EP2569088A1

EP2569088A1 - Dispenser and process for releasing flowable materials

Info

Publication number: EP2569088A1
Application number: EP11720421A
Authority: EP
Inventors: Armin Schriber
Original assignee: Tecan Trading AG
Current assignee: Tecan Trading AG
Priority date: 2010-05-12
Filing date: 2011-05-06
Publication date: 2013-03-20
Also published as: CN102985180A; CH703127A1; US20130092288A1; WO2011141357A1

Abstract

The invention relates to a dispenser (1) for releasing flowable materials (2, 2') and to a corresponding process. The dispenser (1) comprises at least one line (3) with an inlet end (4) and an outlet end (5) for transporting a flowable material (2) from a vessel (6) to the outlet end (5). The line (3) which can be essentially filled with these materials (2, 2') can be positioned with its inlet end (4) in the flowable material (2, 2') of the vessel (6) or connected to the vessel. A barrier valve (7) is configured to control the release of the flowable material (2, 2') from the outlet end (5), and a control unit (8) controls opening and closure of the barrier valve (7). The inventive dispenser (1) is characterized in that the line (3) comprises an elastic section (9) which can be inserted into the barrier valve (7), said barrier valve (7) being configured as a squeeze valve for stationary occlusion of this elastic section (9) and hence for closure of the line (3); in addition, the control unit (8) for release of a defined, discrete amount of the flowable material (2, 2') into a sample vessel (11) controls an appropriate opening time (t) of the barrier valve (7), said opening time (t) being determined exclusively by the properties of the flowable material (2, 2') to be released and the properties of the line (3) essentially filled with these materials (2, 2').

Description

Dispenser and method for dispensing flowable or pourable materials

This International Patent Application claims the benefit of Swiss Patent Application No. 00738/10 of May 12, 2010 and US Provisional Application No. 61 / 334,332 of May 13, 2010. The entire contents of these priority applications are included in the scope of this application for any purpose international registration. The invention relates according to the preamble of independent claim 1, a dispenser for dispensing flowable or free-flowing materials. This dispenser comprises at least one conduit having an inlet end and an outlet end for transporting a flowable material or a flowable material from a container to the outlet end. Here, the line is positioned with its inlet end in the flowable or free-flowing material of the container or connected to the container, but in each case with the flowable or free-flowing material substantially filled. The dispenser also includes a check valve to control the delivery of the flowable or free flowing material from the outlet end. The dispenser further includes a control unit which controls opening and closing of the check valve. The invention furthermore relates, according to the preamble of independent claim 20, to a corresponding method for dispensing flowable or free-flowing materials.

It is known to perform the delivery of liquids (the dispensing) more or less automated. The devices used for this purpose are generally referred to as dispensers. Depending on the requirements on the precision of the delivery with regard to the volume to be dispensed, such dispensers have a different complexity. In laboratories, for example in diagnostic institutes or in other biological or biochemical laboratories, the efficiency and reproducibility of routine experiments can be considerably increased with the help of automated dispensing processes. However, such laboratory dispensers typically have very high demands on the precision of the volume of liquid dispensed during dispensing. This is because they often work with very expensive reagents (eg enzymes, dyes, etc.), and because the sample volumes to be processed are relatively small (about 0.5 μΙ to 2 ml). To meet this stringent dispensing precision requirement, the dispensers include special pumps that control fluid delivery as much as possible. Frequently used pumps are, for example, peristaltic pumps or piston pumps. Peristaltic pumps are preferably used for pure dispensers, which are used for less sensitive laboratory processes. Piston pumps, on the other hand, are installed in dispensers and in combined dispensers with aspirating function, which must dispense liquid volumes with very high precision or - in the case of a pipetting device - also aspirate (aspirate). Common to all dispensers is that the driving force for dispensing the fluid volume is provided by an additional "drive pressure" provided by a pump to the fluid, but the incorporation of such pumps makes the dispensers used in laboratories relatively complex and therefore expensive.

For example, US Pat. No. 6,063,339 discloses a dispenser which can dispense liquids in a preprogrammed array very quickly and with high precision. This dispenser includes a pressure pump that regulates the inflow of liquid to be dispensed to a dispenser head. A control unit then controls a solenoid valve and thus the dispensing (or portioning) of the liquid through the dispenser head. Such a dispenser can deliver accordingly defined volumes of liquid with high precision and speed, but this is very complex in its construction.

Other simpler dispensers are also capable of delivering very small volumes in the nanometer and microliter range. For example, the so-called "PipeJet" of the IMTEK Institute for Microsystems Technology, Freiburg, Germany is known (see Streule et al., Journal of the Association for Laboratory Automation). over 2004: 300-306). In this case, a thin elastic capillary is filled with a liquid by capillary action. An actuator beats on the outside of this capillary and displaces a certain volume of fluid, which is thrown by the impact in a reproducible manner from the line. After retraction of the actuator, the capillary expands elastically again and assumes the initial shape; The capillary fills again by capillary force and is ready for the next stroke. A similar principle is known from the patent US 5,763,278 of the present applicant. There, too, a certain volume of liquid is ejected by means of an actuator acting on an elastic line from the outside. However, here the line is refilled with a precision piston pump. In addition, this device for dispensing volumes in the range of 1-10 μΙ differs from the PipeJet in that after the line and dispenser tip have been completely filled (see US 5,763,278: Fig. 2), a first one used only for priming the device The amount of liquid to be discarded is dispensed from the dispenser tip with the actuator (see US Pat. No. 5,763,278: FIG. 3). The dispenser tip is then brought to the desired dispensing position (eg over the well of a microplate) whereupon the piston of the pump is advanced by exactly the volume now dispensed (see US Pat

5,763,278: 4). Subsequently, the thus defined volume of liquid is thrown out of the dispenser tip by a blow with the actuator and into the well (compare US Pat. No. 5,763,278: FIG.

