JP6609001B2 - High accuracy analyte measurement system and method - Google Patents

Description

  The systems and methods provided herein relate to the field of medical testing, particularly the detection of the presence and / or concentration of an analyte in a sample (eg, a physiological fluid such as blood).

  Determining analyte concentrations in physiological fluids (eg, blood or blood-derived products such as plasma) is becoming more important in today's society. Such quantitative methods find use in a variety of uses and situations, including clinical tests, home tests, etc. The results of such tests play a major role in the diagnosis and treatment of various medical conditions. Plays. Analytes of interest include glucose for diabetes management, cholesterol for monitoring cardiovascular conditions, and the like. In response to the increasing importance of analyte detection, a variety of analyte detection procedures and devices have been developed for both clinical and home use. Some of these devices include electrochemical cells, electrochemical sensors, hemoglobin sensors, antioxidant sensors, biosensors, and immunosensors.

  A common method for analyte concentration determination quantification is based on electrochemistry. In such a method, an aqueous liquid sample is placed in a sample reaction chamber in the sensor, such as an electrochemical cell composed of at least two electrodes, a working electrode and a counter electrode, The electrodes have an impedance that makes them suitable for amperometric or coulometric measurements. The component to be analyzed can react with the reagent to form an oxidizable (or reducible) substance in an amount proportional to the analyte concentration. The amount of oxidizable (or reducible) material present is then estimated electrochemically and correlated with the analyte concentration in the sample.

  One characteristic of blood that can affect analyte detection is the hematocrit value. The level of hematocrit can vary greatly among different people. As a non-limiting example, a person suffering from anemia can have a hematocrit level of approximately 20%, while a newborn can have a hematocrit level of approximately 65%. Even samples taken over a period of time from the same individual can have different hematocrit levels. Furthermore, high hematocrit values can also increase blood viscosity, which in turn can affect other parameters related to analyte detection and account for the effect of hematocrit on the sample. This can be important for accurate analyte concentration quantification.

  One method that accounts for the variation in the level of hematocrit in the blood sample is by separating the plasma from the blood and then recalculating the concentration of the antigen with respect to the adjusted plasma volume. Separation has been achieved, for example, by performing a centrifugation step. Other methods that account for fluctuations in the level of hematocrit in the blood sample include using the average hematocrit value for the calculation, or measuring the hematocrit value in the separation process and then calculating the concentration of the antigen with respect to the plasma value To do. However, these methods are considered unreliable because at least they involve unnecessary sample manipulation, extra time and / or introduce substantial errors in the final quantification. Furthermore, the temperature of the environment in which the sample is analyzed can negatively affect the accuracy of analyte concentration determination.

  A desirable characteristic for all sensor elements is a long shelf life, i.e. the detection characteristics of the sensor element do not change significantly between manufacture and use (i.e. during storage). However, sensor performance may be reduced when stored for extended periods of time and / or under non-optimal storage conditions, such as high temperatures, high humidity, and the like. For example, the accuracy of analyte concentration quantification obtained using such a sensor may be reduced. The object of the present invention is to overcome and ameliorate these and other shortcomings of the prior art.

  Applicants should provide more accurate analyte concentration quantification over a wide range of donors, analyte concentration levels, hematocrit values, temperatures, and sensor storage conditions with little or no associated problems noted above. Recognized that the development of a method to obtain Thus, systems, devices and methods are generally provided for quantifying the exact concentration of an analyte in a sample. In general, the systems, devices, and methods disclosed herein include applying a series of corrections to an optimized analyte concentration quantification to provide a corrected analyte concentration value with improved accuracy.

  In an exemplary embodiment of a method for quantifying an analyte concentration in a sample, the method includes detecting a sample containing an analyte introduced into an electrochemical sensor. An electrochemical sensor may include, for example, two electrodes in a spaced arrangement. In other embodiments, the two electrodes can include facing orientations. In other embodiments, the electrochemical sensor can include two electrodes oriented oppositely. In some embodiments, the electrochemical sensor may include a glucose sensor. In other embodiments, the electrochemical sensor may include an immunosensor. In some embodiments, the sample can include blood or whole blood. In some embodiments, the analyte may comprise a C-reactive protein.

  The method further includes reacting the analyte to cause physical deformation of the analyte between the two electrodes. For example, reacting an analyte can generate an electroactive species that can be measured as an electric current by two electrodes. The method also includes measuring the current output at discrete intervals to derive the sample fill time into the sensor and the capacitance of the sensor containing the sample. The method also includes the step of quantifying the first analyte concentration value from the current output, the step of calculating the second analyte concentration value from the current output and the first analyte concentration value, and the effect of temperature. Correcting the second analyte concentration value to obtain a third analyte concentration value, and correcting the third analyte concentration value according to the filling time of the sensor to obtain a fourth analyte concentration value. And correcting the fourth analyte concentration value according to the capacitance to obtain a final analyte concentration value.

  In an exemplary embodiment of a method for obtaining a test strip with improved accuracy, the method comprises a test strip, each test strip having two electrodes, the two electrodes being spaced apart by a reagent disposed therebetween. Providing a batch. As used herein, the term “batch” refers to multiple test strips from the same manufacturing run that are considered to have similar characteristics. For example, one batch may contain about 500 test strips from a production lot of about 180,000 test strips. The method further includes introducing a reference sample containing a reference concentration of analyte into each of the test strip batches. The method also includes reacting the analyte to cause a physical deformation of the analyte between the two electrodes, measuring the current output at separate intervals, filling the sample with the sensor, and the sample Deriving the capacitance of the sensor including, and quantifying the first analyte concentration value from the current output. The method also includes a step of calculating a second analyte concentration value from the current output and the first analyte concentration, correcting the second analyte concentration value for the effect of temperature, and a third analyte concentration value. , Correcting the third analyte concentration value according to the filling time of the sensor, obtaining the fourth analyte concentration value, and correcting the fourth analyte concentration value according to the capacitance And obtaining a final analyte concentration value for each of the test strip batches such that at least 95% of the final analyte concentration value of the test strip batch is within 10% of the reference analyte concentration.

で表わすことができ、第２の電流和ｉ_ｌは、等式

で表わすことができ、式中、ｉ（ｔ）は、時間ｔにおいて測定された電流の絶対値を含み得る。 In an exemplary embodiment of the method, the current output measured at separate intervals may include a first current sum _ir and a second current sum _il . In some embodiments, the separate interval at which the first current sum i _r and the second current sum i _l are measured can be measured from the time the sample is placed in the test chamber, and is approximately 3.9 seconds. A first interval that is about 4 seconds and a second interval that is about 4.25 seconds to about 5 seconds. For example, the first current sum _ir is equal to the equation

And the second current sum i _l is the equation

Where i (t) may include the absolute value of the current measured at time t.

式中、ｐは約０．５２４６であってよく、ａは約０．０３４２２であってよく、ｉ_２は酸化防止剤で補正した電流値であってよく、ｚｇｒは約２．２５であってよい。 In some exemplary embodiments of the above method, the quantifying step of the first analyte concentration value may include calculating the analyte concentration G1 in an equation of the form:

Where p can be about 0.5246, a can be about 0.03422, i ₂ can be a current value corrected with an antioxidant, and zgr can be about 2.25. Good.

式中、ｐは約０．５２４６からなり、ａは約０．０３４２２からなり、ｉ_２は酸化防止剤で補正した電流値からなり、ＡＦＯは約２．８８からなり、ｚｇｒは約２．２５からなり、ｋは約０．００００１２４からなる。 In some exemplary embodiments of the above method, the step of calculating the second analyte concentration value may include calculating the analyte concentration G2 in an equation of the form:

Where p is about 0.5246, a is about 0.03422, i ₂ is the current value corrected with the antioxidant, AFO is about 2.88, and zgr is about 2.25. And k is about 0.0000124.

  In some exemplary embodiments of the above method, the third analyte concentration value includes a first temperature correction for the second analyte concentration value whenever the ambient temperature exceeds the first temperature threshold. In other words, the second temperature correction can be included whenever the ambient temperature is equal to or lower than the first temperature threshold.

  In some exemplary embodiments of the above methods, the step of correcting the third analyte concentration value as a function of the sensor fill time includes calculating a fill time correction factor based on the fill time. For example, the fill time correction factor can be about zero when the fill time is less than a first fill time threshold. In another example, the fill time correction factor can be calculated based on the fill time when the fill time is greater than a first fill time threshold and less than a second fill time threshold. In yet another example, the fill time correction factor may include a constant value when the fill time is greater than a second fill time threshold. In some embodiments, the first fill time threshold may be about 0.2 seconds and the second fill time threshold may be about 0.4 seconds.

  In some exemplary embodiments of the above methods, when the third analyte concentration value is less than an analyte concentration threshold, eg, less than about 100 mg / dL, the fourth analyte concentration value is the third analyte concentration value. May be equal to the value. When the third analyte concentration value is greater than about 100 mg / dL, for example, the fourth analyte concentration value may include a product of the third analyte concentration value and an offset to the fill time correction factor.

  In some exemplary embodiments of the above methods, the final analyte concentration value is set to be approximately equal to the fourth analyte concentration value when the fourth analyte concentration value is less than the first concentration threshold. Can be done. For example, the first concentration threshold may be about 100 mg / dL. In a further exemplary embodiment of the above method, when the fourth analyte concentration value exceeds the first concentration threshold, the final analyte concentration value is the capacitance correction factor and the fourth analyte concentration value. May contain products. For example, when the capacitance is less than a first capacitance threshold, the capacitance correction factor in the final analyte concentration value may be based on the measured capacitance, and the calculated capacitance correction factor is When the set value is exceeded, the capacitance correction factor can be set to the maximum value.

  In an exemplary embodiment of an analyte measurement device, the device can include a housing, a strip port connector attached to the housing and configured to receive an analyte test strip, and a microprocessor disposed within the housing. The microprocessor is connected to a strip port connector, a power source, and a memory, and when the analyte test strip is coupled to a strip port containing a sample placed in a test chamber of the test strip, between the two electrodes One or more first analyte concentration estimates G1, based on output current values measured over discrete intervals during the reaction of the analyte and measured over separate intervals during the reaction of the analyte. The second analyte concentration estimated value G2 based on the output current value and the second analyte concentration value G2 are temperature corrected. Analyte concentration value G3, analyte concentration value G4 corrected for sample filling time from third analyte concentration G3, and final concentration corrected for test strip capacitance from analyte concentration value G4 corrected for sample filling time The value G5 is provided.

  In an exemplary embodiment of an analyte measurement system, the system may comprise a plurality of test strips, each test strip being disposed between at least two electrodes spaced apart within the test chamber, and the two electrodes, Having a reagent for receiving a sample containing the analyte; The system also includes an analyte measurement device. The analyte measuring device may comprise a strip port having a connector shaped to mate with a corresponding electrode of each test strip, and a microprocessor coupled to the strip port. The microprocessor is configured to measure current, test strip capacitance, and sample fill time using the electrodes of each test strip when a reference sample is placed in each test chamber of the plurality of test strips. Often, the final analyte concentration is quantified based on current, sample fill time, and test strip capacitance, where the percentage of final analyte concentration value from the test strip batch exceeds the analyte value threshold and is Be within 10% of the analyte value.

  In some embodiments, the microprocessor can connect an analyte test strip of the plurality of test strips between the two electrodes when the analyte test strip is coupled to the strip port with the sample disposed therein. A first analyte concentration estimate G1 based on output current values measured over a discrete interval in response, a second analyte concentration estimate G2 based on output current values measured over a discrete interval, a second Test strip from analyte concentration value G3 temperature corrected from analyte concentration value G2, analyte concentration value G4 corrected from sample filling time from third analyte concentration, and analyte concentration value G4 corrected from sample filling time It can be configured to provide a capacitance corrected final density value G5.

であり、式中、ｉ（ｔ）は、時間ｔにおいて測定された電流の絶対値からなる。 In an exemplary embodiment, the separate intervals can be measured from the time that the sample is placed in the test chamber, with a first interval being about 3.9 seconds to about 4 seconds and about 4.25 seconds to about 5 And a second interval that is seconds. The output current value measured over the first and second intervals may include a first current sum i _r and a second current sum i _l , where

Where i (t) consists of the absolute value of the current measured at time t.

式中、ｐは約０．５２４６からなり、ａは約０．０３４２２からなり、ｉ_２は酸化防止剤で補正した電流値からなり、ｚｇｒは約２．２５からなる。 In some embodiments, the first analyte concentration value G1 may include a current value derivation value according to an equation of the form:

In the formula, p is about 0.5246, a is about 0.03422, i ₂ is a current value corrected with an antioxidant, and zgr is about 2.25.

式中、ｐは約０．５２４６からなり、ａは約０．０３４２２からなり、ｉ_２は酸化防止剤で補正した電流値からなり、ＡＦＯは約２．８８からなり、ｚｇｒは約２．２５からなり、ｋは約０．００００１２４からなる。 In some embodiments, the second analyte concentration value G2 may include a derived value by an equation of the form:

Where p is about 0.5246, a is about 0.03422, i ₂ is the current value corrected with the antioxidant, AFO is about 2.88, and zgr is about 2.25. And k is about 0.0000124.

式中、ｉ（４．１）は、第３の電位の間の電流の絶対値からなり、ｉ（１．１）は、第２の電位の間の電流の絶対値からなり、ｉ_ｓｓは、定常状態電流からなる。 In some embodiments, the antioxidant current value i ₂ may include an equation of the form:

Where i (4.1) consists of the absolute value of the current during the third potential, i (1.1) consists of the absolute value of the current during the second potential, and i _ss is , Consisting of steady state current.

式中
ｉ（５）は、第３の電位の間の電流の絶対値からなり、πは、定数からなり、Ｄは、酸化還元種の拡散係数からなり、Ｌは、２つの電極間の距離からなる。

Where i (5) is the absolute value of the current between the third potentials, π is a constant, D is the diffusion coefficient of the redox species, and L is the distance between the two electrodes. Consists of.

  In some embodiments, the temperature corrected analyte concentration value G3 can be corrected by a fill time correction factor based on the fill time. For example, the fill time correction factor can be about zero when the fill time is less than a first fill time threshold. In another example, the fill time correction factor can be calculated based on the fill time when the fill time is greater than a first fill time threshold and less than a second fill time threshold. In yet another example, when the fill time is greater than the second fill time threshold, the fill time correction factor may include a constant value. In some embodiments, the first fill time threshold may be about 0.2 seconds and the second fill time threshold may be about 0.4 seconds.

  In some embodiments, the temperature-corrected analyte concentration value G3 may include a first temperature correction for the second analyte concentration value G2 whenever the ambient temperature exceeds the first temperature threshold, A second temperature correction can be included whenever the ambient temperature is below the first temperature threshold.

  In some embodiments, when the temperature corrected concentration value G3 is less than a concentration threshold, eg, less than about 100 mg / dL, the fill time corrected analyte concentration value G4 is the temperature corrected concentration value G3, Well, when the temperature corrected concentration value G3 exceeds a concentration threshold, eg, about 100 mg / dL, the filling time corrected concentration value G4 is the rate of increase of the third analyte concentration value taking into account the filling time correction factor. May be included.

