RU2569753C2 - Accuracy-improving dehumidifiers - Google Patents

Abstract

FIELD: measurement equipment.

SUBSTANCE: group of inventions relates to electrochemical sensors and can be used for determination of concentration of an analyte in a specimen. A biosensor system includes many test sensors and a container. Each test sensor includes at least two conductors and a composition of reagents, and the container includes a dehumidifier supporting residual moisture level. This biosensor system allows measuring analyte concentration with a systematic error within ±10 mg/dl or ±10%. Besides, the biosensor system is described, which allows preserving at least 75% of activity of an oxidation and reducing ferment.

EFFECT: group of inventions provides increase of useful life of a biosensor, improvement of accuracy, reproducibility of analysis, as well as reduction of time for its performance.

25 cl, 8 dwg, 2 tbl

Description

Link to related applications

[001] This application claims the priority of provisional application US No. 61/297515, entitled "Improving the accuracy of desiccants", filed January 22, 2010, which is incorporated here by reference in its entirety.

BACKGROUND OF THE INVENTION

[002] Biosensors provide analysis of a biological fluid, such as whole blood, serum, plasma, urine, saliva, interstitial or intracellular fluid. Typically, biosensors have a measuring device that analyzes the sample located in the test sensor. The sample is usually in liquid form and may be a biological fluid or a derivative of a biological fluid, such as an extract, a weak solution, a filtrate, or a reconstituted sediment. An analysis performed by a biosensor determines the presence and / or concentration of one or more analytes in a biological fluid. Examples of analytes include alcohol, glucose, uric acid, lactate, cholesterol, bilirubin, free fatty acids, triglycerides, proteins, ketones, phenylalanine or enzymes. The analysis may be useful in the diagnosis and treatment of physiological disorders. For example, a person with diabetes can use a biosensor to determine the level of glucose in whole blood, and this information can be used to correct the diet and / or drug treatment of that person.

[003] The biosensors may be configured to analyze one or more analytes and may use different volumes of samples. Some biosensors can analyze one drop of whole blood, for example, from 0.25 to 15 microliters (µl) in volume. Biosensors can be activated using desktop, portable and similar measuring devices. Portable measurement devices may be manual and include the identification and / or quantification of one or more analytes in a sample. Examples of portable measuring devices include BREEZE® and CONTOUR® meters from Bayer HealthCare in Tarritown, PC. New York, USA, while examples of benchtop measuring devices include an Electrochemical Workstation supplied by CH Instruments in Austin, PA. Texas, USA

[004] In electrochemical biosensors, the analyte concentration is determined by the electrical signal generated by the oxidation / reduction reaction or the redox reaction of the analyte or analyte sensitive substance when an input signal is applied to the sample. The input signal can be supplied in the form of a single electrical pulse or in the form of multiple pulses, sequences or cycles. A redox substance, such as a mediator, enzyme or similar substances, may be added to the sample to enhance electron transfer from the first substance to the second substance during the redox reaction. The redox substance (s) can react with one single analyte, thereby imparting specificity to part of the generated output signal.

[005] Electrochemical biosensors typically include a measurement device with electrical contacts that connect to electrical conductors in a test sensor. The test sensor may be adapted for use outside, inside or partially inside a living organism. When used outside a living organism, a sample of biological fluid is introduced into the sample reservoir in a test sensor. The test sensor can be placed in the measuring device before, after or during the introduction of the sample for analysis. If inside or partially inside a living organism, the test sensor can be constantly immersed in the sample, or the sample can be periodically introduced into the test sensor. The test sensor may include a reservoir that partially separates the volume of the sample, or the test sensor may be open to the sample. Similarly, for the purpose of analysis, a sample can continuously flow through a test sensor or intermittently for analysis.

[006] A test sensor may be formed by placing or printing electrodes on an insulating substrate by placing one or more reagent compositions on one or more of the conductors. More than one of the conductors can be coated with the same reagent composition, for example, when the working electrode and the counter electrode are coated with the same composition. Many techniques known to those of ordinary skill in the art can be used to place the reagent composition on a test sensor. The reagent composition can be placed on conductors in the form of a liquid with reagents, and then dried. When a sample is introduced into a test sensor, the reagent composition begins to rehydrate.

[007] The reagent compositions placed on each conductor may be the same or different. Thus, the working electrode reagent composition may contain an enzyme, a mediator and a binder, while the counter electrode reagent composition may contain only a mediator, which may be the same or different from the working electrode mediator, and a binder. The reagent composition may include an ionizing agent to facilitate oxidation or reduction of the analyte, such as the oxidoreductase enzyme, as well as any mediators or other substances that are involved in electron transfer between the analyte and the working electrode.

[008] One or more components of the reagent composition may undergo a chemical transformation before using a test sensor. In particular, it is believed that the oxidation state of the mediator may change over time under certain conditions. Mediators, such as ferricyanide and organic quinones and hydroquinones, can undergo reduction in the presence of water. The presence of the reduced mediator in the reagent composition can cause an increase in the background current of the sensor, leading to inaccurate analysis results, especially for samples with a low analyte concentration.

[009] In general, unwanted and / or premature chemical transformations into reagent compositions are inhibited by storing the test sensor in the vicinity of the desiccant. Desiccants are typically used in the primary packaging of a test sensor, such as bottles or foil bags, to prevent breakdown of the reagent composition in order to maintain the required shelf life of the test sensor. Conventional desiccants for test sensor storage systems can quickly adsorb moisture, which can seep into the package containing the test sensor. Examples of desiccants used to protect test sensors include molecular sieves that rapidly adsorb moisture even in low humidity environments.

[0010] The disadvantage of protecting the test sensors with a desiccant is that one or more of the components of the reagent composition may require a limiting moisture level to maintain their function in the composition. For example, it is believed that the enzyme FAD-dependent glucose dehydrogenase (FAD-GDH) requires some residual moisture in order to maintain its natural active configuration. The loss of moisture from the reagent composition below the limit level can lead to a conformational change and inactivation of the enzyme.

[0011] The loss of enzyme activity due to excessive drainage of the test sensor is usually prevented either by incorporating excess amounts of the enzyme in the reagent composition, or by adding to the reagent composition a substance that is believed to stabilize the enzyme. Examples of substances that can stabilize an enzyme in a test sensor reagent composition include sugars, such as trehalose or sucrose, and sugar alcohols, such as mannitol, maltitol or sorbitol. These substances can be used in the lyophilization process to maintain the activity of the enzyme. See, for example, EP 1785483 A1. However, high loading of the enzyme or other solids, such as stabilizers, may present other difficulties. Since the enzyme is usually an expensive component, it is undesirable to increase the loading of the enzyme above the level required for analysis. In addition, the enzyme or other solids can slow the rehydration of the reagent composition by the sample, leading to a longer analysis time, especially at lower temperatures. Excess enzyme in the test sensor beyond what is required to interact with the analyte and / or other ingredients in the reagent composition, such as a mediator, can also reduce the accuracy of the sensor.

