EP0668500A2 - Chemical microanalyser - Google Patents

Chemical microanalyser Download PDF

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Publication number
EP0668500A2
EP0668500A2 EP95101811A EP95101811A EP0668500A2 EP 0668500 A2 EP0668500 A2 EP 0668500A2 EP 95101811 A EP95101811 A EP 95101811A EP 95101811 A EP95101811 A EP 95101811A EP 0668500 A2 EP0668500 A2 EP 0668500A2
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Prior art keywords
fluid
micro
chemical
manipulators
calibration
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German (de)
French (fr)
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EP0668500A3 (en
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Minh Tan Dr. Pham
Steffen Dr. Howitz
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Forschungszentrum Dresden Rossendorf eV
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Forschungszentrum Dresden Rossendorf eV
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—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 integrated 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
    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/148—Specific details about calibrations
    • 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
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • 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
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • 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
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
    • 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
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples

Definitions

  • the invention relates to a chemical micro-analyzer for multi-ion detection in fluid media using chemical microsensors based on the difference measurement.
  • micropumps for transporting fluids based on the principle of electrohydrodynamics [A. Richter, A. Plettner, K.A. Hofmann and H. Sandmaier, Electrohydrodynamic pumping and flow measurement, 4th IEEE Workshop on Micro Electro-Mechanical Systems, 30.1 - 2.2.1991, Nara, Japan] and electroosmotic and electrophoretic pumping [C. S. Effenhauser, A. Manz and H. M. Widmer, Glass chips for high-speed capillary electrophoresis separations with submicrometer plate heights, Anal. Chem. 65 (1993) 2637-2642; D. J. Harrison, Z. Fan, K. Seiler and K.
  • the invention has for its object to implement a chemical micro-analyzer with a new concept of fluid handling to eliminate the problems mentioned.
  • An improvement is to be achieved with regard to the manageability of the system, the manufacturing costs and the accuracy in fluid metering and transport.
  • microfluid manipulators with a planar design are used to cope with the fluid handling, each of which consists of micro droplet emitters connected to a microfluidic diode via a closed droplet chamber, each of which chemical micro sensors provided for the actual analysis, preferably 2 micro fluid manipulators connected with calibration solutions, are connected upstream as an injector.
  • microfluid manipulators according to the invention with the microsensors produced in the same technology enables fluid handling without diaphragm pumps and micromechanical valves, with which absolute freedom from leaks is achieved since a complete fluidic decoupling between the metering fluid and the microfluidic diode is ensured when the microdrop emitter is off. Due to the use according to the invention of microdrop emitters which can emit fluids in individual droplets by means of the control frequency of piezoelectric actuators, an injection accuracy in the picoliter range is achieved.
  • micro-drop emitter and the micro-fluid diode which are components of the micro-fluid manipulator, is much simpler than that of micromechanical diaphragm pumps and valves, so that in addition to the smaller space requirement, the production is more cost-effective.
  • micro fluid manipulator MMF
  • MTE micro drop emitter
  • MFD micro fluid diode
  • the MFM consists of two main functional units, the MTE and the MFD.
  • dosing fluid droplets become into the droplet chamber 5 consisting of a gas-filled, closed cavity.
  • the fluid droplets emitted into the droplet chamber by the microdrop emitter wet the entrance surface of the MFD 6 which is used to couple the dosing fluid into the flow channel.
  • This microfluidic diode consists of a microcapillary open on both sides or a system of closely spaced microcapillaries, the ends of which adjoin the flow channel are inevitably wetted by the flowing liquid, the capillary action spreading the flowing liquid up to the opposite open end of the microcapillaries.
  • a defined liquid-gas interface a so-called meniscus, forms on each of these microcapillaries on the side of the droplet chamber. With the formation of each meniscus, the process of spreading the liquid in the corresponding microcapillary is abruptly completed and the flowing out of the flowing liquid from this microcapillary is completely prevented.
  • the MFD 6 is designed here, for example, as a network structure etched through Si with a mesh size of, for example, 30 ⁇ 30 ⁇ m 2 .
  • the outlet-side opening 7 of the MFD establishes the connection to a flowing target fluid.
  • the chemical microsensor 12 arranged in the further course of the capillary is constructed, for example, as already proposed in DE P 43 18 407, from an ISFET 12 installed in a fluid capillary, the sensitive surface of which is arranged in a sectional plane to the direction of flow in order to achieve optimum wetting with the measuring medium .
  • the capillary stopper 11 allows the required redirection of the flow direction while maintaining a planar construction.
  • FIGS. 3 and 4 show flow diagrams for configurations of chemical microanalysers, both of which can carry out the detection of an ion type on a pair (see FIG. 3) or parallel (see FIG. 4) of a pair of chemical microsensors.
  • the measuring fluid is continuously conveyed through the system through an independent flow channel from the MTE2.
  • This channel is shown at the top in FIGS. 3 and 4 and, with MTE1, positioned above the MFD, has the possibility of injecting the measuring fluid into the lower flow channel for the purpose of ionometric measurement.
  • FIG. 5 schematically shows the exemplary coupling between the upper and lower flow channels in the area of the MFD.
  • the lower flow channel of both FIGS. 3 and 4 also has two MTE elements, these are the MTE3 for injecting the calibration fluid K2 and the MTE4 for transporting all fluids through the lower flow channel.
  • the sensor pairs S1 / S2 in FIG. 3 and S / RE in FIG. 4 form the measuring points operated in the differential measuring mode.
  • the particular advantage of these two-channel arrangements is the constant refreshing of the measuring fluid at the injection point MTE1, i.e. H.
  • the measuring fluid which changes in its ion concentration, can be injected and measured at any time.
  • Chemical microanalysers as shown in FIGS. 3 and 4, thus consist of two separate flow channels, the flow channel for transporting and updating the measuring fluid and the flow channel for carrying out the measurement. Both flow channels are coupled to one another via a common MFD.
  • MTE1 to MTE4 there are active and passive states, are responsible for the existence of the corresponding procedure. During the active state, the MTE in question injects a fluid; in the passive state, this does not happen. H. Each MTE combines the functions of transporting and shutting off a fluid.
  • the representation of the procedures of the measuring systems from FIGS. 3 and 4 as a function of the MTE states is listed below.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
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Abstract

