+

WO1999035487A1 - Procedes et appareil permettant l'analyse exacte des composants d'un fluide corporel - Google Patents

Procedes et appareil permettant l'analyse exacte des composants d'un fluide corporel Download PDF

Info

Publication number
WO1999035487A1
WO1999035487A1 PCT/US1999/000023 US9900023W WO9935487A1 WO 1999035487 A1 WO1999035487 A1 WO 1999035487A1 US 9900023 W US9900023 W US 9900023W WO 9935487 A1 WO9935487 A1 WO 9935487A1
Authority
WO
WIPO (PCT)
Prior art keywords
reagent
analyte
site
bodily fluid
test strip
Prior art date
Application number
PCT/US1999/000023
Other languages
English (en)
Inventor
John G. Freund
Original Assignee
Skyline Venture Partners, L.P.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Skyline Venture Partners, L.P. filed Critical Skyline Venture Partners, L.P.
Publication of WO1999035487A1 publication Critical patent/WO1999035487A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G01N21/8483—Investigating reagent band
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/521—Single-layer analytical elements

Definitions

  • the present invention relates to apparatus and methods for detecting the concentration or relative amount of biochemical analytes in various bodily fluids. More particularly, this invention includes test strip systems and methods for determining the concentration of blood glucose levels with chemically treated test strips.
  • Biological fluids are frequently obtained from patients to determine particular levels of certain biochemical analytes in the course of diagnosis and treatment of diseases.
  • Medical research has shown that aggressive management of blood sugar levels significantly decreases the long-term complications of diabetes.
  • Blood sugar level monitoring today may include performing multiple blood glucose measurements per day by some patients, particularly those afflicted by Type I diabetes, for guidance in numerous adjustments of multiple injected doses of insulin during each day.
  • Safety precautions and constant monitoring are needed to prevent known adverse medical consequences of diabetes such as morbidity, degeneration of vision or renal failure, and ulcers of the lower extremities which may even progress to a stage where surgical amputation is required.
  • point of care diagnostic systems may be defined as systems suitable for use by the patient when a clinician is not present, even if such systems are sometimes used by clinicians or medical facilities themselves, or when clinicians and patients are present together. From a practical standpoint, it is extremely difficult for non-hospitalized patients to monitor their blood sugar levels with adequate frequency except by performing self-testing.
  • Blood glucose monitoring systems comprising hand-held equipment plus disposable test strips are widely available today to perform blood glucose measurements. These systems often include a portable battery powered electronic device and a mounted disposable reagent-bearing test strip.
  • a drop of blood or bodily fluid is applied a single time to the strip so that it reacts with the selected reagents.
  • a colorimetric system may be used to measure a change in the color of a dye resulting from a reaction that is in proportion to the level of the analyte being measured.
  • FIG. 1 -A is an illustration of a photometric blood glucose test strip that is currently available for colorimetric systems.
  • Fig. 1-B is a side view and cross- section of the photometric blood glucose test strip shown in Fig. 1-A. As shown in Figs. 1-A and 1-B, these types of test strips basically consist of a holder 1 formed with an opening or a window 2 on the surface of the holder.
  • a reagent pad 3 is positioned within the holder 1 so that some portion of the reagent pad surface is exposed to a fluid sample through the window 2 of the holder.
  • an analyte level reading may be achieved with an electrochemical system that measures a change in current that is proportional to the amount of analyte being measured.
  • Fig. 2-A depicts an electrochemical blood glucose test strip that is currently available.
  • Fig. 2-B is a side view and cross-section of the electrochemical blood glucose test strip shown in Fig. 2-A.
  • the electrochemical test strip also includes a holder 4 formed with a window 5 on the surface of the holder and a recessed wall 7.
  • a reagent pad 6 is positioned within the holder 4 so that some portion of the reagent pad surface is exposed to a fluid sample through the window 5 of the holder. Electrodes 8 are also included in the electrochemical test strip for measuring the blood glucose level of a sample applied to the reagent pad 6. Any of these or other similar types of systems and test strips may provide some concentration level reading or other displayed information for the patient to read.
  • the practice of blood glucose monitoring with test strips typically includes the application of a whole blood sample onto a reagent pad.
  • a reagent pad generally refers to the portion of a test strip where blood or any other fluid may be applied. A whole blood sample is often filtered by a section of the pad to separate serum from other blood components.
  • the separated serum reacts with selected reagents that are typically applied to the pad during the factory manufacturing process.
  • Reagents may include enzymes such as glucose oxidase, horseradish peroxidase, or any other chemically active material used for measuring analyte levels.
  • the applicable chemistry and technology used in colorimetric detection systems provides an end result that is basically an observable change in the color on a reagent pad that is proportional to analyte or glucose concentration levels in a fluid sample.
  • the reaction is typically allowed to occur over a predetermined length of time before the color change on the underside of the test strip is read by a photometer.
  • the photometer translates the magnitude of the color change into analog electronic impulses which may be converted by an appropriate instrument embedded algorithm and displayed digitally on instruments such as LCD displays.
  • Many photometer systems today include an optical light source and a series of focusing elements or lenses, filters and detectors that collectively provide blood glucose level readings.
  • the disposable test strips in use today often provide a single location or pad on the strip that may contain a variety of reagents.
  • the reagent pad is typically designed to be a site that receives samples of blood or any other bodily fluid.
  • the strip is removed and a fresh one mounted before a second drop of blood, control fluid or any other fluid can be applied and measured.
  • a patient typically enters a calibration number into the particular measuring system which is printed on the outside of the strip package or supplied electronically in the strip package.
  • the calibration numbers which are predetermined and selected during the factory manufacturing process, allow for some system correction resulting from factory variation in the manufacture of test strips.
  • Control fluids with a known glucose concentration range may be purchased which allows a patient to determine whether purchased tests strips or point of care systems are performing within an accepted range or set of specifications established by a system manufacturer. When the glucose concentration of the control fluid falls within the specified range set by a manufacturer for the control fluid, the system and strips are supposedly suitable for use. However, if the control fluid measurement is not within defined parameters or specifications, the patient is directed to exchange the system for a new or repaired one, or to replace the test strips.
  • control fluids As practiced today does not account for possible strip-to-strip variability within a package because any indication that the system is performing within specifications applies only to the performance of a single strip or test strip being used with the control fluid.
  • a fresh test strip When a fresh test strip is subsequently applied for use with blood, it may or may not have been manufactured at the same time as the strip that was used and tested with the control fluid. Furthermore, the test strips used may or may not have been subjected to the same environmental conditions since they were manufactured. As a result, use of the control fluid with one test strip does not necessarily indicate that any other strip will perform within similar limits.
  • the use of a strip with control fluid again requires the patient to waste another relatively expensive strip, which alone discourages frequent use of control fluids. Because the result from using control fluid only indicates whether a system and strip combination are within specifications, the use of control fluids as practiced today tacitly accepts that each blood glucose measurement may be substantially inaccurate, yet acceptable, so long as the inaccuracy falls within specified limits set by manufacturers. As a result, clinicians often advise diabetic patients that if a measured blood glucose reading deviates from how the patient "feels," the patient should assume the feelings are correct, administer insulin accordingly, and assume that the measurement was erroneous.
