WO2013060483A2 - Procédé et dispositif de contrôle du volume et de la composition d'au moins un prélèvement - Google Patents

Procédé et dispositif de contrôle du volume et de la composition d'au moins un prélèvement Download PDF

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Publication number
WO2013060483A2
WO2013060483A2 PCT/EP2012/004528 EP2012004528W WO2013060483A2 WO 2013060483 A2 WO2013060483 A2 WO 2013060483A2 EP 2012004528 W EP2012004528 W EP 2012004528W WO 2013060483 A2 WO2013060483 A2 WO 2013060483A2
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WO
WIPO (PCT)
Prior art keywords
pipette
sample
camera
recorded
spectrum
Prior art date
Application number
PCT/EP2012/004528
Other languages
German (de)
English (en)
Other versions
WO2013060483A3 (fr
Inventor
Torsten Matthias
Hans-Peter Schimon
Jens BLECKEN
Markus Wulf
Original Assignee
Torsten Matthias
Hans-Peter Schimon
Blecken Jens
Markus Wulf
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102011117323A external-priority patent/DE102011117323B4/de
Priority claimed from DE102011117310A external-priority patent/DE102011117310B4/de
Application filed by Torsten Matthias, Hans-Peter Schimon, Blecken Jens, Markus Wulf filed Critical Torsten Matthias
Priority to EP12794858.6A priority Critical patent/EP2771699B8/fr
Priority to US14/354,908 priority patent/US9734421B2/en
Priority to ES12794858T priority patent/ES2870855T3/es
Publication of WO2013060483A2 publication Critical patent/WO2013060483A2/fr
Publication of WO2013060483A3 publication Critical patent/WO2013060483A3/fr

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Classifications

    • 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
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016—Control of the volume dispensed or introduced
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01F—MEASURING VOLUME, VOLUME FLOW, MASS FLOW OR LIQUID LEVEL; METERING BY VOLUME
    • G01F23/00—Indicating or measuring liquid level or level of fluent solid material, e.g. indicating in terms of volume or indicating by means of an alarm
    • G01F23/22—Indicating or measuring liquid level or level of fluent solid material, e.g. indicating in terms of volume or indicating by means of an alarm by measuring physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water
    • G01F23/28—Indicating or measuring liquid level or level of fluent solid material, e.g. indicating in terms of volume or indicating by means of an alarm by measuring physical variables, other than linear dimensions, pressure or weight, dependent on the level to be measured, e.g. by difference of heat transfer of steam or water by measuring the variations of parameters of electromagnetic or acoustic waves applied directly to the liquid or fluent solid material
    • G01F23/284—Electromagnetic waves
    • G01F23/292—Light, e.g. infrared or ultraviolet
    • 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
    • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N2035/1025—Fluid level sensing