  In some embodiments, when the sample fill time corrected analyte concentration value G4 is less than the first concentration threshold, the test strip capacitance corrected final concentration value G5 is the fourth analyte concentration value. May be set equal to. For example, the first concentration threshold may be about 100 mg / dL. In some embodiments, when the sample fill time corrected analyte concentration value G4 exceeds a first concentration threshold, the test strip capacitance corrected final concentration value G5 is a capacitance correction factor and sample fill. It may consist of the product of the time-corrected analyte concentration value G4. For example, when the capacitance is less than a first capacitance threshold, the capacitance correction factor in the final analyte concentration value may be based on the measured capacitance, and the calculated capacitance correction factor is When the set value is exceeded, the capacitance correction factor can be set to a maximum value.

  In another embodiment of an exemplary method for quantifying the concentration of an analyte in a sample, the method includes introducing a sample containing the analyte to an electrochemical sensor. The method further includes reacting the analyte to cause physical deformation of the analyte between the two electrodes and quantifying the concentration of the analyte.

  In another exemplary method of measuring a corrected analyte concentration, the method includes detecting the presence of a sample in an electrochemical sensor. The electrochemical sensor can include two electrodes. The method also includes reacting the analyte to cause physical deformation of the analyte, quantifying the first analyte concentration in the sample, the first analyte concentration and one or more corrections. Calculating an analyte concentration corrected based on the factor.

  In some embodiments, the step of quantifying the concentration of the analyte is for one or more of sample fill time, electrochemical cell physical properties, sample temperature, electrochemical sensor temperature, and glucose kinetics. A correction step may be included. In an exemplary embodiment, the step of correcting the glucose kinetics includes calculating a first analyte concentration, such that the degree of correction of the glucose kinetics is proportional to the magnitude of the first analyte concentration. Computing a second analyte concentration determined by the first analyte concentration.

  In some embodiments, the physical characteristics of the electrochemical sensor may be related to at least one of aging of the electrochemical sensor and storage state of the electrochemical sensor. For example, the physical property may be the capacitance of the electrochemical cell.

  In an exemplary embodiment of an electrochemical system, the system includes an electrochemical sensor that includes an electrical contact configured to mate with a test instrument. The electrochemical sensor can include a first electrode and a second electrode that are in a spaced relationship, and a reagent. The test instrument may comprise a processor configured to receive current data from the electrochemical sensor upon application of a voltage to the test strip. The test instrument is further corrected based on one or more of the calculated analyte concentration and sample fill time, electrochemical sensor physical properties, sample temperature, electrochemical sensor temperature, and glucose kinetics. It may be configured to quantify the determined analyte concentration.

  In some embodiments, the test instrument may provide an analyte concentration threshold and one or more of sample fill time, electrochemical sensor physical properties, sample temperature, electrochemical sensor temperature, and glucose kinetics. A data storage device may be provided that includes a plurality of associated thresholds.

  In some embodiments, the electrochemical system can include a heating element configured to heat at least a portion of the electrochemical sensor. In some embodiments, at least one of the electrochemical sensor, the test instrument, and the processor may be configured to measure the temperature of the sample.

  In some embodiments, the system and method can reduce variations in analyte concentration quantification values, for example, between donors and / or genders. This method can also reduce interference due to urate concentration in the determination of analyte concentration.

  In some embodiments, the systems and methods of the present invention are such that for at least 95% of a series of analyte concentration assessments, an analyte concentration value is obtained that is within 10% of the reference analyte measurement error. An accuracy criterion of at least ± 10% can be achieved for a particular analyte (eg, glucose) concentration that exceeds the analyte concentration threshold. In another exemplary embodiment, the method provides an analyte concentration value for which at least 95% of the series of analyte concentration assessments provides an error in the reference analyte measurement within about 10 mg / dL. An accuracy criterion of at least ± 10 mg / dL can be achieved for analyte concentrations below the analyte concentration threshold (eg, plasma glucose in a whole blood sample). For example, the analyte concentration threshold may be about 75 mg / dL plasma glucose in a whole blood sample.

  In another example, accuracy criteria can be achieved over a series of analyte concentration assessments over about 5,000 times. In yet another example, accuracy criteria can be achieved over a series of analyte concentration assessments of more than about 18,000 times.

  These and other embodiments, features and advantages will be apparent to those skilled in the art by reference to the more detailed description of the different exemplary embodiments of the invention described below, first in conjunction with the accompanying drawings briefly described below. It will be.

  Various features of the disclosure are set forth with particularity in the claims. Such features may be better understood with reference to the following detailed description of exemplary non-limiting embodiments and the accompanying drawings.

The perspective view of a test strip. 1B is an exploded perspective view of the test strip of FIG. 1A. FIG. 1B is a perspective view of a distal portion of the test strip of FIG. 1A. FIG. FIG. 1B is a bottom plan view of the test strip of FIG. 1A. FIG. 1B is a side plan view of the test strip of FIG. 1A. FIG. 1B is a top plan view of the test strip of FIG. 1A. FIG. 4B is a partial side view of the distal portion of the test strip consistent with arrows 4B-4B in FIG. 4A. FIG. 3 is a simplified schematic diagram illustrating a test instrument in electrical contact with a test strip contact pad. A typical analyte measurement system including an analyte test instrument and a test strip. FIG. 5B is a simplified schematic diagram of an exemplary circuit board of the instrument of FIG. 5B. 1 is an exploded view of an exemplary embodiment of an immunosensor according to the present invention. FIG. Test voltage waveform when the test meter applies multiple test voltages at specified time intervals. Test current transition generated by the test voltage waveform of FIG. 7A is a test voltage waveform in which the test instrument applies a plurality of test voltages with different polarities during a specified time interval as compared to FIG. 7A. 8A is a test current transition generated by the test voltage of FIG. 8A. 6 is a graph showing the mean bias of male and female donor blood samples using the first and second algorithms disclosed herein. A plot of the bias from the reference glucose measurement against the reference glucose measurement for each component of the data set containing approximately 18,970 glucose assays. Plot of bias from baseline glucose measurements against hematocrit values for each component of a data set containing approximately 18,970 glucose assays. Plot of bias from reference glucose measurements against temperature measurements for each component of a data set containing approximately 18,970 glucose assays. Plot of bias from baseline glucose measurements against test strip storage for each component of a data set with a glucose concentration less than about 75 mg / dL. Plot of bias from baseline glucose measurements against test strip storage for each component of a data set with a glucose concentration above about 75 mg / dL.

  The following detailed description should be read with reference to the drawings, in which like elements in different drawings are designated with like reference numerals. The drawings are not necessarily to scale and illustrate selected embodiments and are not intended to limit the scope of the invention. The detailed description is not intended to limit the principles of the invention but is provided as an example only.

  The term “about” or “approximately” as used herein for any numerical value or range of numerical values means that a component part or set of components functions in accordance with its desired purpose as described herein. The tolerance of an appropriate dimension that enables the Further, as used herein, the terms “patient”, “host”, “user”, and “subject” refer to any human or animal subject, and the use of the invention in human patients is a preferred embodiment. However, it is not intended to limit the system or method to human use.

  Certain exemplary embodiments will now be described to provide a comprehensive understanding of the principles of structure, function, manufacture, and use of the systems and methods disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. The systems and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments, and the scope of the present disclosure is defined only by the claims, Those skilled in the art will appreciate. The features illustrated or described in connection with one exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present disclosure.

  As described in further detail below, the disclosed system and method includes quantifying a first analyte concentration value and calculating a second analyte concentration value from the first analyte concentration value. Correcting the second analyte concentration value for the effect of temperature to obtain a third analyte concentration value, correcting the third analyte concentration value according to the filling time of the sensor, Obtaining an analyte concentration value, and correcting the fourth analyte concentration value in accordance with the capacitance to obtain a final analyte concentration value.

The systems and methods disclosed herein are suitable for use in measuring a wide variety of analytes in a wide variety of samples, such as whole blood, plasma, serum, interstitial fluid, or the like. It is particularly suitable for use in measuring analytes in the body. In an exemplary embodiment, a glucose test system based on a thin cell design with opposing electrodes and a three pulse electrochemical design that is fast (eg, an analysis time of about 5 seconds or less) is small (eg, about 0.4 μL or less). ) Requires a sample and can provide improved reliability and accuracy of blood glucose measurement. In a reaction cell for inspecting an analyte, glucose in a sample can be oxidized to gluconolactone using glucose dehydrogenase, and an electrochemically active medium causes electrons from the enzyme to be applied to the working electrode. Can be used for shuttle transportation. More specifically, the reagent layer that coats at least one of the electrodes in the reaction cell can include pyrroloquinoline quinone (PQQ) coenzyme-dependent glucose dehydrogenase (GDH) and ferricyanide. In another embodiment, the enzyme PQQ coenzyme dependent GDH may be replaced with the enzyme flavin adenine dinucleotide (FAD) coenzyme dependent GDH. When blood or control solution is administered into the reaction chamber, the glucose will undergo a chemical change T.D. 1 is oxidized by GDH (ox), which changes GDH (ox) to GDH (red) in this process. Note that GDH (ox) refers to the oxidation state of GDH, and GDH (red) refers to the reduction state of GDH.
T. T. et al. 1 D-glucose + GDH (ox) → gluconic acid + GDH (red)

  A constant potential can be utilized to apply a three pulse potential waveform to the working and counter electrodes, resulting in a test current transition used to calculate the glucose concentration. In addition, additional information obtained from test current transitions can be used to distinguish between sample matrices and to compensate for hematocrit values, temperature changes, variability of blood samples due to electrochemically active components, and to identify possible system errors. Can be used.

  The marking method can in principle be used with any type of electrochemical cell sensor having spaced apart first and second electrodes and a reagent layer. For example, the electrochemical cell sensor can be in the form of a test strip. In one aspect, the test strip may include two opposing electrodes separated by a thin spacer to define a region in which the sample receiving chamber or reagent layer is disposed. Applicants note that other types of test strips can also be used with the systems and methods described herein, for example, test strips having multiple electrodes on the same plane. Devices used with the systems and methods described herein typically include at least one working electrode between which a potential can be applied and one counter electrode. A sample analysis device may generally be associated with a component for applying a potential between electrodes such as a meter. Applicants note that a variety of test instruments can be used with the systems and methods described herein. However, in one embodiment, the test instrument includes at least a processor, which is configured to perform a calculation that can calculate a correction factor taking into account at least one measured or calculated parameter, as well as data One or more control units configured for classification and / or storage may be included. The microprocessor may be in the form of a mixed signal microprocessor (MSP), such as, for example, Texas Instruments MSP 430. The TI-MSP 430 may also be configured to perform part of the constant potential function and the current measurement function. Further, the MSP 430 may include volatile and non-volatile memory. In another embodiment, many of the electronic components can be integrated with the microcontroller in the form of an application specific integrated circuit.

Electrochemical Cell FIGS. 1A-4B show various views of an exemplary test strip 62 suitable for use in the methods described herein. As shown, test strip 62 can include an elongated body extending from distal end 80 to proximal end 82 and having side edges 56, 58. The distal portion of the body 59 can include a sample reaction chamber 61 having a plurality of electrodes 64, 66 and a reagent 72, while the proximal portion of the test strip body 59 is in electrical communication with a test instrument. May include features configured. In use, a physiological fluid or control solution can be delivered to the sample reaction chamber 61 for electrochemical analysis. As used herein, the term “proximal” indicates that the reference structure is closer to the test instrument, and the term “distal” indicates that the reference structure is further from the test instrument.

  In the exemplary embodiment, test strip 62 can include a first electrode layer 66 and a second electrode layer 64 with spacer layer 60 positioned therebetween. The first electrode layer 66 can provide a first electrode 166 and a first connection path 76 to electrically connect the first electrode 166 to the first electrical contact 67. Similarly, the second electrode layer 64 can provide a second electrode 164 and a second connection path 78 to electrically connect the second electrode 164 to the second electrical contact 63. .

  In one embodiment, the sample reaction chamber 61 is defined by a first electrode 166, a second electrode 164, and a spacer 60, as shown in FIGS. Specifically, the first electrode 166 and the second electrode 164 define the bottom and top of the sample reaction chamber 61, respectively. The notched region 68 of the spacer 60 can define the side wall of the sample reaction chamber 61. In one aspect, the sample reaction chamber 61 can further include a number of ports 70 that provide sample inlets and / or vents. For example, one of the ports can provide an inlet for a fluid sample and the other port can function as a vent.

The sample reaction chamber 61 has a small volume. For example, the volume ranges from about 0.1 microliters to about 5 microliters, preferably from about 0.2 to about 3 microliters, more preferably from about 0.3 microliters to about 1 microliter. As those skilled in the art will appreciate, the sample reaction chamber 61 can have a variety of other such volumes. In order to provide a small sample volume, the notch 68 is about 0.01 cm ² to about 0.2 cm ² , preferably about 0.02 cm ² to about 0.15 cm ² , more preferably about 0.03 cm ² to about it can have an area ranging from 0.08 cm ^2. Similarly, those skilled in the art will appreciate that the volume notch 68 may be of various other such regions. In addition, the first and second electrodes 166, 164 range from about 1 micrometer to about 500 micrometers, preferably from about 10 micrometers to about 400 micrometers, and more preferably from about 40 micrometers. Can be spaced in the range of about 200 micrometers. In other embodiments, such a range can vary between various other values. The close electrode spacing allows the oxidizing medium generated at the first electrode 166 to diffuse to the second electrode 164 to be reduced and then diffuse back to the first electrode 166 to be oxidized again. A redox cycle can also be produced.

  At the proximal end of the test strip body 59, the first electrical contact 67 can be used to establish an electrical connection to the test instrument. The second electrical contact 63 can be accessed by the test instrument through a U-shaped notch 65, as shown in FIG. Applicants note that test strip 62 can include a variety of alternative electrical contacts configured for electrical connection to a test instrument. For example, US Pat. No. 6,379,513, which is incorporated herein by reference in its entirety, discloses electrochemical cell connection means.

  In one embodiment, the first electrode layer 66 and / or the second electrode layer 64 may be gold, palladium, carbon, silver, platinum, tin oxide, iridium, indium, and combinations thereof (eg, indium doped tin oxide). ) And other conductive materials. In addition, the electrodes can be formed by placing a conductive material on an insulating sheet (not shown) by various processes such as, for example, sputtering, chemical plating, or screen printing processes. In one exemplary embodiment, the second electrode layer 64 can be a sputtered gold electrode and the first electrode layer 66 can be a sputtered palladium electrode. Suitable materials that can be used as the spacing layer 60 include various insulating materials such as plastic (eg, PET, PETG, polyimide, polycarbonate, polystyrene), silicon, ceramic, glass, adhesive, and combinations thereof. Materials.