  • control fluids and the use of calibration numbers with existing instruments provide some indication as to whether the system is calibrated within certain tolerances pre-set by the manufacturer, they do not correct the measured blood glucose level by employing the difference observed in the measurement of the calibration fluid when compared to the fluid with known glucose concentration.
  • Control fluids used in existing systems may also vary in glucose concentration from factory-set levels when water content in the fluids diminishes due to evaporation while glucose levels remain constant. As a result, control solutions themselves may be inaccurate because their supposedly constant glucose level concentration may actually vary. In any event, a different test strip with potentially different reagent material is often used for measuring the reference solution. There are many reasons for the inconsistent test results provided by current point of care blood glucose measurement systems which may produce readings varying up to 15% or more.
  • test strips When test strips are exposed to humidity after manufacturing, certain enzymes contained in reagent material on the test strip may become deactivated thereby changing the rate at which a measurable reaction can take place.
  • High or low temperatures during storage (such as if the patient should leave packages of strips in the trunk of a car in the hot sun or in extremely cold weather) can also cause deviation in the rate at which selected enzymes catalyze a reaction.
  • a decrease in oxygen levels such as those observed in cities at high altitudes, i.e., Denver, can further cause the enzyme- mediated reaction to be catalyzed at a slower rate.
  • Other non-environmental factors may further cause inaccuracy, such as variations in the manufacturing of the strips, poor technique followed by a patient in the withdrawal of blood samples or its application to the test strip, or drift in the analog portion of the electronics of the instrument.
  • Diabetics are increasingly encouraged to maintain near normal blood sugar levels for reduction of obvious health risks. For example, patients are especially urged to manage their blood sugar level at bedtime so that it is between approximately 115 and 140 milligrams per deciliter. A reading between this range is recommended so that even if low blood sugar is experienced during the night, it will not be so low that insulin shock or hypoglycemia occurs within the next eight hours or before patients wake up.
  • a 15% error could mean that the actual blood sugar level is as high as 115, which would be within established guidelines, or as low as 85 which would expose the patient to risk of insulin shock or severe hypoglycemia in the morning.
  • existing systems are inconsistent and do not provide readings that are always within 15% of the correct figure. For example, some photometers are within 15% of the correct glucose level only 86% of the time, and other similar products are within 15% of the correct level only 76% of the time. Meanwhile, the American Diabetes Association has stated that self monitoring of blood glucose should be, at all times, within 15% of the results of the reference method.
  • the present invention provides methods and apparatus with the capacity to produce more accurate measurements in monitoring various levels of analytes contained within various bodily fluids.
  • An object of the invention is to provide a system and related methods that accurately measure analyte concentration in bodily fluids such as blood through automatic adjustments within the system to account for variations with the measuring apparatus and chemically active components.
  • a test strip for monitoring a bodily fluid analyte is provided with a substrate member formed with a plurality of reagent sites that includes multiple reagent sites for measuring levels of a particular bodily fluid analyte.
  • Each reagent site includes a containment area with reactive reagent material exposed to substantially similar environmental conditions, but is provided for the analyte level measurement of separate fluid samples.
  • the reagent sites may include a test reagent site and a complementary reagent site for measuring the concentration of the same analyte on the same test strip.
  • a test strip for monitoring multiple bodily fluid analytes that includes a set of reagent sites for measuring each bodily fluid analyte.
  • Each reagent site within each analyte set includes substantially similar reagent material within a containment area and is provided for the measurement of a separate fluid sample.
  • a blood glucose level monitoring test strip is provided with an individual substrate member formed with dual reagent sites each formed with reagent pads exposed to substantially similar environmental conditions for measuring the level of glucose in a fluid sample.
  • a blood sample may be applied to a test reagent site, and a reference or control fluid with a known glucose concentration may be applied to the other reagent site to provide any needed adjustment factor to the blood glucose level reading.
  • An additional object of the invention is to provide a blood glucose level monitoring kit containing a dual pad dipstick formed with a first test site and a second test site each including a containment area with a reagent treated surface exposed to substantially identical environmental conditions, and a measuring instrument system for determining the concentration of blood glucose test sites on the dual pad dipstick.
  • the apparatus may be suited for various bodily fluids including blood, saliva, urine and interstitial fluid.
  • It is yet another object of the present invention to provide a method of measuring levels of a bodily fluid analyte with improved accuracy may include selecting a dual site reagent test strip formed with a first reagent site and a second reagent site each having a containment area with chemically active reagents exposed to substantially similar environmental conditions to measure levels of the same analyte, applying a first bodily fluid sample to the first reagent site to provide an analyte level reading of the first bodily fluid sample, and applying a second fluid sample to the second reagent site to provide an analyte level reading of the second fluid sample.
  • the second fluid sample may be a reference solution with a predetermined concentration of analyte to provide adjustment of the analyte level reading of the first bodily fluid.
  • the second fluid sample may be another bodily fluid sample to provide a separate analyte level reading of the second sample.
  • Another variation of the invention includes a closed loop method of measuring bodily fluid analyte levels with improved accuracy by selecting a dual site reagent test strip formed with a first reagent site and a second reagent site each with a chemically active reagent exposed to substantially similar environmental conditions to measure levels of the same analyte, applying the sample to the first reagent site to provide an analyte level reading, applying a quantity of the reference solution with a predetermined concentration of analyte to the second reagent site included on the test strip to provide a reference analyte level reading, and adjusting the value of the bodily fluid analyte level reading in substantially real-time based upon the analyte level reading of the reference solution.
  • a method for measuring levels of multiple bodily fluid analytes wherein a dual site reagent test strip is selected having at least one set of analyte testing sites which includes a first reagent site and a second reagent site.
  • the bodily fluid may include blood, urine, serum, plasma, interstitial fluid or any other similar fluid.
  • Fig. 1-A is a perspective illustration of a photometric blood glucose test strip that is commercially available today.
  • Fig. 1-B is a side view and cross-section of the photometric blood glucose test strip shown in Fig. 1-A.
  • Fig. 2-A is a top view illustration of an electrochemical blood glucose test strip that is commercially available today.
  • Fig. 2-B is a side view and cross-section of the electrochemical blood glucose test strip shown in Fig. 2-A.
  • Fig. 3- A is a perspective view of a spectrophotometric test strip with multiple reagent sites formed in accordance with one aspect of the present invention for measuring bodily fluid analytes with improved accuracy capabilities.
  • Fig. 3-B is a longitudinal side view and cross-section of another embodiment of the invention that includes at least two reagent sites on a test strip.
