EP2055384A1 - Vorrichtung zum Nachweis von Bestandteilen in einem Fluid - Google Patents

Vorrichtung zum Nachweis von Bestandteilen in einem Fluid Download PDF

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Publication number
EP2055384A1
EP2055384A1 EP07021342A EP07021342A EP2055384A1 EP 2055384 A1 EP2055384 A1 EP 2055384A1 EP 07021342 A EP07021342 A EP 07021342A EP 07021342 A EP07021342 A EP 07021342A EP 2055384 A1 EP2055384 A1 EP 2055384A1
Authority
EP
European Patent Office
Prior art keywords
blood
measuring
filter
detection reagent
opening
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07021342A
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German (de)
English (en)
French (fr)
Inventor
Stefan Dr. Med. Dipl.-Ing. Margraf
Martin Prof. Dr. Scholz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leukocare AG
Original Assignee
Leukocare AG
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 Leukocare AG filed Critical Leukocare AG
Priority to EP07021342A priority Critical patent/EP2055384A1/de
Priority to US12/740,817 priority patent/US20100261223A1/en
Priority to PCT/EP2008/009219 priority patent/WO2009056340A2/de
Priority to JP2010531462A priority patent/JP2011501201A/ja
Priority to EP08845028A priority patent/EP2205355A2/de
Priority to CN2008801144648A priority patent/CN101883634A/zh
Publication of EP2055384A1 publication Critical patent/EP2055384A1/de
Withdrawn legal-status Critical Current

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    • 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
    • B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • 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
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • B01L2300/049—Valves integrated in closure
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • 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
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • 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
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • 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
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum

Definitions

  • the present invention relates to an apparatus and a method for the detection, in particular for the determination of the concentration, of constituents in blood or water. Furthermore, the present invention relates to the use of a device or a method for the determination of constituents in blood. Finally, the invention relates to a kit comprising the device and a DNA standard.
  • US 5,186,843 For example, a material for separating plasma or serum from blood is described.
  • the material includes glass microfibers, cellulosic fibers and synthetic textile staple fibers. This medium is used to obtain small amounts of plasma that collect within the separation layer. However, the still necessary collection and further handling of the liquid for a quick and clean diagnosis hinder.
  • US 4,816,224 describes a device for the separation of plasma or serum from whole blood, which can be designed differently. Glass fibers, which occupy a large volume, serve for separation.
  • the device may comprise a plurality of filter layers.
  • a device which allows the separation of plasma or serum from solid blood components by means of a filter membrane mounted in the device and pressure.
  • the corresponding device may include a detection strip that allows the detection of components in the blood by immunochemical detection methods. However, these strips do not allow direct detection without further steps to be carried out by the staff and without the use of further auxiliaries or auxiliaries.
  • the device is primarily intended for obtaining blood plasma or serum for further study.
  • devices as described above are primarily used to provide small amounts of plasma or serum for further analysis.
  • test strips only provide information on whether or not a substance is present within the detection capacity.
  • these methods or devices are often not suitable because only accurate measurements of the concentration or content of a substance in a fluid, eg, blood, provide information about the exact condition of the patient and appropriate treatment methods.
  • Further or additional objects of the present invention are the provision of a simple, safe and reliable device or method which allows, in particular, laypersons or non-medically trained personnel to provide a device which is simple and inexpensive to manufacture and / or store, and the provision of a corresponding kit.
  • the present invention preferably relates to a device for detecting, in particular for determining the concentration, of constituents in blood, having a measuring range, a filter and at least one detection reagent for interacting with the constituents.
  • detection of, for example, substances is meant in particular the determination of the presence or absence of a substance.
  • the detection limit of the measuring method determines the result within the scope of the desired accuracy.
  • fluids in blood is understood to mean, in particular, substances present in blood and / or dissolved substances.
  • the substances may in particular be organic or inorganic or a mixture of both.
  • components of other fluids can also be determined with the device of the present invention.
  • Fluids are to be understood as liquids with solid constituents or suspensions.
  • the fluid is a body fluid.
  • Body fluids include, for example, blood, cerebrospinal fluid, urine, serous fluids, saliva, sperm, or abnormally altered stool.
  • the fluid is water, in particular from lines, streams or lakes, etc.
  • it can be determined, for example, whether a measured DNA correlates with the load on the water by microorganisms.
  • a “measuring range” in the sense of the present invention is in particular a space, preferably with a defined or definable volume, in which at least one constituent of a fluid is determined. It is preferably at least partially transparent and particularly suitable for the determination of the substance or the constituent with preferably optical methods.
  • the measuring range is preferably for z. B. visible light and the light of the emission wavelengths permeable.
  • the filter in the present invention may include or include any material suitable for separation of blood or other solid-component fluids such exist.
