EP3450020B1 - Dispositif de microdosage permettant le dosage de plus petits échantillons de fluide - Google Patents

Dispositif de microdosage permettant le dosage de plus petits échantillons de fluide Download PDF

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Publication number
EP3450020B1
EP3450020B1 EP17189074.2A EP17189074A EP3450020B1 EP 3450020 B1 EP3450020 B1 EP 3450020B1 EP 17189074 A EP17189074 A EP 17189074A EP 3450020 B1 EP3450020 B1 EP 3450020B1
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EP
European Patent Office
Prior art keywords
microdosing
fluid
displacement element
chamber
actuator
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EP17189074.2A
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German (de)
English (en)
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EP3450020A1 (fr
Inventor
Boris Von Beichmann
Peter Molitor
Uwe Dunker
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Eppendorf SE
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Eppendorf SE
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Priority to EP17189074.2A priority Critical patent/EP3450020B1/fr
Priority to PCT/EP2018/073471 priority patent/WO2019043159A1/fr
Publication of EP3450020A1 publication Critical patent/EP3450020A1/fr
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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
    • B01L3/02—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
    • B01L3/02—Burettes; Pipettes
    • B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons

Definitions

  • the invention relates to a microdosing device for the dosed delivery and / or intake of fluid samples in the microvolume range and a pipetting device provided with such a microdosing device.
  • Pipetting devices are hand-held or automated laboratory devices commonly used in medical, biological, biochemical, chemical, and other laboratories. They are used in the laboratory for precise dosing as well as the transport of fluid samples with small volumes and the transfer of such volumes between different sample containers.
  • pipetting devices e.g. liquid samples are sucked into pipette containers, e.g. pipette tips, by means of negative pressure, stored there, and released again at the destination.
  • the hand-held pipetting devices include, for example, hand-held pipettes and repeater pipettes, the latter also being referred to as dispensers.
  • a pipette is understood to mean a device in which a sample to be pipetted can be sucked into a pipetting container, in particular a pipette tip, detachably connected to the pipette by means of a movement device which is assigned to the device and which can in particular have a piston.
  • the piston is assigned to the device and between the sample to be pipetted and the end of the piston there is an air cushion as a pressure-transmitting fluid which, when the sample is taken up in the pipetting container, is under a vacuum through which the sample is sucked into the pipetting container and / or is held in the pipetting container.
  • a dispenser is understood to mean a device in which, by means of a movement device, which can in particular have a piston, a volume of a liquid fluid to be pipetted can be sucked into a pipetting container connected to the dispenser, in particular a dispenser tip designed according to the syringe principle, wherein the Movement device is at least partially assigned to the pipetting container by, for example, the piston being arranged in the pipetting container.
  • the dispenser With the dispenser, the end of the piston is very close to the fluid sample to be pipetted or in contact with it, which is why the Dispenser also known as positive displacement pipette.
  • Pipetting devices with a displacement element designed as a piston are also referred to as piston-operated pipettes.
  • Pipette tips or dispenser tips consist in particular of plastic and can be thrown away as disposable items after use or replaced with a fresh pipette tip or dispenser tip. But they can also consist of metal or glass or have such a material. Pipette tips or dispenser tips are available in different sizes for dosing in different volume ranges.
  • the amount of sample released by a single actuation can correspond to the amount of sample sucked into the device.
  • a quantity of sample received corresponding to several dispensing quantities is dispensed again in steps.
  • single-channel pipetting devices and multi-channel pipetting devices with single-channel pipetting devices containing only a single delivery / receiving channel and multi-channel pipetting devices containing multiple delivery / receiving channels, which in particular allow the parallel delivery or collection of multiple samples.
  • Examples of hand-held, electronic pipetting devices or pipettes are the Eppendorf Xplorer® and the Eppendorf Xplorer® plus from Eppendorf AG, Germany, Hamburg;
  • Examples of hand-held, electronic dispensers are the Multipette® E3 and Multipette® E3x from Eppendorf AG, Germany, Hamburg.
  • These devices like the pipetting device according to the present invention, are electrically operated in that the pipetting movable part, in particular the piston, is moved by an electric motor device of the pipetting device.
  • An example of an automatic pipetting machine is the Eppendorf epMotion®.
  • Pipetting devices are used for dosing and thus the precise measurement of liquid volumes.
  • dosing very small amounts of liquid with the help of a Piston-operated pipette can considerably increase the systematic and random errors in dosing. Details on the usual procedure for error determination and for the dosing of small volumes, especially through wall dispensing in the container, can be found in DIN EN ISO 8655.
  • dispensing according to the free jet method in which the fluid sample is a jet or free droplet - also referred to as a jet - Leaves the pipetting container, the smallest volumes between 0.1 ⁇ l and 1.0 ⁇ l, in the present case preferably summarized under the term "micro-volumes”, can no longer be dosed sufficiently safely with conventional pipetting devices.
  • the US9221046B2 describes a pipette which has a cylinder piston segmented in the longitudinal direction with segments of different diameters and a piston with differently dimensioned closure elements correspondingly distributed in the longitudinal direction. Due to the different diameters, larger volumes and smaller volumes can be precisely dispensed or absorbed. By means of a suitable configuration, a drop adhering to the outlet opening is released suddenly by "blowout" from this pipette.
  • the EP0119573A1 describes a dispenser for dispensing microdrops of a laboratory sample.
  • a sample chamber formed as an elastic tube with a nearby outlet opening has an elastic section which is compressed by the actuation of an electromagnetically driven anchor bolt. The resulting pressure wave acts in the direction of the outlet opening and causes a micro-drop to be ejected.
  • the EP0876219B1 describes a pipetting apparatus which has a dispenser tip and, connected to this via a fluid channel, a piston displacer provided with a valve, by means of which larger volumes can be pipetted through the pipette tip, i.e. can be sucked in and dispensed.
  • a pulse generator is arranged between the pipette tip and the piston displacer which exerts a pulse on the liquid in the fluid channel in order to eject a small drop of a defined size from the pipette tip.
  • the pulse generator can be an electromagnetic actuator or a piezo element or can have an ultrasound or heat source.
  • the EP1206966B1 describes a pipetting apparatus for the optional dispensing of larger volumes or the smallest of volumes for life science.
  • a cylinder-piston closure that can be moved by means of a spindle drive is provided with a pulse generator, here a piezo element, in a piston chamber.
  • the pulse generator is arranged as part of the cylinder piston between the cylinder piston closure and the piston rod. Drops in the submicroliter range are precisely dosed by the piezo-controlled, abrupt stop of the piston.
  • the EP1654068B1 describes a microdosing device with an elastically deformable fluid line which connects a liquid reservoir to an outlet opening of the fluid line.
  • a displacer driven by a piezo actuator is arranged along a section of the fluid line, the longitudinal position and the stroke of which defines the volume of liquid to be dispensed when pressed onto the fluid line. This leaves the outlet opening as a free-flying droplet or as a free-flying jet.
  • the WO2013167594A1 describes a dispensing arrangement for dispensing laboratory samples, with a piston displacer serving as a liquid reservoir for dispensing and receiving liquid by means of a piston movement.
  • a tapered outlet area of the piston chamber can be excited by a pulse generator, which can be driven piezoelectrically, pneumatically, electromagnetically or by means of ultrasound. Taking into account the liquid meniscus at the outlet opening measured by means of a sensor, a drop with the desired volume is detached from the outlet opening by means of a pulse.
  • the WO 99/37400 A1 describes a metering device for the nanoliter to microliter range with a pressure chamber which is delimited by a displacer, which can be filled via an inlet connected to a liquid reservoir and which can be emptied via an outlet, the liquid volume released in the free jet via the voltage-controlled deflection of the displacer is dosed by a piezo actuator.
  • The also uses a similar dispenser WO 99/10099 A1 .
  • the DE 197 37 173 B4 describes how to manufacture such a free-jet dispenser as a microsystem-technical dispensing element.
  • EP 1 488 106 B1 describes a dosing module with a dosing chamber, actuator and actuator membrane that strikes a chamber wall to generate a free jet.
  • the WO 2006 / 018617A1 describes a device for the dosed delivery of a drug from a pre-filled cartridge to a patient with the aid of a closure element of the cartridge, which moves within the cartridge with the aid of a shape memory material actuator arranged on the closure element and a locking pawl and thus effects a step-by-step dose delivery to the patient.
  • the object of the present invention is to provide an efficiently designed microdosing device for the precise generation of a microdosing volume of a fluid sample in the form of a microfree jet.
  • the invention is based in particular on the results of measurements on microdosing devices with actuators made of a shape memory alloy, which show that even with very compact shape memory material actuators, a sample can be dispensed very precisely and efficiently using the free jet principle.
  • Shape memory alloys show a special behavior due to a phase transition, which is known as the shape memory effect. Below a material-specific critical temperature, a SMA component is particularly in the martensite phase and can (apparently) be plastically deformed by low forces. When heated to a further critical temperature, however, the original component shape is restored within milliseconds, and the material then behaves like an ordinary metal in accordance with Hook's law.
  • the inventors found that such shape memory material components are particularly suitable for generating a microfluid free jet due to the force-deflection characteristics that can be implemented with these components. Preferred configurations of a shape memory material actuator are described below.
  • a microdosing chamber is understood to mean a chamber whose chamber volume - at least in the first position - is in the microliter range (V_mikro), particularly preferably in the V_mikro range of less than 2 ⁇ l, in particular V_mikro less than 1 ⁇ l.
  • the chamber volume can correspond to the volume displaced by a displacement element, but the latter can also be smaller than the chamber volume.
  • a microdosing chamber preferably has an interior space with a maximum volume of less than 10 ⁇ l, particularly preferably less than 3 ⁇ l, particularly preferably less than 2 ⁇ l and more preferably less than 1.5 ⁇ l.
  • the maximum volume is preferably at least 50 nl (nanoliters), at least 100 nl or at least 150 nl, or at least 200 nl.
  • the maximum volume can be measured in the first position of the displacement element, or can correspond to or be derived from the structural-geometric height, measured parallel to the direction between the first and second position, of the interior of the microdosing chamber.
  • a microdosing chamber is particularly suitable for generating a microfludijet, also referred to here as a microfree jet.