  The reagent layer 72 can be placed in the sample reaction chamber 61 using processes such as slot coating, dispensing from the end of the tube, ink jetting, and screen printing. Such processes are described, for example, in the following US Pat. Nos. 6,749,887, 6,869,411, 6,676,995, and 6,830,934. Each of which is incorporated herein by reference in its entirety. In one embodiment, reagent layer 72 can include at least a medium and an enzyme and can be deposited on first electrode 166. Various media and / or enzymes are within the spirit and scope of the present disclosure. For example, suitable media include ferricyanide, ferrocene, ferrocene derivatives, osmium bipyridyl complexes, and quinone derivatives. Examples of suitable enzymes include glucose oxidase, pyrroloquinoline quinone (PQQ) coenzyme dependent glucose dehydrogenase (GDH), nicotinamide adenine dinucleotide coenzyme dependent GDH, and FAD dependent GDH [E. C. 1.1.99.10]. One exemplary reagent formulation suitable for producing the reagent layer 72 is a pending US patent application Ser. No. 10 / 242,951 (titled “Method of Manufacturing a Stabilized and Calibrated Biosensor-Based Medical Device”, US Patent Application). Publication No. 2004/0120848, which is incorporated herein by reference in its entirety.

  Either the first electrode 166 or the second electrode 164 can function as a working electrode that oxidizes or reduces a critical amount of medium, depending on the polarity of the applied test potential of the test instrument. For example, if the current limiting species is a reducing medium, it can be oxidized at the first electrode 166 as long as a sufficient positive potential is applied to the second electrode 164. In such a situation, the first electrode 166 performs the function of the working electrode and the second electrode 164 performs the function of the counter / reference electrode. It should be noted that hereinafter, all potentials applied by the test meter 100 will be described with respect to the second electrode 164 unless otherwise specified with respect to the test strip 62.

  Similarly, if a sufficient negative potential is applied to the second electrode 164, the reducing medium can be oxidized at the second electrode 164. In such a situation, the second electrode 164 can perform the function of the working electrode and the first electrode 166 can perform the function as a counter / reference electrode.

  Initially, the disclosed method can include introducing a fluid sample amount of interest into the test strip 62, which includes the first electrode 166, the second electrode 164, and the reagent layer 72. Including. The fluid sample can be whole blood or a derivative or fraction thereof, or a control solution. A fluid sample, such as blood, can be administered into the sample reaction chamber 61 via port 70. In one aspect, port 70 and / or sample reaction chamber 61 may be configured such that capillary action causes fluid sample to fill sample reaction chamber 61.

  FIG. 5A shows a simplification of test instrument 100 in contact with first electrical contact 67 and second electrical contact 63 in electrical communication with first electrode 166 and second electrode 164 of test strip 62, respectively. A schematic diagram is provided. The test instrument 100 may be configured to be electrically connected to the first electrode 166 and the second electrode 164 via a first electrical contact 67 and a second electrical contact 63, respectively (FIG. 2). And 5A). As those skilled in the art will appreciate, various test instruments can be used with the methods described herein. However, in one embodiment, the test instrument includes at least a processor that is configured to perform a calculation that can calculate a correction factor taking into account at least one measured parameter that correlates with a physical property of the electrochemical cell. And may include one or more control units configured and configured for data classification and / or storage. The microprocessor may be in the form of a mixed signal microprocessor (MSP), such as, for example, Texas Instruments MSP 430. The TI-MSP 430 may also be configured to perform part of the constant potential function and the current measurement function. Further, the MSP 430 may include volatile and non-volatile memory. In another embodiment, many of the electronic components can be integrated with the microcontroller in the form of an application specific integrated circuit.

  As shown in FIG. 5A, the electrical contact 67 can include two prongs 67a, 67b. In one exemplary embodiment, the test instrument 100 is separately connected to the prongs 67a, 67b so that when the test instrument 100 contacts the test strip 62, the circuit is complete. The test meter 100 can measure the resistance or electrical continuity between the prongs 67a and 67b to determine if the test strip 62 is electrically connected to the test meter 100. Applicants note that the test meter 100 can use a variety of sensors and circuits to determine when the test strip 62 is properly positioned relative to the test meter 100.

  In one embodiment, a circuit disposed in the test meter 100 can apply a test potential and / or current between the first electrical contact 67 and the second electrical contact 63. When the test instrument 100 recognizes that the strip 62 has been inserted, the test instrument 100 is switched on and the fluid detection mode is initiated. In one embodiment, the fluid detection mode causes the test meter 100 to apply a constant current of about 1 microampere between the first electrode 166 and the second electrode 164. Since test strip 62 is initially dry, test meter 100 measures the maximum voltage limited by the hardware in test meter 100. However, when the user dispenses a fluid sample into the inlet 70, this fills the sample reaction chamber 61. As the fluid sample fills the gap between the first electrode 166 and the second electrode 164, the test instrument 100 measures the decrease in the measured voltage (see, for example, US Pat. No. 6,193,873). Which is described and incorporated herein by reference in its entirety), which is below a predetermined threshold that causes the test meter 100 to automatically initiate a glucose test.

  It should be noted that if only a portion of the sample reaction chamber 61 is filled, the measured voltage may decrease below a predetermined threshold. The method of automatically recognizing that a fluid has been applied does not necessarily indicate that the sample reaction chamber 61 is completely filled, but only confirms that a certain amount of fluid is present in the sample reaction chamber 61. be able to. Once the test instrument 100 determines that fluid has been applied to the test strip 62, a short non-zero amount of time may still be required so that the fluid completely fills the sample reaction chamber 61.

  FIG. 5B shows a diabetes management system that includes a diabetes data management unit 10 and a biosensor in the form of a glucose test strip 42. Note that the Diabetes Data Management Unit (DMU) may also be referred to as an analyte measurement and management unit, a glucose meter, a meter, and an analyte measurement device. In one embodiment, the DMU may be combined with an insulin delivery device, an additional analyte test device, and a drug delivery device. The DMU may be connected to the computer or server via a cable or any suitable wireless technology such as GSM®, CDMA, BlueTooth®, WiFi, etc.

  Referring again to FIG. 5B, the DMU 10 can include a housing 11, user interface buttons (16, 18, and 20), a display 14, and a strip port opening 22. User interface buttons (16, 18, and 20) can be configured to allow data entry, menu navigation, and command execution. The user interface button 18 can be in the form of a two-way toggle switch. The data can include values that represent information related to the analyte concentration and / or the patient's daily lifestyle. Information related to daily lifestyle habits can include food intake, drug use, health checkups, and individual general health and exercise levels.

  The electronic elements of the DMU 10 may be disposed on the circuit board 34 in the housing 11. FIG. 5C shows (in schematic form) the electronic components disposed on the top surface of the circuit board 34. Electronic components on the top surface include a strip port opening 308, a microcontroller 38, a non-volatile flash memory 306, a data port 13, a real time clock 42, and a plurality of operational amplifiers (46-49). Electronic components on the bottom surface include a plurality of analog switches, a backlight driver, and an electrically extinguished / programmable read only memory (EEPROM, not shown). The microcontroller 38 is electrically connected to the strip port opening 308, the non-volatile flash memory 306, the data port 13, the real time clock 42, a plurality of operational amplifiers (46 to 49), a plurality of analog switches, a backlight driver, and an EEPROM. obtain.

  Referring again to FIG. 5C, the plurality of operational amplifiers may include gain stage operational amplifiers (46 and 47), transimpedance operational amplifier 48, and bias driver operational amplifier 49. The plurality of operational amplifiers may be configured to provide part of the potentiostat function and the current measurement function. The potentiostat function may refer to applying a test voltage between at least two electrodes of the test strip. Current function may refer to measuring the test current caused by the applied test voltage. The current measurement can be performed by a current-voltage converter. The microcontroller 38 may be in the form of a mixed signal microprocessor (MSP), such as, for example, a Texas Instruments MSP 430. The MSP 430 can also be configured to perform part of the potentiostat function and the current measurement function. Further, the MSP 430 may include volatile and non-volatile memory. In another embodiment, many of the electronic components can be incorporated into a microcontroller in the form of an application specific integrated circuit (ASIC).

  The strip port connector 308 may be positioned proximate to the strip port opening 22 and configured to make an electrical connection with the test strip. The display 14 may be in the form of a liquid crystal display for reporting measured blood glucose levels and facilitating entry of information related to lifestyle. The display 14 may optionally have a backlight. The data port 13 can connect the glucose measuring device 10 to an external device such as a personal computer by receiving an appropriate connector attached to the connection lead wire. The data port 13 may be any port that can transmit data, such as a serial, USB, or parallel port.

  Real-time clock 42 may be configured to maintain the current time associated with the geographic region in which the user is located and to measure time. The real time clock 42 may include a clock circuit 45, a crystal 44, and a super capacitor 43. The DMU may be configured to be electrically connected to a power source such as a battery, for example. The supercapacitor 43 may be configured to supply power for a long time to supply power to the real time clock 42 in the event of a power supply failure. Thus, when the battery is discharged or replaced, there is no need for the user to reset the real time clock to a unique time. By using the real time clock 42 together with the supercapacitor 43, the risk that a user may accidentally reset the real time clock 42 can be reduced.

  Another exemplary embodiment of a sample analysis device for use in conjunction with at least some of the methods disclosed herein and immunosensor 110 is illustrated in FIG. 6, “Adhesive Compositions for Use in an Immunosensor”. No. 12 / 570,268, filed Sep. 30, 2009, filed September 30, 2009, which is incorporated herein by reference in its entirety. The plurality of chambers determines a concentration chamber in which a sample can be introduced into the immunosensor, a reaction chamber in which the sample can react with one or more desired substances, and a particular component of the sample. It can be formed in an immunosensor that includes a detection chamber that can. These chambers may be formed in at least a portion of the first electrode, the second electrode, and the separator of the immunosensor. The immunosensor allows air to enter and leak out of the immunosensor as needed, and the first and second sealing components selectively select the first and second sides of the vent. Vents can also be included that allow sealing. The first sealing component can also form the wall of the filling chamber.

  As shown, the immunosensor 110 includes a first electrode 112 on which two liquid reagents 130, 132 are striped. Although the first electrode 112 can be formed using a number of techniques used to form the electrode, in one embodiment, a sheet of polyethylene terephthalate (PET) filled with barium sulfate is sputter coated with gold. Is done. The PET sheet may be filled with titanium dioxide. Other non-limiting examples of forming electrodes are disclosed in Hodges et al., US Pat. No. 6,521,110, entitled “Electrochemical Cell” and filed on Nov. 10, 2000, The contents of which are incorporated herein by reference in their entirety.

  Similarly, the liquid reagents 130, 132 can have many different compositions. In one embodiment, the first liquid reagent 130 is conjugated to an enzyme such as GDH-PQQ in a buffer containing sucrose and a poloxamer such as Pluronics® block copolymer, an anticoagulant such as citraconate, and calcium ions. Antibody. In one embodiment, the second liquid reagent 132 comprises a mixture of ferricyanide, glucose, and a second medium such as phenazine etosulphate in an acidic buffer such as a diluted citraconic acid solution. The first and second liquid reagents 130, 132 can be dried on the first electrode 112. Although many techniques can be used to dry the reagents 130, 132, in one embodiment, after the reagents 130, 132 have been striped over the first electrode 112, one or more An infrared dryer can be applied to the reagents 130, 132. Also, for example, one or more air dryers can be used following the infrared dryer. In this specification, references to a first reagent and a first liquid reagent and a second reagent and a second liquid reagent are used interchangeably, and a reagent is given for a particular embodiment. It is not necessarily implied to be in liquid or dry form at this point. Further, some of the components associated with the first and second liquid reagents can be used interchangeably and / or in both the first and second liquid reagents as desired. As a non-limiting example, the anticoagulant can be associated with one or both of the first liquid reagent 130 and the second liquid reagent 132.

  An electrically insulated wire may be formed as sputter coated gold between reagents 130 and 132 such that the edge of reagent 132 is close to or in contact with the wire. This line can be applied using laser ablation or with sharp metal edges. In one exemplary embodiment, this line can be applied before the reagents 130, 132 are striped on the electrodes. This line can be designed to electrically insulate the portion of the first electrode 112 below the detection chamber from the portion located below the reaction chamber. This allows the working electrode range to be better defined during electrochemical analysis.

  The immunosensor 110 can also have a second electrode 114 having one or more magnetic beads 134 containing surface-bound antigens on top of it. These antigens can be configured to react with the antibody disposed on the first electrode 112 and the sample in the reaction chamber 118, as described in more detail below. Those skilled in the art will appreciate that the components disposed on the first electrode 112 and the second electrode 114 are interchangeable. Thus, the first electrode 112 can include one or more magnetic beads 134, and the second electrode 114 can include two liquid reagents 130, 132 that are striped on top of it. Further, in the illustrated embodiment, the length of the electrode 112 forms the entire length of the immunosensor 110, but in other embodiments, the electrode is the first or second of the layers of the immunosensor. Or a plurality of electrodes can be arranged in a single layer of the immunosensor. Furthermore, since the voltage applied to the immunosensor may be reversed and / or alternating, the first and second electrodes act as working and counter or counter / reference electrodes, respectively, at different stages. be able to. For ease of explanation, in this application, the first electrode is considered the working electrode and the second electrode is considered the counter electrode or counter / reference electrode.

  The separator 116 disposed between the first electrode 112 and the second electrode 114 can have a variety of shapes and dimensions, but generally, the first and second electrodes 112, 114 is configured to engage the immunosensor 110. In one exemplary embodiment, separator 116 includes an adhesive on both sides. Separator 116 may further include a release liner on each of the two sides of separator 116 to facilitate the manufacturing process. Each release liner is removed before the separator is bonded to each electrode. Separator 116 can be cut in a manner that forms at least two cavities. The first cavity can be formed to serve as the reaction chamber 118 and the second cavity can be formed to serve as the detection chamber 120. In one embodiment, the reaction chamber 118 is aligned with the electrodes 112, 114 to allow antigen-antibody reactions within the reaction chamber, while the detection chamber 120 is aligned with the electrodes 112, 114 within the detection chamber. Separator 116 can be kiss-cut to allow electrochemical measurement of ferrocyanide.

  In one embodiment, the separator 116 allows the magnetic beads 134 of the second electrode 114 and the first reagent 130 of the first electrode 112 to be at least partially disposed within the reaction chamber 118 and the first The combination of ferricyanide and glucose of the second reagent 132 of the first electrode 112 may be disposed on the first electrode 112 in a manner that allows at least partial placement in the detection chamber 120. It may be advantageous to include an anticoagulant in each of the first and second liquid reagents 130, 132 so that the anticoagulant is associated with each of the reaction chamber 118 and the detection chamber 120. In some embodiments, a combination of one of the first electrode 112 and the second electrode 114 and the separator 116 can be stacked together to form a two-layer stack, while other embodiments Then, each combination of the 1st electrode 112, the 2nd electrode 114, and the separator 116 can be laminated | stacked on each other, and a 3 layer laminated body can be formed. Alternatively, additional layers can be added.

