Patent Grant
9903830
Electrochemical glucose test strips, such as those used in the OneTouch® Ultra® whole blood testing kit, which is available from LifeScan, Inc., are designed to measure the concentration of glucose in a physiological fluid sample from patients with diabetes. The measurement of glucose can be based on the selective oxidation of glucose by the enzyme glucose oxidase (GO). The reactions that can occur in a glucose test strip are summarized below in Equations 1 and 2.
Glucose+GO(ox)→Gluconic Acid+GO(red) Eq. 1
GO(red)+2Fe(CN)63−→GO(ox)+2Fe(CN)64− Eq. 2
As illustrated in Equation 1, glucose is oxidized to gluconic acid by the oxidized form of glucose oxidase (GO(3x)). It should be noted that GO(ox) may also be referred to as an “oxidized enzyme.” During the reaction in Equation 1, the oxidized enzyme GO(ox) is converted to its reduced state, which is denoted as GO(red) (i.e., “reduced enzyme”). Next, the reduced enzyme GO(red) is re-oxidized back to GO(ox) by reaction with Fe(CN)63− (referred to as either the oxidized mediator or ferricyanide) as illustrated in Equation 2. During the re-generation of GO(red) back to its oxidized state GO(ox), Fe(CN)63− is reduced to Fe(CN)64− (referred to as either reduced mediator or ferrocyanide).
When the reactions set forth above are conducted with a test signal applied between two electrodes, a test current can be created by the electrochemical re-oxidation of the reduced mediator at the electrode surface. Thus, since, in an ideal environment, the amount of ferrocyanide created during the chemical reaction described above is directly proportional to the amount of glucose in the sample positioned between the electrodes, the test current generated would be proportional to the glucose content of the sample. A mediator, such as ferricyanide, is a compound that accepts electrons from an enzyme such as glucose oxidase and then donates the electrons to an electrode. As the concentration of glucose in the sample increases, the amount of reduced mediator formed also increases; hence, there is a direct relationship between the test current, resulting from the re-oxidation of reduced mediator, and glucose concentration. In particular, the transfer of electrons across the electrical interface results in the flow of a test current (2 moles of electrons for every mole of glucose that is oxidized). The test current resulting from the introduction of glucose can, therefore, be referred to as a glucose signal.
Electrochemical biosensors may be adversely affected by the presence of certain blood components that may undesirably affect the measurement and lead to inaccuracies in the detected signal. This inaccuracy may result in an inaccurate glucose reading, leaving the patient unaware of a potentially dangerous blood sugar level, for example. As one example, the blood hematocrit level (i.e. the percentage of the amount of blood that is occupied by red blood cells) can erroneously affect a resulting analyte concentration measurement.
Variations in a volume of red blood cells within blood can cause variations in glucose readings measured with disposable electrochemical test strips. Typically, a negative bias (i.e., lower calculated analyte concentration) is observed at high hematocrit, while a positive bias (i.e., higher calculated analyte concentration) is observed at low hematocrit. At high hematocrit, for example, the red blood cells may impede the reaction of enzymes and electrochemical mediators, reduce the rate of chemistry dissolution since there is less plasma volume to solvate the chemical reactants, and slow diffusion of the mediator. These factors can result in a lower than expected glucose reading as less signal is produced during the electrochemical process. Conversely, at low hematocrit, fewer red blood cells may affect the electrochemical reaction than expected, and a higher measured signal can result. In addition, the physiological fluid sample resistance is also hematocrit dependent, which can affect voltage and/or current measurements.
Several strategies have been used to reduce or avoid hematocrit based variations on blood glucose. For example, test strips have been designed to incorporate meshes to remove red blood cells from the samples, or have included various compounds or formulations designed to increase the viscosity of red blood cells and attenuate the effect of low hematocrit on concentration determinations. Other test strips have included lysis agents and systems configured to determine hemoglobin concentration in an attempt to correct hematocrit. Further, biosensors have been configured to measure hematocrit by measuring an electrical response of the fluid sample via alternating current signals or change in optical variations after irradiating the physiological fluid sample with light, or measuring hematocrit based on a function of sample chamber fill time. These sensors have certain disadvantages. A common technique of the strategies involving detection of hematocrit is to use the measured hematocrit value to correct or change the measured analyte concentration, which technique is generally shown and described in the following respective US Patent Application Publication Nos. 2010/0283488; 2010/0206749; 2009/0236237; 2010/0276303; 2010/0206749; 2009/0223834; 2008/0083618; 2004/0079652; 2010/0283488; 2010/0206749; 2009/0194432; or U.S. Pat. Nos. 7,972,861 and 7,258,769, all of which are incorporated by reference herein to this application.
Applicants have provided various embodiments of a technique to allow for improved glucose measurement using a relationship between batch slope and physical characteristic (e.g., hematocrit) to derive a new batch slope that can be used to determine the analyte concentration based on this derived batch slope of an electrochemical biosensor. Advantageously, this new technique does not rely on correction(s) or modification(s) to be made to an analyte measurement, thereby reducing test time while at the same time improving accuracy.
In a first aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor (which may be in the form of a test strip but is not limited to a test strip) is provided. The biosensor has at least two electrodes and a reagent disposed on at least one of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to measure or estimate a physical characteristic of the sample; deriving a batch slope for the biosensor based on the measured or estimated physical characteristic from an equation of the form:
x=aH2+bH+c
where
where
In a second aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor (which may be in the form of a test strip but is not limited to a test strip) is provided. The biosensor has at least two electrodes and a reagent disposed on at least one of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to measure a physical characteristic of the sample; deriving a batch slope for the biosensor based on the measured or estimated physical characteristic; driving a second signal to the sample; and measuring an output signal from at least one of the at least two electrodes; calculating an analyte concentration based on the measured output signal and derived batch slope from the measured or estimated physical characteristic of the sample.
In any of the aspects described herein the following features may also be utilized in various combinations with the previously disclosed aspects: the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density of the sample; the directing may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; and/or the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz.
In these aspects, the deriving may include calculating a batch slope from an equation of the form:
x=aH2+bH+c
where
Furthermore, the calculating of the analyte concentration may include utilizing an equation of the form:
where
In a third aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate with a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port, and a processor. The strip port connector is configured to connect to the respective electrode connectors of the test strip. The microprocessor is in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes during a test sequence. The microprocessor is configured to, during the test sequence: (a) apply a first signal to the plurality of electrodes so that a batch slope defined by a physical characteristic of a physiological fluid sample is derived and (b) apply a second signal to the plurality of electrodes so that an analyte concentration is determined based on the derived batch slope.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may include two electrodes to measure the physical characteristic and the analyte concentration; the plurality of electrodes may include two electrodes to measure the physical characteristic and the analyte concentration; alternatively, all of the electrodes are disposed on the same plane defined by the substrate; a reagent is disposed proximate the at least two other electrodes and no reagent is disposed on the at least two electrodes; and/or the batch slope may be calculated from an equation of the form:
x=aH2+bH+c
where
Furthermore, in these aspects, the analyte concentration may be determined from an equation of the form:
where
In a fourth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate with a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port, and a processor. The strip port connector is configured to connect to the respective electrode connectors of the test strip. The microprocessor is in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes during a test sequence. The microprocessor is configured to, during a test sequence: (a) apply a first signal to the plurality of electrodes so that a batch slope defined by a physical characteristic of a physiological fluid sample is derived and (b) apply a second signal to the plurality of electrodes so that an analyte concentration is determined based on the derived batch slope obtained from the physical characteristic of the sample within about 10 seconds of a start of the test sequence.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may include two electrodes to measure the physical characteristic and the analyte concentration; the plurality of electrodes may include two electrodes to measure the physical characteristic and the analyte concentration; all of the electrodes may be disposed on the same plane defined by the substrate; a reagent is disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes; and/or the batch slope may be calculated from an equation of the form:
x=aH2+bH+c
where
In these aspects, the analyte concentration may be calculated from an equation of the form:
where
In a fifth aspect of applicants' disclosure, a method of demonstrating increased accuracy of a test strip is provided. The method can be achieved by: providing a batch of test strips; introducing a referential sample containing a referential concentration of an analyte to each test strip of the batch of test strips to initiate a test sequence; reacting the analyte with a reagent on each test strip to cause a physical transformation of the analyte proximate the two electrodes (which may be between the two electrodes); determining a physical characteristic of the referential sample; deriving a batch slope for the batch of test strips based on the determined physical characteristic of the referential sample; sampling an electrical output of the referential sample at a predetermined time point during the test sequence; calculating an analyte concentration based on the defined batch slope and sampled electrical output to provide for a final analyte concentration value for each test strip of the batch of test strips such that at least 95% of the final analyte concentration values of the batch of test strips are within ±15% of the referential analyte concentration.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the determining may include applying a first signal to the sample to measure a physical characteristic of the sample; the sampling may include driving a second signal to the sample; the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density; the directing may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the deriving may include calculating a batch slope from an equation of the form:
x=aH2+bH+c
where
In these aspects, the calculating of the analyte concentration may include utilizing an equation of the form:
where
In a sixth aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) is provided. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on a biosensor; applying signals to the sample to transform the analyte into a different material; measuring or estimating a physical characteristic of the sample; evaluating signal output from the sample; deriving a parameter of the biosensor from the measured or estimated physical characteristic; and determining an analyte concentration based on the derived parameter of the biosensor and the signal output of the sample.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the measuring may include applying a first signal to the sample to measure a physical characteristic of the sample; the evaluating may include driving a second signal to the sample; the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density; the directing may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; the derived parameter may be a batch slope; and/or the deriving may include calculating a batch slope from an equation of the form:
x=aH2+bH+c
where
In these aspects, the calculating of the analyte concentration may include utilizing an equation of the form:
where
In a seventh aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor (e.g. a test strip) is provided. The biosensor has at least two electrodes and a reagent disposed on at least one electrode of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to derive a physical characteristic of the sample; obtaining a physical characteristic of the sample; specifying a sampling time based on the obtained physical characteristic; driving a second signal to the sample; and measuring an output signal at the specified sampling time from at least one electrode of the at least two electrodes; and calculating an analyte concentration based on the measured output signal.
For the seventh aspect of applicants' disclosure, the following features may also be utilized in various combinations: the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density of the sample; the directing may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, in the seventh aspect of applicants' disclosure, the calculating of the analyte concentration may be computed with an equation of the form:
where
In an eighth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and a test meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip and a microprocessor. The microprocessor is in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes during a test sequence. The microprocessor is configured to, during the test sequence: (a) apply a first signal to the plurality of electrodes so that a specified sampling time determined from a physical characteristic of a physiological fluid sample is derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time so that an analyte concentration is determined.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; the plurality of electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; all of the electrodes may be disposed on the same plane defined by the substrate; a reagent may be disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, in these aspects, the analyte concentration is determined from an equation of the form:
where
In a ninth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and a test meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip and a microprocessor. The microprocessor is in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes. The microprocessor is configured to, during a test sequence: (a) apply a first signal to the plurality of electrodes so that a specified sampling time determined from a physical characteristic of a physiological fluid sample is derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time so that an analyte concentration of the sample is determined based on the specified sampling time within about 10 seconds of a start of the test sequence.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; all of the electrodes may be disposed on the same plane defined by the substrate; a reagent may be disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, for these aspects, an analyte concentration may be calculated from an equation of the form:
where
In a tenth aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) is provided. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on a biosensor (e.g. a test strip) having a reagent deposited thereon; applying signals to the sample and the reagent to transform the analyte into a different material; obtaining a physical characteristic of the sample; specifying a time point for sampling of signal output based on the obtained physical characteristic; measuring signal output at the specified sampling time; and determining an analyte concentration based on the measured signal output of the sample.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the obtaining may include driving a second signal to the sample to derive a physical characteristic of the sample; the applying may include applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying may comprise applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density; the directing may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, the calculating of the analyte concentration may include utilizing an equation of the form:
where
In addition to the above, applicants have provided various embodiments of a technique to allow for improved glucose measurement using two somewhat related relationships: (a) a relationship between sampling time point and hematocrit to derive or calculate a specified sampling time at which a measurement of the output from the biosensor is to be taken; and (b) a relationship between batch slope and physical characteristic (e.g., hematocrit) that allows derivation of a new batch slope. Both relationships are utilized to determine a more accurate analyte concentration (i.e., based on the specified sampling time and the derived batch slope). This new technique does not rely on correction(s) or modification(s) to be made to an analyte measurement, thereby reducing test time while at the same time improving accuracy.
