HK1243163B - Measurement device, biosensor system and method for determining concentration of analyte - Google Patents

Description

Measuring device, biosensor system and method for determining analyte concentration

This application is a divisional application of patent application No. 200880120045.5, filed on October 23, 2008, with the invention name “Rapid Reading Gated Current Analysis Method”.

Background Art

Biosensors provide a means for analyzing biological fluids (e.g., whole blood, serum, plasma, urine, saliva, intercellular or intracellular fluids). Typically, a biosensor has a measuring device for analyzing a sample residing on a sensor strip. The sample is typically in liquid form and, in addition to being a biological fluid, may also be a derivative of the biological fluid, such as an extract, dilution, filtrate, or reconstituted precipitate. The analysis performed by the biosensor determines the presence and/or concentration of one or more analytes (e.g., alcohol, glucose, uric acid, lactic acid, cholesterol, bilirubin, free fatty acids, triglycerides, proteins, ketones, phenylalanine, or enzymes) in the biological fluid. This analysis can contribute to the diagnosis and treatment of physiological abnormalities. For example, a diabetic patient can use a biosensor to determine the glucose level in whole blood in order to adjust food and/or medication.

Biosensors can be designed to analyze one or more analytes and can use different sample sizes. Some biosensors can analyze, for example, a single drop of whole blood with a volume of 0.25-15 microliters (μL). Biosensors can be implemented using desktop, portable, and similar measuring devices. Portable measuring devices can be handheld and can identify and/or quantitatively analyze one or more analytes in a sample. Examples of portable measuring devices include the Ascensia and the Meter from Bayer HealthCare of Tarrytown, New York, and examples of desktop measuring devices include the Electrochemical Workstation available from CHInstruments of Austin, Texas, USA. Biosensors with shorter analysis times and the desired accuracy and/or precision would provide significant benefits to users.

Biosensors can use optical and/or electrochemical methods to analyze samples. In some optical systems, the analyte concentration is determined by measuring light that interacts with or is absorbed by a photoidentifiable substance (e.g., an analyte, a reactant, or a product formed by the reaction of a chemical indicator with the analyte). In other optical systems, a chemical indicator fluoresces or emits light in response to the analyte when exposed to an excitation beam. This light can be converted into an electrical output signal (e.g., a current or voltage), which can also be processed electrochemically to produce an output signal. In either optical system, the biosensor measures the light and correlates it with the analyte concentration in the sample.

In an electrochemical biosensor, when an input signal is applied to a sample, the analyte concentration is determined based on an electrical signal generated by the oxidation/reduction or redox reaction of the analyte or a substance corresponding to the analyte. The input signal can be applied as a single pulse, multiple pulses, a sequence, or a periodic wave. An oxidoreductase (e.g., an enzyme or similar substance) can be added to the sample to increase electron migration from the first substance to the second substance during the redox reaction. The enzyme or similar substance can react with a single analyte, thereby providing specificity to a portion of the generated output signal. Examples of some specific oxidoreductases and corresponding analytes are given in Table 1 below.

Table 1

Oxidoreductase (reagent layer) Analytes Glucose dehydrogenase β-glucose Glucose oxidase β-glucose Cholesterol esterase; cholesterol oxidase cholesterol Lipoprotein lipase; Glycerol kinase; Glycerol-3-phosphate oxidase triglycerides Lactate oxidase; lactate dehydrogenase; diaphorase lactic acid Pyruvate oxidase Pyruvate alcohol oxidase alcohol Bilirubin oxidase Bilirubin Uricase uric acid Glutathione reductase NAD(P)H carbon monoxide oxidoreductase carbon monoxide

Mediators may be used to maintain the oxidative state of the enzyme. Table 2 below gives some typical combinations of enzymes and mediators for specific analytes.

Table 2

Electrochemical biosensors typically include a measuring device with electrical contacts connected to conductive wires in a sensor strip. These wires can be made of conductive materials such as solid metal, metal paste, conductive carbon, conductive carbon paste, or conductive polymers. These wires are typically connected to a working electrode, a counter electrode, a reference electrode, and/or other electrodes that extend into a sample container. One or more wires may also extend into the sample container to provide functionality not provided by these electrodes.

In many biosensors, the sensor strip can be used outside, inside, or partially inside living tissue. When used outside living tissue, a biological fluid sample is introduced into a sample container in the sensor strip. Before, after, or during the introduction of the analysis sample, the sensor strip is placed in a measuring device. When used inside or partially inside living tissue, the sensor strip can be continuously immersed in the sample, or the sample can be intermittently introduced onto the sensor strip. The sensor strip can include a container that partially isolates a certain volume of sample or provides access to the sample. Similarly, the sample can flow continuously through the sensor strip or be interrupted for analysis.

The measuring device applies an input signal to the wires of the sensor strip via electrical contacts. The wires transmit the input signal to the sample in the sample container via electrodes. A redox reaction of the analyte generates an electrical output signal based on the input signal. The electrical output signal from the sensor strip can be a current (generated by amperometry or voltammetry), a voltage (generated by potentiometry/amperometry), or an accumulated charge (generated by coulometry). The measuring device can have processing capabilities to measure the presence and/or concentration of one or more analytes in the biological fluid and correlate this with the output signal.

