EP3485974B1 - Microdosing device for dosing minute fluid samples - Google Patents

Description

The invention relates to a microdosing device for the metered delivery and / or intake of fluid samples in the microvolume range, a system comprising such a microdosing device with a pipetting device and a method for the metered delivery and / or intake of fluid samples in the microvolume range.

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. In pipetting devices, for example, liquid samples are sucked into pipette containers, e.g. pipette tips, by means of negative pressure, stored there, and released from them 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. In the case of an air cushion pipette, 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, for example by arranging the piston in the pipetting container. The piston end of the dispenser is very close to the to pipetting fluid sample or in contact with it, which is why the dispenser is also known as a 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 are made 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.

In the case of a pipetting device, the amount of sample released by a single actuation can correspond to the amount of sample sucked into the device. However, it can also be provided that a quantity of sample received corresponding to several delivery quantities is delivered again in steps. In addition, a distinction is made between 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. When dosing very small amounts of liquid with the help of a With a piston-operated pipette, the systematic and random errors in dosing can increase considerably. 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. When 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 μl and 1.0 μl, in the present case preferably summarized under the term "micro-volumes", can no longer be dosed sufficiently safely with conventional pipetting devices. Various physical influences are responsible for this. These influences include, among other things, the formation of satellite droplets as a result of the reflection of the released volume on the surface of the liquid on which they strike; incomplete ejection of the volume in the pipette tip; the geometric relationships within the pipette tip; the surface tension of liquids and pipette tips and the associated wetting behavior or the occurrence of capillary forces; the electrostatic charge on the pipette tip; too low a flow velocity or kinetic energy of the fluid sample at the outlet opening of the pipette tip. The delivery of the smallest volumes is also made more difficult because the total air volume between the piston and the sample liquid, as a damping element, lies behind the volume to be ejected and counteracts the efficient delivery of a free jet.

In order to be able to dispense fluid samples with small volumes in the free jet in a metered manner, various approaches have been pursued in the prior art.

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. Here, a cylinder-piston closure in a piston chamber that can be moved by means of a spindle drive is provided with a pulse generator, here a piezo element. 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 volume of liquid 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.

DE 100 22 398 B4 describes a microdosing system in which a free jet is generated by means of a gas pressure surge and the size of the dispensed dosing volume is regulated by gas pressure measurements.

The approaches mentioned each have certain disadvantages and are in particular either complex or voluminous or inflexible in terms of integration into existing laboratory equipment, or too imprecise to generate the desired microdosing volumes.

DE 10 2007 010 412 A1 describes a device for dosing liquids into gas-filled spaces, in which, according to the positive displacement principle, a pressurized elastic liquid reservoir can be expanded by pushing out a defined volume of liquid. DE 10 2012 209 314 A1 describes below other devices for the delivery of a volume of liquid in the microliter range by free jet, which uses a pressure-dependent electronically controlled sample delivery. EP 2 412 439 A1 describes a pipetting device for dispensing by increasing the pressure of a working fluid, comprising a pressure change device for changing the pressure of the working fluid in a dosing liquid receiving space, the pressure change in the working fluid not suddenly, but only gradually continuing into the dosing liquid receiving space.

Against this background, 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 achieves this object by the microdosing device according to claim 1, the system according to claim 9 and the method according to claim 12. Preferred embodiments are, in particular, the subject matter of the subclaims.

The sudden opening of the first valve causes a very efficient acceleration of a micro air volume out of the first air duct section into the second air duct section, which in turn causes efficient acceleration of a micro air volume out of the second air duct section and the second opening. In this way, the microdosing device is particularly suitable for generating a microfluid jet, 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 fluid transfer container as a jet or free drop - also referred to as a jet. The metering is in particular independent of the process of producing an overpressure in the first air duct section. Since the micro-air volume exiting from the first air channel section determines the size of the micro-metering volume dispensed, precise metering in the micro-volume range is possible.

The micro-air volume moved in the micro-metering device is preferably in the sub-microliter range, that is to say less than 1 μl. Accordingly, 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 - in particular displaced by a displacement element - microdosing volume, in particular the microdosing volume is identical in amount to the microdosing volume. In particular, by repeatedly dispensing a microdosing volume, a total dispensing volume formed by the successively dispensing microdosing volumes can also be greater than 1 μl, and is preferably in the range from 0.1 μl to 10.0 μl, in particular 0.1 μl to 5.0 μl, in particular 0.1 µl to 2.5 µl, in particular 0.1 µl to 1.5 µl.

In a preferred embodiment, the following are provided for generating the overpressure in the first air duct section: an air chamber which can be or is connected to the first opening, a displacement element which is designed to displace a micro-volume (V) of the air chamber, and a drive for the To drive deflection of the displacement element, whereby in the first state of the first valve the overpressure can be generated in the first air duct section. These components can be part of the microdosing device or can be part of an external device, in particular an external pipetting device, the working cone of which can be connected to the first opening in an airtight manner, so that the overpressure in the first air channel section can be generated by means of the external pipetting device in the first state of the first valve . Since the micro-air volume (V) is precisely determined by the volume determined by the displacement element, in particular no pressure sensors are required in the air chamber or in the first air duct section in order to achieve precise metering.

The pipetting device is preferably an air-cushion pipette that works according to the air cushion principle, in particular a commercially available pipette or a dispenser, which can be adapted in particular to control the microdosing device. Examples of such commercially available pipetting devices have been mentioned above. However, the control of the microdosing device can also be at least partially or be arranged completely in the microdosing device. In the present case, it is an electrical control device for the microdosing device. In combination with a conventional pipette, the microdosing device can be used particularly flexibly.