In an eleventh aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor is provided. The biosensor has at least two electrodes and a reagent disposed on at least one electrode of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to derive a physical characteristic of the sample; obtaining a physical characteristic of the sample; specifying a sampling time based on the physical characteristic from the obtaining step; deriving a batch slope for the biosensor based on the physical characteristic from the obtaining step; driving a second signal to the sample; and measuring an output signal at the specified sampling time from at least one electrode of the at least two electrodes; and calculating an analyte concentration based on the measured output signal at the specified sampling time and the derived batch slope.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density of the sample; the directing may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, for these aspects noted above, the derived slope may be determined from an equation of the form:
NewSlope=aH2+bH+c
where
Furthermore, the calculating of the analyte concentration is computed with an equation of the form:
where
In a twelfth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes during a test sequence. The microprocessor is configured to, during the test sequence: (a) apply a first signal to the plurality of electrodes so that a specified sampling time and a batch slope determined from a physical characteristic of a physiological fluid sample are derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time so that an analyte concentration is determined based on the measured signal at the specified time point and the batch slope.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; the plurality of electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; all of the electrodes may be disposed on the same plane defined by the substrate; a reagent may be disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
In these aspects previously noted above, the derived slope is determined from an equation of the form:
NewSlope=aH2+bH+c
where
Furthermore, for these aspects, the calculating of the analyte concentration is computed with an equation of the form:
where
In a thirteenth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes during a test sequence. The microprocessor is configured to, during a test sequence: (a) apply a first signal to the plurality of electrodes so that a specified sampling time and a batch slope of the test strip determined from a physical characteristic of a physiological fluid sample are derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time point so that an analyte concentration of the sample is determined based on the specified sampling time and batch slope within about 10 seconds of a start of the test sequence.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may include at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; the at least two electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; the plurality of electrodes may comprise two electrodes to measure the physical characteristic and the analyte concentration; all of the electrodes may be disposed on the same plane defined by the substrate; a reagent may be disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes; the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
For these aspects previously noted, the derived slope may be determined from an equation of the form:
NewSlope=aH2+bH+c
where
Furthermore, for these aspects, the calculating of the analyte concentration is computed with an equation of the form:
where
In a fourteenth aspect of applicants' disclosure, a method of demonstrating increased accuracy of a test strip is provided. The method can be achieved by: providing a batch of test strips; introducing a referential sample containing a referential concentration of an analyte to each of the batch of test strips to initiate a test sequence; reacting the analyte to cause a physical transformation of the analyte proximate the two electrodes (which may be between the two electrodes); determining a physical characteristic of the referential sample; deriving a batch slope of the batch of test strips based on the determined physical characteristic; sampling an electrical output of the referential sample at a specified time point during the test sequence defined by the measured or estimated physical characteristic; and calculating an analyte concentration based on the specified time point and the derived batch slope to provide for a final analyte concentration value for each of the batch of test strips such that at least 95% of the final analyte concentration values of the batch of test strips are within ±15% of the referential analyte concentration.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the reacting may include driving a second signal to the sample and the determining may include applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the reacting may comprise driving a second signal to the sample and the determining may comprise applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density; the directing may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
Additionally, for these previously disclosed aspects, the derived slope may be determined from an equation of the form:
NewSlope=aH2+bH+c
where
Furthermore, for these aspects, the calculating of the analyte concentration is computed with an equation of the form:
where
In a fifteenth aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample). The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on a biosensor having a reagent deposited thereon; applying signals to the sample and the reagent to transform the analyte into a different material; obtaining a physical characteristic of the sample; specifying a time point for sampling of signal output based on the physical characteristic from the obtaining step; deriving a batch slope of the biosensor; measuring signal output at the specified sampling time; and determining an analyte concentration based on the measured signal output of the sample at the specified sampling time and the derived batch slope.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the obtaining may include driving a second signal to the sample to derive a physical characteristic of the sample; the applying may include applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal and the driving of the second signal may be in sequential order; the applying of the first signal may overlap with the driving of the second signal; the applying may comprise applying a first signal to the sample to derive a physical characteristic of the sample, and the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may include directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may include directing an optical signal to the sample so that a physical characteristic of the sample is determined from an output of the optical signal; the physical characteristic may include hematocrit and the analyte may include glucose; the physical characteristic may include at least one of viscosity, hematocrit, temperature and density; the directing may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may include any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the specified sampling time may be calculated using an equation of the form:
SpecifiedSamplingTime=x1Hx
where
For these aspects previously disclosed, the derived slope may be determined from an equation of the form:
NewSlope=aH2+bH+c
where
Furthermore, the calculating of the analyte concentration is computed with an equation of the form:
where
In a sixteenth aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor is provided. The biosensor has at least two electrodes and a reagent disposed on at least one of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to measure a physical characteristic of the sample; driving a second signal to the sample to cause an enzymatic reaction of the analyte and the reagent; estimating an analyte concentration based on a predetermined sampling time point from the start of the test sequence; selecting a sampling time point from a look-up table that includes a matrix in which different qualitative categories of the estimated analyte are set forth in the leftmost column of the matrix and different qualitative categories of the measured or estimated physical characteristic are set forth in the topmost row of the matrix and the sampling times are provided in the remaining cells of the matrix; measuring signal output from the sample at the selected sampling time point from the look-up table; calculating an analyte concentration from measured output signal sampled at said selected sampling time point in accordance with an equation of the form:
where
G0 represents, or is, an analyte concentration;
IT represents, or is, a signal (proportional to analyte concentration) measured at a specified sampling time T, which may be the total signal measured at the specified sampling time T;
Slope represents, or is the value obtained from calibration testing of a batch of test strips of which this particular strip comes from; and
Intercept represents, or is, the value obtained from calibration testing of a batch of test strips of which this particular strip comes from.
In a seventeenth aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) with a biosensor is provided. The biosensor has at least two electrodes and a reagent disposed on at least one of the electrodes. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on the at least two electrodes to start an analyte test sequence; applying a first signal to the sample to measure or estimate a physical characteristic of the sample; driving a second signal to the sample to cause an enzymatic reaction of the analyte and the reagent; estimating an analyte concentration based on a predetermined sampling time point from the start of the test sequence; selecting a sampling time point from a look-up table that includes a matrix in which different qualitative categories of the estimated analyte are set forth in the leftmost column of the matrix and different qualitative categories of the measured or estimated physical characteristic are set forth in the topmost row of the matrix and the sampling times are provided in the remaining cells of the matrix; measuring signal output from the sample at the selected sampling time point; and calculating an analyte concentration from measured output signal sampled at said selected sampling time point.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the applying of the first signal and the driving of the second signal may be sequential; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may comprise directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the physical characteristic may comprise hematocrit and the analyte may comprise glucose; the physical characteristic may comprise at least one of viscosity, hematocrit, temperature and density; the directing may comprise driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may comprise any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; the measuring may comprise sampling the signal output continuously at the start of the test sequence until at least about 10 seconds after the start; which may further include the step of estimating an analyte concentration based on a measurement of the output signal at a predetermined time; the estimating may comprise comparing the estimated analyte concentration and the measured or estimated physical characteristic against a look-up table having different respective ranges of analyte concentration and physical characteristic of the sample indexed against different sample measurement times so that the point in time for measurement of the output from the sample of the second signal is obtained for the calculating step; and/or the calculating step may comprise utilizing an equation of the form:
where
G0 represents, or is, an analyte concentration;
IT represents, or is, a signal (proportional to analyte concentration) measured at a specified sampling time T, which may be the total signal measured at the specified sampling time T;
Slope represents, or is, the value obtained from calibration testing of a batch of test strips of which this particular strip comes from; and
Intercept represents, or is, the value obtained from calibration testing of a batch of test strips of which this particular strip comes from.
In an eighteenth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes. The microprocessor is configured to: (a) apply a first signal to the plurality of electrodes so that a physical characteristic of a physiological fluid sample is determined; (b) estimate an analyte concentration based on a predetermined sampling time point during a test sequence; and (c) apply a second signal to the plurality of electrodes at a sampling time point during the test sequence dictated by the determined physical characteristic so that an analyte concentration is calculated from the second signal.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may comprise at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; all of the electrodes may be disposed on the same plane defined by the substrate; and/or a reagent may be disposed proximate the at least two other electrodes and no reagent disposed on the at least two electrodes.
In a nineteenth aspect of applicants' disclosure, an analyte measurement system is provided that includes a test strip and an analyte meter. The test strip includes a substrate and a plurality of electrodes connected to respective electrode connectors. The analyte meter includes a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from the plurality of electrodes. The microprocessor is configured to: (a) apply a first signal to the plurality of electrodes so that a physical characteristic of a physiological fluid sample is determined during a test sequence; (b) estimate an analyte concentration based on a predetermined sampling time point during a test sequence; and (c) apply a second signal to the plurality of electrodes at a sampling time point during the test sequence dictated by the determined physical characteristic so that so that an analyte concentration is determined from the second signal within about 10 seconds of a start of the test sequence.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the plurality of electrodes may comprise at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration; the at least two electrodes and the at least two other electrodes may be disposed in the same chamber provided on the substrate; the at least two electrodes and the at least two other electrodes may be disposed in different chambers provided on the substrate; all of the electrodes may be disposed on the same plane defined by the substrate; and/or a reagent may be disposed proximate on the at least two other electrodes and no reagent disposed on the at least two electrodes.
In a twentieth aspect of applicants' disclosure, a method of demonstrating increased accuracy of a test strip is provided. The method can be achieved by: providing a batch of test strips; introducing a referential sample containing a referential concentration of an analyte to each test strip of the batch of test strips to start a test sequence; reacting the analyte with reagent disposed on each of the test strips to cause a physical transformation of the analyte proximate the two electrodes (which may be between the two electrodes); estimating an analyte concentration based on measured signal output of the sample at a predetermined time point from the start of the test sequence; determining a physical characteristic of the referential sample; sampling an electrical output of the referential sample at a dictated time point during the test sequence defined by the measured or estimated physical characteristic and the estimated analyte concentration; calculating an analyte concentration based on the dictated time point to provide for a final analyte concentration value for each test strip of the batch of test strips such that at least 95% of the final analyte concentration values of the batch of test strips are within ±10% of the referential analyte concentration for a range of hematocrit of the sample from about 30% to about 55%.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the determining may comprise applying a first signal to the sample to measure a physical characteristic of the sample; the reacting may comprise driving a second signal to the sample; the applying of the first signal and the driving of the second signal may be sequential; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may comprise directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; the applying of the first signal may comprise directing an electromagnetic signal to the sample so that a physical characteristic of the sample is determined from an output of the electromagnetic signal; the physical characteristic may comprise hematocrit and the analyte may comprise glucose; the physical characteristic may comprise at least one of viscosity, hematocrit, temperature and density; the directing may comprise driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may comprise any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; and/or the measuring may comprise sampling the signal output continuously at the start of the test sequence until at least about 10 seconds after the start; which may further include the step of estimating an analyte concentration based on a measurement of the output signal at a predetermined time; the estimating may comprise comparing the estimated analyte concentration and the measured or estimated physical characteristic against a look-up table having different respective ranges of analyte concentration and physical characteristic of the sample indexed against different sample measurement times so that the point in time for measurement of the output from the sample of the second signal is obtained for the calculating step.
In a twenty-first aspect of applicants' disclosure, a method of determining an analyte concentration from a fluid sample (which may be a physiological sample) is provided. The method can be achieved by: depositing a fluid sample (which may be a physiological sample) on a biosensor to start a test sequence; causing the analyte in the sample to undergo an enzymatic reaction; estimating an analyte concentration in the sample; measuring at least one physical characteristic of the sample; defining a time point from the start of the test sequence to sample output signals of the biosensor based on the estimated analyte concentration and at least one physical characteristic from the measuring step; sampling output signals of the biosensor at the defined time point; determining an analyte concentration from sampled signals at the defined time point.
And for these aspects, the following features may also be utilized in various combinations with these previously disclosed aspects: the measuring may comprise applying a first signal to the sample to measure a physical characteristic of the sample; the causing step may comprise driving a second signal to the sample; the measuring may comprise evaluating an output signal from the at least two electrodes at a point in time after the start of the test sequence, in which the point in time is set as a function of at least the measured or estimated physical characteristic; the determining step may comprise calculating an analyte concentration from the measured output signal at said point in time; the applying of the first signal and the driving of the second signal may be sequential; the applying of the first signal may overlap with the driving of the second signal; the applying of the first signal may comprise directing an alternating signal to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal; which may further include the step of estimating an analyte concentration based on a predetermined sampling time point from the start of the test sequence; the defining may comprise selecting a defined time point based on both the measured or estimated physical characteristic and the estimated analyte concentration; the physical characteristic may comprise hematocrit and the analyte may comprise glucose; the physical characteristic may comprise at least one of viscosity, hematocrit, temperature and density; the directing may comprise driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency; the first frequency may be at least one order of magnitude lower than the second frequency; the first frequency may comprise any frequency in the range of about 10 kHz to about 250 kHz, or about 10 kHz to about 90 kHz; the measuring may comprise sampling the signal output continuously at the start of the test sequence until at least about 10 seconds after the start; which may further include the step of estimating an analyte concentration based on a measurement of the output signal at a predetermined time; and/or the estimating may comprise comparing the estimated analyte concentration and the measured or estimated physical characteristic against a look-up table having different respective ranges of analyte concentration and physical characteristic of the sample indexed against different sample measurement times so that the point in time for measurement of the output from the sample of the second signal is obtained for the calculating step.