In conventional amperometry, the current is measured during a read pulse at a constant potential (voltage) applied to the working and counter electrodes of a sensor strip. The measured current is used to determine the amount of analyte in the sample. Amperometry measures the rate at which an electrochemically active, and therefore measurable, substance is oxidized or reduced at or near the working electrode. Many variations of amperometry for biosensors are described, for example, in U.S. Patents Nos. 5,620,579, 5,653,863, 6,153,069, and 6,413,411.

A disadvantage of conventional amperometry lies in the non-steady-state nature of the current after the potential is applied. The rate of change of the current with respect to time is initially very rapid, but slows as the analysis progresses due to the varying nature of the underlying diffusion process. A steady-state current is not achieved until the rate of consumption of the ionized measurable species at the electrode surface equals the diffusion rate. Therefore, conventional amperometry, which measures the current during the transition period before reaching steady-state conditions, is not as accurate as measurements taken during the steady-state period.

The measurement performance of a biosensor is reflected in its accuracy and/or precision. Improving accuracy and/or precision can improve the measurement performance of a biosensor. Accuracy can be expressed as the deviation of a biosensor analyte reading relative to a reference analyte reading, with larger deviation values indicating lower accuracy, while precision can be expressed as the dispersion or variation of multiple analyte readings relative to an average value. Deviation is the difference between a value determined by a biosensor and a recognized reference value and can be expressed as "absolute deviation" or "relative deviation." Absolute deviation can be expressed in units of measurement such as mg/dL, while relative deviation can be expressed as the percentage of the absolute deviation value relative to a reference value. Reference values can be obtained using a standard instrument (e.g., the YSI 2300 STAT PLUS ^™ available from YSI Inc., Yellow Springs, Ohio).

Many biosensors include one or more methods to correct for errors associated with the assay. Concentration values derived from assays with errors are inaccurate. The ability to correct for these inaccurate assay values can improve the accuracy of the concentration values obtained. Error correction systems can compensate for one or more errors, such as a sample's hematocrit content that differs from a reference sample. For example, a common biosensor can be configured to report a glucose concentration for a hypothetical whole blood sample with a hematocrit of 40% (v/v), regardless of the sample's actual hematocrit. In these systems, any glucose measurement performed on a whole blood sample with a hematocrit of less than or greater than 40% will include errors or bias attributable to the "hematocrit effect."

In a conventional biosensor strip used to determine glucose concentration, glucose can be oxidized by an enzyme, which then transfers electrons to a mediator. The reduced mediator is then transferred to a working electrode, where it undergoes electrochemical oxidation. The amount of mediator oxidized can be correlated with the current between the working and counter electrodes of the sensor strip. Quantitatively, the current measured at the working electrode is directly proportional to the diffusion coefficient of the mediator. The hematocrit effect hinders this process because red blood cells hinder the diffusion of the mediator to the working electrode. Therefore, the hematocrit effect affects the current measured at the working electrode and has no relationship to the amount of glucose in the sample.

Hematocrit bias refers to the difference between a reference glucose concentration obtained using a standard instrument and a test glucose reading obtained by a biosensor for samples with different hematocrit levels. The difference between the reference value and the value obtained by the biosensor is due to the different hematocrit levels between specific whole blood samples.

In addition to the hematocrit effect, measurement inaccuracies can also arise when the concentration of the measurable species is uncorrelated with the analyte concentration. For example, when a sensor system determines the concentration of a reduced mediator produced by analyte oxidation, any reduced mediator not produced by the analyte oxidation reaction will cause the sensor system to indicate that more analyte is present in the sample than is accurately indicated due to mediator background. Therefore, "mediator background" is the bias introduced into the measured analyte concentration due to the measurable species not corresponding to the intrinsic analyte concentration.

In an attempt to overcome one or more of these shortcomings, conventional biosensors have employed a variety of techniques, directed not only to the mechanical design of the sensor strip but also to the manner in which the measuring device applies a potential to the sensor strip. For example, common methods for reducing the hematocrit effect in amperometric sensors include using filters, as disclosed in U.S. Patents 5,708,247 and 5,951,836; reversing the polarity of the applied current, as disclosed in WO 2001/57510; and maximizing the intrinsic resistance of the sample.

Various methods of applying input signals to the sensor strip, generally referred to as pulse methods, sequence methods, or cyclic methods, have been employed to address inaccuracies in the determined analyte concentration. For example, in U.S. Pat. No. 4,897,162, the input signal comprises continuously applied rising and falling voltage potentials that are mixed together to produce a triangular waveform. Additionally, WO 2004/053476, U.S. Pat. Nos. 2003/0178322 and 2003/0113933 disclose input signals comprising continuously applied rising and falling voltage potentials that vary in polarity.

Other common approaches combine specific electrode structures with input signals tailored to that structure. For example, U.S. Patent No. 5,942,102 combines a specialized electrode structure formed from thin-layer units with a continuous pulse, allowing reaction products from the counter electrode to reach the working electrode. This combination drives the reaction until the current becomes constant over time, thereby achieving a true steady-state condition for the mediator moving between the working and counter electrodes during the potential step. While each of these approaches balances various advantages and disadvantages, none is ideal.

