EP3485974B2 - Microdosing device for dosing minute fluid samples - Google Patents

Description

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

Pipetting devices are handheld or automated laboratory devices that are commonly used in medical, biological, biochemical, chemical and other laboratories. They are used in the laboratory for precise dosing and for transporting fluid samples with small volumes and for transferring such volumes between different sample containers. With pipetting devices, for example, liquid samples are sucked into pipette containers, e.g. pipette tips, using negative pressure, stored there, and then dispensed from them again at the destination.

Hand-held pipetting devices include, for example, hand-held pipettes and repeating pipettes, the latter also being referred to as dispensers. A pipette is understood to be a device in which a sample to be pipetted can be sucked into a pipette container, in particular a pipette tip, that is detachably connected to the pipette by means of a movement device that is assigned to the device and which can in particular have a piston. In 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 is under a negative pressure when the sample is taken into the pipette container, through which the sample is sucked into the pipette container and/or held in the pipette container. A dispenser is understood to be a device in which 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, by means of a movement device, which can in particular have a piston, wherein the movement device is at least partially assigned to the pipetting container, e.g. by arranging the piston in the pipetting container. In the dispenser, the piston end is very close to the fluid sample to be pipetted or in contact with it, which is why the dispenser is also referred to as a direct displacement pipette. Pipetting devices with a displacement element designed as a piston are also referred to as piston-stroke pipettes.

Pipette tips or dispenser tips are made primarily of plastic and, as disposable items, can be thrown away after use or replaced with a fresh pipette tip or dispenser tip. They can also be made of metal or glass or contain such material. Pipette tips or dispenser tips are available in different sizes for dosing in different volume ranges.

In a pipetting device, the sample quantity dispensed by a single actuation can correspond to the sample quantity sucked into the device. However, it can also be provided that a sample quantity taken up corresponding to several dispensing quantities is dispensed again step by step. 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 dispensing/receiving channel and multi-channel pipetting devices containing several dispensing/receiving channels, which in particular allow the parallel dispensing or aspirating of several samples.

Examples of handheld, electronic pipetting devices or pipettes are the Eppendorf Xplorer ^® and the Eppendorf Xplorer ^® plus from Eppendorf AG, Germany, Hamburg; examples of handheld, 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 operated electrically 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 device is the Eppendorf epMotion ^® .

Pipetting devices are used for dosing and thus for the precise measurement of liquid volumes. When dosing very small amounts of liquid using a piston-operated pipette, systematic and random dosing errors can increase considerably. Details on the usual procedure for determining errors and dosing small volumes, in particular by dispensing from the wall of the container, can be found in DIN EN ISO 8655. When dispensing using the free jet method, in which the fluid sample leaves the pipetting container as a jet or free drop - also known as a jet - the smallest volumes between 0.1 µl and 1.0 µl, preferably summarized here under the term "microvolumes", can no longer be dosed sufficiently safely with conventional pipetting devices. Various physical influences are responsible for this. These influences include, among others, the formation of satellite drops due to reflection of the dispensed volume on the liquid surface on which they hit; the incomplete ejection of the volume in the pipette tip; the geometric conditions within the pipette tip; the surface tension of liquids and pipette tip and the associated wetting behavior or the occurrence of capillary forces; the electrostatic charge of 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 very small volumes is also made more difficult by the fact that the total air volume between the piston and the sample liquid acts as a damping element behind the volume to be ejected and counteracts the efficient discharge of a free jet.

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

The US9221046B2 describes a pipette that has a cylinder piston segmented lengthwise with segments of different diameters and a piston with differently dimensioned closure elements distributed lengthwise. The different diameters allow larger volumes and smaller volumes to be dispensed or taken up precisely. With a suitable design, this pipette releases a drop adhering to the outlet opening in a jerky manner via a "blowout".

The EP0119573A1 describes a dispenser for dispensing microdroplets of a laboratory sample. A sample chamber formed as an elastic tube with a nearby outlet opening has an elastic section that 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 the ejection of a microdroplet.

The EP0876219B1 describes a pipetting device that has a dispenser tip and, connected to it via a fluid channel, a piston displacer with a valve, by means of which larger volumes can be pipetted, i.e. sucked in and dispensed, through the pipette tip. A pulse generator is arranged between the pipette tip and the piston displacer, which applies a pulse to 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 device for optionally dispensing larger volumes or very small volumes for life science. A cylinder piston closure that can be moved using a spindle drive is fitted with a pulse generator, in this case 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 dispensed in precise doses by the piezo-controlled, abrupt stopping of the piston.