  The filling chamber 122 can be formed by punching a hole in one of the first electrode 112 and the second electrode 114 and the separator 116. In the illustrated embodiment, the filling chamber is formed by punching holes in the first electrode 112 and the separator 116 such that the holes in the first electrode 112 overlap the reaction chamber 118. As shown, the fill chamber 122 can be separated from the detection chamber 120 by a certain distance. With such a configuration, the sample enters the immunosensor 110 through the filling chamber 122 and does not enter the detection chamber 120 and flows into the reaction chamber 118, for example, an enzyme on the first electrode 112. It is possible to react with the first liquid reagent 130 containing the antibody conjugated with and the magnetic beads 134 provided in a striped pattern on the second electrode 114. As the sample reacts, the sample then undergoes a chemical or physical transformation with a second liquid reagent 132, eg, a mixture of the second medium in ferricyanide, glucose, and an acidic buffer, to detect chemical or physical conversion. It becomes possible to flow in.

  The vent 124 may be formed by punching a hole through each of the two electrodes 112, 114 and the separator 116 so that the vent 124 extends throughout the immunosensor 110. The holes can be formed by any suitable method, such as drilling or punching at many different locations, for example, but in one exemplary embodiment, the holes overlap a region of the detection chamber 120 that is remote from the reaction chamber 118. be able to.

  Vent 124 can be sealed in a number of different ways. In the illustrated embodiment, the first sealing component 140 is disposed on the first electrode 112 to seal the first surface of the vent 124, and the second sealing component 142 is the second sealing component 142. It is disposed on the electrode 114 and seals the second surface of the air hole 124. The sealing component can be made from any number of materials and / or can include any number of materials. By way of non-limiting example, either one or both of the sealing components can be a hydrophilic adhesive tape or a Scotch® tape. The adhesive side of the sealing component can face the immunosensor 110. As shown, the first sealing component 140 can not only form a seal against the vent 124, but can also form the wall of the fill chamber 122 so that the sample can be received therein. . The characteristics incorporated on the adhesive side of the first sealing component 140 can be associated with the filling chamber 122. For example, if the first sealing component 140 includes properties that make it hydrophilic and / or water soluble, the filling chamber may remain moist when the sample is placed therein. In addition, the sealing components 140, 142 selectively provide the immunosensor 110 to vent and / or seal as desired to the immunosensor 110 and the components disposed therein. Related and separable.

  Adhesives can generally be used in the construction of immunosensors. A non-limiting example of how the adhesive can be incorporated into the disclosed immunosensors and other sample analysis devices is entitled “Adhesive Compositions for Use in an Immunosensor” and was filed on September 30, 2009. No. 12 / 570,268 to Chatelier et al., The contents of which are already incorporated herein by reference in their entirety.

  Although this disclosure discusses a variety of different embodiments related to immunosensors, other embodiments of immunosensors can also be used with the methods of the present disclosure. Non-limiting examples of such embodiments include US Patent Application Publication No. 2003/0180814, Hodges et al., Entitled “Direct Immunosensor Assay” and filed on March 21, 2002, entitled “Immunosensor”. US Patent Application Publication No. 2004/0203137 to Hodges et al., Filed Apr. 22, 2004, entitled "Biosensor Apparatus and Methods of Use", filed Nov. 21, 2005. Described in US Patent Application No. 2006/0134713 and US Patent Application No. 12 / 563,091 claiming priority to each of US Patent Application Publication Nos. 2003/0180814 and 2004/0203137. Include the is, each of these, by reference, it is incorporated in its entirety herein.

  In one embodiment, the immunosensor 110 is configured in an instrument configured to apply a potential to the electrodes 112, 114, for example, via a suitable circuit, and measure the current resulting from the application of that potential. Can be arranged. In one embodiment, the immunosensor includes one or more tabs 117 for engaging the instrument. Other characteristics can also be used to engage the immunosensor 110 with the instrument. The instrument can have a number of different features. For example, the instrument can include a magnet configured to maintain certain components of the immunosensor 110 in one chamber, while other components flow to the other chamber. In one exemplary embodiment, the meter magnet is positioned such that when the immunosensor 110 is disposed within the meter, the magnet is positioned below the reaction chamber 118. This allows the magnet to help prevent any magnetic beads 134, and more specifically any antibody enzyme complex bound to the beads 134, from flowing into the detection chamber 120. .

  Another feature of the instrument includes a heating element. The heating element can help speed up the reaction rate and can help the sample flow through the immunosensor 110 in the desired manner by reducing the viscosity. The heating element may also allow one or more chambers and / or samples disposed therein to be heated to a predetermined temperature. Heating to a predetermined temperature can help provide accuracy, for example, by reducing or eliminating the effects of temperature changes as the reaction occurs.

  Further, the drilling device can be associated with an instrument. The perforating device perforates at least one of the first and second sealing components at a desired time so that air can flow out of the vent and liquid can flow from the reaction chamber to the detection chamber. Can be configured to.

  Immunosensor 110 and test strip 62 can also be configured to be associated with a control unit. The control unit can be configured to perform various functions. In one exemplary embodiment, the control unit can measure the sample fill time when the sample is introduced into the device. In another embodiment, the control unit can be configured to quantify the hematocrit value of the blood sample. In yet another embodiment, the control unit may be configured to calculate the concentration of the analyte in the sample taking into account the filling time. In fact, the control unit can include many different features that depend at least in part on the way the system is designed to measure the desired functionality and fill time.

  The control unit can also measure other characteristics of the system. As a non-limiting example, the control unit can be configured to measure the temperature of one or more chambers of the immunosensor or test strip. The control unit may also be configured to measure sample temperature, sample color, immunosensor or test strip capacitance, or various other features and / or properties of the sample and / or system. As a further non-limiting example, the control unit can be configured to communicate the results of the filling time measurement, the capacitance measurement result, the analytical concentration measurement result, and / or the hematocrit measurement value to an external facility. This can be achieved in any number of ways. In one embodiment, the control unit can be wired to a microprocessor and / or display device. In another embodiment, the control unit may be configured to wirelessly transmit data from the control unit to the microprocessor and / or display device.

  Other components of the system may also be configured to make such measurements. For example, the immunosensor or instrument measures the temperature of one or more chambers of the immunosensor or test strip, measures or estimates the temperature of the sample, or various other features of the sample and / or system and / or Alternatively, it may be configured to measure, determine, or infer characteristics. Furthermore, those skilled in the art will appreciate that these features of the control unit can be interchanged and selectively combined within a single control unit. For example, the control unit can both perform filling time, capacitance determination, and chamber temperature measurement. In other embodiments, multiple control units can be used together to perform various functions based at least in part on the configuration of the various control units and the desired function to be performed.

Analyte Concentration Test During operation, in one embodiment, once the test instrument 100 determines that fluid has been introduced (eg, administered) onto the test strip 62, the test instrument 100 is as shown in FIG. 7A. In addition, an analyte test can be performed by applying multiple test potentials to the test strip 62 at specified intervals. Time interval t _G of the analyte test analyte time interval t _G tests the first test potential E ₁ with respect to the spacing t ₁ a first test potential _time, for the second test potential time interval t ₂ Represents the amount of time to perform an analyte test that can include a _third test potential E ₃ for a second test potential E ₂ and a third test potential time interval t ₃ (but All calculations are not necessarily related to analyte testing). Further, as shown in FIG. 7A, the second test potential time interval t ₂ can include a constant (DC) test voltage component and an AC / DC superposition (AC) or vibration test voltage component. The AC / DC superimposed test voltage component may be applied at a time interval indicated by t _cap . The time interval t _G of the glucose test is, for example, in the range of about 1 second to about 5 seconds.

  As described above, either the first electrode 166 or the second electrode 164 can function as a working electrode that oxidizes or reduces a critical amount of medium, depending on the polarity of the applied test potential of the test instrument. . It should be noted that hereinafter, all potentials applied by the test instrument 100 will be described with respect to the second electrode 164 unless otherwise specified. However, Applicants note that the test potential applied by the test instrument 100 can be described with respect to the first electrode 166, in which case the test potential described below and the polarity of the measured current are reversed. Keep it.

  The plurality of test current values measured during the first, second, and third test potential time intervals are performed at a frequency ranging from about 1 measurement per nanosecond to about 1 measurement per 100 milliseconds. obtain. Applicants note that the names “first”, “second”, and “third” are chosen for convenience and do not necessarily indicate the order in which the test potentials are applied. For example, an embodiment can have a potential waveform where a third test voltage can be applied before application of the first and second test voltages. Although an embodiment is described that uses three test voltages in a sequential fashion, Applicants note that the analyte test can include a different number of open circuits and test voltages. Applicants note that the analyte test time interval can include any number of open circuit potential time intervals. For example, an analyte test time interval may include only two test potential time intervals and / or open circuit potential time intervals before and / or after one or more test potential time intervals. In another exemplary embodiment, the analyte test may include an open circuit at the first time interval, a second test voltage at the second time interval, and a third test voltage at the third time interval. it can.

As shown in FIG. 7A, the test instrument 100 may have a first test potential E ₁ (eg, in FIG. 7A) for a first test potential time interval t ₁ (eg, a range of about 0 to about 1 second). −20 mV) may be applied as shown. The first test potential time interval t ₁ ranges from zero (0) seconds, which is the starting point in FIG. 7A, to about 0.1 seconds to about 3 seconds, preferably about 0.2 seconds to about 2 seconds. The range, most preferably in the range of about 0.3 seconds to about 1 second. The first test potential time interval t ₁ may be sufficiently long so that the sample reaction chamber 61 is completely filled with sample and the reagent layer 72 can be at least partially dissolved or solvated. In other embodiments, the first test potential time interval t ₁ can include any other desired time range.

In one embodiment, the test instrument 100 includes a first between the electrodes for a period between when the instrument can detect that the strip is filled with sample and before the _second test potential E2 is applied. it can be applied to test potential E _1. Test potential E ₁ in one embodiment is small. For example, the potential can range from about -1 to about -100 mV, preferably from about -5 mV to about -50 mV, and most preferably from about -10 mV to about -30 mV. A smaller potential disturbs the reducing medium concentration gradient, if not so much, as compared to applying a larger potential difference, but is still sufficient to obtain a measurement of the oxidizable material in the sample. Test potential E ₁ can be applied to the entire or may be applied to a portion of the time, or the period between when the detection and the second test potential E ₂ of the filling is applied. If the test potential E ₁ is used to a portion of the time, open circuit may be applied to a portion of the remainder of the time. Any open circuit and the combination of the small voltage potential application number, their order, and the applied time is not critical in the present embodiment, the total period during which the small potential E ₁ is applied is present in the sample oxide As long as it is sufficient to obtain a current measurement indicating the presence and / or amount of possible substances, it can be applied. In a preferred embodiment, the small potential E ₁ is substantially filled test potential E ₂ and the second when it is detected is applied to the entire period between when it is applied.

During the first time interval t ₁ , the test instrument 100 measures the resulting first current transition, which can be referred to as i _a (t). A current transition represents a plurality of current values measured by a test meter during a particular test potential time interval. The first current transition is an integer or a single value measured during the first test potential time interval multiplied by an integer number of current values over the first test potential time interval, or by the time interval of the first test potential time interval. It may be a current value. In some embodiments, the first current transition may include current values measured over various time intervals during the first test potential time interval. In one embodiment, the first current transition i _a (t) ranges from about 0.05 seconds to about 1.0 seconds, preferably from about 0.1 seconds to about 0.5 seconds, most preferably It can be measured for a time in the range of about 0.1 seconds to about 0.2 seconds. In other embodiments, the first current transition i _a (t) can be measured in other desirable time ranges. As described below, some or all of the first current transitions are used in the methods described herein to determine whether a control solution or blood sample has been applied to the test strip 62. obtain. The magnitude of the first transition current is affected by the presence of a readily oxidizable material in the sample. Blood usually contains endogenous and exogenous compounds that are easily oxidized at the second electrode 164. Conversely, the control solution can be formulated to contain no oxidizable compound. However, since the blood sample composition may be different and the sample reaction chamber 61 may not be completely filled after about 0.2 seconds, the magnitude of the first current transition for a high viscosity blood sample is typical. Less than a low viscosity sample (in some cases lower than a control solution sample). Incomplete filling reduces the effective area of the first electrode 166 and the second electrode 164 that simultaneously reduces the first current transition. Thus, the presence of an oxidizable substance in a sample is not always a sufficient discriminating factor by itself due to blood sample differences.

When the first time interval t ₁ hour elapses, the test meter 100 determines that the first electrode 166 for a _second test potential time interval t ₂ (eg, about 3 seconds as shown in FIG. 7A). A second test potential E ₂ (eg, about −300 mV, as shown in FIG. 7A) can be applied between the first electrode 164 and the second electrode 164. The second test potential E ₂ may be a sufficiently negative medium redox potential value such that a limiting oxidation current occurs at the second electrode 164. For example, when using ferricyanide and / or ferrocyanide as the medium, the second test potential E ₂ is in the range of about −600 mV to about 0 mV, preferably in the range of about −600 mV to about −100 mV, more preferably about − 300 mV. Similarly, the time interval shown as t _cap in FIG. 6 may last for various times, but in one exemplary embodiment is about 20 milliseconds. In one exemplary embodiment, the AC / DC superimposed test voltage component is applied about 0.3 seconds to about 0.32 seconds after application of the second test potential E ₂ and has an amplitude of about +/− 50 mV at about 109 Hz. A two-cycle sine wave having a frequency of Among interval _{t 2} the second test potential time, the test meter 100 can measure a second current transition _i b a (t).

The second test potential time interval t ₂ may be long enough to monitor the rate of production of the reducing medium (eg, ferrocyanide) in the sample reaction chamber 61 based on the magnitude of the limiting oxidation current. The reducing medium can be generated by a series of chemical reactions in the reagent layer 72. During the second test potential time interval t ₂ , the limiting amount of reducing medium is oxidized at the second electrode 164, and the non-limiting amount of oxidizing medium is reduced at the first electrode 166, so that the first electrode 166 and the first electrode A concentration gradient is formed between the two electrodes 164. As described, the second test potential time interval t ₂ must be long enough so that a sufficient amount of ferricyanide can be produced at the second electrode 164. A sufficient amount of ferricyanide may be required at the second electrode 164 so that the limiting current can be measured at the first electrode 166 during the third test potential E ₃ to oxidize the ferrocyanide. The second test potential time interval t ₂ is in the range of from about 0 seconds to about 60 seconds, preferably from about 1 second to about 10 seconds, and most preferably from about 2 seconds to about 5 seconds.

FIG. 7B shows the relatively small peak i _{pb at} the beginning of the _second test potential time interval t ₂ , and then the oxidation current during the second test potential time interval (eg, in the range of about 1 second to about 4 seconds). Shows a gradual increase in absolute value. A small peak occurs in about 1 second due to the initial depletion of the reducing medium. The slow increase in oxidation current is due to the formation of ferrocyanide by the reagent layer 72 and its subsequent diffusion to the second electrode 164.