In the sixteenth to the twenty-first aspects, the sampling time point could be selected from a look-up table that includes a matrix in which different qualitative categories of the estimated analyte are set forth in the leftmost column of the matrix and different qualitative categories of the measured or estimated physical characteristic are set forth in the topmost row of the matrix and the sampling times are provided in the remaining cells of the matrix. In any of the above aspects, the fluid sample may be blood. In any of the above aspects, the physical characteristic may include at least one of viscosity, hematocrit, or density of the sample, or the physical characteristic may be hematocrit, wherein, optionally, the hematocrit level is between 30% and 55%. In any of the above aspects, where H represents, or is, the physical characteristic of the sample, it may be the measured, estimated or determined hematocrit, or may be in the form of hematocrit. In any of the above aspects, the physical characteristic may be determined from a measured characteristic, such as the impedance or phase angle of the sample. In any of the above aspects, the signal represented by IE and/or IT may be current.
In the aforementioned aspects of the disclosure, the steps of determining, estimating, calculating, computing, deriving and/or utilizing (possibly in conjunction with an equation) may be performed by an electronic circuit or a processor. These steps may also be implemented as executable instructions stored on a computer readable medium; the instructions, when executed by a computer may perform the steps of any one of the aforementioned methods.
In additional aspects of the disclosure, there are computer readable media, each medium comprising executable instructions, which, when executed by a computer, perform the steps of any one of the aforementioned methods.
In additional aspects of the disclosure, there are devices, such as test meters or analyte testing devices, each device or meter comprising an electronic circuit or processor configured to perform the steps of any one of the aforementioned methods.
These and other embodiments, features and advantages will become apparent to those skilled in the art when taken with reference to the following more detailed description of the exemplary embodiments of the invention in conjunction with the accompanying drawings that are first briefly described.
The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate presently preferred embodiments of the invention, and, together with the general description given above and the detailed description given below, serve to explain features of the invention (wherein like numerals represent like elements), in which:
FIG. 6A1 illustrates a logic diagram of an exemplary method to achieve a more accurate analyte determination.
FIG. 6A2 illustrates one relationship between batch slope and physical characteristic (e.g., hematocrit).
FIG. 6A3 illustrates data from test measurements conducted with the exemplary technique herein such that the data show the bias of less than ±15% for the hematocrit range of about 30% to about 55%.
FIG. 6B1 illustrates a logic diagram of an exemplary method to achieve a more accurate analyte determination.
FIG. 6B2 illustrates one relationship between sampling time point and hematocrits.
FIG. 6B3 illustrates data from test measurements conducted with the exemplary technique herein such that the data show the bias of less than ±25% for the hematocrit range of about 30% to about 55%.
FIG. 6C1 illustrates a logic diagram of an exemplary method to achieve a more accurate analyte determination.
FIG. 6C2 illustrates one relationship between sampling time point and hematocrits.
FIG. 6C3 illustrates a relationship between slope and hematocrits.
FIG. 6C4 illustrates data from test measurements conducted with the exemplary technique herein such that the data show the bias of less than ±25% for the hematocrit range of about 30% to about 55%.
FIG. 6D1 illustrates a logic diagram of an exemplary method to achieve a more accurate analyte determination.
FIG. 6D2 illustrates a signal output transient of the biosensor and the range of time point utilized for determination of the analyte, as well as the estimation of the analyte concentration.
FIG. 6D3 illustrates data from test measurements conducted with the exemplary technique herein such that the data show the bias of less than about ±10% for the hematocrit range of about 30% to about 55%.
The following detailed description should be read with reference to the drawings, in which like elements in different drawings are identically numbered. The drawings, which are not necessarily to scale, depict selected embodiments and are not intended to limit the scope of the invention. The detailed description illustrates by way of example, not by way of limitation, the principles of the invention. This description will clearly enable one skilled in the art to make and use the invention, and describes several embodiments, adaptations, variations, alternatives and uses of the invention, including what is presently believed to be the best mode of carrying out the invention.
As used herein, the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values±10% of the recited value, e.g. “about 90%” may refer to the range of values from 81% to 99%. In addition, as used herein, the terms “patient,” “host,” “user,” and “subject” refer to any human or animal subject and are not intended to limit the systems or methods to human use, although use of the subject invention in a human patient represents a preferred embodiment. As used herein, “oscillating signal” includes voltage signal(s) or current signal(s) that, respectively, change polarity or alternate direction of current or are multi-directional. Also used herein, the phrase “electrical signal” or “signal” is intended to include direct current signal, alternating signal or any signal within the electromagnetic spectrum. The terms “processor”; “microprocessor”; or “microcontroller” are intended to have the same meaning and are intended to be used interchangeably.
Test meter 200 may include a first user interface input 206, a second user interface input 210, and a third user interface input 214. User interface inputs 206, 210, and 214 facilitate entry and analysis of data stored in the testing device, enabling a user to navigate through the user interface displayed on display 204. User interface inputs 206, 210, and 214 include a first marking 208, a second marking 212, and a third marking 216, which help in correlating user interface inputs to characters on display 204.
Test meter 200 can be turned on by inserting a test strip 100 (or its variants 400, 500, or 600) into a strip port connector 220, by pressing and briefly holding first user interface input 206, or by the detection of data traffic across a data port 218. Test meter 200 can be switched off by removing test strip 100 (or its variants 400, 500, or 600), pressing and briefly holding first user interface input 206, navigating to and selecting a meter off option from a main menu screen, or by not pressing any buttons for a predetermined time. Display 104 can optionally include a backlight.
In one embodiment, test meter 200 can be configured to not receive a calibration input for example, from any external source, when switching from a first test strip batch to a second test strip batch. Thus, in one exemplary embodiment, the meter is configured to not receive a calibration input from external sources, such as a user interface (such as inputs 206, 210, 214), an inserted test strip, a separate code key or a code strip, data port 218. Such a calibration input is not necessary when all of the test strip batches have a substantially uniform calibration characteristic. The calibration input can be a set of values ascribed to a particular test strip batch. For example, the calibration input can include a batch slope and a batch intercept value for a particular test strip batch. The calibrations input, such as batch slope and intercept values, may be preset within the meter as will be described below.
Referring to
In embodiments described and illustrated herein, test meter 200 may include an Application Specific Integrated Circuit (ASIC) 304, so as to provide electronic circuitry used in measurements of glucose level in blood that has been applied to a test strip 100 (or its variants 400, 500, or 600) inserted into strip port connector 220. Analog voltages can pass to and from ASIC 304 by way of an analog interface 306. Analog signals from analog interface 306 can be converted to digital signals by an A/D converter 316. Processor 300 further includes a core 308, a ROM 310 (containing computer code), a RAM 312, and a clock 318. In one embodiment, the processor 300 is configured (or programmed) to disable all of the user interface inputs except for a single input upon a display of an analyte value by the display unit such as, for example, during a time period after an analyte measurement. In an alternative embodiment, the processor 300 is configured (or programmed) to ignore any input from all of the user interface inputs except for a single input upon a display of an analyte value by the display unit. Detailed descriptions and illustrations of the meter 200 are shown and described in International Patent Application Publication No. WO2006070200, which is hereby incorporated by reference into this application as if fully set forth herein.
Test strip 100 may include a sample-receiving chamber 92 through which a physiological fluid sample 95 may be drawn through or deposited (
A conductive layer is required for forming electrodes that can be used for the electrochemical measurement of glucose. First conductive layer 50 can be made from a carbon ink that is screen-printed onto substrate 5. In a screen-printing process, carbon ink is loaded onto a screen and then transferred through the screen using a squeegee. The printed carbon ink can be dried using hot air at about 140° C. The carbon ink can include VAGH resin, carbon black, graphite (KS15), and one or more solvents for the resin, carbon and graphite mixture. More particularly, the carbon ink may incorporate a ratio of carbon black:VAGH resin of about 2.90:1 and a ratio of graphite:carbon black of about 2.62:1 in the carbon ink.
For test strip 100, as illustrated in
Variations of the test strip 100 (
In the embodiment of
In alternate version of test strip 100, shown here in
In the embodiment of
In
Referring to
First patterned conductive layer 404 includes three electrodes, a counter electrode 404a (also referred to as a reference electrode), a first working electrode 404b and a second working electrode 404c (see
Second patterned conductive layer 410 includes a first phase-shift measurement electrode 411 and a second phase shift measurement electrode 413. Second patterned conductive layer 410 also includes a first phase-shift probe contact 416 and a second phase-shift probe contact 418.
During use of electrochemical-based analytical test strip 400 to determine an analyte in a bodily fluid sample (e.g., blood glucose concentration in a whole physiological fluid sample), electrodes 404a, 404b and 404c are employed by an associated meter (not shown) to monitor an electrochemical response of the electrochemical-based analytical test strip. The electrochemical response can be, for example, an electrochemical reaction induced current of interest. The magnitude of such a current can then be correlated, taking into consideration the physical characteristic (e.g., hematocrit) of the bodily fluid sample as determined by the bodily fluid sample's phase shift, with the amount of analyte present in the bodily fluid sample under investigation. During such use, a bodily fluid sample is applied to electrochemical-based analytical test strip 400 and, thereby, received in sample chamber 414.
Electrically-insulating substrate layer 402 can be any suitable electrically-insulating substrate known to one skilled in the art including, for example, a nylon substrate, polycarbonate substrate, a polyimide substrate, a polyvinyl chloride substrate, a polyethylene substrate, a polypropylene substrate, a glycolated polyester (PETG) substrate, a polystyrene substrate, a silicon substrate, ceramic substrate, glass substrate or a polyester substrate (e.g., a 7 millimeters thick polyester substrate). The electrically-insulating substrate can have any suitable dimensions including, for example, a width dimension of about 5 mm, a length dimension of about 27 mm and a thickness dimension of about 0.5 mm.
First patterned conductive layer 404 can be formed of any suitable electrically conductive material such as, for example, gold, palladium, carbon, silver, platinum, tin oxide, iridium, indium, or combinations thereof (e.g., indium doped tin oxide). Moreover, any suitable technique or combination of techniques can be employed to form first patterned conductive layer 404 including, for example, sputtering, evaporation, electro-less plating, screen-printing, contact printing, laser ablation or gravure printing. A typical but non-limiting thickness for the patterned conductive layer is in the range of 5 nanometers to 400 nanometers.
As is known, conventional electrochemical-based analyte test strips employ a working electrode along with an associated counter/reference electrode and enzymatic reagent layer to facilitate an electrochemical reaction with an analyte of interest and, thereby, determine the presence and/or concentration of that analyte. For example, an electrochemical-based analyte test strip for the determination of glucose concentration in a fluid sample can employ an enzymatic reagent that includes the enzyme glucose oxidase and the mediator ferricyanide (which is reduced to the mediator ferrocyanide during the electrochemical reaction). Such conventional analyte test strips and enzymatic reagent layers are described in, for example, U.S. Pat. Nos. 5,708,247; 5,951,836; 6,241,862; and 6,284,125; each of which is hereby incorporated by reference herein to this application. In this regard, the reagent layer employed in various embodiments provided herein can include any suitable sample-soluble enzymatic reagents, with the selection of enzymatic reagents being dependent on the analyte to be determined and the bodily fluid sample. For example, if glucose is to be determined in a fluid sample, enzymatic reagent layer 406 can include glucose oxidase or glucose dehydrogenase along with other components necessary for functional operation.
In general, enzymatic reagent layer 406 includes at least an enzyme and a mediator. Examples of suitable mediators include, for example, ruthenium, Hexaammine Ruthenium (III) Chloride, ferricyanide, ferrocene, ferrocene derivatives, osmium bipyridyl complexes, and quinone derivatives. Examples of suitable enzymes include glucose oxidase, glucose dehydrogenase (GDH) using a pyrroloquinoline quinone (PQQ) co-factor, GDH using a nicotinamide adenine dinucleotide (NAD) co-factor, and GDH using a flavin adenine dinucleotide (FAD) co-factor. Enzymatic reagent layer 406 can be applied during manufacturing using any suitable technique including, for example, screen printing.
Applicants note that enzymatic reagent layer 406 may also contain suitable buffers (such as, for example, Tris HCl, Citraconate, Citrate and Phosphate), hydroxyethylcelulose [HEC], carboxymethylcellulose, ethycellulose and alginate, enzyme stabilizers and other additives as are known in the field.
Further details regarding the use of electrodes and enzymatic reagent layers for the determination of the concentrations of analytes in a bodily fluid sample, albeit in the absence of the phase-shift measurement electrodes, analytical test strips and related methods described herein, are in U.S. Pat. No. 6,733,655, which is hereby fully incorporated by reference herein to this application.
Patterned spacer layer 408 can be formed of any suitable material including, for example, a 95 micrometers thick, double-sided pressure sensitive adhesive layer, a heat activated adhesive layer, or a thermo-setting adhesive plastic layer. Patterned spacer layer 408 can have, for example, a thickness in the range of from about 1 micron to about 500 microns, preferably between about 10 microns and about 400 microns, and more preferably between about 40 microns and about 200 microns.
Second patterned conductive layer 410 can be formed of any suitable conductive material including, for example, copper, silver, palladium, gold and conductive carbon materials. Second patterned conductive layer 410 can be, for example, disposed on a lower surface of electrically-insulating top layer 412 (as depicted in
First phase-shift measurement electrode 411 and second phase shift measurement electrode 413 of second patterned conductive layer 410 are separated within sample chamber 414 by a gap (in the horizontal direction of
Electrochemical-based analytical test strip 400 can be manufactured, for example, by the sequential aligned formation of first patterned conductive layer 404, enzymatic reagent layer 406, patterned spacer layer 408, second patterned conductive layer 410 and electrically insulating top layer 412 onto electrically-insulating substrate layer 402. Any suitable techniques known to one skilled in the art can be used to accomplish such sequential aligned formation, including, for example, screen printing, photolithography, photogravure, chemical vapour deposition, sputtering, tape lamination techniques and combinations thereof.