Chemical microanalyser for the dynamic multi-ion detection according to the difference measuring principle is claimed, in which the fluid to be analysed is reacted with carrier or calibrating fluids and the mixed and pure phases are ionometrically detected separately. The analyser consists of a chemical microsensor (12), microcapillaries (1) for fluid transport, and devices for handling the active fluid. The novelty is that, for fluid handling (moving, dosing), microfluid manipulators are arranged and consist of microdrop emitters connected via a closed chamber to a microfluid diode. Microfluid manipulators, pref., 2, are connected to each microsensor as injectors.

Description

Die Erfindung betrifft einen chemischen Mikro-Analysator zur Multiionendetektion in Fluidmedien unter Verwendung von chemischen Mikrosensoren auf der Basis der Differenzmessung.The invention relates to a chemical micro-analyzer for multi-ion detection in fluid media using chemical microsensors based on the difference measurement.

Das Problem Mikrofluidhandling mittels mikrotechnisch hergestellter Aktoren für chemische Analytik tauchte erstmals 1990 in dem Konzept "Miniaturized total chemical analysis system: a novel concept for chemical sensing" von Manz et al. auf [Sensors and Actuators B, 1 (1990) 244-248]. Bekannt ist bisher der Einsatz von Membranpumpen und mikromechanischen Ventilen auf der Basis der Si-Technologie in den Entwicklungsarbeiten von Mikroanalysesystemen. Van der Schoot et al. [A silicon integrated miniature chemical analysis system, Sensors and Actuators B6 (1992) 57-60] berichteten über die Verwendung von piezoelektrisch angetriebenen Mikropumpen und Mikroventilen auf mikromechanischem Wirkprinzip. Der Problemkreis diesbezüglich ist gegenwärtig noch nicht vollständig erfaßbar, da die Entwicklung noch am Anfang steht. Erkennbar sind momentan folgende Probleme. Mechanische Ventile können nicht absolut schließen. Leckraten von 0,25 bis 2,5 ul/min sind in der zitierten Arbeit angegeben worden. Die Nachweisgrenze ist dadurch eingeschränkt. Das zweite Problem ist der große Platzbedarf von solchen mikromechanischen Elementen. Das dritte Problem ist die aufwendige Technologie der Aufbau- und Verbindungstechnik, da die Pumpen- und Ventilstrukturen sehr kompliziert sind.The problem of microfluid handling using microtechnologically manufactured actuators for chemical analysis first appeared in 1990 in the concept "Miniaturized total chemical analysis system: a novel concept for chemical sensing" by Manz et al. on [Sensors and Actuators B, 1 (1990) 244-248]. The use of diaphragm pumps and micromechanical valves based on Si technology has so far been known in the development work of microanalysis systems. Van der Schoot et al. [A silicon integrated miniature chemical analysis system, Sensors and Actuators B6 (1992) 57-60] reported on the use of piezoelectrically driven micropumps and micro valves on a micromechanical principle. The problem area in this regard cannot yet be fully grasped, since the development is still at the beginning. The following problems can currently be identified. Mechanical valves cannot close absolutely. Leakage rates from 0.25 to 2.5 ul / min have been given in the cited work. This limits the detection limit. The second problem is the large space requirement of such micromechanical elements. The third problem is the complex technology of the assembly and connection technology, since the pump and valve structures are very complicated.

