US20120040386A1 - Fine-grained filler substances for photometric reaction films - Google Patents

Fine-grained filler substances for photometric reaction films Download PDF

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US20120040386A1
US20120040386A1 US13/099,601 US201113099601A US2012040386A1 US 20120040386 A1 US20120040386 A1 US 20120040386A1 US 201113099601 A US201113099601 A US 201113099601A US 2012040386 A1 US2012040386 A1 US 2012040386A1
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detection
particles
layer
sample
diagnostic test
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Wolfgang-Reinhold Knappe
Bernd Hiller
Ursula Lehr
Volker Zimmer
Wolfgang Petrich
Luis David Bedon-Gomez
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Roche Diabetes Care Inc
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Assigned to ROCHE DIAGNOSTICS GMBH reassignment ROCHE DIAGNOSTICS GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEDON-GOMEZ, LUIS DAVID, LEHR, URSULA, ZIMMER, VOLKER, HILLER, BERND, KNAPPE, WOLFGANG-REINHOLD, PETRICH, WOLFGANG
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Publication of US20120040386A1 publication Critical patent/US20120040386A1/en
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    • 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
    • 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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • 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
    • 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
    • G01N33/525—Multi-layer analytical elements
    • G01N33/526—Multi-layer analytical elements the element being adapted for a specific analyte
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
    • G01N33/552—Glass or silica
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0825—Test strips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles

Definitions

  • the invention relates to a diagnostic test element for detecting an analyte in a sample of a body fluid and to a process for producing such a diagnostic test element.
  • diagnostic test elements are used, for example, for detecting one or more analytes in body fluids such as whole blood, for example for detecting glucose, uric acid, ethanol, or lactate, or similar analytes.
  • body fluids such as whole blood
  • glucose, uric acid, ethanol, or lactate or similar analytes.
  • other applications are also possible.
  • analyte in a sample of a body fluid.
  • the at least one analyte can be, for example, a metabolite.
  • Qualitative and also, or else, quantitative detection of the analyte can be carried out.
  • Known analytes are, for example, glucose, more particularly blood glucose, uric acid, ethanol, and/or lactate. Other types of analytes are also alternatively or additionally detectable.
  • the body fluid can be, for example, whole blood, blood plasma, interstitial fluid, saliva, urine, or other types of body fluids.
  • Test elements generally comprise at least one detection reagent for the qualitative and/or quantitative detection of the analyte.
  • a detection reagent is to be generally understood to mean a chemical substance or a mixture of chemical substances which, in the presence of the at least one analyte, changes at least one detectable property, more particularly a physically and/or chemically detectable property.
  • this property change occurs specifically only in the presence of the at least one analyte to be detected, but not in the presence of other substances.
  • the at least one property change can be, for example, the change in an optically detectable property, more particularly a color change.
  • diagnostic test elements having optical detection reagents are well known in the prior art.
  • EP 0 821 234 B1 describes a diagnostic test support for determining an analyte from whole blood by means of a reagent system which is present in the support and which includes a color formation reagent.
  • the diagnostic test support comprises a test field which a sample loading side, onto which the sample is added, and a detection side, on which an optically detectable change occurs as a result of the reaction of the analyte with the reagent system.
  • the test field is configured such that the erythrocytes present in the sample do not reach the detection side. Furthermore, the test field has a transparent slide and a first film layer and also a second film layer applied to the first film layer.
  • the first layer located on the transparent slide is in a moist state and thereby exhibits considerably less light scattering than the second layer lying over it.
  • the first film layer comprises a filler whose refractive index is close to the refractive index of water, whereas the second layer contains a pigment having a refractive index of preferably at least or even >2.0, more particularly of at least 2.2, at a concentration of preferably at least 25% by weight or even more than 25% by weight, based on the dried second layer.
  • the first layer can comprise a sodium aluminum silicate as a filler.
  • U.S. Pat. No. 4,312,834 discloses a diagnostic agent for the detection of a component material.
  • a water-insoluble film is disclosed which is composed of a film former and a film opener in the form of fine, insoluble inorganic or organic particles.
  • the film opener serves the purpose of rendering the film porous so that sufficient sample uptake by the film can occur. Accordingly, by way of example, it is proposed to use pigments, i.e., particles having a large particulate size, titanium dioxide pigments for example, as film openers.
  • WO 2006/065900 A1 describes a test strip or electrochemical sensor for measuring the amount of an analyte in a biological fluid.
  • This comprises an enzyme system for the reaction with the analyte.
  • the reactive system is blended into a water-soluble, swellable polymer matrix which comprises small, water-insoluble particles having a nominal size of about 0.05 to 20 micrometers.
  • a reduced porosity using small particulates is described.
  • test elements known from the prior art more particularly test elements having at least one test field
  • customary test fields may result in a granular, inhomogeneous color development.
  • inhomogeneous color development is generally irrelevant for conventional analytical test devices, since these have comparatively large measurement spots.
  • commercially available optical blood glucose measurement devices have measurement spots with a diameter of about 1.5 mm.
  • a mean coefficient of variation i.e., the ratio of a standard deviation to a mean value for the measurement, is, for example, typically about 1.5% over a measurement range of typically about 10 to 600 mg per dl blood glucose.
  • a diagnostic test element for detecting an analyte in a sample of a body fluid
  • a process for producing a diagnostic test element for detecting an analyte in a sample of a body fluid and also a process for detecting an analyte in a sample of a body fluid.
  • the diagnostic test element in one or more of the proposed embodiments may be obtainable as per a process according to the invention, and the production process may be used to produce a diagnostic test element in one or more of the described embodiments.
  • the proposed process for detecting an analyte of a sample of a body fluid is carried out using a diagnostic test element in one or more of the embodiments described hereinafter.
  • a diagnostic test element for detecting an analyte in a sample of a body fluid.
  • the at least one analyte can, for example, be detected quantitatively or qualitatively.
  • the at least one analyte can be in particular one or more of the analytes glucose, uric acid, ethanol, lactate, or a combination of these analytes and/or of other analytes.
