Pipetting device and method

Abstract

Pipetting device for pipetting a liquid driven by a gaseous working medium, the pipetting device having at least one pipette connector adapted to attach a pipette at a connection opening at least one pressurizing and/or suctioning pressure source, a gas flow connection between said connection opening and at least one pressure source, a flow restriction defining at least a section of said gas flow connection, a first sensor configured to measure a quantity indicative of the temperature of the flow restriction. The invention is further directed to a gas flow connection element for a pipetting device and to a method of pipetting a liquid volume.

Claims

1. Pipetting device (10) for pipetting a liquid driven by a gaseous working medium, the pipetting device comprising: at least one pipette connector (13) adapted to attach a pipette (21) at a connection opening (14), at least one pressurizing and/or suctioning pressure source (11, 11, 11), a gas flow connection (12) between said connection opening and said at least one pressurizing and/or suctioning pressure source (11, 11, 11), a flow restriction (15) defining at least a section of said gas flow connection, a first sensor (16) configured to measure a quantity indicative of the temperature of the flow restriction, a heat storage block (19), wherein the flow restriction (15) is formed by an inner wall of the heat storage block or wherein the flow restriction (15) is formed by a flow restriction element (15) embedded in the heat storage block, and wherein said first sensor (16) is a temperature sensor thermally connected to said heat storage block.

2. Pipetting device (10) according to claim 1, further comprising a time controller (17) operatively connected to a controllable valve (18, 18, 18, 18), which controllable valve is configured to selectively open or interrupt said gas flow connection (12) in a time-controlled manner.

3. Pipetting device (10) according to claim 1, wherein said heat storage block (19) comprises a metal.

4. Pipetting device (10) according to claim 1, wherein the flow restriction (15) is formed by inner wall of the heat storage block and wherein said inner wall is the wall of at least a section of a through hole through the heat storage block formed by laser drilling or formed by an additive manufacturing method.

5. Pipetting device (10) according to claim 1, said pipetting device comprising a multiplicity of connection openings (14), a multiplicity of gas flow connections (12) between each of said connection openings and said at least one pressure source (11, 11, 11), and a multiplicity of flow restrictions (15) each defining at least a section of one of said gas flow connections of said multiplicity of gas flow connections, wherein all of said flow restrictions (15) of said multiplicity of flow restrictions are embedded in said heat storage block (19).

6. Pipetting device (10) according to claim 1, wherein an electrically operated valve is accommodated in the heat storage block.

7. Gas flow connection element (20) for a pipetting device (10) according to claim 1, said gas flow connection element comprising: said flow restriction (15), said heat storage block (19), and said temperature sensor (16) being thermally connected to said heat storage block and/or to said flow restriction.

8. Method (100) of pipetting a liquid volume (22) of a liquid by driving said liquid by means of a gaseous working medium, said method comprising the steps of a) providing (101) pipetting device according to claim 1; b) defining (102) a volume of liquid to be pipetted and defining whether pipetting is aspirating or dispensing; c) reading (103) a value from said first sensor (16); d) determining (104) a temperature of said flow restriction (15) as function of at least said value read from said first sensor (16); e) determining (105) at least one pipetting parameter as a function of said volume of liquid to be pipetted and of said temperature determined in step d); f) operating (106) said pipetting device by applying said at least one pipetting parameter determined in step e), which operating involves flowing of an amount of said gaseous working medium across said flow restriction (15), thereby pipetting said liquid volume.

9. Method (100) according to claim 8, wherein said pipetting device (10) is a pipetting device, wherein said at least one pipetting parameter determined in step e) is an opening time (t) of a controllable valve, and wherein operating said pipetting device comprises partial steps f1) starting (107) pipetting of said liquid volume by opening said at least one valve during said opening time determined in step e); and f2) closing (108) said controllable valve after said opening time (t) has elapsed.

10. Method according to claim 9, wherein said opening time (t) is controlled by open-loop control.

11. Method according to claim 9, wherein said opening time (t) is determined further in function of at least one of an ambient temperature (.sub.a), an ambient pressure (p.sub.a), calibration data indicative for a switching time of said controllable valve, a parameter or a set of parameters defining a geometric property of the flow restriction for a fluid having a defined viscosity, a temperature dependence of the viscosity of said gaseous working medium.