Easier dispensers with significantly lower precision are known, for example, from hospital infusion systems (see US 3,667,464). In the simplest form, the hydrostatic pressure of the infusion fluid is used as the driving force, and a desired dropping speed is set by means of a metering valve (eg a roller clamp). If the fluid volume decreases, the metering valve must be readjusted manually. If, however, the delivery of a constant fluid supply is required, additional infusion pumps (infusion pumps) are used in such infusion systems, so that the fluid can be delivered in a controlled manner by the additional pressure. Again, usually peristaltic pumps are used. As already indicated above, such simple, gravity-driven dispensers have the problem that with decreasing liquid level of the liquid to be dispensed in the container (ie with decreasing hydrostatic pressure), the flow rate decreases. In addition, it is known that the hose is increasingly deformed by the roller clamp, so that from time to time has to be readjusted to maintain a desired flow rate. Nevertheless, to maintain the flow rate, additional pressure is often applied by pumping. This can be done by directly applying pressure to the liquid with the help of positive displacement pumps. Alternatively, the pressure can also act on the elastic, bag-shaped container when it is stretched, for example by means of springs (compare FR 2 701 646). In each of these cases described here, however, the hydrostatic pressure is superimposed by the additionally generated pressure.

Alternatively, EP 0 781 521 B1 discloses a dispenser designed as a soap dispenser, in which a uniform dispenser is provided for maintaining the dispenser

Flow rate of the hydrostatic pressure itself is kept constant despite decreasing liquid level. This is achieved by carrying the container with the liquid from an element that responds to weight. If the container is emptied by multiple discharges of a volume of soap, it becomes lighter, whereupon the weight-responsive element raises the container. The height of the container is thus always adjusted to the level of the liquid in this container. According to EP 0 781 521, such weight-responsive elements may be, for example, coil springs adapted to the weight of the container. However, the volumes dispensed from such soap dispensers do not impose any special requirements on precision with regard to the dispensed volume.

According to a first aspect, it is an object of the present invention to provide a dispenser that can deliver flowable or free-flowing materials with a very high precision and yet is simple and inexpensive in construction.

According to a second aspect, it is an object of the present invention to provide an alternative method with which flowable or free-flowing materials can be delivered with a very high precision. This object according to the first aspect is achieved with the features of independent claim 1. In this case, the dispenser according to the invention introduced at the outset is characterized in that the line comprises an elastic section which can be inserted into the check valve and completely separates all parts of the check valve from the flowable or free-flowing material, the check valve acting as a pinch valve for stationary compression of this elastic section and is thus designed to close the line. The inventive dispenser is also characterized in that the control unit for dispensing a defined, discrete amount of the flowable or free-flowing material in a sample vessel controls a corresponding opening time t of the check valve, said opening time t is exclusively determined by the properties of the flowable or free-flowing material to be dispensed and the properties of the line substantially filled with these materials. This object according to the second aspect is achieved with the features of independent claim 20. In this case, the method according to the invention is based on the use of the dispenser according to the invention introduced at the beginning and is characterized in that an elastic section of the line is inserted into the check valve, this elastic section completely separating all parts of the check valve from the flowable or free-flowing material, and wherein

Shut-off valve is designed as a pinch valve and compresses this elastic portion to close the line stationary. The inventive method is also characterized in that the control unit for delivering a defined, discrete amount of the flowable or free-flowing material in a sample vessel controls a corresponding opening time t of the check valve, said opening time t is exclusively determined by the properties of the flowable or free-flowing material to be dispensed and the properties of the line substantially filled with these materials. Additional inventive features will be apparent from the dependent claims, respectively. The dispenser according to the invention comprises the following advantages:

A high precision of the delivered amount of free-flowing material or the volume of liquid delivered with a simple structure of the material-leading parts and thus low equipment costs.

Direct use of containers in which the material to be dispensed is manufactured, delivered or stored.

Sterile packaged liquids can be processed from simultaneously sterilized containers and lines, ie. be dispensed.

The use of all wetted or contaminable individual components as disposable items. Thus, the risk of cross-contamination can be ruled out or at least minimized. Such disposable items can be delivered as consumables and delivered sterilized.

A flexible design of the dispenser ensures that different containers, lines and valves can be used depending on the need.

A gentle dispensing of liquids is made possible, so that liquids (suspensions) which, for example, comprise sensitive material such as cells, do not have to be subjected to any additional pressure except for the locally limited influence of the closing valve.

The flexibly selectable cable lengths and the different selectable positions of the valve allow a design with the lowest dead volume, thus a cost-effective operation is possible.

The dispenser according to the invention and the method for dispensing flowable or free-flowing materials will now be explained in more detail with reference to schematic figures, which show exemplary and preferred embodiments, without restricting the scope of the present invention. Showing:

1 shows a dispenser according to a first embodiment, in which the ascending section of a line is inserted into a standard container for liquids to be dispensed and the descending section is guided through a closing valve, wherein the line is filled when the closing valve is open; FIG. 2 shows a first variant of the dispenser of FIG. 1 in the controlled delivery of liquid into a single sample vessel;

3 shows a second variant of the dispenser of FIG. 1 in the controlled dispensing of liquid in wells of a microplate;

4 shows a container of a dispenser for liquids to be dispensed according to a second embodiment, which comprises a line connected to this container with an exclusively descending part, which is designed to be used in a closing valve;

5 shows a container of a dispenser for liquids to be dispensed or free-flowing solids according to a third embodiment, which comprises an insertable into this container line with an exclusively descending part, which is designed to be used in a closing valve;

Fig. 6 is a side view of a pinch valve with inserted elastic

Section of pipe for transporting the liquids or free-flowing solids to be delivered;

Fig. 7 3D views of dispenser systems, wherein

7A shows a dispenser system with a simple pivoting device, on which one or more dispensers can be arranged in a circle and swiveled into a dispensing position; and where

Fig. 7B shows a dispenser system with a complex pivoting device, on which several dispensers can be arranged in a circle and pivoted to a dispensing position, and to which a co-rotating boom is mounted, on which several dispensers in a linear or circular

Arrangement are attached; FIG. 8A shows a dispenser system with four parallel channels and individual containers; and FIG

Fig. 8B shows a dispenser system with four parallel channels and a common container.