Definitions

  • the invention relates to a method and a device for controlling the volume and / or the composition of at least one, in particular fluid, sample in at least one pipette between at least one sample and at least one adjoining the at least one fluid fluid at least one interface is formed and formed in at least one second pipette between at least one second, in particular fluid sample and at least one adjoining the at least second sample second fluid, an at least second interface.
  • the invention further relates to the use of a camera with a marker in the field of view of the camera for carrying out such a method.
  • DE 10 2008 022 835 B3 describes a device as an analysis device for examining biological or chemical samples by means of a reagent liquid supplied via a pipette.
  • a worktop On a base plate, a worktop is rotatably mounted horizontally arranged for receiving the samples in a sample holder, such as a microtiter plate having a plurality of wells for receiving the samples.
  • the wells are also referred to as depressions, wells or wells, sometimes as droplets.
  • a robot manipulator Above the worktop, a robot manipulator is mounted, which carries a horizontal support arm with a carriage, wherein the carriage is mounted in a vertically movable needle system.
  • the needle system comprises a plurality of hollow needles as pipettes, which simultaneously come to a standstill via a single well, wherein one of the hollow needles fills a reagent liquid into the well.
  • the solution is sucked from a sample located in the well and the supplied reagent liquid by means of a second hollow needle and provided by means of a third Hohlna- del with a washing solution and subsequently aspirated with the second hollow needle.
  • the analyzer itself contains none Elements for evaluating the wells or wells, these being evaluated in a later step by a person skilled in the art.
  • the samples are marked with barcodes for later analysis, the analyzer having in its rear part a device for reading the barcodes.
  • the samples undergo a color change and / or fluorescence which can be analyzed and / or evaluated by a photometer for color measurement.
  • the above-described analyzer is disadvantageous in that the needle system with three needles as pipettes only supplies a reagent liquid in the amount to be pipetted to a well and the amount to be pipetted is adjusted via a drive associated with the first needle, which provides the required process accuracy with respect to the Quantity only guaranteed to a limited extent.
  • the object of the invention is therefore to avoid the disadvantages of the prior art, wherein the production of solutions from in each case a sample and a fluid, for example in the form of a reagent or dilution liquid, using as small amounts as possible for the sample and the fluid should be done at high process speed.
  • the method according to the invention for controlling a volume and / or a composition of at least one, in particular fluid sample comprises providing at least one pipette in which between at least one sample and at least one fluid adjoining the at least one sample is formed with at least one interface optically perceptible outside the pipette as a substantially horizontally extending boundary line between at least one sample and the at least one fluid, arranging at least one marking of a camera in an image field Camera such that the at least one mark and at least a first portion of the at least one pipette are imaged on a captured image, wherein the at least one pipette is arranged between a light source and the camera that at least one spectrum of light rays of the light source from the camera recording whether the at least one mark in the recorded image coincides with the position of the at least one boundary line in the at least first section, comparing at least one recorded spectrum with at least one reference spectrum, and determining whether the composition of the at least one sample according to the at least one recorded spectrum corresponds to the at least one reference spectrum.
  • a further embodiment of the method according to the invention for controlling the volume and / or the composition of the at least one sample comprises providing at least one at least pipette in which at least one interface is formed between the at least one sample and at least one fluid adjacent to the at least one sample which is visually perceptible outside the pipette as a substantially horizontally extending boundary line between the at least one sample and the at least one fluid.
  • the method further comprises providing at least one second pipette in which at least one second boundary surface is formed between at least one second, in particular fluid, sample and at least one second fluid adjoining the at least second sample and which is in each case outside the at least second pipette Essentially horizontally extending at least the second boundary line between the at least second sample and the at least second fluid is visually perceptible.
  • the method further comprises arranging at least one marking of a camera in an image field of the camera such that the at least one marking, at least a portion of the at least one pipette and at least a second section of the at least second pipette can be imaged on a recorded image, and an evaluation as to whether in the recorded image the at least one marking at the level of the at least one boundary line in the at least one section and the at least second boundary line in the at least second section lies.
  • the position of at least one of the first boundary line in the first section and the second boundary line in the second section and thus the position of the first sample within the first pipette and / or the second sample within the second pipette can be accurately determined. Since a section of the at least one pipette and the at least second pipette are shown next to the marking on a picture taken with the camera, it is possible that the at least one and / or the at least second boundary line are imaged on the recorded image. In this case, it can be evaluated, for example by means of a comparison of the recorded image with one or more reference images, whether the marking is at the height of the first and / or second boundary line.
  • the marking which is present only in the field of view of the camera and does not have to be present in an image to be imaged, can be designed as a control point, control spot or check cross next to other variants as a substantially horizontally extending control line first and / or second boundary line, when the first and / or second boundary line is aligned with the control line.
  • this comparison can be carried out, for example, by comparing the brightness levels of different pixels of the recorded image with brightness levels of different pixels of the reference image, which are located at corresponding positions on the recorded image and the reference image and when the brightness levels match in a predetermined value range, a match of the brightness levels of the compared pixels is detected.
  • This pattern matching between the recorded image and the reference image can be done in automated form via a PC (personal computer). If the first sample to the first fluid and / or the second sample to the second fluid / has a high contrast and the first and / or second boundary line in the captured image is / are shown in high quality, may alternatively or in addition to a comparison of this image with a reference image, the evaluation takes place on the basis of a fixed selection criterion, for example based on a predetermined number of pixels in a direction adjacent to one another between the marking and the first and / or second boundary line.
  • first pipette comprising the first sample and the second pipette comprising the second sample
  • first sample is present in the first section and / or the second sample is present in the second section, for example by pattern matching or by a predetermined selection criterion.
  • selection criterion a color value that is characteristic of the sample can be considered, which can be detected by the camera, since the pipette is at least partially transparent.
  • mapping the first boundary line and / or the second boundary line together with the marking it is also possible to determine with only one recorded image whether the boundary line of at least one of the first and second samples at a predetermined position in the longitudinal direction of at least one of first and second pipettes is located.
  • a fill level of the first sample in the first pipette and / or the second sample in the second pipette can be determined, whereby the volume of at least one of the first and second samples can be controlled.
  • the process speed can be increased in the production of solutions comprising these samples.
  • a defined time for the control of the volumes of the first sample and the second sample is determined via the recording of the image of the marking and the optionally two borderlines.
  • the given volumes for the first sample and the second sample by means of the invention Control are controlled, they are immediately thereafter for further analysis or processing, for example, by a transfer of the two samples in adjacent wells of a microtiter plate available.