[0012] Accordingly, there is an ever-growing need for improved biosensor systems, especially systems that can provide an increasingly accurate and / or reproducible determination of analyte concentration in a sample and / or that can provide ever shorter analysis times. Moreover, there is a need for improved biosensor systems that have an extended shelf life in a wider range of storage conditions, while at the same time providing the desired accuracy, reproducibility and / or duration of analysis. The systems, devices, and methods of the present invention overcome at least one of the disadvantages associated with conventional biosensor systems.

SUMMARY OF THE INVENTION

[0013] An object of the invention is to provide a biosensor system in which at least one of the aforementioned disadvantages is overcome. The technical results of the claimed group of inventions consist in increasing the shelf life of the biosensor, increasing the accuracy, reproducibility and / or shorter duration of the analysis of the concentration of analyte in the sample. In one aspect, the invention provides a biosensor system for determining analyte concentration in a sample, which includes a plurality of test sensors. Each test sensor includes at least two conductors, one of the conductors being a working electrode, and further includes a reagent composition located on or near the working electrode. The biosensor system further includes a container containing a desiccant. When a plurality of test sensors are sealed in a container for two weeks at a temperature of 50 ° C, and then removed from the container, and each test sensor is subsequently connected through the at least two conductors to a measuring device, and then brought into contact with one of the plurality of samples containing analyte, and many samples have an analyte concentration that covers a range of 10 mg / dl - 600 mg / dl, and the analyte concentration in each sample is measured using a test sensor and a measuring device, system The mathematical error of each measured analyte concentration is within ± 10 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 10% for samples having an analyte concentration of at least 100 mg / dl.

[0014] In yet another aspect, the invention provides a biosensor system for determining analyte concentration in a sample, which includes a plurality of test sensors. Each test sensor includes at least two conductors, wherein one of the conductors is a working electrode, and further includes a reagent composition located on or near the working electrode, wherein the reagent composition includes a redox enzyme. The biosensor system further includes a container containing a desiccant. When a plurality of test sensors are sealed in a container for two weeks at a temperature of 50 ° C, and then removed from the container, the reagent composition of each test sensor retains at least 75% of the activity of the redox enzyme.

[0015] The scope of the present invention is defined only by the attached claims and is affected by the provisions in this section of the "Summary of the invention".

Brief Description of the Drawings

[0016] The invention may become more apparent with reference to the following drawings and description. Structural elements in the figures are not necessarily shown to scale, instead, emphasis is placed on illustrating the principles of the invention.

[0017] FIGS. 1A-1C represent output signals from test sensors for whole blood samples having glucose concentrations of 400 milligrams per deciliter (mg / dl). Test sensors were sealed with desiccant - molecular sieve (1A), desiccant - silica gel (1B) or without desiccant (1C).

[0018] FIGS. 2A and 2B are graphs of the bias of the analysis for glucose assays in whole blood samples having glucose concentrations of 50, 100, 400, or 600 mg / dl.

[0019] FIGS. 3A and 3B are background current graphs for glucose analyzes in glucose-free whole blood samples for test sensors sealed in containers having various types and levels of desiccant.

[0020] Figure 4 is a graph of intrasensory activity of the enzyme for test sensors stored for two weeks at either -20 ° C, or at 50 ° C, or at room temperature in containers having various types and levels of desiccant.

[0021] Figure 5 presents graphs of intrasensory activity of the enzyme ("% assimilation of the enzyme") for test sensors sealed for two weeks each at 50 ° C. with different types of desiccant, and for reagent compositions with and without an enzyme stabilizer.

[0022] FIG. 6 is a graph of variation of the R5 / 4 ratio parameter for test sensors stored for two weeks at 50 ° C, relative to the R5 / 4 ratio parameter for test sensors stored for two weeks at -20 ° C, This test sensors had varying levels of enzyme density above the working electrode of the test sensors.

[0023] FIG. 7 provides a schematic representation of a biosensor that senses an analyte concentration in a sample of a biological fluid using a test sensor.

[0024] FIG. 8 shows a sealed container comprising a desiccant and a plurality of test sensors.

Detailed description

[0025] The biosensor system includes test sensors sealed in a desiccant container that maintains a residual moisture level in the container. In environments with low humidity, the desiccant does not absorb moisture quickly, which may allow the composition of the reagent composition of test sensors to maintain a moisture level favorable for maintaining the enzyme in its active configuration. Test sensors stored in a container that contains such a desiccant can provide analyte concentration measurements that are more accurate and / or reproducible than measurements of comparable test sensors stored in a container that contains a traditional desiccant or does not contain a desiccant. Thus, test sensors provide consistently accurate analyzes with fast analysis times, even when test sensors are stored for long periods of time in suboptimal conditions.

[0026] The biosensor system includes a plurality of test sensors, with each test sensor containing at least two conductors, one of the conductors being a working electrode, and a reagent composition disposed on or near the working electrode. The biosensor system further includes a container containing a desiccant. A lot of test sensors are sealed in the container.

[0027] The desiccant in the container preferably adsorbs at most 15% of its weight in water when in contact with the environment with a relative humidity (RH) of 10% -20% at 40 ° C. More preferably, the desiccant adsorbs at most 10% water from its mass when in contact with the environment with an organic substance of 10% -20% at 40 ° C. More preferably, the desiccant absorbs 5% to 10% of the water by weight when in contact with the environment with an OM of 10% -20% at 40 ° C.

[0028] An example of a desiccant that absorbs from 5% to 10% of water by mass when in contact with the environment with an OM of 10% -20% at 40 ° C includes silica gel. Silica gels can adsorb moisture at a level approximately proportional to the relative humidity of the environment, for OM values from 0% to about 60%. In contrast, desiccants, molecular sieves traditionally used in test sensor containers, can quickly adsorb large amounts of moisture from environments with 10% -20% OM. Molecular sieves can adsorb 15% -20% water of their mass when in contact with the environment with 5% OM at 40 ° C, and then they can adsorb minimal amounts of additional moisture as relative humidity rises.

[0029] An example of a desiccant that can absorb at most 15% water from its mass when in contact with the environment with an OM of 10% -20% at 40 ° C includes a composition of molecular sieves mixed with a polymer. The effectiveness of the desiccant can be reduced by mixing the desiccant with the polymer. Since the desiccant in the polymer is only partially exposed to the environment, moisture adsorption can occur at a lower rate than the adsorption rate of a pure desiccant. Another example of a desiccant, which can absorb at most 15% water from its mass when in contact with the environment with an OM of 10% -20% at 40 ° C, includes a mixture of molecular sieves with silica gel. The choice of types and relative amounts of molecular sieves and silica gel in this mixture may provide an opportunity to optimize the total moisture adsorbed by the mixed composition at low relative humidity.