The inventive dispenser is suitable both for dispensing liquids and for dispensing free-flowing solid materials. An important field of application is the dispensing of certain volumes of liquid into the wells of microplates. The content of such wells depends on the geometric shape of these containers and on the number of wells per microplate. Based on the SBS standard (American National Standards Institute: ANSI / SBS / 1-2004), the microplates were standardized as far as possible and are available, for example, from Greiner Bio-One GmbH, D-72636 Frickenhausen, Germany. The following Table 1 shows an excerpt of standard formats and contents of exemplary polystyrene microplates, which was taken from the "Microplate Dimensions Guide" by Greiner (July 2007 version).

Table 1

AV = working volume; MV = maximum volume

Exceptions: * polypropylene microplate; ** polypropylene deep-well plate

The inventive dispenser is particularly suitable for dispensing liquid volumes in the range of a few μΙ to more than 100 μΙ. However, special applications also involve dispensing smaller volumes (in the nanoliter range) or larger volumes (in the milliliter range). FIG. 1 shows a dispenser according to a first embodiment. This dispenser 1 is equipped for dispensing flowable materials 2 and comprises a conduit 3 having an inlet end 4 and an outlet end 5 for transporting a flowable material 2 from a container 6 to the outlet end 5. The container shown here is, for example a vial containing an original component from an enzyme-linked immunosorbent assay (ELISA) kit.

The line 3 is positioned with its inlet end 4 in the flowable material 2 of the container 6 and filled with the flowable material 2 substantially. The filling or "priming" of the conduit 3 is shown here: A primer device 17 of the dispenser, in this case a suction balloon, was connected to the discharge end 5 of the conduit 3. By expanding the elastic, initially compressed suction balloon, liquid 2 was discharged the container 6 is sucked into the line 3. Preferably, the liquid is sucked in just as far (see vertical flow arrow) that its meniscus reaches the outlet end 5 of the line 3.

The dispenser 1 also includes a check valve 7 with which the line 3 can be fixed. Further, exemplary attachment possibilities for the line 3 are shown in FIG. This check valve 7 serves to control the delivery of the flowable material 2 from the outlet end 5 of the conduit 3 and is shown here in the open state. The line 3 comprises an elastic and insertable into the check valve 7 section 9 (indicated by dashed lines). This elastic portion 9 is preferably a part of the conduit 3; however, the entire line 3 can also be elastic. In any case, this elastic portion 9 completely separates all parts of the check valve 7 from the flowable material 2.

The check valve 7 is designed as a pinch valve for stationary compression of this elastic portion 9 and thus for the reversible closing of the line 3. A combination of a PS-1615-NC pinch valve (Takasago Electric Inc., Nagoya, Japan) and an elastic silicone line has been well proven (see Fig. 6), with repeated crushing (test: 1 '). OOO x) the silicone line could not permanently deform the same, so that a good repeatability of the discharge quantities was ensured. For disposable items, ie for Silicone tubing used to empty a container once and then disposed of is considered acceptable for a maximum of a few thousand closures. At much higher closing numbers, however, a reduction in the elasticity of the line and thus a change in the opening time at the same dispensing volume must be expected. The shut-off valve mentioned here is preferably of the "normally closed" type and the dimensional stability is specified as approximately 10 ⁷ cycles Depending on requirements, the shut-off valve 7 can be opened by a certain amount so that the opening of the line is either partial or complete If the check valve 7 is only partially opened, this is done with highest reproducibility, preferably by a mechanically defined, adjustable open end position.

Interestingly, it turned out that the priming of the line 3 not only their fullest possible filling (the smallest air bubbles disturb not) but also at least a one-time closing, opening (= conditioning, see horizontal, divergent arrows) and closing again (squeezing, Let go, squeezing) of the conduit 3; only then are the delivery quantities reproducible at the same opening time. In the context of the present invention, a "discrete amount" is considered to be a clearly defined, defined volume.

In the context of the present invention, the term "priming" refers to the first, virtually complete filling of the conduit 3. Here, "practically completely filled" means that smaller gas or air bubbles are tolerable, as long as they have the cohesion of priming Do not endanger the liquid column formed in line 3.

In the context of the present invention, the term "conditioning" designates the opening and closing of the conduit 3 (see Fig. 2 and Fig. 3) .When opening and re-closing the elastic portion 9 of the conduit 3, smaller volumes may be used This conditioning is preferably carried out after priming and immediately before the first dispensing, and it is also preferred after longer periods of use a line 3 (in the range of up to several hours) immediately before the next dispensing to perform such a conditioning step.

The dispenser 1 further comprises a control unit 8, which controls an opening and closing of the check valve 7. Such a control unit 8 preferably comprises an actuator for determining the opening time of the check valve 7. Preferred, with the control unit 8 operatively connected actuators are, for example, rotary capacitors, actuators or a processor which calculates the actual opening time t of the check valve 7. As a result, the control unit 8 controls a corresponding opening time t of the shut-off valve 7 and thus the delivery of a defined, discrete amount of the flowable material 2, which is conducted into a sample vessel 11. According to the invention, this opening time t is determined exclusively by the properties of the flowable material 2 to be delivered and the properties of the essentially filled line 3.

Preferably, software activated in the control unit 8 preferably uses identifications existing on the containers 6 for recognizing these containers, their geometry, content and volume. Such identifications can be, for example, barcodes (eg as a barcode or as a 2D barcode) and / or radiofrequency labels (RFID tags). This software is also preferably suitable for tracking the liquid level in the containers, i. for evaluating the residual volume remaining in the containers (see component C in Fig. 2).

Experience has shown that the volume in the vials (containers 6) with the original ELISA components is always exactly but tight. The automatic recognition of these containers and their contents makes a transfer unnecessary, so that an important source of error (confusion) and losses incurred by the shuffling can be avoided. The control unit 8 is also preferably designed to track the drop in the liquid level in the individual (previously identified) containers 6 and to correct the opening times of the valves for the slightly changed hydrostatic pressure in the container / line combination. This tracking of the liquid level can be done mathematically on the basis of the delivered liquid volumes. Alternatively, there can Liquid level can be determined in the containers with, for example, optical or capacitive methods.