  • a micro free jet is a fluid volume in the microliter range or submicroliter range that leaves the outlet opening of a fluid channel or pipetting container as a jet or free drop - also referred to as a jet.
  • the dosage is determined very precisely by using the stop device to stop the deflection of the displacement element in the first and / or the second position and is also resistant and permanently reliable, since the stop device is realized by solid components.
  • Preferred configurations of a microdosing chamber and a stop device are described below.
  • the invention accordingly relates in particular to a microdosing device for generating a microdosing volume of a fluid sample in the form of a microfree jet by abruptly displacing a predetermined microvolume, which is achieved by a stop device and / or a shape memory material actuator.
  • the micro-volume displaced by means of the micro-metering chamber through the deflection between the first and second position is preferably in the sub-microliter range, that is to say less than 1 ⁇ l. Accordingly, the fluid volume of the microdosing volume dispensed by the microdosing device is in the submicroliter range.
  • the microdosing volume generated as a free jet by a microdosing device preferably corresponds essentially to the microvolume displaced by a displacement element, in particular the microdosing volume is identical to the microvolume displaced by a displacement element. In the case of a microdosing device which has more than one microdosing device, its displacement elements In particular, displacing different volumes, e.g.
  • the combined microdosing volume generated by the microdosing device in the form of a free jet preferably essentially corresponds to the sum of the several micro-volumes displaced by the several displacement elements, e.g. the sum of the first and second micro-volumes.
  • a combined microdosing volume can therefore also be greater than 1 ⁇ l and is preferably in the range from 0.1 ⁇ l to 5.0 ⁇ l, in particular 0.1 ⁇ l to 2.5 ⁇ l, in particular 0.1 ⁇ l to 1.5 ⁇ l .
  • An actuator of the microdosing device is a shape memory material actuator.
  • actuators are used for the actuation which at least partially or completely consist of or have a shape memory alloy (SMA). These are called shape memory material actuators or SMA actuators.
  • SMA actuators have a particularly high energy density, so that even very compact actuators are suitable for driving the microdosing devices defined here.
  • the required voltage sources are compact, so that the present microdosing devices are particularly suitable for the construction of portable dosing devices, in particular pipetting devices and microdosing devices.
  • the shape memory material actuator preferably has or consists of a NiTi alloy.
  • a NiTi alloy also known under the trade name Nitinol
  • Nitinol is particularly biocompatible. It enables changes in shape of up to 8% in particular, which means that microdosing chambers are also efficiently incorporated can generate displaced microvolumes in the microliter range and in the submicroliter range.
  • the shape memory material actuator particularly preferably has an alloy based on TiNiCu. Compared to conventional NiTi, this is particularly fatigue-resistant and therefore guarantees, in particular, a high level of reliability of the microdosing device over its entire service life.
  • the phase transition or switching temperatures of the material can be determined using dynamic differential calorimetry (DSC), see Figure 18 .
  • phase transition that is important for actuation appears as a peak.
  • the diagram shows that the temperature must be increased to at least 67 ° C to switch a NiTi actuator; to reset the temperature, the temperature must again be reduced to a maximum of 50 ° C.
  • Film-based SMA actuators are preferably used.
  • the SMA is in the form of a film which has a thickness between 5 ⁇ m and 50 ⁇ m, in particular between 10 and 30 ⁇ m, in particular approx. 20 ⁇ m. This enables the forces and travel ranges to be set by adapting the two-dimensional geometry.
  • the surface area which is very large in relation to the volume, is retained and ensures rapid heat dissipation or resetting of the SMA actuator in the de-energized state.
  • An SMA actuator is preferably designed in an elongated form, in particular in the form of a wire or web, and in particular made of an SMA film. The ends of the SMA actuator are electrically contacted.
  • a SMA actuator is preferably arranged in the microdosing device in such a way that the load on the SMA actuator is essentially a tensile load.
  • An elongated SMA actuator can be arranged in a curved geometry in the non-activated form. The activated shape can have a less curved shape or a straight alignment, in particular the elongated SMA actuator can have a shorter length in the activated, straight shape than in the non-activated, more strongly curved shape.
  • the SMA actuator is preferably arranged so that the radius of curvature is always at least 50 times corresponds to the diameter perpendicular to the longitudinal direction of the elongated actuator in order to reduce the risk of damage to the SMA actuator.
  • the diameter or the required web width of a web-shaped SMA actuator is preferably adapted to the actuating force required to implement the desired micro-metering device. Force-deflection characteristics of SMA actuators can be determined using a tensile testing machine.
  • the SMA actuator can in particular also be shaped as a spring, in particular a helical, spiral or spiral spring. Such a spring can be relaxed in the first position and tensioned in the second position.
  • a microdosing device has an SMA actuator which is set up to deflect at least two displacement elements.
  • the at least two displacement elements can be mechanically connected to one another or optionally connectable.
  • the microdosing device can have a coupling device by means of which the optional coupling of at least one actuator with one or more displacement elements from one or more microdosing devices can take place, in particular depending on an activation by an electrical control device of the microdosing device.
  • a single actuator, or a combination of several actuators can, in particular by means of the coupling device, optionally deflect one or more displacement elements synchronously, i.e. according to a predetermined time pattern and / or in time coordination, in particular simultaneously.
  • the stroke i.e.
  • the difference in the distance between the first and second position, of at least two displacement elements from at least one microdosing device can be the same or can be different, in particular in that an elastically deformable coupling element, e.g. a spring, is arranged between the actuator and the displacement element.
  • the stroke of a displacement element of a microdosing device is preferably between 5 ⁇ m and 500 ⁇ m, in particular between 50 ⁇ m and 200 ⁇ m, in particular between 75 ⁇ m and 125 ⁇ m, and is in particular constant.
  • the microdosing device can have more than one actuator, in particular at least two actuators, which are arranged to deflect the displacement element are.
  • two SMA actuators can be used to effect the displacement of the displacement element from the first to the second position.
  • the microdosing device and / or the microdosing device preferably has an actuator device.
  • This preferably has one or more actuators, in particular SMA actuators, in particular exactly two actuators or more than two actuators, in particular SMA actuators.
  • two elongated, in particular web-shaped, preferably film-based SMA actuators are arranged crossing one another, that is to say cross-shaped or X-shaped, above a displacement element.
  • the crossing point of the SMA actuators is preferably arranged centrally above a support section of the displacement element, the ends of the SMA actuators are anchored on a base body of the microdosing device.
  • the SMA actuators are preferably tensioned above the support point in such a way that the intersection each forms a point of curvature of the SMA actuator.
  • This as in the Figures 9a, 9b and 9c is shown by way of example, a shell-like area of the actuator arrangement is formed, through which the actuator arrangement is centered above the support point and generates a precisely downward force along the linear direction of movement between the first and second position, which results in a correspondingly precise deflection.
  • SMA actuators can be coupled by a connecting link.
  • the deflection of the actuators is thereby further synchronized and the force vector of the actuator device formed in this way is influenced.
  • a connecting link can be provided at the intersection; this aligns the force vector that acts vertically downward when the SMA actuators contract, and the SMA actuators are held in position at the intersection.
  • the connecting member can also be designed in such a way that the SMA actuators do not contact one another mechanically and, in particular, are electrically isolated from one another by the connecting member.
  • An actuator device can have a first actuator, in particular an SMA actuator, which is set up to exert a first force in a first direction and can in particular have a second actuator, in particular SMA actuator, which is set up to exert a second force in a second direction.
  • the first and second forces can be the same. But they can also be different.
  • the first and second directions can be the same, but can also be different. In this way, an actuator device can be designed flexibly.
  • the first direction can be the direction from the first to the second position
  • the second direction can be the opposite direction, from the second to the first position.
  • the resetting of the displacement element from the second to the first position can also be generated by a second SMA actuator after the deflection from the first to the second position has taken place by a first SMA actuator.
  • the actuator device preferably has at least one coupling element in order to connect the at least one actuator, in particular SMA actuator, to a base body.
  • the displacement element is arranged in particular so as to be movable with respect to the base body.
  • An SMA actuator can be connected to the base body by one or more connecting devices.
  • an SMA actuator can be materially connected, in particular soldered, to the base body or to a component attached to the base body, e.g. a circuit board.
  • An SMA actuator is preferably electrically isolated from the base body and preferably from other SMA actuators and other parts, while its ends are preferably connected or connectable to a voltage source.
  • An actuator device can have a transmission or a mechanism which is driven by the actuator, in particular an SMA actuator, and which drives one or more displacement elements.
  • a transmission, in particular a step-up or step-down, of the actuator deflection caused by the actuator can be generated in order to effect the desired deflection of the displacement element from the first to the second position.
  • a variation of the stroke can also be implemented in this way, in that the actuator deflection is optionally transferred differently to the deflection of the displacement element becomes.
  • the stop device with which the deflection of the displacement element is stopped can in particular be part of the mechanism.
  • the microdosing device preferably has a stop device which is designed to stop the deflection of the displacement element.
  • the stop device is assigned a first stop of the microdosing device, against which the displacement element hits in the first position, and / or a second stop, against which the displacement element hits in the second position.
  • the stop can in each case be an area of a base body of the microdosing device. If a linear movement of the displacement element is referred to as a movement from top to bottom, the direction designations “up” and “down” are sufficiently defined with reference to a single microdosing device.
  • a stop can be formed by an area of the bottom of a microdosing chamber, which is preferably defined by a shape of the base body, or can be formed by a projection, a flange, or a section on the microdosing chamber, which is preferably defined in each case by a shape of the base body and / or is defined by a component attached to the base body, in particular a stop element.
  • the first and / or the second position is precisely defined by the stop, in particular without the need for a high degree of precision in the deflection of the actuator, as long as at least the stroke can be generated by the actuator. This concept is particularly, but not exclusively, a very efficient approach to solving the problem on which the patent is based when using SMA actuators.
  • the positions of the first and second stops are preferably invariable in relation to one another and / or in relation to the base body. In this way, a precisely working microdosing device with a constant stroke can be efficiently provided or manufactured.
  • the stop device can have at least one stop with a variable stop position, so that the first and / or second position can be variable due to the variable position of at least one stop.
