CN1432130A - Rapid response glucose sensor - Google Patents
Rapid response glucose sensor Download PDFInfo
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- CN1432130A CN1432130A CN 01810317 CN01810317A CN1432130A CN 1432130 A CN1432130 A CN 1432130A CN 01810317 CN01810317 CN 01810317 CN 01810317 A CN01810317 A CN 01810317A CN 1432130 A CN1432130 A CN 1432130A
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Abstract
A disposable electrochemical sensor for detecting analyte such as glucose in liquid sample is made by a working electrode and a reference electrode arranged in sample cavity and reagent layer on top of the working electrode. The reagent layer contains at least one enzyme generating electrochemical signal in the presence of analyte. The volume of the sample cavity is less than 1.5 mul, so the sensor can provide measurement related to analyte amount in ten seconds or shorter time. The sensor assembling with an instrument for detecting analyte in liquid sample. A applicable instrument has timing circuit for detecting measurement of sample coated on a strip inserted in the instrument to control current of analyte. The timing circuit measures current in 15 seconds or shorter time after detecting sample application.
Description
Invention field
The application relates to the glucose sensor that the diabetes patient is used for monitoring the disposable electrochemical type of blood sugar concentration.
Background of invention
Disposable banded electrochemical glucose sensor was sold on market more than 10 year, and was described in the various patents, comprised United States Patent (USP) 4,711, and 245,5,708,247 and 5,802,551.These sensors utilize redox mediators to promote charge exchange between enzyme and electrode.These devices provide tangible advantage than optical technologies in the past, and for example can not enter instrument and instrument itself often lighter and more unheavy for blood; But also there are some shortcomings in they.Other electroactive material that Electrochemical results is subjected to exist in the sample usually influences, and is subjected to the oxygen content in the sample and the influence of hematocrit.
The reason that disturbed by electroactive material is very direct.The material of oxidation causes electric current to increase easily, and this causes reading to raise.It is because in the direct oxidation of electrode surface or pass through redox catalysis and produce that electric current increases.Some manufacturers have attempted solving this problem by using auxiliary electrode to carry out background deduction.Though this method is useful, it increases extra manufacturing step; Increase cost and extra measurement and relevant error thereof, thereby reduce precision.Background deduction also may cause excessive correction, because disturb efficient possibility on two electrodes of redox catalysis different, this depends on analyte concentration.
Oxygen is relevant with the hematocrit effect.Oxygen is the natural accessory factor of glucose oxidase, so in the presence of oxygen, have strong competition between oxygen and redox mediators, causes the reduction of signal.Similarly, because haemoglobin is high efficiency oxygen pumped (conveying) medium, high sample hematocrit will cause signal to reduce.Proposed to keep the barrier film of haemocyte, reduced hematocrit effect (United States Patent (USP) 5,658,444) away from electrode surface.This method has increased extra manufacturing step, in any case and only effective based on the effect of oxygen to part.
Therefore, still have demand for the disposable electrochemical appliance of the reading that haemanalysis substrate concentration, particularly concentration of glucose are provided, it is subjected to the minimum that influences that chaff interference exists.
Summary of the invention
According to the present invention, provide a kind of and be used for detecting at the analyte of fluid sample such as the disposable electrochemical sensor of glucose.This sensor comprises working electrode and the contrast electrode that is distributed in the sample container cavity, be distributed in the sample container cavity and cover the reagent layer of working electrode, described reagent layer comprises at least a enzyme that produces electrochemical signals in the presence of analyte, wherein, the volume of sample container cavity is less than 1.5 μ l, and wherein said sensor provides a kind of measurement, its 10 seconds or shorter during in relevant fully goodly (R for example with amount of analyte
2＞0.95), makes and to use this measurement result in the accurate accurately detection of analyte with quantitatively.
This sensor and instrument are united the analyte that is used in the tracer liquid sample.Suitable instrument comprises and is used for being controlled at the timing circuit that detects the electric current of analyte in the sample measurement expression afterwards sample that is applied on the calibration tape that inserts instrument, wherein, timing circuit makes current measurement carry out in back 15 seconds of detection of sample application or shorter time.
