CN110376270A - The method for measuring sample temperature - Google Patents
The method for measuring sample temperature Download PDFInfo
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- CN110376270A CN110376270A CN201910730252.2A CN201910730252A CN110376270A CN 110376270 A CN110376270 A CN 110376270A CN 201910730252 A CN201910730252 A CN 201910730252A CN 110376270 A CN110376270 A CN 110376270A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/49—Systems involving the determination of the current at a single specific value, or small range of values, of applied voltage for producing selective measurement of one or more particular ionic species
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- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
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Abstract
The present invention describes sensing system for measuring the analyte concentration in sample, device and method.Shorter analysis time can be provided including the gated amperometric pulse train that multiple continuous agitations and relaxation to work recycle and/or improves the accuracy and/or precision analyzed.Disclosed gated amperometric pulse train can reduce the analytical error as caused by hematocrit effect, the variation of cap gap volume, unstable state situation, mediator background, unfilled, sample temperature variation and single group calibration constants.
Description
The application be the applying date be on July 19th, 2006, entitled " gated amperometry " application No. is
The divisional application of 201710046533.7 patent applications (referred to hereinafter as " the first sub- case ").The application is recognized in State Intellectual Property Office
Above-mentioned first sub- case does not meet in the case that unicity requires and proposes, and in particular to the first time of the first sub- case examines
Action, posting date are on November 02nd, 2018, dispatch serial number 2018103002254520.
In addition, above-mentioned first sub- case is that application No. is the divisions of 201310479070.5 patent applications (referred to hereinafter as " the second sub- case ")
Application, the applying date of the second sub- case is on July 19th, 2006, and denomination of invention is " gated amperometry ".
In addition, above-mentioned second sub- case is that application No. is the division Shens of 200680026346.2 patent applications (referred to hereinafter as " female case ")
Please, the applying date of the female case is on July 19th, 2006, and denomination of invention is " gated amperometry ".
The reference of related application
This application claims " Gated Amperometry (gated amperometrics submitting, entitled on July 20th, 2005
Method) " U.S. Provisional Application No.60/700,787 and on May 08th, 2006 " Abnormal Output submitting, entitled
The U.S. Provisional Application of Detection system for a biosensor (the unusual output detection system of biosensor) "
No.60/746,771 priority, and the content of the two provisional applications is incorporated herein by reference.
Background technique
The analyte quantitative determined in biofluid is physically different for diagnosing and treating.For example, measurement blood etc.
Glucose level in biofluid, for must running check oneself blood glucose level to adjust diet and/or medication
Diabetic is critically important.
Electro-chemical systems have been used to such analysis.In the analysis process, analyte has occurred and enzyme or similar
The redox reaction of substance (species), to generate electric current can measuring and associated with analyte concentration.Pass through
Time needed for shortening analysis, while desired accuracy and precision being provided, user can be allowed sufficiently to be benefited.
One example of the electrochemical sensor system for the analyte in analyzing biologic fluids include measuring device and
Sensing zone.Sensing zone includes reagent and electrode, which reacts with analyte during analysis and by the electronics of analyte
Transfer, the electrode transmit above-mentioned electronics by the conductor for connecting sensing zone and measuring device.Measuring device have from
Sensing zone receives the contact of electronics and applies the ability of voltage difference between each contact.The device can recorde across sensor
Electric current and the current value is changed into sample analyte content assessed value.These sensing systems can analyze a drop whole blood
(WB), for example, volume be 1~15 microlitre (μ L) whole blood.
The example of desk-top (bench-top) measuring device includes: by Indiana, USA (Indiana) western Lafayette
(West Lafayette) BAS Instruments company sale BAS 100B analyzer, by Texas, USA
(Texas) Austin (Austin) CH Instruments company sale CH instrument analyzer, by Kan.
(Kansas) Lao Lunsi (Lawrence) Cypress Systems company sale Cypress electrochemical workstation and by
The Princeton Research Instruments of the New Jersey Princeton (New Jersey) (Princeton) is public
Take charge of the EG&G electrochemical apparatus of sale.The example of Portable type measurement unit includes Bayer Corporation company
Ascensia WithInstrument.
Sensing zone may include a working electrode and one to electrode, and a kind of electrification occurs at working electrode for analyte
Reaction is learned, and opposite (oppsite) electrochemical reaction occurs to electrode, to allow current between the two electrodes
It flows through.Therefore, it if aoxidized at working electrode, is restored to electrode.For example, with reference to
“Fundamentals Of Analytical Chemistry,4thEdition,D.A.Skoog and D.M.West;
Philadelphia:Saunders College Publishing (1982), pp 304-341 " (D.A.Skoog and
" the analytical chemistry basis " of D.M.West works, fourth edition, Philadelphia, Saunders institute publish (nineteen eighty-two), and the 304-341 pages).
Sensing zone can also include true (true) reference electrode, to provide constant reference electricity to measuring device
Position.Although a variety of reference electrode materials be all it is known, the mixture of silver-colored (Ag) and silver chlorate (AgCl) than more typically because
In aqueous environment of this mixture insoluble in analytical solution.Reference electrode is also used as to electrode.United States Patent (USP) No.5,
The sensing zone using this reference-to electrode combination is described in 820,551.
Electrode print can be formed into sensing zone on a dielectric base by using multiple technologies, above-mentioned technology is for example
It is technology those of described in United States Patent (USP) No.6,531,040, No.5,798,031 and No.5,120,420.It can pass through
One or more electrodes are applied, such as working electrode and/or to electrode, to form one or more reagent layers.A side
Face, more than one above-mentioned electrode can be covered by identical reagent layer, for example, when working electrode and on electrode be coated with phase
Same group timesharing.On the other hand, the U.S. Provisional Patent Application No.60/ submitted on October 24th, 2003 can be used
Reagent layer with different component is printed or microdeposit is in working electrode and on electrode by method described in 513,817.
Therefore, the reagent layer on working electrode may include enzyme, mediator and adhesive, and to the reagent layer on electrode include adhesive and
Dissolvable redox substance that can be identical or different with above-mentioned mediator.
Reagent layer may include the ionization preparation for promoting oxidation or the reduction of analyte, and help to allow electronics
Any mediator shifted between analyte and conductor or other substances.Ionization preparation can be analyte enzyme-specific, example
Such as glucose oxidase or glucose dehydrogenase, with the oxidation for the glucose being catalyzed in WB sample.Reagent layer also may include by
The adhesive that enzyme and mediator keep together.Following Table I provides the normal of the enzyme and mediator used for specific analyte
Rule combination.
Table I
Adhesive may include the various types such as CMC (carboxymethyl cellulose) and/or PEO (polyethylene oxide) and divide
The polymer of son amount.Adhesive can also assist filters red blood cell, prevent them other than each reagent is bonded together
Covering is at the electrode surface.
The example of Conventional electrochemical sensing system for the analyte in analyzing biologic fluids includes: by Erie, the U.S.
The Abbott company sale in noy state (Illinois) Albert park (Abbott Park) Biosensor, by
The Roche company sale of the Indianapolis Indiana, USA (Indiana) (Indianapolis)Biosensor and by California, USA (California) Mir Pitta this (Milpitas)
Lifescan company sale One TouchBiosensor.
A kind of electrochemical method for the analyte having been used in quantization biofluid is coulometry.For example, Heller
Deng the coulometry described in United States Patent (USP) No.6,120,676 for full blood glucose measurement.In coulometry,
It by the analyte exhaustive oxidation of very small volume, and quadratures on oxidization time to electric current, represents analyte concentration to generate
Charge, with this analyte quantification concentration.In other words, coulometry obtains the glucose total amount in sensing zone.
One importance of coulometry is that, towards the end of the integral curve of charge against time, electric current is at any time
Change rate become substantially constant, to stable situation occur.This steady-state portion of coulometry curve forms opposing straight
Flat region, so that corresponding electric current can be measured.However, coulometry require whole volume analyte change completely with
Reach stable situation.As a result, this method is time-consuming, and the electrochemical appliances such as glucose monitoring product cannot be provided
User needed for fast results.Coulometry another problem is that, in order to provide accurately as a result, sensor must be controlled
(sensor cell) keeps its volume small in pond, this may be to be difficult to realize for full-scale plant.
Another electrochemical method for the analyte having been used in quantization biofluid is amperometry.In amperometry
In, when constant potential (voltage) being applied to the working electrode of sensing zone and between electrode, measured during read pulse
Electric current.The measured electric current come out is used to quantify the analyte in sample.Amperometry measure electroactive substance (from
And measure analyte) rate that is easily oxidized or reduced near working electrode.Such as United States Patent (USP) No.5,620,579,
The many of biosensor amperometry has been described in No.5,653,863, No.6,153,069 and No.6,413,411
Variation.
The shortcomings that conventional current analytic approach is the unstable state property of the electric current after applying current potential.Initially, electric current relative to
The change rate of time is very fast, and then as the progress of analysis, the change rate is due to basic (underlying) diffusion process
Qualitative change and it is slack-off.Until the wear rate of the mediator that is reduced at electrode surface is equal to diffusion rate, being can not
It can obtain steady-state current.Therefore, for amperometry, electric current is measured reaching in the stable situation pervious transient state period,
It is more inaccurate when will lead to than being measured within stable state period.
" hematocrit effect " hampers the concentration of glucose accurately analyzed in WB sample.WB sample contains red blood
(RB) cell and blood plasma.Blood plasma is largely water, but contains some protein and glucose.Hematocrit is RB cellular component
The volume shared relative to WB population of samples product, and it is typically expressed as percentage.Whole blood sample generally has 20%~60%
Hematocrit percentage, average level are~40%.
In the conventional sensing zone for measuring concentration of glucose, glucose can be oxidized by enzymes, and then enzyme turns electronics
It moves to mediator.Then, which is moved to working electrode and is electrochemically oxidized there.The mediator being oxidized
Amount can be associated with to the electric current flowed between electrode with the working electrode in sensing zone.At quantitative aspect, in working electrode
The electric current that place measures is directly proportional to the diffusion coefficient of mediator.Hematocrit effect hampers this process, because RB is thin
The embarrassment of fetus hinders mediator to spread to working electrode.Therewith, the electric current measured at working electrode of hematocrit effects
Amount, and there is no any relationship with the amount of the glucose in sample.
The WB sample of modified RB cell concentration may cause the inaccuracy in measurement, because sensor cannot be distinguished
Do not occur higher mediator concentration from such case to working electrode and lower mediator concentration that RB cell prevents mediator from spreading.For example,
When analysis is containing same glucose level and when WB sample that hematocrit is 20%, 40% and 60%, it is based on one group of calibration
The conventional sensors system of constant (for example, slope and intercept) can be reported out three different glucose readings.Even if glucose
Concentration is identical, but spreads since RB cell hampers mediator to working electrode, and system will report 20% hematocrit sample
Product include more glucose than 60% hematocrit sample.