  • a stop element can be provided on a base body of the microdosing device, whose stop surface is variable in its position with respect to the base body.
  • the stop element can in particular have a thread in order to be screw-like countersunk and extendable in the base body, or can have a rotatable eccentric which, depending on the rotational position, offers a different stop height and thus a different stroke.
  • the variable stop element can be designed to be automatically adjustable by a drive and can in particular be controllable by means of an electrical control device. However, it can also be adjusted manually.
  • the microdosing device or a microdosing device preferably has a base body.
  • the base body is preferably formed integrally, but can also be formed in several parts. It is preferably made of metal, plastic or ceramic, or has such materials.
  • the manufacturing method of the microdosing device provides, in particular, that the manufacturing takes place by a primary molding method, in particular a casting method, so that the base body or its components is preferably formed or cast by a primary molding method.
  • the base body forms at least one microdosing chamber.
  • the base body can have a first part which forms at least one fluid chamber. A second part of the base body can be provided in order to be connected to the first part.
  • the second part can in particular have at least one guide section or guide channel in order to guide the displacement element during the deflection and to align it with a perpendicular longitudinal direction of the microdosing chamber.
  • a membrane can be arranged between the first and second part, in particular fastened, in particular fastened by clamping between the first and second part.
  • the membrane can in particular seal the fluid chamber and / or can in particular serve as a restoring element for restoring the displacement element from the second to the first position.
  • the second part can in particular be set up as a carrier for the actuator device or the one or more actuators, which can in particular be anchored to the second part.
  • the first and / or the second part can each have the first and / or the second stop with which the first and second positions are defined.
  • the displacement element is in particular a piston-like part.
  • the shape of the displacement element is preferably adapted to its deflection with the aid of a guide device.
  • the displacement element can be cylindrical or have one or more cylindrical sections. However, it can also have a differently shaped cross-section, measured to the longitudinal axis through the microdosing device, in particular an ellipsoidal, triangular, rectangular, square or polygonal cross-section.
  • the surface of the displacement element that possibly contacts a membrane or a bottom surface of the fluid chamber and abuts this downward can have rounded edges to prevent damage to the membrane, and a damping element can be arranged on the displacement element to dampen the shock if necessary.
  • the displacement element is particularly solid, in contrast to the optionally provided deformable membrane.
  • the displacement element must not be confused with the membrane that is preferably provided.
  • the solid construction makes it possible to implement the stop device for stopping the displacement element precisely and reliably over the long term.
  • the displacement element is preferably made of metal, but it can also be made of a plastic or a composite material.
  • a microdosing chamber has an interior that is designed to at least partially accommodate the displacement element.
  • the interior space is formed in particular by at least one wall section of a base body, but can also be formed by an insert element which is inserted into the base body or is attached there.
  • the interior space can be shaped like a cylinder or can have a rectangular or square cross section perpendicular to the axis of the deflection.
  • At least one wall of the microdosing chamber can be designed as part of a guide device which guides the displacement element during the deflection.
  • the microdosing device preferably has a guide device which guides the displacement element during the deflection.
  • At least one stop can be formed by a wall section of the microdosing chamber.
  • the fluid chamber can be a microdosing chamber, but it can also be a larger fluid chamber with a maximum internal space in the range in particular from 5 ⁇ l to 1000 ⁇ l.
  • the fluid chamber can be assigned to a pipetting device or a dispenser for dosing larger volumes in the range in particular from 5 ⁇ l to 1000 ⁇ l.
  • the microdosing device can in particular be integrated into such a pipetting device or a dispenser for dosing larger volumes, in that the displacement element is installed in particular in a wall of the fluid chamber or in a piston element or a fluid channel that makes fluid contact with the fluid chamber, and in particular the displacement element creates a microvolume by deflecting it displaced abruptly in the fluid chamber.
  • a larger fluid chamber does not have to differ from a micro-dosing chamber.
  • preferred configurations of the micro-metering chamber can also be transferred to a macro-metering chamber.
  • the fluid chamber has in particular an engagement opening for engagement of the displacement element, which during the deflection extends through the engagement opening into the fluid chamber.
  • the engagement opening preferably has a cross section perpendicular to the direction of deflection which corresponds to the dimensions, in particular the diameter, and / or the shape of the displacement element.
  • the engagement opening of an essentially cylinder-like displacement element can also be cylindrical.
  • the microdosing device preferably has a sealing device by which the engagement opening is sealed fluid-tight and / or by which the interior of the fluid chamber or the microdosing chamber is sealed fluid-tight, in particular in every position of the displacement element relative to the base body.
  • the sealing device can have at least one sealing element, in particular an elastic seal, or a membrane, as described below.
  • essentially the entire interior of the microdosing chamber is displaced and reduced to zero.
  • C is different from zero.
  • the sealing device preferably includes a membrane which is elastically deformable and which seals the engagement opening and which is arranged between the interior of the fluid chamber and the displacement element.
  • the microdosing device preferably has a membrane. This membrane is provided in addition to the displacement element.
  • the microdosing device preferably has a resetting element which is elastically deformable and which is tensioned by the deflection and with which a resetting force can be exerted on the displacement element in order to reset it after the deflection from the second position to the first position.
  • the membrane serving as a sealing element can also be the restoring element of the microdosing device.
  • the restoring element can be a spring which is arranged between the base body and the displacement element.
  • the resetting element can be an actuator which is controlled in particular by the electrical control device.
  • an elastically deformable component can also be arranged as a drive element of the deflection, which is tensioned by the actuator.
  • a membrane serving as a sealing element and / or as a restoring element is preferably made of polydimethylsiloxane (PDMS), in particular flexible or highly flexible PDMS or silicone, or has such a material.
  • the thickness of the membrane is preferably between 50 ⁇ m and 500 ⁇ m, preferably between 100 ⁇ m and 300 ⁇ m, preferably between 150 ⁇ m and 250 ⁇ m, and preferably about 200 ⁇ m.
  • the microdosing device preferably has a closable bypass channel which, in the open state, connects the interior of the fluid chamber to the exterior, in particular the environment.
  • the bypass channel is used in particular to ventilate the fluid chamber or to equalize the pressure of the fluid channel that is fluidically connected or optionally connectable to the bypass channel.
  • the microdosing device is set up for repeated delivery of a microdosing volume of a fluid sample and for this purpose preferably has at least one valve.
  • the microdosing device preferably has a shuttle valve.
  • a shuttle valve is preferably provided, which is designed in particular as a slide valve.
  • One or more valves, in particular controllable valves and / or one-way valves, can also be provided.
  • the interior of the microdosing chamber is optionally connected by the shuttle valve to the outlet opening of the fluid channel or to the bypass channel which is fluidically connected to the exterior.
  • a microdosing device is also set up to receive a fluid sample in that the fluid sample is sucked in by resetting the displacement element from the second position to the first position, in particular either in the fluid channel or - via another channel - in the fluid chamber .
  • the microdosing device is preferably designed as a pipetting device with which a fluid sample can be sucked in and dispensed via the fluid channel.
  • the suction can be carried out by a (conventional) piston element of a hand-held piston stroke pipette or a dispenser.
  • the microdosing device is preferably designed so that the displacement element selectively sucks in or displaces a microvolume of a fluid.
  • the microdosing device is preferably designed according to the air cushion principle, and the fluid chamber is filled with the fluid “air”.
  • the microdosing device can, however, also be designed according to the positive displacement principle, the fluid chamber being filled with a liquid or viscous substance, the microvolume of which is displaced by deflection.
  • a pipetting device for the metered uptake and dispensing of fluid samples preferably has: a piston chamber, a movable piston arranged in the piston chamber for sucking in a fluid into the piston chamber and for dispensing the fluid from the piston chamber, a pipetting channel that connects the piston chamber with the outer space the piston chamber connects, and a microdosing device according to the invention, the fluid channel of which can be connected to the piston chamber and / or the pipetting channel, so that a microdosing volume of a fluid sample can be metered by the pipetting device by means of the microdosing device and delivered to the outside space in the form of a microfluid jet via the pipetting channel.
  • the invention further relates to a pipetting device with at least one microdosing device according to the invention for generating a microdosing volume of a fluid sample in the form of a microfree jet, having a fluid chamber, a fluid channel which connects the interior of the fluid chamber with an outer space and which serves to accommodate the microdosing volume of a fluid sample, a displacement element , which is set up to deflect between a first position and a second position and to displace a micro-volume of the fluid chamber, wherein the microdosing device has a shape memory material actuator which is arranged to deflect the displacement element, and wherein the microdosing device is set up so that the Displacement of the micro-volume from the fluid chamber causes the micro-dosing volume to be dispensed in the form of a micro-free jet into the outer space, the pipetting device having a piston drive, in particular an electric one hen motor, and a piston driven by this piston drive, which forms the displacement element, the fluid chamber forming
  • the shape memory material actuator is preferably arranged between the piston serving as a displacement element and the piston drive, that is to say in particular the electric motor.
  • the pipetting device preferably has a drive spindle driven by the piston drive, and in particular a piston coupling.
  • the shape memory material actuator is preferably arranged between the end of the drive spindle and the piston coupling, in particular floating or movable, or above (in the logical drive chain) the coupling between the piston and spindle, in particular floating or movable.
  • the piston can have a first piston section which faces the fluid channel and which works as the displacement element, in addition, in particular a second piston part, in particular a second piston section, which is driven by the piston drive, in particular the electric motor, the shape memory material actuator preferably is arranged between the first piston section and the second piston part so that the second piston part serves as an abutment when the shape memory material actuator is actuated and deflects the first piston section with respect to the second piston part in order to dispense the microdosing volume.
  • a pipetting device can be operated on the one hand in a conventional manner, i.e. by means of a piston drive, for dispensing larger volumes, in particular larger than 1 ⁇ l, e.g. up to several 10 ⁇ l or up to 1 ml, and on the other hand for dispensing microdosing volumes.
  • this shape memory material actuator or several of these shape memory material actuators can be used to implement a piston drive, in particular in the case of a pipetting device designed as a dispenser, so that the movement of the (conventional) piston is carried out by one or more shape memory material actuators.