The EP1654068B1 describes a microdosing device with an elastically deformable fluid line that connects a liquid reservoir with 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 stroke of which when pressed onto the fluid line defines the volume of liquid to be dispensed. 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 taking in 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 a sensor, a drop with the desired volume is released from the outlet opening by means of a pulse.

The WO99/37400 A1 describes a dosing device for the nanoliter to microliter range with a pressure chamber that 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, whereby the liquid volume released in the free jet is dosed via the voltage-controlled deflection of the displacer by a piezo actuator. A similar dosing device is also used by WO99/10099 A1 . The DE 197 37 173 B4 describes how to manufacture such a free jet dosing device as a microsystem technology dosing element. EP 1 488 106 B1 describes a dosing module with a dosing chamber, actuator and actuator membrane, which hits 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 pulse 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 bulky or inflexible with regard to the integration into existing laboratory equipment, or too imprecise to generate the desired microdosing volumes.

EN 10 2007 010 412 A1 describes a device for dosing liquids into gas-filled spaces, in which a pressurized elastic liquid reservoir can be relaxed by pressing out a defined volume of liquid according to the direct displacement principle. EN 10 2012 209 314 A1 describes, among other things, devices for dispensing a liquid volume in the microliter range via a free jet, which uses pressure-dependent electronically controlled sample dispensing. EP 2 412 439 A1 describes a pipetting device for dispensing by increasing the pressure of a working fluid, comprising a pressure changing device for changing the pressure of the working fluid in a dosing liquid receiving chamber, wherein the pressure change in the working fluid does not occur suddenly, but only gradually in the dosing liquid receiving chamber.

Against this background, the present The invention aims to provide an efficiently designed microdosing device for precisely generating a microdosing volume of a fluid sample in the form of a micro free jet.

The invention solves this problem 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 from the first air channel section into the second air channel section, which in turn causes an efficient acceleration of a micro air volume from the second air channel section and the second opening. In this way, the micro dosing device is particularly suitable for generating a micro fluid jet, also referred to here as a micro free 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 dosing is in particular independent of the process of creating an overpressure in the first air channel section. Since the micro air volume emerging from the first air channel section determines the size of the micro dosing volume delivered, precise dosing in the micro volume range is possible.

The micro air volume moved in the micro dosing device is preferably in the submicroliter range, i.e. less than 1 µl. Accordingly, the micro dosing volume delivered by the micro dosing device is in the submicroliter range. The micro dosing volume generated as a free jet by a micro dosing device preferably corresponds essentially to the micro air volume - in particular displaced by a displacement element - and in particular the micro dosing volume is identical in amount to the micro air volume. In particular by repeatedly delivering a micro dosing volume, a total delivery volume formed by the successively delivered micro dosing 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 to generate the overpressure in the first air channel section: an air chamber that can be connected or is connected to the first opening, a displacement element that is designed to displace a micro volume (V) of the air chamber, and a drive to drive the deflection of the displacement element, whereby the overpressure can be generated in the first air channel section in the first state of the first valve. These components can be part of the microdosing device, or can be parts of an external device, in particular an external pipetting device whose working cone 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 channel section in order to achieve precise dosing.

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 that can be adapted in particular to control the microdosing device. Examples of such commercially available pipetting devices were mentioned above. The control of the microdosing device can also be arranged at least partially or completely in the microdosing device. In the present case, it is an electrical control device of the microdosing device. By combining it 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 that can be connected - and then detached - to a corresponding connecting section of an external pipetting device. This connection is preferably a positive plug and clamp connection, in which in particular the working cone of a pipetting device is inserted into a suitable receiving section of the microdosing device. In this case, the microdosing device can be controlled via a data exchange between the microdosing device and the pipetting device, in particular via a wired or wireless connection with the pipetting device. However, the control can 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 designed 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 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 larger than 2 µl, in particular less than or equal to 10 µl, 50 µl, 100 µl, 300 µl or 500 µl. Preferably, the microdosing device, or a pipetting device that has the displacement element, in particular the piston element, or the displacement element is designed to displace the micro air volume (V) in the first state of the first valve and in particular also designed to displace a macro air volume in the second state of the first valve. to displace.

