Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1495—Calibrating or testing of in-vivo probes

Definitions

• the present invention relates in general to analyte detection systems and methods. More specifically, this invention relates to an assay device that detects the presence, amount or other characteristic of an analyte of interest such as a glucose level within a fluid collected from a tissue on a continuous/continual basis.
• an analyte of interest such as a glucose level within a fluid collected from a tissue on a continuous/continual basis.
• U. S. Patent No. 5,961,451 to Reber et al. This patent sets forth a system which monitors the glucose level in the patient's interstitial fluid via an electrochemical assay device. However, this system is for one-time use only. The assay device must be replaced after every use.
• U. S Patent No. 5,391,250 to Cheney II et al. and U. S. Patent No. 5,437,999 to Diebold et al. teach methods for fabricating electrochemical devices for one-time use biological applications.
• the present invention relates to an assay device for detecting an analyte in a fluid, comprising: a) an inlet port to receive fluid; b) a well in fluid communication with the inlet port; c) an outlet port in fluid communication with the well to discharge fluid; d) at least one first working electrode and at least one reference electrode disposed within the well; e) a quantity of reactant that reacts with the analyte to form a reaction product, wherein the reaction product is in fluid communication with the at least one first working electrode; and f) at least one membrane disposed over or around the reactant to regulate contact of the analyte in the fluid with the reactant.
• the membrane serves to extend the useful life of the assay device by slowing consumption of the reactant. As a result, the assay device is well suited for continuous monitoring applications.
• the present invention relates to an assay device for detecting and enabling measurement of an analyte in a fluid
• an assay device for detecting and enabling measurement of an analyte in a fluid
• Figure 1 is a cross-section view of a preferred embodiment of the assay device according to the present invention.
• Figure 2 is a cross-section view of an alternative embodiment of the assay device.
• Figure 3 is a cross-section view of an another alternative embodiment of the assay device.
• Figure 4 depicts an exploded view of still another embodiment of an assay device according to the present invention.
• analyte shall mean the component that is being detected or measured in an analysis.
• the analyte may be any chemical or biological material or compound suitable for passage through a biological membrane technology known in the art, of which an individual might want to know the concentration or activity inside the body.
• Glucose is a specific example of an analyte because it is a sugar suitable for passage through the skin, and individuals, for example those having diabetes, might want to know their blood glucose levels.
• Other examples of analytes include, but are not limited to, such compounds as sodium, potassium, billirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, pharmaceutical compounds, and the like.
• Ranges may 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 expressed, another embodiment comprises from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
• the present invention is directed at an assay device for detecting and enabling measurement of an analyte in a fluid.
• the assay device contains: a) an inlet port to receive fluid; b) a well in fluid communication with the inlet port; c) an outlet port in fluid communication with the well, wherein the outlet port is designed to allow discharge of the fluid; d) at least one first working electrode and at least one reference electrode disposed within the well; e) a quantity of reactant that reacts with the analyte to form a reaction product, wherein the reaction product is in fluid communication with the at least one first working electrode; and f) at least one membrane disposed over or around the reactant to regulate contact of the analyte in the fluid with the reactant.
• the present invention is directed to an assay device containing: a) an inlet port to receive fluid; b) a well in fluid communication with the inlet port; c) an outlet port in fluid communication with the well, wherein the outlet port is designed to allow discharge of the fluid; d) at least one first working electrode and at least one reference electrode disposed within the well; e) a quantity of reactant that reacts with the analyte to form a reaction product, wherein the reaction product is in fluid communication with the at least one first working electrode; and f) calibration port that is in fluid communication with the well.
• the assay device according to the present invention is suitable for use in a continuous/continual analyte monitoring system, such as that disclosed in International Application No. PCT/US99/16378, entitled “System and Method for Continuous Analyte Monitoring,” filed July 20, 1999, which is incorporated herein by reference.
• the assay device 1000 comprises a bottom layer 100 that is in fluid communication with a channel- forming adhesive layer 200 via an inlet port 910.