  • the filter may comprise, for example, polyethylene terephthalate (sold, for example, by Sekisui in a serum recovery product) or BTSSP (sold by Pall).
  • the filter comprises glass fibers but is not completely made of glass fibers. Even more preferably, the volume or weight fraction of glass fibers is between 0% and 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10%, or between about 5% and 50% % of the filter, preferably between about 10% and 50%. Most preferred is a filter material without glass fibers. For filtering blood, the filter material should not cause hemolysis or bind analytes.
  • the term "detection reagent” is used in particular to describe a substance with which the presence and / or concentration of another substance, preferably one in a fluid, eg. B. blood, plasma or water substance, detected or detected, understood.
  • a detection reagent preferably has the property under certain conditions to enable or condition a detectable reaction.
  • a detection reagent preferably interacts directly with the substance to be determined. It is either a covalent or a non-covalent bond with this substance.
  • the detection reagent fluoresces reinforced only by binding to the analyte.
  • the device according to the invention is preferably a ready-to-use or ready-to-use device which makes it possible to detect and in particular determine the concentration of the constituents in a simple and reliable manner without extensive preparatory measures.
  • the present invention proves to be particularly advantageous in that a device is provided which is small, can be read with commercially available devices and / or the separation of the solid constituents of fluids, preferably from Blood, with the simultaneous measurement of components in the liquid phase connects. In this way, not only the centrifugation step is saved, which was previously necessary, for example, to separate solid blood components from the serum or plasma, but it is possible by simple and safe handling even untrained personnel, the analysis of fluids in the context of diagnostic procedures.
  • the present device allows for the instantaneous measurement of the constituents of interest (ready-to-use) without further treatment and / or delay or other necessary measurement steps.
  • the device has an opening for introducing a fluid, wherein the filter between the opening and measuring range is arranged.
  • the device further comprises a fluid input region, which is preferably arranged between the opening and the measuring area, more preferably between the opening and the filter.
  • the area between the opening and the measuring area and / or the fluid channel, preferably comprising the fluid input area is also summarized under the term filter area.
  • the filter area preferably has a capacity of between about 200 and about 2000 ⁇ l. Depending on the fluid or, preferably, the amount and texture of the blood, up to 200 ⁇ l of plasma or serum can be obtained for measurement in the measuring range.
  • the device according to the invention preferably allows the provision of a volume to be measured in the measurement range between about 15 ⁇ l and about 80 ⁇ l, preferably between about 20 ⁇ l and about 60 ⁇ l and most preferably about 40 ⁇ l serum or plasma.
  • Pulsma is preferably understood to mean, in particular, the liquid phase of the blood which is separate from solid constituents such as cells (erythrocytes, white blood cells, etc.) and which can still coagulate.
  • “Serum” is preferably understood to mean, in particular, the liquid fraction of the blood which is obtained after coagulation of the blood by separation of the cellular constituents mixed with platelets and coagulation factors to form the blood cake.
  • each substance can be determined using suitable detection reagents.
  • the ingredient to be detected or determined is a substance found in organisms.
  • Organisms occurring substances may be organic or inorganic nature. Inorganic are, for example, minerals or mineral salts, trace elements, inorganic ions, metals and heavy metals, etc.
  • Organic substances can belong to different substance classes.
  • a group of substances form proteins, including enzymes. Enzymes convert their substrate into an end product. In the context of the present invention, preferably both the enzyme and the substrate and / or the end product can be determined. Also, non-enzyme proteins may preferably be detected or determined by the apparatus of the present invention.
  • Other groups of organic substances include vitamins and coenzymes, nucleic acids, cytokines, hormones, histones, peptides, sugars, etc.
  • nucleic acids comprising DNA and RNA in their single and / or double-stranded forms.
  • the component to be detected or determined is a biological molecule selected from the group comprising DNA, RNA, proteins, hormones, cytokines.
  • the latter substances may be free or associated be with other proteins.
  • DNA in plasma or serum may also occur as a complex with histones and / or elastase as well as microsatellites.
  • the component to be detected or to be determined is preferably the DNA / RNA of intact or intact bacteria, viruses and / or parasites from water samples contaminated with other particles. In this case, particles are retained by the filtration, while the nucleic acid contained in microorganisms can be made accessible to a measurement by suitable fluorescent dyes.
  • the ingredient to be detected or determined is a drug.
  • Drugs are substances which can be administered to an individual for controlling a pathological condition or disease. Drugs may also be the abovementioned biological molecules.
  • DNA is determined or measured.
  • the filter used in the present invention preferably binds little or no DNA.
  • the bound fraction is preferably less than 30%, preferably less than 20%, most preferably less than 10% of the DNA contained in the fluid or blood.
