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WO1988001376A1 - Procede et dispositif permettant de determiner le niveau d'un analyte dans un echantillon de sang total - Google Patents

Procede et dispositif permettant de determiner le niveau d'un analyte dans un echantillon de sang total Download PDF

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Publication number
WO1988001376A1
WO1988001376A1 PCT/GB1987/000573 GB8700573W WO8801376A1 WO 1988001376 A1 WO1988001376 A1 WO 1988001376A1 GB 8700573 W GB8700573 W GB 8700573W WO 8801376 A1 WO8801376 A1 WO 8801376A1
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WO
WIPO (PCT)
Prior art keywords
sample
light
reflection element
analyte
reflection
Prior art date
Application number
PCT/GB1987/000573
Other languages
English (en)
Inventor
Brendan M. Buckley
Original Assignee
Radiometer A/S
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 Radiometer A/S filed Critical Radiometer A/S
Priority to FI881704A priority Critical patent/FI881704A0/fi
Publication of WO1988001376A1 publication Critical patent/WO1988001376A1/fr
Priority to DK201088A priority patent/DK201088A/da

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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
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection

Definitions

  • the invention relates to a method for determining the level of an analyte in a sample of whole blood using internal reflection spectroscopy as the analysis technique.
  • the incident light wave propagates into a narrow boundary layer in the less dense medium. If the less dense medium is absorbing. the propagating wave (the evanescent wave) is attenuated before its return. Alternatively, the evanescent wave may produce scattering or a fluorescence, phosphorescence or luminescence emission in the less dense medium.
  • a characteristic of the modified light i.e., the attenuated radiation passing out of the reflection element, the scattered light or the fluorescence, phosphorescence or luminescence radiation, respectively, may be determined and utilised for analytical purposes to characterise the less dense medium.
  • the light wave propagating into the boundary layer is often referred to as the evanescent wave, the penetration depth of which is only a fraction of the wavelength of the incident wave. More specifically, the penetration depth, dp. as defined by the distance required for the electric field amplitude to fall to e of its value at the surface is given by:
  • US 4321057 (Buckles) corresponding to WO 8100912 which discloses an analytical device comprising an longitudinal waveguide.
  • a preferred embodiment suitable for use in connection with whole blood is provided with a barrier layer excluding large molecules and blood cells;
  • EP 170376 (Unilever) which relate to an optical analysis method utilizing only a particular part of the light emerging from a reflection element for the measurement.
  • IR spectroscopy is of limited use for biological samples because of the interference of water molecules which complicates interpretation and because only a limited range of components can be detected at those wavelengths.
  • citrate ions complex with cations, especially calcium ions which means that the concentration of those ions in the sample cannot be determined.
  • the blood is said to run over the wave guide.
  • Gendreau in Applied Spectroscopy (1987) 35 353-357 describes the use of infra-red spectroscopy with attenuated total reflection techniques to study the adsorption on to a surface of proteins from whole blood.
  • the use of IR spectroscopy has the problems and limitations mentioned above.
  • the waveguide appears to be surrounded by the liquid sample.
  • EP 185126 (Battelle) describes the use of internal reflection spectroscopy in which the light totally reflected at each of two or more surfaces of waveguides in contact with a sample is analysed for simultaneous measurement of two or more parameters.
  • one surface is coated with a reactant which specifically reacts with an analyte in the sample and the other surface is uncoated (or is coated with a component to prevent absorption of compounds in the sample), and the transmitted light from the respective waveguides compared.
  • a reactant which specifically reacts with an analyte in the sample
  • the other surface is uncoated (or is coated with a component to prevent absorption of compounds in the sample)
  • the transmitted light from the respective waveguides compared.
  • DE 3532563 (AVL AG) describes apparatus in which a waveguide carries a coating which is in contact with the sample.
  • the fluorescence of a component in the coating depends on the concentration of an analyte in the sample.
  • Light may be conducted to the coating by total reflection in the uncoated part of the waveguide and refraction into the coating which has a refractive index intermediate that of the waveguide and the sample.
