EP3856139A1 - Couches faites sur mesure à partir de dispersions de cellulose pour la détection d'analytes - Google Patents

Couches faites sur mesure à partir de dispersions de cellulose pour la détection d'analytes

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Publication number
EP3856139A1
EP3856139A1 EP19779792.1A EP19779792A EP3856139A1 EP 3856139 A1 EP3856139 A1 EP 3856139A1 EP 19779792 A EP19779792 A EP 19779792A EP 3856139 A1 EP3856139 A1 EP 3856139A1
Authority
EP
European Patent Office
Prior art keywords
cellulose
cellulose layer
ligand
layer
analyte
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.)
Pending
Application number
EP19779792.1A
Other languages
German (de)
English (en)
Inventor
Eva Ehrentreich-Foerster
Cornelia HETTRICH
Kay Hettrich
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.)
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
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 Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Forderung der Angewandten Forschung eV
Publication of EP3856139A1 publication Critical patent/EP3856139A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/02—Cellulose; Modified cellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/10—Esters of organic acids, i.e. acylates
    • C08L1/12—Cellulose acetate
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D101/00—Coating compositions based on cellulose, modified cellulose, or cellulose derivatives
    • C09D101/02—Cellulose; Modified cellulose
    • 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
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • G01N33/548—Carbohydrates, e.g. dextran
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
    • C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
    • 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
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/12—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar
    • G01N2400/24—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar beta-D-Glucans, i.e. having beta 1,n (n=3,4,6) linkages between saccharide units, e.g. xanthan
    • G01N2400/26—Cellulose

Definitions

  • the present invention relates to a method for producing a cellulose layer for the detection of at least one analyte, comprising (i) producing a cellulose layer by applying a stable dispersion of cellulose and / or a cellulose derivative to a suitable support, and (ii) immobilizing at least of a ligand on the cellulose layer, and on a cellulose layer produced by this method.
  • the present invention additionally relates to associated detection methods, devices, kits and uses.
  • Nanocellulose is an economically important natural material and is u. a. used as building material, for paper manufacture, for clothing, and in the energy industry. In recent times, modifications of cellulose have been developed that enable new applications. For example, cellulose materials with dimensions in the nanometer range have been developed, which are generally referred to as nanocelluloses. Nanocelluloses can be produced with different processes and from different starting materials. A general distinction is made between the types shown in Table 1.
  • Microfibrillated cellulose nano fibrillated cellulose diameter 5 -60 nm
  • nanocellulose and e.g. acrylic polymers have also been proposed (Grüneberger et al. (2014), J Mater Sei 49: 6437). Because of your cheap biological, chemical and physical properties, nanocellulose materials have also been proposed for use in biomedicine, for example as scaffolding material or as a carrier for medicinal products.
  • test strips are made up of a carrier (plastic, paper, glass), an indicator (organic dye) and one or more polymer layers for lixising the indicator.
  • signals can be generated in different ways: Spectroscopic (e.g. lluorescence, luminescence, IR, UV); electrochemical (e.g .: amperometry, potentiometry, conductivity, coulometry); or label-free optical surface analysis (e.g. ellipsometry, reflectometric interference spectroscopy, surface plasmon resonance).
  • Spectroscopic e.g. lluorescence, luminescence, IR, UV
  • electrochemical e.g .: amperometry, potentiometry, conductivity, coulometry
  • label-free optical surface analysis e.g. ellipsometry, reflectometric interference spectroscopy, surface plasmon resonance.
  • the multi-parameter analysis enables the simultaneous determination of several analytes in one measurement run and thus more complex analytical statements after only one laboratory examination.
  • Biochips increasingly dominate such detection techniques due to their ability to carry out a highly parallel measurement of many analytes with limited sample volumes.
  • biomolecules such as DNA, peptides or proteins.
  • these are immobilized on a carrier (chip) in a fixed grid.
  • the biomolecules are dissolved in aqueous liquids which are placed on the solid substrate in the smallest drops in Lorm.
  • a surface with optimal chemical punctures is a basic requirement for the production of biochips for multi-parameter analysis.
  • Corresponding surface properties enable the specific immobilization of different biomolecules and the generation of selective properties hydrophilic or hydrophobic surfaces.
  • Another problem with the previous market-relevant solutions is that only one special biochip can be used for each analytical task.
  • the present invention relates to a method for producing a cellulose layer for the detection of at least one analyte, comprising (i) producing a cellulose layer by applying a stable dispersion of cellulose and / or a cellulose derivative to a suitable support, and (ii) immobilizing at least one ligand on the cellulose layer.
  • the terms “have”, “contain”, or “comprise” and any grammatical variation thereof are preferably used in non-exclusive meaning. These terms can therefore relate both to a situation in which, in addition to the features introduced by the terms, there are no further features in the object described, and to a situation in which one or more further features are present.
  • the phrases “A includes B”, “A contains B” and “A has B” refer to a situation in which there is no element other than B in A, ie a situation in which A only consists of B, but also to a situation in which, in addition to B, one or more further elements are present in A, for example element C, elements C and D, or even further elements.
  • the terms “preferred”, “more preferred”, “most preferred”, “in particular”, “specific” or similar formulations are preferably used in the following in connection with optional features, without restricting further possibilities. Features that are introduced by these formulations are therefore preferably optional features and limit the one claimed in the claims Subject not a. As those skilled in the art will understand, the invention can be practiced with alternative features. The same applies to the wording “in one embodiment” or similar formulations, which also refer to optional features without restriction with respect to further embodiments, without restriction of the subject matter of the invention and without restriction of the possibility of the features thus introduced with other optional or non-optional features to combine.