The microdosing device is preferably designed as a module. For this purpose, the microdosing device preferably has a connecting section which can be connected and disconnected to a corresponding connecting section of an external pipetting device. This connection is preferably a form-fitting plug-in and clamping connection in which, in particular, the working cone of a pipetting device is inserted into a suitable receiving section of the microdosing device. The control of the microdosing device can in this case take place via data exchange between the microdosing device and the pipetting device, in particular via a wired or wireless connection with the pipetting device. The control can, however, also take place independently of the pipetting device, and can in particular be integrated into the microdosing device, and can be partially manually controllable.

The displacement element is preferably a piston element, in particular a piston element of a commercially available pipetting device. The piston element is preferably set up to displace micro-air volumes and macro-air volumes. A macro air volume is larger than the micro air volume. A macro air volume is in particular such an air volume that can typically be pipetted with conventional, commercially available pipetting devices. A macro air volume can therefore in particular be an air volume greater than 2 µl, in particular less than or equal to 10 µl, 50 µl, 100 µl, 300 µl or 500 µl. The microdosing device or a pipetting device that has the displacement element, in particular the piston element, or the displacement element is preferred set up to displace the micro air volume (V) in the first state of the first valve and in particular also set up to displace a macro air volume in the second state of the first valve.

The microdosing device and / or a pipetting device that can be connected to the first opening is preferably set up so that the from Displacement element to be displaced micro air volume can be selected by the user, in particular by means of a user interface device, which can be part of the microdosing device or the pipetting device.

The first opening of the microdosing device can preferably be connected to the working cone of a pipetting device in such a way that the desired overpressure can be set in the first air channel section by means of the displacement element or by means of the pipetting device. For this purpose, the microdosing device can have an opening section which contains the first opening. The opening section of the microdosing device can be connected to an opening section of the air chamber in an airtight manner, e.g. by means of a form-fitting clamping connection. The opening section of the air chamber can be a working cone of the pipetting device.

The first air duct section preferably has a closable third opening which connects the first air duct section to the outside space, and in particular a controllable second valve which is configured to optionally keep the third opening of the air duct closed in a first state in order to to enable the overpressure in the first air duct section compared to the second air duct section, or to keep it open in a second state, as well as to enable a change from the first to the second state to bring about a pressure equalization in the first air duct section to the outside.

The first valve, in particular also the second valve or at least one further valve of the microdosing device or of the system preferably each have: a valve body on which a valve tappet is movably arranged, which can be deflected by means of at least one SMA actuator of the valve. In its first state, the valve tappet is pretensioned in particular by a spring element and closes a passage opening, and in its second state is in particular deflected, as a result of which the passage opening is opened. As the SMA actuator can be electrically activated, the valve can be controlled. Further details of the valve according to the invention can be derived from the description of the microdosing device according to the invention and its preferred configurations.

The first valve preferably has an electrically controllable actuator. The valve, in particular the actuator, is preferably set up for sudden opening. The actuator is preferably a shape memory alloy (SMA) actuator. However, the actuator can also be a piezoelectric element or an electromagnetically operating actuator.

With regard to this microdosing device, the invention is based in particular on the results of measurements on valves with actuators made of a shape memory alloy, which show that a valve opening and thus a sample discharge according to the free jet principle can be realized very precisely and efficiently even with very compact shape memory material actuators. Shape memory alloys (SMA) 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.

An actuator of the microdosing device is preferably a shape memory material actuator, but can also be an actuator without a shape memory material, in particular an electromechanical actuator or a piezoelectric actuator.

In the context of this invention, actuators are preferably used for 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. Compared to Other actuators, SMA actuators have a particularly high energy density, so that very compact actuators are already suitable for driving the microdosing devices defined here. Another decisive advantage when using SMA actuators, especially compared to piezoelectric actuators, is that the SMA actuators can be operated at a relatively low voltage, in particular between 3 V and 10 V, in particular 5 V. 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) is particularly biocompatible. It enables changes in shape of up to 8% in particular, as a result of which, in particular, microdosing chambers with displaced microvolumes in the microliter range and in the submicroliter range can be produced in an efficient manner. 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 6 . In this measurement, the 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 must 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 μm and 50 μm, in particular between 10 and 30 μm, in particular approx. 20 μm. 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 on the valve 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. As a result of the contraction upon activation, a force can be exerted on a valve tappet when the ends of the actuator are anchored on a base body of the valve. The SMA actuator is preferably arranged such that the radius of curvature always corresponds to at least 50 times 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 for realizing the desired valve. 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.

The valve can have more than one actuator, in particular at least two actuators, which are arranged to deflect a valve tappet. In particular, two SMA actuators can be used.

The at least one actuator or the actuator device causes the valve tappet to be deflected from a first to a second position, the valve being open in the second position, that is to say opening the passage opening of the air duct.

The valve 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. Preferably, 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 intersection of the SMA actuators is preferably arranged centrally above a support section of the valve tappet, the ends of the SMA actuators being anchored to a base body of the valve. The SMA actuators are preferably tensioned above the support point in such a way that the intersection point in each case forms a point of curvature of the SMA actuator. This, as in the Figures 3a, 3b and 3c 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 of the valve tappet.

If several SMA actuators are provided, they 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. In the case of an X-shaped arrangement, 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.

The actuator device preferably has at least one coupling element in order to connect the at least one actuator, in particular SMA actuator, to the valve tappet and / or to a base body of the valve. The valve tappet 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. In particular For example, an SMA actuator can be materially connected, in particular soldered, to the base body or to a component attached to the base body, for example a circuit board of the valve. 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.