As can be seen from the above description, there is a continuing need for improved biosensors, particularly biosensors that can more accurately determine analyte concentrations in a shorter time. The systems, devices, and methods of the present invention overcome at least one disadvantage of conventional systems.

Summary of the Invention

The present invention provides a method for determining the concentration of an analyte in a sample, comprising the following steps: applying an input signal to the sample, the input signal comprising at least three duty cycles within 10 seconds, wherein each duty cycle comprises an excitation pulse and a relaxation period; measuring an output signal corresponding to a measurable substance within 300 milliseconds of applying the excitation pulse in at least one duty cycle; and determining the concentration of the analyte in the sample based on the measured output signal. Each of the duty cycles may comprise excitation at a fixed potential during which current may be recorded, and relaxation. The pulse sequence may include a terminal read pulse, which may be applied to a sensor strip comprising a diffusion barrier. The determined analyte concentration is less biased by the mediator background than the same or other methods measured without an output signal within 300 milliseconds. By using transient current data, the analyte concentration can be determined when a steady-state condition is not reached during the excitation pulse of the input signal duty cycle. The measured current may be processed to determine the analyte concentration in the sample.

A handheld measurement device for receiving a sensor strip is configured to determine the concentration of an analyte in a sample. The device includes contacts, at least one display, and circuitry electrically connecting the contacts and the display. The circuitry includes a charger and a processor, wherein the processor is electrically connected to a storage medium. The storage medium includes computer-readable software code that, when executed by the processor, causes the charger to perform an input signal between the contacts that includes at least three duty cycles within 10 seconds. Each duty cycle includes excitation and relaxation. The processor is configured to measure at least one current value at at least two contacts within 300 milliseconds of applying excitation from the charger. The processor is further configured to determine the analyte in the biological fluid based on the at least one current value.

The present invention provides a biosensor system for determining the concentration of an analyte in a sample. The system includes a sensor strip having a sample interface adjacent to a container formed by the sensor strip, and a measurement device having a processor connected to the sensor interface. The sensor interface is electrically connected to the sample interface, and the processor is electrically connected to a storage medium. The processor determines an output signal value corresponding to the analyte concentration in the sample from the sensor interface within 300 milliseconds of applying an excitation pulse to the sample interface. The excitation pulse is a portion of an input signal that includes at least three duty cycles within 10 seconds, each duty cycle comprising excitation and relaxation.

The present invention also provides a method for reducing bias due to a hematocrit effect in determining the concentration of an analyte in a sample, the method comprising applying an input signal comprising at least three duty cycles within 10 seconds to the sample, and recording an output signal based on which the analyte concentration in the sample is determined within 300 milliseconds of applying the excitation pulse.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood with reference to the following drawings and descriptions, wherein the components in the drawings are not necessarily drawn to scale, emphasis being placed upon illustrating the principles of the present invention.

FIG1 illustrates an electrochemical analysis method for determining the presence and/or concentration of an analyte in a sample.

FIG2 is a graph showing an output signal generated based on an input signal measured by a gate current.

FIG. 3A illustrates the hematocrit bias present in the analyte concentration values determined from each of the three current values measured from each of the seven pulses shown in FIG. 2 .

FIG3B shows the range of hematocrit deviation for samples including 50, 100, and 400 mg/dL glucose.

FIG. 4 shows the hematocrit deviations from the first and third current values of P5 in FIG. 3A for a plurality of whole blood samples.

FIG5 shows a schematic diagram of a biosensor used to determine the concentration of an analyte in a sample.

DETAILED DESCRIPTION

WO 2007/013915, entitled "Gated Amperometry," employs a pulsed input signal to analyze analytes in a sample. The input signal comprises alternating excitation and relaxation periods. The present invention relates to systems and methods for analyzing an output signal based on the pulsed input signal to reduce bias due to, for example, media background and hematocrit effects. By correlating output signal values measured within the first 300 milliseconds of the excitation pulse, the accuracy and/or precision of the analysis can be improved.

FIG1 illustrates an electrochemical analysis method 100 for determining the presence and/or concentration of an analyte in a sample. In step 110, the sample is introduced into a biosensor. In step 120, a portion of the analyte in the sample undergoes a redox reaction. In step 130, electrons are selectively transferred from the analyte to the mediator. In step 140, the measurable substance is electrochemically excited using an input signal. In step 150, an output signal is generated and measured. In step 160, the sample is allowed to relax, and in step 170, another excitation pulse is input. In step 180, the presence and/or concentration of the analyte in the sample is determined based on the output signal, and in step 190, the concentration is displayed, stored, etc.

In step 110, a sample is introduced into the sensor portion of the biosensor (e.g., a sensor strip). The sensor strip includes at least one working electrode and at least one counter electrode. These electrodes may include one or more reagent layers. The working electrode may include a diffusion barrier layer that is integral with the reagent layer or separate from the reagent layer. When the working electrode includes a separate diffusion barrier layer, the reagent layer does not necessarily have to be disposed on the diffusion barrier layer.