[0030] FIG. 1A-1C show the output signals of test sensors for whole blood samples having a glucose concentration of 400 milligrams per deciliter (mg / dl) and having a hematocrit of 40%. The test sensors were sealed in a container having either 22.5 mg of a traditional 13x molecular sieve desiccant per test sensor (FIG. 1A), or 30 mg of silica gel per test sensor (FIG. 1B), or lacking a desiccant (FIG. 1C) . For each type of container, half of the containers were stored at 50 ° C for two weeks, and half were stored at -20 ° C for two weeks. An environment with a heat load of two weeks at 50 ° C is a forced load condition typically used to evaluate the action of a biosensor at the end of its shelf life. After a storage period, test sensors were used to conduct an electrochemical analysis of a whole blood sample.

[0031] The signal sent to the test sensors by the measuring device was a sequence of gated amperometric pulses, one or more output current values being correlated with the analyte concentration in the sample, for example, as described in US Patent Publication 2008/0173552, as well as in Patent Publication USA 2009/0145779. Disclosures of patent application data relating to gated amperometric pulse sequences and correlation of output current values with analyte concentrations are hereby incorporated by reference. The pulses used to create the graphs in FIG. 1A-1C included eight excitations separated by seven relaxations. Second to eighth excitations were approximately 0.4 second in duration, and second to seventh excitations were approximately 1 second in duration. Three values of the output current were recorded during the second to eighth excitations.

[0032] A correlation of one or more values of the output current with the analyte concentration of the sample can be obtained by plotting the dependence of the output current at a particular point in time when analyzing the known analyte concentration in a series of stock solutions containing analyte. To correlate the values of the output current from the input signal with the analyte concentration in the sample, the value of the initial current due to excitation is preferably larger than the values that follow with attenuation. Preferably, the value or values of the output current, correlated with the concentration of analyte in the sample, is taken from the attenuation current data reflecting the maximum kinetic characteristic of the test sensor. The kinetics of the redox reaction that underlies the output currents is influenced by many factors. These factors may include the rate at which the reagent composition is rehydrated, the rate at which the enzyme system reacts with the analyte, the rate at which the enzyme system transfers electrons to the mediator, and the rate at which the mediator transfers the electrons to the electrode.

[0033] The maximum kinetic characteristic of the test sensor can be achieved during the excitation of a sequence of gated amperometric pulses, when the value of the initial excitation current with decaying current values is the largest for many excitations. Preferably, the maximum kinetic characteristic of the test sensor is achieved when the most recent current value obtained for excitation with decaying current values is the largest recent most current value obtained for a plurality of excitations. More preferably, the maximum kinetic characteristic of the test sensor is achieved when the value of the initial excitation current with decaying current values is the largest for the set of excitations, and the most recent current value obtained for the same excitation is the highest most recent current value obtained for the many excitations . The maximum kinetic characteristic can be achieved during the first excitation with decaying current values, or it can be achieved with subsequent excitation, for example, with a second, third or later excitation with decaying current values.

[0034] The maximum kinetic characteristic can be described in terms of the “peak time” parameter, which is the time that the electrochemical test sensor receives its maximum output current value after the sample containing analyte has come into contact with the test sensor. The maximum value of the output current is preferably used to correlate with the analyte concentration in the sample. Preferably, the peak time for the test sensor is less than about 7 seconds, and more preferably less than about 5 seconds, from the introduction of the sample into the test sensor. Preferably, the peak time is in the range of about 0.4 to about 7 seconds, more preferably in the range of about 0.6 to about 6.4 seconds, more preferably in the range of about 1 to about 5 seconds, more preferably in the range of about 1.1 to about 3.5 seconds from the introduction of the sample into the test sensor.

[0035] Referring to FIG. 1A, a test sensor that was sealed in a container containing a conventional desiccant had a longer peak time after being stored at 50 ° C. for two weeks than after being stored for two weeks at -20 ° C. In contrast, sensors sealed with either silica gel desiccant (FIG. 1B) or without a desiccant (FIG. 1C) did not increase their peak time when stored at 50 ° C for two weeks relative to their storage for two weeks at -20 ° C.

[0036] Any change in the current profile of the test sensor may lead to inconsistent glucose analysis results, since glucose test sensor results are usually derived from the measured current at a fixed point in time. This increased inaccuracy is especially evident for analyzes performed in a shorter time, such as 10 seconds or less. For the test sensors discussed in FIG. 1A-1C, changing the current profile for test sensors sealed with a conventional desiccant resulted in an undesirable increase in biosensor bias.

[0037] The measurement characteristics of a biosensor are determined in terms of its accuracy and / or reproducibility. Improving accuracy and / or reproducibility provides improved measurement performance of the biosensor. Accuracy can be expressed in terms of the systematic error in the readings of the analyte by the biosensor compared to the control readings of the analyte, and large values of the systematic error reflect less accuracy. Reproducibility can be expressed in terms of the dispersion or variance of the systematic error among the many readings of the analyte in relation to the average. A systematic error is the difference between one or more values determined by a biosensor and one or more accepted control values of an analyte concentration in a biological fluid. Thus, one or more errors in the analysis leads to a systematic error in the analyte concentration established by the biosensor system. Systematic error can be expressed in terms of “absolute systematic error” or “percentage systematic error”, depending on the concentration of analyte in the sample. Absolute systematic error can be expressed in units of measure, such as mg / dl, and can be used for analyte concentrations of less than 100 mg / dl. Percent systematic error can be expressed as a percentage of the absolute systematic error relative to the control value and can be used for analyte concentrations of at least 100 mg / dl. Accepted control values can be obtained with a control device such as a YSI 2300 STAT PLUS ™ glucose analyzer supplied by YSI Inc., Yellow Springs, pc. Ohio, USA

[0038] FIG. 2A and 2B depict bias graphs for glucose analyzes in whole blood samples having a hematocrit content of 40% and having glucose concentrations of 50, 100, 400, or 600 mg / dl. The test sensors used in this analysis were sealed in containers having from 0 to 22.5 mg of a traditional desiccant 13x molecular sieve per test sensor (FIG. 2A), or containing from 0 to 30 mg of silica gel per test sensor, and stored at 50 ° C for two weeks.