  • the fluorescence radiation emitted is transmitted directly to detection means.
  • the exciting radiation transmitted is not analysed, nor is the attenuation of the radiation by absorption of the evanescent wave detected.
  • the following description of currently practiced optical methods for the analysis of blood samples is relevant to the background of the invention. All such methods utilize various provisions so as to produce an optically clear sample.
  • the object of the present invention is to provide an improved, analysis method for use on whole blood.
  • the method according to the present invention for determining the level of an analyte in a sample of whole blood using internal reflection spectroscopy as the analysis technique and with a reflection element exposed to the sample is characterized by orienting the reflection element so relative to the sample and the gravity field or a superimposed force field that the blood cells under the influence of the said field are removed from one or several reflection sites, the active reflection sites, of the reflection element. and performing the determination after a boundary layer comprising essentially blood cell free plasma phase has been provided contiguous to the said active reflection sites.
  • the method according to the present invention provides a highly advantageous and easily implementable optical method of analyzing whole blood eliminating the need for pretreating the blood sample in order to make it optically clear.
  • the field of gravity is utilized to draw the blood cells away from the active reflection sites of the reflection element leaving a boundary layer of blood cell free plasma phase contiguous to the active sites of the reflection element.
  • the removal of the cells from the reflection site(s) may be accelerated by addition of an additive, such as an anti-coagulant, preferably one which does not form complexes with cations, more preferably heparin.
  • This boundary layer will be established within a very short period. If heparin is used as an anticoagulant, aggregation of blood cells occurs resulting in their more rapid migration under gravity and accelerating the formation of the boundary layer. We have found that from a resting heparinised blood sample a boundary layer of adequate thickness ( ⁇ 1 ⁇ m) will be formed within a fraction of a second. Thus, the separation provided for according to the method of the invention does not to any significant extent add to the time per analysis.
  • a superimposed force field such as e.g. a centrifugal field or any other field which is able to move the blood cells in order to achieve the blood cell free plasma phase.
  • the reflection element may have any suitable shape such as a plate, a prism or a fiber and may be produced from any material of adequate optical properties. Glass, quartz as well as plastics material may be used for the reflection element.
  • the waveguide comprising the reflection element is made very thin; a thickness less than 100 urn, preferably 10-50 ⁇ m is advantageous. The reason is that for a given length of the reflection element the number of reflection sites is greater for a thinner reflection element than for a thicker reflection element. The increased sample interaction seen for thin reflection elements results in greater sensitivity.
  • the reflection element in order to provide adequate mechanical properties it may be advantageous to provide the reflection element as a coating on a substrate.
  • the substrate should be made from or comprise a material giving rise to total reflection at the interface between the reflection element and the substrate.
  • those reflection sites on the reflection element which do not contact the blood cell free layer should be subjected to surroundings of standard optical conditions such as constant refractivity index and absorptivity.
  • the method according to the invention may be used for the determination of a great number of species present in blood.
  • those species should be mentioned hemoglobins, bilirubin. total protein, glucose and creatinine.
  • a suitable wavelength or wavelength range for the performance of the method is chosen from the spectral properties of the species to be detected. It is highly preferred to use UV or visible light, since IR light is absorbed by water molecules which renders the analysis of the transmitted light complex.
  • a wavelength from the IR range preferably the near IR range
  • a wavelength selected from the visible or near IR range is assumed to be appropriate and for the determination of total protein a wavelength from the UV range should be selected.
  • the method is of particular value in the measurement of bilirubin, and even more, preferably of haemoglobin in the plasma. By this method the extent of haemolysis can be estimated.
  • Analytes which are not directly detectable may be determined after exposure of the sample to a suitable reagent and formation of a reaction product between the analyte and the reagent which reaction product may
  • the reagent may be added to the sample or may be immobilized as a thin, preferably monomolecular coating, at the blood contacting surface of the reflection element.
  • Illustrative examples of such analytes/reagents are H + /pH indicators; O 2 /redox indicators.