The properties of the flowable material include, for example, the viscosity of a liquid, its vapor pressure, its friction on the inner surface of the conduit 3 and their specific gravity.

The properties of the line include, for example, its geometry (inner diameter, length and height difference) and their material and elasticity (in particular in section 9, which is inserted into the check valve 7).

The properties of a substantially filled conduit 3 include the properties of the flowable material 2 (the hydrostatic pressure prevailing in the conduit) and of the flowable material 2 '(the potential energy of the material particles). When liquids are to be dispensed, the hydrostatic pressure can be superimposed by a pressure additionally generated in the container 6 and / or in the line 3.

In the first embodiment shown in FIG. 1, the rising section 14 of the line 3 is inserted through an opening 16 into a standard container 6 for liquids to be dispensed. The descending portion 15 of this line comprises the outlet end 5 and is guided by the closing valve 7. When the closing valve 7 is open, the line is filled during priming. The dispenser 1 preferably comprises a holding device 12 with the aid of which the container 6 can be arranged with the inlet end 4 of the line 3 at a first height level H 1 (cf. also FIG. 2). The holding device 12 is preferably designed for placing the container 6 so that the inlet end 4 of the line 3 is located at the lowest point of the container 6 as possible. FIG. 2 shows a first variant of the dispenser 1 of FIG. 1 in the controlled dispensing of liquid 2 into a single sample vessel 11. As in FIG. 1, not all the conduit 3 and, unlike FIG. 1 drawn the whole valve 7. In this case, the outlet end 5 of the conduit 3 is arranged at a second, lower level height H2, the value A being the height. difference H 1-H2. Due to this difference in height (H1-H2), there is a hydrostatic pressure in the line 3 filled essentially with flowable material 2. However, the hydrostatic pressure is increased by a value C, which is determined by the level of the liquid in the container 6. Thus, the hydrostatic pressure prevailing in the line 3 is determined by the sum of the mass A + C, independently of the dimension B. The resulting hydrostatic pressure here determines the transport of the flowable material 2 from the container 6 to the outlet end 5 of the conduit 3. The check valve 7 is here arranged close to the outlet end 5 of the conduit 3. However, it could also be fastened, for example, to the holding device 12 (not shown). The line 3 preferably comprises a removable, the line reversibly closing plug 20 at its outlet end 5; this serves to protect the outlet end against contamination when the dispenser 1 is not currently in operation, for example. The plug 20 was removed here and deposited on a housing in which the control unit 8 and at least one processor 10 are housed. In the illustrated moment, the check valve 7 is opened, so that soon a certain volume (shown here in drop form) will leave the outlet end 5 of the line 3. If, as shown here, the blunt end of the line is used as outlet end 5, preferably larger volumes in the microliter or milliliter range are reproducible as single drops (> 10 μΙ) or in constant flow (> 100 μΙ) (C _v <1.6%). ). The Cv value indicates the coefficient of variation; this is calculated according to the formula

VK = ^σ x 100

X (1) from the quotient standard deviation / mean and is usually given in%.

Experimental data of the reproducibility test

In order to determine this C _v value, the following experimental setup was selected: A container 6 was placed on a holding device 12, as shown in FIG. 2 can be seen. The current hydrostatic pressure was 17 hPa for the section A (H 1 -H2 = 17 cm) and for the current liquid level in the tank 6 (Section C) about 8 hPa. This resulted in a total for the effective hydrostatic pressure of 25 hPa.

The silicone tube selected as line 3 was designated "SF 1303 medical grade 0.062 ID x 0.125 AD" (article No. FT 06 5205 3162, Angst + Pfizer AG, Zurich, Switzerland), was 410 mm long and had an inner diameter of 1.6 mm and an outside diameter of 3.2 mm., This line 3 was fixed in the container 6 so that its inlet end 4 was placed close to the bottom of the vessel 6. The container 6 contained 100 ml of deionized water used as the test liquid 2. Before dispensing the test volumes were given a "conditioning dispensing" for 80 ms. At the control unit 8, the valve opening time of 110 ms per dispensing was set; The accuracy of the total valve opening time, which was controlled in steps of 10 ms, was about 1 ms or +/- 1%.

Dispensing was carried out in a collecting vessel, which was located in a room protected against drafts on a calibrated analytical balance (SAG 285, Mettler-Toledo, Greifensee, Switzerland). The experiments were carried out at a room temperature of 21.3 ° Celsius and a relative humidity of 41%. The following amounts of fluid (in mg) were measured:

Table 2

51.0 51.9 50.3 51.6 52.0 50.7 52.2 51.4 52.6 50.7

52.1 50.4 52.0 50.1 51.1 52.2 50.7 52.2 50.7 52.0

50.5 51.4 52.3 50.9 51.6 52.3 49.9 51.5 52.1 50.4

51.4 51.8 50.1 51.1 52.2 50.5 51.1 52.0 50.0 51.3

52.0 50.2 51.2 51.7 49.7 51.0 51.4 49.7 50.4 51.7

52.2 50.6 51.6 52.0 50.2 51.2 51.7 49.9 50.9 51.5

49.8 50.7 51.7 49.7 50.6 51.5 49.3 50.4 51.4 52.0

50.4 51.2 51.9 50.0 51.0 50.9 49.9 50.6 51.8 49.7

50.8 51.6 49.6 50.6 51.4 52.1 50.6 51.3 52.0 50.2

51.1 51.8 50.2 50.9 51.6 49.7 The total amount of liquid dispensed in the 96 dispensing actions (about 51 μΙ) was 4,896 ml or about 5% of the contents of the container 6. The error in the hydrostatic pressure caused by these dispensing operations was thus about 1/20 of 8 hPa, ie 0.4 hPa and was not corrected in the software of the control unit 8. The standard deviation calculated from the data listed in Table 2 is 0.80958011, the corresponding mean corresponds to a volume of 51.07395833 μΙ. Calculated according to the formula above, the C _{v is} 1.59%. As a theoretical basis for flow rate calculations of the dispenser is the law of Hagen-Poiseuille (after Gotthilf Heinrich Ludwig Hagen, 1797-1884, Jean Louis Marie Poiseuille, 1797-1869). The volume flow, d. H . the volume V flow per unit time, with a laminar flow of a homogeneous viscous liquid through a tube (capillary of radius r and length I) is described by this law of Hagen-Poiseuille as follows:

TFT * Δϊ?

dt 8η

(2)

Mean (the units are in square brackets):

V flow through the pipe [m ³ / s]

r inner radius of the pipe [m]

I length of the pipe [m]

η dynamic viscosity of the flowing liquid [Pa-s]

Δρ pressure difference between the beginning and end of the pipe [Pa].

