US20060008386A1 - Supply element for a laboratory microchip - Google Patents

Supply element for a laboratory microchip Download PDF

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Publication number
US20060008386A1
US20060008386A1 US11129420 US12942005A US2006008386A1 US 20060008386 A1 US20060008386 A1 US 20060008386A1 US 11129420 US11129420 US 11129420 US 12942005 A US12942005 A US 12942005A US 2006008386 A1 US2006008386 A1 US 2006008386A1
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supply
microchip
element
substances
substance
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US11129420
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Manfred Berndt
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Agilent Technologies Inc
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Agilent Technologies Inc
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00Supporting devices; Holding devices
    • B01L9/52Supports for flat sample carrier, e.g. used for plates, slides, chips
    • B01L9/527Supports for flat sample carrier, e.g. used for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093Microreactors, e.g. miniaturised or microfabricated reactors
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502715Containers 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
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781Aspects relating to microreactors
    • B01J2219/00783Laminate assemblies, i.e. the reactor comprising a stack of plates
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781Aspects relating to microreactors
    • B01J2219/00801Means to assemble
    • B01J2219/0081Plurality of modules
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781Aspects relating to microreactors
    • B01J2219/00891Feeding or evacuation
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/025Align devices or objects to ensure defined positions relative to each other
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/026Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/04Exchange or ejection of cartridges, containers or reservoirs
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14Process control and prevention of errors
    • B01L2200/143Quality control, feedback systems
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/04Closures and closing means
    • B01L2300/041Connecting closures to device or container
    • B01L2300/043Hinged closures
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0645Electrodes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/18Means for temperature control
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0403Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0442Moving fluids with specific forces or mechanical means specific forces thermal energy, e.g. vaporisation, bubble jet
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00Moving or stopping fluids
    • B01L2400/04Moving fluids with specific forces or mechanical means
    • B01L2400/0475Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/25Chemistry: analytical and immunological testing including sample preparation
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/25Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/2575Volumetric liquid transfer

Abstract

A supply element for a laboratory microchip includes a sealed substance source. A seal in the substance source is opened in response to the supply element and the microchip being joined together. While the seal is open, the substance is transferred from the substance source to a supplier in the microchip. The substance is moved from the supplier in the microchip to the microfluid structure by applying a potential to the microchip. The supply element is releasably attached to the supply equipment by releasably attaching the supply element with a bayonet lock.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This application is a continuation and claims priority under 35 U.S.C. §120 of application Ser. No. 09/598,890, filed Jun. 22, 2000, which claims priority under 35 U.S.C. §119 based on German Application No. 199 28 412.1, filed Jun. 22, 1999, the disclosures of which are incorporated by reference in their entireties.
  • BACKGROUND OF THE INVENTION
  • [0002]
    1. Field of the Invention
  • [0003]
    In general, the present invention concerns microchip laboratory systems that carry out chemical and chemical-physical, physical, biochemical and/or biological processes, especially for analyzing or synthesizing substances on a substrate with a microfluid structure by means of controlling the movement of substances on the substrate electronically, mechanically or in another manner. In particular, the invention concerns a supply element for such a microchip that has a first supplier to supply substances and a second supplier to transmit the potential necessary for moving the substances corresponding to the microfluid structure.
  • [0004]
    2. Background Art
  • [0005]
    The continuous development in this area is best illustrated by a comparison with corresponding developments in the field of microelectronics. In addition, in the field of chemical analysis (for example, in the areas of chromatography or electrophoresis), there is a substantial need to integrate existing stationary laboratory devices into portable systems and correspondingly miniaturize them for laboratory and clinical diagnostics. An overview of the most recent developments in the field of microchip technology is found in a collection of relevant professional publications edited by A. van den Berg and P. Bergveld and published by Kluwer Academic Publishers (Holland, 1995), Micro Total Analysis Systems. The starting point for these developments was the established method of capillary electrophoresis. Efforts had been made in the past to implement this method on a planar glass microstructure.
  • [0006]
    The basic required components for such a microchip system are shown in FIG. 1. They are basically divided into systems that have a material flow 1, and systems that represent an information flow 2 that occurs during an experiment. In the area of the material flow 1, means are necessary to supply 3 and transport 4 substances on the chip, and means are required to treat or pretreat 5 the investigated substances. Furthermore, sensors are required for detection of the results of an experiment. The arising flow of information is essentially for controlling substance transport on the chip using, e.g., control electronics 7. In addition, information flow occurs while processing the signals in the signal processing step 8 of the detected measured results, and especially while evaluating or interpreting them 9. Additional needed transport steps 4′, 4″, and 4′″ are also shown.