  • other analytes are also detectable in principle, for example one or more of the abovementioned analytes.
  • the sample of the body fluid can be in particular whole blood.
  • other embodiments are also possible in principle, and reference can be made to the above description.
  • the diagnostic test element comprises at least one test field having at least one detection reagent.
  • a test field is to be understood to mean a continuous area of the detection reagent, more particularly a film having one or more layers, which, as will be more particularly elucidated below, can be applied to, for example, at least one support element.
  • the detection reagent is set up to perform at least one detectable change in the presence of the analyte. More particularly, this detectable change can be a physically and/or chemically detectable change.
  • the detection reagent can in particular comprise at least one enzyme, for example glucose dehydrogenase (e.g., FAD-, NAD + -, or PQQ-dependent) and/or glucose oxidase.
  • glucose detection methods which comprise one or more of the following enzymatic detection methods or detection reagents: GOD, GlucDOR (PQQ-dependent GDH and mutants thereof), FAD-GDH, NAD-dependent GDH with mediator (e.g., diaphorase) for transferring the redox equivalents of NADH to a nitrosoaniline mediator.
  • the detection reagent can, alternatively or additionally, comprise one or more mediators, i.e., substances capable of transferring electrical charges from one substance to another. More particularly, mediators can be used which are suitable for electron transfer. For example, this substance can be nitrosoaniline.
  • the detection reagent can, again alternatively or additionally, comprise at least one indicator.
  • An indicator can be understood to be a substance which as such can change at least one property which can be detected, depending on in which form this substance is present. For example, substances can be used which, in an oxidized and a reduced form, can have different optical properties, for example different colors. Alternatively or additionally, the indicator can comprise a substance which, in different charge states, has different optical properties, for example different color properties.
  • a detection reagent can be understood to be a single substance or a mixture of substances, for example, as explained above, a mixture of at least one enzyme, at least one mediator, and at least one indicator.
  • detection reagents are known in principle from the prior art, for example from the prior art described above.
  • the test field has at least one detection layer comprising the detection reagent.
  • a system having a single detection layer can be used, or multiple detection layers can be used which can be applied on top of one another, directly or by interposing one or more further layers.
  • a layer is to be understood in the context of the present invention to mean in general an element in which a layer material is applied flat to a support element or is formed as a freestanding film.
  • the layer can, but need not necessarily, be closed, but can have, for example, openings as well.
  • a substantially uniform, preferably hole-free, homogeneous embodiment of the detection layer having a homogeneous layer thickness is preferably 3 to 60 micrometers, more particularly 5 to 15 micrometers, for example 8 micrometers.
  • the detection layer comprises particles, Particles are to be understood in general in the context of the present invention to mean solid bodies in the micrometer range or nanometer range which are not directly connected to one another and which are thus able to form, for example, a free-flowing powder in the dry state and without other substances of the detection layer.
  • Particles can, for example, form in general solid constituents of aerosols, suspensions, or powders.
  • the particles have a particle size distribution, more particularly in the dry state of the detection layer, in which at least 90% of all particles of the detection layer have an actual particle size of less than 10 micrometers, preferably of less than 3 micrometers, or even less than 1 micrometer.
  • the detection layer to which this condition shall apply is to be understood to mean the entire detection layer whose change is measureable. More particularly, it can be, when an optically detectable change such as a color change for example is measured, the entire optically recognizable detection layer, optionally right up to a reflection layer or removal layer which is applied to the detection layer on a sample loading side, as will be more particularly elucidated below.
  • the detection layer can, as will be more particularly elucidated below, be overlaid by at least one further layer which can have, for example, reflective properties.
  • the layers do not necessarily have to be clearly delimited from one another. Locally, the detection layer is, viewed from the detection side, to be understood to mean each layer which is measured, right up to, for example, the reflecting particles and/or another reflecting object of a directly or indirectly adjacent layer.
  • a particle size is to be understood to mean an equivalent diameter of a particle, i.e., a diameter of a bead which has a volume and/or a surface similar to that of the particles.
  • Various processes for determining the particle size distribution can be used. There are different cases which have to be distinguished from one another.
  • the particle size can, for example, be determined by means of laser scattering and/or laser diffraction.
  • optical processes can also be used, for example processes which are based on image recognition.
  • a particle size distribution for example, within the detection layer for example can be determined down to a range of 3 micrometers to 10 micrometers.
  • other processes as well can be alternatively or additionally used, such as for example scanning electron microscopy of samples, for example microtome cross sections.
  • a clear identification of the particles can also be carried out by, for example, additionally using energy dispersive X-ray spectroscopy (EDX).
  • EDX energy dispersive X-ray spectroscopy
  • the resolution is typically sufficient in the nanometer range, where it is possible to record, for example, all particles having a particle size >1 nanometer.
  • apparatuses and processes for determining the particle size distribution are known to a person skilled in the art and commercially available.
  • optical determination of the particle size distribution can be used, since preferably the detectable change is an optically detectable change.
  • it can be automatic image analysis of an image of the detection layer, as will be more particularly developed below.
  • This automatic image recognition can be carried out, for example, by capturing an image of at least one part of the detection layer by means of a camera or another spatially resolving image detector and then by recognizing individual particles by means of image recognition and assigning them to a size distribution. It is possible in general to use, for example, all recognized particles to determine the particle size distribution. However, in practice, since particles are generally only recognized as such only above a minimum size, only particles above a predefined minimum size as well, for example, can be considered in the determination of the particle size distribution, for example only above a minimum size of 10 nanometers to 200 nanometers, more particularly a particle size of 50 nanometers to 100 nanometers.
  • An actual particle size is, in the context of the present invention, to be understood to mean the particle size of the particles in the detection layer, in the form in which the particles are actually present in the detection layer. If the particles in the detection layer are composed of multiple primary particles, for example in the form of agglomerates and/or aggregates which adhere together, the equivalent diameter of the aggregate or agglomerate should be used, and not the equivalent diameter of the primary particles.
