WO2013156408A1 - Pipetting arrangement and method of controlling pipetting - Google Patents

Pipetting arrangement and method of controlling pipetting Download PDF

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Publication number
WO2013156408A1
WO2013156408A1 PCT/EP2013/057711 EP2013057711W WO2013156408A1 WO 2013156408 A1 WO2013156408 A1 WO 2013156408A1 EP 2013057711 W EP2013057711 W EP 2013057711W WO 2013156408 A1 WO2013156408 A1 WO 2013156408A1
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WO
WIPO (PCT)
Prior art keywords
column
pump
stroke
pipette
liquid
Prior art date
Application number
PCT/EP2013/057711
Other languages
French (fr)
Inventor
Pius Fink
Original Assignee
Sias Ag
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Filing date
Publication date
Application filed by Sias Ag filed Critical Sias Ag
Publication of WO2013156408A1 publication Critical patent/WO2013156408A1/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02Burettes; Pipettes
    • B01L3/021Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14Process control and prevention of errors
    • B01L2200/143Quality control, feedback systems
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14Process control and prevention of errors
    • B01L2200/148Specific details about calibrations

Definitions

  • the present invention generically relates to the field of accurately preparing and handling very small doses of liquids, down to e.g. several hundreds nano-liters.
  • Such liquid handling techniques are especially used in context with medical, chemical or biochemical analyses, e.g. in pharmaceutical, medical or food industry laboratories.
  • probes e.g. to be analyzed
  • small samples of liquids of accurately known volumes and often at a high repetition rate e.g. in context with blood analyses of large populations, are handled.
  • Figure 1 shows schematically and simplifies a known
  • a pipette 1 Via a flow connection line 3 as of a pipe, a pipette 1 is connected to a suction/ejection port SE of a bi-directionally actuatable pressure source, i.e. a pump 5.
  • An ejection / suctioning port ES thereof is connected (not shown in figure 1) customarily to a liquid reservoir.
  • connection line 3 up to the pipette 1 may be filled with at least one different medium which may be liquid or gaseous.
  • the pump 5 is activated in S-pumping direction to suction a dose of liquid L into pipette 1.
  • the addressed dose is conveyed or, more
  • Pump 5 as shown by example as a rotary gear pump 5 G , is driven by a rotary drive 7. E.g. by an angle encoder as a position detector 9, the prevailing angular position of gear pump 5 G is monitored.
  • the output signal of detector 9 is led to a difference forming unit 11.
  • a difference signal ⁇ is formed from the signal dependent on actual angular position X and from a desired angular position signal W, which is preset at a presetting unit 13.
  • the difference signal ⁇ accords with the difference of the momentarily prevailing angular position of pump 5 G and the preset or desired value W, preset at unit 13.
  • This difference signal ⁇ as a control deviation signal is fed via a controller unit 15 to a control input C 7 of the rotary drive 7.
  • a negative feedback control loop a highly accurate control of movement and position of the pump 5 G in suctioning S and in ejecting E directions.
  • control and especially negative feedback control of the movement of the gear pump 5 G may also be established for any kind of be-directionally acting pump 5- as more
  • valve arrangement 17 which is controlled by a control unit 18 in open or close state to most accurately interrupt the suctioning effect of pump 5 as well as the ejection effect of the pump when the desired dose is suctioned into or ejected from pipette 1.
  • a method according to the present invention of controlling pipetting in which a pump is operationally connected to a pipette by a flow connection line. At least a part of the flow connection line to the pipette is filled with a liquid medium column. A volume of a liquid is suctioned into the pipette, a volume of liquid is ejected from the pipette. Both these actions of suctioning and of ejecting do include moving the column of the liquid medium by the pump.
  • the method comprises further the step of monitoring at least one of in or along the flow connection a stroke of the column and controlling the pump in dependency of the result of such monitoring.
  • stroke of the column an amount of displacement of the column of liquid medium within the flow connection line between the pipette and the pump .
  • a stroke of a column of liquid medium in the flow connection line is monitored, whereby such column may be preceded towards the pump by one or more than one columns of a gaseous medium or may be succeeded towards the mouth of the pipette by one or more than one columns of gaseous medium.
  • the addressed liquid column the stroke of which being monitored, is preceded in direction towards the pump by at least one column or cushion of a gaseous medium this will affect the transmission characteristics of the operation of the pump upon the movement of the addressed liquid column within the connection line. This due to the fact that such column of gaseous medium spring-like interacts between the pump and the addressed column of liquid medium due to compressibility of the gaseous medium.
  • the column of liquid medium the stroke of which being monitored has an end face which is directly exposed either to the mouth of the pipette or to an end phase of a liquid suctioned into the pipette and directed towards the pump.
  • the stroke of which being monitored needs not necessarily be formed by one single liquid medium, but may be formed by two or more liquid media, it is often possible to establish the extent of such liquid column practically up to the mouth of the pipette, thereby taking care of providing a liquid medium directly exposed to the mouth of the pipette which is compatible with the liquid to be suctioned into the pipette and ejected from the pipette.
  • monitoring of the stroke of the liquid medium column comprises monitoring the stroke of an interface surface between different media in or at the column the stroke of which being monitored.
  • such interface may be an interface between two different liquid media, both forming the column of liquid medium the stroke of which being monitored or may be a front or end face of the addressed column exposed to a gaseous medium.
  • a desired value of a stroke for the liquid medium column is preset.
  • a difference signal dependent from such preset desired value and from a signal dependent from monitoring of the prevailing stroke is formed.
  • the stroke of the liquid medium column is negative feedback controlled whereby the difference signal is exploited as a control deviation and the pump is exploited as an adjusting member in that the control derivation signal is operationally connected to a control input for the pump.
  • Negative feedback controlling the stroke of the column is performed thereby exploiting first a first difference signal dependent from the first of the desired values and then exploiting a second difference signal dependent from the second of the desired values as control deviation and, in both cases, the pump as an adjusting member. Thereby, there is established the stroke as monitored to become first equal to the first desired value then equal to the second desired value with an accuracy according to the controlling effect of negative feedback controlling.
  • the first desired value may be the desired stroke value for suctioning of a liquid into the pipette and the second desired value of the stroke may accord with the stroke of the column for ejecting the liquid from the pipette.
  • the two desired values are established with inverse signums as the desired stroke for suctioning the liquid is directed towards the pump and the stroke for ejecting the liquid is directed from the pump.
  • the extents of these strokes may be unequal or equal.
  • monitoring the stroke comprises monitoring relative position of the column in the flow connection over time .
  • Presetting the desired value comprises presetting a desired course of relative positions over time of the column, i.e. a desired movement of the column over time.
  • the negative feedback controlling thus comprises negative feedback controlling the movement of the column by exploiting a difference result of the signal which
  • the suctioning stroke as well as the ejecting stroke may be accurately negative feedback controlled by presetting the respective forward and backward movements of the liquid medium column and additionally the desired stroke may be realised with a desired movement characteristic e.g. with slow or more rapid approach towards the desired stroke value .
  • the volume suctioned into the pipette and/or ejected from the pipette is controlled without operating an opening/closing valve arrangement in the flow connection line between the pipette and the pump.