After the second potential time interval t ₂ has elapsed, the test meter 100 determines that for a third test potential time interval t ₃ (eg, a range of about 4 to about 5 seconds as shown in FIG. 6). A third test potential E ₃ (eg, about +300 mV as shown in FIG. 7A) can be applied between the first electrode 166 and the second electrode 164. During the third test potential time interval t ₃ , the test instrument 100 can measure a third current transition, which can be referred to as i _c (t). The third test potential E ₃ may be a sufficiently positive medium redox potential value such that the limiting oxidation current is measured at the first electrode 166. For example, when using ferricyanide and / or ferrocyanide as the medium, the magnitude of the _third test potential E ₃ is in the range of about 0 mV to about 600 mV, preferably in the range of about 100 mV to about 600 mV, more preferably about 300 mV. is there.

The second test potential time interval t ₂ and the third test potential time interval t _3, respectively, in the range of from about 0.1 seconds to about 4 seconds. For the embodiment shown in FIG. 7A, the second test potential time interval t ₂ was about 3 seconds and the third test potential time interval t ₃ was about 1 second. As described above, an open circuit potential time period can be allowed to elapse between the second test potential E ₂ and the third test potential E _3. Alternatively, the third test potential E ₃ can be applied after applying the second test potential E _2. A portion of the first, second, or third current transition may generally be referred to as a cell current or current value.

The third test potential time interval t ₃ may be sufficiently long to monitor the diffusion of the reducing medium (eg, ferrocyanide) near the first electrode 166 based on the magnitude of the oxidation current. During the third test potential time interval t ₃ , a limiting amount of reducing medium is oxidized at the first electrode 166 and a non-limiting amount of oxidizing medium is reduced at the second electrode 164. The third test potential time interval t ₃ ranges from about 0.1 seconds to about 5 seconds, preferably from about 0.3 seconds to about 3 seconds, and most preferably from about 0.5 seconds to about 2 seconds. It is a range.

FIG. 7B shows a relatively large peak i _{pc at} the beginning of the _third test potential time interval t ₃ and then a decrease to the steady state current. In one embodiment, both the first test potential E ₁ and the second test potential E ₂ have a first polarity and the third test potential E ₃ is opposite to the first polarity. Has a second polarity. However, applicants may determine that the polarity of the first, second, and third test potentials may be selected by the manner in which the analyte concentration is determined and / or by the manner in which the test sample and control solution are distinguished. Note that.

Capacitance Measurement In some embodiments, capacitance can be measured. The capacitance measurement can basically measure the ion double layer capacitance due to the formation of the ion layer at the electrode-liquid contact surface. The magnitude of the capacitance can be used to determine whether the sample is a control solution or a blood sample. For example, when the control solution is in the reaction chamber, the measured capacitance magnitude may be greater than the measured capacitance magnitude when a blood sample is present in the reaction chamber. As described in more detail below, the measured capacitance is a variety of methods for correcting for the effect of changes in the physical properties of the electrochemical cell on the measurements made using the electrochemical cell. Can be used. For example, the measured change in capacitance may be related to at least one of electrochemical cell aging and electrochemical cell storage conditions.

  As a non-limiting example, methods and mechanisms for performing capacitance measurements on test strips can be found in US Pat. Nos. 7,195,704 and 7,199,594, Each of which is incorporated herein by reference in its entirety. In one exemplary method for measuring capacitance, a test voltage having a constant component and a vibration component is applied to the test strip. In such cases, the resulting test current can be mathematically processed to determine a capacitance value, as described in more detail below.

  In general, when the limit test current occurs at a working electrode with a well-defined region (ie, a region that does not change during capacitance measurement), the most accurate and precise capacitance measurement is performed on the electrochemical test strip. Can be done. A well-defined electrode region that does not change over time occurs when there is an airtight seal between the electrode and the spacer. The test current is relatively constant when the current does not change rapidly due to either analyte oxidation or electrochemical corrosion. Alternatively, any time when the increase in signal that would be seen by analyte oxidation is effectively balanced by a decrease in signal with electrochemical corrosion is a time interval appropriate for the capacitance measurement. But it can be.

  The area of the first electrode 166 can potentially change over time after administration with the sample, if the sample penetrates between the spacer 60 and the first electrode 166. In the test strip embodiment, the reagent layer 72 can have a region where a portion of the reagent layer 72 is larger than the notch region 68 located between the spacer 60 and the first electrode layer 66. Under certain circumstances, placing a portion of the reagent layer 72 between the spacer 60 and the first electrode layer 66 can increase the wet electrode area during testing. As a result, leakage can occur during testing that increases the area of the first electrode over time, which can simultaneously distort the capacitance measurement.

  Conversely, the region of the second electrode 164 can be more stable over time than the first electrode 166 because there is no reagent layer between the second electrode 164 and the spacer 60. Thus, the sample is unlikely to penetrate between the spacer 60 and the second electrode 164. Capacitance measurements using the limit test current at the second electrode 164 can thus be more precise because the region does not change during the test.

As described above and shown in FIG. 7A, when liquid is detected in the test strip, the first test potential E ₁ (eg, −20 mV as shown in FIG. 7A) monitors the liquid filling behavior and controls To distinguish between solution and blood, it is applied between the electrodes for about 1 second. In Equation 1, the test current is used from about 0.05 to about 1 second. The first test potential E _1, as the distribution of the ferrocyanide in the cell is not disturbed as much as possible by the electrochemical reactions occurring at the first and second electrodes may be relatively low.

A second test potential E ₂ having a larger absolute scale (eg, about −300 mV as shown in FIG. 7A) is after the first test potential E ₁ so that the limiting current can be measured at the second electrode 164. You may apply. The second test potential E ₂ may comprise an AC voltage component and a DC voltage component. AC voltage component may be applied with the default amount of time after the application of the second test potential E _2, further can be a sine wave having an amplitude of frequency and approximately +/- 50 millivolts to about 109 Hertz. In a preferred embodiment, the default amount of time after the application of the second test potential E _2, ranges from about 0.3 seconds to about 0.4 seconds. Alternatively, the predetermined amount of time may be a time when the test current transition as a function of time has a slope of about zero. In another embodiment, the predetermined amount of time may be the time required for the peak current value (eg, i _pb ) to decay by about 50%. For the DC voltage component, it can be applied at the beginning of the first test potential. The DC voltage component can have a magnitude sufficient to provide a limiting test current at the second electrode, eg, about −300 mV for the second electrode.

According to FIG. 4B, the reagent layer 72 is not coated on the second electrode 164 which makes the magnitude of the absolute peak current i _pcb relatively small compared to the magnitude of the absolute peak current i _pc . The reagent layer 72 can be configured to produce a reducing medium in the presence of the analyte, and the amount of reducing medium proximate to the first electrode contributes to a relatively high absolute peak current i _pc . In one embodiment, when the sample is introduced into the test strip, at least the enzyme portion of the reagent layer 72 can be configured to not substantially diffuse from the first electrode to the second electrode.

The test current after i _pb tends to settle in a flat area in about 1.3 seconds, after which the current increases again when generated at the first electrode 166 where the reducing medium can be coated with the reagent layer 72. Then, it diffuses into the second electrode 164 that is not coated with the reagent layer 72. In one embodiment, the capacitance measurement can be performed in a relatively flat region of the test current value, which can be performed from about 1.3 seconds to about 1.4 seconds. In general, if the capacitance is measured one second ago, the capacitance measurement can be used to measure the first current transition i _a (t), which is a relatively low first test potential E _1. Can interfere with. For example, an oscillating voltage component of approximately ± 50 mV superimposed on a −20 mV constant voltage component can significantly disturb the measured test current. Oscillating voltage component not only interfere with the first test potential E _1, may interfere with the correction of the antioxidant at the same time, may perturb the test currents measured at about 1.1 seconds significantly There is. After numerous tests and experiments, surprisingly, a control solution / blood discrimination test or blood analyte (eg, glucose) algorithm is measured by measuring the capacitance from about 1.3 seconds to about 1.4 seconds. Finally, it was confirmed that accurate and precise measurement values that do not interfere with the above were obtained.

After the second test potential E ₂ , a third test potential E ₃ (eg, about +300 mV as shown in FIG. 7A) can be applied and measured at the first electrode 166 that can be coated with the reagent layer 72. A test current is generated. The presence of the reagent layer on the first electrode can allow liquid penetration between the spacer layer and the electrode layer, which can increase the electrode area.

As shown in FIG. 7A, in an exemplary embodiment, a 109 Hz AC test voltage (peak-to-peak ± 50 mV) may be applied in two cycles during the time interval t _cap . The first cycle can be used as an adjustment pulse and the second cycle can be used to determine capacitance. Capacitance estimation is done by summing the test current over a portion of the alternating current (AC) wave, subtracting the direct current (DC) offset, and normalizing the result using the AC test voltage amplitude and AC frequency. Can be obtained. This calculation provides a measure of the capacitance of the strip occupied by the strip sample chamber when the strip sample chamber is filled with sample.

式中、項ｉ_ｏ＋ｓｔは、定試験電圧成分によって生じた試験電流を表す。一般に、ＤＣ電流成分は、経時的に直線的に変化すると考えられ（フェロシアニドを生成する進行中のグルコース反応により）、よって、時間０でのＤＣ電流（０交差点）である定数ｉ_ｏ、及び経時的なＤＣ電流変化の傾きｓにより表される。ＡＣ電流成分は、Ｉｓｉｍ（ωｔ＋φ）により表され、式中、Ｉは、電流波の振幅であり、ωは、その周波数であり、φは、入力電圧波に関するその位相変化である。項ωは、２πｆとも表され、式中、ｆは、ヘルツでのＡＣ波の周波数である。項Ｉは、式２に示されるようにも表すことができ、

式中、Ｖは、印加された電圧シグナルの振幅であり、│Ｚ│は、複素インピーダンスの規模である。項│Ｚ│は、式２２に示されるように表すこともでき、

式中、Ｒは、インピーダンスの実数部であり、Ｃは、静電容量である。
式１は、式４を得るために、０交差点前の４分の１波長から０交差点後の４分の１波長までが統合され得、

これは、式５に簡略化され得る。

式２を式１に代入し、その後、式４に代入した後、再整理すると、式６となる。

式６における積分項は、式７に示される電流の合計を使用して近似され得、

式中、試験電流ｉ_ｋは、０交差点前の４分１波長から０交差点後の４分の１波長までが合計される。式７を式６に代入して、式８を得、

式中、ＤＣオフセット電流ｉ_ｏは、０交差点付近の１つの完全な正弦サイクルに対して試験電流を平均化することにより得ることができる。 In one embodiment, in a blood glucose assay, the capacitance is the AC on either side of the time when the input AC voltage exceeds the DC offset, ie, when the AC component of the input voltage is zero (0 crossing point). It can be measured by summing the test current over a quarter of the wave. The derivation of how this translates into a capacitance measurement is described in more detail below. Equation 1 shows the test current magnitude as a function of time during the time interval t _cap ,

In the formula, the term i _o + st represents the test current generated by the constant test voltage component. In general, the DC current component is believed to change linearly over time (due to the ongoing glucose reaction producing ferrocyanide), and thus the constant i _o , which is the DC current at time 0 (the zero crossing point), and the time It is represented by the slope s of the typical DC current change. The AC current component is represented by Isim (ωt + φ), where I is the amplitude of the current wave, ω is its frequency, and φ is its phase change with respect to the input voltage wave. The term ω is also expressed as 2πf, where f is the frequency of the AC wave in Hertz. The term I can also be expressed as shown in Equation 2,

Where V is the amplitude of the applied voltage signal and | Z | is the magnitude of the complex impedance. The term │Z│ can also be expressed as shown in Equation 22,

Where R is the real part of the impedance and C is the capacitance.
Equation 1 can be integrated from a quarter wavelength before the zero crossing to a quarter wavelength after the zero crossing to obtain equation 4.

This can be simplified to Equation 5.

Substituting Equation 2 into Equation 1 and then substituting it into Equation 4, then rearranging, yields Equation 6.

The integral term in Equation 6 can be approximated using the sum of the currents shown in Equation 7,

In the equation, the test current i _k is summed from the quarter wavelength before the zero crossing to the quarter wavelength after the zero crossing. Substituting Equation 7 into Equation 6 yields Equation 8,

Where the DC offset current i _o can be obtained by averaging the test current over one complete sine cycle near the zero crossing.

In another embodiment, the capacitance measurement can be obtained by summing near the maximum AC component of the current rather than the current near the voltage zero crossing. Thus, in Equation 7, the quarter-wave test currents near the current maximum can be summed rather than summing the quarter-wave on either side of the voltage zero crossing. Since this is equivalent to assuming that the circuit element responding to AC excitation is a pure capacitor, φ is approximately π / 2. Thus, Equation 5 can be summarized as Equation 9.

  In this case, this is because the uncoated electrode is polarized such that the DC, or the actual component of the current flow, is independent of the voltage applied to the range of voltages used for AC excitation. This is considered a reasonable assumption. Thus, the real part of the impedance in response to AC excitation is infinite, suggesting a pure capacitive element. Equation 9 can then be used with Equation 6 to obtain a simplified capacitance equation that does not require integral approximation. The net result is that the capacitance measurements were more precise when summing currents near the maximum AC component of the current, rather than near the voltage crossing.

CS / Blood Discrimination Test In some embodiments, a control solution (CS) / blood discrimination test can be performed. If the CS / blood discrimination test determines that the sample is blood, a series of steps can be performed that can include application of a blood glucose algorithm, hematocrit correction, blood temperature correction, and error checking, and CS If the sample is determined to be CS (ie not blood) by the / blood discrimination test, a series of steps may be performed that may include application of a CS glucose algorithm, CS temperature correction, and error checking. If there is no error, the test meter outputs the glucose concentration, but if there is an error, the test can output an error message.

  In one embodiment, a control solution (CS) feature is used to distinguish the control solution from blood. For example, the presence and / or concentration of redox species in the sample, reaction rate, and / or capacitance can be used to distinguish the control solution from blood. The methods disclosed herein include calculating a first reference value that represents the redox concentration in the sample and a second reference value that represents the rate of reaction of the sample with the reagents. In one embodiment, the first reference value is an interference oxidation current and the second reference value is a reaction completion rate.

  In some embodiments, the third reference value can be calculated by multiplying the first reference value by the capacitance ratio. The capacitance ratio may be any calculated value that is, or is proportional to, for example, a capacitance value. The capacitance ratio may be, for example, a measured capacitance, a known or predetermined capacitance, or any combination thereof. Also, the capacitance ratio may be related to any of the above capacitances and empirically obtained constants. In an exemplary embodiment, the capacitance ratio may be a ratio of a known capacitance to a measured capacitance or a ratio of a measured capacitance to a known capacitance. The known capacitance may be the average capacitance measured when the blood sample is placed on the same type of test strip as used in the current test. The measured capacitance can be measured using, for example, the above algorithm.

