CA2363300A1 - Method and device for separating samples from a liquid - Google Patents
Method and device for separating samples from a liquid Download PDFInfo
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- CA2363300A1 CA2363300A1 CA002363300A CA2363300A CA2363300A1 CA 2363300 A1 CA2363300 A1 CA 2363300A1 CA 002363300 A CA002363300 A CA 002363300A CA 2363300 A CA2363300 A CA 2363300A CA 2363300 A1 CA2363300 A1 CA 2363300A1
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- pump
- microejection
- liquid
- computer
- dispensing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
- B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L13/00—Cleaning or rinsing apparatus
- B01L13/02—Cleaning or rinsing apparatus for receptacle or instruments
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/02—Burettes; Pipettes
- B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
- G01F25/00—Testing or calibration of apparatus for measuring volume, volume flow or liquid level or for metering by volume
- G01F25/0092—Testing or calibration of apparatus for measuring volume, volume flow or liquid level or for metering by volume for metering by volume
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1004—Cleaning sample transfer devices
- G01N2035/1006—Rinsing only the inside of the tip
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N2035/1027—General features of the devices
- G01N2035/1034—Transferring microquantities of liquid
- G01N2035/1039—Micropipettes, e.g. microcapillary tubes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/12—Condition responsive control
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Physics & Mathematics (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Fluid Mechanics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Sampling And Sample Adjustment (AREA)
- Reciprocating Pumps (AREA)
- Devices For Use In Laboratory Experiments (AREA)
- Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
Abstract
The invention concerns a computer (4), a computer program product, and a method for synchronizing a system for aspirating and/or dispensing liquid sam-ples that comprises a microejection device (1) and a pump (2) which are con-nected with one another via tubing (3), with this computer (4) being imple-mented for loading an activatable computer program product for synchronizing the microejection device (1) and pump (2). The computer (4), computer pro-gram product, and method are characterized in that the computer (4) is made capable, on the basis of the loaded and activated computer program product, of controlling and synchronizing the following functions of this system:
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to prevent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
The invention also includes a corresponding system for performing this method.
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to prevent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
The invention also includes a corresponding system for performing this method.
Description
Method and device for separating samples from a liquid The invention concerns -- according to the preamble of independent claim 1 --a computer for synchronizing a system for aspirating and/or dispensing liquid sam-ples that comprises a microejection device and a pump which are connected with one another via tubing, with this computer being implemented for loading an ac-tivatable computer program product for synchronizing the microejection device and pump. The invention also concerns a corresponding system, method, and computer program product.
It is known that droplets with a volume of more than 10 pl can be dispensed from the air very easily, since if the pipette is correctly manipulated, the droplets leave the pipette tip of their own accord. The droplet size is then determined by the physical properties of the sample liquid, such as surface tension or viscosity.
The droplet size thus limits the resolution of the quantity of liquid to be dis-pensed.
It is known that droplets with a volume of more than 10 pl can be dispensed from the air very easily, since if the pipette is correctly manipulated, the droplets leave the pipette tip of their own accord. The droplet size is then determined by the physical properties of the sample liquid, such as surface tension or viscosity.
The droplet size thus limits the resolution of the quantity of liquid to be dis-pensed.
The aspirating and dispensing, i.e. the pipetting of liquid samples with a volume of less than 10 pl, in contrast, typically requires instruments and techniques which guarantee the dispensing of such small samples. The dispensing of a liquid with a pipette tip, i.e. with the endpiece of a device for aspirating and/or dis-pensing sample liquid, can occur from the air {"from air") or by touching a sur-face. This surface can be the solid surface of a container {"on tip touch"), into which the liquid sample is to be dispensed. It can also be the surface of a liquid in this container ("on liquid surface"). A mixing procedure following the dispens-ing is recommended -- particularly for very small sample volumes in the nanoliter or even picoliter range -- so that uniform distribution of the sample volume in a diluent is ensured.
Disposable tips significantly reduce the danger of unintentional transfer of parts of the sample (contamination). Simple disposable tips are known (so-called "air displacement tips"), whose geometry and material is optimized for the exact as-pirating and/or dispensing of very small volumes. The use of so-called "positive-displacement tips", which have a pump plunger inside, is also known.
Systems for separating samples from a liquid are known as pipettors. Such sys-terns serve, for example, for dispensing liquids into the wells of Standard Micro-titration PlatesT'" (trademark of Beckman Coulter, Inc., 4300 N. Harbour Blvd., P.O. Box 3100 Fullerton, CA, USA 92834) and/or microplates with 96 wells. The reduction of the sample volumes (e.g. for filling high-density microplates with 384, 864, 1536, or even more wells) plays an increasingly important role, with the precision of the sample volume dispensed being assigned a great importance.
The elevation of the number of samples typically also requires miniaturization of the experiment, so that the use of a pipettor is necessary and special require-ments must be placed on the precision of sample volumes and the accuracy of the movement control and/or of the dispensing of this pipettor.
The precision of a pipetting system is judged on the basis of the accuracy (ACC =
accuracy) and reproducibility (CV = coefficient of variation) of the liquid samples dispensed. The reproducibility has greater significance assigned to it in this case, since systematic errors can, if necessary, be compensated by means of suitable correction parameters. In principle, two basic modes are differentiated in pipet-ting: single pipetting and multipipetting. In the single pipetting mode, a liquid sample is aspirated and dispensed at another location. .In the multipipetting mode, a larger volume of liquid is aspirated at one time and subsequently dis-pensed in several -- typically equivalent -- portions (aliquots) at one or more different locations, e.g. in various wells of a Standard Microtitration PIateT"'.
Simpler pipettors, so-called "open systems", connect the reservoir for the liquid to be pipetted with the pipette tip via a line into which a dispensing pump can be inserted. The dispensing pumps are typically implemented as piston pumps. For aspirating the sample, only the pump is set into operation, the pipette tip merely passively relays the liquid flow. For dispensing a sample volume, the pump is then switched off or bridged. For example, a pipette tip in the form of a rnicroe-jection pump is known from EP 0 725 267, with which a liquid sample is actively separated. The supply of the liquid occurs due to the hydrostatic pressure ob-taining in the line between the reservoir and the pipette tip. Such systems are relatively economical, but they have the disadvantage that the hydrostatic pres-sure can vary within a wide range. The reproducible dispensing of very small volumes in the nanoliter or even picoliter range is impaired by this.