  • the pump is a rotary gear pump.
  • the present invention is further directed on a method of producing a dose of a liquid by pipetting in which method a pump is operationally connected to a pipette by a flow connection line, at least a part of the flow connection line is filled with a liquid medium column. Liquid is suctioned into the pipette and liquid is ejected from the pipette, both including moving the column by the pump.
  • the method further comprises the step of monitoring, in or adjacent the flow connection line, a stroke of the
  • monitoring the stroke is established by sensing a geometric entity which finally defines for a difference of positions of the column of liquid medium in the flow connection line, be it e.g. sensing directly the relative position of the
  • the liquid column is established up to the pump and the liquid medium of the column fills the pump .
  • the liquid medium column has an end face directly exposed to the mouth of the pipette or to an end face of a liquid volume suctioned into the pipette .
  • the extent of a column of gaseous medium between the end face of the liquid medium column and the mouth of the pipette is minimized e.g. to an extent for ensuring material isolation from the column of liquid medium or the liquid to be suctioned into the pipette.
  • a desired value of a stroke for the liquid medium column is preset.
  • a difference signal which depends from the preset desired value and from a signal, which is dependent from monitoring the prevailing stroke.
  • the stroke of the column within the flow connection line is negative feedback controlled thereby exploiting a signal which is dependent from the addressed difference signal as a control deviation signal and the addressed pump as an adjusting member.
  • a signal dependent on the addressed difference signal is operationally connected to a control input for controlling operation of the pump.
  • At least two desired values of a stroke for the liquid medium column are preset. Two difference signals are formed respectively dependent from one of the two desired values and from the signal dependent from monitoring the stroke.
  • connection line is negative feedback controlled, thereby exploiting first a signal dependent from a first of the two difference signals, and then exploiting a second signal dependent from the second of the difference signals as respective control deviation signals and, in both cases, the pump as an adjusting member.
  • monitoring the stroke of the liquid medium column in the flow connection line comprises monitoring a position of the column in the flow connection line over time.
  • Presetting the desired value thereby comprises presetting a desired course of relative positions over time of the column and thus, in fact, presetting a desired movement of the
  • Negative feedback controlling comprises negative feedback controlling a movement of the column by exploiting a difference result of a signal representing the desired course of positions and of a signal representing the monitored instantaneously
  • the addressed position may be said "relative" position in the flow connection line, as defined with respect to an arbitrarily selected fixed position along the flow
  • connection line Because according to the generic approach of the present invention it is the stroke of the liquid medium column in the flow connection line which is
  • the instantaneously prevailing position of the column as monitored is negative feedback controlled to follow, over time, a desired sequence of desired positions and thus to follow a desired movement.
  • one or more than one stroke forwards and/or backwards are negative feedback controlled and additionally the time course of movement of the liquid medium column to achieve the desired stroke value is controlled. If, e.g., there is provided between the liquid medium column and the pipette mouth a relevant column or cushion of a gaseous medium, it may be advisable, to negative feedback the movement of the addressed liquid medium column so slowly that the gaseous medium column does not act as an
  • the volume as suctioned into the pipette and/or as ejected from the pipette is controlled without operating an opening/closing valve arrangement in the flow connection line.
  • the pump is selected to be a rotary gear pump.
  • the invention is further directed on a pipetting apparatus, which comprises a bi-directionally operable pump.
  • a flow connectional line is provided from the pump to a pipette mouth and a continuous liquid medium column fills at least a part of the addressed flow connection line.
  • a controlling unit is provided for the operation of the pump which unit comprises a control input for a signal to control the addressed operation.
  • the addressed output of the sensing arrangement is operationally connected to the control input of the controlling unit for the operation of the pump .
  • the liquid column is established up to the pump and a liquid of the addressed column fills also the pump.
  • the column has an end face directly exposed to the mouth of the pipette.
  • the extent of a column of a gaseous medium between the end face of the addressed column of liquid medium and the mouth of the pipette is minimal as just to ensure material isolation of the column from a liquid suctioned into the pipette or there is no such column of gaseous medium provided at all.
  • such apparatus further comprises a
  • the apparatus comprises a difference forming unit with a first and with a second input for signals the difference therefrom being formed by the difference forming unit and with an output for a result signal of the difference forming by the addressed unit.
  • the output of the sensing arrangement and the output of the presetting unit are respectively
  • the sensing arrangement generates an output signal which represents a prevailing relative position of the column in the flow connection line.
  • the presetting unit generates an output signal which represents a desired time course of positions of the column in the flow connection line.
  • the sensing arrangement senses a prevailing position of the column along the flow connection line.
  • the pump is a rotary gear pump.
  • Figure 1 A schematical representation of a prior art embodiment for controlling pipetting.
  • Figure 2 Still schematically a prior art embodiment for pipetting control in which the movement of a pipetting pump is negative feedback controlled.
  • Figure 3 In a schematical representation a pipetting arrangement according to the present invention and operating a method of controlling pipetting as well as a method of producing a dose of a liquid according to the present invention.
  • Figure 4 A part of a pipetting arrangement according to the present invention, still schematically, wherein the interface between two media in a flow connection line between a pump and the nozzle of the pipette is position- monitored.
  • Figure 5 A part of an arrangement according to the present invention, wherein a volume of gaseous medium is minimized just to establish material isolation between a liquid medium within the arrangement from a medium to be suctioned into and ejected from a pipette.
  • Figure 6 Still schematically a part of an embodiment according to the present invention, wherein a bubble of gaseous medium is applied within a liquid medium in a flow communication line between a pump and a pipette so as to monitor position and/or movement of the liquid medium column .
  • Figure 7 A further embodiment of the present invention, still schematically, which operates the methods according to the present invention.
  • Fig. 3 shows simplified and schematically a signal
  • a bi-directionally operable pump 35 is linked by a flow connection line 33 as of a tube to a pipette 31.
  • the pump 35 has a suctioning/ejection port SE and an e ection/suctioning port ES.
  • port SE is connected to the flow connection line 33
  • port ES may be, in the embodiment of fig. 3, open to ambient.
  • a column of liquid medium 37 fills the pipette 31 as well as a part of the flow connection line 33.
  • the position of the column of liquid medium within pipette 31 and flow connection line 33 may be defined by the end face 39 of the liquid medium column pointing towards the pump. In this embodiment there succeeds in direction towards the pump 35 adjacent to end face 39 a column of gaseous medium 41.
  • end face 39 is a liquid/gas interface.
  • the bi- directionally operable pump 35 is operated forwards and backwards according to the double-arrow S-E by a drive 43 which has a control input C43 for control signals
  • the pump 35 is operated in direction S by drive 43 the liquid medium column 37 is suctioned towards pump 35. If pump 35 is operated by drive 43 in inverse direction E, the column of liquid medium 33 is moved in direction towards pipette 31.
  • the pump is operated in S direction, generating a stroke H of the liquid medium column 37 towards pump 35.
  • a liquid L is suctioned into pipette 31 with a volume which accords with the volume of liquid medium displacement in the flow connection line 33 according to stroke H.
  • the pump 35 is disabled or stopped and the dose of liquid L within pipette 31 is handled according to the respective application and needs.