式中、項ｉ_ｓｕｍは、電流値の合計であり、ｔは時間である。いくつかの実施形態において、静電容量率が既知の静電容量の測定された静電容量に対する比であり得る場合、第１の参照値は静電容量率で乗じてよい。このような実施形態では、第３の参照値ｉ_{ｃａｐｓｕｍ}は、式１０Ｂにより表わすことができ、

式中、Ｃ_ａｖは既知の平均静電容量であり、Ｃ_ｍは測定された静電容量であり、ｔは時間である。式１０Ｂの例示的実施形態では、Ｃ_ａｖとＣ_ｍの比は、静電容量率と称することができる。例示的な一実施形態において、本発明の実施形態による代表的な試験ストリップの既知の平均静電容量Ｃ_ａｖは、約５８２ナノファラッドである。
残留反応率と称される場合もある第２の参照値は、式１１に示されるように、第２の時間間隔及び第３の時間間隔中の電流値の比率Ｙにより得ることができ、

式中、ａｂｓは、絶対値の関数を表し、３．８及び４．１５は、この特定の例において、それぞれ、第２及び第３の時間間隔の秒での時間を表す。 In one embodiment, the CS / blood discrimination test can include a first reference value and a second reference value. The first value can be calculated based on the current value of the first time interval t _1, the second reference value, both in the second time interval t _2, and the third time interval t ₃ Current value. In one embodiment, the first reference value can be obtained by summing the current values obtained during the first time current transition when using the test voltage waveform of FIG. 7A. As a non-limiting example, the first reference value i _sum can be represented by Equation 10A:

In the equation, the term i _sum is the _sum of current values, and t is time. In some embodiments, the first reference value may be multiplied by the capacitance ratio if the capacitance ratio can be the ratio of the known capacitance to the measured capacitance. In such an embodiment, the third reference value i _capsum can be represented by Equation 10B:

_Where C _av is the known average capacitance, C _m is the measured capacitance, and t is time. In the exemplary embodiment of Equation 10B, the ratio of C _av to C _m can be referred to as the capacitance ratio. In an exemplary embodiment, the known average capacitance C _av of a representative test strip according to an embodiment of the invention is about 582 nanofarads.
The second reference value, sometimes referred to as the residual reaction rate, can be obtained by the ratio Y of the current values during the second time interval and the third time interval, as shown in Equation 11:

Where abs represents a function of absolute value, and 3.8 and 4.15 represent time in seconds of the second and third time intervals, respectively, in this particular example.

であり得、式中、Ｚは、例えば、約０．２等の定数であり得る。よって、ＣＳ／血液識別試験は、式１０Ａのｉ_ｓｕｍ、又は式１０Ｂのｉ_{ｃａｐｓｕｍ}が、既定の閾値以上、例えば、約１２マイクロアンペアである場合、かつ、式１１に示されるように、第２の時間間隔及び第３の時間間隔中の電流値の比率Ｙが、既定の閾値関数Ｆ_ｐｄｔの値より小さい場合、サンプルを血液と識別することができ、そうでなければ、サンプルは対照溶液である。一実施形態では、ＣＳ／血液識別試験は、例えば、式１３によっても表わすことができる。

の場合、サンプルは血液であり、そうでなければ対照溶液である。 The discrimination criterion is based on the first reference value in Equation 10A or the third reference value in Equation 10B and the second reference value in Equation 11 to determine whether the sample is a control solution or blood. Can be used. For example, the first reference value of Equation 10A or the third reference value of Equation 10B can be compared to a predefined threshold value, and the second reference value of Equation 11 can be compared to a predefined threshold function. it can. The predetermined threshold may be, for example, about 12 microamperes. The predetermined threshold function may be based on a function that uses the first reference value of Equation 10A or Equation 10B. More specifically, as illustrated in Equation 12, if any of the calculated value of _{i Capsum} the _{i sum} or formula 10B of formula 10A is represented by X, the default threshold function _{F pdt} is

Where Z may be a constant, such as about 0.2. Thus, the CS / blood discrimination test is performed when the i _{sum of} formula 10A or i _{capsum of} formula 10B is greater than or _equal to a predetermined threshold, eg, about 12 microamps, and as shown in formula 11, If the ratio Y of the current value during the time interval and the third time interval is less than the value of the predefined threshold function F _pdt , the sample can be distinguished from blood, otherwise the sample is in the control solution is there. In one embodiment, the CS / blood discrimination test can also be represented by Equation 13, for example.

In this case, the sample is blood, otherwise it is a control solution.

  As a non-limiting example of the embodiment described above, US patent application Ser. No. 12 / 895,067 filed Sep. 10, 2010 (Catalier et al.), Entitled “Systems and Methods of Discriminating Between a Control Sample and a Test ID”. Usable Capacitance "and U.S. Patent Application No. 12 / 895,168 (Chatelier et al.) Filed Sep. 30, 2010, entitled" Systems and Methods for Improved Stability of Electrochemical Sensors ". Each of which is incorporated herein by reference in its entirety.

Blood glucose algorithm If a sample is identified as a blood sample, a blood glucose algorithm may be performed on the test current value. As shown in FIGS. 1A-4B, assuming that the test strip has an opposing or frontal array and that a potential waveform is applied to the test strip as shown in FIG. 7A or FIG. 8A, the first The analyte concentration G1 is shown in formula (Eq.) 14.

In Equation 14, G1 is the glucose concentration, i ₁ is the first current value, _ir is the second current value, i ₂ is the current value corrected with the antioxidant, and the term p, zgr and a are calibration constants obtained empirically. For example, p can be about 0.5246, a can be about 0.03422, and zgr can be about 2.25. In one embodiment of the invention, p can range from about 0.2 to about 4, preferably from about 0.1 to about 1. The calibration factor a is specific to the individual dimensions of the electrochemical cell.

The calibration factor zgr is used to describe a typical background signal due to the reagent layer. The presence of oxidizable species in the reagent layer of the cell prior to sample addition can contribute to the background signal. For example, if the reagent layer contains a small amount of ferrocyanide (eg, reduced medium) before the sample is added to the test strip, there is an increase in measured test current that is not due to analyte concentration. This results in a constant bias across the measured test current for the test strip, so this bias can be corrected using the calibration factor zgr. Similar to the terms p and a, zgr can also be calculated during the calibration process. An exemplary method for calibrating the strip section is described in US Pat. No. 6,780,645, which is incorporated herein by reference in its entirety. The derivation of Equation 13 is pending US Patent Application Publication No. 2007/0074977 (U.S. Patent Application No. 11 / 240,797), entitled “Method and Apparatus for Rapid Electrochemical, filed Sep. 30, 2005. Analysis ”, which is incorporated herein by reference in its entirety. The absolute value of the current is used for all test current values of Equation 13 (eg, i _l , i _r , and i ₂ ).

In one embodiment, the current value i _r can be calculated from the third current transition, and the current value i _l can be calculated from the second current transition. The absolute value of the current may be used for all current values shown in Equation 14 and subsequent equations (eg, i _r , i _l , and i ₂ ). The current values i _r , i _l , in some embodiments, were multiplied by an integer number of current values over the current transition time interval, the sum of the current values over the current transition time interval, or the current transition time interval. It can be the average of the current transition or a single current value. In the case of the sum of current values, a range of continuous current measurements can be added together from only two current values to all current values. Current i ₂ can be calculated as follows.

For example, as shown in the following equation 15A and 15B, if the time interval of the analyte test is the length of 5 seconds, i _l is 3.9 to 4 of the length of 5 seconds be a sum of the second current, i _r may be a sum of the currents of 4.25 to 5 seconds of the 5 seconds in length analyte test time interval.

項ｉ_ｓｓは、第２の試験電位Ｅ_２の印加後の定常状態電流であり、Ｄは媒体の拡散係数であり、Ｌはスペーサの厚さである。式１６においてｔは、第２の試験電位Ｅ_２が印加された後に経過した時間を示すことに留意されたい。第３の電流遷移の電流の規模は、式１７によって時間の関数として表すことができる。

The current magnitude of the first current transition can be expressed as a function of time by Equation 16.

Term i _ss is the second steady state current after the application of the test potential E _2, D is the diffusion coefficient of the medium, L is the thickness of the spacer. In Equation 16 t It should be noted that indicating the time that has elapsed after the second test potential E ₂ is applied. The current magnitude of the third current transition can be expressed as a function of time by Equation 17.

The exponent term in Equation 17 is twice as large as the exponent term in Equation 16, because the third current transition results from the _third test potential E3. the second test potential E ₂ at opposite polarity, is applied immediately after the second test potential E _2. In Formula 17 t It should be noted that indicating the elapsed time after the third test potential E ₃ is applied.

The peak current for the second test potential time interval t ₂ can be denoted as i _pb and the peak current for the third test potential time interval t ₃ can be denoted as i _pc . Both the second peak current i _pb and the third peak current i _pc are measured at the same timing immediately after the application of the second test potential E ₂ and the third test potential E ₃ , for example, in 0.1 second. If so, Equation 18 can be subtracted from Equation 17 to obtain Equation 18.

Since i _pb is determined to be mainly controlled by the interfering substance, i _pc can be used together with i _pb to determine the correction factor. For example, as shown below, i _pc can be used with i _{pb in} a mathematical function to quantify a corrected current that is proportional to glucose and less sensitive to interfering substances. it can.

項ｉ_ｐｂは、第２の試験電位時間間隔ｔ_２のピーク電流値を表し、項ｉ_ｐｃは、第３の試験電位時間間隔ｔ_３のピーク電流値を表す。項ｉ_ｓｓは、進行中の化学反応の不在下で、第３の試験電位Ｅ_３の印加後長時間生じると予測される電流である、定常状態の電流の推定である。項ｉ_ｓｓを式１９の分子及び分母の両方に加え、グルコースが存在しないとき、分子をゼロに近づかせる。ｉ_ｓｓを算出する方法のいくつかの例は、米国特許第５，９４２，１０２号及び同第６，４１３，４１０号に見出すことができ、当該特許のそれぞれは参照によりその全体が本明細書に組み込まれる。生理学的サンプルにおける干渉を説明するためのピーク電流値の使用は、「Ｍｅｔｈｏｄｓ ａｎｄ Ａｐｐａｒａｔｕｓ ｆｏｒ Ａｎａｌｙｚｉｎｇ ａ Ｓａｍｐｌｅ ｉｎ ｔｈｅ Ｐｒｅｓｅｎｃｅ ｏｆ Ｉｎｔｅｒｆｅｒｅｎｔｓ」と題する、２００６年３月３１日に出願された米国特許出願公開第２００７／０２２７９１２号（米国特許出願第１１／２７８，３４１号）に説明されており、その全体は参照により本明細書に組み込まれる。 Equation 19 is proportional to the analyte concentration, the relative proportion of current caused by the interfering substance has been induced to calculate the current i ₂ being removed.

The term i _pb represents the peak current value of the _second test potential time interval t ₂ , and the term i _pc represents the peak current value of the third test potential time interval t ₃ . The term i _ss is an estimate of the steady state current, which is the current that is expected to occur for a long time after application of the third test potential E ₃ in the absence of an ongoing chemical reaction. The term i _ss is added to both the numerator and denominator of Equation 19 to bring the numerator closer to zero when no glucose is present. Some examples of methods for calculating i _ss can be found in US Pat. Nos. 5,942,102 and 6,413,410, each of which is hereby incorporated by reference in its entirety. Embedded in. The use of peak current values to explain interference in physiological samples is described in US Patent Application Publication No. 2007, filed March 31, 2006, entitled “Methods and Apparatus for Analyzing a Sample in the Presence of Interferents”. No. 0227912 (US patent application Ser. No. 11 / 278,341), which is incorporated herein by reference in its entirety.

式２０中、ｉ（４．１）は、第３の電位Ｅ_３の間の電流の絶対値からなり、ｉ（１．１）は、第２の電位Ｅ_２の間の電流の絶対値からなり、ｉ_ｓｓは、定常状態電流からなる。 In one exemplary embodiment, the antioxidant corrected current value i ₂ can be calculated by Equation 20.

In Equation 20, i (4.1) is composed of the absolute value of the current during the _third potential E3, and i (1.1) is composed of the absolute value of the current during the _second potential E2. I _ss consists of a steady state current.

In some embodiments, i _ss can be calculated by Equation 21.

  In Equation 21, i (5) is composed of the absolute value of the current between the third potentials, π is composed of a constant, D is composed of the diffusion coefficient of the redox species, and L is between the two electrodes. Of the distance.

In some embodiments, the second analyte concentration value can be calculated based on the first analyte concentration value G1. For example, Equation 22 can be used to calculate a second analyte concentration value G2 that does not emphasize kinetic correction at low analyte concentrations.

In Equation 22, p may be about 0.5246, a may be about 0.03422, i ₂ may be a current value corrected with an antioxidant, and AFO is about 2.88. Zgr may be about 2.25 and k may be about 0.0000124. Subtracting the asymmetry factor offset AFO from the asymmetry factor i _r / i _l and raising the new smaller asymmetry factor term to a power that depends on the analyte concentration emphasizes the effect of the kinetic correction at low analyte concentrations. I don't get it. As a result, a higher level of accuracy can be achieved over a wide range of analyte concentrations.

  In the example shown in FIGS. 7A and 7B, in voltage measurement, when an electrode not coated with a reagent serves as a reference electrode, the polarity of the first and second applied voltages is set to be negative, and the third applied voltage is set. Is shown as positive. However, if the electrode coated with the reagent serves as a reference electrode in the voltage measurement, the applied voltage may be of the opposite polarity than the series shown in FIG. 7A. For example, in the preferred embodiment of FIGS. 8A and 8B, the polarity of the first and second applied voltages is positive and the polarity of the third applied voltage is negative. In either case, the electrode not coated with the reagent acts as the anode during the first and second applied voltages, and the electrode coated with the reagent acts as the anode during the third applied voltage, The calculation of glucose is the same.

  In addition, if the test instrument determines that the sample is a control solution (as opposed to blood), the test instrument will allow the user to review the test sample concentration data separately from the control solution data. The resulting glucose concentration can be preserved. For example, the glucose concentration of the control solution can be stored in another database, marked, and / or deleted (ie, not stored or stored for a short time).

  Another advantage of being able to recognize the control solution is that the test meter can be programmed to automatically compare the control solution test results (eg, glucose concentration) with the expected glucose concentration of the control solution. is there. For example, the test meter can be preprogrammed with the expected glucose level (s) of the control solution (s). Alternatively, the user can enter the expected glucose concentration of the control solution. When the test meter recognizes the control solution, the test meter can compare the measured control solution glucose concentration to the expected glucose concentration to determine whether the meter is functioning normally. If the measured glucose concentration is outside of the expected range, the test meter can output a warning message to alert the user.

Temperature Correction In some embodiments of the present systems and methods, blood temperature correction can be applied to the test current value to provide analyte concentration with improved accuracy because the effect of temperature is reduced. The method for calculating the temperature corrected analyte concentration may include measuring a temperature value, and calculating the temperature correction value C _T, a. Temperature correction value C _T is the temperature value and the analyte concentration, for example, can be based on the glucose concentration. Thus, the temperature correction value _CT can then be used to correct the analyte concentration for temperature.