In addition, a "closed" system of this class according to the preamble of inde-pendent claim 1 is known from US 5,927,547. In this system as well, only the pump is set in operation for aspirating, the pipette tip merely passively relays the liquid flow. In this system, however, the dispensing pump is put in operation --for generating a specific pressure in the tubing system to the pipette tip --for dispensing the liquid. For separating volumes in the picoliter to nanoliter range, piezoelectric driven tips and/or microejection pumps -- as also known from EP 0 725 267 -- are used, in which the liquid or sample volumes are actively ejected out of the pipette tip. The pressure between the dispensing pump and the pipette tip is monitored with a sensor. The feed of the dispensing pump of this rather expensive and complex system is then regulated via a pressure sen-sor and an attached processing unit. Thus, synchronization between the mi-croejection pump and the dispensing pump occurs.
The determination of the sample volume with a valve located in the immediate vicinity of the pipette tip or in the pipette tip itself, which, for example, is imple-mented as a solenoid or a piezovalve and is opened briefly, is also known. In this case, an initial pressure is used in the system. This opening is known in single action form or also in intervals. For dispensing a defined volume, the initial pres-sure must be adjusted very exactly to the liquid properties and the atmospheric conditions (above all to the air pressure). The effects influence each other strongly, so that the system must be readjusted upon a change of the liquid and/or its properties or the surrounding conditions.
The object of the present invention is to suggest alternative devices and methods which allow both economical and highly reproducible separation of volumes in the nanoliter to picoliter range.
The object is achieved according to a first aspect with a computer corresponding to the features of claim 1; according to a second aspect with a system corre-sponding to the features of claim 4; according to a third aspect with a method corresponding to the features of claim 10, and according to a fourth aspect with a computer program product corresponding to the features of claim 18. Addi-tional and/or refining features arise from the dependent claims.
The invention will now be described in more detail with reference to schematic drawings, which merely represent exemplary embodiments and are not to restrict the extent of the invention.
Fig. 1 shows a system for aspirating and/or dispensing liquid samples according to a first embodiment;
Fig. 2 shows a system for aspirating and/or dispensing liquid samples according to a second embodiment;
Disposable tips significantly reduce the danger of unintentional transfer of parts of the sample (contamination). Simple disposable tips are known (so-called "air displacement tips"), whose geometry and material is optimized for the exact as-pirating and/or dispensing of very small volumes. The use of so-called "positive-displacement tips", which have a pump plunger inside, is also known.
Systems for separating samples from a liquid are known as pipettors. Such sys-terns serve, for example, for dispensing liquids into the wells of Standard Micro-titration PlatesT'" (trademark of Beckman Coulter, Inc., 4300 N. Harbour Blvd., P.O. Box 3100 Fullerton, CA, USA 92834) and/or microplates with 96 wells. The reduction of the sample volumes (e.g. for filling high-density microplates with 384, 864, 1536, or even more wells) plays an increasingly important role, with the precision of the sample volume dispensed being assigned a great importance.
The elevation of the number of samples typically also requires miniaturization of the experiment, so that the use of a pipettor is necessary and special require-ments must be placed on the precision of sample volumes and the accuracy of the movement control and/or of the dispensing of this pipettor.
The precision of a pipetting system is judged on the basis of the accuracy (ACC =
accuracy) and reproducibility (CV = coefficient of variation) of the liquid samples dispensed. The reproducibility has greater significance assigned to it in this case, since systematic errors can, if necessary, be compensated by means of suitable correction parameters. In principle, two basic modes are differentiated in pipet-ting: single pipetting and multipipetting. In the single pipetting mode, a liquid sample is aspirated and dispensed at another location. .In the multipipetting mode, a larger volume of liquid is aspirated at one time and subsequently dis-pensed in several -- typically equivalent -- portions (aliquots) at one or more different locations, e.g. in various wells of a Standard Microtitration PIateT"'.
Simpler pipettors, so-called "open systems", connect the reservoir for the liquid to be pipetted with the pipette tip via a line into which a dispensing pump can be inserted. The dispensing pumps are typically implemented as piston pumps. For aspirating the sample, only the pump is set into operation, the pipette tip merely passively relays the liquid flow. For dispensing a sample volume, the pump is then switched off or bridged. For example, a pipette tip in the form of a rnicroe-jection pump is known from EP 0 725 267, with which a liquid sample is actively separated. The supply of the liquid occurs due to the hydrostatic pressure ob-taining in the line between the reservoir and the pipette tip. Such systems are relatively economical, but they have the disadvantage that the hydrostatic pres-sure can vary within a wide range. The reproducible dispensing of very small volumes in the nanoliter or even picoliter range is impaired by this.
In addition, a "closed" system of this class according to the preamble of inde-pendent claim 1 is known from US 5,927,547. In this system as well, only the pump is set in operation for aspirating, the pipette tip merely passively relays the liquid flow. In this system, however, the dispensing pump is put in operation --for generating a specific pressure in the tubing system to the pipette tip --for dispensing the liquid. For separating volumes in the picoliter to nanoliter range, piezoelectric driven tips and/or microejection pumps -- as also known from EP 0 725 267 -- are used, in which the liquid or sample volumes are actively ejected out of the pipette tip. The pressure between the dispensing pump and the pipette tip is monitored with a sensor. The feed of the dispensing pump of this rather expensive and complex system is then regulated via a pressure sen-sor and an attached processing unit. Thus, synchronization between the mi-croejection pump and the dispensing pump occurs.
The determination of the sample volume with a valve located in the immediate vicinity of the pipette tip or in the pipette tip itself, which, for example, is imple-mented as a solenoid or a piezovalve and is opened briefly, is also known. In this case, an initial pressure is used in the system. This opening is known in single action form or also in intervals. For dispensing a defined volume, the initial pres-sure must be adjusted very exactly to the liquid properties and the atmospheric conditions (above all to the air pressure). The effects influence each other strongly, so that the system must be readjusted upon a change of the liquid and/or its properties or the surrounding conditions.
The object of the present invention is to suggest alternative devices and methods which allow both economical and highly reproducible separation of volumes in the nanoliter to picoliter range.