  • Fig. 4 is a top view of another embodiment of the present invention that provides a electrochemical test strip with multiple reagent sites for measuring bodily fluid analytes with improved accuracy capabilities.
  • Fig. 5 is a simplified schematic and side view diagram of a spectrophotometric monitoring system with multiple detectors for measuring levels of bodily fluid analytes within multiple reagent sites on a test strip that is provided in accordance with another aspect of the present invention.
  • Fig. 6 is a simplified analyte level measuring flow chart and block diagram illustrating various combinations of several analyte level measuring components including sensing apparatus provided in accordance with the invention for spectrophotometric or electrochemical test strips.
  • Fig. 7 is a simplified sectional view of another embodiment of the invention that provides a test strip for measuring multiple analytes with different analyte test sets for each particular analyte, and multiple reagent sites within each set containing chemically reactive material that is exposed to the substantially similar environmental conditions.
  • Fig. 8 is a simplified drawing of another aspect of the invention that is directed to a method of manufacturing test strips containing sets of analyte test sites with multiple reagent sites within each set.
  • Fig. 3-A provides an illustration of a spectrophotometric test strip 10 formed in accordance with one aspect of the present invention.
  • the test strip 10 includes multiple reagent sites 11 with two reagent pads 12 for measuring bodily fluid analyte levels wherein each reagent pad is spaced apart and positioned within a separate window or opening 14 in the housing or body 16 of the test strip.
  • the windows 14 in the strip body preferably include tapered edges 15 to assist in the containment of fluid samples when applied to the reagent sites 11.
  • the containment area for each reagent site may of course be formed with other configurations to avoid cross-contamination or exposure between samples within the different reagent sites.
  • Fluid separation between reagent sites may be achieved with or without a physical barrier, and may be formed by simply spacing the reagent sites and pads sufficiently far apart on a substrate member to minimize the possibility of cross-contamination between reagent sites.
  • a single reagent site may of course be divided or separated into smaller distinct sites on the test strip, and alternatively, the reagent sites on the test strip may be separated with perforations such that break away of certain sites may be achieved but not without significant tearing force.
  • the overall test strip housing 16 may be a single continuous substrate member formed of supportive polymer material or any other suitable material that may provide support and fluid control.
  • the strip body 16 and the reagent sites 11 may be adapted for use with different spectrophotometric systems, and may have different shapes, dimensions and configurations.
  • the strip body 16 may include notches, holes or extensions that are utilized by test strips for various systems available today.
  • the test strip 10 shown in Fig. 3-B also includes two reagent sites 11 on a test strip.
  • a separator element 18 may be formed in the strip body 16 to provide physical support for the test strip 10 and to provide liquid separation between the multiple compartments or sites on the test strip.
  • the test strip 10 may further include a test reagent site and any number or additional complementary sites that are spaced apart and separate to form distinct containment areas.
  • Each reagent site 11 shown in Figs. 3-A and 3-B includes a chemical reagent pad 12 for reacting with glucose in blood, or any other type of analyte in bodily fluids.
  • the reaction generally provides a measurable color change as an indication of analyte concentration.
  • an analyte such as glucose reacts with reagents such as glucose oxidase to produce hydrogen peroxide.
  • a peroxidase such as horse radish peroxidase, and redox indicators such as o- tolidine, o-dianisdine, 3,3,5,5-tetramethylbenzidine (TMB), 4-aminoantipyrine, and other reagents well known in the art, are capable of being oxidized in the presence of hydrogen peroxide to produce a colored product.
  • the present invention provides test strip apparatus and methods for monitoring analyte levels with these or other chemical reagents that provide measurable color changes, or similar results, with spectrophotometric measurement systems. Chemically reactive material may also be impregnated in the reagent pads at various stages of manufacturing.
  • the dual reagent sites in the test strips shown in Figs. 3-A and 3-B are provided for measurement of separate fluid samples.
  • analyte levels are currently derived from direct placement of bodily fluids samples onto a test strip
  • the present invention may be modified for non-invasive techniques to include a plurality of reagent sites that monitor or measure analyte levels in samples that do not require the withdrawal of any bodily fluid.
  • the reactive material provided in each reagent site 11 is exposed to substantially similar environmental conditions.
  • the pads 12 and their reagent material preferably originate from the same manufacturing batch. Environmental changes in the post-manufacturing surroundings of the test strip 10 affect both reagents sites 11 , if at all, in substantially the same manner, and to substantially the same extent.
  • At least one complementary site is provided for the measurement of a separate fluid sample such as control solution for calibration of the test strip system.
  • this separate fluid sample may simply be another bodily fluid sample.
  • bodily fluids referred to herein include but are not limited to blood, saliva, urine and interstitial fluid.
  • Each reagent site 11 may also include a membrane covering or mesh 13 for separation of blood components. Hydrophilic meshes are well known in the art, and preferably cover the reagent sites. These coverings or meshes 13 may assist in the separation and measurement of bodily fluid components or analytes.
  • a reagent pad 12 may also include other separation layers (not shown) such as an interference removal layer, a radiation layer, or other types of additional layers that are well known in the art.
  • Fig. 4 is an illustration of another embodiment of the present invention that includes a electrochemical test strip 20 with multiple reagent sites 21 for measuring bodily fluid analytes.
  • glucose level measurement may be derived from the reaction of glucose with various reagents to produce hydrogen peroxide.
  • an electron mediator such as ferrocene interacts with the hydrogen peroxide to produce a measurable current that is proportional to measured glucose levels.
  • a variety of compatible electron mediators may be used or any other material that will generate current or a measurable result in the presence of hydrogen peroxide.
  • the test strip 20 may include two or more reagent sites 21 that contain reagent pads 22 and 29. Windows or openings 24 with tapered edges 25 may be formed in a strip housing or body 26.
  • the test strip 20 may further include a physical division between the reagent sites 21 to maintain the fluid within a controlled containment area.
  • Another aspect of the present invention provides a method of measuring levels of a bodily fluid analyte with a dual site reagent test strip 10 and 20 as shown in Figs. 3 and 4.
  • Each reagent site 11 and 21 includes a chemically active reagent exposed to substantially similar environmental conditions to measure levels of the same analyte.
  • a first bodily fluid sample may be applied to the first reagent site to provide an analyte level reading of the first bodily fluid sample
  • a second fluid sample may be applied to the second reagent site to provide an analyte level reading of the second fluid sample.
  • the second fluid sample may be a reference solution with a predetermined concentration of analyte to provide adjustment of the analyte level reading of the first bodily fluid based upon the analyte level reading of the reference solution.
  • the second fluid sample may be a second bodily fluid sample to provide a separate analyte level reading of the second sample.
  • the existence of complementary sites formed on test strips provide a closed loop method of measuring levels of a bodily fluid analyte with improved accuracy capacity.
  • the present invention provides for bodily fluid analyte level readings in substantially real-time based upon the analyte level reading of the reference solution.
  • the accuracy of level readings may be increased in that upward or downward adjustments to the reading may be derived from a meaningful reference solution reading obtained from a reagent site on the same test strip.
  • a closed loop system is provided with increased accuracy in real-time or near real-time.
  • the time differential that exists between measuring analyte levels in a test sample and a reference solution may be further considered to provide an even more accurate adjustment value for a level reading.