A numerical example of the experimental setup described gives the following data: Table 3

A good match of the actual amount of liquid dispensed per dispensation of 51 μΙ with the calculated valve activation time can be established. A small deviation results, for example, from the fact that a somewhat smaller inner diameter of the line 3 was assumed for the calculation (caused by a slight deformation of the silicone tube in the valve seat 29). FIG. 3 shows a second variant of the dispenser 1 of FIG. 1 in the controlled delivery of liquid 2 in wells of a microplate 11 '. In contrast to Fig. 2 here is a filter 30 inserted into the opening 16 of the container 6, so that no contaminating bacteria from the ambient air can get into the liquid by the resulting suction in the container in the delivery of the liquid 2. As in the figures 1 and 2, the closing elements of the valve 7 are arranged here so that the elastic portion 9 of the line 3 is stationary, ie locally scattered and always pressed together at the same point. The line 3 here comprises a dispenser tip 19 at its outlet end 5. The dispenser tip 19 preferably comprises a removable stopper 20, which reversibly closes the dispenser tip 19; this serves to protect the outlet end 5 from contamination if, for example, the dispenser 1 is not currently in operation. The plug 20 was also removed here (not shown). While in FIG. 2 a single sample vessel 11 is depicted on a sample holder 21 specially provided for this purpose, a microplate 11 'with a number of 96 flat-bottomed wells was placed on this sample holder 21 or placed in this sample holder 21. sets. A motorized drive 22 moves the sample holder 21 with the microplate 11 'so that certain wells of the microplate 11' and the outlet end 5 of the conduit or dispenser tip 19 can be correctly positioned relative to each other. The positioning of the sample holder 21 and / or the outlet end 5 of the line 3 relative to one another preferably takes place by means of at least one motorized drive 22, the corresponding movements being controlled by the control unit 8 and the processor 10.

In general, the sample vessels 11, 11 'that can be positioned by the sample holder 21 are selected from the group consisting of wells of microplates, sample tubes and gel cassettes and MALDI-TOF mass spectrometry targets (Matrix Assisted Laser Desorption / Ionization-Time Of Flight) and slide (for example, for light microscopy). Thus, the sample vessels can define a certain volume, have only small depressions or even be formed completely flat. The flowable material 2 is preferably selected from the

Group comprising liquids, suspensions, gels and emulsions. In the illustrated moment, the check valve 7 is closed, so that just a certain volume (in drop form) leaves the outlet end 5 of the line 3 (not visible). If, as shown here, a dispenser tip 19 is used as the outlet end 5, preferably smaller volumes in the nanoliter or microliter range are reproducibly delivered as single drops (<10 μΙ). Instead of a small diameter dispensing tip, a smaller diameter tube may also be used to dispense smaller volumes with its end simply cut clean and serving as a "dispenser outlet." In any event, dispensing smaller volumes in nanoliters or microliter region, the demolition of a drop or liquid jet to be delivered is reproducibly effected by the closing momentum of the check valve 7. This effect of a pulse on the line 3 is likewise known from US 5,763,278 however, the provision of a jet of liquid made possible by means of longer opening times of the shut-off valve 7 also makes it possible to reproduce reproducibly larger quantities of liquids. FIG. 4 shows a container 6 of a dispenser 1 for liquids to be dispensed according to a second embodiment. The container 6 comprises a line 3 connected to this container with an exclusively descending section 15 which is designed to be usable in a closing valve 7. This container 6 is here a plastic bag, as used for example in hospitals for infusions. The holding device 12 is slightly beveled to store the container 6 so that the inlet end 4 of the conduit 3 is arranged at the lowest point of the bag-shaped container 6. In addition, a simple printing device 13 (in the form of a weight placed on the bag) is shown here. With this printing device 13 in the flowable material 2 containing container 6 and in the line 3, an overpressure is generated.

This weight is thus intended to superimpose the already prevailing hydrostatic pressure and on the one hand to contribute to a more precise delivery of fluid. In this case, preferably, an ideal target pressure is generated for each individual container / line combination (with or without dispenser tip). The ideal target pressure is z. For example, influenced by an intended volume to be dispensed, the properties of the liquid to be dispensed (vapor pressure, viscosity, specific gravity, etc.) and the properties of the conduit 3. On the other hand, the pressure in a container / conduit combination can be increased to the same Dispense liquid volumes in a shorter time.

Alternatively, for example, a motor-driven punch could be pressed onto the bag (not shown). It can also be provided to place a bag between two surfaces, wherein at least one of these two surfaces is pressed against the other surface (clamp or press, not shown). It can also be provided that the line 3 from the flexible container 6 (bag) is at least partially formed as an ascending line (not shown).

FIG. 5 shows a container 6 of a dispenser 1 for liquids 2 to be dispensed or free-flowing solids 2 'according to a third embodiment. The container 6 is designed as a plastic bag, in which a line 3 is inserted. This line comprises an exclusively descending section 15, which in a Closing valve 7 is designed to be used. The holding device 12 is formed here as a suspension hook, which engages in a suspension eyelet 26 of the container 6. The inlet end 4 of the conduit 3 pierces a membrane 18, which otherwise closes the container 6. In the event that the container 6 exclusively contains free-flowing material 2 ', this is preferably selected from the group comprising powders, grains, spheres and comminuted solids. Due to the height difference H1-H2 (see Fig. 2), the free-flowing material 2 'in the substantially filled with this line 3 potential energy, which transporting the flowable material 2' from a container 6 to the outlet end the line 3 determined. Container 6 and lines 3 as shown in Figures 1 to 3, or bags and lines, as shown in Figures 5 and 6, regardless of whether they are each separable from each other or not, are preferably designed as plastic disposable articles , Also, glass containers are preferably treated as disposable articles in order to exclude cross-contamination as possible.

