EP2285492A2 - Puce à blocage de flux - Google Patents

Puce à blocage de flux

Info

Publication number
EP2285492A2
EP2285492A2 EP09765577A EP09765577A EP2285492A2 EP 2285492 A2 EP2285492 A2 EP 2285492A2 EP 09765577 A EP09765577 A EP 09765577A EP 09765577 A EP09765577 A EP 09765577A EP 2285492 A2 EP2285492 A2 EP 2285492A2
Authority
EP
European Patent Office
Prior art keywords
chip
cross
sectional area
section
base plate
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Withdrawn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
EP09765577A
Other languages
German (de)
English (en)
Inventor
Rainer Gransee
Thomas Hansen-Hagge
Friedhelm SCHÖNFELD
Frithjof Von Germar
Nico Scharpfenecker
Franz-Josef Meyer-Almes
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.)
Institut fuer Mikrotechnik Mainz GmbH
Original Assignee
Institut fuer Mikrotechnik Mainz 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 Institut fuer Mikrotechnik Mainz GmbH filed Critical Institut fuer Mikrotechnik Mainz GmbH
Publication of EP2285492A2 publication Critical patent/EP2285492A2/fr
Withdrawn legal-status Critical Current

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
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B01F25/4336—Mixers with a diverging cross-section
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles or throttle valves
    • 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
    • B01L3/502769—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 multiphase flow arrangements
    • B01L3/502784—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 multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F2025/91—Direction of flow or arrangement of feed and discharge openings
    • B01F2025/918—Counter current flow, i.e. flows moving in opposite direction and colliding
    • 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
    • B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
    • 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
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • 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
    • 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
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • 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
    • B01L2300/087—Multiple sequential chambers
    • 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
    • B01L2300/0877—Flow chambers
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/168—Specific optical properties, e.g. reflective coatings
    • 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
    • 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
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break