  • analytes may be measured enzymically by coupling analyte-specific enzyme reactions either directly or via further enzyme reactions to the formation or consumption of reduced nicotinamide adenine dinucleotide or reduced nicotinamide dinucleotide phosphate.
  • Such reactions may be measured by means of this invention in whole blood by measurement of absorbance of the evanescent wave at 340 nm or 366 nm, or by measurement of fluorescence due to the evanescent wave.
  • Illustrative examples of such analytes/enzyme are: glucose/hexokinase, glucose-6-phosphate dehydrogenase; urate/uricase, xanthine oxidase.
  • analytes may be measured enzymically in whole blood by measuring O 2 or H + generation or consumption, directly or via intermediate reactions, by observing changes in pH indicators or in redox dyes by means of this invention.
  • Illustrative examples of such analytes/enzymes are: amino acids/amino acid decarboxylases; glucose/glucose oxidase.
  • analytes may be measured in whole blood by enzyme-linked or by other non-isotopic immunochemical techniques which may be observed by optical means by the method of this invention. It is noted that an essential element of all of the given examples is that neither the reagents nor the reaction products cause damage to the cellular elements present in the blood sample. This method may be used in conjunction with a separate measurement step in which hemolysis or cytolysis is caused for the purpose of including the contents of the cells in the measurement.
  • the method includes a step of analysing the said sample by a different technique, suitably using an electrochemical measuring electrode, for instance an ion selective electrode, e.g., K + , Na + or Ca + ion selective electrode, a pH electrode or an oxygen electrode.
  • an electrochemical measuring electrode for instance an ion selective electrode, e.g., K + , Na + or Ca + ion selective electrode, a pH electrode or an oxygen electrode.
  • the method is used to estimate the extent of hemolysis in the sample, and this allows the values obtained by the analysis by the electrode to be corrected to give the plasma levels of the species observed.
  • the invention also relates to an apparatus for determining the level of an analyte in a sample of whole blood, said apparatus comprising a reflection element having an entrance part for receiving light transmitted to the reflection element and an exit part for said light having passed the reflection element, said apparatus being characterised by an active front part having a sample contact surface with one or several reflection sites, said reflection element being so located relative to the sample in the normal use of the apparatus that the blood cells under the influence of the gravity field or a superimposed force field be removed from the active front part of the reflection element.
  • the light is totally internally reflected in the reflection element between the entrance part and the exit part, and is attenuated in use by the sample.
  • the exit part is, for instance, suitable for connection to a detector for analysing the attenuation of the totally internally reflected incident light.
  • any reflection sites located out of contact with the sample should be subjected to surroundings of standard optical conditions.
  • a light source means for transmitting light to the reflection element and a light detection means for receiving light transmitted from the exit part of the reflection element have been provided.
  • the light source means and the light detection means may be any convenient means well known per se. They are preferably suitable for emitting and detecting, respectively, ultra violet or visible light.
  • the light source may emit monochromatic light or polychromatic light.
  • means for selecting the wavelength useable in the performance of the method according to the invention may be provided in the light path either upstream to the entrance part of the reflection element or downstream to the exit part of the reflection element but upstream to the light detection means.
  • a suitable light detector means is a photoelectric device producing a current or voltage signal reflecting the intensity of the light received.
  • the apparatus according to the invention preferably contains, or is connected to, suitable signal processing means and output means which are well known per se.
  • the apparatus for some purposes it would appear appropriate to provide the apparatus according to the invention as a disposable unit.
  • the light source means and the light detector means are preferably located in a device adapted to receive the disposable unit and
  • the apparatus according to the invention is characterized by comprising light inlet means for optically coupling the apparatus to external light source means and light exit means for optically coupling the apparatus to external light detection means.
  • further measuring means e.g. an electrochemical measuring electrode, in the apparatus.
  • the apparatus according to the invention may also be embodied as a device suited for insertion in a sample contained in a test tube or the like.
  • the invention also relates to an analyzer for the determination of the level of potassium in a sample of whole blood, and comprising potassium measuring means; said analyzer further comprising means for detecting the level of hemolysis in the said sample.