The diffusion barrier layer provides a porous space with an internal volume within which a measurable substance can reside. The pores of the diffusion barrier layer can be selected to allow the measurable substance to diffuse into the diffusion barrier layer while substantially excluding larger sample components (e.g., red blood cells). While conventional sensor strips have employed various materials to filter red blood cells from the surface of the working electrode, the diffusion barrier layer provides an internal porous space to contain and isolate a portion of the measurable substance from the sample. A more detailed description of the diffusion barrier layer can be found in U.S. Patent Publication No. 2007/0246357.

In step 120 of Figure 1, a portion of the analyte present in the sample is chemically or biochemically oxidized or reduced, for example, by an oxidoreductase, due to the sample and the reagent undergoing a hydration reaction. Once an oxidation reaction or reduction reaction occurs, electrons can be selectively transferred between the analyte and the medium in step 130. Thus, for example, an ionized measurable substance is formed by the analyte or the medium. It is best to provide an initial time delay or "incubation" for the reagent to react with the analyte. Preferably, the initial time delay can be 1 to 10 seconds. A more detailed description of the initial time delay can be found in U.S. Patents US5620579 and US5653863.

In step 140 of FIG. 1 , a measurable species, which can be the charged analyte from step 120 or the charged mediator from step 130, is electrochemically excited (oxidized or reduced) using an input signal. The input signal can be a pulsed electrical signal (e.g., current or potential) that is switched on and off in a set sequence. The input signal is a sequence of excitation pulses separated by relaxation. During the amperometric pulse, the potential applied during the excitation is preferably applied at a substantially constant voltage and polarity throughout its duration. This is in direct contrast to some conventional excitations, in which the voltage changes or "swept" through multiple voltage potentials and/or polarities during data recording.

During relaxation, the electrical signal is off. Off includes periods when the electrical signal is absent, and preferably excludes periods when the electrical signal is present but substantially devoid of any amplitude. The electrical signal can be switched between on and off by closing and opening the circuit, respectively. Closing and opening the circuit can be accomplished mechanically, electrically, or by other methods.

The input signal may have one or more pulse intervals. The pulse interval is the sum of the pulses and relaxations that make up the duty cycle. Each pulse has an amplitude and a width. The amplitude represents the strength of the electrical signal, such as the potential or current. The amplitude can vary or be substantially constant, for example, during a current measurement or during a pulse. The pulse width is the duration of the pulse. The pulse width of the input signal can vary or be substantially constant. Each relaxation has a relaxation width, which is the duration of the relaxation. The relaxation width of the input signal can vary or be substantially constant.

By adjusting the width of the excitation and relaxation duty cycles, gated input signals can improve the accuracy and/or precision of the analysis. While not wishing to be bound by any particular theory, this improvement in accuracy and/or precision is a result of extracting the measurable species excited at the working electrode from within the diffusion barrier. In contrast to the measurable species outside the diffusion barrier, which have varying diffusion rates due to red blood cells and other sample components, the measurable species within the diffusion barrier have a relatively constant diffusion rate with respect to the conductor. For example, as described in U.S. Patent Publication No. 2007/0246357, entitled "Concentration Determination in a Diffusion Barrier Layer," the pulse width can be selected to substantially confine the excitation of the measurable species to the diffusion barrier.

Preferred input signals include at least 3, 4, 6, 8 or 10 duty cycles applied over a period of less than 30, 10 or 5 seconds. More preferably, at least 3 duty cycles are applied within 10 seconds. An input signal comprising at least 4 duty cycles applied within less than 7 seconds is currently particularly preferred. Preferably, the width of each excitation pulse is independently selected from 0.1 to 2 seconds, more preferably from 0.2 to 1 second. Currently, it is particularly preferred that the input signal pulse width is independently selected from 0.3 to 0.8 seconds. Preferred pulse intervals are in the range of less than 3, 2.5 or 1.5 seconds. Currently, input signals having pulse widths of 0.3 to 0.5 seconds and pulse intervals of from 0.7 to 2 seconds are particularly preferred. The input signal may also have other pulse widths and intervals.

In step 150 of FIG. 1 , the biosensor generates an output signal based on the measurable substance and the input signal. The output signal (e.g., one or more current values) can be measured continuously or intermittently, and can also be recorded as a function of time. The output signal can include a signal that initially decreases, a signal that increases and then decreases, a signal that reaches a steady state, and a transient signal. A steady-state current is observed when the current changes substantially constant with time (e.g., within ±10% or ±5%). Instead of a conventional steady-state or slowly decaying current, a transient (rapidly decaying) current value can be obtained based on a pulsed input signal.

FIG2 is a graph showing the output signal generated based on the gated current measurement input signal. When plotted as a function of time, each excitation pulse results in a transient decay curve in which the initial high current value decays. For a total of seven operating cycles, the input signal applied by the biosensor includes eight pulses and seven relaxations. FIG2 omits the first operating cycle, showing that there is no relaxation after the eighth pulse. The pulses are applied at approximately 200 mV with a pulse width of approximately 0.4 seconds. The pulse interval between the operating cycles is approximately 1.4 seconds, providing a relaxation width of approximately 1 second. Relaxation is provided by a disconnected circuit. Although square wave pulses are used, other waveforms suitable for the sensor system and test sample may also be used.