The linear movement of the valve tappet is preferably carried out in such a way that the valve tappet is moved away from the passage opening when it is deflected from the first to the second position, and vice versa, when it is moved back into the first position, it is moved in the direction of the passage opening.

The microdosing device or a valve, in particular the first and / or the second valve, 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 base body in particular forms the air duct. It is also preferred that the air duct is formed by at least one tubular component. The valve preferably has a membrane which, in the first state of the valve, is deflected by a valve tappet and closes the passage opening in an airtight manner in order to enable the overpressure to develop in the first air duct section compared to the second air duct section.

The base body can have a first part that forms the air duct. 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 valve tappet during deflection and to align it with a longitudinal direction of the valve of the valve. The 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 passage opening and / or can in particular serve as a resetting element for resetting the valve tappet from the second to the first position. The second part, or a circuit board arranged on it, can be set up in particular as a carrier for the actuator device or the one or more actuators, which can in particular be anchored on the second part or the circuit board.

The valve tappet is in particular a piston-like part. The shape of the valve tappet is preferably adapted to its deflection with the aid of a guide device. In particular, the valve tappet can be cylindrical or have one or more cylindrical sections.

The valve preferably has a membrane. 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 μm and 500 μm, preferably between 100 μm and 300 μm, preferably between 150 μm and 250 μm, and preferably about 200 μm.

The valve 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 valve tappet in order to reset it after the deflection from the first position to the second position. In particular, a membrane serving as a sealing element can also serve as a restoring element. The restoring element is preferably a spring which is arranged between the base body and the valve tappet. Furthermore, the resetting element can be an actuator which is controlled in particular by the electrical control device. An elastically deformable component, in particular a spring, can also be arranged as the drive element of the deflection, which is tensioned by the actuator - in this case the passage opening is opened, for example, by releasing a locking connection that holds the valve tappet in the first position.

The microdosing device preferably has the third opening, which can in particular be designed as a closable bypass channel which, in the open state, connects the first air channel section to the outside space, in particular to the ambient pressure. The third opening or the bypass channel is used in particular to Ventilation of the first air duct section or for pressure equalization of the first air duct section which is fluidically connected or optionally connectable to the bypass duct.

In further preferred embodiments, the microdosing device is set up for the repeated delivery of a microdosing volume of a fluid sample. The microdosing device can thus be operated as a dispensing device or in a dispensing mode. A system according to the invention has in particular a microdosing device according to the invention and a pipetting device, and / or at least one device, by means of whose control device the microdosing device, in particular its first and / or second valve, can be controlled.

In preferred embodiments, a microdosing device according to the invention is also set up to receive a fluid sample by sucking a fluid sample into the fluid transfer container in the second state of the first valve - and if provided: in the first state of the second valve by the displacement element.

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 take place through a (conventional) piston element of a hand-held piston-stroke pipette or air-cushion pipette or a dispenser. The microdosing device is preferably designed so that the displacement element selectively sucks in or displaces a micro air volume.

A pipetting device according to the invention, in particular a commercial pipetting device provided with the microdosing device, for the dosed intake and delivery of fluid samples, preferably has: a piston chamber that forms the air chamber, a movable piston arranged in the piston chamber that forms the displacement element for sucking in Air into the piston chamber and for the delivery of the air from the piston chamber, a pipetting channel that connects the piston chamber with the outer space of the piston chamber. According to the invention, such a pipetting device is provided with a microdosing device according to the invention, the The first opening can be connected to the piston chamber and / or the pipetting channel, so that a microdosing volume of a fluid sample can be dosed by the pipetting device by means of the microdosing device and can be delivered to the outside space in the form of a microfluid jet via the pipetting channel.

The invention also relates to a pipetting device with a microdosing device according to the invention for generating a microdosing volume of a fluid sample in the form of a microfree jet, having an air chamber, a displacement element, in particular a piston element, which is used to deflect between a first position and a second position and to displace a microvolume of the air chamber is set up, wherein the pipetting device preferably has a shape memory material actuator, which is arranged in particular to deflect the displacement element, wherein the pipetting device has a piston drive, in particular an electric motor that drives the piston element, the air chamber being the piston chamber for receiving the inside of the piston chamber movably arranged piston forms, so that in particular the piston and piston chamber work in the manner of a conventional piston stroke pipette or in the manner of a conventional dispenser. In particular, a first valve operated by means of an SMA actuator, in combination with the piston drive, allows either very precise microdosing or dosing of larger volumes, whereby the pipetting device can be used flexibly. If the shape memory material actuator is provided, the pipetting device can be set up to accommodate and / or compress micro-volumes by means of a movement of the displacement element caused by the SMA actuator. Alternatively or additionally, the absorption and / or compression of the micro-volumes can be brought about by the piston drive. In the second, open state of the first valve, pipetting of in particular larger volumes (greater than or equal to 2 μm) can take place by means of the piston drive, that is to say by conventional means.

The displacement element can in particular be driven by means of an SMA actuator, which can be part of the microdosing device or the pipetting device.

A typical use of the microdosing device is in the dosing of biological, biochemical, chemical or medical fluid samples in a laboratory.

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 to control the at least one controllable valve, in particular the first and / or the second valve, in particular an actuator or SMA actuator to control. 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 connected or connected to the microdosing device by a connecting device, e.g. a cable. The control device is preferably set up to control the at least one valve, in particular to effect the deflection of the valve tappet from the first position into the second position. In addition or as an alternative, it can also be set up to control the deflection of the displacement element. The control device is preferably set up so that the actuator exerts a force on the valve tappet that moves it from the first position into the second position, in particular accelerates it suddenly. The actuator is preferably controlled by the control device in such a way that the actuator exerts a force on the valve tappet even after the valve tappet has reached the second position, in particular strikes a stop on the base body of the valve.