• the channel-forming adhesive layer 200 has a layer of adhesive with a channel cut into it to form a well 250.
• Within the well 250 are the membrane 300 and electrodes 400.
• electrode 410 is a working electrode
• electrode 420 is a working electrode
• electrode 430 is a reference electrode
• electrode 440 is a counter-electrode. At least one of the working electrodes 420 is coated with a reactant 500.
• the electrodes 400 are disposed on or in a support base 600.
• the support base 600 is adjacent to an adhesive layer 700.
• An outlet port 920 extends through the support base layer 600, the adhesive layer 700, and a top layer 800.
• the bottom layer 100 provides structural support to the assay device 1000 and serves as the interface between the fluid source and the assay device 1000.
• Any suitable material, in any thickness or shape may be used for the bottom layer 100.
• Example suitable materials include acrylic, polyester, plastic, ceramic, polycarbonate and polyvinylchloride.
• the inlet port 910 which provides fluid communication between the bottom layer 100, the channel-forming adhesive layer 200, and the well 250, may be in any position and in any dimension/shape to allow sufficient flow to the electrodes 400.
• the inlet port 910 is suitable for alignment with holes/porations in a tissue from which fluid is to be drawn, such as interstitial fluid.
• An example of a mechanism to facilitate alignment of the assay device 1000 with the holes/porations in the tissue is disclosed in U.S. Provisional Application Serial No. 60/140,257 filed June 18, 1999 entitled “System and Method for Alignment of Micropores for Efficient Fluid Extraction and Substance Delivery,” which is incorporated herein by reference.
• the channel-forming adhesive layer 200 forms the well 250 to limit the volume of fluid within the assay device 1000.
• Suitable materials for the channel- forming adhesive layer 200 are compatible with the fluid of interest, provide adhesive support to the assay device 1000, and are thick enough to provide a well 250 from a channel cut into the channel-forming adhesive layer 200.
• the fluid of interest is blood or interstitial fluid, thereby requiring the channel- forming adhesive layer 200 to be constructed from adhesive-like materials that are not water-soluble.
• the electrodes 400 are disposed on or in a support base 600 using screen- printing, pad printing, sputter coating, photolithography or other suitable techniques, using known inks and dielectrics.
• the support base 600 may be of any thickness effective to provide support and bind the electrodes 400.
• One preferred embodiment includes a support base 600 of 10 mil thick transparent polyester.
• Other suitable materials may be used including ceramic, polycarbonate, and polyvinylchloride.
• an adhesive layer 700 and a top layer 800 provide additional support to the assay device 1000.
• the adhesive layer 700 binds the support base 600 to the top layer 800.
• the material of construction and dimension of the adhesive layer 700 is not critical to the present invention, thereby allowing any effective adhesive to be used.
• the top layer 800 like the bottom layer 100, provides structural support to the assay device 1000.
• the top layer 800 is constructed of the same material or compatible material as the bottom layer 100.
• An outlet port 920 allows discharge of the fluid from the well 250 through the support base 600, adhesive layer 700, and the top layer 800. It may be in any position and in any dimension/shape to allow sufficient flow to the electrodes 400.
• the outlet port 920 also is suitable for connection to a supply of vacuum sufficient to draw fluid through the well 250. In one preferred embodiment, the vacuum is sufficient to produce fluid from the skin at a site of where small holes/porations have been made in the tissue.
• the well 250 serves to expose the membrane 300 and electrodes 400 to the fluid that is monitored. Therefore, the well 250 is preferably of a dimension that the membrane 300 and the electrodes 400 do not obstruct the flow of fluid.
• a reactant 500 reacts with the analyte to form a reaction product.
• the reaction product is in fluid communication with one or both of the working electrodes 410 and 420 whereby electrons are created.
• the reactant 500 may react with glucose, which may in turn form hydrogen peroxide.
• oxygen gas, hydrogen ions and electrons are produced.
• Each working electrode 410 and 420 may be made from a variety of materials such as carbon and metals such as gold or silver.