The microdosing device and/or a pipetting device connectable to the first opening is preferably designed so that the micro air volume to be displaced by the displacement element 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 that contains the first opening. The opening section of the microdosing device can be connected in an airtight manner to an opening section of the air chamber, e.g. by means of a positive clamp connection. The opening section of the air chamber can be a working cone of the pipetting device.

Preferably, the first air duct section 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 designed to keep the third opening of the air duct optionally closed in a first state in order to enable the overpressure in the first air duct section with respect to the second air duct section, or to keep it open in a second state and to enable a change from the first to the second state to bring about a pressure equalization in the first air duct section with the outside space.

The first valve, in particular also the second valve or at least one further valve of the microdosing device or 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 prestressed in particular by a spring element and closes a passage opening, and in its second state is particularly deflected, whereby the passage opening is opened. The valve can be controlled by the electrical activation of the SMA actuator. 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 embodiments.

The first valve has an electrically controllable actuator. The valve, in particular the actuator, is designed for sudden opening. The actuator is a shape memory alloy (SMA) 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 release according to the free jet principle can be achieved very precisely and efficiently with very compact shape memory material actuators. Shape memory alloys (SMA) exhibit a special behavior due to a phase transition, which is known as the shape memory effect. Below a material-specific critical temperature, an SMA component is in the martensite phase in particular and can be (apparently) plastically deformed by even small forces. When heated to a further critical temperature, however, the original component shape is restored within milliseconds, and the material then behaves like a normal metal in accordance with Hooke'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 realized with these components. Preferred embodiments of a shape memory material actuator are described below.

An actuator of the microdosing device is a shape memory material actuator.

For the actuation, actuators are used within the scope of this invention which consist of or comprise at least partially or completely of a shape memory alloy (SMA). These are referred to as shape memory material actuators or SMA actuators. In comparison to other actuators, SMA actuators have a particularly high energy density, so that even very compact actuators are suitable for driving the microdosing devices defined here. Another decisive advantage of using SMA actuators, particularly compared to piezoelectric actuators, is that the SMA actuators can be operated at a relatively low voltage, which is 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.

Preferably, the shape memory material actuator comprises or consists of a NiTi alloy. A NiTi alloy (also known under the trade name Nitinol) is particularly biocompatible. It enables shape changes of up to 8%, which makes it possible to efficiently produce microdosing chambers with displaced microvolumes in the microliter and submicroliter range. Particularly preferably, the shape memory material actuator comprises an alloy based on TiNiCu This is particularly fatigue-resistant compared to conventional NiTi and therefore guarantees 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 differential scanning calorimetry (DSC), see Figure 6 In this measurement, the phase transition that is important for the actuation appears as a peak. From the diagram it can be seen that in order to switch a NiTi actuator, the temperature must be increased to at least 67 °C; in order to reset, the temperature must be reduced to a maximum of 50 °C.

Preferably, film-based SMA actuators are used. The SMA is in the form of a film with a thickness of between 5 µm and 50 µm, in particular between 10 and 30 µm, in particular around 20 µm. This enables the forces and travel to be adjusted 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 SMA actuator when de-energized.

Preferably, an SMA actuator is designed in an elongated form, in particular wire-shaped or web-shaped, and in particular made of an SMA film. The ends of the SMA actuator are electrically contacted. An 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 form can have a less curved shape or a straight orientation; in particular, the elongated SMA actuator can have a shorter length in the activated, straight form than in the non-activated, more curved form. Due to the contraction upon activation, a force can be exerted on a valve tappet if the ends of the actuator are anchored to a base body of the valve. The SMA actuator is preferably arranged so that the radius of curvature is always 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 to create the desired valve. Force-deflection characteristics of SMA actuators can be determined using a tensile testing machine. The SMA actuator can also be shaped as a spring, in particular a helical, spiral or bending 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 arranged to deflect a valve tappet. In particular, two SMA actuators can be used.

By means of the at least one actuator or the actuator device, the deflection of the valve tappet from a first into a second position is effected, wherein the valve is open in the second position, i.e. the passage opening of the air duct opens.