Bezüglich des Mikro-Fluidhandlings sind weiterhin Mikropumpen zum Transportieren von Fluiden nach dem Prinzip der Elektrohydrodynamik [A. Richter, A. Plettner, K. A. Hofmann and H. Sandmaier, Electrohydrodynamic pumping and flow measurement, 4th IEEE Workshop on Micro Electro-Mechanical Systems, 30.1 - 2.2.1991, Nara, Japan] und des elektroosmotischen und elektrophoretischen Pumpens [C. S. Effenhauser, A. Manz und H. M. Widmer, Glass chips for high-speed capillary electrophoresis separations with submicrometer plate heights, Anal. Chem. 65 (1993) 2637-2642; D. J. Harrison, Z. Fan, K. Seiler and K. Flurri, Miniaturized Chemical Analysis Systems based on Electrophoretic Separations and Electroosmotic Pumping, 7th Inter. Conf. on Solid-State Sensors and Actuators, June 7 - 10, 1993 Yokohama, Japan, Digest of technical papers, pp. 403-406] vorgestellt worden. In den zitierten Arbeiten werden Labormuster auf der Basis der mikrotechnischen Verfahren der Si-Technologie beschrieben. Beiden Prinzipien gemeinsam ist die Voraussetzung, daß ein starkes elektrisches Feld innerhalb des Fluids besteht, für dessen Erzeugung Spannungen von einigen hundert Volt bis Kilovolt und Elektroden in direktem Kontakt mit dem Fluidmedium erforderlich sind. Der Einsatz beschränkt sich auf nichtwässrige oder niederleitfähige Fluidmedien. Darüber hinaus besteht das Problem der Leckrate, die die Dosiergenauigkeit im Submikroliter-Bereich einschränkt.With regard to micro-fluid handling, micropumps for transporting fluids based on the principle of electrohydrodynamics [A. Richter, A. Plettner, K.A. Hofmann and H. Sandmaier, Electrohydrodynamic pumping and flow measurement, 4th IEEE Workshop on Micro Electro-Mechanical Systems, 30.1 - 2.2.1991, Nara, Japan] and electroosmotic and electrophoretic pumping [C. S. Effenhauser, A. Manz and H. M. Widmer, Glass chips for high-speed capillary electrophoresis separations with submicrometer plate heights, Anal. Chem. 65 (1993) 2637-2642; D. J. Harrison, Z. Fan, K. Seiler and K. Flurri, Miniaturized Chemical Analysis Systems based on Electrophoretic Separations and Electroosmotic Pumping, 7th Inter. Conf. on Solid-State Sensors and Actuators, June 7-10, 1993 Yokohama, Japan, Digest of technical papers, pp. 403-406]. In the cited works, laboratory samples are described based on the microtechnical processes of Si technology. Common to both principles is the prerequisite that there is a strong electric field within the fluid, for the generation of which voltages of a few hundred volts to kilovolts and electrodes in direct contact with the fluid medium are required. The use is limited to non-aqueous or low-conductivity fluid media. There is also the problem of the leak rate, which limits the dosing accuracy in the submicroliter range.

Der Erfindung liegt die Aufgabe zur Realisierung eines chemischen Mikro-Analysators mit einem neuen Konzept des Fluidhandlings zur Beseitigung der genannten Probleme zugrunde. Erreicht werden soll eine Verbesserung bezüglich der Handhabbarkeit des Systems, der Herstellungskosten sowie der Genauigkeit bei Fluiddosierung und Transport.The invention has for its object to implement a chemical micro-analyzer with a new concept of fluid handling to eliminate the problems mentioned. An improvement is to be achieved with regard to the manageability of the system, the manufacturing costs and the accuracy in fluid metering and transport.