  • the present invention thus does not include cases in which the detection layer is produced such that production thereof makes use of powders which nominally have the mentioned properties but in which the particles of the powder, for example during the production of the detection layer, interact with one another such that agglomerates and/or aggregates are present in the final and preferably dry detection layer and so, altogether for all particles in the finished detection layer, the mentioned condition is no longer fulfilled.
  • At least 80% of all particles of the detection layer can have an actual particle size of less than 5 micrometers, more particularly of less than 1 micrometer, It is particularly preferred for at least 70% of all particles of the detection layer to have an actual particle size of less than 900 nanometers, preferably of less than 800 nanometers.
  • the particles of the detection layer can have in particular an average particle size of 10 nanometers to 5 micrometers, preferably of less than 1 micrometer.
  • the average particle size can be preferably from 20 nanometers to 1 micrometer and particularly preferably from 20 nanometers to 500 nanometers.
  • the average particle size can be preferably from 70 nanometers to 5 micrometers, more particularly from 70 nanometers to 1 micrometer, and particularly preferably from 70 nanometers to 500 nanometers.
  • the particles of the detection layer can have in particular an average particle size of less than 1 micrometer, more particularly of less than 500 nanometers, and particularly preferably of up to 300 nanometers, or even less than 100 nanometers, for example 25 nanometers or less.
  • An average particle size can be understood to mean, for example, the median of all particle sizes of the particle size distribution, which is usually referred to as d 50 . This median is selected such that about 50% of the particles have a particle size below the d 50 value, and about 50% of the particles have a particle size above this median.
  • the particles can comprise in particular one or more of the following materials: SiO 2 ; diatomaceous earth; a silicate, more particularly a sodium aluminum silicate; a metal oxide, more particularly an aluminum oxide and/or a titanium oxide; a synthetic oxidic material, more particularly a nanoparticulate oxidic material, more particularly a nanoparticulate silicon oxide and/or aluminum oxide and/or titanium oxide; kaolin; powder glass; precipitated silica; calcium sulfate ⁇ 2 H 2 O.
  • a silicate more particularly a sodium aluminum silicate
  • a metal oxide more particularly an aluminum oxide and/or a titanium oxide
  • a synthetic oxidic material more particularly a nanoparticulate oxidic material, more particularly a nanoparticulate silicon oxide and/or aluminum oxide and/or titanium oxide
  • kaolin powder glass
  • precipitated silica calcium sulfate ⁇ 2 H 2 O.
  • particles of the detection layer having a particle size of more than 10 nanometers, more particularly of more than 20 nanometers or of more than 100 nanometers, to be inorganic particles.
  • particle shall not include an organic film former and an organic film formed therefrom, since films are generally not composed of loose particulates which are not connected with one another, but since films generally form a continuous layer.
  • the particles of the detection layer can, as will be more particularly developed below, be embedded in at least one such film former.
  • the detection layer can have in particular a refractive index of 1.1 to 1.8, preferably of 1.2 to 1.5.
  • the detection layer can have in particular, whether in a dry state or in a moist state, a refractive index which is close to the refractive index of water (about 1.33).
  • the diagnostic test element can be set up in particular such that the detectable change is completed within a period which is less than 60 seconds, preferably less than 40 seconds, and particularly preferably 20 seconds or less. This period can also be referred to as the reaction time.
  • reaction time can be defined by, for example, that timespan from the application of the sample to the test field within which a color reaction is completed to the extent that the relative reflectance subsequently changes by less than 1% per half a second.
  • the relative reflectance can, for example, be the ratio of the reflectance to a reflectance of a test element with no sample and/or to a calibration standard.
  • the reaction time can, for example, be set by appropriate selection of the test chemistry of the detection reagent and/or by the total composition of the test field and/or by the particle size distribution used in the context of the present invention.
  • the test field can have in particular a loading side for applying the sample of the body fluid and a detection side for detecting a change in the detection reagent, more particularly an optical change, for example a color change.
  • the test field can have at least one removal layer.
  • This removal layer can have multiple functions. For example, this layer can be set up for partitioning coarse constituents of the sample, more particularly for partitioning erythrocytes. Alternatively or additionally, the removal layer can also be set up to cover the inherent color of the sample, for example the inherent color of blood.
  • the removal layer can, as is yet to be explained in detail below, comprise, for example, at least one pigment, preferably at least one white pigment.
  • the removal layer can also be set up to fulfill a reflective function, for example to reflect a measurement light which is interspersed into the detection layer, and/or light emitted in the detection layer, such as fluorescent light for example.
  • the removal layer can be arranged in particular on a side of the detection layer facing the loading side.
  • the removal layer can be applied directly or indirectly to the detection layer.
  • An indirect application can be understood to mean, for example, the interposition of one or more further layers.
  • the removal layer can be set up in particular such that coarse constituents of the sample, more particularly in the case of whole blood erythrocytes, are not able to reach the detection side of the detection layer or are not able to reach the detection layer at all.
  • Coarse constituents can be understood to mean in general constituents which have a size, for example a particle size and/or an equivalent diameter, of more than 1 micrometer, more particularly of more than 5 micrometers. Erythrocytes in particular, which have a characteristic and intensive inherent color, are able to interfere with or even prevent the customary color detection of blood glucose, for example by means of the detection reagents described above, on the detection side.
  • the removal layer can in particular be coarse-grained, i.e., can be likewise particulate, and the particles of this removal layer can be coarser than the particles of the detection layer. More particularly, the removal layer can have particles of more than one micrometer in size. More particularly, the removal layer can have at least one pigment, i.e., one particulate dye, preferably an inorganic dye, with particles having an average particle size which is above the light wavelength used for optical detection, for example above a wavelength of 660 nanometers. More particularly, the removal layer, as explained above, can have at least one pigment for optically covering any inherent color of blood. The removal layer can comprise in particular at least one white pigment.