  • Another aspect of the present invention is directed to a method of measuring levels of bodily fluid analytes comprising the steps of: selecting a dual site reagent test strip for testing of one or multiple bodily fluid analytes having at least one set of analyte testing sites including a first reagent site and a second reagent site each with a chemically active reagent exposed to substantially similar environmental conditions to measure levels of the same analyte within the same set of testing sites, applying a bodily fluid sample to the first reagent site of the at least one set of analyte testing sites to provide an analyte level reading, selecting a reference solution with a predetermined concentration of analyte, applying a quantity of the reference solution with the predetermined concentration of analyte to the second reagent site of the at least one set of analyte testing sites included on the test strip to provide a reference analyte level reading, and adjusting the bodily fluid analyte level reading in substantially real-time based upon the
  • the methods and apparatus provided herein may produce more accurate measurements of bodily fluid analytes such as glucose. For example, fewer temperature adjustment factors are needed for the calculation of test results. As explained above, the reactivity of reagent material in test strips are known to fluctuate as a result of surrounding temperature changes. Analyte level readings also vary from test strip to test strip. Temperature adjustments may be reduced by systems and test strips formed in accordance with the principles of the invention.
  • reagent pads on the test strip may originate from the same manufacturing batch in a preferred embodiment of the invention, and are exposed to the same environment conditions which may vary from place to place.
  • various embodiments of the present invention may effectively provide glucose level results that would not vary at high altitudes.
  • the proposed method and apparatus will be less affected by varying altitudes or environment due to the closed system feedback from a control reading on the same test strip in order to provide any necessary adjustments in analyte level readings or values.
  • test reagent site and at least one complementary reagent site on a single continuous test strip also provides that exposure to moisture and storage temperatures of the dipstick, which are known to affect the reactivity of test strips, have minimal or less of an effect on the test results.
  • An adjustment factor derived from the control reading is provided with this system since reagent pads for either test samples or control solutions are exposed to substantially the same environment after manufacturing. Similarly, lot to lot calibration is not required by the factory or the patient, and no bar code identification is needed on the dipstick to attempt any corrections for variations which will inevitably occur with reference solutions on different test strips.
  • glucose control solution may adjust for any changes in the glucose value of the control solution over time and exposure to climate changes since fluid in the solution may diminish as a result of evaporation.
  • the reference solution may be applied by a patient with a dropper or similar apparatus, or contained within a tiny "bleb" or vial within the strip.
  • the test strip system may further provide for spreading or mixing of suitable chemicals on the strip with those in the control solution so that, after the measurement has been completed, the chemicals used to measure the control solutions and the control solutions themselves are self contained within the test strip.
  • the present invention also provides automatic calibration of an analyte measuring instrument on a measurement-by-measurement basis.
  • This readily provides increased accuracy of glucose or analyte measurements in actual field use, and greater patient and clinician confidence in instrument reading accuracy regardless of the test strip variations and the possibility of "drift" in measurement instrument or test strips due to changes in surrounding temperature, barometric pressure, humidity, instrument and/or strip defects, and the like.
  • the invention may be further useful because, as a result of the automatic calibration on a measurement-by-measurement basis, the system requires less sophisticated or less expensive chemicals than other types of measurement systems that attempt to use more sophisticated or expensive chemicals in an effort to provide more accurate measurements without automatic measurement-by-measurement calibration.
  • the present invention provides for the output derived from a glucose level reading in a control or reference fluid to be fed back into the glucose level reading obtained from the blood sample in order to correct in real-time, or near real-time, the reading obtained for glucose in the blood sample.
  • This provides a reliable point of care glucose measuring instrument and test strip system for home, office, or similar use to measure blood, interstitial fluid, urine, or other bodily substance or fluid.
  • Analyte levels are measured by each chemical strip with multiple reagent sites to perform simultaneous or near-simultaneous readings.
  • One reagent site may be for a blood sample and the other site may be for the reference solution which is used in near real-time to correct the blood glucose measurements.
  • test strip may be used more than once.
  • a dual pad dipstick may be used like a single pad dipstick, at lower cost, if the patient decides not to use the glucose control solution and would want to use both pads for measuring two different samples during the day.
  • Other reagent sites provided on the same test strip may be for application of another blood sample for performing two separate blood glucose measurements with the same strip which lowers the cost per blood glucose reading. Even if a patient decides not to use reference solution, blood glucose measurements may be performed with approximately the same accuracy as with instruments on the market today.
  • another embodiment of the present invention includes a spectrophotometric sensing system 30 with multiple detectors 52 and 82 for measuring levels of bodily fluid analytes of samples located within multiple reagent sites 31 and 61 on a single test strip.
  • the spectrophotometer system 30 may include a light source 34 that is supplied with electrical power 32. Multiple light sources may be used to measure analyte levels in different reagent sites on the test strip, or a single light source 34 such as an LED may be used in combination with beam splitting element 33.
  • a portion of light from the light source 34 may be directed with a first mirror 36 or reflective element to a first focusing element 38.
  • Selected portions of light with particular wavelengths may be further propagated through a first filter 40 before reaching a second mirror 42 in the system 30.
  • An incident light ray portion 44 may then be directed towards a first reagent site 31 to produce a reflected light ray portion 46.
  • the reflected light portion 46 may subsequently pass through a second focusing element 48 and a second filter 50 to eventually reach a first optical sensor or detector 52.
  • the portion of light reaching the first optical sensor 52 is detected and converted to an electrical signal 54 for further processing in the system 30.
  • analyte levels may be measured at a second reagent site 61 on the test strip by directing light emanating from the light splitter 33 through its respective first mirror 66, first focusing element 68 and filter 70.
  • the light portion may be further propagated towards a second mirror 72 to provide an incident light ray portion 74 that is directed at the reagent pad located at the second site 61.
  • the reflected light portion 76 from the second site 61 may subsequently pass through a second lens 78 and a second filter 80 to reach a second detector 82 which provides a second electrical signal.
  • spectrophotometric measurements are obtained for each reagent site 31 and 61 with a single light source 34 and dual detectors 52 and 82. It should be understood that additional light directing and filtering elements may be added to the system 30, or alternatively, the function of the aforementioned components may be performed by common components.
  • the spectrophotometric measurement system in Fig. 5 may also be alternately configured with a single optical sensor or detector.
  • the light directing and filtering components in the system 30 may be positioned and modified to direct reflected light 46 and 76 to a single detector.
  • the use of a single detector in a preferable measurement system may provide more consistent analyte level readings of samples since different meters with different detectors are known to provide varying readings.