Die Aufgabe wird entsprechen den Patentansprüchen erfindungsgemäß dadurch gelöst, daß unter Verzicht auf das bisherige Konzept mit mikromechanischen Membranpumpen und Ventilen, zur Bewältigung des Fluidhandlings planar aufgebaute Mikrofluidmanipulatoren eingesetzt werden, die aus jeweils über eine geschlossene Tröpfchenkammer mit einer Mikrofluiddiode verbundenen Mikrotropfenemittern bestehen, wobei jedem der für die eigentliche Analyse vorgesehenen chemischen Mikro-Sensoren vorzugsweise 2, mit Kalibrierlösungen verbundene Mikro-Fluidmanipulatoren als Injektor vorgeschaltet sind.The object is achieved in accordance with the invention in that, while dispensing with the previous concept with micromechanical diaphragm pumps and valves, microfluid manipulators with a planar design are used to cope with the fluid handling, each of which consists of micro droplet emitters connected to a microfluidic diode via a closed droplet chamber, each of which chemical micro sensors provided for the actual analysis, preferably 2 micro fluid manipulators connected with calibration solutions, are connected upstream as an injector.

Die erfindungsgemäße Kombination der Mikrofluidmanipulatoren mit den in gleicher Technik hergestellten Mikrosensoren ermöglicht ein Fluidhandling ohne Membranpumpen und mikromechanische Ventile, womit eine absolute Leckfreiheit erzielt wird, da im Aus-Zustand des Mikrotropfenemitters eine vollständige fluidische Entkopplung zwischen dem Dosierfluid und der Mikrofluiddiode gewährleistet ist. Auf Grund der erfindungsgemäßen Verwendung von Mikrotropfenemittern, welche mittels Steuerfrequenz piezoelektrischer Aktoren Fluide in Einzeltröpfchen emittieren können, wird eine Injektionsgenauigkeit im Pikoliter-Bereich erreicht. Die Konstruktion des Mikro-Tropfenemitter und der Mikro-Fluiddiode, welche Bestandteile des Mikro-Fluidmanipulators sind, ist wesentlich einfacher als jene bei mikromechanischen Membranpumpen und Ventilen, so daß neben des kleineren Platzbedarfs die Herstellung kostengünstiger ist.The combination of the microfluid manipulators according to the invention with the microsensors produced in the same technology enables fluid handling without diaphragm pumps and micromechanical valves, with which absolute freedom from leaks is achieved since a complete fluidic decoupling between the metering fluid and the microfluidic diode is ensured when the microdrop emitter is off. Due to the use according to the invention of microdrop emitters which can emit fluids in individual droplets by means of the control frequency of piezoelectric actuators, an injection accuracy in the picoliter range is achieved. The construction of the micro-drop emitter and the micro-fluid diode, which are components of the micro-fluid manipulator, is much simpler than that of micromechanical diaphragm pumps and valves, so that in addition to the smaller space requirement, the production is more cost-effective.

Unter Bezugnahme auf die beiliegenden Zeichnungen wird die erfindungsgemäße Lösung an folgenden bevorzugten Ausführungsbeispielen näher erläutert. Dabei wird für die Konstruktionselemente Mikro-Fluidmanipulator (MFM), Mikro-Tropfenemitter (MTE) sowie Mikro-Fluiddiode (MFD) die jeweilige Abkürzung verwendet.With reference to the accompanying drawings, the solution according to the invention is explained in more detail using the following preferred exemplary embodiments. The abbreviation is used for the construction elements micro fluid manipulator (MFM), micro drop emitter (MTE) and micro fluid diode (MFD).