  • [0007]
    Further motivation for corresponding miniaturization in the chemical analysis field is to minimize the transport paths of the substances, especially between the substance supply and the respective detection point of a possibly occurring chemical reaction (see FIG. 2). It is known from the liquid chromatography and electrophoresis fields that substances can be separated more quickly in such systems (and test results are, therefore, available more quickly), and that individual components can be separated with greater resolution than is possible in conventional systems. In addition, the amount of substances (especially reagents) that micro-miniaturized laboratory systems use is greatly reduced, and the substance components are mixed much more efficiently.
  • [0008]
    The above-mentioned background is detailed in an article by Andreas Manz et al. on page 5 ff. of the above-cited collection. The article also states that the authors have already manufactured a microchip consisting of a layer system of individual substrates that permits a three-dimensional transport of substances.
  • [0009]
    In contrast to creating a micro-laboratory system on a glass substrate, systems are mentioned in the above-cited article that utilize a silicon-based microstructure, including apparently already-integrated enzyme reactors (e.g., for a glucose test), micro-reactors for immunoassays, and miniaturized reaction vessels for DNA quick assays using the polymerase chain reaction method.
  • [0010]
    A microchip laboratory system of the initially cited type is also discussed in U.S. Pat. No. 5,858,195, where the relevant substances are moved by a system of connected channels integrated in a microchip. The movement of these substances in these channels can be precisely controlled using electrical fields that are applied along the transport channels. Given this highly accurate control of substance movement, together with very exact dosing of the moved substances, the substances can be precisely mixed or separated, and/or a chemical or physical-chemical reaction can be induced with the desired stoichiometry. In this laboratory system, the integrated channels also have numerous substance reservoirs that contain the necessary substances for chemical analysis or synthesis. These substances are also moved out of the reservoirs along the transport channels by means of electrical potential differences. The substances moved along the transport channels, therefore, contact different chemical or physical environments that allow the necessary chemical or chemical-physical reaction to take place among the respective substances. In particular, the prior art substrate has one or more transport channel intersections at which substances are mixed. By simultaneously using different electrical potentials at different substance reservoirs, the volumetric flow of the various substances through one or more intersections can be selectively controlled. A precise stoichiometric template is, therefore, possible based just on the applied electrical potentials.
  • [0011]
    By means of the cited micro-technology, complete chemical or biochemical experiments can be carried out using microchips tailored to respective applications. Supplying the microchip with the substances to be investigated, as well as the existing reagents, is of decisive importance.
  • [0012]
    In handling microchips in measurement set-ups for experiments, the chip of the measuring system must be easily exchangeable, and the measuring set-up must be easily adaptable to different microchip layouts. This adaptability is related not only to the respective arrangement of the substance reservoirs, but also to the high voltage necessary for moving the substances on the chip, and the corresponding application of the voltage to the microchip. Such a measuring set-up, therefore, requires running electrodes to the contact surfaces correspondingly provided on the microchip, together with devices to supply the substances to the cited reservoirs. In particular in the cited cases, the microchip dimensions range from a few millimeters to approximately 1 centimeter, which makes the chip relatively difficult to handle.
  • [0013]
    Moving substances by high voltage is, however, only one of several variations. For example, the force or potential difference necessary to move the substances can also be created by applying a pressurized medium, preferably compressed air or another suitable gas medium such as a rare gas. The movement of the substances can also be generated by a suitable temperature gradient where the movement is effected by thermally expanding or compressing the respective substance.
  • [0014]
    In particular, the selection of the respective medium to provide the potential or force to move the substances on the microchip depends on the physical properties of the substances themselves. With substances that have charged particles, for example, charged or ionized molecules or ions, the substances are preferably moved using electrical or electromagnetic fields of suitable strength. The paths travelled by these substances depend in particular on field strength and how long the field is applied.
  • [0015]
    In contrast, electrically uncharged substances are preferably moved using a flow medium such as compressed air. Given the very small dimensions of the transport channels in the microchip, only a relatively small volume of air, on the level of picoliters, is required. For substances that have a relatively large coefficient of thermal expansion, a thermal procedure may be desirable to move them, but only when the resulting increase in temperature does not influence reaction kinetics during the experiment.
  • [0016]
    Given the potential complexity of the reactions, the number of required contact electrodes can be several hundred or more. In addition, these substances can be moved in transport channels of any three-dimensional design, e.g., in troughs or grooves, or hollow channels that are enclosed on all sides. Hollow channels can be filled with a liquid or gelatinous buffer medium to further control or adjust the precise flow rates of these substances. The flow rates can be very precisely set by the applied electrical fields based on the movement of charged particles through such a gel.