  • DNA can be detected in many ways. These include PCR as well as detection by detectable agents interacting specifically with DNA.
  • the present invention preferably permits the determination of non-cell-bound DNA. Non-cell-bound DNA can be determined by different methods. In addition to the measurement of the fluorescence after addition of an intercalating dye, the measurement of the UV absorption of DNA is also used to determine the concentration. The sample volumes required for this have now reached the low ⁇ l range (eg measurement by NanoDrop in the range from 2 ⁇ l). The lower measurement limit for DNA is z. At about 10 ng / ml for the fluorescence method.
  • ischemia / reperfusion disease After major operations, especially with heart-lung machine, but also after accidents with polytrauma, sepsis, burns and after ischemia / reperfusion disease (after arterial occlusion) there are strong, sometimes over-activations of the immune system.
  • exemplary, but not exclusive, disease states are surgery, polytrauma, soft tissue trauma, ischemia / reperfusion disease, infarct, ischemia, embolism, infection, sepsis, transplantation, intoxication, eclampsia, drug side effects or transfusions. These can cause temporary or permanent damage in organs, but can also lead to death.
  • the cellular component of this immune response is mediated by neutrophil granulocytes. To assess the consequences of activation, it is important to be up-to-date about the extent of the event.
  • the present invention provides an apparatus and method for detecting the NETs that are already released within minutes of activation of the granulocytes producing them. Proofing in patient samples can lead to timely responses from the attending physicians who can save lives.
  • More free DNA in the blood is released from dead cells. These cells may be dead by apoptotic or necrotic events.
  • some therapies for example of cancer with chemo- or Radiotherapy induces apoptosis of cells, including blood cells. The therapeutic success can thus be detected directly and finely graded with the present invention.
  • the presence and / or concentration of the component in the measuring range preferably depending on the detection reagent used, by means of luminescence, fluorescence, chemiluminescence, electrochemiluminescence, spectral absorption photometry, autofluorescence and / or bioluminescence determinable.
  • the filter is adapted to separate solid components of the fluid flowing through the filter, and in particular to separate the solid and liquid phases of the fluid from each other.
  • Some filter materials can be very brittle or fragile, so stabilization is necessary.
  • it may contain an element for stabilization.
  • Stabilizing elements are preferably stabilizing frames or frames or superimposed or integrated networks of a stable material, such as metal or plastic.
  • the fluid input region, which is preferably encompassed by the filter region, of the device is designed such that an above ambient pressure is exerted on the fluid.
  • the device is preferably designed such that such a pressure during the introduction of the fluid, preferably by a syringe or the like, is constructed.
  • the device is designed such that the fluid is introduced under pressure through the filter in the measuring range.
  • This pressure can preferably be exercised manually, for. B. by the piston of a syringe containing the unfiltered fluid to be measured.
  • the device is a pressure lying below the ambient pressure, preferably a vacuum. If the sample to be determined is brought into contact with the device, causes the low pressure or the vacuum that the sample is passed or sucked without externally applied force in the device and inside the device, the solid components are separated from the fluid.
  • the measuring range is preferably made of a preferably elastic material, which endeavors to assume a defined position or shape.
  • the device is made of elastic material that is deformed such that the inner volume of the measuring chamber is smaller than that of the defined position, so that it unfolds eg when introducing the sample or the sample is sucked in during deployment.
  • the measurement region is made of an inelastic material, wherein the region within the measurement region has a lower pressure than the ambient pressure before the sample enters the device.
  • the detection reagent is provided in the measuring area or in a cavity / lumen located just before the measuring area, which preferably extends between the filter and the measuring area.
  • the detection reagent is provided in the filter or in spatial proximity to the filter.
  • the detection reagent interacts directly or indirectly with the constituent to be determined. Direct interaction is preferably in the case of the determination of DNA with reagents that attach to the DNA. In this case, the attachment can be covalent or noncovalent. Certain substances integrate into double-stranded and single-stranded DNA without covalent binding with the DNA (intercalators). In part, the substances only gain the property of fluorescence. By accumulation in the DNA and irradiation with light of certain wavelengths, these substances emit light of different wavelengths, which is quantitatively measurable and correlated with the amount of DNA. Fluorescent dyes may also be other than intercalators and be contacted by chemical modification with the DNA to be measured. In a further preferred embodiment, the detection reagent is selected from the group comprising Pico-Green TM, Alexa or Sytox® dyes, ethidium bromide and SYBR® dyes.
  • a quantitative determination of a substance in the measuring range is carried out.
  • the detection reagent when interacting with the target molecule, it is advantageous for the detection reagent, when interacting with the target molecule, to change its properties such that it becomes detectable.