Analytical test strips according to embodiments can be configured, for example, for operable electrical connection (via, for example, first and second phase shift probe contacts 416 and 418) and use with the analytical test strip sample cell interface of a hand-held test meter as described in co-pending patent application Ser. No. 13/250,525, which is hereby incorporated by reference herein to this application with a copy provided in the Appendix.
It has been determined that a relationship exists between the reactance of a whole fluid sample and the physical characteristic (e.g., hematocrit) of that sample. Electrical modeling of a bodily fluid sample (e.g., a whole blood sample) as parallel capacitive and resistive components indicates that when an alternating current (AC) signal is forced through the bodily fluid sample, the phase shift of the alternating signal will be dependent on both the frequency of the alternating signal voltage and the physical characteristic (e.g., hematocrit) of the sample. Therefore, the physical characteristic (e.g., hematocrit) of a bodily fluid sample can be measured by, for example, driving alternating signals of a known frequency (or known frequencies) through the bodily fluid sample and detecting their phase shift. The phase-shift measurement electrodes of analytical test strips of various embodiments described herein are particularly suitable for use in such phase-shift measurements since the first and second phase shift measurement electrodes are in direct contact with a bodily fluid sample present in the sample chamber. Moreover, a bodily fluid sample physical characteristic (e.g., hematocrit) ascertained from a phase shift measurement(s) can be employed to compensate for the effect of physical characteristic (e.g., hematocrit) during analyte determination.
Applicants note that for various embodiments of analytical test strips (e.g., an electrochemical-based analytical test strip) described here for use with a hand-held test meter in the determination of an analyte (such as glucose) in a bodily fluid sample (for example, a whole blood sample) may include an electrically insulating substrate, a first patterned conductor layer disposed on the electrically insulating substrate and having a working electrode and a reference electrode. The analytical test strip may also include an enzymatic reagent layer disposed on the working electrode, a first patterned spacer layer disposed over the first patterned conductor layer and defining both a first sample-receiving channel and an analyte determination sample chamber within the analytical test strip, and a second patterned spacer layer disposed over the first patterned spacer layer and defining at least a second sample-receiving channel. In addition, the analytical test strip further includes a bodily fluid phase-shift sample chamber in fluidic communication with the second sample-receiving channel. Moreover, the first sample-receiving channel and analyte determination sample chamber of the analytical test strip are isolated from the second sample-receiving channel and bodily fluid phase-shift sample chamber of the analytical test strip.
Analytical test strips of various embodiments described herein are believed by applicants to be beneficial in that, for example, the isolation (fluidic and electrical) between the analyte determination sample chamber and the bodily fluid phase-shift sample chamber prevents potential interference between the determination of the analyte in the bodily fluid sample and a phase-shift measurement of the bodily fluid. Applicants note that certain advantages are obtained by having the first sample-receiving channel and analyte determination chamber separated from the second sample-receiving channel and bodily fluid phase-shift sample chamber by portions of the first and/or second patterned spacer layers that can be thinner, thus providing for an analytical test strip with a small, yet mechanically stable, cross-section.
Referring to
First patterned spacer layer 508 is configured such that electrochemical-based analytical test strip 500 also includes a first sample-receiving channel 512 and an analyte determination sample chamber 514. First patterned spacer layer 508 is also configured to define a bodily fluid phase-shift sample chamber 516 and an analyte determination sample chamber vent 518 (for clarity not depicted in
Second patterned spacer layer 510 is configured to define a second sample-receiving channel 520 and a bodily fluid phase-shift chamber vent 522 (for clarity not depicted in
First patterned conductor layer 504 includes a first phase-shift measurement electrode 524, a second phase-shift measurement electrode 526, two working electrodes 528a and 528b and a reference electrode 530. For clarity,
First sample-receiving channel 512 and analyte determination sample chamber 514 are isolated, both fluidically and electrically, from second sample-receiving channel 520 and bodily fluid phase-shift sample chamber 516 (see
During use of electrochemical-based analytical test strip 500 to determine an analyte in a bodily fluid sample (e.g., blood glucose concentration in a whole blood sample), working and reference electrodes are employed by an associated meter (not shown) to monitor an electrochemical response of the electrochemical-based analytical test strip. The electrochemical response can be, for example, an electrochemical reaction induced current of interest. The magnitude of such a signal can then be correlated, taking into consideration the haematocrit of the bodily fluid sample as determined by the bodily fluid sample's phase shift, with the amount of analyte present in the bodily fluid sample under investigation. During such use, a bodily fluid sample is applied to electrochemical-based analytical test strip 500 and, thereby, received in both analyte determination sample chamber 514 and bodily fluid phase-shift sample chamber 516.
Electrically-insulating substrate 502 can be any suitable electrically-insulating substrate known to one skilled in the art including, for example, a nylon substrate, polycarbonate substrate, a polyimide substrate, a polyvinyl chloride substrate, a polyethylene substrate, a polypropylene substrate, a glycolated polyester (PETG) substrate, a polystyrene substrate, a silicon substrate, ceramic substrate, glass substrate or a polyester substrate (e.g., a 7 millimeters thick polyester substrate). The electrically-insulating substrate can have any suitable dimensions including, for example, a width dimension of about 5 mm, a length dimension of about 27 mm and a thickness dimension of about 0.5 mm.
First patterned conductor layer 504 can be formed of any suitable electrically conductive material such as, for example, gold, palladium, carbon, silver, platinum, tin oxide, iridium, indium, or combinations thereof (e.g., indium doped tin oxide). Moreover, any suitable technique or combination of techniques can be employed to form first patterned conductor layer 504 including, for example, sputtering, evaporation, electro-less plating, screen-printing, contact printing, laser ablation or gravure printing. A typical but non-limiting thickness for the patterned conductor layer is in the range of 5 nanometers to 500 nanometers.
Applicants note that conventional electrochemical-based analyte test strips employ a working electrode along with an associated counter/reference electrode and enzymatic reagent layer to facilitate an electrochemical reaction with an analyte of interest and, thereby, determine the presence and/or concentration of that analyte. For example, an electrochemical-based analyte test strip for the determination of glucose concentration in a fluid sample can employ an enzymatic reagent that includes the enzyme glucose oxidase and the mediator ferricyanide (which is reduced to the mediator ferrocyanide during the electrochemical reaction). Such conventional analyte test strips and enzymatic reagent layers are described in, for example, U.S. Pat. Nos. 5,708,247; 5,951,836; 6,241,862; and 6,284,125; each of which is hereby incorporated by reference herein to this application. In this regard, the reagent layer employed in various embodiments provided herein can include any suitable sample-soluble enzymatic reagents, with the selection of enzymatic reagents being dependent on the analyte to be determined and the bodily fluid sample. For example, if glucose is to be determined in a fluid sample, enzymatic reagent layer 506 can include glucose oxidase or glucose dehydrogenase along with other components necessary for functional operation.
In general, enzymatic reagent layer 506 includes at least an enzyme and a mediator. Examples of suitable mediators include, for example, ferricyanide, ferrocene, ferrocene derivatives, osmium bipyridyl complexes, and quinone derivatives. Examples of suitable enzymes include glucose oxidase, glucose dehydrogenase (GDH) using a pyrroloquinoline quinone (PQQ) co-factor, GDH using a nicotinamide adenine dinucleotide (NAD) co-factor, and GDH using a flavin adenine dinucleotide (FAD) co-factor. Enzymatic reagent layer 506 can be applied during manufacturing using any suitable technique including, for example, screen printing.
Applicants note that enzymatic reagent layer 506 may also contain suitable buffers (such as, for example, Tris HCl, Citraconate, Citrate and Phosphate), hydroxyethylcelulose [HEC], carboxymethylcellulose, ethycellulose and alginate, enzyme stabilizers and other additives as are known in the field.
Further details regarding the use of electrodes and enzymatic reagent layers for the determination of the concentrations of analytes in a bodily fluid sample, albeit in the absence of the phase-shift measurement electrodes, bodily-fluid phase-shift sample chambers and second sample receiving channels analytical test strips and related methods described herein, are in U.S. Pat. No. 6,733,655, which is hereby fully incorporated by reference herein to this application.
First and second patterned spacer layers 508 and 510 respectively can be formed of any suitable material including, for example, a 95 micrometers thick, double-sided pressure sensitive adhesive layer, a heat activated adhesive layer, or a thermo-setting adhesive plastic layer. First patterned spacer layer 508 can have, for example, a thickness in the range of from about 1 micron to about 500 microns, preferably between about 10 microns and about 400 microns, and more preferably between about 40 microns and about 600 microns.
Electrochemical-based analytical test strip 500 can be manufactured, for example, by the sequential aligned formation of first patterned conductor layer 504, enzymatic reagent layer 506, first patterned spacer layer 508, and second patterned spacer layer 510 onto electrically-insulating substrate 502. Any suitable techniques known to one skilled in the art can be used to accomplish such sequential aligned formation, including, for example, screen printing, photolithography, photogravure, chemical vapour deposition, sputtering, tape lamination techniques and combinations thereof.
Analytical test strips according to embodiments can be configured, for example, for operable electrical connection and use with the analytical test strip sample cell interface of a hand-held test meter as described in co-pending patent application Ser. No. 13/250,525, which is hereby incorporated by reference herein to this application with a copy provided in the Appendix.
It has been determined that a relationship exists between the reactance of a fluid sample and the physical characteristic (e.g., hematocrit) of that sample. Electrical modeling of a bodily fluid sample (e.g., a whole blood sample) as parallel capacitive and resistive components indicates that when an alternating signal such as, for example, alternating-current (AC) signal is forced through the bodily fluid sample, the phase shift of the alternating signal will be dependent on both the frequency of the alternating signal voltage and the physical characteristic (e.g., hematocrit) of the sample. Therefore, the physical characteristic (e.g., hematocrit) of a bodily fluid sample can be measured by, for example, driving alternating signals of known frequencies through the bodily fluid sample and detecting their phase shift. The phase-shift measurement electrodes of analytical test strips of various embodiments described herein are particularly suitable for use in such phase-shift measurements since the first and second phase shift measurement electrodes are in direct contact with a bodily fluid sample present in the sample chamber. Moreover, a bodily fluid sample physical characteristic (e.g., hematocrit) ascertained from a phase shift measurement(s) can be employed to compensate for the effect of physical characteristic (e.g., hematocrit) during analyte determination.
Referring to
First patterned spacer layer 608 is configured such that electrochemical-based analytical test strip 600 also includes a first sample-receiving channel 612, an analyte determination sample chamber 614 and an analyte determination sample chamber vent 618 (not depicted in
Second patterned spacer layer 610 is configured to define a second sample-receiving channel 620, a bodily fluid phase-shift sample chamber 616 and a bodily fluid phase-shift chamber vent 622 (not depicted in
First patterned conductor layer 604 includes two working electrodes 628a and 628b (depicted in
First sample-receiving channel 612 and analyte determination sample chamber 614 are isolated, both fluidically and electrically, from second sample-receiving channel 620 and bodily fluid phase-shift sample chamber 616 (see
In the various embodiments of the test strip, there are two measurements that are made to a fluid sample deposited on the test strip. One measurement is that of the concentration of the analyte (e.g. glucose) in the fluid sample while the other is that of physical characteristic (e.g., hematocrit) in the same sample. The measurement of the physical characteristic (e.g., hematocrit) is used to modify or correct the glucose measurement so as to remove or reduce the effect of red blood cells on the glucose measurements. Both measurements (glucose and hematocrit) can be performed in sequence, simultaneously or overlapping in duration. For example, the glucose measurement can be performed first then the physical characteristic (e.g., hematocrit); the physical characteristic (e.g., hematocrit) measurement first then the glucose measurement; both measurements at the same time; or a duration of one measurement may overlap a duration of the other measurement. Each measurement is discussed in detail as follow with respect to
Hereafter, a description of how glucose concentration is determined from the known signal transients (e.g., the measured electrical signal response in nanoamperes as a function of time) that are measured when the test voltages of
In
Referring back to
From knowledge of the parameters of the test strip (e.g., batch calibration code offset and batch slope) for the particular test strip 100 and its variations, the analyte (e.g., glucose) concentration can be calculated. Output transient 702 and 704 can be sampled to derive signals IE (by summation of each of the current IWE1 and IWE2 or doubling of one of IWE1 or IWE2) at various time positions during the test sequence. From knowledge of the batch calibration code offset and batch slope for the particular test strip 100 and its variations in
It is noted that “Intercept” and “Slope” are the values obtained by measuring calibration data from a batch of test strips. Typically around 1500 strips are selected at random from the lot or batch. Physiological fluid (e.g., blood) from donors is spiked to various analyte levels, typically six different glucose concentrations. Typically, blood from 12 different donors is spiked to each of the six levels. Eight strips are given blood from identical donors and levels so that a total of 12×6×8=576 tests are conducted for that lot. These are benchmarked against actual analyte level (e.g., blood glucose concentration) by measuring these using a standard laboratory analyzer such as Yellow Springs Instrument (YSI). A graph of measured glucose concentration is plotted against actual glucose concentration (or measured current versus YSI current) and a formula y=mx+c least squares fitted to the graph to give a value for batch slope m and batch intercept c for the remaining strips from the lot or batch. The applicants have also provided methods and systems in which the batch slope is derived during the determination of an analyte concentration. The “batch slope”, or “Slope”, may therefore be defined as the measured or derived gradient of the line of best fit for a graph of measured glucose concentration plotted against actual glucose concentration (or measured current versus YSI current). The “batch intercept”, or “Intercept”, may therefore be defined as the point at which the line of best fit for a graph of measured glucose concentration plotted against actual glucose concentration (or measured current versus YSI current) meets the y axis.