  • the removal layer can comprise, for example, one or more of the following pigments: titanium dioxide; zirconium dioxide; barium titanate; barium zirconate; zirconium silicate.
  • a combination of the mentioned pigments and/or of other pigments is also possible. Particular preference is given to the use of zirconium dioxide and/or titanium dioxide.
  • the pigment preferably has an average particle size of between 200 nanometers and 400 nanometers for optimal reflection of the light.
  • the removal layer can optionally have at least one filler, preferably a filler with a refractive index of ⁇ 2.0.
  • This filler makes it possible to confer, for example, a sucking behavior and/or a transparency on the removal layer.
  • the at least one filler can comprise, for example, silica and/or a silicate.
  • the filler can have an average particle size of ⁇ 5 micrometers.
  • the removal layer can have a pigment with a refractive index of at least 2.0, preferably of at least 2.2 or even at least 2.5, at a concentration of at least 25% by weight, based on a dried layer, i.e., a dried removal layer.
  • This pigment can be in particular titanium dioxide particles and/or zirconium dioxide particles, or the pigment can comprise these types of particles.
  • the titanium dioxide particles or zirconium dioxide particles can have in particular an average particle size of, for example, at least approximately 300 nanometers. However, deviations of preferably not more than 50%, particularly preferably of not more than 10%, may be tolerable. A particle size of 300 nanometers is generally optimal for white pigment reflecting visible light.
  • Titanium dioxide particles have in particular light scattering properties so that the removal layer can also act at the same time as a reflection layer in order to reflect light radiated from the detection side.
  • the layer assembly of the test field can also comprise in addition at least one reflection layer which can have the mentioned properties.
  • the diagnostic test element can, as explained above, be formed as a layer assembly and/or can comprise a layer assembly. In addition to the at least one detection layer, it can comprise in addition the at least one removal layer and/or at least one reflection layer.
  • the test field can be applied to at least one support element with its detection side. More particularly, the diagnostic test element can thus comprise at least one support element, with the support element preferably having at least one transparent region. The test field can be applied to the transparent region with its detection side.
  • the support element can be, for example, a flat support element, more particularly a support element in the form of a strip.
  • the support element can comprise a plastics layer, a paper layer, a ceramic layer or a laminate assembly and/or a combination of the mentioned layers.
  • the support element can be substantially opaque outside the transparent region so that the detection side of the test field is perceptible only through the transparent region.
  • the loading side of the sample can then be arranged on a side of the test field facing away from the support element.
  • the diagnostic test element can be formed such that the sample of the body fluid is directly applied to the loading side and so, for example, the loading side is directly accessible to a user of the diagnostic test element and the user can, for example, directly drip, dab, or apply in some other way a sample onto the area of the loading side which is at least partly accessible.
  • a transport system may also be provided which is set up to transport the sample of the body fluid from a loading site arranged at another location to the loading side, but this is less preferred.
  • the detection layer can, as already mentioned repeatedly above, comprise not only the particles and the detection reagent but also further substances.
  • the particles are preferably not identical to the detection reagent or at least not completely identical to the detection reagent, and, as described above, the detection reagent can also be a mixture of multiple detection reagents or multiple substances which together form the detection reagent.
  • the detection layer can be, for example, analogous to the first film layer described in EP 0 821 234 B1 of the diagnostic test support, apart from the particle size distribution described above.
  • the detection layer can comprise, for example, at least one organic film former.
  • this at least one film former can comprise a polyvinyl propionate dispersion.
  • other film formers can also be alternatively or additionally used.
  • this diagnostic test element can be more particularly a diagnostic test element as per one or more of the embodiments described above or one or more of the exemplary embodiments yet to be described below.
  • the diagnostic test element has at least one test field having at least one detection reagent.
  • the detection reagent is set up to pass through at least one change in the presence of the analyte, more particularly an optical change.
  • the test field has at least one detection layer comprising the detection reagent.
  • the detection layer is generated such that these particles has, with at least 90% of all particles of the detection layer having an actual particle size of less than 10 micrometers, preferably of less than 3 micrometers or even of less than 1 micrometer.
  • an actual particle size of less than 10 micrometers, preferably of less than 3 micrometers or even of less than 1 micrometer.
  • the detection layer can be generated in particular by means of at least one wet chemical process, more particularly from one or more dispersions, preferably aqueous dispersions.
  • Such layer-forming processes from one or more dispersions are known in principle to a person skilled in the art, and reference can be exemplarily made in turn to, for example, the abovementioned prior art, more particularly EP 0 821 234 B 1.
  • At least one powder for example a pigment powder
  • This powder may comprise agglomerates of primary particulates, which may already be directly present in the starting powder or which may temporarily form as well only during the production process, for example in the dispersion.
  • the pigment powder in the proposed production process is processed by means of at least one mechanical dispersion process in order to break up the agglomerates at least partly so that the abovementioned particle size distribution is present in the detection layer.
  • a dispersion process is generally to be understood to mean a process in which the powder, for example the pigment powder, is distributed in at least one liquid medium, preferably an aqueous medium, without the powder dissolving in this medium, so that a dispersion forms.
  • the dispersion can be admixed with further substances.
  • a mechanical dispersion process is—in contrast to chemical dispersion processes, which may nevertheless be additionally used, though this is less preferred—to be understood to mean a dispersion process in which the distribution of the powder in the medium is maintained by means of a mechanical action on the dispersion.
  • This mechanical action can be effected in particular such that, with this mechanical action, high shear forces have an effect on the dispersion and more particularly on the powder and the agglomerates present therein, whereof aggregates shall also be included, and so these are broken up at least partly to form smaller particles which fulfill the abovementioned particle size distribution condition.
  • a dissolver can be used for carrying out the mechanical dispersion process.
  • a dissolver is generally to be understood to mean an apparatus which can maintain the distribution of the powder in a medium, more particularly a substantially homogeneous distribution, and can exert at the same time high shear forces on the dispersion.
  • these shear forces can be exerted by means of two or more surfaces running against one another and closely spaced to one another, between which the dispersion is received.
