0.1 to 10 μl of sample fluid may be used, preferably 0.1 to 3 μl, and where the device is being used as an immunoassay, approximately 5 to 20 μl of the sample fluid may be used. The meter then performs the test and reads the result from the analyte specific electrode 20, the storage sensitive electrode 22 and the background electrode 32. Then the background reading is subtracted from the storage sensitive electrode reading to get a measure of the true storage sensitive reading with no interfering substance component. This corrected storage sensitive reading may then be compared to a predetermined storage related test strip viability threshold. This allows the reliable determination of when a test strip has been damaged through poor storage independent of the amount of any interfering substances present in the test sample. Hence, not only can the device of Figure 4 detect when the strip 18 has been damaged by storage and correct for that, it can also detect if the strip 18 is fully covered with sample or if it is damaged, as well as allowing the working electrode 20 reading to be corrected for the effects of interfering substances.

The present invention provides a device that gives an indication of whether it has been compromised following manufacture, for instance through being stored under adverse conditions. If the device had been damaged following manufacture, for instance through being stored under adverse conditions, this damage will automatically be identified and the test strip rejected by the system. Because the same reagents are being used, this means that not only is the risk of inaccurate results being returned to the user is greatly reduced, thereby improving the safety over prior art devices of a similar nature, but inaccuracies can be corrected, thereby extending the shelf lifetime of the product. This is a significant advance.

Various modifications and variations to the described embodiments of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. For example, whilst in the embodiments shown in Figures 1 to 4, the analyte specific measurement electrode 20 and the storage sensitive measurement electrode 22 have the same surface area, this it not essential. As shown in Figure 5, in some cases it may be desirable for the storage sensitive measurement electrode 22 to have a larger surface area. This can increase its sensitivity. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention, which are obvious to those skilled in the art are intended to be covered by the present invention.

Claims

1. An analyte measuring device for measuring the amount of analyte in a test sample, typically a biological fluid, the device comprising: analyte specific measuring means reactable with the analyte to generate a change indicative of the presence or the amount of analyte in the test sample, and storage sensitive means sensitive to storage conditions and responsive to contact with the test sample to indicate viability of the analyte specific measuring means, wherein the analyte specific measuring means and the storage sensitive means both include at least one storage sensitive component that is the same.

2. A device as claimed in claim 1 wherein storage sensitive component that is common to the analyte specific measuring means and the storage sensitive means is involved in the measurement of the analyte at the analyte specific measuring means.

3. A device as claimed in claim 1 or claim 2 comprising means for comparing a measured response from the storage sensitive means with a predetermined threshold value, thereby to determine the effects of storage and provide an indication of the viability of the analyte specific measuring means.

4. A device as claimed in any of the preceding claims comprising means for using the measurement taken by the storage sensitive means to correct the measurement taken by the analyte specific measuring means.

5. A device as claimed in claim 4 comprising means for differencing the responses from the storage sensitive means and the analyte specific measuring means, thereby to correct the measurement taken by the analyte specific measuring means.

6. A device as claimed in any of the preceding claims wherein the analyte specific measuring means and the storage sensitive means both include more than one storage sensitive component, for example a storage sensitive reagent.

7. A device as claimed in claim 6 wherein the storage sensitive component that is common to both of the analyte specific measuring means and the storage sensitive measuring means is more sensitive than all of the other storage sensitive components.

8. A device as claimed in any of the preceding claims, wherein the storage sensitive component that is common to the analyte specific measuring means and the storage sensitive means is present in the same quantity on both the analyte specific measuring means and the storage sensitive means

9. A device as claimed in any of the preceding claims, wherein the storage sensitive component is a reagent, preferably potassium ferricyanide.

10. A device as claimed in any of the preceding claims wherein the storage sensitive means comprises a plurality of storage sensitive measuring sensors.

11. A device as claimed in claim 10 wherein the storage sensitive sensors are disposed at different parts of the reaction zone, preferably with two positioned at extremities of that zone.

12. A device as claimed in claim 10 or claim 11 comprising means for comparing measurements from two or more of the storage sensitive sensors and rejecting the results from the analyte specific measurement means in the event that the difference exceeds a pre-determined threshold.

13. A device as claimed in claim 12 wherein the pre-determined threshold is a difference of more than 10 to 60 %.

14. A device as claimed in any of the preceding claims wherein the analyte specific measuring means comprises an electrode.

15. A device as claimed in any of the preceding claims wherein the storage sensitive means comprises an electrode.

16. A device as claimed in any of the preceding claims wherein the storage sensitive means is formed at least in part from the same material as the analyte specific measuring means.

17. A device as claimed in any of the preceding claims wherein the analyte sensitive measuring means and the separate storage sensitive means are disposed together on a single test strip.