The valve preferably has an actuator device. This preferably has one or more actuators, including at least one SMA actuator, 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 above a displacement element so as to cross over one another, i.e. cross-shaped or X-shaped. The crossing point of the SMA actuators is preferably arranged centrally above a support section of the valve tappet, with 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 crossing point forms a bend point of the SMA actuator. As a result, as in the Figures 3a, 3b and 3c As shown by way of example, a shell-like region of the actuator arrangement is formed, through which the actuator arrangement centers itself above the support point and generates a force directed downwards precisely along the linear direction of movement between the first and second positions, which results in a correspondingly precise deflection of the valve tappet.

If several SMA actuators are provided, these can be coupled by a connecting link. This further synchronizes the deflection of the actuators and influences the force vector of the actuator device thus formed. In an X-shaped arrangement, a connecting link can be provided at the intersection point; this aligns the force vector acting vertically downwards when the SMA actuators contract, and the SMA actuators are held in position at the intersection point. The connecting link can also be designed so that the SMA actuators do not mechanically contact one another and are in particular electrically isolated from one another by the connecting link.

The actuator device preferably has at least one coupling element to connect the SMA actuator to the valve tappet and/or a base body of the valve. The valve tappet is arranged in particular so as to be movable relative to the base body. An SMA actuator can be connected to the base body by one or more connecting devices. In particular, an SMA actuator can be integrally connected, in particular soldered, to the base body or to a component attached to the base body, e.g. a circuit board of the valve. An SMA actuator is preferably electrically insulated 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 conversely, when it is moved back to 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 integrally formed, but can also be formed in several parts. It preferably consists of metal, plastic or ceramic, or comprises such materials. The base body in particular forms the air channel. It is also preferred that the air channel 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 seals the passage opening in an airtight manner in order to enable the formation of excess pressure in the first air channel section relative to the second air channel section.

The base body can have a first part that forms the air channel. A second part of the base body can be provided to be connected to the first part. The second part can in particular have at least one guide section or guide channel to guide the valve tappet during the deflection and to align it with a longitudinal direction of the valve. The membrane can be arranged between the first and second parts, in particular fastened, in particular by clamping between the first and second parts. The membrane can in particular seal the through-opening and/or can in particular serve as a return element for returning the valve tappet from the second to the first position. The second part, or a circuit board arranged thereon, can in particular be designed as a carrier for the actuator device or the one or more actuators, which can in particular be anchored to 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 preferably consists of polydimethylsiloxane (PDMS), in particular flexible or highly flexible PDMS or silicone, or has such 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 return element that is elastically deformable and that is tensioned by the deflection, and with which a return force can be exerted on the valve tappet in order to return 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 return element. The return element is preferably a spring that is arranged between the base body and the valve tappet. Furthermore, the return element can be an actuator that is controlled in particular by the electrical control device. An elastically deformable component, in particular a spring, can also be arranged as a drive element for 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 be designed in particular as a closable bypass channel which, when opened, connects the first air channel section to the outside space, in particular to the ambient pressure. The third opening or the bypass channel serves in particular for ventilating the first air channel section or for equalizing the pressure of the first air channel section which is fluidically connected to the bypass channel or can be optionally connected.

In further preferred embodiments, the microdosing device is designed for the repeated dispensing 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 designed to receive a fluid sample by sucking a fluid sample into the fluid transfer container through the displacement element in the second state of the first valve - and if provided: in the first state of the second valve.

Preferably, the microdosing device is designed as a pipetting device with which a fluid sample can be sucked in and dispensed via the fluid channel. Suction can be carried out by a (conventional) piston element of a hand-held piston-stroke pipette or air cushion pipette or a dispenser. Preferably, the microdosing device is designed so that the displacement element selectively sucks in or displaces a micro volume of air.

A pipetting device according to the invention, In particular, a commercial pipetting device provided with the microdosing device for the dosed intake and dispensing 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 air into the piston chamber and for dispensing the air from the piston chamber, a pipetting channel that connects the piston chamber to the outside of the piston chamber. According to the invention, such a pipetting device is provided with a microdosing device according to the invention, the first opening 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 dosed by the pipetting device by means of the microdosing device and can be dispensed to the outside in the form of a microfluid jet via the pipetting channel.