  • the pipette is arranged between a light source and the camera such that a spectrum of light beams of the light source can be picked up by the camera which have passed through the sample.
  • the evaluation device which compares the marking in the recorded image with the position of the boundary line, comprises additional means which compares the recorded spectrum with a reference spectrum and determines whether the composition of the sample according to the recorded spectrum corresponds to that of the reference spectrum.
  • the pipette (s) is / are preferably arranged between a light source and the camera such that in each case a spectrum of light beams of the light source is picked up by the camera, which have traversed a meniscus and / or a sample part directly below the meniscus of the sample (s) formed at an edge of the interface with an inner wall of the pipette (s) which becomes the recorded spectrum (s) / are compared with one or more reference spectra / reference spectra and it is determined whether the composition of the sample (s) according to the spectrum (s) recorded corresponds to that of the reference spectrum (s).
  • the term "directly below the meniscus” at least the height of 0.5 times, in particular 1, 0-fold and preferably of 1, 5 times the meniscus, and at most the height of 3 times or 4 -fold, in particular of 5, 6, 7, 8-fold, particularly preferably 10 times the height of the meniscus understood.
  • sample is used.
  • samples are, for example, blood, serum and / or cell fluid.
  • Other substances for the sample which may be present as a biological or chemical sample, are possible.
  • substances dissolved in the sample or undissolved constituents of the sample for example impurities, can also be determined in this way.
  • the evaluation of the composition of the sample is used to determine whether haemolytic and / or lipemic factors are present in the sample.
  • serum or plasma it can be determined in this way whether the tests are disturbed by lipids, hemoglobin or bilirubin. Interferences in increased amounts (lipids up to 20 mg / mL, hemoglobin up to 800 pg / mL, bilirubin up to 200 pg / mL) can interfere with the reaction kinetics and distort the results.
  • the adulterations are due in part to the fact that the fats and / or lipids floating on the surface of the samples, which possibly contain cholesterol-rich components, are increasingly sucked in instead of the serum or the plasma by means of the pipette for volume determination. This can then lead to a volume corruption of the sample to be determined and thus disturb or falsify the analysis result.
  • the composition of a sample is preferably carried out on the surface, since the fatty and / or lipid-containing layers preferably deposit on the surface.
  • the measurement of the composition of the sample in the region of the upper limit line of the sample is preferably carried out.
  • the invention it is also possible to perform a turbidimetric measurement across the sample.
  • hemolytic constituents of a sample when present in a sample, affect the measurement primarily by their red and brown colors, and secondarily by inhibiting certain reactions by the hemolytic constituents.
  • a more precise control of the volume and composition of a sample provides a higher level of control security, which in turn allows more reliable exclusion of false-positive and false-negative samples.
  • the recorded image defines a starting time for a control process step of the two samples which is downstream of the control.
  • it is possible to drain the two samples for example a blank or a reference sample as a first sample and a sample to be analyzed as a second sample, under exactly the same conditions in wells assigned to each other separately from one another. For example, at different times entering color envelopes or fluorescence occurring can be evaluated in this way under simple comparable process conditions and at increased process speed due to a uniform time base, which is set by the recording time as a time stamp.
  • Each of the two pipettes can be calibrated in such a way that, when the marking is at the level of the respective boundary line, there is a predetermined volume of the first or second sample, which is delimited by a tip of the respective pipette next to the first or second interface.
  • calibrating the pipette in each case in a region of the pipette which comprises the pipette tip it is possible to determine with only one recorded image whether the first sample and / or the second sample have a predetermined volume. If the resolution and photosensitivity of the camera are sufficient, it is also possible to record more than two pipettes with samples in sections at a time in an image.
  • the captured image can be viewed, for example, with an electronic matrix camera, in particular a CCD (Charge Coupled Device) or CMOS (Complementary Metal Oxide Semiconductor) camera.
  • CCD Charge Coupled Device
  • CMOS Complementary Metal Oxide Semiconductor
  • Another device for image acquisition is possible, provided that their resolution, focal length, aperture, depth of focus and photosensitivity ensure an adequate image quality for evaluation.
  • the first fluid is formed as a gas bubble, in particular air bubble.
  • this gas bubble is arranged between the first sample and a further fluid adjoining the gas bubble, wherein a further interface formed between the further fluid and the gas bubble outside the pipette acts as a further horizontally extending further boundary line between the further fluid the gas bubble is visually perceptible.
  • the gas bubble avoids unwanted mixing of the first sample with the further fluid.
  • both the first sample and the further fluid may be liquids that are to be sequentially ejected into a single well or into different wells.
  • the further fluid may also be present as a dilution or comparison fluid for diluting the sample or for comparison with the sample instead of another sample.
  • the first partial image comprises a first section of the first pipette, which includes a first tip of the first pipette and the first boundary line and a second section of the second pipette with a second tip of the second pipette.
  • a third section of the first pipette with the further borderline is shown.
  • the gas bubble serves as an "interface" between the first partial image and the second partial image, wherein the In the longitudinal direction of the pipette between the first borderline and the third borderline, there is no further borderline that could be evaluated the portion in the gas bubble between the first boundary line and the third boundary line is used as the edge of the first field.
  • the first borderline and in the second partial image the third borderline are depicted, it can be determined in the composite captured image under optimized camera-optical conditions for the first borderline and the third borderline whether the first borderline and the third borderline are at altitude the (respective) mark are. Since the composite image also shows the second section of the second pipette and thus possibly the second boundary line running in the second pipette, the volumes of three samples can be controlled in two pipettes by means of only one recorded image.
  • a boundary line depicted in the first partial image and a further borderline depicted in the second partial image in one or in different pipettes can advantageously always be combined to form a recorded image if the boundary lines are vertically spaced apart so far that an optical parameter of FIG Camera, for example, the depth of field, resolution or image field range of constant focal length is no longer sufficient to represent both borderlines evaluable.
  • an optical parameter of FIG Camera for example, the depth of field, resolution or image field range of constant focal length is no longer sufficient to represent both borderlines evaluable.
  • the captured image is composed of partial images taken with the camera, wherein on a first partial image a first portion of the first pipette, which includes a first tip of the first pipette and the first borderline, and a second portion of the second pipette a second tip of the second pipette, and on the second partial image a fourth portion of the second pipette with the second Borderline is shown.
  • the second boundary line shown in the second partial image in the second pipette can be referred to the tip of this pipette depicted in the first partial image.
  • the pipettes in the area of the pipette tip and parallel alignment of the longitudinal axes of both pipettes and at the same height tips of the two pipettes, it is also possible alternatively or in addition to composite partial images, the pipettes to the lens of the camera to align so that the lens facing ends of boundary lines in the first and / or second pipette have the same or similar distances to the lens.
  • the longitudinal axes of the pipettes not the longitudinal axes of the pipettes, but the outer edges of the pipettes facing the lens are substantially perpendicular to the optical axis of the lens or the camera and the ends of the boundary lines facing the lens have the same or similar distances to an intersection of the optical axis the lens facing the outer edge of the pipette, in which the respective boundary line is arranged.