The accompanying drawing summary
Fig. 1 represents that near the diffusion of reagent material disposable electrode move;
Fig. 2 represents the sectional view of biology sensor according to the first embodiment of the present invention;
Fig. 3 represents the sectional view of the biology sensor of second embodiment according to the present invention;
Fig. 4 represents to be used for the equipment of the web printing of face-to-face sensor device;
Fig. 5 represents the face-to-face sensor device of section construction;
Fig. 6 represents the sectional view according to sensor of the present invention;
Fig. 7 represents the curve of related coefficient and test duration;
Fig. 8 represents the outward appearance according to instrument of the present invention;
Fig. 9 A-C represents the structure according to sensor of the present invention;
Figure 10 represent the commodity band with according to the comparison of rapid reaction band of the present invention.
Detailed Description Of The Invention
The key of improving galvanochemistry band performance is to design described band makes the reaction of mediation carry out than disturbance reponse is preferential.Under the glucose detection situation, the special reaction of analyte is a kind of mediated responses, and it relates to and reduces the enzyme of amboceptor and produce, and amboceptor is in the electrode surface oxidation then.So we sum up, should set up this test and make these be reflected at generation, so that maximum collection efficiency is provided near the electrode surface place.
It is considerable in test process diffusion process taking place.Consider the coating of sample to the calibration tape as shown in Figure 1.Calibration tape comprises electrode E and a kind of amboceptor M that coating contains the reagent layer of enzyme in its drying regime.Specimen contains glucose G, galvanochemistry chaff interference I and oxygen O
2, it can be bound on the Hb H b.When sample application, exist E and M away from electrode towards the clean diffusion flux of specimen and G and I clean diffusion flux towards electrode.Therefore, after sample application in very short time, most of enzymes are still near electrode, have the high likelihood that causes the reduction amboceptor molecule at captive close enough electrode to produce with the reaction of glucose.When the long period, many enzymes be diffused in the sample " darker " and can with the glucose response here.This has two kinds of effects, and at first, the enzyme that has reduction is by O
2Rather than by the high likelihood of M oxidation, because the concentration of M is along with ionization electrode reduces and O apart from increase
2Concentration can increase (because this identical reaction) away from the electrode place.Even the enzyme of reduction does not react with M, along with the generation of detectable signal, the M of the reduction diffusion telegram in reply utmost point is little by the possibility of oxidation again.Secondly, the reaction sequence of just having described has the effect of the G that exhausts inside diffusion, and therefore, near the actual G amount of electrode that arrives reduces, and near electrode, G can be detected with certain efficient.Very clear, these two kinds of elements all are the reasons that signal reduces when having oxygen in the sample.
Similarly, common chaff interference is easy oxidized material, and as ascorbic acid, acetaminophen and uric acid, they are oxidized with the amboceptor of the reduction that may exist when arriving electrode surface.Because this effect only produces when I exists near electrode surface, so it will be in its minimum value in the short time before the diffusion of electrode in that I takes place.
Obviously finding out from this mechanism explain, is to measure in the very short time to a solution of chaff interference and these two problems of hematocrit/oxygen content.Another kind of solution is the restriction sample volume, makes and compare with sample volume that the surface area of electrode is very big.A kind of good structure is the structure that guarantees sample layer on the electrode extremely thin (for example＜200 micron).The fluid dynamics that a benefit of restriction sample volume is a solution is rapider stable.With big sample volume, the convection action in the sample causes measurement noise.By keeping small sample volume with form of film, convection action is minimized.This means with small sample volume to make measurement more early.
In fact, these solutions are correlated with, and all implement in biology sensor of the present invention.Therefore, the invention provides disposable electrochemical sensor and correlate meter, they can be used at the electrochemical measurement that carries out amount of analyte in the sample than previously known system in the shorter time, for example for blood sugar concentration quantitatively.Synergy between short Measuring Time of sensor utilization of the present invention and the small sample volume obtains excellent performance.Low sample volume makes and can carry out the more measurement of morning, because hydrodynamic action is more early stable, therefore helps to measure at short notice.Therefore the also essential short time measurement of small sample volume because small-signal can disappear when the long period, and can not provide reliable reading.By selecting this structure, we guarantee to keep high mediator concentration to make amboceptor can more effectively compete the enzyme of reduction with oxygen.
From patient's point of view, obtain to utilize the device of small sample volume to wish very much.Problem is to create the reliable determination that the device that utilizes small sample volume produces analyte concentration.The first of this process is determining of small samples container cavity.The volume of determining this chamber by the area and the gaps between electrodes thickness of electrode.For having lower limit by the electrode area that any given print process obtains, this lower limit is by marginal sharpness and the decision of printing tolerance.A kind of method of improving this precision when using the known electrodes printing-ink is that this patented claim is incorporated herein by reference with the printing process described in the common international patent application No.WO 00/42422 that transfers the possession of.
In case " area " of electrode minimizes, then further determine sample volume by the gap between the electrode surface.Main target is thin and consistent gap.But, should remember, if, then do not satisfy the normal condition that semiinfinite spreads by using extremely thin gap (promptly＜200 micron) to obtain small sample volume.Because this point, diffusion layer can extend on the whole gap, and obviously exhaust sample.In these cases, the precision of device is subjected to determining the extra factor influence of precision of the assembling process of gap size.Have a kind of relation between the size that Measuring Time and gap size precision become important, it can be understood by considering following formula:
Wherein, L is a diffusion length, and D is a coefficient of diffusion, and t is the time.When the test duration when 15 seconds are reduced to 5 seconds, diffusion length reduces
Doubly.In fact this mean by shortening minute, can further reduce gap size, and can not enter in the restrictive condition that gap precision becomes device precision principal element.Therefore, for example suppose that coefficient of diffusion is 10
-5Cm
2Sec
-1, then 5 seconds test need be greater than 70 microns gap, and by contrast, 15 seconds test needs 125 microns gap.Consider these factors, a kind of being used for has the sample container cavity of volume less than 1.5 μ l according to the suitable construction of sensor of the present invention.In conjunction with consideration, this means that the hope size of working electrode should make that approximately O.5-100mm the surface area of working electrode and the ratio of gap size are about gap size.In a kind of particularly preferred structure, the area of each electrode is 0.8mm
2, the gap is the 100-150 micron, defines volume and is the sample container cavity of μ l O.5-O.8.
Fig. 2 represents the electrochemical sensor 10 according to first kind of embodiment of the present invention.Electrode 11 and 12 forms on substrate 13.Substrate 13 is determined chamber 17 with pad 14,15 and loam cake 16 combinations, and electrochemical reaction takes place therein.In a typical embodiment, the surface area of electrode is 5mm
2, what cavity volume was suitable is less than 1.5 μ l, preferably less than 1 μ l, most preferably less than 0.5 μ l.
The device of type shown in Fig. 2 can be made as follows.Electrode 11 and 12 is deposited on the substrate 13.Concrete depositional mode is determined by electrode property, although serigraphy is preferred technology for many materials.The electrode area that is exposed to sample in cavity is determined by deposition insulation shielding on electrode.(seeing the open No.WO/00/42422 of international monopoly of common transfer).Deposited reagent layer then.This layer can cover this two electrodes, and perhaps it is limited at the zone on the working electrode.Pad 14 and 15 forms around electrode with graphics mode then.In a preferred embodiment, these pads form by the cementing agent of the highly about 150 μ m of printing one deck drying.This pad has been determined the capillary gap, and does not need to utilize preformed solid material, therefore obviously helps the production of apparatus of the present invention.Last step is to use cover plate 16 to finish chamber 17.In this embodiment preferred, cover plate 16 is fixed on this device by pasting pad 14 and 15.
Fig. 9 A-C represents to be used to produce the specific embodiments according to the manufacturing technology of sensor of the present invention.The figure shows a single sensor, but should be appreciated that, generally can prepare more than one sensor.Fig. 9 A is illustrated in the structure that cover plate piles up former device.Sensor in this stage has two electrodes 11,12 that are deposited on substrate (for the sake of clarity, not shown).Electrical connection to these electrodes is not shown.Reagent liner 100 for example contains the suitable enzyme that is useful on analyte, is deposited on two electrodes.Cementing agent pad 101,102 and 103 is deposited on three sides of reagent pad.Then two hydrophilic films (as 3M9962,100 microns optically transparent mylars that the rear surface activating agent is handled) 104,105 be placed on two positions, one strides across cementing agent pad 101 and 102 also coated electrode and reagent pad, another covers the part of cementing agent pad 103, to be provided for holding the support (Fig. 9 B) with consistent height of cover plate 116.The position of these sheet hydrophobic films produces the capillary action chamber on two electrodes.The hydrophilic coating of film promotes that by capillary action test liquid moves in the sample cavity that is produced.The gap 106 that forms in the zone that does not have pad or film makes that air can be overflowed from the back, chamber when test liquid enters in the sample cavity that is produced.Use pressure-sensitive adhesive tape as the loam cake 116 on hydrophilic film.Loam cake 116 is made with mylar suitably and can be applied heat-activated binder or pressure sensitive adhesives.Last step is that for example the solid line C-C along Fig. 9 B cuts the sample cavity of this device of cutting with the generation appropriate openings.Fig. 9 C is illustrated in the end view of this device after the solid line C-C cutting.As shown in the figure, the capillary action import 110 to sample cavity is limited by substrate 13, adhesive pad 101,102 and hydrophilic film 104 and loam cake 116. Film 104 and 105 is supported by adhesive pad 101 and 102.
Fig. 3 represents the electrochemical sensor 20 of second embodiment according to the present invention.Electrode 21 and 22 be respectively formed on the substrate 23 and loam cake 26 on.Substrate 23 combines with pad 24,25 and loam cake 26 and limits chamber 27, in chamber 27 electrochemical reaction takes place.This sensor arrangement is to have small size and the thin gap between substrate 23 and loam cake 26, for example 50-200 micron.Should be noted that the device for same size, the surface area of electrode is two times, because its folding aspectant structure.
Device with this structure can use the manufacturing of web printing technology, and described in the U.S. Patent application 09/537,599 of the common transfer that proposes on March 28th, 2000, this patent is incorporated herein by reference.This technology is utilized the equipment of the type that schematically illustrates among Fig. 4.The mobile reel of substrate 31 is provided on the feed roll 32, and is transferred by some print stations 33,34 and 35, its each on substrate, print different layers.The quantity of print station can be any amount and depend on and be used to make the required number of plies of specific device.Between continuous print station, roll web preferably is transferred by exsiccator 36,37 and 38, makes each layer dry before entering next time deposition.After last exsiccator 38, the roll web after the printing is collected on the take up roll or is introduced directly in the process equipment 39 of back.In order in this equipment, to make device with structure shown in Figure 3, as shown in Figure 5, parallel guide rail 71 and 72, reagent layer 73 and the insulation course 74 of deposition on substrate 70.Folding substrate then along the fold line between two guide rails, produce a kind of wherein two sensors that face-to-face electrode is separated by reagent layer.Electrode geometry with electrode that the opposite is arranged in sample cavity is favourable, because because the voltage drop that solution resistance produces is little, this is the thin result of solution layer of spaced electrode.
In above-mentioned each embodiment of the present invention, described chamber is limited by insulating material.The suitable insulative materials that is used for this purpose comprises nylon, polyester, polycarbonate and Polyvinylchloride.Suitable material as substrate comprises mylar, for example 300 microns polyester films and other insulated substrate material such as Polyvinylchloride (PVC) and polycarbonate.It is ERCON R488-B (HV)-B2 Blue that the concrete polyester-based that can be used for forming insulation shielding can be printed dielectric material.In cavity, form working electrode and contrast electrode with conductive material.Suitable conductive material comprises the semiconductor material such as the n type SnO of conductive carbon, gold, platinum, aluminium or doping
2Preferred conductive carbon material is ERCON ERC1, ERCON ERC2 and Acheson Carbon Electrodag 423.Carbon with these specifications can derive from Ercon, and Inc. (Walham, Massachusetts, USA), or Acheson Colloids (Princes Rock, Plymouth, England).Semi-conducting electrode provides a kind of attractive selection, because they can be used for carrying out the surface connection of enzyme or other composition of reagent layer.This provides and fixing relevant benefit, can also be between reagent and electrode carry out direct electron transfer.
Electrode can or can have identical materials by the different materials manufacturing.Wherein the embodiment of electrode with same composition (for example, carbon electrode) can provide some advantages.Particularly, the use of unitary electrode material makes can deposit working electrode and contrast electrode in one step, thereby gets rid of the electrode print steps from production run.These two electrodes can print very closely, because the interval between the two is only by former figure decision on a silk screen (about 200 microns of tolerance) and the interval that can realize not lining up between each printing process (tolerance is above 0.5 millimeter).This makes that conversion zone is compacter and therefore cause the required blood volume of coated electrode to reduce.
Working electrode has one or more reagent layers that are deposited on the electrode, and it contains enzyme and the amboceptor that is useful on the detection target analytes.Therefore, for example in glucose sensor, reagent layer may comprise the osmium compound of a kind of enzyme such as glucose oxidase and a kind of amboceptor such as ferricyanate, Metallocenic compound, benzoquinones, azophenlyene (phenazinium) salt, redox indicator DCPIP and imidazoles replacement.Reagent layer can be the individual layer that comprises enzyme and amboceptor simultaneously, also can be made of a plurality of subgrades, and the some of them subgrade contains enzyme or enzyme and amboceptor, and some subgrades only contain amboceptor.
Because device of the present invention is intended to use with short time interval, so, an ability that key property is a fast hydrating of electrode.Hydration rate is formed decision by reagent layer.Utilization is at US5, and the electrode system of the silicon-dioxide-substrate reagent layer of type described in the open WO 00/42422 of 708,247 (they are incorporated herein by reference) and international monopoly can quick humidification and hydration and therefore it is suitable for using in sensor of the present invention.The optimal material of reagent layer that is used for the electrode of sensor of the present invention is that fast hydrating forms and electrode surface keeps in touch and reagent is remained near the material of the gel the electrode.If reagent layer disperses after hydration fast, then reagent (particularly enzyme reagent) loses near the electrode surface fast, but they are of value to the signal that produces analyte concentration in the reflection sample most near electrode surface.
Reagent layer also must comprise a kind of amboceptor, precipitation immediately during the signal that its form is used in the response analysis substrate concentration produces.As under, this means that amboceptor must dissolve and exist with oxidised form fast at analyte by the situation of the glucose of oxydasis.By Medisense with trade name QID
TMAnd EXACTECH
TMIn the commodity glucose strip of selling, in fact amboceptor exists with the reduction form and must be by in-situ oxidation before can participating in the glucose detection reaction.This has limited the response time of strip, and has hindered it and used to lack the test duration.
Under the situation of contrast electrode, electrode needs fast hydrating, and can also stablize fast enough, so that moment produces by the needed electric current of working electrode, i.e. hydration in 200 milliseconds.Conventional silver/silver chloride contrast electrode can not be stablized fast enough.On the other hand, iron-ferricyanate contrast electrode balance very rapidly.In this design, that uses fast and stable or dispersion contains the amboceptor layer.In specific embodiments of the present invention, use to have the carbon printing ink electrode that contains as the reagent layer of the potassium ferricyanate of amboceptor.In hydroxyethyl cellulose-silicon dioxide substrate, use glucose oxidase as enzyme, add the water wettability that polymkeric substance improves this prescription.This system has very high surface area and wetting very fast.
Except working electrode and contrast electrode, device of the present invention can be configured to comprise the 3rd electrode.The 3rd electrode can be empty (dummy) electrode, is used for the compensate for background reaction, or the counter electrode of traditional three-electrode system.The 3rd electrode can also be identical working electrode.
In embodiment of the present invention discussed above, solubilization or the hydration fast of all layers.Though rapidly solubilization or at least the hydration of oxidized mediator be not the problem that chaff interference consumes, and have and help realize this requirement, but it but is not a good characteristic for containing the enzyme layer fully, as previously mentioned, because this has promoted enzyme to spread out rapidly from its most helpful electrode near zone.So, be shown among Fig. 6 in conjunction with a kind of useful structural table of this two aspect.In this embodiment of the present invention, sensor 60 has chamber 67, and it is made of base plate 63, pad 64,65 and loam cake 66.Two carbon electrodes 61,62 are distributed on the base plate 63 in the chamber 67.The thin viscogel layer that contains enzyme and amboceptor (for example 5 microns) of electrode 62 coatings.Two electrodes 61,62 use then thicker (for example 25 microns) contain amboceptor but the dispersion layer 69 that do not contain enzyme covers.
In another embodiment of the invention, constitute two independent layers further to reduce the influence of chaff interference.A kind of method of listing when the chemical depletion of chaff interference provides the reagent layer that excessive oxidized amboceptor is arranged outside.In a kind of attractive especially structure, the electrode coating contains the thin reagent layer of enzyme and amboceptor and applies the thick-layer that only contains amboceptor then.Two-layer all being deposited in the matrix that limits the still rapid hydration of diffusion, so it can carry electric current.By enzyme is limited in the thin layer, the enzyme major part remains near the electrode, makes that above-mentioned subsidiary reaction is inessential.Thick outer amboceptor layer provides the obstacle of inside diffusion chaff interference owing to its diffusion limited matrix and has remained on the position of hope.But can contain a kind of optional the 3rd layer outside first and second layers of amboceptor in the disperse matrix of rapidly hydration containing.By guaranteeing that sample volume is little, it is minimum that the chaff interference total amount in the sample is held again, and the concentration height of oxidized amboceptor when regeneration, and therefore, amboceptor is removed chaff interference effectively.Significantly, when the longer time, the local concentration of amboceptor can reduce, because it is diffused in the sample, and interference also can be more obvious.In our experience, sample volume is less than 1 μ l, and preferably 0.5 μ l is desirable.
Sensor constructed in accordance can be measured in more than the shorter time of using known sensor to obtain.By shortening the test duration, the hematocrit effect can reduce.Use the electrode that has the reagent layer of inhibition to cover to some blood constituents such as leucocyte and red blood cell if this sensor comprises, the fluid that then arrives electrode at short notice will obviously contain when long-time these compositions still less.
Fig. 7 represents the curve of related coefficient to the test duration.In the very short test duration, correlativity is poor, because system is also unstable.In the very long test duration, correlativity also begins to reduce.Given by shortening the purpose of test duration limit interferences, testing suitable is to use the system of being represented by solid line to carry out, and it will preferably be about 5 seconds less than 10 seconds for following sensor.Disposable sensor of the present invention provides accurate mensuration glucose in test instrumentation is operated in this time range.Therefore, structure sensor provides the signal of information accurately and reliably at short notice, and the instrument of insertion sensor is suitable for acquisition of information in this time.
Fig. 8 represents the outward appearance according to typical handheld instrument of the present invention.Identical with conventional instrument, instrument of the present invention has shell 81, has the display 82 and the groove 83 that are used for display result, is used to insert disposable sensor.Can comprise button 85 and/or switch, be used to operate this instrument, comprise the accessing of store results, rectifying inspection etc.Instrument of the present invention and conventional instrument difference are interior electronic sections in the enclosure.In conventional instrument, the disposable sensor that fluid sample (for example drop of blood) joins in shell begins to measure circulation, agent dissolves and reading during this period.The circulation beginning also can trigger by pressing button by the user, though this is not preferred.Microprocessor in instrument periodically is in " dormancy " pattern and " reviving " pattern usually (for example per 1/2 second), to check look-at-me.If program detects interrupt identification and is set, show that then strip has been inserted in the instrument or start button is pressed, program enters RUN (operation) pattern.Under this pattern, apply the output of voltage and microprocessor monitors pulse width monitor usually to strip, it shows any magnitude of current that is formed by strip.In case sample application is to strip, electric current just flows through, because strip has applied polarizing voltage.The monitoring of this initial current has begun timing program.By microprocessor control timing.There are two kinds of crystal: be used for the 4MHz clock (promptly measuring) of operating function and keep the 32mHz clock of " shut " mode" time.When timing course began, the voltage that applies can (1) remains on steady state value or (2) according to predetermined curvilinear motion.In any of both of these case, the amount of electric current with analyte in the assessment sample measured in the back at the fixed time.By embodiment, the data that are illustrated among Fig. 7 are collected in the system, and in this system, sample application detects when t=0, and impressed voltage is removed 2 seconds, and during this period, strip is opened a way, and apply identical voltage then again.At a plurality of point in time measurement electric currents and determine the correlativity of electric current and analyte concentration at each time point.
In the known commercially available instrument of prior art, set up and measure circulation so that 20-60 carries out current measurement second after sample detection.In instrument of the present invention, it is specially adapted to use with quick response strip of the present invention, set up to measure circulation, so as after sample detection 15 seconds or shorter time carry out current measurement, preferably the time of 5-10 second is carried out current measurement after sample detection.
With reference now to following unrestricted form embodiment, further describes the present invention.
Use in the program shown in Fig. 9 A-C and following material preparation according to rapid response glucose sensor of the present invention:
Substrate: mylar
Carbon ink prescription: Ercon conductive carbon
Reagent layer is formed: as described below
Cementing agent: water based acrylic copolymer cementing agent (Apollo Adhesives)
Hydrophilic film: 3M100 micron hydrophilic film 9962
Loam cake: the polyester belt (Tape Specialities) of pressure sensitive adhesives coating
Reagent layer forms as follows: by adding the 1M citric acid, the 100mM trisodium citrate aqueous solution of 100ml is adjusted to pH=5.In this solution, add 5g hydroxyethyl cellulose (HEC), 1g polyvinyl alcohol (PVA), 1g PVP-VA S-630 poly-(vinyl pyrrolidone vinyl acetate) and 0.5ml DC 1500 Dow Corning defoamers, and homogenizing is mixed.This potpourri is left standstill bubble is disperseed, then as the raw material of preparing coating composition.Manually 7.5g Cab-o-Sil TS610 is joined in the HEC solution gradually, until adding about 4/5 of total amount.Adding remainder and homogenizing mixes.Then this potpourri roll-in 12 hours.Adding 11g potassium ferricyanate and homogenizing then mixes until dissolving fully.At last, add 2.8g glucose oxidase preparation (250 units/mg), fully be mixed into solution then.The batching of gained is ready to, and is used for printing, and can refrigerated storage.
Use these sensor test standard glucose solution and different timing electric current after glucose joins in the sensor.For each time interval, determine the related coefficient between actual glucose concentration and mensuration concentration of glucose.Fig. 7 ecbatic curve.As shown in the figure, when adding behind the glucose 5 seconds in sensor, related coefficient reaches maximum high value.
With 1 the same preparation of embodiment according to rapid response glucose sensor of the present invention.The magnitude of current when utilizing these sensors to determine after being exposed to variable concentrations glucose 5 seconds.For relatively, test the MedisenseQID glucose sensor under the same conditions.The result that Figure 10 graphic representation should be tested.As shown in the figure, the very good (R of the linearity that responds according to fast response transducer of the present invention
2=0.999).The so not good (R of the linearity of QID sensor in the time of 5 seconds
2=0.863).
Claims (16)
1. disposable electrochemical sensor that is used for tracer liquid sample analyte, it is included in working electrode and the contrast electrode arranged in the sample container cavity, is arranged in the sample container cavity and the reagent layer on working electrode, described reagent layer is included in analyte and has the enzyme that produces electrochemical signals down, and wherein the volume of sample container cavity provides a kind of measurement that is associated with amount of analyte less than 1.5 μ l and wherein said sensor in 10 seconds or shorter time.
2. the sensor of claim 1, wherein, described reagent layer also comprises the electron transfer amboceptor.
3. the sensor of claim 2, wherein, described analyte is a glucose, and enzyme is a glucose oxidase, and amboceptor is a ferricyanate.
4. each sensor of aforementioned claim, wherein, described reagent layer contains silicon dioxide.
5. each sensor of aforementioned claim, wherein, described reference electrode is iron-ferricyanate electrode.
6. each sensor of aforementioned claim, wherein, described working electrode is made by the semiconductor material that mixes.
7. each sensor of aforementioned claim, it also comprises three cementing agent pads that form on described substrate, first cementing agent pad is arranged on first limit of reagent layer, second cementing agent pad is arranged on second limit of the reagent layer relative with first cementing agent pad, thereby make reagent layer and following arrangement of electrodes between first and second cementing agent pad, and the 3rd cementing agent pad is arranged on the 3rd limit of the reagent layer different with first and second limits and with reagent layer and separates, and described cementing agent pad defines the thickness of sample container cavity.
8. each sensor of aforementioned claim, wherein, described working electrode and contrast electrode are with on the apparent surface of aspectant structural arrangement in the sample container cavity.
9. each sensor of aforementioned claim, wherein, described reagent layer covers working electrode and contrast electrode.
10. instrument that is used in combination with disposable electrochemical sensor, be used for detecting and/or the analyte of quantitative liquid sample, it comprises a timing circuit, be used in sample application after the test of the test-strips of inserting this instrument, the current measurement of analyte in the control expression sample, wherein, described timing circuit makes and applied back 15 seconds or the shorter time is carried out current measurement in test sample.
11. the instrument of claim 10, wherein, described timing circuit makes and applied back 10 seconds or the shorter time is carried out current measurement in test sample.
12. the instrument of claim 10, wherein, described timing circuit makes and applied back 5 seconds or the shorter time is carried out current measurement in test sample.
13. the instrument of each of claim 10-12, wherein, described instrument comprises a kind of hand-held shell, arranges timing circuit therein, and described shell has an opening that is used for holding therein sensor.
14. the system of the analyte in the Electrochemical Detection fluid sample, it comprises:
(a) a kind of disposable electrochemical sensor, it comprises working electrode and the contrast electrode that is arranged in the sample container cavity, be arranged in the described sample container cavity and the reagent layer on working electrode, described reagent layer is included in analyte and has the enzyme that produces electrochemical signals down, wherein, the volume of described sample container cavity less than 1.5 μ l and wherein said sensor provide a kind of in 10 seconds or shorter time with amount of analyte to related measurement; With
(b) a kind of test instrumentation that is used to hold described disposable electrochemical sensor, described instrument comprises a timing circuit, be used for after specimen is coated to the test-strips of inserting this instrument, the current measurement of analyte in the control expression sample, wherein, described timing circuit made after detecting sample application 15 seconds or the shorter time is carried out current measurement.
15. a method of making the disposable electrochemical sensor of check and analysis thing, it may further comprise the steps:
(a) on substrate, form working electrode and contrast electrode;
(b) form insulation course on working electrode and contrast electrode, described insulation course has the opening that wherein forms, and is exposed by this opening at least a portion working electrode and contrast electrode;
(c) form reagent layer at least on the expose portion of working electrode, described reagent layer comprises at least a enzyme that produces electrochemical signals in the presence of analyte in fast hydrating matrix;
(d) on described substrate, form three cementing agent pads, first cementing agent pad is arranged in first limit of reagent layer, second cementing agent pad is arranged in second limit of the reagent layer relative with first cementing agent pad, thereby make reagent layer and following arrangement of electrodes between first and second cementing agent pad, and the 3rd cementing agent pad is arranged on the 3rd limit of the reagent layer different with first and second limits and with reagent layer and separate;
(e) stacked first hydrophilic film on first and second cementing agent pad, described hydrophilic film stride across the gap between first and second cementing agent pad, and second hydrophilic film covers on the 3rd the cementing agent pad; With
(f) sticking and on hydrophilic film loam cake, thus a sample cavity formed, and it is limited by described substrate, described first and second cementing agent pad and described first hydrophilic film.
16. the method for claim 15, it also is included in the step of cutting this device along the line that prolongs by first and second cementing agent pads near near the position the 4th limit of the reagent layer relative with the 3rd limit of described reagent layer.
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| GB0075226 | 2000-03-08 | ||
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| US53706500A | 2000-03-28 | 2000-03-28 | |
| US09/537,065 | 2000-03-28 |
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| CN1432130A true CN1432130A (en) | 2003-07-23 |
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