FIG. 6 shows a side view of a pinch valve of the type PS-1615-NC with an inserted elastic section of the silicone line 3 for transporting the liquids 2 or free-flowing solids 2 'to be delivered. The diameter of the silicone pipe 3 is for example 3.2 mm outside and 1.6 mm inside and the permissible working pressure 0 to 1.5 bar. In this pinch valve 7 only one driven by an electric coil slide 27 is moved back and forth. The elastic portion 9 of the conduit 3 is inserted into one of the two seats 29, so that the slide 27 presses this line 3 against an immovable counterpart 28 in an end position. In the other end position of the spool 27 (not shown), the conduit 3 is open. After removing the line 3, as required, the part of the valve 7 with the two counterparts 28 and the slide 27 is dismantled and replaced by new, uncontaminated or no Abrasion pointing spare parts with the two counterparts 28 and the slider 27.

FIG. 7 shows 3D views of dispenser systems 23 with at least one, but preferably at least two, of the previously described dispenser 1. Such a dispenser system 23 preferably comprises at least two lines 3 each having an inlet end 4, outlet End 5 and elastic section 9; two as Pinch valves formed check valves 7 for inserting the elastic portions 9 of the lines 3; and a control unit 8 with a processor 10 for calculating the opening time t of the shut-off valves 7 and for controlling these shut-off valves 7. In this case, each outlet end 5 of the lines 3 preferably comprises a dispenser tip 19, these dispensing tips 19 in one row or in one Circle can be arranged.

Preferably, such a dispenser system 23 comprises a pivoting device 24, with which each dispenser tip 19 with the outlet end 5 of a line 3 in this dispenser system 23 is pivotable into a specific dispensing position 25. Alternatively, it is preferred that the dispensing tips 19 at the outlet ends 5 of the lines 3 in this dispenser system 23 can be arranged linearly at a distance from each other, this distance corresponding to the center distance of wells of a microplate 11 '.

FIG. 7A shows a dispenser system with a simple swiveling device 24, on which several dispensers 1 can be arranged in a circle and can be swiveled into a dispensing position 25. Shown is a mounted dispenser 1, as shown in FIG. This dispenser 1 can with the

Pivoting device 24 are rotated about a central axis 31, wherein the pivoting device 24 can be moved by means of a motorized drive 22. The sample holder 21 with the microplate 11 'can also be moved linearly by means of a motorized drive 22 here. Thus, certain wells can be positioned under the dispensing tip 19, which is currently in the dispensing position 25. These movements are preferably controlled and controlled by the control unit 8 or by the processor 10 or another computer.

The container 6 shown is a commercially available liquid container and preferably comprises an identification 36 in the form of a barcode (preferably as a barcode or as a 2D barcode) and / or in the form of an RFID label (= Radio Frequency Identification Tag). To read this identification, a dispenser system 23 comprises a corresponding reading device (not shown), which forwards the read information to the control unit 8. So the control unit 8 knows every- time, which liquid is present in the container 6, so that it can be used on stored physical characteristic data and the dispensing process can be modified accordingly (preferably automatically). At the same time, the control unit 8 knows the initial volume present in the container 6 and (because the control unit 8 controls the dispensing) also the current volume of the liquid 2 in the container 6.

FIG. 7B shows a dispenser system 23 with a complex swivel device 24, on which several dispensers 1 can be arranged in a circle and swiveled into a dispensing position 25. In addition, a pivoting boom 32 is mounted on this pivoting device 24 to which a plurality of dispensers 1 are mounted in a linear (not shown) or circular arrangement (shown). If the dispensers 1 of the cantilever 32 are arranged linearly, several wells of a microplate 11 'can be filled simultaneously. All other elements correspond to the representation in FIG. 7A.

On the pivoting device 24 11 containers 6 are arranged substantially circular. Four of these containers 6 are bags which are suspended in their suspension eye 26 (see Fig. 8) on a bracket of the holding device 12 (see front side of the

20 pivoting device), wherein the outlet end 5 of the line 3 of one of these bags is located near the dispensing position 25. Two of these containers 6 arranged on the swivel device 24 are vials with an original component from an ELISA kit (see left side of the swivel device). Three of these containers are other customary liquid containers with an open screw cap (see

25 side of the pivoting device) and two of these containers are troughs (see right side of the pivoting device), as these usually in automatic pipetting of liquid handling systems such. B. be used in the Freedom EVO ^® the current applicant. Two of the containers 6 arranged on the arm 32 are also vials with an original component of an ELISA kit with an open

30 screwed lid. All other elements correspond to the illustration in FIG. 7A.

All containers 6 shown preferably comprise an identification 36 in the form of a barcode (preferably as a barcode or as a 2D barcode) and / or in the form of a barcode. RFID tag (= Radio Frequency Identification Tag). This was symbolized in FIG. 7B by showing at least one container of the different types of containers with an identification 36 attached or arranged on the container 6. In this case, the alignment of the identifications which are to be optically read out must advantageously be positioned so that all of these identifications 36 are arranged at substantially the same height and thus are easy to read, for example when the pivoting device is rotated. According to the scanning direction of the optical reading device while the identification is arranged standing or lying. Because RFID labels are not optically read, these identifications 36 can be arbitrarily arranged on the containers 6.

FIGS. 7A and 7B impressively show how the most varied containers 6 (in the form of bags, bottles or troughs) can be held with identical or only slightly modified holding devices 12 of the dispenser system 23 according to the invention.

Deviating from the representation in FIGS. 1 to 7, but still belonging to the scope of the present invention, provision can be made for a plurality of lines 3 to be arranged with their inlet ends 4 in a common container 6 or connected to this common container 6 (cf. Fig. 8B).