The normal plasma cell specific volume ranges (RBC concentration) of the mankind are 20%~60%, and value is 40% or so among it.Blood is thin
Born of the same parents' specific-volume anomaly refers to, for the sample comprising different hematocrit levels, the reference glucose obtained from reference instrument is dense
Degree and from the difference between the experiment glucose readings that portable sensor system obtains.Above-mentioned reference instrument is, for example, by Russia's last of the twelve Earthly Branches
The YSI 2300STAT PLUS of the YSI Inc. company sale in Russia, the city (Ohio) Huang Wenquan, state (Yellow Springs)TM.With reference to
The hematocrit levels of variation of the difference between each specific whole blood sample between concentration and experiment reading.
Other than hematocrit effect, when measurable material concentration and analyte concentration onrelevant, it is also possible to draw
Play measurement inaccuracy.For example, when the concentration for the mediator being reduced that sensing system measurement is generated by analyte oxidation,
Any is not that the mediator being reduced generated by analyte oxidation can all cause sensing system to provide due to mediator background
Following judgement: there are analytes more more than correct option in the sample.
Other than hematocrit effect and mediator background effect, other factors may also lead to Conventional electrochemical sensing
There is inaccuracy in the ability of analyte concentration in the measurement sample of device system.In one aspect, because containing the sensing of sample
Band part may be different on volume, therefore can introduce these above-mentioned inaccuracies.It is next when not providing enough samples
When being fully filled with cap gap volume, this is known as unfilled situation, it is also possible to introduce inaccuracy.It is in other respects, random that " noise is dry
Disturb " and when sensing system lacks the ability of Accurate Determining sample temperature variation, inaccuracy may be introduced into survey
In amount.
In order to overcome one or more disadvantages in these disadvantages, conventional sensors system has had attempted to multiple technologies,
These technologies are not selected only about the Machine Design of sensing zone and reagent, but also apply current potential to sensing zone about measuring device
Mode.For example, for reducing the hematocrit effect of amperometric sensor conventional method include: using filter,
As disclosed in United States Patent (USP) No.5,708,247 and No.5,951,836;Invert the polarity of applied electric current, such as WO
As disclosed in 01/57510;And using making the maximized method of the intrinsic impedance of sample, such as United States Patent (USP) No.5,
As disclosed in 628,890.
It is used for a variety of methods for applying current potential to sensing zone, commonly referred to as pulse method, pulse train or pulse
Circulation, to solve the problems, such as the inaccuracy in measured analyte concentration.For example, in United States Patent (USP) No.4, in 897,162,
Pulse method includes continuously applying lifting current potential, they are mixed to obtain triangular form wave.In addition, in WO 2004/
053476 and U.S. patent documents 2003/0178322 and 2003/0113933 described in pulse method, including continuously apply
The go up and down and polar current potential of change.
Other conventional methods are by special electrodes structure in conjunction with the pulse train for being suitable for the structure.For example, United States Patent (USP)
No.5,942,102 combine the special electrodes structure provided by sheet cell with continuous impulse, so as to electrode
Reaction product can reach working electrode.This combination is used to driving a reaction, until electric current changes with time and becomes constant,
To make to reach in working electrode and to the mediator moved between electrode in (potential step) the step of applying current potential
To a real stable situation.Although each method in these methods has all weighed various merits and demerits, do not have
Any method is ideal.
From the foregoing, it will be seen that there is still a need for improved electrochemical sensor systems, especially those can be shorter
The electrochemical sensor system of analyte concentration is more accurately measured in time.Systems, devices and methods of the invention overcome
Related with conventional system at least one disadvantage.
Summary of the invention
A kind of method for signaling user and adding additional sample to sensing zone is provided, the method includes walking as follows
It is rapid: to apply input signal to the working electrode of the sensing zone and to the sample that electrode contacts, the input signal was at 180 seconds
Interior includes at least three working cycles, and each working signal includes excitation and relaxation;It is followed according to the work of described at least three
The excitation of at least two working cycles in ring, measurement include the output signal of electric current;According at least two excitations
The interior output signal, determines decay coefficient curve;The decay coefficient curve during being excited according to described at least two,
Determine whether the sensing zone is unfilled;If the sensing zone is unfilled, signals user and add to the sensing zone
Add additional sample;And according to the output signal, measure the concentration of the analyte in the sample.
A kind of method of the temperature of sample that measurement sensing zone is contained is provided, described method includes following steps: in advance
Determine relationship between the rate of disintegration and temperature;According at least two of the input signal in 180 seconds including at least three working cycles
The electric current recorded during excitation measures current curve;And by relationship between the current curve and the rate of disintegration and temperature
It associates, to measure the temperature of the sample.
It a kind of determination is provided is applied to the input signal in 180 seconds including at least three working cycles of sample and continue
The method of time, for measuring the analyte concentration in sample, each working cycles at least three working cycles include
Excitation, described method includes following steps: according to the electric current recorded according to output signal in the set time, predefining multiple groups school
On schedule;The input signal in 180 seconds including at least three working cycles is applied to the sample;According to according to
The excitation of at least one working cycles at least three working cycles and the output signal measured, measure the sample
Analyte concentration in product;And in response to the analyte concentration of the sample measured, the institute for being applied to the sample is determined
State the duration of input signal.
Some definition are given below, so as to it is clear, verily understand specification and claims.
Term " analyte " is defined as being present in one of sample or many kinds of substance.Divide in the analysis measurement sample
Analyse the presence of object and/or the concentration of existing analyte.
Term " sample " be defined as it is a kind of may be containing the composition of unknown quantity analyte.In general, electrochemical analysis
Sample is liquid form, it is preferable that sample is aqueous mixture.Sample can be the biological sample such as blood, urine or saliva
Product.Sample is also possible to the derivative of biological sample, for example, extract, dilution, filtrate or rehydration sediment.
Term " measurable substance " be defined as can at the working electrode of electrochemical sensor strip under suitable potential quilt
Any electroactive substance for aoxidizing or being reduced.The example that can measure substance includes analyte, oxidoreducing enzyme and mediator.
Term " amperometry " is defined as a kind of analysis method, wherein by analyte under a certain current potential
Oxidation or rate of reduction carry out electrochemical measurement, measure the analyte concentration in sample.
Term " system " or " sensing system " are defined as a kind of sensing zone, it passes through the conductor and measuring device of oneself
Mutual telecommunication makes it possible to quantify the analyte in sample.
Term " sensing zone " is defined as one kind and contains sample during analysis and provide between sample and measuring device
The device of telecommunication.The sensing band part for containing sample is commonly referred to as " cap gap (cap-gap) ".
Term " conductor " is defined as a kind of being kept fixed constant conductive materials during electrochemical analysis.
Term " measuring device " is defined as one or more electronic devices, and current potential can be applied to leading for sensing zone
Body simultaneously measures obtained electric current.Measuring device also can have the current value in response to being recorded and measure one or more points
Analyse the presence of object and/or the processing capacity of concentration.
Term " accuracy " is defined as the true of the analyte in the amount and sample of the analyte measured by sensing zone
The degree of closeness of actual quantities.In one aspect, accuracy can be expressed as the form of deviation.
Term " precision " is defined as the degree of closeness to the multiple analysis measurement of same sample.In one aspect, smart
Degree can be expressed as the form of difference (spread) or difference between repeatedly measurement.
Term " redox reaction " be defined as between two substances, be related at least one electronics from the first substance turn
Move on to the chemical reaction of the second substance.Therefore, redox reaction includes oxidation and reduction.Oxidation half cell reaction is related to first
Substance loses at least one electronics, and restores half-cell reaction and be related to the second substance and increase at least one electronics.It is oxidized substance
Ionic charge increment value be equal to the electron number that loses.Equally, the ionic charge decreasing value for being reduced substance is equal to obtained electricity
Subnumber.
Term " mediator ", which is defined as one kind, can be easily oxidized or reduced and can shift one or more electronics
Substance.Mediator is the reagent in electrochemical analysis, it is not target analytes, and is to provide the indirect measurement to analyte.?
In the system of simplification, mediator in response to analyte oxidation or reduction and redox reaction occurs.Then, be oxidized or by
Opposite reaction occurs at the working electrode of sensing zone for the mediator of reduction, and is restored to its initial oxidation number.
Term " adhesive " is defined as a kind of material, it provides physical support to reagent and accommodates reagent, has simultaneously
With the chemical compatibility of reagent.
Term " mediator background " is defined as the deviation being introduced into measured analyte concentration, can be attributed to not
In response to the measurable substance of fundamental analysis object concentration.
Term " unfilled " is defined as when insufficient sample is introduced into sensing zone to obtain accurate analysis.
Term " redox couple " is defined as two kinds of pairing materials of the chemical substance of different oxidation numbers.To have
The substance reduction of higher oxygen number can generate the substance with lower oxidation number.Optionally, by the substance with lower oxidation number
Oxidation can generate the substance with higher oxygen number.
Term " oxidation number " is defined as the form ionic charge of the chemical substances such as atom.Oxidation number is higher, such as
(III), then electropositive is bigger;Oxidation number is lower, such as (II), then electropositive is smaller.
Term " dissolvable redox substance " be defined as capable of occurring aoxidizing or restore and can in water (pH value is
7,25 DEG C) in the substance that is dissolved with the magnitudes of at least 1.0 grams per liters.Dissolvable redox substance include electroactive organic molecule,
Organotransition metal complex and transition metal coordination complexes.Term " dissolvable redox substance " does not include elemental metals
It does not especially include those of not dissolving in or being insoluble in water with isolated metal ion.
Term " oxidoreducing enzyme " is defined as that any enzyme of the oxidation of analyte or reduction can be promoted.Oxidoreducing enzyme is
A kind of reagent.Term " oxidoreducing enzyme " includes: " oxidizing ferment " that can promote oxidation reaction, in the oxidation reaction, molecular oxygen
It is electron acceptor;It can promote " reductase " of reduction reaction, in the reduction reaction, analyte is reduced, and molecular oxygen is not
Analyte;And " dehydrogenase " of oxidation reaction can be promoted, in the oxidation reaction, molecular oxygen is not electron acceptor.For example, ginseng
See " Oxford Dictionary of Biochemistry and Molecular Biology, Revised Edition,
A.D.Smith,Ed.,New York:Oxford University Press(1997)pp.161,476,477,and 560”
(" biochemistry and the molecular biology oxford dictionary " that A.D.Smith, Ed. write, revised edition, New York, Oxford University Press
(1997), page 161,476,477 and 560).
Term " electroactive organic molecule " is defined as being free of metal and can occur organic point of oxidation or reduction reaction
Son.Electroactive organic molecule can be used as mediator.
Term " organotransition metal complex ", also referred to as " OTM complex compound ", are defined as a kind of complex compound, wherein mistake
Cross metal by σ key and at least one carbon atom bonding (formal charge on carbon atom being bonded with transition metal with σ key for-
1) or pass through pi bond and at least one carbon atom bonding (formal charge on carbon atom being bonded with transition metal with pi bond is 0).
For example, ferrocene is a kind of tool there are two the OTM complex compound of ring cyclopentadienyl dialkylene (Cp) ring, each ring passes through the five carbon originals of oneself
Son is bonded by two pi bonds and a σ key with iron center.Another example of OTM complex compound is the iron cyanide (III) and its process
Ferrocyanide (II) counter pair of reduction, six of them cyano ligands (the form electricity in each of six ligands
Lotus is -1) it is bonded by carbon atom with iron center with σ key.