Alternatively, 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 valve tappet that moves it from the first position to the second position emotional. The valve tappet can be releasably fixed in the second position by a fixing device, in particular it can be latched. It can be 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 in particular to control the deflection of an SMA actuator from the first to the second position. For this purpose, 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 preferably set up to activate the SMA actuator with a very short voltage or current pulse. The time span is preferably a few 10 milliseconds (ms), preferably 1 ms to 100 ms, preferably 10 ms to 100 ms, in particular approximately 10 ms. This enables the SMA actuator to be deflected quickly. The control device is preferably set up to control the SMA actuator, in particular after a period of activation, by means of 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. However, it is also possible to control the microdosing device by means of analog-electronic control of the actuator, that is to say without a data processing 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 can make the electrical The control device controls, in particular by influencing the program parameters used to control the microdosing device, in particular those generating control signals, through user inputs or, in the case of an analog electronic control, by triggering the delivery or recording of the desired microdosing volume and the generation of the control signals that trigger the actuator of the at least activate and / or deactivate a valve. The user interface device can each have one or more electrical switches, buttons and / or sensors, and can have output devices, for example 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. In particular, 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 designed as a control interface between the control device of an external device and 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. In particular, if an internal control device can be connected 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 into 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 can, however, also be designed as a module of an external device. The module is an optional accessory that can be connected to the external device. The module can be 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.

The invention also relates to a system for generating a microdosing volume of a fluid sample in the form of a microfree jet, containing a microdosing device according to the invention and a conventional pipetting device or a pipetting device set up to control the microdosing device, which serves to generate this overpressure in the first air channel section, the first opening of the microdosing device is or is connected to an air chamber of the pipetting device, which also has: a displacement element, which is set up to displace a micro-volume (V) of the air chamber, and a drive to drive the displacement of the displacement element, whereby in the first state of the first valve the Overpressure can be generated in the first air duct section.

The invention further relates to a method for generating a microdosing volume of a fluid sample in the form of a microfree jet by means of a microdosing device, in particular a microdosing device according to the invention, having the step (dispensing step) that the first valve is controlled in such a way that the passage opening is suddenly opened by means of the first valve , whereby, due to the pressure equalization between the first and second air duct section, a micro air volume from the first air duct section exits and a micro air volume (V) leaves the air duct through the second opening, so that a microdosing volume determined by the micro volume (V) of the fluid sample held in the fluid transfer container is displaced and released in the form of a micro free jet from the fluid transfer container into the outside space.

The method preferably has the steps of using a pipetting device, which has an air chamber connected to the first opening and a displacement element, to produce an overpressure in the first air channel section by displacing a microvolume (V) in the air chamber before the dispensing step takes place.

The method can include steps that implement a pipetting process, i.e. the delivery of the previously taken up volume of the fluid sample. The method can also include steps that implement a dispensing process, i.e. the step-by-step delivery of partial volumes of the previously taken up volume of the fluid sample.

The method according to the invention is used in particular in a microdosing device which has an air chamber which is connected to the first opening, a displacement element which is set up to displace a micro volume (V) of the air chamber, and a drive to drive the deflection of the displacement element, whereby, in the first state of the first valve, the overpressure can be generated in the first air duct section.

The method is used in particular in a microdosing device in which the first air duct section has a closable third opening which connects the first air duct section with the outside space, and a controllable second valve which is set up to selectively open the third opening of the air duct in one first state, to be kept closed in order to enable the overpressure in the first air duct section compared to the second air duct section, or, in a second state, to be kept open, as well as a change from the first to the second state to bring about a pressure equalization in the first air duct section to the outside enable.

The method preferably has the step that a fluid sample, in particular a liquid, e.g. a liquid laboratory sample, is taken up in a fluid transfer container, e.g. a pipette tip, connected to the microdosing device. To receive the fluid sample, the displacement element, in particular a piston element, is moved from a first to a second position.

In a pipetting process, the method for taking up the fluid sample by suction preferably provides at least one of the following steps, in particular in this order: that the first and the second valve are closed and the displacement element is in the first position; that the first valve is opened to open the passage opening; that the displacement element is moved from the first to the second position; that the first valve and thus the passage opening is closed again. The fluid sample, in particular with the desired microdosing volume, is now in the fluid transfer container and is held there in the usual way by the slight negative pressure / capillary forces.

The method for dispensing the fluid sample preferably provides at least one of the following steps, in particular in this order: that the displacement element is in the second position and that the first and second valves are closed (initial situation); that the displacement element is moved into the first position while the valves are closed, whereby the air volume in the air chamber and in the first air duct section is compressed, so that the overpressure is generated; that the first valve is opened after the displacement element has reached the first position - thereby the compressed air relaxes immediately and accelerates the fluid sample at maximum speed. The fluid sample with the desired microdosing volume emerges from the opening of the fluid transfer container. The step of performing an overstroke of the displacement element is preferably also provided in order to perform a “blowout” of the entire remainder of the fluid sample possibly still contained in the fluid transfer container. This is done by further moving (in the same direction of the displacement element, which corresponds to the direction of movement from the second to the first position) of the Displacement element from the first position into a further delivery position. Alternatively, the overstroke can also be carried out immediately with the first-mentioned delivery step; this causes a further (higher) acceleration of the fluid sample.

In a dispensing process, the method for taking up the fluid sample by suction preferably provides at least one of the steps mentioned below, in particular in this order: that the first and the second valve are closed and the displacement element is in the first position; that the first valve is opened to open the passage opening; that the displacement element is moved from the first to the second position; that the first valve and thus the passage opening is closed again. The fluid sample, in particular with the desired total volume, is now in the fluid transfer container and is held there in the usual way by the slight negative pressure / capillary forces.