Figure 8 shows piping schemes for the parallel dispensing of liquid samples. Preferably, the outlet ends 5 of the conduits 3 are arranged so that they have an average distance from each other, which corresponds just to the center distance of the wells of a standard microplate. Shown here are embodiments with a microplate 11 'with 384 flat-bottomed wells. These microplates 11 'are arranged on a sample holder 21, which can be moved in a motorized manner preferably in an X direction and in a Y direction substantially horizontally (see arrows in FIGS. 8A and 8B). These movements are preferably controlled via the control unit 8 of the dispenser system 23, which also controls the dispensing of liquid samples from the containers 6. Particularly preferably, such a control unit comprises a processor with corresponding software. Not only the outlet ends 5 of the lines 3 are arranged in parallel here, also the opening and closing of these lines 3 happens here synchronously via a common Shut-off valve 7. Even if just here four lines 3 are operated with a check valve 7, the number of lines 3 per check valve 7 may also be larger or smaller. Figure 8A shows a dispenser system 23 with four parallel channels (lines 3) and four individual containers 6. These containers 6 are each preferably designed as a bag and hooked into a respective hook of the holding device 12. Such commercially available bags include z. B. a bag wall of a laminate whose innermost layer of polypropylene and / or polyethylene. The laminate preferably comprises an aluminum layer as light protection for sensitive liquids.

The lines 3 are guided through the valve 7, that a single slide 27 whose elastic portions 9 (not marked here, see Fig. 3) can see closing quet-. The check valve 7 is preferably operatively connected to the control unit 8, so that its opening time can be controlled by the control unit 8. The outlet ends 5 of the conduits 3 are held in a straight line by means of a guide 35 in the vicinity of the outlet ends 5 so that their average distance from one another corresponds to the spacing of the wells of the 384 microplate of 4.5 mm.

FIG. 8B shows a similar dispenser system 23 with four parallel channels (lines 3), but with a single, common container 6 resting on a holding device 12. The inlet ends 4 of the lines 3 are embedded in the bottom of the container 6 and the descending portions 15 of the lines 3 are also guided by a common check valve 7 and held near its outlet end 5 by a guide 35.

In contrast to Fig. 8A, the closing member of this stopper valve 7 is an elastic pipe 33 which can be pressurized by a pressing unit 34 so that the elastic pipe 33 expands and squeezes the elastic portions 9 of the pipes 3. Such a pressure unit 34 includes, for example, a pump, a pressure vessel and a valve (all not shown). This pressure unit 34 is also operatively connected to the control unit 8, so that the opening time of this pinch valve 7 is regulated and controlled as already described. can be. Preferably, the control unit 8 is always equipped with a processor 10.

It can be provided to equip at least one dispenser 1 or an entire dispenser system 23 with magnetic stirrers. Such magnetic stirrers are known per se to a person skilled in the art and serve, for example, to keep suspended particles (eg living cells) in liquids. Alternative means for maintaining suspensions, such. B. Rockers can be provided as an alternative or in addition to the magnetic stirrers. Magnetic stirrers are preferably used in bottle-shaped containers 6, whereas rockers are more suitable when using containers 6 in the form of lying bags. For controlling the magnetic stirrers and / or rockers, the control unit 8 (with or without processor 10) is preferably used again. For monitoring, calibration and / or adjustment of the dispensed liquid amount with one of the dispenser 1 or dispenser systems 23 according to the invention, several possibilities are considered, wherein the corresponding measuring device is arranged next to, at or below the sample vessels 11 / microplates 11 'or under their carriers can be :

A. Gravimetric monitoring, calibration, adjustment

This can be done with a load cell as used in the reproducibility test described above. B. Capacitive monitoring, calibration, adjustment

The discharged liquid droplet or jet is collected in the sample vessel 11 or in the well of a microplate 11 ', whereby it disturbs or alters the electric field of a capacitive circuit. The severity of this disorder or change is proportional to the volume of liquid dispensed.

C. Optical monitoring, calibration, adjustment

The delivered liquid droplet or jet is monitored optically (eg by CCD) in flight between outlet end 5 and upper edge of the sample vessel. Thereby, the stop time of the opening time of the shut-off valve 7 at runtime for the set the desired volume. This is done by means of a processor that converts the shadow of the liquid that has already passed the CCD sensor into a corresponding volume. Thus, in addition to the fixed influencing variables, the variable environmental influences are continuously recorded, so that device parameters can preferably be corrected immediately. This provides a delivery monitor or self-correcting delivery control.

D. Acoustic monitoring, calibration, adjustment

The dispensed liquid droplet or jet is collected in the sample vessel 11 or in the well of a microplate 11 ', where it changes the acoustic signal of an ultrasound source circuit. The strength of this change is proportional to the dispensed volume of liquid.

The same reference numerals in the figures always refer to the same or corresponding elements, although not in any way described in detail combinations of the embodiments shown and discussed are within the scope of the present invention.

Reference numerals:

1 Dispenser 19 Dispenser tip

2 flowable material 20 plugs

2 'free-flowing material 21 sample holder

3 line 22 motorized drive

4 inlet end 23 dispenser system

5 outlet end 24 pivoting device 6 container 25 dispensing position

7 check valve 26 suspension eyelet

8 Control unit 27 Slider

9 elastic section of 3 28 counterpart

10 processor 29 seat of 9

11 sample vessel 30 filters

11 'microplate 31 central axis

12 holding device 32 boom

13 printing device 33 elastic control line

14 rising section of 3 34 printing unit

15 descending section of 3 35 guide

16 opening of 6 36 ID

17 primer device

18 membrane of 6

Hl first height level

H2 second, lower lying height level

A height difference between Hl and H2

B Height of the container

C level in the tank

Claims

claims

Dispenser (1) for dispensing free-flowing or pourable materials

(2), which at least comprises:

(A) a conduit (3) having an inlet end (4) and an outlet end (5) for transporting a flowable material (2) or a flowable material (2 ') from a container (6) to the outlet end (5), wherein the line (3) with its inlet end (4) in the flowable or free-flowing material (2,2 ') of the container (6) positionable or connected to the container, but in each case with the flowable or free-flowing material ( 2,2 ') is substantially fillable;

(b) a check valve (7) for controlling the delivery of the flowable or free-flowing material (2,2 ') from the outlet end (5); and

(c) a control unit (8) which controls opening and closing of the check valve (7),

characterized in that the conduit (3) comprises an elastic and in the check valve (7) insertable portion (9) which completely separates all parts of the check valve (7) from the flowable or free-flowing material (2,2 '), wherein the check valve (7) is designed as a pinch valve for stationary compression of this elastic portion (9) and thus for closing the conduit (3),

and in that the control unit (8) controls a corresponding opening time (t) of the shut-off valve (7) for dispensing a defined, discrete amount of the flowable or free-flowing material (2,2 ') into a sample vessel (11), this opening time (t). is determined solely by the properties of the flowable or free-flowing material to be delivered (2,2 ') as well as the properties of substantially filled with these materials (2,2') line

(3).