  • standard conditions refers to the IUPAC standard ambient temperature and pressure conditions (SATP), that is to say preferably a temperature of 25 ° C. and an absolute pressure of 100 kilo-Pascals; Standard conditions preferably also refer to a pH of 7.
  • SATP standard ambient temperature and pressure conditions
  • Standard conditions preferably also refer to a pH of 7.
  • approximately relates to the value indicated with the generally accepted technical precision in the relevant field of work and preferably to the value indicated ⁇ 20%, preferably ⁇ 10 %, more preferably ⁇ 5%.
  • the term “essentially” preferably refers to the fact that there are no possible deviations which have an influence on the stated result or the use, i.e.
  • Consisting essentially of thus preferably means the presence of the specified ingredients to the exclusion of other components with the exception of impurities, components that are inevitable as a result of the manufacturing process and / or components that have been added for a purpose that is not related to the technical effect of the present invention relates.
  • a composition which is defined by the formulation "consisting essentially of” can therefore contain additives, auxiliaries, solvents, diluents, carriers and the like.
  • a composition which is to consist essentially of the specified components preferably contains at most a mass fraction of 5%, preferably at most 2%, more preferably at most 1%, of components not specified.
  • the method according to the invention can additionally contain further steps; Such further steps can relate, for example, to the production of a stable dispersion before the application or to further steps following the application, such as drying the cellulose layer. Individual or all steps can be repeated; for example, several ligands can be applied in different application processes.
  • the cellulose layer according to the invention can remain on the support or, for example as a film or Strips, can be removed from it after a drying process.
  • aqueous dispersions of differently modified celluloses are preferably produced.
  • two or more stable cellulose dispersions with the desired concentration ratios are preferably first mixed intensively with one another. This mixture is then preferably applied as a layer to a desired carrier. In this way, layers can be produced from different dispersions.
  • carrier is used in the context of the present description in the meaning familiar to the person skilled in the art; the carrier is preferably an object or a device which is preferably rigid or flexible and which in principle can consist of any material.
  • the carrier preferably has a planar, cylindrical or elypsoid shape, more preferably the carrier is a solid in the form of a plate, film, tube, membrane or one or more beads.
  • the stable dispersion can also be applied to e.g. applied to a roll and dried there.
  • the carrier can likewise preferably be a packaging material, a laboratory material and / or a disposable article.
  • Preferred packaging materials are films, for example made of polyethylene, polypropylene, polyvinyl chloride, or similar plastics.
  • Preferred laboratory materials are supports for a biochip, for example slides or similar materials, multi-well plates, such as e.g. Microtiter plates, semiconductor plates or similar items.
  • Preferred disposable articles are, for example, urine cups, syringes, cannulas, tubes, tissue articles, swabs, breathing masks or parts thereof, or air filters.
  • the carrier preferably contains glass, paper, plastic, ceramic and / or metal, more preferably the carrier consists of glass, paper, plastic, ceramic and / or metal.
  • the carrier is transparent.
  • the cellulose layer is transparent.
  • the carrier and cellulose layer are transparent.
  • transparent is used in the context of the present description in the meaning familiar to the person skilled in the art; preferably the term transparent refers to the property of a material essentially not absorbing radiation, preferably visible light. Preferably, wavelengths in a range between 300 nm and 700 nm are essentially not absorbed, more preferably in a range between 350 nm and 650 nm.
  • the absorption coefficient of a transparent material is preferably at most 10 cm 1 , more preferably at most 2 cm 1 , even more preferably at most 1 cm 1 .
  • cellulose is known to the person skilled in the art and relates to an organic polymer composed of beta-1,4-glycosidically linked glucose units.
  • the production of cellulose is also known to the person skilled in the art.
  • Cellulose is preferably obtained from wood, annual plants, cotton and / or waste paper.
  • a derivative of cellulose can preferably also be used; ester and / or ether groups are preferably introduced as derivatization, in particular one or more functional group (s) selected from carboxyl, carbonyl, sulfate, carboxymethyl, methyl, ethyl, silyl, acetyl, carbamate, and amino.
  • the degree of substitution (DS), i.e. the average number of substituted hydroxy groups per glucose unit is preferably at most 1, more preferably at most 0.5.
  • the cellulose is preferably a nanocellulose or a derivative thereof.
  • analyte is used in the context of the present description in the meaning familiar to the person skilled in the art; the analyte is preferably a chemical substance, preferably a substance soluble in a solvent, preferably water.
  • the analyte is preferably a low or high molecular weight metabolite of a cell, a tissue, an organ or a body or a substance which is used to change the chemical composition of a cell, a tissue, an organ or a body.
  • Preferred low molecular weight analytes are those which are used in medical diagnostics, that is to say in particular analytes in which a changed concentration in a body tissue or in a body fluid indicates a disease.
  • Preferred low molecular weight analytes are therefore glucose, hormones, especially estrogens, lipids, especially cholesterol, uric acid, ammonia and the like.
  • Preferred macromolecular analytes are in particular polypeptides and polynucleotides.
  • Antibodies, glycoproteins and phosphoproteins are particularly preferred among the polypeptides.
  • autoantigens, allergens, and cells or components thereof for example of bacterial cell envelopes or of viral particles.