Definitions

  • the invention relates to a chip for carrying out and measuring chemical reactions interactions (bonds) and Konformationsa Weg, especially fast-running chemical reactions and Vorgange, which consists of a base plate made of a polymer material transparent at least in the measuring range and having therein parallel to the plane of the base plate extending fluid channels
  • Stopped-flow devices are commonly used to study very rapid chemical and biochemical reactions, protein folding, and binding reactions in the order of a millisecond. Usually, the rate of reaction occurring after mixing the reactants under color change is observed. Frequently, reactions of two with one another occur However, known reacting reactants may also be known.
  • Known stopped-flow devices are usually of very complex construction, require complex control and are therefore expensive and error-prone.
  • the structure of most previously used stopped-flow devices is very similar and differs only in a few details
  • the components which are to be reacted with one another are located in separate storage containers, preferably syringes, and can be reduced to smaller workpieces by means of a hydraulic system.
  • the actual stopped-flow reaction is initiated by simultaneously driving the working syringes and pressing the reactants quickly into a mixing chamber and from there into an observation or measuring cuvette.
  • the color change, fluorescence change, absorption change taking place in the measuring cuvette or change in the circular dichroism due to the progressing reaction between the reactants is measured and the time course is recorded.
  • the passage of the reaction solutions through the mixing chamber and the The measuring cuvette is stopped abruptly (stopped-flow), in that behind the outlet of the measuring cuvette is again provided a syringe for receiving the reaction solutions whose fluid intake is limited or stopped by a stop.
  • the point in time at which the flow of the reaction solutions is stopped abruptly usually defines the beginning of the measurement.
  • Modifications in the individual stopped-flow apparatuses are the type of control and the pressure transmission, as well as in the selection of the appropriate mixing chamber and the structure of the liquid flow stopping device (triggering).
  • Stopped-Flow-Apparatuses are currently used in many ways in research. In addition to studying simple enzyme-substrate reactions and their kinetics for detecting and explaining reaction mechanisms, many other kinetics are also covered, such as protein folding, conformational changes to enzymes or other proteins. With the stopped-flow technique, for example, the substrate transport in vesicles can be observed and resulting intermediates can be detected and determined.
  • the solution which is present when the fluid flow is stopped in the measuring cuvette has already reacted to a certain extent. This is because the starting solutions can not mix with each other infinitely fast and the mixed solution still has to be transported from the mixing chamber into the measuring cuvette. It is therefore called the period of time from the first contact of the starting solutions until the start of the measurement as dead time. It is an important quality criterion for stopped-flow devices. Chemical reactions that occur within the dead time can not be quantified by the measuring system. To determine the dead time, one must use a chemical reaction, which runs partly after and partly also within the dead time.
  • the dead time can be determined from an extrapolation of the time curve, for example by pseudo-first-order color reactions which run exponentially and can be linearized by a semilogarithmic representation.
  • the dead time can then be read by extrapolation from the measured value at the time of recording to the zero value of the color reaction.
  • the methods for dead time determination of stopped-flow apparatuses are known per se to the person skilled in the art.
  • the dead time is a fixed device constant, so should always be the same, and is usually checked at certain intervals by re-measurement. However, it can also be determined separately for each experiment. The shorter the dead time of a stopped-flow apparatus, the faster reactions can be measured.
  • microfluidics is characterized by the fact that important basic procedural operations are carried out using apparatuses with microstructured reaction areas and fluid channels, so-called microstructure apparatuses Compared to conventional apparatus Considerably reduced dimensions of the fluid structures result in large specific surfaces and small diffusion paths, which in turn results in improved mass transfer and heat transfer conditions.
  • microfluidics is a part of micro process engineering, from which the development of lab-on-a-ch ⁇ p systems (US Pat.
  • microfluidics stands for both components and processes, with which liquids and gases in the long range of less than 1 mm moves, controls and a
  • the applications range from micro dosing systems for medical active substances to hm to fully miniaturized analysis systems. Liquids and gases are conducted in microchannels, dosed through microvalves and measured in their flow and other chemical and physical properties
  • the object of the present invention was to provide a microfluidic stopped-flow chip, which is less expensive compared to known stopped-flow apparatus, requires less movable mechanical elements and thus has a lower susceptibility and causes lower material and reagent costs
  • a chip for carrying out and measuring chemical reactions, interactions and / or conformational changes, in particular rapid chemical reactions and processes which consist of a base plate of a polymer material which is transparent at least in the measuring region and which then runs parallel to the plane of the base plate extending fluid channels having at least the following functional sections comprises at least two reagent leads,
  • the mixer structure has a number of inlets corresponding to the number of reagent feed lines and an outlet,
  • the output of the measuring section is connected to the outlet section
  • the outlet section is guided out of the base plate or into a reservoir arranged on the chip,
  • the pressure lines for connection to a pressure reservoir via at least one Renomur led out of the base plate and / or the at least two reagent feed lines out via NASAoffnun- gene out of the base plate may be accommodated, for example, which can avoid the risk of contamination with hazardous reagents or products