  • the invention further relates to microdosing device for generating a microdosing volume of a fluid sample in the form of a microfree jet, having a fluid chamber, a fluid channel that connects the interior of the fluid chamber with an outer space and that serves to accommodate the microdosing volume of a fluid sample, a displacement element that is used for deflection between a first position and a second position and is set up to displace a micro volume of the fluid chamber, wherein the microdosing device has a shape memory material actuator which is arranged to deflect the displacement element, and wherein the microdosing device is set up so that by displacing the microvolume from the fluid chamber the delivery of the microdosing volume is effected in the form of a micro-free jet into the outer space, the displacement element being at least partially or completely formed by this shape memory material actuator.
  • microdosing device A typical use of the microdosing device is in the dosing of biological, biochemical, chemical or medical fluid samples in a laboratory.
  • a microdosing device for generating a combined microdosing volume of a fluid sample in the form of a microfree jet has: at least a first and a second microdosing device, each of which is in particular a microdosing device according to the invention, the first microdosing device having a first fluid chamber and a first displacement element that is used to displace one first microvolume of the first fluid chamber is set up, and wherein the second microdosing device has a second fluid chamber and a second displacement element that is set up to displace a second microvolume of the second fluid chamber, a fluid channel that the interior of the first and second fluid chamber connects to an outer space and which serves to receive the microdosing volume of a fluid sample, wherein the microdosing device has an actuator device which is set up for the synchronized deflection of the first and the second displacement element, and wherein the microdosing device is set up so that the synchronized displacement of the first and second microvolume from the first and second
  • the microdosing device can be part of another device, in particular a pipetting device.
  • the microdosing device can furthermore be set up as a pipette device which is set up in particular for sucking in a fluid sample from the outer space, for example from an external liquid container, into the fluid channel or into a pipetting container connected to it.
  • the microdosing device or the microdosing device or the pipetting device, which has a microdosing device, or an external device has an electrical control device in order to control the actuator or the SMA actuator. In particular, it is an internal control device if it is not arranged in an external device.
  • the microdosing device preferably has an electrical voltage source, in particular a battery, in order to supply the actuator or the SMA actuator with energy. Alternatively or additionally, an interface for connecting an external voltage source is provided.
  • An external device or external part is not part of the microdosing device and can in particular be or can be connected to the microdosing device by a connecting device, for example a cable.
  • the control device is set up to control the actuator in order to effect the displacement of the displacement element from the first position into the second position. In addition or as an alternative, it can also be set up to cause the displacement element to be deflected from the second position into the first position.
  • the control device is preferably set up so that the actuator exerts a force on the displacement element which moves the displacement element from the first position into the second position, in particular accelerates it.
  • the actuator is preferably controlled by the control device in such a way that the actuator exerts a force exerts on the displacement element even after the displacement element has reached the second position, in particular by striking a second stop of a stop device.
  • the displacement element accelerates until it reaches the second position, is stopped abruptly there and a force is applied in the second position, in particular for a predetermined period of time, a shock or shock-like displacement of the fluid in the fluid chamber is generated.
  • the microfree jet is generated reliably and with the desired microdosing volume.
  • the microdosing device can have an elastically deformable drive element, in particular a spring, which is tensioned by the actuator, in particular is elastically compressed or expanded, and which, through its relaxation, exerts the force on the displacement element that moves the displacement element from the first position into the second Position moved.
  • the displacement element can be releasably fixed, in particular locked, in the second position by a fixing device.
  • a release device can be provided in order to release the fixation so that the drive element carries out the deflection.
  • the control device is set up to control the deflection of an SMA actuator from the first to the second position.
  • the SMA actuator is electrically contacted, in particular at a first contact point and a second contact point, in order to have a current flowing through it when an electrical voltage is applied between the two contact points, which heats the SMA actuator in order to use the shape memory effect (FGE) To cause deflection.
  • the control device is set up in particular to specify the time profile and the amplitude of the voltage applied to the SMA actuator.
  • the control device is set up to activate the SMA actuator with a very short voltage or current pulse.
  • the time span is 1 ms to 100 ms, preferably a few 10 milliseconds (ms), preferably 10 ms to 100 ms, in particular about 10 ms.
  • the control device is preferably set up to control the SMA actuator, in particular after a period of activation, to be controlled by a pulse width modulation. This is done in particular in such a way that the effective voltage is throttled to such an extent that the switching position or the mechanical tension of the SMA actuator can just be maintained.
  • the control device has in particular an electronic data processing device, in particular a CPU or a microprocessor.
  • the control device can be program-controlled, in particular by means of program parameters, which determine the point in time and / or type of deflection of the displacement element of the microdosing device.
  • program parameters which determine the point in time and / or type of deflection of the displacement element of the microdosing device.
  • the microdosing device or the microdosing device or the pipetting device, which has a microdosing device, or an external device, preferably has a user interface device with which a user controls the electrical control device, in particular by using the program parameters that are used to control the microdosing device, in particular that generate control signals influenced by user inputs or, in the case of an analog electronic control, it triggers the delivery or intake of the desired microdosing volume and the generation of the control signals that activate and / or deactivate the actuator.
  • the user interface device can each have one or more electrical switches, buttons and / or sensors, and can have output devices, e.g. displays, in particular a display.
  • the control device can have at least one electrical interface with which control signals can be exchanged, in particular can be exchanged with an external device.
  • the control device can be set up to be controlled by an external device, so that the control device, and thus the microdosing device or microdosing device, can be controlled by an external device by means of the electrical interface.
  • the control device can in particular be used as a control interface between the control device of an external device and be formed at least one microdosing device or a microdosing device.
  • the control interface can have an electrical circuit in order to apply voltage to at least one actuator of the at least one microdosing device as a function of a control signal.
  • the control signal can be generated by an internal control device or an external control device.
  • the voltage supply for at least one actuator from at least one microdosing device can be integrated into the control device or can be implemented via the at least one electrical interface.
  • the electrical interface can be designed to send and / or receive electrical signals, in particular data.
  • the signal exchange can take place via a wired or wireless connection device.
  • an internal control device can be or is temporarily connected to the device, in particular the pipetting device, via an electrical interface by means of a connecting device, this device is referred to as an external device.
  • the external device can be a pipetting device, in particular a portable, hand-held pipetting device or a hand-held pipette or a hand-held dispenser. If the microdosing device is integrated in a beeper device, the pipetting device is not referred to as an external device.
  • the microdosing device or a microdosing device can be a stand-alone or autonomously operating device that can basically be operated without the intermediation of an external device.
  • the microdosing device or a microdosing device can, however, also be designed as a module of an external device.
  • the module is characterized in that it is operated or can be operated — in particular exclusively — as a function of the external device, in that in particular a control device of the external device controls the deflection of at least one displacement element of at least one microdosing device.
  • a microdosing device preferably has a constant stroke of the displacement element which is defined by the difference between the first and second positions. In particular, the stroke is not varied by changing the voltage that is applied to an actuator, in particular an SMA actuator. Rather is the control device is preferably set up to always control the actuator with the same voltage or to always execute the same stroke of the displacement element.
  • An SMA actuator is particularly suitable for performing a constant stroke.
  • the microdosing device works particularly precisely thanks to the constant stroke.
  • microdosing device with more than one microdosing device
  • several microdosing devices with a constant stroke generate a combined microdosing volume.
  • This can be varied by controlling different combinations of microdosing devices each with a constant stroke, the height of the constant stroke and / or the microvolume displaced by the constant stroke depending on the individual microdosing device.
  • the constant stroke results in a constant, displaced micro-volume of the microdosing device for each microdosing device.
  • the combined micro-dispensing volume generated overall can be varied on the basis of the different possible combinations of displaced, constant individual volumes of the microdosing devices. This summation takes place in particular in that, in a microdosing device with more than one microdosing device, the respectively displaced microvolume is output into a common fluid channel, so that it leads in particular to a combined or summed microvolume there.
  • a microdosing device preferably has a plurality of microdosing devices with a constant stroke, each of which displaces a different microvolume, in particular at least two of the microvolumes 0.1 ⁇ l, 0.2 ⁇ l, 0.4 ⁇ l and 0.8 ⁇ l.
  • a microdosing device preferably has several microdosing devices with a constant stroke, each of which displaces a different microvolume, in particular at least two of the microvolumes 0.05 ⁇ l, 0.1 ⁇ l, 0.15 ⁇ l, 0.2 ⁇ l, 0.25 ⁇ l, 0, 3 ⁇ l, 0.35 ⁇ l, 0.4 ⁇ l, 0.45 ⁇ l, 0.5 ⁇ l, 0.55 ⁇ l, 0.6 ⁇ l, 0.65 ⁇ l, 0.7 ⁇ l, 0.75 ⁇ l, 0.8 ⁇ l, 0.85 ⁇ l, 0.9 ⁇ l and 0.95 ⁇ l, 1.0 ⁇ l is also a possible value.
  • the Figures 1a to 8b each show an exemplary microdosing device according to the invention, either in the first position P1 (each figure “a”) or in the second position P2 (each figure “b”) of the displacement element.
  • the Figures 11a to 13 show how such a microdosing device can be integrated into a pipetting device or a microdosing device.
  • Figure 1a shows, in the first position P1, and Figure 1b in the second position P2 of the displacement element 13, the microdosing device 10, which is set up here as a positive displacement device.
  • Figure 2a shows, in the first position P1, and Figure 2b in the second position P2 of the displacement element 23, the microdosing device 20, which is set up according to the air cushion principle.
  • the microdosing device 10 or 20 is used to generate a microdosing volume of a fluid sample in the form of a microfree jet 99.
  • the microdosing device has a fluid chamber designed as a microdosing chamber 11 or 21, a fluid channel 12 or 22, which connects the interior of the microdosing chamber with an outside space and which is used to receive the microdosing volume of a fluid sample, a displacement element 13 or 23, which is set up to deflect between the first position P1 and the second position P2 and to displace a microvolume of the microdosing chamber.
  • the microdosing device 10 or 20 has a stop device 14a, 14b or 24a, 24b, which is set up to stop the deflection of the displacement element, and an actuator 15 or 25, which is arranged to deflect the displacement element.
  • the stop device has a first stop 14a or 24a, which is formed on a projection of the base body 16 or 26 of the microdosing device.