  • dissolvers in the form of disk stirrers are commercially available in which high shear forces are exerted on the dispersion by means of a stirring disk, which is brought into a rotary motion, and so the agglomerates are torn apart.
  • dissolvers in accordance with a rotor/stator principle can be used. By means of such dissolvers, it is thus possible to generate or process a dispersion from which the detection layer is generated, and so the abovementioned condition for the particle size distribution is fulfilled.
  • a three-roll mill (also called a three-roller mill) can be used for carrying out the mechanical dispersion process, more particularly for dispersing the fillers.
  • a three-roll mill use is made of at least three rolls or cylinders which run against one another at different speeds.
  • the gap between the rolls or cylinders is generally set such that it is comparatively small, for example to 1 mm, down to the nanometer range.
  • a grinding step is to be understood to mean a process in which the powder in a dry or in a wet state is ground by the action of mechanical forces.
  • the at least one grinding step can comprise, for example, a wet grinding step, more particularly in a bead mill, and/or a dry grinding step, more particularly in an air jet mill.
  • Other grinding processes are also known to a person skilled in the art and are commercially available, and so corresponding mills can be selected which can be adapted to the type of powder and/or the type of desired particle size distribution.
  • the at least one synthetic oxidic material can be a nanoparticulate oxidic material.
  • a nanoparticulate material is to be understood in the context of the present invention to mean in general a material which has particles having an average particle size of below 100 nanometers.
  • the oxidic material can be silicon oxide and/or aluminum oxide and/or titanium oxide, for example Al 2 O 3 and/or TiO 2 and/or SiO 2 .
  • the mentioned oxides which may also be present as mixed oxides, can be present in nanoparticulate form.
  • a process for detecting an analyte in a sample of a body fluid, more particularly whole blood Use is made here of a diagnostic test element in one or more of the embodiments described above and/or in one or more of the embodiments yet to be described in detail below.
  • the sample has a volume of less than 2 microliters, more particularly of less than 0.5 microliters, and particularly preferably of less than 0.3 microliters, for example of 100 nanoliters.
  • the detectable change of the at least one detection reagent of the test field of the diagnostic test element used, as explained above can be an optically detectable change.
  • a spatially resolving optical detector is to be understood to mean an optical detector which has a multiplicity of optical sensors which are able to record regions of the detection side of the detection layer which are not completely congruent.
  • the spatially resolving optical detector can comprise at least one image sensor, i.e., an array of optical detectors which can be one-dimensional or else two-dimensional. More particularly, the optical detector can thus comprise a CCD chip and/or CMOS chip.
  • the spatially resolving optical detector can comprise at least one optical element for imaging the detection side and/or the detection layer onto an image-sensitive surface of the spatially resolving optical detector.
  • a spatially resolving optical detector and the mentioned small sample volumes make the advantages of the present invention, which are yet to be described in detail below, particularly apparent, since conventional detection layers lead to great uncertainty in the detection owing to the disadvantageous wetting effects and the coarseness of the detectable change, more particularly of the optically detectable change.
  • the proposed diagnostic test element, the proposed production process, and the proposed detection process have numerous advantages compared to known apparatuses and processes of the type mentioned.
  • an important basis for the present invention is the recognition that the use of small particulates in the form of particles for producing a detection layer generally results in aggregate formation, and so the detection layer is no longer able to profit from the low particulate size of the primary particles.
  • a test strip which is produced as per known processes of the prior art from substances having the described particulate sizes will thus in general have accordingly only particulates in an aggregated state.
  • the particulate sizes which are known from customary production processes and which are used as starting material in powders are thus only nominal values which are generally not found again in the actual particle size distribution in the detection layer.
  • the starting material (which is referred to here in general as a filler or which may contain at least one filler) has to be finely dispersed in the production of the detection layer.
  • some fillers such as Aerosils and/or Aeroxides for example, this does not generally have to be considered in particular, since such substances have been optimized by the manufacturer in many cases for easy disk convenience.
  • production of the diagnostic test element having a detection layer can be carried out which results in a considerably more favorable particle size distribution in the finished detection layer.
  • starting powders having average particle sizes of, for example, up to 50 nanometers, preferably up to 30 nanometers, in which dispersing of the particles can be provided before the production of the detection layer, for example before the application of a dispersion for producing the detection layer to the support element, and so the particle sizes fulfill the mentioned condition.
  • the particle sizes of the primary particles of the starting powder can, for example, remain substantially preserved, or agglomeration and/or aggregation of the primary particles may occur only to a slight extent during production.
  • Starting materials which can be used for producing the dispersion are commercially available materials, for example commercially available powders which already have the desired particulate size or particle size distribution.
  • at least parts of the starting substances, for example of the at least one powder to be initially ground as described above before the generation of the detection layer in order to achieve a corresponding particle size distribution having preferred grain sizes.
  • the present invention is further based on overcoming technical prejudices which are often advanced against fine-grained detection layers. For example, the effect of small particles on depth of shade and reaction time in detection layers was hitherto unknown.
  • optical detection it is necessary in the case of, for example, optical detection to achieve in general reflectance differences, also referred to as a reaction shift, of more than 40%, preferably of more than 50% or even more than 60%, relative reflectance, based on the blank value of the dry detection layer, between the glucose concentrations of 10 mg/dl and 600 mg/dl, which typically form a measurement range.
  • Reflectance is generally to be understood to mean the diffuse, undirected reflection of waves, more particularly of light, in contrast to a regular, directed reflection.
  • Reflectance is often related to the surface of the detection side and also referred to as degree of reflectance.
  • Degree of reflectance is to be understood to mean the ratio of the luminance remitted by a surface to the luminance of a surface in a reference white. Reflectance is a customary measured value in optical test elements, such as the test elements described in the prior art for example, and known in this field to a person skilled in the art.
  • reaction times of less than 10 seconds have to be achieved in general with customary diagnostic test elements.
  • Reaction time is to be understood to mean the time within which a substantially steady state has occurred after application of the sample to the test field.