  • Analytes are particularly preferred antibodies or antigens, preferably antigens that bind to antibodies.
  • the term “ligand” is used in the context of the present description in the meaning familiar to the person skilled in the art; the ligand is preferably a chemical substance which, preferably specifically, binds to an analyte.
  • a specific binding is preferably present when the binding of the ligand to the analyte is at least 5 times, preferably at least 100 times, even more preferably at least 100 times, most preferably at least 100 times as strong as to a substance that is not the analyte; the affinity is preferably given as the dissociation constant of the corresponding complexes.
  • specificity can also be determined by determining the signal / background ratio, the signal / background ratio for specific binding preferably being at least 3, more preferably at least 10, even more preferably at least 100, most preferably at least 1000.
  • Appropriate methods are known to the person skilled in the art.
  • the specificity is preferably a group specificity, that is, a specificity for a group of non-identical molecules with at least one common structural feature; a corresponding group is, for example, that of the IgG molecules.
  • the specificity is more preferably a specificity for a specific chemical substance, for example for a polypeptide.
  • the affinity of the ligand for the analyte is preferably high enough to enable detection of the analyte in the planned detection procedure.
  • the dissociation constant K d of the ligand / analyte complex is preferably at most 10 3 M, more preferably at most 10 4 M, even more preferably at most 10 6 M, most preferably at most 10 8 M.
  • the ligand is preferably a polypeptide, a polynucleotide, a carbohydrate, or a fat. Even more preferably, the ligand is an antibody, a hormone, a glycolipid, a phospholipid, a gly coprotein or a phosphoprotein.
  • the ligand is also preferably a recombinant protein, a native protein, an autoantigen, an allergen and / or a cell or a component thereof, for example of bacterial cell envelopes or of viral particles.
  • the term "immobilize” is used in the context of the present description in the meaning familiar to the person skilled in the art;
  • the immobilization preferably leads to the ligand remaining essentially bound to the cellulose layer during use.
  • a maximum of 10%, preferably a maximum of 2%, even more preferably a maximum of 1% of an immobilized ligand is washed out into a surrounding solution under standard conditions over a period of one hour.
  • the ligand can preferably at least partially penetrate into the cellulose layer during the immobilization process; the term “immobilization on” a cellulose layer therefore preferably includes at least partial immobilization in the cellulose layer.
  • the ligand is preferably not covalently immobilized on or in the cellulose layer; the binding of the ligand to the cellulose layer is therefore preferably based on hydrogen bonds, van der Waals forces and / or ionic interactions.
  • the strength of the immobilization can be controlled in particular by using suitable cellulose derivatives; the person skilled in the art may prefer cationic cellulose derivatives for the immobilization of anionic ligands, but more hydrophobic cellulose derivatives for binding hydrophobic ligands.
  • the binding of the ligand to the cellulose layer is covalent; suitable reagents and side groups are known to the person skilled in the art.
  • a large number of non-identical ligands are preferably immobilized on the cellulose layer, the term large number preferably referring to a number of at least two, more preferably at least five, more preferably at least ten, most preferably at least 20 non-identical ligands.
  • the term multitude likewise preferably refers to a number from 2 to 15, preferably 2 to 10, particularly preferably 1 to 6, non-identical ligands.
  • the non-identical ligands can in principle be immobilized as a mixture; they are preferably separated, more preferably applied and immobilized in a spatially structured arrangement on or in the cellulose layer.
  • the cellulose layer for the detection of at least one analyte thus preferably comprises a spatially structured arrangement ("array") of ligands, which preferably allows the location of the application of the individual ligands to be identified.
  • the term “dispersion” is known to the person skilled in the art as a term for a heterogeneous mixture of at least two substances.
  • the dispersion is preferably a liquid / solid dispersion, that is to say a suspension.
  • the mass fraction in the dispersion is preferably in a range between 0.01% and 10%, more preferably between 0.05% and 5%.
  • the mass fraction of cellulose and / or cellulose derivative in the dispersion is more preferably between 0.01% and 10%, even more preferably between 0.05% and 5%.
  • the dispersion medium is preferably an aqueous solution, more preferably water.
  • stable dispersion is used in the context of the present description in the meaning known to the person skilled in the art and preferably relates to a dispersion in which the degree of dispersion over a period of at least one month, preferably at least one year, even more preferably at least three years remains essentially unchanged.
  • the stable dispersion preferably only comes in during the aforementioned period negligible scope for flocculation, aggregation or sedimentation.
  • the cellulose and / or the cellulose derivative in the stable dispersion preferably has a particle size of at most 1000 nm, more preferably 750 nm, most preferably 600 nm, even more preferably all ingredients of the stable dispersion have a particle size of at most 1000 nm, more preferably
  • the person skilled in the art is familiar with 750 nm, most preferably from at most 600 nm, using methods for determining particle sizes; the particle size is preferably determined as described in the present description in the examples.
  • the stable dispersion is preferably a dispersion of nanocellulose.
  • the expression "applications of a stable dispersion of cellulose and / or a cellulose derivative” is therefore preferably equivalent to the expression "applications of a stable dispersion of nanocellulose and / or a nanocellulose derivative”.
  • Methods for producing stable cellulose dispersions are known to the person skilled in the art.
  • the stable cellulose dispersion is preferably produced by means of high-pressure homogenization, as specified, for example, in DE 2009021688 or WO 2009/021687.