  • the first position P1 is structurally predetermined by the first stop.
  • the stop device also has a second stop 14b or 24b, which is formed by a bottom section of the base body 16 or 26 of the microdosing device.
  • the second position P2 is structurally predetermined by the second stop.
  • the linear movement of the displacement element is limited by the two stops to the area between P1 and P2. In particular, that will Displacement element stopped abruptly by striking the second stop.
  • the actuator is operated in particular in such a way that the displacement element is pressed against the second stop, at least for a short period of time.
  • the microdosing device is set up so that by displacing the microvolume from the microdosing chamber, the microdosing volume 99 is released in the form of a microdosing into the outside space.
  • the fluid chamber is set up in particular as a microdosing chamber: the one in Fig. 1a present maximum internal volume of the fluid chamber is 2 ⁇ l or less. In Figure 1b the internal volume is reduced to zero: the fluid chamber is here essentially completely occupied by the displacement element.
  • the fluid chamber is preferably that portion of a structurally predetermined space of the base body that is occupied by the fluid to be displaced (eg air or liquid) in the first position of the displacement element.
  • the upper edge region of the fluid chamber which is provided with the reference numeral 11 'and in which the displacement element engages during the movement from the first to the second position, is therefore referred to as the engagement opening 11' of the fluid chamber.
  • the microdosing devices shown in the other figures have the engagement openings 21 ', 31', 41 ', 51', 61 ', 71'.
  • the components of the microdosing device 10 or 20 are arranged essentially within the base body 16 or 26 of the microdosing device, in particular in the first and second position of the displacement element or in its first or second position (not shown). As a result, a modular design of the microdosing device can advantageously be implemented.
  • Microdosing volume 99 of a liquid laboratory sample, e.g. an aqueous solution or suspension, to be generated as a free jet, is contained in position P1 in the fluid chamber 11 according to the positive displacement principle and is released from the fluid chamber in a jolt-like manner through the actuation of the actuator 15 as a free jet through the fluid channel 12 .
  • a liquid laboratory sample e.g. an aqueous solution or suspension
  • the microdosing volume 99 of a liquid laboratory sample, for example an aqueous solution or suspension, to be generated as a free jet is contained in the pipetting container 98.
  • a liquid laboratory sample for example an aqueous solution or suspension
  • the microdosing volume 99 of a liquid laboratory sample for example an aqueous solution or suspension
  • the pipetting container 98 According to the air cushion principle, an amount of air is contained in the fluid chamber 21 in the fluid chamber 21 in the position P1, which air is discharged from the fluid chamber through the fluid channel 22 in a jolting manner through the actuation of the actuator 25.
  • a corresponding micro-volume is displaced by the micro-air jet penetrating into the interior of the pipetting container, so that the microdosing volume 99 is pushed out of the pipetting container as a free jet.
  • microdosing devices described below can be designed either as positive displacement devices or according to the air cushion principle, without this being expressly mentioned in each case.
  • Fig. 3a shows a microdosing device 30 for generating a microdosing volume of a fluid sample in the form of a microfree jet (99), having a fluid chamber 31, a fluid channel 32 which connects the interior of the fluid chamber with an outer space and which serves to receive the microdosing volume of a fluid sample, a displacement element 33, which is set up to deflect between a first position P1 and a second position P2 and to displace a micro-volume of the fluid chamber.
  • a microdosing device 30 for generating a microdosing volume of a fluid sample in the form of a microfree jet (99), having a fluid chamber 31, a fluid channel 32 which connects the interior of the fluid chamber with an outer space and which serves to receive the microdosing volume of a fluid sample, a displacement element 33, which is set up to deflect between a first position P1 and a second position P2 and to displace a micro-volume of the fluid chamber.
  • the microdosing device 30 has a shape memory material actuator 35, which is arranged to deflect the displacement element, and is set up so that the displacement of the microdosing volume from the fluid chamber causes the microdosing volume in the form of a microfree jet 99 to be released into the outside space.
  • the functionality of the microdosing device in Figures 3a, 3b corresponds to that in Figures 1a, 1b : the displacement element is stopped abruptly by the second stop 34b and the free jet is generated. This is favored by the way the shape memory material actuator 35 works:
  • the shape memory material actuator 35 is firmly connected to the base body 36 by means of a connecting device, in particular by means of a coupling element 38, e.g. a clamp, in particular a first end of the shape memory material actuator is connected to the base body at a first connection point and a second end is connected to the shape memory material -Actuator connected to the base body at a second connection point.
  • the displacement element 33 lies in Fig. 3a on the first (upper) stop - this can be achieved by a return element, a second actuator or a holding device, in particular a locking device (not shown in each case).
  • the shape memory material actuator 35 rests on a support section 33 a of the displacement element 33.
  • the shape memory material actuator 35 can be wire-shaped or web-shaped, and in this case is preferably supported by a guide device, for example a U-shaped section 85a '(cf. Figure 9c ) guided on the displacement element. It could also be fixed or held captive on the support section, for example by being guided through an opening in the support section. Alternatively, other arrangements of an actuator device can be implemented, which have already been or will be described above.
  • a contraction of the shape memory material actuator 35 leads to the displacement element 33 being moved from the first to the second position in a very short time, that is to say in a pulse-like manner.
  • the shape memory material actuator is an alloy based on TiNiCu, which is even more fatigue-resistant than conventional NiTi and thus offers advantageous long-term stability and reliability of the shape memory material actuator.
  • the phase transition or switching temperatures of the material are determined by means of dynamic differential calorimetry (DSC), see diagram of Fig. 18 . In this measurement, the phase transition that is important for actuation appears as a peak. The diagram shows that the temperature of the actuator must be increased to at least 67 ° C in order to switch the actuator; to reset the temperature, the temperature must again be reduced to a maximum of 50 ° C.
  • the shape memory material actuator is particularly in the martensite phase and can (apparently) be plastically deformed by low forces.
  • the shape memory material actuator is in the in Fig. 3a shown first position of the displacement element.
  • the shape memory material actuator can in particular be arranged in the first position in such a way that it is under mechanical tension. But he can also be relaxed.
  • the critical temperatures of the shape memory material actuator can be set in that an electric current I flows through the shape memory material actuator.
  • a voltage supply 88 is provided with which a circuit leading through the shape memory material actuator can be closed optionally for heating ( Figure 3b ) or lets open the shape memory material actuator to cool down ( Fig. 3a ).
  • the shape memory material actuator 35 is preferably not only arranged in the first position but also in the second position of the displacement element so as to be deflected, in particular curved, with respect to a linear orientation.
  • the original component shape of the shape memory material actuator corresponds to a straight line.
  • the shape memory material actuator is under mechanical tension in the second position, which is expressed as a downward force component in the direction of the deflection arrow A.
  • the displacement element 33 is also pressed downwards against the second stop 34b in the second position, at least for a certain period of time.
  • the components of the microdosing device 16 and 26 are arranged essentially within the base body 36 of the microdosing device, in particular in the second position of the displacement element. In the first position, the displacement element 33 protrudes from an opening of a space framed by the base body.
  • Figure 4a shows a microdosing device 40, which essentially corresponds to the microdosing device 30, but which does not have a stop device. Instead, the shape memory material actuator 45 is suddenly transferred into the martensite phase by the flow of current - and thus promoting the formation of the free jet 99 - in which the shape memory material actuator has a linear arrangement.
  • the displacement element 43 has holding elements 43a with which the displacement element 43 is held immovably on the shape memory material actuator 45 at least in the vertical direction, that is to say along the direction of the deflection A. This clearly defines the second position of the displacement element, which further promotes the formation of the free jet 99.
  • the first position can be defined by the maximum length of the shape memory material actuator anchored on the base body, or by the maximum length of one or more cable elements (not shown) that are anchored on the base body and are arranged on the displacement element in such a way that it is in the first position against the force of a return element (not shown in Figure 4a , but in Figure 5a ) is held on the base body 46.
  • a resetting element another resetting device can be implemented in which a further shape memory material actuator (not shown) can be provided which, in its martensite phase, has a shape similar to that in FIG Fig. 3a having shown actuator.
  • a holding device for releasably holding the displacement element in the first position can be provided (not shown), in particular a releasable locking device, so that the displacement element can be transferred into the first position and in particular locked in place by means of the further shape memory material actuator (not shown), with to move the displacement element into the second position, the locking is released and the displacement element is actuated by means of the shape memory material actuator 45.
  • the locking can be released in an electronically controlled manner by means of the control device which is preferably provided.
  • Figure 5a shows a microdosing device 50, which essentially corresponds to the microdosing device 30, and which may or may not have a stop device.
  • the microdosing device 50 has a restoring element 57, here a spring 57, which in the first position between the base body 56 and Displacement element is clamped and compressed, and thereby presses the displacement element 53, in particular against its gravitational force, upwards into the clearly defined first position. This can be defined upwards by a stop or some other holding device (not shown).
  • the displacement element 53 By heating the shape memory material actuator 55 above the upper critical temperature, the displacement element 53 is suddenly actuated, the deflection force along direction A being greater than the restoring force of the spring 57 pointing in the opposite direction B, so that the spring 57 compresses further is, the displacement element is suddenly transferred to the second position and the free jet 99 is emitted.
  • the shape memory material actuator 55 After the shape memory material actuator 55 has cooled to the lower critical temperature, the shape memory material actuator leaves the martensite phase, the restoring force of the spring 57 dominates and pushes the displacement element back into the first position.
  • Figure 6a shows a microdosing device 60, which essentially corresponds to the microdosing device 30 or 50, and which has a stop device with a movable second stop 64b, against which a projection 63a of the displacement element 63 strikes.
  • the micro-volume of the fluid chamber can be adjusted in that the second position P2 is variable.
  • the preferred principle of the remains unchanged Figure 1a, 3a and 5a that the displacement element is deflected by means of an actuator and is suddenly stopped by the second stop.
  • a first stop which defines the first position could alternatively (not shown) have a variably adjustable vertical position
  • the second stop then, as in FIG Figure 5a shown as a stop 54b, could hit a bottom portion of the fluid chamber 61 in the second position.