  • the sensor arrangement 45 may be e.g. an optical/electrical converter, e.g. a digital picturing sensor with e.g. a CCD optical/electrical converter followed by a picture recognition unit to recognize the instantaneous location of face 39.
  • an optical/electrical converter e.g. a digital picturing sensor with e.g. a CCD optical/electrical converter followed by a picture recognition unit to recognize the instantaneous location of face 39.
  • a very high accuracy of locating the interface 39 along the sensor arrangement 45 may be reached.
  • the sensor arrangement 45 generates at its output ⁇ 45 an output signal X which is indicative of the instantaneous position of interface 39.
  • This signal X or a signal dependent therefrom is fed to one input of a difference forming unit 47.
  • a signal W is applied which is dependent from or which represents a desired position to which the end face 39 of liquid medium column 37 is to be brought.
  • the desired position is selected at preselecting unit 49.
  • the difference of the initial position of interface 39 p Q to the desired position pi is the stroke H which the interface 39 and therewith all the column of liquid medium 37 shall be moved.
  • the difference forming unit 47 generates a signal ⁇ which is representative of the difference of the preselected "desired" signal W and the signal representing the momentarily prevailing position of the interface 39, X.
  • a controller unit 51 provides for a frequency dependent amplification of the signal ⁇ .
  • the output of the controller unit 51, O51 is operationally connected to the control input C43 of driver unit 43.
  • the frequency behaviour of controller unit 51 as perfectly known to the skilled artisan in negative feedback control art is tailored to establish a high gain, thereby maintaining stability of the overall negative feedback loop so as to achieve that the interface 39 reaches the desired position pi with a desired accuracy.
  • the liquid column 37 A in the flow connection line 33 is established up to port SE A of the pump 35 A and further fills the pump 35 A .
  • a rotary gear pump 35A is applied as a bi-directionally operating pump 35 as of fig. 3.
  • the column of liquid medium extends in analogy to the embodiment of fig. 3 from the mouth of the pipette 31, but now up to the port SE A of rotary gear pump 35A and the liquid of the column 37 A fills the pump 35 A and at least a part of the downstream line 55. So as to establish a clearly position-detectable area along the column of liquid medium 37 A and as schematically shown in fig.
  • the liquid column 37 A is established by a first liquid medium 37 A i , which liquid medium also fills the pump 35A and by a second liquid medium 37 A2 , which is different from the first addressed liquid medium 37 A i and extends to the mouth of pipette 31.
  • an interface surface 39 A is
  • the embodiment of fig. 4 has for some applications the advantage that the liquid medium operated in the pump is selected different from the liquid medium down to the mouth of pipette 31 so that latter may be selected according to the liquid L to be handled to make sure that the addressed liquid L is not negatively influenced in an unacceptable manner by the liquid medium of the liquid medium column 37 A .
  • a column or a cushion of gaseous medium In some applications it might be necessary to separate the liquid of the liquid medium column from the liquid L to be handled by a column or a cushion of gaseous medium. Whereas a column or cushion of gaseous medium upstream, i.e. from the liquid medium column towards the pump, does not harm accuracy with which a predetermined stroke is realized due to the negative feedback control, a gaseous medium column or cushion upstream, i.e. towards the pipette 31 of the liquid medium column, does in fact affect the accuracy with which a predetermined stroke of the liquid medium column is decisive for the volume of liquid L suctioned into the pipette or respectively is ejected from the pipette. This due to compressibility of such gas.
  • the volume of such gaseous medium 57 as schematically shown in fig. 5 should be minimized just sufficient to establish material isolation from the liquid medium of column 37 from a liquid L to be suctioned into and ejected from the pipette.
  • a good marking within the column of liquid medium the stroke of which being sensed may also be realized by a bubble or cushion 59 within the liquid medium forming the liquid medium column 37 B .
  • the two different liquid media 37 A i and 37 A 2 of the embodiment of fig. 4 may be replaced by one single liquid medium 37 B having a position marker as of an air bubble or air cushion 59 therein.
  • two or more than two desired values for a stroke of the liquid medium column may be applied by the preselecting unit 49 consecutively in time so as to either consecutively suction equal or unequal volumes of liquid L into the pipette, e.g. of different liquids, and/or to eject from the pipette equal or unequal doses of liquid consecutively in time towards respective targets.
  • the presetting unit generates an output signal which accords with the desired approach of interface 39 to a predetermined position pi or back to position p 0 according to the respective forwards and backwards strokes of the liquid medium column 37.
  • the predetermining unit 49a generates a predetermined time course of output signal U(t) e.g.
  • connection line between a bi-directionally operable pump and a pipette so as to most accurately control the volume of a liquid or possibly even a powderous medium suctioned into the pipette and respectively ejected from the pipette

Abstract

The stroke of a liquid column (37) within a flow connection line (33) interconnecting a pump (35) and a pipette (31) is monitored by a sensor arrangement (45) and is negative feedback controlled on a settleable, desired value (W) by acting upon the operation of the pump (35) as an adjusting member within the negative feedback loop.

Description

PIPETTING ARRANGEMENT AND METHOD OF CONTROLLING PIPETTING
The present invention generically relates to the field of accurately preparing and handling very small doses of liquids, down to e.g. several hundreds nano-liters. Such liquid handling techniques are especially used in context with medical, chemical or biochemical analyses, e.g. in pharmaceutical, medical or food industry laboratories.
Thereby, as probes e.g. to be analyzed, small samples of liquids of accurately known volumes and often at a high repetition rate, e.g. in context with blood analyses of large populations, are handled.
Figure 1 shows schematically and simplifies a known
pipetting arrangement which operates according to known methods of controlling. Via a flow connection line 3 as of a pipe, a pipette 1 is connected to a suction/ejection port SE of a bi-directionally actuatable pressure source, i.e. a pump 5. An ejection / suctioning port ES thereof is connected (not shown in figure 1) customarily to a liquid reservoir. The pump 5, e.g. a piston pump, a flexible-hose pump or a gear pump, and further a part of connection line 3 and of a downstream flow connection line 3' from the ejection / suctioning port ES to and including the
addressed liquid reservoir are customarily filled with a liquid medium, whereas the remaining part of connection line 3 up to the pipette 1 may be filled with at least one different medium which may be liquid or gaseous.
As schematically shown in figure 1, the pump 5 is activated in S-pumping direction to suction a dose of liquid L into pipette 1. The addressed dose is conveyed or, more
generically, handled during a handling time and is then ejected at least to a predetermined part from the pipette 1 by activating pump 5 in ejecting direction E so as to eject the or a dose e.g. into a reception recipient for further treatment as for analysis. Pump 5 is controlled for most accurately performing the suction movement in S direction and the ejection movement in ejecting direction E.