  • Stable cellulose dispersions are also preferably obtained by treatment in an Ultra-Turrax at approx. 20,000 revolutions / min for 15 minutes and preferably subsequent two-stage treatment in a high-pressure homogenizer.
  • the treatment in the high-pressure homogenizer preferably comprises six cycles in a 200 pm cell at 500 bar and preferably comprises twelve cycles in a 50 pm cell at 1000 bar.
  • the application of the cellulose layer can be carried out by all methods that appear appropriate to the person skilled in the art; the application is preferably carried out by knife coating, spraying, spin coating, spray drying and / or dipping.
  • the cellulose dispersion is preferably applied homogeneously.
  • the layer thickness of the cellulose layer after drying is preferably from 0.01 pm to 10 pm, more preferably from 0.02 pm to 5 pm, even more preferably at most 2.5 pm. It is known to the person skilled in the art that the layer thickness can be controlled in addition to the choice of the application method, in particular by selecting the application volume and the cellulose content of the dispersion. Examples of the implementation of exemplary layer thicknesses are shown in particular in the examples.
  • the cellulose layer is preferably dried after the application.
  • the drying is preferably carried out at a temperature between 15 ° of 100 °, more preferably between 30 ° and 80 °, even more preferably between 35 ° and 65 °. Drying is preferably carried out to constant layer thickness and / or constant weight. Those skilled in the art are suitable Drying process known. Preferred drying times are essentially determined by the application volume and the drying temperature.
  • the ligand can preferably be immobilized while the cellulose layer is drying, for example by admixing the ligand with the stable dispersion.
  • the ligand is more preferably immobilized on the dried or pre-dried cellulose layer, for example by locally limited application of small volumes of one or more ligand solution (s) ("spotting").
  • the cellulose layer is preferably dried again after immobilization or used directly.
  • the cellulose layer according to the invention is preferably not activated before further use.
  • the cellulose layer according to the invention is therefore preferably not modified with chemical side chains which form covalent bonds to form ligands, preferably the ligands described herein.
  • the surfaces can be functionalized with biomolecular probes or receptors.
  • biomolecular probes or receptors Depending on the type of this functionalization, the multifunctional layers developed can be used in a wide variety of applications. Possible probe molecules are DNA for the investigation of diseases or for determining the identity of sample material, antibodies for the detection of antigens, and antigens or fragments of antigens for the serological detection of antibodies in biological samples.
  • the substances to be applied can be selectively and covalently immobilized on the multifunctional layers.
  • -thin stable layers can be represented with different methods
  • the present invention also relates to a cellulose layer with an immobilized ligand, produced or producible by the method for producing a cellulose layer of the present invention.
  • the present invention also relates to a method for detecting an analyte in a sample, comprising contacting the sample with a cellulose layer and / or a cellulose layer of the present invention produced by the method for producing a cellulose layer of the present invention, and detecting the in of the cellulose layer containing ligand interacting analyte.
  • the method for the detection of an analyte is preferably an in vitro method and can additionally contain further steps. Further steps can relate, for example, to obtaining a sample and / or adding (further) reactants to a detection reaction. One or more steps of the method can also be carried out automatically.
  • contacting is used in the context of the present description in the meaning known to the person skilled in the art; contacting preferably comprises the application of a liquid sample to the cellulose layer according to the invention and the enabling of an interaction between the ligand and any analyte present in the sample.
  • a liquid sample to the cellulose layer according to the invention
  • the cellulose layer is preferably moistened or pre-swollen.
  • contacting e.g. by bringing the surface of the sample into contact with the cellulose layer, e.g. by hanging up.
  • sample is familiar to the person skilled in the art and includes all sample materials which can potentially contain an analyte.
  • the sample can be the complete object to be examined, for example when examining food.
  • the sample is preferably part of the object to be examined.
  • Preferred sample materials are liquid or gaseous samples; solid samples are preferably extracted with a suitable extraction liquid and then used like liquid samples.
  • the samples are preferably pretreated, for example in order to detach the analyte from bonds or complexes or to remove potentially disruptive sample components, even more preferably the sample is not pretreated before it is brought into contact with the cellulose layer.
  • the sample is preferably a biological sample, in particular a food or a sample taken for diagnostic purposes.
  • the sample is preferably a tissue sample of a living organism, preferably a mammal, more preferably a human.
  • Solid samples are preferably tissue samples or stool.
  • the sample is more preferably a gaseous sample, for example a breath air sample, in particular an exhaled air sample.
  • the sample is a sample of a body fluid, preferably blood, plasma, serum, saliva, urine, liquor, pleural fluid, ascitic fluid, bile, sweat, breast milk, menstrual fluid, ejaculate, swab material, in particular from the nose, mouth, or others Mucous membranes, or irrigation fluid of a body opening (lavage); samples of blood, serum, plasma or urine are most preferred.
  • the sample is also preferred a sample matrix from the environmental or life sciences, especially fresh and drinking water, process and waste water, soil, air or exhaust air.
  • the interaction of the ligand with the analyte is preferably detected by methods known to the person skilled in the art, which are selected by the person skilled in the art depending on the requirements which result in particular from sample material, identity of the analyte and identity of the ligand.
  • the detection can e.g. via a secondary antibody that is linked to a detectable chemical grouping, e.g. a dye or an enzyme is coupled.
  • the ligand can e.g. be an enzyme that uses the analyte as a substrate.