The biosensor intermittently measures the output signal during each pulse in Figure 2 and records three current values in a memory device. Starting approximately 125 milliseconds after the start of each pulse, the output signal values are recorded at approximately 125 millisecond (ms) intervals. The intervals between consecutive recordings can be the same or different. In Figure 2, the three current values recorded from the output signal are labeled with the letter i, with the pulse and measurement numbers indicated by subscripts. Therefore, the third current value measured for the fifth pulse is labeled i _5,3 .

Figure 3A shows the hematocrit bias present in the analyte concentration values determined from each of the three current values measured from each of the seven pulses shown in Figure 2 , with larger absolute values on the Y-axis indicating greater hematocrit error. For each pulse, the first current value indicates the smallest hematocrit bias of the three values, and the bias between the first and third values becomes larger with each subsequent pulse. With each subsequent pulse, a lower average hematocrit bias in the measured current is observed; however, each additional pulse increases the analysis time. Therefore, while the current value from P8 contains almost no hematocrit bias, the first current value from P5 provides an optimal balance between hematocrit bias and analysis time. It is also noteworthy that the first current value measured for P5 has approximately the same hematocrit bias as the third current value from P8, measured more than three seconds later. These results indicate that the current value measured earlier in the pulse width contains the smallest hematocrit bias.

Figure 3B shows the range of hematocrit deviation for samples containing 50, 100, and 400 mg/dL glucose, with larger range values on the Y-axis indicating greater hematocrit error. As shown in Figure 3A, the first current value indicates the minimum hematocrit deviation of the four current values measured during each pulse, with the deviation between the first and fourth values becoming larger with each subsequent pulse. The unexpectedly low hematocrit deviation of the first current value measured for each pulse is more pronounced at the higher glucose concentration level of 400 mg/dL. Therefore, accuracy is improved by measuring current earlier in the decay, which increases with increasing glucose concentration in whole blood samples.

Figure 4 shows the hematocrit deviations from the first and third current values of P5 in Figure 3A for multiple whole blood samples including varying hematocrit and glucose contents. The first current value i _5,1 exhibits an ^R² correlation of 0.18, while the third current value i _5,3 exhibits an ^R² correlation of 0.08, representing a reduction of over 50%. The higher analyte concentration accuracy achieved from current values acquired early in the decay is unexpected and stands in direct contrast to the prior art, which achieves accuracy from measurements taken in the later, steady-state portion of the decay. These results demonstrate that higher accuracy and/or precision can be achieved based on measurements taken early in the rapidly changing, transient portion of the decay.

Preferably, the output current value based on which the analyte concentration is determined is measured within less than 300 ms of applying the excitation pulse. More preferably, the output current value used to determine the analyte concentration of the sample is measured within less than 175 ms from the start of applying the excitation pulse or within 10 to 150 ms of applying the pulse. Still more preferably, the output current value based on which the concentration is determined is measured within 30 to 150 ms of applying the excitation pulse. Currently, it is particularly preferred to determine the analyte concentration based on the output current value measured within 60 to 150 ms of applying the excitation pulse. Preferably, the pulse from which the analyte output current value is measured to determine the analyte concentration in the sample is applied within 11 seconds or less of applying the initial excitation pulse, more preferably within 7 seconds or less of applying the initial pulse.

In step 160 of Figure 1, the sample undergoes relaxation. The measuring device can disconnect the circuit by the sensing strip, thereby allowing relaxation. During the relaxation period of step 160, the current present during the excitation period of step 140 is substantially reduced by at least half, preferably reduced by an order of magnitude, and more preferably reduced to zero. Preferably, the zero current state is achieved by disconnecting the circuit or other methods known to those of ordinary skill in the art, providing substantially zero current. Preferably, no output signal is recorded during the relaxation period of step 160.

During the relaxation period of step 160, an ionizing agent (e.g., an oxidoreductase) can react with the analyte to produce additional measurable species without potential influence. For example, a glucose biosensor comprising glucose oxidase as a reagent and a ferrocyanide mediator produces additional ferrocyanide (reduced mediator) corresponding to the sample analyte concentration without potential interference during the relaxation period of step 160.

1, the biosensor continues to apply pulses from the input signal to the working electrode and the counter electrode for a specified time. The duty cycle comprising the excitation period of step 140 and the relaxation period of step 160 can be repeated, or duty cycles with different pulse widths and/or intervals can be applied.

In step 180 of FIG. 1 , the biosensor analyzes the output signal values recorded within 300 milliseconds of the applied pulse to determine the analyte concentration in the sample. Other current, time, and/or other values may also be analyzed. In step 190, the analyte concentration value may be displayed and stored for future reference and/or for use in additional calculations.

FIG5 shows a schematic diagram of a biosensor 500 that uses a pulsed input signal to determine the concentration of an analyte in a biological fluid sample. Biosensor 500 includes a measuring device 502 and a sensor strip 504. The biosensor can be implemented as any analytical instrument, including a desktop device, a portable or handheld device, or the like. Biosensor 500 can be used to determine the concentration of analytes, including glucose, uric acid, lactate, cholesterol, bilirubin, and the like. Although a specific configuration is shown, biosensor 500 may also have other configurations, including those with additional components.