  • the test strip may be repositioned to obtain a spectrophotometric reading of different reagent sites instead of repositioning the measurement components of the system 30.
  • a similar system with multiple measurement componentry may be provided for application with electrochemical test strips in order to obtain readings of current changes in proportion to levels of glucose or analyte levels in multiple reagent sites.
  • the measurement system 30 may still provide a reading for a test sample or a reference solution in a single reagent site, or multiple readings for samples in multiple reagent sites.
  • the additional reagent sites may be suitable for subsequent test samples or for reference solutions to provide for correction or adjustment factors to test sample readings when necessary.
  • Separate strips with single reagent sites formed from the same manufacturing batch may be used with the measurement system shown in Fig. 5 to correct readings from a test strip sample.
  • a blood glucose monitoring kit is also provided in accordance with the present invention.
  • the kit may include a dual pad dipstick with two reagent sites wherein each site includes a reagent treated surface exposed to substantially identical environmental conditions, and a measuring instrument system as described above for determining the concentration of blood glucose test sites on the dipstick.
  • a reference solution which may also be included in the kit or otherwise sold separately, may be applied to a reagent site in order to calibrate the blood glucose monitoring system and provide an adjustment value for a test reading.
  • the reference solution may also include a stable colored dye for indicating relative glucose level changes in the reference solution itself.
  • a stable dye may be added to the control fluid to account for any loss of water in the control solution due to evaporation in between the time of manufacturing and the time of use. Although an inaccurate high glucose level would ordinarily result, the stable dye in this system would allow the increased concentration to be measured by the system, and used to correct the accuracy of the reference solution itself.
  • another embodiment of the present invention includes an analyte measurement system 90 that may be adapted for use with different types of test strips for spectrophotometric, electrochemical, or a combination of any other similar type of testing.
  • the system 90 which is shown in a simplified block diagram in Fig. 6, may include various sensing and processing apparatus for both spectrophotometric or electrochemical test strips.
  • a disposable section may be provided in the system 90 for measuring analyte levels of samples on spectrophotometric test strips.
  • the analyte levels in samples contained within the disposable section may be measured by spectrophotometric apparatus that is supplied with a power line for an optical source 92 and further includes a connection for relaying optical sensor signals 94 from the disposable section.
  • electrode signals 96 may be obtained from the disposable section when electrochemical test strips are used. Because the temperature of the area surrounding the disposable section may affect the reactivity of the test strip reagents as explained above, the disposable section may also include a heater connected to a heater line 97 and a temperature sensor connected to a temperature sensor line 98. As a result, more consistent and accurate readings may be obtained when the temperature of the reagent sites within the disposable section is kept within a desired range even in colder climates. Other temperature and environmental regulating components may be included in the dual measurement system 90 to compensate for operation in different climates. Because different analog signals of various types may be measured before processing, the system 90 may include an analog/digital interface card.
  • Different measurement signals may be converted to information that may be processed by a digital computing module.
  • the system 90 may of course include a central processing unit or a microprocessor to accept signals relating to analyte level information from the disposable section. Because readings are known to fluctuate over a period of time, a clock may also be used to time the reactions taking place in the reagent sites in the disposable section.
  • appropriate software may be implemented to perform various functions including an algorithm that provides an adjustment value for correcting a test sample reading. Any of this information relating to the disposable section of the system 90 may be further communicated to displays, modems, printers or any other type of output device.
  • the invention disclosed herein specifically provides bodily fluid monitoring apparatus for either an electrochemical or spectrophotometric measurement detection system in determining the concentration of a bodily fluid constituent.
  • the measurement detection system may include a electrochemical detector that provides for the relative measurement of the bodily fluid constituent and a reference solution with a previously determined constituent concentration.
  • the measurement detection system may be a spectrophotometric detector that provides for testing or the color comparison between a test sample and a reference solution.
  • the concepts of the present invention are equally applicable to each testing system as either single or dual measurement apparatus as explained above.
  • Fig. 7 is a simplified sectional view of another embodiment of the invention that provides a test strip 100 for measuring multiple analytes which contains different analyte test sets for Analyte A 102, Analyte B 104 and
  • Analyte C 106 Multiple reagent sites A 108, A' 110 and A" 112 are located within each analyte test set that contains chemically reactive material exposed to substantially similar environmental conditions.
  • the test strip 100 may further provide at least one test reagent site A 108 and one or more complementary reagent sites A' 110 and A" 112 for measuring levels of the same bodily fluid analyte within each set.
  • Each reagent site on the test strip 100 includes reactive reagent material exposed to substantially similar post-manufacturing environmental conditions and is provided for the analyte measurement of separate fluid samples.
  • test strip 100 may be formed with as a traditional oblong configuration or any other shape such as a sheet with various lengths and widths of different proportions.
  • the overall test strip 100 may of course simply be a sheet with spaced apart reagent pads placed directly onto the surface of a supportive substrate layer.
  • Fig. 8 illustrates yet another aspect of the present invention that is directed to a method of manufacturing test strips containing multiple sets of analyte test sites for Analyte A and Analyte B. Multiple reagent sites 124 and 126 may provide measurement of different fluid samples for Analyte A. Meanwhile, multiple reagent sites 128, 130 and 132 are provided for different fluid samples of Analyte B.
  • test reagent site A 124 and B 128 is provided for each test strip 122.
  • At least one complementary reagent site A' 126 and B' 130 is also formed on each strip 122.
  • Each tested analyte may include varying numbers of additional reagent sites within each set such as a second complementary site B" 132.
  • the present invention further provides a method of manufacturing these dual or multiple site test strips for monitoring bodily fluid constituents by selecting a continuous sheet of support material 120 for the test strips, forming at least two set of test site openings along a predetermined path on the continuous sheet of support material for receiving bodily fluid samples, applying reagent material exposed to substantially similar environmental conditions in the proximity to the at least two sets of test site openings formed on the continuous sheet of support material, and forming dual site test strips by selectively separating portions of the continuous sheet of support material and reagent material to provide at least two distinctive sets of test sites on each test strip for improved accuracy capacity.
  • the test strips 122 may further be bar coded with an identification number uniquely identifying the batch of reagent material.
  • reagent pads may be positioned within a containment area and spaced apart from the edges of the strip or other pads. While the present invention has been described with reference to the aforementioned applications, this description of the preferred embodiments and methods is not meant to be construed in a limiting sense. It shall be understood that all aspects of the present invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables including the types of bodily fluids that are monitored or measured, and the use of any combination of the embodiments of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Hematology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