  • the addition of further reactants, buffers, ions and the like may be necessary for the detection in order to obtain a detectable reaction.
  • Appropriate methods are known to the person skilled in the art.
  • the detection is preferably carried out visually or by means of fluorescence, luminescence or absorption optics, by scanning densitometry or electrochemically.
  • the detection is more preferably carried out by imaging fluorescence, luminescence, or absorption optics or by scanning densitometry.
  • the present invention also relates to a device comprising a cellulose layer according to the invention.
  • the term “device” is used in the context of the present description in the meaning known to the person skilled in the art; preferably the device is a device for determining an analyte in a sample or a part thereof, e.g. a probe or test strip.
  • the device preferably comprises the cellulose layer according to the invention as a membrane, film or in another suitable form.
  • the device more preferably comprises the cellulose layer according to the invention on a carrier.
  • the device is therefore preferably a packaging material, a laboratory material, preferably a biochip or a multi-well plate, or a disposable article, preferably a urine cup, a syringe, a cannula, a tube, a tissue article, a swab, a breathing mask or a part thereof, or a Air filter.
  • the present invention also relates to a kit for the detection of at least one analyte, comprising at least one cellulose layer with at least one immobilized ligand and a device for sampling, the cellulose layer preferably being present on a support.
  • kit is used in the context of the present description in the meaning known to the person skilled in the art; the term preferably refers to a combination of the specified components, which is preferably adapted to enable the detection of at least one analyte in a sample.
  • the components can be packed together or individually.
  • the kit is preferably set up to carry out the method for detecting an analyte in a sample according to the present invention.
  • the components are preferably made available ready for use.
  • the kit preferably contains further components, for example buffers, washing solutions, one or more detection reagents, and / or optionally an instruction manual.
  • the cellulose layer is preferably fixed on a support, in particular on a plate, film, membrane or a bead.
  • the cellulose layer is likewise preferably present on a biochip, a multi-hole plate, a packaging material or a disposable article, in particular a urine cup, a syringe, a cannula, a tube, a tissue article, a swab, a breathing mask or part thereof, or an air filter.
  • the term "device for sampling” refers to any device which is suitable or set up for taking a sample as specified above.
  • the person skilled in the art knows which devices are suitable for the respectively intended sampling.
  • Swabs, scalpels, punches, ventilation cannulas or tubes are preferably used to take biological samples.
  • Syringes and / or cannulas are even more preferred as devices for sampling.
  • the device for taking samples is preferably a pipette, a swab, a spoon, a spatula or in particular a disposable pipette
  • the present invention further relates to the use of a cellulose layer produced by the method of the present invention for the detection of an analyte, preferably in medical diagnostics, (bio) analysis, environmental analysis, the agricultural, food or packaging industry, process engineering or forensic medicine.
  • analyte preferably in medical diagnostics, (bio) analysis, environmental analysis, the agricultural, food or packaging industry, process engineering or forensic medicine.
  • Embodiment 1 A method for producing a cellulose layer for the detection of at least one analyte, comprising
  • Embodiment 2 Method according to embodiment 1, wherein at least two non-identical celluloses and / or cellulose derivatives are dispersed together before application.
  • Embodiment 3 Method according to embodiment 1 or 2, wherein the cellulose layer is present on a support, preferably on an essentially transparent support, more preferably on a transparent support.
  • Embodiment 4 Method according to one of the embodiments 1 to 3, wherein the ligand is a compound with affinity for the at least one analyte.
  • Embodiment 5 Method according to one of the embodiments 1 to 4, the ligand selectively binding the at least one analyte.
  • Embodiment 6 Method according to one of the embodiments 1 to 5, wherein the ligand is a polypeptide, a polynucleotide, a carbohydrate, or a fat.
  • Embodiment 7 Method according to one of the embodiments 1 to 6, wherein the ligand is an antibody, a hormone, a glycolipid, a phospholipid, a glycoprotein or a phosphoprotein.
  • Embodiment 8 Method according to one of the embodiments 1 to 7, wherein the ligand is or contains a recombinant protein, a native protein, an autoantigen, an allergen and / or a cell.
  • Embodiment 9 Method according to one of the embodiments 1 to 8, wherein a large number of non-identical ligands are immobilized on the cellulose layer, which preferably have affinity for non-identical analytes.
  • Embodiment 10 Method according to one of the embodiments 1 to 9, the immobilization being spatially structured.
  • Embodiment 11 Method according to one of the embodiments 1 to 10, the coated carrier being set up for visual evaluation, imaging evaluation by means of fluorescence, luminescence or absorption optics, evaluation by scanning densitometry and / or electrochemical evaluation.
  • Embodiment 12 Method according to one of the embodiments 1 to 11, the ligand being covalently bound to the cellulose layer.
  • Embodiment 13 Method according to one of the embodiments 1 to 12, wherein the cellulose layer obtained is essentially transparent, preferably wherein the cellulose layer obtained is transparent.
  • Embodiment 14 Method according to one of the embodiments 1 to 13, the stable dispersion having a solids content (mass fraction) between 0.05% (w / w) and 5% (w / w), preferably a content of cellulose and / or cellulose derivative between 0.05% (w / w) and 5% (w / w).
  • Embodiment 15 Method according to one of the embodiments 1 to 14, wherein the cellulose and / or the cellulose derivative have a particle size of at most 600 nm, preferably wherein the constituents of the stable dispersion have a particle size of at most 600 nm.