The object is achieved according to a first aspect with a computer corresponding to the features of claim 1; according to a second aspect with a system corre-sponding to the features of claim 4; according to a third aspect with a method corresponding to the features of claim 10, and according to a fourth aspect with a computer program product corresponding to the features of claim 18. Addi-tional and/or refining features arise from the dependent claims.
The invention will now be described in more detail with reference to schematic drawings, which merely represent exemplary embodiments and are not to restrict the extent of the invention.
Fig. 1 shows a system for aspirating and/or dispensing liquid samples according to a first embodiment;
Fig. 2 shows a system for aspirating and/or dispensing liquid samples according to a second embodiment;
Fig. 3 shows a system for aspirating and/or dispensing liquid samples according to third embodiment;
Fig. 4 shows a system for observing and/or dispensing liquid samples according to a fourth embodiment.
Figs. 1 to 4 show a system for aspirating and/or dispensing liquid samples.
This system, which is designed as a pipettor, comprises a microejection device 1 and a pump 2, which are connected with one another via tubing 3. In addition, the system comprises a computer 4 for loading an activatable computer program product. When this computer program product has been loaded into the com-puter 4 and activated, it allows this computer 4 to control and synchronize the following functions of the system:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is ~Iled with sample liquid;
Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
Fig. 1 shows a system for aspirating and/or dispensing liquid samples, according to a first embodiment, in which the microejection device 1 comprises an endpiece 5 implemented as a microejection pump. In this embodiment, a microejection device 1 implemented as a piezoelectric micropump is preferred.
Fig. 2 shows a system for aspirating and/or dispensing liquid samples according to a second embodiment, in which the microejection device 1 comprises an end-piece 5, implemented as a disposable pipette tip, a pulse generator 6, and tubing 7 which connects an endpiece 5 and pulse generator 6. The pulse generator, whose functional principle is known from, for example, US 5,763,278, triggers pressure waves in the tubing 7, which cause the liquid droplets to be driven out of the endpiece 5 -- implemented in US 5,763,278 as a needle.
Fig. 3 shows a system for aspirating and/or dispensing liquid samples according to a third embodiment, in which the microejection device 1 comprises an end-piece 5 implemented as a microejection pump. In this embodiment, a microe-jection device 1 in the form of a piezoelectric micropump is preferred. This em-bodiment additionally comprises a reservoir 8 and/or a three-way valve 9, with the three-way valve 9 being positioned between pump 2 and reservoir 8. The reservoir 8 and the three-way valve 9 and the pump 2 are connected with one another via tubing 10. Notwithstanding the illustration in Fig. 3, the liquid trans-port can occur from the microejection device 1 into the pump 2 and from the pump 2 in the direction of the reservoir 8 via two separate valves (not shown).
The first three embodiments share the feature that the pump 2 is a piston pump which comprises a cylinder 11, a piston 12, and a drive 13. Among the many possible pumps for highly precise aspirating and dispensing of liquids, a commer-cially available device with the name "CAVRO XP3000 plus Modular Digital Pump", which is sold by the firm Cavro Scientific Instruments Inc., Sunnyvale, California, USA, has, for example, proven itself.
Fig. 4 shows a system for aspirating and/or dispensing of liquid samples accord-ing to a fourth embodiment, in which the microejection device 1 comprises an endpiece 5 implemented as a microejection pump. In this embodiment, a mi-croejection device 1 in the form of a micrvpump and endpiece is preferred. Pre-ferred micropumps function, for example, according to the piezoelectric principle or according to the principle of thermal actuation. This embodiment additionally comprises a reservoir 8 and/or a valve 14, with the valve 14 being positioned between pump 2 and microejection device 1. The reservoir 8 and the pump 2 are connected with one another via tubing 15. The pump 2 is not a piston pump in this case, in which a piston 12 represents the part of the pump which conveys the liquid, but another conveyance device for liquids which operates according to the pass-through principle. Such pumps are, for example, squeeze pumps or peristaltic pumps, which deform (squeeze) a tube 12" filled with a liquid by means of rollers 12' and thus perform transportation of the liquid. Such peristal-tic pumps are known from many other laboratory devices for supplying liquids (e.g. in heart/lung machines etc.). Such pumps typically operate less precisely than the preferred piston pump "CAVRO XP3000 plus Modular Digital Pump".
All of these exemplary embodiments preferably comprise the use of a non-com-pressible system liquid for relaying the liquid movements in a way known per se.
The method according to the invention -- on which this system, as well as the computer program product, are based -- in principle allows the use of pumps which operate less precisely and are therefore more economical, such as a squeeze and/or peristaltic pump. This method for synchronization of the system for aspirating and/or dispensing liquid samples that comprises a microejection device 1 and a pump 2, which are connected with one another via tubing 3, with the system being assigned a computer 4 for loading an activatable computer program product for synchronizing microejection device 1 and pump 2, is char-acterized in that the computer 4 controls and synchronizes the following func-tions of the system on the basis of the activated computer program product:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is filled with sample liquid;
~ Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
The dispensing of the sample volume preferably occurs in volume-defined partial steps. The special geometric dimensions and physical properties of the microe-jection pumps used allow reproducible dispensing of liquid samples with a volume of a few nanoliters. The active displacement of liquid from the microejection de-vice 1 causes a slight drop in pressure in the tubing 3 and/or 7. Although part of this drop in pressure can possibly be compensated by the use of flexible tubing 3, 7, this drop in pressure is nonetheless not to exceed a maximum value. The amount of this maximum value depends on the individual characteristics of an appropriately constructed pipettor. In a prototype of the applicant, this maxi-mum value was defined at 100 nl of residual or error volume.
The method according to the invention at least approximately compensates for this error volume by tracking the part 12, 12', 12" of the pump 2 which conveys the liquid. This tracking can occur continuously or in partial steps. Tracking in partial steps is preferred, with the partial steps for the tracking of the part 12, 12', 12" of the pump 2 which conveys the liquid being combined into step series.
A step series in this case always includes the same number of conveyance steps, preferably eight partial steps. If a "CAVRO XP3000 plus Modular Digital Pump"
is used, then 3.000 steps and/or 24.000 partial steps can be completed by means of a highly precise stepping motor used as drive 13. Eight of these partial steps are preferably combined into one step, so that only one whole-number multiple of 8 partial steps has to be executed. The dispensing time of a specific sample volume results from the individual droplet volume and the dispensing frequency of the microejection device 1. The computer according to the invention thus controls the tracking of the part 12, 12', 12" of the pump 2 which conveys the liquid in such a way that it occurs uniformly over the entire dispensing time.
