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WO2025223824A1 - Revêtement pour réseau de cavités pour un dispositif microfluidique dans des diagnostics délocalisés - Google Patents

Revêtement pour réseau de cavités pour un dispositif microfluidique dans des diagnostics délocalisés

Info

Publication number
WO2025223824A1
WO2025223824A1 PCT/EP2025/059553 EP2025059553W WO2025223824A1 WO 2025223824 A1 WO2025223824 A1 WO 2025223824A1 EP 2025059553 W EP2025059553 W EP 2025059553W WO 2025223824 A1 WO2025223824 A1 WO 2025223824A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
cavity
polymer matrix
reagents
polymer
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
PCT/EP2025/059553
Other languages
German (de)
English (en)
Inventor
Ulrich Hasenkox
Gabriele Kirschbaum
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.)
Robert Bosch GmbH
Original Assignee
Robert Bosch GmbH
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 Robert Bosch GmbH filed Critical Robert Bosch GmbH
Publication of WO2025223824A1 publication Critical patent/WO2025223824A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6848—Nucleic acid amplification reactions characterised by the means for preventing contamination or increasing the specificity or sensitivity of an amplification reaction
    • 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
    • B01L2200/12—Specific details about manufacturing 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
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • 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
    • B01L2300/0819—Microarrays; Biochips
    • 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