  • FIG. 7a shows a microdosing device 70, which essentially corresponds to the microdosing device 50, and which additionally has a membrane 79, which instead of a spring (like the spring 57 in FIG Figure 5a ) serves as a restoring element 77, which returns the displacement element 73 from the second position to the first position.
  • the Membrane 79 serves at the same time as a sealing element, that is to say as part of a sealing device through which the engagement opening 71 'is sealed in a fluid-tight manner.
  • the sealing device prevents the liquid sample 99, which is initially arranged in a pipetting container 98 here, from reaching the area of the base body in which the displacement element and the actuator are arranged. This reduces the wear and tear on the moving parts.
  • the microdosing device 70 has a stop device 74b, which is designed here as an upper edge 74b of the base body 76, against which a projection 73a of the displacement element strikes in the second position.
  • the stop device is designed such that the forces acting when the displacement element is stopped are preferably predominantly, in particular completely, absorbed by the base body 76. In contrast, these forces are predominantly, in particular completely, not transmitted to the membrane 79, in that the lower surface 73b of the displacement element predominantly, in particular completely, avoids hitting the membrane. In this way, damage to the membrane is avoided and the operation of the metering device is permanently reliable.
  • FIG. 8 shows a microdosing device 80, the aspects of the microdosing devices in FIG Figure 3a and 7a implements.
  • the microdosing device 80 is used to generate a microdosing volume of a fluid sample in the form of a microfree jet (99), and has a fluid chamber 81, a fluid channel 82, which connects the interior of the fluid chamber with an outer space and which serves to receive the microdosing volume of a fluid sample, a displacement element 83, which is set up to deflect between a first position P1 and a second position P2 and to displace a microvolume of the fluid chamber.
  • the microdosing device has a shape memory material actuator 85, which is arranged to deflect the displacement element, and is set up so that the displacement of the microdosing volume from the fluid chamber causes the microdosing volume to be dispensed in the form of a microfree jet into the outside space.
  • the fluid chamber is designed as a microdosing chamber which, for example, can have a maximum internal volume of the fluid chamber of less than 2 ⁇ l, with the displaced micro volume being in particular between 0.1 ⁇ l and 1 ⁇ l.
  • the microdosing device 80 of Figure 8a has a base body 86, within which the components of the microdosing device are arranged.
  • the base body 86 has a first part 86a and a second part 86b, which are preferably each formed integrally, in particular each manufactured by an original molding process. It is also preferred that the first part 86a and / or the second part 86b consist of at least two further parts which are joined together to form the microdosing device.
  • the base body 86 has a second part 86b, which forms the fluid chamber 81 and which here forms at least one fluid channel, in this case the fluid channel 82.
  • the fluid channel 82 can be fluidically connected to a pipetting container (not shown) in such a way that a microdosing volume contained in the pipetting container is a Liquid sample can be emitted as a free jet according to the air cushion principle from the air microvolume suddenly displaced from the fluid chamber 81.
  • the microdosing device 80 has a stop device 84a, 84b which is set up to stop the deflection of the displacement element when it is moved from the first in the direction of the second position.
  • the stop device has a first, upper, stop 84a, which is designed as a projection of the base body 86, and a second, lower, stop 84b, which is also designed as a projection of the base body 86.
  • a projection 83a of the displacement element strikes the stop 84b of the base body in the second position, and an upper section of the displacement element strikes the stop 84a in the first position.
  • the membrane When it hits the second position, the membrane can contact the lower surface of the chamber, but is mainly mechanically relieved, since the forces acting in the direction of stop A are mainly, preferably completely, absorbed by the stop 84b.
  • the base body 86 has a first part 86a, which serves as a guide device in the form of a guide channel for the displacement element 83, which is essentially cylindrical here.
  • the stop device is formed by the first part 86a, in particular both the first - upper - stop 84a and the second - lower - stop 84b.
  • the displacement element 83 strikes when it is deflected out of the first part the second position in direction A, or analogously in the opposite direction B, to a lesser extent - or not - on the second part 86b, so that a lower - or no - force on the second part 86b compared to striking the displacement element on the second stop 84b second part 86b is exercised.
  • the bottom section of the displacement element 83 or the bottom section of the fluid chamber does not serve, or not primarily, as a stop.
  • the microdosing device 80 in particular the displacement element 83 or its length, is preferably set up in such a way that the displacement element guides the membrane 89 during the movement into the second position against the bottom section of the fluid chamber 81.
  • the greater part of the pulse-shaped deflection force A is absorbed by striking the second stop 84b.
  • the microdosing device 80 of Figure 8a has a membrane 89, which - analogously to the membrane 79 - serves as a restoring element 77 and which returns the displacement element 83 from the second position to the first position as soon as the restoring force exceeds the deflection force of the shape memory material actuator 85.
  • the membrane 79 serves at the same time as a sealing element, that is to say as a component of a sealing device, through which the engagement opening 81 'is sealed in a fluid-tight manner.
  • the fluid chamber 81 is designed as a microdosing chamber, which is formed as a cylindrical chamber with radius R, which can be or is connected to the pipetting container, e.g. a pipette tip, via an outlet opening of the fluid channel 82 on the underside.
  • the fluid chamber 81 is closed off by the membrane 89, as a result of which the shape memory material actuator never comes into contact with the fluid inside the chamber (media separation).
  • a ball is inserted between the plunger and the actuator which centers itself under the X-shaped, pocket-like curved actuator device 85.
  • the Figures 9a and 9b show the actuator device 85 which is arranged in an X-shape and has a pocket-like design
  • FIG Figure 9a the first position is shown in which the The displacement element is held in the first position by the restoring element 87, that is to say the membrane 89
  • FIG Figure 9b the second position is shown in which the actuator device 85 has been activated and the displacement element has been pushed against the second stop.
  • the actuator device 85 has two shape memory material actuators based on a NiCuTi alloy, namely two elongated, bar-shaped shape memory material actuators produced on the basis of sputtered film, which cross one another, i.e.
  • the ends of the shape memory material actuators are on the base body 86 of the microdosing device 80 at the two coupling points 88 ( Figure 9a ) anchored.
  • the shape memory material actuators are tensioned above the support point in such a way that the intersection point 85a in each case forms a point of curvature of the shape memory material actuator.
  • This, as in the Figures 9a, 9b and 9c is shown by way of example, a shell-like area of the actuator device is formed, through which the actuator device centers itself above the support point and generates a precisely downward force along the linear direction of movement between the first and second position, which results in a correspondingly precise deflection.
  • the two shape memory material actuators can be coupled by a connector (not shown). While in Figures 9a to 9c the displacement element 83 'is made up of cuboid sections, the displacement element 83 in FIG Figures 8a and 8b cylindrical sections, as well as a ball as a support surface for the actuator device 85.
  • the membrane 89 consists of highly flexible PDMS with a thickness of 200 ⁇ m and is already deflected in advance when the shape memory material actuators are de-energized. This is desired in order to apply sufficient force to reset the actuator device.
  • the membrane is deflected by the displacement element by the stroke.
  • the stroke is predetermined by the mechanical stops 84a, 84b of the guide of the displacement element and is 100 ⁇ m here.
  • a stop device with adjustable stops can also be implemented, as in FIG Figure 6a shown, which allows an adjustment of the dispensing volume.
  • the membrane 89 deflected by the displacement element forms a truncated cone.
  • the actuator device is actuated, the height of the truncated cone increases by 100 ⁇ m, and the flanks of the truncated cone become steeper.
  • the displaced volume results from the difference in volume between the cylindrical space, reduced by the volume of the two truncated cones, which forms the fluid chamber 81.
  • the mechanical behavior of the module consisting of microdosing chamber 81, membrane 89 and displacement element 83 can be examined by means of a compression test in a tensile testing machine.
  • the displacement element is slowly pressed into the microdosing chamber until the lower stop 84b is reached, the deflection and the force being recorded.
  • the membrane 89 is pretensioned, a certain minimum force is already required in order to release the displacement element from the upper stop 84a.
  • the force increases continuously. After reaching the lower stop 84b, an increase in the force does not lead to any further deflection of the membrane.
  • a typical characteristic curve for a 0.1 ⁇ l microdosing chamber is in Figure 17 shown.
  • the actuator device is designed in such a way that it can fully deflect the diaphragm when power is supplied, while in the de-energized state it is returned to the upper stop 84a by the pretensioned diaphragm.
  • the actuators of the actuator device 85 are, for example, each applied in pairs to a carrier plate with integrated conductor tracks and are electrically contacted, see FIG Figures 9a, 9b .
  • the electrical control of the shape memory material actuators takes place via an electrical control device which is set up to apply a voltage simultaneously to both shape memory material actuators and to apply these synchronously to contract.
  • both actuators are connected to a power source via a three-wire cable.
  • a middle wire serves as a common ground electrode.
  • the actuators are activated during operation with a very short voltage or current pulse that lasts a few 10 ms, and then the effective voltage is throttled by pulse width modulation to such an extent that the switching position of the shape memory material actuators can be kept straight.
  • the supply voltage is set to 4 V, the duration of the initial voltage pulse to 10 ms, and the pulse width modulation, for example, to a duty cycle of 1/128.
  • the actual switching time is determined, for example, by observing the actuator (or the ball below) with a high-speed camera.
  • a shape memory material actuator needs less than 2 ms to cover the stroke.
  • the force-deflection characteristics of the actuators can be determined using a tensile testing machine. Examples for the coordination of micro-dispensing chambers with displaceable micro-volumes of 0.1 ⁇ l ( Fig. 19 ) and 0.4 ⁇ l (the pair of curves in Fig. 20 in lighter color) and 0.8 ⁇ l (the pair of curves in Fig. 20 in darker color) and actuator are in the Figures 19 and 20 shown.
  • the force-deflection characteristic curve is shown in the cold (lower curve beginning on the left) and in the heated state (upper curve beginning on the left).
  • the equilibrium points of the actuator in the de-energized and switched state result from the intersection of the actuator characteristics with the micro-metering chamber characteristic. Since the switching forces required to deflect the membrane are about three times as great for the larger chambers as for the smallest chamber, actuators of different web widths are used.
  • Figures 11a, 11b and 11c each show a schematic side view of a pipetting device 100 with a connected microdosing device according to the invention.