  • Embodiment 16 Method according to one of the embodiments 1 to 15, the cellulose layer being applied by knife coating, spraying, spin coating, spray drying and / or dipping, optionally followed by drying.
  • Embodiment 17 Method according to one of the embodiments 1 to 16, wherein the stable dispersion is a stable aqueous dispersion or a stable dispersion in a mixture of water and a water-miscible solvent.
  • Embodiment 18 Method according to one of the embodiments 1 to 17, the cellulose derivative having a derivatization with ester and / or ether groups.
  • Embodiment 19 Method according to one of the embodiments 1 to 18, wherein the cellulose derivative has a derivatization with at least one functional group selected from carboxyl, carbonyl, sulfate, carboxymethyl, methyl, ethyl, silyl, acetyl, carbamate and amino.
  • Embodiment 20 Method according to embodiment 18 or 19, wherein the cellulose derivative has a DS value of less than 0.5.
  • Embodiment 21 Method according to one of the embodiments 1 to 20, wherein the cellulose layer contains at least two non-identical celluloses and / or cellulose derivatives.
  • Embodiment 22 Method according to one of the embodiments 1 to 21, the cellulose being obtained from wood, annual plants, cotton and / or waste paper.
  • Embodiment 23 Method according to one of the embodiments 1 to 22, wherein the carrier contains glass, paper, plastic, ceramic and / or metal, preferably consists of glass, paper, plastic, ceramic and / or metal.
  • Embodiment 24 Cellulose layer with an immobilized ligand, produced or producible by the process according to one of the embodiments 1 to 23.
  • Embodiment 25 cellulose layer according to embodiment 24, the cellulose layer being transparent.
  • Embodiment 26 cellulose layer according to embodiment 24 or 25, the coated support being in the form of a solid, preferably a plate, film, membrane or bead.
  • Embodiment 27 Cellulose layer according to one of the embodiments 24 to 26, the coated carrier being a packaging material, a laboratory material, preferably a biochip or a multi-well plate, or a disposable article, preferably a urine cup, a syringe, a Cannula, tube, tissue article, swab, breathing mask or part thereof, or an air filter.
  • the coated carrier being a packaging material, a laboratory material, preferably a biochip or a multi-well plate, or a disposable article, preferably a urine cup, a syringe, a Cannula, tube, tissue article, swab, breathing mask or part thereof, or an air filter.
  • Embodiment 28 A method for detecting an analyte in a sample comprising
  • Embodiment 29 Method according to embodiment 28, the evaluation being carried out visually or by means of fluorescence, luminescence or absorption optics using imaging, scanning densitometry or electrochemically.
  • Embodiment 30 Method according to embodiment 28 or 29, wherein the analyte is present in a sample of a body material.
  • Embodiment 31 Method according to one of the embodiments 28 to 30, wherein the body material is a body fluid, preferably blood, plasma, serum or urine, or a gas, preferably exhaled air.
  • the body material is a body fluid, preferably blood, plasma, serum or urine, or a gas, preferably exhaled air.
  • Embodiment 32 Device comprising a cellulose layer according to one of the embodiments 24 to 29.
  • Embodiment 33 Device according to embodiment 32, the device being a packaging material, a laboratory material, preferably a biochip or a multi-well plate, or a disposable article, preferably a urine cup, a syringe, a cannula, a tube, a tissue article, a swab, a breathing mask or part of it, or an air filter.
  • Embodiment 34 Kit for the detection of at least one analyte, comprising at least one cellulose layer with an immobilized ligand and a device for sampling.
  • Embodiment 35 kit according to embodiment 34, the cellulose layer being present on a support.
  • Embodiment 36 Use of a cellulose layer produced by the method according to one of the embodiments 1 to 23 and / or a cellulose layer according to one of the embodiments 24 to 29 for the detection of an analyte, preferably in medical diagnostics, (bio) analytics, environmental analysis, the Agricultural, food or packaging industries, process engineering or forensic medicine.
  • an analyte preferably in medical diagnostics, (bio) analytics, environmental analysis, the Agricultural, food or packaging industries, process engineering or forensic medicine.
  • Embodiment 37 Process for the production of transparent cellulose layers and their use as a multifunctional carrier of ligands, characterized in that a) the cellulose layer is applied to a carrier, such as glass, paper, plastic, ceramic or metal,
  • the layer immobilized with ligands is used for the detection of an analytical problem.
  • Embodiment 38 Method according to embodiment 37, wherein cellulose is applied to the carrier in the form of a stable aqueous dispersion or cellulose is also dispersed in a mixture of water and a water-miscible solvent and can be applied to the carrier.
  • Embodiment 39 Process according to embodiments 37 to 38, wherein cellulose from all possible sources is used for the production of the cellulose dispersions (wood, annual plants, cotton, waste paper) and cellulose from cellulose derivatives which can be used for the production of the cellulose dispersions.
  • cellulose dispersions wood, annual plants, cotton, waste paper
  • cellulose from cellulose derivatives which can be used for the production of the cellulose dispersions.
  • Embodiment 40 Method according to embodiment 37 to 39, wherein the dispersions which contain cellulose or cellulose derivatives have a solids content (mass fraction) between 0.05 and 5% (w / w) and the ingredients have particle sizes ⁇ 600 nm.
  • Embodiment 41 Application of a homogeneous cellulose layer, which can also consist of a mixture of several different dispersions which contain cellulose or cellulose derivatives according to embodiments 1 to 4, by knife coating, spraying, spin coating, dipping or spray drying or a combination of the methods mentioned is produced.