The invention further 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 micro free jet, comprising an air chamber, a displacement element, in particular a piston element, which is designed to deflect between a first position and a second position and to displace a microvolume of the air chamber, wherein the pipetting device preferably has a shape memory material actuator, which is arranged in particular for deflecting the displacement element, wherein the pipetting device has a piston drive, in particular an electric motor, which drives the piston element, wherein the air chamber forms the piston chamber for receiving the piston arranged movably within the piston chamber, 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. The first valve operated by means of an SMA actuator allows, in combination with the piston drive, either very precise microdosing or dosing of larger volumes, which means that the pipetting device can be used flexibly. If the shape memory material actuator is provided, the pipetting device can be set up to carry out the absorption and/or compression of microvolumes by means of a movement of the displacement element caused by the SMA actuator. Alternatively or additionally, the absorption and/or compression of the microvolumes can be caused by the piston drive. In the second, open state of the first valve, the pipetting of larger volumes in particular (greater than or equal to 2 µm) can be carried out by means of the piston drive, i.e. by conventional means.

The displacement element can be driven in particular 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 the dosing of biological, biochemical, chemical or medical fluid samples in a laboratory.

The microdosing device, or the microdosing apparatus or the pipetting apparatus 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 valve which has an SMA actuator, and/or the second valve, in particular an actuator or this SMA actuator. It is in particular 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, to supply the actuator or the SMA actuator with energy. Alternatively or additionally, an interface is provided for connecting an external voltage source. An external device or external part is not a component of the microdosing device and can be connected or connected to the microdosing device in particular by a connecting device, e.g. cable. The control device is preferably designed to control the at least one valve, in particular to cause the valve tappet to be deflected from the first position to the second position. Additionally or alternatively, it can also be designed to control the deflection of the displacement element. The control device is preferably designed so that the actuator exerts a force on the valve tappet, which moves it from the first position to 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 when it 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 elastically compressed or expanded, and which, when relaxed, exerts the force on the valve tappet that moves it from the first position to the second position. The valve tappet can be releasably fixed in the second position by a fixing device, in particular locked. A release device can be provided to release the fixing so that the drive element carries out the deflection.

The control device is particularly designed 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 be traversed by a current when an electrical voltage is applied between the two contact points, which heats the SMA actuator in order to cause the deflection by the shape memory effect (FGE). The control device is particularly designed to to specify the time course 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 period is preferably a few tens of milliseconds (ms), preferably 1 ms to 100 ms, preferably 10 ms to 100 ms, in particular about 10 ms. This achieves rapid deflection of the SMA actuator. The control device is preferably set up to control the SMA actuator, in particular after a period of activation, by means of 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 be kept straight.

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 that determine the 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 analog electronic control of the actuator, i.e. without a data processing device.

The microdosing device, or the microdosing apparatus or the pipetting apparatus having 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 influencing the program parameters used to control the microdosing device, in particular those that generate control signals, through user inputs or by, in the case of an analog electronic control, triggering the dispensing or intake of the desired microdosing volume and the generation of the control signals that activate and/or deactivate the actuator of the at least one valve. The user interface device can each have one or more electrical switches, buttons and/or sensors, and can have output devices, e.g. indicators, in particular a display.

The control device can have at least one electrical interface with which control signals can be exchanged, in particular 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 apparatus, 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 microdosing apparatus. The control interface can have an electrical circuit in order to supply voltage to at least one actuator from at least one microdosing device depending on 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 connection device, this device is referred to as an external device.

The external device can be a pipetting device, in particular a portable, handheld pipetting device or a handheld pipette or a handheld dispenser. If the microdosing device is integrated into a pipetting device, the pipetting device is not referred to as an external device. The microdosing device or a microdosing device can be an independent or autonomously operating device that can basically be operated without the intervention of an external device. However, the microdosing device can also be designed as a module of an external device. The module is an independent accessory that can be optionally connected to the external device. The module can be characterized in that it is operated or can be operated - in particular exclusively - depending on the external device, in particular in that a control device of the external device controls the deflection of at least one displacement element of at least one microdosing device.

The invention further relates to a system for generating a microdosing volume of a fluid sample in the form of a micro free jet, comprising a microdosing device according to the invention and a conventional pipetting device or one configured to control the microdosing device, which serves to generate this overpressure in the first air channel section, wherein the first opening of the microdosing device is connectable or is connected to an air chamber of the pipetting device, which also has: a displacement element configured to displace a microvolume (V) of the air chamber, and a drive to drive the deflection of the displacement element, whereby the overpressure in the first air channel section can be generated in the first state of the first valve.