The total volume includes the dispensing volume and an additional volume. A residual volume or a discard volume can be provided by means of the additional volume. The remaining volume remains in the fluid transfer container after all partial volumes have been dispensed and ensures that at least the desired partial volume is also available for the last dispensing step. The discard stroke is used to generate a first discharge amount according to the free jet principle before the partial volumes are released according to the discard stroke, so that the meniscus of the fluid sample at the discharge opening of the fluid transfer container is defined in the same way in all subsequent steps - the meniscus can be that is, immediately after the exposure, different from after a demolition according to the free jet principle. The second position of the displacement element is set in accordance with the total volume in particular.

During the dispensing process, the method for dispensing the fluid sample without providing a discarding stroke preferably provides at least one of the following steps, in particular in this order: that the displacement element is in the second position and that the first and second valves are closed (initial situation); that the second valve is opened, whereby the first air duct section is ventilated; that the displacement element by the distance of the Additional stroke is moved in the direction of the first position, whereby in particular a possible play of the drive mechanism is compensated, which drives the displacement element; that the second valve is closed again; that the displacement element is moved by the distance of a desired partial volume in the direction of the first position to an intermediate position, thereby compressing the air in the first air duct section, so that the overpressure is generated; that the first valve is opened after the displacement element has reached the intermediate position - thereby the compressed air relaxes immediately and accelerates the fluid sample at maximum speed, the fluid sample with the desired microdosing partial volume emerges from the opening of the fluid transfer container and the first valve is then closed again (delivery of the partial volume); that the last-mentioned step of dispensing the partial volume is repeated in the desired manner; in the last dispensing step, the displacement element can be in the first position. Preferably, the step is also provided to carry out an overtravel of the displacement element in order to carry out a "blowout" of the entire remaining volume of the fluid sample possibly still contained in the fluid transfer container. This is done by further moving (in the same direction of the displacement element, which corresponds to the direction of movement from the second to the first position) of the displacement element from the first position into a further dispensing position.

During the dispensing process, the method for dispensing the fluid sample with the provision of a discarding stroke preferably provides at least one of the following steps, in particular in this order: that the displacement element is in the second position and that the first and second valves are closed (initial situation); that the displacement element is moved by the distance of the additional stroke in the direction of the first position up to a starting position, thereby the air in the first air duct section is compressed so that the overpressure is generated, and in particular a possible play of the drive mechanism that the displacement element is compensated for drives; that the first valve is opened after the displacement element has reached the starting position - thereby the compressed air relaxes immediately and accelerates the fluid sample at maximum speed Meniscus at its delivery port is defined; that the first valve is closed again; that the displacement element is moved by the distance of a desired partial volume in the direction of the first position to an intermediate position, thereby compressing the air in the first air duct section, so that the overpressure is generated; that the first valve is opened after the displacement element has reached the intermediate position - thereby the compressed air relaxes immediately and accelerates the fluid sample at maximum speed, the fluid sample with the desired microdosing partial volume emerges from the opening of the fluid transfer container and the first valve is then closed again (delivery of the partial volume); that the last-mentioned step of dispensing the partial volume is repeated in the desired manner; in the last dispensing step, the displacement element can be in the first position. The step of performing an overtravel of the displacement element is preferably also provided in order to discharge the last partial volume in step with the "blowout" of a possible small residual volume of the fluid sample possibly still contained in the fluid transfer container. This is done by further moving (in the same direction of the displacement element, which corresponds to the direction of movement from the second to the first position) of the displacement element from the first position into a further dispensing position.

Further preferred configurations of the microdosing device according to the invention, the system and the method and further aspects of the invention emerge from the following description of the exemplary embodiments in connection with the figures. The same reference symbols denote essentially the same components.

• Fig. 1a zeigt in einer seitlichen Querschnittsansicht eine erfindungsgemäße Mikrodosiereinrichtung gemäß einem ersten Ausführungsbeispiel.
• Fig. 1b zeigt in einer seitlichen Querschnittsansicht ein erfindungsgemäßes Ventil einer Mikrodosiereinrichtung wie in Fig. 1a gezeigt, gemäß einem ersten Ausführungsbeispiel.
• Fig. 1c zeigt in einer seitlichen Querschnittsansicht ein zweites Ventil der Mikrodosiereinrichtung aus Fig. 1a.
• Fig. 2 zeigt in einer perspektivischen Ansicht die Mikrodosiereinrichtung der Fig. 1a.
• Fig. 3a zeigt in einer schematischen Perspektivansicht eine Aktuatoreinrichtung auf Basis einer Formgedächtnislegierung, in einer ersten nicht-ausgelenkten Position.
• Fig. 3b zeigt die Aktuatoreinrichtung der Fig. 3a, in einer zweiten ausgelenkten Position.
• Fig. 3c zeigt in einer schematischen Perspektivansicht eine weitere Aktuatoreinrichtung auf Basis einer Formgedächtnislegierung, in einer ersten nicht-ausgelenkten Position.
• Fig. 4 zeigt in einer schematischen Perspektivansicht eine Aktuatoreinrichtung der Fig. 3a mit angeschlossener elektrischer Steuereinrichtung.
• Fig. 5 zeigt eine typische Kraft-Auslenkungs-Kennlinie eines FGL-Aktuators, der mit einer erfindungsgemäßen Mikrodosiereinrichtung in einem Ausführungsbeispiel verwendet wird.
• Fig. 6 zeigt ein Diagramm des Ergebnisses einer Dynamischen Differenzkalorimetrie (engl. DSC) zur Bestimmung der Phasenübergangs- oder Schalttemperaturen eines in einer erfindungsgemäßen Mikrodosiereinrichtung gemäß einem Ausführungsbeispiel verwendeten NiTi-Formgedächtnismaterials.