The displacement volume (one stroke) of such a pump is preferably 50 to 500 NI.
From this, at a displacement volume of, for example, 50 pl in the cylinder 11 of a pump 2, volumes of 2.1 nl per partial step and/or 16.7 nl per step result. At a displacement volume of 500 NI, the volumes are greater by a factor of 10.
The beginning of the tracking of the part of the pump which conveys the liquid can occur with a time shift relative to the beginning of the dispensing of the sam-ple volume: if the tracking begins somewhat before the beginning of dispensing, excess pressure is built up in the tubing 3 and/or 7, which is advantageous for the separation of higher viscosity liquids, such as dimethyl sulfoxide (DMSO).
If the tracking begins somewhat after the beginning of dispensing, a negative pres-_g_ sure is built up in the tubing 3 and/or 7, which is advantageous for the separa-tion of very low viscosity liquids, such as acetone.
The end of the tracking of the part of the pump which conveys the liquid can oc-cur with a time delay relative to the end of the dispensing of the sample volume:
if the tracking ends somewhat before the end of dispensing, a drop in pressure results in the tubing 3 and/or 7 as dispensing finishes, which successfully pre-vents dripping of very low viscosity liquids. If the tracking ends somewhat after dispensing is finished, excess pressure is built up in the tubing 3 and/or 7, which is advantageous for subsequent separation of higher viscosity liquids, such as DM50.
Merely by temporally varying the driving of microejection device 1 and pump 2, the system can be individually adjusted to the liquid to be pipetted and/or dis-pensed. If a residual or error volume arises in liquids with a viscosity less than or equal to water through the dispensing of the sample volume and the tracking of the part of the pump which conveys the liquid in partial steps, it has been proven for dispensing and tracking to thus be adjusted to one another in such a way that this residual volume is always borne by the tracking of the part of the pump which conveys liquid, i.e. that a .smaller drop in pressure is always generated between pump 2 and microejection device 1. This error or residual volume was determined in practice for a pipettor and should be smaller than 100 nl. In order that residual volumes cannot add up in larger series of dispensed samples and possibly impair the functioning and/or the reproducibility of a pipettor or dis-penser, a value corresponding to the residual volume is preferably stored in the computer 4 and taken into consideration in a following dispensation of samples.
The invention also comprises a corresponding system, such as a pipettor and/or dispenser for performing this method. A machine~of this type can have one or more individually drivable channels, each with an endpiece 5. The endpieces 5 and/or the pipette tips can be positioned either in a two-dimensional or in a three-dimensional array.
All embodiments share the feature that the computer 4 is integrated into the system as an electronic component. However, the computer could also be part of an external computer which is made available to the system. An integrated computer has the advantage, however, that it can be implemented very com-pactly -- e.g, as a single board equipped with microelectronic elements in the housing of a pipettor or even in a pump integrated therein. The computer is preferably able to be externally operated and read out, regardless of whether it is integrated in the system or is made available to the system, in order that, for example, automatic protocols about the liquid samples aspirated and/or dis-pensed can be drawn up.
The computer program product according to the invention for synchronization of a system of this type for aspirating and/or dispensing liquid samples as described above can be loaded in a computer 4, which can be made available to the system or which is already integrated in the system, and activated there. In addition, it can be stored on in any typical data carrier for electronic systems for data proc-essing, such as a hard drive, a "floppy disk", a "compact disc" (CD), a "digital versatile disc" (DVD), but also in a "read-only memory" (ROM), a "random access memory" (RAM), or similar things, and can be retrieved from there. The com-puter program product according to the invention is able to communicate with other programs and/or computers. It can also comprise commands for control-ling a three-way valve 9, which is connected upstream from the pump 2, and/or commands for controlling the pump 2 for the aspiration of a liquid.
The computer program product according to the invention thus serves for making a computer 4 capable of synchronizing a system for aspirating and/or dispensing liquid samples, with the system comprising a microejection device 1 and a pump 2, which are connected with one another via tubing 3 -- regardless of whether the computer 4 is only made available to the system for this purpose or is inte-grated therein. At the same time, this computer program can already be loaded in the computer and/or installed in a memory of the computer. In its activated state, the computer program product makes the computer 4 capable of control-ling and synchronizing the following functions of the system:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is filled with sample liquid;
~ Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
The functioning of devices (and/or systems) according to the invention and methods according to the invention can be verified with three independent meth-ods, as follows.
A Optical measurements:
By means of a high-speed camera, the individual droplets which were dis-pensed with a microejection device 1 could be measured directly. With a device as shown in Fig. 1, liquid was aspirated and dispensed in the multi-pipetting mode. 43 aliquots of 25 nl each (= 1075 nl total volume dis-pensed) were dispensed, with each aliquot consisting of 48 individual droplets. Each individual droplet was measured individually.
Intended Average volume of the ACC of the CV of the volume 43 aliquots aliquots aliquots nl 26.5 nl 5.9% 1.91%
Average volume of all individualCV over all individual droplets (n=2064) droplets (n=2064) 551.6 pl 2.9 B Gravimetric measurements:
Liquid was aspirated and dispensed in the multipipetting mode (12 ali-quots) with a device as shown in Fig. 1. The volumes were determined with a Mettler UMT2 scale (measurement range 0.1 Ng to 2.1 g). 90% di-methyl sulfoxide was pipetted. 100, 500, and 1000 individual droplets, re-spectively, (intended droplet volume = 400 pl) were dispensed. A density of 1.09 g/ml was assumed for the evaluation.
Multipipetting Mode Intended Average volume of the ACC of the CV of the volume 12 aliquots aliquots aliquots 40 nl 40.7 nl 1.8% 1.9 80 nl 82.0 nl 2.5% 2.3 400 nl 409.4 nl 2.3% 1.1 C Photometric measurements:
Liquid was pipetted both in the single pipetting mode (12 single pipettings each) and in the multipipetting mode (12 aliquots) with a device as shown in Fig. 1. 20, 100, 200, or 1000 individual droplets, (intended droplet vol-ume = 500 pl) respectively, were dispensed.