  • an analyzer for the determination of the level of potassium in a sample of whole blood, and comprising potassium measuring means; said analyzer further comprising means for detecting the level of hemolysis in the said sample.
  • plasma potassium concentration is increased by about 2 mmol/L. This could result in a patient with life-threatning hypokalaemia being adjudged to be normal and being thereby denied appropriate treatment, or in a patient with normal plasma potassium concentration being adjudged to be hyperkalaemic and thereby treated inappropriately.
  • the means for detecting the level of hemolysis in the blood sample comprises a reflection element.
  • a preferred potassium analyzer according to the present invention is characterized by comprising sample inlet means and sample cuvette means connected to the sample inlet means for accomodating the sample and exposing the sample to the reflection element the reflection element being provided in an upper wall of the sample cuvette means.
  • "accomodating the sample” should mean accomodating the entire sample volume or only part thereof.
  • FIG. 1 illustrates an experimental set-up for performing the method according to the invention
  • FIG.2 is a graph showing the results obtained by the experimental set-up of FIG. 1;
  • FIG.3 shows diagrammatically a whole blood potassium analyzer provided with a reflection element for detecting the level of hemolyzation
  • FIG. 4 shows diagrammatically a whole blood analyzer provided with means for adding a reagent to the sample
  • FIG. 5 is a longitudinal section through a cuvette of an automated analyzer
  • FIG. 6 is a longitudinal section through a similar disposable cuvette
  • FIG. 7 shows a device suitable for insertion in a test tube
  • FIG. 8 shows in enlarged fragmentary longitudinal section, the active front part of the device of FIG. 7.
  • FIG.1 illustrates diagrammatically an experimental set-up used in the evaluation of the method according to the present invention.
  • a block-shaped container means 1 comprises two half parts 15 and 16 having a 0.15 mm thick glass plate 3 sandwiched between them. Each half part is made from a 10 x 10 x 30 mm 3 block of a black coloured polyoxymethylene material sold under the trade name
  • the glass plate 3 is a 0.15 mm thick microscope glass cover slip manufactured by Chance Propper Ltd., England.
  • the glass plate is fixed to each of the two half parts 15 and 16 of container means 1 by means of an optically clear silicone adhesive.
  • a recess 17 of length about 14 mm, width about 9 mm and depth about 1 mm has been provided.
  • a recess 18 of length about 20 mm, width about 4 mm and depth about 2 mm has been provided forming a cuvette for accomodating a blood sample.
  • Light guide means 7 and 11 are light guide monofilaments sold under the designation Crofon OE-1040 by Du Pont de Nemours.
  • the blood sample is introduced by means of a syringe into recess of cuvette 18 through a capillary bore (not shown) of diameter 1.1 mm provided in the lower half part 16.
  • the capillary bore extends perpendicularly to the plane of FIG. 1 and opens into the front wall (not shown) of cuvette 18 adjacent to the right side wall of and the bottom wall of cuvette 18.
  • Surplus sample is discharged through capillary bore 14. Due to the gravity field a blood cell free plasma phase 4 is formed in cuvette 18 contiguous to glass plate 3.
  • the monochromatic light beam emerging from monochromator 5 is guided to glass plate 3 through plastics waveguide 7.
  • the refractive indices of plastics waveguide 7 and glass plate 3 and the angle between the longitudinal axis of waveguide 7 and glass plate 3 are so chosen that the light traverses the interface between waveguide 7 and glass plate 3 without being reflected at that interface.
  • the actual angle from the glass plate to the longitudinal axis of the waveguide is 20 (counter clockwise).
  • glass plate 3 acts as a reflection element. After having traversed glass plate 3 a number of times the light reaches interface 10 between glass plate 3 and plastics waveguide 11. At that point the light emerges from glass plate 3 and is transmitted through waveguide 11 to a photodector 12 (BPX 90 photodiode, Siemens).
  • the current signal of photodetector 12 is proportional to the intensity of the light reaching photodetector 12 and is measured by means of a galvanometer 13 suited for measuring current intensities from the pA range (GVM30, Radiometer A/S).