It is worthwhile here to note that the various components, systems and procedures described earlier allow for applicants to provide an analyte measurement system that heretofore was not available in the art. In particular, this system includes a test strip that has a substrate and a plurality of electrodes connected to respective electrode connectors. The system further includes an analyte meter 200 that has a housing, a test strip port connector configured to connect to the respective electrode connectors of the test strip, and a microcontroller 300, shown here in
Referring to
P=tan−1{Z″/Z′} Eq. 3.1
and magnitude M (in ohms and conventionally written as |Z|) from line Z′ and Z″ of the interface 306 can be determined where
M=√{square root over ((Z′)2+(Z″)2)} Eq. 3.2
In this system, the microprocessor is configured to: (a) apply a first signal to the plurality of electrodes so that a batch slope defined by a physical characteristic of a fluid sample is derived and (b) apply a second signal to the plurality of electrodes so that an analyte concentration is determined based on the derived batch slope. For this system, the plurality of electrodes of the test strip or biosensor includes at least two electrodes to measure the physical characteristic and at least two other electrodes to measure the analyte concentration. For example, the at least two electrodes and the at least two other electrodes are disposed in the same chamber provided on the substrate. Alternatively, the at least two electrodes and the at least two other electrodes are disposed in different chambers provided on the substrate. It is noted that for some embodiments, all of the electrodes are disposed on the same plane defined by the substrate. In particular, in some of the embodiments described herein, a reagent is disposed proximate the at least two other electrodes and no reagent is disposed on the at least two electrodes. One feature of note in this system is the ability to provide for an accurate analyte measurement within about 10 seconds of deposition of a fluid sample (which may be a physiological sample) onto the biosensor as part of the test sequence.
As an example of an analyte calculation (e.g., glucose) for strip 100 (
G0=[(IE)−Intercept]/Slope Eq. 3.3
where
From Eq. 3.3; G0=[(1600+1300)−500]/18 and therefore, G0=133.33 nanoamp˜133 mg/dL.
It is noted here that although the examples have been given in relation to a biosensor 100 which has two working electrodes (12 and 14 in
Now that a glucose concentration (G0) can be determined from the signal IE, a description of applicant's technique to determine the physical characteristic (e.g., hematocrit) of the fluid sample is provided in relation to
where
Details of this exemplary technique can be found in Provisional U.S. Patent Application Ser. No. 61/530,795 filed on Sep. 2, 2011, entitled, “Hematocrit Corrected Glucose Measurements for Electrochemical Test Strip Using Time Differential of the Signals”, which is hereby incorporated by reference.
Another technique to determine physical characteristic (e.g., hematocrit) can be by two independent measurements of physical characteristic (e.g., hematocrit). This can be obtained by determining: (a) the impedance of the fluid sample at a first frequency and (b) the phase angle of the fluid sample at a second frequency substantially higher than the first frequency. In this technique, the fluid sample is modeled as a circuit having unknown reactance and unknown resistance. With this model, an impedance (as signified by notation “|Z|”) for measurement (a) can be determined from the applied voltage, the voltage across a known resistor (e.g., the intrinsic strip resistance), and the voltage across the unknown impedance Vz; and similarly, for measurement (b) the phase angle can be measured from a time difference between the input and output signals by those skilled in the art. Details of this technique is shown and described in provisional patent application Ser. No. 61/530,808 filed Sep. 2, 2011, which is incorporated by reference. Other suitable techniques for determining the physical characteristic (e.g., hematocrit, viscosity, temperature or density) of the fluid sample can also be utilized such as, for example, U.S. Pat. No. 4,919,770, U.S. Pat. No. 7,972,861, US Patent Application Publication Nos. 2010/0206749, 2009/0223834, or “Electric Cell—Substrate Impedance Sensing (ECIS) as a Noninvasive Means to Monitor the Kinetics of Cell Spreading to Artificial Surfaces” by Joachim Wegener, Charles R. Keese, and Ivar Giaever and published by Experimental Cell Research 259, 158-166 (2000) doi:10.1006/excr.2000.4919, available online at http://www.idealibrary.com1; “Utilization of AC Impedance Measurements for Electrochemical Glucose Sensing Using Glucose Oxidase to Improve Detection Selectivity” by Takuya Kohma, Hidefumi Hasegawa, Daisuke Oyamatsu, and Susumu Kuwabata and published by Bull. Chem. Soc. Jpn. Vol. 80, No. 1, 158-165 (2007), all of these documents are incorporated by reference.
Another technique to determine the physical characteristic (e.g., hematorcrits, density, or temperature) can be obtained by knowing the phase difference (e.g., phase angle) and magnitude of the impedance of the sample. In one example, the following relationship is provided for the estimate of the physical characteristic or impedance characteristic of the sample (“IC”):
IC=M2*y1+M*y2+y3+P2*y4+P*y5 Eq. 4.2
where:
It is noted here that where the frequency of the input AC signal is high (e.g., greater than 75 kHz) then the parametric terms y1 and y2 relating to the magnitude of impedance M may be ±200% of the exemplary values given herein such that each of the parametric terms may include zero or even a negative value. On the other hand, where the frequency of the AC signal is low (e.g., less than 75 kHz), the parametric terms y4 and y5 relating to the phase angle P may be ±200% of the exemplary values given herein such that each of the parametric terms may include zero or even a negative value. It is noted here that a magnitude of H or HCT, as used herein, is generally equal to the magnitude of IC. In one exemplary implementation, H or HCT is equal to IC as H or HCT is used herein this application.
In another alternative implementation, Equation 4.3 is provided. Equation 4.3 is the exact derivation of the quadratic relationship, without using phase angles as in Equation 4.2.
where:
By virtue of the various components, systems and insights provided herein, at least four techniques of determining an analyte concentration from a fluid sample (which may be a physiological sample) (and variations of such method) are achieved by applicants.
With reference to FIG. 6A1, the method involves depositing a fluid sample (which may be a physiological sample) on a biosensor at step 904A (e.g., in the form of a test strip as show in
The setting of a new batch slope to derive a more accurate analyte concentration measurement merits a discussion with reference to
Based on these observations, applicants have found that a relationship exists between the batch slope of these test strips tested at the Lo-G, Mid-G, and Hi-G levels with respect to 30%, 42%, and 55% hematocrit levels. In particular, applicants have found that the batch slope for these strips is generally curved with respect to hematocrit level, shown here in FIG. 6A2. In FIG. 6A2, the batch slope declines in a generally curved manner at low (e.g., 30%), medium (e.g., 42%), and high (e.g., 55%) hematocrits. As a consequence, by knowing the physical characteristic of the sample (e.g., hematocrit) from Equation 4 above, the relationship in FIG. 6A2 can be exploited to allow the slope in Equation 3.3 to accommodate the different levels of physical characteristic (e.g., hematocrit) so as to achieve much more accurate glucose concentration measurements.
It should be noted that while slope “x” in FIG. 6A2 appears to be a linear line, slope “x” is in fact a curved line and a curve has been fitted for the relationship between physical characteristic (e.g., hematocrit) and slope implicit in FIG. 6A2. This fitted curve for FIG. 6A2 is found by applicants to be a second order equation of the form:
NewSlope=aH2+bH+c Eq. 5
where
Equation 5 can be used instead of plotting against FIG. 6A2, depending on the available computing power of the processor. The viability of this approach can be seen here in FIG. 6A3 which is a plot of a large number of test strips at different glucose ranges and hematocrit levels versus percent bias by use of Equations 5 and 6. In FIG. 6A3, it can be seen that virtually all of the glucose concentration at different glucose ranges (low, medium, and high) across about 30%, 42%, and about 55% hematocrit have a bias of less than +10%.
Continuing on with the exemplary process of FIG. 6A1, once the physical characteristic is known at step 908A from Equation 4, such as for example Hct˜55%, the graph of FIG. 6A2 is utilized to determine the appropriate batch slope, designated here as “NewSlope” which is about 0.019. Alternatively, Equation 5 can be utilized to derive the NewSlope from the measured or estimated physical characteristic (e.g., hematocrit). This NewSlope (from FIG. 6A2 or Eq. 5) is used along with the batch intercept (Intercept) of the particular batch of test strip in Equation 3.3, as set forth below in Equation 6.
where
Once the signal output IE of the test chamber is measured at the designated time, typically at about 2.5 seconds or about 5 seconds, the signal IE is thereafter used with the NewSlope (of the batch) and Intercept (of the batch) in the calculation of the analyte concentration (in this case glucose) with Eq. 6 above. It is noted here that IE could be a current from only one working electrode where the biosensor has only one working electrode, a sum of current outputs from two working electrodes, a current from one working electrode multiplied by two or an average current from the two working electrodes. It should be noted that the step of applying the first signal and the driving of the second signal is in sequential order in that the order may be the first signal then the second signal or both signals overlapping in sequence; alternatively, the second signal first then the first signal or both signals overlapping in sequence. Alternatively, the applying of the first signal and the driving of the second signal may take place simultaneously.
In the method, the step of applying of the first signal involves directing an alternating signal provided by an appropriate power source (e.g., the meter 200) to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal. The physical characteristic being detected may be one or more of viscosity, hematocrit, temperature or density. The directing step may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency. Preferably, the first frequency is at least one order of magnitude lower than the second frequency. As an example, the first frequency may be any frequency in the range of about 10 kHz to about 100 kHz and the second frequency may be from about 250 kHz to about 1 MHz or more. As used herein, the phrase “alternating signal” can have some portions of the signal alternating in polarity or all alternating current signal or an alternating current with a direct current offset or even a multi-directional signal combined with a direct-current signal.
Although the method may specify only one sampling time point, the method may include sampling as many time points as required, such as, for example, sampling the signal output continuously (e.g., at specified sampling time such as, every 10 milliseconds to 100 milliseconds) from the start of the test sequence until at least about 10 seconds after the start and the results stored for processing near the end of the test sequence. Applicants note that the appropriate sampling time is measured from the start of the test sequence but any appropriate datum may be utilized in order to determine when to sample the output signal. As a practical matter, the system can be programmed to sample the output signal at an appropriate time sampling interval during the entire test sequence such as for example, one sampling every 100 milliseconds or even as little as about 1 milliseconds. In this variation, the sampled signal output at the specified sampling time is the value used to calculate the analyte concentration.
It is noted that in the preferred embodiments, the measure of a signal output for the glucose concentration is performed prior to the measurement or estimation of the hematocrit. Alternatively, the hematocrit level can be measured or estimated prior to the measurement of the glucose concentration.
Thus, as another benefit of the teaching provided herein, a method of demonstrating increased accuracy of a test strip than heretofore is achieved. This method involves providing a batch of test strips, typically in a batch of at least about 1500 test strips (and in some cases up to 1 million test strips per batch), introducing a referential sample containing a referential concentration of an analyte to each of the batch of test strips to initiate a test sequence (a “referential sample” contains a “referential” or “known” concentration of an analyte, e.g. glucose). The method involves, reacting the analyte with a reagent on the test strip to cause a physical transformation of the analyte proximate the two electrodes, determining a physical characteristic of the referential sample, deriving a biosensor parameter (e.g., a batch slope) for the batch of test strips based on the determined physical characteristics of the referential sample; sampling an electrical output of the referential sample at a predetermined time point during the test sequence, and calculating an analyte concentration based on the derived biosensor parameter and sampled electrical output to provide for a final analyte concentration value for each of the batch of test strips such that at least 95% of the analyte concentration values of the batch of test strips are within about +15% of the referential analyte concentration for the range of hematocrit from about 30% to about 55%, shown here in FIG. 6A3 (an example of a “physical transformation”, specifically an “enzymatic reaction”, of an analyte to form a different material is the oxidation of glucose to D-glucono-δ-lactone and hydrogen peroxide by glucose oxidase (e.g. where the analyte is glucose and the reagent comprises glucose oxidase)).
In FIG. 6A3, experiments were performed to quantify the improvement in the glucose measurements from the method noted above. The quantification of the improvement can be shown by the “bias” at different levels of hematocrit. The bias, which is an estimate of the relative error in the glucose measurement, was calculated for each glucose concentrations determined with the method described in this example. The bias for each glucose concentration was determined with equations of the form:
where
As can be seen in FIG. 6A3, most or virtually all of the glucose concentration using this technique are within about ±15% bias for hematocrit from about 30% hematocrit to about 55% hematocrit. Specifically, at region 1010A, only one glucose concentration greater than 100 mg/dL is outside the bias of −15%; at region 1012A of intermediate hematocrit, a few glucose concentrations are outside the bias range of −15% and at region 1014A of high hematocrit, more glucose concentrations are dispersed outside the bias of −15% as compared to regions 1010A and 1012A.