  • the pipetting device 100 designed according to the invention is used for the dosed uptake and delivery of fluid samples, in particular microdosing volumes 99. It has a conventional pipetting device 101 (not shown), hereinafter referred to as a pipetting device for better differentiation, which has a piston chamber and one in the Arranged piston chamber, movable piston for sucking a fluid into the piston chamber and for dispensing the fluid from the piston chamber.
  • the pipetting device 100 furthermore has a pipetting channel 102 which connects the piston chamber with the outer space of the piston chamber.
  • the pipetting device 100 also has a microdosing device according to the invention, here is a microdosing device 70 ', which essentially corresponds to the microdosing device 70, but which additionally has a bypass channel 103, which connects the interior of the microdosing chamber of the microdosing device 70' fluidically with the outside space, the environment, connects.
  • a microdosing device 70 ' which essentially corresponds to the microdosing device 70, but which additionally has a bypass channel 103, which connects the interior of the microdosing chamber of the microdosing device 70' fluidically with the outside space, the environment, connects.
  • the bypass channel 103 can optionally be opened / closed by means of a controllable valve 104.
  • the fluid channel 72 'of the microdosing device 70' can be connected to the pipetting channel 102 so that a microdosing volume of a fluid sample can be dosed by the pipetting device 100 by means of the microdosing device 70 'and delivered to the outside space in the form of a microfluid jet via the pipetting channel 102.
  • “connectable” means that a valve 105 is provided which enables the fluidic connection between the fluid channel 72 ′ and the pipetting channel 102.
  • the valve 105 is also a controllable valve 105, the open or closed state of which can be determined by electrical control.
  • the microdosing device 70 works according to the air cushion principle, the displaced fluid is air, the microdosing volume of an aqueous sample is initially ( Figure 11a ) contained in the pipetting container 98 and is held there by the negative pressure in the pipetting channel 102, which in Figure 11a is closed up by the valves 104 and 106 are closed.
  • the controllable valve 106 makes it possible to selectively open or close the pipetting channel 102 in the area between the conventional pipetting device and the confluence of the fluid channel of the microdosing device into the pipetting channel.
  • valves 104 and 106 are closed, the valve 105 is open.
  • the actuation of the shape memory material actuator generates a microdosing volume of an amount of air which is emitted as a microjet from the microdosing device 70 'through its fluid channel 72' into an outer space of the microdosing device.
  • This outer space is the inner space of the pipetting channel 102 here.
  • the microvolume that is suddenly displaced there leads into Figure 11b for dispensing the microdosing volume of the liquid sample from the pipetting container 98 in the form of a microfree jet 99.
  • the valves 104, 105 and 106 are shown in FIG Figure 11b across from Figure 11a unchanged.
  • valve 105 is closed, the valves 104 and 106 are each open.
  • a new liquid sample can be aspirated into the pipetting container 98 by means of the pipetting device 101 or the pipetting channel 102 which is now open to the environment.
  • the displacement element of the microdosing device 70 ' can be moved into the first position, which is possible when the valve 105 is closed due to the open valve 104, which enables air to be sucked in from the environment into the fluid chamber (ventilate) via the bypass channel 103.
  • Fig. 12 is a microdosing device 200 for generating a combined microdosing volume 99 'of a fluid sample in the form of a micro free jet.
  • the microdosing device 200 has four microdosing devices 70a, 70b, 70c and 70d, which are essentially identical in construction to the microdosing device 70 or the microdosing device 80.
  • the first microdosing device 70a has a first fluid chamber and a first displacement element that is set up to displace a first microvolume of the first fluid chamber.
  • the second microdosing device 70b has a second fluid chamber and a second displacement element that is set up to displace a second microvolume of the second fluid chamber.
  • the third microdosing device 70c has a third fluid chamber and a third displacement element that is set up to displace a third microvolume of the third fluid chamber.
  • the fourth microdosing device 70d has a fourth fluid chamber and a fourth displacement element that for displacing one fourth microvolume of the fourth fluid chamber is set up.
  • the respectively displaced micro-volumes all have different sizes, in the present case the values 0.1 ⁇ l, 0.2 ⁇ l, 0.4 ⁇ l and 0.8 ⁇ l.
  • the microdosing device 200 also forms an exemplary pipetting device according to the invention; here, too, the liquid sample is sucked in by means of a pipetting device 101 via the pipetting channel 202.
  • a bypass channel 203 is provided, which connects the interior of the pipetting channel 202 - by means of the controllable valve 204 optionally - with the Environment connects in order to ventilate the pipetting channel 202 and, via its intermediary, also, depending on the activity of the respective displacement element, the fluid chamber (s) of the desired microdosing device 70a, 70b, 70c and / or 70d.
  • the fluid channels 72a, 72b, 72c and 72d of the four microdosing devices which connect the interior of the fluid chambers of the microdosing devices with an outer space of the microdosing device, namely here the inside of the pipetting channel 202 and which serve to accommodate the microdosing volume of a fluid sample, are opposite the pipetting channel 202 here permanently open and have no valve.
  • a controllable valve 205 is provided between the transitions of the fluid channels into the pipetting channel 202 and the outlet opening, which valve is closed to close the outlet of the pipetting channel 202 when the fluid chambers are ventilated.
  • the controllable valve 206 is arranged between the transitions of the fluid channels into the pipetting channel 202 and the pipetting device 101 and is opened for conventional pipetting, in particular for picking up and / or dispensing a pipetting sample, but is closed for dispensing the microdosing volume 99 of a microfree jet.
  • the microdosing device 200 has the four actuator devices of the microdosing devices 70a, 70b, 70c and 70d, which are set up for the synchronized deflection of the first and the second displacement element.
  • the microdosing device 300 is set up so that the output of a combined microdosing volume 99 'in the form of a microfree jet into the outside space is effected by the synchronized displacement of at least two microvolumes of the total of four microvolumes from a first and second fluid chamber.
  • n 4 of such microdosing devices 70a, 70b, 70c and 70d, each of which has different volumes
  • FIG. 3 shows an embodiment of the microdosing device 200 according to FIG Fig. 12 as a microdosing device 300 in the form of an autonomous device or module that can be combined with a conventional pipetting device 101, the valves each being implemented by means of a shape memory material actuator.
  • the module 300 consists of a base body 316 with two connections 311 and 312.
  • the proximal connection 311 which is closer to a connected conventional pipetting device 101 (pipette or the like), can be connected via a cone.
  • a cone for connecting a disposable article (pipette tip 98 ') is connected to the distal connection 312.
  • microdosing devices 380a, 380b, 380c, 380d - each in principle identical to the microdosing device 80- with displaced microvolumes of 100nl, 200nl, 400nl, and 800nl, and three controllable valves 304, 305, 306 are integrated in the pump body are provided with separate drives - one drive based on a shape memory material actuator.
  • the valves 305 and 306, as well as the displacement elements of the microdosing devices 380a, 380b are guided or held by a guide part 317 of the base body, which is arranged on the first part 316 of the base body and is covered by the cover part 331, which is covered with the first part 316 of the base body connected is.
  • a common silicone membrane 379 which is located between the cover part 331 and the first part 316 of the Base body is clamped and thereby fixed.
  • the valve 304 which opens and closes the bypass to the environment, and the displacement elements of the microdosing devices 380c, 380d, are guided or held by the guide part 317 of the base body, which is arranged on the first part 316 of the base body and is covered by the cover part 332, which is connected to the first part 316 of the base body.
  • a (further) common silicone membrane 379 which is clamped between the cover part 332 and the first part 316 of the base body and thereby fixed, also serves as a seal to the microdosing chambers of the microdosing devices 380c and 380c and the valve seat.
  • valves 304, 305, 306 each consist of the valve 306 in FIG Fig. 14 is shown by way of example, composed of a valve tappet 306a, a valve spring 306b and a clamping pin 306d.
  • the clamping pin is used to adjust the preload of the shape memory material actuator 306e.
  • microdosing devices 380a, 380b, 380c and 380d By combining the microdosing devices 380a, 380b, 380c and 380d, the combined microdosing volumes between 100nl and 1500nl with an increment of 100nl are possible, as shown in the table in FIG Fig. 16 is listed.
  • the liquid sample is received in the pipetting container 98 'by means of a conventional piston drive of a pipette 101 that can be connected to the module 300.
  • the piston of the pipette 101 is in the lower position. All valves are closed.
  • the valves 306 and 305 are now opened (connection to the pipette tip is open).
  • the piston is moved upwards and thus picks up the liquid via the pipetting channel 302.
  • the valves 306 and 305 are now closed again.
  • the procedure is as follows: In the initial situation, the piston of the pipette 101 is in the upper position (neutral state). All valves are closed (neutral state). The valve 304 (ambient level) is opened. All displacement elements of the microdosing devices 380a to 380d or the desired number / selection of displacement elements are moved downward in the direction of the respective membrane 379 (against the respective second stop of the microdosing devices 380a to 380d). Valve 304 is now closed and valve 305 is opened.
  • valve 305 is now closed again and the liquid is thus fixed in the pipetting channel by negative pressure.
  • valve 304 is briefly opened and then closed again in order to carry out a pressure equalization.
  • the system is now back in its original position. This process can now be repeated as required until the desired total volume has been absorbed.
  • the brief opening and closing of valve 304 is omitted; this only takes place after the displacement elements have moved again in the direction of the membrane 379.
  • the (repeated) delivery of the liquid aspirated into the pipetting container 98 'or for the pump operation is proceeded as follows:
  • the displacement elements of the microdosing devices 380a to 380d are in the upper position (neutral state).
  • the pressure level is neutral. All valves are closed (neutral state).
  • the valve 305 is opened.
  • a displacement element or any number of displacement elements is moved in the direction of the membrane 379 and the desired micro-volume is emitted, and as a result the desired combined (or simple) microdosing volume 99 'is emitted as a micro-free jet.
  • valve 305 is closed again and the displacement element or displacement elements are moved back into their starting position (s).
  • To the Pressure equalization valve 304 is opened briefly and then closed again. The process now starts from the beginning.
  • the control of these methods for operating the module 300 are preferably implemented by an electrical control device 350 set up in the desired manner, in particular programmed ( Fig. 10 , 15th ).