12. Pipetting device (10) according to claim 1, wherein said heat storage block (19) comprises sintered metal.

13. Pipetting device (10) according to claim 1, wherein said heat storage block (19) consists of a monolithic sintered metal structure.

14. Pipetting device (10) according to claim 1, wherein said first sensor (16) is positioned at the end of a blind hole formed into the heat storage block at a position closer to the inner wall thereof or to the flow restriction element (15) therein than to an outer surface of the heat storage element.

15. Pipetting device (10) for pipetting a liquid driven by a gaseous working medium, the pipetting device comprising: at least one pipette connector (13) adapted to attach a pipette (21) at a connection opening (14), at least one pressurizing and/or suctioning pressure source (11, 11, 11), a gas flow connection (12) between said connection opening and said at least one pressurizing and/or suctioning pressure source (11, 11, 11), a flow restriction (15) defining at least a section of said gas flow connection, a first sensor (16) configured to measure a quantity indicative of the temperature of the flow restriction, a heat storage block (19), wherein the flow restriction (15) is formed by a flow restriction element (15) embedded in the heat storage block, wherein said first sensor (16) is a temperature sensor thermally connected to said heat storage block, and wherein a wall of said flow restriction element (15) consists of a first material having a first specific thermal conductivity, wherein said heat storage block (19) consists of a second material having a second specific thermal conductivity, and wherein said second specific thermal conductivity is higher than said first specific thermal conductivity.

16. Pipetting device (10) according to claim 15, wherein said flow restriction element (15) is formed as a tubular capillary, which tubular capillary extends through a cavity (41) formed in said heat storage block (19).

17. Pipetting device (10) according to claim 16, wherein an inner surface of said cavity is arranged such that thermal radiation can be exchanged with an outer surface of said tubular capillary and/or wherein an inner surface of said cavity is in thermally conducting contact with an outer surface of said tubular capillary and/or wherein said cavity is partially or completely filled with a material having a specific thermal conductivity of at least the specific thermal conductivity of said tubular capillary.

18. Pipetting device (10) according to claim 15, wherein said first sensor (16) is positioned at the end of a blind hole formed into the heat storage block at a position closer to the flow restriction element (15) therein than to an outer surface of the heat storage element.

19. Pipetting device (10) for pipetting a liquid driven by a gaseous working medium, the pipetting device comprising: at least one pipette connector (13) adapted to attach a pipette (21) at a connection opening (14), at least one pressurizing and/or suctioning pressure source (11, 11, 11), a gas flow connection (12) between said connection opening and said at least one pressurizing and/or suctioning pressure source (11, 11, 11), a flow restriction (15) defining at least a section of said gas flow connection, a first sensor (16) configured to measure a quantity indicative of the temperature of the flow restriction, a heat storage block (19), wherein the flow restriction (15) is formed by an inner wall of the heat storage block, the flow restriction (15) being formed as a through hole in the heat storage block (19), the through hole forming three separate sections, an inlet section, a middle section and an outlet section, the middle section of the through hole being narrower than the inlet section and the outlet section thereof, and wherein said first sensor (16) is a temperature sensor thermally connected to said heat storage block.

20. Pipetting device (10) according to claim 19, wherein said first sensor (16) is positioned at the end of a blind hole formed into the heat storage block at a position closer to the flow restriction element (15) therein than to an outer surface of the heat storage element.

Description

(1) The invention shall now be further exemplified with the help of figures. The figures show:

(2) FIG. 1 shows a schematic view of the pipetting device according to the invention;

(3) FIG. 2 shows a schematic view of an embodiment of the pipetting device;

(4) FIG. 3 shows a schematic view of a further embodiment of the pipetting device;

(5) FIG. 4a shows a schematic view of a gas flow connection element according to the invention;

(6) FIG. 4b, FIG. 4c, FIG. 4d each show a cross-section through different examples of an embodiment of the gas flow element;

(7) FIG. 5 shows a perspective view of a heat storage block;

(8) FIG. 6 shows a flow chart of the method of pipetting a liquid volume of a liquid according to the invention.

(9) FIG. 1 shows schematically and simplified, a pipetting device 10 according to the invention. To illustrate its functionality, the present view shows in addition to the pipetting device itself some further elements in a specific pipetting situation. The pipetting device is shown with a pipette 21 attached to the connection opening 14 of the pipette connector 13. The pipette shown in this view contains a liquid, which at the moment is set under pressure by a gaseous working volume entering through the connection opening 14 into the pipette 21. A drop of liquid is pushed out of an opening of the pipette opposite to the opening of the pipette, which is in connection with the connection opening of the pipetting device. A previously produced liquid volume 22 is situated in one of the wells 23 of a well plate arranged below the pipette tip.