[0039] Without a desiccant (0 mg desiccant / test sensor), blood glucose analyzes after the heat load of the test sensor had a positive systematic error of 15 mg / dl for samples containing low glucose (50 mg / dl), a systematic error of 7- 10% for samples having glucose concentrations of 100 mg / dl and 400 mg / dl, and had almost no systematic error for samples containing high glucose (600 mg / dl). Sealing test sensors with a traditional molecular sieve desiccant (FIG. 2A) corrected a positive systematic error for samples with low and normal glucose levels; however, the systematic error of the analysis for samples with 600 mg / dl glucose increased to -10% and -15% as the desiccant level increased. In contrast, the systematic error of the analysis for sensors stored with 30 mg / silica gel sensor was within 5 mg / dl for samples containing less than 100 mg / dl glucose and was within ± 5% for samples containing from 100 mg / dl to 600 mg / dl glucose (Figure 2B).

[0040] The increase in peak analysis time and systematic error of analysis for test sensors sealed at 50 ° C for two weeks in the presence of a traditional desiccant is unexpected when compared with results for similarly processed test sensors sealed without a desiccant or with a weaker desiccant silica gel. As a rule, desiccants are used to prevent transformations of the components of the reagent layer, including the mediator, before using the test sensor. Thus, it was unexpected that storing a test sensor with a traditional desiccant deteriorated the accuracy of the test sensor and / or its shelf life relative to those of a comparable test sensor stored without a desiccant or with a less aggressive desiccant, especially when analyzing samples with high glucose concentrations.

[0041] For a biosensor system that includes multiple test sensors sealed in a desiccant container, the system can be evaluated by using test sensors to measure analyte content in samples containing known analyte concentrations that span a range of concentrations and then count systematic measurement error relative to actual concentrations. In one example, a plurality of test sensors are sealed in a container containing a desiccant for two weeks at a temperature of 50 ° C., wherein each test sensor includes at least two conductors, one of which is a working electrode, and a reagent composition placed on a working electrode or near it. The test sensors are then removed from the container, and each test sensor is connected through these at least two conductors to a measuring device. After connection, each test sensor is brought into contact with one of the samples and used to measure the analyte concentration in the sample. In this example, for samples having an analyte concentration that spans a range of 10 mg / dL to 600 mg / dL, the systematic error of each measured analyte concentration is preferably within ± 10 mg / dL for samples having an analyte concentration of less than 100 mg / dL and within ± 10% for samples having an analyte concentration of at least 100 mg / dl. The phrase "analyte concentration, which covers a range of 10 mg / dl - 600 mg / dl" means that at least one of the samples has an analyte concentration of 10 mg / dl and at least one of the other samples has an analyte concentration of 600 mg / dl. The remaining samples, if any, may have analyte concentrations between 10 mg / dl and 600 mg / dl.

[0042] In the above example, the systematic error of each measured analyte concentration is preferably within ± 7 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 7% for samples having an analyte concentration of at least 100 mg / dl. More preferably, the systematic error of each measured analyte concentration is within ± 5 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 5% for samples having an analyte concentration of at least 100 mg / dl. Preferably, in this example, the number of test sensors in their set is at least 10, and preferably is at least 25, at least 50, or at least 100. Preferably, in this example, the samples have an analyte concentration that spans a range of 50 mg / dl - 600 mg / dl.

[0043] For a biosensor system that includes multiple test sensors sealed in a desiccant container, the system can be evaluated by using test sensors to measure analyte content in samples containing a known analyte concentration, and then calculate the coefficient of variation (% CV) measurements. In the above example,% CV for each measured analyte concentration is at most 2.5%. More preferably, in this example,% CV for each measured analyte concentration is at most 2%.

[0044] Table 1 lists the% CV for glucose assays of whole blood samples having a hematocrit content of 42% and having glucose concentrations of 50, 100, 400, or 600 mg / dl. The test sensors used in this analysis were sealed in containers containing 0 to 22.5 mg of a traditional desiccant 13x molecular sieve per test sensor or containing 0 to 30 mg of silica gel per test sensor, and stored at 50 ° C for two weeks . Each result listed is based on 10 test sensors.

Table 1
Repeatability analysis for test sensors exposed to thermal stress at 50 ° C for 2 weeks Dehumidifier % CV (n = 10) for glucose concentrations: Type of Amount (mg / sensor) 50 mg / dl 100 mg / dl 400 mg / dl 600 mg / dl No 0 1.9 1.8 2,4 1.3 Molecular sieves 7.5 2,4 4.9 1,5 2,8 22.5 2.9 2,4 2.1 2.0 Silica gel 10.0 3.3 1,6 2,5 1.4 30,0 1,5 1,1 1.3 1,1

[0045] Table 2 lists the% CV for glucose assays as described for Table 1, but the test sensors were stored for two weeks at -20 ° C. Each result listed is based on 10 test sensors.

table 2
Repeatability assay for test sensors stored at -20 ° C for 2 weeks Dehumidifier % CV (n = 10) for glucose concentrations: Type of Amount (mg / sensor) 50 mg / dl 100 mg / dl 400 mg / dl 600 mg / dl No 0 2.9 2.9 1,6 1,0 Molecular sieves 7.5 1.3 1,5 3.4 1.3 22.5 5.8 4.2 1.9 1,5 Silica gel 10.0 1.8 3.3 1,6 1.3 30,0 1.8 2.1 2.0 1.3

[0046] Without a desiccant (0 mg desiccant / test sensor), blood glucose analyzes after the heat load of the test sensor (2 weeks at 50 ° C) had variation coefficients of 1.3-2.4% for samples having analyte concentrations that covered the range 50 mg / dl - 600 mg / dl. Sealing test sensors with a traditional molecular sieve desiccant (7.5 or 22.5 mg / test sensor) or 10.0 mg / test silica gel sensor did not reduce the upper limit of% CV for blood glucose assays. However, sealing test sensors with 30.0 mg / test silica gel sensor reduced the upper limit of% CV for blood glucose assays to 1.5%. A similar trend was also measured for blood glucose analyzes after the test sensors were sealed at -20 ° C for 2 weeks. For both sets of storage conditions, blood glucose analyzes using test sensors sealed with 30.0 mg / silica gel test sensor had% CV values below 2.1% for samples having analyte concentrations that spanned the 50 mg / dl range - 600 mg / dl.

[0047] FIG. 3A and 3B depict background current plots for glucose analyzes in glucose-free whole blood samples. The test sensors used in this analysis were sealed in a container containing 0 to 22.5 mg of a traditional desiccant, a 13x molecular sieve per test sensor (FIG. 3A) or containing 0 to 30 mg of silica gel per test sensor (FIG. 3B), and stored for two weeks at -20 ° C, at room temperature ("RT", 25 ° C) or at 50 ° C. Since the samples did not contain glucose, the measured background current results from the presence of substances in low oxidation states, such as a reduced mediator.