Definitions

  • nucleic acid biomarkers DNA or RNA
  • rapid pathogen detection can determine the preferred treatment options.
  • clinical routine increasingly demands the simultaneous detection or screening of as many pathogens as possible.
  • probe-based methods qPCR, microarray, CRISPR/Cas
  • sequencing NGS
  • the relevant biomarkers/targets are often present only in very small quantities in the patient sample, detection usually takes place during or after nucleic acid amplification of the sample, especially via (quantitative) polymerase chain reaction (qPCR) or isothermal amplification methods.
  • microfluidic systems whereby a patient sample is entered into a microfluidic cartridge and the cartridge is controlled in an analyzer to perform nucleic acid amplification inside the cartridge.
  • a large number of targets that could be responsible for a specific set of symptoms are screened in parallel, requiring the unambiguous detection of each individual target. This can be achieved, for example, by...
  • the use of different detection wavelengths of the specific probe used in qPCR can be achieved, which is typically limited to a few targets.
  • Another way to detect multiple targets simultaneously is to perform individual detections in multiple cavities of a cavity array in parallel. Such a
  • patent EP 3 993 905 B1 describes a microfluidic cartridge with such a cavity array (referred to there as a cavity array or chip) containing pre-filled reagents in the cavities.
  • a challenge here is ensuring that, during sample filling, the specific reagents within the individual cavities are not carried out and into other cavities, as the cavities are interconnected via the liquid front during this phase. This would significantly complicate target detection, as the necessary reagents would no longer be sufficiently available, and could also lead to a false positive signal in another cavity.
  • the invention relates to a coating for a cavity array.
  • the coating comprises a polymer matrix and a cover layer.
  • Reagents are embedded in the polymer matrix, in particular reagents for carrying out nucleic acid amplification, for example oligonucleotides, primers and/or probes.
  • the cover layer is applied to the polymer matrix and comprises a water-soluble polymer upon heating for the release of the reagents.
  • the invention relates to a cavity array for a microfluidic device and to a microfluidic device with such a cavity array, wherein at least one cavity, preferably several cavities, have such a coating.
  • the microfluidic device can, in particular, be configured as a microfluidic cartridge for processing with an analytical instrument.
  • the invention also relates to a method for coating one, preferably several, cavities of a cavity array.
  • the cavity array can, in particular, be a substrate, especially a substrate comprising or consisting of silicon, with recesses on one side serving as cavities.
  • the cavities can, for example, be at least partially cup-shaped, cylindrical, honeycomb-shaped, hemispherical, and/or rounded.
  • the cavities with lateral recesses for example, one or more prongs
  • the recesses are preferably also filled with the coating and, in particular, covered by the top layer of the coating.
  • the opening into the respective cavity can have one or more prongs.
  • Such recesses facilitate filling the cavities, as capillary forces acting in the narrow points of the recesses allow liquid to enter more easily, and air can also escape more easily during filling.
  • At least some of the cavities can have a volume between 10 picoliters (pl) and 10 microliters (pl), preferably 10 nanoliters (nl) and 300 nl.
  • the invention advantageously significantly reduces the risk of carryover of specific reagents located upstream of cavities, particularly into other cavities, during the filling of the cavities (filling phase) with a liquid sample to be processed or analyzed. Due to the embedding of the reagents in a polymer matrix and subsequent coating with a polymer that is only soluble at higher temperatures, the release of these reagents can be selectively controlled, particularly when the reagents are used for a processing or detection reaction, which advantageously increases reaction efficiency.
  • the polymer matrix contributes in particular to the delayed release of the embedded substances and thus reduces the risk of carryover into other cavities.
  • the coating layer prevents carryover up to a certain temperature, as it is still sparingly soluble or insoluble at moderate temperatures, particularly a filling temperature between, for example, 40 and 45 °C.
  • the top layer can be dissolved only after completion of the filling phase and during the denaturation of nucleic acids introduced into the cavities with the sample via heating, especially in the first cycle of a PCR or as preparation for isothermal amplification, in order to release reagents required for amplification, especially primers and probes, from the polymer matrix.
  • This ensures good availability of the specific reagents in time for the actual amplification, while effectively preventing the transfer of reagents into neighboring cavities.
  • the invention eliminates the need for the otherwise conventional covalent bonding of the reagents to the surface of the cavities, thus enabling better reagent mobility.
  • the polymer matrix may include or consist of one or more polysaccharides, polyamides, polyacrylamides, and/or polyvinyl alcohols, for example dextran as a polysaccharide or poly(2-ethyl-2-oxazoline) as a polyamide.
  • the polymer matrix can in particular be formed from a polymer solution, wherein the polymer solution is polyacrylamide with a molecular weight
  • the polymer solution comprises between 10,000 and 1,000,000, preferably between 40,000 and 150,000.
  • the polymer solution comprises short-chain polyacrylamide with a molecular weight of less than 50,000, preferably between 10,000 and 40,000, and/or medium- or long-chain polyacrylamide with a molecular weight greater than 100,000, preferably between 100,000 and 1,000,000.
  • the weight ratio between the short-chain and the medium- or long-chain polymers is between 8:1 and 12:1, preferably 10:1.
  • the concentration of the polyacrylamide does not exceed 1.0% by weight, and most preferably does not exceed 0.4% by weight in distilled water, in order to maintain sufficient dispensability of the polymer solution.
  • the reagents to be embedded include oligonucleotides, especially primers, the polyacrylamides can advantageously form hydrogen bonds with the oligonucleotides via the amide group, thus effectively delaying their release.
  • Trehalose can be added to the polymer solution to stabilize the oligonucleotides.
  • the top layer preferably comprises or consists of a water-soluble polymer, in particular a polysaccharide and/or polyacrylamide, when heated. Due to its temperature-dependent solubility, the protective effect of the top layer can be selectively removed at a desired time, as described above.
  • the top layer comprises or consists of agarose, in particular agarose with a melting point below 55°C, which is also referred to as low-melt agarose.
  • An additional substance such as a surfactant, can be added to the top layer to improve and ensure the filling of at least one cavity with the sample liquid during the filling phase. This can at least partially compensate for the hydrophobicity of the polysaccharide, particularly agarose, and improve the fillability for a subsequently added aqueous sample liquid.