(10) The gaseous working medium is pressurized by the pressure source 11. A gas flow connection leads from the pressure source 11 across a flow restriction 15 to the pipette connector and thus establishes connection from the pressure source 11 to the connection opening 14, through which the gaseous working medium can flow. A first sensor 16 is configured to measure a quantity indicative of the temperature of the flow restriction. The first sensor 16 is in close proximity of the flow restriction 15. A measuring device and possible a calculation device may be operatively connected to the first sensor 16.

(11) FIG. 2 shows a schematic view of an embodiment of the pipetting device. In addition to the elements already discussed in the context of FIG. 1, this embodiment comprises a controllable valve 18. The controllable valve 18 is operatively connected to a time controller 17, wherein the operative connection is indicated by a dashed line. The controllable valve is arranged in the gas flow connection, in the example shown here in the upstream part of the gas flow connection with respect to the flow restriction. The controllable valve 18 is configured to selectively open or interrupt the gas flow connection 12 in a time-controlled manner. The controllable valve may e.g. be a magnetic valve, which is normally held in a closed state by means of a spring and can be opened by applying an electric current to a coil, the timing of the electrical current being controlled by the time controller 17. In this example, the operative connection between the time controller 17 and the controllable valve may be provided by a pair of electrically conducting wires.

(12) FIG. 3 shows a schematic view of a further embodiment of the pipetting device. The pipetting device shown here comprises a positive pressure source 11 and a negative pressure source 11, each of which is built as pressure tank. The flow connection 12 to the pipette connector branches into two arms, one leading to the positive pressure source, the other leading to the negative pressure source. The branching is in the upstream section with respect to the flow restriction 15. A two-way valve 18 and a two-way valve 18 are provided in each of the two arms. A third valve, being a switching valve 18 allows to selectively connect the first arm of the flow connection to either the positive pressure source 11 or to reference pressure 30, e.g. atmosphere pressure. All three valves 18, 18, 18 mentioned above are operatively connected to a time controller 17, as indicated by dashed lines. The first two-way valve 18 and the switching valve 18 in combination form a controllable discharge valve arrangement. The first two-way valve 18 and the second two-way valve 18 are both controllable valves being configured to selectively open or interrupt said gas flow connection 12 in a time-controlled manner. The flow restriction 15 is arranged in the flow connection 12. A first sensor 16 is configured to measure a quantity indicative of the temperature of the flow restriction 15.

(13) In partial FIG. 4a a schematic view of a gas flow connection element 20 according to the invention and in partial FIGS. 4b, 4c and 4d cross-sections through possible realization of the gas flow connection element 20 shown schematically in FIG. 4a. The gas flow connection element 20 comprises a heat storage block 19, into which the flow restriction 15 is embedded. All partial FIGS. 4a to 4d show embodiments comprising a heat storage block 19, such that the elements shown in these partial figures may be seen as the respective part of a pipetting device according to one of the above-mentioned embodiments comprising a heat storage block. A first sensor 16, which in this case is a temperature sensor, is thermally connected to the heat storage block 19. A first section of the gas flow connection 12 is shown immediately adjacent to the flow restriction 15 in FIG. 4a. These sections may be coupled in a releasable way to further sections of the gas flow connection 12 in a complete pipetting device. In the embodiment shown in FIG. 4b a cavity 41 is formed into the heat storage block 19. Tubular capillary extends across the cavity and is glued at opposite ends to the heat storage block. Glue 42 provides thermally conducting contact between an outer surface of the tubular capillary and the heat storage block and further seals a gap between the heat storage block and the tubular capillary, such that gas flow is forced through the narrow inner bore of the capillary forming the flow restriction element 15. The inner surface of the cavity 41 is arranged around the capillary and without radiation blocking elements between them, such that thermal radiation can be exchanged between an outer surface of the tubular capillary and the inner surface of the cavity. The first sensor 16 being a temperature sensor is positioned at the end of a blind hole formed into the heat storage block at a position closer to the inner walls of the cavity than to an outer surface of the heat storage element. The heat storage element may e.g. comprise metal or may be made of metal.