  • Embodiment 42 Coated supports produced by the process according to embodiments 37 to 41, which can be solid, flexible, planar, beads, foils and membranes, packaging materials of all kinds.
  • Embodiment 43 Method according to embodiment 37 to 42, the cellulose layers produced being used in medical diagnostics, (bio) analytics, environmental analysis, agriculture, food and packaging industries, process engineering or forensic medicine and the lifestyle field.
  • Embodiment 44 Method according to embodiment 37 to 43, wherein all molecules are used as ligands with which a selective binding of analytes from a sample can be realized, the binding of which subsequently after washing (heterogeneous assay) or subsequently or simultaneously without washing (more homogeneous Assay) can be detected.
  • Embodiment 45 Method according to embodiment 37 to 43, the selection of the ligands being strongly dependent on the intended use.
  • Proteins, peptides, nucleic acids, oligonucleotides, carbohydrates, lipids or fats, in particular antibodies, antigens, hormones, glycolipids, phospholipids, glycoproteins, phosphoproteins, recombinant proteins, native proteins, autoantigens, allergens and cells can be understood as ligands.
  • Embodiment 46 Method according to embodiment 37-45, characterized in that the evaluation is carried out visually or by means of fluorescence, luminescence and absorption optics, imaging, or by scanning densitometry or electrochemically.
  • Embodiment 47 Process for the production of transparent cellulose layers and their use as multifunctional carriers of ligands, characterized in that a) the cellulose layer is applied to a (also flexible) support, such as glass, paper, plastic, ceramic or metal,
  • the layer immobilized with ligands is used for the detection of an analytical problem.
  • Embodiment 48 Method according to embodiment 47, cellulose being applied to the support as a stable aqueous dispersion.
  • Embodiment 49 Method according to embodiment 47 or 48, a homogeneous cellulose layer being produced by knife coating, spraying, spin coating, dipping or spray drying or a combination of the methods mentioned.
  • Embodiment 50 Method according to one of the embodiments 47 to 49, wherein cellulose from all possible sources is used for the production of the cellulose dispersions (wood, annual plants, cotton, waste paper).
  • Embodiment 51 Method according to one of the embodiments 47 to 50, the cellulose derivatives containing functional ethers and / or ester groups, such as carboxyl, alkyl and aryl, sulfate, phosphate, carbonyl, carboxymethyl, acetate, carbamate , Amino, ammonium, silyl groups, the degree of substitution DS ⁇ 0.5.
  • functional ethers and / or ester groups such as carboxyl, alkyl and aryl, sulfate, phosphate, carbonyl, carboxymethyl, acetate, carbamate , Amino, ammonium, silyl groups, the degree of substitution DS ⁇ 0.5.
  • Embodiment 52 Method according to one of the embodiments 47 to 51, the cellulose layer also comprising a mixture of a number of different dispersions which may contain cellulose or cellulose derivatives.
  • Embodiment 53 Method according to one of the embodiments 47 to 52, wherein the dispersions which contain cellulose or cellulose derivatives have a solids content (mass fraction) between 0.05 and 5% (w / w).
  • Embodiment 54 Method according to one of the embodiments 47 to 53, wherein the dispersions which contain the cellulose or cellulose derivatives are characterized in that the ingredients mentioned have particle sizes ⁇ 600 nm, preferably in the range between 300-100 nm.
  • Embodiment 55 Use of a cellulose layer produced according to one of the embodiments 47 to 54 in medical diagnostics, (bio) analysis, environmental analysis, agriculture and the food industry, packaging industry, forensic medicine.
  • Embodiment 56 Method according to one of the embodiments 47 to 54, the cellulose layer being applied to solid, flexible, planar, cylindrical or elypsoid carriers, such as beads, tubes, tubes, foils or membranes.
  • Embodiment 57 Use of a cellulose layer produced according to one of the embodiments 47 to 54 for coating all types of packaging materials, laboratory materials such as biochips, microtiter plates or disposable medical articles such as urine beakers, syringes and cannulas, tubes, tissue articles, swabs, breathing masks or parts thereof, or air filters .
  • Embodiment 58 Subject of one of the embodiments 47 to 57, ligands being all molecules with which a selective binding of analytes from a sample can be realized, the binding of which can subsequently be detected after washing or subsequently or simultaneously without washing, the selection the ligand strongly depends on the application, such as. B. the use in medical diagnostics, bioanalytics, environmental analysis, forensic medicine.
  • Embodiment 59 Subject of embodiment 58, ligands being exemplary proteins, peptides, nucleic acids, oligonucleotides, carbohydrates, fats, preferably antibodies, antigens, hormones, glycolipids, phospholipids, glycoproteins, phosphoproteins, recombinant proteins, native proteins, autoantigens, allergens or allergen complexes , or cells, are preferably molecules that are in living systems or killed systems and these systems are immobilized in whole or in part.
  • Embodiment 60 Subject of one of the embodiments 47 to 59, characterized in that the evaluation is carried out visually or by means of fluorescence, luminescence and absorption optics, imaging, or by scanning densitometry or electrochemically.
  • Embodiment 61 Subject of one of the embodiments 47 to 60, the coated and liganded carrier comprising washing and / or detection reagents.