  • the stopped-flow chip according to the invention which is referred to below simply as a chip, consists of a base plate made of a polymer material which is transparent at least in the measuring region, with then running fluid ducts. It represents the central functional element of a stopped-flow apparatus.
  • the essential fluid conduit processes run in it
  • the chip according to the invention is provided as a part or replacement part of an entire stopped-flow apparatus, which further comprises an operator device for receiving the chip.
  • the operator device expediently has a space for receiving the chip, in which the
  • the chip according to the invention can be provided as a disposable or disposable component for a single measurement or a limited number of measurements.
  • An operator device for use with the chip according to the invention has at least one detector or a plurality of detectors for detecting light coupled out of the chip.
  • the operator device can furthermore have connections for a connection to the fluid channels of the chip, in particular the reagent circuits, and furthermore to electronic devices Components for the evaluation and / or forwarding of the received signals from the detectors, and Chemikahenvorrate, a Fluidaktuatonk for requesting the fluids and a pressure reservoir, such as a Gastikbehalter or a compressor, and one or more fast switching valves
  • the operator device expediently one or more light sources for the coupling of light into the chip and optionally one or more filters that yenb only certain Wellenlan-
  • the detectors for the detection of light signals are per se known components which are available on the market. For this example, CCD chips are suitable
  • Fluids in the sense of the invention include gases and liquids, but preferably liquids particularly preferably liquids with a viscosity similar to water. High-viscosity liquids are less suitable since they can only be pressed through the microchannels of the chip more slowly and more slowly than low-viscosity liquids.
  • the reagents and the pressure fluids are not miscible with each other, for example aqueous reagents on the one hand and organic apolar pressure fluids on the other hand or different phase states have liquid reagents on the one hand and gaseous pressure fluids on the other hand
  • transparent in connection with the polymer material of the base plate of the chip according to the invention means herein that the material is permeable at least in the measuring range (in the region of the measuring path) at least for the light wavelengths to be measured in a stopped-flow exponent. It is not necessary that the polymer material is transparent or permeable, for example, in the entire visible spectrum of the light or in the ⁇ -visible wavelength range which can also be used for measurements.
  • the wavelength ranges of the coupled-in light and the coupled-out light at which the measurements are carried out are essential
  • Em particular advantage of the inventive chip is then that the base plate of Polymermate ⁇ al very inexpensive and with high precision by molding, such as example Sp ⁇ tzguss, hot stamping or reaction molding, can be produced as einstuckiges molding
  • the chip according to the invention further comprises reflection surfaces on the base plate which are arranged such that they direct light coupled into the measuring path from a light source arranged outside the chip and / or light emitted and / or scattered by the measuring path decouple the chip and preferably steer toward a light detector provided in a Whygerat
  • production methods and materials are preferably selected so that the reflection surfaces will suffer without further post-processing
  • the chip according to the invention comprises at least two reagent feed lines, which in a preferred embodiment start at an edge of the base plate and have inlet openings there. These inlet openings of the reagent feed lines are in operation of the stopper flow apparatus via connections to the storage containers for the reagents for carrying out These Befullreservoirs may be syringe pumps or the like, as they are known from conventional stopped-flow apparatus.
  • the reagent feed lines can be filled in an alternative embodiment, but also by capillary forces and / or gravitational forces
  • the reagent feed lines are into the mixer structure, which has a number of inlets and an outlet corresponding to the number of reagent feeds.
  • the mixer structure In one embodiment of a chip, the reaction of two reactants is to be measured, ie having two reagent feeders , the mixer structure is a T-piece or Y-piece with two inlets and one outlet The reagents are pressed in here by the two inlets simultaneously, the fluid streams meet each other, are already premixed very intense and through the outlet into the adjoining mixing section
  • the outlet of the mixer structure flows into a mixing zone, which is expediently designed in such a way that it also requires very rapid and intensive mixing of the reaction solutions, the geometry of the mixing zone having a considerable influence on the intensity and the rate of mixing of the reactants
  • the mixing section is designed such that its cross-sectional area, starting from the connection at the outlet of the mixer structure, increases in size in the direction of its outlet, where it reaches the measuring section.
  • the interior of the mixing section widens
  • other geometries of the mixing section can also be used in accordance with the invention, such as mixing sections with so-called lifting-cone structures, as are known from WO-A-03/011443, which are incorporated by reference herein
  • the cross-sectional area of the mixing section increases, starting from the connection at the outlet of the mixer structure, towards its exit to twice the cross-sectional area or three times the cross-sectional area or four times the cross-sectional area or five times the cross-sectional area the 10-fold cross-sectional area
  • the cross-sectional area of the fluid channels may vary according to the purpose and function of the respective fluid channel section. In one embodiment, the cross-sectional area of the fluid channels is at least partially in the range of zero , 05 to 4 mm 2 or from 0.1 to 3 mm 2 or from 0.25 to 2 mm 2
  • the chip according to the invention has sections of the fluid conduit channels with a larger cross-sectional area and those with conversely smaller cross-sectional areas with a smaller cross-sectional area form, for example, stop structures for the fluids flowing in the chip