Dispenser (1) according to claim 1, characterized in that the control unit (8) with a processor (10) is operatively connected, the opening time (t) of the check valve (7) calculated. Dispenser (1) according to claim 1 or 2, characterized in that it comprises a holding device (12) with the aid of which the container (6) with the inlet end (4) of the conduit (3) at a first height level (H l ) is bar.

Dispenser (1) according to claim 3, characterized in that the

Outlet end (5) of the line (3) on a second, lower level height (H2) can be arranged.

Dispenser (1) according to claim 4, characterized in that by the sum of the height differences (A + C) a hydrostatic pressure prevails in the We sentlichen with flowable material (2) filled line (3), which transporting a flowable material ( 2) from a container (6) to the outlet end (5) of the conduit (3).

Dispenser (1) according to one of the preceding claims, characterized in that it comprises a pressure device (13), whereby in the flowable material (2) containing container (6) or in the conduit (3), an overpressure can be generated.

Dispenser (1) according to one of the preceding claims, characterized in that the check valve (7) is arranged close to the outlet end (5) of the line (3).

Dispenser (1) according to one of the preceding claims, characterized in that the conduit (3) comprises a rising portion (14) with the inlet end (4) and a descending portion (15) with the outlet end (5), wherein the rising portion (14) is insertable through an opening (16) of the container (6).

Dispenser (1) according to claim 8, characterized in that it comprises a primer device (17) for first and substantially complete filling of the conduit (3) with flowable material (2). Dispenser (1) according to claim 4, characterized in that by the difference in height (H1-H2) the free-flowing material (2 ') in the substantially filled with this line (3) has a potential energy, which transporting the free-flowing material ( 2 ') from a container (6) to the outlet end (5) of the conduit (3).

Dispenser (1) according to one of claims 1 to 7, 9 or 10, characterized in that the conduit (3) comprises a descending section (15) with the inlet end (4) and the outlet end (5) the inlet end (4) is insertable into or connected to the container (6) through an opening (16) or membrane (18) of the container (6).

Dispenser (1) according to one of the preceding claims, characterized in that the line (3) or a combination of line (3) and container (6) are designed as plastic disposable articles.

Dispenser (1) according to one of the preceding claims, characterized in that the line (3) at its outlet end (5) comprises a dispenser tip (19).

Dispenser (1) according to one of claims 2 to 13, characterized in that it comprises a sample holder (21) for positioning one or more sample vessels (11), said sample holder (21) and / or the outlet end (5) of Line (3) by means of at least one motorized drive (22) are designed to be movable to each other, wherein the corresponding movements of the control unit (8) and the processor (10) are controlled.

Dispenser system (23) with at least one dispenser (1) according to one of claims 1 to 14, characterized in that the dispenser system (23) comprises at least:

(a) two conduits (3) each having an inlet end (4), outlet end (5) and elastic portion (9);

(B) at least one stop valve designed as a check valve (7) for inserting the elastic portions (9) of the lines (3); and (C) a control unit (8) having a processor (10) for calculating the opening time (t) of the check valves (7) and for controlling these check valves (7).

Dispenser system (23) according to claim 15, characterized in that the outlet ends (5) of the conduits (3) can be arranged in a straight line or in a circle.

Dispenser system (23) according to claim 15 or 16, characterized in that the each outlet end (5) of the lines (3) each comprise a dispenser tip (19).

Dispenser system (23) according to one of Claims 15 to 17, characterized in that it comprises a pivoting device (24) with which each dispensing tip (19) is connected to the outlet end (5) of a conduit (3) in this dispenser System (23) in a certain dispensing position (25) is pivotable.

Dispenser system (23) according to claim 16, characterized in that the Dispenserspitzen (19) at the outlet ends (5) of the lines (3) in this dispenser system (23) are linearly arranged at a distance from each other, said Distance corresponds to the center distance of wells of a standard microplate (11 '). 20. A method for dispensing free-flowing or pourable materials (2) with a dispenser (1), which comprises at least:

(b) a check valve (7) for controlling the delivery of the flowable or free-flowing material (2,2 ') from the outlet end (5); and (c) a control unit (8) which controls opening and closing of the check valve (7),

characterized in that an elastic portion (9) of the conduit (3) is inserted into the check valve (7), said elastic portion (9) completely enclosing all parts of the check valve (7) of flowable or free-flowing material (2,2 ') separates, and wherein the check valve (7) is designed as a pinch valve and this elastic portion (9) for closing the conduit (3) stationary compresses,

and that with the control unit (8) the delivery of a defined, discrete amount of the flowable or free-flowing material (2,2 ') in a sample vessel (11) is controlled, said opening time (t) is determined solely by the properties of the flowable to be delivered or free-flowing material (2, 2 ') and the properties of the line (3) substantially filled with these materials (2, 2').

21. The method according to claim 20, characterized in that prior to the dispensing of a flowable material (2) with this dispenser (1), the line (3) by means of a primer device (17) substantially completely filled with flowable material (2) ,

22. The method according to claim 20 or 21, characterized in that for the

Dispensing of a defined, discrete amount of the flowable or free-flowing material (2,2 ') with a with the control unit (8) operatively connected processor (10) a corresponding opening time (t) of the check valve (7) is calculated.