With reference to FIG. 6B1, another technique involves depositing a fluid sample (which may be a physiological sample) on a biosensor at step 904B (e.g., in the form of a test strip as show in
In a variation of the method, the step of applying of the first signal involves directing an alternating signal provided by an appropriate power source (e.g., the meter 200) to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal. The physical characteristic being detected may be one or more of viscosity, hematocrit or density of the sample (which may not be physiological fluid such as, for example, calibration fluid). The directing step may include driving first and second alternating signals at different respective frequencies in which a first frequency is lower than the second frequency. Preferably, the first frequency is at least one order of magnitude lower than the second frequency. As an example, the first frequency may be any frequency in the range of about 10 kHz to about 100 kHz and the second frequency may be from about 250 kHz to about 1 MHz or more. As used herein, the phrase “alternating signal” can have some portions of the signal alternating in polarity or all alternating current signal or an alternating current with a direct current offset or even a multi-directional signal combined with a direct-current signal.
Once the physical characteristic of the sample is determined or obtained from a suitable technique, the physical characteristic can be used to specify a sampling time point at which point during the test sequence the output signal of the test chamber could be measured. In particular, applicants have found a relationship between the physical characteristic and the sampling time point, as shown here in
Referring back to
From data in
SamplingTime=x1Hx
where,
Although the method may specify only one sampling time point, the method may include sampling as many time points as required, such as, for example, sampling the signal output continuously (e.g., at specified sampling time such as, every 10 milliseconds to 100 milliseconds) from the start of the test sequence until at least about 10 seconds after the start and the results stored for processing near the end of the test sequence. Applicants note that the appropriate sampling time is measured from the start of the test sequence but any appropriate datum may be utilized in order to determine when to sample the output signal. As a practical matter, the system can be programmed to sample the output signal at an appropriate time sampling interval during the entire test sequence such as for example, one sampling every 100 milliseconds or even as little as about 1 milliseconds. In this variation, the sampled signal output at the specified sampling time is the value used to calculate the analyte concentration.
Referring back to FIG. 6B1, the method can now determine the analyte concentration (step 914B) based on the measured signal (step 912B) sampled at the specified time point, which specified time point is a function of the obtained or measured or estimated physical characteristic of the sample (e.g., from plot of FIG. 6B2 or Equation 7). That is, once the sampling time T has been specified from Equation 7, the method provides for measuring the output signal from the test chamber (e.g., chamber 92) so that the sampled output can be utilized with Equation 3.3 to provide for an analyte (e.g., glucose) concentration.
Alternatively, a look-up table, represented exemplarily here with reference to Table 1 can also be utilized in place of Equation 7 or in addition to Equation 7 to specify an appropriate sampling time point. In Table 1, the value of the physical characteristic is used by the processor of the system to look up the appropriate time at which the signal output of the biosensor is sampled or measured to determine the analyte concentration. For example, once the physical characteristic has been determined, in this case about 33% hematocrit, the time at which the signal output of the biosensor 100 is utilized in determining the analyte concentration can be gleaned from Table 1, which shows that the time at which the system must sample the signal output is at approximately 5.32 seconds after the start of the test sequence.
It should be noted that the step of applying the first signal and the driving of the second signal is in sequential order in that the order may be the first signal then the second signal or both signals overlapping in sequence; alternatively, the second signal first then the first signal or both signals overlapping in sequence. Alternatively, the applying of the first signal and the driving of the second signal may take place simultaneously.
It is noted that in the preferred embodiments, the measurement of a signal output for the glucose concentration is performed prior to the estimation of the physical characteristic (e.g., hematocrit). Alternatively, the physical characteristic (e.g., hematocrit) level can be estimated, measured, or obtained prior to the measurement of the glucose concentration.
Thus, as another benefit of the teaching provided herein, a method of demonstrating increased accuracy of a test strip than heretofore is achieved. This method involves providing a batch of test strips, typically in a batch of at least about 1500 test strips (and in some cases up to 1 million test strips per batch), introducing a referential sample containing a referential concentration of an analyte to each of the batch of test strips to initiate a test sequence. The method involves reacting the analyte to cause a physical transformation of the analyte with the reagent between the two electrodes, determining a physical characteristic of the referential sample, estimating the analyte concentration, sampling an electrical output of the referential sample at a specified time point during the test sequence defined by the measured or estimated physical characteristic of the sample and the estimated analyte concentration, and calculating an analyte concentration based on the specified sampling time such that at least 95% of the analyte concentration values of the batch of test strips are within about 25% of the referential analyte concentration for the range of hematocrit from about 30% to about 55%, shown here in FIG. 6B3.
As can be seen in FIG. 6B3, most or virtually all of the glucose concentration using this technique are within about ±25% bias for hematocrit from about 30% hematocrit to about 55% hematocrit. Specifically, at region 1010B, only one glucose concentration greater than 100 mg/dL is outside the bias of −15%; at region 1012B of intermediate hematocrit, a few glucose concentrations are outside the bias range of about −25% and at region 1014B of high hematocrit, more glucose concentrations are dispersed outside the bias of about −25% as compared to regions 1010B and 1012B.
Yet another technique can be understood with reference to FIG. 6C1. This technique involves depositing a fluid sample (which may be a physiological sample) on a biosensor at step 904C (e.g., in the form of a test strip as show in
In a variation of the method, the step of applying of the first signal involves directing an alternating signal provided by an appropriate power source (e.g., the meter 200) to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal. The physical characteristic being detected may be one or more of viscosity, hematocrit or density. The directing step may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency. Preferably, the first frequency is at least one order of magnitude lower than the second frequency. As an example, the first frequency may be any frequency in the range of about 10 kHz to about 100 kHz and the second frequency may be from about 250 kHz to about 1 MHz or more. As used herein, the phrase “alternating signal” can have some portions of the signal alternating in polarity or all alternating current signal or an alternating current with a direct current offset or even a multi-directional signal combined with a direct-current signal.
Once the physical characteristic of the sample is determined or obtained from a suitable technique, the physical characteristic can be used to specify a sampling time point (step 909) at which point during the test sequence the output signal of the test chamber could be measured. In particular, applicants have found a relationship between the physical characteristic and the sampling time point, as shown here in
Referring back to
Although the method may specify only one sampling time point, the method may include sampling as many time points as required, such as, for example, sampling the signal output continuously (e.g., at specified sampling time such as, every one millisecond to 100 milliseconds) from the start of the test sequence until at least about 10 seconds after the start and the results stored for processing near the end of the test sequence. Applicants note that the appropriate sampling time is measured from the start of the test sequence but any appropriate datum may be utilized in order to determine when to sample the output signal. As a practical matter, the system can be programmed to sample the output signal at an appropriate time sampling interval during the entire test sequence such as for example, one sampling every 100 milliseconds or even as little as about 1 milliseconds. In this variation, the sampled signal output at the specified sampling time T is the value used to calculate the analyte concentration.
Alternatively, a look-up table, represented exemplarily here with reference to Table 1 can also be utilized in place of Equation 7 or in addition to Equation 7 to determine the appropriate sampling time point T. In Table 1, the value of the physical characteristic is used by the processor of the system to look up the appropriate time at which the signal output of the biosensor is sampled or measured to determine the analyte concentration. For example, once the physical characteristic has been determined, in this case about 33% hematocrit, the time at which the signal output of the biosensor 100 is utilized in determining the analyte concentration can be gleaned from Table 1, which shows that the time at which the system must sample the signal output is at approximately 5.32 seconds after the start of the test sequence.
To further improve the accuracy of the results, the method may entail evaluating an output signal from the at least two electrodes at a point in time after the start of the test sequence, in which a new batch slope is derived (at step 910C) as a function of at least the measured or estimated physical characteristic (step 908C).
The setting of a new batch slope (step 910C) to derive a more accurate analyte concentration measurement merits a discussion with reference to
It should be noted that while slope “x” in FIG. 6C3 appears to be a linear line, slope “x” is in fact a curved line and a curve has been fitted for the relationship between physical characteristic (e.g., hematocrit) and slope implicit in FIG. 6C3. This fitted curve for FIG. 6C3 was found by applicants and defined in Equation 5 previously. It is noted that due to an adjustment at which the sampling time was taken for the embodiment described herein, Equation 5 is preferably used with the following coefficients: a is about −1.98e−6; b is about −2.87e−5; and c is about 2.67e−2 and ±10% for each of the magnitudes provided. The adjustment stems from the fact that the new coefficients (a, b, and c) are calculated at different sampling time, whereas before, the sampling time was fixed at about 5 seconds. This will cause coefficients a, b and c to be different in order to maximise accuracy. If one skilled in the art were to use the same coefficients a, b and c as before, such skilled person can still obtain the analyte concentration but the resulting estimates will deteriorate. The driver here is that slope of glucose relation to haematocrit is changing within the signal transient, so different slopes are needed as the sampling time is varied between about 3.5 seconds to about 6 seconds.
It is noted that Equation 5 can be used instead of plotting against FIG. 6C3, depending on the available computing power of the processor. Continuing on with the exemplary process of FIG. 6C1, once the physical characteristic is known at step 908C from Equation 4, such as for example Hct˜55%, the graph of FIG. 6C3 or Equation 5 is utilized to determine the appropriate batch slope, designated here as “NewSlope” which is about 0.019. Alternatively, Equation 5 can be utilized to derive the NewSlope from the measured or estimated physical characteristic (e.g., hematocrit). This NewSlope (from FIG. 6C3 or Eq. 5) is used along with the batch intercept (Intercept) with the sampling time relationship that applicants have found, as set forth previously with respect to Eq. 5.
Referring back to FIG. 6C1, the method can now determine the analyte concentration (step 914C) based on a new batch slope (i.e., NewSlope) derived from the measured or estimated physical characteristic of the sample (at step 910C) along with the measured signal (step 912C) sampled at the specified time point (at step 909), which specified time point is a function of the obtained or measured or estimated physical characteristic of the sample (e.g., from plot of FIG. 6C2 or Equation 5). That is, once the sampling time has been specified from Equation 5 and the NewSlope from Equation 6, the method provides for measuring the output signal from the test chamber (e.g., chamber 92) so that the sampled output can be utilized with Equation 3.3 to provide for an analyte (e.g., glucose) concentration.
In one embodiment the analyte (e.g., glucose) concentration is determined based on a modified form of Equation 3.3, delineated here as Equation 8:
where
Once the signal output IE of the test chamber is measured at the specified time (step 909) at any point between about 3 seconds to about 8 seconds, the signal IE is thereafter used with the NewSlope (of the batch) and Intercept (of the batch) in the calculation of the analyte concentration (in this case glucose) with Eq. 8 above. Intercept comprises a manufacturing parameter for a batch of biosensors, and in the embodiments described herein, Intercept typically varies from about 0.7 to about 0.6. It should be noted that the step of applying the first signal and the driving of the second signal is in sequential order in that the order may be the first signal then the second signal or both signals overlapping in sequence; alternatively, the second signal first then the first signal or both signals overlapping in sequence. Alternatively, the applying of the first signal and the driving of the second signal may take place simultaneously.
It is noted that in the preferred embodiments, the measurement of a signal output for the analyte (e.g., glucose) concentration is performed prior to the estimation of the physical characteristic (e.g., hematocrit). Alternatively, the physical characteristic (e.g., hematocrit) level can be estimated, measured, or obtained prior to the measurement of the analyte (e.g., glucose) concentration.
Thus, as another benefit of the teaching provided herein, a method of demonstrating increased accuracy of a test strip is heretofore is achieved. This method involves providing for a batch of test strips, typically in a batch of at least about 1500 test strips (and in some cases up to 1 million test strips per batch), introducing a referential sample containing a referential concentration of an analyte to each of the batch of test strips to initiate a test sequence. The method involves reacting the analyte to cause a physical transformation of the analyte with the reagent between the two electrodes, determining a physical characteristic of the referential sample, deriving a batch slope for the test strip, sampling an electrical output of the referential sample at a specified time point during the test sequence defined by the measured or estimated physical characteristic of the sample, and calculating an analyte concentration based on the dictated time and the derive batch slope such that at least 95% of the analyte concentration values of the batch of test strips are within about ±15% of the referential analyte concentration for the range of hematocrit from about 30% to about 55%, shown here in FIG. 6C4.
As can be seen in FIG. 6C4, most or virtually all of the glucose concentration using this technique are within about ±15% bias for hematocrit from about 30% hematocrit to about 55% hematocrit. Specifically, at region 1010C, none of the glucose concentration greater than 100 mg/dL is outside the bias of −15%; at region 1012C of intermediate hematocrit, a few glucose concentrations are outside the bias range of 15% and at region 1014C of high hematocrit, a few more glucose concentrations are dispersed outside the bias of 15% as compared to regions 1010C and 1012C.