  • the inlets of the mixer structure have a cross-sectional area which is smaller than half the cross-sectional area of the portion of the reagent feed line which in each case extends into the inlet of the mixer structure.
  • the cross-sectional area of the inlet of the mixer structure is less than one-third of the cross-sectional area or less than one quarter of the cross-sectional area or less than one-fifth of the cross-sectional area or less than one-tenth of the cross-sectional area of the portion of the reagent conduit that opens into the inlet of the mixer structure.
  • the mixer structure contains a so-called “stop structure”, which causes the liquid in the reagent feed line, if it is not under elevated pressure, to be stopped at or in the mixer structure prior to contact and will not flow further into it.
  • the "stop structure” is essentially formed by a channel constriction with subsequent channel widening within the mixer structure (T-piece).
  • the two inlets on the T-piece or Y-piece with channel sections with a small cross section form a channel constriction. Where the two inlet channels meet and form the T-shaped intersection with the outlet channel, the channel widening is located.
  • the stop structure is formed at the transition from a wide to a narrow channel section.
  • stop structure such as diaphragms with vent openings, which break when a pressure is applied, or channel sections with different surface wettability in front of the mixer structure.
  • the pressure lines provided on the chip according to the invention open into the reagent feed lines.
  • the pressure lines are connected to a pressure reservoir, wherein on the pressure lines is not permanently applied an increased pressure, but an increased pressure can be applied if necessary. If a branching pressure line is connected to a pressure reservoir, by connecting the Pressure on the one pressure line, a pressure pulse synchronously be applied to several mouths in the Reagenzienzulei- lines pressure lines, provided that the pressure lines are designed the same
  • the reagents whose reaction is to be measured after mixing are first introduced into the reagent feed lines until at least the transition to the mixer structure.
  • the reagent feed lines are thus in the section between the inlet of the mixer structure and at least the location of The forwarding of the reagents in the mixer structure, from there into the mixing section and further into the measuring section is thereby introduced and causes an increased gas pressure is applied to the pressure lines, which in the In this case, the reagent feed lines can expediently be closed off from the side of the reagent feed, in order to ensure as defined a form of the pressure pulse as possible on the reagents to be demanded th
  • the gas pressure applied to the pressure lines is precisely controlled and limited in time, so that the liquid pressed through the mixer structure and the mixing section flows into the measuring section and stops there, which is effected by removing or reducing the increased pressure.
  • a fast switching valve is preferably used.
  • a piezo valve inserted in the chip or externally
  • Another essential difference of the invention compared with known stopped-flow apparatuses is that the known apparatuses at the outlet of the measuring section have a syringe for receiving the liquid flowing out of the measuring section and for stopping the fluid flow.
  • the piston is disconnected from the outlet. pushed out liquid flowing and the liquid flow stopped by the piston z. B. impinges on a stop and thereby prevents further leakage of fluid.
  • This mechanical component is no longer necessary in the chip according to the invention, since the fluid flow can be controlled very accurately by the application and removal of the pressure on the pressure lines in connection with the microstructured channel dimensions.
  • the present invention has the further advantage that the amount of fluid required to stop the fluid flow may be lower. It is not necessary, as in the prior art, for fluid to flow from the measurement path, for example into a syringe, until the flow of the fluid can be mechanically stopped.
  • the pressure control can be so accurate that the measuring section is just filled with the reaction mixture and no or little fluid exits on the outlet side of the measuring section when the fluid flow is stopped. This allows the implementation of kinetic measurements with significantly lower reagent costs than before.
  • transition sections of the pressure lines with a reduced cross-section are provided at the lateral junctions of the pressure lines into the reagent feed lines, with a cross-sectional area which is smaller than half the cross-sectional area of the pressure lines.
  • the cross-sectional areas of the transition sections are less than one-third of the cross-sectional area or less than a quarter of the cross-sectional area or less than one-fifth of the cross-sectional area or less than one tenth of the cross-sectional area of the pressure lines.
  • the chip of the present invention is described herein by way of illustration as a unique structure in which a simple set of fluid channel structures having said functional portions are provided in a unique design in a baseplate of transparent polymeric material.
  • the invention is not limited thereto.
  • the present invention also includes those chips in which the fluid channel structures with the functional sections are provided several times in a single base plate or as part of a chip with otherwise different functional areas.
  • Structural units consisting of reagent feed lines, mixer structure, mixing section, measuring section and outlet section as well as pressure lines are provided. Simultaneous arrangement of such structural units on a baseplate allows several reactions and measurements to be carried out simultaneously.
  • the invention also encompasses those chips in which only some of the functional sections described are included
  • a plurality of mixing sections arranged one behind the other can be provided in order to improve the type and intensity of the mixing.
  • a parallel arrangement of a plurality of measuring sections behind the mixing section can be different for the parallel feedthrough Measuring methods are used on the same reaction, such as the parallel measurement of absorption and fluorescence or the parallel measurement the absorption or excitation with light of different wavelengths