  • [0017]
    By using a buffer gel or buffer solution, mixtures of charged molecules can be advantageously moved through the medium by an electrical field. Several electrical fields can be applied simultaneously or sequentially to separate substances or correspondingly supply the respective substances on a precise schedule, possibly with different time profiles. This procedure can be used to create complex field distribution or fields that migrate beyond the separating medium. Charged molecules that travel through gels with a greater degree of mobility than through other substances can thereby be separated from slower substances with less mobility. The precise spatial and temporal distribution of the fields can be determined by corresponding control or computer programs.
  • [0018]
    In addition, micromechanical or micro-electromechanical sensors are presently being considered for use in the cited area of microfluid technology, e.g., micromechanical valves, motors or pumps. A perspective on possible future technologies in this field is provided in a relevant article by Caliper Technologies Corporation.
  • [0019]
    When this new technology becomes accepted by the affected circle of users, the cited microchip will quickly become a mass-produced article and catch on, similar to immunoassays as quick tests in laboratory and clinical diagnostics. There is, therefore, a substantial need for a measuring set-up to practically handle and operate such a microchip that allows for an easy and especially low contamination or contamination-free supply of the investigated substances, possibly along with the necessary reagents for the respective experiment. There is also a need for a highly simplified method to handle the microchips to make them easy to use in the cited laboratory environment by chemistry or biology lab assistants, who generally have a relatively low level of technical skill.
  • [0020]
    This would also allow corresponding large-scale acceptance of the chip and relatively easy and quick evaluation of the measuring results. In addition to the appropriate and easy manipulation of the chip, users should have to deal as little as possible with the cited supply devices for supplying the microchips with the cited substances (and especially any required high voltage) or any other necessary technical devices.
  • [0021]
    It should be noted that the connecting elements between the supply lines of the supply devices and corresponding means of conveyance on the microchip are subject to more-or-less strong mechanical, electrical and/or chemical wear or corrosion, and often are heavily soiled when they are in direct contact with the substances on the microchip. Yet, the utilized substances (especially reagents) in many of the relevant chemical experiments require an extremely high degree of purity. The slightest impurity in the supply lines can torpedo measurement results. In addition, a generic device should be easily and quickly convertible for measurements using microchips with different layouts.
  • SUMMARY OF THE INVENTION
  • [0022]
    The cited problems are solved with a supply element according to the present invention by providing a laboratory microchip having a supply element including a first substance-containing suppliers that, in turn, has seals which open the first supplier to the microchip when the supply element and microchip are joined, thereby allowing for transfer of the substance from the supply element to the microchip.
  • [0023]
    The suggested supply element according to the present invention hence allows the microchip to be supplied easily according to the cited requirements with the substances needed for the respective experiment. According to a first embodiment, the supply element can serve merely as an intermediate storage for the substances to be investigated and/or the reagents required for the respective experiment and can, e.g., be removed from the microchip after transferring the substances from the supply element to the microchip. Afterwards, the required supply equipment for operating the microchip, e.g., an electrical power supply, can be brought into contact with the microchip.
  • [0024]
    According to an alternative embodiment, the supply element can have other supply lines, in addition to the cited supply lines for the substances, that bridge corresponding supply lines of the supply equipment to the microchip. In this embodiment, the supply element can remain connected to the microchip after the substances are transferred to the microchip and need not be removed prior to performing an experiment.
  • [0025]
    A particular advantage of all the alternative embodiments of the supply element is that only the supply element directly contacts the microchip and, therefore, be subject to soiling or wear. The supply element can also be advantageously exchanged with new elements between individual experiments to minimize the danger of cross-contamination by substances on the microchip.
  • [0026]
    In addition, the supply element allows any supply equipment to be easily and quickly adapted to different microchip layouts.
  • [0027]
    The suggested supply element preferably has electrodes or supply channels for supplying the microchip with electrical, mechanical or thermal energy by which the necessary potential can be generated for the microfluid movement of substances on the microchip. If the substances on the microchip are moved by means of a compressed gaseous medium, such as compressed air, supply channels are provided in the supply element to supply the microchip with the respective compressed gaseous medium.
  • [0028]
    In an embodiment where additional suppliers are provided to supply the microchip with at least some of the necessary substances to operate the microchip, the supply element has corresponding supply channels to supply the microchip with these substances. It must be emphasized in this context that the supply lines for the power supply and the supply channels to supply the microchip with the substances can be designed as a single unit, for example, metallic hollow tubes, through which electrical power can be supplied to the microchip in addition to the substances.