  • a rotation of the longitudinal axes of the pipettes to the optical axis by a half cone angle can be done by the pipettes to the lens or the lens is rotated to the pipettes /, for example via a computer-controlled electric motor.
  • a recorded image composed of sub-images and / or a rotation of the longitudinal axis of the pipette to the optical axis by half a cone angle can / can not only take place when taking an image of portions of two pipettes, but even when taking an image from a pipette.
  • the first partial image and the second partial image can be recorded by virtue of the fact that at least one of the first and second pipettes is positioned relative to the image. field of the camera to be moved.
  • the first pipette and the second pipette can be in the form of a double pipette, also referred to as a double pipetting module, the pipettes being aligned parallel to one another with respect to their longitudinal axes and conical sections of the pipettes with the pipette tips being opened in a same direction. If the first pipette is displaceable in its longitudinal direction relative to the second pipette, the pipette tips can be aligned horizontally relative to one another to a common height relative to the image field of the camera, which facilitates subsequent evaluation after the image has been taken.
  • the double pipette may comprise separate drives for the first pipette and the second pipette for moving a fluid in the respective pipette. In this way, a simultaneous transfer of the fluids in the first pipette and in the second pipette to one or different wells can be ensured.
  • more than two pipettes can be aligned parallel to one another with respect to their longitudinal axes and open at the conical sections of the pipettes with the pipette tips to a same direction and each with separate drives for second-same carry the contained in the pipettes
  • the first pipette and the second pipette are mounted on a common carrier, which is movable relative to the camera
  • the first pipette and the second pipette (common ) are driven through the field of view of the camera.
  • the camera is stationary and the first pipette and the second pipette are arranged, for example, in a robot manipulator.
  • it is also possible that the first pipette and the second pipette are arranged stationary and a camera is moved relative to the pipettes.
  • the first partial image is shown overlapping with respect to the second partial image.
  • This has the advantage that a contour of each pipette in the representation of the two partial images can be restored in an overlapping manner, whereby the portions of the first pipette and the second pipette shown in the second partial image with respect to the tip of the first pipette shown in the first partial image and Tip of the second pipette can be aligned.
  • the tip of the first pipette and the tip of the second pipette can are used as geometric reference points for volume determination of volumes of fluids in the pipettes.
  • the camera used for image recording has an automatically adaptable focal length (autofocus) to the image ratio, it can be ensured by recording the first partial image and the second partial image that the first, second and third boundary lines are recorded with the camera's optimum focal point, so that the first partial image and the second partial image are each sufficiently sharply imaged in order to ensure an evaluation as to whether the boundary lines are at the level of the marking with sufficient accuracy.
  • autofocus focal length
  • the recorded image can be assigned a time stamp which triggers a process step following the assignment of the time stamp, in particular a simultaneous ejection of the first sample from the first pipette and the second sample from the second pipette. If the recorded image is composed of at least two partial images, this time stamp can be assigned to the last acquired partial image.
  • the process step following the assignment of the time stamp may include, inter alia, color envelopes of the first sample to be evaluated at different times in a first well and the second sample in a second well.
  • the camera for taking a further image can be rotated or swiveled such that one or more wells in which the first sample and / or the second sample is / are arranged on the further image , is mappable / are.
  • the camera can be used not only to control the volume of the first and / or second sample, but additionally or alternatively to determine a color change of the first and / or second sample in one or more wells after ejection of the first and / or second Sample from the first and / or second pipette.
  • any camera with a marking in the image field of the camera can be used for carrying out the method (s) according to the invention described above.
  • the camera used should have sufficient resolution, depth of field, aperture and photosensitivity for evaluation.
  • Spectrum of light rays of the light source can be recorded by the camera, which have crossed the sample, and
  • a further embodiment of the device according to the invention for controlling the volume and composition of at least one sample comprises a first pipette in which a first interface is formed between a first sample and a first fluid adjacent to the first sample, which is substantially horizontal outside the pipette a second pipette in which a second interface is formed between a second sample and a second fluid adjoining the second sample and which is external to the second pipette as substantially the first boundary line between the first sample and the first fluid horizontally extending second boundary line between the second sample and the second fluid is visually perceptible, a camera with a marker, which in an image field of the camera is arranged such that the mark, a first portion of the first pipette and a second portion of the second pipette are imaged on a captured
  • the pipette is arranged between a light source and the camera in such a way that a spectrum of light beams of the light source can be picked up by the camera, which have passed through the sample.
  • the evaluation device which compares the marking in the recorded image with the position of the boundary line, comprises additional means which compares the recorded spectrum with a reference spectrum and determines whether the composition of the sample according to the recorded spectrum corresponds to that of the reference spectrum.
  • the pipette (s) can be arranged between a light source and the camera such that a spectrum of light rays of the light source can be picked up by the camera, which is a meniscus have traversed the sample (s) formed at one edge of the interface with an inner wall of the pipette (s), and the evaluation device may comprise additional means including one or more of the picked spectrum (s) Reference spectrum / reference spectra compares and determines whether the composition of the sample (s) according to the recorded spectrum (s) corresponds to that of the reference spectrum (s).
  • the evaluation device may comprise additional means which compares the recorded spectrum (s) to one or more reference spectrum / reference spectra and determines that whether haemolytic and / or lipemic factors are present in the sample (s).
  • the mark is arranged on the recorded image between the first section of the first pipette and the second section of the second pipette.
  • the distance between the marking and the outer, the marking facing the end of the optionally depicted first boundary line and the distance between the mark and the outer, the mark facing the end of the optionally imaged second boundary line is minimized. In this way, the evaluation of whether the
  • Marking is at the level of the first boundary line, with the same or similar high accuracy to be made as the control of whether the mark is at the level of the second boundary line.
  • the marking is arranged in a longitudinal direction of the symmetry axes of both pipettes and additionally or alternatively in a direction perpendicular to this longitudinal direction centrally or substantially centrally between the marking of the facing ends of the first and second boundary lines.
  • the first sample is advantageously present as an analysis sample and the second sample as a comparison sample for comparison with the analysis sample. It is also possible that the second sample is present as a blank.
  • the device according to the invention is comprised of an analyzer for examining biological or chemical samples by means of a supplied via a pipette reagent.
  • an analyzer for example, the device described in DE 10 2008 022 835 B3 or each of the in the parallel German patent applications of the applicant of the present application with file number DE 10 2011 117 311.4 and the internal reference AES 80205 and the file number DE 10 2011 117 320.3 and contemplated by the internal reference AES 80206, which is incorporated by reference as a disclosure in the present application.
  • the device according to the invention and / or the analyzer according to the invention and / or the method according to the invention can / can be used to record one or more wells, for example a microtiter plate in another image and the further recorded image information, for example one or more color envelopes of one or more samples in one or multiple wells, evaluate.