  • the polymer material from which the base plate of the inventive chip is made is preferably made of transparent acrylate, polymethyl acrylate, polymethyl methacrylate, polycarbonate, polystyrene, polyimide, cycloolefin copolymer (COC), cycloolefin polymer (COP), polyurethane, epoxy resin, halogenated acrylate, deuter ⁇ ertem polysiloxane , PDMS, fluorinated polyimide, polyetheridine, perfluorocyclobutane, perfluorovinyl ether copolymer (Teflon AF), perfluorovinyl ether cyclopolymer (CYTOP), polytetrafluoroethylene (PTFE), fluorinated polyarylethersulfide (FRAESI) 1 inorganic polymer glass, polymethyl methacrylate copolymer (P2ANS)
  • polymer material is also understood to mean glasses which are suitable for the production of the chip according to the invention
  • the present invention includes not only the transparent polymer material base chip but also an overall apparatus for conducting and measuring chemical reactions comprising both the inventive chip and an operator device having a space for receiving the chip, at least one Light source for the coupling of light into the chip and one or more detectors for the detection of coupled out of the chip light
  • At least one pressure reservoir for the provision of a gas pressure and connections for a connection of the pressure reservoir to the pressure lines of the chip are provided on the device according to the invention.
  • further reagent reservoirs are provided for the provision of liquid or gaseous reagents and connections for a connection of the reagent reservoirs to the reagent feed lines of the chip
  • Figure 1 shows a schematic representation of an embodiment of the inventive chip from above
  • FIG. 2 shows a schematic representation of another embodiment of the inventive chip from above
  • FIG. 3 shows a schematic representation of a device according to the invention with a chip according to FIG. 2 and components arranged outside the chip for carrying out stopped-flow analyzes
  • Figure 1 shows a schematic representation of a chip according to the invention, which consists of a base plate made of a transparent Polymermate ⁇ al
  • the chip of Figure 1 comprises two reagent feed lines 4 with inlet openings 4 'at the edge of the base plate for the Connection to Reagent Reservoirs
  • the two reagent feed lines 4 are symmetrical and have the same cross-section with a cross-sectional area of approximately 2.5 mm 2.
  • a pressure line 5 is provided with an inlet opening 5 at the edge of the base plate for connection to a pressure reservoir
  • the pressure line 5 is divided into two sections, each of which opens into one of the two reagent feed lines 4 at a distance from the mixer structure 1.
  • the reagent feed lines 4 pass into a T-shaped mixer structure 1 which, according to the number of reagent feed lines 4, has two inlets and one outlet.
  • the mixer structure 1 contains a so-called "trough”. Stop structure "This initially comprises fluid channels at the inlets with respect to the reagent columns. The cross-sectional area of these fluid channels of the mixer structure 1 is approximately one fifth of the cross-sectional area of the fluid channels of the reagent feed lines.
  • the channel cross-section is further enlarged. This transition from the narrow channel cross-section to the channel extension represents the actual one "Stop structure" (see above)
  • the outlet of the mixer structure 1 is rounded in a mixing section 2 whose internal geometry is designed in accordance with an expanding cone, wherein the cross-sectional area at the inlet of the mixing section 2 corresponds to that at the outlet of the mixer structure 1 and the cross-sectional area at the outlet of the mixing section 2 corresponds to that at the inlet or the inlet the subsequent measuring section 3 corresponds to the mixing section 2 into the measuring section 3, in which the kinetic measurement of the reaction to be investigated takes place
  • the reflection path 10 are arranged on the base plate reflection surfaces 10 which extend substantially parallel to the measuring section 3.
  • the reflection surfaces are preferably arranged at an angle of 45 ° to the base plate and serve to light which is emitted laterally from the measuring path, such as Fluorescence radiation or scattered light to direct to a arranged below the base plate of the light receiver or detector
  • FIG. 2 shows an alternative embodiment of the chip according to the invention, which differs from the embodiment according to FIG. 1 only in that instead of the holes 9 provided for the chip according to FIG. 1 for the import of optical fibers, emitter and output mirror surfaces 11 are provided. and Auskopplungsaptflachen 11 are arranged similar to the reflection surfaces 10, but at the input and output sides of the measuring section 3 light, which falls from a source of excitation light below the base plate on one of the input and Auskopplungsspiegelflachen 11, is deflected into the measuring section 3 into the kicking Light on the opposite side of the measuring section 3 again, so it hits the second of the input and output mirror surfaces 11 and is in turn deflected substantially perpendicularly out of the base plate
  • the embodiments of the chip according to the invention according to Figures 1 and 2 agree, wesh alb same parts are also designated by the same reference numerals FIG.
  • FIG. 3 shows a schematic representation of a device according to the invention with a chip according to FIG. 2 and some components required for carrying out stopped-flow analyzes in addition to the chip.
  • these components are shown arranged outside the chip, but individual components can be included in FIG Other embodiments may also be integrated on or in the chip
  • the device according to FIG. 3 initially comprises a source for excitation light 21, from which excitation light falls onto a coupling mirror surface on the chip and is deflected into the measuring path on the chip at this mirror surface.
  • the light passed through the measuring section impinges on the opposite side of the measuring path a coupling mirror surface which redirects the light out of the base plate of the chip to a receiver and a coupled light meter 22.
  • the apparatus further comprises a power supply 23 and a device with a control electronics 24 which controls at least the high speed valve 25.
  • the device comprises Furthermore, a pressure regulator 26, which supplies compressed air, which is fed via a compressed air supply 27, to the high-speed valve 25.
  • the apparatus further comprises reagent and sample feeds 28, via which reagents and / or samples are introduced into corresponding inlets of the R eacenzienu ein be introduced on the chip