  • intercalators become detectable only upon incorporation into nucleic acids, whereas in the unbound state they do not exhibit this property.
  • the detection reagent used in the present invention may already be detectable prior to interaction with the target molecule, but preferably alters its pertinent properties upon interaction with the target molecule. This is preferably done by shifting the absorption maximum or the emission wavelength of a detection reagent.
  • the measurement of the non-cell-bound DNA preferably comprises the determination of the fluorescence emission after addition of a fluorescent dye to the plasma or serum.
  • fluorophores can be used within the scope of the invention.
  • suitable fluorophores 1.5 IAEDANS, 1,8-ANS, 4-methylumbelliferone, 4 ', 6-diamidino-2-phenylindole, 5- (and-6) -carboxy-2' , 7'-dichlorofluorescein pH 9.0, 5-carboxy-2,7-dichlorofluorescein, 5 carboxyfluorescein (5-FAM), 5-carboxynapthofluorescein (pH 10), 5-carboxytetramethylrhodamine (5-TAMRA), 5-FAM (5-carboxyfluorescein ), 5-FAM pH 9.0, 5-HAT (hydroxy tryptamine), 5-hydroxy tryptamine (HAT), 5-ROX (5-carboxy-X-rhodamine, triethylammonium salt), 5-ROX (carboxy-X-rhodamine) , 5-ROX pH 9.0, 5-HAT (hydroxy tryptamine),
  • Particularly preferred here are 4 ', 6-diamidino-2-phenylindole, 7-AAD (7-aminoActinomycin D), acridine orange, DNA & RNA, acridine red, Alexa Fluor 594 TM, Alexa Fluor 610 R-Phycoerythrin streptavidin pH 7.2, Alexa Fluor 647 R-Phycoerythrin Streptavidin pH 7.2, Alexa Fluor 633 TM, Alexa Fluor 647 TM, Alexa Fluor 660 TM, Alexa Fluor 680 TM, Alexa Fluor 700, Alexa Fluor 750, allophycocyanin (APC), BOBO-3 DNA, BOBO TM -3, Bodipy 650/665-X, Cy5.5 TM , Cy5 TM , DAPI, DDAO, Draq5, ethidium bromide , Ethidium monoazide, ethidium homodimer, ethidium homodimer-1 (Eth
  • Pico-Green TM and / or SYTOX Green are preferred.
  • the dose of Pico-Green TM is preferably about 0.01 to 5 ⁇ l of reagent, preferably 0.05 to 2 ⁇ l, more preferably 0.1 to 0.5 ⁇ l of reagent, most preferably 0.15 to 0.3 ⁇ l Reagent per measurement at approx. 40 ⁇ l sample volume.
  • the amount of reagent used is adjusted to the sample volume.
  • the amount of solid in its content of detection reagent corresponds to the content of dissolved solid in o.g. Volumes.
  • the opening of the device has a one-way valve.
  • the opening has a Luer lock.
  • the filter area is formed or delimited by a, preferably elastic, film.
  • the film is preferably made of an artificial or natural polymer or mixed polymer.
  • the device is a disposable device.
  • the filter is designed to separate serum and / or plasma from the blood. In this case, preferably no lysis of the blood cells takes place, which can influence the measurement result.
  • Such substances may be, for example, titanium dioxides or colestyramine.
  • the device in particular with respect to their dimensions, compatible with commercially available detection devices.
  • detection devices include, in particular, commercially available photometers, such as, for example, the Picofluor, TBS380 (Turner Biosystems, USA) or the qubit (Invitrogen, USA).
  • the device and / or at least portions of the device to the dimensions of a commercially available cuvette and preferably has a diameter of about 10mm and / or a length of about 50 mm +/- 15 mm or by means of an adapter to the size of a commercially available cuvette customized.
  • the device in particular for use with the qubit device, a cuvette in the form of a PCR tube (preferably with a use volume of 0.5 ml) on.
  • the cuvette may be miniaturized, z. B. from a clear tube made of plastic or glass, with a filling volume of about 20-100 ul, a length of about 5-25mm and an inner diameter of about 1-4 mm.
  • the device has at least one venting device.
  • the venting takes place preferably by means of a narrow groove, a channel or a gap, preferably of a few mm length, which (r) opens into the measuring chamber or from this and the other end via a membrane of the outside air or environment is disconnected.
  • This membrane is preferably a semi-permeable membrane which is permeable to air or gas but not aqueous fluid.
  • the semipermeable membrane is particularly preferably attached to the lower end of the tube, preferably as a closure of the tube.
  • the present apparatus provides an apparatus having an integrated automatic size measurement chamber.