  • Either of the above-mentioned wavelengths of 506 nm and 548 nm are isobestic as to Hb and HbO 2 , i.e. the molar absorptivity of Hb and HbO 2 at either one of these wavelengths is the same (but different from the molar absorptivity at the other wavelength).
  • a series of measurements was made with the experimental set-up of FIG. 1.
  • basis material was used a heparinised blood sample containing 13.4 g% (8.32 mM) Hb + HbO 2 as measured on an oximeter of the type OSM2 manufactured and sold by Radiometer A/S, Copenhagen. Denmark.
  • the blood sample was divided into two fractions one of which was hemolyzed by freezing at -20 °C. Unhemolyzed sample material and hemolyzed sample material was mixed in the ratios:
  • ⁇ 1 and ⁇ 2 are the actual wavelengths.
  • log I/I o is plotted against degree of hemolysis.
  • FIG. 3 shows diagrammatically an analyzer 21 according to the invention for analyzing samples of whole blood.
  • a sampling device in the present case a syringe 22
  • a sample is introduced in the analyzer 1 through sample inlet means 23.
  • the sample is drawn through a sample conduit 24 of analyzer 1 by means of pump means shown as 25.
  • pump means shown as 25.
  • the sample reaches particular measuring locations or cuvettes 26 and 27 in conduit 24 the sample transport is stopped.
  • the sample is contacted with a potassium measuring electrode 28 and a reference electrode 29.
  • a reflection element 30 forms part of the upper wall of cuvette 27, reflection element 30 further being connected to light source means 31 and light detector means 32 via light guides 33, 34, respectively.
  • Light guides 33, 34 are so oriented relative to reflection element 30 that no reflection takes place at interfaces 35, 36 between light guides 33, 34 and reflection element 30.
  • a modification of the light intensity takes place if any-light absorbing compounds are present in the sample boundary layer contiguous to the sample contact surface of reflection element 30.
  • the reflection sites which are out of contact with the sample are subjected to surroundings, the optical properties of which remain constant ("standard optical properties") during at least one measurement sequence including measurement on a sample as well as on a reference standard and are shielded against stray light.
  • the total concentration of hemoglobins (Hb + HbO 2 ) is determined utilizing light of appropriate wavelengths. It is to be understood that between light source means 31 and reflection element 30 as well as between reflection element 30 and light detector means 32 appropriate optical equipment may be provided, such as monochromator means, lenses etc..
  • the signals from the electrochemical measuring system comprising electrodes 28 and 29 and from light detector means 32 are fed to suitable data processing means 37 and output means 38 via A/D converting means 39.
  • Means 37, 38, 39 are considered as well known per se in connection with analyzers of the present nature and will not be further described in the present context.
  • the sample After completion of the measurement procedure in cuvette 27 the sample is transported via sample conduit 24 to the outlet 40 of analyzer 21 and discharged into waste container 41.
  • the apparatus 1 is intermittently calibrated on a calibration or reference standard to which values for the analyte(s) in question have been assigned.
  • FIG. 4 shows diagrammatically an analyzer 111 for determining the level of an analyte in a sample of whole blood. From a syringe 112 a sample is introduced through sample inlet means 113 and drawn through a sample conduit 114 of analyzer 111 by means of pump means 115.
  • Reagent forming with the analyte a light absorbing reagent/analyte complex or a complex otherwise modifying the light transmittance is pumped from reagent reservoir llfi by means .of pump means 117 through a reagent conduit 118 into sample conduit 114.
  • the sample/reagent mixture is further transported to a particular measuring location or cuvette 119 in sample conduit 114.
  • the transport of the mixture is stopped.
  • a reflection element 129 forms part of the upper wall the reflection element being connected to light source means 120 emitting light of a relevant wavelength and light detector means 121 via light guides 122, 123. respectively.
  • the cuvette and appended optical devices are constructed as explained above in connection with FIG. 3.
  • the level of analyte/reagent complex is determined and correlated to the level of the analyte originally present in the sample.
  • sample/reagent mixture is transported via sample conduit 114 to the outlet 127 of analyzer and discharged into waste container 128.