[0048] Test sensors stored without a desiccant in the container showed a large increase in the background biosensor current after a heat load. This was consistent with the traditional theory that a desiccant is important for maintaining a low background current in the test sensor, probably by preventing the mediator from self-healing. An increase in the background current of the sensor could contribute to a positive systematic analysis error for the low glucose samples shown in FIG. 2A and 2B. Test sensors stored in the presence of a traditional molecular sieve desiccant (FIG. 3A) require less dehumidifier to maintain a low background current than test sensors stored in the presence of silica gel (FIG. 3B). Thus, it seems that the traditional desiccant performs its intended function of inhibiting premature recovery of the mediator.

[0049] The mediator in the reagent compositions of the test sensors used in FIG. 1-6, was a mediator of the transfer of two electrons 3- (2 ', 5'-disulfophenylimino) -3H-phenothiazine bis-sodium salt. The observed action of moisture during storage of the test sensors seems to be applicable to other two electron transfer mediators, such as other organic quinones and hydroquinones. Examples of such mediators include quinone phenatrolin; phenothiazine and phenoxazine derivatives such as 3-phenylimino-3H-phenothiazines (PIPT) and 3-phenylimino-3H-phenoxazines (PIPO); 3- (phenylamino) -3H-phenoxazines; phenothiazines; and 7-hydroxy-9,9-dimethyl-9H-acridin-2-one and its derivatives. The observed action of moisture during storage of test sensors also seems to be applicable to single electron transfer mediators, such as 1,1'-dimethylferrocene, ferrocyanide and ferricyanide, ruthenium (III) and ruthenium (II) hexamine.

[0050] One possible explanation for unexpected results regarding peak time, bias, and / or reproducibility is that a less aggressive desiccant can protect the enzyme at a level that is unexpectedly high. A less aggressive desiccant, such as silica gel, has proven to be more compatible with the FAD-GDH enzyme than traditional desiccants, which still provide adequate protection for the mediator. The influence of the loss of enzyme activity on the bias of the analysis could be underestimated earlier, especially for samples with high glucose levels.

[0051] Figure 4 depicts a graph of the intra-sensor activity of the FAD-GDH enzyme for test sensors sealed for two weeks at either -20 ° C (diamond-shaped characters), or at 50 ° C (triangular characters), or at room temperature (square symbols) in containers containing various types and levels of desiccant. The filled symbols correspond to a traditional molecular sieve desiccant, and the empty symbols correspond to a silica gel desiccant. It appears that not one of the desiccants produced a loss of enzyme activity at -20 ° C. For sensors packaged without desiccant (0 mg desiccant / sensor), there was an approximately 10% loss of intrasensory activity of the enzyme after storage of the sensors at 50 ° C for two weeks. Enzyme activity decreased to about 60% for sensors packaged with a molecular sieve (filled triangular symbols), even at relatively low levels of 7 mg of desiccant per sensor. In contrast, the enzyme activity for sensors packaged with silica gel was approximately 25% higher, while maintaining the enzyme activity by 75-80% (open triangular characters). Even at room temperature, test sensors stored with a molecular sieve (filled square symbols) showed an enzyme activity that was approximately 5% lower than that of test sensors stored with silica gel (open square symbols).

[0052] The results of FIG. 4 combined with the results of FIG. 1-3 are consistent with the analysis that the FAD-GDH enzyme requires a limiting moisture level to maintain its natural structure and activity. The increase in negative bias with increasing desiccant content of the molecular sieve for 600 mg / dl glucose (Fig. 2A) was correlated with an approximately 40% loss of activity of the FAD-GDH enzyme for test sensors stored with the desiccant molecular sieve (Fig. 4). In contrast, a relatively constant and almost zero systematic error with increasing silica gel desiccant content for 600 mg / dl glucose (FIG. 2B) correlated only with a 20–25% loss of FAD-GDH enzyme activity for test sensors stored with desiccant silica gel (figure 4).

[0053] Figure 5 depicts graphs of the intra-sensor activity of the FAD-GDH enzyme ("% assimilation of the enzyme") for test sensors sealed for two weeks each at 50 ° C, for containers containing various types of desiccant, and for reagent compositions with stabilizer enzyme sorbitol and without it. The desiccants used were silica gel (SG), 13x molecular sieve (MS-13x), a narrow bottle containing a 4A molecular sieve (Bottle-MS), and two different desiccants mixed with polymers - a polypropylene film coated with molecular sieves (SLF / MS), and polypropylene film coated with silica gel (SLF / SG). Desiccant-mixed desiccants were obtained from Multisorb Technologies (Buffalo, NY, USA).

[0054] The reagent compositions for test sensors, designated "PD18 control" and "PD16 control", were obtained by applying and drying a fluid with reagents, which included water, 80 millimolar (mm) mediator 3- (2 ', 5' -disulfophenylimino) -3H-phenothiazine bis-sodium salt, 3.75 enzyme units FAD-GDH per microliter, 0.2% (w / w) hydroxyethylene cellulose binder (HEC) with a weight average molecular weight (M _w ) of 300,000, 0.362 % (w / w) of a HEC binder with M _w 90,000, 112.5 mM Na ₂ HPO ₄ buffer salt, 0.225% (w / w) N-octanoyl-N-methyl-D-glutamine (MEGA-8 ) and 0.01% (w / w) methyl sodium koiltaurata (Geropon TC-42). The reagent composition for the test sensors labeled “PD18 plus 0.4% sorbitol” was prepared in the same way as the sensors labeled “PD18 control," except that the reagent fluid also contained 0.4% (w / w) wt.) sorbitol.

[0055] Test sensors stored with a clean desiccant of molecular sieve (MS-13x) or with a narrow desiccant bottle (Bottle-MS) had an approximately 30% decrease in enzyme activity, while test sensors stored with a desiccant of silica gel (SG) had only a 15% decrease. Stabilization of the enzyme with 0.4% sorbitol reduced the loss of enzyme activity; however, test sensors stored with molecular sieve desiccants again produced twice the amount of enzyme inactivation. Differences in enzyme uptake between the PD18 control test sensors and the PD16 control test sensors stored with a clean desiccant molecular sieve or desiccant silica gel appear to be within the experimental error.

[0056] The mixing of the desiccant with a molecular sieve with polypropylene (SLF / MS) ensured that the activity of the enzyme was comparable to that provided by desiccant silica gel. Thus, the inhibition of the drying ability of molecular sieves allowed the enzyme to maintain its activity during heat load. The drying ability of silica gel has also been inhibited. A decrease in the accuracy of the analysis may be due to insufficient protection of the other ingredients of the reagent compositions from moisture during heat load.