This is e.g. performed as schematically shown in figure 2. Pump 5, as shown by example as a rotary gear pump 5G, is driven by a rotary drive 7. E.g. by an angle encoder as a position detector 9, the prevailing angular position of gear pump 5G is monitored. The output signal of detector 9 is led to a difference forming unit 11. There a difference signal Δ is formed from the signal dependent on actual angular position X and from a desired angular position signal W, which is preset at a presetting unit 13. At the output of difference forming unit 11, the difference signal Δ accords with the difference of the momentarily prevailing angular position of pump 5G and the preset or desired value W, preset at unit 13. This difference signal Δ as a control deviation signal is fed via a controller unit 15 to a control input C7 of the rotary drive 7. Thus, there is established by a negative feedback control loop a highly accurate control of movement and position of the pump 5G in suctioning S and in ejecting E directions. Clearly such control and especially negative feedback control of the movement of the gear pump 5G, may also be established for any kind of be-directionally acting pump 5- as more
generically shown in figure 1.
By such control of the position or movement of pump 5 the volume of liquid suctioned into the pipette 1 and of liquid ejected from pipette 1 may customarily not be controlled accurately enough. Therefore and as schematically shown in figure 1, there is provided customarily upstream the pipette 1 a valve arrangement 17 which is controlled by a control unit 18 in open or close state to most accurately interrupt the suctioning effect of pump 5 as well as the ejection effect of the pump when the desired dose is suctioned into or ejected from pipette 1.
It is an object of the present invention to improve prior art methods of controlling pipetting and, respectively, of methods of producing a dose of liquid and of pipetting arrangements .
This is achieved by a method according to the present invention of controlling pipetting, in which a pump is operationally connected to a pipette by a flow connection line. At least a part of the flow connection line to the pipette is filled with a liquid medium column. A volume of a liquid is suctioned into the pipette, a volume of liquid is ejected from the pipette. Both these actions of suctioning and of ejecting do include moving the column of the liquid medium by the pump. The method comprises further the step of monitoring at least one of in or along the flow connection a stroke of the column and controlling the pump in dependency of the result of such monitoring.
We thereby understand under the term "stroke of the column" an amount of displacement of the column of liquid medium within the flow connection line between the pipette and the pump .
We further understand under a "column of a liquid medium" an amount of at least one liquid medium continuously filling a part of the flow connection line. If a cushion or bulb of gaseous medium is present within such column it has only neglectable effect upon overall incompressibility of the column.
Thus, under the most generic aspect of the present
invention a stroke of a column of liquid medium in the flow connection line is monitored, whereby such column may be preceded towards the pump by one or more than one columns of a gaseous medium or may be succeeded towards the mouth of the pipette by one or more than one columns of gaseous medium.
If the addressed liquid column, the stroke of which being monitored, is preceded in direction towards the pump by at least one column or cushion of a gaseous medium this will affect the transmission characteristics of the operation of the pump upon the movement of the addressed liquid column within the connection line. This due to the fact that such column of gaseous medium spring-like interacts between the pump and the addressed column of liquid medium due to compressibility of the gaseous medium.
Therefore and to establish a rigid movement transmission between operation of the pump and the addressed column of liquid medium, the stroke of which being monitored, in one variant of the method according to the invention, which may be combined with any variant succeedingly addressed, if not in contradiction, the liquid column the stroke of which being monitored is established up to the pump and the liquid medium of this column further fills the pump. There is thereby established a rigid movement transmission of the operation of the pump upon the movement of the addressed liquid medium column due to incompressibility of liquid media .
Further, if the addressed liquid column the stroke of which being monitored is succeeded towards the pipette by at least one column or cushion of a gaseous medium, this may affect the accuracy with which the stroke as monitored of the liquid medium column is decisive for a volume of a liquid suctioned into the pipette or of the volume of a liquid ejected from the pipette. This again due to
compressibility of gaseous medium.
Thus and as a further variant of the methpd according to the present invention, which may be combined with any variant already addressed and with any variant to be succeedingly addressed, if not in contradiction, the column of liquid medium the stroke of which being monitored has an end face which is directly exposed either to the mouth of the pipette or to an end phase of a liquid suctioned into the pipette and directed towards the pump.
Thereby, at most one single column or cushion of gaseous medium affects the addressed accuracy by which the stroke which is monitored determines the volume of liquid
suctioned into or ejected from the pipette.
Further departing from the fact that the extent of such column or cushion of gaseous medium interposed between the end face of the liquid medium column the stroke of which being monitored and the mouth of the pipette or the end face of a liquid suctioned into the pipette may affect the accuracy with which the stroke as monitored is decisive for the volume of liquid suctioned into the pipette or ejected from the pipette, in a further variant of the method according to the invention, the extent of such column of gaseous medium is minimized.
Taking into account that the addressed column of liquid medium the stroke of which being monitored needs not necessarily be formed by one single liquid medium, but may be formed by two or more liquid media, it is often possible to establish the extent of such liquid column practically up to the mouth of the pipette, thereby taking care of providing a liquid medium directly exposed to the mouth of the pipette which is compatible with the liquid to be suctioned into the pipette and ejected from the pipette.
If interposing a gaseous medium between the column and the mouth of the pipette the extent thereof is minimized just to ensure material isolation from the liquid of the column of the liquid structure into the pipette.
Practically every be-directionally acting pump as e.g. and especially a gear pump has e.g. unequal pumping effects in one direction and in the other direction. Such different pumping effects may additionally vary over time due to aging, temperature of the liquid medium filling the pump and its viscosity etc. so that the pumping effect of the pump in both directions is a source of error. This source becomes mute if, according to the present invention, it is the stroke of the addressed column which is monitored instead of monitoring position or movement of the pump.
In one variant of the method according to the present invention, which may be combined with any of the already addressed or subsequently addressed variants, if not in contradiction, monitoring of the stroke of the liquid medium column comprises monitoring the stroke of an interface surface between different media in or at the column the stroke of which being monitored.
Thereby, such interface may be an interface between two different liquid media, both forming the column of liquid medium the stroke of which being monitored or may be a front or end face of the addressed column exposed to a gaseous medium.
In one further variant of the method according to the present invention which may be combined with any already addressed or subsequently addressed variants, if not in contradiction, a desired value of a stroke for the liquid medium column is preset. A difference signal dependent from such preset desired value and from a signal dependent from monitoring of the prevailing stroke is formed. The stroke of the liquid medium column is negative feedback controlled whereby the difference signal is exploited as a control deviation and the pump is exploited as an adjusting member in that the control derivation signal is operationally connected to a control input for the pump. Thereby, there is established the addressed stroke as monitored to become equal to the desired stroke with an accuracy which accords with the controlling effect of the negative feedback controlling .
Please note that we understand under the difference of two signals A and B the expression (A-B) .
Thereby, it is perfectly known to the artisan skilled in negative feedback control art that by accordingly shaping e.g. the frequency course of the open loop amplification of the negative feedback control, very high accuracy may be achieved with respect to the monitored entity becoming equal to the desired entity e.g. by tailoring the addressed frequency characteristic of the open loop with
proportional/integral behaviour thereby maintaining
stability of the closed negative feedback control loop.
In a further variant of the method according to the
invention, which may be combined with any pre-addressed or succeedingly addressed variants, unless in contradiction, at least two desired values of a stroke for the liquid medium column are preset. Difference signals from signals dependent on the preset desired values and a signal
dependent from the monitoring of the stroke are formed. Negative feedback controlling the stroke of the column is performed thereby exploiting first a first difference signal dependent from the first of the desired values and then exploiting a second difference signal dependent from the second of the desired values as control deviation and, in both cases, the pump as an adjusting member. Thereby, there is established the stroke as monitored to become first equal to the first desired value then equal to the second desired value with an accuracy according to the controlling effect of negative feedback controlling.