Term " co-ordination complex " is defined as a kind of complex compound with clearly defined coordination geometry, such as eight
Face body complex compound or square plane (shape) complex compound.It is different with the OTM complex compound as defined in itself be bonded, co-ordination complex
It is to be defined by their geometry.Therefore, co-ordination complex can be (such as the previously mentioned iron cyaniding of OTM complex compound
Object) or such a complex compound, wherein the non-metallic atom other than carbon, the heterocycle for example including nitrogen, sulphur, oxygen and phosphorus
Atom, (datively) is bonded with transition metal centre in a manner of giving.For example, it is a kind of coordination network that hexa, which closes ruthenium,
Object is closed, with clearly defined octahedral geometry, six of them NH3Ligand (the shape in each of 6 ligands
Formula charge is 0) to be bonded in a manner of giving with ruthenium center.Organotransition metal complex, co-ordination complex and transition metal bonding
Be discussed more fully and may refer to " Collman et al., Principles and Applications of
Organotransition Metal Chemistry (1987) " and " Miessler & Tarr, Inorganic Chemistry
(1991) " (" principle and application of organotransition metal chemistry " (1987) of the works such as Collman and Miessler and Tarr
" inorganic chemistry " (1991) of works ".
Term " stable state " is defined as when electrochemical signals (electric current) is relative to its independent input variable (voltage or time)
Variation it is substantial constant when, such as when the variation is within ± 10% or ± 5%.
Term " instantaneous point " is defined as being transformed into relatively when measurable substance to the cumulative diffusion rate of conductive surface
When constant diffusion rate, the current value of the function obtained as the time.Before instantaneous point, electric current changes rapidly at any time
Become.Similarly, after instantaneous point, current decay rate becomes relative constant, to reflect measurable substance to conductive surface
Relative constant diffusion rate.
Term " relative constant " is defined as the variation when current value or diffusion rate ± 20%, ± 10% or ± 5%
Within when.
Term " average initial thickness " refers to the average height of the layer before introducing fluid sample.It uses term " average "
It is that there is protrusion and recess because the top surface of layer is uneven.
Term " redox intensity (RI) " is defined as total firing time of pulse train divided by total firing time and total
The sum of relaxation time.
Term " handheld apparatus " is defined as that device in manpower and portable can be held in.The one of handheld apparatus
A example isMeasuring device provisioned in Elite blood glucose monitoring system, by the state of Indiana (IN) Ai Erkeha
Bayer HealthCare, the LLC company sale of special (Elkhart).
Term " ... upper (on) " be defined as " ... above " and be for described direction.Example
Such as, it if first element is deposited at least part of second element, is write as first element and is deposited in second element.
In another example, if first element is located above at least part of second element, write as first element in second element
On.Using term " ... on " when be not precluded between described upper element and lower element that there is also substances.Example
Such as, first element can have a coating on its top face, and above first element and its at least part of Topcoating
Two element can be write as " on the first element ".Therefore, using term " ... on " can indicate that related two elements carry out
It is physically contacted or without physical contact.
Detailed description of the invention
The present invention may be better understood in conjunction with following attached drawing and explanation.Component part in attached drawing need not according to than
Example, but focus on explaining the principle of the present invention.In addition, in the accompanying drawings, the corresponding part in all different views is by similar
Appended drawing reference indicate.
Figure 1A is the perspective view of the sensing zone of assembly.
Figure 1B is the top view for removing the later sensing zone of lid.
Fig. 2 shows the end-views of sensing zone in Figure 1B.
Fig. 3 shows the electrochemical analysis method for measuring the presence of analyte and concentration in sample.
Fig. 4 A and Fig. 4 B are shown during applying long read pulse and short read pulse, have surface conductor and DBL
Working electrode.
Fig. 5 A~Fig. 5 E shows five examples of pulse train, is used for after introducing sample, by multiple working cycles
It is applied to sensing zone.
Fig. 6 A is shown for the 40% hematocrit WB sample comprising 50,100,200,400 and 600mg/dL glucose
Product, the instantaneous output current of pulse train shown in Fig. 5 B.
Fig. 6 B show by draw and connection figure 6A shown in each transient current profile the last one current value and
Obtained current profile curve.
Fig. 6 C shows the current profile curve obtained from the transient current profile that the pulse train as shown in Fig. 5 E generates.
Fig. 6 D explains associated with input signal defeated in the electro-chemical systems using gated amperometric pulse train
Signal out.
Fig. 7 A and Fig. 7 B explain the raising of accuracy of measurement when DBL is in conjunction with short read pulse.
Fig. 7 C and Fig. 7 D are explained when gated amperometric pulse train is in conjunction with DBL, the drop of hematocrit bias
It is low.
Fig. 8 is depicted when the pulse train of Fig. 5 B to be applied to the WB sample comprising various concentration of glucose, multiple
The endpoint electric current recorded at working cycles.
Fig. 9 A is shown when 2.0 μ L samples are introduced into 10 different sensing zones, the pulse train shown in Fig. 5 B
Obtained transient current profile.
Fig. 9 B shows the curve of the rate of disintegration of each pulse train changed from Fig. 9 A as the function of time.
Figure 10 is depicted for 50,100 and 400mg/dL concentration of glucose, and the K constant come is determined from pulse train and is made
For the function of temperature.
Figure 11 is the schematic diagram of measuring device.
Specific embodiment
Present invention utilizes such a discoveries, that is, the gated amperometric pulse train containing multiple working cycles can
To provide improved accuracy and precision for analysis while shorten the deadline of above-mentioned analysis.Each working cycles include one
The secondary excitation that can be provided under relative constant voltage.Each working cycles further include once can be by (the open that opens a way
Circuit) the relaxation provided.Pulse train of the invention is without the need for additional delay and pulse, such as providing reagent
" latent (incubation) " delay of rehydration, " fusing (the burn-off) " pulse for updating electrode and it is situated between for updating
The mediator of body oxidation state restores pulse, analysis time is reduced with this, thus the time needed for can shortening above-mentioned analysis.
Even if having shorter analysis time, gated amperometric pulse train of the invention compared with conventional method still
Accuracy and/or precision can be improved.In one aspect, can by the combination of diffusion barrier layer and pulse train of the present invention,
Come reduce the accuracy error introduced by hematocrit effect and due to variation cap gap volume and the trueness error that introduces.?
On the other hand, it can reduce in addition by the error caused by unstable state sensor situation and/or mediator background.Door of the invention
Control pulse train also allows for measurement transient current and the contour curve for simulating stable situation.Transient current profile is available
Come provide multiple groups calibration constants, it is unfilled detection and measurement sample temperature ability, rather than rely on from measuring device
Temperature.
Figure 1A and Figure 1B, which is shown, can be used for sensing zone 100 of the invention.Figure 1A is the solid of the sensing zone 100 of assembly
Figure, sensing zone 100 include sensor base 110, it is at least partly by including that discharge orifice 130, recessed area 140 and input terminal are opened
The lid 120 of mouth 150 covers.Partially enclosed space 160 (that is, cap gap) is formed between pedestal 110 and lid 120.?
Other sensing zones being consistent with the present invention can be used to design, such as in United States Patent (USP) No.5,120,420 and No.5,798,031
Those described sensing zones.
The fluid sample for being used to analyze can be transported in cap gap 160 by inserting the liquid into opening 150.Liquid
Cap gap 160 is filled, while the air for previously having included being discharged by discharge orifice 130.Cap gap 160 can containing one kind facilitate by
Fluid sample is maintained at the component (not shown) in the cap gap.The example of this component includes such as carboxymethyl cellulose and poly- second
The water-swellables polymer such as glycol, and the porous polymers matrix such as glucan and polyacrylamide.
Figure 1B shows the top view for removing the later sensing zone 100 of lid 120.Conductor 170 and 180 can be in dielectric layer
190 extend to working electrode 175 from opening 150 separately below and to electrode 185.In one aspect, as shown, working electrode
175 and same plane can be located substantially on to electrode 185.In related fields, working electrode 175 and can phase to electrode 185
Every the distance greater than 200 or 250 μm, and at least 100 μm can be separated by with the top of lid 120.Dielectric layer 190 can part
Ground covers electrode 175,185, and can be made of any suitable dielectric material such as insulating polymer.
The current potential of sensing zone 100 electrode 185 balanced at working electrode 175.In one aspect, which can be
The reference potential obtained in the following way: by the redox couples shape such as Ag/AgCl paired electrode 185, to provide reference-
To electrode combination.On the other hand, which can be provided in the following way sensing system: lazy by carbon etc.
The material shape paired electrode 185 of property, and in cap gap 160 including the iron cyanide etc. dissolvable redox substance.It can
Selection of land, sensing zone 100 can be equipped with third conductor and electrode (not shown), to provide reference potential to sensing system.
Fig. 2 shows the end-views of sensing zone shown in Figure 1B, the layer for illustrating working electrode 175 and to electrode 185
Structure.Conductor 170 and 180 can be placed directly on pedestal 110.Optionally, deposition table can be distinguished on conductor 170 and 180
Face conductor layer 270 and 280.Surface conductor layer 270,280 can be made of identical or different material.
The material (or each material) for being used to form conductor 170,180 and surface conductor layer 270,280 may include arbitrarily leading
Electric body.Preferred electric conductor is non-ionic (non-ionizing), so that the material will not occur during sample analysis
Net oxidation (net oxidation) or net reduction (net reduction).Conductor 170,180 preferably includes a metal film or gold
Belong to thin layer, such as Au Ag Pt Pd, copper or tungsten.Surface conductor layer 270,280 preferably includes carbon, gold, platinum, palladium or their group
It closes.If conductor does not have surface conductor layer, which is preferably made of non-ionic material.
Conductor is deposited on and any usual manner that the surface conductor material can be consistent by the work with sensing zone
170, on 180, these modes include foil deposition, chemical vapor deposition, paste deposition, etc..It, can in the case where paste deposition
It is equally applied to conductor 170,180 so that image ink will be mixed, such as United States Patent (USP) No.5, as described in 798,031.
Reagent layer 275 and 285 can be respectively deposited on conductor 170 and 180, and including reagent, optionally further include
Adhesive.Adhesive material is preferably polymeric material, at least has part aqueous.Part aqueous appropriate, be used as
The polymeric material of adhesive may include polyethylene oxide (PEO), carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), hydroxyl
Ethylidene cellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose, ethyl cellulose, ethylhydroxyethylcellulose, carboxylic
The polyaminoacid such as methylethylcellulose, polyvinylpyrrolidone (PVP), polylysine, Polystyrene Sulronate, gelatin, third
Olefin(e) acid, methacrylic acid, starch, their maleic anhydride salt, their derivative and their combination.Currently,
In above-mentioned adhesive material, PEO, PVA, CMC and PVA are preferably that wherein CMC and PEO is preferred.
Reagent layer 275 and 285 can also include identical or different reagent other than including above-mentioned adhesive.One
A aspect can choose the reagent being present in the first reagent layer 275 to be used together with working electrode 175, and can choose
The reagent being present in the second reagent layer 285 with to electrode 185 to be used together.For example, the reagent in layer 285 can promote electricity
Son moving freely between sample and conductor 180.Similarly, the reagent in layer 275 can promote the reaction of analyte.