Show it:

• Fig. 1a shows a side cross-sectional view of a microdosing device according to the invention according to a first embodiment.
• Figure 1b shows a side cross-sectional view of a valve according to the invention of a microdosing device as in FIG Fig. 1a shown according to a first embodiment.
• Figure 1c shows in a lateral cross-sectional view a second valve of the microdosing device from Fig. 1a .
• Fig. 2 shows in a perspective view the microdosing device of FIG Fig. 1a .
• Fig. 3a shows in a schematic perspective view an actuator device based on a shape memory alloy, in a first non-deflected position.
• Figure 3b shows the actuator device of Fig. 3a , in a second deflected position.
• Figure 3c shows a schematic perspective view of a further actuator device based on a shape memory alloy, in a first non-deflected position.
• Fig. 4 shows in a schematic perspective view an actuator device of FIG Fig. 3a with connected electrical control device.
• Fig. 5 shows a typical force-deflection characteristic curve of an SMA actuator which is used with a microdosing device according to the invention in an exemplary embodiment.
• Fig. 6 shows a diagram of the result of a dynamic differential calorimetry (English. DSC) for determining the phase transition or switching temperatures of a NiTi shape memory material used in a microdosing device according to the invention according to an embodiment.

Figure 1a shows the microdosing device 1, connected on one side to a connecting section 100, which serves as a working cone and on which a pipette tip 99 is attached, and connected on the other side to a connecting section 200 of a conventional pipette. The microdosing device 1 is used to generate a microdosing volume of a fluid sample in the form of a micro-free jet. It has an air duct 10 which has a passage opening 14 which connects a first air duct section 11 and a second air duct section 12 of the air duct 10. The first air duct section 11 has a first opening 21 and the second air duct section 12 has a second opening 22 to which the fluid transfer container 99 containing the fluid sample is connected by a plug-in clamp connection. The microdosing device 1 has a controllable first valve 31, which is set up to hold the passage opening 14 of the air channel optionally, in a first state, closed in order to enable an overpressure in the first air channel section 11 compared to the second air channel section 12, or, in a second state, to be kept open, and to enable a sudden change from the first to the second state.

The microdosing device 1 and the pipetting device (symbolized by their connecting section 200, 200 ', form a system according to the invention for generating a microdosing volume of a fluid sample in the form of a microfree jet.

The microdosing device has a cable connection 50, which is in particular part of the system 400, by means of which the valves 31, 32 are each connected to the electrical control device of the pipetting device and can thereby be controlled by it. Here the pipetting device (not shown in full) has an air chamber which is connected to the first opening via the connecting section 200, a displacement element which is designed to displace a microvolume (V) of the air chamber, and a drive to deflect the displacement element to drive, whereby in the first state of the first valve, the overpressure can be generated in the first air duct section. The micro-volume V is here identical to the micro-dosing volume to be dispensed during a pipetting process. The displacement element of the pipetting device is a piston element, which is used by the User selectable displacement of micro-volumes and of volumes greater than 2 µl, and in particular less than or equal to 100 µl, is set up. The first opening 21 of the microdosing device 1 can be connected to the working cone 201 of the pipetting device via a plug / clamping connection so that the desired overpressure can be set in the first air channel section 11 by means of the pipetting device.

The microdosing device 1 can, however, also have its own control device (not shown) which operates independently of the control device of the pipetting device. In this case, the overpressure in the first air duct section is generated by the pipetting device, and the user in particular manually triggers the opening of the first valve. The microdosing device can also be designed (not shown) in such a way that it also has the air chamber, e.g. a piston chamber, the displacement element, e.g. a piston element, and / or the drive with optional drive mechanism. This turns the microdosing device into an independent device that can be operated completely independently of an external pipetting device.

The electrical control device, in particular an electrical control device of the microdosing device, is set up to control the first valve 31 in such a way that the passage opening 14 is opened suddenly by means of the first valve 31, whereby, due to the pressure equalization between the first 11 and second air duct section 12 , a micro air volume exits from the first air channel section 11 and a micro air volume (V) leaves the air channel 10 through the second opening 22, so that a micro-metering volume determined by the micro air volume (V) of the fluid sample held in the fluid transfer container 99 is displaced and in the form of a micro free jet the fluid transfer container is discharged into the exterior space.

The first air duct section 11 has a closable third opening 23 which connects the first air duct section 11 with the outside space, and a controllable second valve 32 which is configured to selectively close the third opening 23 of the air duct 10 in a first state hold to enable the overpressure in the first air duct section 11 compared to the second air duct section, or, in a second state, to keep it open, as well as a change from the first to the to enable the second state to bring about a pressure equalization in the first air duct section 11 to the outside space.

The air duct 10 with its first 11 and second 12 sections is formed in a base body 40 of the microdosing device 1. The air duct 10 runs essentially linearly. To implement the passage opening 14, the air duct is closed by a wall at the level of the passage opening 14. A bypass section 15, which is formed in the base body, deflects the first section 11 of the air duct 10 to the passage opening 14, from where the second air duct section 12 begins, which merges again into the linear area via the bypass section 15. The passage opening 14 can be closed by the membrane 49 when it is pressed against the passage opening 14 by the valve tappet of the first valve 31 which is tensioned by means of the spring. To open the valve, the valve tappet is suddenly deflected by means of an actuator device. The actuator device has two SMA actuators arranged crosswise, the intersection point of which is centered above the valve tappet. The activation of these actuators by means of the current controlled by the control device is maintained as long as the opening of the valve is desired or predetermined.