  • the image can be recorded by rotating or swiveling the camera away from the sections of the pipette after the recorded image has been taken, for example by substantially 90 degrees, in the direction of the or of the well.
  • the camera is directed vertically onto the pipettes and, after this image acquisition, horizontally onto one or more wells disposed below the camera.
  • FIG. 1 shows a three-dimensional schematic illustration of a double pipetting module
  • FIG. 2 shows a further three-dimensional representation of a double pipetting module with staggered pipettes in a longitudinal direction of both pipettes
  • FIG. 1 shows a three-dimensional schematic illustration of a double pipetting module
  • FIG. 2 shows a further three-dimensional representation of a double pipetting module with staggered pipettes in a longitudinal direction of both pipettes
  • FIG. 1 shows a three-dimensional schematic illustration of a double pipetting module
  • FIG. 2 shows a further three-dimensional representation of a double pipetting module with staggered pipettes in a longitudinal direction of both pipettes
  • FIG. 3 shows an arrangement according to the invention consisting of two pipettes which are arranged between a light source and a camera,
  • FIG. 4 shows a schematic illustration of an image composed of two partial images of two pipettes filled with fluids
  • FIG. 5 shows the device according to the invention, wherein three pipettes are arranged between a light source and a camera.
  • FIG. 1 schematically shows a double pipetting module 10 with a first pipette 1 and a second pipette 2, the tips of which have a distance dx in an X direction from one another.
  • the pipette 1 is received by a first pipette carrier 5 and the pipette 2 by a second pipette carrier 6, the pipette carriers 5, 6 and the pipettes 1, 2 parallel to one another in a Z-direction, that of the longitudinal direction of each of the two pipettes 1, 2 corresponds, are aligned.
  • the first pipette carrier 5 of the first pipette 1 is mounted on a first holding plate 7 via a first holding element 5a.
  • the second pipette carrier 6 of the second pipette 2 is mounted on a second holding plate 8 via a second holding element 6a.
  • the first holding plate 7 and the second holding plate 8 are arranged together on a support plate 9a, the first holding plate 7 for holding the first pipette 1 and the second holding plate 8 for holding the second pipette 2 in the Z direction against each other and relative to the support plate 9 slidably are.
  • the support plate 9a is attached to a base support 9b, which can be moved in the X direction and / or Y direction.
  • the in FIG. 1 Doppelipipettiermodul shown can be designed as part of a robot manipulator.
  • the pipettes 1, 2 can be moved arbitrarily three-dimensional in a limited space.
  • the Doppelpipettiermodul 10 between a camera and a Leerpipettenreservoir be designed to be movable.
  • a control of the motion Conditions of the Doppelpipettiermoduls 10 can be done by means of a computer or PC.
  • the pipette module 10 is equipped with a drive for displacing a fluid within the first pipette 1 relative to the first pipette 1 and with a further drive for displacing a further fluid within the second pipette 2 relative to the second pipette 2.
  • a drive for displacing a fluid within the first pipette 1 relative to the first pipette 1 and with a further drive for displacing a further fluid within the second pipette 2 relative to the second pipette 2.
  • the pipettes 1, 2 a fluid in particular in liquid form supplied or removed. Due to the separate drives for the pipettes 1, 2, the volumes of the fluids contained in the pipettes 1, 2, push and / or pull parameters, the drive speeds, etc. can be set and controlled separately for each of the two pipettes 1, 2 and / or or regulated.
  • a fluid in the first pipette 1, for example in the form of a sample liquid, and another fluid in the second pipette 2, for example a reagent liquid, at the same time on below the pipettes in the Z direction arranged wells (not shown) are transmitted, wherein the transfer of liquids no or almost no delay between the transfer of the first pipette 1 and the transfer of the second pipette 2 occurs and the sample liquid is not mixed with the control liquid.
  • FIG. 2 shows another double pipetting module 10 with pipettes 1, 2 displaced relative to one another in the Z direction.
  • a first pipette tip 1a of the first pipette 1 is displaced in the Z direction to a second pipette tip 2a of the second pipette 2 by the value / amount dz.
  • the displacement is achieved in that the first holding plate 7 is designed as a carriage and fixed to a belt 7a, which can be displaced in the Z direction relative to the base plate 9a.
  • pulleys 7b are mounted at upper and lower ends of the support plate 9a in the Z direction, and one or both of the pulleys 7b are driven by a motor such as an electric motor.
  • the second pipette is 2 via a relative to the base plate 9a slidable belt 8a, on which the second holding plate 8 is fixed to the second pipette carrier 6, in the Z direction via pulleys 8b slidably.
  • the in Figs. 1 and 2 Doppelipipettiermodule allow an accurate and cost-effective positioning of the pipettes 1, 2 with minimal space and with the possibility for automation. If necessary, those shown in FIGS. 1 and 2 illustrated Doppelpipettiermodule 10 by more pipettes (not shown) and corresponding elements are extended to their positioning.
  • the double pipetting module 10 can have five or ten pipettes, with a corresponding number of pipette carriers, holding elements and holding plates per pipetting module being present, which are arranged on a common carrier plate 9a. With more than two pipettes per module, instead of a double pipetting module, one should speak of a multiple pipetting module.
  • FIG. 3 an arrangement according to the invention is shown in perspective from a first pipette 1 and a second pipette 2, which are arranged between a light source 40 and a camera 30 with a lens 31 in the Y direction.
  • the first pipette 1 comprises a first section with a first tip 1a
  • the second pipette 2 comprises a second section with a second tip 2a.
  • the pipettes 1, 2 are aligned parallel to one another in the Z direction, the first tip 1a of the first pipette 1 and the second tip 2a of the second pipette 2 lying in the Z direction at the same or comparable height.
  • the X direction which is shown in FIG. 3 corresponds to a direction into the plane of the page, the tips 1a, 2a of the pipettes 1, 2 are arranged at a distance dx from one another.
  • the Y-direction corresponds to the optical axis of the camera 30 and in particular of the lens 31 of the camera 30.
  • a plurality of point-like or quasi-point-shaped light sources 40a to 40e are used as the light source 40.
  • Suitable light sources are, for example, LED, gas discharge, laser light sources and / or conventional halogen lamps. Instead of a plurality of punctiform or virtually point-shaped light sources, it is also possible to use a surface radiator, so that it is ensured that an ambient brightness sufficient for image acquisition is present over a desired section of the pipettes 1, 2 in the Z direction.
  • a first sample 11 which reaches up to the tip 1a of the first sample 1, is drawn up, the first sample 11 being suspended via a first fluid 15 in the form of a gas bubble, which may be configured in particular as an air bubble, is separated from a second fluid 13.
  • a second sample 22 is separated from another fluid 23 by a second fluid 25, which may be in the form of a gas bubble, in particular an air bubble, like the first fluid 15.
  • the first sample 11 and the second sample 22 are present as blood and / or serum and / or cell fluid.
  • Other substances for the first sample and the second sample, each of which may be biological or chemical samples, are possible.
  • the first sample and the second sample, which are in the form of fluids, respectively form menisci as vaulted interfaces with the first fluid 15 and the second fluid 25 in pipette 1 and in pipette 2. These arise when the present as liquid first sample 11 adjacent to the present as gas first fluid 15.
  • the third fluid 13 is also in liquid form and forms an interface with the gas bubble of the first fluid 15
  • the first sample 11 is separated from the third fluid 13 by the gas bubble of the first fluid, so that a mixture between the first sample 11 and the third Fluid 13 does not take place.
  • the second sample 22 is separated from the further fluid 23 by the gas bubble of the second fluid 25, so that a mixture between the second sample 22 and the further fluid 23 is excluded.
  • the first pipette 1 has a conical shape with the tip 1a and an end 1b open in the direction opposite to the Z direction.
  • the second pipette 2 with the tip 2a has an open end 2b in the direction opposite to the Z direction.
  • a captured image 38 of the camera 30 is shown by the first pipette 1 and the second pipette 2, the first pipette 1 being connected to the first pipette carrier 5 and the second pipette 2 being connected to the second pipette carrier 6 in the direction opposite to the Z direction ,
  • the pipette 1 is displaceable in a Z1 direction and the second pipette 2 in a Z2 direction, so that the first pipette 1 can be moved relative to the second pipette 2 and both pipettes in the Z direction or in the direction opposite to the Z direction