The invention further relates to a method for Generating a microdosing volume of a fluid sample in the form of a micro free jet by means of a microdosing device, in particular a microdosing device according to the invention, comprising the step (dispensing step) that the first valve is controlled such 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 sections, a micro air volume exits the first air duct section and a micro air volume (V) leaves the air duct through the second opening, so that a microdosing volume of the fluid sample held in the fluid transfer container determined by the micro volume (V) is displaced and is released from the fluid transfer container into the outside space in the form of a micro free jet.

Preferably, the method comprises the steps of using a pipetting device having an air chamber connected to the first opening and a displacement element to create 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 may include steps that implement a pipetting process, i.e. the dispensing of the previously taken volume of the fluid sample. The method may also include steps that implement a dispensing process, i.e. the step-by-step dispensing of partial volumes of the previously taken volume of the fluid sample.

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

The method is particularly applied to a microdosing device in which the first air duct section has a closable third opening which connects the first air duct section to the outside space, and has a controllable second valve which is designed to keep the third opening of the air duct optionally closed in a first state in order to enable the overpressure in the first air duct section with respect to the second air duct section, or to keep it open in a second state and to enable a change from the first to the second state to bring about a pressure equalization in the first air duct section with respect to the outside space.

The method preferably comprises the step of receiving a fluid sample, in particular a liquid, e.g. a liquid laboratory sample, 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.

During a pipetting process, the method for taking up the fluid sample by suction preferably provides for at least one of the following steps, in particular in this order: that the first and second valves 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 for 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 to the first position while the valves are closed, whereby the air volume in the air chamber and in the first air channel section is compressed so that the overpressure is generated; that the first valve is opened after the displacement element has reached the first position - as a result, the compressed air immediately relaxes and accelerates the fluid sample at maximum speed. The fluid sample with the desired microdosage volume exits the opening of the fluid transfer container. Preferably, the step of carrying out an overstroke of the displacement element is also provided in order to carry out 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 that corresponds to the direction of movement from the second to the first position) the displacement element from the first position to another dispensing position. Alternatively, the overstroke can also be carried out at the same time as the first dispensing step, which causes a further (higher) acceleration of the fluid sample.

In a dispensing process, the method for receiving the fluid sample by suction preferably provides for 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 in order 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 by the slight negative pressure/capillary forces in the usual way.

The total volume includes the dosing volume and an additional volume. The additional volume can be used to provide a residual volume or a discard volume. The residual volume remains in the fluid transfer container after all partial volumes have been dispensed and ensures that at least the desired partial volume is available for the last dispensing step. The discard stroke is used to generate a first dispensing quantity according to the discard stroke before the partial volumes are dispensed according to the free jet principle, so that the meniscus of the fluid sample at the dispensing opening of the fluid transfer container is defined in the same way in all subsequent steps - the meniscus can be different during the first dispensing, i.e. directly after collection, than after a break according to the free jet principle. The second position of the displacement element is set in particular according to the total volume.

During the dispensing process, the method for dispensing the fluid sample without providing a discard stroke preferably provides for 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 channel section is ventilated; that the displacement element is moved by the distance of the additional stroke in the direction of the first position, whereby in particular any possible play in the drive mechanism that drives the displacement element is compensated; 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 channel section, so that the overpressure is generated; that the first valve is opened after the displacement element has reached the intermediate position - as a result, the compressed air immediately relaxes 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 (dispensing the partial volume); that the last-mentioned step of dispensing the partial volume is repeated as desired, during the last dispensing step the displacement element can be in the first position. Preferably, the step of carrying out an overstroke of the displacement element is also provided 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 that corresponds to the direction of movement from the second to the first position) the displacement element from the first position to a further dispensing position.