18. A device as claimed in any of the preceding claims wherein the surface area of the analyte sensitive measuring means and the storage sensitive means are different.

19. A device as claimed in any of claims 1 to 18 wherein the surface area of analyte sensitive measuring means and the separate storage sensitive means are the same.

20. A device as claimed in any of the preceding claims wherein the analyte is glucose, for example β-D-Glucose, cholesterol, alcohol, ketones or free fatty acids.

21. A device as claimed in any of the preceding claims wherein the test sample is one of blood, urine, interstitial fluid, plasma, serum, saliva or spinal fluid.

22. A device as claimed in any of the preceding claims wherein the analyte specific measurement means includes an enzyme, preferably Glucose Oxidase or Glucose Dehydrogenase.

23. An analyte measuring device for measuring the amount of analyte in a test sample, typically a biological fluid, the device comprising: analyte specific sensor reactable with the analyte to generate a change indicative of the presence or the amount of analyte in the test sample, and a storage sensitive sensor sensitive to storage conditions and responsive to contact with the test sample to indicate viability of the analyte specific measuring means, wherein the analyte specific sensor and the storage sensitive sensor both include at least one storage sensitive component that is the same.

24. A device as claimed in any of the preceding claims further comprising a background sensor for measuring the effect of substances that interfere with the analyte specific measurement means and the storage sensitive means.

25. A device as claimed in claim 24 wherein the background sensor comprises a background electrode.

26. A method of measuring the amount of analyte in a fluid sample, typically a biological fluid sample from a patient, the method comprising the steps of: contacting the fluid sample with an analyte measurement means reactable with the analyte to generate a response; and contacting the fluid with storage sensitive measuring means responsive to contact with the test sample to indicate the viability of the analyte specific measuring means, wherein the analyte specific measuring means and the storage sensitive means both include at least one storage sensitive component that is the same.

27. A method as claimed in claim 26 comprising comparing the storage sensitive measuring element response with a predetermined threshold value, wherein if the storage sensitive measuring element response exceeds the threshold the test is abandoned.

28. A method as claimed in claim 27 comprising subtracting the storage sensitive measuring element response from the analyte specific measurement means response to provide a measure of the amount of analyte in the fluid sample.

29. A method as claimed in any of claims 26 to 28 wherein when the device is an electrochemical device the analyte measurement means and the storage sensitive measurement means are at the same voltage.

30. A method as claimed in any of claims 26 to 29 comprising using a storage sensitive measuring means that includes a plurality of storage sensitive measuring sensors.

31. A method as claimed in claim 30 wherein the storage sensitive measuring sensors are disposed at different parts of a reaction zone, preferably with two positioned at extremities of that zone.

32. A method as claimed in claim 30 or claim 31 comprising comparing measurements from two or more of the storage sensitive measuring sensors and rejecting the results from the analyte specific measurement means in the event that the difference between the measurements from the two or more storage sensitive measuring sensors exceeds a pre-determined threshold.

33. A method as claimed in claim 32 wherein the pre-determined threshold is a difference of more than 10 to 60 %, for example more than 30% or more than 40% or more than 50% or more than 60%.

34. An analyte measuring device for measuring analyte in a test sample, typically a biological fluid, comprising: analyte specific measuring means contactable with the analyte to generate a change indicative of the amount of analyte in the test sample; storage sensitive measuring means responsive to contact with the test sample to generate a measurable change indicative of the viability of the analyte specific measuring means, and correction means for correcting the measured amount of analyte in the test sample indicated by the analyte specific measuring means using the measurement at the storage sensitive measuring means.

35. A device as claimed in claim 34 wherein the analyte specific measuring means and the storage sensitive means both include at least one storage sensitive component that is the same.

36. An analyte measuring device for measuring analyte in a test sample, typically a biological fluid, comprising: analyte specific measuring means contactable with the analyte to generate a change indicative of the amount of analyte in the test sample and at least two storage sensitive measuring sensors each responsive to contact with the test sample to generate a measurable change indicative of the viability of the analyte specific measuring means.

37. A device as claimed in claim 36 wherein the storage sensitive sensors are disposed at different parts of a reaction zone, preferably at extremities of that zone.

38. A device as claimed in claim 36 or claim 37 wherein the two sensors are positioned on opposing sides of the analyte specific measuring means.

39. A device as claimed in any of claims 36 to 38 comprising means for comparing measurements from two or more of the storage sensitive sensors and rejecting the results from the analyte specific measurement means in the event that the difference exceeds a pre-determined threshold.

40. A device as claimed in claim 39 wherein the pre-determined threshold¹ is a difference of more than 10 to 60 %.