  • the measuring range preferably connects in the filling direction or flow direction of the fluid behind the filter and fills due to the design, arrangement and vent preferably free of air bubbles with filtrate or filtered fluid. This is preferably done in a precisely determinable and correct amount, suitable or matched to the amount of Detektionsreagenz so that after filling to the semipermeable membrane no further flow can take place.
  • the volume is determined by the volumes of the fluid spaces in the cuvette part.
  • the present invention thus allows, in particular, an automatic quantity measurement or quantity predetermination with the advantage that in particular pipetting or other fluid handling is not necessary.
  • the measuring region can also already be partially prefilled, wherein this prefilling can have a dilution buffer with a detection reagent.
  • the remaining fillable volume of the measuring range can then be filled with a quantity of filtered fluid limited by the residual volume and thus defined and can be measured after a short incubation time in a fluorescence photometer. After balancing the measured value thus obtained with a standard taking into account one blank value (or blanks), the amount of a substance that is contained in the fluid can be determined.
  • the venting device is connected to the measuring chamber by a narrow groove or a gap, which is arranged opposite to the inlet opening of the measuring chamber.
  • the measuring range is in the form of a conventional (PCR) tube, more preferably with a ventilation device, before or is designed as such, on which the remaining device is attached.
  • PCR PCR
  • the device preferably has at least one second measuring range. This enables the simultaneous determination of several measured values or the simultaneous determination of one or more calibration values. Preferably, the device has at least one further measuring range for providing a blank or calibration value.
  • the component to be determined interacts with two detection reagents.
  • the detection or the concentration determination is carried out with two detection reagents in a two-step reaction.
  • the first binding detection reagent interacts specifically with the constituent to be determined.
  • This first reagent is preferably coupled to a detectable substance.
  • the detectable substance preferably corresponds to one of the above-mentioned fluorescent dyes.
  • the second detection reagent is immobilized to a certain area in the measurement area.
  • the first detection reagent is preferably located in the device in an area in front of the measuring area, for example in a fluid channel, filter area or in a mixing chamber leading thereto.
  • the blood or the separated plasma or serum should come into contact with the first detection reagent, so that the latter can bind to the substance to be determined.
  • the complex of the substance to be determined and the first detection reagent then passes with the plasma or serum into the measurement area, where it binds to a second detection reagent which is in a certain range of the measurement range is immobilized. By accumulating the complex at this point, the constituent to be determined becomes detectable. Excess first detection reagent remains evenly distributed in serum or plasma.
  • a control value can be determined which reflects the concentration of the first detection reagent distributed throughout the solution.
  • This control value can also be programmed as a threshold or limit value into a suitable measuring instrument via software.
  • both reagents added for the detection are regarded as detection reagents, whereby the first detection reagent does not have to change its property of detectability upon binding of the constituent to be determined, as described above. However, it is preferred that the first detection reagent has this property.
  • Both detection reagents bind directly to the component to be determined, so that the actual detection or determination of the component by detection of the first detection reagent, while the second detection reagent fixes the antigen at a position and this position after enrichment as a result of a finite flow with antigen-containing Liquid is supplied to a photo-optical measurement.
  • the detection reagents are preferably antibodies or antibody fragments.
  • the antibody is coupled to a substance to be detected.
  • a substance to be detected for example, R-phycoerythrin (PE), fluorescein isothiocyanate (FITC), PE-Cy5 allophycocyanin (APC), PE-Texas Red TM , Peridinin Chlorophyll Protein (PerCP), PerCP-Cy5.5, APC-Cy7, and / or Texas Red TM , etc.
  • Components to be determined in a two-step reaction are, for example, endogenous substances such as interleukin 6 (IL-6), hemoglobin, bilirubin, CRP, lactoferrin, procalcitonin, AT-III, protein C, p24 (HIV) or antibodies. Even foreign substances such as viruses, bacteria, drugs, toxins, drugs or fragments of the substances mentioned can thus be determined.
  • endogenous substances such as interleukin 6 (IL-6), hemoglobin, bilirubin, CRP, lactoferrin, procalcitonin, AT-III, protein C, p24 (HIV) or antibodies.
  • the device according to the invention thus enables the qualitative and / or quantitative determination of a blood component, in particular without further, manual or laboratory work steps.
  • the present invention also relates to a method for detecting, in particular, for determining the concentration of constituents in blood, preferably using a device of the present invention.
  • the method comprises the steps of (a) providing a device comprising a measurement region, a filter and a detection reagent, (b) introducing a fluid into the device, and (c) detecting the concentration of the component using the device.
  • the step of detecting the concentration of the component is preferably carried out using a conventional measuring device, preferably a fluorescence photometer.