During the dispensing process, the method for dispensing the fluid sample with provision of a discard stroke preferably provides for 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 to a starting position, thereby compressing the air in the first air channel section so that the overpressure is generated and in particular any possible play in the drive mechanism that drives the displacement element is compensated; that the first valve is opened after the displacement element has reached the starting position - as a result, the compressed air immediately relaxes and accelerates the fluid sample at maximum speed, the discard stroke leaves the fluid transfer container according to the free jet principle and the meniscus at its discharge opening 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 channel section so that the overpressure is generated; that the first valve is opened after the displacement element has reached the intermediate position - as a result, the compressed air immediately relaxes and accelerates the fluid sample at maximum speed, the fluid sample with the desired micro-dosing partial volume emerges from the opening of the fluid transfer container and the first valve is then closed again (dispensing the partial volume); that the last-mentioned step of dispensing the partial volume is repeated in the desired manner, during the last dispensing step the displacement element can be in the first position. Preferably, the step of carrying out an overstroke of the displacement element is also provided in order to carry out the dispensing of the last partial volume at the same time as 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 that corresponds to the direction of movement from the second to the first position) the displacement element from the first position to another discharge position.

Further preferred embodiments 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 conjunction with the figures. The same reference numerals designate 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 in a side cross-sectional view a microdosing device according to the invention according to a first embodiment.
• Fig. 1b shows in a side cross-sectional view a valve according to the invention of a microdosing device as in Fig. 1a shown, according to a first embodiment.
• Fig. 1c shows a side cross-sectional view of a second valve of the microdosing device from Fig. 1a .
• Fig.2 shows in a perspective view the microdosing device of the 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.
• Fig. 3b shows the actuator device of the Fig. 3a , in a second deflected position.
• Fig. 3c shows in a schematic perspective view 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 the 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 one embodiment.
• Fig.6 shows a diagram of the result of a dynamic differential calorimetry (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 1 a 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 serves to generate a microdosing volume of a fluid sample in the form of a micro free jet. It has an air channel 10, which has a passage opening 14, which connects a first air channel section 11 and a second air channel section 12 of the air channel 10. The first air channel section 11 has a first opening 21 and the second air channel section 12 has a second opening 22, to which the fluid transfer container 99 containing the fluid sample is connected by a plug-clamp connection. The microdosing device 1 has a controllable first valve 31 which is designed to keep the passage opening 14 of the air channel optionally closed in a first state in order to enable an overpressure in the first air channel section 11 compared to the second air channel section 12, or to keep it open in a second state 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 micro free jet.

The microdosing device has a cable connection 50, which is in particular part of the system 400, through which the valves 31, 32 are each connected to the electrical control device of the pipetting device and can thus be controlled by it. Here, the pipetting device (not shown in full) has an air chamber that is connected to the first opening via the connecting section 200, a displacement element that is designed to displace a microvolume (V) of the air chamber, and a drive to drive the deflection of the displacement element, whereby the overpressure in the first air channel section can be generated in the first state of the first valve. The microvolume V is here identical to the microdosing volume to be dispensed during a pipetting process. The displacement element of the pipetting device is a piston element that is designed to displace microvolumes and volumes greater than 2 µl, and in particular less than or equal to 100 µl, which can be selected by the user. The first opening 21 of the microdosing device 1 can be connected to the working cone 201 of the pipetting device via a plug/clamp 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 also have its own control device (not shown) that works independently of the control device of the pipetting device. In this case, the overpressure in the first air channel section is generated by the pipetting device, and the user triggers the opening of the first valve manually. 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 mechanics. 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 designed to control the first valve 31 so that the passage opening 14 is closed by means of the first Valve 31 is suddenly opened, whereby, due to the pressure equalization between the first 11 and second air channel section 12, a micro air volume exits 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 dosing volume of the fluid sample held in the fluid transfer container 99, determined by the micro air volume (V), is displaced and released from the fluid transfer container into the outside space in the form of a micro free jet.

The first air duct section 11 has a closable third opening 23 which connects the first air duct section 11 to the outside space, and a controllable second valve 32 which is designed to keep the third opening 23 of the air duct 10 optionally closed in a first state in order to enable the overpressure in the first air duct section 11 with respect to the second air duct section, or to keep it open in a second state and to enable a change from the first to the second state to bring about a pressure equalization in the first air duct section 11 with the outside space.

The air channel 10 with its first 11 and second 12 sections is formed in a base body 40 of the microdosing device 1. The air channel 10 runs essentially linearly. To create the passage opening 14, the air channel is closed off by a wall at the level of the passage opening 14. The first section 11 of the air channel 10 is diverted to the passage opening 14 by a bypass section 15 formed in the base body, from where the second air channel section 12 begins, which merges back into the linear region via the bypass section 15. The passage opening 14 can be closed off 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 the spring. To open the valve, the valve tappet is suddenly deflected by an actuator device. The actuator device has two crosswise arranged SMA actuators, the crossing 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 serves to ventilate the first air duct section. In Fig. 1c is a cross section through a valve that is constructed like the second valve 32. In Fig. 1b a cross-section through a valve is shown, which is constructed like the first valve 31.