  • [0029]
    The supply element according to the invention can also be formed by a substrate consisting especially of a ceramic or polymer material in which the cited electrodes or supply channels are embedded. With these materials, the interface element can be highly resistant to the utilized chemical substances, and can also be easily cleaned with chemicals and then reused.
  • [0030]
    In an advantageous development of the inventive idea, the supply element can be affixed to the supply equipment by a bayonet lock. Such an attachment allows the supply element to be easily and quickly exchanged, e.g., after an experiment.
  • [0031]
    For identification purposes, a first coder can be included on the supply element that interacts with a corresponding second coder on the corresponding supplier. This measure makes the device according to the invention particularly safe to use, since it effectively prevents accidentally using or installing a supplier incompatible with the supply element. To further increase operational reliability, a magnetic sensor (especially a Hall sensor) can be provided to identify the supply elements, or a shut-off or warning device that works with the sensor can be provided.
  • [0032]
    Finally, the microchip can be in a first assembly, and the supply equipment as well as the supply element can be in a module releasably connected to a second assembly.
  • [0033]
    The module is preferably designed as an insertable cassette or cartridge. The entire device can be designed to be set up as a stationary unit or a portable device for ambulatory local experiments, e.g., for a patient.
  • [0034]
    Other tasks, advantages, and features of the device according to the invention can be found in the following detailed description of the exemplary embodiments.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0035]
    Shown in particular are:
  • [0036]
    FIG. 1 is a schematic block diagram of the functional components required for a laboratory microchip system under discussion;
  • [0037]
    FIG. 2 is a view of laboratory microchip for use with a supply element according to the invention;
  • [0038]
    FIG. 3 is a block diagram of an exemplary embodiment of the device according to the invention for operating a laboratory microchip;
  • [0039]
    FIGS. 4 a 1, 4 a 2, 4 b 1, and 4 b 2 are sectional and perspective side views of a supply element according to the invention;
  • [0040]
    FIGS. 5 a-5 d is a sequence of illustrations of the operating steps of another embodiment of the invention, especially with an exchangeable cartridge to receive a supply element according to the invention; and
  • [0041]
    FIGS. 6 a and 6 b is an exemplary embodiment of a device according to the invention in which two assemblies are connected to each other by means of an articulation.
  • DETAILED DESCRIPTION OF THE DRAWINGS
  • [0042]
    The functional components required for the laboratory microchip system under discussion and the typical functional sequence in an experiment using such a system are schematically represented in FIG. 1. In this functional sequence, a microchip (outlined in FIG. 2) is required. In this representation, a distinction is drawn between the material flow 1 that arises in such a system (i.e., the investigated substances or the reagents used) and the information flow 2 in relationship to the controlled movement of the individual substances on the microchip, and in relation to the detection of the experimental results.
  • [0043]
    The substances to be investigated (possibly along with the required reagents for the respective experiment) are first fed to a supply area of the microchip, where the material is to flow. Then the substances are moved or transported 4 on the microchip (e.g., by means of electrical force in the case of ionized substances). Both the supply and the movement of the substances are effected by suitable control electronics 7 as indicated by the broken line. In the present example, the substances are pretreated before they are subjected to the actual experiment. They can be, e.g., preheated by a heater or precooled by a suitable cooling device to precisely reproduce thermal test conditions. Of course, the temperature of a chemical experiment normally substantially influences the experimental kinetics. As indicated by the arrow, this pretreatment can also be sequential, whereby a pretreatment step 5 and another transport step 4′ are correspondingly triggered. The cited pretreatment is particularly useful for separating substances so that only specific components of the starting substance will be available for the respective experiment. Both the amount of substance (quantity) and rate of the substance (quality) can be determined by the described means of transport. By precisely setting the amount of substance, the individual substances or substance components can be precisely dosed. These procedures are also preferably controlled by means of the control electronics 7.
  • [0044]
    The actual experiment may occur after several pretreatments; the experimental results can be detected 6 at a suitable detection point on the microchip. The means of detection are preferably optical, e.g., a laser diode is in conjunction with a photocell, or a conventional mass spectrometer. The resulting optical measurement signals are sent to a signal-processing device for signal processing in ohp 8 and then to an evaluation unit (e.g., a suitable microprocessor) for interpretation 9 of the measurement results.
  • [0045]
    After the above-cited detection 6 occurs, other test series, analyses or substance separations can occur, concerning, for example, various stages of a complex chemical experiment. To this end, the substances are transported further 4′ after the first detection step 6 and moved to a different detection point for another detection step 6′. At this point, steps 4′ and are basically repeated. Finally, the substances are supplied to a drain (pot shown) in a final transport step or collection step 4′ following completion of all reactions or experiments.