  • FIG.5 shows in more detail a cuvette generally designated 100 for use in an automated analyzer and corresponding to cuvettes 7, 119 of FIG. 3 and 4.
  • a reflection element 103 made from an optically clear material provides the upper wall of cuvette 100. In order to facilitate entrance and exit of light and at the same time provide an appropriate sensitivity the reflection element 103 has been given the configuration shown with enlarged end parts and a thin sample contact part.
  • the reflection element 103 is supported on substrate 104 made from a material of lower refractivity index than reflection element 103.
  • the thickness of reflection element 103 is preferably less than 1 mm, preferably less than 100 urn and particularly 10-50 um.
  • FIG. 6 shows another embodiment of the apparatus according to the invention.
  • a disposable cuvette unit 200 is adapted to fit into a permanent part 201.
  • the two parts 200 and 201 are interlocked by means of snap lock 202.
  • Sample is introduced into the space 203 of cuvette unit 201 so as to contact an upper reflection element 204 supported on a substrate 205.
  • light guide means 206 and 207 are provided in the permanent part 201 .
  • Light guide means 206 guides light from external light source means (not shown) to light inlet means 208 of reflection element 204 and light guide means 207 guides light from light exit means 209 of reflection element 204 to external light detector means (not shown).
  • light inlet means 208 and light exit means 209 provides for optical coupling of the apparatus according to the invention, i.e. the disposable unit, to the permanent part 201 with the appended light source and light detector means.
  • FIG. 7 shows a further device 300 useful in the performance of the method according to the present invention.
  • the device 300 is an elongate member having an active front part comprising a reflection element 301 and a shielding 302 covering the peripheral edge of reflection element 301 as well as the body part 303 of device 300.
  • collar means 304 for mounting device 300 to a sample container, e.g. a test tube.
  • a sample container e.g. a test tube.
  • collar means 304 instead of collar means 304 other suitable means could be used for attaching the device to a sample container in order to keep device 300 quiet relative to the sample during a measurement sequence.
  • cable 305 connecting device 300 with external light quide and light detection means is shown.
  • Device 300 may be held in any upwardly oriented direction.
  • reflection element 301 has been rearwardly extended providing longitudinally extending light guide means 306 and 307.
  • Reflection element 301 and light guide means 306 and 307 are supported on substrate 308 of lower refractivity index.
  • the bevelled edges 309 and 310 of the reflection element direct the light into and away from the sample contact part of the reflection element, respectively.
  • material 311 and 312 of lower refractivity index than reflection element 301 e.g. air.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)
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Abstract

Sont décrits un procédé de détermination du niveau d'un analyte dans un échantillon de sang total par une technique de spectroscopie à réflexion interne et un dispositif indiqué pour cette technique. Ce procédé est particulièremnt utile pour détecter l'atténuation de la lumière entièrement réfléchie, suite à l'absorption de l'onde évanescente, p. ex. par les hémoglobines. Dans le dispositif (1) la lumière incidente est dirigée par un guide de lumière (7) vers l'élément de réflexion (3) et la lumière atténuée entièrement réfléchie est dirigée à l'extérieur de l'élément vers un photodétecteur (12) par un guide de lumière (11). Dans le sang total contenu dans la cuvette (18), les celleules sont extraites de l'interface (8) par la force de gravité et laissent un plasma (4) exempt de cellules sanguines à proximité de l'interface (8). Il est ainsi possible de détecter les analytes présents dans le plasma et d'évaluer l'étendue de l'hémolyse.
PCT/GB1987/000573 1986-08-14 1987-08-14 Procede et dispositif permettant de determiner le niveau d'un analyte dans un echantillon de sang total WO1988001376A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FI881704A FI881704A0 (fi) 1986-08-14 1987-08-14 En metod och apparat foer bestaemning av analytnivaon i ett helblodsprov.