  • the control device 350 can be part of the module 300.
  • the control device 350 can be an external device or a component thereof.
  • the control device 350 can be part of a modified pipetting device, in particular a conventional pipetting device 101 supplemented by the control device 350.

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Claims (16)

  1. Dispositif de microdosage (30 ; 40 ; 50 ; 60 ; 70 ; 70' ; 80) pour la production d'un volume de microdosage d'un échantillon de fluide sous la forme d'un microjet libre (99), donc d'un volume de fluide dans la plage du microlitre ou du sous-microlitre, qui sort de l'ouverture d'évacuation d'un canal de fluide sous forme de jet ou de gouttes libres, comprenant
    une chambre de fluide (31 ; 41 ; 51 ; 61 ; 71 ; 81),
    un canal de fluide (32 ; 42 ; 52 ; 62 ; 72 ; 72' ; 82), qui relie l'intérieur de la chambre de fluide à un espace extérieur et qui sert à accueillir le volume de microdosage d'un échantillon de fluide,
    un élément de refoulement (33 ; 43 ; 53 ; 63 ; 73 ; 83), qui est aménagé pour la déviation entre une première position (P1) et une deuxième position (P2) et pour refouler un microvolume de la chambre de fluide,
    ledit dispositif de microdosage présentant un actionneur de matériau de mémoire de forme (35 ; 45 ; 55 ; 65 ; 75 ; 85) qui est disposé pour la déviation de l'élément de refoulement et un dispositif de commande électrique pour commander un actionneur de matériau de mémoire de forme,
    caractérisé en ce que
    le dispositif de microdosage est aménagé de telle sorte que l'élément de refoulement (33 ; 43 ; 53 ; 63 ; 73 ; 83) est déplacé à la manière d'une impulsion depuis la première position (P1) en la deuxième position (P2) et que le refoulement du microvolume depuis la chambre de fluide provoque l'émission du volume de microdosage sous la forme d'un microjet libre dans l'espace extérieur et
    le dispositif de commande électrique est aménagé de manière à activer l'actionneur de matériau de mémoire de forme avec une impulsion de courant et/ou de tension très courte dont la période est comprise entre 1 ms et 100 ms.
  2. Dispositif de microdosage selon la revendication 1, dans lequel la chambre de fluide est conçue sous forme de chambre de microdosage.
  3. Dispositif de microdosage selon l'une des revendications 1 ou 2, qui présente un dispositif de butée (34a, 34b ; 44a, 44b ; 54b ; 64a, 64b ; 74a, 74b ; 84a, 84b) qui est aménagé pour stopper la déviation de l'élément de refoulement.
  4. Dispositif de microdosage selon l'une des revendications précédentes, dans lequel la chambre de fluide présente une ouverture de prise (11' ; 21' ; 31' ; 41' ; 51' ; 61' ; 71' ; 81') pour la mise en prise de l'élément de refoulement qui s'étend dans la chambre de fluide à travers l'ouverture de prise pendant la déviation,
    dans lequel se trouve un dispositif d'étanchéité permettant d'étanchéifier l'ouverture de prise de manière étanche aux fluides.
  5. Dispositif de microdosage selon la revendication 4, dans lequel le dispositif d'étanchéité comporte une membrane (79 ; 89) qui est déformable élastiquement, qui étanchéifie l'ouverture de prise et qui est disposée entre l'espace intérieur de la chambre de fluide et l'élément de refoulement.
  6. Dispositif de microdosage selon l'une des revendications précédentes, qui comporte un élément de retour (57 ; 67 ; 77 ; 87) qui est déformable élastiquement et qui est tendu par la déviation et avec lequel une force de retour élastique peut être exercée sur l'élément de refoulement pour faire revenir élastiquement celui-ci après la déviation de la deuxième position en la première position.
  7. Dispositif de microdosage selon l'une des revendications 4 ou 5, et la revendication 6, dans lequel ladite membrane (79 ; 89) est aménagée sous la forme dudit élément de retour élastique (77 ; 87).
  8. Dispositif de microdosage selon l'une des revendications précédentes, qui présente au moins deux chambres de fluide conçues sous forme de chambres de microdosage, qui sont conçues pour émettre des microvolumes de différentes tailles et qui sont reliées respectivement avec ledit canal de fluide pour émettre le microvolume.
  9. Dispositif de microdosage selon l'une des revendications précédentes qui présente un canal de dérivation refermable, qui relie à l'état ouvert l'espace intérieur de la chambre de fluide avec l'espace extérieur.
  10. Dispositif de microdosage selon l'une des revendications précédentes, qui présente un corps de base, dans lequel se trouve au moins un actionneur de matériau de mémoire de forme qui est ancré sur le corps de base et est disposé sur l'élément de refoulement de telle sorte que la contraction électriquement commandée de l'actionneur de matériau de mémoire de forme dévie l'élément de refoulement.
  11. Dispositif de microdosage selon l'une des revendications précédentes, qui est un dispositif de pipetage permettant d'aspirer et d'émettre un échantillon de fluide par le biais du canal de fluide.
  12. Dispositif de microdosage selon l'une des revendications précédentes, dans lequel le dispositif de pipetage est conçu selon le principe du coussin d'air et la chambre de fluide est remplie d'air.
  13. Dispositif de pipetage (100 ; 200) pour la réception et l'émission dosées d'échantillons de fluide, comportant
    une chambre à piston,
    un piston mobile, disposé dans la chambre à piston, pour l'aspiration d'un fluide dans la chambre à piston et pour l'émission du fluide hors de la chambre à piston,
    un canal de pipetage (102) qui relie la chambre à piston à l'espace extérieur de la chambre à piston,
    un dispositif de microdosage (10 ; 20 ; 30 ; 40 ; 50 ; 60 ; 70 ; 70' ; 80) selon l'une des revendications précédentes 1 à 12, dont le canal de fluide (12 ; 22 ; 32 ; 42 ; 52 ; 62 ; 72 ; 82) peut être relié à la chambre à piston et/ou au canal de pipetage de telle sorte qu'un volume de microdosage (99) d'un échantillon de fluide peut être dosé par le dispositif de pipetage au moyen du dispositif de microdosage et peut être émis sous la forme d'un microjet de fluide par le biais du canal de pipetage dans l'espace extérieur.
  14. Dispositif de pipetage selon la revendication 13, qui est conçu selon le principe du coussin d'air ou est conçu sous forme de distributeur selon le principe du refoulement direct et qui est conçu en particulier sous forme de dispositif portable.
  15. Utilisation du dispositif de microdosage selon l'une des revendications précédentes 1 à 12 pour le dosage d'échantillons de fluides biologiques, biochimiques, chimiques ou médicaux dans un laboratoire.
  16. Dispositif de microdosage (200 ; 300) pour la production d'un volume de microdosage combiné d'un échantillon de fluide sous la forme d'un microjet libre, présentant
    au moins un premier et un deuxième dispositif de microdosage, qui est respectivement un dispositif de microdosage selon l'une des revendications 1 à 12,
    dans lequel le premier dispositif de microdosage présente une première chambre de fluide et un premier élément de refoulement qui est aménagé pour refouler un premier microvolume de la première chambre de fluide,
    et dans lequel le deuxième dispositif de microdosage présente une deuxième chambre de fluide et un deuxième élément de refoulement qui est aménagé pour refouler un deuxième microvolume de la deuxième chambre de fluide,
    un canal de fluide (202 ; 302) qui relie l'intérieur de la première et de la deuxième chambre de fluide à un espace extérieur et qui sert à accueillir le volume de microdosage d'un échantillon de fluide,
    dans lequel le dispositif de microdosage présente au moins un dispositif actionneur qui est aménagé pour la déviation synchronisée du premier et du deuxième élément de refoulement, et
    dans lequel le dispositif de microdosage est aménagé de telle sorte que le refoulement synchronisé du premier et du deuxième microvolume depuis la première et la deuxième chambre de fluide provoque l'émission d'un volume de microdosage combiné sous la forme d'un microjet libre dans l'espace extérieur.
EP17189074.2A 2017-09-01 2017-09-01 Dispositif de microdosage permettant le dosage de plus petits échantillons de fluide Active EP3450020B1 (fr)

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PCT/EP2018/073471 WO2019043159A1 (fr) 2017-09-01 2018-08-31 Dispositif de microdosage pour le dosage de micro-échantillons de fluide

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EP3838412A1 (fr) * 2019-12-20 2021-06-23 MT.DERM GmbH Dispositif et procédé de distribution d'une quantité de fluide microfluidique de l'ordre du picolitre et du microlitre et appareil portatif permettant de piquer localement une peau humaine ou animale
CN111707434B (zh) * 2020-06-24 2021-07-06 西南交通大学 一种传热管和梅花孔支撑板微动损伤试验装置及其实施方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2519184A (en) 1983-03-21 1984-09-27 Miles Laboratories Inc. Microdroplet dispensing apparatus
US5763278A (en) 1995-11-01 1998-06-09 Tecan Ag Automated pipetting of small volumes
DE19737173B4 (de) 1997-08-26 2007-04-05 Eppendorf Ag Mikrodosiersystem
DE19802368C1 (de) 1998-01-22 1999-08-05 Hahn Schickard Ges Mikrodosiervorrichtung
CH695544A5 (de) 2000-11-17 2006-06-30 Tecan Trading Ag Vorrichtung zur Abgabe bzw. Aufnahme/Abgabe von Flüssigkeitsproben.
DE10220371A1 (de) 2002-05-07 2003-11-27 Fraunhofer Ges Forschung Freistrahldosiermodul und Verfahren zu seiner Herstellung
DE10337484B4 (de) 2003-08-14 2005-05-25 Zengerle, Roland, Prof. Dr. Mikrodosiervorrichtung und Verfahren zur dosierten Abgabe von Flüssigkeiten
GB0418256D0 (en) * 2004-08-16 2004-09-15 The Technology Partnership Plc Liquid dispensing device
EP2662137A1 (fr) * 2012-05-08 2013-11-13 Roche Diagniostics GmbH Ensemble de distribution
US9221046B2 (en) 2014-01-30 2015-12-29 Rainin Instrument, Llc Air displacement pipette with enhanced blowout

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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