  • the present invention also relates to the use of a device or method of the present invention for determining constituents in blood, such as, bilirubin, free hemoglobin, IL-6 or p24 (HIV protein), CRP. Further preferred is the use for the determination of cell-free DNA. Hemoglobin or bilirubin is preferably measured by measuring the photoabsorption using appropriate wavelengths or by measuring the intrinsic characteristic fluorescence of these substances.
  • the present invention further relates to a kit comprising at least one device according to the present invention, and a (fluorescence) standard of e.g. B. may contain DNA.
  • the kit preferably further comprises a syringe, preferably with accessories for taking blood from a patient, and / or a measuring device.
  • the kit preferably comprises a manual with interpretation aids.
  • the measuring device may further comprise a device, which is particularly suitable for measuring the samples which were produced with the device. This may include software that allows storage and management of the data. This may include an adapter cable. It may further include a battery pack that allows off-grid measurements.
  • the inventive device such as in FIG. 1 and 8th is used to detect and preferably determine the concentration of constituents in fluids.
  • the fluid is blood and the component to be determined is DNA.
  • the device after Fig. 1-7 comprises a measuring region 3 and a filter region 5 in fluid communication with the latter.
  • the filter region 5 and the measuring region 3 are preferably connected to one another via a first fluid channel 7.
  • the device 1 preferably further comprises an opening 9, which is preferably designed as a Luer-lock and further preferably with a one-way valve.
  • the opening 9 is preferably located directly at the fluid inlet region of the filter region 5 or is connected thereto via a tube 11, preferably comprising a polymer, preferably of polyvinyl chloride (PVC) or polyethylene (PE).
  • PVC polyvinyl chloride
  • PE polyethylene
  • the filter region 5 is preferably elastic and bag-like and further or additionally preferably made of soft PVC, PE, a mixed or composite polymer.
  • the opening 9 is preferably formed, for example by training as Luer-Lock, that a commercial syringe (not shown) can be connected to it.
  • a such syringe filled fluid, in particular blood introduced via the opening 9 and optionally the tube 11 in the filter area 5.
  • the filter region 5 is preferably designed such that it experiences a predetermined expansion when introducing a certain amount or a certain volume of fluid, which in turn causes a certain pressure on the interior of the filter region 5. Materials to be introduced or required volume and the like are preferably coordinated accordingly.
  • the formation of the opening 9 with a one-way valve prevents the escape of the pressurized, in the fluid input area of the or filter area (s) 5 existing fluid.
  • the fluid contained in it is forced through a filter, preferably a special membrane, which is furthermore preferably welded into the filter region 5.
  • the filter area 5 preferably has an outlet which opens into the fluid channel 7, which in turn leads to the measuring area 3.
  • the filter is preferably arranged in such a way that the pressurized fluid present in the filter region 5 is transported through the filter (not shown) into the fluid channel 7 and thus into the measuring region 3.
  • the fluid thus filtered preferably the blood plasma, and in particular preferably a predetermined volume of blood plasma, is thus provided in the measuring chamber 3.
  • the apparatus further comprises a detection reagent, preferably Pico-Green TM , which is provided in the measuring chamber 3 and / or in the fluid channel 7 in such a way that it collects with the blood plasma or serum flowing through the fluid channel and / or with that collected in the measuring chamber 3 Blood plasma or serum comes into contact and in particular interacts, preferably such that a detection, in particular a determination of the concentration of constituents in the fluid or blood plasma, is made possible.
  • a detection reagent preferably Pico-Green TM
  • the device and in particular the volumes of measuring area 3, filter area 5 and fluid channel 7 (respectively part 17) and the properties of the filter area 5 with respect to elasticity and pressure build-up and the filter with respect to the filter and passage properties are coordinated such that in the measuring chamber. 3 or in the fluid channel 7 (or part 17) a predetermined amount of blood plasma is present, which interacts with a predetermined amount of detection reagent.
  • the measuring chamber 3 and / or the fluid channel 7 (or part 17) is preferably coated on its interior area communicating with the blood plasma, at least partially with a detection reagent, which preferably contains or consists of Pico-Green TM or SytoxGreen. Furthermore, a rapidly dissolvable pellet which has a detection reagent can also be positioned in the region of the measuring chamber 3 or the fluid channel 7 (or part 17).
  • a channel descends from the measuring area 3.
  • a channel preferably opens into a vent opening or vent recess or recess 15, which is preferably arranged in the outer region of the device and is sealed with a semi-permeable membrane (not shown) from the environment.
  • a semi-permeable membrane (not shown) from the environment.
  • a membrane preferably has the property that, seen from the inside of the device, it is permeable to air or gaseous media, but not to liquid media or blood plasma.
  • the channel and the venting area 15 are designed to discharge excess air present outwardly into the environment when filling the filter area 5 or the fluid channel 7 and the measuring area 3 in the device 1, in other words to vent the device 1. This advantageously allows, in particular, the introduction of a defined volume of liquid into the measuring area.