[0057] In the case of a biosensor system that includes a plurality of test sensors sealed in a desiccant container, this system can be evaluated by measuring the activity of the redox enzyme in the reagent composition of the test sensors, which is stored after storage of the test sensors under various conditions. In one example, a plurality of test sensors are sealed in a container containing a desiccant for two weeks at a temperature of 50 ° C., wherein each test sensor includes at least two conductors, one of which is a working electrode, and a reagent composition comprising oxidation a reducing enzyme located on or near the working electrode. The test sensors are then removed from the container and the redox enzyme activity is measured in the reagent composition of each test sensor. In this example, the reagent composition of each test sensor preferably retains at least 75% of the activity of the redox enzyme. More preferably, in this example, the reagent composition of each test sensor preferably retains at least 80% of the activity of the redox enzyme, and more preferably retains at least 85% of the activity of the redox enzyme. Preferably, in this example, the number of test sensors in their set is at least 10, and preferably is at least 25, at least 50, or at least 100.

[0058] Correlation of one or more output current values, such as output current values shown in FIG. 1A-1C, with analyte concentration in the sample, can be adjusted to account for measurement errors. One approach to correcting errors associated with biosensor analysis is to correct the correlation to determine analyte concentrations in the sample from the output current values by index functions derived from intermediate current values from these output current values. Index functions may introduce corrections to determine analyte concentrations from the output current values for one or more errors in the analyzes that could lead to a systematic error in the analyte concentrations determined. Index functions correspond to the% systematic error in the correlation between analyte concentrations and output current values due to one or more errors in the analysis.

[0059] This% systematic error in glucose analysis can be represented by one or more ΔS values obtained from one or more error parameters. The ΔS values represent deviations of the slope of the correlation between analyte concentrations and output current values determined from one or more error parameters. The correlation slope corresponds to a change in the output current for a given change in glucose concentration in the sample. Index functions corresponding to a slope or a change in slope can be normalized in order to reduce the statistical effect of changes in the values of the output current, to improve the differentiation of fluctuations in the values of the output current, to standardize the measurements of the values of the output current, their combination, and the like. Corrected correlation can be used to determine analyte concentrations in biological samples from the output current values and can have increased accuracy and / or reproducibility compared to traditional biosensors. Error correction using index functions and ΔS values is described, for example, in US Patent Publication 2009/0177406 and in International Patent Application No. PCT / US2009 / 067150, filed December 8, 2009, entitled "Complex Index Functions". Disclosures of patent application data related to error correction using index functions and ΔS values are incorporated herein by reference.

[0060] Thus, the value of the output current sensitive to the glucose concentration in the sample can be converted to the adjusted glucose concentration in the sample using an index function representing ΔS / S. Alternatively, the adjusted glucose concentration value can be determined from the uncorrected glucose concentration value using an index function and an equation such as G _corr = G _ref / (1 + f (index)), wherein G _corr is the adjusted glucose concentration in sample, G _ref is the analyte concentration in the sample determined without compensation, and f (index) is an index function.

[0061] Index functions may include ratios derived from an output signal, such as the output signals shown in FIGS. 1A-1C. For example, the values of the output signal can be compared within a separate pulse-attenuation cycle of the signal, for example, the ratio R3 = i _3.3 / i _3.1 , where i _3.3 indicates the third current value recorded for the third signal attenuation, and i _{3 , 1} denotes the first current value recorded for the third signal attenuation. In yet another example, the values of the output signal can be compared between individual pulse-attenuation cycles of the signal, for example, the ratio R4 / 3 = i _4.3 / i _3.3 , where i _4.3 denotes the third current value recorded for the fourth signal attenuation . Index functions may include combinations of relationships derived from the output signal. In one example, the index function may include a simple ratio relationship, such as Ratio 3/2 = R3 / R2. In yet another example, an index function may include a more complicated combination of simpler index functions. For example, the index function Index-1 can be represented as Index-1 = R4 / 3-Ratio 3/2. In another example, the index function Index-2 can be represented as Index-2 = (R4 / 3) ^p - (Ratio 3/2) ^q , where p and q are independently positive numbers.

[0062] Preferably, the index function corrects errors associated with fluctuations in the hematocrit content. For example, traditional biosensor systems can be configured to report glucose concentrations, assuming 40% (v / v) hematocrit for a whole blood sample, regardless of the actual hematocrit in the sample. In these systems, any glucose measurement performed on a blood sample containing less than or more than 40% hematocrit will contain an error and thus have a systematic error attributed to the action of the hematocrit.

[0063] The calculation of an index function that corrects errors associated with fluctuations in the hematocrit content can be facilitated by using a test sensor that provides an output signal that varies with the hematocrit content. For some biosensors, the ratio parameter R5 / 4 served as an indicator of hematocrit in the sample and was used to adjust the measured analyte concentration to take into account the hematocrit content in the sample. Parameter ratio R5 / 4, represents the relationship between the currents generated by the analyte in response to the 4 ^th and 5 ^th pulses of gated amperometric pulse sequences of Fig. 1A-1C.

[0064] FIG. 6 shows graphs of variation of the R5 / 4 ratio parameter for test sensors stored for two weeks at 50 ° C, relative to the R5 / 4 ratio parameter for test sensors stored for two weeks at -20 ° C, This test sensors had varying levels of enzyme density above the working electrode of the test sensors. Two types of experimental points represent two different anionic surfactants Phospholan CS131 (nonyl phenol ethoxyl phosphate) and Geropon TC-42.

[0065] At higher enzyme concentrations, the difference between the R5 / 4 ratio parameters for test sensors stored at 50 ° C and for test sensors stored at -20 ° C was smaller. This trend was evident for both types of anionic surfactants used in reagent compositions. Since the ratio parameter R5 / 4 can be used as a variable in the index function to correct analyte measurements, lower fluctuation of this parameter due to environmental factors is desirable. Thus, the increased retention of enzyme activity provided by less aggressive desiccants can provide an additional advantage of reducing the variability of correction factors.

[0066] The enzyme in the test sensor reagent compositions used in FIGS. 1-6 was the FAD-GDH enzyme. The observed effects of residual moisture during storage of test sensors seems to be applicable to other enzymes, such as alcohol dehydrogenase, lactate dehydrogenase, β-hydroxybutyrate dehydrogenase, glucose-6-phosphate dehydrogenase, glucose oxidase (GOx), glucose dehydrogenase, formaldehyde dehydrogenase, dehydrogendehydrogenase.

