Pipetting arrangement and method of controlling a pipetting arrangement or of producing liquid product doses

Abstract

A pipetting arrangement includes at least two sets of pipettes (9a; 9b; 9c; 9d). Each set of pipettes (9a; 9b; 9c; 9d) is operationally connected, via a controllable ON/OFF valve (11a; 11b; 11e; 11d) to a common aspiration port (7). Latter is connectable to a pumping arrangement. The valves (11a; 11b; 11e; 11d) are controlled by a timing-control unit (15) conceived to establish, by control of the valves (11a; 11b; 11e; 11d), the operational connections of the at least two sets of pipettes (9a; 9b; 9c; 9d) to the aspiration port (7) in a time-multiplexed manner.

Claims

1. A pipetting arrangement comprising: at least two sets of pipettes; an aspiration port of a pumping arrangement; one or more controllable ON/OFF valves configured and arranged to operationally connect each of said at least two sets of pipettes to the aspiration port; a timing-control unit configured and arranged to establish, by control of said valves, said operational connection of the at least two sets of pipettes to said aspiration port in a time-multiplexed manner; wherein said pumping arrangement is configured and arranged to be continuously operated while the timing-control unit establishes the operational connection; and a gaseous transmitter medium positioned between the at least two sets of pipettes and the aspiration port, the gaseous transmitter medium configured and arranged to facilitate the operational connection between the at least two sets of pipettes, via the said valves, and the aspiration port.

2. The pipetting arrangement of claim 1, wherein said pumping arrangement is further configured and arranged to generate at said aspiration port an aspirating effect.

3. The pipetting arrangement of claim 1, wherein said pumping arrangement is further configured and arranged to generate at said aspiration port an ejecting effect.

4. The pipetting arrangement of claim 1, wherein said timing-control unit is further configured and arranged to establish, by control of said one or more controllable ON/OFF valves, another operational connection directly subsequent the operational connection.

5. The pipetting arrangement of claim 4, wherein said timing-control unit is further configured and arranged to alternatively and selectably establish said operational connection and the other operational connection simultaneously.

6. The pipetting arrangement of claim 1, wherein at least one of said at least two sets of pipettes includes one single pipette.

7. The pipetting arrangement of claim 1, wherein said one or more controllable ON/OFF valves are further configured and arranged to eject or to aspirate a volume which is negligible when actuated from an OFF to an ON state, or inversely.

8. The pipetting arrangement of claim 1, further including a flow sensor interconnected between said at least two sets of pipettes and said pumping arrangement.

9. A liquid handling device comprising: a pipetting arrangement according to claim 1, and a controlled positioning drive configured and arranged to control position of said pipetting arrangement along at least two spatial coordinate axes.

10. The liquid handling device of claim 9, wherein said controlled positioning drive is further configured and arranged to control position of said pipetting arrangement or at least said at least two sets of pipettes of the pipetting arrangement along a third spatial coordinate axis.

11. The pipetting arrangement of claim 1, wherein the one or more controllable ON/OFF valves are further configured and arranged to operate on the gaseous transmitter medium to effect the operational connection between the at least two sets of pipettes to the aspiration port.

12. The pipetting arrangement of claim 11, wherein the one or more controllable ON/OFF valves are further configured and arranged to define a volume of a liquid product dose aspirated or released from a respective set of the at least two sets of pipettes by operating the valves.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The present invention shall further be exemplified with the help of the attached drawings, which show:

(2) FIG. 1 schematically and simplified an embodiment of a pipetting arrangement according to the present invention, operated according to the method for producing or of controlling according to the invention;

(3) FIG. 2 in a representation in analogy to that of FIG. 1, a single pipette/valve/pump arrangement as of prior art, to explain the technique of aspirating of a dose of liquid, as principally also exploited according to present invention although with a different approach of realization;

(4) FIG. 3 qualitatively, a timing diagram of the control of the valves as incorporated in the embodiment of FIG. 1;

(5) FIG. 4 qualitatively, a timing diagram, to be considered in context with FIG. 3, of intermittent pump operation, synchronized with occurrence of time slots as of FIG. 3, as one form of realization of the invention;

(6) FIG. 5 schematically and simplified, a liquid sample processing device according to the invention and comprising a pipetting arrangement according to the invention.