  • [0046]
    FIG. 2 shows a typical laboratory microchip suitable for use in connection with a suggested supply element according to the invention. Referring first to the technical design of such a microchip, which substantially influences the design of the device according to the invention, microfluid structures have been created in the displayed top of a substrate or carrier 20 to receive and transport the substances. The substrate 20 can, e.g., be made of glass or silicon, and the structures can be created by chemical etching or laser etching.
  • [0047]
    There are one or more recesses 21 on the substrate that serve as reservoirs for the investigated substance (termed “substance sample” in the following) to be applied to the microchip. In the experiment, the substance sample is first moved along a transport channel 25 in the microchip. In the present exemplary embodiment, the transport channel 25 is formed by a V-shaped trough. However, any other design is possible for the transport channels, e.g., recesses or grooves with rectangular or circular cross-sections.
  • [0048]
    The reagents required for the experiment are introduced into other recesses 22, also serving as substance reservoirs. The present example concerns two different substances, which are first via corresponding transport channels 26 to an intersection 27, where they mix and (possibly after a chemical reaction) form the reagent that is finally used. This reagent contacts the substance sample to be investigated at another intersection 28, where both substances mix.
  • [0049]
    The substance formed in this manner then passes through a meandering transport channel section 29 that basically serves to artificially lengthen the path available for the reaction between the substance sample and the reagents. In another recess 23 serving as a substance reservoir, there is another reagent which, in the present example, is fed to the existing substance mixture at another intersection 31.
  • [0050]
    In this example, it is assumed that the actual investigated substance reaction occurs directly after the cited intersection 31, and the reaction can be detected within an area or measuring field 32 of the transport channel by means of a detector (not shown), preferably without contact. The corresponding detector can be above or below the area 32. After the substance passes through the cited area 32, it is fed to another recess 24 that forms a drain for waste created during the reaction.
  • [0051]
    Recesses 33 in the microchip serve as contact surfaces for introducing electrodes, and allow the required electrical or high voltage to operate the microchip. Alternatively, the chip can be contacted by directly introducing corresponding electrode tips into the recesses 21, 22, 23, 24 provided for receiving the substances. By suitably arranging the electrodes 33 along the transport channels 25, 26, 29, 30 and correspondingly harmonizing the sequence and/or strengths of the fields used, the individual substances can be moved according to a precisely set sequence and rate so that the kinetics of the basic reaction process can be precisely controlled or maintained.
  • [0052]
    When the substances are moved within the microfluid structure propelled by compressed gas (not shown), it is necessary to design the transport channels as enclosed pathways, e.g., as hollow channels with any desired cross-section. With this embodiment, the recesses 33 must be designed so that the corresponding pressure supply lines end in the enclosed pathways in a sealed manner so that a compressed medium (such as air) can be introduced into the transport channels.
  • [0053]
    A typical design of the overall device to handle and operate the microchip having a supply element according to the invention is explained with reference to FIG. 3. The individual components of the entire device are strictly modular to allow the greatest possible flexibility when operating the device. A first assembly 50 has a mounting plate 51 to receive the initially described microchip 52. In this example, the microchip 52 contains two different types of connecting elements: Recesses 53 receive electrical contacts to provide the required electrical voltage for moving the substances on the microchip. Recesses 53 can either serve as a mechanical seat for electrode tips, or they themselves represent electrodes, e.g., by suitably metallizing the inner surface of the recesses. In addition, the possibly metallized recesses can be connected with other electrode surfaces (not shown) on the microchip that provide the required electrical field to move the substances. Such electrode surfaces can also be manufactured using prior art coating techniques.
  • [0054]
    Optional recesses 54 can be provided to accept substances, especially reagents. In addition, a second assembly 55 is provided that contains the required supply device 56 for operating the microchip 52. By suitably miniaturizing the required components, the supply device 56 preferably represents a microsystem that provides the required electrical voltage or compressed medium via corresponding electrodes 58 (or lines 58 for a pressure supply system) in the form of a cartridge that can be inserted in the assembly. If the microchip is supplied with electricity, the electrical voltage supply can be miniaturized using conventional integrated circuitry; if pressure is supplied, the miniaturization can be provided by corresponding techniques familiar in the fields of modern laboratory technology or micromechanics. The supply containers for the compressed gas can also be integrated since, as noted, the required gas volume is in the picolitre range.