Thereby, the first desired value may be the desired stroke value for suctioning of a liquid into the pipette and the second desired value of the stroke may accord with the stroke of the column for ejecting the liquid from the pipette. Clearly in such case the two desired values are established with inverse signums as the desired stroke for suctioning the liquid is directed towards the pump and the stroke for ejecting the liquid is directed from the pump. The extents of these strokes may be unequal or equal.
In a further variant of the method according to the present invention, which may be combined with any of the previously and suceedingly addressed variants, unless in contradiction, monitoring the stroke comprises monitoring relative position of the column in the flow connection over time .
By monitoring the relative position of the column in the flow connection over time in fact the movement of such column is monitored. Presetting the desired value comprises presetting a desired course of relative positions over time of the column, i.e. a desired movement of the column over time. The negative feedback controlling thus comprises negative feedback controlling the movement of the column by exploiting a difference result of the signal which
represents the desired course of positions with a signal which represents the monitored and. thus actual position as a control deviation. By such negative feedback control, the suctioning stroke as well as the ejecting stroke may be accurately negative feedback controlled by presetting the respective forward and backward movements of the liquid medium column and additionally the desired stroke may be realised with a desired movement characteristic e.g. with slow or more rapid approach towards the desired stroke value .
We speak of a "relative" position of the column in the flow connection line, because it is only important what position the column assumes with respect to a freely selectable reference position along the flow connection line. The absolute position of the column along the flow connection line is of no relevancy.
In a further variant of the method according to the
invention which may be combined with any of the previously addressed or subsequently addressed variants, unless in contradiction, the volume suctioned into the pipette and/or ejected from the pipette is controlled without operating an opening/closing valve arrangement in the flow connection line between the pipette and the pump.
In a further variant of the method according to the
invention, which may be combined with any of the previously addressed variants, unless in contradiction, the pump is a rotary gear pump.
The present invention is further directed on a method of producing a dose of a liquid by pipetting in which method a pump is operationally connected to a pipette by a flow connection line, at least a part of the flow connection line is filled with a liquid medium column. Liquid is suctioned into the pipette and liquid is ejected from the pipette, both including moving the column by the pump. The method further comprises the step of monitoring, in or adjacent the flow connection line, a stroke of the
addressed column in the' flow connection line and
controlling the pump in dependency of the result of the addressed monitoring.
As for the controlling method addressed above, monitoring the stroke is established by sensing a geometric entity which finally defines for a difference of positions of the column of liquid medium in the flow connection line, be it e.g. sensing directly the relative position of the
addressed column or propagation speed over time etc.
In one variant of the method of producing a dose according to the present invention, which variant may be combined with any of the succeedingly addressed variants, unless in contradiction, and as was already addressed in context with the method of controlling, the liquid column is established up to the pump and the liquid medium of the column fills the pump .
In a further variant of the addressed method of producing a dose, which may be combined with any of the precedingly addressed and succeedingly addressed variants of such method, unless in contradiction, the liquid medium column has an end face directly exposed to the mouth of the pipette or to an end face of a liquid volume suctioned into the pipette .
In a variant of the just addressed variant of the method of producing a dose the extent of a column of gaseous medium between the end face of the liquid medium column and the mouth of the pipette is minimized e.g. to an extent for ensuring material isolation from the column of liquid medium or the liquid to be suctioned into the pipette.
In a further variant of the method of producing a dose which may be combined with any of the preaddressed and of the succeedingly addressed variants, unless in
contradiction, monitoring the stroke of the column
comprises monitoring the stroke of an interface between different media in or of the addressed column. In one variant of the method of producing, which may be combined with any preaddressed and succeedingly addressed variants of such producing method, if not in contradiction, a desired value of a stroke for the liquid medium column is preset. There is formed a difference signal, which depends from the preset desired value and from a signal, which is dependent from monitoring the prevailing stroke.
The stroke of the column within the flow connection line is negative feedback controlled thereby exploiting a signal which is dependent from the addressed difference signal as a control deviation signal and the addressed pump as an adjusting member. Thus, a signal dependent on the addressed difference signal is operationally connected to a control input for controlling operation of the pump. There is established the stroke as monitored and thus the prevailing stroke in the flow connection line to become equal to the desired stroke with an accuracy which accords to the controlling effect of the negative feedback control loop.
In a further variant of the method of producing, which may be combined with any previously addressed variant of that method and with any subsequently addressed variant of that method, unless in contradiction, at least two desired values of a stroke for the liquid medium column are preset. Two difference signals are formed respectively dependent from one of the two desired values and from the signal dependent from monitoring the stroke.
Consecutively, the stroke of the column in the flow
connection line is negative feedback controlled, thereby exploiting first a signal dependent from a first of the two difference signals, and then exploiting a second signal dependent from the second of the difference signals as respective control deviation signals and, in both cases, the pump as an adjusting member. Thereby, there is
established the stroke as monitored, i.e. the momentarily prevailing stroke, to be or to become first equal to the first desired value then equal to the second desired value with an accuracy which accords to the controlling effect of the negative feedback control loop.
In a further variant of the producing method, which may be combined with any of the pre-addressed or to be addressed variants of such producing method, unless in contradiction, monitoring the stroke of the liquid medium column in the flow connection line comprises monitoring a position of the column in the flow connection line over time. Presetting the desired value thereby comprises presetting a desired course of relative positions over time of the column and thus, in fact, presetting a desired movement of the
addressed column over time. Negative feedback controlling comprises negative feedback controlling a movement of the column by exploiting a difference result of a signal representing the desired course of positions and of a signal representing the monitored instantaneously
prevailing position as a control deviation signal.
The addressed position may be said "relative" position in the flow connection line, as defined with respect to an arbitrarily selected fixed position along the flow
connection line. Because according to the generic approach of the present invention it is the stroke of the liquid medium column in the flow connection line which is
monitored, it is of no importance at which absolute
positioning of the column along the flow connection line such stroke is established and monitored. Therefore, and if the stroke is monitored via subsequent monitoring of the position of the liquid medium column, such positions may be said "relative" to an arbitrarily selected fixed position along the addressed flow connection line.
Thus, the instantaneously prevailing position of the column as monitored is negative feedback controlled to follow, over time, a desired sequence of desired positions and thus to follow a desired movement.
On one hand, one or more than one stroke forwards and/or backwards are negative feedback controlled and additionally the time course of movement of the liquid medium column to achieve the desired stroke value is controlled. If, e.g., there is provided between the liquid medium column and the pipette mouth a relevant column or cushion of a gaseous medium, it may be advisable, to negative feedback the movement of the addressed liquid medium column so slowly that the gaseous medium column does not act as an
oscillating spring member.
In a further variant of the method of producing which may be combined with any of the preaddressed variants and with any of the succeedingly addressed variants of such
producing method, if not in contradiction, the volume as suctioned into the pipette and/or as ejected from the pipette is controlled without operating an opening/closing valve arrangement in the flow connection line.
In a further variant of the method of producing, which may be combined with any of the preaddressed variants of such producing method, if not in contradiction, the pump is selected to be a rotary gear pump.