An aqueous 0.25 M FeS04 solution with FerroZine~ was used for the cali-bration curve. "FerroZine~" is the registered trademark of Hach Company, P.O. Box 389, Loveland, CO 80539 USA. The resulting complex solution was stabilized with ascorbic acid. From this initial solution, measurement solutions were produced by dilution which corresponded to pipetting vol-umesof2.5n1,5.On1,10.On1,20.On1,40.Onl,and80.OnIin200N1.
12 aliquots of 200 NI each of these measurement solutions were pipetted by hand into a microplate and the optical absorption and/or the optical densities (OD) were measured with a microplate photometry reader. The calibration curve was calculated through the measurement points by means of linear regression.
For the volume determinations, 100 pl at a time of a 3.25 mM FerroZine~
solution with ascorbic acid buffered with ammonium acetate was placed into the wells of a microplate. 10 nl and 50 nl of a 0.25 M FeS04 solution stabilized with ascorbic acid was pipetted into this with the pipettor. The pipettings of 100 nl and 500 nl were performed with a 0.025 M FeS04 so-lution stabilized with ascorbic acid.
After the pipetting procedure, the volume was topped up with demineral-ized water in the individual wells to 200 pl total volume. The optical ab-sorption of the colored complex solution in the wells of a microplate was then measured in a microplate photometry reader and the volumes were calculated with reference to the calibration curve.
Single Pipetting Mode Intended Average volume of the ACC CV
volume 12 single pipettings 10 nl 9.7 nl 3.0% 2.9 50 nl 48.0 nl 4.0% 1.2 100 nl 10i.8 nl 1.8% 1.5 500 nl 497.5 nl 0.5% 1.5 Multipipetting Mode Intended Average volume of the ACC of CV of volume 12 aliquots the the aliquots aliquots nl 9.8 nl 2.0% 1.4 50 nl 48.1 nl 3.8% 2.5 100 nl 99.3 nl 0.7% 4.0 500 nl 509.0 nl 1.8% 2.8 The object initially stated, to suggest alternative devices and methods which al-low both economical and highly reproducible separation of volumes in the nano-liter to picoliter range, is thus fulfilled.
Fig. 4 shows a system for observing and/or dispensing liquid samples according to a fourth embodiment.
Figs. 1 to 4 show a system for aspirating and/or dispensing liquid samples.
This system, which is designed as a pipettor, comprises a microejection device 1 and a pump 2, which are connected with one another via tubing 3. In addition, the system comprises a computer 4 for loading an activatable computer program product. When this computer program product has been loaded into the com-puter 4 and activated, it allows this computer 4 to control and synchronize the following functions of the system:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is ~Iled with sample liquid;
Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
Fig. 1 shows a system for aspirating and/or dispensing liquid samples, according to a first embodiment, in which the microejection device 1 comprises an endpiece 5 implemented as a microejection pump. In this embodiment, a microejection device 1 implemented as a piezoelectric micropump is preferred.
Fig. 2 shows a system for aspirating and/or dispensing liquid samples according to a second embodiment, in which the microejection device 1 comprises an end-piece 5, implemented as a disposable pipette tip, a pulse generator 6, and tubing 7 which connects an endpiece 5 and pulse generator 6. The pulse generator, whose functional principle is known from, for example, US 5,763,278, triggers pressure waves in the tubing 7, which cause the liquid droplets to be driven out of the endpiece 5 -- implemented in US 5,763,278 as a needle.
Fig. 3 shows a system for aspirating and/or dispensing liquid samples according to a third embodiment, in which the microejection device 1 comprises an end-piece 5 implemented as a microejection pump. In this embodiment, a microe-jection device 1 in the form of a piezoelectric micropump is preferred. This em-bodiment additionally comprises a reservoir 8 and/or a three-way valve 9, with the three-way valve 9 being positioned between pump 2 and reservoir 8. The reservoir 8 and the three-way valve 9 and the pump 2 are connected with one another via tubing 10. Notwithstanding the illustration in Fig. 3, the liquid trans-port can occur from the microejection device 1 into the pump 2 and from the pump 2 in the direction of the reservoir 8 via two separate valves (not shown).
The first three embodiments share the feature that the pump 2 is a piston pump which comprises a cylinder 11, a piston 12, and a drive 13. Among the many possible pumps for highly precise aspirating and dispensing of liquids, a commer-cially available device with the name "CAVRO XP3000 plus Modular Digital Pump", which is sold by the firm Cavro Scientific Instruments Inc., Sunnyvale, California, USA, has, for example, proven itself.
Fig. 4 shows a system for aspirating and/or dispensing of liquid samples accord-ing to a fourth embodiment, in which the microejection device 1 comprises an endpiece 5 implemented as a microejection pump. In this embodiment, a mi-croejection device 1 in the form of a micrvpump and endpiece is preferred. Pre-ferred micropumps function, for example, according to the piezoelectric principle or according to the principle of thermal actuation. This embodiment additionally comprises a reservoir 8 and/or a valve 14, with the valve 14 being positioned between pump 2 and microejection device 1. The reservoir 8 and the pump 2 are connected with one another via tubing 15. The pump 2 is not a piston pump in this case, in which a piston 12 represents the part of the pump which conveys the liquid, but another conveyance device for liquids which operates according to the pass-through principle. Such pumps are, for example, squeeze pumps or peristaltic pumps, which deform (squeeze) a tube 12" filled with a liquid by means of rollers 12' and thus perform transportation of the liquid. Such peristal-tic pumps are known from many other laboratory devices for supplying liquids (e.g. in heart/lung machines etc.). Such pumps typically operate less precisely than the preferred piston pump "CAVRO XP3000 plus Modular Digital Pump".
All of these exemplary embodiments preferably comprise the use of a non-com-pressible system liquid for relaying the liquid movements in a way known per se.