  • [0055]
    In the shown exemplary embodiment, the supply element according to the invention has electrical linkages or connecting channels 60 that bridge the electrodes 58 or the channels of the supply device 56 and the recesses 53 of the microchip. On one hand, bridging serves to prevent wear and soiling of the electrodes of the supply device 56 that can occur when the microchip is contacted such that the supply element basically assumes this function as a disposable product. As shown in the present exemplary embodiment, the supply element can also serve to spatially adapt the supply device 56 electrodes to the respective surface or spatial arrangement of the microchip's electrode surfaces. The entire measuring and operating device can be advantageously adapted to a special microchip layout, just by exchanging the supply device 56 and/or supply element 57. In particular, by exchanging the entire supply device, the handling device can be quickly and easily adapted to different test series or types of operation as, for example, when changing from an electrical to pressure supply of the microchip.
  • [0056]
    Two exemplary embodiments of a supply element according to the invention are described with reference to FIGS. 4 a 1, 4 a 2, 4 b 1, and 4 b 2. FIGS. 4 a 1 and 4 a 2 are sectional views and FIGS. 4 b 1 and 4 b 2 are corresponding perspective side views of the two embodiments. The shown supply element illustrates a typical state before the supply element is joined with a microchip (not shown).
  • [0057]
    It should be noted that the suggested supply element (as discussed in detail with reference to FIGS. 5 a-5 d in relation to the two different embodiments) can also be designed to function as a transport medium to supply the substances to the microchip, and as a bridging medium or intermediate carrier to advantageously bridge electrodes or the like, as described, to supply the microchip with the force required to move the substances on the microchip. This contrasts with the above-described embodiment, where the element only serves to supply the microchip with substances and is not used again after supplying them. When both purposes are fulfilled, it serves a dual function.
  • [0058]
    In the embodiment of FIGS. 4 a 1 and 4 b 1, the supply lines (hollow tubes or channels) 70 for transferring substances are designed as capillaries or cavities that extend above an interface element with respect to the side surfaces thereof and are sealed at ends 79 with, e.g., wax or filling compound so that the supply lines 70 are air- and gas-tight to the outside.
  • [0059]
    In the embodiment of FIGS. 4 a 2 and 4 b 2, the ends of the supply lines 79′ are flush with the respective side surfaces of the interface element and are sealed to the outside with a flush membrane 69 on both sides. The supply lines 79′ hidden or invisible under the membrane 69 are also indicated here by circles and semicircles drawn in broken lines. The membrane 69 is only occasionally penetrated by the provided electrodes or contacts (contact pins) 76, 78. The contacts form an electrically conductive connection with the corresponding counter electrodes provided for the supply device or on the microchip without the membrane 69 having to be penetrated. The membrane can also, for example, be a metal film for a gas-tight seal or made of a gas permeable material such as a polymer.
  • [0060]
    The substances 72 in the hollow paths 70 can be moved in two ways: The membrane 69 can be penetrated on both sides in the area of the supply lines 70, and the substances can be propelled merely by capillary force from the interface element to the microchip without other required measures. In one variation, however, the membrane 69, formed of a chemically resistant material, is only penetrated on one side, and the sealed part of the membrane 69 is pressurized with a gas so that the substance at the open side of the membrane 69 automatically exits due to the rise in pressure in the supply line 70. The pressure is supported by the entrance of gas into the cavity when a gas-permeable membrane is used.
  • [0061]
    In FIGS. 4 a 1, 4 a 2, 4 b 1, and 4 b 2, the shown supply element for both embodiments has supply lines or reservoirs 70 that serve to supply the microchip (not shown) with the required substances or reagents 72 for the respective experiment. The supply lines 70 in the embodiment of FIGS. 4 a 1 and 4 b 1 are capped or sealed at both ends 79 by means of, e.g., wax 71 to effectively prevent the substances 72 from leaving the supply element and/or to prevent contamination of the substances 72 contained therein prior to the experiments. The seal can be created with known means using vacuum technology so that the substances 72 remain airtight prevent contact with environmental air. Different substances A, B and C are contained in the supply channels or lines 70 in both embodiments. The supply lines that contain substances A and B are designed as tubular sections, and the line containing substance C has an offset 73 inside of the carrier of the supply element. In particular, the offset 73 serves to spatially adapt lines of a supply system joined with one side of the supply element and corresponding supply means on the side of the microchip. Different microchip layouts can be operated with the same operating or supply device, whereby the required adaptation of the lines or contacts is carried out solely by the supply element suggested according to the invention.