  • the device 1 thus allows automatic filling of the measuring region 3 with a defined amount of blood plasma and mixing with a detection reagent.
  • the device and the fluid present in the measuring range preferably blood plasma, are accessible in particular to a photo-optical detection.
  • a photo-optical detection As described above, for example, for the purpose of detecting free DNA by means of an intercalating fluorescent dye such as Pico-Green TM .
  • the detection reagent is preferably applied to the inside of the measuring chamber 5 or the measuring channel, preferably via ink jet, and dried. Alternatively or additionally, the detection reagent is present as dust or pellet present in the measuring chamber or, for example, within the inflow channel as easily soluble material.
  • the device preferably has a diameter of about 10 mm and a length or height of about 50 mm +/- 15 mm.
  • the measuring area is preferably at least partially transparent or translucent, in particular in order to ensure an optical detection of the component to be detected or determined, preferably by means of a fluorescence measurement.
  • FIGS. 2 to 6 or 7
  • FIGS. 2 to 4 Devices that are basically related to the design and operation of FIG. 1
  • these devices have a plurality of measuring regions 3, and preferably 2 or 3 measuring regions, wherein these measuring regions can be arranged differently.
  • the general structure and the operation is on the above description of FIG. 1 directed.
  • Ventilation channels 13 and vent areas 15 are adapted to perform several parallel measurements, or evidence or determinations, each of the measuring ranges 3 and / or fluid channels 7 may have the same or different detection reagents.
  • At least one of the measuring ranges is provided for determining a blank value.
  • a blank or zero value is a value used to compare the sample to be measured.
  • blood plasma filtered as a blank can be measured without reagent in the blank measurement range, which then indicates approximately autofluorescence.
  • a calibration value can be formed, preferably with the measurement of a fluid of the same type, which is mixed with standardized amounts of the substance to be measured. More preferably, a calibration value can be formed by measuring a cuvette, which is filled, for example, with a fluid that is optically similar to the blood plasma or else a plastic and has a stable, defined fluorescence. Based on these values, the corresponding measured value of the sample (s) is evaluated. So you can z. B. make a standard daily measurement and make each of the patient a blank and a reading of the analyte of interest.
  • the corresponding preferred embodiments thus allow the simultaneous performance of parallel, identical measurements or parallel different measurements.
  • the preferred embodiments also have the same design as in FIGS. 2 to 6 (or 7), the volumes of measuring range 3, filter area 5 and fluid channels 7 and the properties of the Filter range 5 in terms of elasticity and pressure build-up and the filter with respect to the filter and passage properties matched to one another such that in the measuring chambers 3 and in the fluid channels 7, a predetermined amount of blood plasma is present, which interacts with a predetermined amount of Detektionsreagenz (ien).
  • FIG. 5 again shows a preferred embodiment according to the invention of a device having a measuring chamber, wherein only a modified, flow-optimized measuring region 3 (see FIG FIG. 5a, FIG. 5 ) is shown.
  • a modified, flow-optimized measuring region 3 see FIG FIG. 5a, FIG. 5 .
  • FIG. 6 shows a further preferred embodiment of a device according to the invention according to a mixing chamber 25, in which there is preferably a reagent which binds to the / to be measured component (s), a further chamber 20 is arranged downstream.
  • a detection reagent for example an antibody, is firmly bound to a substrate which preferably at least partially contains silicon dioxide (eg glass) or polystyrene or polyurethane.
  • a component to be measured for example an antigen
  • a component to be measured then combines in the filter region 5, mixing chamber 25 and / or the channel 7 with a first detection reagent, for example a fluorescence-labeled antibody, and on further flow in the chamber 20 by another to the substrate bound antibody to the substrate and thus determines the presence of the antigen and / or its concentration by fluorescence photometric measurement of the chamber 20.
  • a first detection reagent for example a fluorescence-labeled antibody
  • Both detection reagents can bind to different regions of the component to be determined, in the case of antibodies to different epitopes of the antigen.
  • FIG. 7 shows a schematic view of a preferred device according to the invention with a disc-shaped filter 16.
  • Fig. 7a shows a schematic plan view of the device and
  • Fig. 7b a schematic View of the device according to Fig. 7a from above from above Fig. 7a , The remaining arrangement shown corresponds to those already described.
  • FIG. 8 shows a schematic plan view of a preferred embodiment of a device according to the invention with a tube-like cuvette 17, which has a z. B. may contain pelleted, readily soluble reagent 23.
  • This device according to the invention also allows automatic filling of the measuring range with a defined amount of blood plasma and mixing with a detection reagent.
  • the part 17 is preferably provided with a semi-permeable membrane 15 as a closure.