The invention is further directed on a pipetting apparatus, which comprises a bi-directionally operable pump. A flow connectional line is provided from the pump to a pipette mouth and a continuous liquid medium column fills at least a part of the addressed flow connection line. A controlling unit is provided for the operation of the pump which unit comprises a control input for a signal to control the addressed operation. There is further provided a sensing arrangement, at least one of in and of along the flow connection line, which arrangement generates at an output an output signal indicative for a stroke of said column in the flow connection line. The addressed output of the sensing arrangement is operationally connected to the control input of the controlling unit for the operation of the pump .
In one embodiment of the apparatus according to the present invention, which may be combined with any of the
subsequently addressed embodiments, unless in
contradiction, the liquid column is established up to the pump and a liquid of the addressed column fills also the pump.
In a further embodiment of the apparatus, which may be combined with any of the precedingly and of the
succeedingly addressed embodiments, unless in
contradiction, the column has an end face directly exposed to the mouth of the pipette.
This means that between the addressed end face of the column of liquid medium and the mouth of the pipette there is at the most a column of a gaseous medium.
In a further embodiment of the just addressed embodiment, the extent of a column of a gaseous medium between the end face of the addressed column of liquid medium and the mouth of the pipette is minimal as just to ensure material isolation of the column from a liquid suctioned into the pipette or there is no such column of gaseous medium provided at all.
In a further embodiment of the apparatus, which may be combined with any precedingly and succeedingly addressed embodiments, unless in contradiction, the sensing
arrangement senses a position of an interface in or of said column of liquid medium, which interface is established between different media. Thus, either such interface is formed by different liquid media forming together the addressed column or the addressed end face is established by an end face of the column towards a gaseous medium.
It might even be possible to provide within the column just for sensing purposes a minimum volume gaseous bubble or cushion and sensing position of such cushion or bubble of gaseous medium within the addressed column and along the connection line.
In one embodiment of the apparatus according to the
invention, which may be combined with any precedingly and subsequently addressed embodiments, unless in
contradiction, such apparatus further comprises a
presetting unit with an output. Further, the apparatus comprises a difference forming unit with a first and with a second input for signals the difference therefrom being formed by the difference forming unit and with an output for a result signal of the difference forming by the addressed unit. The output of the sensing arrangement and the output of the presetting unit are respectively
operationally connected to the first and to the second input of the difference forming unit and the output of this unit is operationally connected to the control input of the controlling unit for the operation of the pump.
In a further embodiment of the pipetting apparatus
according to the invention, which may be combined with any embodiment already addressed and with any embodiment as will be addressed, unless in contradiction, the sensing arrangement generates an output signal which represents a prevailing relative position of the column in the flow connection line. The presetting unit generates an output signal which represents a desired time course of positions of the column in the flow connection line. Thus and by the pre-addressed negative feedback control, the prevailing position of the column in the flow connection line is negative feedback controlled to follow the course of positions and thus the movement as desired and as preset by the presetting unit.
In a further embodiment of the apparatus according to the invention, which may be combined with any precedingly and succeedingly addressed embodiments, unless in
contradiction, the sensing arrangement senses a prevailing position of the column along the flow connection line.
In a further embodiment of the apparatus according to the invention, which may be combined with each embodiment as was already addressed, the pump is a rotary gear pump.
The present invention shall now be further exemplified with the help of figures. The figures show:
Figure 1: A schematical representation of a prior art embodiment for controlling pipetting.
Figure 2: Still schematically a prior art embodiment for pipetting control in which the movement of a pipetting pump is negative feedback controlled.
Figure 3: In a schematical representation a pipetting arrangement according to the present invention and operating a method of controlling pipetting as well as a method of producing a dose of a liquid according to the present invention.
Figure 4: A part of a pipetting arrangement according to the present invention, still schematically, wherein the interface between two media in a flow connection line between a pump and the nozzle of the pipette is position- monitored.
Figure 5: A part of an arrangement according to the present invention, wherein a volume of gaseous medium is minimized just to establish material isolation between a liquid medium within the arrangement from a medium to be suctioned into and ejected from a pipette.
Figure 6: Still schematically a part of an embodiment according to the present invention, wherein a bubble of gaseous medium is applied within a liquid medium in a flow communication line between a pump and a pipette so as to monitor position and/or movement of the liquid medium column .
Figure 7: A further embodiment of the present invention, still schematically, which operates the methods according to the present invention.
Fig. 3 shows simplified and schematically a signal
flow/functional block diagram of a pipetting arrangement according to the present invention operating a method of controlling pipetting and of producing a dose of liquid according to the present invention. A bi-directionally operable pump 35 is linked by a flow connection line 33 as of a tube to a pipette 31. The pump 35 has a suctioning/ejection port SE and an e ection/suctioning port ES. Whereas. port SE is connected to the flow connection line 33, port ES may be, in the embodiment of fig. 3, open to ambient.
A column of liquid medium 37 fills the pipette 31 as well as a part of the flow connection line 33. The position of the column of liquid medium within pipette 31 and flow connection line 33 may be defined by the end face 39 of the liquid medium column pointing towards the pump. In this embodiment there succeeds in direction towards the pump 35 adjacent to end face 39 a column of gaseous medium 41.
Thus, end face 39 is a liquid/gas interface. The bi- directionally operable pump 35 is operated forwards and backwards according to the double-arrow S-E by a drive 43 which has a control input C43 for control signals
controlling, via drive 43, the operation of pump 35.
If the pump 35 is operated in direction S by drive 43 the liquid medium column 37 is suctioned towards pump 35. If pump 35 is operated by drive 43 in inverse direction E, the column of liquid medium 33 is moved in direction towards pipette 31. For taking up a dose of a liquid L the pump is operated in S direction, generating a stroke H of the liquid medium column 37 towards pump 35. Thereby, a liquid L is suctioned into pipette 31 with a volume which accords with the volume of liquid medium displacement in the flow connection line 33 according to stroke H. Once the dose of liquid L is taken up into pipette 31 and as customarily known from the pipetting art, the pump 35 is disabled or stopped and the dose of liquid L within pipette 31 is handled according to the respective application and needs.
Then the pump 35 is restarted operating in direction E, thereby propelling the liquid medium column 37 towards the pipette 31 to eject a dose of liquid L' into a reception recipient (not shown in fig. 3).
If a dose to be ejected has a same volume as the volume of liquid which was previously suctioned into pipette 31, then the ejection stroke of liquid column 37 will be equal to the stroke for suctioning, but clearly in inverse
direction, i.e. towards pipette 31.
As shown in fig. 3 the stroke of the liquid medium column 37 is clearly identified by the stroke of end face 39.
There is provided a sensor arrangement 45. For simplicity reasons it is assumed that the flow connection line 33 is transparent. Thus, the sensor arrangement 45 may be e.g. an optical/electrical converter, e.g. a digital picturing sensor with e.g. a CCD optical/electrical converter followed by a picture recognition unit to recognize the instantaneous location of face 39. With today's very high resolutions of optical/electrical pixel-based converters a very high accuracy of locating the interface 39 along the sensor arrangement 45 may be reached.