Reagent layer 275 may include the oxidoreducing enzyme for having specificity to analyte, can promote the reaction of analyte,
Enhance specificity of the sensing system to the specificity of analyte, especially to the analyte in complex compound biological sample simultaneously.
Provide the example of some specific oxidation reductases and respective analyte in table ii below.
Oxidoreducing enzyme (reagent layer) | Analyte |
Glucose dehydrogenase | β-glucose |
Glucose oxidase | β-glucose |
Cholesterol esterase;Cholesterol oxidase | Cholesterol |
Lipoprotein lipase;Glycerokinase;Glycerol-3-phosphate oxidase | Triglycerides |
Lactate oxidase;Lactic dehydrogenase;Diaphorase | Lactate |
Pyruvate oxidase | Acetonate |
Alcohol oxidase | Alcohol |
Bilirubin oxidase | Bilirubin |
Uricase | Uric acid |
Glutathione reductase | NAD(P)H |
Oxidation of Carbon Monoxide reductase | Carbon monoxide |
Table II
Currently, the oxidoreducing enzyme for being particularly preferred for glucose analysis include glucose oxidase, glucose dehydrogenase, it
Derivative or their combination.
Reagent layer 275 can also include mediator, the result of analyte response is effectively communicated to surface conductor 270
And/or conductor 170.The example of mediator includes OTM complex compound, co-ordination complex and electroactive organic molecule.Specific example packet
It includes: ferrocene-containing compound, ferrocyanide, the iron cyanide, the pyrroloquinoline quinone for being substituted or being unsubstituted (PQQ) coenzyme, warp
3- phenylimino -3H- the phenthazine (PIPT) for replacing or being unsubstituted, 3- phenylimino -3H- phenoxazine (PIPO), warp
The benzoquinones for replacing or being unsubstituted, the naphthoquinones for being substituted or being unsubstituted, nitrogen (N) oxide, nitroso compound, azanol, hydroxyl
Base quinoline, flavine, azophenlyene, phenazene derivative, phenthazine, indophenols and indamines.May include in reagent layer these and its
His mediator can with reference to United States Patent (USP) No.5,653,863, No.5,520,786, No.4,746,607 and No.3,791,988 with
And European patent No.0 354 441 and No.0 330 517.
Currently, the mediator for being particularly preferred for glucose analysis include the iron cyanide, hexa close ruthenium,
PIPT, PIPO or their combination.The summary that can be used for the electrochemical mediator of biological oxidation system may refer to
Analytica Clinica Acta.140 (1982), the 1-18 pages.
Reagent layer 275,285 can by printing, liquid deposition or any convenient mode such as inkjet deposited sink
Product.In one aspect, each layer is deposited by printing.In the identical situation of other factors, the angle meeting of knife is printed
The thickness of reagent layer is influenced in turn.For example, thickness can be greatly when printing knife and pedestal 110 is moved at about 82 ° of angles
About 10 μm.Similarly, when using spending with pedestal 110 at about 62 ° of printing nose angle, it can produce 30 μm of relatively thick-layer.Cause
This, printing nose angle degree is smaller, then the reagent layer that can be provided is thicker.Other than printing nose angle degree, such as material therefor glues
Property and the other factors such as step sizing (screen-size) and emulsion compound also will affect obtained reagent layer 275,
285 thickness.
Working electrode 175 can also include diffusion barrier layer (DBL), and the DBL and reagent layer 275 are integrally formed, or solely
Vertical layer 290, as shown in Figure 2.Therefore, DBL can be formed as to reagent/DBL combination layer on conductor, the independent stratum on conductor
Or the independent stratum on reagent layer.When working electrode 175 includes independent DBL 290, reagent layer 275 can be located at or not be located at
On DBL 290.Reagent layer 275 can not be located on DBL 290, but being located at can make reagent be dissolved in the sensing zone in sample
On 100 arbitrary portion.For example, reagent layer 175 can be located on pedestal 110 or lid 120.
DBL provides the porous space with internal capacity, and measurable substance can be placed in the space.It can choose
The hole of DBL, so that can measure substance the biggish sample in volume such as can be spread in DBL, while making RB cell
Component is substantially all to foreclose.Although conventional sensing zone is used for a variety of materials to filter from the surface of working electrode
Except RB cell, but DBL provides the internal porous space of the measurable substance of a part for receiving and being isolated sample.
When reagent layer 275 includes water-soluble binder, any adhesive insoluble in sample before being excited
Part can act as the effect of a complete DBL.It is micro- that the average initial thickness of DBL/ reagent combination layer is preferably smaller than 30 or 23
Rice (μm), more preferably less than 16 μm.Currently, the average initial thickness of particularly preferred DBL/ reagent combination layer is 1~30 μm or 3
~12 μm.It, can be based on can measure substance (such as conductor 170 in Fig. 2 from DBL to conductive surface for specific energised length
Surface or surface conductor 270 surface) diffusion rate when become relative constant, to select required DBL/ reagent to combine
The average initial thickness of layer.
In addition, the too thick DBL of use may postpone can measure substance from DBL to conductive surface for short energised length
Diffusion rate at the time of become relative constant.For example, when the work for including excitation in 1 second that is continuous, being separated by 0.5 second relaxation
When circulation is applied on the working electrode for the DBL/ reagent combination layer for the use of average initial thickness being 30 μm, work at least six
Before circulation has applied (>~10 seconds), preferred diffusion rate may be not achieved.In turn, when identical working cycles are applied
When being added on the working electrode for the DBL/ reagent combination layer for the use of average initial thickness being 11 μm, second of excitation (~2.5 seconds)
Relative constant diffusion rate can be reached later.Therefore, for scheduled working cycles, DBL's is preferred average initial thick
Degree has a upper limit.About DBL thickness, energised length and between the time for reaching relative constant diffusion rate it is associated more
It thoroughly discusses, on 2 22nd, 2005 " Concentration Determination in a submitting, entitled can be referred to
The U.S. Provisional Application No.60/655,180 of Diffusion Barrier Layer (concentration mensuration in diffusion barrier layer) ".
Independent DBL 290 may include that can provide required space with holes, simultaneously partially or slowly be dissolved in sample
Any material.In one aspect, independent DBL 290 may include the reagent adhesive material without reagent.Independent DBL
290 average initial thickness can be at least 5 μm, preferably 8~25 μm, and more preferable 8~15 μm.
Fig. 3 shows electrochemical analysis method 300, for measuring the presence of analyte 322 in sample 312, optionally also
Measure the concentration of analyte 322 in sample 312.In the step 310, sample 312 is introduced into sensing zone 314, such as Figure 1A~
Figure 1B and sensing zone shown in Fig. 2.The reagent layers such as the reagent layer 275 and/or 285 in Fig. 2, start to be dissolved in sample 312,
So that can react.About this point in analysis, the initial time that reagent is reacted with sample 312 is provided and is prolonged
Late or " incubation period " may be beneficial.Preferably, initial time delay can be 1 second~10 seconds.Initial time delay is more
United States Patent (USP) No.5,620,579 and No.5,653,863 can be referred to by thoroughly discussing.
During reaction, in step 320, a part of the analyte 322 contained in sample 312 is for example gone back by oxidation
Chemistry or biochemical oxidation or reduction occur for protoenzyme etc..Using oxidation or reduction, electronics can optionally in a step 330
It is shifted between analyte 322 and mediator 332.
In step 340, measurable substance 342 is subjected to electrochemistry excitation (oxidation or reduction), this can measure substance can
To be the electrically charged analyte 322 from step 320 or the electrically charged mediator 332 from step 330.For example, working as sample
312 be containing shifting electronics in a step 330 by glucose oxidase, then in step 320 to by iron cyanogen
Compound (III) mediator reduction at the glucose of ferrocyanide (II) whole blood when, the excitation of step 340 is by ferrocyanide
(II) iron cyanide (III) is oxidized at working electrode.By this method, it is transferred to from glucose analysis object to electronic selection
The working electrode of sensing zone, it can be measured device detection there.
The electric current as caused by exciting step 340 can be used as the function of time during exciting step 340, in step 350
In record.In step 360, sample experienced relaxation.Preferably, the not record current during the relaxation of step 360.
In step 370, according to this mode of at least three working cycles a total of in 180 seconds or shorter time section,
Repeat exciting step 340, recording step 350 and relaxation step 360 at least twice.In step 380, it can analyze and to be recorded
Electric current and time value, to measure the presence and/or concentration of analyte 322 in sample 312.
Amperometric sensor system, which applies a current potential (voltage) to sensing zone, can measure substance to excite, and supervise simultaneously
It surveys electric current (amperage).Conventional amperometric sensor system can maintain the current potential, while measure such as 5~10 seconds continuously
The electric current of read pulse length.Compared with conventional method, working cycles used in electrochemical analysis method 300 are with multiple short
Duration excitation and relaxation are instead of continuous long duration read pulse.
Because unlike being present in the cap gap of sensing zone from measurable substance, being excited at working electrode in 540
Measurable substance substantially from the inside DBL, therefore, the accuracy of analyte determination result can be improved in analysis method 300
And/or precision.Fig. 4 A and Fig. 4 B are shown during applying long read pulse and short excitation, with surface conductor 430 and solely
The working electrode 400 of vertical DBL 405.When WB sample is placed on working electrode 400, RB cell 420 covers DBL 405.Sample
Present in analyte DBL 405 it is external formed outside can measure substance 410.A part of the measurable substance 410 in outside
It is diffused into independent DBL 405, to obtain internal measurable substance 415.
As shown in Figure 4 A, when by one read pulse is applied to working electrode 400 within continuous 10 seconds when, can outwardly and inwardly survey
Quantity of material 410 and 415 is all excited at surface conductor 430 by oxidation state variation.During long read pulse, outside can
Measurement of species 410, which diffuses through the sample area of RB cell 420 and passes through DBL 405, reaches surface conductor 430.Outside can measure
Substance 410 diffuses through RB cell 420 during read pulse, this is just introduced into hematocrit effect in analysis.Because
The major part of the measurable substance excited at surface conductor 430 derives from the outside of DBL 420, therefore, in hematocrit
In terms of effect, the result of the long read pulse being applied on the sensing zone with DBL may be with the sensing zone that is applied to not DBL
On short read pulse result it is similar.
On the contrary, Fig. 4 B, which is shown, is applied to the sensing zone 400 equipped with DBL for short excitation, to excite internal measurable object
Not the case where matter 415 does not excite measurable substance 410 outside DBL 405 substantially simultaneously.During short excitation, substance can measure
410 are perhaps maintained at outside DBL 405 or will not substantially diffuse through DBL arrival surface conductor 430.In this way,
Short excitation can be substantially reduced influence of the hematocrit effect to analysis.
By controlling the energised length at working electrode, the measurable substance inside DBL can analyze, while substantially
The measurable substance outside DBL is not analyzed.Diffusion rate relative to external measurable substance 410, it is believed that the thickness of DBL 405
Internal measurable diffusion rate of the substance 415 to working electrode surface conductor 430 should be able to be changed with internal capacity.