  • the process for coating one, preferably several, cavities of a cavity array may comprise the following steps: i. Filling, in particular contactless dispensing, for example spotting or printing, of at least one cavity with a polymer matrix and with reagents in order to form the polymer matrix with the reagents embedded therein in the at least one cavity. ii. Filling, in particular contactless dispensing, for example spotting or printing, of at least one cavity with a cover layer, wherein the cover layer comprises a water-soluble polymer upon heating for the release of the reagents from the polymer matrix.
  • the reagents to be embedded can be dissolved in the polymer matrix.
  • At least one cavity can be at least partially or partially hydrophilized, for example via contactless dispensing, such as spotting or printing with a surfactant and/or trehalose.
  • this solution is preferably dried before filling with the top layer. Drying can be achieved, for example, by waiting a predetermined time, such as 15 minutes, at room temperature, for example, 20 °C. Alternatively, the cavity or cavity array can be heated for drying, for example, to 40 °C.
  • Filling with the top layer may involve multiple filling processes, especially spot-filling with the polymer.
  • cavities have lateral recesses, as described above, these recesses are preferably also filled and thus coated.
  • Figure 1 shows an embodiment of a microfluidic device according to the invention with an embodiment of a cavity array according to the invention.
  • Figures 2a-c are schematic snapshots of an embodiment of the coating process and coating according to the invention.
  • FIG. 3 shows a flowchart for the embodiment of the coating process according to the invention.
  • Figure 1 shows an embodiment of a microfluidic device according to the invention as a microfluidic cartridge 100, which includes an embodiment of the cavity array 110 according to the invention with an embodiment of the coating 10 according to the invention.
  • the microfluidic cartridge 100 can, for example, be based on a microfluidic cartridge disclosed in German patent EP 3 993 905 B1.
  • the microfluidic device, in particular the microfluidic cartridge 100 can be part of a microfluidic system for molecular diagnostics, especially for the detection of pathogens.
  • the system can include an analyzer for receiving and processing the cartridge, as described, for example, in German patent documents DE 10 2016 222 075 A1 and DE 10 2016 222 072 A1.
  • a biological sample such as a swab, sputum, or blood
  • a biological sample can be taken into a receiving chamber 101 of the cartridge 100 and transferred to a processing chamber 102.
  • nucleic acids contained in the sample can be purified, for example, by binding the nucleic acids to a filter (not shown) and subsequently removing sample residues using a wash buffer located upstream in the cartridge, for example, in a reagent chamber 104. This wash buffer is then passed through the processing chamber 102 into a waste chamber 105.
  • the cells can be lysed to release the nucleic acids, for example, by mixing the sample with a lysis buffer located upstream in a further reagent chamber 103 before purification.
  • the lysis buffer can also be a combined lysis and binding buffer, which, in addition to lysis, also establishes favorable chemical conditions for the binding of nucleic acids to the filter.
  • the nucleic acids can be released from the filter, for example, with the aid of an eluate medium, and transferred to the amplification chamber 106, which contains the cavity array 110, for example, in the form of a silicon substrate (schematically shown from above in Figure 1).
  • the cavity array 110 comprises several cavities 111—Figure 1 shows an example of 16 cavities 111 with circular boundaries—in which the amplification reactions, for example, PCR, can proceed in parallel.
  • the cavities 111 are formed as pot-shaped, hemispherical, or cylindrical recesses in the top surface of the silicon substrate and have, for example, a volume between 2 and 80 nanoliters (nl).
  • reagents required for PCR and optical luminescence detection can be pre-packaged, in particular (freeze-)dried reagents, for example polymerases, nucleotides, or optical probes.
  • At least one, preferably several or all, cavities 111 have a coating according to the invention in which at least some of these reagents 13 are contained.
  • the coating can contain different primers and/or probes for the respective nucleic acid segments to be amplified, depending on the cavity.
  • Figures 2a, 2b and 2c show a single cavity 111 of the cavity array 110 in cross-section and sketch three snapshots of an embodiment of the coating process 500 according to the invention in this cavity 111.
  • Figure 3 shows the steps of this coating process 500 as a flowchart 500.
  • the reagents 13 to be incorporated into the coating in particular primers (oligonucleotides) and probes for pathogen-specific detection, can be dissolved in an aqueous polymer matrix.
  • the polymer matrix can contain polysaccharides, for example dextran dissolved at a concentration of more than 2 wt%, polyamides, for example poly(2-ethyl-2-oxazoline), polyacrylamides, or polyalcohols, in particular polyvinyl alcohols.
  • the cavity 111 can be at least partially hydrophilized in a second step 502 of the process 500, for example by spotting with a surfactant or trehalose, such as aqueous Tween® 20 with a concentration of 0.01 to 0.1 wt% or a 1.5% trehalose solution.
  • a surfactant or trehalose such as aqueous Tween® 20 with a concentration of 0.01 to 0.1 wt% or a 1.5% trehalose solution.
  • the hydrophilization can be carried out by dispensing or spotting with drops 9 in the picoliter range, for example 300 to 400 picoliters per drop, from a commercially available dispenser 200, such as the sciFLEXARRAYER S12 from SCIENION GmbH, and alternatively also before the first step 501.
  • a commercially available dispenser 200 such as the sciFLEXARRAYER S12 from SCIENION GmbH
  • cavity 111 has a volume between 2 and 80 nanoliters (nLI), so that, for example, between 2 and 80 nanoliters (nLI) of polymer matrix solution can be introduced into cavity 111.
  • the polymer matrix solution can comprise polyacrylamides with a molecular weight between 10,000 and 1,000,000, preferably between 40,000 and 150,000, the concentration of which does not exceed 0.4 wt% in distilled water for sufficient dispensability.
  • the polyacrylamides can form hydrogen bonds with the oligonucleotides via the amide group and thus delay their release when dissolved in an aqueous solution.
  • trehalose for example approximately 1% by weight, can be added to the solution.
  • a protective coating 12 is applied to the cavity 111 and to the introduced polymer matrix 11 together with the reagents (13) embedded therein, in particular by spotting.
  • a water-soluble polysaccharide that dissolves when heated above a certain temperature can be used as the coating.
  • so-called low-melt agarose with a melting point below 55 °C can be used, for example, in concentrations up to 0.4 wt%.
  • a small amount of surfactant can be added to this solution to facilitate filling the cavity 111, for example, Tween® 20 at a concentration of 0.1 wt%.
  • Tween® 20 instead of agarose, another polysaccharide or a polyacrylamide can also be introduced, preferably repeatedly, as a cover layer 12, in particular by spot application.
  • nLI nanoliters
  • the cover layer 12 has the advantage that when the cavity 111 is filled below the melting temperature of the cover layer material, for example at a temperature between 40 and 45 °C in the case of low-melt agarose, the coating 10 does not yet dissolve, whereas when heated to temperatures above 50 to 60 °C, for example above 52 °C in the case of low-melt agarose, particularly during the denaturation step of the first cycle of a PCR, which usually involves heating to over 90 °C, the cover layer 12 dissolves and the reagents 13 are preferably released from the polymer matrix 11 in a delayed manner. ...