• each working electrode 410 and 420 is made from catalytic metals such as platinum, palladium, chromium, ruthenium, rubidium, or mixtures thereof.
• the working electrodes 410 and 420 contain platinum.
• At least one working electrode and at least one reference electrode are necessary. However, more than one working electrode and one or more counter-electrodes may also be present.
• the working electrode 410 does not contain the reactant and therefore it produces an electrical signal that is indicative of the fluid without the analyte. This allows reduction or elimination of the signal due to various interferent compounds by subtracting the electrical signal of the working electrode 410 from the electrical signal of the working electrode 420.
• one working electrode may be used if the levels of interference are not significant or if an interference blocking layer is included.
• This interference blocking layer could be positioned anywhere between the fluid to be analyzed and the working electrodes 410 and 420.
• the interference blocking layer is placed directly over the working electrodes 410 and 420.
• the interference blocking layer is placed adjacent to the membrane 300.
• Suitable interference blocking layers include NAFIONTM and cellulose acetate.
• the reference electrode 430 establishes a potential relative to the fluid.
• the reference electrode 430 contains silver/silver-chloride.
• the counter- electrode 440 which is optional, serves to ground the current generated by the working electrodes 410 and 420.
• the counter-electrode 440 contains substantially the same materials as the working electrodes 410 and 420.
• the assay device 1000 may contain more than one working electrode, more than one reference electrode and more than one counter-electrode, as is well known in the art.
• the active surface of the electrodes 400 may be any shape and dimension to effectively operate. Particularly, the surface area of the any of the electrodes 400 can be varied as long as there is sufficient sensitivity to measuring the current. Preferably, the electrodes 400 have active surface areas between 0.1 mm 2 and 10 mm 2 . Most preferably, the electrodes 400 have a surface area of lmm 2 .
• the working electrodes 410 and 420 may be pre-conditioned by running at a specific voltage, such as +1.6 V relative to the reference electrode 430 for a suitable amount of time, such as 30 minutes, in a buffer system. This conditions the surface of the working electrodes 410 and 420 and increases their sensitivity to the reaction product generated by the reactant 500. Alternately, the working electrodes 410 and 420 could be conditioned for shorter times at higher voltages.
• the working potential will depend on the composition and shape of catalytic surface area. As such, the working potential can vary from 200 mV to 2 V. Such potential may be supplied via a monitoring unit coupled to the assay device wherein the monitoring unit utilizes an amperometric or coulometric measurement technique, known in the art.
• the working potential is generated either by holding the working electrodes 410 and 420 at a positive potential or by holding the counter-electrode 440 at a negative potential.
• the working electrodes 410 and 420 may be held at +800 mV and the reference electrode 430 and counter-electrode 440 at 0 mV, or the working electrodes 410 and 420 may be held at 0 mV and the reference electrode 430 and counter- electrode 440 at -800 mV.
• the electrodes may be connected to leads that in turn are connected to a monitoring unit ( Figure 4), patient worn or otherwise, via traces of graphite or silver/silver-chloride.
• traces may be applied via any method that provides a sufficient resolution such as ink-jet printing or pad printing.
• the printed traces could be replaced with traditional connection techniques.
• a quantity of reactant 500 that reacts with the analyte to form a reaction product is disposed proximate to the at least one first working electrode such that when the analyte contacts the reactant 500, the reaction product is in fluid communication with the working electrode.
• the quantity of reactant 500 covers a portion of the first working electrode (working electrode 420 shown in Figure 1).
• the quantity of reactant 500 may also be disposed on or in at least one working electrode.
• the reactant 500 is selected to react with a specific analyte.
• the quantity of reactant 500 is suitable to react with glucose.
• suitable reactants for the analyte glucose include glucose oxidase enzyme ("GOX"), glucose dehydrogenase (“GDH”), or mixtures thereof.
• the glucose in the fluid makes contact with the reactant(s) to produce reaction products, which in the case of GOX, are gluconolactone and hydrogen peroxide.