Because the measurable substance inside DBL can be diffused to according to the rate for the measurable substance being different from outside DBL
The conductor of working electrode, therefore the length excited at working electrode can choose the measurable substance preferentially analyzed.From molecule
Viewpoint it will also be appreciated that, the different diffusion rates of DBL inside and outside measurable substance allow for difference.
Although being not intended to be limited to any particular theory, it is now recognized that can measure substance outside DBL to
Diffusion rate in DBL is variation, and it is relative constant for can measure diffusion rate of the substance from DBL inner space to conductor
's.Can measure the diffusion rate of the variation of substance outside DBL may be that RB cell and other components as present in sample cause
, and may cause hematocrit effect.It therefore, can be by sufficiently limiting to relative constant with being spread to conductor
The measurable substance of diffusion rate is analyzed, and is reduced by the introduced analytical error of the sample component for including RB cell (partially
Difference).
Selectively analyze DBL inside measurable substance another advantage is that reducing due to different cap gaps
Inexactness is measured caused by the sensing zone of volume.If read pulse continues and is more than all present in cap gap can measure
Substance substantially has not been analyzed the time used, then the above-mentioned analysis just measurable material concentration no longer in representative sample,
But determine the amount of the measurable substance in cap gap;This is a very different measurement result.Due to energised length relative to
Cap gap volume is longer, therefore current measurement result will depend on cap gap volume, rather than basic analyte concentration.Therefore,
When measurable substance in the presence of pulse length " overshoot in (overshoot) " cap gap, long read pulse be may result in
Measurement result is grossly inaccurate about analyte concentration.
Such as " Concentration Determination in a submitting, entitled on October 12nd, 2004
In the U.S. Provisional Application No.60/617,889 of Diffusion Barrier Layer (concentration mensuration in diffusion barrier layer) "
As described, single short read pulse or excitation can choose to fully limit the measurable substance excitation of DBL.When making
When with single-shot, energised length and the thickness of DBL can be preferably chosen so that during exciting period realize can measure substance from
Relative constant diffusion rate of the DBL to conductive surface.If being not carried out relative constant diffusion rate during exciting period,
Measurable material concentration in DBL would not accurately in representative sample measurable material concentration, to be generated not to analysis
Benefit influences.In addition, single-shot will not be effectively reduced the back end signal from mediator.
Referring to Fig. 3, exciting step 340, recording step 350 and relaxation step 360 constitute a working cycles, it can be
It is at least applied to sensing zone three times in 180 seconds or shorter time period.It is highly preferred that in 120 seconds, 90 seconds, 60 of independent choice
In second, 30 seconds, 15 seconds, 10 seconds or 5 second time cycle, apply at least four, 6,8,10,14,18 or 22 work
Circulation.In one aspect, applied above-mentioned working cycles within 5~60 second time cycle.On the other hand, can at 30 seconds or
Apply 3~18 or 3~10 working cycles in shorter time.On the other hand, 4 can be applied within 3~16 second time
~8 working cycles.
The current potential applied during 340 part of exciting step of working cycles, preferably according in entire continue
Between upper substantially invariable voltage and polarity and apply.This with during recording data voltage change or " after
(swept) " multiple voltage potentials and/or polar regular readings pulse shaping directly compare.In one aspect, exciting step
340 duration is at most 4 seconds or 5 seconds, preferably smaller than 3 seconds, 2 seconds, 1.5 seconds or 1 second.On the other hand, exciting step
340 duration is 0.01~3 second, 0.01~2 second or 0.01~1.5 second.It is highly preferred that exciting step 340 it is lasting when
Between be 0.1~1.2 second.
After exciting step 340, in step 360, measuring device can open circuit by sensing zone 314, thus
So that system relaxation.During relaxation step 360, the electric current occurred during exciting step 340 is substantially reduced at least one
Half, preferably reduce a biggish magnitude, is more preferably decreased to zero.Preferably, zero current condition is common by open circuit or this field
The known other methods for providing the electric current being substantially zero of technical staff provide.In the working cycles phase of pulse train
Between at least 3 relaxation can be provided.
In one aspect, the duration of relaxation step 360 be at least 10 seconds, 5 seconds, 3 seconds, 2 seconds, 1.5 seconds, 1 second or 0.5
Second.On the other hand, the duration of relaxation step 360 is 0.1~3 second, 0.1~2 second or 0.1~1.5 second.More preferably
The duration on ground, relaxation step 360 is provided for 0.2~1.5 second and by open circuit.
During relaxation step 360, ionization preparation can be given birth under the action of no current potential with analyte response
At additional measurable substance.Therefore, it is passed for including glucose oxidase and iron cyanide mediator as the glucose of reagent
Sensor system can not can be generated the analyte concentration in response to sample by the interference of the current potential during relaxation step 360
Additional ferrocyanide (mediator being reduced).
Many conventionals method of analysis continuously apply voltage in a period of the read pulse duration.The voltage applied can
It has fixed current potential, or can have following current potential, change to negative potential from positive potential or from positive potential or negative potential
Change to the zero potential relative to a current potential.Even in zero relative potentials, these methods also continue during read pulse
Electric current is obtained from sensing zone, this recurs electrochemical reaction during entire read pulse.Therefore, generation corresponds to
Diffusion of the reaction and measurable substance of the measurable substance of analyte concentration to working electrode all can be by regular readings arteries and veins
The influence of electric current during the zero potential part of punching.
Continuously apply voltage to sensing zone in the zero potential relative to a current potential and obtains electricity from sensing zone
The conventional method of stream, with relaxation fundamental difference of the invention.Due to multiple relaxation of the invention, multiple works of the present invention
Recycle the conventional method for being also significantly different from and taking multiple measurements using single long duration pulse, such as United States Patent (USP)
Those conventional methods disclosed in No.5,243,516.With these conventional methods on the contrary, each work of pulse train of the invention
Make circulation and both provides independent diffusion and the analyte response time during relaxation.
Fig. 5 A~Fig. 5 E shows five examples of gated amperometric pulse train, wherein after introducing sample, it is more
A working cycles are applied to sensing zone.In these examples, square-wave pulse is used;But it is also possible to using with sensing system
Other wave modes being consistent with sample to be tested.Fig. 5 C~Fig. 5 D show including it is multiple have identical firing time and open circuit delay when
Between working cycles pulse train.
Fig. 5 A~Fig. 5 B shows the pulse train including 9 working cycles, in addition to having longer duration and voltage increasing
Other than big terminal read pulse 510, these working cycles have identical firing time and open circuit delay time.This terminal is read
The increase voltage of rapid pulse punching, which provides, detects the mediator with higher oxygen current potential (oxidation potential)
Ability.It may refer to " Oxidizable submitting, entitled on April 8th, 2005 about being discussed more fully for terminal read pulse
The U.S. of Species as an Internal Reference in Control Solutions for Biosensors " faces
When apply for No.60/669,729.
Fig. 5 A shows 9 duty cycle pulse sequences, wherein excitation in each 0.5 second was spaced from each other by open circuit delay in 1 second,
It is 0.357 (5/14) to obtain redox intensity (RI).In this way, in fig. 5, second working cycles has excitation portion
Divide 520 and relaxation part 530.Fig. 5 B shows 9 duty cycle pulse sequences, wherein excitation in each 1 second was prolonged by 0.5 second open circuit
It is spaced from each other late, so that obtaining RI is 0.69 (10/14.5).Fig. 5 C shows 7 duty cycle pulse sequences, wherein each 1 second
Excitation was spaced from each other by open circuit delay in 1 second, so that obtaining RI is 0.53 (8/15).The duration of terminal read pulse 540
It is identical as duration and voltage used during 7 working cycles with voltage.Fig. 5 D shows 6 duty cycle pulse sequences
Column, wherein excitation in those 1.5 seconds was spaced from each other by open circuit delay in 1 second, so that obtaining RI is 0.636 (10.5/16.5).Such as figure
In 5C like that, duration and voltage phase of the duration and voltage of terminal read pulse 540 with previous work cycle pulse
Together.Fig. 5 E shows 7 duty cycle pulse sequences, wherein those of relatively short 0.25 second excites by relatively long
Relaxation is spaced from each other within 1.5 seconds.The pulse train of Fig. 5 E was started with 1 initial pulse per second (PPS) 550, and with 1.25 seconds terminal count arteries and veins
Punching 540 terminates, so that providing RI is 0.25 (4/16).
The RI of pulse train is higher, will be fewer by the back end that mediator is introduced into analysis.Arteries and veins shown in Fig. 5 A~Fig. 5 E
Rushing sequence is oxidisability pulse, is designed to mediator that excitation (that is, oxidation) is reduced and as measurable substance.Cause
This, the oxidation current being applied on sensing zone within the scheduled time cycle is bigger, then because analyte oxidation except approach due to
The mediator being reduced is smaller to the contribution possibility of institute's record current value.
Following Table III provide the contour curve of last four working cycles of pulse train (a) and (b) slope,
Intercept and the ratio between intercept and slope.For pulse train (a):
9 × (open for 0.5 second+1.0 seconds and interrupt)+0.5 second=14 seconds, RI=5/14=0.357.
For pulse train (b):
9 × (open for 1.0 seconds+0.375 second and interrupt)+1.0 seconds=13.375 seconds, RI=10/13.375=0.748.
Table III
The ratio between intercept and slope provide the assessment for being attributed to the amount of back end signal of mediator, wherein higher ratio table
Show that the major part of recorded signal is attributed to mediator background.Therefore, when sequence (a) and (b) pulse frequency (excitation number/
Total chemical examination time (second)) similar and about 0.7sec-1When, the increase of the RI as provided by pulse train (b), so that due to
The signal section of mediator background reduces more than half.When being combined, pulse train it is multiple excitation can eliminate to
In the needs for the inceptive impulse for updating mediator oxidation state.Since back end electric current may be influenced by mediator, for iron cyaniding
The pulse train that object, preferably RI value are at least 0.01,0.3,0.6 or 1, more preferable RI value are 0.1~0.8,0.2~0.7 or 0.4
~0.6 pulse train.
Fig. 3 is referred again to, in step 350, each working cycles of pulse train can be directed to, pass through sensing zone 314
The electric current of conductor be recorded as the function of time.Fig. 6 A is shown for containing 50,100,200,400 and 600mg/dL glucose
40% hematocrit WB sample, function of the output electric current of pulse train shown in Fig. 5 B as the time.With cause to survey
Unlike the conventional long duration read pulse that quantity of material largely aoxidizes, in current curve, excitation has one below every time
A interruption.
In fig. 6, when drawing out output electric current as the function of time, excitation leads to an instantaneous electricity every time
Flow curve has the initial higher current value to decay with the time.Preferably, working cycles include short, independent sharp
Hair and prevent that system reaches stable state during each excitation or electric current slowly decays the relaxation of situation, such as the reading arteries and veins of conventional system
As needed for during punching.Unlike the electric current of conventional stationarity or slow decay, from gated amperometric pulse train
Instantaneous (quickly decay) current value is obtained, because can measure electrochemical reaction of the substance at working electrode than measurable substance
Diffusion is supplied to the rate of working electrode faster.