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

Fig. 3a to 3c show by way of example how a moving element, e.g. a displacement element or similarly a valve tappet, can be deflected.

A contraction of the shape memory material actuator 85 results in, see Fig. 3a and 3b that the movable element 83' is moved in a very short time, i.e. in an impulse-like or sudden manner, from the first position P1 to the second position P2.

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 using differential scanning calorimetry (DSC), see diagram of the Fig.6 . In this measurement, the phase transition that is important for the actuation appears as a peak. From the diagram, it can be seen that in order to switch the actuator, the temperature of the actuator must be increased to at least 67 °C; in order to reset it, 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 in the martensite phase in particular and can be (apparently) plastically deformed by even small forces. In this state, the shape memory material actuator is in the Fig. 3a shown first position of the movable element. The shape memory material actuator can be arranged in the first position in particular so that it is under mechanical tension. However, it can also be relaxed. When heated to the further critical temperature of 67°C, the original component shape is restored within milliseconds, the material then behaves like a normal metal according to Hooke's law. The critical temperatures of the shape memory material actuator are adjustable by passing an electric current I 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 ( Fig. 3b ) or to cool the shape memory material actuator ( Fig. 3a ). Preferably, a ball 83b' or a holding element 85a' is inserted between the movable element and the actuator, which centers itself under the X-shaped, pocket-like curved actuator device 85.

The Figures 3a and 3b show the X-shaped, pocket-like actuator device 85, wherein in Fig. 3a a first position is shown in which the movable element is held in the first position by the return element, e.g. a spring, and wherein in Fig. 3b the second position is shown in which the actuator device 85 was activated and the movable element was deflected to the second position into the stop. The actuator device 85 has two shape memory material actuators based on a NiCuTi alloy, namely two elongated, web-shaped shape memory material actuators made from sputtered film, which are arranged crossing each other, i.e. in an X-shape, centrally above the ball of the movable element 83'. The use of film-based actuators enables the forces and travel distances to be adjusted by adapting the two-dimensional geometry. The surface, which is very large 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 connected to the base body 86, 40 or to the circuit board of the microdosing device 80 at the two coupling points 88 ( Fig. 3a ). The shape memory material actuators are tensioned above the support point in such a way that the intersection point 85a forms a bending point of the shape memory material actuator. As a result, as shown in the Figures 3a, 3b and 3c As shown by way of example, a shell-like region of the actuator device is formed, through which the actuator device centers itself above the support point and generates a force directed downwards precisely along the linear movement direction between the first and second position, which results in a correspondingly precise deflection. The two shape memory material actuators can be coupled by a connecting member (not shown). While in Fig. 3a to 3c the movable element 83' is constructed from cuboid-shaped sections, it can also be shaped differently, in particular with cylindrical sections, as well as with a ball as a support surface for the actuator device 85.

The membrane 49 is made of highly flexible PDMS with a thickness of 200 µm and is deflected forward in the de-energized state of the shape memory material actuators in order to close the valve opening.

The actuators of the actuator device 85 are, for example, mounted in pairs on a carrier plate or circuit board with integrated conductor tracks and electrically contacted, see Fig. 3a, 3b The electrical control of the shape memory material actuator is carried out via an electrical control device that 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-core cable. A middle core serves as a common ground electrode. To ensure 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.

To ensure that the shape memory material actuators switch as quickly as possible, the supply voltage is set to 4 V, the duration of the initial voltage pulse to 10 ms, and the pulse width modulation is set to a duty cycle of 1/128, for example. The actual switching time is determined, for example, by observing the actuator (or the ball underneath) with a high-speed camera. A shape memory material actuator in particular 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 is preferably implemented by a desired, in particular programmed, electrical control device 350 ( 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 part 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, wherein the first air duct section (11) comprises a first opening (21) and the second air duct section (12) comprises 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,

   wherein the first valve (31) comprises a shape-memory alloy (SMA) actuator.
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 second valve comprises a SMA actuator.
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 by 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 one 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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