The method according to the invention -- on which this system, as well as the computer program product, are based -- in principle allows the use of pumps which operate less precisely and are therefore more economical, such as a squeeze and/or peristaltic pump. This method for synchronization of the system for aspirating and/or dispensing liquid samples that comprises a microejection device 1 and a pump 2, which are connected with one another via tubing 3, with the system being assigned a computer 4 for loading an activatable computer program product for synchronizing microejection device 1 and pump 2, is char-acterized in that the computer 4 controls and synchronizes the following func-tions of the system on the basis of the activated computer program product:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is filled with sample liquid;
~ Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
The dispensing of the sample volume preferably occurs in volume-defined partial steps. The special geometric dimensions and physical properties of the microe-jection pumps used allow reproducible dispensing of liquid samples with a volume of a few nanoliters. The active displacement of liquid from the microejection de-vice 1 causes a slight drop in pressure in the tubing 3 and/or 7. Although part of this drop in pressure can possibly be compensated by the use of flexible tubing 3, 7, this drop in pressure is nonetheless not to exceed a maximum value. The amount of this maximum value depends on the individual characteristics of an appropriately constructed pipettor. In a prototype of the applicant, this maxi-mum value was defined at 100 nl of residual or error volume.
The method according to the invention at least approximately compensates for this error volume by tracking the part 12, 12', 12" of the pump 2 which conveys the liquid. This tracking can occur continuously or in partial steps. Tracking in partial steps is preferred, with the partial steps for the tracking of the part 12, 12', 12" of the pump 2 which conveys the liquid being combined into step series.
A step series in this case always includes the same number of conveyance steps, preferably eight partial steps. If a "CAVRO XP3000 plus Modular Digital Pump"
is used, then 3.000 steps and/or 24.000 partial steps can be completed by means of a highly precise stepping motor used as drive 13. Eight of these partial steps are preferably combined into one step, so that only one whole-number multiple of 8 partial steps has to be executed. The dispensing time of a specific sample volume results from the individual droplet volume and the dispensing frequency of the microejection device 1. The computer according to the invention thus controls the tracking of the part 12, 12', 12" of the pump 2 which conveys the liquid in such a way that it occurs uniformly over the entire dispensing time.
The displacement volume (one stroke) of such a pump is preferably 50 to 500 NI.
From this, at a displacement volume of, for example, 50 pl in the cylinder 11 of a pump 2, volumes of 2.1 nl per partial step and/or 16.7 nl per step result. At a displacement volume of 500 NI, the volumes are greater by a factor of 10.
The beginning of the tracking of the part of the pump which conveys the liquid can occur with a time shift relative to the beginning of the dispensing of the sam-ple volume: if the tracking begins somewhat before the beginning of dispensing, excess pressure is built up in the tubing 3 and/or 7, which is advantageous for the separation of higher viscosity liquids, such as dimethyl sulfoxide (DMSO).
If the tracking begins somewhat after the beginning of dispensing, a negative pres-_g_ sure is built up in the tubing 3 and/or 7, which is advantageous for the separa-tion of very low viscosity liquids, such as acetone.
The end of the tracking of the part of the pump which conveys the liquid can oc-cur with a time delay relative to the end of the dispensing of the sample volume:
if the tracking ends somewhat before the end of dispensing, a drop in pressure results in the tubing 3 and/or 7 as dispensing finishes, which successfully pre-vents dripping of very low viscosity liquids. If the tracking ends somewhat after dispensing is finished, excess pressure is built up in the tubing 3 and/or 7, which is advantageous for subsequent separation of higher viscosity liquids, such as DM50.
Merely by temporally varying the driving of microejection device 1 and pump 2, the system can be individually adjusted to the liquid to be pipetted and/or dis-pensed. If a residual or error volume arises in liquids with a viscosity less than or equal to water through the dispensing of the sample volume and the tracking of the part of the pump which conveys the liquid in partial steps, it has been proven for dispensing and tracking to thus be adjusted to one another in such a way that this residual volume is always borne by the tracking of the part of the pump which conveys liquid, i.e. that a .smaller drop in pressure is always generated between pump 2 and microejection device 1. This error or residual volume was determined in practice for a pipettor and should be smaller than 100 nl. In order that residual volumes cannot add up in larger series of dispensed samples and possibly impair the functioning and/or the reproducibility of a pipettor or dis-penser, a value corresponding to the residual volume is preferably stored in the computer 4 and taken into consideration in a following dispensation of samples.
The invention also comprises a corresponding system, such as a pipettor and/or dispenser for performing this method. A machine~of this type can have one or more individually drivable channels, each with an endpiece 5. The endpieces 5 and/or the pipette tips can be positioned either in a two-dimensional or in a three-dimensional array.
All embodiments share the feature that the computer 4 is integrated into the system as an electronic component. However, the computer could also be part of an external computer which is made available to the system. An integrated computer has the advantage, however, that it can be implemented very com-pactly -- e.g, as a single board equipped with microelectronic elements in the housing of a pipettor or even in a pump integrated therein. The computer is preferably able to be externally operated and read out, regardless of whether it is integrated in the system or is made available to the system, in order that, for example, automatic protocols about the liquid samples aspirated and/or dis-pensed can be drawn up.
The computer program product according to the invention for synchronization of a system of this type for aspirating and/or dispensing liquid samples as described above can be loaded in a computer 4, which can be made available to the system or which is already integrated in the system, and activated there. In addition, it can be stored on in any typical data carrier for electronic systems for data proc-essing, such as a hard drive, a "floppy disk", a "compact disc" (CD), a "digital versatile disc" (DVD), but also in a "read-only memory" (ROM), a "random access memory" (RAM), or similar things, and can be retrieved from there. The com-puter program product according to the invention is able to communicate with other programs and/or computers. It can also comprise commands for control-ling a three-way valve 9, which is connected upstream from the pump 2, and/or commands for controlling the pump 2 for the aspiration of a liquid.
The computer program product according to the invention thus serves for making a computer 4 capable of synchronizing a system for aspirating and/or dispensing liquid samples, with the system comprising a microejection device 1 and a pump 2, which are connected with one another via tubing 3 -- regardless of whether the computer 4 is only made available to the system for this purpose or is inte-grated therein. At the same time, this computer program can already be loaded in the computer and/or installed in a memory of the computer. In its activated state, the computer program product makes the computer 4 capable of control-ling and synchronizing the following functions of the system:
~ Active definition of a sample volume and dispensing of this defined sample volume with the microejection device 1, which is filled with sample liquid;
~ Tracking of a part 12, 12', 12", which conveys the liquid, of the pump 2 around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device 1, to prevent excessive pressure differences in the microejection device 1, tubing 3, and pump 2.