  • [0062]
    With the supply element in FIGS. 4 a 1 and 4 a 2, supply lines 74, 75 are provided for both embodiments that are designed in the present example as contact pins to transfer electrical voltages from the supply device to the microchip and provide the required electrical potential for moving the substances corresponding to the microfluid structure of the microchip. Contact pins 74, 75, therefore, have corresponding contacts 76, 78 on both ends. Supply lines 74, 75 can also have spatial adaptations (a side offset 77 in the present case) between the electrical lines of a supply device and the corresponding contacts on the microchip through a corresponding path in the substrate. In addition, conventional seals can be provided on the ends 79 of the supply lines 70 to effectively prevent substances from flowing out after establishing a substance-conducting connection between the supply element and the supply device or the microchip. In the embodiment of FIGS. 4 b 1 and 4 b 2, the hollow paths (channels) 70 are efficiently sealed to the outside by pressing on the membrane 69.
  • [0063]
    FIGS. 4 b 1 and 4 b 2 are corresponding perspective views of the supply element shown in FIGS. 4 a 1 and 4 a 2, whereby corresponding functional parts are given identical reference numbers. A further description of this partial figure would, therefore, be superfluous.
  • [0064]
    A typical procedure for handling or operating a microchip using a supply element according to the invention having the above-described dual functionality is explained with reference to the schematic sequence of illustrations in FIGS. 5 a-5 d, in which corresponding components are designated with the same reference numbers.
  • [0065]
    FIG. 5 a shows a cartridge 80 in which is integrated a supply system (not shown) for a microchip. The supply lines of the supply system lead to the outside via a corresponding contact electrode field. In the present exemplary embodiment, this electrode field is designed as an exchangeable contact plate 81 made, e.g., of a ceramic. The cartridge is connected to the internal basic supply system (not shown) of the entire handling device via plug connections 82 that mate conventionally with corresponding counterpieces in a second assembly, and activate corresponding contact connections when the cartridge is inserted into the assembly.
  • [0066]
    In the present example, the contact electrodes of the supply system make contact with corresponding contacts on the microchip via a supply element 83 according to the invention in such a way that the contact electrodes are bridged without changing their spatial arrangement in relationship to the microchip. The basic advantages of the supply element 83 have already been described. The supply element is releasably connected to the cartridge via a bayonet lock 84, 85. A corresponding bayonet thread 85, provided on the cartridge 80, receives a bayonet 84. The bayonet lock 84, 85 allows the supply element 83 to be quickly and easily exchanged as a replacement or disposable part, e.g., after each experiment.
  • [0067]
    In the present exemplary embodiment, first coders 100, 100′ operate according to the pin/hole principle to identify the supply element and work together with corresponding second coders 101, 101′ on the supply equipment. The first and second coders 100, 100′, 101, 101′ ensure that only a supply element compatible with the corresponding supplier can be used or, respectively, inserted in the cartridge 80. To further increase operational reliability, a magnetic sensor (not shown), especially a Hall sensor, can be provided to identify the supply element, and a shut-off or warning device that works with the sensor can also be provided. In addition to the shown embodiment that uses a pin and hole, other coding means can be used such as electrical/magnetic coding, or recognition of corresponding ID chip cards, or optical coding, e.g., a color code, bar code, etc.
  • [0068]
    It should also be noted that the supply element according to the invention can be modular and correspondingly multifunctional. This functionality can, for example, be realized by a multilayer arrangement of channels including supply lines that correspondingly lead outward. It is, for example, possible to switch between experiments lead outward. It is, for example, possible to switch between experiments that use the same microchip by simply rotating the supply element on its axis (e.g., by 90°). Different channels or channel systems can be activated in the microchip, depending on respective rotational angle. In particular, the existing rotational angle can correspondingly connect different supply lines of the supply element to different channels.
  • [0069]
    The supply element can be advantageously very thin or flat, e.g., in the form of a bank card, to facilitate easy use. To prevent accidents, suitable seals can be provided in the lines or channels of the supply element to externally insulate the high voltage that may be required to operate the microchip. Alternatively, when a flow of substance or gas is used, suitable seals can be provided to prevent the substances from escaping after connection of the supply element to the supply device and microchip.
  • [0070]
    FIGS. 5 b and 5 c show individual installation steps for installing the supply element 83 in the cartridge 80. As shown in FIG. 5 b, the supply element 83 is first inserted into the cartridge 80 in the installation position and then, as shown in FIG. 5 c, affixed to the cartridge 80 by means of the bayonet lock 84, 85. A ring section 86 of the bayonet 84 mates with the corresponding bayonet thread 85. Another advantage of the cartridge or module suggested according to the invention is shown in FIGS. 5 b and 5 c, wherein, the supply element 83 can be easily installed in the cartridge 80 after the cartridge 80 is removed from the second assembly.