  • the sample liquid can be, for example, blood or blood plasma recovered therefrom after removal of the erythrocytes.
  • FIG. 1 shows a schematic cross-sectional view of a diagnostic test element according to the present invention
  • FIGS. 2A and 2B show examples of wetting a test field surface of a test field of a conventional diagnostic test element ( FIG. 2A ) and of a diagnostic test element according to the invention ( FIG. 2B );
  • FIG. 3 shows reflectance curves of diagnostic test elements as per FIGS. 2A and 2B ;
  • FIG. 4 shows reflectance curves of further exemplary embodiments of diagnostic test elements according to the present invention.
  • FIG. 5 shows reflectance curves of samples with ingredients dispersed in different ways
  • FIGS. 6A to 6D show microscope images of samples of varying granularity
  • FIGS. 7A and 7B show standard deviations of the gray values in FIGS. 6A to 6D ;
  • FIGS. 8A and 8B show autocorrelation functions of the gray values in FIGS. 6A to 6D .
  • FIG. 1 schematically shows a possible assembly of a diagnostic test element 110 in a cross-sectional view, which assembly can also be used in the context of the present invention.
  • the diagnostic test element 110 comprises a support element 112 which can be, for example, in the form of a strip. As a whole, the diagnostic test element 110 can thus be in the form of a test strip.
  • the support element 112 comprises at least one transparent region 114 .
  • a layer assembly which can completely or partly cover the transparent region 114 .
  • this comprises two layers and forms a test field 116 .
  • this test field 116 comprises by way of example a detection layer 118 having a detection side 120 facing the support element 112 and the transparent region 114 .
  • the test field 116 optionally comprises a removal layer 122 on the side of the detection layer 118 facing away from the support element 112 .
  • This removal layer 122 serves to remove coarse constituents of a sample 126 of a body fluid which, on a loading side 128 , can be applied to a test field surface 124 .
  • the transparent region 114 can, for example, be simply in the form of an opening, for example a hole, in the support element 112 .
  • a support slide or another type of support preferably a transparent support slide.
  • This optional support slide is indicated in FIG. 1 by the reference number 119 .
  • This support slide 119 can, for example, be introduced between the support element 112 and the detection layer 118 in the layer assembly shown in FIG. 1 .
  • the support slide 119 can be part of a reaction film, where the at least one detection layer 118 and, optionally, the at least one removal layer 122 are applied to the support slide 119 , for example by means of a printing process and/or a blade-coating process. Subsequently, this reaction film is then applied to the actual support element 112 having the transparent region 114 , and so the detection layer 118 is perceptible through the transparent region 114 .
  • the transparent region 114 can, however, also be completely or partially filled with a transparent material, for example a transparent plastics material, and/or the entire support element 112 can be in the form of a transparent support element.
  • a transparent material for example a transparent plastics material
  • the layer assembly having the at least one detection layer 118 and, optionally, the at least one removal layer 122 can also be directly applied to the support element 112 .
  • FIG. 1 of the diagnostic test element is to be understood merely as an example and that other types of assemblies are also possible.
  • multiple detection layers 118 and/or multiple removal layers 122 or no removal layer 122 at all can be provided.
  • the assembly shown in FIG. 1 can be supplemented by various other elements which are not depicted.
  • a spreading mesh can be provided on the test field surface 124 .
  • parts of the test field surface 124 can be covered, for example with a hydrophobic material, in order, for example, to make only part of the loading side 128 accessible for applying the sample 126 .
  • the present invention relates essentially to configuring and producing the detection layer 118 .
  • diagnostic test elements 110 having the above-described particle size distribution according to the invention use may be made in principle of layer assemblies, as described in EP 0 821 234 B1 for example.
  • layer assemblies of the test field 116 which are produced as follows:
  • the comparative sample (sample A) produced is a diagnostic test element 110 corresponding to the following assembly:
  • two part solutions (part solutions 1 and 2) are initially prepared, and these are then combined to form a part batch.
  • solution is used irrespective of whether a real solution is actually present or only a dispersion for example.
  • An enzyme solution is prepared, and the part batch 1 and the enzyme solution are mixed to give a coating composition. To this end, the following is carried out:
  • Part solution 1 0.34 g of xanthan gum are preswollen for 24 h in 35.5 g of 0.02 M glycerol 3-phosphate buffer, pH 6.5 and mixed with 5.0 g of polyvinyl propionate dispersion.
  • Part solution 2 5.2 g of Transpafill are dispersed for 10 min with an Ultraturrax in 21.5 g of water.
  • Part batch 1 Both part solutions are combined and, after addition of 0.15 g of tetraethylammonium chloride, 0.17 g of N-octanoyl-N-methylglucamide, 0.06 g of N-methyl-N-octadecenyl taurate (“Geropon T 77”), and 0.88 g of PVP (MW: 25 000), are stirred moderately for 1 h with a paddle stirrer, Then the following part solutions are added in the order shown:
  • Enzyme solution 5 mg of PQQ disodium salt and 0.28 g of GDH (mutant 31) and also 0.16 g of a 1 M CaCl 2 solution are added to 25.6 g of 0.1 M glycerol 3-phosphate buffer, pH 6.5 and stirred for >3 h.
  • the part batch 1 and enzyme solution are mixed, admixed with a solution of 20 mg of K 3 [Fe(CN) 6 ] in 0.4 g of water and also 1.0 g of 2-methyl-2-butanol, and stirred for 30 min. This gives a coating composition for producing the detection layer 118 .
  • the coating composition produced in this way is, with a grammage of 90 g/m 2 , applied to a support slide 119 in the form of a polycarbonate slide having a thickness of 125 micrometers and dried.
  • Transpafill® is a commercially available sodium aluminum silicate powder from Evonik Industries AG.
  • the precision-improving effect of N-methyl-N-octadecenyl taurate (“Geropon T 77”) has been described in EP 0 995 994.