In Fig. 1 ist der Schnitt durch eine beispielhafte Ankopplung eines MFM an eine mit dem Meßfluid durchströmte Kapillare, in deren weiterem Verlauf ein chemischer Mikrosensor 12 angeordnet ist, dargestellt. Der MFM besteht aus den zwei Haupt-Funktionseinheiten, dem MTE und der MFD. Die mit einer externen oder aber in den Chip integrierten Vorratskammer 13 für das Dosierfluid verbundene Kapillare 1, die Fluidkammer 2, die Emitterdüse 3 und der piezoelektrisch angetriebene auf der Fluidkammer 2 plazierte Aktor 4, bilden den MTE. Durch eine Spannungsbeaufschlagung des Aktors 4 werden Dosierfluidtröpfchen in die aus einem gasgefüllten, abgeschlossenen Hohlraum bestehende Tröpfchenkammer 5 emittiert Die vom Mikrotropfenemitter in die Tröpfchenkammer emittierten Fluidtröpfchen benetzen dort die Eingangsoberfläche der MFD 6 die zur Einkopplung des Dosierfluids in den Strömungskanal eingesetzt wird. Diese Mikrofluiddiode besteht aus einer beidseitig offenen Mikrokapillare oder einem System von dicht nebeneinander angeordneten Mikrokapillaren, deren im Strömungskanal anliegende Enden zwangsläufig von der strömenden Flüssigkeit benetzt werden, wobei durch die Kapillarwirkung die strömende Flüssigkeit bis zum gegenüberliegenden offenen Ende der Mikrokapillaren emporspreitet. Unter dem Einfluß der Oberflächenspannung der emporspreitenden Flüssigkeit bildet sich auf jeder dieser Mikrokapillaren auf der Seite der Tröpfchenkammer eine definierte Flüssigkeit-Gas-Grenzfläche, ein sogenannter Meniskus aus. Mit der Ausbildung jedes Meniskus wird der Vorgang des Spreitens der Flüssigkeit in der entsprechenden Mikrokapillare abrupt abgeschlossen und das Herausfließen der strömenden Flüssigkeit aus dieser Mikrokapillare vollständig verhindert. Wird nun das Dosierfluid in den Meniskusbereich der MFD emittiert, kommt es zur schlagartigen Benetzung zwischen beiden Flüssigkeiten und das Dosierfluid kann ohne Hinderung durch die Mikrokapillare in das Innere des Strömungskanales gelangen. Der ungehinderte Eintritt des Dosierfluids über den Meniskus erfolgt über Diffusion und Konvektion. Die MFD 6 ist hier beispielhaft als eine in Si durchätzte Netzstruktur mit einer Maschenweite von z.B. 30 x 30 u.m2 ausgebildet. Die ausgangsseitige Öffnung 7 der MFD stellt die Verbindung zu einem fließenden Ziel-Fluid her. Der im weiteren Verlauf der Kapillare angeordnete chemische Mikrosensor 12 ist z.B. wie in DE P 43 18 407 bereits vorgeschlagen aus, einem in einer Fluidkapillare installierten ISFET 12 aufgebaut, dessen sensitive Fläche zur Erzielung einer optimalen Benetzung mit dem Meßmedium in einer Schnittebene zur Strömungsrichtung angeordnet ist. Der Kapillar-Stopper 11 gestattet die geforderte Umlenkung der Strömungsrichtung unter Bewahrung einer planaren Konstruktion.1 shows the section through an exemplary coupling of an MFM to a capillary through which the measuring fluid flows, in the further course of which a chemical microsensor 12 is arranged. The MFM consists of two main functional units, the MTE and the MFD. The capillary 1, the fluid chamber 2, the emitter nozzle 3 and the piezo-electrically driven actuator 4 placed on the fluid chamber 2, connected to an external or integrated chip chamber 13 for the dosing fluid, form the MTE. By applying voltage to the actuator 4, dosing fluid droplets become into the droplet chamber 5 consisting of a gas-filled, closed cavity. The fluid droplets emitted into the droplet chamber by the microdrop emitter wet the entrance surface of the MFD 6 which is used to couple the dosing fluid into the flow channel. This microfluidic diode consists of a microcapillary open on both sides or a system of closely spaced microcapillaries, the ends of which adjoin the flow channel are inevitably wetted by the flowing liquid, the capillary action spreading the flowing liquid up to the opposite open end of the microcapillaries. Under the influence of the surface tension of the spreading liquid, a defined liquid-gas interface, a so-called meniscus, forms on each of these microcapillaries on the side of the droplet chamber. With the formation of each meniscus, the process of spreading the liquid in the corresponding microcapillary is abruptly completed and the flowing out of the flowing liquid from this microcapillary is completely prevented. If the metering fluid is now emitted into the meniscus area of the MFD, there is a sudden wetting between the two liquids and the metering fluid can get into the interior of the flow channel without hindrance by the microcapillary. The unhindered entry of the dosing fluid through the meniscus takes place via diffusion and convection. The MFD 6 is designed here, for example, as a network structure etched through Si with a mesh size of, for example, 30 × 30 μm 2 . The outlet-side opening 7 of the MFD establishes the connection to a flowing target fluid. The chemical microsensor 12 arranged in the further course of the capillary is constructed, for example, as already proposed in DE P 43 18 407, from an ISFET 12 installed in a fluid capillary, the sensitive surface of which is arranged in a sectional plane to the direction of flow in order to achieve optimum wetting with the measuring medium . The capillary stopper 11 allows the required redirection of the flow direction while maintaining a planar construction.