  • the first pipette 1 comprises the sample 11, which forms an interface with the first fluid 15 in the form of a gas bubble, which is visually perceptible outside the pipette 1 as a substantially horizontal boundary line 11a.
  • the boundary line 11a is due to a concave meniscus in the Z direction curved opposite direction at one edge of the first pipette 1, so that a to a mark 33 of the camera 30 in the image field of the camera 30 same height in the Z direction is advantageously present when the marker 33 is in the form of a control bar in the Z direction at the same height like a first line 34 of the underside of the meniscus (shown in phantom).
  • the third fluid 13 is drawn up, which forms a third interface 13a for the first fluid 15 present as a gas bubble, which is visually perceptible outside the pipette as a substantially horizontal boundary line 13a.
  • the third fluid 13 is in liquid form and the first fluid is in gaseous form, the third fluid to the first fluid forms a convex meniscus, so that a second line 37 to another marker 36, which as the mark 33 is a control line the top of the convex meniscus is used to determine whether the third boundary line 13a of the third fluid 13 is at the level of the further mark 36.
  • the fluid 22 is drawn up as the second fluid, the second fluid 25 a
  • Forming interface that appears outside of the second pipette 2 as a substantially horizontally oriented boundary line 22a.
  • FIG. 4 on a captured image 38 composed of the partial images 32, 35, both the marker 33 and the first boundary line 11a, the second boundary line 22a, and the third boundary line 13a are depicted.
  • the marker 33 in the captured image 38 is at the level of at least one of the first to third boundary lines 11a, 13a, 22a, the volumes of the first sample 11, the second sample 22, and the first fluid 15 can be controlled. This is particularly simple in the case where the first sample 15 extends to the first tip 1a of the first pipette 1 and the second sample 22 to the second tip 2a of the second pipette 2.
  • a distance of the mark 33 in the Z direction to the first tip 1a of the first pipette 1 and / or to the second tip 2a of the second pipette 2 detected by means of the recorded image can be used to determine the volumes of the first sample 11 and / or the second sample 22 and / or the first fluid to determine.
  • the tips 1a, 2a of the first pipette 1 and the second pipette 2 as reference points for determining an absolute distance of the first tip 1a of the first pipette 1 to the first boundary line 11a and the third boundary line 13a and the second pipette 2 to the second boundary line 22a in presence a captured image.
  • first pipette 1 and / or the second Pipette 2 is calibrated such that when lying the marker 33 at the level of the first boundary line 11a and / or the second boundary line 22a, a predetermined volume of the first sample 11 and / or the second sample 22 is present, it is possible with only one recorded image 38 determine whether a predetermined volume of the first sample 11 and / or the second sample 22 is present. If no border line is depicted in the recorded image 38, recorded sections 1c, 1d, 2c, 2d can be used for the evaluation, if in the first pipette 1 the first sample 11 and / or in the second pipette 2 the second sample 22 is mounted ,
  • one of the first 11a, second 22a, and third 13a borderlines may blur the third boundary line 13a or even two of these boundary lines from one of the boundary lines on the captured image be. If the first boundary line 11a and / or the third boundary line 13a is blurred, the evaluation as to whether the marking 33 is at the level of the first boundary line 11a and / or the third boundary line 13a can be made more difficult or even impossible.
  • An increased image quality of the recorded image 28 can be achieved if, instead of a recorded image, two partial images 32, 35 are recorded, from which the recorded image 38 is composed.
  • a first partial image 32 On a first partial image 32, a first section 1c of the first pipette 1 is illustrated, which includes the tip 1a of the first pipette 1 and the first boundary line 11a.
  • the first partial image 32 in the X direction comprises a further section 2c of the second pipette 2 with the second tip 2a of the second pipette 2.
  • On the second partial image 35 is a third section 1d of the first pipette 1 with the third boundary line 13a displayed.
  • the second partial image in the case of FIG.
  • a portion 2d of the second pipette with the second boundary line 22a When aligning the first tip 1a of the pipette 1 and the second tip 2a of the pipette te 2 in the X direction, ie the same height in the Z direction, can be used to divide the captured image 38 in the first sub-image 32 and the second sub-image 35 an axis XX through the detectable by the camera portion of the first pipette, the of the first fluid 15 is filled. Through the axis XX, the first pipette 1 is divided into an upper portion 1d having the third boundary line 13a and a lower section 1c in the Z direction having the first boundary line 11a.
  • the first boundary line 11a lies at the focal point of the camera 30 and / or in the depth of field of the camera 30 in such a way that an evaluation as to whether the first boundary line 11a is at the level of the marking 33, due to a sufficiently high image quality process stable can be made.
  • the third boundary line 13a in the focal point of the camera 30 or at least in the depth of field is such that an evaluation of whether the third boundary line 13a is equal to the mark 36, due to sufficient image quality with high Process stability can be made.
  • the second boundary line 22a lies in the focal point of the camera 30 or at least in its depth of field for image quality sufficient for the evaluation.
  • the first partial image 32 may overlap with the second partial image 35 after the composition of both images 32, 35.
  • a lower edge 35a of the second partial image 35 is arranged in the Z-direction below an upper edge 32a of the first partial image 32 in a direction opposite to the Z-direction. Therefore, on the second partial image 35, as on the first partial image 32, the first boundary line 11a is shown. Due to the overlapping of the overlap of the first partial image 32 and the second partial image 35 contour of the first pipette 1, the second partial image 35 can be aligned with respect to the first tip 1a of the first pipette 1.
  • the second partial image 35 is also used to align the second partial image 35 on the second tip 2a of the second pipette 2 based on the contour of the second pipette 2.
  • the captured image 38 may have a time stamp For example, the time of the recording of the second partial image 35.
  • a process step subsequent to the recording of the second image can be triggered.
  • the first sample 11 and the third fluid 13 in one well and the second sample 22 in another well may be ejected from the pipettes 1, 2, for example by means of the double pipetting module 10.
  • the device according to the invention is shown in the form of three pipettes 1, 2, 3, which are arranged between the light source 40 and the camera 30 with the objective 31.
  • a surface radiator 41 is used as the light source 40.
  • the first pipette comprises the first sample 11, the first fluid 15 and the third fluid 13, as shown in FIGS. 3 and 4 shown.
  • the second pipette 2 comprises the sample 22, wherein this sample does not extend to the tip of the second pipette 2.
  • a third pipette 3 with the first sample 11, second fluid 25 arranged above it and further fluid 23 arranged above it are also shown on the recorded image 38 in a direction opposite to the Z direction.
  • the image 38 taken by the camera 30, on which the pipettes 1, 2, 3 are shown in sections is supplied to a computer serving as the evaluation device 130, which displays the image information contained in the image 38 on a monitor 140.
  • the evaluation device 130 can be controlled via a keyboard 142 and / or a mouse 144.
  • the evaluation device In addition to the representation of the pipettes 1, 2, 3, the evaluation device also performs an evaluation as to whether in the recorded image 38 the marking 33 is at the level of at least one of the first 11a and second 22a and third 13a borderlines.
  • This information can be displayed in tabular form as binary information for further processing in a further evaluation device connected to the evaluation device 130 or graphically in the form of a function 39 or relation.
  • a suitable, executable on the evaluation device 130 software or a computer program 148 which may be stored for example on a CD or DVD 146 as a disk can, it is evaluated whether in the captured image 38, the marker 33 is at the level of at least one of the first 11a or second 22a border lines.
  • This evaluation can be done, for example, by comparing the brightness distributions of the recorded image 38 with corresponding brightness distributions of reference images.
  • the computer program product 148 for the evaluation device 130 of the device 150 for controlling volumes of at least two samples therefore serves as the data carrier 146 with the computer program product 148 stored thereon for carrying out the method according to the invention.