• the hydrogen peroxide diffuses to the working electrode 420 and reacts with the catalytic metal to produce electrons as described above.
• the reactants may include a mediator as an electron receptor instead of using oxygen.
• the mediator reacts with the working electrode 420 to produce electrons.
• Mediators that are commonly used are ferrocene, ferrocyamide and their derivatives.
• the reactant 500 is prepared by mixing 8 mg/mL GOX with 60 mg/mL bovine serum albumen ("BSA”) that is dissolved in phosphate buffered saline (“PBS”) that contains 10% glycerol and 0.01% NaN 3 .
• BSA bovine serum albumen
• PBS phosphate buffered saline
• 20 ⁇ L of 25% glutaraldehyde is added to the mixture immediately before application.
• a l ⁇ L drop of this mixture is placed onto one of the working electrodes. The mixture is then allowed to solidify and cure at room temperature for approximately eight to sixteen hours.
• the BSA serves as a carrier for the GOX due to its multiple cross-linking sites. As such, it can be replaced with any material that has multiple surface amine groups.
• the combination of BSA and glutaraldehyde as a cross linking system can be replaced with a system that will immoblize the active enzyme (in this case, GOX or GDH) without inhibiting its activity. Suitable replacements include other cross-linkers, polymer films, avidin-biotin linkages, antibody linkages, and covalent attachment to colloidal gold or agarose beads.
• the PBS acts to maintain the reactant in a neutral pH range (such as a pH of about 6.5 to about 7.5).
• a neutral pH range such as a pH of about 6.5 to about 7.5.
• Any suitable buffer may be used.
• Example buffers include phosphate, citrate, Tris-HCl, MOPS, HEPES, MES, Bis-Tris, BES, ADA, ACES, MDPSO, Bis-Tris Propane, and TES.
• the glycerol serves to prevent the reactant 500 from becoming dehydrated which reduces the wetting time for later use.
• any suitable additive may be used.
• the NaN 3 acts as an anti-bacterial agent.
• the NaN 3 could be replaced by any anti-microbial agent including antibiotics and detergents.
• the glutaraldehyde is a cross-linking agent that links the GOX and BSA into a matrix that will not dissolve or move from the electrode surface.
• the glycerol could be present in an amount of 5% to 50%o (by weight).
• the glycerol can be replaced or supplemented by any hygroscopic preservative or wetting agents including mild detergents such as TWEEN-20TM, SPANTM, TRITONTM, BRIJTM, MYRJTM and PLURONICSTM familes of detergents .
• any of the components to the reactant 500 and the overall amount of reactant 500 are not critical to the present invention as long as the amount is effective. These proportions and overall amount of reactant 500 are limited by the preference of having an excess of reactant 500 as well as maintaining the reactant' s solubility in the available volume. Preferably, the concentration of the reactant 500 is a minimum of 1 mg/mL.
• the reactant 500 may be applied to a working electrode with any method that allows for volume and position control capable with techniques such as screen printing, ink-jet printing, air brush, and pad printing.
• the reactant 500 is preferably applied without glutaraldehyde, and then, the glutaraldehyde is placed down. This avoids fouling the nozzle with solidifying material.
• the reactant 500 is dried and cured with the times of each varying based upon the amount and thickness of reactant layer(s) and the composition. Suitable drying conditions include temperatures up to 150°C, controlled humidity, and cure times of 15 minutes to 24 hours.
• the GOX enzyme will saturate at concentrations of approximately 3 mM glucose. In order to detect higher levels of glucose, the concentration reaching the reactant 500 must be held to a fraction of the total concentration.
• a membrane 300 is disposed over or around the reactant 500. In one preferred embodiment, the membrane 300 is disposed over or around all of the electrodes 400 as shown in Figure 3 In another preferred embodiment, the membrane 300 is disposed over or around the working electrodes 410 and 420 as shown in Figure 2. Alternatively, the membrane 300 is disposed over or around each electrode 400 or each working electrode 410 and 420 as shown in Figures 1.