Fig. 2 zeigt ein Fließdiagramm für die beispielhafte gesamte Konfiguration eines chemischen Mikro- Analysators zur Detektion von 2 lonenkomponenten, z.B. NOa- und H+. Als chemische Mikrosensoren dienen ISFETs (ionensensitive Feldeffekttransistoren). pH-ISFETs sind an S1 und S2, und pN03-ISFETs an S3 und S4 plaziert. S2 und S3 sind jeweils 2 MFM vorgeschaltet, welche fluidisch mit Vorratsgefäßen für Kalibrierlösungen K1, K2 (für pH) und K3, K4 (für pN03) verbunden sind. Ausgangsseitig sind alle ISFETs fluidisch miteinander verbunden. ISFETs an S1 und S4 werden nur von Kalibrierlösung K2 bzw. K4 angeströmt und dienen als Referenzsensoren. ISFETs an S2 und S3 werden von Meß- und Kalibrierfluiden angeströmt und als Indikator-Sensoren benannt. Der MFM 5 am Eingang dient zur Einkopplung des Meß- bzw. Trägerfluids in den Analysator. Am Ausgang ist ein Mikrotropfenemitter (MTE - eine Komponente des MFM) installiert, welcher für den Fluidtransport durch das System sorgt. Die Differenzmessung erfolgt jeweils zwischen S1 und S2 bzw. zwischen S3 und S4 unter Verwendung einer Pseudoreferenzelektrode aus Platin (RE), welche am Ausgang der Fluidkapillare plaziert ist. Im Meßmodus erfolgt die Einkopplung des Meßfluids über den MFM 5. Im Kalibriermodus werden Kalibrierfluide durch den MFM 1/2 bzw. 3/4 in das System injiziert, während der MFM 5 in dieser Zeit kein Meßfluid einkoppelt. Die Steuerung des Fluidhandlings wird beispielhaft wie folgt organisiert:

  • MTE ist ständig aktuiert. Während der Kalibrierung bleibt MFM5 im Aus-Zustand, MFM 1...4 sind aktuiert. Im Meßmodus bleiben MFM 1...4 im Aus-Zustand und MFM 5 ist aktuiert. Während der Messung der Sensor-Offset-Signale bleiben MFM5, MFM1 und MFM3 im Aus-Zustand, dagegen arbeiten MFM2, MFM4 und der MTE.
2 shows a flow diagram for the exemplary overall configuration of a chemical micro-analyzer for the detection of 2 ion components, for example NO a - and H +. ISFETs (ion-sensitive field effect transistors) serve as chemical microsensors. pH ISFETs are placed on S1 and S2, and pN0 3 ISFETs are placed on S3 and S4. S2 and S3 are each connected upstream of 2 MFMs, which are fluidly connected to storage vessels for calibration solutions K1, K2 (for pH) and K3, K4 (for pN0 3 ). All ISFETs are fluidly connected to one another on the output side. ISFETs at S1 and S4 are only exposed to calibration solution K2 or K4 and serve as reference sensors. Measuring and calibration fluids flow towards ISFETs at S2 and S3 and are named as indicator sensors. The MFM 5 at the input is used to couple the measuring or carrier fluid into the analyzer. A microdrop emitter (MTE - a component of the MFM) is installed at the exit, which ensures fluid transport through the system. The difference is measured between S1 and S2 or between S3 and S4 using a pseudo-reference electrode made of platinum (RE), which is placed at the outlet of the fluid capillary. In the measuring mode, the measuring fluid is injected via the MFM 5. In the calibration mode, calibration fluids are injected into the system by the MFM 1/2 or 3/4, while the MFM 5 does not inject any measuring fluid during this time. The control of fluid handling is organized as follows, for example:
  • MTE is constantly updated. During the calibration, MFM5 remains in the off state, MFM 1 ... 4 are activated. In measuring mode, MFM 1 ... 4 remain in the off state and MFM 5 is activated. During the measurement of the sensor offset signals, MFM5, MFM1 and MFM3 remain in the off state, while MFM2, MFM4 and the MTE work.