Landscapes

  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

L'invention concerne une puce permettant la mise en oeuvre et la mesure de réactions chimiques, d'interactions (liaisons) et/ou de modifications de conformation, en particulier de processus et réactions chimiques à déroulement rapide. La puce est constituée d'un support en matériau polymère transparent au moins dans la gamme de mesure, ledit support étant pourvu de canaux d'écoulement fluidique s'étendant parallèlement au plan du support et présentant au moins les parties fonctionnelles suivantes : au moins deux conduites d'alimentation en réactifs (4), des conduites à pression (5), une structure mélangeuse (1), une section de mélange (2), une section de mesure (3), une section de sortie (8), les deux conduites d'alimentation en réactifs (4) débouchant dans la structure mélangeuse (1), la structure mélangeuse (1) comportant un nombre d'entrées qui correspond au nombre de conduites d'alimentation en réactifs (4) et une sortie, la sortie de la structure mélangeuse (1) débouchant dans la section de mélange (2), la sortie de la section de mélange (2) débouchant dans la section de mesure (3), la sortie de la section de mesure (3) étant reliée à la section de sortie (8), la section de sortie (8) menant à l'extérieur du support ou dans un réservoir placé sur la puce et les conduites à pression (5) débouchant dans les conduites d'alimentation en réactif (4) à une certaine distance de la structure mélangeuse (1).
EP09765577A 2008-06-18 2009-06-12 Puce à blocage de flux Withdrawn EP2285492A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008002509A DE102008002509A1 (de) 2008-06-18 2008-06-18 Stopped-Flow-Chip
PCT/EP2009/004235 WO2009152997A2 (fr) 2008-06-18 2009-06-12 Puce à blocage de flux