(14) In the example embodiment shown in FIG. 4c, there is no separate flow restriction element, but the flow restriction 15 is rather formed by an inner wall of the heat storage block. A middle section of the through hole 43 is narrower than an inlet and an outlet section of the through hole and forms the flow restriction. A temperature sensor 16 is mounted in close proximity of the section forming the flow restriction 15. In the further example embodiment shown in FIG. 4d, a flow restriction element in the form of a capillary is present. The flow restriction element 15 is embedded in a cavity 41, which is partially filled with a thermally conductive glue 44. A temperature sensor 16 is embedded in the thermally conductive glue 44 and sits in close proximity to the flow restriction element 15. In the embodiment shown, the distance from the temperature sensor 16 to the capillary is less than the diameter of the capillary. As illustrated at the left end of the capillary, an additional sealing element may be arranged between the capillary and the heat storage element 19 in order to insure that the gaseous working medium flows through the flow restriction element 15, which in this case has the form of a capillary.

(15) FIG. 5 shows a perspective view of an embodiment of a heat storage block 19. The heat storage block shown provides through holes for accommodating four flow restriction elements 15. The four flow restriction elements 15 are shown in a position offset in the axial direction towards the openings visible in the current view. In their finally mounted position, the flow restriction elements 15 may not be visible from the viewpoint used in this figure. The final mounting position of the restriction elements may correspond to the situations illustrated in FIG. 4b or 4d, such that the flow restriction elements are well protected by the surrounding heat storage block. Two arrows indicate possible positions of two temperature sensors 16. The temperature sensors may e.g. be mounted on a printed circuit board, which may be arranged on a surface of the heat storage block. The embodiment of the heat storage block shown here provides structures for holding a printed circuit board, which is not shown, in place. Two temperature sensors allow to determine a mean temperature of the heat storage block as well as to detect the presence of a temperature gradient across the heat storage block. With this sensor configuration, the temperature of each of the four flow restriction elements 15 can be determined with even higher precision. The temperature sensors and possibly further sensor, as e.g. pressure sensors or differential pressure sensor may be arranged on a print, for which a cutout is foreseen. A heat storage block with complicated geometry as shown here may be produced as a monolithic sintered metal structure, e.g. by laser sintering a metal powder or a similar additive production method. These production methods allow for non-straight holes inside the heat storage block. The inventors have recognized that such an arrangement leads to a very compact design and very little dead volumes in the gas flow connection element 20 and in the pipetting device 10 according to the invention.

(16) FIG. 6 shows a flow chart of the method 100 of pipetting a liquid volume of a liquid. Begin and end of the method are marked with START and END. In the variant of the method shown in this figure, steps 101 to 106 corresponding to the steps a) to f) are executed one after the other, step 101 being the first step and step 106 being the last step. According to the inventive method, some of the steps may overlap or partially overlap in time. Steps which do not depend on the result of another step may be executed in a different order, e.g. step b) (step 102) and step c) (step 103) may be exchanged, as reading a value from said first sensor 16 is independent of the defining of a volume to be pipetted. Step c) may even be performed continuously in parallel to the other steps of the method. In a specific variant of the method, wherein the at least one pipetting parameter determined in step e) is an opening time t of the controllable valve, the last step 106 comprises partial steps 107 and 108 denoted as f1) and f2), namely

(17) f1) starting 107 pipetting of the liquid volume by opening said at least one valve during the opening time determined in step e); and

(18) f2) closing 108 the controllable valve after the opening time t has elapsed.

LIST OF REFERENCE SIGNS

(19) 10 pipetting device 11 pressure source 11 pressurizing pressure source 11 suctioning pressure source 12 gas flow connection 13 pipette connector 14 connection opening 15 flow restriction 15 flow restriction element 16 first sensor 17 time controller 18, 18, 18, 18 controllable valve 19 heat storage block 20 gas flow connection element 21 pipette 22 liquid volume 23 well 30 reference pressure 41 cavity (formed in the heat storage block) 42 glue 43 through hole 44 thermally conductive glue 100 method of pipetting a liquid volume 101 step a) of the method 102 step b) of the method 103 step c) of the method 104 step d) of the method 105 step e) of the method 106 step f) of the method 107 partial step f1) 108 partial step f2) p+ positive pressure p negative pressure t opening time of controllable valve temperature of the flow restriction .sub.a ambient temperature p.sub.a ambient pressure viscosity of gaseous working medium