• the membrane 300 preferably is a diffusion-limiting membrane that extends the linear range and the lifetime of the assay device 1000 system and makes it useful in a continuous/continual monitoring system.
• the membrane 300 has pores which regulate diffusion of an analyte therethrough. Therefore, the membrane 300 may be sized to limit the rate at which the analyte or an interferent makes contact with the reactant 500, thereby increasing the linear range of the assay device 1000.
• the membrane 300 may have low porosity to reduce glucose flux.
• the membrane 300 limits the amount of analyte that is present at the electrodes at any one time, allowing the electrodes 400 to operate continuously over long periods of time without depleting the reactant.
• a monitoring unit coupled to the at least one working electrode may continuously draw fluid through the assay device and detect the presence or level of an analyte in excess of 24 hours, more preferably in excess of 48 hours, and still more preferably in excess of 70 hours.
• One preferred membrane 300 is a 0.01 ⁇ m pore diameter polycarbonate ("PC") track-etch member 6 ⁇ m thick.
• PC polycarbonate
• Other suitable membranes that effectively produce a diffusion rate include dialysis membranes, polyurethane membranes, or polyvinylchloride membranes. Castable membranes such as NAFIONTM, cellulose acetate, silastics and alkoxy silanes are also effective for this use. Additionally, multiple membranes may be used.
• the membrane 300 may be secured by a layer of cross-linked BSA in the same buffer as the reactant 500.
• the cross-linked BSA consists of 60 mg/mL BSA dissolved in PBS containing 10%o glycerol and 0.01% NaN3.
• 20 ⁇ L/mL of 25% glutaraldehyde may be added immediately before use.
• any effective amount of this layer of cross-linked BSA may be used.
• a 2 ⁇ L drop of the cross-linked BSA is placed on the reactant covered electrode.
• a 5 mm diameter circle of the 0.01 ⁇ m PC membrane is placed over the drop of cross-linked BSA or other suitable, large polyamine.
• the membrane 300 is gently pressed into place under a sheet of parafilm. It is allowed to cure for 16 hours at room temperature under the parafilm, and then the parafilm is removed.
• the membrane 300 may be disposed over or around the reactant 500 by any suitable method including lamination, gluing, pressing, rolling and stretching. Any such method should not be destroyed by the fluid to be collected and analyzed. However, if an additional component is added, such as glue or other adhesion material, the additional component should be permeable in the fluid, such as Nafion is permeable in an aqueous-based fluid.
• suitable adhesives include epoxies, UV curable adhesives, pressure sensitive adhesives and hydrogels such as HEMA.
• the assay device 1000 is positioned on a tissue site overlying one or more openings made in the tissue.
• the openings in the tissue may be made by a variety of means, such as those disclosed in commonly assigned U.S. Patent No. 5,885,211.
• Fluid enters the assay device 1000 of Figure 1 through the inlet port 910. Under application of vacuum at the outlet port 920, the fluid travels through the well 250 and contacts the membrane 300.
• the membrane 300 is permeable to the analyte in the fluid and thereby allows the analyte to contact the electrodes 400 and the reactant 500.
• the analyte reacts with the reactant 500 to generate a reaction product.
• the reaction product contacts the working electrode 420 and creates electrons, thereby generating a current flow.
• the fluid continues through the outlet port 920 whereupon it exits the assay device 1000.
• Current flow across the working electrode(s) is measured, and from this a measurement of the analyte is obtained.
• the assay device 1000 may be used in conjunction with amperometric and coulometric measuring techniques.
• the current (charge/second) is measured at the applied voltage. This can be measured continuously, which is a preferred method in a flowing system.
• the total charge accumulated over a period of time is measured after a voltage is applied.
• the fluid is allowed to react with the reactant over a fixed period of time, thereby generating a reaction product. Then a voltage is applied and the current, which is measured over a fixed period of time, is integrated (added) to calculate the total amount of charge produced by the reaction product.
• This alternative method has the advantage of generating larger signals and reducing the impact of electroactive interfering substances.