The sensor strip 504 has a base 506 that forms a container 508 and a channel 510 with an opening 512. The container 508 and channel 510 can be covered with a lid having a hole. The container 508 defines a partially enclosed space. The container 508 can contain components that help retain a liquid sample, such as a water-swellable polymer or a porous polymer matrix. Reagents can be placed in the container 508 and/or channel 510. The reagents can include one or more enzymes, adhesives, mediators, and other substances. The sensor strip 504 can also have a sample interface 514 disposed near the container 508. The sample interface 514 can partially or completely surround the container 508. The sensor strip 504 can also have other structures.

The sample interface 514 has wires connected to the working electrode and the counter electrode. These electrodes can be substantially in the same plane or in more than one plane. Other spacing distances between the electrodes and the lid can also be used. These electrodes can be arranged on the surface of the substrate 506 forming the container 508. The electrodes can extend into or extend into the container 508. The dielectric layer can partially cover the wires and/or electrodes. The sample interface 514 can also have other electrodes and wires.

The measurement device 502 includes circuitry 516 coupled to a sensor interface 518 and a display 520. The circuitry 516 includes a processor 522 coupled to a signal generator 524, an optional temperature sensor 526, and a storage medium 528.

Signal generator 524 provides an electrical input signal to sensor interface 518 in response to processor 522. The electrical input signal can be transmitted by sensor interface 518 to sample interface 514 to apply the electrical input signal to the biological fluid sample. The electrical input signal can be a potential or a current and can be a constant value, a variable value, or a combination thereof, such as a DC signal offset when applying an AC signal. The electrical input signal can be applied in the form of a single pulse, multiple pulses, a sequence, or a periodic wave. Signal generator 524 can also record the output signal from the sensor interface and act as a generator-recorder.

Optional temperature sensor 526 determines the temperature of the sample in the container of sensor strip 504. The sample temperature can be measured, calculated based on the output signal, or assumed to be the same as or similar to the ambient temperature or the temperature of the device comprising the biosensor system. The temperature can be measured using a thermistor, thermometer, or other temperature sensing device. Other techniques can also be used to determine the sample temperature.

The storage medium 528 may be a magnetic, optical or semiconductor memory, or other storage device, etc. The storage medium 528 may be a fixed storage device, a removable storage device (eg, a memory card, remote access, etc.).

The processor 522 uses computer-readable software code and data stored in the storage medium 528 to perform analyte analysis and data processing. The processor 522 can start analyte analysis based on the presence of the sensor strip 504 at the sensor interface 518, the application of the sample to the sensor strip 504, in response to user input, etc. The processor 522 controls the signal generator 524 to provide an electrical input signal to the sensor interface 518. The processor 522 can receive the sample temperature from the optional temperature sensor 526. The processor 522 receives an output signal from the sensor interface 518. The output signal is generated in response to the redox reaction of the analyte in the sample. The processor 522 measures the output signal within 300ms of the excitation pulse from the signal generator 524. One or more relationship equations are used in the processor 522 to associate the output signal with the analyte concentration of the sample. The results of the analyte analysis can be output to the display 520 and can be stored in the storage medium 528.

The relationship relating the analyte concentration to the output signal can be represented graphically, mathematically, or a combination thereof. These relationships can be represented by a program sequence number (PNA) table, another lookup table, or the like stored in the storage medium 528. Instructions for performing the analyte analysis can be provided by computer-readable software code stored in the storage medium 528. The code can be object code or any other code that describes or controls the functions described herein. One or more data processing operations (including determining decay rate, K factor, ratio, etc.) can be performed on the data from the analyte analysis in the processor 522.

The sensor interface 518 has contacts that connect or electrically communicate with wires in the sample interface 514 of the sensor strip 504. The sensor interface 518 transmits electrical input signals from the signal generator 524 to the connector in the sample interface 514 via the contacts. The sensor interface 518 also transmits output signals from the sample to the processor 522 and/or the signal generator 524 via the contacts.

The display 520 may be analog or digital. The display may be an LCD display suitable for displaying digital readouts.

In use, a liquid sample for analysis is transferred to container 508 by introducing the liquid into opening 512. The liquid sample flows through channel 510, displacing previously contained air while filling container 508. The liquid sample reacts chemically with reagents contained in channel 510 and/or container 508.

Sensor strip 504 is positioned adjacent to measurement device 502. This adjacent location includes a location where sample interface 514 is in electrical and/or optical communication with sensor interface 518. Electrical communication includes transmitting input and/or output signals between contacts in sensor interface 518 and wires in sample interface 514. Optical communication includes transmitting light between an optical port in sample interface 514 and a detector in sensor interface 518. Optical communication also includes transmitting light between an optical port in sample interface 514 and a light source in sensor interface 508.

Although various embodiments of the present invention have been described above, it is obvious to those skilled in the art that other embodiments and implementations are possible within the scope of the present invention. Therefore, the present invention is not limited except by the appended claims and their equivalents.

References to related applications

This application claims priority to U.S. Provisional Patent Application No. 61/012,729, filed December 10, 2007, entitled "Rapid-read Gated Amperometry," the contents of which are incorporated herein by reference.