Initially, an uncorrected analyte concentration for temperature, such as analyte concentration G2, can be obtained from Equation 22 above. Temperature values can also be measured. The temperature may be measured using a thermistor or other temperature reading device incorporated into the test meter, or by any other number of mechanisms or means. Subsequently, in order to determine whether the temperature value T is greater than the first temperature threshold value T _1, the determination can be performed. For example, the temperature threshold T ₁ can be about 15 ° C. If the temperature value T is greater than 15 ° C., in order to determine a temperature correction value C _T, the first temperature function can be applied. If the temperature value T is 15 ℃ less, in order to determine a temperature correction value C _T, the second temperature function can be applied.

First temperature function for calculating the temperature correction value C _T may be in the form of Equation 23,
Formula 23 C _T = + K ₉ (T−T _RT ) + K ₁₀ G2 (T−T _RT )
Where C _T is a correction value, K ₉ is a ninth constant (eg, −0.866), T is a temperature value, T _RT is a room temperature value (eg, 22 ° C.), K ₁₀ is the tenth constant (eg, 0.000687), and G 2 is the analyte concentration. When equal to T approximately _{T RT, C T} is about zero. In some cases, the first temperature function can be configured to be essentially uncorrected at room temperature so that the deviation can be reduced under routine ambient conditions. The second function of temperature for calculating the second correction value C _T, may be in the form of Equation 24,
Formula 24 C _T = + K ₁₁ (T−T _RT ) + K ₁₂ G 2 (T−T _RT ) + K ₁₃ (T−T ₁ ) + K ₁₄ G 2 (T−T ₁ )
Where C _T is a correction value, K ₁₁ is an eleventh constant (eg, −0.866), T is a temperature value, T _RT is a room temperature value, and K ₁₂ is a twelfth value. constant (e.g., 0.000687) is, G2 is the analyte _{concentration, K 13} is the 13 th constant (e.g., -0.741), _{T 1} is the first temperature threshold value (e.g., about 15 ° C) and K ₁₄ is the 14th constant (eg, 0.00322).

After calculating the C _T using equation 23, to ensure that the C _T is limited to predetermined ranges, thereby to reduce the risk of outlier, some truncation function can be performed. In one embodiment, _{C T} may be limited to have a range of -10 to + 10. For example, determination, C _T may be performed to determine if 10 or greater. If the C _T exceeds 10, the temperature exceeds a threshold value, for example 15 ° C., _{C T} is set to 10. If C _T is less than 10, the determination is, _{C T} is performed to determine whether less than -10. If C _T is less than -10, _{C T} may be set to -10. If C _T is already a value of -10 to + 10, generally, truncation is not necessary. However, the temperature threshold value, for example, of less than 15 ° C., can be set the maximum value of _{C T} to 10 + 0.92 (15-T) .

Once _CT is determined, the temperature corrected analyte concentration can be calculated. For example, a determination can be made to determine whether the uncorrected analyte concentration (eg, G2) for temperature is less than 100 mg / dL. If G2 is less than 100 mg / dL, the temperature-corrected analyte concentration G3 can be calculated by using Equation 25 and adding the correction value _CT to the glucose concentration G2.
Formula 25 G3 = G2 + C _T

If G2 is not less than 100 mg / dL, using Equation 26, dividing the _{C T} 100, 1 is added, by subjecting the analyte concentration G2 then able to calculate the analyte concentration G2 with temperature compensation (this method It is used as a virtually percentage correction term a C _T).
Formula 26 G3 = G2 [1 + 0.01 (C _T )]

  Once the analyte concentration, corrected for temperature effects, is quantified, further corrections can be made based on the sample fill time.

Fill Time Correction In some embodiments, the concentration of the analyte can be corrected based on the fill time of the sample. An example of such a method is Ronald C., entitled “Systems, Devices and Methods for Improving Accuracy of Biosensors Using Fill Time,” filed Dec. 30, 2009. Chatelier and Alastair M.M. Hodges co-pending patent application (Application No. 12 / 649,594) as well as “Systems, Devices and Methods for Improving Accuracy of Biosensors Using File Time,” filed Dec. 17, 2010. C. Chatelier and Alastair M.M. By Hodges (Application No. 12 / 971,777), which is incorporated herein by reference in its entirety. In an alternative embodiment for detecting the concentration of the analyte in the sample, the error can be corrected based on an initial fill rate that is quantified rather than the determined fill time. An example of such a method is Ronald C., filed Dec. 30, 2009, entitled “Systems, Devices and Methods for Measuring for Whole Blood Haematocrit Based on Initial Fill Velocity”. Chatelier, Dennis Rylatt, Linda Raineri, and Alastair M. et al. Disclosed in co-pending patent application by Hodges (Application No. 12 / 649,509), which is incorporated herein by reference in its entirety.

In the exemplary embodiment of the correction related to the filling time, the temperature-corrected analyte concentration G3 is corrected in consideration of the filling time by the following equations 27A and 27B to obtain the filling time-corrected analyte concentration value G4. be able to. For example, when G3 <100 mg / dL, no correction is necessary, and G4 may be an uncorrected value of G3. However, when G3 ≧ 100 mg / dL, equation 27B can be used with equations 28A, 28B, and 28C to correct G3.
When Expression 27A G4 = G3 G3 <100 mg / dL Expression 27B When G4 = G3 (1 + C _FT / 100) G3 ≧ 100 mg / dL

The correction factor C _FT in Equation 27B can be calculated taking into account FT based on a series of thresholds for fill time (FT). For example, C _FT can be calculated using the following formulas using Th ₁ and Th ₂ which are two thresholds of _FT .
When Formula 28A Th ₁ <FT <Th ₂ C _FT = FT _f (FT-Th ₁ )
If Equation 28B FT <Th ₁ C _FT = 0
When Formula 28C FT> Th ₂ C _FT = 10

In an exemplary embodiment, threshold Th ₁ may be about 0.2 seconds, threshold Th ₂ may be about 0.4 seconds, and fill time factor FT _f may be about 41. For example, if the blood fills the sensor in less than about 0.2 seconds, the filling mode can be described as close to ideal. A fill time of less than about 0.2 seconds usually occurs when the hematocrit value is sufficiently low that the sample viscosity has minimal impact on the sample fill mode. As a result of the low hematocrit value, it is believed that most of the glucose is partitioned into the plasma phase where it can be rapidly oxidized. Under these conditions, there is little need to correct the glucose result for the effect of filling time, so that the correction factor can be set to zero. Alternatively, if the hematocrit value in the sample is high, the viscosity of the sample can affect the filling time of the sample. As a result, the sample can take more than about 0.4 seconds to fill the sensor. As a result of the high hematocrit value, most of the glucose is thought to be distributed into the red blood cells, so that a smaller percentage of glucose is oxidized. Under these conditions, the glucose result can be corrected to account for the filling time. However, it may be important not to overcorrect the glucose value, so in an exemplary embodiment, the correction factor may be limited to a maximum of about 10 mg / dL plasma glucose or about 10% of the signal. Empirical linear equations are used to increase the correction term stepwise from about 0 to about 10 as the fill time increases from about 0.2 to about 0.4 seconds. be able to.

Aging / Storage Correction In some embodiments of the systems and methods of the present invention, additional correction factors can be applied to the fill time corrected analyte concentration value G4. This correction factor can be used to provide improved accuracy by correcting the effects of aging and / or storage conditions on sensor performance. For example, a parameter that corrects the physical characteristics of the sensor can be measured, and the corrected analyte concentration can be calculated using the parameter. In some embodiments, the parameter that corrects the physical characteristics of the sensor may be the measured capacitance of the sensor.

  The measured capacitance of a sensor, eg, an electrochemical cell of the type described in detail above, can be related to the aging and / or storage state of the sensor. As a non-limiting example, the capacitance of the electrochemical cell can be affected by the slow flow of the adhesive used to manufacture the electrochemical cell from the spacer layer into the sample reaction chamber. For example, when the sensor ages during storage, particularly at high temperatures, the adhesive may flow into the reaction chamber and cover the sensor reference and / or counter electrode. For example, the adhesive can cause a reduction in the area of the electrode and can affect the accuracy of measurements made by the sensor. Smaller electrode areas can also be associated with lower sensor capacitance. Thus, the measured capacitance of the sensor may be used to calculate a correction factor that can be used to improve the reading accuracy performed with that sensor.

In one exemplary embodiment, a method for calculating a corrected analyte concentration comprises measuring a physical property of an electrochemical cell, such as capacitance, and calculating a correction factor C _c. May include. The correction factor C _c may be based on the measured physical property. Therefore, using a correction factor C _c, it can be calculated a corrected analyte concentration.

First, an analyte concentration such as the analyte concentration value G4 corrected for the filling time can be obtained. For example, the measured capacitance of the sensor can also be obtained using the above-described capacitance measurement method. Subsequently, the measured capacitance value C in order to determine whether less than the capacitance threshold C _1, the determination can be performed. In some embodiments, the capacitance threshold C ₁ may be an average or ideal value of the capacitance of the same type of sensor. The capacitance value C is less than the capacitance threshold C _1, uncorrected (or pre corrected) analyte concentration G4 is exceed the analyte concentration threshold G _th, using the capacitance correction function The correction factor _Cc can be determined. The capacitance value C is not more capacitance threshold C ₁ or more, and / or uncorrected (or pre corrected) analyte concentration G4 is equal to or smaller than the analyte concentration threshold G _th, the correction factor C _c May be set to zero. For example, in one embodiment, the capacitance threshold C ₁ may be about 577 nanofarads and the analyte concentration threshold G _th , eg, glucose concentration, may be about 100 mg / dL. Therefore, if the capacitance value C and / or the analyte concentration G4 is within a predetermined range, the correction factor C _c can be determined using the capacitance correction function, otherwise the correction factor C _{c is set} to zero. May be set to

The capacitance correction function for calculating the capacitance correction factor C _c is such that the measured capacitance value C is less than the capacitance threshold C ₁ and the uncorrected (or pre-corrected) analyte. When the concentration G4 exceeds the analyte concentration threshold _Gth , it may be in the form of equation 29,
Formula 29 C _c = K _c (C ₁ -C)
Where C _c is a correction factor, K _c is an empirically obtained constant (eg, 0.051), C ₁ is a capacitance threshold (eg, 777 nanofarads), and C is It is the measured capacitance value.

For example, after calculating C _c using Equation 29, it is ensured that C _c is limited to a predetermined range by limiting the maximum correction applied to the data, thereby reducing the risk of outliers. Several truncation functions can be performed to mitigate. In one embodiment, if the C _c exceeds the cut-off value may be set to C _c the cutoff value. For example, a determination can be made to determine whether C _c exceeds a cutoff value, eg, 5. When C _c exceeds a cutoff value, for example, 5, C _c is set to a cutoff value, for example, 5. If C _c is less than or equal to the cut-off value, there is generally no need for truncation.

Once _Cc is determined, the capacitance corrected analyte concentration can be calculated. For example, the determination may be to determine whether the uncorrected (or precorrected) analyte concentration G4 is less than the analyte concentration threshold G _th , eg, 100 mg / dL, if the analyte is glucose. Can be implemented. If G4 is less than the analyte concentration threshold _Gth , no further correction is applied. If the G4 exceeds analyte concentration threshold G _th, using Equation 30, dividing the C _c 100, 1 is added, by subjecting the analyte concentration [G] Next, the electrostatic capacitance corrected glucose concentration ( That is, the final density value) G5 can be calculated.
Formula 30 G5 = G4 [1 + 0.01 (C _c )]

  Once the analyte concentration corrected for aging and / or storage effects is quantified, the analyte concentration can be output, for example, on a display.

  As described above, the system and method of the present invention sets the glucose concentration threshold so that a glucose concentration value that is within 10% of the reference glucose measurement error is obtained for at least 95% of a series of glucose concentration evaluations. An accuracy criterion of at least ± 10% can be achieved for glucose concentrations above. In another exemplary embodiment, the method provides a glucose concentration threshold such that for at least 95% of a series of glucose concentration assessments, a glucose concentration value is obtained that is within about 10 mg / dL of reference glucose measurement error. An accuracy standard of at least ± 10 mg / dL can be achieved for glucose concentrations below. For example, the glucose concentration threshold may be about 75 mg / dL. Applicants note that the algorithm and method of the present invention can achieve this accuracy criterion over a series of analyte concentration assessments of more than about 5,000 and even more than about 18,000 analyte concentration assessments. Keep it. For example, the system and method of the present invention may meet or exceed the latest standards of the US Food and Drug Administration and recommendations for the accuracy of portable invasive blood glucose monitoring systems.

Example 1
This example demonstrates the reduction in inter-donor variation in glucose concentration determination using the current sum time frame. In the following examples, the system included a sensor with two opposing electrodes, where the reagent designed to react with the sample was dry on one electrode. Multiple samples from different donors were prepared for analysis of performance tests of the systems, devices, and methods disclosed herein. Samples were 10,240 blood samples from 31 donors, with hematocrit values ranging from 37% to 45%. Measure the current transition, for _{i l} about 1.4 seconds to about 4.0 seconds, and analyzed using a first algorithm that depends on the time frame of about 4.4 seconds to about 5 seconds for _{i r.} The second algorithm, specifically, by using the current value i _r and i _l calculated by the above formula 15A and 15B, were also measured measured current transition. The standard deviation of the test results using the first algorithm was about 2.83. The standard deviation of test results using the second algorithm shown and described herein was about 1.72. This result shows that the accuracy is unexpectedly improved when the current values i _r and i _l are calculated by equations 15A and 15B.

(Example 2)
This example demonstrates a decrease in inter-sex variation in glucose concentration determination using the current sum time frame. In the following examples, the system included a sensor with two opposing electrodes, where the reagent designed to react with the sample was dry on one electrode. Multiple samples from 30 different donors (15 men, 15 women) were prepared for analysis of performance tests of the systems, devices, and methods disclosed herein. Measure the current transition, for _{i l} about 1.4 seconds to about 4.0 seconds, were analyzed using the first algorithm including a time frame of about 4.4 seconds to about 5 seconds for _{i r.} The second algorithm, specifically, by using the current value i _r and i _l calculated by the above formula 15A and 15B, were also measured measured current transition.

  As shown in FIG. 9, blood samples from women tend to have a positive bias from the baseline glucose measurements measured with the YSI 2700 medical device (mean bias = 1.6 ± 2.1 SD) and are from men Blood samples tend to have a negative bias from the baseline glucose measurement measured with the YSI 2700 medical device (mean bias = −2.5 ± 1.9 SD). Without being limited to any particular theory, one reason for the gender difference is that glucose oxidation rates are different between men and women (perhaps changes in glucose efflux rates in blood cells, or differences in plasma viscosity). Is considered). Accordingly, Applicants examined various time frames for current transitions used for quantification of glucose concentration and determined time frames where the observed error was less clear.