The frame Y marks the second valve 32, which is used to ventilate the first air duct section. In Figure 1c a cross section through a valve is shown that is constructed like the second valve 32. In Figure 1b a cross section through a valve is shown that is constructed like the first valve 31.

The valves 31, 32 each have, as shown on the basis of the valve 31 in FIG Figure 1b is shown by way of example, a valve tappet 36a, a valve spring 36b and a clamping pin 36d. The clamping pin is used to adjust the preload of the shape memory material actuator 36e. The valve guide 37 is fitted into a recess in the base body; the membrane 49 (36c), which is used as a closure element for both valves 31, 32, is clamped between the valve guide 37 and the base body. A cover part 42 covers the valve guide 37 over the base body 40, is attached to it and serves as an abutment for the spring 36b, which is located between the cover part and the flange of the valve tappet 36a is clamped. The circuit board 41 is fastened over the cover part. The SMA actuators are attached to this by soldering in order to deflect the clamping pin 36d and the valve tappet 36a connected to it in the event of contraction in order to open the valve.

In the Figure 1b the first, closed state of the valve 31 can be seen, in which the passage opening 14 is closed. In the Figure 1c the closed state of the second valve 32 can be seen, in which the third opening 23, namely the passage opening 23, which connects the bypass channel 43 connected to the environment with the first air channel section 11, is closed by means of the membrane 49.

Figures 3a to 3c show by way of example how a movable element, for example a displacement element or a similar valve tappet, can be deflected.

A contraction of the shape memory material actuator 85 results in, see FIG Figures 3a and 3b that the movable element 83 ′ is moved from the first P1 to the second position P2 in the shortest possible time, that is to say in a pulsed or abrupt 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. 6 . 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 must be reduced to a maximum of 50 ° C. Below the material-specific critical temperature of 50 ° C, the shape memory material actuator is particularly in the martensite phase and can (apparently) be plastically deformed by low forces. In this state, the shape memory material actuator is in the in Fig. 3a shown first position of the movable 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. He but can also be relaxed. When heated to the further critical temperature of 67 ° C, the original component shape is restored within milliseconds, and the material then behaves like an ordinary metal according to Hook's law. 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. For this purpose, a voltage supply is provided with which a circuit leading through the shape memory material actuator can be closed optionally for heating ( Figure 3b ) or open the shape memory material actuator to cool down ( Fig. 3a ). A ball 83b 'or a mounting element 85a' is preferably used between the movable element and the actuator, which is self-centering under the X-shaped, pocket-like, curved actuator device 85.

the Figures 3a and 3b show the actuator device 85 which is arranged in an X-shape and has a pocket-like design, with FIG Fig. 3a a first position is shown in which the movable element is held in the first position by the restoring element, for example a spring, and in which FIG Figure 3b the second position is shown in which the actuator device 85 has been activated and the movable element has been deflected up to the second position in the 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. in an X-shape, centrally above the ball of the movable element 83 ' are arranged. The use of film-based actuators enables the forces and travel ranges to be set by adapting the two-dimensional geometry. The very large surface area in relation to the volume is retained and ensures rapid heat dissipation or resetting of the actuator in the de-energized state.

The ends of the shape memory material actuators are on the base body 86, 40 or on the circuit board of the microdosing device 80 at the two coupling points 88 ( Fig. 3a ) 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 3a, 3b and 3c 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 3a to 3c the movable element 83 ′ is made up of cuboid sections, it can also be shaped differently, in particular with cylindrical sections and with a ball as a support surface for the actuator device 85.

The membrane 49 consists of highly flexible PDMS with a thickness of 200 μm and, when the shape memory material actuators are de-energized, is deflected in advance in order to close the valve opening.

The actuators of the actuator device 85 are, for example, each applied in pairs to a carrier plate or circuit board with integrated conductor tracks and are electrically contacted, see FIG Figures 3a, 3b . The electrical control of the shape memory material actuators takes place via an electrical control device which is set up to apply a voltage to both shape memory material actuators at the same time and to contract them synchronously. For example, both actuators are connected to a power source via a three-wire cable. A middle wire serves as a common ground electrode. For the fastest possible switching, 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.

For the fastest possible switching of the shape memory material actuators, 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 In particular, the shape memory material actuator requires less than 2 ms to cover the stroke. The force-deflection characteristics of the SMA actuators can be determined using a tensile testing machine.

The control of these methods for operating the module 1 are preferably implemented by an electrical control device 350 that is set up in the desired manner, in particular programmed, ( Fig. 4 ). The control device 350 can be part of the module 1. Alternatively, the control device 350 can be an external device or a component thereof. In particular, the control device 350 can be part of a modified pipetting device, in particular a conventional pipetting device supplemented by the control device 350.