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Genetics & Genomics (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne un revêtement (10) pour un réseau de cavités (110), le revêtement (10) comprenant une matrice polymère (11), des réactifs (13) étant incorporés dans la matrice polymère (11), en particulier des réactifs (13) pour effectuer une amplification d'acide nucléique, et le revêtement (10) comprenant une couche de recouvrement (12), la couche de recouvrement (12) ayant un polymère, qui est soluble dans l'eau lorsqu'il est chauffé, pour libérer les réactifs (13), la couche de recouvrement (12) étant appliquée à la matrice polymère (11).
PCT/EP2025/059553 2024-04-25 2025-04-08 Revêtement pour réseau de cavités pour un dispositif microfluidique dans des diagnostics délocalisés Pending WO2025223824A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102024203913.6A DE102024203913B3 (de) 2024-04-25 2024-04-25 Beschichtung für ein Kavitätenarray für eine mikrofluidische Vorrichtung in der Point-of-Care-Diagnostik
DE102024203913.6 2024-04-25

Publications (1)

Publication Number Publication Date
WO2025223824A1 true WO2025223824A1 (fr) 2025-10-30

Family

ID=95157844

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/059553 Pending WO2025223824A1 (fr) 2024-04-25 2025-04-08 Revêtement pour réseau de cavités pour un dispositif microfluidique dans des diagnostics délocalisés

Country Status (2)

Country Link
DE (1) DE102024203913B3 (fr)
WO (1) WO2025223824A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000301A1 (fr) * 1994-06-24 1996-01-04 The University Of Houston Reactifs encapsules pour amplification pcr
DE102016222075A1 (de) 2016-11-10 2018-05-17 Robert Bosch Gmbh Prozessiersystem und Verfahren zur Prozessierung einer mikrofluidischen Kartusche mit einer Prozessiereinheit
DE102016222072A1 (de) 2016-11-10 2018-05-17 Robert Bosch Gmbh Vorrichtung und Verfahren zur geneigten Prozessierung von mikrofluidischen Kartuschen
CN113680406A (zh) * 2021-08-26 2021-11-23 清华大学 一种微流控芯片多指标检测方法
EP3993905B1 (fr) 2019-07-03 2023-08-23 Robert Bosch GmbH Dispositif microfluidique et procédé pour le traitement et le fractionnement en aliquote d'un échantillon liquide
EP3568234B1 (fr) * 2017-01-13 2023-09-06 Cellular Research, Inc. Revêtement hydrophile des canaux fluidiques
KR102626963B1 (ko) * 2017-05-11 2024-01-18 일루미나, 인코포레이티드 플로우 셀용 표면 보호 코팅

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000301A1 (fr) * 1994-06-24 1996-01-04 The University Of Houston Reactifs encapsules pour amplification pcr
DE102016222075A1 (de) 2016-11-10 2018-05-17 Robert Bosch Gmbh Prozessiersystem und Verfahren zur Prozessierung einer mikrofluidischen Kartusche mit einer Prozessiereinheit
DE102016222072A1 (de) 2016-11-10 2018-05-17 Robert Bosch Gmbh Vorrichtung und Verfahren zur geneigten Prozessierung von mikrofluidischen Kartuschen
EP3568234B1 (fr) * 2017-01-13 2023-09-06 Cellular Research, Inc. Revêtement hydrophile des canaux fluidiques
KR102626963B1 (ko) * 2017-05-11 2024-01-18 일루미나, 인코포레이티드 플로우 셀용 표면 보호 코팅
EP3993905B1 (fr) 2019-07-03 2023-08-23 Robert Bosch GmbH Dispositif microfluidique et procédé pour le traitement et le fractionnement en aliquote d'un échantillon liquide
CN113680406A (zh) * 2021-08-26 2021-11-23 清华大学 一种微流控芯片多指标检测方法

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