The time frame during the current transition that gave the best results (ie, the smallest bias from the baseline glucose measurement) was about 3.9 seconds to about 4.0 seconds for i _l (see Equation 15B above). For i _r (the above formula 15A), it was a frame of about 4.25 seconds to about 5 seconds. As shown in FIG. 9, these new time frame and the previous time frame, i.e. _{i l} In about 1.4 seconds to about 4.0 seconds, and _{i r} in about 4.4 seconds to about 5 seconds compared Thus, for both male and female donors, the bias from baseline glucose measurements measured with the YSI 2700 medical device was reduced. Specifically, the bias from baseline glucose measurements measured with a YSI 2700 medical device is an average bias of 0.7 ± 1.6 SD for samples from female donors and −0.4 for samples from male donors. Reduced to an average bias of ± 1.7 SD. Thus, in both sexes, when using the time frame in Equations 15A and 15B, the bias average approached zero and the bias SD decreased.

(Example 3)
This example demonstrates the reduction in interference due to urate concentration in glucose concentration determination using the current sum time frame. In the following examples, the system included a sensor with two opposing electrodes, where the reagent designed to react with the sample was dry on one electrode. Multiple samples were provided for analysis to test the performance of the systems, devices, and methods disclosed herein. Measure the current transition, for _{i l} about 1.4 seconds to about 4.0 seconds, were analyzed using the first algorithm including a time frame of about 4.4 seconds to about 5 seconds for _{i r.} Shown herein, and the second algorithm described, specifically, by using the current value i _r and i _l calculated by equation 15A and 15B, it was also measured measured current transition. For samples with a target plasma glucose concentration of 65, 240 or 440 mg / dL, the bias from a baseline glucose measurement measured with a YSI 2700 medical device was determined. These data were plotted against the concentration of urate added to normal hematocrit blood. The slope of each line was calculated. A small slope indicates that the interference with urate is small. As shown in Table 1 below, the bias for the first algorithm was much greater than the bias for the second algorithm. More specifically, the current values i _r and i _l calculated by equations 15A and 15B were surprisingly shown to be 5 to 13 times less sensitive to blood urate than the first algorithm.

Example 4
This example demonstrates the effectiveness of the fill time correction algorithm disclosed herein for blood with high hematocrit values. In the following examples, the system included a sensor with two opposing electrodes, where the reagent designed to react with the sample was dry on one electrode. Multiple samples have been provided for analysis to test the performance of the systems, devices and methods disclosed herein. The sample was a blood sample containing a hematocrit value in the range of about 15% to about 70%. The algorithm disclosed herein can counteract slow blood filling and accurately report glucose values even at hematocrit values as high as 70%. This has implications for testing newborns that can have very high hematocrit values at 16 hours after birth. The glucose value bias from the baseline glucose measurement measured with the YSI 2700 medical device was plotted against the hematocrit value. The slope of the line that best fits this data is an indicator of the hematocrit dependence of the glucose response. The smaller the inclination, the more ideal. New time frame, specifically, by using the current value i _r and i _l calculated by the above formula 15A and 15B, Analysis of the data obtained in 15-70% hematocrit blood, the bias pair The slope of the hematocrit plot was -0.0278. When the filling time correction was included in the analysis, the slope decreased to -0.0098. Applicants have unexpectedly discovered that the filling time correction reduces the hematocrit dependence of the glucose response by 2.8 times.

(Example 5)
An improved test strip shelf life when using a capacitance correction algorithm according to the present invention is demonstrated in this example. A test strip was typically made using a hot melt adhesive between two electrodes. If the sensor is stored at high temperatures for extended periods of time, the adhesive may flow slowly and partially cover the electrodes. This reduces the current measured when a voltage is applied. However, as the electrode area decreases, the measured capacitance value also decreases. As shown in the above formula, the change in capacitance can be used to correct the glucose response.

  A plot of bias versus shelf life can be used to predict the shelf life of the product (by noting the time at which the fit line crosses one of the upper and lower limits of the error amount). The capacitance correction only affects the high glucose population (> 100 mg / dL).

  In practice, the small slope tends to correlate with the length of shelf life. When capacitance correction is not used, the slope of the bias versus shelf life plot is -0.0559. However, when the data is corrected for the change in capacitance, the slope of the bias versus storage period plot decreases to -0.0379. Therefore, when the capacitance correction due to sensor aging is corrected using the capacitance correction algorithm, the product has a shelf life of about 50% longer.

(Example 6)
The high overall accuracy provided by the correction algorithm will be proved in this embodiment. In the following examples, the system included a sensor with two opposing electrodes, where the reagent designed to react with the sample was dry on one electrode. Multiple samples from different donors were prepared for analysis of performance tests of the systems, devices and methods disclosed herein. This data set consists of 18,970 glucose assays and is organized as follows.
・ 7,460 assays from stability studies (6 lots of strips stored at 30 ° C./65% RH for 1-18 months, 50, 250 and 500 mg / dL plasma glucose plus normal hematocrit blood) Inspection)
-5,179 assays from a temperature test performed at 5-45 ° C (tested with normal hematocrit blood)
• 6,331 assays from hematocrit test (15-70% hematocrit value).

  The above algorithm was used to analyze the data from these assays. Adapting the entire algorithm to this “validation superset” yielded the following adaptation parameters, which were described with respect to the equations disclosed above.

  The stepwise improvement in sensor performance by adding aspects of the algorithm is shown in Table 3 below. The above large data set is first used only in a new time frame (G1), then with the filling time used to correct G1, then with the capacitance used to correct the previous result, and then with the previous result. The AF offset ("AFO") used to correct for the last was fitted with the glucose-dependent power term added (to obtain a complete algorithm). Implementing this showed a gradual improvement brought about by each step of the algorithm. The major change is in the results obtained with G> 75 mg / dL. Performance improvements are seen at each step of the algorithm. RMS bias is the root mean square bias between a calculated equal amount of plasma glucose and a measured reference value. This bias is expressed in mg / dL for G <75 mg / dL and in% for G> 75 mg / dL with respect to the reference glucose concentration. P10 indicates the ratio of the result of glucose value within 10% / dL of the reference value or within 10%.

  “Asymmetric factor offset” and “glucose-dependent power term” were designed to overcome the tendency to be slightly positive at low glucose values and slightly negative at high glucose values. This non-ideal behavior is often seen as a negative slope when plotting bias against baseline plasma glucose values. By including “asymmetric factor offset” and “glucose-dependent power term” in the algorithm, this negative slope could be reduced by 26%. This change was sufficient to include an additional 1.55% point within 10% of the baseline plasma glucose value when the glucose concentration exceeded 80 mg / dL.

  Details of the results from the dataset are shown in Table 4. In all cases, P10> 95% meeting the preferred performance criteria by the American Diabetes Association.

  This result is also shown as a graph in FIGS. 10-14 to allow evaluation of outliers that do not fall within 10 mg / dL or 10% of the reference plasma glucose value. Figures 10-12 show the entire data set plotted against baseline glucose values, hematocrit values, and temperature. FIGS. 13-14 show stability data divided into G <75 mg / dL and G> 75 mg / dL.

  Although the present invention has been described with respect to particular variations and illustrations, those skilled in the art will recognize that the present invention is not limited to the variations or figures described above. Furthermore, if the methods and processes described above indicate specific events that occur in a specific order, those skilled in the art can change the order of specific processes, and such changes are subject to variations of the present invention. You will recognize. Furthermore, some of these steps are performed sequentially as described above, but may be performed simultaneously in parallel processes as the case may be. Accordingly, it is intended that the appended claims cover such modifications as come within the spirit of the disclosure and the scope of equivalents of the present invention as found in the claims. All publications and references cited herein are hereby incorporated by reference in their entirety.

Claims (23)

A plurality of test strips, each test strip having at least two electrodes spaced within a test chamber and a reagent disposed between the two electrodes and receiving a sample containing an analyte With strips,
An analyte measuring device comprising:
A strip port having a connector shaped to mate with a corresponding electrode of each test strip;
When coupled to the strip port and the sample is placed in the test chamber of each of the plurality of test strips, the electrodes of each test strip are used to determine current, test strip capacitance, and sample fill time. A microprocessor configured to measure;
An analyte measuring device comprising:
An analyte measurement system comprising:
The microprocessor is
When a sample is disposed within the analyte test strip with the analyte test strip of the plurality of test strips coupled to the strip port,
Analyte in the sample reacts between the two electrodes,
A first analyte concentration estimate G1, based on output current values measured over separate intervals,
A second analyte concentration estimate G2 based on the output current value measured over a separate interval and the first analyte concentration estimate G1;
A third analyte concentration value G3, temperature-corrected from the second analyte concentration value G2,
A fourth analyte concentration value G4 corrected for sample filling time from the third analyte concentration value G3, and a final test strip capacitance corrected value from the fourth analyte concentration value G4 corrected for sample filling time. Configured to provide a density value G5 ;
In the test strip capacitance correction that corrects the fourth analyte concentration value G4 to provide a final concentration value G5, the test strip capacitance is greater than or equal to a first capacitance threshold and / or If the fourth analyte concentration value G4 is less than or equal to the first concentration threshold, the capacitance correction factor is set to zero,
When a reference sample is used as the sample, the error in the corrected final analyte concentration value from the test strip batch is within 10% of the reference analyte value above the analyte value threshold;
The separate intervals include a first interval that is between about 3.9 seconds and about 4 seconds, and a second interval that is between about 4.25 seconds and about 5 seconds, wherein the first and second An interval is measured from the time that the sample is placed in the test chamber, and the output current values measured over the first and second intervals are defined as a first current sum _ir and a second current sum i. _l , where

Where i (t) comprises the absolute value of the current measured at time t, which is measured from the time at which the sample is placed in the test chamber, and the time t is In 0 to 1 second, a test potential E1 is applied between the two electrodes, and when the time t is 1 to 4 seconds, a second test potential E2 having a value larger than the absolute value of the test potential E1 is applied to the two electrodes. A third test potential E3 having a polarity opposite to that of the second test potential E2 is applied between the two electrodes after the time t is 4 seconds or more.
When the sample fill time corrected analyte concentration value G4 exceeds a first concentration threshold, the test strip capacitance corrected final concentration value G5 is corrected for a capacitance correction factor and the sample fill time. When the capacitance is less than a first capacitance threshold, the capacitance correction factor for the final concentration value G5 is based on the measured capacitance When the calculated capacitance correction factor exceeds a set value, the capacitance correction factor is set to a maximum value,
Analyte measurement system. The first analyte concentration value G1 is

Where p is comprised of about 0.5246, a is comprised of about 0.03422, i ₂ is comprised of a current value corrected with an antioxidant, and zgr The system of claim 1 , comprising approximately 2.25. The second analyte concentration value G2 is

Where p is approximately 0.5246, a is approximately 0.03422, i ₂ is an antioxidant corrected current value, and AFO is approximately 2 The system of claim 1 , comprising: .88, zgr comprising about 2.25, and k comprising about 0.0000124. i2

Where i (4.1) is the absolute value of the current when the time is 4.1 seconds and i (1.1) is 1.1 seconds absolute consist value, i _ss of current when made from the steady state current, the system according to claim 2 or 3. i _ss is

Where i (5) is the absolute value of the current when the time is 5 seconds, π is a constant, D is the diffusion coefficient of the redox species, and L is The system according to claim 2 or 3 , comprising a distance between the two electrodes. The temperature corrected analyte concentration value G3 is corrected by a filling time correction factor based on a filling time, and when the filling time is less than a first filling time threshold, the filling time correction factor is about zero, When the filling time exceeds the first filling time threshold and is less than the second filling time threshold, the filling time correction factor is calculated based on the filling time, and the filling time is the second filling time. The system of claim 2 , wherein when the threshold is exceeded, the filling time correction factor comprises a constant value. The temperature-corrected analyte concentration value G3 includes a first temperature correction for the second analyte concentration value G2 whenever the ambient temperature exceeds a first temperature threshold, the ambient temperature being the first The system of claim 2 , including a second temperature correction whenever the temperature threshold is less than one. A method for quantifying the concentration of an analyte in a sample, the method comprising:
Introducing a sample containing an analyte into an electrochemical sensor, the electrochemical sensor comprising a test strip comprising two electrodes in a spaced configuration;
Reacting the analyte to cause a physical change of the analyte between the two electrodes;
Measuring current, test strip capacitance, and sample fill time using the electrodes;
When a sample is placed inside the analyte test strip, with the analyte test strip of the test strip coupled to a strip port,
Analyte in the sample reacts between the two electrodes,
A first analyte concentration estimate G1, based on output current values measured over separate intervals,
A second analyte concentration estimate G2 based on the output current value measured over a separate interval and the first analyte concentration estimate G1;
A third analyte concentration value G3, temperature-corrected from the second analyte concentration value G2,
A fourth analyte concentration value G4 corrected for sample filling time from the third analyte concentration value G3, and a final test strip capacitance corrected value from the fourth analyte concentration value G4 corrected for sample filling time. comprising the steps of: providing a concentration value G5, only including,
In the test strip capacitance correction that corrects the fourth analyte concentration value G4 to provide a final concentration value G5, the test strip capacitance is greater than or equal to a first capacitance threshold and / or If the fourth analyte concentration value G4 is less than or equal to the first concentration threshold, the capacitance correction factor is set to zero,
Over a series of analyte concentration assessments over about 5,000 times, for at least 95% of the series of analyte concentration assessments, an analyte concentration value is obtained with an error of the reference analyte measurement within 10%. Achieving an accuracy criterion of at least ± 10% for an analyte concentration that exceeds an analyte concentration threshold . Analyzes below the analyte concentration threshold such that the method yields an analyte concentration value with a reference analyte measurement error within about 10 mg / dL for at least 95% of a series of analyte concentration assessments. The method of claim 8 , wherein an accuracy criterion of at least ± 10 mg / dL is achieved for the object concentration. 9. The method of claim 8 , wherein the analyte concentration threshold is about 75 mg / dL. 9. The method of claim 8 , wherein the accuracy criterion is achieved over a series of analyte concentration assessments in excess of about 18,000. 9. The method of claim 8 , wherein the method reduces variability in analyte concentration quantification values between donors and genders. 9. The method of claim 8 , wherein the method reduces interference due to urate concentration in quantifying the analyte concentration. The step of quantifying the concentration of the analyte corrects for one or more of the filling time of the sample, the physical characteristics of the electrochemical cell, the temperature of the sample, the temperature of the electrochemical sensor, and the glucose reaction rate. The method of claim 8 comprising: The step of correcting the glucose reaction rate comprises:
Calculating a first analyte concentration;
Calculating a second analyte concentration determined by the first analyte concentration such that the degree of correction of the glucose reaction rate is proportional to the magnitude of the first analyte concentration; 15. The method of claim 14 , comprising. The method of claim 14 , wherein a physical property of the electrochemical sensor is related to at least one of aging of the electrochemical sensor and a storage state of the electrochemical sensor. 9. The method of claim 8 , wherein reacting the analyte produces an electroactive species that is measured as a current by the two electrodes. The method of claim 8 , wherein the two electrodes comprise opposing facing orientations. Including an orientation in which the two electrodes facing method of claim 8. The method of claim 8 , wherein the electrochemical sensor comprises a glucose sensor. The method of claim 8 , wherein the electrochemical sensor comprises an immunosensor. The method of claim 8 , wherein the sample comprises blood. Wherein the sample comprises whole blood, the method of claim 8.

Images