The sensor arrangement 45 generates at its output Ο45 an output signal X which is indicative of the instantaneous position of interface 39. This signal X or a signal dependent therefrom is fed to one input of a difference forming unit 47. To the second input of the difference forming unit 47 a signal W is applied which is dependent from or which represents a desired position to which the end face 39 of liquid medium column 37 is to be brought. The desired position is selected at preselecting unit 49. The difference of the initial position of interface 39 pQ to the desired position pi is the stroke H which the interface 39 and therewith all the column of liquid medium 37 shall be moved.
At the output C>47 the difference forming unit 47 generates a signal Δ which is representative of the difference of the preselected "desired" signal W and the signal representing the momentarily prevailing position of the interface 39, X. A controller unit 51 provides for a frequency dependent amplification of the signal Δ. The output of the controller unit 51, O51, is operationally connected to the control input C43 of driver unit 43. Thus, there is established a negative feedback control loop with the pump 35 as an adjusting member so as to accurately drive the position of interface 39 to that position which is selected by unit 49 and thus to perform by the liquid medium column 39 the desired stroke H. The frequency behaviour of controller unit 51 as perfectly known to the skilled artisan in negative feedback control art is tailored to establish a high gain, thereby maintaining stability of the overall negative feedback loop so as to achieve that the interface 39 reaches the desired position pi with a desired accuracy.
Because the stroke H performed in direction towards the pump 35 is decisive for the respective stroke of the liquid medium column 39, it is also decisive for the volume of liquid L suctioned into pipette 31. Any leakage of the pump 35 or any other occurrence which influences the instantaneous position of interface 39 may be disregarded, due to the negative feedback loop. No valve arrangement is necessary to determine the exact volume of the dose of liquid L suctioned into the pipette and arranged e.g.
between the pipette 31 and the pump 35 as shown in dashed line at 53.
In context with fig. 3 sensing of the momentarily
prevailing stroke to be negative feedback controlled to accurately perform a desired stroke is realized by making use of digital picture evaluation techniques for the interface 39 of the liquid medium column. Nevertheless, it is evident that dependent on the optical and/or electrical characteristics of the wall of flow connection line 33, on optical and/or electrical characteristics of the liquid medium of column 37, etc. different sensing methods and sensing arrangements may be used to accurately trace the buildup of a desired stroke H.
Further and with an eye on fig. 3 in this embodiment the column of liquid medium 37 precedes a column of gaseous medium 41, pump 35 is possibly also operating in a gaseous medium. Generically an inclusion of a gaseous medium between the liquid medium column 37 and the pump 35 does not affect final reach of a desired stroke according to position pi of fig. 3, but does possibly affect the transmission of pump operation upon the liquid column 37 due to compressibility of gas.
Nevertheless, to establish a "quasi" rigid movement transmission from pump 35 upon the liquid medium column 37 in one embodiment according to fig. 4 the liquid column 37A in the flow connection line 33 is established up to port SEA of the pump 35A and further fills the pump 35A.
According to fig. 4 and as an example a rotary gear pump 35A is applied as a bi-directionally operating pump 35 as of fig. 3. The column of liquid medium extends in analogy to the embodiment of fig. 3 from the mouth of the pipette 31, but now up to the port SEA of rotary gear pump 35A and the liquid of the column 37A fills the pump 35A and at least a part of the downstream line 55. So as to establish a clearly position-detectable area along the column of liquid medium 37A and as schematically shown in fig. 4 the liquid column 37A is established by a first liquid medium 37Ai , which liquid medium also fills the pump 35A and by a second liquid medium 37A2, which is different from the first addressed liquid medium 37Ai and extends to the mouth of pipette 31. Thereby, an interface surface 39A is
established between the respectively selected liquid media, in opposition to the interface surface 39 of fig. 3 which is formed between liquid and gaseous media.
The remaining members of the embodiment according to fig. 4 are equal to those explained in context with fig. 3 and are thus not explained again.
The embodiment of fig. 4 has for some applications the advantage that the liquid medium operated in the pump is selected different from the liquid medium down to the mouth of pipette 31 so that latter may be selected according to the liquid L to be handled to make sure that the addressed liquid L is not negatively influenced in an unacceptable manner by the liquid medium of the liquid medium column 37A.
In some applications it might be necessary to separate the liquid of the liquid medium column from the liquid L to be handled by a column or a cushion of gaseous medium. Whereas a column or cushion of gaseous medium upstream, i.e. from the liquid medium column towards the pump, does not harm accuracy with which a predetermined stroke is realized due to the negative feedback control, a gaseous medium column or cushion upstream, i.e. towards the pipette 31 of the liquid medium column, does in fact affect the accuracy with which a predetermined stroke of the liquid medium column is decisive for the volume of liquid L suctioned into the pipette or respectively is ejected from the pipette. This due to compressibility of such gas.
If the necessity arises to separate the liquid medium of the liquid medium column from a liquid as of L to be handled in the pipette by a gaseous medium, then the volume of such gaseous medium 57 as schematically shown in fig. 5 should be minimized just sufficient to establish material isolation from the liquid medium of column 37 from a liquid L to be suctioned into and ejected from the pipette.
With an eye on fig. 4 we have established two different liquid media forming the interface 39A to be position- tracked by the sensor arrangement 45. In one further embodiment according to fig. 6 a good marking within the column of liquid medium the stroke of which being sensed may also be realized by a bubble or cushion 59 within the liquid medium forming the liquid medium column 37B. Thus, according to the embodiment of fig. 6 and having an eye on the embodiment of fig. 4 the two different liquid media 37Ai and 37A2 of the embodiment of fig. 4 may be replaced by one single liquid medium 37B having a position marker as of an air bubble or air cushion 59 therein.
In the embodiment of fig. 3, which may be combined with all the embodiments as addressed in context with fig. 4 to 6 with respect to different tailoring of the liquid medium column, the stroke of which or the position of which being monitored, it is perfectly clear that once by applying e.g. a steplike positive signal W at the preselecting unit 49 and thereby suctioning a predetermined volume of liquid L into pipette 31, the equal volume will be ejected from the pipette 31 as W returns to the initial value established by the selection unit 49 as shown in fig. 3. Thus, in fact two different strokes are pre-established by unit 49 of equal extent, but with inverse signum.
Nevertheless, it is perfectly clear that two or more than two desired values for a stroke of the liquid medium column may be applied by the preselecting unit 49 consecutively in time so as to either consecutively suction equal or unequal volumes of liquid L into the pipette, e.g. of different liquids, and/or to eject from the pipette equal or unequal doses of liquid consecutively in time towards respective targets.
Whereas by applying as a signal representing a desired stroke a step-like signal as exemplified in context with fig. 3 the movement of the liquid medium column by the adjusting member, namely pump 35, results from the settings and from the behaviour of the overall negative feedback control loop, possibly including a proportional integral controller unit 51 to optimize accuracy, it might be desired in some applications to also control the movement of the liquid medium column as approaching the desired stroke value. This is accomplished by the embodiment according to fig. 7 which resides on the explanations in context with fig. 3 and may be combined with all other embodiments described.
The embodiment of fig. 7 accords with that of fig. 3 and therefore the respective units and signals are addressed by the same reference signs.