In den Figuren 3 und 4 sind Fließdiagramme für Konfigurationen chemischer Mikroanalysatoren dargestellt, welche beide die Detektion einer lonensorte an einem seriell (vgl. Fig. 3) bzw. parallel (vgl. Fig. 4) liegenden Paar chemischer Mikrosensoren vornehmen können. In beiden Anordnungen wird das Meßfluid durch einen unabhängigen Strömungskanal vom MTE2 permanent durch das System gefördert. Dieser Kanal ist in den Figuren 3 und 4 jeweils oben dargestellt und besitzt mit MTE1, positioniert über der MFD, die Möglichkeit, daß Meßfluid zum Zwecke der ionometrischen Vermessung in den unteren Strömungskanal zu injizieren.FIGS. 3 and 4 show flow diagrams for configurations of chemical microanalysers, both of which can carry out the detection of an ion type on a pair (see FIG. 3) or parallel (see FIG. 4) of a pair of chemical microsensors. In both arrangements, the measuring fluid is continuously conveyed through the system through an independent flow channel from the MTE2. This channel is shown at the top in FIGS. 3 and 4 and, with MTE1, positioned above the MFD, has the possibility of injecting the measuring fluid into the lower flow channel for the purpose of ionometric measurement.

In Figur 5 ist die beispielhafte Verkopplung zwischen dem oberen und dem unteren Strömungskanal im Bereich der MFD schematisch dargestellt.FIG. 5 schematically shows the exemplary coupling between the upper and lower flow channels in the area of the MFD.

Der untere Strömungskanal beider Figuren 3 und 4 besitzt neben den Sensoren zur Kalibrierung und Vermessung ebenfalls zwei MTE-Elemente, dies sind der MTE3 zur Injektion des Kalibrierfluides K2 und der MTE4 zum Transport aller Fluide durch den unteren Strömungskanal. Die Sensorpaare S1/S2 in Fig. 3 und S/RE in Fig. 4 bilden die im Differenzmeßmodus betriebenen Meßstellen.In addition to the sensors for calibration and measurement, the lower flow channel of both FIGS. 3 and 4 also has two MTE elements, these are the MTE3 for injecting the calibration fluid K2 and the MTE4 for transporting all fluids through the lower flow channel. The sensor pairs S1 / S2 in FIG. 3 and S / RE in FIG. 4 form the measuring points operated in the differential measuring mode.

Der besondere Vorteil dieser Zweikanalanordnungen besteht in der ständigen Auffrischung des Meßfluids an der Injektionsstelle MTE1, d. h. das in seiner lonenkonzentration veränderliche Meßfluid kann zu jedem Zeitpunkt aktuell injiziert und vermessen werden.The particular advantage of these two-channel arrangements is the constant refreshing of the measuring fluid at the injection point MTE1, i.e. H. The measuring fluid, which changes in its ion concentration, can be injected and measured at any time.

Chemische Mikroanalysatoren, wie sie in den Figuren 3 und 4 dargestellt werden, bestehen damit aus zwei getrennten Strömungskanälen, dem Strömungskanal zum Transport und zur Aktualisierung des Meßfluides und dem Strömungskanal zur Ausführung der Messung. Beide Strömungskanäle sind über eine gemeinsame MFD miteinander verkoppelt.Chemical microanalysers, as shown in FIGS. 3 and 4, thus consist of two separate flow channels, the flow channel for transporting and updating the measuring fluid and the flow channel for carrying out the measurement. Both flow channels are coupled to one another via a common MFD.

Zur Erläuterung der Funktionsweise der Meßsysteme in Fig. 3 und 4 muß zwischen Offset-Kalibier- und Meßprozeduren differenziert werden. Die Zustände der MTE1 bis MTE4, es gibt den aktiven und den passiven Zustand, sind für das Vorliegen der entsprechenden Prozedur verantwortlich. Während des aktiven Zustandes injiziert der betreffende MTE ein Fluid, im passiven Zustand geschieht dies nicht, d. h. jeder MTE vereint in sich die Funktionen des Transports und der Absperrung eines Fluides. Die Darstellung der Prozeduren der Meßsysteme aus Figur 3 und 4 in Abhängigkeit der MTE-Zustände ist nachstehend aufgelistet.3 and 4, a distinction must be made between offset calibration and measurement procedures. The states of MTE1 to MTE4, there are active and passive states, are responsible for the existence of the corresponding procedure. During the active state, the MTE in question injects a fluid; in the passive state, this does not happen. H. Each MTE combines the functions of transporting and shutting off a fluid. The representation of the procedures of the measuring systems from FIGS. 3 and 4 as a function of the MTE states is listed below.