The functioning of devices (and/or systems) according to the invention and methods according to the invention can be verified with three independent meth-ods, as follows.
A Optical measurements:
By means of a high-speed camera, the individual droplets which were dis-pensed with a microejection device 1 could be measured directly. With a device as shown in Fig. 1, liquid was aspirated and dispensed in the multi-pipetting mode. 43 aliquots of 25 nl each (= 1075 nl total volume dis-pensed) were dispensed, with each aliquot consisting of 48 individual droplets. Each individual droplet was measured individually.
Intended Average volume of the ACC of the CV of the volume 43 aliquots aliquots aliquots nl 26.5 nl 5.9% 1.91%
Average volume of all individualCV over all individual droplets (n=2064) droplets (n=2064) 551.6 pl 2.9 B Gravimetric measurements:
Liquid was aspirated and dispensed in the multipipetting mode (12 ali-quots) with a device as shown in Fig. 1. The volumes were determined with a Mettler UMT2 scale (measurement range 0.1 Ng to 2.1 g). 90% di-methyl sulfoxide was pipetted. 100, 500, and 1000 individual droplets, re-spectively, (intended droplet volume = 400 pl) were dispensed. A density of 1.09 g/ml was assumed for the evaluation.
Multipipetting Mode Intended Average volume of the ACC of the CV of the volume 12 aliquots aliquots aliquots 40 nl 40.7 nl 1.8% 1.9 80 nl 82.0 nl 2.5% 2.3 400 nl 409.4 nl 2.3% 1.1 C Photometric measurements:
Liquid was pipetted both in the single pipetting mode (12 single pipettings each) and in the multipipetting mode (12 aliquots) with a device as shown in Fig. 1. 20, 100, 200, or 1000 individual droplets, (intended droplet vol-ume = 500 pl) respectively, were dispensed.
An aqueous 0.25 M FeS04 solution with FerroZine~ was used for the cali-bration curve. "FerroZine~" is the registered trademark of Hach Company, P.O. Box 389, Loveland, CO 80539 USA. The resulting complex solution was stabilized with ascorbic acid. From this initial solution, measurement solutions were produced by dilution which corresponded to pipetting vol-umesof2.5n1,5.On1,10.On1,20.On1,40.Onl,and80.OnIin200N1.
12 aliquots of 200 NI each of these measurement solutions were pipetted by hand into a microplate and the optical absorption and/or the optical densities (OD) were measured with a microplate photometry reader. The calibration curve was calculated through the measurement points by means of linear regression.
For the volume determinations, 100 pl at a time of a 3.25 mM FerroZine~
solution with ascorbic acid buffered with ammonium acetate was placed into the wells of a microplate. 10 nl and 50 nl of a 0.25 M FeS04 solution stabilized with ascorbic acid was pipetted into this with the pipettor. The pipettings of 100 nl and 500 nl were performed with a 0.025 M FeS04 so-lution stabilized with ascorbic acid.
After the pipetting procedure, the volume was topped up with demineral-ized water in the individual wells to 200 pl total volume. The optical ab-sorption of the colored complex solution in the wells of a microplate was then measured in a microplate photometry reader and the volumes were calculated with reference to the calibration curve.
Single Pipetting Mode Intended Average volume of the ACC CV
volume 12 single pipettings 10 nl 9.7 nl 3.0% 2.9 50 nl 48.0 nl 4.0% 1.2 100 nl 10i.8 nl 1.8% 1.5 500 nl 497.5 nl 0.5% 1.5 Multipipetting Mode Intended Average volume of the ACC of CV of volume 12 aliquots the the aliquots aliquots nl 9.8 nl 2.0% 1.4 50 nl 48.1 nl 3.8% 2.5 100 nl 99.3 nl 0.7% 4.0 500 nl 509.0 nl 1.8% 2.8 The object initially stated, to suggest alternative devices and methods which al-low both economical and highly reproducible separation of volumes in the nano-liter to picoliter range, is thus fulfilled.
Claims (20)
1. Computer (4) for synchronization of a system for aspirating and/or dis-pensing of liquid samples that comprises a microejection device (1) and a pump (2), which are connected with one another via tubing (3), with this computer (4) being implemented for loading an activatable computer pro-gram product for synchronizing the microejection device (1) and the pump (2), characterized in that the computer (4) is, on the basis of the loaded and activated computer program product, made capable of controlling and synchronizing the following functions of this system:
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
2. Computer (4) according to claim 1, characterized in that it is integrated into the system as an electronic component.
3. Computer (4) according to claim 1 or 2, characterized in that it can also be externally operated and read out.
4. System for aspirating and/or dispensing liquid samples that comprises a microejection device (1) and a pump (2), which are connected with one another via tubing (3), with the system also comprising a computer (4) for loading an activatable computer program product for synchronizing the mi-croejection device (1) and pump (2), characterised in that it comprises a computer (4) according to one or more of the claims 1 to 3.
5. System according to claim 4, characterized in that the microejection device (1) comprises an endpiece (5) implemented as a microejection pump.
6. System according to claim 5, characterized in that the microejection device (1) is a piezoelectric micropump.
7. System according to claim 4, characterized in that the microejection device (1) comprises an endpiece (5), which is implemented as a dispos-able pipette tip, a pulse generator (6), and tubing (7) connecting the end-piece (5) and pulse generator (6).
8. System according to one of the claims 4 to 7, characterized in that it also comprises a reservoir (8) and/or a three-way valve (9), with the three-way valve (9) being located between the pump (2) and the reservoir (8), and with the reservoir (8) and/or the three-way valve (9) and the pump (2) being connected with one another via tubing (10).
9. System according to one of the claims 4 to 8, characterized in that the pump (2) is a piston pump which comprises a cylinder (11), a piston (12), and a drive (13).
10. Method for synchronizing a system for aspirating and/or dispensing liquid samples that comprises a microejection device (1) and a pump (2), which are connected with one another via tubing (3), with the system also being assigned a computer (4) for loading an activatable computer program product for synchronizing the microejection device (1) and the pump (2), characterized in that the computer (4) controls and synchronizes the following functions of this system on the basis of the loaded and activated computer program product:
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
11. Method according to claim 10, characterized in that the dispensing of the sample volume occurs in volume-defined partial steps.