  • the removal layer 122 is also produced by initially preparing two part solutions (part solution 1 and part solution 2) and then combining them. This is carried out as follows:
  • Part solution 1 A slurry of 1.37 g of Gantrez S 97 in 13.5 g of water is admixed with 2.2 g of 16% NaOH and preswollen overnight. Then 0.40 g of tetraethylammonium chloride, 0.34 g of N-octanoyl-N-methylglucamide, 0.06 g of N-methyl-N-octadecenyl taurate (“Geropon T 77”), and 1.87 g of PVP (MW: 25 000) are added and stirred for 1 h.
  • Part “solution” 2 14.3 g of titanium dioxide E 1171 from Kronos and 1.95 g of precipitated silica FK 320 from Degussa are dispersed for 10 min with an Ultraturrax in 36.4 g of water.
  • Gantrez® is a product name from ISP International Speciality Products, Cologne, Germany. Chemically, it is a copolymer of maleic acid and methyl vinyl ether.
  • the coating composition produced in this way by combining part solutions 1 and 2 is then, with a grammage of 45 g/m 2 , applied to the first coated polycarbonate support slide 119 described as above, i.e., to the detection layer 118 , and dried.
  • a grinding process is carried out in the detection layer 118 on the raw material Transpafill® which is substantially responsible for the coarseness of this detection layer 118 .
  • the likewise coarse-grained raw material diatomaceous earth in the removal layer 122 which acts as precipitated silica, can also be subjected to a grinding process.
  • the removal layer 122 there should be no grinding of the titanium dioxide, which serves as a white pigment and should thus exhibit reflectivity for the radiated light, for example light having a wavelength of 660 nanometers.
  • This light is, for example, radiated through the transparent region 114 , radiated through the detection layer 118 , and is reflected at the removal layer 122 , and so the removal layer 122 in the exemplary embodiment depicted in FIG. 1 can simultaneously serve as a reflection layer.
  • a wet grinding step To make the abovementioned coarse-grained fillers Transpafill® and, optionally, precipitated silica finer, they are subjected to a wet grinding step. This can be carried out with an agitator bead mill, for example for 20 minutes, which correspondingly leads to a measurement giving a particle size d 50 of about 0.3 micrometers and a particle size d 90 of about 0.5 micrometers.
  • the value d 90 refers to the particle size at which 90% of the particles are finer than the value d 90 .
  • Samples A and samples B produced in this way enable various comparative experiments to be carried out. These comparative experiments can eliminate in particular the prejudice that more densely packed ingredients need a longer time for penetrating and thus need to dissolve through the sample fluid.
  • FIGS. 2A and 2B depict wetting experiments which were carried out on samples of type A ( FIG. 2A ) and samples of type B ( FIG. 2B ). These experiments firstly show the influence of the grinding step on wetting.
  • the comparative experiments each show test fields 116 having a test field surface 124 to which a drop 130 of the sample 126 is applied.
  • Subimages 132 in FIGS. 2A and 2B each show microscope images of the test field surface 124
  • subimages 134 show the change in gray value in the microscope images 132 along an intersection line 136 through the drop 130 of the sample 126 .
  • the sample 126 used was a test fluid having a concentration of 50 mg/dl glucose.
  • FIG. 2A shows a test field surface 124 of sample A, i.e., a test field material as is currently used in commercially available test strips.
  • FIG. 2B shows by contrast a test field 116 having the test field material according to sample B as per the present invention.
  • the particles 137 in conventional sample A as per FIG. 2A are considerably larger and have a broader particle size distribution than the particles 137 in sample B according to the invention as per FIG. 2B .
  • a particle size distribution can also be readily created by image recognition and automatic recognition of particles at an appropriate magnification.
  • a change in gray value as per subimages 134 may also be used.
  • Analytical processes of this kind with automatic image recognition are known in principle from the field of image processing to a person skilled in the art.
  • the results of these reflectance measurements are depicted in FIG. 3 .
  • the concentration c of glucose in the sample 126 is shown on the horizontal axis, whereas the relative reflectance R is plotted on the vertical axis.
  • EDTA venous blood was used as the sample 126 , and the concentrations of glucose were varied in this test fluid.
  • the curve 138 in FIG. 3 shows the remissions which were measured on a conventional diagnostic test element, i.e., a sample of type A, whereas the curve 140 shows remissions of a sample according to the invention of type B.
  • FIGS. 1 to 3 clearly show that the use of ground fillers is not accompanied by impairment of the properties of the diagnostic test elements 110 in the form of a lengthening of the reaction time or in the form of a worsening of the reflectance shift.
  • FIGS. 2A and 2B clearly demonstrate, the homogeneity and the precision of the measurements can be distinctly improved by the use of ground test field chemistry.
  • CV coefficient of variation
  • grinding can also be alternatively or additionally carried out with, for example, a dry grinding step. Accordingly, use can be made of, for example, an air jet mill, by means of which particulate sizes of up to, for example, 100 nanometers are achievable in principle.
  • raw materials for the detection layer 118 represents an additional process step and can increase the costs of the diagnostic test elements 110 . Therefore, in a second phase, raw materials are tested which are commercially available and which entail from the start an average particulate size in the range of ⁇ 1 micrometer. Available for this purpose is, inter alia, the Aerosil product range from Evonik Industries AG. These are hydrophilic, nanoparticulate oxides, more particularly metal oxides.
  • samples are produced in which, compared to sample A above, the Transpafill® in the detection layer 118 has been replaced 1:1 with the following materials:
  • a wet-ground mixture of precipitated silica and titanium dioxide having an overall average particle size of 0.3 micrometers is used instead of Transpafill®.
  • Reflectance measurements are again carried out in part on these samples, analogously to the experiment as per FIG. 3 .
  • the results of these measurements are plotted in FIG. 4 , the data depicted analogously to those in FIG. 3 .
  • the curve 142 indicates the reflectance of sample A
  • the curve 144 indicates the reflectance of sample D
  • the curve 146 indicates the reflectance of sample E
  • the curve 148 indicates the reflectance of sample F.