Yet a further technique can be understood with reference to FIG. 6D1. This technique involves depositing a fluid sample (which may be a physiological sample) on a biosensor at step 904 (e.g., in the form of a test strip as show in
The determination of the appropriate point in time as a function of the measured or estimated physical characteristic(s) in step 912 can be determined by the use of a look-up table programmed into the microprocessor of the system. For example, a look-up table may be provided that allows for the system to select the appropriate sampling time for the analyte (e.g., glucose or ketone) with measured or known physical characteristic (e.g., hematocrit or viscosity) of the sample.
In particular, an appropriate sampling time point may be based on an early estimation of the analyte and the measured or known physical characteristic to arrive at the appropriate sampling time that gives the lowest error or bias as compared to referential values. In this technique, a look up table is provided in which the defined sampling time point is correlated to (a) the estimated analyte concentration and (b) the physical characteristic of the sample. For example, Table 2 may be programmed into the meter to provide a matrix in which qualitative categories (low, medium, and high glucose) of the estimated analyte form the main column and the qualitative categories (low, medium, and high) of the measured or estimated physical characteristic form the header row. In the second column, t/Hct is a value determined experimentally of the time shift per % hematocrit difference from nominal hematocrit of 42%. As one example, for 55% hematocrit at “Mid-Glucose” would indicate a time shift of (42−55)*90=−1170 ms. The time of −1170 milliseconds is added to the original test time of about 5000 milliseconds giving (5000−1170=3830 milliseconds)˜3.9 seconds.
The time T at which the system should be sampling the output signal of the biosensor is based on both the qualitative category of the estimated analyte and measured or estimated physical characteristic and is predetermined based on regression analysis of a large sample size of actual physiological fluid samples. Applicants note that the appropriate sampling time is measured from the start of the test sequence but any appropriate datum may be utilized in order to determine when to sample the output signal. As a practical matter, the system can be programmed to sample the output signal at an appropriate time sampling interval during the entire test sequence such as for example, one sampling every 100 milliseconds or even as little as about 1 milliseconds. By sampling the entire signal output transient during the test sequence, the system can perform all of the needed calculations near the end of the test sequence rather than attempting to synchronize the sampling time with the set time point, which may introduce timing errors due to system delay.
Applicants hereafter will discuss the look-up Table 2 in relation to the particular analyte of glucose in physiological fluid samples. Qualitative categories of blood glucose are defined in the first column of Table 2 in which low blood glucose concentrations of less than about 70 mg/dL are designated as “Lo-Glucose”; blood glucose concentrations of higher than about 70 mg/dL but less than about 250 mg/dL are designated as “Mid-Glucose”; and blood glucose concentrations of higher than about 250 mg/dL are designated as “Hi-Glucose”.
During a test sequence, an “Estimated Analyte” can be obtained by sampling the signal at a convenient time point, typically at five seconds during a typical 10 seconds test sequence. The measurement sampled at this five second time point allows for an accurate estimate of the analyte (in this case blood glucose). The system may then refer to a look-up table (e.g., Table 2) to determine when to measure the signal output from the test chamber at a specified sampling time T based on two criteria: (a) estimated analyte and (b) qualitative value of the physical characteristic of the sample. For criteria (b), the qualitative value of the physical characteristic is broken down into three sub-categories of Low Hct, Mid Hct and High Hct. Thus, in the event that the measured or estimated physical characteristic (e.g., hematocrit) is high (e.g., greater than 46%) and the estimated glucose is also high, then according to Table 2, the test time for the system to measure the signal output of test chamber would be about 3.6 seconds. On the other hand, if the measured hematocrit is low (e.g., less than 38%) and the estimated glucose is low then according to Table 2, the test time T for the system to measure the signal output of test chamber would be about 5.5 seconds.
Once the signal output IT of the test chamber is measured at the designated time (which is governed by the measured or estimated physical characteristic), the signal IT is thereafter used in the calculation of the analyte concentration (in this case glucose) with Equation 9 below.
where
G0 represents an analyte concentration;
IT represents a signal (proportional to analyte concentration) determined from the sum of the end signals measured at a specified sampling time T, which may be the total current measured at the specified sampling time T;
Slope represents the value obtained from calibration testing of a batch of test strips of which this particular strip comes from and is typically about 0.02; and
Intercept represents the value obtained from calibration testing of a batch of test strips of which this particular strip comes from and is typically from about 0.6 to about 0.7.
It should be noted that the step of applying the first signal and the driving of the second signal is sequential in that the order may be the first signal then the second signal or both signals overlapping in sequence; alternatively, the second signal first then the first signal or both signals overlapping in sequence. Alternatively, the applying of the first signal and the driving of the second signal may take place simultaneously.
In the method, the step of applying of the first signal involves directing an alternating signal provided by an appropriate power source (e.g., the meter 200) to the sample so that a physical characteristic of the sample is determined from an output of the alternating signal. The physical characteristic being detected may be one or more of viscosity, hematocrit or density. The directing step may include driving first and second alternating signal at different respective frequencies in which a first frequency is lower than the second frequency. Preferably, the first frequency is at least one order of magnitude lower than the second frequency. As an example, the first frequency may be any frequency in the range of about 10 kHz to about 100 kHz and the second frequency may be from about 250 kHz to about 1 MHz or more. As used herein, the phrase “alternating signal” or “oscillating signal” can have some portions of the signal alternating in polarity or all alternating current signal or an alternating current with a direct current offset or even a multi-directional signal combined with a direct-current signal.
Further refinements of Table 2 based on additional investigations of the technique allowed applicants to devise Table 3, shown below.
As in Table 2, a measured or estimated physical characteristic is used in Table 3 along with an estimated analyte concentration to derive a time S at which the sample is to be measured. For example, if the measured characteristic is about 30% and the estimated glucose (e.g., by sampling at about 2.5 to 3 seconds) is about 350, the time at which the microcontroller should sample the fluid is about 7 seconds. In another example, where the estimated glucose is about 300 mg/dL and the measured or estimated physical characteristic is 60%, specified sampling time would be about 3.1 seconds.
For the embodiments utilized with Table 3, the estimated glucose concentration is provided with an equation:
where
From the estimated glucose, the glucose concentration can be determined from:
where:
Although the method may specify only one sampling time point, the method may include sampling as many time points as required, such as, for example, sampling the signal output continuously (e.g., at specified sampling time such as, every 1 milliseconds to 100 milliseconds) from the start of the test sequence until at least about 10 seconds after the start and the results stored for processing near the end of the test sequence. In this variation, the sampled signal output at the specified sampling time (which may be different from the predetermined sampling time point) is the value used to calculate the analyte concentration.
It is noted that in the preferred embodiments, the measurement of a signal output for the value that is somewhat proportional to analyte (e.g., glucose) concentration is performed prior to the estimation of the hematocrit. Alternatively, the hematocrit level can be estimated prior to the measurement of the preliminary glucose concentration. In either case, the estimated glucose measurement GE is obtained by Equation 3.3 with IE sampled at about one of 2.5 seconds or 5 seconds, as in FIG. 6D2, the physical characteristic (e.g., Hct) is obtained by Equation 4 and the glucose measurement G is obtained by using the measured signal output ID at the designated sampling time point(s) (e.g., the measured signal output ID being sampled at 3.5 seconds or 6.5 seconds) for the signal transient 1000.
Thus, as another benefit of the teaching provided herein, a method of demonstrating increased accuracy of a test strip is heretofore is achieved. This method involves providing for a batch of test strips, typically in a batch of at least about 1500 test strips (and up to a million or more test strips in certain cases), introducing a referential sample containing a referential concentration of an analyte to each of the batch of test strips to initiate a test sequence. The method involves, reacting the analyte to cause a physical transformation of the analyte with the reagent between the two electrodes, determining a physical characteristic of the referential sample, estimating the analyte concentration, sampling an electrical output of the referential sample at a dictated time point during the test sequence defined by the measured or estimated physical characteristic of the sample and the estimated analyte concentration, and calculating an analyte concentration based on the dictated time such that at least 95% of the analyte concentration values of the batch of test strips are within ±10% of the referential analyte concentration for the range of hematocrit from about 30% to about 55%, shown here in FIG. 6D3.
In FIG. 6D3, experiments were performed to quantify the improvement in the glucose measurements from the method noted above. The quantification of the improvement can be shown by the “bias” at different levels of hematocrit. The bias, which is an estimate of the relative error in the glucose measurement, was calculated for each glucose concentration determined with the method described in this example.
As can be seen in FIG. 6D3, most or virtually all of the glucose concentration using this technique are within about ±10% bias for hematocrit from about 30% hematocrit to about 55% hematocrit. This is believed to be a breakthrough as the prior technique of sampling the output signal transient at a fixed time point (typically at about one of 2.5 seconds or 5 seconds from the start of test sequence) for this specific type of test strip generally fails to show any bias of less than ±20%.
By virtue of the descriptions and teachings provided herein, we were able to devise a glucose test strip that has a substrate, a plurality of electrodes disposed on the substrate and connected to respective electrode connectors. The test strip 100 includes at least a reagent disposed on at least one of the plurality of electrodes, in which at least one of the electrodes is configured to sense a physical characteristic of fluid sample deposited on the at least one electrode and at least another of the electrodes is configured to measure output signal from the sample upon application of input signal to the sample. Included with the test strip are instructions for use with a glucose meter. The instructions include indicia embedded in an appropriate communication medium (e.g., paper, computer, internet, audio or visual medium or the like) to a user to insert the electrode connectors of the test strip to a test strip port of the glucose meter. The meter indicated for use with the glucose test strip includes a test strip port connector configured to connect to respective electrode connectors of a test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from a plurality of electrodes of the test strip connected to the respective electrode connectors of the test strip during a test sequence. The instructions further include indicia embedded in an appropriate communication medium (e.g., paper, computer, internet, audio or visual medium or the like) to the user to deposit a fluid sample proximate at least one of the plurality of electrodes so that the microprocessor 300 is operable to: (a) apply a first signal to the plurality of electrodes so that a physical characteristic of a fluid sample deposited on the plurality of electrodes is determined; (b) estimate an analyte concentration based on a predetermined sampling time point during a test sequence; and (c) apply a second signal to the plurality of electrodes at a sampling time point during the test sequence dictated by the determined physical characteristic so that an analyte concentration is calculated from the second signal.
Similarly, we were able to devise a glucose test strip 100 that has a substrate, a plurality of electrodes disposed on the substrate and connected to respective electrode connectors. The test strip includes at least a reagent disposed on at least one of the plurality of electrodes, in which at least one of the electrodes is configured to sense a physical characteristic of fluid sample deposited on the at least one electrode and at least another of the electrodes is configured to measure output signal from the sample upon application of input signal to the sample. Included with the test strip are instructions for use with a glucose meter. The instructions includes indicia embedded in an appropriate communication medium (e.g., paper, computer, internet, audio or visual means and the like) to a user to insert the electrode connectors of the test strip to a test strip port of the glucose meter. The meter indicated for use with the glucose test strip includes a test strip port connector configured to connect to respective electrode connectors of a test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from a plurality of electrodes of the test strip connected to the respective electrode connectors of the test strip during a test sequence. The instructions further include indicia to the user to deposit a fluid sample proximate at least one of the plurality of electrodes so that the microprocessor is operable to: (a) apply a first signal to the plurality of electrodes so that a specific sampling time determined from a physical characteristic of a fluid sample is derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time so that an analyte concentration is determined.
Likewise, we were able to devise a glucose test strip that has a substrate, a plurality of electrodes disposed on the substrate and connected to respective electrode connectors. The test strip includes at least a reagent disposed on at least one of the plurality of electrodes, in which at least one of the electrodes is configured to sense a physical characteristic of fluid sample deposited on the at least one electrode and at least another of the electrodes is configured to measure output signal from the sample upon application of input signal to the sample. Included with the test strip are instructions for use with a glucose meter. The instructions includes indicia embedded in an appropriate communication medium (e.g., paper, computer, internet, audio or visual means and the like) to a user to insert the electrode connectors of the test strip to a test strip port of the glucose meter. The meter indicated for use with the glucose test strip includes a test strip port connector configured to connect to respective electrode connectors of a test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from a plurality of electrodes of the test strip connected to the respective electrode connectors of the test strip during a test sequence. The instructions further include indicia to the user to deposit a fluid sample proximate at least one of the plurality of electrodes so that the microprocessor is operable to: (a) apply a first signal to the plurality of electrodes so that a specified sampling time and a batch slope determined from a physical characteristic of a fluid sample are derived, (b) apply a second signal to the plurality of electrodes, and (c) measure a signal output from one of the plurality of electrodes at the specified sampling time so that an analyte concentration is determined based on the measured signal at the specified sampling time and the batch slope.