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  • Physics & Mathematics (AREA)
  • Electromagnetism (AREA)
  • General Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Thermal Sciences (AREA)
  • Fluid Mechanics (AREA)
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Abstract

Procédé et dispositif de contrôle d'un volume et/ou d'une composition d'au moins un prélèvement (11), en particulier fluide. Ledit procédé consiste à utiliser au moins une pipette (1) dans laquelle est formée entre le prélèvement (11) et au moins un fluide (15) adjacent au prélèvement (11) au moins une surface limite qui peut être perçue optiquement à l'extérieur de la pipette (1) sous la forme d'une ligne de séparation (11a) sensiblement horizontale s'étendant entre le prélèvement (11) et le fluide (15), à disposer au moins un repère (33) d'une caméra (30) dans le champ d'images de la caméra (30) de sorte que le repère (33) et au moins un premier segment (1c, 1d) de la pipette (1) sont représentés sur une image prise (38), la pipette (1) étant placée entre une source de lumière (20, 20a-20e) et la caméra (30) de manière telle qu'au moins un spectre (13) de rayons lumineux (22-24) de la source de lumière (20, 20a-20e) est enregistré par la caméra (30), lesdits rayons ayant traversé le prélèvement (11), et à évaluer si le repère (33) sur l'image prise (38) coïncide avec la position de la ligne de séparation (11a) dans le premier segment (1c, 1d), à comparer le spectre enregistré (13) avec au moins un spectre de référence et à constater si la composition du prélèvement (11) selon le spectre enregistré (13) correspond à la composition selon le spectre de référence.
PCT/EP2012/004528 2011-10-28 2012-10-29 Procédé et dispositif de contrôle du volume et de la composition d'au moins un prélèvement WO2013060483A2 (fr)