Claims (63)

1. A handheld measuring device for determining the concentration of an analyte in a sample, comprising: A sensor interface suitable for receiving a sensor strip, the sensor interface including at least two contacts; At least one display; and A circuit for establishing an electrical connection between the at least two contacts and the display. The circuit includes an electrically connected signal generator and a processor. The processor is electrically connected to a storage medium having computer-readable software code. The processor is programmed to cause the signal generator to provide an input signal between the at least two contacts. The input signal has at least three operating cycles within 10 seconds, each of the at least three operating cycles including an excitation pulse and a relaxation pulse. The processor is programmed to measure at least one current value at the at least two contacts within 300 milliseconds of an excitation pulse having a pulse width of 0.3 to 0.8 seconds during at least one of the at least three operating cycles applied by the signal generator. The processor is programmed to determine the concentration of an analyte in a biological liquid or a derivative thereof in response to the at least one current value. 2. The measuring device according to claim 1, wherein the signal generator is selected from the group consisting of a charger and a generator-recorder. 3. The measuring device according to claim 2, wherein the signal generator is a charger. 4. The measuring device according to claim 1, wherein the computer-readable software code includes relational expressions. 5. The measuring device according to claim 4, wherein the relation is selected from the group consisting of a program number table, a lookup table, and combinations thereof. 6. The measuring device of claim 1, wherein the processor is programmed to measure the at least one current value during the instantaneous portion of current decay. 7. The measuring device of claim 6, wherein the processor is programmed to determine the concentration of the analyte in the biological fluid or the derivative thereof in response to the at least one current value measured during the instantaneous portion of the current decay. 8. The measuring device of claim 1, wherein the processor is programmed to measure the at least one current value within 175 milliseconds from the start of the excitation pulse having a pulse width of 0.3 to 0.8 seconds in the at least one operating cycle. 9. The measuring device of claim 1, wherein the processor is programmed to apply at least one data processing to the at least one current value. 10. The measuring apparatus of claim 9, wherein the at least one data processing determines at least one of the decay rate, the K coefficient, and the proportional value. 11. The measuring device of claim 3, wherein the processor is programmed to measure the at least one current value as a function of time at the at least two contacts while the charger provides the input signal between the contacts. 12. The measuring device of claim 3, wherein the charger is programmed to provide the input signal between the at least two contacts, comprising at least four operating cycles within 7 seconds. 13. The measuring device of claim 3, wherein the charger is programmed to provide the input signal between the at least two contacts, comprising square wave excitation. 14. The measuring device of claim 3, wherein the charger is programmed to implement the excitation pulse at a constant voltage. 15. The measuring device according to claim 3, wherein the excitation pulse provided by the charger is programmed to have a pulse width of 0.3 to 0.5 seconds. 16. The measuring device according to claim 3, wherein the excitation pulse provided by the charger is programmed to have a pulse width of 0.3 to 0.5 seconds and a pulse interval of 0.7 to 2 seconds for at least one of the at least three operating cycles. 17. The measuring device of claim 3, wherein the charger is programmed to provide the input signal between the at least two contacts, which includes a terminal readout pulse that is not subsequently relaxed. 18. The measuring device of claim 3, wherein the processor is programmed to make the pulse interval of at least one of the at least three operating cycles provided by the charger less than 3 seconds. 19. The measuring device of claim 3, wherein the processor is programmed to cause the relaxation provided by the charger to include a current reduction of at least half that at the excitation peak of the excitation pulse. 20. The measuring device of claim 3, wherein the processor is programmed to cause the relaxation provided by the charger to include a current reduction of at least one order of magnitude smaller than the current at the excitation peak of the excitation pulse. 21. The measuring device of claim 3, wherein the processor is programmed to cause the relaxation provided by the charger to include a zero current. 22. The measuring device of claim 3, wherein the processor is programmed to measure the at least one current value based on the at least one duty cycle applied by the charger within 7 seconds of the charger applying an initial excitation pulse to the sample. 23. The measuring device of claim 3, wherein the processor is programmed to measure the at least one current value at the at least two contacts within 60 to 150 milliseconds of the excitation pulse having a pulse width of 0.3 to 0.8 seconds applied by the charger. 24. The measuring device according to claim 3, The processor is programmed to cause the charger to provide a disconnect circuit between the at least two contacts, and The disconnect circuit provides the relaxation, and the relaxation is at least 0.5 seconds. 25. The measuring device according to claim 1, The input signal provided by the signal generator between the at least two contacts is capable of exciting the measurable material within the diffusion barrier layer, and The processor is programmed to measure the at least one current value at the at least two contacts based on the measurable material inside the diffusion barrier layer, while excluding the measurement of the measurable material outside the diffusion barrier layer. 26. A biosensor system for determining the concentration of an analyte in a sample, comprising: A sensor strip having a sample interface adjacent to a container formed by the sensor strip; and The measuring device has a processor that connects to the sensor interface. The sensor interface is electrically connected to the sample interface. The processor is electrically connected to the storage medium. The processor is programmed to determine, within 300 milliseconds of applying an excitation pulse with a pulse width of 0.3 to 0.8 seconds to the sample interface, an output signal value from the sensor interface corresponding to the analyte concentration in the sample. The excitation pulse is part of an input signal comprising at least three working cycles within 10 seconds, wherein each working cycle includes an excitation pulse and a relaxation. 