La présente invention concerne un système de bandelette d'analyse et des procédés associés permettant de détecter des analytes contenus dans un fluide corporel tel que le sang. La bandelette d'analyse comprend un substrat présentant plusieurs sites réactifs, y compris un site d'analyse et au moins un site complémentaire situés chacun à l'intérieur d'une zone de rétention comportant un matériau réactif exposé à des conditions ambiantes sensiblement similaires, ce qui permet de mesurer les niveaux d'au moins un analyte dans des prélèvements de fluide séparés. L'invention concerne également un procédé en boucle fermée permettant de mesurer les niveaux d'un analyte de fluide corporel tel que le glucose, procédé selon lequel on choisit une bandelette d'analyse à double site réactif comprenant un premier site réactif destiné à un prélèvement de fluide corporel et un deuxième site réactif destiné à une solution de référence d'une concentration prédéterminée, qui permet d'obtenir une valeur de réglage destinée à corriger pratiquement en temps réel l'indication du niveau d'analyte contenu dans le prélèvement de fluide corporel.
PCT/US1999/000023 1998-01-06 1999-01-04 Procedes et appareil permettant l'analyse exacte des composants d'un fluide corporel WO1999035487A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US355198A 1998-01-06 1998-01-06
US09/003,551 1998-01-06

Publications (1)