Priority Applications (3)

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EP12794858.6A EP2771699B8 (fr) 2011-10-28 2012-10-29 Procédé et dispositif de contrôle du volume et de la composition d'au moins un prélèvement
US14/354,908 US9734421B2 (en) 2011-10-28 2012-10-29 Method and device for inspecting the volume and the composition of at least one sample
ES12794858T ES2870855T3 (es) 2011-10-28 2012-10-29 Procedimiento y dispositivo para el control del volumen y de la composición al menos de una muestra

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE102011117323.8 2011-10-28
DE102011117310.6 2011-10-28
DE102011117323A DE102011117323B4 (de) 2011-10-28 2011-10-28 Verfahren und Vorrichtung zur Kontrolle des Volumens mindestens einer Probe
DE102011117310A DE102011117310B4 (de) 2011-10-28 2011-10-28 Vorrichtung und Verfahren zur Kontrolle eines Volumens einer Probe
EPPCT/EP2012/004491 2012-10-26
EP2012004491 2012-10-26

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Cited By (2)

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JP2015200527A (ja) * 2014-04-04 2015-11-12 株式会社東芝 臨床検査装置
WO2017075153A1 (fr) 2015-10-27 2017-05-04 Haemonetics Corporation Système et procédé de mesure de volume et de pression

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US20070021929A1 (en) * 2000-01-07 2007-01-25 Transform Pharmaceuticals, Inc. Computing methods for control of high-throughput experimental processing, digital analysis, and re-arraying comparative samples in computer-designed arrays
DE10215270B4 (de) * 2002-04-06 2007-04-19 Robert Bosch Gmbh Verfahren zur Messung eines Meniskusvolumens oder einer Meniskushöhe eines Flüssigkeitströpfchens
EP2133668A1 (fr) * 2008-06-12 2009-12-16 CSL Behring GmbH Mesure non destructive du volume de remplissage d'un récipient rempli de liquide

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DE102008022835B3 (de) 2008-05-12 2009-10-22 Torsten Dr. Matthias Analysegerät

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015200527A (ja) * 2014-04-04 2015-11-12 株式会社東芝 臨床検査装置
WO2017075153A1 (fr) 2015-10-27 2017-05-04 Haemonetics Corporation Système et procédé de mesure de volume et de pression
EP3368869A4 (fr) * 2015-10-27 2019-07-17 Haemonetics Corporation Système et procédé de mesure de volume et de pression

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