27. The system of claim 26, wherein the measuring device is portable. 28. The system of claim 26, wherein the excitation pulse has a constant voltage. 29. The system of claim 26, wherein the processor is programmed to determine the output signal value corresponding to the analyte concentration in the sample during the instantaneous portion of the current decay. 30. The system of claim 26, wherein the pulse interval of at least one of the at least three working cycles is less than 3 seconds. 31. The system according to claim 26, wherein the pulse width of the excitation pulse is 0.3 to 0.5 seconds, and wherein the pulse interval of at least one of the at least three working cycles is 0.7 to 2 seconds. 32. The system of claim 26, wherein the relaxation comprises a current reduction of at least half the current reduction at the excitation peak of the excitation pulse. 33. The system of claim 26, wherein the relaxation comprises a current reduction of at least one order of magnitude smaller than the current at the excitation peak of the excitation pulse. 34. The system of claim 26, wherein the relaxation includes a zero current. 35. The system of claim 26, wherein the processor is programmed to determine, within 60 to 150 milliseconds of applying the excitation pulse to the sample interface, the output signal value corresponding to the concentration of the analyte in the sample. 36. The system of claim 26, wherein the relaxation is at least 0.5 seconds and corresponds to the disconnection of the circuit. 37. The system of claim 26, wherein the sample is at least one of a biological liquid and a biological liquid derivative. 38. A method for determining the concentration of an analyte in a sample for non-diagnostic purposes, comprising: An input signal is applied to the sample, wherein the input signal has at least three working cycles within 30 seconds, and wherein each of the at least three working cycles includes an excitation pulse and a relaxation. The output signal corresponding to the measurable substance is measured within 300 milliseconds, starting from the start of the excitation pulse in at least one of the at least three operating cycles, wherein the pulse width of the excitation pulse is 0.1 to 2 seconds; and In response to the measured output signal, the concentration of the analyte in the sample is determined. 39. The method of claim 38, wherein the input signal comprises at least four operating cycles within 7 seconds. 40. The method of claim 38, wherein the input signal comprises at least 3 operating cycles within 10 seconds. 41. The method of claim 38, wherein the pulse width of the excitation pulse is 0.3 to 0.8 seconds. 42. The method of claim 38, wherein the pulse interval of at least one of the at least three working cycles is less than 3 seconds. 43. The method of claim 38, wherein the pulse width of the excitation pulse is 0.3 to 0.5 seconds, and wherein the pulse interval of at least one of the at least three working cycles is 0.7 to 2 seconds. 44. The method of claim 38, wherein the output signal is measured within a time period of less than 175 milliseconds of the excitation pulse. 45. The method of claim 38, wherein the output signal is measured within 60 to 150 milliseconds from the start of the excitation pulse. 46. The method of claim 38, further comprising: At least one electron is transferred from the analyte in the sample to the medium in the sensing band; and In response to the input signal, the measurable substance is electrochemically excited, wherein the measurable substance is derived from at least one of the analyte and the medium. 47. The method of claim 38, wherein the excitation pulse has a constant voltage. 48. The method of claim 38, wherein the input signal comprises square wave excitation. 49. The method of claim 38, wherein the concentration of the analyte in the sample is determined with less deviation than the concentration of the analyte determined in response to an output signal measured at a time greater than 300 milliseconds from the start of the excitation pulse in one of the operating cycles. 50. The method of claim 49, wherein the concentration of the analyte in the sample is determined with a smaller deviation than the concentration of the analyte determined in response to an input signal having less than 3 working cycles within 10 seconds. 51. The method of claim 38, further comprising: recording at least one current as a function of time during the application of the input signal. 52. The method of claim 38, further comprising: applying at least one data processing to at least one current of the output signal, wherein the at least one data processing determines at least one of a decay rate, a K constant, and a scaling factor. 53. The method of claim 38, further comprising: Excite the measurable material within the diffusion barrier layer; and The measurable material outside the diffusion barrier layer is excluded from the excitation. 54. The method of claim 38, wherein the relaxation comprises a current reduction of at least half the current reduction at the excitation peak of the excitation pulse. 55. The method of claim 38, wherein the relaxation comprises a current reduction of at least one order of magnitude smaller than the current at the excitation peak of the excitation pulse. 56. The method of claim 38, wherein the relaxation comprises zero current or a disconnected circuit. 57. The method of claim 56, wherein the relaxation is at least 0.5 seconds. 58. The method of claim 38, wherein determining the concentration of the analyte comprises determining the concentration of the analyte by instantaneous attenuation, wherein the output signal includes the instantaneous attenuation. 59. The method according to claim 38, wherein the sample is at least one of a biological liquid and a biological liquid derivative. 60. The method of claim 38, wherein the measurement is performed by a handheld measuring device. 61. The method of claim 38, wherein the input signal includes a terminal readout pulse that is not followed by relaxation. 62. The method of claim 38, wherein the output signal is measured within a time period of less than 175 milliseconds from the start of the excitation pulse, wherein the excitation pulse has a pulse width of 0.3 to 0.8 seconds. 63. The method of claim 38, wherein the output signal is measured over a period of 60 to 150 milliseconds from the start of the excitation pulse, wherein the excitation pulse has a pulse width of 0.3 to 0.8 seconds.