[0067] Preferred enzyme systems are oxygen-independent, thus substantially non-oxidized by oxygen. One such family of oxygen-independent enzymes is glucose dehydrogenase (GDH). Using various coenzymes or cofactors, GDH can be mediated in various ways by different mediators. Depending on their association with GDH, a cofactor, such as flavin adenine dinucleotide (FAD), can be firmly held by the main enzyme, as in the case of FAD-GDH; or a cofactor, such as pyrroloquinolinequinone (PQQ), can be covalently linked to a major enzyme, for example, PQQ-GDH. The cofactor in each of these enzyme systems can either be permanently retained by the main enzyme, or the coenzyme and apoenzyme can be reduced before the enzyme system is added to the reagent fluid. A coenzyme can also be independently added to a fragment of the main enzyme in a reagent fluid to promote the catalytic function of the main enzyme, for example, in the cases of NAD / NADH ⁺ nicotinamide adenine dinucleotide or NADP / NADPH ⁺ nicotinamide adenine dinucleotide phosphate in combination with NAD-dependent glucose dehydrogen D-hydrogenase .

[0068] The ingredients of the reagent compositions for test sensors and reagent fluids for creating reagent compositions are described, for example, in US Patent Publication 2009/0178936 and International Patent Application No. PCT / US2009 / 066963, filed December 7, 2009, entitled "Low Total Salt Reagent Compositions And Systems For Biosensors. " The disclosures of these patent applications relating to ingredients of reagent compositions and fluids for creating reagent compositions are incorporated herein by reference.

[0069] The type of desiccant used in the sensor container apparently affects the enzyme activity in the test sensors and the analytical characteristics of the test sensors. A desiccant that adsorbs at most 15% water from its mass, or which preferably adsorbs at most 10% or 5% to 10% water from its mass when in contact with the environment with an organic substance 10% -20% at 40 ° C, can provide a level of residual moisture in the reagent composition that allows the enzyme to remain in its active state. In contrast, excessive drying of the reagent composition with an aggressive desiccant, such as a molecular sieve, can lead to inactivation of the enzyme. Less aggressive desiccants can balance the opposite moisture requirements of the mediator and enzyme in the containers for test sensors by adsorbing water from the atmosphere only when the moisture level in the package exceeds 20% RH. Thus, less aggressive desiccants can protect the mediator from high humidity without adversely affecting enzyme activity.

[0070] FIG. 7 provides a schematic representation of a biosensor 700 that senses an analyte concentration in a sample of a biological fluid using a test sensor. The biosensor 700 includes a measuring device 702 and a test sensor 704, which can be made in the form of any analytical device, including a desktop device, a portable or handheld device, or the like. The biosensor 700 can be used to determine analyte concentrations, including concentrations of glucose, uric acid, lactate, cholesterol, bilirubin, and the like. While a specific configuration is shown, the biosensor 700 may have other configurations, including configurations with additional features.

[0071] The test sensor 704 has a base 706 forming a reservoir 708 and a channel 710 with a hole 712. The tank 708 and a channel 710 can be closed by a lid with a vent. The reservoir 708 forms a partially enclosed volume. Reservoir 708 may contain a composition that facilitates retention of a liquid sample, such as water-swellable polymers or porous polymer matrices. Reagents may be placed in reservoir 708 and / or channel 710. The reagent composition on the working electrode 707 includes a reagent composition with a low total salt content and may include one or more enzyme systems, a mediator, and the like. The counter electrode 705 may be formed using the same or different reagent composition, preferably a composition with no enzyme system. The test sensor 704 may also have a sample interface 714 located adjacent to the reservoir 708. The sample interface 714 may partially or completely surround the reservoir 708. The test sensor 704 may have other configurations.

[0072] The sample interface 714 has conductors 709 connected to a working electrode 707 and a counter electrode 705. The electrodes may be in substantially the same plane or in more than one plane. The electrodes 704, 705 may be placed on the surface of the base 706, which forms the reservoir 708. The electrodes 704, 705 may extend or protrude into the reservoir 708. The dielectric layer may partially cover the conductors 709 and / or the electrodes 704, 705. The sample interface 714 may have other electrodes and conductors.

[0073] The measurement device 702 includes an electrical circuit 716 connected to an interface 718 with a sensor and a screen 720. The electrical circuit 716 includes a processor 722 connected to a signal generator 724, an optional temperature sensor 726, and a storage medium 728.

[0074] The signal generator 724 supplies an electrical input signal to the sensor interface 718 at the command of the processor 722. The electrical input signal may be transmitted by the sensor interface 718 to the sample interface 714 for supplying an electrical input signal to the biological fluid sample. The electrical input signal may be potential or current and may be applied in the form of multiple pulses, pulse sequences or cycles. A signal generator 724 can also register an output signal from an interface with a sensor as a recorder generator.

[0075] An optional temperature sensor 726 senses the temperature of the sample in the reservoir of the test sensor 704. The temperature of the sample can be measured, calculated from the output signal, or assumed to be the same or similar to measuring the ambient temperature or the temperature of a device implementing the biosensor system. Temperature can be measured using a thermistor, thermometer, infrared sensor, thermocouple, or other thermosensitive device. Other methods can be used to determine the temperature of the sample.

[0076] The storage medium 728 may be magnetic, optical, or semiconductor memory, another storage device, and the like. The storage medium 728 may be a non-removable storage device, a removable storage device such as a memory card, a remote access storage device and the like.

[0077] The processor 722 implements analyte analysis and data processing using computer readable program code and data stored in the storage medium 728. The processor 722 may start analyte analysis in response to the presence of a test sensor 704 at the sensor interface 718, applying a sample to the test sensor 704, in response to user input and the like. The processor 722 instructs the signal generator 724 to provide an electrical input signal to the sensor interface 718. The processor 722 may receive a sample temperature from an optional temperature sensor 726. A processor 722 receives an output from an interface 718 with a sensor. An output signal is generated in response to the redox reaction of the analyte in reservoir 708.

[0078] The processor 722 preferably measures the output signal to obtain a current value from the drive, where the initial current value is greater than those that follow the attenuation and within less than about 3 seconds from the introduction of the sample into the test sensor 704. More preferably, the processor 722 measures the output signal to obtain a current value within less than about 3 seconds from the introduction of the sample into the test sensor 704, and obtains a first current value recorded from the excitation, where the current values that follow the first current value is continuously decreasing. Even more preferably, the processor 722 measures the output signal to obtain a current value within less than about 3 seconds from the introduction of the sample into the test sensor 704 to obtain a first current value recorded from the excitation, where the current values that follow the first current value, continuously decrease, and to get the current value during the maximum kinetic characteristics of the test sensor.

[0079] The correlation of one or more obtained current values with the analyte concentration in the sample is established using one or more correlation equations in a processor 722. The results of the analyte analysis can be displayed on a screen 720 and can be stored in a storage medium 728. Preferably, the results of the analyte analysis are displayed on the screen 720 within five seconds or less from the introduction of the sample into the test sensor, more preferably the results are displayed on the screen 720 within three seconds or less from the introduction of the sample into the test sensor.