DETAILED DESCRIPTION OF THE DRAWINGS

(7) FIG. 1 schematically shows an embodiment of a pipetting arrangement 1 according to the present invention. A pumping arrangement, exemplified in the figure by a pump 3 with a drive motor 5 is operationally connected to an aspiration port 7. As addressed by the dash line, the pumping arrangement may be remote from aspiration port 7 and thus from the pipetting arrangement, may be realised, e.g., by a central pumping station of a laboratory building feeding a vacuum line network throughout such building. Nevertheless in a today realized embodiment the pumping arrangement is integral with the pipetting arrangement and comprises a pump 3. The aspiration port 7 is operationally connected to at least two, as exemplified to four sets of pipettes 9a, 9b, 9c and 9d via respective ON/OFF valves 11a, 11b, 11c, 11d, each being ON/OFF controlled by ON/OFF control signals applied to control inputs 13a, 13b, 13c, 13d. The valves may be pneumatically controlled or electrically which latter is the case in today's realized embodiment. The sets of pipettes may comprise one single pipette as represented in the figure, all of them or selected sets may nevertheless be realized by more than one pipette operated in parallel, as exemplified at 9d in dash line.

(8) If we speak throughout the present description and claims from a valve being OFF we mean the valve is closed.

(9) If we speak throughout the present description and claims from a valve being ON we mean the valve is open.

(10) The ON/Off control signals for the valves 11a to 11d are generated and timed by a timing-control unit 15.

(11) ON/OFF operation of pump 3 is controlled by a control signal to the drive motor control input 17. The control signal to control input 17 is, e.g., generated by the timing-control unit 15 as well.

(12) Known operation of pipetting shall now be explained with the help of FIG. 2 to facilitate understanding of the present invention.

(13) A pipette 9 is operationally connected to a pumping arrangement, as to a pump 3a via an ON/OFF valve 11. The pump 3a on one hand is permanently filled with a liquid medium which is conveyed forth and back by respective operation of the pump 3a as schematically shown by double arrow m. The system of pipette 9 and commonly also of valve 11 is filled with a gaseous or liquid medium M, we call this liquid transmitter medium.

(14) First the valve 11 is OFF, i.e., closed and thereby prevents any escape of liquid transmitter medium M from pipette 9, which customarily is vertically oriented. The bottom level of liquid transmitter medium M in the pipette is at a predetermined position at or adjacent to the mouth 10 of the pipette.

(15) The mouth 10 of pipette 9 is then immersed into a liquid 21 to be aspired as shown in dash line in FIG. 2 at 10a. We call this liquid the dose liquid.

(16) The pump 3a is started and simultaneously valve 11 is controlled into ON state, i.e., open state. The aspiration effect at the aspiration port 7a to pump 7 is transmitted by the transmitter medium M, irrespective whether liquid or gaseous, to the mouth 10a of the pipette: Dose liquid 21 is aspired into pipette 9.

(17) As soon as a predetermined volume of dose liquid 21 is in the pipette 9 valve 11 is closed. The arrangement customary comprising pipette 9, valve 11 and pump 3a is lifted, so that the mouth 10 of pipette is freed from the remaining dosing liquid 21 in a receptacle 22.

(18) With the valve kept close, the arrangement with the pipette 9 containing the dose of dosing liquid 21, e.g., up to a level L as indicated in FIG. 2 may now be conveyed as desired in a respective application.

(19) Different techniques exist to accurately determine the level L and thereby, at a predetermined cross-section of the interior tube-space of the pipette 9, the volume of dose liquid 21 having been aspired in the pipette 9. Such techniques may for instance be based on light-barrier level detection as perfectly known to the skilled artisan. Simultaneously with turning valve 11 in OFF (closed) state or shortly before or afterwards, pump 3a is customarily stopped or, more generically an aspirating effect to the pipette is disabled.

(20) For releasing the dose of dosing liquid from pipette 9 into a destination receptacle (not shown), valve 9 is switched ON (open). E.g., the pump 3a is inversed in operation, and thus actively ejects the dose of liquid 21 into the destination receptacle. Here too different techniques are known to accurately control that exactly the same dose volume of liquid 21 is ejected into the destination receptacle as has been seized from the source recipient 22. Important to note, that in such prior art technique technique one pumping arrangement is dedicated to each pipette or set of pipettes.

(21) After having explained the known generic technique of pipetting in automated liquid handling art in context with FIG. 2, let's turn back to the invention as represented in FIG. 1.

(22) Here one common pumping arrangement, as of pump 3 is provided to serve more than one, as exemplified, four sets of pipettes 9a to 9d. This is done by time-multiplexing the aspiration effect at the aspiration port 7 from pump 3 consecutively to one set of pipettes after the other. Thereby the order of such sequence may be selected as desired, for clearness sake, multiplexing of the aspiration effect shall be from 9a to 9b to 9c to 9d in FIG. 1.

(23) With respect to provision of the media m and M the same prevails as was described in context with FIG. 2.