12. Method according to claim 10 or 11, characterized in that the tracking of the part (12, 12', 12") of the pump (2) which conveys the liquid occurs continuously or in partial steps.
13. Method according to claim 12, characterized in that the partial steps for tracking of the part (12, 12', 12") of the pump (2) which conveys the liquid are collected into series of steps, with a series of steps always comprising the same number of partial steps, preferably 8.
14. Method according to one of the claims 10 to 13, characterized in that the beginning and/or the end of the tracking of the part (12, 12', 12") of the pump (2) which conveys the liquid occurs with a time shift relative to the beginning and/or the end of dispensing of the sample volume.
15. Method according to one of the claims 10 to 14, characterized in that --if a residual volume occurs due to the dispensing of the sample volume and the tracking of the part (12, 12', 12") of the pump (2) which conveys the liquid in partial steps -- the dispensing and tracking are adjusted to one another in such a way that this residual volume is always borne by the tracking of the part (12, 12', 12") of the pump (2) which conveys the liq-uid.
16. Method according to claim 15, characterized in that the residual volume borne by the tracking, which generates a drop in pressure in the tubing between the pump (2) and the microejection device (1), is smaller than 100 nl.
17. Method according to claim 16, characterized in that a value corre-sponding to the residual volume is stored in the computer (4) and is taken into account in a following dispensation of samples.
18. Computer program product for synchronizing a system for aspirating and/or dispensing liquid samples, with the system comprising a microejec-tion device (1) and a pump (2), which are connected with one another via tubing (3), and the system also able to be assigned a computer (4) for loading an activatable computer program product for synchronizing the mi-croejection device (1) and the pump (2), characterized in that this com-puter program product, in its activated state, makes the computer (4) ca-pable of controlling and synchronizing the following functions of this sys-tem:
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
.cndot. Active definition of a sample volume and dispensing of this defined sample volume with the microejection device (1), which is filled with sample liquid;
.cndot. Tracking of a part (12, 12', 12"), which conveys the liquid, of the pump (2) around a value, dependent on this sample volume, which is defined and is actively dispensed only by the microejection device (1), to pre-vent excessive pressure differences in the microejection device (1), tubing (3), and pump (2).
19. Computer program product according to claim 18, characterized in that it also comprises commands for controlling a three-way valve (9), which is connected upstream from the pump (2).
20. Computer program product according to claim 18 or 19, characterized in that it also comprises commands for controlling the pump (2) for the aspiration of a liquid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH22522000 | 2000-11-17 | ||
| CH20002252/00 | 2000-11-17 |
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| CA2363300A1 true CA2363300A1 (en) | 2002-05-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002363300A Abandoned CA2363300A1 (en) | 2000-11-17 | 2001-11-15 | Method and device for separating samples from a liquid |
Country Status (8)
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|---|---|
| US (1) | US6926866B2 (en) |
| EP (1) | EP1206967B1 (en) |
| JP (1) | JP2002236130A (en) |
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| AU (1) | AU2001295360A1 (en) |
| CA (1) | CA2363300A1 (en) |
| DE (1) | DE50112925D1 (en) |
| WO (1) | WO2002040160A1 (en) |
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| US6325932B1 (en) * | 1999-11-30 | 2001-12-04 | Mykrolis Corporation | Apparatus and method for pumping high viscosity fluid |
| US6579724B2 (en) * | 2001-09-13 | 2003-06-17 | First Ten Angstroms | Dispensing method and apparatus for dispensing very small quantities of fluid |
| US7410615B2 (en) * | 2002-01-24 | 2008-08-12 | Perkinelmer Las, Inc. | Precision liquid dispensing system |
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| DE10225931A1 (en) * | 2002-06-11 | 2003-12-24 | Basf Ag | Reactor system for carrying out chemical reactions in parallel, in particular polymerization reactions |
| US7204960B2 (en) * | 2003-03-03 | 2007-04-17 | Asm Assembly Automation Ltd. | Apparatus and method for calibration of a dispensing system |
| FR2862890B1 (en) * | 2003-11-27 | 2007-11-16 | Gilson Sas | PIPETTE COMPRISING MEANS FOR TRANSMITTING INFORMATION |
| US7976793B2 (en) * | 2003-11-27 | 2011-07-12 | Gilson S.A.S. | Electronic pipette |
| AU2005252242A1 (en) * | 2004-06-07 | 2005-12-22 | Irm Llc | Dispensing systems, software, and related methods |
| FI116612B (en) | 2004-07-05 | 2006-01-13 | Biohit Oyj | A suction device |
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| JP5079516B2 (en) | 2004-11-23 | 2012-11-21 | インテグリス・インコーポレーテッド | System and method for a variable home position dispensing system |
| US8753097B2 (en) | 2005-11-21 | 2014-06-17 | Entegris, Inc. | Method and system for high viscosity pump |
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-
2001
- 2001-10-29 WO PCT/CH2001/000637 patent/WO2002040160A1/en active Application Filing
- 2001-10-29 AU AU2001295360A patent/AU2001295360A1/en not_active Abandoned
- 2001-10-30 AT AT01125826T patent/ATE371499T1/en not_active IP Right Cessation
- 2001-10-30 EP EP01125826A patent/EP1206967B1/en not_active Expired - Lifetime
- 2001-10-30 DE DE50112925T patent/DE50112925D1/en not_active Expired - Fee Related
- 2001-11-14 JP JP2001348706A patent/JP2002236130A/en active Pending
- 2001-11-15 CA CA002363300A patent/CA2363300A1/en not_active Abandoned
- 2001-11-19 US US09/992,304 patent/US6926866B2/en not_active Expired - Fee Related
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| AU2001295360A1 (en) | 2002-05-27 |
| EP1206967A2 (en) | 2002-05-22 |
| EP1206967B1 (en) | 2007-08-29 |
| DE50112925D1 (en) | 2007-10-11 |
| ATE371499T1 (en) | 2007-09-15 |
| WO2002040160A1 (en) | 2002-05-23 |
| US20020095240A1 (en) | 2002-07-18 |
| JP2002236130A (en) | 2002-08-23 |
| EP1206967A3 (en) | 2002-06-12 |
| US6926866B2 (en) | 2005-08-09 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |