JP2002541441A - Analytical device for continuous measurement of fluid properties - Google Patents

Abstract

SUMMARY The present invention contemplates an analytical device that enables the detection and measurement of an analyte in a fluid. The analysis device comprises: (a) an inlet for receiving a fluid, (b) a reservoir in communication with the inlet, (c) an outlet in communication with the reservoir to release the fluid, and (d) at least one fluid disposed in the reservoir. A first working electrode and at least one reference electrode, and (e) a predetermined amount of reactant that reacts with the analyte to produce a reaction product, wherein the reaction product flows through the at least one first working electrode. And (f) at least one membrane disposed on or around the reactant to regulate contact between the analyte in a fluid and the reactant.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates generally to analyte detection devices and methods. More particularly, the present invention relates to an analytical device for detecting the presence, amount or other characteristic of an analyte of interest, such as the concentration of glucose, in a fluid that is continuously / frequently collected from tissue.

BACKGROUND OF THE INVENTION Medical research has shown that by properly controlling blood glucose levels, the serious complications of diabetes are significantly reduced. Thus, a large number of diabetics monitor blood glucose levels daily using conventional methods of stabbing a finger with a blood sample into a test device. Some diabetics must monitor blood glucose levels more than once a day. These individuals benefit greatly from devices that can continuously monitor blood glucose levels without having to prick their fingers multiple times.

[0003] Many attempts have been made to simplify the test method and eliminate the need for blood. One method was to illuminate the skin and determine the glucose concentration. Unfortunately, these methods do not provide a usable product for continuous monitoring of blood glucose levels.

Another device under study is disclosed in US Pat. No. 5,961,451 to Reber et al. This patent shows an apparatus for monitoring the glucose concentration in interstitial fluid of a patient by an electrochemical analysis device. However, this device can only be used once. Therefore, the analysis device must be replaced after each use.
Similarly, U.S. Patent No. 5,391,250 to Cheney II et al. And U.S. Patent No. 5,437,999 to Diebold et al.
The specification teaches a method of manufacturing an electrochemical device for a single use biological application.

[0005] Existing electrochemical test equipment has certain disadvantages for personal users. This is due to the fact that these devices are generally expensive and inaccurate. Further, it is often difficult with these devices to detect low concentrations of analytes present in the interstitial fluid. Also, many conventional devices are too large for a personal user to use continuously or regularly throughout the day.

[0006] It would therefore be advantageous to develop a convenient analyte analysis device for continuously monitoring blood glucose levels.

SUMMARY OF THE INVENTION The present invention is an analytical device for detecting an analyte in a fluid, comprising: (a) an inlet for receiving a fluid; (b) a well communicating with the inlet; c) an outlet for communicating with the reservoir to release a fluid, (d) at least one first working electrode and at least one reference electrode disposed in the reservoir, and (e) reacting with the analyte to produce a reaction. A predetermined amount of a reactant, wherein the reaction product is in flow with the at least one first working electrode, and (f) is disposed on or around the reactant. And at least one membrane that regulates contact between the analyte and the reactant in a fluid. This membrane serves to extend the useful life of the analytical device by slowing the consumption of the reactants. As a result, this analytical device
Suitable for continuous monitoring applications.

The present invention further provides an analytical device for detecting and measuring an analyte in a fluid, comprising: (a) an inlet for receiving a fluid; (b) a reservoir communicating with the inlet; c) an outlet for communicating with the reservoir to release a fluid, (d) at least one first working electrode and at least one reference electrode disposed in the reservoir, and (e) reacting with the analyte to form a reaction. An amount of a reactant to produce a product, wherein the reaction product is in flow with the at least one first working electrode, and (f) a calibration port in flow with the reservoir.
An analysis device having:

[0009] The advantages of the invention will be apparent from the description of the invention, or may be learned by practicing the invention. Other advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is understood that both the foregoing general description and the following detailed description are exemplary and exemplary of preferred embodiments of the present invention, and do not limit the invention, which is different from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this patent application, illustrate preferred and different aspects of the invention, together with a description of the invention, and serve to explain the principles of the invention. is there.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention can be understood more readily by reference to the following numbers and the description, including the detailed description and examples of the invention before and after it. It is to be understood that this invention is not limited to the particular apparatus and methods described, as specific device portions and / or process conditions may, of course, vary. It is also to be understood that the terminology used herein is for describing particular embodiments and is not intended to be limiting.

[0012] Further, when used in the detailed description of the invention and the claims, a case where a plurality is not shown and a case where "the above" is used include a plurality unless otherwise specified. You should be careful. For example, reference to a component in the singular includes reference to a plurality of components.

As used herein, “analyte” refers to a component that is detected or measured in an analysis. In particular, the analyte may be any chemical or biological material or compound suitable for passing through biological membranes known in the art, and may want to know the activity or concentration in the organism It can be a material or a compound. Glucose is a suitable sugar to pass through the skin, for example, people with diabetes want to know their blood glucose levels,
Glucose is a particular example of an analyte. Other examples of analytes include, but are not limited to, sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, pharmaceutical compounds, and the like.

Ranges can be expressed herein as from “about” or “approximately” one particular value, and / or to “about” or “approximately” another particular value. When such a range is indicated, other aspects can include from one particular value and / or to another particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value provides another aspect.

[0015] The present invention contemplates an analytical device that detects and allows measurement of an analyte in a fluid. The analysis device comprises (a) an inlet for receiving a fluid, (b) a reservoir in communication with the inlet, and (c) an outlet in communication with the reservoir, wherein the outlet allows for the release of a fluid. (D) at least one located in the reservoir;
One first working electrode and at least one reference electrode, (e) a predetermined amount of reactant that reacts with the analyte to produce a reaction product, wherein the reaction product comprises the at least one first working electrode And (f) at least one membrane disposed on or around the reactant to regulate contact between the analyte in a fluid and the reactant.

Further, the present invention provides (a) an inlet for receiving a fluid, (b) a reservoir communicating with the inlet, (c)
A) an outlet in communication with the reservoir, wherein the outlet is designed to allow the discharge of the fluid; (d) at least one first working electrode disposed in the reservoir and at least One reference electrode, (e) an amount of reactant that reacts with the analyte to produce a reaction product, wherein the reaction product is in flow with the at least one first working electrode; f) Intended for analysis devices having a calibration port in communication with the reservoir.

The analytical device of the present invention is suitable for use in an apparatus that continuously / frequently monitors analytes. This is described, for example, in PCT International Application PCT / US99 / 16378, `` Sytem a
nd Method for Continuous Analyte Monitoring, filed July 20, 1999. The description of this patent application is incorporated herein by reference.

Referring now to FIG. 1, a preferred embodiment of the analysis device 1000 of the present invention is shown. In this embodiment, the analysis device 1000 has a bottom layer 100 that is in flow communication with the flow path forming adhesive layer 200 via the inlet 910. This flow path forming adhesive layer 200 has a reservoir 250 formed by cutting the adhesive layer. In the reservoir 250, the membrane 300 and the electrode 4
00 exists.

In the preferred embodiment shown in FIG. 1, there are four electrodes 400. Here, the electrode 410 is a working electrode, the electrode 420 is a working electrode, the electrode 430 is a reference electrode, and the electrode 440 is a counter electrode. At least one of the working electrodes 420 is coated with a reactant 500. The electrode 400 is disposed on or in the support substrate 600. The support substrate 600 is
Adjacent to the adhesive layer 700. The outlet 920 extends through the support substrate layer 600, the adhesive layer 700, and the upper layer 800.

The bottom layer 100 provides structural support to the analysis device 1000 and serves as an interface between the fluid source and the analysis device 1000. Any suitable material of any thickness or shape,
Available for bottom layer 100. Examples of suitable materials include acrylic, polyester, plastic, ceramic, polycarbonate, and polyvinyl chloride.

An inlet 910 that provides flow between the bottom layer 100, the flow-forming adhesive layer 200, and the reservoir 250 allows for sufficient flow to the electrode 400 at any location and in any size / shape. I do. Inlet 910 is suitable for aligning holes / holes for extracting fluid, such as interstitial fluid, from tissue. An example of a mechanism that facilitates aligning the analysis device 1000 with the holes / holes in the tissue is described in US Provisional Application No. 60 / 140,257, filed June 18, 1999, entitled "System and Method for Alignment of Micropores." for Efficient Fluid
Extraction and Substance Delivery, " The description of the specification of the provisional patent application is hereby incorporated by reference into the present specification.

The channel forming adhesive layer 200 creates a reservoir 250 to limit the amount of fluid in the analysis device 1000. Suitable materials for the channel-forming adhesive layer 200 are compatible with the fluid of interest, provide an adhesive support for the analytical device 1000, and are cut into the channel-forming adhesive layer 200. It is of sufficient thickness to provide a reservoir 250 by the flow path. Preferably, the fluid of interest is blood or interstitial fluid, thus requiring a flow-forming adhesive layer 200 made of a water-insoluble adhesive-like substance.

Using screen printing, pad printing, sputtering coating, photolithography, or other suitable techniques, using known inks and dielectrics, the electrodes 400 are formed on or in the support substrate 600. Place. The support substrate 600 can be of any thickness effective to provide support and couple the electrodes 400. In one preferred embodiment, a 10 mil thick transparent polyester support substrate 600 is used. Other suitable materials can be used, which may be, for example, ceramic, polycarbonate or polyvinyl chloride.

Further, the adhesive layer 700 and the top layer 800 provide additional support for the analysis device 1000. The adhesive layer 700 bonds the support substrate 600 and the upper layer 800. The size and structural material of this adhesive layer 700 is not critical to the invention, and any effective adhesive can be used. The top layer 800 is, like the bottom layer 100, the analysis device 1000.
Provides structural support for Preferably, the top layer 800 is made of the same or compatible material as the bottom layer 100.

The outlet 920 stores fluid through the support substrate 600, the adhesive layer 700 and the upper layer 800.
Allows emission from zero. It can be anywhere and in any size / shape that allows sufficient flow to the electrode 400. Outlet 920 is also suitable for connection to a source of vacuum sufficient to draw fluid through reservoir 250. In a preferred embodiment, the reduced pressure is sufficient to obtain fluid from the skin where small holes / holes have been made in the tissue. Reservoir 250 allows membrane 300 and electrode 400 to be exposed to the fluid being monitored. Accordingly, the size of the reservoir 250 is preferably such that the membrane 300 and the electrode 400 do not block the flow of fluid.

As described in the examples below, reactant 500 reacts with an analyte to produce a reaction product. This reaction product flows through one or both of working electrodes 410 and 420, thereby providing electrons. Depending on the composition of the reactants, reactant 500 can react with glucose and thereby provide hydrogen peroxide. In this embodiment, oxygen gas, hydrogen ions and electrons are provided when the hydrogen peroxide contacts the working electrode.

Each of the working electrodes 410 and 420 can be made of various materials such as carbon and metal, for example, gold or silver. Preferably, each of the working electrodes 410 and 420 is made of a catalytic metal such as platinum, palladium, chromium, ruthenium, rubidium or a mixture thereof. Most preferably, working electrodes 410 and 420 include platinum.

To measure and / or sense the concentration of an analyte present in a fluid, at least one working electrode and at least one reference electrode are required. However, there may be more than one working electrode and one or more counter electrodes. For example, in the embodiment shown in FIG. 1, the working electrode 410 does not contain a reactant, and thus the working electrode 410 provides an electrical signal indicative of a fluid free of analyte. This allows the electrical signal of the working electrode 420 to be subtracted from the electrical signal of the working electrode 420, thereby eliminating or reducing electrical signals due to various interfering compounds.

Alternatively, if the concentration of the interferent is not significant or if an interferent blocking layer is used, a single working electrode can be used. This obstruction barrier layer can be located anywhere between the fluid to be analyzed and the working electrodes 410 and 420. In a preferred embodiment, the obstacle blocking layer is located directly on the working electrodes 410 and 420. In another preferred embodiment, an obstacle blocking layer is located adjacent to the membrane 300. Suitable obstacle blocking layers may include NAFION ™ and cellulose acetate. Interferers include acetaminophen, ascorbic acid, unconjugated bilirubin-, cholesterol, creatinine, dopamine, gentisic acid, heparin, ibuprofen, salicylate, tetracycline, tolbutamide, triglyceride, and uric acid.

The reference electrode 430 has a potential with respect to the fluid. Preferably, the reference electrode 430 is silver /
Contains silver chloride. Optional counter electrode 440 serves to ground the current provided by working electrodes 410 and 420. Preferably, counter electrode 440 comprises substantially the same material as working electrodes 410 and 420. The analysis device 1000, as known in the art,
It can have more than one working electrode, more than one reference electrode, and more than one counter electrode.

The active surface of electrode 400 may be of any shape and size effective for operation. In particular, the surface area of any electrode 400 may vary as long as it is sufficiently sensitive to measure current. The size of preferably electrode 400 active surface is a 0.1 mm ² to 10 mm ^2. More preferably, the surface area of electrode 400 is 1 mm ² .

After assembling the analysis device 1000, the working electrodes 410 and 420 can be preconditioned. This is done by operating at a specific voltage, for example + 1.6V, on the reference electrode 430 for a suitable time, for example 30 minutes, in a buffer system. This conditions the surfaces of the working electrodes 410 and 420 and makes them more sensitive to the reaction products provided by the reactants 500. Alternatively, the working electrodes 410 and 420 can be adjusted at a relatively high voltage for a relatively short time.

The working voltage depends on the composition and shape of the catalyst surface area. The working voltage itself is
It can be changed from 200mV to 2V. Such a voltage can be supplied via a monitor connected to the analysis device. Here, the monitoring device uses coulometric or amperometric techniques known in the art. The working voltage is generated by maintaining working electrodes 410 and 420 at a positive voltage or by maintaining counter electrode 440 at a negative voltage. For example, maintaining working electrodes 410 and 420 at +800 mV and maintaining reference electrode 430 and counter electrode 440 at 0 mV, or maintaining working electrodes 410 and 420 at 0 mV and maintaining reference electrode 430 and counter electrode 440 at −800 mV. can do.

The electrodes can be connected to leads via graphite or silver / silver chloride traces, which can be connected to a monitoring device worn by the patient (FIG. 4) or other. However, other conductive materials, such as gold or tin, are also suitable for connecting the electrodes to the wires. These traces can be applied in any way that provides sufficient resolution, such as ink jet printing or pad printing. Furthermore, the print trace can be replaced by a conventional association technique.

An amount of the reactant 500 that reacts with the analyte to produce a reaction product is positioned proximate the at least one first working electrode, such that when the analyte contacts the reactant 500 The reaction product is allowed to flow through the working electrode. Preferably, a predetermined amount of reactant 500 covers a portion of the first working electrode (working electrode 420 shown in FIG. 1). The predetermined amount of reactant 500 can also be located on or within at least one working electrode. Reactant 500 is selected to react with a particular analyte. 1
In one preferred embodiment, the quantity of reactant 500 is suitable for reacting with glucose. Such suitable reactants for the analyte glucose include glucose oxidase enzyme ("GOX"), glucose dehydrogenase ("GDH").
) Or mixtures thereof.

When the reactant 500 is selected from this group, glucose in the fluid is brought into contact with the reactant to produce a reaction product. Here, in the case of GOX, gluconolactone and hydrogen peroxide are produced. The hydrogen peroxide diffuses to the working electrode 420 and reacts with the catalytic metal to provide electrons as described above. Alternatively, the reactants may include a mediator such as an electron acceptor instead of using oxygen. In such embodiments, the mediator is the working electrode 420
Reacts with to create electrons. Commonly used mediators are ferrocene, ferrocyanide, and derivatives thereof.

In one preferred embodiment, 60 mg / mL bovine serum albumin (“BSA”) dissolved in phosphate buffered saline (“PBS”) containing 10% glycerol and 0.01% NaN _3.
) Is mixed with 8 mg / mL GOX to prepare reactant 500. In this preferred embodiment, 20 μL of 25% glutaraldehyde is added to the mixture just before application. A drop of preferably 1 μL of this mixture is placed on one working electrode. The mixture can then solidify and harden at room temperature in about 8-16 hours.

BSA acts as a carrier for GOX due to its multiple crosslinking sites. This can be replaced by any material having multiple surface amine groups. In addition, the combination of BSA and glutaraldehyde as a cross-linking system is combined with an active enzyme (in this case, G
OX or GDH) can be replaced with a system that fixes the active enzyme without inhibiting the activity. Suitable substitutions may include other crosslinkers, polymer films, avidin-biotin linkages, antibody linkages, and covalent substitutions to colloidal gold or agarose beads.

In a preferred embodiment of the present invention, the PBS comprises reactants in a neutral pH range (eg, from about 6.5 to
(PH range of about 7.5). Any suitable buffer can be used.
Examples of buffers include phosphate, citrate, Tris-HCl, MOPS, HEPES, MES
, Bis-Tris, BES, ADA, ACES, MDPSO, Bis-Tris propane, and TES. Glycerol serves to prevent reactant 500 from being dehydrated and to reduce the wetting time for later use. Any suitable additives can be used for this purpose. NaN ₃ acts as an antimicrobial agent. The NaN ₃ can be replaced with any antimicrobial, including antibiotics and detergents.

Glutaraldehyde is a crosslinker that binds GOX and BSA to a matrix that does not dissolve and migrate from the electrode surface. In one preferred embodiment, the glycerol is
It can be present in an amount of 50 wt%. Alternatively, glycerol can be used as a wetting agent, such as any hygroscopic preservative or mild detergent, eg, TWEEN-20 ™, SPAN ™
, TRITON ™, BRIJ ™, MYRJ ™ and PLURONICS ™ family of detergents.

The proportions of the optional components for reactant 500 and the total amount of reactant 500 are not critical to the invention, as long as they are effective. The proportions and total amounts of reactants 500 are limited only to the fact that reactants 500 are preferably in excess and that it is preferable to maintain the solubility of the reactants in the available volume. Preferably, the concentration of reactant 500 is at least 1 mg / mL.

Reactant 500 can be applied to the working electrode in any manner that allows control of volume and position. This method is, for example, screen printing, inkjet printing, airbrush, and pad printing. For example, in an application method that uses a nozzle or screen that must pass through the solution continuously, preferably reactant 500 is applied without glutaraldehyde, followed by placement of glutaraldehyde. this is,
Prevents nozzles from becoming dirty with solidified material. After application, the reactant 500 is dried and cured at various times based on the thickness and amount and composition of the reactant layer. Suitable drying conditions can include temperatures up to 150 ° C., controlled humidity, and cure times of 15 minutes to 24 hours.

The GOX enzyme saturates at a glucose concentration of about 3 mM. In order to detect higher glucose concentrations, the concentration that reaches reactant 500 should be maintained as part of the total concentration. To accomplish this, the membrane 300 is placed around or on the reactant 500. In one preferred embodiment, the membrane 300 is disposed on or around all electrodes 400 as shown in FIG. In another preferred embodiment, the membrane 300 is disposed on or around the working electrodes 410 and 420, as shown in FIG. Alternatively, the membrane 300 is disposed on or around each of the electrodes 400 or each of the working electrodes 410 and 420 as shown in FIG.

Preferably, the membrane 300 is a diffusion limiting membrane that increases the useful life and linear range of the analytical device 1000 apparatus, and also benefits its use in continuous / frequent monitoring equipment. This membrane
300 has pores that control the diffusion of the analyte. Accordingly, the size of the membrane 300 can be varied to reduce the rate at which analytes or interfering substances come into contact with the reactants 500, thereby increasing the linear range of the analysis device 1000. For example, the porosity of the membrane 300 is low, and the flux of glucose can be reduced. In this way, the membrane 300 always limits the amount of analyte present at the electrode, and allows the electrode 400 to operate continuously over an extended period of time without running out of reactants. In fact, the monitoring unit connected to the at least one working electrode continuously passes the fluid through the analysis device,
Over a period of time, more preferably over a period of 48 hours, even more preferably 70
Over a period of time, the presence and concentration of the analyte can be detected.

One preferred membrane 300 is a polycarbonate (“PC”) track-etch membrane with a pore diameter of 0.01 μm and a thickness of 6 μm. Other suitable membranes that provide effective diffusion rates can include dialysis membranes, polyurethane membranes, or polyvinyl chloride membranes. Castable membranes such as NAFION ™, cellulose acetate, plastics and alkoxysilanes are also suitable for this application. Further, multiple membranes can be used.

The membrane 300 can be protected with a layer of cross-linked BSA in the same buffer as the reactant 500. In one preferred embodiment, the cross-linked BSA comprises 10% glycerol and 0.01% NaN ₃
Consists of 60 ng / mL BSA dissolved in PBS containing In addition, 20 μL / mL of 25% glutaraldehyde can be added just before use.

[0047] Any effective amount of this layer of cross-linked BSA can be used. In one preferred embodiment, a drop of 2 μL of cross-linked BSA is placed on the electrode over which the reactants cover. A 5 mm diameter circle of 0.01 μm PC membrane is then placed over the drop of cross-linked BSA or other suitable bulk polyamine. The membrane 300 is gently pressed into a point below the parafilm sheet. This is cured for 16 hours at room temperature under parafilm, after which the parafilm is removed.

The membrane 300 can be placed on or around the reactant 500 by any suitable method, including lamination, gluing, pressing, rolling, and pulling. Any such method should be one that is not disrupted by the fluid being collected and analyzed. Also, if additional components such as glue or other adhesive materials are added, the other additional components should be permeable in the fluid, eg, Nafion is permeable in aqueous fluids. Other suitable adhesives include epoxies, UV curable adhesives, pressure sensitive adhesives, and hydrogels such as HEMA.

In operation, the analysis device 1000 is placed at a tissue site on one or more openings made in the tissue. The tissue opening can be made by various means, such as those commonly disclosed in US Pat. No. 5,885,211. Fluid enters the analysis device 1000 of FIG. By evacuating outlet 920, fluid enters reservoir 250 and contacts membrane 300. The membrane 300 permeates the analyte in the fluid, thereby bringing the analyte into contact with the electrode 400 and the reactant 500. The analyte contacts the reactant 500 to provide a reaction product. The reaction product contacts the working electrode 420 and generates electrons, thereby providing a current. The fluid passes to outlet 920, where it exits analysis device 1000. The current through the working electrode is measured, and the measurement of this current gives the measurement of the analyte. The analysis device 1000 can be used in combination with current and coulometry techniques.

In the current measurement, a current (charge / secondary current) is measured at the applied voltage.
It can be measured continuously, and this measurement method is the preferred method in the following system. In the coulometric technique, the total charge accumulated during a predetermined period after applying a voltage is measured. Typically, the fluid reacts with the reactants over a period of time, thereby generating a reaction product. Thereafter, a voltage is applied, the current measured over a period of time is integrated (added), and the total charge created by the reaction products is calculated.
This alternative is advantageous in that it provides a relatively large signal and reduces the effects of electrically active interferers.

The membrane 300 extends the useful life of the reactant 500 by helping to fix the position of the reactant 500 and reducing the risk of the reactant 500 rapidly dissolving in the fluid. Also, by limiting the amount of analytes and interfering substances that reach reactant 500,
Membrane 300 can be used to reduce the amount of reactant 500 required to fully accommodate the analyte.
Ensure that the amount is greater than zero. In this manner, the reactants 500 gradually degrade, so that it is possible to keep the reactants 500 in excess and to minimize performance degradation.

Referring to FIG. 2, various analysis devices 1000 are shown, where a reservoir 25 is shown.
0 is open to exit 920. In such a configuration, outlet 920 does not provide flow through support substrate 600, adhesive layer 700 and top layer 800. Outlet 920 stores fluid 250
Suitable for connection to a source of reduced pressure sufficient to pass through. Outlet 920 can be filled with wiring and withdrawal tubing and subsequently sealed with epoxy.

FIG. 3 shows another preferred embodiment of the analysis device 1000. As shown in FIG. 2, reservoir 250 is connected to outlet 920. However, FIG.
And an analysis device having only the bottom layer 100. Bottom layer 100 provides a reservoir 250 to expose membrane 300 and electrode 400 to fluid.

FIG. 4 shows another embodiment of the analysis device 1000 of the present invention. This embodiment includes a bottom layer 100, a flow path forming adhesive layer 200, a support substrate 600, an adhesive layer 700, and an upper layer 800. FIG. 4 also includes an inlet 910, a reservoir 250, an outlet 920, a calibration port 950, and an extraction line 940. Although not shown, this embodiment has at least one working electrode, a reference electrode, and a reactant proximate the working electrode, as shown in FIGS. This embodiment optionally has at least one membrane, as shown in FIG. The electrodes are also connected to the monitoring unit 970 via the conductor 960. Further, the monitoring unit 970 is connected to the analysis device 1000 via the extraction pipe 940. Withdrawal line 940 provides reduced pressure to analysis device 1000.

Similar to the analysis device 1000 of FIG. 2, the reservoir 250 shown in FIG. Calibration port 950 is connected to a reservoir 980 holding a calibration fluid. In addition, the calibration port 950 can have a membrane 990 that is permeable to the calibration fluid.

In one aspect, the calibration fluid comprises water and the analyte to be detected. Other compounds such as surfactants or other detergents described herein may be present.
Here, a surfactant, for example SDS, ensures a relatively smooth flow by lowering the surface tension. In addition, preservatives that do not degrade the performance of the reactants, such as azide, EDTA, or any germicide or suitable biocide, can be added to the calibration fluid. In addition, the calibration fluid may contain thickeners, such as polymers and proteins, to simulate the fluid properties of the analyte-containing fluid being measured.

The reservoir 980 is in communication with the reservoir 250 such that the calibration fluid flows into the reservoir 250 and makes contact with the electrodes. The calibration fluid is removed from reservoir 250 through outlet 920 by applying a vacuum.

The reservoir 980 can discharge the calibration fluid into the reservoir 250 using any effective mechanism. In one embodiment, the reservoir 980 has a bag-like membrane,
It opens in response to the reduced pressure applied to the outlet 920 to release the calibration fluid into the reservoir 250.
Further, reservoir 980 may be made of a material that releases a calibration fluid into reservoir 250 when mechanically pierced.

Alternatively, membrane 990 may be a self-sealing membrane that can be ruptured to introduce a calibration fluid, such as a membrane that ruptures with a syringe and introduces calibration fluid into reservoir 250. Preferably, the calibration fluid is introduced into reservoir 250 while applying reduced pressure to outlet 920. In another preferred aspect, a valve or analysis device that operates as a one-way valve
Calibration fluid is introduced into reservoir 250 via a valve operated externally to 1000.

In this specification, various documents have been referred to. The descriptions of these documents are hereby incorporated by reference in their entireties, and thereby provide a more complete description of the prior art to which this invention pertains.

[0061] Various modifications and changes may be made by those skilled in the art without departing from the spirit and scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art from reference to the description of the specification or practice of the invention disclosed herein. The descriptions and examples herein are merely exemplary, and the true scope and nature of the invention is indicated by the following claims.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view of a preferred embodiment of the analysis device of the present invention.

FIG. 2 is a cross-sectional view of another embodiment of the analysis device of the present invention.

FIG. 3 is a sectional view of still another embodiment of the analysis device of the present invention.

FIG. 4 is an exploded view of still another embodiment of the analysis device of the present invention.

[Procedure amendment]

[Submission date] October 17, 2001 (2001.10.17)

[Procedure amendment 2]

[Document name to be amended] Drawing

[Correction target item name] Fig. 4

[Correction method] Change

[Contents of correction]

FIG. 4

──────────────────────────────────────────────────続 き Continuation of the front page (31) Priority claim number 60 / 139,976 (32) Priority date June 18, 1999 (June 18, 1999) (33) Priority claim country United States (US) ( 31) Priority claim number 60 / 165,809 (32) Priority date November 16, 1999 (November 16, 1999) (33) Priority claim country United States (US) (31) Priority claim number 60 / 182,698 (32) Priority Date February 15, 2000 (Feb. 15, 2000) (33) Priority Claimed States United States (US) (81) Designated States EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN , MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Farkhar, Jay. David United States, Georgia 30530, Comers, Craig Road 234 (72) Inventor Taylor, Reims United States, Georgia 30008, Marietta, Lakeside Place 2381 (72) Inventor Smith, Alan M. United States, Georgia 30305-2733, Atlanta, Northeast, Greenview Avenue 736 (72) Inventors Brig, Mark S. United States, Indiana 46530, Granger, Harbridge Drive 11595 (72) Inventor Hatch, Michael Earl. United States, Georgia 30518, Sugar Hill, Price Hills Trail 131 (72) Inventor Schiffer, Jarad United States of America, Georgia 30324, Atlanta, Woods Circle 1195 (72) Inventor Forpel, Mark El. United States, Georgia 30022, Alfaretta, Fallgarth Way 160 (72) Inventor Connolly, James United States, Georgia 30243, Lawrenceville, Marsh Creek Drive 1924 F-term (reference) 2G045 AA13 CA25 DA31 FB01 FB05 HA09 JA02

Claims (24)

[Claims] 1. An inlet for receiving a fluid, (b) a reservoir communicating with the inlet, (c) an outlet communicating with the reservoir to release a fluid, and (d) disposed in the reservoir. At least one first working electrode and at least one reference electrode; (e) an amount of a reactant that reacts with the analyte to produce a reaction product, wherein the reaction product comprises the at least one first In communication with the working electrode; and (f) at least one membrane disposed on or around the reactant to regulate contact between the analyte and the reactant in the fluid. An analytical device that detects analytes. 2. The analytical device of claim 1, wherein the inlet is suitable for aligning with a hole / hole in a tissue from which fluid is to be drawn. 3. The analytical device of claim 1, wherein said outlet is suitable for connecting to a source of vacuum sufficient to pass fluid through said reservoir. 4. The analysis device according to claim 1, wherein the at least one first working electrode is made of a catalyst metal. 5. The analytical device according to claim 1, wherein the at least one first working electrode is made of platinum, palladium, chromium, ruthenium, rubidium, or a mixture thereof. 6. The analytical device according to claim 1, wherein said at least one reference electrode is comprised of silver / silver chloride. 7. The analysis device according to claim 1, further comprising at least one counter electrode disposed in the reservoir. 8. The analysis device according to claim 1, further comprising a second working electrode disposed in the reservoir. 9. The analytical device according to claim 1, further comprising at least one counter electrode and a second working electrode disposed in the reservoir. 10. A monitoring apparatus comprising the analysis device according to claim 1, and further comprising a monitoring unit combined with the analysis device. 11. A monitoring device comprising the analysis device of claim 1 and further comprising a monitoring unit associated with the analysis device, wherein the monitoring unit uses a coulomb or current measurement technique. A monitoring device for providing an analyte measurement from the analysis device. 12. The analytical device according to claim 1, wherein the predetermined amount of the reactant is disposed on or around the at least one working electrode. 13. The analytical device according to claim 1, wherein the predetermined amount of the reactant is composed of a glucose oxidase enzyme, a glucose dehydrogenase, or a mixture thereof. 14. The analytical device of claim 1, wherein said predetermined amount of reactant is suitable for reacting with glucose. 15. The analytical device of claim 1, wherein the at least one membrane has pores sized to limit the percentage of the analyte that contacts the reactant. 16. The analytical device of claim 1, wherein said at least one membrane has pores sized to limit the percentage of interfering substances in contact with said reactants. 17. The analysis device according to claim 1, wherein the at least one membrane is disposed on or around the at least one first working electrode. 18. The method according to claim 18, wherein the at least one membrane is disposed on or around the at least one first working electrode and the at least one reference electrode.
The analysis device according to claim 1. 19. The apparatus further comprising a second working electrode disposed in the reservoir, wherein the at least one membrane is on or around the at least one first working electrode and the second working electrode. The analysis device according to claim 1, wherein the analysis device is arranged. 20. The apparatus of claim 20, further comprising a reservoir holding a calibration fluid, said reservoir communicating with said reservoir, whereby said calibration fluid flows into said reservoir and through said outlet. The analysis device of claim 1, wherein the analysis device is removed from the device. 21. The analytical device of claim 20, wherein the reservoir has a bag that opens in response to a vacuum applied to the outlet to release the calibration fluid into the reservoir. 22. The analytical device of claim 20, wherein the reservoir is made of a material that releases the calibration fluid into the reservoir when mechanically pierced. 23. The analytical device of claim 20, further comprising a calibration port connecting said reservoir to said reservoir, said calibration port having a membrane permeable to said calibration fluid. 24. An inlet for receiving fluid, (b) a reservoir communicating with the inlet, (c) an outlet communicating with the reservoir to release fluid, and (d) disposed in the reservoir. At least one first working electrode and at least one reference electrode; (e) an amount of a reactant that reacts with the analyte to produce a reaction product, wherein the reaction product comprises the at least one first An analytical device for detecting and measuring an analyte in a fluid, comprising: a calibration port in communication with the working electrode; and (f) a calibration port in communication with the reservoir.