DK201088A DK201088A (da) 1986-08-14 1988-04-13 Fremgangsmaade og apparat til bestemmelse af indholdet af en analyt i en blodproeve

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB868619823A GB8619823D0 (en) 1986-08-14 1986-08-14 Determining level of analyte
GB8619823 1986-08-14

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WO1988001376A1 true WO1988001376A1 (fr) 1988-02-25

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EP (1) EP0282505A1 (fr)
JP (1) JPH01500928A (fr)
DK (1) DK201088A (fr)
FI (1) FI881704A0 (fr)
GB (1) GB8619823D0 (fr)
WO (1) WO1988001376A1 (fr)

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WO1990001697A1 (fr) * 1988-08-05 1990-02-22 Red Kite Technology Limited Controle de la glycemie
WO1990007106A1 (fr) * 1988-12-22 1990-06-28 Radiometer A/S Methode de determination photometrique in vitro d'un parametre gazeux dans un echantillon de sang
WO1991015751A1 (fr) * 1990-04-11 1991-10-17 Applied Research Systems Ars Holding N.V. Procede d'amelioration de la sensibilite d'une analyse
DE4124920A1 (de) * 1990-07-27 1992-02-06 Hitachi Ltd Biochemischer analysator und in dem analysator verwendete prismazelle fuer abgeschwaechte totalreflektion
DE9110757U1 (de) * 1991-08-30 1992-02-13 Klein, Rainer, 5840 Schwerte Integriert-optischer Stoffsensor
EP0488947A1 (fr) * 1990-11-26 1992-06-03 Ciba-Geigy Ag Cellule détectrice
DE4128846A1 (de) * 1991-08-30 1993-03-04 Rainer Klein Integriert-optischer stoffsensor
DE4333560A1 (de) * 1993-10-01 1995-04-06 Bayer Ag Vorrichtung zur kontinuierlichen spektroskopischen Analyse nach dem Prinzip der abgeschwächten Totalreflexion
DE10030920C2 (de) * 2000-06-24 2003-01-02 Glukomeditech Ag Messvorrichtung zur gleichzeitigen refraktrometrischen und ATR-spektrometrischen Messung der Konzentration flüssiger Medien und Verwendung dieser Vorrichtung s
WO2003056327A1 (fr) * 2001-12-28 2003-07-10 Hemocue Ab Procede de mesure quantitative de l'hemoglobine dans un sang entier non hemolyse non dilue
EP1416263A2 (fr) 2002-10-29 2004-05-06 Bayer Healthcare, LLC Appareil pour l'analyse optique de petites quantités d'échantillons
US7221440B2 (en) 2004-07-22 2007-05-22 Eastman Kodak Company System and method for controlling ink concentration using a refractometer
US7375813B2 (en) 2004-10-21 2008-05-20 Eastman Kodak Company Method and system for diffusion attenuated total reflection based concentration sensing
US8377381B2 (en) 2003-01-21 2013-02-19 Bayer Healthcare Llc Optical format
CN104136911A (zh) * 2012-02-13 2014-11-05 国立大学法人东京医科齿科大学 血液信息的测定方法及装置
WO2017200907A1 (fr) * 2016-05-20 2017-11-23 Instrumentation Laboratory Company Détection d'hémolyse évanescente
WO2018071255A1 (fr) * 2016-10-13 2018-04-19 Instrumentation Laboratory Company Mesure de protéine totale à l'aide de la réfractométrie de sang entier
EP3370058A1 (fr) * 2017-03-01 2018-09-05 Danmarks Tekniske Universitet Dispositif de guide d'onde planaire avec filtre de taille nanométrique
JP2021518910A (ja) * 2018-04-12 2021-08-05 ラジオメーター・メディカル・アー・ペー・エス 多孔質膜センサ素子
EP4052022A1 (fr) * 2019-10-28 2022-09-07 Ricoh Company, Ltd. Appareil de mesure et appareil de mesure d'informations biologiques

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DK201088D0 (da) 1988-04-13
FI881704L (fi) 1988-04-13
FI881704A0 (fi) 1988-04-13
JPH01500928A (ja) 1989-03-30
GB8619823D0 (en) 1986-09-24
DK201088A (da) 1988-06-14
EP0282505A1 (fr) 1988-09-21

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