  • the very finely divided fillers should be dispersed close to their primary particulate size in order to avoid agglomeration and/or aggregate formation.
  • conventional dissolvers are used, and use can be made of, for example, Polytron® or Megatron® devices from Kinematica AG or Ultra-Turrax® devices for example from IKA Maschinenbau.
  • Sodium aluminum silicates such as Sipernat 44 MS (Degussa/Evonik) for example. These fillers are either already available in the desired particle size or particle size distribution or can be processed by grinding to the required particulate size or particle size distribution.
  • sample D is studied again in different ways.
  • Aeroxide TiO 2 P 25 is dispersed either with a dissolver (sample G) or with a propeller stirrer having a low speed.
  • the addition of Aeroxide TiO 2 P 25 is carried out either after mixing beforehand with water to form a paste (sample H) or by solid introduction into the thickener solution (xanthan gum) (sample I).
  • the comparative sample used is, as before, sample A as per the above description. Altogether, the samples for the experiment described below are thus as follows:
  • Sample G as per sample D, but dispersing of Aeroxide TiO 2 P 25 with a dissolver
  • Sample H as per sample D, but dispersing of Aeroxide TiO 2 P 25 with a propeller stirrer having a low speed, addition after mixing beforehand with water to form a paste, and
  • Sample I as per sample D, but dispersing of Aeroxide TiO 2 P 25 with a propeller stirrer having a low speed by solid introduction into the thickener solution (xanthan gum).
  • samples G to I are prepared in which Transpafill® is replaced 1:1 by weight with Aeroxide TiO 2 P 25. Otherwise, the diagnostic test elements 110 are produced as described above.
  • FIG. 5 depicts, analogously to the data depicted in FIG. 4 , reflectance curves for samples A′, G, H, and I.
  • the curve 150 indicates reflectance measurements for sample A′
  • the curve 152 indicates reflectance measurements for sample G
  • the curve 154 indicates reflectance measurements for sample H
  • the curve 156 indicates reflectance measurements for sample I.
  • the measurement curves show that the depth of shade is virtually the same for the four different coatings.
  • the reaction rate as well is in the range of 6 to 8 seconds for all the samples.
  • the major advantage of the detection films having fine-grained fillers is the distinctly improved homogeneity of the reaction colors, which therefore allows the measurement of smaller areas and thus smaller blood volumes.
  • diagnostic test elements 110 in the form of test strips are spotted with plasma containing 100 mg/dl glucose, and the reaction color is measured with a CCD camera. Since the individual pixels can be read separately, a number of pixels are analyzed statistically with regard to their precision (i.e., with regard to their standard deviation). Here, 10 pixels (edge length: 10 micrometers) are analyzed at the highest resolution, i.e., an overall area of 1000 ⁇ m 2 . For lower resolutions, i.e., larger areas, averaging is carried out over more pixels.
  • Sample A′′ as per sample A above, unground fillers, comparative sample
  • Sample J as per sample A′′, but Transpafill® and precipitated silica are ground,
  • Sample A′′′ as per sample A above, coarse ingredients, comparative sample, and
  • Sample K replacement of Transpafill® with Aeroxide TiO 2 P 25.
  • FIGS. 6A to 6C show microscope images of the measurement spots which are the basis of the subsequent measurements.
  • FIG. 6A shows a microscope image of a region of sample A′′ spotted with the solution, i.e., of a sample having unground fillers.
  • FIG. 6B shows an analogous image for sample J, i.e., of a sample having ground test chemistry.
  • FIG. 6C shows an image for sample A′′′, which essentially represents again a sample having coarse ingredients and corresponds to sample A′′
  • FIG. 6D shows an analogous image for sample K, in which Transpafill® is replaced with Aeroxide TiO 2 P 25.
  • the axes labels in FIGS. 6A to 6D display in each case the pixel position on a CCD chip in arbitrary units. Furthermore, measurement fields in FIGS. 6A to 6C are indicated by means of corresponding squares, the coordinates of which are displayed in the images.
  • FIGS. 7A and 7B depict standard deviations for the samples of FIGS. 6A to 6D .
  • Plotted on the vertical axis in each case is the standard deviation s of the gray values in FIGS. 6A to 6D .
  • This standard deviation s is specified as a percentage, based on the average gray value shift between a blank measurement and a fully reacted sample.
  • This standard deviation s is specified as a function of the area A plotted on the horizontal axis, via which averaging was carried out.
  • FIG. 7A shows a comparison of samples A′′ and J, i.e., a comparison of the standard sample with a sample having ground test chemistry.
  • the curve 158 displays the course of the standard deviation for sample A′′, whereas the reference number 160 indicates the curve of sample J having ground test chemistry.
  • standard sample A′′′ (reference number 162 ) is compared with sample K (reference number 164 ) in terms of its standard deviation.
  • a further option which can be alternatively or additionally applied involves calculating autocorrelation functions via the gray value distribution in microscope images, such as those in FIGS. 6A to 6D for example.
  • the autocorrelation function is a cross-correlation function of a signal with itself, which is a function of a shift ⁇ .
  • FIGS. 8A and 8B Autocorrelation functions (indicated by ACF) for samples A′′ to K are plotted in FIGS. 8A and 8B .
  • FIG. 8A shows a comparison of comparative sample A′′ (curve 166 ) with sample J having ground ingredients (curve 168 )
  • FIG. 8B shows a comparison of comparative sample A′′′ having coarse ingredients (curve 170 ) with sample K having fine ingredients (curve 172 ).
  • the autocorrelation function ACF is shown on the vertical axis
  • the shift ⁇ of the autocorrelation function in millimeters is shown on the horizontal axis.
  • the autocorrelation functions were determined by analyzing FIGS. 6A to 6D .
  • the autocorrelation function ACF correlates with the particle size distribution.
  • the half-height width of the autocorrelation functions 166 to 172 can be a measure of the granularity of the detection layer 118 .
  • direct reading of the particle size distribution from these curves 166 to 172 is not possible.

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