Publication Number Publication Date
WO1999035487A1 true WO1999035487A1 (fr) 1999-07-15

Family

ID=21706398

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/000023 WO1999035487A1 (fr) 1998-01-06 1999-01-04 Procedes et appareil permettant l'analyse exacte des composants d'un fluide corporel

Country Status (1)

Country Link
WO (1) WO1999035487A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6759190B2 (en) 2002-06-15 2004-07-06 Acon Laboratories, Inc. Test strip for detection of analyte and methods of use
EP1696226A2 (fr) * 2005-02-23 2006-08-30 Ushiodenki Kabushiki Kaisha Dispositif de mesure du facteur de réflexion
EP2069776A2 (fr) * 2006-08-08 2009-06-17 Hach Company Procédé et appareil pour analyser des solutions
EP2216649A1 (fr) 2009-02-06 2010-08-11 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Dispositif embarqué d'analyse d'un fluide corporel
EP2367004A1 (fr) * 2008-11-20 2011-09-21 Arkray, Inc. Dispositif de mesure optique
EP2367003A1 (fr) * 2008-11-20 2011-09-21 Arkray, Inc. Dispositif de mesure optique
EP2408931A2 (fr) * 2009-03-20 2012-01-25 Roche Diagnostics GmbH Élément d'essai pour déterminer un fluide corporel, et procédé de mesure
AU2006257904B2 (en) * 2005-06-10 2012-04-19 Mannatech, Inc. Rapid saccharide biomarker assay
US8333717B1 (en) * 2011-06-21 2012-12-18 Yofimeter, Llc Test unit cartridge for analyte testing device
US8961432B2 (en) 2011-06-21 2015-02-24 Yofimeter, Llc Analyte testing devices
JP2017201282A (ja) * 2016-05-07 2017-11-09 ニプロ株式会社 クロマトグラフィー試験片呈色測定装置
JP2018105886A (ja) * 2012-12-18 2018-07-05 アイセンサー・カンパニー・リミテッドＩｘｅｎｓｏｒ Ｃｏ．， Ｌｔｄ． 分析物の測定方法及び装置

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4059405A (en) * 1972-04-11 1977-11-22 Damon Corporation Method and apparatus for analysis of constituent carried in fibrous medium
GB2090659A (en) * 1981-01-02 1982-07-14 Instrumentation Labor Inc Analytical device
US4676653A (en) * 1984-03-02 1987-06-30 Boehringer Mannheim Gmbh Apparatus for determining the diffuse reflectivity of a sample surface of small dimensions
US4894552A (en) * 1987-08-21 1990-01-16 Lre Relais & Elektronik Gmbh Differential-reflectance photometer
US5073484A (en) * 1982-03-09 1991-12-17 Bio-Metric Systems, Inc. Quantitative analysis apparatus and method
US5116729A (en) * 1989-03-10 1992-05-26 Miles Inc. Stabilization of oxidase enzyme-based test strips
US5132097A (en) * 1987-02-11 1992-07-21 G.D. Research Apparatus for analysis of specific binding complexes
EP0653625A1 (fr) * 1993-11-12 1995-05-17 Unipath Limited Dispositif de lecture des bandes d'analyse

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4059405A (en) * 1972-04-11 1977-11-22 Damon Corporation Method and apparatus for analysis of constituent carried in fibrous medium
US4059405B1 (fr) * 1972-04-11 1984-02-07
GB2090659A (en) * 1981-01-02 1982-07-14 Instrumentation Labor Inc Analytical device
US5073484A (en) * 1982-03-09 1991-12-17 Bio-Metric Systems, Inc. Quantitative analysis apparatus and method
US4676653A (en) * 1984-03-02 1987-06-30 Boehringer Mannheim Gmbh Apparatus for determining the diffuse reflectivity of a sample surface of small dimensions
US5132097A (en) * 1987-02-11 1992-07-21 G.D. Research Apparatus for analysis of specific binding complexes
US4894552A (en) * 1987-08-21 1990-01-16 Lre Relais & Elektronik Gmbh Differential-reflectance photometer
US5116729A (en) * 1989-03-10 1992-05-26 Miles Inc. Stabilization of oxidase enzyme-based test strips
EP0653625A1 (fr) * 1993-11-12 1995-05-17 Unipath Limited Dispositif de lecture des bandes d'analyse