Similarly, applicant was able to devise a glucose test strip that has a substrate, a plurality of electrodes disposed on the substrate and connected to respective electrode connectors. The test strip includes at least a reagent disposed on at least one of the plurality of electrodes, in which at least one of the electrodes is configured to sense a physical characteristic of fluid sample deposited on the at least one electrode and at least another of the electrodes is configured to measure output signal from the sample upon application of input signal to the sample. Included with the test strip are instructions for use with a glucose meter. The instructions include indicia embedded in an appropriate communication medium (e.g., paper, computer, internet, audio or visual means and the like) to a user to insert the electrode connectors of the test strip to a test strip port of the glucose meter. The meter indicated for use with the glucose test strip includes a test strip port connector configured to connect to respective electrode connectors of a test strip, and a microprocessor in electrical communication with the test strip port connector to apply electrical signals or sense electrical signals from a plurality of electrodes of the test strip connected to the respective electrode connectors of the test strip during a test sequence. The instructions further include indicia to the user to deposit a fluid sample proximate at least one of the plurality of electrodes so that the microprocessor is operable to: (a) apply a first signal to the plurality of electrodes so that a batch slope defined by a physical characteristic of a fluid sample is derived, and (b) apply a second signal to the plurality of electrodes so that an analyte concentration is determined based on the derived batch slope.
Although the techniques described herein have been directed to determination of glucose, the techniques can also applied to other analytes (with appropriate modifications by those skilled in the art) that are affected by physical characteristic(s) of the fluid sample in which the analyte(s) is disposed in the fluid sample. For example, the physical characteristic (e.g., hematocrit, viscosity or density and the like) of a physiological fluid sample could be accounted for in determination of ketone or cholesterol in the fluid sample, which may be physiological fluid, calibration, or control fluid. Other biosensor configurations can also be utilized. For example, the biosensors shown and described in the following US Patents can be utilized with the various embodiments described herein: U.S. Pat. Nos. 6,179,979; 6,193,873; 6,284,125; 6,413,410; 6,475,372; 6,716,577; 6,749,887; 6,863,801; 6,890,421; 7,045,046; 7,291,256; 7,498,132, all of which are incorporated by reference in their entireties herein.
As is known, the detection of the physical characteristic does not have to be done by alternating signals but can be done with other techniques. For example, a suitable sensor can be utilized (e.g., US Patent Application Publication No. 20100005865 or EP1804048 B1) to determine the viscosity or other physical characteristics. Alternatively, the viscosity can be determined and used to derive for hematocrits based on the known relationship between hematocrits and viscosity as described in “Blood Rheology and Hemodynamics” by Oguz K. Baskurt, M.D., Ph.D., 1 and Herbert J. Meiselman, Sc. D., Seminars in Thrombosis and Hemostasis, volume 29, number 5, 2003.
As described earlier, the microcontroller or an equivalent microprocessor (and associated components that allow the microcontroller to function for its intended purpose in the intended environment such as, for example, the processor 300 in
A short discussion of the embodiments of the meter for the present disclosure is worthwhile at this point. In particular, hand-held test meters for use with an analytical test strip in the determination of an analyte (such as glucose) in a bodily fluid sample (i.e., a whole blood sample) according to embodiments of the present disclosure include a housing, a microcontroller block disposed in the housing, and a phase-shift-based hematocrit measurement block (also referred to as a phase-shift-based hematocrit circuit). In such hand-held test meters, the phase-shift-based hematocrit measurement block includes a signal generation sub-block, a low pass filter sub-block, an analytical test strip sample cell interface sub-block, a transimpedance amplifier sub-block, and a phase detector sub-block. In addition, the phase-shift-based hematocrit measurement block and microcontroller block are configured to measure the phase shift of a bodily fluid sample in a sample cell of an analytical test strip inserted in the hand-held test meter and the microcontroller block is also configured to compute the hematocrit of the bodily fluid sample based on the measured phase shift.
Hand-held test meters according to embodiments of the present disclosure are beneficial in that they provide improved accuracy of analyte determination (such as glucose determination) in whole blood samples by measuring the hematocrit of the whole blood sample and then employing the measured hematocrit during analyte determination.
Once one skilled in the art is apprised of the present disclosure, he or she will recognize that an example of a hand-held test meter that can be readily modified as a hand-held test meter according to the present disclosure is the commercially available OneTouch® Ultra® 2 glucose meter from LifeScan Inc. (Milpitas, Calif.). Additional examples of hand-held test meters that can also be modified are found in U.S. Patent Application Publications Nos. 2007/0084734 (published on Apr. 19, 2007) and 2007/0087397 (published on Apr. 19, 2007) and in International Publication Number WO2010/049669 (published on May 6, 2010), each of which is hereby incorporated herein in full by reference.
Referring to
Display 102 can be, for example, a liquid crystal display or a bi-stable display configured to show a screen image. An example of a screen image may include a glucose concentration, a date and time, an error message, and a user interface for instructing an end user how to perform a test.
Strip port connector 106 is configured to operatively interface with an analytical test strip TS, such as an electrochemical-based analytical test strip configured for the determination of glucose in a whole blood sample. Therefore, the analytical test strip is configured for operative insertion into strip port connector 106 and to operatively interface with phase-shift-based hematocrit measurement block 114 via, for example, suitable electrical contacts.
USB Interface 108 can be any suitable interface known to one skilled in the art. USB Interface 108 is essentially a passive component that is configured to power and provide a data line to hand-held test meter 100.
Once an analytical test strip is interfaced with hand-held test meter 100, or prior thereto, a bodily fluid sample (e.g., a whole blood sample) is introduced into a sample chamber of the analytical test strip. The analytical test strip can include enzymatic reagents that selectively and quantitatively transform an analyte into another predetermined chemical form. For example, the analytical test strip can include an enzymatic reagent with ferricyanide and glucose oxidase so that glucose can be physically transformed into an oxidized form.
Memory block 118 of hand-held test meter 100 includes a suitable algorithm and can be configured, along with microcontroller block 112 to determine an analyte based on the electrochemical response of analytical test strip and the hematocrit of the introduced sample. For example, in the determination of the analyte blood glucose, the hematocrit can be used to compensate for the effect of hematocrit on electrochemically determined blood glucose concentrations.
Microcontroller block 112 is disposed within housing 110 and can include any suitable microcontroller and/or micro-processer known to those of skill in the art. One such suitable microcontroller is a microcontroller commercially available from Texas Instruments, Dallas, Tex. USA and part number MSP430F5138. This microcontroller can generate a square wave of 25 to 250 kHz and a 90 degree phase-shifted wave of the same frequency and, thereby, function as a signal generation s-block described further below. MSP430F5138 also has Analog-to-Digital (A/D) processing capabilities suitable for measuring voltages generated by phase shift based hematocrit measurement blocks employed in embodiments of the present disclosure.
Referring in particular to
As described further below, phase-shift-based hematocrit measurement block 114 and microcontroller block 112 are configured to measure the phase shift of a bodily fluid sample in a sample cell of an analytical test strip inserted in the hand-held test meter by, for example, measuring the phase shift of one or more high frequency electrical signals driven through the bodily fluid sample. In addition, microcontroller block 112 is configured to compute the hematocrit of the bodily fluid based on the measured phase shift. Microcontroller 112 can compute the hematocrit by, for example, employing an A/D converter to measure voltages received from a phase-detector sub-block, convert the voltages into a phase-shift and then employing a suitable algorithm or look-up table to convert the phase-shift into a hematocrit value. Once apprised of the present disclosure, one skilled in the art will recognize that such an algorithm and/or look-up table will be configured to take into account various factors such as strip geometry (including electrode area and sample chamber volume) and signal frequency.
It has been determined that a relationship exists between the reactance of a whole blood sample and the hematocrit of that sample. Electrical modeling of a bodily fluid sample (i.e., a whole blood sample) as parallel capacitive and resistive components indicates that when an alternating current (AC) signal is forced through the bodily fluid sample, the phase shift of the AC signal will be dependent on both the frequency of the AC voltage and the hematocrit of the sample. Moreover, modeling indicates that hematocrit has a relatively minor effect on the phase shift when the frequency of the signal is in the range of approximately 10 kHz to 25 kHz and a maximum effect on the phase shift when the frequency of the signal is in the range of approximately 250 kHz to 500 KHz. Therefore, the hematocrit of a bodily fluid sample can be measured by, for example, driving AC signals of known frequency through the bodily fluid sample and detecting their phase shift. For example, the phase-shift of a signal with a frequency in the range of 10 kHz to 25 kHz can be used as a reference reading in such a hematocrit measurement while the phase shift of a signal with a frequency in the range of 250 kHz to 500 kHz can be used as the primary measurement.
Referring to
The signal generated by signal generation sub-block 120 is communicated to dual low pass filter sub-block 122, which is configured to convert the square wave signal to a sine wave signal of a predetermined frequency. The dual LPF of
Referring to
Although a specific dual LPF is depicted in
The sine wave produced by low pass filter sub-block 122 is communicated to analytical test strip sample cell interface sub-block 124 where it is driven across the sample cell of the analytical test strip (also referred to as an HCT measurement cell). Analytical test strip sample cell interface block 124 can be any suitable sample cell interface block including, for example, an interface block configured to operatively interface with the sample cell of the analytical test strip via first electrode and second electrodes of the analytical test strip disposed in the sample cell. In such a configuration, the signal can be driven into the sample cell (from the low pass filter sub-block) via the first electrode and picked-up from the sample cell (by the transimpedance amplifier sub-block) via the second electrode as depicted in
The current produced by driving the signal across the sample cell is picked-up by transimpedance amplifier sub-block 128 and converted into a voltage signal for communication to phase detector sub-block 130.
Transimpedance sub-block 128 can be any suitable transimpedance sub-block known to one skilled in the art.
Phase detector sub-block 130 can be any suitable phase detector sub-block that produces either a digital frequency that can be read back by microcontroller block 112 using a capture function, or an analog voltage that can be read back by microcontroller block 112 using an analog to digital converter.
The Quadrature DEMUX phase detector circuit of
Φ=tan1(VQUAD-PHASE/VIN-PHASE)
Such a Quadrature DEMUX phase detector circuit can also be employed to measure the impedance of a bodily fluid sample in the sample cell. It is hypothesized, without being bound, that the impedance could be employed along with the phase-shift, or independently thereof, to determine the hematocrit of the bodily sample. The amplitude of a signal forced through the sample cell can be calculated using the two voltage outputs of the Quadrature DEMUX circuit as follows:
Amplitude=SQR((VQUAD-PHASE)+(VIN-PHASE))
This amplitude can then be compared to an amplitude measured for the known resistor of calibration load block 126 to determine the impedance.
The XOR phase detector portion has a measurement range of 0° to 180°, or alternatively a measurement range of −90° to +90°, depending whether the “Square wave input from μC” is in phase to the sine wave or is set to a 90° phase shift. The XOR phase detector produces an output frequency that is always double the input frequency, however the duty cycle varies. If both inputs are perfectly in phase, the output is LOW, if both inputs are 180° shifted the output is always HIGH. By integrating the output signal (e.g. via a simple RC element) a voltage can be generated that is directly proportional to the phase shift between both inputs.
Once apprised of the present disclosure, one skilled in the art will recognize that phase detector sub-blocks employed in embodiments of the present disclosure can take any suitable form and include, for example, forms that employ rising edge capture techniques, dual edge capture techniques, XOR techniques and synchronous demodulation techniques.
Since low pass filter sub-block 122, transimpedance amplifier sub-block 128 and phase detector sub-block 130 can introduce a residual phase shift into phase-shift-based hematocrit measurement block 114, calibration load block 126 can be optionally included in the phase-shift-based hematocrit measurement block. Calibration load block 126 is configured to be essentially resistive in nature (for example a 33 k-ohm load) and, therefore, induces no phase shift between excitation voltage and generated current. Calibration load block 126 is configured to be switched in across the circuit to give a “zero” calibration reading. Once calibrated, the hand-held test meter can measure the phase shift of a bodily fluid sample, subtract the “zero” reading to compute a corrected phase shift and subsequently compute the bodily sample hematocrit based on the corrected phase shift.
At step 220, a phase shift of the whole blood sample in the sample cell is measured using a phase-shift-based measurement block and a microcontroller block of a hand-held test meter. Method 200 further includes computing the hematocrit of whole blood sample based on the measured phase shift using the microcontroller block (see step 230 of
Moreover, while the invention has been described in terms of particular variations and illustrative figures, those of ordinary skill in the art will recognize that the invention is not limited to the variations or figures described. In addition, where methods and steps described above indicate certain events occurring in certain order, it is intended that certain steps do not have to be performed in the order described but in any order as long as the steps allow the embodiments to function for their intended purposes. Therefore, to the extent there are variations of the invention, which are within the spirit of the disclosure or equivalent to the inventions found in the claims, it is the intent that this patent will cover those variations as well.
This National Stage application of International Application PCT/GB2012/053276 filed on Dec. 28, 2012 claims the benefits of priority of prior filed International Patent Applications PCT/GB2012/053277 and PCT/GB2012/053279 on Dec. 28, 2012, in which each of the referenced herein International Patent Applications claims benefits of priority to U.S. Provisional Patent Application Ser. Nos. 61/581,087 filed Dec. 29, 2011; 61/581,089 filed Dec. 29, 2011; 61/581,099 filed Dec. 29, 2011; and 61/581,100 filed Dec. 29, 2011, and U.S. Provisional Patent Application Ser. No. 61/654,013, filed on 31 May 2012, in which all the prior patent applications referenced herein are hereby incorporated by reference as if fully set forth herein this application.
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| WO2013/098563 | 7/4/2013 | WO | A |
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