  • [0071]
    FIG. 5 d shows how a correspondingly preassembled cartridge can be installed in a device housing 87 containing all the cited assemblies. In the shown exemplary embodiment, the cartridge 80 is inserted into a slot in a second assembly 88. However, other fixing means are conceivable, e.g., a snap or magnetic lock. When the second assembly 88 is closed, it contacts the first assembly 89, which serves to receive the microchip, and automatically creates the necessary contact connections for operating the microchip.
  • [0072]
    Finally, FIGS. 6 a and 6 b schematically illustrate an embodiment of the device housing 87 corresponding to FIG. 5 d, where the two components 88, 89 according to the invention are connected via an articulation 90. The advantageous spatial arrangement of the articulation is such that contact pins 93 on a supply element 91 do not become skewed when they are inserted in the assigned recesses in the microchip which, in a worse-case scenario, could destroy the contact pins 93 or even the microchip 92.
  • [0073]
    In conclusion, the objects of the present invention are achieved by providing a supply element for a laboratory microchip (elements 20 or 52, for example) with a microfluid structure for at least one of chemical, physical, or biological processing, the microchip having a first supplier (element 54, for example) to supply substances to the microchip, and a second supplier (element 53, for example) to supply a potential to the microchip to move substances corresponding to the microfluid structure, the supply element comprising at least one substance-containing third supplier (elements 61 or 70, for example) to contain a substance, the at least one third supplier having a seal (elements 69 or 71, for example) arranged to be opened to the microchip in response to the supply element and the microchip being joined together to enable the substance to be transferred from the at least one third supplier to the first supplier of the microchip.
  • [0074]
    The supply element noted above may also include a fourth supplier (elements 74 or 75, for example) to transfer the potential to the microchip, the fourth supplier being arranged to be coupled to the corresponding second supplier on the microchip.

Claims (15)

  1. 1. A supply element for a laboratory microchip with a microfluid structure for at least one of chemical, physical, or biological processing, the microchip having a first supplier to supply substances to the microchip and a second supplier to supply a potential to the microchip to move substances corresponding to the microfluid structure, the supply element comprising:
    at least one substance-containing third supplier adapted to contain a substance, said at least one third supplier having a seal arranged to be opened to the microchip in response to the supply element and the microchip being joined together to enable said substance to be transferred from said at least one third supplier to the first supplier of the microchip.
  2. 2. The supply element of claim 1, wherein said seal comprises a chemically resistant substance.
  3. 3. The supply element of claim 1, wherein said seal comprises a wax.
  4. 4. The supply element of claim 1, wherein said at least one third supplier comprises at least one end sealed by a membrane that is flush with a side surface of the supply element.
  5. 5. The supply element of claim 4, wherein said membrane comprises a chemically resistant material.
  6. 6. The supply element of claim 4, wherein said membrane comprises one of a metal or a gas-permeable polymer.
  7. 7. The supply element of claim 1, wherein said substance of said third supplier comprises at least one substance sample.
  8. 8. The supply element of claim 1, wherein said substance of said third supplier comprises at least one substance reagent.
  9. 9. The supply element of claim 1, wherein said substance of said third supplier comprises at least one substance sample and at least one substance reagent.
  10. 10. The supply element of claim 1, further comprising a fourth supplier to transfer the potential to the microchip, said fourth supplier being arranged to be coupled to the corresponding second supplier on the microchip.
  11. 11. The supply element of claim 1, further comprising an attachment arrangement to releasably attach the supply element to supply equipment.
  12. 12. The supply element of claim 11, wherein said attachment arrangement comprises a bayonet lock.
  13. 13. The supply element of claim 1, further comprising a first coding arrangement to identify the supply element to a second corresponding coding arrangement of supply equipment.
  14. 14. The supply element of claim 1, further comprising first and second assemblies, said first assembly being adapted to contain a module carrying said supply element and supply equipment and said module being adapted to be releasably connected to said second assembly.
  15. 15. The supply element of claim 1, wherein said seal of said at least one third supplier is adapted to be pierced by an end of said first supplier to enable said substance to be transferred from said at least one third supplier to the first supplier of the microchip.
US11129420 1999-06-22 2005-05-16 Supply element for a laboratory microchip Abandoned US20060008386A1 (en)

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CN104597268A (en) * 2015-01-28 2015-05-06 烟台艾德康生物科技有限公司 Integrated enzyme immunoassay analyzer
WO2016180087A1 (en) * 2015-05-12 2016-11-17 天津微纳芯科技有限公司 Portable full-automatic biochemical analysis device

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