• the membrane 300 preserves the life of the reactant 500 by helping to hold the reactant 500 in place and to thereby reduce the risk of rapid dissolution of the reactant 500 in the fluid. Also, by restricting the amount of analyte and interferents to the reactant 500, the membrane 300 helps ensure that the reactant 500 is in excess than what is needed to fully engage the analyte. In this way, as the reactant 500 degrades over time, it may remain in excess and deterioration in performance will be minimized.
• a variation of the assay device 1000 is shown in which a well 250 opens into an outlet port 920.
• the outlet port 920 does not provide fluid communication through the support base 600, the adhesive layer 700, and the top layer 800. However, the outlet port 920 is suitable for connection to a supply of vacuum sufficient to draw fluid through the well 250.
• the outlet port 920 may be filled with wiring and drain tubing, and then epoxy sealed.
• Figure 3 shows another alternative preferred embodiment of the assay device 1000.
• the well 250 is coupled to the outlet port 920.
• Figure 3 shows an assay device that comprises only a support base 600 and bottom layer 100.
• the bottom layer 100 provides the well 250 to expose the membrane 300 and electrodes 400 to the fluid.
• Figure 4 shows another embodiment of an assay device 1000 according to the present invention.
• This embodiment includes a bottom layer 100, a channel- forming adhesive layer 200, a support base 600, an adhesive layer 700, and a top layer 800.
• Figure 4 also includes an inlet port 910, a well 250, an outlet port 920, a calibration port 950, and drain tubing 940.
• this embodiment includes at least one working electrode, a reference electrode, and a reactant proximate to the working electrode as shown in Figures 1-3.
• This embodiment may optionally include at least one membrane, as shown in Figure 1.
• the electrodes are connected to a monitoring unit 970 via leads 960.
• the monitoring unit 970 is also connected to assay device 1000 via the drain tubing 940.
• the drain tubing 940 provides vacuum to the assay device 1000.
• the calibration port 950 is suitable for connection to a reservoir 980 containing calibration fluid.
• the calibration port 950 may include a membrane 990 permeable to the calibration fluid.
• the calibration fluid consists of water and the analyte to be detected.
• Other compounds may also be present, such as surfactants, which ensure smoother flow by reducing surface tension, such as SDS, or any of the detergents herein described.
• preservatives such as azide, EDTA, or any antibacterial or appropriate biocide that will not degrade of interfere with the reactant's performance may be added to the calibration fluid.
• the calibration fluid may include thickeners, such as polymers and proteins, to simulate the flow characteristics of the analyte-containing fluid that is being measured.
• the reservoir 980 is in fluid communication with the well 250 such that the calibration fluid flushes the well 250 to contact the electrodes with the calibration fluid.
• the calibration fluid is removed from the well 250 through the outlet port 920 under application of vacuum.
• the reservoir 980 may release the calibration fluid into the well 250 using any effective mechanism.
• the reservoir 980 comprises a bag-like member that opens and releases the calibration fluid into the well 250 in response to application of vacuum applied at the outlet port 920.
• the reservoir 980 may be formed of a material that when mechanically punctured releases the calibration fluid into the well 250.
• the membrane 990 is a self-sealing membrane that is rupturable to allow introduction of the calibration fluid such as by a syringe containing calibration fluid to deliver the calibration fluid into the well 250.
• the calibration fluid is delivered into the well 250 while vacuum is applied at the outlet port 920.
• the calibration fluid is introduced into the well 250 via a valve that operates as a one-way valve or is controlled external to the assay device 1000.

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  • 2000-04-07 JP JP2000608941A patent/JP2002541441A/ja active Pending
  • 2000-04-07 CA CA002366753A patent/CA2366753A1/en not_active Abandoned
  • 2000-04-07 BR BR0009581-8A patent/BR0009581A/pt not_active IP Right Cessation
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  • 2000-04-07 WO PCT/US2000/009393 patent/WO2000059373A1/en not_active Application Discontinuation
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