  • the device and the fluid present in the measuring range, preferably blood plasma, are accessible in particular to a photo-optical detection.
  • the tube-like, translucent measuring cuvette has a length of about 20 mm, an inner diameter of about 1-4 mm and an outer diameter of about 2-6 mm;
  • FIG. 9 shows a schematic plan view of a preferred embodiment according to the invention of a device in a variant with two tube-like cuvettes 17, in which one can be provided with detection reagent while the other can be measured without reagent, a blank or blank,
  • FIG. 10 shows a schematic plan view of a preferred embodiment according to the invention of a device in a variant with a mixing chamber 20 which may contain a reagent, wherein the reagent in the chamber 20 particularly advantageously mixes with the filtrate.
  • FIG. 11 shows a schematic plan view of a preferred embodiment according to the invention of a device in a variant which allows the automatic filling of the measuring range with a defined amount of previously prepared by conventional methods blood plasma.
  • the tube or tube-like The cuvette has a length of approximately 20 mm and an outer diameter of approximately 2-6 mm and may contain a reagent in the region 19.
  • the present invention thus provides an advantageous apparatus, methods and kit that overcomes the disadvantages of the prior art.
  • the present invention allows separation of plasma or serum from whole blood and analysis of serum or plasma without the need for centrifugation or similar laboratory processing steps of the recovered serum or plasma.
  • the present invention provides a device, a method and a kit that are easy to handle, safe and reliable, and are particularly suitable for use by laymen or non-medically trained personnel as well as simple and inexpensive to manufacture to perform and / or store.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
EP07021342A 2007-10-31 2007-10-31 Vorrichtung zum Nachweis von Bestandteilen in einem Fluid Withdrawn EP2055384A1 (de)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP07021342A EP2055384A1 (de) 2007-10-31 2007-10-31 Vorrichtung zum Nachweis von Bestandteilen in einem Fluid
US12/740,817 US20100261223A1 (en) 2007-10-31 2008-10-31 Device for detecting components in a fluid
PCT/EP2008/009219 WO2009056340A2 (de) 2007-10-31 2008-10-31 Vorrichtung zum nachweis von bestandteilen in einem fluid
JP2010531462A JP2011501201A (ja) 2007-10-31 2008-10-31 液体中の成分を検出するための装置
EP08845028A EP2205355A2 (de) 2007-10-31 2008-10-31 Vorrichtung zum nachweis von bestandteilen in einem fluid
CN2008801144648A CN101883634A (zh) 2007-10-31 2008-10-31 用于检测流体中组分的装置

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EP07021342A EP2055384A1 (de) 2007-10-31 2007-10-31 Vorrichtung zum Nachweis von Bestandteilen in einem Fluid

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EP08845028A Withdrawn EP2205355A2 (de) 2007-10-31 2008-10-31 Vorrichtung zum nachweis von bestandteilen in einem fluid

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CN104880442A (zh) * 2015-05-21 2015-09-02 桂林理工大学 一种测定盐酸多巴胺的方法

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RU2645091C2 (ru) * 2012-08-08 2018-02-15 Конинклейке Филипс Н.В. Способ и устройство для отделения плазмы от крови для оценки содержания билирубина
AT513559B1 (de) * 2012-11-06 2016-02-15 Gerhard Bonecker Photometrische Messeinrichtung und photometrisches Messverfahren für eine Probenflüssigkeit
US9386948B2 (en) 2012-12-05 2016-07-12 Theranos, Inc. Systems, devices, and methods for bodily fluid sample transport
US10248765B1 (en) 2012-12-05 2019-04-02 Theranos Ip Company, Llc Systems, devices, and methods for bodily fluid sample collection, transport, and handling
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CN103323590B (zh) * 2013-06-08 2015-05-06 上海云泽生物科技有限公司 一种基于纤维膜捕集分离的定量检测装置及其检测方法
JP6566319B2 (ja) * 2013-12-03 2019-08-28 国立大学法人 東京大学 分離ユニット、分離方法、流体デバイス、複合型流体デバイス及びキット
CN105772117A (zh) * 2014-12-22 2016-07-20 卡梅德生物科技（天津）有限公司 一种用于生物实验室检测化学成份的实验芯片
US10371606B2 (en) 2015-07-21 2019-08-06 Theraos IP Company, LLC Bodily fluid sample collection and transport
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JP6874432B2 (ja) * 2017-03-10 2021-05-19 東洋紡株式会社 イムノクロマト試験片
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WO2009056340A3 (de) 2009-11-05
CN101883634A (zh) 2010-11-10
JP2011501201A (ja) 2011-01-06
WO2009056340A2 (de) 2009-05-07
EP2205355A2 (de) 2010-07-14

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