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EP2285492A2 true EP2285492A2 (fr) 2011-02-23

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Country Link
US (1) US20110165025A1 (fr)
EP (1) EP2285492A2 (fr)
DE (1) DE102008002509A1 (fr)
WO (1) WO2009152997A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8665439B2 (en) * 2009-06-30 2014-03-04 Microbix Biosystems, Inc. Method and apparatus for limiting effects of refraction in cytometry
US8748191B2 (en) * 2010-08-02 2014-06-10 Ecolab Usa Inc. Stop-flow analytical systems and methods
MX338778B (es) 2011-02-15 2016-05-02 Microbix Biosystems Inc Metodos, sistemas y aparato para realizar citometrias de flujo.
CN204832037U (zh) 2012-04-03 2015-12-02 伊鲁米那股份有限公司 检测设备
US12502647B2 (en) 2019-11-29 2025-12-23 Merck Patent Gmbh Multi-branch static mixers
CN113295645A (zh) * 2021-05-20 2021-08-24 天津工业大学 基于四叶草型的太赫兹混合网络检测芯片
GB202317081D0 (en) * 2023-11-07 2023-12-20 Francis Crick Institute Ltd Test phase system

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19648695C2 (de) * 1996-11-25 1999-07-22 Abb Patent Gmbh Vorrichtung zur automatischen und kontinuierlichen Analyse von Flüssigkeitsproben
US6790662B1 (en) * 1999-03-12 2004-09-14 Ortho-Mcneil Pharmaceutical, Inc. Method of isolating CD8+ cells, and related hybridoma cells antibodies and polypeptides
EP1412065A2 (fr) 2001-07-27 2004-04-28 President And Fellows Of Harvard College Appareil et procedes de melange de flux laminaires
US7247274B1 (en) * 2001-11-13 2007-07-24 Caliper Technologies Corp. Prevention of precipitate blockage in microfluidic channels
US20050011582A1 (en) * 2003-06-06 2005-01-20 Haug Jeffrey S. Fluid delivery system for a flow cytometer
US7524464B2 (en) * 2003-09-26 2009-04-28 Ahn Chong H Smart disposable plastic lab-on-a-chip for point-of-care testing
US20050130226A1 (en) * 2003-09-26 2005-06-16 The University Of Cincinnati Fully integrated protein lab-on-a-chip with smart microfluidics for spot array generation
US8105849B2 (en) * 2004-02-27 2012-01-31 Board Of Regents, The University Of Texas System Integration of fluids and reagents into self-contained cartridges containing sensor elements
US20060193730A1 (en) * 2005-02-25 2006-08-31 Jacob Rosenstein Method and apparatus for controlling microfluidic flow
JP4543986B2 (ja) * 2005-03-24 2010-09-15 コニカミノルタエムジー株式会社 マイクロ総合分析システム
US20090145485A1 (en) * 2005-08-11 2009-06-11 Eksigent Technologies, Llc Microfluidic methods and apparatuses for fluid mixing and valving
US20080038714A1 (en) * 2005-11-02 2008-02-14 Affymetrix, Inc. Instrument to Pneumatically Control Lab Cards and Method Thereof
JPWO2008044387A1 (ja) * 2006-10-06 2010-02-04 コニカミノルタエムジー株式会社 マイクロ総合分析チップおよびマイクロ総合分析システム

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009152997A2 *

Also Published As

Publication number Publication date
WO2009152997A2 (fr) 2009-12-23
DE102008002509A1 (de) 2009-12-31
WO2009152997A3 (fr) 2010-02-18
US20110165025A1 (en) 2011-07-07

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