Fig. 6 B show by by the last one current value of every transient current profile shown in Fig. 6 A (that is, swashing every time
The last one current value of hair) the contour curve figure that connects, and obtain.The contour curve can be used to simulate in the steady state
The data obtained from conventional system, electric current changes with time substantially constant under the stable state.
The transient current profile and obtained profile current value obtained from gated amperometric pulse train is not
It is same as the current curve obtained using single read pulse from conventional analysis.The electric current recorded from single read pulse is from single
A relaxation/diffusion, and each time point in the contour curve of transient current is after independent relaxation/diffusion process
Excitation.In addition, the correlation between electric current and analyte concentration is typically due to hematocrit effect when energised length lengthens
And it may reduce.Therefore, with the analysis phase that uses read pulse longer, with the duration repeatedly excited combined
Than the accuracy of the analysis using multiple short excitation can be improved.
Fig. 6 A is referred again to, when maximum last from exciting the expression of obtained last moment current value to obtain from any excitation
When moment current value, just reach the instantaneous point 605 in current curve.Therefore, according to Fig. 6 A, reach instantaneous when 5 seconds approximate
Point.For every kind of concentration of glucose, can reach at the maximum current value in the contour curve of every kind of concentration of glucose about
The balance of DBL rehydration.Therefore, when the transient current of Fig. 6 A is transformed into the profile electric current in Fig. 6 B, for the Portugal 600mg/dL
Grape sugar concentration, reads 610 (highests) and 620 (lower) to reach the expansion about measurable substance to DBL at about 5 seconds
Dissipate the balance with DBL rehydration.
The current value recorded under relative constant diffusion rate minimizes inaccuracy, on the contrary, the expansion of reagent
The variation for dissipating rate and rehydration will introduce inaccuracy.Therefore, once reaching relative constant diffusion rate, remembered
The current value of record will correspond more accurately to can measure substance concentration, and thus correspond more accurately to the dense of analyte
Degree.In addition, can complete entirely to analyze in short 7 seconds according to Fig. 6 B, as long as because the highest of known profile curve
Current value 610, its value can be directly associated with analyte concentration.As previously mentioned, additional data point can be obtained, thus
Reduce the back end error for being attributed to mediator.
Fig. 6 C shows the song of current profile obtained from the transient current profile according to caused by the pulse train in Fig. 5 E
Line.During each excitation in 0.25 second, in intermediate time (~0.125 second) and finish time (~0.25 second) record current
Value can be used to determine decay coefficient.Utilize the longer inceptive impulse with short excitation and relatively long relaxation, Ke Yi
Analysis is completed in about 4 seconds.
Fig. 6 D shows output related with input signal in the electro-chemical systems using gated amperometric pulse train
Signal.Input signal is applied to the current potential of biologicfluid sample.Input signal includes Polling (polling) input signal
With chemical examination input signal.Output signal is the electric current generated from sample.Output signal includes Polling output signal and chemical examination
Output signal.Sample response generates chemical examination output letter from the redox reaction of the glucose in whole blood in chemical examination input signal
Number.Input and output signal can be for working electrode and the biosensor to electrode.Other biologies can be used
Sensor, the biosensor including those with additional electrode and different structure.Other analyte concentrations can be measured, are wrapped
Those of include in other biological fluid analyte concentration.It can produce those of other output signals, including initial attenuation letter
Number and in whole pulses decaying those of signal.
In use, biologicfluid sample is placed in biosensor.Biosensor applies about -1.25 seconds to sample
~0 second Polling signal.Pulse has about 5~10 milliseconds of pulse width and about 125 milliseconds of pulse spacing.It is raw
Object sensor generates Polling output signal in response to Polling input signal.It is defeated that biosensor measures Polling
Signal out.Biosensor can have the voltage-stablizer that Polling output signal is provided to the input terminal of analog comparator.
When Polling output signal is equal to or more than Polling threshold value, biosensor applies to electrode from about
0 second to about 7 seconds chemical examination input signal.Polling threshold value may be about 250nA.It is defeated that comparator can compare Polling
Signal and Polling threshold value out.When Polling output signal is more than Polling threshold value, the output signal of comparator can
To trigger the transmission of chemical examination input signal.
During chemically examining input signal, biosensor applies to working electrode and to electrode with about 1 second time
The working cycles of first pulse of about 400mV current potential.0.5 second relaxation is ensued after first pulse, which actually may be used
To be open circuit etc..It measures the chemical examination output signal or electric current in the first pulse and stores in the storage device.Biosensor can
To apply the second pulse of the about 200mV current potential of about 1 second time to working electrode and to electrode.Measure the change in the second pulse
It tests output signal or electric current and stores in the storage device.Biosensor from chemical examination input signal continuously to working electrode and
Pulse is applied to electrode, until the time needed for chemically examining end cycle or reaching biosensor.The chemical examination period may be about 7
Second.Biosensor can measure and store the chemical examination output signal in each pulse.
Polling input signal is a kind of electric signals such as electric current or current potential, it according to setting frequency or partition
It is continuous to occur or open and interrupt.Sample response generates Polling output signal in Polling input signal.It examines in turn
Surveying output signal is a kind of electric signals such as electric current or current potential.Biosensor can show Polling output signal
And/or it can be by the storage of chemical examination output signal in the storage device on display.Biosensor can apply Polling letter
Number to detecting when that sample is connect with electrode.Other methods and device can be used to detect when to analyze in biosensor
Sample.
Polling input signal is that one kind wherein followed by the work that Polling relaxation separates by Polling pulse train
Ring.During Polling pulse, electric signal is to open.During Polling relaxation, electric signal is to interrupt.Unlatching can
To include the time cycle in the presence of electric signal.Interruption may include the time cycle in the presence of no electric signal.It interrupts not
Should include electric signal exist but time cycle when it there is no much amplitudes.Electric signal can pass through pass respectively
It closes and opens circuit and converted between unlatching and interruption.Circuit can be opened and closed by modes such as machinery, electric power.
Polling input signal can have one or more Polling pulse spacings.Between one Polling pulse
Every being the sum of a Polling pulse and a Polling relaxation.Each Polling pulse has amplitude and Polling
Pulse width.Amplitude indicates the intensity of current potential, electric current of electric signal etc..Amplitude can change during Polling pulse or
It is a constant.Polling pulse width is the duration of Polling pulse.Inspection in turn in Polling input signal
Surveying pulse width can change or substantially the same.Each Polling relaxation has Polling relaxation width, it is in turn
Detect the duration of relaxation.Polling relaxation width in Polling input signal can change or substantially the same.
Polling input signal can have the Polling pulse width less than about 300 milliseconds (ms) and be less than big
About 1 second Polling pulse spacing.Polling input signal can have the Polling pulse less than about 100 milliseconds
Width and Polling pulse spacing less than about 500 milliseconds.Polling input signal can have about 0.5 millisecond~
75 milliseconds of Polling pulse width and about 5 milliseconds~300 milliseconds of Polling pulse spacing.Polling input letter
Number it can have about 1 millisecond~50 milliseconds of Polling pulse width and about 10 milliseconds~250 milliseconds of Polling
Pulse spacing.Polling input signal can have about 5 milliseconds of Polling pulse width and about 125 milliseconds of wheel
The stream detection pulse spacing.Polling input signal can have other pulse widths and pulse spacing.
Biosensor can apply Polling input signal to sample during the Polling period.Polling week
Phase can be less than about 15 minutes, 5 minutes, 2 minutes or 1 minute.Biosensor, Polling how are used dependent on user
Period can be longer.The Polling period can be about 0.5 second (sec)~15 minute.The Polling period can be about 5
Second~5 minutes.The Polling period can be about 10 seconds~2 minutes.The Polling period can be about 20 seconds~60 seconds.
The Polling period can be about 30 seconds~40 seconds.The pulse spacing in Polling period can be less than about 200,100
It is a, 50 or 25.The pulse spacing in Polling period can be about 2~150.The pulse spacing in Polling period
It can be about 5~50.The pulse spacing in Polling period can be about 5~15 pulse spacings.Polling week
The pulse spacing of phase can be about 10.Other Polling periods can be used.
When Polling output signal is equal to or more than Polling threshold value, biosensor applies chemical examination input letter
Number.Polling threshold value can be greater than about 5% of desired chemical examination input signal when the first pulse starts.Polling threshold
Value can be greater than about 15% of desired chemical examination input signal when the first pulse starts.Polling threshold value can be first
About the 5%~50% of desired chemical examination input signal when pulse starts.Other Polling threshold values can be used.Biology
Sensor can show the Polling output signal for being equal to or more than Polling threshold value over the display.
Chemical examination input signal is a kind of electric signal, e.g. electric current or current potential, it is interrupted according to the frequency of setting or interval
Occur or opens and interrupt.Sample response generates chemical examination output signal in chemical examination input signal.Chemically examining output signal is one
Kind electric signal, e.g. electric current or current potential.
Chemically examining input signal is the chemical examination pulse train separated by chemical examination relaxation.During chemically examining pulse, electric signal is out
It opens.During chemically examining relaxation, electric signal is to interrupt.Unlatching includes the time cycle in the presence of electric signal.Interruption includes
There is no the time cycle in the presence of electric signal, and does not include that electric signal exists but when it there is no much amplitudes
Time cycle.Electric signal can be converted between unlatching and interruption by closing and opening circuit respectively.Circuit can pass through
The modes such as machinery, electric power and open and close.
Chemical examination input signal can have one or more chemical examination pulse spacings.One chemical examination pulse spacing is a chemical examination
The sum of pulse and a chemical examination relaxation.Each chemical examination pulse has amplitude and chemical examination pulse width.The electricity of amplitude expression electric signal
The intensity of position, electric current etc..Amplitude can change either constant during chemically examining pulse.Chemical examination pulse width is chemical examination pulse
Duration.Chemical examination pulse width in chemical examination input signal can change or substantially the same.Each chemical examination relaxation has
Relaxation width is chemically examined, it is the duration for chemically examining relaxation.Chemical examination relaxation width in chemical examination input signal can change or base
It is identical in sheet.
Chemical examination input signal can have the chemical examination pulse width less than about 5 seconds and the chemical examination pulse less than about 15 seconds
Interval.Chemical examination input signal, which can have, is less than about 3 seconds, 2 seconds, 1.5 seconds or 1 second chemical examination pulse widths and less than about 13
The chemical examination pulse spacing of second, 7 seconds, 4 seconds, 3 seconds, 2.5 seconds or 1.5 seconds.Chemical examination input signal can have about 0.1 second~3 seconds
Chemical examination pulse width and about 0.2 second~6 seconds chemical examination pulse spacings.Chemical examination input signal can have about 0.1 second~2
The chemical examination pulse width of second and about 0.2 second~4 seconds chemical examination pulse spacings.Chemical examination input signal can have about 0.1 second
~1.5 seconds chemical examination pulse widths and about 0.2 second~3.5 seconds chemical examination pulse spacings.Chemical examination input signal can have greatly
About 0.4 second~1.2 seconds chemical examination pulse widths and about 0.6 second~3.7 seconds chemical examination pulse spacings.Chemically examining input signal can be with
The chemical examination pulse spacing with about 0.5 second~1.5 seconds chemical examination pulse widths and about 0.75 second~2.0 seconds.Chemical examination input
Signal can have about 1 second chemical examination pulse width and about 1.5 seconds chemical examination pulse spacings.Chemical examination input signal can have
There are other pulse widths and pulse spacing.