[0080] Correlation equations related to analyte concentrations and output current values can be represented graphically, mathematically, combinations thereof, and the like. Correlation equations can be represented by a program number table (PNA), another look-up table, and the like, which is stored in the storage medium 728. Commands related to the implementation of analyte analysis may be provided by a computer-readable program code stored in the storage medium 728. This code may be object code or any other code that describes or controls the functionality described here. Data from analyte analysis may be subjected to one or more data processing, including determining attenuation rates, constant Ks, ratios, and the like, in processor 722.

[0081] The sensor interface 718 has contacts that connect or provide electrical communication with the conductors 709 in the interface 714 with a sample of the test sensor 704. The sensor interface 718 transmits an electrical input signal from the signal generator 724 through the contacts to the conductors 709 in the sample interface 714 . The interface 718 with the sensor also transmits the output signal from the sample through the contacts to the processor 722 and / or to the signal generator 724.

[0082] The screen 720 may be analog or digital. The screen may be an LCD, LED, OLED, TFT, or other screen adapted to display a numerical indication.

[0083] In use, the sample for analysis is transferred to the reservoir 708 by introducing the sample into the opening 712. The sample flows through the channel 710, filling the reservoir 708, displacing the previously contained air therein. The sample chemically reacts with reagents located in channel 710 and / or reservoir 708. Preferably, the sample is a fluid, more preferably a liquid.

[0084] A test sensor 704 is located adjacent to the measuring device 702. Nearby are positions in which the interface 714 with the sample is in electrical communication with the interface 718 with the sensor. Electrical communication includes wired or wireless transfer of input and / or output signals between the contacts in the sensor interface 718 and the conductors 709 in the sample interface 714.

[0085] FIG. 8 depicts a biosensor system 800 that includes a container 810 comprising a desiccant and a plurality of test sensors 830. A container 810 includes a cover 812 that can seal (hermetically seal) test sensors 830 in a container 810. A container 810 may contain desiccant 820 in separate packaging in a container. The container 810 may contain a desiccant 822 in the lid 812. The container 810 may contain a desiccant 824 in the wall of the container. The container 810 may include a desiccant 826 at the base of the container. The container 810 may be made of various materials, including plastic, metal foil and / or glass. The amount and type of desiccant in the container 810 may be selected so as to provide a predetermined level of moisture in the container.

[0086] Although various embodiments of the invention have been described above, one of ordinary skill in the art will appreciate that other embodiments and implementations are possible within the scope of the invention. Accordingly, the invention should not be limited by anything other than the appended claims and their equivalents.

Claims (25)

1. A biosensor system designed to determine the concentration of analyte in a sample, including:
many test sensors, and each test sensor includes
at least two conductors, wherein one of the conductors is a working electrode, and
reagent composition placed on or near the working electrode; and
a container containing at most 30 mg of a silica gel desiccant per test sensor, the desiccant maintaining a residual moisture level in the container;
wherein the amount of residual moisture level maintained in the container is such that when a plurality of test sensors are sealed in the container for two weeks at a temperature of 50 ° C, and then removed from the container, and each test sensor is subsequently connected through at least two conductors to measuring device, and then brought into contact with one of the many samples containing analyte, and measure the concentration of analyte in each sample using a test sensor and a measuring device, and the set of Samples were have a concentration of analyte, which covers the range of 50-600 mg / dl
the systematic error of each measured analyte concentration is within ± 10 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 10% for samples having an analyte concentration of at least 100 mg / dl. 2. The biosensor system according to claim 1, wherein the desiccant adsorbs at most 15% of the water of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 3. The biosensor system according to claim 1, wherein the desiccant adsorbs at most 10% of the water of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 4. The biosensor system according to claim 1, wherein the desiccant absorbs from 5% to 10% of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 5. The biosensor system according to claim 1, wherein the plurality of test sensors comprises at least 10 test sensors. 6. The biosensor system according to claim 1, wherein the plurality of test sensors comprises at least 25 test sensors. 7. The biosensor system according to claim 1, wherein the plurality of test sensors comprises at least 50 test sensors. 8. The biosensor system according to claim 1, wherein many test contains at least 100 test sensors. 9. The biosensor system according to claim 1, wherein the systematic error of each measured analyte concentration is within ± 7 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 7% for samples having an analyte concentration of at least 100 mg / dl. 10. The biosensor system according to claim 1, wherein the systematic error of each measured analyte concentration is within ± 5 mg / dl for samples having an analyte concentration of less than 100 mg / dl, and within ± 5% for samples having an analyte concentration of at least 100 mg / dl. 11. The biosensor system according to claim 1, wherein many samples have an analyte concentration that spans a range of 50-600 mg / dl. 12. A biosensor system designed to determine the concentration of analyte in a sample, including:
many test sensors, and each test sensor includes
at least two conductors, wherein one of the conductors is a working electrode, and
a reagent composition located on or near the working electrode, the reagent composition containing a redox enzyme; and
a container containing a desiccant and a plurality of test sensors sealed in the container;
wherein the desiccant maintains the residual moisture level in the container such that when a plurality of test sensors are sealed in the container for two weeks at a temperature of 50 ° C, and each test sensor is subsequently removed from the container, the reagent composition of each test sensor retains at least 75% redox enzyme activity. 13. The biosensor system according to claim 12, wherein the desiccant adsorbs at most 15% of the water of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 14. The biosensor system according to claim 13, wherein the desiccant contains molecular sieves mixed with the polymer. 15. The biosensor system according to claim 13, wherein the desiccant contains a mixture of molecular sieves and silica gel. 16. The biosensor system according to claim 12, wherein the desiccant adsorbs at most 10% of the water of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 17. The biosensor system according to claim 12, wherein the desiccant absorbs from 5% to 10% of the water of its mass when in contact with the environment with a relative humidity of 10-20% at 40 ° C. 18. The biosensor system according to claim 17, wherein the desiccant contains silica gel. 19. The biosensor system according to claim 18, wherein the container contains at most 30 mg of silica gel per test sensor. 20. The biosensor system of claim 12, wherein the plurality of test sensors comprises at least 10 test sensors. 21. The biosensor system according to claim 12, wherein the plurality of test sensors comprises at least 25 test sensors. 22. The biosensor system of claim 12, wherein the plurality of test sensors comprises at least 50 test sensors. 23. The biosensor system of claim 12, wherein the plurality of test sensors comprises at least 100 test sensors. 24. The biosensor system of claim 12, wherein the reagent composition of each test sensor retains at least 80% of the activity of the redox enzyme. 25. The biosensor system of claim 12, wherein the reagent composition of each test sensor retains at least 85% of the activity of the redox enzyme.

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