According to the embodiment of fig. 7 the presetting unit generates an output signal which accords with the desired approach of interface 39 to a predetermined position pi or back to position p0 according to the respective forwards and backwards strokes of the liquid medium column 37. As exemplified in fig. 7 the predetermining unit 49a generates a predetermined time course of output signal U(t) e.g.
according to a course asymptotically approaching slowly an end value. The negative feedback control loop which is tailored to accurately follow the signal U(t) as
established by the preselecting unit 49a, controls pump 35 in such a manner that the end face 39 performs a movement according to U(t), thus propelling the liquid medium column with the preselected movement towards the desired end value of the stroke Hs or respectively HE.
The skilled artisan recognizes that there are multiple possibilities also dependent on specific applications to realize the present invention which in fact reside
generically on the fact of negative feedback controlling the stroke of the liquid medium column in the flow
connection line between a bi-directionally operable pump and a pipette so as to most accurately control the volume of a liquid or possibly even a powderous medium suctioned into the pipette and respectively ejected from the pipette

Claims

Claims
1. A method of controlling pipetting in which a pump is operationally connected to a pipette by a flow connection line, at least a part of the flow connection line to the pipette is filled with a liquid medium column, and wherein a volume of liquid or powder is suctioned into the pipette or a volume of liquid is ejected from said pipette, which both include moving said column in said flow connection line by said pump, comprising the step of monitoring a stroke of said column and controlling said pump in
dependency of the result of said monitoring.
2. The method of claim 1, wherein said liquid column is established up to the pump and a liquid medium of said column fills said pump.
3. The method of one of claims 1 or 2, wherein said liquid medium column has an end face directly exposed to the mouth of said pipette.
4. The method of claim 3, wherein an extent of a column of gaseous medium between said end face and the mouth of said pipette is minimized.
5. The method of one of claims 1 to 4, wherein monitoring said stroke comprises monitoring the stroke of an interface surface between different media in or of said column.
6. The method of one of claims 1 to 5, comprising · presetting a desired value of a stroke for said liquid medium column; • forming a difference signal dependent from said preset desired value and a signal dependent from said
monitoring of said stroke;
• negative feedback controlling said stroke of said
column exploiting a signal dependent on said
difference signal as a control deviation and said pump as an adjusting member.
7. The method of one of claims 1 to 6, comprising
• presetting two desired values of a stroke for said
liquid medium column;
• forming two difference signals from signals dependent from said preset desired values and a signal dependent from said monitoring of said stroke;
• negative feedback controlling consecutively said
stroke of said column, thereby exploiting first a first difference signal dependent from a first of said two desired values and then exploiting a second difference signal dependent from the second of said desired values as control deviations and said pump as an adjusting member.
8. The method of one of claims l.to 7, wherein monitoring said stroke comprises monitoring a position of said column in said flow connection line over time and presetting said desired value comprises presetting a desired course of positions over time of said column.
9. The method of one of claims 1 to 8, wherein said volume suctioned into the pipette and/or said volume ejected from said pipette is controlled without operating an opening/closing valve arrangement in the flow connection line .
10. The method of one of claims 1 to 9, wherein said pump is a rotary gear pump.
11. A method of producing a dose of a liquid or powder by pipetting in which a pump is operationally connected to a pipette by a flow connection line, at least a part of the flow connection line is filled with a liquid medium column and wherein liquid is suctioned into the pipette and liquid is ejected from said pipette which both include moving said column by said pump comprising the step of monitoring a stroke of said column and controlling said pump in
dependency of the result of said monitoring.
12. The method of claim 11, wherein said liquid column is established up to the pump and the liquid medium of said column fills said pump.
13. The method of one of claims 11 or 12, wherein said liquid medium column has an end face directly exposed to the mouth of said pipette or to an end face of a liquid volume suctioned into said pipette.
14. The method of claim 13, wherein an extent of a column of gaseous medium between said end face and the mouth of said pipette is minimized.
15. The method of one of claims 11 to 14, wherein
monitoring said stroke comprises monitoring the stroke of an interface between different media in or of said column.
16. The method of one of claims 11 to 15, comprising presetting a desired value of a stroke for said liquid medium column; forming a difference signal dependent from said preset desired value and a signal dependent from said monitoring of said stroke;
• negative feedback controlling said stroke of said column, thereby exploiting a signal dependent from said difference signal as a control deviation and said pump as an adjusting member.
17. The method of one of claims 11 to 16, comprising presetting two desired values of a stroke for said liquid medium column;
• forming two difference signals dependent from said preset desired value and a signal dependent from said monitoring of said stroke;
• negative feedback controlling consecutively said
stroke of said column, thereby exploiting first a signal dependent from a first of said difference signals and then exploiting a second signal dependent from the second difference signal as control deviation signals and said pump as an adjusting member.
18. The method of one of claims 11 to 17, wherein
monitoring said stroke comprises monitoring a position of said column in said flow connection line over time and presetting said desired value comprises presetting a desired course of positions of said column.
19. The method of one of claims 11 to 18, said volume suctioned into said pipette and/or said volume ejected from said pipette is controlled without operating an
opening/closing valve arrangement in said flow connection line.
20. The method of one of claims 11 to 19, wherein said pump is a rotary gear pump.
21. Pipetting apparatus comprising a bi-directionally operable pump, a flow connection line from the pump to a pipette mouth, a liquid medium column filling at least a part of said flow connection line, a controlling unit for the operation of said pump comprising a control input for a signal to control operation of said pump, a sensing
arrangement at least one of in and of along said flow connection line generating at an output an output signal dependent on a stroke of said column in said flow
connection line, said output being operationally connected to said control input.
22. The apparatus of claim 21, wherein said liquid column is established up to said pump and a liquid of said column fills said pump.
23. The apparatus of one of claims 21 or 22, wherein said column has an end face directly exposed to the mouth of said pipette.
24. The apparatus of claim 23, wherein an extent of a column of a gaseous medium between said end face and said mouth is minimal just to ensure material isolation of said column from a liquid suctioned into said pipette or there is no such column of gaseous medium provided.
25. The apparatus of one of claims 21 to 24, wherein said sensing arrangement senses position of an interface between different media in or of said column of liguid medium.
26. Pipetting apparatus according to one of claims 21 to 25, further comprising a presetting unit with an output, a difference forming unit with a first and with a second input, a difference of signals applied thereto being formed by said difference forming unit and with an output for a result signal of said difference forming, the output of said sensing arrangement and the output of said presetting unit being respectively operationally connected to said first and second inputs, the output of said difference forming unit being operationally connected to said control input .
27. The pipetting apparatus of one of claims 21 to 26, wherein said sensing arrangement generates an output signal representing prevailing position of said column in said flow connection line, said presetting unit generating an output signal representing a desired time course of
positions of said column in said flow connection line.
28. The pipetting apparatus of one of claims 21 to 27, wherein said sensing arrangement senses a prevailing position of said column along said flow connection line.
29. The pipetting apparatus of one of claims 21 to 28, wherein said pump is a rotary gear pump.
PCT/EP2013/057711 2012-04-18 2013-04-12 Pipetting arrangement and method of controlling pipetting WO2013156408A1 (en)

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