Biosensor applies chemical examination input signal to sample during chemically examining the period.Chemical examination the period can have in turn
The detection cycle identical or different duration.The chemical examination period of chemical examination input signal can be less than about 180 seconds, 120 seconds, 90
Second, 60 seconds, 30 seconds, 15 seconds, 10 seconds or 5 seconds.The chemical examination period can be about 1 second~100 seconds.The chemical examination period can be about 1
Second~25 seconds.The chemical examination period can be about 1 second~10 seconds.The chemical examination period can be about 2 seconds~3 seconds.Chemically examining the period can be with
It is about 2.5 seconds.The chemical examination pulse spacing in chemical examination period can be less than about 50,25,20,15,10,8,6
It is a or 4.The chemical examination pulse spacing in chemical examination period can be about 2~50.The chemical examination pulse spacing in chemical examination period can be
About 2~25.The chemical examination pulse spacing in chemical examination period can be about 2~15.The chemical examination pulse spacing for chemically examining the period can
To be about 10.Other chemical examination periods can be used.
Fig. 7 A and Fig. 7 B show the raising of accuracy of measurement when DBL is in conjunction with short read pulse.By whole blood sample with
Ferrocyanide mixes, as basic concentration of glucose, then to be surveyed with read pulse in 1 second according to 1:5 dilution ratio
Amount.Therefore, the hematocrit WB sample of initial 20%, 40% and 60% is diluted to 16%, 32% and 48% haemocyte ratio
Hold (three hematocrite values all have dropped 20%).20%, 40% and 60% line is respectively represented from containing 16%, 32% and
The electric current measured in the blood sample sample of 48% hematocrit.
Fig. 7 A show as hematocrit and due to without DBL bare exposed conductor sensing zone caused by other effects and
The inaccuracy of introducing.Difference (total hematocrit inaccuracy being expressed as between 20% and 60% hematocrit line
Deviation spacing), and represent the maximum measurement inaccuracy for being attributed to hematocrit effect.Smaller deviation represents more quasi-
True result.As referring to as being discussed above Fig. 4 A, when DBL is used together with longer read pulse, observe similar
Effect.
On the contrary, Fig. 7 B is shown when DBL is in conjunction with read pulse in 1 second, spacing is aobvious between 20% and 60% lubber-line
It writes and reduces.As used in above-mentioned Fig. 7 A, the independent DBL being made of PEO polymer and 10%KCl (not having reagent) is printed
Brush is on conductor.Between total deviation when having total deviation hematocrit spacing when the short read pulse of DBL/ almost than no DBL
Away from small by 2/3rds.Therefore, measurement standard can be improved significantly including multiple working cycles, the pulse train combined with DBL
Exactness simultaneously desirably reduces mediator background.
Fig. 7 C and Fig. 7 D are shown when gated amperometric pulse train is in conjunction with DBL, can reduce hematocrit
Deviation.Fig. 7 C shows as DBL in conjunction with the pulse train of Fig. 5 E and is separated by 0.125 second at 14.875 seconds or with final pulse
When record current value, due to the measured deviation of hematocrit effect is within ± 5%.In order to compare, Fig. 7 D, which is shown, to be worked as
When concentration of glucose using the current value at moment 16 seconds (being separated by 1.25 seconds with final pulse) to measure sample, deviation is increased to
± 15%.Therefore, the duration of excitation is longer, then the hematocrit bias observed is bigger.
In addition to the present invention can reduce the ability of the inaccuracy from hematocrit effect and mediator background signal with
Outside, can be used the transient current profile excited every time combination and obtained contour curve, to be provided to sensing system
Multiple groups calibration constants, to improve the accuracy of analysis.Every group of calibration constants obtained can be used thus will specific electricity
Stream reading associates with the measurable substance certain concentration in sample.It therefore, in one aspect, can be by using multiple groups
The dextrose equivalent that calibration constants obtain is averaged to improve accuracy.
Conventional electrochemical sensing system turns current indication usually using calibration constants such as one group of slope and intercepts
Become the analyte concentration in corresponding sample.However, single group calibration is normal because in the measurements including random noise disturbance
Number may result according to the current value recorded and to determine the analyte concentration that comes inaccurate.
Current value is obtained by the set time in each working cycles of pulse train of the present invention, can establish multiple groups
Calibration constants.Fig. 8 is depicted when pulse train shown in Fig. 5 B to be applied to the WB sample comprising various concentration of glucose,
The end of 8.5 seconds, 10 seconds, 11.5 seconds, 13 seconds and 14.5 seconds (first parts of working cycles 6~9 and terminal read pulse) record
Point electric current.Each in this five lubber-lines is all mutually indepedent with others, and can make according at least two approach
With.
It is possible, firstly, to measure the number for the working cycles that should apply during pulse train using multiple groups calibration constants
Amount, to obtain the accuracy wanted, precision and chemical examination time.For example, if exciting the electric current obtained three times from beginning
Value shows high glucose concentration, such as > 150 or 200mg/dL, then sensing system can be terminated at about 5.5 seconds divides
Analysis, to shorten the time needed for analysis significantly.This shortening is feasible, because of inexactness when high glucose concentration
Inexactness when usually less than compared with low glucose concentrations.On the contrary, if exciting the current value obtained to show three times from beginning
Low glucose concentrations, such as≤150 or 100mg/dL, then sensing system can extend to analysis greater than 7 seconds, such as greatly
In 8 seconds or 10 seconds, to improve the accuracy and/or precision of analysis.
Secondly, multiple groups calibration constants can be used to improve the accuracy and/or precision of analysis by being averaged.Example
Such as, if target glucose time of measuring is 11.5 seconds, electric current when can use 8.5 seconds, 10 seconds and 11.5 seconds uses correspondence
The slope and intercept of lubber-line calculate concentration of glucose;Therefore just have, G8.5=(i8.5–Int8.5)/Slope8.5, G10=
(i10–Int10)/Slope10And G11.5=(i11.5–Int11.5)/Slope11.5.Theoretically, these three dextrose equivalents should be
Equivalent, it the difference is that only random deviation (random variation).It therefore, can be to dextrose equivalent G8.5、G10With
G11.5It is averaged, and calculates final dextrose equivalent (G8.5+G10+G11.5)/3.Being averaged according to lubber-line can be by noise
Interference reduces by 1/ √ 3.
It include the gated amperometric pulse sequence of relatively short excitation and relatively long relaxation shown in such as Fig. 5 E
Column, unexpected effect are to simplify the ability of calibration.Although the multiple groups calibration that can be obtained from instantaneous and contour curve is normal
Number can be conducive to the accuracy of analysis, but pulse train shown in such as Fig. 5 E also can provide with using multiple groups calibration constants and
The similar accuracy of the accuracy of acquisition is obtained by single group calibration constants.Although being not intended to any specific theory
It is limited, but this result may be attributed to the relatively long relaxation time opposite with short relaxation.The long relaxation time can
To provide such a state, in this state, the Mean Speed and measurable substance that substance changes during exciting period can measure
Diffuse to the rate equation in DBL.In this manner it is achieved that multiple groups calibration constants can collapse, (collapse) is single group, and can
With by carrying out taking average process to the current data recorded before measuring analyte concentration, and simplify record data to point
Analyse the transformation of object concentration.
Also the combination and obtained contour curve that the transient current profile excited every time can be used determine sensing zone
Whether do not filled up by sample, enables a user to add additional sample to sensing zone.Conventional sensors system is in addition to using
Working electrode and to electrode other than, can also be by using third electrode or electrode to determining unfilled situation;However, third
Electrode or electrode are to the complexity and cost for increasing sensing system.
Two conventional electrode systems can identify whether primary analysis result is " bad ", but not can determine that this bad point
Caused by whether the reason of analysing result be due to unfilled or defective sensing zone.Determine whether to result in due to unfilled
The ability of bad analysis result be it is beneficial because it is unfilled be can be by adding additional sample and repetition to same sensing zone
Analysis discards excellent sensing zone to prevent come what is corrected.
Fig. 9 A shows the transient current profile that the pulse train shown in Fig. 5 B obtains, wherein 10 analyses have been carried out,
Different sensing zones is all employed every time, and 2.0 μ L samples are introduced into sensing zone.According to the filling speed of specific sensing zone
With cap gap volume, 2.0 μ L samples may be enough or be not enough to fill sensing zone.
In figures 9 b and 9, the transient current profile of Fig. 9 A is converted into the rate of disintegration as the contour curve of the function of time.?
On one side, the rate of disintegration can be expressed as determining the K constant come from following any equation:
Wherein, the unit of value 0.125,0.5 and 1.0 is the second.It therefore, can be by the electric current of Fig. 9 A using the K constant of decay process
Curve transform at Fig. 9 B decay coefficient curve.
Fig. 9 B shows the decay curve of unfilled sensor between the decay curve of sensor that normally fills up
Significant difference, the especially difference in 3 seconds~7 seconds time ranges.It can be by comparing practical decay coefficient and previously selection
Value between difference, determined according to decay coefficient curve unfilled.For example, if selecting -0.1 as normally being filled out in Fig. 9 B
The upper limit of full sensor determines any K for being lower than -0.1 come from the excitation during 3~5 second time cycle1Constant value is all
It may be considered and normally fill up.Similarly, K1Value is construed as unfilled higher than -0.1 any sensor.According to this
Kind mode, so that it may determine in response to the rate of disintegration obtained from transient current profile unfilled.
Therefore, it is adequately filled up in Fig. 9 B by the sensing zone that series 3 and series 8 indicate, and by series 1~2, series 4
~7 and serial 9~10 eight sensing zones indicated are unfilled.In this manner it is achieved that gated amperometric arteries and veins of the invention
The unfilled detection in sequence two electrode sensing bands of permission is rushed, this is that conventional sensors system usually requires third electrode ability in fact
Existing function.In addition, can be carried out unfilled judgement within the time less than 10 seconds, user is signaled for measuring device
More Multi-example is added to sensing zone and provides the time, and above-mentioned signalling is, for example, to send a signal to light-emitting display device or display
Device.
Because can determine from transient current profile unfilled, presence for measuring analyte and/or dense can be used
The same current value of degree determines whether that there are unfilled situations.Therefore, it is not necessary to extremely by the duration extension of electrochemical analysis
More than the time needed for concentration mensuration, so that it may determine during multiple working cycles of pulse train unfilled.
Also the combination and obtained contour curve that the transient current profile excited every time can be used determine sample temperature
Whether degree variation adversely affects analysis.Conventional sensors system include in measuring device or sensing zone on temperature-sensitive electricity
Resistance, to provide the temperature of measuring device or sensing zone respectively.In general, although this temperature is measured close to sample temperature
The temperature of device or sensing zone is different from sample temperature.Measuring device or the temperature difference of sensing zone and sample may be by deviations
It is introduced into analysis.