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6759190B2 (en) 2002-06-15 2004-07-06 Acon Laboratories, Inc. Test strip for detection of analyte and methods of use
EP1696226A2 (fr) * 2005-02-23 2006-08-30 Ushiodenki Kabushiki Kaisha Dispositif de mesure du facteur de réflexion
EP1696226A3 (fr) * 2005-02-23 2008-01-23 Ushiodenki Kabushiki Kaisha Dispositif de mesure du facteur de réflexion
US7382462B2 (en) 2005-02-23 2008-06-03 Ushiodenki Kabushiki Kaisha Device for measuring the reflection factor
AU2006257904B2 (en) * 2005-06-10 2012-04-19 Mannatech, Inc. Rapid saccharide biomarker assay
EP2069776A2 (fr) * 2006-08-08 2009-06-17 Hach Company Procédé et appareil pour analyser des solutions
EP2069776A4 (fr) * 2006-08-08 2014-04-02 Hach Co Procédé et appareil pour analyser des solutions
EP2367003A4 (fr) * 2008-11-20 2012-07-04 Arkray Inc Dispositif de mesure optique
CN101821624B (zh) * 2008-11-20 2014-01-22 爱科来株式会社 光学测定装置
US9417235B2 (en) 2008-11-20 2016-08-16 Arkray, Inc. Optical measurement apparatus
EP2367004A1 (fr) * 2008-11-20 2011-09-21 Arkray, Inc. Dispositif de mesure optique
EP2367004A4 (fr) * 2008-11-20 2012-07-04 Arkray Inc Dispositif de mesure optique
EP2367003A1 (fr) * 2008-11-20 2011-09-21 Arkray, Inc. Dispositif de mesure optique
US8277752B2 (en) 2008-11-20 2012-10-02 Arkray, Inc. Optical measurement apparatus
FR2942041A1 (fr) * 2009-02-06 2010-08-13 Commissariat Energie Atomique Dispositif embarque d'analyse d'un fluide corporel.
EP2216649A1 (fr) 2009-02-06 2010-08-11 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Dispositif embarqué d'analyse d'un fluide corporel
EP2408931A2 (fr) * 2009-03-20 2012-01-25 Roche Diagnostics GmbH Élément d'essai pour déterminer un fluide corporel, et procédé de mesure
US8333716B1 (en) * 2011-06-21 2012-12-18 Yofimeter, Llc Methods for using an analyte testing device
US20120329164A1 (en) * 2011-06-21 2012-12-27 Gadlight, Inc. Test Unit Cartridge for Analyte Testing Device
US8333717B1 (en) * 2011-06-21 2012-12-18 Yofimeter, Llc Test unit cartridge for analyte testing device
US8961432B2 (en) 2011-06-21 2015-02-24 Yofimeter, Llc Analyte testing devices
JP2018105886A (ja) * 2012-12-18 2018-07-05 アイセンサー・カンパニー・リミテッドＩｘｅｎｓｏｒ Ｃｏ．， Ｌｔｄ． 分析物の測定方法及び装置
JP2020112563A (ja) * 2012-12-18 2020-07-27 アイセンサー・カンパニー・リミテッドＩｘｅｎｓｏｒ Ｃｏ．， Ｌｔｄ． 分析物の測定方法及び装置
US10921259B2 (en) 2012-12-18 2021-02-16 Ixensor Co., Ltd. Method and apparatus for analyte measurement
JP2017201282A (ja) * 2016-05-07 2017-11-09 ニプロ株式会社 クロマトグラフィー試験片呈色測定装置

Similar Documents

Publication Publication Date Title
US6541266B2 (en) Method for determining concentration of an analyte in a test strip
US20200271615A1 (en) Biosensor Systems for Determining Analyte Concentration Based On Complex Index Functions
EP1359409B1 (fr) Appareils et méthodes pour la détermination des concentrations des analytes
EP0471986B1 (fr) Méthode d'analyse quantitative et système associé utilisant un capteur jetable
JP3568624B2 (ja) 患者血液中の分析すべき物質の分析監視システム
US8101062B2 (en) System and methods for determination of analyte concentration using time resolved amperometry
US8088272B2 (en) System and methods for determination of analyte concentration using time resolved amperometry
US8241488B2 (en) Auto-calibrating test sensors
US4397956A (en) Means for monitoring the status of control of ketoacidosis-prone diabetics
US20120111739A1 (en) Dual Frequency Impedance Measurement of Hematocrit in Strips
EP2550520B1 (fr) Dispositif de diagnostic in vitro autonome
EP0451981A2 (fr) Unité réactive à jeter après usage
US20080248581A1 (en) Method for performing correction of blood glucose assay bias using blood hemoglobin concentration
EP0283285A2 (fr) Procédé et appareil pour contrôler des substances analytiques dans des fluides
WO1999035487A1 (fr) Procedes et appareil permettant l'analyse exacte des composants d'un fluide corporel
US20030007893A1 (en) Volume meter testing device
EP1430303A1 (fr) Systeme de bande d'essai a relief
Lassea et al. 18th International Symposium on Critical Care Testing in the New Millennium: The Integration of Point of Care Testing, Helsingor, Denmark
EP2126108A1 (fr) Appareil de détection
Galimany Bedside Chemistry

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载