Figure imgb0001
Figure imgb0001

Claims (6)

1. Chemischer Mikro-Analysator zur dynamischen Multiionendetektion nach dem Differenz-Meßprinzip, bei dem das zu analysierende Fluid mit Träger- und/oder Kalibrierfluiden versetzt und sowohl die Mischals auch die Reinphasen getrennt ionometrisch detektiert werden, bestehend aus chemischen Mikro- sensoren, Mikrokapillaren für den Fluid-Transport sowie aus Einrichtungen für das aktive Fluid- Handling, dadurch gekennzeichnet, daß für das Fluid-Handling (Bewegen, Dosieren) Mikrofluidmanipulatoren angeordnet sind, die aus jeweils über eine geschlossene Tröpfchenkammer mit einer Mikrofluiddiode verbundenen Mikkrotropfenemittern bestehen, und daß jedem chemischen Mikro-Sensor vorzugsweise 2, mit Kalibrier- oder Meßlösungen verbundene Mikro-Fluidmanipulatoren als Injektor vorgeschaltet sind.1. Chemical micro-analyzer for dynamic multi-ion detection according to the differential measurement principle, in which the fluid to be analyzed is mixed with carrier and / or calibration fluids and both the mixed and the pure phases are separately detected ionometrically, consisting of chemical micro sensors, micro capillaries for the fluid transport and from devices for active fluid handling, characterized in that for fluid handling (moving, dosing) microfluid manipulators are arranged, each consisting of a micro droplet chamber connected to a microfluidic diode by a micro droplet chamber, and each chemical Micro-sensor preferably 2, connected with calibration or measurement solutions micro-fluid manipulators are connected upstream as an injector. 2. Chemischer Mikro-Analysator nach Anspruch 1, dadurch gekennzeichnet, daß sowohl für den FluidEinlaß als auch für den Fluid-Auslaß je ein Mikrotropfenemitter angeordnet ist, und daß jedem Indikator-Sensor vorzugsweise 2 Mikro-Fluidmanipulatoren als Injektoren für Kalibrier- oder Meßlösungen vorgeschaltet sind (Zwischen-Mikro-Fluidmanipulatoren), und daß alle von Meß- und Referenzlösungen angeströmten Indikator-Sensoren parallel oder in Reihe zwischen Ein- und Auslaß geschaltet sind, während die nur von Referenzlösung benetzten Referenz-Sensoren zwischen Auslaß und Kalibrierlösung angeordnet sind.2. Chemical micro-analyzer according to claim 1, characterized in that a microdrop emitter is arranged for both the fluid inlet and for the fluid outlet, and that each indicator sensor is preferably connected upstream of 2 micro-fluid manipulators as injectors for calibration or measurement solutions are (intermediate micro-fluid manipulators), and that all of the indicator sensors flowed from measuring and reference solutions are connected in parallel or in series between inlet and outlet, while the reference sensors, which are only wetted by reference solution, are arranged between outlet and calibration solution. 3. Chemischer Mikro-Analysator nach Anspruch 1 dadurch gekennzeichnet, daß für die Messung im Injektionsmodus ein Trägerfluid zwischen Ein- und Auslaß befördert und der Analyt durch einen der Zwischen-Mikro-Fluidmanipulatoren in das Trägerfluid injiziert wird.3. Chemical micro-analyzer according to claim 1, characterized in that a carrier fluid is conveyed between the inlet and outlet for the measurement in the injection mode and the analyte is injected into the carrier fluid by one of the intermediate micro-fluid manipulators. 4. Chemischer Mikro-Analysator nach Anspruch 1 dadurch gekennzeichnet, daß für die Messung im Durchflußmodus das Meßfluid durch den Eingangs-Mikro-Fluidmanipulator oder einen Zwischen-Mikro-Fluidmanipulator in das Meßsystem transportiert wird.4. Chemical micro-analyzer according to claim 1, characterized in that for the measurement in the flow mode, the measuring fluid is transported through the input micro-fluid manipulator or an intermediate micro-fluid manipulator in the measuring system. 5. Chemischer Mikro-Analysator nach Anspruch 1 dadurch gekennzeichnet, daß Indikator- und Referenz- Sensoren die gleiche Sensitivität bezüglich einer lonensorte besitzen.5. Chemical micro-analyzer according to claim 1, characterized in that the indicator and reference sensors have the same sensitivity with respect to an ion type. 6. Chemischer Mikro-Analysator nach Anspruch 1 dadurch gekennzeichnet, daß die Herstellung der Systemkomponenten und deren Montage zu einem gesamten System mittels mikrotechnischer Verfahren und mikrosystemtechnischer Aufbau- und Verbindungstechniken auf der Basis der Si-Glas-Technologie erfolgen.6. Chemical micro-analyzer according to claim 1, characterized in that the production of the system components and their assembly to an entire system by means of microtechnical methods and microsystem engineering and connection techniques based on the Si-glass technology.
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