Claims (15)

1. Microdosing device (1) for generating a microdosing volume of a fluid sample in the form of a microjet, comprising

   an air duct (10) that comprises a passage opening (14), which connects a first air duct section (11) and a second air duct section (12) of the air duct, with the first air duct section (11) comprising a first opening (21) and the second air duct section (12) comprising a second opening (22), to which a fluid transfer container (99) containing the fluid sample can be connected,

   a controllable first valve (31) that is configured to selectively keep the passage opening (14) of the air duct (10) in a first state closed, in order to allow for an overpressure in the first air duct section (11) relative to the second air duct section (12), or in a second state open, and to allow for an abrupt switching from the first to the second state,

   an electric control device,

   in which the electrical control device is configured to control said first valve (31) in such a way that said passage opening (14) is opened abruptly by means of the first valve, whereby, due to the pressure equalization between said first (11) and said second air duct (12), a microvolume of air exits the first air duct section and a microvolume of air (V) exits said air duct (10) through said second opening (22), so that a microdosing volume, with that volume being determined by the microvolume of air (V), of the fluid sample contained in the fluid transfer container (99) is displaced and emitted in the form of a microjet from the fluid transfer container into an external volume.
2. Microdosing device according to claim 1, in which the first opening of the microdosing device can be connected to an air chamber of a pipetting apparatus.
3. Microdosing device according to claim 1, in which the microdosing device comprises an air chamber that is connected to the first opening, a displacement element that is configured for displacing a microvolume (V) of the air chamber, and a drive system for driving the deflection of the displacement element, whereby an overpressure can be generated in said first air duct section when said first valve is in said first state.
4. Microdosing device according to claim 3, in which the displacement element is a piston element that is configured to displace the microvolume (V) when the first valve (31) is in the first state, and that is configured to displace a macrovolume of air when the first valve is in the second state.
5. Microdosing device according to any one of the preceding claims, in which the first opening of the microdosing device can be connected to the nose cone of a pipetting apparatus, so that the desired overpressure can be adjusted in the first air duct section by means of the pipetting apparatus.
6. Microdosing device according to any one of the preceding claims, in which the first air duct section comprises a closable third opening (23) that connects said first air duct section with the external volume, and a controllable second valve (32) that is configured to selectively keep the third opening of the air duct in a first state - closed - in order to allow for the overpressure in the first air duct section relative to the second air duct section, or in a second state - open -, and to allow for switching from the first to the second state in order to achieve a pressure equalization between the first air duct section and the external volume.
7. Microdosing device according to any one of the preceding claims, in which the first valve comprises a shape memory alloy (SMA) actuator, and in which in particular the second valve comprises a SMA actuators.
8. Microdosing device according to any one of the preceding claims that comprises an electrical control device, which is configured to control said first valve (31) such that said passage opening (14) is opened abruptly by means of said first valve, whereby, due to the pressure equalization between said first (11) and said second air duct section (12), a microvolume of air exits said first air duct section and a microvolume of air (V) exits said air duct (10) through the second opening (22), so that a microdosing volume, with that volume being determined by the microvolume of air (V), of the fluid sample contained in the fluid transfer container (99) is displaced and emitted in the form of a microjet from the fluid transfer container into the external space.
9. System (400) for generating a microdosing volume of a fluid sample in the form of a microjet, comprising a microdosing device according to any one of the preceding claims and a pipetting apparatus, which has the purpose of generating said overpressure in said first air duct section, in which the first opening of the microdosing device can be connected or is connected to an air chamber of the pipetting apparatus, and which comprises furthermore: a displacement element that is configured to displace a microvolume (V) of the air chamber, and a drive system for driving the deflection of said displacement element, whereby an overpressure can be generated in said first air duct section when said first valve is in said first state.
10. System according to claim 9, in which the pipetting apparatus is in particular a commercially available pipetting apparatus, in which the pipetting apparatus comprises an electrical control device that is configured to control the first valve (31) in such a way that the passage opening (14) is opened abruptly by means of said first valve whereby, due to the pressure equalization between said first (11) and said second air duct section (12), a microvolume of air exits said first air duct section and a microvolume of air (V) exits said air duct (10) through the second opening (22), so that a microdosing volume, with that volume being determined by the microvolume of air (V), of the fluid sample contained in the fluid transfer container (99) is displaced and emitted in the form of a microjet from the fluid transfer container into the external space.
11. System according to claim 9 or 10, comprising a cable connection that connects the microdosing device with an electrical control device of the pipetting apparatus, so that said at least one valve of the microdosing device can be controlled by the electrical control device, in particular for controlling said first valve (31) such that the passage opening (14) is opened abruptly by means of said first valve, whereby, due to the pressure equalization between said first (11) and said second air duct section (12), a microvolume of air exits said first air duct section and a microvolume of air (V) exits said air duct (10) through the second opening (22), so that a microdosing volume, with that volume being determined by the microvolume of air (V), of the fluid sample contained in the fluid transfer container (99) is displaced and emitted in the form of a microjet from the fluid transfer container into the external space.
12. Procedure (500) for generating a microdosing volume of a fluid sample in form of a microjet by means of a microdosing device according to any one of the preceding claims, comprising the step (release step) of controlling said first valve such that the passage opening is opened abruptly bu means of said first valve, whereby, due to the pressure equalization between the first and the second air duct section, a microvolume of air exits said first air duct section and a microvolume of air (V) exits said air duct (10) through the second opening, so that a microdosing volume, with that volume being determined by the microvolume of air (V), of the fluid sample contained in the fluid transfer container is displaced and emitted in the form of a microjet from the fluid transfer container into the external space.
13. Procedure according to claim 12, comprising the steps of generating an overpressure in the first air duct section by means of a pipetting apparatus, which comprises an air chamber connected to the first opening and a displacement element, and with the overpressure being generated by displacing a microvolume (V) in the air chamber before the release step occurs.
14. Procedure according to claim 12 or 13, comprising steps that serve for the uptake and/or the release of a fluid sample in a pipetting- or dispensing process.
15. Usage of the microdosing device according to any one of the claims 1 through 8, of the system according to any on of the claims 9 through 11, or of the procedure according to any one of the claims 12 through 14 for generating a microdosing volume of a laboratory sample in a jet, in particular of an aqueous laboratory sample, in particular of a biological, medical, chemical, biochemical, pharmaceutical, or forensic sample.

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