  • Embodiment 62 Use of a cellulose layer produced according to one of the embodiments 47 to 54 for the analysis of a sample matrix from human and veterinary diagnostics; especially for the analysis of urine, blood, serum, breathing gas, sweat, or smears from faeces, pharynx, nose and relevant surfaces from human and
  • Embodiment 63 Use of a cellulose layer produced according to one of the embodiments 47 to 54 for analyzing a sample matrix from the environmental and life sciences, in particular in the analysis of fresh and drinking water, process and waste water, soil, air and waste air.
  • Embodiment 64 Device comprising a cellulose layer produced according to one of the embodiments 47 to 54, set up for the analysis of a sample from human or veterinary diagnostics; especially for the analysis of urine, blood, serum, breathing gas, sweat, or smears from faeces, pharynx, nose and relevant surfaces from human and
  • Embodiment 65 Device comprising a cellulose layer prepared according to one of the embodiments 47 to 54, set up for the analysis of a sample from the environmental and life sciences, in particular in the analysis of fresh and drinking water, process and waste water, soil, air and waste air.
  • Fig. 1 Comparison of the signal background (BG) intensities of peptides (Cl - C2) and proteins (wtC) on cellulose coating (excitation at 635 nm); small bars for background signals (use of slide O D3)
  • Fig. 2 Comparison of the signal background intensities of peptides (Cl - C2) and proteins (wtC) on (in-house) epoxy slide (excitation at 635 nm)
  • Fig. 8 Spot morphology, comparison of cellulose and (in-house) epoxy slide coating
  • Fig. 9 Stress test: surface; Comparison of different layer thicknesses of cellulose, in-house epoxy coating
  • the present invention relates to the production of transparent cellulose films from aqueous cellulose dispersions and their use as multifunctional carriers for tests in medical diagnostics, food and environmental analysis and other areas in which analytical questions arise.
  • the transparent films can be applied to various, also flexible, carriers made of plastic, glass, ceramic, metal and paper and are stable in storage.
  • aqueous cellulose dispersions were used for the following examples. First, 0.8 g of the cellulose or the respective cellulose derivative was weighed in and made up to 100 g with deionized water. The samples were then treated with an Ultraturax at approx. 20,000 rpm for 15 minutes. After a 15 minute rest period, the procedure is repeated. This is followed by a two-stage treatment in a high-pressure homogenizer. Here 6 cycles are carried out in a 200 pm cell at 500 bar and 12 cycles in a 50 pm cell at 1000 bar. Homogeneous aqueous dispersions are obtained which have a position stability of more than 3 years. All of the dispersions listed were each placed on a commercial slide and distributed homogeneously on the surface using a doctor blade. Table 1: Dispersions
  • ligand molecules such as DNA, peptides and proteins, dissolved in liquids and in the form of tiny drops (spots) are applied to the surfaces described for the production of arrays (microarray technology).
  • the ligand molecules can bind specifically to the surface via the reactive surface coating. None of the surfaces have been activated beforehand.
  • FIGS. 1 and 2 A comparison of the signal background intensities is shown in FIGS. 1 and 2, FIG. 1: cellulose layer, FIG. 2: epoxy slide.
  • peptides and proteins are bound and detected as figand molecules on the surfaces described in different concentrations.
  • the great diversity of the chemical properties of proteins makes these molecules sensitive to the properties of the coated supports.
  • the proteins or peptides to be analyzed are secondarily detected with labeled ligands (antibodies).
  • Example 4 Production of the Layers Using Different Methods and Determination of the Layer Thickness Using AFM (Bruker Dimension Icon) Different layers were used to produce transparent layers on commercial glass slides. For this purpose, an aqueous cellulose dispersion (0.71%, w / w) was applied to the support using the respective method and the layer thickness was then determined using AFM (Atomic Force Microscope) from Bruker (type Dimension Icon). The results are shown in Table 2. After the slides had been coated, they were dried for 5 minutes in a forced-air drying cabinet at 45 ° C. The layer thicknesses were measured at three points on the slides. The value of the table corresponds to the arithmetic mean. Table 2:
  • Example 5 Production of the layers depending on the content of cellulose
  • FIG. 3A A coating with a functionality (FIG. 3A), generation of a coating with different functional groups which serve to immobilize the ligands (FIG. 3B).
  • FIG. 5 A schematic exemplary representation of the production of layers according to the invention and examples of the transparency properties of the cellulose layers according to the invention are shown in FIG. 5.
  • FIG. 8 a stress test of the surface; Comparison of different layer thicknesses of cellulose slides with epoxy slide in FIG. 9. An example of immobilization and detection of proteins and peptides on a support is shown in FIG. 10.

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Abstract

La présente invention concerne un procédé de préparation d'une couche de cellulose pour la détection d'au moins un analyte, comprenant (i) la préparation d'une couche de cellulose en appliquant une dispersion stable de cellulose et/ou d'un dérivé de cellulose sur un support approprié, et (ii) l'immobilisation d'au moins un ligand sur la couche de cellulose, et une couche de cellulose fabriquée par ce procédé. La présente invention concerne en outre des procédés de détection, des dispositifs, des kits et des utilisations associés.
EP19779792.1A 2018-09-24 2019-09-24 Couches faites sur mesure à partir de dispersions de cellulose pour la détection d'analytes Pending EP3856139A1 (fr)

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EP2022802B1 (fr) 2007-08-10 2017-03-22 Dow Global Technologies LLC Nanoparticule en cellulose peu oxydée
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