(24) FIG. 3 qualitatively shows the timing diagram of the multiplexing control of the valves 11a to 11d by the control signals generated by control unit 15 and applied to control inputs 13a to 13d of the respective valves. In FIG. 3 cl. addresses close (OFF State) and op. addresses open (ON state) of the respective valves. Further .sub.11a to .sub.11d address the respective time slots a respective valve 11a to 11d is open. T is the overall cycle time to fill all the four sets of pipettes.

(25) Thus with an eye on FIG. 3, first valve 11a is opened during time slot .sub.11a. At the end of .sub.11a valve 11a is closed and at least substantially simultaneously, possibly with a small time lag, valve 11b is opened for the time slot .sub.11b. In perfect analogy to multiplexing the sets of pipettes 9a and 9b as just described to the aspiration effect at aspiration port 7 of pump 3, subsequently, the sets of pipettes 9c and then 9d are multiplexed to the aspiration effect at port 7 during respective time slots .sub.11c, .sub.11d. Thus it becomes apparent that one time slot is associated to every pipette.

(26) The extents and the time sequence of the time slots is freely selectable. Further and if desired it is absolutely possible to flexibly establish two or more of the time slots to occur simultaneously or overlappingly and thereby to operate respectively selected setsif desired even all setssimultaneously and thus in parallel. Still further and if desired one set considered may be operated during more than one time slot. This, e.g., if a fixed time slot duration for all sets is established, in the sense of a system clock, and doses of different volumes are to be aspirated at different sets of pipettes.

(27) There is aspirated into each set of pipettes a dose with a volume which is proportional to the time slot duration the addressed set is operationally connected to the common aspiration port 7. In today's realization form which has proven most accurate, a gear pump, preferably an annular gear pump as described, e.g., in the EP 0 852 674 B1 is integrated to the pipetting arrangement thereby forming with the addressed arrangement a commonly moved and positioned unit.

(28) Clearly ejecting accurately the same doses as aspirated at the destination is performed by opening the respective valve and inversely operating the pump exactly during the respective duration according to .sub.11x.

(29) As exemplified in FIG. 3, the extents of the multiplexing time slots .sub.11x may be selected to be equal or, as shown, different. Thereby by means of controlling the extents of these time slots .sub.11x the volume of each aspirated dose may be separately selected.

(30) Although it may be possible to operate pump 3 ongoingly during cycle time T and thereby performing multiplexing the aspiration effect merely by ON/OFF control of the valves 11a to 11d, it is today preferred to operate the pump 3 intermittently, synchronized with multiplexing.

(31) FIG. 4 shows, associated with FIG. 3, a timing diagram of such intermittent pump operation. Here the respective ON times .sub.a to .sub.d of the pump control the respectively aspirated volumes of the doses, whereas the valves 11a to 11d control time multiplexing and accurate retention of the aspirated dosing liquid within the sets of pipettes.

(32) The valves 11a to 11d should propel a vanishing volume of transmitter medium M (see FIG. 2) in the transients ON to OFF and OFF to ON, so as not to falsify the aspirated volume of the respective doses controlled on one hand by the operation state of the pump and, on the other hand, by the respective time spans .sub.a to .sub.d.

(33) So as to monitor proper functioning of the pipette arrangement, it might be advisable to provide a flow sensor arrangement in the common line from the sets of pipettes to the pumping arrangement. Such flow sensor is shown in FIG. 1 in dash line and by reference number 19. By monitoring the flow by means of a single flow sensor at the addressed one location it becomes possible to detect a failing aspiration in any of the time-multiplexed sets of pipettes.

(34) FIG. 5 schematically shows a liquid handling apparatus or device 33 with a pipetting arrangement 1 according to the present invention integrated in a conveyor arm 34. The conveyor arm 34 provides for driven movability of the pipettes 9 in x- and z-direction as is schematically shown in FIG. 1 with respect to an apparatus frame 35. The arm 34 itself is drivingly movable in y-direction with respect to the frame 35. The valves 11 as well as pump 3 are integrated in the arrangement 1.

(35) The sets of pipettes 9 can be dipped by controlled movement in z-direction into sample receptacles 37 with the respective dose liquids. The aspirated doses are then conveyed in x and y direction to destination receptacles 39. Thereby in one embodiment all the sets of pipettes are commonly driven and positioned in z-direction, in an other embodiment (not shown) distinct sets or groups of sets may be driven and positioned in z direction mutually independently.

(36) We understand in context with the present description and claims under a device comprising the pipetting arrangement, and with an eye on FIG. 5, e.g., the overall apparatus or the arm 34 or the arm with the frame, in other words all parts at which a pipetting arrangement is provided up to the complete apparatus.

(37) By the present invention under all its aspects, a significant reduction of hardware effort for multiple pipette liquid handling is achieved.