Such as the rate of disintegration is determined by using K constant previously discussed, so that it may measure sample temperature.Figure 10 is shown
The relation curve of K constant and temperature, it is 50,100 and 400mg/dL that these K constants, which are for concentration of glucose, from pulse train
The 5th excitation obtain.The relation curve shows absolute value as the temperature rises and the rate of disintegration of increase.Although not
It is intended to be limited with any specific theory, but this phenomenon may be attributed to the diffusion speed so that the various components in cap gap
The lower temperature that rate reduces.In this way it is possible to measure sample in response to the rate of disintegration obtained from transient current profile
Temperature.
Because sample temperature can be determined according to transient current profile come therefore, it is possible to use for measuring analysis
The same current value of the presence of object and/or concentration measures sample temperature.So can be in multiple working cycles of pulse train
Period determines sample temperature, without by the duration extension of electrochemical analysis time to needed for exceeding concentration mensuration.
In one aspect, the temperature of sample can be measured by solving K according to following equations:
Wherein i0.125And i0.375Electric current when being 0.125 second and 0.375 second since the excitation most sensitive to temperature change, should
Excitation is, for example, to generate the excitation of the current decay most sensitive relative to temperature change.Ln (0.125) and ln (0.375) are respectively
0.125 second and the natural logrithm form at 0.375 second moment.As shown in Figure 10, according to the relationship of these K constants and temperature song
Line can measure sample temperature from the correlation function of relation curve.Correlation function can be the fitting of a polynomial of curve.From this
The temperature of one relation curve measurement may be different from the temperature of device, thereby increases and it is possible to can more accurately reflect sample temperature.
Opposite with above-mentioned apparatus, the advantages of being measured to sample temperature, is that the time of adjustable analysis is long
It is short, so that thering is time enough to reach balance by DBL rehydration, to improve the accuracy of analysis.For example, if in arteries and veins
Rush the sample temperature that is measured during sequence be then pulse train can be made elongated lower than at least 5 DEG C or 10 DEG C of environment temperature, such as
It is recycled with extra work.
Figure 11 is the schematic diagram of measuring device 1100, including the contact with circuit 1110 and the mutual telecommunication of display 1130
1120.In one aspect, measuring device 1100 be it is portable and be suitable for it is hand-held and receive band 100 such as shown in figure 1A it
The sensing zone of class.On the other hand, measuring device 1100 is suitable for receiving sensing zone and implements gated amperometric pulse
The handheld measuring device of sequence.
Contact 1120 is suitable for providing and the contact of circuit 1110 and sensing zone (such as sensing zone 100 shown in Figure 1B
Contact 170 and telecommunication 180).Circuit 1110 may include charger 1150, processor 1140 and computer-readable storage medium
Matter 1145.Charger 1150 can be voltage-stablizer, signal generator, etc..Therefore, charger 1150 can be applied to contact 1120
Making alive, while obtained electric current is recorded to play the role of charger-logger.
Processor 1140 can be logical with charger 1150, computer readable storage medium 1145 and display 1130 mutually electricity
Letter.If charger is not suitable for record current, processor 1140 may adapt to the electric current at record contact 1120.
It is any that computer readable storage medium 1145 can be magnetic memory, optical memory, semiconductor memory etc.
Storage medium.Computer readable storage medium 1145 can be that fixed memory device or mobile memory card etc. are removable to be deposited
Store up equipment.Display 1130 can be it is simulation or digital, can be suitable in one aspect display quantities read LCD
Display.
When containing the contact of sensing zone of sample and 1120 mutual telecommunication of contact, processor 1140 can indicate to charge
Device 1150 applies gated amperometric pulse train to sample, to start to analyze.Processor 1140 can be for example in response to passing
Feel the insertion of band, sample is applied to the sensing zone being previously inserted into or in response to user's input, starts to analyze.
It can be by being stored in computer readable storage medium 1145 about the instruction for implementing gated amperometric pulse train
Computer-readable software code provide.The code can be object code or can illustrate or control any of function described herein
Other codes.One or many data processings can be carried out to the data obtained from gated amperometric pulse train, be included in place
It manages and measures the rate of disintegration, K constant, slope, intercept and/or sample temperature and by the analyte concentration after such as correcting in device 1140
Etc. results be output to display 1130.Using the instruction about pulse train, data processing can be by processor 1140 according to storage
Computer-readable software code in computer readable storage medium 1145 carries out.
Under the premise of being not intended to limit range, application or implementing, method and system above-mentioned can use following steps
To realize:
Step 1: starting biosensor power supply
Step 2: carrying out biosensor self-test
Step 3: being configured, Polling sample is applied in sensor
It is v by ASIC Polling potential settingpoll
It is i by ASIC set of threshold levelstrigger
Polling cycle timer is set as in intpollExpire at place
Step 4: the setting of the sensor current for chemical examination
Wait Polling cycle timer expiration
Start ASIC charge pump (charge pump)
Make ASIC threshold dector (itrigger) work
Make Polling current potential (vpoll) work
Select the sensor channel for applying current potential to sensor
Wait settling time tpoll
Step 5: whether detection sensor electric current is more than threshold value
Step 6: delay and again detection sensor electric current
Step 7: the detection based on sample application
Start timing
Issue pulse train
Step 8: pulse 1-measurement sensor electric current i1,1And i1,8
In tp1Moment, pulse 1 start
1 duration of pulse is set as dp1
It is v by 1 sensor potential setting of pulsep1
Select the sensor channel for applying current potential to sensor
In t1,1Value is stored as AD by moment, measurement sensor signalS11
In t1,8Value is stored as AD by moment, measurement sensor signalS18
Step 9: 1-standardized electronic device (electronics) again of delay
In AD2At the end of reading, delay 1 starts, and disconnects sensor channel
When pulse 2 starts, delay 1 terminates
It is V by potential settingstandardize
In tc1Moment selects reference resistor channel then measuring signal, value is stored as ADR1
In tc2Moment, selection compensation channel and then measuring signal, are stored as AD for valueO1
Note: the sensor current started at pulse 1 is from ADR1And ADO1What measurement result was calculated
Step 10: pulse 2-measurement sensor electric current i2,1And i2,8
In tp2Moment, pulse 2 start
2 duration of pulse is set as dp2
It is v by 2 sensor potential setting of pulsep2
Select the sensor channel for applying current potential to sensor
In t2,1Value is stored as AD by moment, measurement sensor signalS21
In t2,8Value is stored as AD by moment, measurement sensor signalS28
Step 11: delay 2-
In ADS3At the end of reading, delay 2 starts, and disconnects sensor channel
When pulse 3 starts, delay 2 terminates
Selection compensation (offset) channel, to disconnect sensor
Step 12: pulse 3-measurement sensor electric current: i3,1And i3,8
In tp3Moment, pulse 3 start
3 duration of pulse is set as dp3
It is v by 3 sensor potential setting of pulsep3
Select the sensor channel for applying current potential to sensor
In t3,1Value is stored as AD by moment, measurement sensor signalS31
In t3,8Value is stored as AD by moment, measurement sensor signalS38
Step 13: 3-T of delay1And iwet
In ADS38At the end of reading, delay 3 starts, and disconnects sensor channel
When pulse 4 starts, delay 3 terminates
It is V by potential settingstandardize
In tc3Moment selects thermistor channel then measuring signal, value is stored as ADT1
In twetMoment, selection compensation channel and then measuring signal, are stored as AD for valuewet
Step 14: pulse 4-measurement sensor electric current: i4,1、i4,4And i4,8
In tp4Moment, pulse 4 start
4 duration of pulse is set as dp4
It is v by 4 sensor potential setting of pulsep4
Sensor channel is selected, to apply current potential to sensor
In t4,1Value is stored as AD by moment, measurement sensor signalS41
In t4,4Value is stored as AD by moment, measurement sensor signalS44
In t4,8Value is stored as AD by moment, measurement sensor signalS48
Step 15: delay 4-
In ADS48At the end of reading, delay 4 starts, and disconnects sensor channel
When pulse 5 starts, delay 4 terminates
Selection compensation channel, to disconnect sensor
Step 16: pulse 5-measurement sensor electric current: i5,1、i5,4And i5,8
In tp5Moment, pulse 5 start
5 duration of pulse is set as dp5
It is v by 5 sensor potential setting of pulsep5
Sensor channel is selected, to apply current potential to sensor
In t5,1Value is stored as AD by moment, measurement sensor signalS51
In t5,4Value is stored as AD by moment, measurement sensor signalS54
In t5,8Value is stored as AD by moment, measurement sensor signalS58
Keep ASIC analog functuion ineffective
Step 17: searching the slope and intercept of one group of amount of calibration
The slope value of current this group of amount of calibration of S=
The values of intercept of current this group of amount of calibration of Int=
Step 18: for temperature effect, adjusting slope and intercept
Step 19: calculating the concentration of glucose at 25 DEG C
Step 20: being converted into targeted reference (blood plasma and WB reference)
Step 21: checking unfilled
Step 22: checking " abnormal behaviour "
Step 23: if glucose is low, reexamining " abnormal behaviour "
Step 25: checking limit glucose level
Step 26: display result
Above-mentioned algorithm can have other subprograms, including those are used to check such as sample temperature and unfilled situation
The subprogram of equal error.The constant that can be used in above-mentioned algorithm is listed in lower Table III.Also other constants can be used.
Table III
Although it have been described that various embodiments of the present invention, but it is obvious to those of ordinary skill in the art
It is within the scope of the invention, can also there is other embodiments and embodiment.
Claims (5)
1. a kind of method of the temperature for the sample that measurement sensing zone is contained, described method includes following steps:
Predefine relationship between the rate of disintegration and temperature;
The electric current recorded during being excited according at least two of the input signal in 180 seconds including at least three working cycles,
Measure current curve;And
Relationship between the current curve and the rate of disintegration and temperature is got up, to measure the temperature of the sample.
2. according to the method described in claim 1, wherein, the electric current of at least one of described at least two excitation excitation
Curve is represented as K constant.
3. method according to claim 1 or 2 further includes following steps:
According to the current curve of at least two excitation, contour curve is generated.
4. method according to claim 1 or 2, wherein the current curve is transient current profile.
5. method according to claim 1 or 2 further includes following steps:
In response to the temperature of the sample measured, according to the electric current recorded according to the input signal, described in measurement
The analyte concentration of sample.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US70078705P | 2005-07-20 | 2005-07-20 | |
US60/700,787 | 2005-07-20 | ||
US74677106P | 2006-05-08 | 2006-05-08 | |
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BR112012009291A2 (en) * | 2009-11-10 | 2016-05-31 | Bayer Healthcare Llc | underfill recognition system for a biosensor |
BR112012023984A2 (en) * | 2010-03-22 | 2016-08-02 | Bayer Healthcare Llc | residual compensation for a biosensor |
BR112012031375A2 (en) * | 2010-06-07 | 2016-10-25 | Bayer Healthcare Llc | filler management system below what is required for a biosensor |
US9395319B2 (en) * | 2013-05-02 | 2016-07-19 | Lifescan Scotland Limited | Analytical test meter |
CN114230378B (en) * | 2021-12-27 | 2022-11-15 | 复旦大学 | Preparation method of redox-driven super-assembly intelligent door control system |
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CN106970135B (en) | 2019-09-06 |
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